Surfactants in cosmetics vol 68

title: Surfactants in Cosmetics Surfactant Science Series ; V.68

author: Rieger, Martin M.publisher: CRC Press

isbn10 | asin: 0824798058print isbn13: 9780824798055

ebook isbn13: 9780585373423language: English

subject Surface active agents, Cosmetics.publication date: 1997

lcc: TP994.S8763 1997ebddc: 668/.55

subject: Surface active agents, Cosmetics.

Surfactants in Cosmetics

SURFACTANT SCIENCE SERIES

CONSULTING EDITORS

MARTIN J. SCHICKConsultant

New York, New York

FREDERICK M. FOWKES(19151990)

1. Nonionic Surfactants, edited by Martin J. Schick (see also Volumes 19, 23, and 60)

2. Solvent Properties of Surfactant Solutions, edited by Kozo Shinoda (see Volume 55)

3. Surfactant Biodegradation, R. D. Swisher (see Volume 18)

4. Cationic Surfactants, edited by Eric Jungermann (see also Volumes 34, 37, and 53)

5. Detergency: Theory and Test Methods (in three parts), edited by W. G. Cutler and R. C.Davis (see also Volume 20)

6. Emulsions and Emulsion Technology (in three parts), edited by Kenneth J. Lissant

7. Anionic Surfactants (in two parts), edited by Warner M. Linfield (see Volume 56)

8. Anionic Surfactants: Chemical Analysis, edited by John Cross (out of print)

9. Stabilization of Colloidal Dispersions by Polymer Adsorption, Tatsuo Sato and RichardRuch (out of print)

10. Anionic Surfactants: Biochemistry, Toxicology, Dermatology, edited by ChristianGloxhuber (see Volume 43)

11. Anionic Surfactants: Physical Chemistry of Surfactant Action, edited by E. H. Lucassen-Reynders (out of print)

12. Amphoteric Surfactants, edited by B. R. Bluestein and Clifford L. Hilton (see Volume59)

13. Demulsification: Industrial Applications, Kenneth J. Lissant (out of print)

14. Surfactants in Textile Processing, Arved Datyner

15. Electrical Phenomena at Interfaces: Fundamentals, Measurements, and Applications,edited by Ayao Kitahara and Akira Watanabe

16. Surfactants in Cosmetics, edited by Martin M. Rieger (out of print)

17. Interfacial Phenomena: Equilibrium and Dynamic Effects, Clarence A. Miller and P.Neogi

18. Surfactant Biodegradation: Second Edition, Revised and Expanded, R. D. Swisher

19. Nonionic Surfactants: Chemical Analysis, edited by John Cross

20. Detergency: Theory and Technology, edited by W. Gale Cutler and Erik Kissa

21. Interfacial Phenomena in Apolar Media, edited by Hans-Friedrich Eicke and GeoffreyD. Parfitt

22. Surfactant Solutions: New Methods of Investigation, edited by Raoul Zana

23. Nonionic Surfactants: Physical Chemistry, edited by Martin J. Schick

24. Microemulsion Systems, edited by Henri L. Rosano and Marc Clausse

25. Biosurfactants and Biotechnology, edited by Naim Kosaric, W. L. Cairns, and Neil C. C.Gray

26. Surfactants in Emerging Technologies, edited by Milton J. Rosen

27. Reagents in Mineral Technology, edited by P. Somasundaran and Brij M. Moudgil

28. Surfactants in Chemical/Process Engineering, edited by Darsh T. Wasan, Martin E.Ginn, and Dinesh O. Shah

29. Thin Liquid Films, edited by I. B. Ivanov

30. Microemulsions and Related Systems: Formulation, Solvency, and Physical Properties,edited by Maurice Bourrel and Robert S. Schechter

31. Crystallization and Polymorphism of Fats and Fatty Acids, edited by Nissim Garti andKiyotaka Sato

32. Interfacial Phenomena in Coal Technology, edited by Gregory D. Botsaris and Yuli M.Glazman

33. Surfactant-Based Separation Processes, edited by John F. Scamehorn and Jeffrey H.Harwell

34. Cationic Surfactants: Organic Chemistry, edited by James M. Richmond

35. Alkylene Oxides and Their Polymers, F. E. Bailey, Jr., and Joseph V. Koleske

36. Interfacial Phenomena in Petroleum Recovery, edited by Norman R. Morrow

37. Cationic Surfactants: Physical Chemistry, edited by Donn N. Rubingh and Paul M.Holland

38. Kinetics and Catalysis in Microheterogeneous Systems, edited by M. Grätzel and K.Kalyanasundaram

39. Interfacial Phenomena in Biological Systems, edited by Max Bender

40. Analysis of Surfactants, Thomas M. Schmitt

41. Light Scattering by Liquid Surfaces and Complementary Techniques, edited by

Dominique Langevin

42. Polymeric Surfactants, Irja Piirma

43. Anionic Surfactants: Biochemistry, Toxicology, Dermatology. Second Edition, Revisedand Expanded, edited by Christian Gloxhuber and Klaus Künstler

44. Organized Solutions: Surfactants in Science and Technology, edited by Stig E. Fribergand Björn Lindman

45. Defoaming: Theory and Industrial Applications, edited by P. R. Garrett

46. Mixed Surfactant Systems, edited by Keizo Ogino and Masahiko Abe

47. Coagulation and Flocculation: Theory and Applications, edited by Bohuslav Dobias *

48. Biosurfactants: Production · Properties · Applications, edited by Naim Kosaric

49. Wettability, edited by John C. Berg

50. Fluorinated Surfactants: Synthesis · Properties · Applications, Erik Kissa

51. Surface and Colloid Chemistry in Advanced Ceramics Processing, edited by Robert J.Pugh and Lennart Bergström

52. Technological Applications of Dispersions, edited by Robert B. McKay

53. Cationic Surfactants: Analytical and Biological Evaluation, edited by John Cross andEdward J. Singer

54. Surfactants in Agrochemicals, Tharwat F. Tadros

55. Solubilization in Surfactant Aggregates, edited by Sherril D. Christian and John F.Scamehorn

56. Anionic Surfactants: Organic Chemistry, edited by Helmut W. Stache

57. Foams: Theory, Measurements, and Applications, edited by Robert K. Prud'hommeand Saad A. Khan

58. The Preparation of Dispersions in Liquids, H. N. Stein

59. Amphoteric Surfactants: Second Edition, edited by Eric G. Lomax

60. Nonionic Surfactants: Polyoxyalkylene Block Copolymers, edited by Vaughn M. Nace

61. Emulsions and Emulsion Stability, edited by Johan Sjöblom

62. Vesicles, edited by Morton Rosoff

63. Applied Surface Thermodynamics, edited by A. W. Neumann and Jan K. Spelt

64. Surfactants in Solution, edited by Arun K. Chattopadhyay and K. L. Mittal

65. Detergents in the Environment, edited by Milan Johann Schwuger

66. Industrial Applications of Microemulsions, edited by Conxita Solans and HironobuKunieda

67. Liquid Detergents, edited by Kuo-Yann Lai

68. Surfactants in Cosmetics: Second Edition, Revised and Expanded, edited by Martin M.Rieger and Linda D. Rhein

69. Enzymes in Detergency, edited by Jan H. van Ee, Onno Misset, and Erik J. Baas

ADDITIONAL VOLUMES IN PREPARATION

StructurePerformance Relationships in Surfactants, edited by Kunio Esumi and Minoru

Ueno

Powdered Detergents, edited by Michael S. Showell

Page i

Surfactants in CosmeticsSecond Edition, Revised and Expanded

Edited byMartin M. Rieger

M & A Rieger AssociatesMorris Plains, New Jersey

Linda D. Rhein

Johnson & Johnson Consumer ProductsSkillman, New Jersey

Page ii

Library of Congress Cataloging-in-Publication Data

Surfactants in cosmetics. 2nd ed., rev. and expanded / edited byMartin M. Rieger and Linda D. Rhein.p. cm. (Surfactant science series ; v. 68)Includes index.ISBN 0-8247-9805-8 (hc : alk. paper)1. Surface active agents. 2. Cosmetics. I. Rieger, Martin M.,II. Rhein, Linda D. III. Series.TP994.S8763 1997668'.55dc21 97-57 CIP

The publisher offers discounts on this book when ordered in bulk quantities. For moreinformation, write to Special Sales/Professional Marketing at the address below.

This book is printed on acid-free paper.

Copyright © 1997 by Marcel Dekker, Inc. All Rights Reserved.

Neither this book nor any part may be reproduced or transmitted in any form or by anymeans, electronic or mechanical, including photocopying, microfilming, and recording, orby any information storage and retrieval system, without permission in writing from thepublisher.

Marcel Dekker, Inc.270 Madison Avenue, New York, New York 10016

Current printing (last digit):10 9 8 7 6 5 4 3 2

PRINTED IN THE UNITED STATES OF AMERICA

Page iii

Preface to the Second EditionThe need for surfactants in consumer acceptable cosmetic products formed the stimulusfor the preparation of the first edition of Surfactants in Cosmetics ten years ago. Sincethat time much progress has been made in creating novel surfactants for the personalcare industry and in understanding the fundamental behavior of surfactants in solutionand their interactions with skin. More importantly, there has been steady movementtoward the selection of surfactants for cosmetics that have no objective adverse impacton human skin and elicit noor at most minimalnegative subjective reaction. Thus, thissecond edition not only reflects the search for milder surfactants but also presents up-to-date information on the activity of mixtures that interact in solution and on the skin toenhance perceived as well as absolute safety. In addition, this edition updates theeverchanging nomenclature of surfactants in the cosmetic industry and relies onInternational Nomenclature Cosmetic Ingredient (INCI) names and designations, asprovided in the sixth edition of the International Cosmetic Ingredient Dictionary (availablefrom the Cosmetics, Toiletries, and Fragrance Association in Washington, D.C.).

The editors determined early on that the scientific information presented in the firstedition of Surfactants in Cosmetics remains valid. In order to avoid unnecessary repetitionand unwanted redundancy, the editors decided to depend primarily on a new set ofauthors and to select alternative topics for the second edition. As a result, the secondedition provides a unique and novel aspect of the topic of surfactants in cosmetics.Readers are urged to view the second edition not as a replacement for the first but as anextension and an addition. The table of contents from the first edition is thereforeincluded to assist readers in their endless search for information.

The first three chapters of this book address the fundamentals of surfactants, withemphasis on their uses in cosmetics. These chapters provide the basic science requiredfor the effective use of surfactants.

Chapters 49 discuss the current status of research on the application of surfactants

Page iv

in cosmetic emulsions. Chapters 1012 introduce the reader to microemulsions andvesicles. These nine chapters are intended to help in the formulation of cosmeticproducts.

Chapters 1317 provide current information on surfactant usage in the formulation ofvarious types of cosmetic products, and chapters 1825 deal with the critical topic of theinteraction of surfactants with the skin. Chapters 1325 mayat timesappear to coversimilar topics, primarily because this material is of great interest and is often viewed fromvaried perspectives.

The last three chapters cover topics of importance to practitioners which result from theuse of surfactants in cosmetic products.

The editors thank the authors for their contributions and for accepting our editorialsuggestions with alacrity. We regretfully note that Dr. Morton Pader passed away shortlyafter submitting his contribution. The editors also recognize with deep appreciation thehelp provided by the staff of the publisher.

As noted, the second edition differs materially from the first edition, and it is hoped thatreaders will find the book useful and of current and continuing interest.

MARTIN M. RIEGERLINDA D. RHEIN

Page v

Preface to the First EditionThe monetary value of worldwide sales of cosmetics and toiletries is extremely large;however, the value of these consumer products might better be measured in terms oftheir psychological and health benefits and their impact on our daily lives. Most moderncosmetic preparations could not be produced without the use of a variety of surfactants,and it is appropriate, therefore, to devote a volume to this topic in the Surfactant Scienceseries.

The editor of a collective volume, such as this one, establishes the book's objectives,which in turn determine its makeup and contents. It is the principal purpose of thisvolume to provide a comprehensive survey of the use of surfactants in cosmetics. Thereader can expect to find specific information on all types of surfactants used in cosmeticsand toiletries and, equally important, references to the vast original literature on thissubject.

More specifically, the goal of this book is to provide answers to some pertinent questionssuch as those listed below:

What surfactants are used in cosmetics?

Why are surfactants required in cosmetics?

What functions are served by surfactants in cosmetics?

How are surfactants used in cosmetics?

What problems are caused by the use of surfactants in cosmetics?

What interactions take place between surfactants in cosmetics and the substrate, i.e., theskin and its appendages?

It should be noted that there are some omissions in this text; these are intentional. Weare attempting to avoid redundancy from chapter to chapter in this book and also withinthe Surfactant Science series, which now includes about 21 books. Thus, details of thecomplex chemistry of the surfactants are deliberately excluded since this subject isexpertly covered in other volumes in the series. Also avoided is the use of (the ever

Page vi

changing) commercial or trade names for surfactants. Instead, the nomenclatureemployed in the current issue (1982) of the CTFA Cosmetic Ingredient Dictionary is usedextensively. Last but not least, an effort is made not to create an assembly of recipes forthe preparation of cosmetic formulations; the few formulations included are presentedonly for illustrative purposes.

The editor sincerely hopes that these goals have been achieved. The editor also hopesthat readers of the book will find it not only scientifically useful but readable as well.

Special thanks are due to the authors of the various chapters who have patiently enduredthe need for editorial changes and the unavoidable delays incurred in a multi-authoredbook. Thanks are also due the Cosmetic, Toiletries, and Fragrance Association whichgranted permission to utilize CTFA surfactant nomenclature as well as many ingredientdescriptions from the Cosmetic Ingredient Dictionary. Finally, gratitude is expressed tomy faithful secretaries, Ms. G. Pilewski and Ms. G. Salmon, and to the editorial staff ofMarcel Dekker without whose help this book could not have been produced.

MARTIN M. RIEGER

Page vii

Contents of the Second Edition

Preface to the Second Edition iii

Preface to the First Edition v

Contents of the First Edition xi

Contributors xiii

1. Surfactant Chemistry and ClassificationMartin M. Rieger 1

2. Physical Properties of Surfactants Used in CosmeticsDrew Myers 29

3. The Analysis of Surfactants in CosmeticsJane M. Eldridge 83

4. Principles of Emulsion FormationThomas Förster 105

5. Emulsifier Selection/HLBDonald L. Courtney, Sr. 127

6. Multiple Emulsions in CosmeticsMonique Seiller, Francis Puisieux, and J. L. Grossiord 139

7. Multiphase EmulsionsH. E. Junginger 155

8. Stability of EmulsionsChristopher D. Vaughan 183

Page viii

9. Phase Inversion in Emulsions: CAPICOConcept andApplicationArmin Wadle, Holger Tesmann, Mark Leonard, and ThomasFörster

207

10. Solubilization in Cosmetic SystemsStig E. Friberg and Jiang Yang 225

11. Selection of SolubilizersFrancesc Comelles and Carles Trullás 237

12. Liposomes and NiosomesDaniel D. Lasic 263

13. Surfactants for Skin CleansersPaul Thau 285

14. Cleansing Bars for Face and Body: In Search of MildnessRichard I. Murahata, M. P. Aronson, Paul T. Sharko, and AlanP. Greene

307

15. Topical Antibacterial Wash ProductsBoyce M. Morrison, Jr., Diana D. Scala, and George E.Fischler

331

16. Hair CleansersCharles Reich 357

17. Surfactants in Dental ProductsMorton Pader 385

18. In Vitro Interactions: Biochemical and Biophysical Effectsof Surfactants on SkinLinda D. Rhein

397

19. Surfactant MildnessGenji Imokawa 427

20. Surfactant Effects on Skin BarrierWilliam Abraham 473

21. Bioengineering Techniques for Investigating the Effectsof Surfactants on SkinPerveen Y. Rizvi, Gary L. Grove, and Boyce M. Morrison, Jr.

489

22. Skin Penetration Enhancement by SurfactantsJoel L. Zatz and Belinda Lee 501

23. Human in Vivo Methods for Assessing the IrritationPotential of Cleansing SystemsF. Anthony Simion

519

24. The Challenge of Using the ''Inarticulate" Consumer Asan R & D Partner in Cosmetic Product DevelopmentDavid W. Ingersoll

533

Page ix

25. Toxicology of Surfactants Used in CosmeticsWalter Sterzel 557

26. Chemical Instability of SurfactantsMartin M. Rieger 573

27. Inactivation of Preservatives by SurfactantsDonald S. Orth 583

28. Solubilization of Fragrances by SurfactantsJohn N. Labows, John C. Brahms, and Robert H. Cagan 605

Index 621

Page xi

Contents of the First Edition

1. Surfactants for Cosmetic Macroemulsions: Properties andApplicationBernard Idson

1

2. Microemulsions and Application of Solubilization inCosmeticsT. Joseph Lin

29

3. Surfactant Association Structures of Relevance toCosmetic PreparationsStig E. Friberg and Magda A. El-Nokaly

55

4. Low-Energy EmulsificationT. Joseph Lin 87

5. Surfactant Analysis in Cosmetic PreparationsDonald E. Deem 103

6. Interaction of Surfactants with Epidermal Tissues:Biochemical and Toxicological AspectsEdward J. Singer and Eugene P. Pittz

133

7. Interaction of Surfactants with Epidermal Tissues:Physicochemical AspectsEugene R. Cooper and Bret Berner

195

8. Surfactants and the Preservation of Cosmetic PreparationsKarl Heinz Wallhäusser 211

Page xii

9. Surfactants in ShampoosGraham Barker 251

10. Surfactants in Oral Hygiene ProductsMorton Pader 293

11. Surfactants for Skin CleansersPaul Thau 349

12. The Role of Surfactants in AerosolsHans Breuer 377

13. Surfactants in Cosmetic SuspensionsCharles Fox 401

14. Index to Surfactant Structures and CTFA NomenclatureMartin M. Rieger 431

Page xiii

ContributorsWilliam Abraham Research and Development, CYGNUS, Inc., Redwood City, California

M. P. Aronson Personal Washing Research, Unilever Research Laboratory Port Sunlight,Merseyside, United Kingdom

John C. Brahms Research and Development, Colgate-Palmolive Company, Piscataway,New Jersey

Robert H. Cagan Research and Development, Colgate-Palmolive Company, Piscataway,New Jersey

Francesc Comelles Surfactant Technology, Centro de Investigación y Desarrollo,Barcelona, Spain

Donald L. Courtney, Sr. Emulsions REZ, Landenberg, Pennsylvania

Jane M. Eldridge Analytical Services, Rhône-Poulenc, Inc., Cranbury, New Jersey

George E. Fischler Analytical Sciences/Microbiology, Colgate-Palmolive Company,Piscataway, New Jersey

Thomas Förster Chemical Research, Henkel KGaA, Düsseldorf, Germany

Stig E. Friberg Department of Chemistry, Clarkson University, Potsdam, New York

Alan P. Greene Personal Washing Product Development, Lever Brothers Company,Edgewater, New Jersey

J. L. Grossiord Physique Pharmaceutique, Université de Paris-Sud, Châtenay-Malabry,France

Page xiv

Gary L. Grove KGL's Skin Study Center, Broomall, Pennsylvania

Genji Imokawa Biological Science Laboratories, Kao Corporation, Haga, Tochigi, Japan

David W. Ingersoll Consumer and Marketing Research, Givaudan-Roure, Teaneck, NewJersey

H. E. Junginger Department of Pharmaceutical Technology, Leiden/Amsterdam Center forDrug Research, Leiden, The Netherlands

John N. Labows Research and Development, Colgate-Palmolive Company, Piscataway,New Jersey

Daniel D. Lasic Consultant, Drug and Gene Delivery Consultations, Newark, California

Belinda Lee Skin Research, Colgate-Palmolive Company, Piscataway, New Jersey

Mark Leonard COSPHA, Henkel Organics, Belvedere, Kent, England

Boyce M. Morrison, Jr. Skin Clinical Investigations, Colgate-Palmolive Company,Piscataway, New Jersey

Richard I. Murahata Clinical and Appraisal Science, Unilever Research U.S., Edgewater,New Jersey

Drew Myers Consultant, Rio Tercero, Córdoba, Argentina

Donald S. Orth Research and Development, Neutrogena Corporation, Los Angeles,California

Morton Pader* Consumer Products Development Resources, Inc., Teaneck, New Jersey

Francis Puisieux Physico-Chimie-Pharmacotechnie-Biopharmacie, Université de Paris-Sud,Châtenay-Malabry, France

Charles Reich Advanced Technology/Hair Care, Colgate-Palmolive Company, Piscataway,New Jersey

Linda D. Rhein World Wide Therapeutic Skin Care, Johnson & Johnson ConsumerProducts, Skillman, New Jersey

Martin M. Rieger Consultant, M & A Rieger Associates, Morris Plains, New Jersey

Perveen Y. Rizvi Skin Clinical Investigations, Colgate-Palmolive Company, Piscataway,New Jersey

*Deceased.

Page xv

Diana D. Scala Skin Clinical Investigations, Colgate-Palmolive Company, Piscataway, NewJersey

Monique Seiller Physico-Chimie-Pharmacotechnie-Biopharmacie, Université de Paris-Sud,Châtenay-Malabry, France

Paul T. Sharko Personal Washing Product Development, Lever Brothers Company,Edgewater, New Jersey

F. Anthony Simion Research and Development, The Andrew Jergens Company, Cincinnati,Ohio

Walter Sterzel Department of Toxicology, Henkel KGaA, Düsseldorf, Germany

Holger Tesmann CFTCOSPHA, Henkel KGaA, Düsseldorf, Germany

Paul Thau Technology Surveillance, Cosmair, Inc., Clark, New Jersey

Carles Trullás Research Department, Laboratories Isdin, Barcelona, Spain

Christopher D. Vaughan SPF Consulting Labs, Inc., Ft. Lauderdale, Florida

Armin Wadle Product Development Skin CareCOSPHA, Henkel KGaA, Düsseldorf, Germany

Jiang Yang Surfactants and Specialties North America, Rhône-Poulenc, Inc., Cranbury,New Jersey

Joel L. Zatz Department of Pharmaceutics, Rutgers University College of Pharmacy,Piscataway, New Jersey

Page 1

1Surfactant Chemistry and ClassificationMartin M. RiegerConsultant, M & A Rieger Associates, Morris Plains, New Jersey

I. Introductory Comments 1

A. Definitions and Structural Requirements 1

B. Utility and Selection of Surfactants in Cosmetics 2

C. Classification 3

D. Nomenclature 3

II. Group Description 4

A. Amphoterics 4

B. Anionics 6

C. Cationics 15

D. Nonionics 19

References 28

IIntroductory Comments

ADefinitions and Structural Requirements

The term surfactant is shorthand for the more cumbersome "surface active agent."Surfactants as a group have the ability to modify the interface between various phases.Their effects on the interface are the result of their ability to orient themselves inaccordance with the polarities of the two opposing phases. Thus the polar (hydrophilic)part of the surfactant molecule can be expected to be oriented toward the more polar(hydrophilic) phase at a given interfacial contact site. Similarly, the nonpolar (lipophilic)portion of the surfactant molecule should contact the nonpolar (lipophilic) phase. Eachsurfactant molecule has a tendency to reach across (bridge) the two phases, and suchsubstances have, therefore, also been called amphiphilic.

One of the prerequisites for an amphiphilic molecule is possession of at least one polar

Page 2

and at least one essentially nonpolar portion. The orientation of a 1,2-dodecanediolmolecule at a mineral-oil/water interface is readily predictable from the precedingdiscussion, but the positioning of 1,12-dodecanediol at a similar interface is not asobvious; it would be expected to be different and more complex than that of the 1,2-isomer. Despite their chemical similarity, the surfactant activities of these two compoundscan be expected to be different. It is apparent from this that a surfactant's behavior orutility, e.g., as an emulsion stabilizer, is unrelated to its empirical formula. Instead, asurfactant's spatial configuration, i.e., the molecule's structure, plays a critical role indetermining its application in cosmetics.

BUtility and Selection of Surfactants in Cosmetics

Those who require and use surfactants tend to define surfactants on the basis ofperformance. Regardless of diverse theoretical considerations, practicing cosmeticformulators have developed a usage classification that they find practical in their day-to-day activities. As a rule, a surfactant is soluble in at least one of the contacting phasesand is used to perform one or more of the following tasks:

Clean (Detergency),Wet,Emulsify,Solubilize,Disperse, orFoam.

Surfactants are useful for creating a wide variety of dispersed systems, such assuspensions and emulsions. They cleanse and solubilize and are required not only duringmanufacture but are also essential for maintaining an acceptable level of physicalstability of thermodynamically unstable systems, such as emulsions. Few moderncosmetic products exist that do not depend on one or more surfactants to create andmaintain their desired characteristics.

It is the practitioner's responsibility to select one or more surfactants that can performthe task at hand. As a result of prior experience, formulators usually can identify thosesurfactant structures that can be expected to be most useful for achieving the desiredgoal.

The cosmetic formulator's choice of surfactants is more limited than that of the industrialchemist. Some of the criteria influencing selection are briefly noted below:

SafetyAdverse reactions to any surfactant used in a finished cosmetic must be minimized.

Odor and ColorOdoriferous or deeply colored surfactants can affect the esthetics of afinished product and should be avoided.

PurityImpurities present in some surfactants may make the surfactant unacceptable forcosmetic use.

Despite these and other limitations and the obvious requirement of cost, the cosmeticchemist must make a selection from about 2000 different commercially availablesurfactants.

The selection for the specific formulation task requires insight into the general

Page 3

chemical characteristics of surfactants (this chapter) and an understanding of thephysichochemical behavior of these amphiphiles (Chapter 2).

CClassification

Classification or categorization of the thousands of different surfactants on the basis ofgenerally recognized principles is clearly desirable. Thus it would appear practical to basesuch a scheme on the surfactant's functionality. Creating groupings based on suchfunctional groups could in all likelihood be made without regard to commonly acceptedchemical or physical characteristics. A typical functional scheme was developed in theCTFA (Cosmetic Ingredient Handbook) [1] by creating six functional categories forsurfactants:

Surfactants, Cleansing AgentsSurfactants, Emulsifying AgentsSurfactants, Foam BoostersSurfactants, HydrotropesSurfactants, Solubilizing AgentsSurfactants, Suspending Agents

An entirely different means for classification might be based on the nature of thehydrophobic portions of surfactants. Such a classification would create groups based onthe presence of hydrophobes derived from paraffinic, olefinic, aromatic, cycloaliphatic, orheterocyclic hydrophobes. This type of classification could be of particular interest tospecialists who may wish to compare substances on the basis of physiological effectsrelated to the origin of the lipophilic constituents.

The most useful and widely accepted classification is based on the nature of thehydrophilic segment of the surfactant molecules. This classification system has universalacceptance and has been found to be practical throughout the surfactant industry. Thisapproach creates four large groups of chemicals: amphoterics, anionics, cationics, andnonionics. This system categorizes surfactants on the basis of their ionic or nonioniccharacter, does not consider differences in the hydrophobic (nonpolar) segment, andignores functionality.

It is common practice to depict surfactant molecules as ball and stick figures:

In this cartoon, the hydrophobe is represented by a stick; the ball represents thehydrophilic grouping, which may carry a positive and/or a negative charge or no charge; Xrepresents the counter ion required for electroneutrality of the molecule.

DNomenclatureThe nomenclature of surfactants can become very complex and confusing. For thepurpose of labeling of cosmetics in accordance with U.S. regulation, the Cosmetics,

Page 4

Toiletry and Fragrance Association has created names for cosmetic ingredients. It is likelythat these names will soon be accepted in many other countries in the hope that aworldwide agreement on this INCI* nomenclature can be reached between governmentalregulatory agencies and the trade associations concerned with cosmetics.

Rules for creating these names are included in the International Cosmetic IngredientDictionary [2]. The names are intended to be descriptive for laypersons as well as themore technically oriented. The assigned names are not as precise as the names assignedby Chemical Abstracts and eliminate the need for using proprietary trade names. TheINCI names are used in this chapter wherever possible.

Some abbreviations used in the text are identified below:

DEAEOHLBMEAPOE orPEGPPGTEA

DiethanolamineEthylene OxideHydrophile/LipophileBalanceMonoethanolaminePolyoxyethylenePolyoxypropyleneTriethanolamine

IIGroup Description

AAmphoterics

Surfactants are classified as amphoteric ifand only ifthe charge(s) on the hydrophilic headchange as a function of pH. Such surfactants must carry a positive charge at low pH and anegative charge at high pH and may form internally neutralized ionic species (zwitterions)at an intermediate pH. These features of amphoterics are illustrated below with thebehavior of lauraminopropionic acid at various pH levels:

Low pH: The surfactant molecule is a cation.

Intermediate pH: The surfactant molecule is a zwitterion.

High pH: The surfactant molecule is an anion.

In this example, R represents the lauryl alkyl group, while X and C+ are the required

counter ions. The behavior of this substance must be compared with that of laurylbetaine:

Low pH: The surfactant molecule is a cation.

Intermediate pH: The surfactant molecule may be a zwitterion.*INCI = International Nomenclature Cosmetic Ingredient

Page 5

Lauryl betaine contains a quaternary nitrogen atom regardless of pH. The ionization ofthe carboxylic acid group is, however, pH dependent, and internal compensation ispossible. Lauryl betaine is properly classified as a quaternary surfactant. In cosmeticusage, betaines and related molecules exhibit some functions associated withamphoterics. Although some authorities have at times classified betaines as amphoterics,they are classified here as quaternaries.

The hydrophilic groups in amphoterics commonly are primary, secondary, or tertiaryamino groups and an ionizable acidic group, i.e., COO, , or rarely on the samemolecule. Two types of amphoterics exist:

A 1. Alkylamido Alkyl Amines

A 2. Alkyl Substituted Amino Acids

A. 1Alkylamido Alkyl Amines

These substances are synthesized by acylation of the primary amino group of aminoethylethanolamines (NH2CH2CH2NHCH2CH2OH) with a long chain (fatty) acid derivative. Theresulting cyclic 2-alkyl hydroxyethyl imidazoline is hydrolyzed in the subsequent alkylationstep with chloroacetic acid or ethylacrylate to yield a complex mixture of mono- ordicarboxy alkyl derivatives:

Alkylation with, for example, hydroxypropylsulfonic acid, yields a more complex tertiaryamine. Commercial products are mixtures containing soaps and the hydrolysis product ofthe alkylating agent. They are sold as salts (usually sodium) or as free acids. At or nearneutral pH they may exist in zwitterionic form. The amide linkage in these molecules maybe subject to hydrolysis, but no report of chemical instability in cosmetics has beenpublished.

Alkylamido alkyl amines are generally water soluble and are compatible with most othercosmetically useful surfactants. They reportedly reduce the tendency of anionics to eliciteye irritation without significantly interfering with their foaming characteristics.

These amphoterics exhibit substantivity to hair and skin proteins and act as conditioning

and antistatic agents. Their primary use is in shampoos and miscellaneous skin cleansers.They are, however, not widely used as detersive surfactants (cleansing agents) and arenot effective emulsifying agents.

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A. 2Alkyl Substituted Amino Acids

Alkyl substituted amino acids are prepared by alkylation of various synthetic and naturalamino acids or by the addition of an amine to an a, b unsaturated alkanoic acid. Sometypical structures follow:

As a group, these compounds exhibit excellent stability under conditions of cosmetic use.

Alkyl substituted amino acids foam copiously, especially above their isoelectric point. Atlow pH levels they behave as cationics and foam poorly. They can be used as emulsifiers.As amphoterics, they are substantive to hair and find their most important uses in varioushair coloring and hair conditioning products.

BAnionics

All surfactants in which the hydrophilic head of the molecule carries a negative charge areclassified as anionics. The group of anionic surfactants includes types of great industrialimportance and substances widely used in cosmetics. As a rule, they are inactivated oreven form complex precipitates in the presence of cationic surfactants. This complexationis generally attributed to salt formation in which the ionized species react instoichiometric proportions. The complexes may be solubilized in aqueous systemscontaining large amounts of anionics.

For the sake of classification, anionic surfactants may be subdivided into five majorchemical classes and subgroups:

B. 1. Acylated Amino Acids and Acyl Peptides

B. 2. Carboxylic Acids (and Salts)

B. 2. (a) Alkanoic Acids

B. 2. (b) Ester-functional Carboxylic Acids

B. 2. (c) Ether-functional Carboxylic Acids

B. 3. Sulfonic Acid Derivatives

B. 3. (a) Taurates

B. 3. (b) Isethionates

B. 3. (c) Alkylaryl Sulfonates

B. 3. (d) Olefin Sulfonates

B. 3. (e) Sulfosuccinates

B. 3. (f) Miscellanous Sulfonates

B. 4. Sulfuric Acid Derivatives

B. 4. (a) Alkyl Sulfates

B. 4. (b) Alkyl Ether Sulfates

B. 5. Phosphoric Acid Derivatives

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The members of these five classes form water soluble salts with alkali metals and lowmolecular weight amines, especially alkanol amines.

The members of subgroups B.1 and B.2 above depend on ionization of the carboxylic acidgroup for aqueous solubility. On the other hand, salts formed with alkaline earths orheavy metals exhibit limited or no solubility in water.

B. 1Acylated Amino Acids and Acyl Peptides

These substances are usually prepared by the reaction of a natural amino acid or of apeptide with a long-chain fatty acid derivative. In this reaction, primary amino groups areconverted into acylated amido groups. This destroys the zwitterionic character of theamino acid or of the peptide and increases the acidity of the carboxylic acids. Aftercompletion of the acylation, these acid groups are frequently neutralized with a suitablealkali. The following examples illustrate some of the structures:

Collagen or some of its hydrolysis products are the most common sources of the protein.The level of hydrolysis (enzymatic or chemical) is not generally specified, and so-calledacylated peptides are likely to contain considerable amounts of acylated amino acids.Since some of the amino acids contain more than one site for acylation (e.g.,hydroxyproline), the end products are probably rather complex mixtures and may includesome simple soaps.

The acyl sarcosinates (derived from N-methyl glycine) occupy a special niche incosmetics. These substances behave like soaps. The key to their performance andmildness is the fact that the carboxyl group has a lower pKa than that of typical fattyacids. The salts of the sarcosinates are water soluble and can be used at pH levels nearor even slightly below neutrality.

Acylated amino acids, depending on molecular weight and complexity, foam modestlyand are generally viewed as exceptionally mild. They find use in skin and hair cleansingproducts and have been included in syndet bars. They reportedly exhibit substantivity tohair and skin proteins. Members of this class are sometimes identified as amphoteric.Under conditions of cosmetic usage (pH 4 to 9), acylated amino acids or peptides carry ananionic charge that is neutralized by a suitable cation. Their reported substantivity to hair

or skin is the result of some unidentified proteinprotein interaction unrelated to thecharge on the surfactant's head group.

Acylated amino acids are amides and subject to chemical (or enzymatic) hydrolysis.

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They are, however, stable at the pH commonly found in cosmetics but are subject tomicrobial attack. Preservation against spoilage remains a major problem, especially in thecase of the peptide-derived products.

B. 2Carboxylic Acids (and Salts)

B. 2. (a)Alkanoic Acids

The most important members of this subgroup are the fatty acids derived from plant andanimal glycerides. These natural acids normally possess an even number of carbon atomsand carry only one carboxylic acid group. The unsaturation in natural fatty acid is almostexclusively cis. A few natural fatty acids also contain a hydroxy group. In addition, somealkanoic acids are prepared synthetically, especially those in which the alkyl group isbranched (iso).

Fatty acids are obtained by the alkaline hydrolysis of fats and oils. Acidification afterremoval of unsaponifiables yields a water insoluble fatty acid blend named on the basis ofits source, e.g., olive oil fatty acids. Specific fatty acids (e.g., oleic acid), can be isolatedfrom these mixtures by various chemical and physical techniques.

Alkanoic acids, as a group, are important industrial chemicals and are used in thesynthesis of many types of substances. One of the most important modifications ofalkanoic acids is reduction to fatty alcohols, which are then processed further to yield avariety of surfactants. Free alkanoic acids are of limited use in cosmetics, but the watersoluble salts (soaps) are amongst the most useful surfactants known. Soaps have beenutilized as cleansers and detersive agents since antiquity. In modern practice, soaps arethe alkali or low molecular weight amine salts of alkanoic acids. Their water solubilitydepends on the pH of the system and on the cation. As a rule, potassium salts are moresoluble than the sodium salts. The alkanoic acids are weak acids, with a reported pKa ofabout 56. Therefore soapsas salts of weak acidsyield alkaline aqueous solutions due totheir dissociation in water.

The solubility of alkali or amine salts of alkanoic acids in water decreases as the length ofthe alkyl chain increases. Thus, sodium stearate, especially in the presence of some freestearic acid, is insoluble enough to permit manufacture into soap bars. The alkaline earthand metal salts of alkanoic acids are water insoluble. Thus, calcium salts precipitate inaqueous systems leading to the formation of so-called soap scum.

Alkanoic acid salts in which the alkyl chain contains about ten or fewer cations are notuseful as surfactants, i.e., they do not foam well, have no detersive qualities, and arepoor emulsifiers. The stearic acid of commerce contains about 45% of octadecanoic and55% of hexadecanoic acids. The product may include small amounts of oleic acid andother acids normally found in the starting lipid. Modern grades of stearic acid are

primarily prepared by hydrogenation of soybean fatty acids. For illustrative purpose, thefollowing structures are included:

Water soluble soaps are used as skin and hair cleansing agents, while the insoluble

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derivatives (e.g., zinc laurate or magnesium stearate) are used for lubricating solids toimprove flow properties, act as binders, and increase the viscosity of nonaqueoussystems. Sodium stearate is soluble in warm ethanol and tends to gel upon cooling. Thusthis substance has found extensive use in the formulation of alcohol-based stickdeodorants.

Water soluble and water insoluble soaps are good emulsifiers, the former primarily foro/w emulsions, while soaps such as aluminum stearate tend to form w/o emulsions. As arule, oleic acid salts are especially useful emulsifiers, but their usage is restricted by thetendency of this unsaturated acid to form malodorous or discolored peroxidation products.

One of the most important applications of soaps is represented by shaving soaps ingeneral. Regardless of the method of shaving (brush, brushless, or aerosol), soap stocksfrom various sources are commonly blended to provide the shaver with copious andrapidly generated foam that lasts until shaving is completed.

The topical use of soaps for skin cleansing is considered safe, although it has been shownthat soaps can elicit adverse reactions on skin during closed patch testing [3].

B. 2. (b)Ester-functional Carboxylic Acids

One type of ester-functional carboxylic acid is the small group of esters derived frompolycarboxylic acids in which at least one of the carboxylate groups is free to form a salt.A typical example is stearyl citrate, the monoester of stearyl alcohol with citric acid.

An entirely different type is represented by the acylation compounds of lactyl lactate. Intheir synthesis, two molecules of lactic acid are believed to react with each other, and thedimer then reacts with a fatty acid. The structure of a typical emulsifier created by thisreaction is shown below:

Compounds belonging to this class are safe for use in foods (baked goods), areoccasionally used as cosmetic emulsifiers, and are reported to condition hair and skin.

B. 2. (c)Ether-functional Carboxylic Acids

Compounds belonging to the group of ether-functional carboxylic acids have recentlygained some prominence in cosmetic usage. They may be viewed as alkylethers ofpolyethyleneglycol in which the terminal OH group has been oxidized to a carboxy group.The principal synthetic route depends on the alkylation (e.g., with chloroacetic acid) of anethoxylated alcohol (D.3.a). As derivatives of glycolic acid, their pKa is quite low. Thepresence of the polymeric ether group increases the water solubility of these substanceseven if the starting alcoholic hydrophobe is relatively bulky. A typical structure is provided

below for illustrative purposes:

The water solubility of the free acids increases with increasing levels of ethoxylation. Inthis form, these compounds are useful as emulsifiers. Neutralization (usually with sodiumion) yields surfactants with detersive and solubilizing properties. These compounds arestable under normal conditions of cosmetic use. Compounds of this type have been shownto reduce the skin irritation potential of other anionic surfactants [4,5] and are generallymilder themselves [6].

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B. 3Sulfonic Acid Derivatives

The extremely stable CS bonds of these alkyl sulfonic acids distinguish them fromcompounds containing hydrolyzable COS bonds. The oxidative state of the sulfur atomalso precludes most elimination reactions. Organic sulfonic acids are strong acids and incosmetics are used only as salts. The sulfonates are generally divided into six subgroups.All sulfonates are chemically stable in cosmetics, and most are well tolerated on the skin.

B. 3. (a)Taurates

The taurates are a small group of compounds which are derived from taurine or N-methyltaurine by acylation. In aqueous solutions these amides are not stable and are subject toself-hydrolysis. Oh the other hand, they are stable in neutralized (generally sodium salt)form. A typical structure of a taurate follows:

Taurates as a group foam well and have found usage in bubble baths and cosmetic skinand hair cleansing products.

B. 3. (b)Isethionates

Isethionates are the esters formed between isethionic acid (HOCH2CH2SO3H) and long-chain alkanoic acids. Like the taurates, the isethionic acid esters are strong acids and aresubject to self-hydrolysis in aqueous systems. They are, therefore, useful in cosmeticsprimarily as sodium salts, as shown below:

Isethionates are compatible with other anionic and nonionic surfactants.

The limited number of cosmetically useful isethionates does not reflect their importancein liquid and solid skin cleansing products. Their irritation potential is considered to bevery low, and they are important constituents of syndet bars.

B. 3. (c)Alkylaryl Sulfonates

Alkylaryl sulfonates are prepared by sulfonation of a number of alkyl substituted aromatichydrocarbons. The starting hydrocarbon may be obtained by alkylation of benzene,naphthalene, toluene, or similar aromatic compounds. The alkyl substituent in modernalkylaryl sulfonates is straight chain (to increase biodegradability) and is attached to the

aromatic nucleus via a Friedel-Crafts reaction. The sulfonation of the resulting alkylarylhydrocarbon is generally accomplished with sulfuric acid and oleum or with SO3. Foroptimal detersive properties, the length of the alkyl chain rarely exceeds twelve carbonatoms.

The best known members of this group of substances are the salts of dodecylbenzenesulfonic acid.

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The commercially distributed alkylaryl sulfonic acids and their salts are water soluble andstable. The free acids are strong acids and are rarely used in this form.

The salts of alkylaryl sulfonates foam well and are effective cleansing agents. They tendto be somewhat harsher on skin than the more commonly used alkyl sulfates (GroupB.4.a). They are not widely used by themselves in cosmetic cleansing products since theytend to leave an unpleasant taut sensation on the skin and must be blended withconditioning ingredients.

Alkylaryl sulfonates without long alkyl chains (e.g., xylene sulfonates) have no foamingpower and are poor detergents. They are, however, useful as hydrotropes since they canenhance the water solubility of other surfactants especially in the presence of inorganicdetergent builders.

B. 3. (d)Olefin Sulfonates

Sulfonation of a-olefins yields a group of surfactants that has found wide use in shampoosand liquid soaps. The most useful olefin starting materials are C14 and C16 (Ziegler)hydrocarbons. Sulfonation yields not only the alkene sulfonate but some alkyl sultonesand disultones. The latter byproducts of the sulfonation reaction are hydrolyzed beforecommercial distribution as sodium olefin sulfonates in the form of 40% aqueous solutions.A typical commercial product may consist of

The most important member of this group, sodium C1416 olefin sulfonate, generates rapidflash foam and can tolerate higher levels of calcium ions than the alkylaryl sulfonates orthe alkyl sulfates. The stability of the olefin sulfonates at moderately low pH levels makesthem suitable for use in acidic shampoos and body cleansing preparations.

B. 3. (e)Sulfosuccinates

The sulfosuccinate group of surfactants includes a broad range of different chemicalsubstances, all of which are derivatives of sulfosuccinic acid, HOOCCH2CHSO3HCOOH. Thereaction of maleic anhydride with a compound carrying a reactive H-atom (alcohol oramine) yields a monoester or monoamide. The reactant may be a simple alcohol oramine or an alkoxylated alcohol, amide, or even a silicone. This monoderivative can be

further reacted to yield a diester or diamide. The resulting maleic acid derivatives arethen reacted with sodium bisulfite to yield the desired sulfosuccinate.

The sulfosuccinates comprise a group of chemicals exhibiting different applicationproperties. Sulfosuccinates are salts of strong acids, regardless of the number and typesof substituents carried on the two COOH groups. Sulfosuccinic acid per se is a stablecompound, but the ester or amide groupings on the COOH groups are subject tohydrolysis at extreme pH levels.

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Some typical sulfosuccinate structures follow:

Sulfosuccinates are widely used in cosmetic hair and skin cleansing products. They do notproduce stable foams but do not interfere with foaming generated by other surfactants.They are relatively mild and reportedly can reduce the irritative potential of othersurfactants.

B. 3. (f)Miscellaneous Sulfonates

A few other alkyl sulfonates have found applications in cosmetics. One of these is thegroup of alkoxylated alcohol sulfonates. Their synthesis is complex and proprietary. Theirstructure is typified by the following:

These water soluble substances exhibit good chemical stability and can be used asprimary cleansing surfactants. They are also reported to lower the irritation potential ofalkyl sulfates.

The other group, the acylglyceride sulfonates, has only one important representative.Sodium cocomonoglyceride sulfonate can be prepared from monochlorohydrin sulfonateby reaction with a sodium soap. This substance has been known for many years and hasbeen safely used in dentifrices for some time.

B. 4Sulfuric Acid Derivatives

In contrast to the sulfonic acids, the compounds derived from sulfuric acid contain a COSlinkage. They are half-esters of sulfuric acid and are subject to hydrolysis. Acidichydrolysis occurs more readily than alkaline hydrolysis, and these half-esters are not usedat acid pH levels. The sulfuric acid half-ester based surfactants consist of two groups, thealkyl sulfates and the alkylether sulfates. Both types are available only as salts ofmonoesters of sulfuric acid. The free acids are unstable in the presence of water andhave no commercial utility. As a rule, the salts are stable at the pH levels normallyencountered in cosmetics.

B. 4. (a)Alkyl Sulfates

The alkyl sulfates are synthesized by sulfation of a fatty or synthetic primary alcohol. Theuse of a secondary alcohol results in products that do not foam well. Short chainhydrophobic alcohols up to decanol also do not foam well and exhibit poor detergency.The alcohols having carbon chains between about 12 and 16 are used as thehydrophobes of choice in cosmetically useful alkyl sulfates. Alcohol sulfates having a chainlength of 18 or more carbon atoms exhibit poor water solubility and are of limited use.Sulfated Guerbet alcohols (e.g., butyloctanol) have only recently been introduced intocosmetics.

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Originally lauryl alcohol (from reduction of natural lauric acid) was the preferredhydrophobe. Today, the starting alcohol may be obtained from the Ziegler process, whichyields a blend of even-number carbon-atom alcohols, or from the Oxo process, whichyields a mixture of odd- and even-chain alcohols. The Oxo alcohol blends also includesome branched-chain and secondary alcohols. Alkyl sulfates may be expected to bemixtures of various alcohols.

The sulfating agents include chlorosulfonic acid (ClSO2OH), sulfamic acid (NH2SO3H) andSO3. Upon completion of the reaction, prompt neutralization with an alkali is required tolimit autohydrolysis of the desired alkyl sulfuric acid. Commercial interest centers on thesodium salt but ammonium, alkanolamine, and other salts are available to theformulator. Of these, the sodium salt is the most insoluble. Alkyl sulfates are marketed as30% solutions or pastes, although solid grades are available for special applications (e.g.,dentifrices). The viscosity may vary widely and depends on the presence of impurities(salts or unsulfated alcohol) or deliberately added solvents or hydrotropes. The structureof a typical alkyl sulfate is illustrated below:

The alkyl sulfates foam readily, but this flash foam requires stabilization (with a foambooster) in many cosmetic applications. For cosmetic use, especially in shampoos, thecommercially distributed alkyl sulfates are diluted to about 1015% active. The viscosity ofthese dilutions can be adjusted with salts, gums, and various lipidic substances. Alkylsulfates can be blended with other anionic, amphoteric, and nonionic surfactants. As ageneral rule, alkyl sulfates form complexes with cationics or quaternaries.

Alkyl sulfates are considered somewhat irritating to skin and have been claimed todelipidize the skin (cf., e.g., Chapter 19). By contrast, recent experimentation has refutedthe degreasing action of these surfactants [7]. Despite this controversy, formulatorscontinously attempt to modify the irritancy of alkyl sulfates by combining them with othermaterials. The exact reasons for these adverse skin effects remain unknown, although itis widely accepted that the dodecyl homologue is the most damaging [6]. In normalcosmetic use, alkyl sulfates do not remain on the skin for prolonged periods of time andcause only transient minimal discomfort to the user. Alkyl sulfates are useful assuspending agents, emulsifiers, and solubilizers. However, formulators avoid highconcentrations (more than about 0.5 to 1.0%) in products that are not rinsed off the skin.

B. 4. (b)Alkylether Sulfates

Alkylether sulfates are the sulfuric acid monoesters of alkoxylated alcohols (see D.3.a.below). For this purpose the same alcohols used in the synthesis of alkyl sulfates areethoxylated by reaction with ethylene oxide before sulfation. This group also includessulfated ethoxylated alkyl phenols. As a rule, the level of ethoxylation does not exceed

about 4 moles of ethylene oxide. After sulfation, the sulfuric acid monoesters must beneutralized to avoid self-hydrolysis.

The structures of some typical representatives are shown below:

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The salts of alkylether sulfates are more water soluble than the alkyl sulfates. As a result,commercial grades may contain as much as 60% active surfactant. They foam almost aswell as the alkyl sulfates and like them require the presence of foam boosters for mostcosmetic applications.

Alkylether sulfates are used as cosmetic cleansing agents just like the alkyl sulfates. Theiruse as emulsifiers is relatively rare. Alkylether sulfates are considered less irritating thanalkyl sulfates and can help reduce the irritancy of alkyl sulfate [4].

B. 5Phosphoric Acid Derivatives

The mono- and diesters of phosphoric acid are useful cosmetic surfactants. Theesterifying alcohols include fatty alcohols, synthetic alcohols, and their alkoxylatedderivatives. Interest in these esters has increased markedly in recent years since it wasreported that they elicit less irritation on skin than the analogous esters of sulfuric acid.Phosphoric esters derived from mono- or diglycerides are of biological importance. If suchphosphates are further esterified with lower molecular weight alcohols (e.g., inositol orcholine) the resulting phospholipids (lecithins) are commonly viewed as ''natural"emulsifiers.

Synthetic phosphate esters are prepared from the alcohol by reaction with P2O5 or asolution of P2O5 in orthophosphoric acid (known as polyphosphoric acid). The esters areneutralized with different alkalies to achieve water solubility. The polarity of the startingalcohol(s) determines the solubility characteristics of the esters. Lecithin, which is notvery soluble in water and includes a diglyceride as one of the alcohols, illustrates thisprinciple.

Some typical structures of phosphoric acid derivatives are shown below:

Most synthetic phosphate esters are mixtures of mono-, di-, and triesters. Triesters are anundesirable impurity in products intended for cleansing or emulsification. The salts of themonoesters, especially, are important emulsifiers and solubilizing agents. Some of theesters reportedly foam well and can be employed in cosmetic cleansing preparations. The

phosphates as a group are relatively resistant to hydrolysis except at extremely low pHlevels. The limited evidence currently available suggests that the phosphoric acid estersare relatively innocuous.

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The second group of phosphoric acid esters is represented by the so-called phosphatidesor phospholipids. The most important phosphatide used in cosmetics is a zwitterioniccompound in which a phosphatidic acid, a monophosphate of diacyl glycerol, is furtheresterified with a positively charged (methyl substituted) amino alcohol (choline).Substances of this type are generically known as lecithins and are isolated from naturalsources (eggs or soybeans). These compounds play an important role in living tissues byenhancing the self-assembly of membranes.

Phosphatidic acids may also be esterified with ethanolamine to form another amphotericsubstance. In addition, this acid may be esterified with inositol with the formation of ananionic substance. Lecithin is used only rarely as an emulsifier in cosmetics. However,lecithins are key constituents for the formation of liposomes and have attracted muchattention in recent years. The mixture of natural substances contains unsaturated fattyacids that are subject to oxidation. Synthetically prepared lecithins, in which R and R' aresaturated, are particularly useful for the preparation of liposomes.

CCationics

The cationic surfactants used in cosmetics are substances that carry a positively chargednitrogen atom on the hydrophobe. The positive charge may be permanent, i.e.,independent of pH, as in the true quaternaries, or may be pH dependent, as in amines.Cationics can be further subdivided as follows:

C. 1. Quaternaries

C. 1. (a) Alkyl Benzyl Dimethylammonium Salts

C. 1. (b) Alkyl Betaines

C. 1. (c) Tetraalkylammonium Salts

C. 1. (d) Heterocyclic Ammonium Salts

C. 2. Alkyl Amines

C. 3. Alkyl Imidazolines

C. 1Quaternaries

This important group of cosmetic surfactants is distinguished from alkyl amines andamphoterics by the fact that all quaternaries carry a tetrasubstituted N-atom.Quaternaries can elicit toxic and allergic responses. They are customarily used at lowlevels (for antimicrobial or conditioning effects), and documented reports of adversereactions are relatively rare. Quaternaries are substantive to proteins and their tendencyto penetrate stratum corneum is limited [8].

C. 1. (a)Alkyl Benzyl Dimethylammonium SaltsThis group of quaternaries is derived from aliphatic tertiary amines carrying at least twomethyl groups by reaction with a benzyl halide. The nature of the alkyl groups on the N-atom is variable and may include chains carrying other heteroatoms. A typical illustrativestructure follows:

The INCI names of these compounds do not include the "benzyl" notation.

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These substances are solids but are available as solutions or suspensions. They areexcellent hair-conditioning agents, and some are useful antimicrobial agents, especiallybenzalkonium chloride. In this compound, the broad spectrum antimicrobial activitydepends on the length of the alkyl group, with the C10 to C14 chains being the mosteffective. The benzalkonium salts are also used as emulsifiers and suspending agents.They also react with clays to yield substances that are widely employed as suspendingagents in aerosols and solvent-based products (nail lacquers). The benzalkonium saltsare stable at all conditions encountered in cosmetic practice. As a rule they are notcompatible with anionic surfactants.

C. 1. (b)Alkyl Betaines

The primary substances in this group are the N-alkyl derivatives of N-dimethyl glycine.The alkyl groups may include some heteroatoms. The group also includes a fewhydroxypropyl sulfonates (sultaines). The betaines are manufactured by reaction of analkyldimethylamine with chloroacetic acid. Unless carefully purified, these products maybe contaminated with starting product or glycolic acid.

The betaines exhibit good water solubility. As a rule, they are compatible with all types ofsurfactants but may form complexes with anionics near their isoelectric pH. Some typicalstructures follow:

The betaines are solids but are available primarily in aqueous solutions. They are stableand foam well. They are used primarily as hair- and skin-conditioning agents and arewidely employed in shampoos. They reportedly have the ability to lower the protein-swelling tendencies and irritation potential of alkyl sulfates [6]. They act as foamboosters and viscosity-increasing agents in shampoos. Due to their mildness and ability tolower irritation of anionics they are often used in baby shampoos.

C. 1. (c)Tetraalkylammonium Salts

This group of quaternaries differs from the other quaternaries in the fact that none of thefour substituent groups on the N-atom is specified. As a result, these compounds includewidely varying members exhibiting different solubilities and physical properties.

The substituent groups on the N-atom may be identical or may include one or two

polyoxyethylene or polyoxypropylene chains. The solubilities are dependent on thecharacteristics of the substituent groups. The tetraalkyl ammonium saltsin common withother cationicsexhibit substantivity to skin and hair proteins and are generallyincompatible with anionic surfactants. Under conditions of cosmetic use, these substancesare stable. Some illustrative examples follow:

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Some tetraalkylammonium salts can be used as emulsifiers. Those with two long alkyl(e.g., hydrogenated tallow) groups are useful conditioners in miscellaneous hair products.

C. 1. (d)Heterocyclic Ammonium Salts

Substances in this group result from the alkylation of heterocyclic N-containing amineswith a suitable alkylhalide. The number of surfactants in this class is limited; most ofthem are derived from pyridine, morpholine, isoquinoline, or imidazoline.

Except for the imidaozoline (imidonium) derivatives, these quaternaries are stable underconditions of cosmetic use. Almost all of them are water soluble solids. Somerepresentative structures follow:

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The heterocyclic quaternaries include an important group of antimicrobial agents, e.g.,cetylpyridinium chloride and dequalinium chloride, a bisquaternary. Most of theheterocyclic ammonium salts find use as hair and skin conditioning agents.

C. 2Alkyl Amines

Long chain alkyl amines, whether primary, secondary, or tertiary, are hydrophobic. Theyact as surfactants only after they have been neutralized, usually with a strong inorganicor organic acid. The free amines can be made more hydrophilic by forming an amidoamine from an acid chloride and an aliphatic diamine. Hydrophilicity of the free amine canbe further enhanced by treating a primary or secondary amine with ethylene oxide, whichattaches a polyoxyethylene chain to the amino-N.

The alkyl amines are waxy solids of variable water solubility. They are stable underconditions of cosmetic usage.

Structures of some typical examples follow:

Ethoxylation creates amines that are sometimes compatible with anionics. Unethoxylatedamines are more basic and thus generally not compatible with anionics.

Neutralized alkyl amines are positively charged and are used as substantive hair and skinconditioning agents. As a group the alkylamines are useful emulsifying and dispersingagents.

C. 3Alkyl Imidazolines

The heterocyclic alkyl imidazolines are the precursors of the alkylamido alkylamines(A.1.) and of the quaternized imidonium derivatives (C.1.d.). The alkyl imidazolines areavailable as aqueous solutions. They are not resistant to hydrolysis under adverse pHconditions. The structure of a typical example is shown below:

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Alkyl imidazolines can be used as emulsifiers and conditioning agents. Their use incosmetic formulation is limited by their questionable stability and the need forneutralization.

DNonionics

Nonionic surfactants are substances in which the molecule carries no charge at the pHlevels of cosmetic use. The hydrophobe can be highly variable, but the hydrophilic headgenerally includes a polyether group or at least one OH group. For the sake of thisdiscussion, nonionics are subdivided into five large groups:

D. 1. Alcohols

D. 2. Esters

D. 3. Ethers

D. 4. Alkanolamides

D. 5. Amine Oxides

D. 1Alcohols

Primary alcohols ranging from 8 to about 18 carbon atoms exhibit useful surfactantproperties. The "natural" alcohols were obtained by the reduction of fatty acids derivedfrom various lipids. Today the Ziegler process is used to synthesize even-numberedstraight-chain alcohols, while the Oxo process yields even- and odd-numbered alcoholswith some branching and some secondary alcohols. Most commercially available alcoholsare mixtures; they are the starting raw materials for esters and ethers for cosmetic useas surfactants (groups D.2 and D.3) or emollients.

Alcohols are chemically inert and stable in cosmetic preparations. They are available asliquids or waxy solids, depending on molecular weight. They can crystallize in finishedproducts, and care is required during formulation. A typical structure is shown below:

The alcohols cannot be used as primary surfactants but contribute surfactant-likeproperties in the presence of other amphiphiles.

The alcohols are useful as cosurfactants in the presence of soaps or alkyl sulfates. Suchmixtures are commercially available as emulsifying waxes. They are popular systems foro/w multiple-phase emulsions [9]. See also Chapter 7.

D. 2Esters

Esters are among the most frequently used surfactants in cosmetics. Esters are subject tohydrolysis, but the pH conditions for such reactions in cosmetics do not prevail. Inaddition, nonionic esters are among the safest surfactants available to formulators andare common constituents of processed foods. For the sake of facilitating the discussion ofspecific groups, nonionic ester-type surfactants are divided as follows:

D. 2. (a) Ethoxylated Glycerides

D. 2. (b) Glycol Esters

D. 2. (c) Monoglycerides

D. 2. (d) Polyglyceryl Esters

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D. 2. (e) Carbohydrate Derived Esters

D. 2. (f) Ethoxylated Carboxylic Acids

D. 2. (g) Sorbitan Esters

D. 2. (h) Trialkyl Phosphates

D. 2. (a)Ethoxylated Glycerides

Substances belonging to this class of compounds are derived from mono-, di-, or triacylglycerides. Ethoxylation of an a-monoglyceride leads primarily to alkoxylation of the g-OHgroup of the glyceride, although some b-ethoxylation is possible. The structure of thesederivatives probably conforms to the following:

Diacylglycerides can also be ethoxylated to yield compounds of the following type:

Finally, triacyl glycerides undergo ethoxylation with some transesterification to yieldcomplex mixtures that may include some ethoxylated carboxylic acids and some morecomplex esters resembling those derived from sorbitan (cf. D.2.g.). One of manypotential structures is shown below:

When reactions of this type are carried out on glycerides containing OH-acids (e.g., castoroil) ethoxylation of OH groups may occur.

The water solubility of ethoxylated glycerides depends on the degree of ethoxylation,which can be quite high, e.g., PEG-200 castor oil. These substances are stable tohydrolytic reactions at the pH levels normally encountered in cosmetic practice. They areused as emulsifiers, suspending agents, and solubilizers.

D. 2. (b)Glycol Esters

This group, consisting of long-chain carboxylic acid monoesters of ethylene or propylene

glycol, is hydrophobic and of limited practical use as a primary surfactant. The so-calledself-emulsifying grades find applications in o/w emulsifying systems, while the pure estersfind occasional use in w/o emulsification and

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for opacification. The self-emulsifying mixtures resemble the emulsifying waxesmentioned in the discussion of alcohols.

A typical structure, which includes potassium stearate, follows:

D. 2. (c)Monoglycerides

Mono-substituted glycerides are obtained by transesterification of di- or triglycerides withglycerine. They can also be prepared by controlled acylation of glycerine (e.g., byreaction of a fatty acid methyl ester with glycerine). Commercially availablemonoglycerides are mixtures of a- and b-monoglycerides. Complex interconversions ofthese two forms occur with some formation of diglycerides. Unless the monoglyceridesare distilled, the commercial grades of monoglycerides may contain large amounts (inexcess of 50%) of diglycerides. Users of monoglycerides must select the required gradewith considerable care and must be aware of polymorphic changes and stereoisomerismand must control specifications [10]. Self-emulsifying grades may include soaps andanionic, cationic, or nonionic surfactants. Pure grades (90% + monoglyceride) are quitehydrophilic. They can be further reacted with ethylene oxide or with hydrophilic acids toyield useful food-grade emulsifiers.

Monoglycerides are generally water insoluble liquids or waxy or hard solids. Someillustrative structures follow:

Monoglycerides are combined with other surfactants in all types of emulsions. They havea tendency to increase product viscosity. Monoglycerides are stable at the pH levelstypically found in cosmetics.

D. 2. (d)Polyglyceryl Esters

These substances are prepared by acylation of glycerin polymers formed by dehydration.This latter reaction results in a wide variety of complex polyethers of glycerin. Similarhydrophiles may be synthesized from glycidol. Most of the polyglycerins retain at leastone OH group per starting molecule of glycerin. The degree of polymerization normally

does not exceed 10. The fatty acids used for esterification are generally derived fromnatural lipids. The resulting polyglyceryl esters may include linear and cyclic polymers ofglycerin exhibiting different molecular weights.

An idealized structure of one of these substances follows:

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The polyglyceryl esters in commerce are complex mixtures and contain beige to browncolored impurities. They are stable in normal cosmetic use. Their water solubility dependson the length of the hydrophile and the degree of acylation. Their primary use is asemulsifiers.

D. 2. (e)Carbohydrate Derived Esters

Acylation of simple carbohydrates yields cosmetically useful compounds. If sucrose isused as the hydrophile, the primary products are mono-, di-, and triesters. Another typeof ester is derived from methyl glucose; in order to increase their hydrophilicity, theseesters can be further modified by ethoxylation. The solubility, as in most other nonionicsurfactants, is dependent on the degree of hydrophilic substitution. Only two structuresare shown to illustrate the nature of these surfactants:

This group of surfactants includes some useful emulsifiers, some of which have beenclaimed to act as skin conditioners.

D. 2. (f)Ethoxylated Carboxylic Acids

These esters of long-chain (fatty) acids can be obtained by ethoxylation of the free acids,which leads to monoesters. The esters can also be prepared by acylation of preformedpolyethylene glycol ethers. Depending on the reaction conditions and the ingredient ratio,mono- or diesters will be formed. These esters have properties similar to those of theethoxylated alcohols (D.3.a.) except for the fact that the esters are subject to acid oralkali hydrolysis. The so-called PEG mono-acylates with fewer than about 6 ETO units arewater insoluble, while those with 8 to 10 or more ETO groups are water soluble. Diestersare likely to be much more hydrophobic.

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The esters belonging to this group are liquids or solids and, depending on the degree ofethoxylation, possess different hydrophilicities (HLBs). They are widely used in cosmetics,and they are considered innocuous.

The following structures are typical of products belonging in this group.

The alkoxylated carboxylic acids are used as emulsifiers and solubilizers. Some diestershave found use as opacifying agents. They are considered safe for general use incosmetics and are stable under normal conditions.

D. 2. (g)Sorbitan Esters

The hydrophile of this group of acyl esters is either sorbitol or 1,4-sorbitan. Despite someconfusion, true sorbitol esters are probably only impurities in commercially distributedsorbitan esters. When sorbitol, obtained by reduction of glucose, is acylated understandard (acid) conditions, 1,4-sorbitan is formed. Sorbitan contains four OH groups, eachof which can be acylated. As a rule, the monoacyl derivative on the terminal CH2OH (the7 position in the structure below) is the preferred substance for further processing withethylene oxide. Under the conditions of this ethoxylation reaction, some rearrangementstake place, to yield a polysorbate from the precursor monoacylate.

For illustrative purposes the structures of some of these compounds are shown below:

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In polysorbates the major substitution is on the carbon atom identified as 7, and most ofthe 20 ETO units are believed to bridge the acyl radical to the sorbitan segment at thissite. In addition, the commercially sold polysorbates may contain derivatives of isosorbideand other constituents.

The hydrophilicity of these substances, i.e., their HLB, depends on the degree ofethoxylation and the number of esterifying acyl groups. The sorbitan esters do not foamwell. They are used as emulsifiers and solubilizers and are available as liquids or waxysolids. Their safety is well documented, and they can be used in foods.

D. 2. (h)Trialkyl Phosphates

Trialkyl phosphates, the triesters of phosphoric acid, are included here only for the sakeof completeness. These substances exhibit surfactant properties only if the esterifyingalkyl substituents are (hydrophilic) ethoxylated alcohols (D.3.a.). They are generallyprepared by reacting phosphorus oxychloride with an alkoxylated alcohol.

The following structure is believed to be descriptive:

Despite their hydrophilicity, these phosphoric acid esters find some use as w/o emulsifiersand as emollients.

D. 3Ethers

Ethers as a group are widely used in cosmetic and pharmaceutical products because oftheir good resistance to hydrolytic reactions. The ethers of interest contain not only a(repeated) COC grouping but also a terminal COH grouping. They could, therefore, alsobe classified chemically as alcohols.

For the sake of convenience, some ethers derived from naturally occurring lipids are alsoincluded in this group. The ether group is subdivided as follows:

D. 3. (a) Ethoxylated Alcohols

D. 3. (b) Ethoxylated Lanolin and Castor Oil

D. 3. (c) Ethoxylated Polysiloxanes

D. 3. (d) Alkyl Glucosides

D. 3. (e) POE/PPG Ethers

D. 3. (a)Ethoxylated Alcohols

In the synthesis of these ethers, a hydrophobic alcohol, a sterol, or a phenol is treatedwith ethylene oxide. The alcohols are those already described in the synthesis of alkylsulfates (B.4.a.) and those useful as secondary emulsifiers (D.1). In addition, thesealcohols are sometimes modified by reacting them with propylene oxide beforeethoxylation. The sterols are those found in nature (cholesterol and its reduction product,soybean sterols, and other phytosterols). Alkyl phenols (octyl from diisobutylene andnonyl from tripropylene) are the starting materials for useful nonionic surfactants.

The ethoxylation is carried out under pressure and in the presence of alkaline catalysts.Usually ethoxylated alcohols yield a mixture of POE ethers of varying levels ofethoxylation. Free alcohols are common contaminants. The n values areat bestanapproximation of the average number of ether-forming ethylene oxide units. A myristyl

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alcohol ethoxide identified as Myreth-8 commonly contains no more than about 15 to20% of the 8-mole POE derivative of the starting alcohol. The remaining substances showa Gaussian distribution of EO units with a peak of about 8 [11].

The water solubility is a function of the degree and distribution of ethoxylation. The HLBof these ethers can range from about 3 to 18. They may be liquid or pasty solids. Theyfoam poorly and are used primarily as o/w, or w/o emulsifiers or solubilizers. Most ofthem are considered innocuous. Three typical structures follow to illustrate the chemistryof the alkoxylated alcohols:

D. 3. (b)Ethoxylated Lanolin and Castor Oil

Lanolin is an esterfied mixture of lanolin fatty acids, lanolin alcohols, and sterols andcontains some free OH groups. Castor oil, a triglyceride of ricinoleic acid, also possessesOH groups. During ethoxylation of these lipids, ethoxylation of free OH occurs as well assome transesterification that is accompanied by the formation of alkoxylated acids andalcohols. The hydrophilicity of the resulting complex mixtures depends on the level ofethoxylation. In light of the uncertainty concerning the predominant structures in thesesubstances, no structures for compounds such as PEG-33 Castor Oil or PEG-5 lanolin areprovided.

These substances are useful emulsifiers, solubilizers, suspending agents, or even skincleansers. Their specific application in cosmetics depends on their hydrophilicity.

D. 3. (c)Ethoxylated Polysiloxanes

The synthesis of this group of substances is proprietary. In principle, a medium to lowmolecular weight polysiloxane with a silanol grouping is formed. The OH groups in thepolymer are then reacted with ethylene oxide and/or propylene oxide. The degree ofalkoxylation can vary widely, and a high degree of ethoxylation is required to assurewater solubility. These hydrophilic polysiloxanes are emulsifying agents, especially forsilicone oils.

D. 3. (d)

Alkyl GlucosidesThis interesting group of surfactants is prepared by reaction of hydrophobic alcohols withglucose. During the ether formation, some oligosaccharide is formed, and the reactionproducts could be described as the monoalkyl ethers of a polyglycoside exhibiting anaverage degree of polymerization of 1.4. The structure is represented as follows:

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These substances foam well and are used in skin and hair cleansing products. Theglucosides are acetals and may exhibit poor stability at low pH levels. They are reportedto be mild on skin and to lower the skin irritation potential of alkyl sulfates.

D. 3. (e)POE/PPG Ethers

The ethers in this category are block polymers, consisting of polyoxyethylene andpolyoxypropylene blocks. The hydrophobe is an ether alcohol synthesized from propyleneoxide with the aid of a short-chain alcohol (e.g., propylene glycol or butanol). This di- ormonohydroxy polymer can then be further reacted with EO. It is also possible to form apolyoxyethylene ether first, which is subsequently propoxylated.

The HLB of these ethers is clearly dependent on the ratio of the PPG polymers to the POEpolymers. Some structures of substances in this group are provided below:

They are chemically inert and are available as colorless liquids or solids. They find wideapplications as emulsifiers, solubilizers, and lime soap dispersants. The higher molecularweight poloxamers tend to reduce skin penetration and in addition can be used as gellingagents. Some of these ethers have been approved for use in injectables, and a few areconsidered safe for parenteral nutrition emulsions.

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D. 4Alkanolamides

Alkanolamides are the acylation products of various alkanolamines. Two types ofalkanolamides exist. One of these, the superamides, are prepared from the 1:1 mole ratioof the amine and the acylating species, yielding primarily water insoluble N-acylalkanolamide. This type of product is contaminated with esteramine and probably theester amide in which both the OH and NH functions are acylated. When two moles of analkanol amine are reacted with one mole of the acylating species, the so-calledKritchevsky condensates are formed. They may contain all of the components identified inthe description of the 1:1 product. In addition, these water soluble condensates maycontain alkanolamine soaps and derivatives of morpholine and piperazine. The INCInomenclature does not differentiate between these two types, both of which areavailable commercially.

A third group of compounds results when an acid amide is allowed to react with ethyleneoxide. In this case, water solubility is determined by the degree of ethoxylation.

Some representative structures, describing the predominant components provided in theINCI Dictionary, follow:

The 1:1 and the Kritchevsky condensates find their primary uses as foam boosters andfoam stabilizers in shampoos. They are only rarely used as emulsifiers. The ethoxylatedamides are relatively stable to hydrolysis and find use as emulsifiers at low pH levels(e.g., in antiperspirants).

D. 5Amine Oxides

Amine oxides are formed from tertiary aliphatic amines by oxidation, generally withhydrogen peroxides. The tertiary amine may be a straight chain or part of a heterocyclicsystem. There has been some claim that amine oxides can be protonated at pH levelslower than those occurring in cosmetic practice. Amine oxides are generally contaminatedwith unreacted amines, which may account for some of the cationic behaviors of amineoxides. Pending further evidence, it seems advisable to classify amine oxides as nonionicsurfactants. A typical structure is shown below:

Amine oxides are water soluble and foam well. They are used as foam boosters inshampoos and as lime soap dispersants. Amine oxides are used in hair-coloring productsand reportedly can reduce the skin irritant characteristics of anionic surfactants [6].

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References

1. International Cosmetic Ingredient Handbook, 2nd ed., (J. A. Wenninger and G. N.McEwen, Jr., eds.), Cosmetics, Toiletry, and Fragrance Association, Washington, DC, 1992and Supplement, 1993.

2. International Cosmetic Ingredient Dictionary, 5th ed., (J. A. Wenninger and G. N.McEwen, Jr., eds.) Cosmetics, Toiletry, and Fragrance Association, Washington, DC, 1993(or later edition).

3. P. Frosch and A. Kligman. J. Am. Acad. Dermatol. 1:3541 (1979).

4. L. Rhein, F. Simion, R. Hill, R. Cagan, J. Mattai, and H. Maibach, Dermatologica180:1823 (1990).

5. S. Zehnder, R. Mark, S. Manning, A. Sakr, J. Lichtin, and K. Gabriel, J. Soc. Cosm.Chem. 43:313330 (1992).

6. L. Rhein, C. Robbins, K. Fernee, and R. Cantore, J. Soc. Cos. Chem. 37:125139 (1986).

7. J. Leveque, J. de Rigal, D. Saint-Leger, and D. Billy, Skin Pharmacol. 6:111115 (1993).

8. E. Singer, and E. Pitts, in Surfactants in Cosmetics, 1st ed. (M. Rieger, ed.), MarcelDekker, New York, 1985.

9. G. M. Eccleston, J. Soc. Cosm. Chem. 41:122 (1990).

10. M. Rieger, Cosm. & Toil 105 XI:5157 (1990).

11. K. Matheson, T. Matson, and K. Yang, J.A.O.C.S. 63:365370 (1986).

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2Physical Properties of Surfactants Used in CosmeticsDrew MyersConsultant, Rio Tercero, Córdoba, Argentina

I. Solution Properties of Surfactants 30

A. Introductory Comments 30

B. The Phase Spectrum of Surfactants in AqueousSystems 30

C. Surfactant Solubility and the Krafft Temperature 31

D. Micelles, Vesicles, and Liquid Crystals 33

II. SurfactantPolymer Interactions in Solution 48

A. Polymers As Surfactants 48

B. SurfactantPolymer Interactions 48

III. Surfactant Adsorption 52

A. LiquidFluid Interfaces 52

B. Adsorption at SolidLiquid Interfaces 57

IV. Wetting, Spreading, and Capillary Flow 64

A. The Contact Angle 64

B. The Thermodynamics of Wetting 66

C. The Critical Surface Tension of Wetting 67

D. Competitive Wetting 68

E. The Effects of Surfactants on Wetting Processes 68

F. The Wetting of Powders and Porous Materials 70

G. Capillary Action in Cleaning Processes 70

V. Foams 71

A. The Importance of Foams 71

B. Foam Formation 72

C. Basic Properties of Foams 73

D. Practical Control of Foam Formation and Persistence 74

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E. Foam Inhibition 79

VI. A Final Comment 80

References 80

ISolution Properties of Surfactants

AIntroductory Comments

The applications and functions of surfactants in cosmetics are old but still not extremelywell understood combinations of science and art, rivaled in complexity by few otherareas, food applications being one. In order to take maximum advantage of the directand indirect effects of surfactants in cosmetic formulations, it is important to have a goodworking idea of what one can expect from the presence of a given surface activematerial. Such ideas must be based on both fundamental knowledge and empiricalexperience. Theoretical concepts and characteristic properties determined for ''pure"surfactant systems are indispensible for providing a good basis for the development of acomplex cosmetic formulation. However, knowledge of the basic principles can serve tonarrow significantly the possible options for surfactants to fulfill a given need and thussave the formulator significant time and money.

Because of their chemical composition, surfactants exhibit a "lovehate" relationship withmost solvents, particularly water, which results in a tug-of-war between forces tendingtoward a comfortable accommodation within a given solvent environment and a driving"desire" to escape to a more energetically favorable situation. Anthropomorphically,surfactants seem to feel that the grass is always greener on the other side of the fenceand, as a result, spend much of their time sitting on the "fence" between phases. Thatfence-sitting characteristic is manifested in many ways including adsorption at variousphase interfaces, interaction with materials dissolved or dispersed in the liquid phase,and the formation of so-called association colloids. Some of the effects of suchinteractions will be discussed below.

BThe Phase Spectrum of Surfactants in Aqueous Systems

For those concerned with the physico-chemical properties of surfactants it is important tounderstand the basic solution properties of such species. Most discussions of surfactantsin solution are concerned with properties at low concentrations, i.e., systems that containwhat may be thought of as "simple" species such as free surfactant molecules and basicaggregates such as micelles (even though micelles may be quite complex). In manyapplications, however, cosmetics included, the situation may be much more complex, so

that one must consider the presence and effects of higher level association structures andother interactions. The variety of possible surfactant interactions that one may encountermay be thought of as its "spectrum" in terms of the potential effects the surfactant mayhave in a given system.

A visual idea of the potential complexity of surfactant interactions in solution is given inFig. 1, where S, L, and V refer to solid, liquid, and vapor phases, respectively. Asillustrated, the range of possible states or interactions in the presence of solvents,solutes, or interfaces is quite wide. The possibilities range from the highly orderedcrystalline

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Fig. 1A "spectrum" of surfactant interactions in aqueous solution.

phase to the dilute monomeric solution which, although not completely structureless, hasorder only at the level of molecular dimensions. Between the extremes lies a variety ofphases and interactions whose natures depend intimately on the chemical structure ofthe surfactant, the total bulk phase composition, and the environment of the system(temperature, pH, cosolutes, etc.). Knowledge of those structures, and the reasons forand consequences of their formation, influences both our academic understanding ofsurfactants and their technological application. The following sections will offer anintroduction to the most significant possibilities for surfactant behavior in solution.

CSurfactant Solubility and the Krafft Temperature

The chemical nature of surfactant molecules is responsible for their unique characteristicsin terms of self-association (or aggregation), adsorption at interfaces, and variouspossible interactions with co-solutes. However, before activity can become apparent, thesystem must contain a surfactant concentration sufficiently high so that the relevantcharacteristics of the system will be altered enough to be notable. Leaving aside thepossibility of simply not introducing enough surfactant into the system, an important firstaspect of the surfactant in question is its solubility.

A primary driving force for the development of synthetic surfactants in this century

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was the problem of the precipitation of the fatty acid soaps in the presence of multivalentcations such as calcium and magnesium. While most common surfactants have asubstantial solubility in water, that characteristic can change significantly with changes inthe length of the hydrophobic tail, the nature of the head group, the valency of thecounter ion, and other aspects of the solution environment. For many ionic materials, forinstance, it is found that water solubility increases as the temperature increases. It isoften observed that the solubility of such materials will undergo a sharp, discontinuousincrease at some characteristic temperature, referred to as the Krafft temperature, Tk.Below Tk, the solubility of the surfactant is determined by the crystal lattice energy andheat of hydration of the system, as with normal crystalline materials. The concentrationof the monomeric species in solution will be limited to some equilibrium value determinedby those properties. Above Tk, the solubility of the surfactant monomer may increase tothe point at which self-association or micelle formation begins and the associated speciesbecomes the thermodynamically favored form. The concentration of monomericsurfactant will again be limited by the energetics of the system.

A micelle may be viewed simplistically as structurally resembling the solid crystal or acrystalline hydrate, so that the energy change in going from the crystal to the micelle willbe less than the change in going to the monomeric species in solution, even though theprocess is usually seen as going through the monomeric solution phase.Thermodynamically, the formation of micelles favors an overall increase in solubility. Theconcentration of surfactant monomer may increase or decrease slightly at higherconcentrations (at a fixed temperature), but micelles will be the predominant form ofsurfactant present above a certain concentrationthe critical micelle concentration or cmc.The total solubility of the surfactant, then, will depend not only on the solubility of themonomeric material, but also on the "solubility" of the micelles.

The Krafft temperatures of a few common surfactant types are given in Table 1. It can beseen that Tk varies as a function of both the nature of the hydrophobic group and theionic character of the head group. Note that no data are listed for nonionic surfactants.Nonionic surfactants, because of their different mechanism of solubilization (i.e.,hydrogen bonding) do not exhibit a Krafft temperature. They do, however, have acharacteristic temperature/solubility relationship in water in that they tend to becomeless soluble as the temperature increases. In some cases, phase separation will be foundto occur,TABLE 1 The Krafft Temperatures (Tk) of TypicalIonic SurfactantsSurfactant Tk Tk

38 3248 6157 3616 2430 1945

Source: Refs. 13.

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producing a cloudy suspension of surfactant or even two separate phases. Thetemperature at which this occurs is referred to as the cloud point.

The fundamental relationship between the Krafft temperature, the crystal lattice energy,and the heat of hydration of the surfactant is confirmed by the fact that there is a goodcorrelation between Tk for a surfactant of a given hydrocarbon chain and the meltingpoint of the corresponding hydrocarbon material. Such correlations can also be found forthe appearance of other structural changes in surfactant solutions discussed in thefollowing sections.

DMicelles, Vesicles, and Liquid Crystals

Association colloids form as a result of the unique molecular character of the class ofmaterials described in Chapter 1 as surfactants or surface active agents. The adsorptionof surfactants at interfaces will be discussed in later sections. The formation of thevarious associated structures such as micelles, vesicles, membranes, and liquid crystalsmay be seen as a fundamental characteristic of a given molecular structure in a definedenvironment. The exact solution behavior of a surfactant will depend on a number ofinternal (molecular) and external factors, which will be discussed in turn. At this point itwill be useful to take a look at the possibilities open to surface active molecules in thevarious environments that may be encountered.

Surfactant association is a spontaneous process resulting from the energetics ofinteractions among the individual surfactant molecules and the solvent medium, as is thatof crystallization. However, the size, shape, and basic nature of the associated structuresare controlled by a complex series of factors distinctly different from those involved incrystallization. The size and internal structure of associated surfactants, in particular, willbe much more limited than those of normal crystals. This class of units is generallyreferred to as association or self-assembled colloids.

The general class of association colloids can be further divided into subgroups thatinclude micelles, vesicles, microemulsions, bilayer membranes, and liquid crystals. Eachsubgroup can play an important role in many applications of surfactants, both astheoretical probes that help us to understand the basic principles of molecularinteractions and in many practical applications including biological systems, cosmetics,medicine, detergency, foods, crude oil recovery, etc.

1Micellization

The simplest class of association colloids is the micelle. The number of publicationsrelated to micellization, micelle structures, and the thermodynamics of micelle formationis enormous. Extensive interest in the self-association phenomenon is evident in suchwide-ranging chemical and technological areas as organic and physical chemistry,

biochemistry, polymer chemistry, pharmaceuticals, petroleum and minerals processing,cosmetics, and food science. Even with the vast amount of experimental and theoreticalwork devoted to the understanding of the aggregation of surface active molecules, nocomplete theory or model has emerged that unambiguously satisfies all of the evidenceand the interpretations of the evidence for micelle formation.

The solution behavior of surfactants reflects the unique "split personality" of such species.The thermodynamic pushing and pulling that occurs in aqueous solution (or nonaqueoussolution, for that matter) result from a complex combination of effects

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including (1) interactions of the hydrocarbon portions of the molecules with water, (2)attractive interaction among hydrocarbon tails on separate molecules, (3) interactionsamong solvated head groups (generally repulsive) and between the head groups and co-ions, in the case of ionic materials, and (4) geometric and packing constraints derivingfrom the particular molecular structure involved.

It is generally accepted that most surface active molecules in aqueous solution canaggregate to form micellar structures with an average of from 30 to 200 molecules insuch a way that the hydrophobic portions of the molecules are associated and mutuallyprotected from extensive contact with the bulk of the water phase. Not so universallyaccepted are some of the ideas concerning micellar shapes, the nature of the micellarinterior, surface "roughness," the sites of adsorption (or solubilization) into (or onto)micelles, and the size distribution of micelles in a given system. Although ever moresophisticated experimental techniques continue to provide new insights into thosequestions, we still have a lot to learn.

(a)Manifestations of Micelle Formation

Early in the study of surfactants, it became obvious that the solution properties of suchmaterials were unusual and could change dramatically over very small concentrationranges. The measurement of solution properties such as surface tension, electricalconductivity, or light scattering as a function of surfactant concentration will producecurves that exhibit relatively sharp discontinuities at a comparatively low concentration(Fig. 2). The sudden change in a measured solution property is interpreted as indicating achange in the nature of the solute species affecting the measured quantity. In themeasurement of conductivity (curve A), the break is associated with an increase in themass per unit charge of the conducting species. For light scattering (curve B), the changein solution turbidity indicates the appearance of a scattering species of significantlygreater size than the monomeric solute. These and many other types of measurementserve as evidence for the formation of aggregates or micelles in solutions of surfactantsat relatively well-defined concentrations.

Results of early studies of such solution properties were classically interpreted in

Fig. 2Typical variations in solution physical

properties with surfactant concentration.

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terms of a spherical association of surfactant moleculesthe micelle. The structure wasassumed to be an aggregate of from 50 to 100 molecules with a radius approximatelyequal to the length of the hydrocarbon chain of the surfactant. The interior of the micellewas described as being essentially hydrocarbon in nature, while the surface consisted of ashell of the head groups and associated counter ions, solvent molecules, etc.

Modern studies using techniques unavailable just a few years ago have produced moredetailed information about the submicroscopic nature of micelles. For example, they arenot static species; they may be very dynamic with a constant, rapid interchange ofmolecules between the aggregates and the solution phase. It is therefore unreasonableto assume that surfactant molecules pack into a micelle in such an orderly manner as toproduce a smooth, perfectly uniform surface structure. If one could photograph a micellewith ultra-high speed film, freezing the motion of the molecules, the picture wouldcertainly show an irregular molecular cluster more closely resembling a cocklebur than abilliard ball.

Although the classical picture of a micelle is that of a sphere, most evidence suggeststhat spherical micelles are probably the exception rather than the rule. Due to geometricpacking requirements (to be discussed below) ellipsoidal, disk-shaped, and rod likestructures may be the more common micellar shapes. However, for the purpose ofproviding a basic concept of micelles and micelle information for the nonspecialist, thespherical model remains a useful and meaningful tool.

Leaving aside for the moment questions concerning particular concepts and models ofmicelles, it is known that the processes of micelle formation is thermodynamically driven.It is important, therefore, to have a general understanding of the rules that govern theprocess.

(b)Classical Thermodynamics of Micelle Formation

In the literature on micelle formation, two primary models have gained generalacceptance as useful (although not necessarily accurate) tools for understanding theenergetics of self-association. The two approaches are the mass-action model, in whichthe micelles and monomeric species are considered to be in a kind of chemicalequilibrium, and the phase-separation model, in which the micelles are considered toconstitute a new phase formed in the system at and above the critical micelleconcentration. In each case, classical thermodynamic approaches are used to describethe overall process.

A full discussion of the nature and consequences of each model would require much morespace than is available here, and in the end the choice of the appropriate approach willdepend as much on the inclinations of the interested party as on the validity of themodel. The interested reader is therefore referred to one of the more complete texts onsurfactant related phenomena [46].

In the mass-action model, it is assumed that an equilibrium exists between themonomeric surfactant and the micelles. For the case of nonionic (or un-ionized)surfactants, the monomermicelle equilibrium can be written

with a corresponding equilibrium constant, Km, given by

where brackets indicate molar concentrations and n is the number of monomers in the

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micelle, the aggregation number. Theoretically, one should use activities rather thanconcentrations in Eq.(2); however, the substitution of concentrations is generally justifiedby the fact that the cmc occurs at such low concentrations that activity coefficients can beassumed to be unity.

The alternative approach to modeling micelle formation is to think in terms of a phaseseparation model in which, at the cmc, the concentration of the free surfactant moleculesbecomes constant (like a solubility limit or Ksp), and all additional molecules go into theformation of micelles. An analysis of the phase separation model similar to the aboveproduces the same general result in terms of the energetics of micelle formation (withsome slight differences in detail), so that the choice of model is really a matter ofpreference and circumstances. There is some evidence that the activity of free surfactantmolecules actually increases above the cmc, which tends to support the mass actionmodel; however, for most purposes, that detail is of little consequence.

While exact thermodynamic data on micelle formation is of little practical use indetermining surfactant suitability in most applications, it may be useful as a guide innarrowing down the wide selection of possibilities available to the formulator.

From Eq.(2), the standard free energy for micelle formation per mole of micelles is givenby

while the standard free energy change per mole of free surfactant is

At or near the cmc, S » Sn, so that the first term on the right side of Eq.(4) can beneglected, and an approximate expression for the free energy of micellization per mole ofsurfactant will be

In general, but not always, micelle formation is found to be an exothermic process,favored by a decrease in temperature. The enthalpy of micellization, DHm, given by

may therefore be either positive or negative, depending on the system and conditions.The process, however, always has a substantial positive entropic contribution toovercome any positive enthalpy term, so that micelle formation is primarily an entropydriven process.

(c)Surfactant Structure, Environment, and Micellization

While the various approaches to describing surfactant association phenomena are useful

from a fundamental point of view, in practice the characteristics (cmc, aggregationnumber, etc.) of a surface active material are very sensitive to such factors as theisomeric purity of the sample, the presence of contaminants, pH, electrolyte content,temperature, etc. A good working knowledge of micelle formation, therefore, mustinclude some idea of how such factors will affect the behavior of the surfactant. Theliterature on these various topics is extensive; however, there have developed over theyears a number of good generalizations that can be helpful in making "educated"extrapolations from ideality to reality. The

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following sections will be devoted to the presentation of summaries and generalizationsthat illustrate many of the significant measurable effects of surfactant chemical structureand solution environment on the micellization process.

Aggregation Number

Aggregation numbers (n) for many surfactants are found to fall in the range of 50100molecules, although the numbers can vary significantly according to structure andconditions. Some typical aggregation numbers for various surfactant types are given inTable 2. Because the size and dispersity of micelles are sensitive to many internal(hydrophobic structure, head group type, etc.) and external (temperature, pressure, pH,electrolyte content, etc.) factors, one may question the significance of reported values ofn. However, some generalizations can be made.

1. In aqueous solutions, it is generally observed that the longer the hydrophobic chain foran homologous series of surfactants the larger will be the aggregation number.

2. A similar increase in n is seen when there is a decrease in the "hydrophilicity" of thehead groupfor example, a higher degree of ion binding, a shorter polyoxyethylene chain,etc.

3. External factors that result in a reduction in the hydrophilicity of the head group suchas high electrolyte concentrations will also cause an apparent increase in n.

4. Changes in temperature will affect nonionic and ionic surfactants differently. Ingeneral, higher temperatures will result in small decreases in aggregation numbers forionic surfactants but significant increases for most nonionics.

5. The addition of small amounts of nonsurfactant organic materials of low watersolubility will often produce an apparent increase in micelle size, although that may bemore an effect of solubilization than an actual increase in the number of surfactantmolecules present in the micelle.

6. The addition of a water-miscible organic material such as an alcohol will generallyTABLE 2 Aggregation Numbers for Representative Surfactants inWaterSurfactant Temperature, T

(°C)Aggregation number,

n30 4040 5460 10723 7160 8023 50

C8H17O(CH2CH2O)6H 30 41C10H21O(CH2CH2O)6H 35 260C12H25O(CH2CH2O)6H 15 140C12H25O(CH2CH2O)6H 25 400

C12H25O(CH2CH2O)6H 35 1400C14H29O(CH2CH2O)6H 35 7500Source: Ref. 4.

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reduce the apparent aggregation number, presumably due to a change in the "solventquality" of the system or to the formation of microemulsions.

The Critical Micelle Concentration

Because there are many factors that have been shown to strongly affect the criticalmicelle concentration, the following discussion has been divided so as to somewhatisolate the more important factors.

Any discussion of cmc data must be tempered with the knowledge that the reportedvalues must not be taken to be absolute, but reflect certain variable factors inherent inthe procedures employed in their determination. The variations in cmc found in theliterature for nominally identical materials under supposedly identical conditions must beaccepted as minor "noise" that should not significantly affect the overall picture(assuming, of course, that good experimental technique has been employed).

The length of the hydrocarbon chain in a surfactant is a major factor determining thecmc. The cmc for an homologous series of surfactants decreases logarithmically as thenumber of carbons in the chain increases. For straight-chain hydrocarbon surfactants ofabout 16 carbon atoms or less bound to a single terminal head group, the cmc is usuallyreduced to approximately one-half of its previous value with the addition of eachmethylene group. For nonionic surfactants, the effect can be much larger, with a decreaseby a factor of 10 following the addition of two carbons to the chain. The insertion ofphenyl and other nonhydrocarbon linking groups, branching of the alkyl group, and thepresence of polar substituents on the chain can produce different effects on the cmc.

The relationship between the hydrocarbon chain length and cmc for ionic surfactantsgenerally fits the Klevens equation [7]

where A and B are constants specific to the homologous series under constant conditionsof temperature, pressure etc., and nC is the number of carbon atoms in the chain. Valuesof A and B for a wide variety of surfactant types have been determined, and some arelisted in Table 3.

For more complex surfactant structures, the following generalizations serve as a goodguide.TABLE 3 Klevens Constants [Eq. (7)] for Common SurfactantClassesSurfactant Class Temperature (°C) A BCarboxylate soaps (Na+) 20 1.850.30Carboxylate soaps (K+) 25 1.920.29n-Alkyl-1-sulfates (Na+) 45 1.420.30n-Alkyl-2-sulfates (Na+) 55 1.280.27n-Alkyl-1-sulfonates 40 1.590.29p-n-Alkylbenzene sulfonates 55 1.680.29

n-Alkylammonium chlorides 25 1.250.27n-Alkyltrimethylammonium bromides 25 1.720.30n-Alkylpyridinium bromides 30 1.720.31Source: Ref. 5.

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1. Ionic surfactants having two or three neighboring ionic groups exhibit a linearrelationship between cmc and chain length similar to Eq. (7), although they usually havea lower Krafft temperature and a higher cmc than the corresponding singly chargedmolecule of the same hydrophobic group.

2. In surfactants having branched structures, with the head group attached at some pointother than the terminal carbon, the additional carbon atoms off of the main chaincontribute about one-half the effect of main chain carbons. Except for the lower membersof a series, the relationship between carbon number and cmc follows a linear relationshipsimilar to Eq. (7).

3. For surfactants that contain two hydrophobic chains, such as the sodiumdialkylsulfosuccinates, it is generally found that the cmc for the straight-chain estersfollow the Klevens relationship. The cmc levels for the branched esters of equal carbonnumber occur at higher concentrations.

4. In the alkylbenzene sulfonates, the aromatic ring makes a contribution equivalent toabout 3.5 carbon atoms.

5. For surfactants that contain ethylenic unsaturation in the chain, the presence of asingle double bond increases the cmc by a factor of 34 compared to the analogoussaturated compound. In addition to the electronic presence of the double bond, theisomer configuration (cis or trans) will also have an effect, with the cis isomer usuallyhaving a higher cmc.

6. The presence of polar atoms such as oxygen or nitrogen in the hydrophobic chain (butnot associated with a head group), results in an increase in the cmc. The substitution ofan OH for hydrogen, for example, reduces the effect of the carbon atoms between thesubstitution and the head group to half that expected in the absence of substitution. Ifthe polar group and the head group are attached at the same carbon, that carbon atommakes little or no contribution to the hydrophobic character of the chain.

7. A number of commercial surfactants are available in which all or most of thehydrophobic character is derived from the presence of polyoxypropylene groups. Theobserved effect of such substitution has been that each propylene oxide group isequivalent to approximately 0.4 methylene carbons.

Two classes of materials that cannot easily be fitted into the known schemes forconventional hydrocarbons are the silicone-based surfactants and those in which most orall of the hydrogens have been replaced by fluorine atoms. The hydrophobic unit of thesilicone-based surfactants consists of low molecular weight polyorganosiloxanederivatives, usually polydimethylsiloxanes. Possibly because of their "nonclassical" naturethey have received little attention in the general scientific literature, although theirunique surface characteristics have proved useful in many technological applications,especially in nonaqueous solvent systems.

The substitution of fluorine for hydrogen on the hydrophobic chain has produced severaltypes of surfactants with extremely interesting and useful properties. The presence of thefluorine atoms results in large (i.e., orders of magnitude) decreases in cmc values relativeto the base hydrocarbon. Because of the electronic character of the carbonfluorine bond,fluorinated materials have been found to have much lower surface energies and producelower surface tensions than conventional materials. In general, a

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fully fluorinated surfactant with nC carbon atoms will have a cmc roughly equal to that ofa hydrocarbon material with 2nC carbons.

The effect of the hydrophilic head group on the cmc values of a series of surfactants withthe same hydrocarbon chain will vary considerably, depending upon the nature of thechange. In aqueous solution the cmc for a C12 hydrocarbon with an ionic head group willlie in the range of 0.001 M while a nonionic material with the same chain will have a cmctwo orders of magnitude smaller. The exact nature of the ionic group (excluding changesin counter ion) has no dramatic effect, since the main driving force for micelle formationis the entropy gain on reduction of waterhydrocarbon interactions. The cmc values ofseveral ionic surfactants are given in Table 4. Of the more common anionic head groups,the order of decreasing cmc values for a given hydrocarbon chain is found to becarboxylates (containing one more carbon atom) > sulfonates > sulfates. For cationicsurfactants, one often finds that the cmc increases with methyl substitution on thenitrogen, probably due to increased steric requirements of the added methyl groupsforcing an increase in ionization (i.e., less ion pairing).

In ionic surfactants the cmc is related to the interactions of solvent with the ionic headgroup. The degree of ionization, in terms of tight ion binding, solvent-separated ionpairing, or complete ionization, will therefore influence the value of the cmc and theaggregation number. Since electrostatic repulsions among the ionic groups would begreatest for complete ionization, one finds that the cmc of surfactants in aqueous solutiondecreases as the degree of ion binding increases.

From regular solution theory it is found that the extent of ion pairing in a system willincrease as the polarizability and valence of the counterion increase. Conversely, a largerradius of hydration will result in greater ion separation. It has been found that, for a givenhydrophobic tail and anionic head group, the cmc decreases in the order Li+ > Na+ > K+> Cs+ > > > Ca2+» Mg2+. In the case ofTABLE 4 The Effect of the Hydrophilic Group on the CMC Valuesof Surfactants with Common HydrophobesHydrophobe Hydrophile Temperature (°C) cmc (mM)C12H25 COOK 25 12.5

'' SO3K 25 9.0" SO3Na 25 8.1" NH3Cl 30 14

C16H33 NH3Cl 55 0.85" N(CH3)3Cl 30 1.3

C8H17 OCH2CH2OH 25 4.9" (OCH2CH2)2OH 25 5.8

C9H19 COO(CH2CH2O)9CH3 27 1.0" COO(CH2CH2O)16CH3 27 1.8

C10H21 O(CH2CH2O)8CH3 30 0.6" O(CH2CH2O)12CH3 29 1.1

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cationic surfactants such as dodecyltrimethyl ammonium halides, the cmc values arefound to decrease in the order F > Cl > Br > I.

Although within a given valency the size of the hydrated counterion will have some effectupon the micellization of an ionic surfactant, a more significant effect is produced bychanges in valency. As the counterion is changed from monovalent to di- and trivalent,the cmc is found to decrease rapidly. The divalent and higher salts of carboxylic acidsoaps generally have very low water solubility. They are not useful as surfactants inaqueous solution but find use in nonaqueous solvents due to their increased solubility inthose systems and in the preparation of water-in-oil emulsions.

Many industrial applications of surfactants involve the presence in the solution ofcosolutes and other additives that can potentially affect the micellization process throughspecific interactions with the surfactant molecules (thereby altering the effective activityof the surfactant in solution). Cosolutes may alter the thermodynamics of themicellization process by changing the nature of the solvent or the various interactionsleading to or opposing micelle formation. Solution changes that might be expected toaffect the association process include the presence of electrolytes, changes in pH, and theaddition of organic materials that may be essentially water insoluble (e.g.,hydrocarbons), water miscible (short-chain alcohols, acetone, dioxane, etc.), or of lowwater solubility but containing polar groups that impart some surface activity althoughthey are not classified formally as surfactants.

In aqueous solution the presence of electrolyte causes a decrease in the cmc of mostsurfactants with the greatest effect occurring with ionic species. Nonionic and zwitterionicsurfactants exhibit a much smaller effect. For ionic materials, the effect of addition ofelectrolyte can be empirically quantified with the relationship [8]

where a and b are constants for a given ionic head group at a particular temperature, andci is the total concentration of monovalent counterions in moles per liter. For nonionic andzwitterionic materials, the impact of added electrolyte is significantly less and therelationship in Eq. (8) does not apply.

For most modern, industrially important surfactants consisting of long alkyl-chain salts ofstrong acids, solution pH has a relatively small, if any, effect on the cmc. Unlike the saltsof strong acids, however, the carboxylate soap surfactants exhibit a significant sensitivityto pH. Since the carboxyl group is not fully ionized near or below the pKa, pH changesmay result in significant changes in the cmc as well as the Krafft temperature. A similarresult will be observed for the cationic alkylammonium salts near and above the pKb.Changes in pH will have little or no effect on the cmc of nonionic surfactants except,perhaps, at very low pH where it is possible that protonation of the ether oxygen ofpolyoxyethylene (POE) surfactants could occur.

In the case of amphoteric surfactants, pH sensitivity is related to the pK values of theirsubstituent groups. The possibilities can be grouped in the following way.

1. Quaternary ammonium-strong acid salts will show little or no significant pH sensitivity.

2. Quaternary ammonium-weak acid combinations will be zwitterionic at high pH andcationic below the pKa of the acid, with changes in cmc being expected in going from onesituation to another.

3. Amineweak-acid combinations will be anionic at high pH, cationic at low pH, and

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zwitterionic at some pH between the respective pK values, again producing changes incmc with changing conditions.

4. Aminestrong-acid combinations will be anionic at high pH and zwitterionic below thepKb of the amine, with results similar to situation 2.

Organic materials that have low water solubility can be solubilized in micelles to producesystems with substantial organic content where no solubility would occur in the absenceof micelles, the process being referred to as "solubilization." It is usually found thatimmiscible hydrophobic materials will have relatively little effect on cmc, althoughevidence for slight decreases have been reported.

Small amounts of organic additives with substantial water miscibility such as the loweralcohols, dioxane, acetone, glycol, and tetrahydrofuran have relatively minor effects oncmc. As the alkyl groups for alcohols or amines go beyond C3, their inherent surfaceactivity can begin to become significant. Otherwise, it will be only at high concentrations,where the additive may be considered a cosolvent, that major effects on cmc will beevident. In general, large amounts of water miscible organics will increase the cmc byincreasing the solubility of the tail, although the opposite effect may occur for highlyionized species, where the lower dielectric constant reduces head group repulsion.

The properties of a surfactant solution are found to change much more rapidly with theintroduction of small amounts of long-chain alcohols, especially C ³ 4. Many classes ofsurfactants of importance are derived from raw materials containing alcohol impurities,and most of the observed effects can be attributed to the inherent surface activity of thelonger alcohols. The interactions between surfactants and alcohols have become ofgreater importance in recent years as a result of the intense interest in microemulsionsand their potential application in various areas of technological importance.

The effects of temperature changes on cmc in aqueous solution have been found to bequite complex. It has been shown, for example, that the cmc of most ionic surfactantspasses through a minimum as the temperature is varied from 0° through 70°C. Nonionicand zwitterionic materials behave not quite so predictably, although it is has been foundthat some nonionics reach a cmc minimum around 50°C.

The temperature dependence of the cmc values of polyoxyethylene nonionic surfactantsis especially important since the head group interaction is essentially hydrogen bonding innature. Materials relying solely on hydrogen bonding for solubilization in aqueous solutionare commonly found to exhibit an inverse temperaturesolubility relationship. A majormanifestation of such a relationship is the presence of the cloud point for many nonionicsurfactants. The cloud point is a lower critical solution temperature for the (low molecularweight) polyoxyethylene chain. At the cloud point, a normally transparent solution ofnonionic surfactant becomes cloudy, and bulk phase separation occurs. That is not to saythat the material precipitates from solution; rather, a second swollen phase containing ahigh fraction of the POE surfactant appears, and its domains are significantly larger than

those of a normal micelle.

Micelle Formation in Mixed Surfactant Systems

When one discusses the solution behavior of many, if not most, industrially importantsurfactants, it is important to remember that experimental results must be interpreted inthe context of a surfactant mixture rather than a pure homogeneous material. Studies ofsuch systems are important

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since most detergents and soaps contain homologs of higher or lower chain length thanthat of the primary component.

Determinations of the cmc of well-defined, binary mixtures of surfactants have shownthat the greater the difference in the cmc between the components of the mixture, thegreater is the effect of the chain length of the more hydrophobic member. The analysis ofresults for binary mixtures of surfactants must take into consideration the fact that at thecmc the mole fractions of the monomeric surfactants in solution are not necessarily equalto the stoichiometric mole fractions; each value must be decreased by the amounts ofeach mole fraction incorporated into the micellar phase. Interpretations may also becomplicated by such effects as relatively small changes in the mole fraction of the smallerchain component due to preferential aggregation of the more hydrophobic material andthe difficulty of inclusion of the longer chain into micelles of the shorter material. In somecases where the difference is very large, the component with the higher cmc may simplyact as an added electrolyte, rather than becoming directly involved in the micellizationprocess. When ternary surfactant mixtures are considered, it is usually found that the cmcof the mixture will fall somewhere between that of the highest and lowest valuedetermined for the individual components.

The presence of an ionic surfactant in mixture with a nonionic usually results in anincrease in the cloud point of the nonionic component. In fact, the mixture may not showa cloud point, or the transition may occur over a broad temperature range, indicating theformation of mixed micelles. As a result, it is possible to formulate mixtures of ionic andnonionic surfactants for use at temperatures and under solvent conditions (electrolyte,etc.) in which neither component alone would be effective.

Many surfactant mixtures, especially ionics with nonionics, exhibit surface propertiessignificantly better than those obtained with either class alone. Such synergistic effectsgreatly improve many technological applications in areas such as emulsion formulations,emulsion polymerization, surface tension reduction, coating operations, personal care andcosmetics products, pharmaceuticals, and petroleum recovery, to name a few. The use ofmixed surfactant systems should always be considered as a method for obtaining theoptimal performance from any practical surfactant application.

Micelle Formation in Nonaqueous Media

The formation of micelle-like aggregates in nonaqueous solvents has received far lessattention than the related phenomenon in water. In fact, there exists some controversyas to whether such a phenomenon in fact occurs in the same sense as in aqueoussolutions. There can be no doubt, however, that some chemical species, many surfactantsincluded, do associate in hydrocarbon and other nonpolar solvents.

Since unambiguous experimental data on micelle formation in nonaqueous solvents aremuch less available than for aqueous systems, it is far more difficult to identify trends anddraw conclusions concerning the relationships between chemical structures, cmc, and

aggregation numbers. However, some generalizations can be made.

1. In hydrocarbon solvents, the nature of the polar head group is extremely important inthe aggregation process. It has generally been found that ionic surfactants form largernonaqueous micelles than nonionic ones, with anionic sulfates surpassing the cationicammonium salts.

2. The aggregation number for an ionic surfactant in a given solvent will usually change

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little with changes in the counterion, indicating a lack of sensitivity to the nature of thatspecies.

3. The effect of the hydrocarbon tail length in an homologous series of surfactants isrelatively small when compared to that in water. However, the aggregation number tendsto decrease as the carbon number increases within an homologous series.

4. The presence of small amounts of water in a nonaqueous surfactant environment canhave a significant effect on some systems. It can be presumed that the effects of waterand other solubilized impurities on nonaqueous micelle formation stems from alterationsin the dipolar interactions between head groups induced by the additive or impurity.

2Vesicles and Liquid Crystals

Surfactants, including the natural surfactants or lipids, can spontaneously associate into avariety of structures in solution. In many cases, such assemblies can transform from oneclass into another as a result of subtle changes in the solution conditions (e.g.,concentration, solvent composition, added electrolyte, temperature changes, pH, etc.)The basic concepts that govern self-association into micelles also apply to the formationof the larger or more extended aggregate systems consisting of vesicles, bilayers, andmembranes. An excellent discussion of the general field of molecular associationstructures can be found in the work of Israelachvili [9].

Some surfactants, because of inherent molecular geometry or as a result of specificconditions, cannot conveniently aggregate into compact structures such as micelles.However, they may be able to form more open structures such as vesicles and bilayersmembranes. In general, such materials will have relatively low water solubility, smallhead groups, or, as is more common, very large hydrophobic groups too bulky to bepacked in a manner necessary for normal thermodynamically controlled micelleformation. Such a state of affairs is particularly common for molecules having more thanone hydrocarbon chain, very highly branched chains, or structural units that producemolecular geometries incompatible with effective packaging (e.g., large, flat ringstructures such as steroids).

Extended planar bilayers (membranes) are a thermodynamically favorable option for theassociation of some bulky surfactants in aqueous solution; however, there are someconditions under which it is more favorable to form closed bilayer systems (vesicles).Such a situation can be seen to arise from two basic causes. First, even large, highlyextended planar bilayers possess edges along which the hydrocarbon core of thestructure must be exposed to an aqueous environment, resulting in an unfavorableenergetic situation. Second, the formation of an infinitely extended structure isunfavorable from an entropic standpoint. The formation of vesicles, then, addresses bothof those factorsthe edge effect is removed by the formation of a closed system and theformation of structures of finite size reduces much of the entropy loss. As long as the

curvature of the vesicle is gentle enough to allow the packed molecules to occupy closeto their optimum area, vesicles represent viable structures for the association of manysurfactants.

(a)Vesicles

Many naturally occurring and synthetic surfactants that cannot aggregate to form micellesspontaneously form closed bilayered structures when dispersed in water. Such structuresare referred to as vesicles or liposomes. They consist of alternating layers of surfactantbilayers spaced by aqueous layers or compartments arranged in approxi-

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mately concentric circles. If the multilayer vesicles are subjected to ultrasound or othervigorous agitation, the complex multilayer structure may be disrupted to produce a singlebilayer assembly consisting of unilamellar vesicles in which a portion of the aqueousphase is encapsulated within the bilayer membranes. Typically, a vesicle so produced willhave a diameter of between 30 and 100 nm, much larger than that of typical micelles.

Surfactants that form vesicles are, by their nature, of limited solubility in aqueoussystems, so that the exchange of individual molecules in the bilayer is often very slow. Inaddition, the bilayer structure has a significant degree of internal stability so thatvesicles, once formed, can have a relatively long existence. Lifetimes of from a few daysto several months are reported. After extended periods, the unilamellar vesicles maybegin to fuse to produce the more complex multilayer structures of the original systems.

A potentially useful characteristic of vesicles is their ability to entrap within the assemblya portion of the aqueous phase present at the time of their formation. They thereforerepresent an interesting microencapsulating technique, since residual solute locatedoutside the vesicle can be removed by dialysis or some other purification techniques. Oilsoluble materials can, in principle, be incorporated into vesicle membrane, much likematerials solubilized in conventional surfactant micelles. The potential for theincorporation of both aqueous and nonaqueous additives into vesicles poses theinteresting possibility of producing systems containing two active components, forexample, a water and an oil soluble drug, for simultaneous delivery.

Other interesting and potentially useful characteristics of vesicles include their activity asosmotic membranes, their ability to undergo phase transitions from liquid crystalline to amore fluid state, and their permeability to many small molecules and ions, especiallyprotons and hydroxide. Because of their similarity to natural biological membranes,vesicles also have great potential as models for naturally occurring analogues that maybe difficult to manipulate directly.

(b)Surfactant Liquid Crystals

When materials are crystallized from water or other solvents that can become stronglyassociated with some part of the molecule it is possible for the crystalline form to retain adefinite amount of solvent as an integral part of the structure. In the case of water, thematerial would be a hydrate. The presence of solvent associated with the moleculesmakes possible the existence of several unique compositions and morphologicalstructures that, although crystalline, differ from each other and from the "dry" crystal,depending on the amount of associated solvent and the arrangement, mobility, etc., ofthe various components in the structure. In Surfactants, the ability of the molecules toaggregate in various crystal structures (depending on the conditions prevailing at thetime of crystallization) is referred to as polymorphism.

Polymorphic behavior is a characteristic of many Surfactants that can, when not taken

into consideration, lead to a great deal of confusion in the interpretation of phenomenaassociated with the presence of the surfactant. In complex surfactant systems such ascosmetics formulations, the presence of and importance of liquid crystals is often difficultto discern. While they constitute an interesting area of surfactant study, they will not betreated further here. The interested reader is referred to the works of Laughlin [10] andFendler [11] for more detailed treatments of the subject.

3Molecular Geometry and the Formation of Association Colloids

A different, and perhaps more useful, approach to understanding surfactant aggregationphenomena emphasizes the importance of molecular structure and geometry in defining

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the characteristics of an aggregating system. The previously introduced classes ofsurfactant aggregates, vesicles, membranes, liquid crystals, as well as micelles can beanalyzed by the geometric approach, while the thermodynamic models are of little use inunderstanding their formation and characteristics.

As seen above, surfactants can undergo processes of self-association or aggregation toform the various structures mentioned. In addition, those structures can change rapidly assolution conditions are altered. Simple thermodynamic analyses of the associationprocesses are not usually sufficient to explain the reasons for the observedtransformations. In order to better understand the phenomena in question it is necessaryto examine the subtle interactions within the molecule, among the individual surfactantmolecules making up the structure, and among neighboring structures.

Tanford [12] introduced the idea that there exist two opposing forces that control self-association or aggregationhydrocarbon/water interactions that favor aggregation andhead group interactions that work in the opposite sense. It was suggested that the twoopposing actions could be viewed as an attractive interfacial-tension term resulting fromthe basically fluid nature of the hydrocarbon tails and a complex repulsion term thatdepends on the nature of the head group.

Israelachvili [9] and Ninham, et al. [13] have quantified the basic ideas proposed byTanford resulting in the concept of surfactant association controlled by the geometry ofthe surfactant molecule. In brief, the geometric treatment of surfactant aggregationrelates the overall free energy of association to three critical geometric characteristics ofthe molecule: (1) the minimum interfacial area occupied by the surfactant hydrophile orhead group, a0; (2) the volume of the hydrophobic tail or tails, v; and (3) the maximumextended chain length of the tail in a "fluid" environment such as the core of a micelle,etc., lc.

Using those three molecular parameters, all of which can be measured or calculated withsome degree of accuracy, the geometric approach allows one to predict the shape andsize of aggregates that will produce a minimum in free energy for a given surfactantstructure.

Quantitatively, one defines a critical packing parameter, Pc, as

A surfactant will be able to form spherical micelles only if the radius of the micelle, R, isless than or equal to the lc so that

Similar analyses for surfactants for which 0.33 £ Pc£ 0.5 predict that cylindrical or disk-shaped micelles will result.

Insertion of the appropriate values for sodium dodecyl sulfate (SDS) into Eq. (10) predicts

the formation of spherical micelles, in agreement with experimental observations.Solution conditions that alter one or more of the critical values (e.g., high saltconcentrations that reduce the effective value of a0) would, according to Eq. (10), lead tocylindrical or disk-shaped micelles, again in agreement with observation. A summary ofthe predicted aggregation characteristics of surfactants covering the whole range ofgeometric possibilities is given in Table 5 [9].

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TABLE 5 Expected Aggregate Characteristics in Relation to Surfactant CriticalPacking Parameter, PcPc Surfactant type Expected structure

< 0.33 Simple, single chains and relatively largehead groups

Spherical or ellipsoidalmicelles

0.330.5Simple, relatively small head groups, ionicsin electrolyte

Relatively large cylindrical orrod-shaped micelles

0.51.0 Double-chain, large head groups andflexible chains

Vesicles and flexible bilayerstructures

1.0 Double-chain, small head groups or rigid,immobile chains Planar extended bilayers

> 1.0 Double-chain, small head groups, verylarge, bulky hydrophobic groups

Reversed or invertedmicelles

It has been found experimentally that the form of aggregate structure produced by agiven surfactant depends to a great extent on its solution environment. Geometricconsiderations explain fundamental processes operating in the aggregation process basedon the various effects the solution has on a0, v, and lc. The main effects to be expectedcan be summarized as follows.

1. Molecules with relatively small head groups, and therefore large values for Pc, willnormally form extended bilayers, large (low curvature) vesicles, or inverted micellarstructures. Such results can also be brought about in "normal" anionic surfactant systemsby changes in pH, high salt concentrations, or the addition of multivalent cations.

2. Molecules containing unsaturation, especially multiple cis double bonds, will havesmaller values of lc, and thus will tend toward the formation of larger vesicles or invertedstructures.

3. Multichained molecules held above the melting temperature of the hydrocarbon chainmay undergo increased chain motion, allowing trans-gauche chain isomerization, reducingthe effective value of lc and resulting in changes in aggregate structures. This effect maybe of particular importance in understanding the effects of temperature on biologicalmembranes.

While the geometric approach to explaining surfactant aggregation phenomena showsgreat promise, it has not worked its way into the general thinking on micelles. As moreexperimental data become available and can be correlated with the predictions ofgeometric "rules," this approach may become the basis for the design of surfactantmolecules with specific desirable aggregation characteristics. In multiple surfactantsystems, a situation commonly encountered in cosmetics, the geometric approach tounderstanding aggregation will require a great deal more investigation before itsapplicability becomes general.

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IISurfactantPolymer Interactions in Solution

Macromolecular species have played an indispensible role in the stabilization of colloidalsystems since the first prelife protein complexes came into existence. Todaymacromolecules play a vital role in many important industrial processes and products: asdispersants, stabilizers, and flocculants; as polymeric surfactants and emulsifiers; assurface coatings for corrosion protection, lubrication, and adhesion; as modifiers ofrheological properties; and, of course, as contributors to biological processes.

APolymers as Surfactants

There exists a wide variety of polymeric materials that, because of their molecularcompositions, might be expected to exhibit the interfacial properties of surfactants. Alarge number of natural and synthetic polymers is employed exactly like the more"classical" surfactants. However, because of their limited solubility and configurationallimitations their use as a single surfactant is restricted. Because of slow and/or limitedadsorption characteristics, they seldom equal monomeric surfactants in terms of loweringinterfacial tension. However, their ability to lower to some extent interfacial tensionswhile at the same time modifying rheological properties and providing colloidal stability,makes them indispensible in many applications, including cosmetics.

In most modern applications of polymers as surfactants, stabilizers, dispersants, foamingagents, etc., the macromolecular species may be employed primarily for its rheologicaleffects or as a stabilizer in dispersed systems. Interfacial-tension lowering andemulsification are most often accomplished by the use of one or more monomericsurfactants. In such situations, it is very important to take into consideration possibleinteractions that may result in some unexpected (and often unpleasant) surprises.

BSurfactantPolymer Interactions

Surfactants constitute some of the functionally most important ingredients in cosmeticsand toiletry products, foods, coatings, pharmaceuticals, and many other systems of wideeconomic and technological importance. In many, if not most, of those applications,polymeric materials are present in the final product formulations and/or in the targets oftheir action. Other surfactant applications, especially in the medical and biological fields,also potentially involve the interaction of polymers (including proteins, nucleosides, etc.)with surfactants.

Interactions between surfactants and natural and synthetic polymers have been studiedfor many years with varying degrees of understanding and experimental control [1416].Although the basic mechanisms of surfactantpolymer interaction are reasonably wellknown, there still exists substantial disagreement as to the details of some of the

interactions at the molecular level. It is generally recognized that surfactantpolymerinteractions may occur between individual surfactant molecules and the polymer chain(i.e., simple adsorption), or in the form of polymeraggregate complexes. In the lattercase, there may be complex formation between polymer chains and micelles,pseudomicellar aggregates (hemimicelles), or liquid crystalline phases.

The forces controlling surfactant interactions with polymers are fundamentally the sameas those involved in other solution or interfacial phenomena, namely van der Waals ordispersion forces, hydrophobic effects, dipolar or acidbase interactions, and electro-

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static interactions. The relative importance of each type of interaction will vary with thenatures of the polymer and the surfactant so that the exact character of the complexesformed may be almost as varied as the types of materials available for study.

1SurfactantPolymer Complex Formation

The most generally accepted model for surfactantpolymer interaction is based on astepwise sequence of binding between surfactant monomers and the polymer chain, witheach step being governed by the law of mass action, and with unique rate constantscontrolling each step [15].

The values of the various constants and their dependence on experimental conditions(e.g., temperature, solvent, ionic strength, pH, etc.) serve as a basis for formulatingfeasible descriptions of the molecular processes involved in the interactions. In themodel, it is assumed that the stepwise binding process occurs initially through surfactantmonomeric units without significant direct association of micelles or other aggregateswith the polymer chain. The formation of such aggregatepolymer complexes is notexcluded, however, since they may form on the chain as the total concentration of boundsurfactant increases.

Surfactantpolymer interactions, like all surfactant-related phenomena, involve a complexbalance of factors encouraging and retarding association and can be understood only ifthose factors can be reasonably estimated. Polymers in solution can form secondary andtertiary structures that may be altered during the surfactant binding process in order toaccommodate the surfactant molecules, thereby adding new terms to the total energybalance. The nature of the surfactantpolymer complex may significantly alter the overallenergetics of the system so that major changes in polymer chain conformation will result.Any and all of those changes may result in major alterations in the macroscopic andmicroscopic properties of the system.

Four general types of polymers can be defined based on the electronic nature of thespecies: anionics, cationics, nonionics, and amphoterics. Not surprisingly, each polymertype will exhibit characteristic interactions with each surfactant class, with variationsoccurring within each group.

2Surfactant Interactions with Nonionic Polymers

The largest volume of published work in the field of surfactantpolymer interactionsconcerns surfactants and water soluble nonionic polymers. In general, the results indicatethat the more hydrophobic the polymer the greater the interaction with anionicsurfactants. The primary driving forces for surfactantpolymer interaction in such systemsseem to be van der Waals forces and the hydrophobic effect. Dipolar and acidbaseinteractions may be present, depending on the exact nature of the system, but ionic

interactions will be minimal or nonexistent. For the polymer, it is reasonable to infer thatthe overall impact of hydrophobic effects and dispersion interactions will be related to therelative availability of nonpolar binding sites along the polymer chain.

The adsorption of surfactant molecules may produce changes in the polymer chainconformation, expanding the coil due to repulsions between the ionic surfactant headgroups. The properties of the solution (e.g., viscosity) will be altered as a result of suchchanges. If neutral salt is added, repulsion between neighboring groups will be screened,and the expanded coil will contract or collapse, again affecting various macroscopicproperties of the solution. Such expansion and collapse of surfactantpolymer complexes

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as a function of the extent of surfactant adsorption may be seen as being analogous tothe solution behavior of polyelectrolytes as a function of the degree of dissociation andelectrolyte content.

Work on cationic-surfactantnonionic-polymer interactions involving the use of long-chainalkylammonium surfactants in aqueous solution has shown that the interactions betweensuch species become stronger as the chain length of the surfactant is increased, reflectingthe drive to substitute surfactantpolymer for surfactantwater and polymerwaterinteractions. The nature of the cationic head group seems to have some effect onpolymersurfactant interactions.

The relative binding strengths between nonionic polymers and cationic or anionicsurfactants are difficult to compare. The general trend is that anionics will exhibitstronger interactions with a given polymer than analogous cationic surfactants, all otherthings (e.g., chain length of the tail) being equal.

The limited number of reports available indicate that there exists little evidence forextensive association of nonionic surfactants and nonionic polymers. Considering the sizeof the hydrophilic groups of most nonionic surfactants, their low CMC values, and theabsence of significant possibilities for head-grouppolymer interactions, the apparentabsence of substantial interactions is not conceptually hard to accept. An assertion thatbinding does not occur under any circumstance, however, would be erroneous. In foodcolloids especially, it has been shown qualitatively that many nonionic surfactants (e.g.,monoglycerides, sorbitan esters, etc.) form rather strong complexes with starches andproteins, although the inherent complexity of such systems makes quantification of sucheffects difficult or impossible.

3Interactions with Ionic Polymers and Proteins

In practice, it is commonly found that surfactants will interact more strongly with chargedpolymeric species than with the nonionic examples discussed above. Practically all naturalpolymers, including proteins, cellulosics, gums, and resins, carry some degree of electricalcharge. Many of the most widely used synthetic polymers do as well. When one comparesthe possibilities for interactions between ionic polymers and surfactants with those fornonionic polymers, it is likely that the presence of discrete electrical charges along thepolymer backbone introduces the possibility of significant electrostatic interaction, inaddition to the nonionic factors mentioned previously.

Ionic polymers, whether natural or synthetic, are of particular interest to cosmeticsformulators because of their application as viscosity enhancers (thickening agents),dispersing aids, stabilizers, gelling agents, membranes, binders, etc. They are alsoencountered, of course, in biological membranes, fibers, and textiles. Common syntheticpolyelectrolytes include polyacrylic and methacrylic acids and their salts, cellulosicderivatives such as carboxymethyl cellulose (CMC), polypeptides such as poly-L-lysine,

sulfonated polystyrenes and related strong-acid-containing polymers, and polymericpolyammonium salts and quaternized polyamines. Natural polyelectrolytes would includecellulose, gelatin, and other proteins, gums, lignins, etc. In most cases, the charge on thepolymer is fixed as either positive or negative, so that possible interactions withsurfactants of a given charge type can be reasonably well defined. While such factors aspH, electrolyte content, and the nature of the polymer counterion will affect the extent ofinteraction in given systems, the sense of the interaction (e.g., anionanion, anioncation,etc.) will not change unless protonation or deprotonation of weak acids and bases

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occurs. Other polymers, proteins in particular, may be amphoteric in nature, the netcharacter of the charge being determined by pH.

Not surprisingly, interactions between surfactants and polymers of similar charge areusually found to be minimal, with electrostatic repulsion serving to limit the importance ofany noncoulombic attractions. This is especially true for polymers having relatively high(and evenly distributed) charge densities along the chain. An exception is the case wherethe polymer charge is highly localized, as in many proteins, exposing significant areas ofnonionic units that become available for van der Waalshydrophobic interactions withsurfactant tails. When opposite charges are present, however, the expected high degreeof interaction is usually found to occur. In aqueous solution, the result of surfactantbinding by electrostatic attraction is normally a reduction in the viscosity of the system, aloss of polymer solubility, at least to the point of charge reversal, and a reduction in theeffective concentration of surfactant, as reflected by surface tension increases over whatwould be measured for that surfactant concentration in the absence of polymer.

Many naturally occurring random coil polyelectrolytes of a single charge type, includingsome carbohydrates, pectins, keratins, etc., are anionic and exhibit the same generalsurfactant interactions as their synthetic cousins. Proteins on the other hand are usuallyamphoteric and have a net charge character that will depend on pH. Unlike mostsynthetic polyelectrolytes, proteins generally have well-defined secondary and tertiarystructures resulting from an uneven distribution of charged and hydrophobic sites alongthe chain. When secondary and tertiary structures are present, complications can arisedue to alterations in those structures caused by surfactant interactions. Obviously, thechoice of surfactant to be used in the presence of a particular protein becomes veryimportant since the rheological or gelling effects of the polymer may be significantlyaffected by the presence of surfactant.

Interactions between surfactants and polymers of opposite charge can usually besummarized as follows: (1) an initial phase in which coulombic attraction leads to alowering of the net charge on the polymer chain, probably a reduction in solubility andchain dimensions, and a lower viscosity for the system; and (2) a second phase in whichthe interactions are of the van der Waalshydrophobic types leading to an increase in theeffective charge on the polymer chain, expansion of the coil in solution, and enhancementof the rheological effects of the polymer.

When the degree of surfactantpolymer interaction is high, there is evidence that both thehead group and the tail of the surfactant molecule can become involved in the bindingprocess. In fact, there is some evidence that the bound surfactant molecules may beassociated into micelle-like structures, forming a ''string of pearls" along the polymerchain. Behavior suggesting complex formation between surfactants and polymers hasbeen found for deionized bone gelatin in the presence of several anionic surfactants [17].A bridging mechanism has been suggested to explain the effect of some surfactants onthe plasticity of bread doughs via the formation of junctions between protein chains in the

gluten fraction of wheat flour. It is generally found that the extent of surfactantpolymerinteractions, as reflected by increases in the viscosity (or plasticity) of a system, is highlydependent upon the length of the hydrocarbon tail of the surfactant.

The interactions between cationic and nonionic surfactants and proteins has received lessattention than the anionic case. Some alkylbenzene-polyoxyethylene surfactants appearto undergo limited binding with proteins, although there is little evidence for sufficientinteraction to induce the conformational changes found in the case of anionic

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surfactants. This may explain the observed "mildness" of many nonionic surfactants withrespect to skin irritation and related effects. The limited results published on protein-cationic surfactant systems indicate that little cooperative association occurs in mostsystems, even though the native protein charge may be of the opposite sign. In the caseof some charged surfaces and fibers, the well-known "softening" effect of cationic andsome nonionic surfactants results from the interaction of the surfactant head group withthe fiber surface, forming a lubricating hydrophobic layer that produces the "soft" feel.

Although a great deal is known about the interactions between polymers and surfactants,there is a lack of good experimental data in the form of adsorption isotherms. While it isclear that the surfactant binding processes are controlled by the same basic forces as theother solution and surface properties of surfactants, the location of binding sites on thepolymer molecule, the relative importance of the surfactant tail and head group, and theexact role of the polymer structure remain to be more accurately defined. In any case,anyone proposing to use a surfactant in a formulation containing polymers, or in anapplication where surfactantpolymer interactions will occur, must always consider theeffect of each on the performance of the other.

A useful characteristic of many micellar systems is their ability to solubilize water-insoluble materials. Surfactantpolymer complexes or combinations have also been shownto solubilize these materials, often being effective at total surfactant concentrations wellbelow the normal cmc (i.e., in the absence of polymer). Such systems may also have agreater solubilizing capacity (e.g., solubilized molecules per molecule of surfactant) thana surfactant solution alone [1821]. Unfortunately, our present state of knowledge in thisarea is not sufficient to allow quantitative predictions.

IIISurfactant Adsorption

Adsorptionthe tendency of atoms or molecules to locate at a particular interface inconcentrations different from those in the surrounding bulk mediais an important processin practically all aspects of our lives. The adsorbing species may be gas, solvent, or soluteand the interface may be solidsolid, solidliquid, solidvapor, liquidliquid, or liquidvapor. Inaddition, adsorption may be termed "positive," where the concentration of adsorbedspecies at the interface is greater than that in the bulk, or "negative" when the oppositeis true.

On a rather simple basis adsorption can be divided into two main classes: (1) physicaladsorption or physisorption, in which the forces and processes leading to adsorption maybe reversible, nonspecific, and of relatively low energy (on a molecular basis); or (2)chemisorption, in which the forces and processes of adsorption are specific in nature,more irreversible, and of higher energy.

The possibilities for variations in the energy and mechanism of an adsorption process are

limited only by the number of combinations of materials and circumstances one canimagine. There also exists, of course, the possibility of combined or hybrid processes thatcannot be so simply classified.

ALiquidFluid Interfaces

Liquids have several distinct characteristics which differentiate them from solid and gasphases. One of the more important ones (from the point of view of surface chemistry, at

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least) is that, unlike a gas, liquids have a relatively high density and fixed volume, whilethey possess a mobility at the molecular level that is many orders of magnitude greaterthan that in solids. As a result of that mobility, interfaces involving liquids and anotherfluid generally behave as if homogeneous and lack many of the complicationsencountered when considering solid surfaces.

1The Nature of a Liquid SurfaceSurface Tension

It is common practice to describe a liquid surface as having an elastic "skin" that causesthe liquid to assume a shape of minimum surface area, its final shape being determinedby the "strength" of that skin relative to other external factors such as gravity. In theabsence of gravity, or when suspended in another immiscible liquid of equal density, aliquid will spontaneously assume the shape of a sphere. In order to distort the sphere,work must be done on the liquid surface, increasing the total surface area and thereforethe free energy of the system. When the external force is removed, the contractile "skin"then forces the drop to return to its equilibrium shape.

While the picture of a skin like a balloon on the surface of a liquid is easy to visualize andserves a useful educational purpose, it can be quite misleading, since there is no skin ortangential force as such at the surface of a pure liquid. It is actually an imbalance offorces on surface molecules pulling into the bulk liquid and out into the adjoining fluidphase which produces the apparent skin effect. The forces involved are, of course, thesame van der Waals interactions that account for the liquid state and for most physicalinteractions between atoms and molecules. Because the liquid state is of higher densitythan the vapor, surface molecules are pulled away from the surface and into the bulkcausing the surface to contract spontaneously. For that reason, it is more accurate tothink of surface tension (or surface energy) in terms of the amount of work or energyrequired to increase the surface area of the liquid isothermally and reversibly by unitamount, rather than in terms of some tangential contractile force. Thermodynamically thesurface tension, s, is defined as

where DG is the free energy change associated with the creation of new surface area, DA.

Most commonly encountered room-temperature liquids have surface tensions against airor their vapors that lie in the range of 1080 mN/m. Water, the most important liquidcommonly encountered in both laboratory and practical situations, lies at the upper scaleof what are considered normal surface tensions with a value in the range of 7273 mN/mat room temperature, while hydrocarbons reside at the lower end, falling in the lowermiddle 20s.

Because of the mobility of molecules at fluid interfaces, it is not surprising to find that

temperature has a large effect on the surface tension of a liquid (or the interfacial tensionbetween two liquids). An increase in surface mobility due to an increase in temperaturewill clearly increase the total entropy of the surface, and thereby reduce its free energy,resulting in a negative temperature coefficient for s.

2Surface Tensions of Solutions

The presence of solute will often result in the alteration of the surface tension of asolution relative to that of the pure liquid. Most commonly, such an effect lowers thesurface tension, although the opposite effect is also found. Intuitively, one might expect

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that the surface tension of a solution should be some mathematical average of that of thetwo pure components. The simplest such combination for a binary mixture would be anadditive combination related to the quantity of each component in the mixture, such asmole fraction. Such a relationship may be written as

where smix is the surface tension of the solution, s1 and s2 are the surface tensions ofthe respective components, and X is the mole fraction of component 1 in the mixture. Inideal systems where the vapor pressure of solutions is a linear function of thecomposition, such relationships are found. Normally, however, there will be some positiveor negative deviation from linearity, with the latter being most commonly encountered.

The presence of an organic material in aqueous solution, unlike inorganic electrolytes,will result in a decrease in the surface tension of the system. The extent of such loweringwill depend upon a number of factors including the relative miscibility of the two liquids(or the solubility of the organic solute) and the tendency of the organic material topreferentially adsorb at the waterair interface. Liquids such as ethanol or acetic acidproduce gradual decreases in the surface tension of their aqueous solutions, while longerchain organics such as butanol can produce more dramatic effects.

When the organic solute has a limited solubility in water, the effect on surface tensionbecomes characteristic of surfactant solutions. For such solutions, one usually encountersa steady decrease in surface tension with increased solute concentration. At some point,a minimum value of s will be obtained indicating surface saturation or some form ofsolute behavior change (phase separation, micelle formation, etc.) that prevents furtherchange in the surface tension.

3Surfactants and the Reduction of Surface Tension

A typical surface-tensionconcentration curve is shown in Fig. 2(C). Since the surfacetension of a liquid is determined by the excess energy of the molecules in the interfacialregion, the displacement of surface solvent molecules by adsorbed solute will directlyaffect the measured value of s. It is the relationship between the chemical structure ofan adsorbing molecule and the rate and extent of adsorption under given circumstancesthat differentiates the various surfactant types and determines their utility in applicationswhere surface tension lowering is of importance.

In aqueous solutions, the interface between the liquid and vapor phases involvesinteractions between relatively densely packed, highly polar water molecules, andrelatively sparse, nonpolar gases. The result is a large imbalance of forces acting on thesurface molecules and the observed high surface tension of water (72.8 mN/m). If thesurface solvent molecules are replaced by adsorbed surfactant molecules with lowerspecific excess energy, the surface tension of the solution will be decreased accordingly,

with the amount of reduction being related to the surface excess concentration of solute(i.e., the excess over the concentration in the bulk solution) and the nature of theadsorbed molecule.

If the vapor phase is replaced by a condensed phase that has a higher molecular densityand more opportunity for attractive interaction between molecules in the interfacialregion, the interfacial tension will be reduced significantly. In the case of water, thepresence of a liquid such as octane, which interacts only by relatively weak dispersionforces, lowers the interfacial free energy to 52 mN/m. If the extent of molecular

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interaction between phases can be increased by the introduction of polar groups thatinteract more specifically with the water, as, for instance, in octanol, the interfacialenergy lowering will be greater (to 8.5 mN/m). Clearly, any alteration in the nature of themolecules composing the liquid surface would be expected to result in a lowering of theinterfacial energy of the system. And therein lies the basic explanation for the action ofsurfactants in lowering the surface and interfacial tension of aqueous solutions.

The same qualitative reasoning also explains why most surfactants will not affect thesurface tension of organic liquidsthe molecular nature of the liquid and the surfactant arenot sufficiently different to make adsorption a particularly favorable process. Or ifadsorption occurs, the energy gain is not sufficient to produce a significant change in thesurface energy. The actions of fluorocarbon and siloxane surfactants are exceptions sincethe specific surface free energy of such materials may be significantly lower than that ofmost hydrocarbons. They will therefore be positively adsorbed at hydrocarbon surfacesand lower the surface tension of their solutions.

4Surfactant Adsorption and Gibbs Monolayers

The basic concept governing our understanding of the adsorption of surface activemolecules at interfaces is the Gibbs adsorption isotherm, which relates the surface'sexcess concentration of the adsorbed species to the surface or interfacial tension of thesystem. The surface excess may be functionally defined as the concentration of adsorbingspecies (i.e., surfactant) at the interface over and above that in the bulk phase or phases.Because of its simplicity, the Gibbs approach to quantifying surfactant adsorption is opento some criticism on theoretical grounds. However, its long and useful service as afundamental tool for understanding the phenomena involved warrant discussion.

The fundamental principle underlying our present understanding of surface activity is theGibbs adsorption equation [22]

where G2 is the surface excess concentration of adsorbed species (i.e., surfactant) abovethat in the bulk phase, R is the gas constant, T the temperature (K), s the surface orinterfacial tension, and c the solute concentration.

In the discussion of the performance of a surfactant in lowering the surface tension of asolution it is necessary to consider two aspects of the process: (1) the concentration ofsurfactant in the bulk phase required to produce a given surface tension reduction, and(2) the maximum reduction in surface tension that can be obtained, regardless of theconcentration of surfactant present.

Because the extent of reduction of the surface tension of a solution depends on thesubstitution of surfactant for solvent molecules at the interface, the relative concentrationof surfactant in the bulk and interfacial phases [from Eq. (13)] should serve as an

indicator of the adsorption efficiency of a given surfactant and, therefore, as aquantitative measure of the activity of the material at the solutionvapor interface. For ahomologous series of straight-chain surfactants in water, CH3(CH2)nS, where S is thehydrophilic head group and n is the number of methylene units in the chain, an analysisof the thermodynamics of transfer of a surfactant molecule from the bulk phase to theinterface indicates that the effectiveness of surfactant adsorption, reflected as a givensurface-tension lowering, will be directly related to the length of the hydrocarbon chain,in agreement with experimental observation [4].

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It is reasonable to expect that changes in the hydrophobic character of the surfactant willproduce parallel changes in adsorption efficiency, as is found for cmc values. In nitrogen-based cationic surfactants, the presence of short-chain alkyl groups (fewer than fourcarbon atoms) attached to the nitrogen seems to have little effect on the efficiency ofadsorption of the molecule. The dominant factor will always be the length of the primaryhydrophobic chain. That effect is true whether the alkyl groups are attached to aquaternary ammonium group, an amine oxide, or a heterocyclic nucleus such as pyridine.

Within limits, the nature of the charge on an ionic surfactant will have little effect on theefficiency of surfactant adsorption. It will, again, be the nature of the hydrophobic groupthat predominates. Some increase in adsorption efficiency will be seen if the counterion isone that is highly ion paired. The addition of neutral electrolyte to an ionic surfactantsolution will produce a similar result in increasing the efficiency of adsorption.

Polyoxyethylene (POE) nonionic surfactants with the same hydrophobic group and anaverage of 730 oxyethylene (OE) units, exhibit adsorption efficiencies that follow anapproximately linear relationship based on the free energy of transfer of CH2 and OEgroups, respectively, from the bulk phase to the interface. Available data indicate that theefficiency of adsorption decreases slightly as the number of OE units on the surfactantincreases.

Although the efficiency of surfactant adsorption at the solutionvapor interface isdominated by the nature of the hydrophobic group and is relatively little affected by thehydrophilic head group, it is often found that the second characteristic of the adsorptionprocess, the minimum surface tension obtainable (adsorption effectiveness), will be muchmore sensitive to other factors and will quite often not parallel the trends found foradsorption efficiency. When one discusses the effectiveness of adsorption, as defined asthe maximum lowering of surface tension regardless of surfactant concentration, thevalue of smin is determined by the system (i.e., the combination of temperature, solutecontent, surfactant characteristics, etc.) and represents a fixed point of reference. Thevalue of smin for a given surfactant will be determined by one of two factors: (1) thesolubility limit or Krafft temperature (Tk) of the compounds, or (2) the critical micelleconcentration. In either case, the maximum amount of surfactant adsorbed will bereached, for all practical purposes, at the maximum bulk concentration of free (i.e.,monomeric) surfactant.

Because the activity of a surfactant below Tk cannot reach its theoretical maximum asdetermined by the thermodynamics of surfactant aggregation, it will also be unable toachieve its maximum level of adsorption at the solutionvapor interface. It is thereforeimportant to know the value of Tk for a given system before considering its application.Most surfactants, however, are employed well above their Krafft temperature, so that thecontrolling factor for the determination of their effectiveness will be the cmc.

When one examines the shape of the surface tensionln c curve for a surfactant, it can be

seen that the curve becomes approximately linear at some concentration below the cmc.The effectiveness of surfactant adsorption, Dscmc, can be quantitatively related to theconcentration of surfactant at which the Gibbs equation becomes linear, C1, the surfacetension attained at C1, s1, and the cmc. The relationship has the general form

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where so is the surface tension of the pure solvent and Gm is the maximum in surfaceexcess of adsorbed surfactant at the interface. The factor W in Eq. (14) is related to thenumber of molecular or atomic units that will be adsorbed at the interface with theadsorption of each surfactant molecule; for nonionic surfactants or ionic materials in thepresence of a large excess of neutral electrolyte, W = 1; for fully dissociated ionicsurfactants W = 2, since one counterion must be adsorbed for each surfactant moleculegiving a total of two species. The effectiveness of a surfactant can be convenientlyquantified by using a value of C1 at which the surface tension has been reduced by 20mN/m, assuming G20»Gm. Application of Eq. (14) then allows for the calculation of astandard quantity, cmc/C20, which serves as a useful measure of overall surfactanteffectiveness.

It is often found that the efficiency and effectiveness of surfactants do not run parallel; infact, it is commonly observed that materials that produce significant lowering of thesurface tension at low concentrations (i.e., are more efficient) will be less effective (i.e.,will have a smaller Gm). This follows from the complex relationship between adsorption atthe interface and micelle formation in the solution.

While the role of molecular structure in determining surfactant efficiency is primarilythermodynamic, its role in effectiveness is more directly related to the size of thehydrophobic and hydrophilic portions of the adsorbing molecules; that is, it becomes aquestion of space. The maximum number of molecules that can be fitted into a givenarea depends on the area occupied by each molecule, which in turn is determined byeither the cross-sectional area of the hydrophobic chain or the area required for thearrangement for closest packing of the head groups, whichever is greater. For straight-chain 1:1 ionic surfactants, it is usually found that the head group requirement willpredominate, so that for a given homologous series, the surface tension minimumobtained will vary only slightly with the length of the hydrocarbon chain.

An increase in the hydrocarbon chain length in a series of normal alkyl surfactants willalso have a minor effect on the effectiveness of a surfactant. However, other structuralchanges may produce more dramatic effects. Structural features such as branching andmultiple-chain hydrophobes will generally result in increases in the cmc of surfactantswith the same total carbon content. Those changes have a smaller effect on the efficiencyof the surfactant (C20) than on its effectiveness (smin).

More detailed discussions of the effects of various molecular changes on the efficiencyand effectiveness of surfactant adsorption can be found in the works of Rosen [4],Shinoda [5], and Myers [6].

BAdsorption at SolidLiquid Interfaces

This section will complete the brief discussion of adsorption. While being treated last,adsorption at the solidliquid interface is far from the least important in terms of functional

importance in nature or technology. Interactions between solid surfaces and solutions areof fundamental importance in many biological systems (joint lubrication and movement,implant rejection, etc.), in mechanics (lubrication and adhesion), in agriculture (soilwetting and conditioning and pesticide application), in communications (ink and pigmentdispersions), in electronics (microcircuit fabrication), in energy production (secondary andtertiary oil recovery techniques), in foods (starchwater interactions

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in bakery doughs), in paint production and application (latex polymer and pigmentdispersion stabilization), and of course in cosmetic dispersions.

1The Adsorption Model

The adsorption of molecules at a solidliquid interface creates a transition region on theorder of molecular dimensions in which the composition of the system changes from thatof the bulk solid to that of the bulk liquid. In the case of positive adsorption, theconcentration of adsorbed molecules at the interface will be somewhat higher than thatin the bulk, as in the Gibbs case already discussed. In a pure liquid, that component willbe nothing more than liquid molecules solvating the surface. If specific interactions occurbetween the liquid and the solid the liquid molecules near the interface can undergo aspecific orientation (i.e., solvation of the surface) that may change the density, dielectricconstant, or other physical (or even chemical) characteristics of the liquid near thesurface. Except for the most delicate experimental work or in the context of catalyticprocesses, such effects are of little practical concern. It is the adsorption of solutemolecules (i.e., surfactant) at the solidsolution interface that is generally of most interest.

For a solution, a higher concentration of the solute molecules near the interface willreflect the specific adsorption of that species in terms of its surface excess, G2. From botha theoretical and practical standpoint, it is of interest to know the characteristics of suchadsorption profiles for a given system in order to understand the mechanism ofadsorption, as well as its consequences.

We have already seen the Gibbs adsorption equation in the context of adsorption atliquidvapor, and liquidliquid interfaces. The relationship is every bit as applicable anduseful for solidliquid systems. While for liquidfluid systems, the equation is normallyemployed to determine the amount of adsorbed material at an interface as a function ofinterfacial tension, s, in the case of solid surfaces, it is difficult or impossible to determines directly. It is, however, relatively easy to determine the amount of adsorbed materialdirectly and use that information to calculate a value of the interfacial tension.

Some degree of adsorption will occur at any solidliquid interface, although it may benegligible. In fact, the adsorption may even be negative; that is, the concentration of the"adsorbed" component may be lower near the interface than in the bulk. Such situations,however, are rather rare (in electrical double layer theory and some polymer solutions).Of more interest are systems in which one or more components of the liquid phase arestrongly (and positively) adsorbed at the interface, bringing about a significant loweringof the interfacial tension and, in some cases, a significant change in the nature of theinterface. The effects of such strong adsorption are of great practical importance andallow us to manipulate solidliquid interfaces to our own best advantage.

When the adsorption of surfactant onto a solid surface is considered, there are severalquantitative and qualitative points that are of interest. They include (1) the amount of

surfactant adsorbed per unit mass or area of solid; (2) the surfactant concentrationrequired to produce a given surface coverage or degree of adsorption; (3) the surfactantconcentration at which surface saturation occurs; (4) the molecular orientation of theadsorbed molecules relative to the surface and solution; and (5) the effect of adsorptionon the properties of the solid relative to the rest of the system. In all of the above, it isassumed that such factors as temperature and pressure are held constant.

The classical method for determining the above quantities in a given system is by way ofthe adsorption isotherm. The basic concepts and equations describing the adsorption

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of one component of a binary solution onto a solid substrate are found in the work byAveyard and Haydon [23].

For surfactant systems, the concentration of adsorbed material can be calculated from theknown amount of material present before adsorption and that present in solution afterequilibrium has been reached. A wide variety of analytical methods for determining thesolution concentration are available. The utility of a specific method will dependultimately on the nature of the system under study and the resources available to theinvestigator.

2Adsorption Isotherms

The experimental evaluation of the adsorption from solution of surface active agents atthe solid-liquid interface usually involves the measurement of changes in theconcentration of the active solute in the solution after adsorption has occurred. The usualmethod for evaluating the adsorption mechanism is through the adsorption isotherm. Theimportant factors to be considered are (1) the nature of the interaction(s) between theadsorbate and the adsorbent; (2) the rate of adsorption; (3) the shape of the adsorptionisotherm and the significance of plateaus, points of inflection, etc.; (4) the extent ofadsorption (i.e., monolayer or multilayer formation); (5) the interaction of solvent withthe solid surface (solvation effects); (6) the orientation of the adsorbed molecules at theinterface; and (7) the effect of environmental factors such as temperature, solventcomposition, and pH.

Interactions between the adsorbent and adsorbate may fall into two categoriesrelativelyweak, reversible physical adsorption and stronger, sometimes irreversible chemisorption.Because of the varied possibilities of adsorption mechanisms, several isotherm shapeshave been identified experimentally, and a classification of isotherms with various shapeshas been developed [24]. Perhaps the most useful in surfactant systems is the Langmuirisotherm, identified by having its initial region concave to the concentration axis. As theconcentration of adsorbate increases, the isotherm may reach a plateau, followed by asection convex to the concentration axis. In some cases the curve may attain a secondplateau. The other classes are less commonly encountered in surfactant systems and willnot be discussed further here.

3Modification of the SolidLiquid Interface

The adsorption of surface active materials onto a solid surface from solution is animportant process in many situations including those in which we may want to (1)remove unwanted materials from a system (detergency); (2) change the wettingcharacteristics of a surface (coating and waterproofing); (3) stabilize a finely divided solidsystem in a liquid where stability may otherwise be absent (dispersion stabilization); andmany more. In these and related applications, the ability of surface active materials to

adsorb at the solidliquid interface with a specific orientation and produce a desired effectis controlled by the chemical natures of the components of the system: the solid, thesurfactant, and the solvent.

In general, a solid surface cannot be considered to be truly homogeneous, at least at thelevel assumed for fluid surfaces. The exact nature of the adsorption process will dependto a great extent on the nature of the surface and its potential for interaction with thecontacting solvent and dissolved species. For that reason we may say that adsorption atsolid surfaces is to some extent history dependent; that is, the details of adsorption

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interactions may depend on the manner in which the surface is prepared as well as itsexact composition.

(a)The Nature of the Adsorbent Surface

The nature of the solid surface involved in the adsorption process is a major factor indetermining the manner and extent of surfactant adsorption. When one considers thepossible nature of an adsorbent surface, three principal groups readily come to mind (1)surfaces that are essentially nonpolar and hydrophobic such as polyethylene; (2) thosethat are polar but possess few, if any, discrete surface charges such as polyesters andsome natural fibers; and (3) those that possess strongly charged surface sites.

(b)Nonpolar, Hydrophobic Surfaces

Adsorption of surfactants into nonpolar surfaces is by dispersion force interactions. Fromaqueous solution, it is obvious that the orientation of the adsorbed molecules will be suchthat the hydrophobic groups are associated with the solid surface with the hydrophilicgroup directed toward the aqueous phase. In the early stages of adsorption it is likelythat the hydrophobe will be lying on the surface much like trains or Ls (Fig. 3). As thedegree of adsorption increases, however, the molecules will gradually be oriented moreperpendicular to the surface until, at saturation, an approximately close-packed assemblywill result. It is generally found that surface saturation is attained at or near the cmc forthe surfactant. In many cases the isotherm is continuous, while in others an inflectionpoint may be found. The existence of an inflection point is usually attributed to arelatively sudden change in surfactant orientationfrom train or L-shaped to a moreperpendicular arrangement. Because the orientation of the adsorbed molecules is withthe hydrophilic group directed outward from the solid surface, there will normally be littleinclination for the formation of a second adsorbed layer. That is, the process will usuallybe limited to monolayer formation.

(c)Polar, Uncharged Surfaces

Polar, uncharged surfaces include many of the synthetic polymeric materials such aspolyesters, polyamides, and polyacrylates, as well as many natural materials such ascotton and silk. As a result of their surface makeup, the mechanism and extent ofsurfactant adsorption may be of potential technological importance. The mechanism ofadsorption onto these surfaces will be much more complex than that of the nonpolarcase, since such factors as orientation will be determined by a balance of several forces.

The forces operating at a polar surface may include the ever-present dispersion forces,dipolar interactions, and hydrogen bonding and other acidbase interactions. The balancebetween dispersion forces and the uniquely polar interactions is of importance in

Fig. 3Basic modes of adsorption of surfactants on solid surfaces:

(a) trains, (b) "L"s, and (c) perpendicular.

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determining the mode of surfactant adsorption. If dispersion forces predominate,adsorption will occur in a manner similar to that for the nonpolar surfaces. If polarinteractions dominate, adsorption may occur in a reverse mode with the surfactantmolecules oriented with the hydrophilic head group at the solid surface and thehydrophobic group toward the aqueous phase. The result of the two adsorption modeswill be drastically different. In aqueous systems, the final orientation will also be affectedby the relative strength of solventadsorbent and solventadsorbate interactions. Inmarginal cases, the mode of adsorption may be reversed by small, subtle changes in thenature of the solvent (e.g., pH, electrolyte content, presence of a cosolvent, etc.)

(d)Charged Surfaces

The final class of adsorbent surfaces is the most complex of the three for several reasons.From the standpoint of the nature of the surface, these materials are capable ofundergoing adsorption by all of the previously mentioned mechanisms. Possibly moreimportant, however, is the fact that adsorption involving chargecharge interactions issignificantly more sensitive to external conditions such as pH, neutral electrolyte, and thepresence of non-surface-active cosolutes than are the other mechanisms.

Materials possessing charged surfaces include almost all of the inorganic oxides and saltsof technological importance (silica, alumina, titania, etc.), the silver halides, latexpolymers containing ionic comonomers, and many natural surfaces such as proteins andcellulose. It is very important, therefore, to be able to understand the interactions of suchsurfaces with surfactants in order to optimize their effects in such applications as paintand pigment dispersions, paper making, textiles, pharmaceuticals, biomedical implants,cosmetic applications, etc.

Because of the large number of possible interactions in systems containing chargedsurfaces and ionic surfactants, it is very important to closely control all of the variables inthe system. As adsorption proceeds, the dominant mechanism may go from ion exchangethrough ion bonding to dispersion or hydrophobic interactions. As a result, adsorptionisotherms may be much more complex than those for the simpler systems.

Studies of the adsorption of surfactants onto surfaces of opposite charge have resulted inthe identification of three principle regions of adsorption in which the rates vary due tochanges in the mechanisms of adsorption. It is generally assumed that such adsorptionpatterns involve three mechanisms as illustrated in Fig. 4. In the early stages (a,b regionI), adsorption occurs primarily as a result of ion exchange in which adsorbed counterionsare displaced by surfactant molecules. During that stage the electrical characteristics(i.e., the surface charge or surface potential) of the surface may remain essentiallyunchanged. As adsorption continues (c), ion pairing may become important (region II),resulting in a net decrease in surface charge. Such electrical properties as the surface andzeta potentials will tend toward zero during this process. It is often found that in region II

the rate of adsorption will increase significantly. The observed increase may be due tothe cooperative effects of electrostatic attraction and lateral interaction betweenhydrophobic groups of adsorbed surfactants as packing density increases.

As the adsorption process approaches the level of complete neutralization of the nativesurface charge by adsorbed surfactant (d), the system will go through its zero point ofcharge (zpc), where all of the surface charges have been paired with adsorbed surfactantmolecules (region III). In that region, lateral interactions between adjacent surfactanttails may become significant, often leading to the formation of aggregate structures or

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Fig. 4Stages of surfactant adsorption onto a surface of opposite charge.

hemimicelles. If the interaction between surfactant tails is weak (due to short or bulkystructures) or if electrostatic repulsion between head groups cannot be overcome (due tothe presence of more than one charge of the same sign or low ionic strength), theenhanced adsorption rate of region II may not occur and hemimicelle formation in regionIII may be absent. An additional result of the onset of dispersion force-dominatedadsorption may be the occurrence of charge reversal as adsorption proceeds.

Surfaces possessing charged groups in aqueous solvents are especially sensitive toenvironmental conditions such as electrolyte content and the pH of the aqueous phase. Inthe presence of high electrolyte concentrations, the surface of the solid may possess sucha high degree of bound counterions that ion exchange is the only mechanism ofadsorption available other than dispersion or hydrophobic interactions. Not only will theelectrical double layer of the surface be collapsed to a few angstroms thickness, butattraction between unlike charge groups on the surface and the surfactant and repulsionbetween the like charges of the surfactant molecules will be suppressed. The result willoften be an almost linear adsorption isotherm, lacking any of the characteristics of themechanisms described above.

An increase in the electrolyte content will generally cause a decrease in adsorption ofsurfactants onto oppositely charged surfaces and an increase in adsorption of like chargedmolecules. The presence in the solution of polyvalent cations such as Ca2+ or Al3+ willgenerally increase the adsorption of anionic surfactants. Such ions are characteristicallytightly bound to a negatively charged surface, effectively neutralizing charge repulsions.

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They also can serve as an efficient bridging ion by association with both the negativesurface and the anionic surfactant head group.

An increase in the temperature will usually result in a decrease in the adsorption of ionicsurfactants, although the change may be small when compared to those due to pH andelectrolyte changes. Nonionic surfactants solubilized by hydrogen bonding, which usuallyhave an inverse temperature-solubility relationship in aqueous solution, will generallyexhibit the opposite effect. That is, adsorption will increase as the temperature increases,often having a maximum near the cloud point of the particular surfactant.

Adsorption onto solid surfaces having weak acid or basic groups such as proteins,cellulosics, and many polyacrylates can be especially sensitive to variations in solutionpH. As the pH of the aqueous phase is reduced, the net charge on the solid surface willtend to become more positive. That is not to say that actual positive charges willnecessarily develop; rather, ionization of the weak acid groups (e.g., carboxylic acids) willbe suppressed. The net result will be that the surface may become more favorable for theadsorption of surfactants of like charge (e.g., anionic surfactants onto carboxyl surfaces)and less favorable for adsorption of oppositely charged surfactants. For surfacescontaining weak basic groups such as amines, the opposite would be true. That is,lowering the pH will lead to ionization of surface basic groups, increased adsorption ofoppositely charged (negative) molecules, and decreased interaction with materials of thesame charge.

(e)Effects of Adsorption of the Nature of the Surface

When a surfactant is adsorbed onto a solid surface, the resultant effect on the characterof that surface will depend largely on the dominant mechanism of adsorption. For a highlycharged surface, if adsorption is a result of ion exchange, the electrical nature of thesurface will not be altered significantly. If, on the other hand, ion pairing becomesimportant, the potential at the Stern layer will decrease until it is completely neutralized.In a dispersed system stabilized by electrostatic repulsion, such a reduction in surfacepotential will result in a loss of stability and perhaps eventual flocculation or coagulationof the particles.

In addition to the electrostatic consequences of specific chargecharge interactions,surfactant adsorption by ion exchange or ion pairing results in the orientation of themolecules with their hydrophobic groups toward the aqueous phase. The surfacebecomes hydrophobic and less easily wetted by that phase. Once the solid surface hasbecome hydrophobic, it is possible for adsorption to continue by dispersion forceinteractions. When that occurs, the charge on the surface will be reversed, acquiring acharge opposite to that of the original surface, because the hydrophilic group will now beoriented toward the aqueous phase. In a system normally wetted by water, theadsorption process reduces the wettability of the solid surface making its interaction with

other less polar phases (e.g., air) more favorable. Industrially, the production of ahydrophobic surface by the adsorption of surfactant lies at the heart of the froth flotationprocess for mineral ore separation.

Although surfactant adsorption and its effect on solid surface properties is often discussedin terms of colloidal systems, the same results can be of technological importance formacrosurfaces, especially in the control of the wetting or nonwetting properties ofmaterials (in waterproofing), detergency, lubrication (with cutting oils and otherlubricants), the protection of skin and other membrane surfaces, the control of fluid flowthrough porous media (crude oil production), and corrosion control. Almost any process orproduct that involves the interaction of a solid and a liquid phase will be

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affected by the process of surfactant adsorption; thus the area represents a majorsegment of the technological application of surfactants.

IVWetting, Spreading, and Capillary Flow

The wetting of a surface by a liquid and the ultimate extent of spreading of that liquidover the surface are important aspects of practical surface chemistry. Many of thephenomenological aspects of the wetting processes have been recognized and quantifiedsince early in the history of observation of such processes. Despite the new informationdeveloped during the last twenty-five years, a great deal remains to be learned about themechanisms of movement of a liquid across a surface.

AThe Contact Angle

One of the primary characteristics of any immiscible, two- or three-phase systemcontaining two condensed phases, at least one of which is a liquid, is the contact angle ofthe liquid, q, on the second condensed phase. The contact angle of one liquid on another,while being of theoretical interest, is normally of little practical importance. Of morepractical and widespread importance is the contact angle of a liquid directly on a solid.For liquids on solids, the contact angle can be viewed as a material property of thesystem, assuming that certain precautions are taken in the collection and interpretationof data, and that liquid absorption and surface penetration (i.e., swelling) are taken intoconsideration.

When a drop of liquid is placed on a solid surface, the liquid will either spread across thesurface to form a thin, approximately uniform film or it will spread to a limited extent butremain as a discrete drop on the surface. The final condition of the applied liquid on thesurface is taken as an indication of the wettability of the surface by the liquid or thewetting ability of the liquid on the surface. The quantitative measure of the wettingprocess is taken to be the angle, q, that the drop forms on the solid as measured throughthe liquid in question (Fig. 5).

In the case of a liquid that forms a uniform film (i.e., where q = 0°), the solid is said to becompletely wetted by the liquid; or the liquid wets the solid. If a finite contact angle isformed (q > 0°), some investigators describe the system as being partially wetted. If q is90° or more, the system is generally considered as nonwetting.

While the contact angle of a liquid on a solid may be considered a characteristic of

Fig. 5The mechanical equilibrium of surfaceforces leading to the contact angle as

given by Young's equation.

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the system, that will be true only if the angle is measured under specified equilibriumconditionstime, temperature, component purities, etc. Contact angles are very easymeasurements to make (with a little practice) and can be very informative; but if theproper precautions are not taken, they can be very misleading.

The contact angle may be geometrically defined as the angle formed by the intersectionof the two planes tangent to the liquid and solid surfaces at the perimeter of contactbetween the two phases and the third surrounding phase. Typically, the third phase willbe air or vapor, although systems in which it is a second liquid essentially immiscible withthe first are of great practical importance. The perimeter of contact among the threephases is commonly referred to as the three-phase contact line or the wetting line.

The great utility of contact angle measurements stems from their interpretation based onequilibrium thermodynamic considerations. As a result, most studies are conducted onessentially static systems in which the liquid drop has (presumably) been allowed tocome to its final equilibrium value under controlled conditions. In many practicalsituations, however, it is just as important, or perhaps more important, to know how fastwetting and spreading occur as to know what the final equilibrium situation will be. Thatwill especially be true in situations where the process in question requires that wettingbring about the displacement of one phase by the wetting liquid. Typical examples wouldbe detergency, in which a liquid or solid soil is displaced by the wash liquid; petroleumrecovery, in which the liquid petroleum is displaced by an aqueous fluid; textileprocessing, in which air must be displaced by a treatment solution (dyeing orwaterproofing treatments, for example) in order to obtain a uniform treatment; andcertain cosmetic and pharmaceutical applications. Because of the economic importance ofthese and other processes, the dynamic aspects of the wetting processes may be ofimportance.

The interpretation of data on contact angles must be done with the understanding thatthe system in question has been sufficiently well controlled so that the angle measured isthe ''true" angle and not a reflection of some contaminant on the solid surface or in theliquid phase of interest. Contact angles, for example, can be extremely useful as a spottest of the cleanliness of sensitive surfaces such as glass or silicon wafers formicroelectronics fabrication. If the surface is contaminated by something such as an oil, adrop of water placed on it will have a relatively large contact angle and thecontamination will be immediately apparent.

For systems which have "true" nonzero contact angles, the situation may be furthercomplicated by the existence of contact angle hysteresis. That is, the contact angle oneobserves may vary depending on whether the liquid is advancing across fresh surface (theadvancing contact angle, qA) or receding from an already wetted surface (the recedingcontact angle, qR). As an operational convenience, many, if not most, static contactangles reported are in fact advancing angles. It is generally found that qA³q³qR.

Obviously, contact angle measurements and their interpretation are not withoutproblems. However, because of the ease of making such measurements, the low cost ofthe necessary apparatus, and the potential utility of the concept, they should be seriouslyconsidered as a rapid diagnostic tool for any process in which wetting phenomena play arole.

There exists a variety of simple and inexpensive techniques for measuring contact angles,most of which are described in detail in various texts and publications [25,26] and willonly be mentioned here. The most common direct methods include the

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sessile drop, the captive bubble, the sessile bubble, and the tilting plate. Indirectmethods include tensiometry and geometric analysis of the shape of a meniscus. Forsolids for which the above methods are not applicable, such as powders and porousmaterials, methods based on capillary pressures, sedimentation rates, wetting times,imbibition rates etc. have been developed.

BThe Thermodynamics of Wetting

The basic framework for the application of contact angles and wetting phenomena lies inthe field of thermodynamics. However, in practical applications it is often difficult to makea direct correlation between observed phenomena and basic thermodynamic principles.Nevertheless, the fundamental validity of the analysis of contact angle data and wettingphenomena helps to instill confidence in its application to nonideal situations.

1Young's Equation

If one considers the three-phase system depicted in Fig. 5, in which the liquid drop isdesignated as fluid 1, the surrounding medium fluid 2, and the solid surface as S, then atequilibrium, the contact angle q will be given by Young's equation [27] as

where s12, sS1, and sS2 are the interfacial tensions at the respective interfaces. AlthoughEq. (15) was originally proposed based upon a mechanical analysis of the resultant forcesat the three-phase contact line, it has since been derived rigorously on the basis offundamental thermodynamic principles. Readers interested in the derivation of Young'sand related equations are referred to the work by Adamson [25].

2The Spreading Coefficient

Young's equation is usually found to be a very useful and adequate means of describingwetting equilibria in most circumstances. However, it is sometimes found useful to defineanother term that will indicate from a thermodynamic point of view whether a givenliquidsolid system will be wetting (q = 0°) or nonwetting (q > 0°). Such a term is thespreading coefficient, S.

If a liquid is placed on a surface, which may be a solid or another liquid, there are twothings that may occur: (1) the liquid may spread across the surface to form a uniformduplex film, or (2) the liquid may form a drop (on a solid) or lens (on a liquid) with afinite, nonzero contact angle. The free energy change for the spreading of liquid B overthe surface A is called the spreading coefficient of B on A, SB/A, and is given by

If we define the works of cohesion (Wc) and adhesion (Wa(AB)) as

and

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it can be seen that SB/A is the difference between the work of adhesion of B to A and thework of cohesion of B

Based on this analysis, the spreading coefficient will be positive if there is a net decreasein free energy on spreading; that is, the spreading process will be spontaneous. If SB/A isnegative, then the cohesive forces will dominate and a drop or lens will result. Additionalinformation on the spreading coefficient is found in Adamson [25].

Unfortunately, complications arise in spreading phenomena due to the fact that liquids,solids, and gases tend to interact in bulk processes as well as at interfaces, and thosebulk phase interactions may have significant effects on interactions at interfaces. A classicexample of such a complication is that pure benzene will spread spontaneously on purewater; however, once the two liquids reach equilibrium in terms of their mutual solubility,film retraction will occur and a lens of water-saturated benzene will form on the surfaceof the benzene-saturated water [6].

Situations like that for benzene are not uncommon for low surface-tension liquids onwater. There may be initial spreading followed by retraction and lens formation. A similareffect can in principle be achieved if a third component (e.g., a surfactant) that stronglyadsorbs at the waterair interface, but not the oilwater interface, is added to the system.Conversely, if the material is strongly adsorbed at the oilwater interface, lowering theinterfacial tension, spreading may be achieved where it did not occur otherwise.

CThe Critical Surface Tension of Wetting

Before the introduction of theories allowing the calculation (really estimation) ofsolidliquid interfacial tensions, Zisman and coworkers [28] developed a useful andpractical systematic method for characterizing the "wettability" of solid surfaces. Thesystem is based on the observation that for solid surfaces having a surface tension (sS) <100 mN/m (generally classed as "low-energy surfaces"), the contact angle formed by adrop of liquid on the solid surface will be primarily a function of the surface tension of theliquid, s12 (where phase 2 is air saturated with the vapor of liquid 1). They found, inparticular, that for a given solid surface and an homologous series of related liquids (e.g.,alkanes, dialkyl ethers, siloxanes, etc) cos q was an approximately linear function of s12.For nonpolar liquids, the relationship holds very well, while for more polar materials, theline broadens and begins to curve for high surface tension, polar liquids.

The general limitation of the technique to the so-called low energy surfaces must bemade because such materials as metals, metal oxides, ionic solids, etc., which havesurface free energies in the hundreds of mJ/m2, are almost always covered with anadsorbed layer of a low energy substance such as gases, water, oils, etc., from theatmosphere. Under rigorously controlled experimental conditions, the technique may be

applied to such materials, but interpretation of the results can be difficult.

From a plot of cos q vs. s12 one can obtain the value of the liquid surface tension at whichcos q = 1, a value that has been termed the critical surface tension of wetting sc. It isdefined as the surface tension of a liquid which would just spread on the surface of thesolid to give complete wetting. In other words, if s12£sc, the liquid will spread; if s12³sc,the liquid will form a drop with a nonzero contact angle. Typical values of sc forcommonly encountered materials are given in Table 6.

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TABLE 6 Values of the Critical Surface Tension of Wetting (sc, mN/m)for a Variety of MaterialsSolid sc Solid scTeflon 18Polytrifluoroethylene 22Polyvinylidene fluoride 25Polyvinylidene chloride 40Polyvinyl fluoride 28Polyvinyl chloride 39Polyvinyl alcohol 37Polyethylene 31Polystyrene 33Nylon 6,6 46Polyethyleneterephthalate 43

DCompetitive Wetting

The above discussion of wetting phenomena was restricted to the situation in which fluid2 was air. In many practical situationsi.e., cleansing and detergency, petroleum recovery,etc.the second fluid may also be a liquid. Not surprisingly, such systems may exhibit evenmore complex behavior than those having one vapor phase. Qualitatively, one cananalyze the situation as follows: at the interface between water and a nonpolar solid inthe presence of a nonpolar liquid (SW2), one expects that the work of adhesion betweenwater and solid, WaSW will be significantly smaller than that between the nonpolar liquidand the solid, WaS2. The reason being that the only attractive interactions possiblebetween water and solid are dispersion forces, which will be of similar magnitude foreach side of the system (» 22 mN/m for water and 2428 mN/m for a nonpolarhydrocarbon solid). In comparison, the internal binding in water, including hydrogenbonding, etc., will be much greater (WcW = 2sW» 144 mJ/m2). As a result qW will be quitelarge, values of well over 110° being common. Clearly, any wetting process that requiresthe displacement of an oil from a nonpolar solid surface by an aqueous solution mustwork against a considerable thermodynamic barrier.

Of particular practical importance is the primary mechanism of detergency for oily soils. Inthat case, the main role of the cleaning solution is to displace or "roll up" the oily soilfrom the solid surface so that it can be more easily and completely removed from thesurface by mechanical action. Obviously, for a nonpolar surface, such action must belimited by the balance of adhesive and cohesive forces. The simplest way to alter thevarious interfacial interactions is by the addition of a surfactant to the system.

EThe Effects of Surfactants on Wetting Processes

In the above context, we now consider specifically some of the effects the presence ofsurfactants can have on contact angles and wetting. The action of surfactants derivesfrom their adsorption at the various interfaces and the resultant modification of interfacialtensions. In terms of the Gibbs equation, the relationship between the specificadsorption, G of a surfactant and surface tension is given by

where T, P, R, and c have their usual significance. Looking again at Young's equation

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[Eq. (15)] one can see that q will decrease if either sS1 or s12 or both are reduced andsS2 remains essentially unchanged. The effect of such changes will be greater if sS2 islarger, that is, if the second fluid in the system is air. The contact angle will increase withsurfactant addition only if the surfactant is adsorbed at the S2 interface. Such a situationrequires some sort of transport mechanism for carrying surfactant from the solution tothat interface. For most surfactants of low volatility, such a mechanism is not readilyavailable when fluid 2 is a vapor. If the second fluid is a liquid, transport of surfactantfrom liquid 1 through liquid 2 can result in significant adsorption at the S2 interface. Formore mobile surface active materials such as alcohols, molecular diffusion may besufficient.

A general relationship between contact angle, surfactant concentration, and specificadsorption can be obtained by differentiating Young's equation with respect to ln c andcombining with the Gibbs equation to give

In Eq. (20), s12 sin q will always be positive, so that (dq/dlnc) must always have thesame sign as the right-hand side of the equation. Using that relationship, one can definethree situations for changes in contact angle and wetting.

1. The addition of surfactant lowers q and improves wetting. This situation corresponds tothe inequality GS2 < GS1G12 cos q.

2. The addition of surfactant increases q and dewetting occurs. In that case GS2 >GS1G12cos q.

3. If GS2 = GS1G12 cos q the addition of surfactant has no net effect on q and wetting isunaffected.

In some practical situations it is found that the effect of surfactant addition on wetting isvariable, with behavior 1 being observed in one concentration range and behavior 2 inanother. In general one finds that situations 1 and 3 are most commonly encountered insystems where the solid substrate is a low-energy, nonpolar material. Situation 2 isusually observed only with higher energy, more polar substrates.

In some cases it is found that solutes that adsorb strongly at solidliquid interfaces are notadsorbed at the fluid (12) interface. The effect of such materials on wetting will dependon how the adsorbed layer interacts with liquid 1. If the adsorbing material presents alower energy surface to the liquid, dewetting will be observed; if a higher energy surfaceis developed, improved wetting will result. In practice, it is often found that in order toeffectively coat (i.e., wet) a relatively low energy substrate with an aqueous solution, it isnecessary to first "activate" the surface by applying or creating a more polar surface.Such "priming" may also improve adhesion where desirable.

The importance of being able to modify the wetting properties of solids is seen in many

important industrial processes including detergency, petroleum recovery, mineral oreflotation, the wetting of powders and pigments prior to dispersion, the wetting of stoneby road tars, etc. When surfactants are added to a system, wetting can becomecomplicated by the many specific interactions that can occur between surfactant andsolid, surfactant and water, and surfactant and oil. The exact effect of a given surfactanton a system will be determined by the degree and mode (i.e., orientation) of itsadsorption at the various interfaces and the reversibility of that adsorption.

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While wetting is obviously a complex process, careful evaluation of the structures of thesurfactant and surface involvedand the application of a bit of intuition and commonsensecan help one arrive at a pretty good analysis of most situations.

FThe Wetting of Powders and Porous Materials

In the practical application of wetting phenomena, it is common to encounter systems inwhich the solid of interest is a powder or porous material that cannot be obtained as asmooth solid surface, but rather must be studied "as is" in its applied form. Examples ofsuch systems would be metal oxides to be dispersed in cosmetic, food, andpharmaceutical applications, in which it may be important to know how an aqueoussolution will wet the solid in manufacturing processes or in the final application. Thedirect determination of contact angles of powdered materials is usually difficult if notimpossible. However, because of the utility of wetting concepts as practical tools forcomparing surfaces and defining limits and boundary conditions for liquid dispersionsystems, indirect methods are available that can provide much needed data.

If a solid of interest is a powder or porous solid it may be prepared as a plug and thecapillary pressure developed against the liquid in question determined. If the poroussample is considered to be a bundle of uniform capillaries of average radius r, the Laplaceequation [29] provides that the capillary pressure required to force the liquid into thesample or to prevent its entry, DP, will be given by

For a wetting liquid (q = 0°) of surface tension sLV0,

By measuring the pressure required to prevent the liquid from entering the pores, onecan calculate the effective capillary radius, r. By then measuring the pressure required toforce a nonwetting liquid (sLV) into the system and substituting the value of r previouslydetermined, the contact angle of the second liquid is found as

The contact angle so determined will be approximate, since the effective capillary radius,r, will include a number of evils resulting from variations in pore sizes, closed pores, andother irregularities. However, those drawbacks do little to diminish the practical utility ofthe method as a comparative tool.

GCapillary Action in Cleaning Processes

One of the most important capillary problems in cosmetic applications is that of cleansingand detergency. In its simplest form, detergency can be viewed as the process of

separating a liquid (oil, O) from contact with a solid (S) by the action of a second liquid(water, W). The same principles can be applied to the case of separating two solidsurfaces by the action of a liquid, but for present purposes the discussion will center onSWO systems. Probably the most familiar detergency system is that involving the removalof an oily soil from a fabric through the action of an

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aqueous wash. However, similar principles are involved in the removal of dirts and oilsfrom skin and hair.

Although mechanical aggitation is obviously important in cleansing processes, thefundamental physical chemical process for removal of the soil is the capillarydisplacement of one liquid on the solid surface by a second liquid. In such a process, thecontact angles of the two liquids on the solid surface are the primary factors controllingthe rate of capillary displacement, although viscosity (lower is better) and sWO (higher isbetter) are also important. For an aqueous detergency system, the optimum condition isto have qA/SW (i.e., the advancing contact angle) as small as possible relative to qR/SO(the receding contact angle). If qA/SW is greater than 90°, water will not readily displacethe oil and little or no capillary action will result. Conventionally, such situations areavoided by the addition of surfactants which will lower qA/SW and aid the capillaryprocess. Since most natural surfaces (e.g., skin and hair) are slightly swollen by water butnot by oils, soaking can allow time for the aqueous solution to penetrate not only into thecapillary system, but also into the surface, producing swelling and improving the contactangle situation in favor of oil removal.

VFoams

Emulsions and foams are related by the fact that each represents a physical state inwhich one fluid phase is finely dispersed in a second phase, the state of dispersion andthe long-term stability (persistence) normally being dependent on the composition of thesystem. In emulsions, each phase is a liquid so that such factors as mutual solubility andthe solubility of additives in each phase must be considered. In foams, the dispersedphase is a gas so that problems of solubility are less critical, although far fromunimportant. While most of the basic principles involved in the preparation andstabilization of emulsions and foams are the same, the nature of foams tends to placethem in their own colloidal class.

Because of the forces involved in their formation and stabilization, foams will have adefinite macrostructure. If the volume of liquid in the foam is large relative to the volumeof gas, individual bubbles will be spherical and will not directly interact to any significantextent. Such systems are sometimes referred to as gas emulsions. In what some prefer tolabel "true" foams, the bubbles are so closely packed that they may no longer bespherical, but take on the shape of polyhedrons separated by thin bilayer or lamellarliquid films.

In polyhedric foams at equilibrium, three contacting bubbles will form three equal anglesof 120°. The interfacial tension of the liquid between the bubbles, s, must be the same atequilibrium so that identical forces will be involved. Mechanical equilibrium thereforerequires that the three angles between them be equal. In an ideal foam, with all bubblesof the same size, the foam would assume the shape of pentagonal dodecahedrons. In

almost all foams, however, there will be a variety of different volumes present and theirshapes will be far from the ideal.

AThe Importance of Foams

The presence of foam in an industrial product or process may or may not be desirable.Foams have wide technical importance, as such, in the fields of fire fighting,

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polymeric foamed insulation, foam rubbers, and foamed structural materials such asconcrete, whipped cream, shaving cream, hair mousse, and many areas of the bakingindustry. They also have certain esthetic utility in many detergent and personal careproducts, although their presence may not add much to the overall effectiveness of theproduct. Foams also serve useful purposes in industrial processes such as mineralseparation (froth flotation), in the secondary recovery of petroleum by fluid displacement,and for environmental reasons in some electroplating operations. Unwanted foams, onthe other hand, may be a significant problem in some processes, including sewagetreatment, coatings applications, surfactant manufacture, extraction processes, andemulsion and dispersion preparation.

A primary characteristic of foams is their very low density. An aqueous foam with bubblediameters of about 1 cm and lamellar thicknesses of 10-3 cm will have a density ofapproximately 0.003 g cm-3. Related to the low density of foams is the characteristic thatthey will have a large surface area for a given weight of foam. The foam in the examplewill have a surface area of about 2000 cm2g-1. Such a large surface area may impartadvantages (i.e., in froth flotation, shaving creams, hair mousses, etc.) or disadvantages(depletion of available surfactant, air entrainment, etc.) to a system and must beunderstood and controlled in any practical industrial process.

BFoam Formation

Foams may be formed by either dispersion or condensation processes. In the former, theincipient gas phase is present as a condensed phase. Small volumes of the future gas areintroduced into the liquid and converted into gas by some mechanism such as heating,pressure reduction, etc. In the case of condensation, the gas phase is introduced at themolecular level and allowed to "condense" within the liquid to form bubbles.

The formation of the "head" on a glass of beer is a classic example of foam formation bycondensation. In such a system, when the can, bottle, or tap is opened, the pressurizedgas in the container is liberated. The solution becomes supersaturated and the excessgas forms a dispersed phase that rises to the top and forms the head. Many industrialprocesses for the formation of solid foams employ a similar process in which a "blowingagent" is added to the polymerizing system creating the foam.

The simplest way to form a nearly ideal monodisperse foam is to introduce gas slowlyinto the liquid through a capillary tube. In that way individual bubbles of equal (almost)size will break off from the capillary tip under the action of surface tension. A much morerapid, but less controllable procedure is to bubble gas into the system through a porousplug. In that process a highly polydisperse foam will result since many small bubbles willhave the opportunity to coalesce while still attached to the plug. Even less consistentresults will be obtained in foams produced by agitation.

In many of the methods for the formation of foams, the initial bubbles will be separated

by relatively thick layers of the continuous phase to produce spherical foams. However, inmany cases gravity will rapidly transform them into the polyhedral structure, with thefoam at the top of the container and a reservoir of liquid accumulated at the bottom. Asthe bubbles rise, the external hydrodynamic pressure will decrease and the bubblevolume increase, reducing the internal pressure of each bubble, although that internalpressure will still be greater than that prevailing externally. There will therefore be amechanical driving force impelling the bubble to release the excess pressure by

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rupture. The fact that in many cases a reasonably long-lived foam is established indicatesthat some mechanism acting within the narrow lamellar films separating the bubbles issufficient to withstand that mechanical pressure.

CBasic Properties of Foams

The continuous phase of foams may consist entirely of liquid components or a mixture ofvarious liquids and solutes. The long term stability of a given foam will depend on thatcomposition, but in the presence of special additives, even a completely fluid lamellar filmwill have some degree of ridigity. When a "stable" polyhedral foam structure is formed, itrepresents a transient minimum in the surface energy of the systema metastableconfiguration that could, in theory, remain for a significant period of time. It wouldrequire a "push" from some external source to cause it to increase its surface area and"break." Under normal circumstances, such "pushes" are common enough in the form ofdust particles, air movement, convection due to temperature differentials, etc. Thereforethe weaker foams will rapidly fall out of that metastable state and revert to a phase-separated state. If the liquid phase is ''fortified" by the addition of various componentsthat can increase lamellar rigidity, greatly enhanced stability will result.

1Foam Stability or Persistence

Foams are inherently metastable systems; that is, like most systems of two or moreimmiscible fluid phases, they are thermodynamically unstable. Because they areencountered in so many technological areas, foams have been the subject of a significantamount of discussion in the literature. A number of reviews have been published over theyears that cover most aspects of foam formation and stabilization [30,31]. While thetheoretical aspects of stabilization are reasonably well worked out, a great deal remainsto be understood concerning the practical details of foam formation, persistence, andprevention. In spite of their ultimate tendency to collapse, foams can be prepared thathave a lifetime (persistence) of minutes, days, or even months.

There are three fundamental physical mechanisms for the collapse of a foam: (1) thediffusion of the gas phase from one bubble (small, high internal pressure) to another(larger, lower internal pressure) or into the bulk gas phase surrounding the foam; (2)bubble coalescence due to rupture of the lamellar film between the gas phase (slowerthan mechanism 1 and occuring even in stabilized systems); and (3) rapid hydrodynamicdrainage of liquid between bubbles leading to rapid collapse (in the absence of anystabilizing mechanisms discussed below). In most nonrigid systems, however, all threemechanisms will be operative to some extent during some phase of the collapsingprocess.

The first mechanism results from a difference in the pressure inside the bubbles. Forexample, consider a system of two contacting bubbles, A and B, with a common lamellar

interface or septum. The Laplace equation states that the pressure difference DP, oneither side of a curved surface will be given by

where s is the interfacial tension and r1 and r2 are the principal radii of curvature. Forspherical bubbles r1 = r2 = R, so that DPA = 2s/RA and DPB = 2s/RB. The net pressureacross the septum will be greater in B, so that gas will be forced out causing a

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shrinkage of B and enlargement of A. If A and B are of similar size at the time of bubbleformation gas exchange will be slow. However, as differences in R become greater theprocess will accelerate.

The second mechanism for bubble disappearance is film drainage and rupture due tocapillary flow. When several bubbles are in contact, the region of multiple bubble contactwill have a smaller radius of curvature than the lamellar films, which may be almostplanar (Fig. 6). Those regions of high curvature toward the gas phase, the Plateauborders, act as capillary "pumps" tending to evacuate the region between bubbles.Pressure differences between the Plateau borders and lamellar regions cause thinning ofthe lamellar film and advance the process of film rupture. Liquid will also be drained fromthe lamellae due to gravitational forces (hydrodynamic flow). As a result the lamellae willbecome thinner until a critical thickness may be reached at which time the system can nolonger sustain the pressure and collapse occurs.

Of the three mechanisms, hydrodynamic drainage due to gravity is usually the most rapidand, if the foam is particularly unstable, leads to total collapse before other mechanismscan become important. In those cases, once the loss of liquid from the lamellar layerproduces a critical thickness of 5 to 15 nm, the liquid film can no longer support thepressure of the gas in the bubble and film rupture occurs.

DPractical Control of Foam Formation and Persistence

Practical mechanisms for improving the persistence of foams must overcome themechanisms of bubble collapse discussed above. Effective measures may include one orseveral of the following conditions: (1) a high viscosity in the liquid phase, which retardshydrodynamic drainage, as well as providing a cushion effect to absorb shocks resultingfrom random or induced motion; (2) a high surface viscosity, which also retards liquid lossfrom between interfaces and dampens film deformation prior to bubble collapse; (3)surface effects such as the GibbsMarangoni effects (see below) that act to "heal" areas offilm thinning due to liquid loss; (4) electrostatic and steric repulsion between adjacentinterfaces due the adsorption of ionic and nonionic surfactants, polymers, etc., which canoppose drainage through the effects of the disjoining pressure; and (5) retardation of gasdiffusion from smaller to larger bubbles.

The addition of surfactants and/or polymers to a foaming system can alter any or all ofthe above system characteristics and therefore enhance the stability of the foam. Theymay also have the effect of lowering the surface tension of the system, thereby reducing

Fig. 6Critical features of foam structure that induce

(reduced Laplace pressure at Plateau borders) andretard (disjoining pressure) film drainage.

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the work required for the initial formation of the foam, as well as producing smaller, moreuniform bubbles.

For a liquid to produce a foam of any degree of stability, it must be able to (1) expand itssurface area so as to form a membrane around gas bubbles; (2) possess the correctrheological and surface properties to retard the excessive thinning of the lamellae leadingto bubble coalescence; and/or (3) retard the diffusion of trapped gas from small to largebubbles or to the surrounding atmosphere. Foaming does not occur in pure liquidsbecause they lack mechanisms for any of those three tasks. When surface activemolecules or polymers are present, however, rheological effects and adsorption at thegasliquid interface serve to retard the loss of liquid from the lamellae and, in someinstances, to produce a more mechanically stable system.

Theories related to such film formation and persistence, especially film elasticity, derivefrom a number of experimental observations about the surface tension of liquids. First, asis well known from the Gibbs adsorption equation, the surface tension of a liquid willdecrease as the concentration of the surface active material in solution increases(assuming positive adsorption) up to the point of surface saturation. Second, theinstantaneous (dynamic) surface tension at a newly formed surface is always higher thanthe equilibrium value; that is, there is a finite time requirement during which the surfaceactive molecules diffuse to the interface and lower the surface tension. The time lag inreaching the equilibrium surface tension due to diffusion is generally known as theMarangoni effect. The two surface tension effects due to adsorption and diffusion areusually complementary and are often referred to as the combined GibbsMarangoni effect.

The fundamental impact of surfactant concentration and diffusion rate in lamellar filmscan be visualized as follows: as the lamellar film between adjacent bubbles is stretcheddue to gravity, agitation, drainage, or other mechanical action, new surface will beformed having a lower transient surfactant concentration, and a local surface tensionincrease will occur. A surface tension gradient along the film will be produced, causingliquid to flow from regions of low s toward the new stretched surface, thereby opposingfilm thinning. Additional stabilizing action is thought to result from the diffusion of newsurfactant molecules to the surface, which must also involve the transport of associatedsolvent into the area, countering the thinning effect of liquid drainage. The mechanismcan be characterized as producing a "healing" effect at the site of thinning. Although theGibbsMarangoni effects are complementary, they are generally important in differentsurfactant concentration regimes. The Marangoni effect is usually of importance in fairlydilute surfactant solutions and over a relatively narrow concentration range.

Two surfactant-related processes, then, must be considered in conjunction with thesefoam-stabilizing mechanisms. One is the rate of surface diffusion of surfactant moleculesfrom regions of low to high surface tension. The second is the rate of adsorption ofsurfactant from the underlying bulk phase into the surface. In each case, a too rapidarrival of surfactant molecules at the new surface will destroy the surface tension

gradient and prevent the restoring action of the GibbsMarangoni "healing" process.Conversely, a very low bulk concentration will result in equally ineffective action.

1Foam Formation and Surfactant Structure

The relationship between the foaming power of a surfactant and its chemical structurecan be quite complex. The correlation is further complicated by the fact that there is not

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necessarily a direct relationship between the ability of a given structure to produce foamand its ability to stabilize that foam. One usually finds that the amount of foam producedby a surfactant under a given set of circumstances will increase with its bulkconcentration up to a maximum, which occurs somewhere near the cmc. It would appear,then, that surfactant cmc could be used as a guide in predicting the initial foaming abilityof a material, but not necessarily the persistence of the resulting foam. Any structuralmodification that leads to a lowering of the cmc of a class of surfactants, such asincreasing the chain length of an alkyl sulfate, can be expected to increase its efficiencyas a foaming agent. Conversely, branching of the hydrophobic chain or moving thehydrophilic group to an internal position, all of which increase the cmc, will result in alower foaming efficiency.

The ability of a surfactant to function as a foaming agent is dependent primarily on itseffectiveness at reducing the surface tension of the solution, its diffusion characteristics,the elastic properties it imparts to interfaces, and interfacial interactions betweenopposing sides of the lamellar film. Since each "face" of the thinning film can beconsidered an independent surface, the drainage process causes the two to approach towithin a few nanometers. If surfactant is adsorbed at the interface, a net repulsion(electrostatic and/or steric), the disjoining pressure, will result. In many cases, thedisjoining pressure can significantly retard the process leading to film rupture. Themagnitude of the disjoining pressure depends on the distance of separation betweenfaces and therefore becomes more important in the final stages of the drainage process.

The foam produced in a solution under given conditions (i.e., for a set amount of workinput) will be related to the product of the surface tension and the new surface areagenerated during the foaming process. Obviously, the lower the surface tension of thesolution the greater will be the surface area that can be expected to be produced by theinput of a given amount of work. Maintenance of the foam, however, may be asimportant as its original formation.

The amount of foam produced by solutions of a homologous series of surfactants willusually go through a maximum as the chain length of the hydrophobic group increases.This is probably due to the conflicting effects of the structural changes. In one case, alonger chain hydrophobe will result in a more rapid lowering of surface tension and alower cmc. However, if the chain length grows too long, low solubility, slow diffusion,and/or limited adsorption may become problems.

It has been found in many instances that surfactants with branched hydrophobic groupswill lower the surface tension of a solution more rapidly than a straight-chain material ofequal carbon number. However, since the branching of the chain increases the cmc andreduces the amount of lateral chain interaction, the cohesive strength of the adsorbedlayer, the film elasticity, will be reduced, yielding a system with higher initial foam heightbut reduced foam stability. Similarly, if the hydrophilic group is moved from a terminal toan internal position along the chain, higher foam heights, but lower persistence, can be

expected. In all such cases, comparison of foaming abilities must be at concentrationsabove their cmcs.

Ionic surfactants can contribute to foam formation and stabilization as a result of thepresence at the interface of the electrical double layer that can interact with the opposinginterface in the form of the disjoining pressure. Not surprisingly, it is found that theeffectiveness of such surfactants as foaming agents can be related to the nature of thecounterion associated with the adsorbed surfactant molecules. The effectiveness of

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ammonium dodecylsulfate surfactants as foam stabilizers, for example, decreases in theorder .

Nonionic surfactants generally produce less initial foam and less stable foams than ionicsin aqueous solution. Because such materials must by nature have rather large surfaceareas per molecule, it becomes difficult for the adsorbed molecules to interact laterally toa significant degree, resulting in a lower interfacial elasticity. In addition, the bulky,highly solvated nonionic groups will generally result in lower diffusion rates and lessefficient "healing" via the GibbsMarangoni effect. Polyoxyethylene nonionic surfactants inparticular exhibit a strong sensitivity of foaming ability to the length of the POE chain.This characteristic of POE nonionic surfactants has made it possible to design highlysurface active, yet low foaming surfactant formulations. Even more dramatic effects canbe obtained by the use of "double-ended" surfactants in which both ends of the POE chainare substituted. In many cases only a single methyl group on the end of a surfactantchain will significantly reduce foaming where such a result is desired.

If the solubility of a surfactant is highly temperature dependent, as is the case for manyPOE nonionics, it will be found that foaming ability will increase in the same direction asits solubility. Nonionic POE surfactants, for example, exhibit a decrease in foamproduction as the temperature is increased and the cloud point is approached. Long-chaincarboxylate salts, on the other hand, which may have limited solubility in water and poorfoaming properties at room temperature, will be more soluble and will foam more as thetemperature increases.

In recent years, a greater understanding of the potential importance of liquid crystalformation to emulsion stability has developed. Not surprisingly, an equally important rolefor such structures has been identified in foaming applications. In addition, Friberg et al.[32,33] have shown that the presence of a liquid crystalline phase can serve as asufficient condition for the production of stable foams.

The role of the liquid crystal in stabilizing a foam can be related to its effect on severalmechanisms involved in foam loss, including hydrodynamic drainage, the mechanicalstrength of the liquid film, and the diffusion rate of entrapped gas. The production of aliquid crystal phase can not only add to the stability of the foam from a surface chemicalstandpoint, but it can also significantly enhance the mechanical strength of the system.When thinning reaches the point at which bubble rupture can become important, themechanical strength and rigidity of such structures can help the system withstand thethermal and mechanical agitation that might otherwise result in film rupture and foamcollapse.

Finally, because the liquid crystal structure is more highly ordered and, potentially, moredense than a normal fluid, the diffusion rate of gas molecules between bubbles may beexpected to be slowed significantly.

2

Effects of Additives on Surfactant Foaming Properties

The foaming properties of a surfactant can be related to its solution properties throughthe cmc. It is not surprising, then, that additives in a formulation can affect foamingproperties in much the same way that they affect other surfactant solution properties.The presence of additives may, for example, increase the viscosity of the liquid phase orthe interfacial layer or it may alter the interfacial interactions related to GibbsMarangonieffects or electrostatic repulsions. By the proper choice of additive, a high foamingsurfactant can be transformed into one exhibiting little or no foam formation. Conversely,

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a low foaming material may produce large amounts of foam in the presence of smallamounts of another surface active material, which itself has few if any useful surfactantproperties. It is theoretically possible, then, to custom build a formulation to achieve theoptimum combination of foaming action to suit the individual needs of the system. Theaddition of small amounts of such additives has become the primary way of adjusting thefoaming characteristics of a formulation in many, if not most, practical surfactantapplications.

Additives that alter the foaming properties of a surfactant can be divided into three mainclasses: (1) inorganic electrolytes, which are most effective with ionic surfactants; (2)polar organic additives, which can affect all types of surfactants; and (3) macromolecularmaterials. The latter materials can affect the foaming properties of a system in manyways, some unrelated to the surface properties of the surfactant itself. Electrolyteadditives can act to increase foamability by reducing the cmc of ionic foaming agents. Onthe other hand, an excessive amount of electrolyte may, and probably will, greatly reducefoam persistence by reducing the electrostatically induced disjoining pressure.

From a practical point of view, the most important additives are the polar organicmaterials. They have received a great deal of attention because of the relative ease ofapplication and control of the additive. The ability of additives to increase foamability andfoam stability by lowering the cmc of the primary surfactant can be related to the extentof such lowering. Straight-chain hydrocarbon additives whose chain length isapproximately the same as that of the surfactant are generally the most effective atlowering the cmc and increasing initial foam height. Bulky chains on the additives producemuch smaller effects. The effectiveness of polar additives of various types as foamstabilizers is found to be in the following approximate order: primary alcohols < glycerylethers < sulfonyl ethers < amides < N-substituted amides. This is essentially the sameorder found for the effects of such materials on the cmc of surfactants.

3Polymers and Foam Stabilization

Very stable foams can be prepared if surface active polymers such as albumins,carboxymethyl cellulose, and many vegetable gums are included in the formulation.When polymers (and proteins in particular) are adsorbed at the liquidair interface, theywill assume configurations significantly different from those in the bulk solution; in thecase of proteins, they will become partially denatured. The relatively dense, structured,adsorbed polymer layer will impart a significant degree of rigidity or mechanical strengthto the lamellar walls, producing an increase in the stability of the final foam. Thepresence of polymer will also aid stability in the initial stages after foam formation sincethe liquid viscosity increase that results from its presence will slow the process of filmdrainage. Polymers will not generally be effective in the context of the GibbsMarangonieffect since their diffusion rates will be much slower than those of low molecular weightsurfactants.

The presence of polymers in foaming systems can cause particularly difficult problemswhere foam stability is not desirable. Proteins in particular will chelate strongly withpolyvalent ions and may form surface films so rigid that they approach the strength ofsolid foams. Obviously, such a situation will be detrimental to some processes. In thefood industry, fire fighting, and many areas of cosmetics, the formation of rigid foamwalls can be particularly advantageous.

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EFoam Inhibition

Although the presence of certain additives can enhance the foaming ability andpersistence of a surfactant system, other materials can significantly reduce foamformation or stability. Such materials may be termed foam inhibitors, which act toprevent the formation of foam, or foam breakers, which increase the rate of foamcollapse. Foam breakers may include inorganic ions, which counteract the effects ofelectrostatic stabilization or reduce the solubility of many ionic surfactants and organic orsilicone materials that act by spreading on the interface and displacing the stabilizingsurfactant species.

A foam breaker that acts by spreading may do so as a monolayer or as a lens (Fig. 6). Ineither case, it is assumed that the spreading foam breaker sweeps away the stabilizinglayer, leading to rapid bubble collapse. The rate of spreading of the defoamer will, ofcourse, depend on the nature of the initially present adsorbed layer. If the foaming agentcan be desorbed rapidly, the defoamer will spread rapidly resulting in fast foam collapse.If the foamer does not desorb rapidly, spreading will be retarded, or even halted. Foamcollapse will then be a much slower process relying on the thinning of the lamellae byother drainage mechanisms.

In some cases it is found that the mode of action of defoaming agents may depend onthe concentration of the surfactant present. If the surfactant concentration is below thecmc, the defoamer will usually be most effective if it spreads as a lens on the surfacerather than as a monolayer film. Above the cmc, however, where the defoamer may besolubilized, the micelles may act as a reservoir for extended defoaming action byadsorption as a surface monolayer. If the solubilization limit is exceeded, the initialdefoaming effect may be due to the lens spreading mechanism with residual actionderiving from solubilized material.

Materials that are effective as defoaming agents can be divided into several generalchemical classifications, with the best choice of material depending on such factors ascost, the nature of the liquid phase, the nature of the foaming agent present, and thenature of the environment to which it may be subjected. One of the most commonclasses of antifoaming agents consists of the polar organic materials such as highlybranched aliphatic alcohols. Linear alcohols in conjunction with surfactants can result inincreased foam production and stability due to mixed monolayer formation and enhancedfilm strength. The branched materials, on the other hand, reduce the lateral cohesivestrength of the interfacial film, which increases the rate of bubble collapse. The higheralcohols also have limited water solubility and are strongly adsorbed at the airwaterinterface, displacing surfactant molecules and reducing or eliminating some of theimportant stabilizing mechanisms mentioned above.

Fatty acids and esters with limited water solubility are also often used as foam inhibitors.

Their mode of action is similar to that of the analogous alcohols. In addition, theirgenerally low toxicity often makes them attractive for use in food applications. Organiccompounds with multiple polar groups are, as a rule, found to be effective foaminhibitors. The presence of several polar groups generally acts to increase the surfacearea per molecule of the adsorbed antifoamer and results in a loss of stabilization.

Metallic soaps of carboxylic acids, especially the water insoluble polyvalent salts such ascalcium, magnesium, and aluminum can be effective as defoamers in both aqueous andnonaqueous systems. In water, they are usually employed as solutions in an organicsolvent, or as a fine dispersion in the aqueous phase.

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Alkyl phosphate esters are found to possess good antifoaming characteristics in manysystems due to their low water solubility and large spreading coefficient. They also findwide application in nonaqueous systems such as inks and adhesives. Organic siliconecompounds are also usually found to be outstanding antifoaming agents in both aqueousand organic systems. Because of their inherently low surface energy and limited solubilityin many organics, the silicone materials constitute one of the two most effective classesof materials that are available to modify the surface properties of most organic liquids.

The final class of materials that has found some application as antifoaming agents arethe fluorinated alcohols and acids. Due to their very low surface energies they are activein liquids where hydrocarbon materials have no effect. They are, in general, expensive,but their activity at very low levels and in very harsh environments may overcome theirinitial cost barrier.

VIA Final Comment

The subject of surfactant physical properties and their relation to the performance of agiven material in a specific application is one that can (and does) fill volumes. Asindicated in the above comments, small changes in the molecular structure of asurfactant or in the chemical and physical environment in which it is expected to functioncan produce significant alterations in its overall effectiveness. Since cosmeticsformulations in particular are constantly being modified and reevaluated due to economic,competitive, or regulatory pressures, the formulating professional should always be alertto the possibility of alterations in surfactant function that may result from subtle changesin the overall system.

References

1. J. K. Weil, F. S. Smith, A. J. Stirton, and R. G. Bristline, Jr., J. Amer. Oil Chem. Soc.40:538 (1963).

2. F. D. Smith, A. J. Stirton, and M. V. Niñez-Ponzoa, J. Amer. Oil Chem. Soc. 43:501(1966).

3. J. K. Weil, A. J. Stirton, R. G. Bristline, Jr., and E. Q. MmMaurer, J. Amer. Oil Chem. Soc.36:241 (1959).

4. M. J. Rosen, Surfactants and Interfacial Phenomena, Wiley-Interscience, New York,1989.

5. K. Shinoda, T. Nakagawa, B. Tamamushi, and T. Isemura, Colloidal Surfactants: SomePhysicochemical Properties, Academic Press, New York, 1963.

6. D. Y. Myers, Surfactant Science and Technology, 2nd ed., VCH Publishers, New York,1992.

7. H. B. Klevens, J. Amer. Oil Chem. Soc. 30:74 (1953).

8. M. L. Corrin and W. D. Harkins, J. Am. Chem. Soc. 69:684 (1947).

9. J. N. Israelachvili, Intermolecular and Surface Forces with Application to Colloidal andBiological Systems, Academic Press, New York, 1985.

10. R. G. Laughlin, in Surfactants (Th. F. Tadros, ed.), Academic Press, London, 1984, pp.5381.

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11. J. A. Fendler, Membrane Mimetic Chemistry, Wiley-Interscience, New York, 1975, pp.99148.

12. C. Tanford, The Hydrophobic Effect, 2nd ed., Wiley-Interscience, New York, 1980.

13. J. D. Mitchell and B. W. Ninham, J. Chem. Soc. Faraday Trans. 2 77:601 (1981).

14. Microdomains in Polymer Solutions (P. Dubin, ed.), Plenum Press, New York, 1985,pp. 357415.

15. I. D. Robb, in Anionic Surfactants: Physical Chemistry of Surfactant Action (E. H.Lucassen-Reynders, ed.), Marcel Dekker, New York, 1981, pp. 109142.

16. J. Steinhart and J. A. Reynolds, Multiple Equilibria in Proteins, Academic Press, NewYork, 1969.

17. J. Greener, B. A. Contestable, and M. D. Bales, Macromolecules 20:2490 (1987).

18. M. M. Breuer and V. P. Strauss, J. Phys. Chem. 64:22 (1960).

19. S. Saito, Kolloid-Z. 154:49 (1957).

20. M. J. Schuger and H. Lange, Proc. 5th Int. Cong. Surf. Activ. 2:955 (1968).

21. S. Saito, J. Colloid Interface Sci. 15:283 (1960).

22. J. W. Gibbs, The Collected Works of J. W. Gibbs, vol. 1, Longmans Green, New York,1931.

23. R. Aveyard and D. A. Haydon, An Introduction to the Principles of Surface Chemistry,Cambridge University Press, Cambridge, 1973.

24. C. H. Giles, T. H. MacEwen, S. N. Nakhwa, and D. Smith, J. Chem. Soc. 3973 (1960).

25. A. W. Adamson, Physical Chemistry of Surfaces, 5th ed., Wiley-Interscience, NewYork, 1990.

26. R. D. Vold and M. J. Vold, Colloid and Interface Chemistry, Addison-Wesley, Reading,MA,1983.

27. T. Young, Phil. Trans. R. Soc. (London) 95:65 (1805).

28. W. A. Zisman, in Adhesion and Cohesion (P. Weiss, ed.), Elsevier, Amsterdam, 1962,p. 176ff.

29. P. S. LaPlace, Mecanique Celeste, Supplement to Book 10, 1806.

30. S. Berkman and G. Egloff, Emulsions and Foams, Reinhold, New York, 1961.

31. J. J. Bikerman, Foams, Springer-Verlag, New York, 1973.

32. S. Friberg, L. Mandell, and M. Larsson, J. Colloid Interface Sci. 29:155 (1969).33. S. Friberg and L. Mandell, J. Pharm. Sci. 59:1001 (1970).

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3The Analysis of Surfactants in CosmeticsJane M. EldridgeAnalytical Services, Rhône-Poulenc, Inc., Cranbury, New Jersey

I. Introduction 84

II. Anionics 84

A. Sulfates and Sulfonates 85

B. Phosphate Esters 86

C. General Tests 86

D. Isethionate Esters 87

III. Nonionics 87

A. Ethoxylated Alcohols and Phenols 88

B. Ethoxylated Fatty Acids 90

C. Alkanolamides 91

IV. Cationics 91

A. Amine Oxides 91

B. Quaternary Ammonium Compounds 91

V. Amphoterics 92

A. Active 93

B. Water 93

C. Salt 94

D. Amines 94

E. Acids 94

VI. Preservatives 94

A. General 94

B. Formaldehyde and Formaldehyde Releasers 95

C. Parabens 95

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D. Triclosan 95

E. Miscellaneous 96

VII. Impurities 96

A. Ethylene Oxide and Acetaldehyde 96

B. Dioxane 97

C. Nitrosamines 98

D. Sultones 98

VIII. Analysis of Formulated Products 98

A. General Separation Schemes 98

B. Preliminary Screening 99

C. Separation and Quantitation 100

D. Alkoxylate Ratios 101

Abbreviations 101

References 101

IIntroduction

The purpose of this chapter is to acquaint the cosmetic chemist with the methods used toanalyze surfactants. The exact conditions for carrying out the procedures are not givenhere but rather a general description that will allow the chemist to select the appropriateanalysis and obtain the specific conditions from the literature.

Since surfactants are raw materials in many cosmetic products the chemist should beaware of the quality control tests that are used to ensure that the product is consistentfrom lot to lot. These tests confirm the nature of the surfactant itself, the character andquantity of the impurities from the manufacture, and the amount of any preservative thatmay have been added to ensure the absence of microbial contamination. The first sectionof this chapter is concerned with the quality control tests that are used. It will describethe traditional methods and the newer techniques that are being used to reduce the timefor the analyses and to better characterize the surfactant. This section is organized bysurfactant type for those analyses that are specific for a particular type of surfactant andby analyte for the impurities and preservatives that may be found in various types ofsurfactants. Cosmetic chemists may also want to identify and quantitate a surfactant

present in a formulated product. The second section of this chapter will deal with theseparation of surfactants from mixtures and the identification and quantitation of thesesurfactants.

Several useful texts are available that describe in detail the traditional methods used inthe analysis of surfactants [110]. These references include those most useful for theseparation and identification of unknown surfactants [4,9,10].

IIAnionics

Anionic surfactants are those which owe their water solubility to the negative charge onthe molecule and their lipid compatibility to a long hydrocarbon chain.

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ASulfates and Sulfonates

A large number of anionic surfactants are either sulfates or sulfonates of fatty alcohols orethoxylated fatty alcohols. The quality control tests for these two groups havetraditionally been very similar.

Active. The concentration of the anionic in the water solution is determined by a two-phase titration using a cationic surfactant (usually Hyamine 1622) as the titrant andvarious indicators (usually methylene blue) to determine when the endpoint is reached.Longman [3] explains how this titration works and how to select the best titrant andindicator. He also gives the specific details for carrying out the assay. The ASTMprocedure [11] provides the specific details for carrying out this analysis. Although thistwo-phase technique has been relatively successful and gives good, reproducible resultswhen carried out by an experienced operator, it is subject to interferences. It requires asubjective decision by the operator and it requires a significant amount of operator time.

In order to resolve some of these problems several electrode methods have beendeveloped for the determination of anionic active. The American Society for Testing andMaterials (ASTM) method D 4251 [11] outlines a method for determining the active bytitrating an aqueous solution of the surfactant with Hyamine 1622 using a nitrate-ion-selective electrode. Orion has developed a surfactant electrode that determines theendpoint when an anionic surfactant is titrated with benzethonium chloride (Hyamine1622). Oei et al. [12] have compared the standard two-phase titration using visualjudgement of the endpoint with the use of the electrode to determine the endpoint. Theirwork showed that the electrode gave a lower relative standard deviation and a slightlyhigher concentration of anionic than the standard two-phase titration.

Other Components

Chlorides, sulfates, and moisture are also commonly determined in the quality control ofsulfates and sulfonates. Chlorides and sulfates are usually determined by potentiometrictitration as described by Schmitt [1]. Chlorides and sulfate may also be determined bymanual titration if a potentiometric titrator is not available. Moisture is usuallydetermined either by Karl Fisher titration (either manually or potentiometrically) or ovendrying at 105°C for two hours or to constant weight. Schmitt [1] describes the Karl Fishertechnique using hydranal (pyridine free titration reagent) as the titrant.

Characterization

The HPLC technique is being used to better characterize commercially produced sulfatesand sulfonates. Several research groups have developed methods for determining thealkyl chain length distribution in alkyl sulfates and sulfonates and for separating thesulfate peaks from the sulfonate peaks. The methods discussed here show several waysto detect the non-UV-absorbing alkyl sulfates and sulfonates. One method [13] uses iron

1,10-phenanthroline salts as a mobile-phase additive for the separation on areversed-phase PRP-1 column with a photometric detector at 510 nm. Another method[14] for separating alkyl sulfates and sulfonates based on alkyl chain length uses areversed-phase PRP-1 column and an acetonitrile/water mobile phase modified withLiOH. A conductivity detector is used to detect the analytes.

Larson [15] has developed an interesting technique for the characterization of alkylsulfates by alkyl chain length. Using indirect photometric chromatography he adds a UV-absorbing counter ion to the mobile phase and employs a UV-detector. The peaks ofinterest appear as negative peaks in an elevated baseline as they are displaced from thecolumn.

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Kunitani and Kresin [16] use an ion chromatographic system with a conductivity detectorto achieve separation of alkyl chain lengths ranging from C-8 to C-20. The separation isperformed on a hydrophobic resin-based column utilizing tetrabutyl ammonium hydroxideas an ion-pair reagent and acetonitrile as an organic modifier.

Another method [17] that depends on a conductivity detector uses a porous resin columnwith ammonium and tetra-alkyl ammonium salts as the ion-pairing reagents to separatethe alkyl sulfates and sulfonates by chain length and from each other.

A method [18] has also been developed that can be used to determine whether the alkylgroup in an alkyl benzene sulfonate is branched or linear. The method uses a reversed-phase column and a water/methanol mobile phase that is buffered with sodium acetate.

Castles et al. [19] describe a method for determining the concentration of linearalkylbenzesulfonates using a reversed-phase column and a THF/water mobile phasemodified with sodium perchlorate. In this system the benzene sulfonate chromatographsas a single peak. Although they developed this method to determine the concentration ofalkylbenzenesulfonates in environmental samples it could be modified to determine thebenzene sulfonate in other mixtures and perhaps used in place of active titrations.

One of the newest techniques for the characterization of sulfates and sulfonates iscapillary electrophoresis. Chen and Pietrzyk [20] have developed a separation scheme forsulfate and sulfonate surfactants using capillary electrophoresis. They separate sulfatesfrom sulfonates and then separate each on the basis of alkyl chain length. They use a UVdetector to detect both aromatic and nonaromatic surfactants. The aromatic surfactantsare detected by direct UV at 220 nm and the nonaromatic are detected by indirect UV at230 nm, using salicylate anion as a chromophoric buffer additive. Desbene et al. [21]have developed a system for the characterization of alkyl aromatic sulfonates using high-performance capillary electrophoresis. Using acetonitrile as the organic modifier, theyachieve baseline separation for alkyl chain lengths between C-2 and C-12.

BPhosphate Esters

Phosphate esters are also anionic surfactants but require somewhat different qualitycontrol tests from those used for S-containing esters.

Ester Ratio. For the phosphate esters, the ratio of monoester to diester is important aswell as the concentration of residual phosphoric acid. Schmitt [1] describes how to do thistitration and how to carry out the calculations. This titration is only useful if the materialwas not neutralized as a part of the manufacturing process and if there is no residualpyrophosphate in the surfactant solution. An HPLC method has been developed [22]which separates the monoester and diester on a reversed-phase column. The esters arefirst derivatized to produce UV-absorbing species and are then chromatographed using aUV detector for detection. This method requires extracting the surfactant into diethyl

ether before derivatization.

CGeneral Tests

Starting Alcohol

The concentration of unreacted starting alcohol must be determined in phosphates,sulfates, and sulfonates. These nonionics (often called free fats) have traditionally beenquantitated gravimetrically. The ASTM procedures [11] D1570 (alkyl sulfates), D1568(alkyl aryl sulfonates), and D3673 (2-olefinsulfonates) describe

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the extraction procedures. The extraction and quantitation of the unreacted alcohol inphosphate esters is described by Schmitt [1]. When the starting alcohol is ethoxylated,the extraction procedure may not extract all of the nonionic since this alcohol is morewater soluble. It may thus be more appropriate to use an ion-exchange technique inwhich all of the ionic materials are removed by an ion-exchange column while thenonionics that are eluted from the column are determined gravimetrically. Longmandescribes such a procedure [3]. It is possible to develop modifications of this procedureusing mixed-bed resins and simply stirring an aliquot of the resin in a solution of thesurfactant.

If a new procedure using ion exchange techniques is being developed for thedetermination of nonionics it is necessary to be sure there is no anionic in the residue.This may be confirmed with the aid of an IR spectrum of the residue or by doing astandard anionic titration of the residue. All of these techniques calculate everything thatis nonionic or which extracts into the nonpolar solvent as unreacted alcohol.

The HPLC technique is used to obtain more reliable assays of the unreacted alcohol andto reduce the time required for the determination. When HPLC is used for thequantitation, the alcohol standard must be the exact alcohol (same carbon andethoxylate distribution) as that used in the synthesis of the anionic.

Yoshimura et al. [23] have developed a procedure using a back-flush technique forchromatographing an alcohol ethoxylate in which the alcohol chromatographs as a singlepeak regardless of carbon chain or ethoxylate distribution. It would seem reasonable touse this technique to determine unreacted starting alcohol.

It should be noted that the concentration of alcohol determined by HPLC will probably notequal the concentration determined gravimetrically since the gravimetric analysis willinclude materials that are not starting alcohol.

Characterization

The determination of alkyl chain-length distribution is an important part of thecharacterization of sulfates, sulfonates, and phosphates. Usually this is done by thehydrolysis of the product and gas or liquid chromatography of the hydrolyzed product. It ispossible to simply chromatograph the extracted unreacted alcohol but this may not give atrue distribution since all the chain lengths may not have reacted at the same rate.Schmitt [1] provides the conditions for the hydrolysis and desulfonation of sulfonates andthe chromatographic conditions for these products.

DIsethionate Esters

Another group of anionic surfactants are the isethionate esters. In general, testing is verysimilar to that of other sulfonates. It is important to determine the concentration of

sodium isethionate, which is usually performed by HPLC using an anion column and aconductivity detector [24].

IIINonionics

Nonionic surfactants have no charge on the molecule but owe their hydrophilic characterto a polar group in the molecule, while their hydrophobic properties result from thepresence of a long chain hydrocarbon. Only a few major groups of nonionics are discussedbelow. Ethoxylated fatty alcohols and phenols form one of the major classes of nonionicsurfactants. Two other classes of nonionics are the ethoxylated fatty acids and thealkanol amides.

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AEthoxylated Alcohols and Phenols

Determination of Average EO Chain Length

Traditionally the tests for assessing the level of ethoxylation in nonionics determined onlyan average value for the number of moles of added ethylene oxide. The easiest test forthis determination is the cloud point. Longman [3] describes this technique and tells howto run the test. Cloud point is a valuable test for quickly determining the approximatenumber of ethylene oxide units in the molecule. Another somewhat more accuratemethod for determining ethylene oxide content of the molecule is hydroxyl number. Themolecular weight of the starting alcohol must be known in order to determine the degreeof ethoxylation by hydroxyl number. Cross [25] describes the procedures that are used todetermine hydroxyl numbers and thus the average number of moles of ethylene oxidethat have been added.

Spectroscopy has also been used to determine the average EO chain length inethoxylated alcohols and phenols. Meszlenyi et al. [26] described an IR technique fordetermining the average ethylene oxide chain length in nonyl phenol ethoxylates bycalculation using the ration of the absorbance at 1350 and 1610 cm-1. Nuclear MagneticResonance has been used to characterize the hydrophobic group and to determine theaverage number of moles in the ethoxylate chain. Cross and Mackay [27] have describeda method that allows determination of the average chain length of the alkyl group as wellas the degree of polymerization of the ethylene oxide chain by forming the trimethylsilylderivative of the ethoxylate before carrying out the proton NMR analysis.

These techniques are useful for providing information about the average molecularweight of the surfactant, but some recently introduced techniques provide informationabout both the ethoxylate distribution and the alkyl chain length distribution.

Chain length distribution. The distribution of the carbon chain lengths in the alkylethoxylates has usually been established by gas chromatography. If the alcohol has beenethoxylated, some cleavage is required before chromatography to determine the carbonchain-length distribution. Cross [25] gives a summary of these techniques and theconditions for carrying them out.

Recently it has become more important to know both the carbon chain-length distributionand the ethoxylate distribution for the quality control of ethoxylated surfactants and formatching formulated products. Gas, liquid, and supercritical fluid chromatography have allbeen used to better define these distributions.

High performance liquid chromatography has been used to identify and quantitate thecomponents of alcohol ethoxylates. In general normal-phase chromatography has beenused to determine the ethylene oxide distribution and reversed-phase chromatographyhas been used to determine the hydrophobe distribution. Kudoh [28] has developed a

method that can separate alcohol ethoxylates according to their alkyl chain lengths. Usinga C-18 column with an acetone/water mobile phase he separates the ethoxylates by alkylchain length and not by ethylene oxide distribution. He uses refractive index to detect thepeaks. A method for characterizing fatty alcohol (C16C18) ethoxylates (up to 30 moles ofEO) by ethoxylate chain length has been developed by Desmazieres et al. [29] They usea cation exchange column with an acetonitrile/water (98:2) mobile phase to which theyadd sodium acetate. They find that elevated temperatures improve the separation. Sincethere is no mobile phase gradient, it is possible to use a refractive index detector. Okada[30] describes an HPLC method for separating both the hydrophobic and ethoxylatedoligomers. He uses a cation exchange resin in the alkali metal form to

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separate the ethylene oxide units and a reversed-phase system for the hydrophobicseparations. He emphasizes the need for temperature control and sometimes the use oftemperatures above ambient. Trathnigg and his coworkers [31] have developed atechnique using two-dimensional chromatography to determine both the carbon chain-length distribution of the alkyl group and the ethoxylate distribution in fatty alcoholethoxylates. Liquid Chromatography under critical conditions is used as the firstdimension and size-exclusion chromatography as the second.

The ethoxylate distribution is also important in the phenol ethoxylates. Wang and Fingas[32] have developed a method for separating the oligomers of octyl phenol ethoxylatesby ethylene oxide adduct up to 40 moles of ethylene oxide using a reversed-phasesystem (Supelcosil LC-1 column and a water/methanol mobile phase). A UV detector isused, and quantitation is carried out using molar response factors.

Supercritical Fluid Chromatography is being used to determine the ethoxylate distributionin alcohol ethoxylates. Geissler [33] has developed a method for both carrying out theseparation of the ethoxylate (by EO unit) and calculating the mole percent of eacholigomer. His method separates branched- from straight-chain alcohol ethoxylates butthere is some overlap when the straight-chain alcohol is based on a mixture of carbonchain lengths. He has developed a calculation scheme that allows the determination ofthe individual components even without complete separation. Pinkston et al. [34] use SFCwith an FID to separate both the ethoxylate and carbon chain oligomers. When thechromatogram becomes too complicated to permit simple interpretation, they use massspectrometry to identify the peaks. Another group (Kalinoski and Hargiss [35]) also usescapillary SFC to characterize alcohol ethoxylates and mass spectrometry to identify thepeaks. The paper describes the specialized conditions necessary to obtain usable massspectra.

Several researchers have compared HPLC and SFC in the analysis of alcohol ethoxylates.The evaporative light scattering detector (ELSD) has increased the possibilities fordeveloping methods to determine the ethoxylate distribution of an alcohol ethoxylateusing both HPLC and SFC. Since the ELSD allows the detection of non-UV absorbingspecies and since its performance is not affected by changes in the mobile phase, itallows much more versatility in the method development. Lafosse et al. [36] developedschemes carrying out the separation of ethylene oxide oligomers by both HPLC and SFCusing the ELSD. Using the ELSD as the detector, Brossard et al. [37] compare HPLC andSFC in the analysis of ethoxylated fatty alcohols. They show that they can carry outseparations for higher molecular weight ethoxylates using SFC rather than HPLC.

Methods have also been developed for separating the ethylene oxide oligomers of thephenol ethoxylates using SFC and HPLC. Wang and Fingas [38] have developed aprocedure using SFC for separating the ethylene oxide oligomers of octylphenol from 0 to25 ethylene oxide units. They identify the individual adducts by comparison to the peakfor octylphenol and octylphenol plus one EO. The area percent method was used to

calculate the oligomer distribution. The paper outlines the detailed conditions used forthe analysis and shows the effect of varying the SFC conditions. The same group has alsodeveloped a simple, rapid, and reproducible capillary SFC method for the separation andidentification of the ethoxylate distribution in nonylphenol ethoxylates [39]. Theycompared the separation achieved by SFC to that achieved by HPLC and find the SFCseparation is better and the analysis time is shorter.

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Desbene and Desmazieres [40] developed an HPLC procedure that provides a satisfactoryseparation of the ethoxylate oligomers for both alkyl alcohol ethoxylates and phenolethoxylates. They have achieved a baseline resolution of 1 to 80 EO units using a p-nitrophenyl-bonded silica with an n-propyl spacer and an n-heptane-dichloromethane-methanol mobile phase at 45°C. They used either a UV detector (derivatizing wherenecessary) or a lightscattering detector. They found the separation was satisfactory whenthey derivatized before chromatography.

Some work has also been done to compare SFC to high-temperature gas chromatography(GC) in the analysis of alcohol ethoxylates. Silver and Kalinoski [41] show the advantagesand limitations of both techniques for the quantitative characterization of alcoholethoxylates. Sandra and David [42] have also compared the two techniques for theanalysis of nonionics. They conclude that the two techniques are complementary and themain advantage of SFC is the lower temperature required for analysis, which permits theanalysis of thermally labile compounds. Chromatographic conditions are shown for bothSFC and high temperature GC.

Carbon NMR has been used to characterize alcohol ethoxylates. Kalinoski and Jensen [43]developed a method for determining the distribution of alcohol ethoxylates and comparedthe information so obtained to that obtained from SFC.

Impurities

When alcohols and phenols are ethoxylated there is always some polyethylene glycol(PEG) formed. The concentration of PEG in the ethoxylate is critical to some applications;so testing for PEG is part of the quality control of the product. The most widely usedmethod for determining PEG is an extraction procedure in which the PEG is extracted fromthe surfactant and its concentration determined gravimetrically. In an HPLC technique areversed-phase column and a methanol/water mobile phase are used. This HPLC methodis not totally reliable since the PEG is eluted from the column almost in a void volume andthus is subject to interferences. Both these procedures are described in detail by Schmitt[1].

Several researchers have used the evaporative light scattering detector as the detector intheir work to separate the PEG from the ethoxylate and to determine the distribution ofthe PEG. Brossard et al. [37] showed that they could elute higher molecular weight PEGbetter by SFC than by HPLC. They were also able to resolve the distribution of the PEG,but the PEG and ethoxylated alcohol distribution overlapped. Lafosse et al. [36] have alsodeveloped some schemes for separating PEG from the surfactant using HPLC and SFC.Neither of these methods is being used routinely for PEG determinations at this time.

BEthoxylated Fatty Acids

Another group of nonionic surfactants is the ethoxylated fatty acids that are really esters

of fatty acids and polyethylene glycol. In addition to the monoester these products mayalso contain some diester, some free acid, and some PEG. These esters can be analyzedby gas chromatography for low-molecular-weight ethoxylates. The ratio of monoester todiester can be calculated from hydroxyl number and ester-number determinationsperformed on the product after the removal of the PEG [1].

Ethoxylated fatty acids may also be analyzed by HPLC. Aserin et al. [44] developed amethod for characterizing the monoester by separating the EO adducts up to 20 EO

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units. They used normal-phase chromatography with gradient elution(isopropanol/methanol/hexane mobile phase) and a UV detector at 220 nm.

Kudoh et al. [45] developed an HPLC technique to separate and quantitate thepolyethylene glycols, the monoester and the diester. They used a preparative scheme toseparate and then quantitate gravimetrically; their system employed a reversed-phasecolumn with acetone/water as the mobile phase.

CAlkanolamides

Alkanolamides and ethoxylated alkanolamides comprise another group of nonionics thatare widely used in cosmetic products. Several researchers have developed HPLCtechniques to analyze for alkanolamides. Cross [25] described several methods fordetermining the concentration of alkanolamides. Ben-Bassat and Wasserman [46]developed a reversed-phase HPLC procedure that can be used to quantitatealkanolamides. They used a reversed-phase column, a ternary mobile phase(tetrahydrofuran/acetonitrile/water) and a refractive index detector. This method alsoseparated the fatty acids and could be used to quantitate unreacted fatty acid in theamide.

It is often necessary to know the concentration of ester in alkanol amides. This is mostoften determined by the Cosmetics, Toiletry and Fragrance Association (CTFA) method,which uses IR spectroscopy [6]. Residual amine and fatty acid may be determined bytitration or chromatography as described by Schmitt [1].

IVCationics

Cationic surfactants are those that owe their water solubility to a positively chargednitrogen and any fat-like properties to a hydrophobic long-chain group that usuallyconsists of a mixture of homologs. The major classes of these cationics are quaternaryammonium compounds and amine oxides. Amine oxides are sometimes classified asnonionics or amphoterics since their character changes with pH.

AAmine Oxides

Amine oxides are widely used in cosmetic applications. Since they are made by theoxidation of tertiary amines and since the tertiary amine is usually insoluble in water it isimportant to determine the concentration of the tertiary amine and that of the amineoxide. Wang and Metcalfe [47] developed a nonaqueous titration technique that permitsthe determination of both the amine and the amine oxide. The potentiometric titrationshows two breaks that allow the calculation of both. Schmitt [1] also outlines severaltitration techniques for determining both the tertiary amine and the amine oxide in the

same solution. Recently, some methods have been developed for determining the tertiaryamine using HPLC. Both Schmitt [1] and Metcalfe [48] outline systems that may be used.

BQuaternary Ammonium Compounds

Quaternary ammonium compounds (quats) made from long-chain fatty acids are the mostwidely used cationic surfactants. The most common method for the determination of theconcentration of the quaternary compounds is a two-phase titration in which the cationicsurfactant is titrated with an anionic surfactant. Both Metcalfe [48] and Schmitt [1]

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describe the procedure and give the exact conditions. Metcalfe [48] also describes severaldirect single-phase titration methods.

The surfactant electrode developed by Orion is currently being used to determine theendpoint in the titration of cationics with anionics. As noted above Oei et al. [12] describethe use of this electrode as well as one that they developed in house. They describe howthe titration is performed and compare the results obtained by the electrode titration withthose obtained from the standard two-phase titration. They show that the electrodemethod has many advantages over the standard titration: it gives better precision, it isless time consuming, there is no organic waste, and the presence of nonionic substancesdoes not interfere. It does not always give the same concentration as that found from thestandard two-phase titration so it can not be substituted for that titration in the qualitycontrol lab without prior validation and perhaps adjustment of the specification range.

Liquid chromatographic methods are being developed for the analysis of the quaternaryammonium compounds as well as amines that may be present. Metcalfe [48] referencesprocedures that will separate the quats by class or by chain length. He also describes amethod that is being used routinely to separate the desired quat from the impurities inthe reaction mix. Schmitt [1] gives the conditions and references for a number of HPLCsystems that have been developed for chromatographing cationic surfactants. Wilkes etal. [49] have developed a normal phase HPLC method for the separation of quaternaryammonium surfactants that uses a silica gel column with gradient elution and anevaporative light scattering detector. They use trifluoroacetic acid as an ion-pairingreagent in the nonpolar mobile phase to improve peak shape and to avoid columncontamination with amines that are often present in the quaternary ammonium salts. Themethod is useful for the characterization of the surfactant as well as the quantitation ofthe surfactant in a formulated product. The procedure separates compounds on the basisof the number of alkyl groups on the nitrogen. When there is only one alkyl group it alsoseparates on the basis of chain length; when there is more than one alkyl group onlysome separation by chain length occurs and the system needs to be refined to separatethese components completely.

It may be necessary to both quantitate the amine in the surfactant and to determine thealkyl chain length of the amine and some ion chromatographic procedures have beendeveloped to carry out these determinations. Vialle et al. [50] have designed a methodusing alkali metal ions as eluting ions and an organic solvent in the aqueous mobilephase to improve the efficiency for long chain amines. They find the system is veryefficient for separating amino compounds but the sensitivity of the detection of theamines may not be great enough for quantitating low levels of amines. Other detectionmodes will be necessary to improve the detection for low levels. Krol et al. [51] have alsoused ion chromatography and conductivity detection for the analysis of alkyl and alkanolamines. Their method allows the detection of low ppm levels of the amines by using anindirect conductivity detection system.

VAmphoterics

Amphoteric surfactants contain at least two oppositely charged ionizable sites. These areusually provided by a ternary amine group (cationic) and a carboxylate or sulfonate group(anionic).

For analysis purposes the amphoterics may be divided into three groups [1]. First is

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the amino acid type, which is usually made by the addition reaction of a fatty amine withan unsaturated methyl ester followed by hydrolysis of the ester. The general structure is

where R is a long chain alkyl group.

Another group of amphoterics are the betaines, which are usually prepared byquaternization of a tertiary amine with chloroacetic acid. The surfactant betaines arecompounds in which one of the methyl groups in betaine (trimethyl glycine) has beenreplaced by a fatty chain. The general structure is

where R is long chain alkyl group.

The third group of amphoterics is imidazoline derived, and they contain an amido groupin their structure. These products are mixtures of the general structure

and

AActive

The methods used for the routine analysis of amphoterics are not well defined at thistime, but new techniques are being developed for improved assays of the product and itsimpurities. The required analyses performed on any amphoteric depend on the processused for the production. There are currently no direct methods used routinely todetermine the active ingredient in the amphoteric surfactant. In the customary indirectassay, water and any known impurities are subtracted from 100%. Schmitt [1] lists someHPLC methods that have been developed for amphoterics, but they are rarely being usedfor quality control of the product. He discusses a method developed by Koenig andStrobel [52] that seems to have some potential as the basis of a quantitative test. Oei etal. [12] describe the use of the Orion surfactant electrode to determine the concentrationof betaines. Capillary electrophoresis is another technique that would seem perfectlysuited to the analysis of amphoteric surfacts that are very similar to amino acids instructure. Chadwick et al. [53] developed a procedure that uses capillary zoneelectrophoresis to separate and quantitate sodium cocoamphocarboxyacetate in less than12 minutes.

BWater

The determination of water is a critical part of the analysis of amphoterics. It is mostcommonly done by an oven technique (convection, microwave, moisture balance). Sinceamphoterics decompose easily, it is critically important to remove the water using thegentlest conditions possible. Karl Fisher analysis is difficult since the concentration ofwater is so high.

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CSalt

The concentration of sodium chloride must be determined in all types of amphoterics.This is usually done by direct potentiometric titration as described by Longman [3].

DAmines

All amphoterics contain some level of amines or amido amines. One method ofdetermining the amine is extraction from a basic solution into a nonpolar solvent andtitration to quantitate. The concentration of a specific amine may also be determined bychromatographic techniques. Amines may be determined by gas chromatography using acolumn specifically designed for amine analysis and preferably a nitrogen-specificdetector. Some ion chromatographic procedures have recently been developed for aminequantitation. Although they may need to be modified for the particular amine of interest,the methods should provide a general starting place in the analysis to determine theconcentration of amine in amphoterics. Vialle et al. [50] use alkali metal ions as elutingions and add an organic solvent to the aqueous mobile phase to improve the efficiencyfor long-chain amines. Krol et al. [51] also use ion chromatography for the quantitation ofamines but they use indirect conductivity detection to provide detection limits in the ppmrange.

EAcids

Since monochloroacetic acid is used in the synthesis of amphoterics and it is undesirablein the finished product, the surfactant is often analyzed to determine the concentration ofmonochloroacetic acid and its hydrolysis product, glycolic acid. This is usually done bysome form of liquid chromatography. Very recently Nair et al. [54] developed two ionchromatographic techniques that may be used to determine the concentration ofmonochloroacetic acid. One method is based on an anion-exchange separation withsuppressed electrical conductivity detection, and the second is based on anion-exclusionseparation with UV detection. Another method uses an organic ion column and aconductivity detector to determine the concentration of both chloroacetic and glycolicacids [55].

Acrylic acid or methyl acrylate are also used in the synthesis of some amphoterics, so itmay be necessary to determine the concentration of acrylic acid in the surfactant. This iseasily done by HPLC using a reversed-phase column and an ion-pair reagent in thewater/tetrahydrofuran mobile phase [56].

VIPreservatives

Preservatives are sometimes added to surfactants to ensure they will not supportmicrobial growth. The cosmetic chemist may need to analyze for the presence ofpreservatives either in the surfactant raw material or in the formulated product. In somecases it may be necessary both to identify and quantitate the preservative that ispresent.

AGeneral

Several schemes have been published for the separation, identification, and quantitationof preservatives. Richard et al. [57] used thin layer chromatography to determine whatpreservative may be present. De Kruijf and Schouten [58] developed a very extensiveprogram for the identification and quantitation of many of the more commonly usedpreservatives. Although their methods are designed for determining preservatives in

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cosmetics they may easily be adapted to identify and quantitate the preservatives insurfactants. They use TLC and HPLC for screening and HPLC for quantitation. Both Liem[50] and Wilson [60] have developed TLC schemes for identifying the preservative that ispresent in a surfactant. De Kruijf et al. [61] also developed a method for identifyingpreservatives by the use of HPLC. The chromatographic systems described in thispublication could be used to quantitate as well as identify the preservatives in thesurfactant raw material.

BFormaldehyde and Formaldehyde Releasers

Formaldehyde or formaldehyde-releasing preservatives are widely used in the surfactantindustry. In many cases the analysis to determine the concentration of formaldehyde insurfactants is quite easily carried out using standard wet chemical methods. The best testfor the determination is the Hantzsch reaction method developed by Nash, which is basedon the reaction of formaldehyde with acetyl acetone and an ammonium salt to givediacetyldihydrotoluidine, which absorbs at 412 nm [62]. This same method can be usedto determine the concentration of a formaldehyde-releasing preservative if the solution isfirst treated to release the formaldehyde. Benassi et al. [63] developed a method fordetermining formaldehyde concentration in which the formaldehyde is derivatized with2,4-dinitro phenylhydrazine and HPLC is used to separate and quantitate the hydrazone.The quantitation is carried out by the method of standard additions. Again the methodcould be used for determining the concentration of formaldehyde donors if the solution ispretreated.

Summers [64] has developed a method to separate and quantitate imidazolidinyl urea(Germall 115), DMDM Hydantoin (Glydant), trans-1-(3-chloroallyl)-3,5,7-triaza-1-azoniadamantane chloride (Quaternium 15, Dowicil 75) and formaldehyde using HPLCwith post-column derivatization. This system allows the quantitation of formaldehyde inthe presence of these formaldehyde-releasing preservatives since it separatesformaldehyde from the others. The derivatization uses Nash's reagent and the derivativeproduced absorbs at 410 nm and fluoresces at 510 nm. Semenzato et al. [65] developedan HPLC method for determining the concentration of Quaternium 15 withoutdecomposing it to formaldehyde. They used a Li-CN column, a UV detector at 200 nm anda mobile phase of acetonitrile and phosphate buffer. Another method for determining theconcentration of formaldehyde in the presence of Quaternium 15 was developed byBenassi et al. [66]. In this method the Quaternium 15 (Dowicil 200) is retained on acationic stationary phase while free formaldehyde is eluted and determined by HPLC afterderivatization.

CParabens

The esters of p-hydroxybenzoic acid (parabens) are also used as preservatives in

surfactants. The methyl, ethyl, propyl and butyl esters are most commonly used. Masseet al. [67] outlined a procedure for identifying the presence of parabens by TLC andquantitating by HPLC. De Kruijf and Schouten [58] have also developed a method forquantitating the parabens by HPLC using a reversed-phase system.

DTriclosan

Irgasan DP-300 (Triclosan) is sometimes used as a preservative in surfactants. Methodshave been published for determining Irgasan concentration using both gas and liquid

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chromatography. Hoar and Sissons [68] developed a GC method that uses a mixed SE-30-QF1 stationary phase and either an FID or electron capture detector (ECD). The ECD ismore sensitive, but this sensitivity is usually not necessary for the concentrations thatwould be expected. Marquardt et al. [69] also described a method for quantitating DP-300 in various substrates using gas chromatography. They extracted the DP-300 from thesubstrate, formed the acetyl derivative and analyzed by gas chromatography using anOV-17 column and an ECD. Several researchers have developed methods for quantitatingTriclosan using HPLC. Achari and Chin [70] reported on an HPLC technique. Theseparation and quantitation were carried out using a micro Bondapac Alkylphenyl columnwith a 1:1 (v/v) acetonitrile/water mobile phase and a UV-vis detector. George et al. [71]developed a quick, accurate, and reproducible method for determining the concentrationof Triclosan in soaps. They used a reversed-phase column with a water/THF mobile phaseand a UV detector at 280 nm.

EMiscellaneous

Another preservative used in surfactants is PCMX (p-chloro-m-xylenol). The USP [72]describes a standard gas chromatographic method for the assay of PCMX that could beadapted for the quantitation of PCMX in a surfactant.

Kathon CG (5-chloro-2-methyl-4-isothiazoline-3-one and 2-methyl-4-isothiazdin-3-one) isbeing used to some extent to preserve surfactants where the chemistry of the surfactantwill permit. Since Kathon is used at low levels, its analysis in a surfactant may sometimesbe very difficult. Rohm and Haas [73] developed a reversed-phase HPLC method fordetermining the concentration of Kathon in solution. They recommend a Spherisorb ODScolumn and an isocratic mobile phase of 50:50 methanol and water. Matissek et al. [74]developed a method in which the Kathon CG is first derivatized and then quantitated byion-pair HPLC.

VIIImpurities

There are some impurities in surfactants that may have harmful effects if they arepresent in cosmetics. Reliable methods to quantitate these impurities in the raw materialare critical to good quality control.

Ethoxylated materials may contain trace levels of ethylene oxide (EO), acetaldehyde, anddioxane.

AEthylene Oxide and Acetaldehyde

Most of the methods for determining residual ethylene oxide use headspace sampling andgas chromatography to determine the EO concentration. The EO standards are somewhat

difficult to prepare and various techniques have been used to prepare them.Acetaldehyde will almost certainly also be present and may chromatograph very close tothe ethylene oxide so acetaldehyde standards should be chromatographed to determineretention time and verify that it is not cochromatographing with EO. When using aheadspace sampling technique it is very important that the standards and samples are inthe same size container and the headspace above the liquid is the same for both. It isalso important that the standard be in the same matrix as the analytes.

Dahlgran and Shingleton [75] reported a headspace sampler/GC technique using aChromasorb 102 column and a flame ionization detector. They prepared the primary

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ethylene oxide standard by adding ethylene oxide gas to hexane but the workingstandards were prepared by diluting this primary standard in a surfactant that had beenvacuum stripped to remove all traces of EO. They reported a quantitation limit of 1.0 ppmand a detection limit of 0.5 ppm. Leskovsek et al. [76] also used a headspace techniqueto quantitate residual EO. They prepared their standards and samples in gas-tight systemvials, which they heated for a specified time in a temperature-controlled sonic bath.Aliquots of the headspace were injected into the gas chromatograph with gas-tightsyringes. They chromatographed the EO using a column packed with 0.8% THEED onCarbopak C and used the method of standard additions for their quantitation. Cardeal etal. [77] described a novel way of preparing the EO standards by synthesizing the EO insitu. They compared a headspace technique to a direct injection method for quantitatingresidual EO.

Reaction products of ethylene oxide (ethylene chlorohydrin and ethylene glycol) may alsobe present in the surfactant and may need to be quantitated. Sasaki et al. [78] havedeveloped a procedure for detecting and quantitating very low levels of ethylene oxide(EO) and ethylene chlorohydrin (ECH) in surfactants (detection limits 0.0050.03 µg/g ofEO and 0.010.07 µg/g for ECH). They desorb them from the solution and convert the EOand ECH to ethylene iodohydrin, which is then quantitated by gas chromatography usingan electron capture detector. Danielson et al. [79] describe a procedure for quantitatingethylene oxide, ethylene chlorohydrin, and ethylene glycol by a single gaschromatographic analysis using a DB-Wax Column.

BDioxane

1,4-Dioxane must also be quantitated in ethoxylated products, both nonionic andsulfated. Usually the concentration of dioxane is higher in the sulfated products than inthe nonionics. Gas chromatography is most commonly used in the analysis of dioxanewith various sample preparations by either headspace or direct injection. The USP [72]procedure requires that the dioxane be removed from the surfactant by vacuumdistillation and that the distillate be gas chromatographed using a column packed with across-linked copolymer of acrylonitrile and divinyl benzene. The quantitation is carried outusing a standard prepared in water, and the quantitation limit is 10 ppm.

Scalia et al. [80] use a solid-phase extraction procedure before direct injection onto thePoroplot Q capillary column. They use a selected ion-monitoring mass spectrometrydetector and achieve a quantitation limit of 3 mg/kg. Although this method wasdeveloped for determining dioxane in cosmetics it could be easily adapted to surfactants.Italia and Nunes [81] have determined the concentration of 1,4-dioxane in shampoos bydirect injection onto a column packed with OV-1 as the stationary phase and the use of aflame ionization detector. They use an internal standard for the quantitation.

A number of methods have been reported in the literature for determining dioxane

concentrations by gas chromatography using headspace sampling. Goetz et al. [82] use acolumn packed with SP-1000 on Carbopak C and a flame ionization detector. Using themethod of standard addition for the quantitation they could quantitate 1 µg/g and detect0.5 µg/g. They showed that dioxane was not being generated during the warmingprocess before injection. Beernaert et al. [83] use a capillary column coated with CP sil 8CB film and a flame ionization detector. They prepare their working standards in aproduct that is similar to the one being analyzed but which contains no ethoxylatedmaterial. They report a detection limit of 2 mg/kg. Rastogi [84] uses a Supelcowax 10

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capillary column and mass spectrometry for the identification and quantitation of thedioxane. He found a detection limit of 0.3 ppm. He prepared the standards in a materialsimilar to those that were to be analyzed but which did not contain any ethoxylatedproducts.

High performance liquid chromatography has also been used to quantitate dioxane. Scalia[85] reported a procedure for determining dioxane in sulfated, ethoxylated alcoholsurfactants in which the impurities are removed by solid phase extraction and are thenquantitated by HPLC using a reversed-phase column and an acetonitrile/water mobilephase with a UV detector at 200 nm. The minimum quantifiable amount was 18 µg/g.

CNitrosamines

Nitrosamines may be found in any surfactant that is synthesized from secondary amines(or a tertiary that contains some secondary). Since nitrosamines are consideredhazardous, it may be necessary to quantitate any nitrosamine in the surfactant.Quantitation may be carried out by first separating and purifying the amine and thenquantitating by a colorimetric technique. This is a time-consuming technique that must becarried out by an experienced analyst to avoid loss and contamination. It does, however,determine all nitrosamines that are present.

Probably the most common way to analyze for nitrosamines is to separate them by gas orliquid chromatography and detect and quantitate the nitrosamines by use of the TEAanalyzer. This analyzer was developed and produced by Thermedics, Inc. (Waburn, MA)specifically for the analysis of nitrosamines and it is very sensitive and selective fornitrosamines.

Erickson et al. [87] described a method for analyzing for N-nitroso-diethanolamine(NDELA) in cosmetic ingredients. After a clean-up step the solutions werechromatographed by HPLC, and NDELA was detected and quantitated by use of a TEAanalyzer. A similar procedure could be used for the determination of nitrosamines insurfactants, but less sample preparation would be necessary.

Meili et al. [88] have developed a method of analyzing for nitrosamines using gaschromatography and a photoionization detector. They use a capillary column coated withoctoxynol-3 for the separation. Gorski and Cox [89] have reported an amperometricmethod for determining the concentration of nitrosamines using an electrode coated witha ruthenium-based inorganic polymer.

DSultones

Sultones are also harmful compounds that may be present in certain anionic surfactants.Porter [4] describes several techniques that may be used for the quantitation of sultones.

The most commonly used technique is to extract the neutral oil from the anionic andquantitate the sultones in the neutral oil by gas chromatography.

VIIIAnalysis of Formulated Products

AGeneral Separation Schemes

It is often necessary for the cosmetic chemist to determine the composition of formulatedproducts. There are many schemes for the complete breakdown and analysis of these

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products but these schemes should not be followed routinely without thought. Decisionsmust be made at each step of the procedure to decide on the best next step. It is alsouseful to work with a chemist who knows at least generally what ingredients may be inthe formulation in order to reduce the time required for the analysis and to make a moreaccurate determination. Schmitt [1] outlines a good general approach for identifying thecomponents of an unknown mixture and provides a general list of the most commoningredients in a cosmetic product.

There are several authors who have developed separation and analysis schemes forthese products. Both Longman [3] and Hummel [9] outline general schemes for thebreakdown and analysis of formulated products using standard wet methods.

Milwidsky and Gabriel [2] outline methods necessary to determine the composition ofunknown surfactant mixtures. They include an ion-exchange scheme for the separation ofthe surfactant groups and depend on standard wet techniques for the analysis of theseparated surfactants. Porter [4] also shows an ion-exchange system for separatingsurfactants from each other. He presents the use of many techniques in the analysis ofthe products including many chromatographic and spectroscopic techniques.

BPreliminary Screening

It is generallly useful to conduct some preliminary screening of a formulated productbefore deciding how to proceed with the analysis. Probably the most widely used tool forthis purpose is infrared spectroscopy. A number of volumes of spectra of surface-activeagents have been published. In general these volumes not only show the spectra butindicate the characteristic frequencies for each group of surfactants. Stadler's book of IRspectra [10] groups the spectra by surfactant class and notes the characteristic groupfrequencies. Hummel [9] has also published a volume of spectra that is part of the two-volume set Identification and Analysis of Surface-Active Agents. There is an ASTMmonograph (D2357-74) [90] which includes a table of the infrared absorption bands ofcommercial detergents. Nettles [91] has published a summary of the IR spectra of somecommonly used surfactants with a discussion of the distinguishing characteristics of eachspectra.

Several schemes have also been reported for using thin layer chromatography to screen aproduct for the tentative identification of the surfactants present. Desmond and Borden[92] developed a thin-layer chromatographic system that uses both Rf value and a specialcolor development technique to identify the surfactants present by type. The systemseparates anionics from nonionics, and the color development further identifies thespecific type of anionic or nonionic. They also suggest a column chromatographic schemethat will separate anionics from nonionics and will allow enough sample to be collectedfor IR identification of the surfactant. Henrich [93] has chromatographed over 150surfactants in six different thin-layer chromatographic systems, and an unknown

surfactant may be tentatively identified by comparison of the Rf of the unknown to the Rfof the knowns in the various systems. Spray reagents are used for visualization andcharacterization. Armstrong and Stine [94] describe a technique that uses a reversed-phase thin-layer system to separate the surfactants by class and a silica-gel system toseparate individual anionic or cationic surfactants from others that are similarly charged.They described a two-dimensional technique that allows separation of complex mixturesof surfactants. These thin-layer techniques provide the chemist with a quick and easy

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scan of an unknown formulation for surfactant composition without the use of expensiveinstrumentation.

Nuclear Magnetic Resonance Spectroscopy (NMR) has also been suggested as a tool forpreliminary screening of formulated products. Carminati et al. [95] have shown that it ispossible to use 13C NMR to identify the surfactants in commercial products. Where this ispossible it eliminates the necessity for the time-consuming separation steps.

CSeparation and Quantitation

The thin-layer and NMR schemes may give an idea what surfactants are present but it isimpossible to quantitate using these methods. High performance liquid chromatography(HPLC) may be used to both identify and quantitate the surfactants. Nakamura andMorikawa [96] have developed a system for separating nonionic, anionic, and amphotericsurfactants from each other using a reversed phase technique with sodium perchlorate inthe mobile phase. The surfactants, all of which contained n-dodecyl groups, wereseparated from each other and determined in formulations without any pretreatmentsuch as ion exchange. Ban et al. [97] have shown that simultaneous and isocraticseparations of alkybenzenesulfonates, nonylphenol ethoxylates, fatty acid ethoxylates,and fatty amine ethoxylates can be achieved using a reversed-phase HPLC technique. Insome cases a preliminary separation on an anion exchange resin was necessary.

Yoshimura et al. [23] have developed an HPLC method that allows the quantitation ofalkyl ethoxylates in formulated products. Using a backflush technique, they developed amethod in which the ethoxylate chromatographs as a single peak with no splitting due toeither alkyl chain length or ethoxylate distribution. Since the ethoxylate chromatographsas a single peak, quantitation is fairly straightforward.

Some work has been done using HPLC to identify and quantitate surfactants inenvironmental samples. These methods might be adapted to quantitate the surfactant ina formulation. Matthijs and Hennes [98] describe an HPLC procedure for thedetermination of anionic, nonionic, and cationic surfactants and compare the technique tothe curretly used colorimetric techniques. Evans et al. [99] present a method for thequantitative determination of linear primary-alcohol ethoxylates using LC/MS. Thismethod allows the quantification of the individual alcohol ethoxylates. Some HPLCtechniques have also been used to characterize the alkyl and EO distribution inethoxylated alkyl amines. Schreuder et al. [100] describe a system in which they use acyano-modified silica column to determine the alkyl distribution and an amino-modifiedsilica to determine the ethylene oxide distribution. Henrich [93] describes an HPLCsystem for identifying octyl and nonylphenols by their oligomer distribution.

Nakamura and Morikawa [101] developed a methodology that can separate surfactantsfrom each other and can also separate them by their individual homolog distribution.They used representatives from each class of surfactants to illustrate their separations

but did not use any ethoxylated surfactants. Konig and Strobel [102] describe an HPLCmethod that separates, identifies, and quantitates the surfactants found in toothpaste.They use a reversed-phase column with a methanol/water mobile phase (modified withsodium perchlorate) and a refractive index detector to carry out the analysis. Since theycan separate the surfactants based on the carbon chain length, they can use this systemto identify as well as quantitate the surfactant.

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DAlkoxylate Ratios

When alkoxylated surfactants have been used it is often advantageous to know thenumber of moles of EO or PO that are present in the molecule. There are severalapproaches used to determine the ratio of alkoxylate to hydrophobe. Gaschromatography was used by Kusz et al. [103] to determine the EO/PO ratio in blockcopolymers. The gas chromatography was carried out after degradation using acetylchloride.

Another approach uses FTIR spectroscopy. Das and Kumar [104] developed a method todetermine the moles of EO on the lauryl alcohol in lauryl alcohol ethoxylates using a ratioof the peak absorbances at 720 cm-1 and 843 cm-1. The ratio of peak heights can be usedto predict the moles of EO on an unknown ethoxylate once a calibration curve has beenestablished using known ethoxylates. Nuclear Magnetic Resonance has been widely usedto determine the ethylene oxide content of ethoxylated surfactants. Proton NMR was usedby Hammond and Kubik [105] to determine the EO content of alcohol ethoxylates. Theyalso determined the precision and accuracy of their method. Carbon-13 NMR was used byGronski et al. [106] to characterize ethylene-oxide/propylene-oxide adducts. They wereable to determine whether it was a block or random polymer, the mean sequence lengthsof the EO/PO sequences, the number of blocks per 100 monomeric units, and the starterand end groups.

Abbreviations

ECDELSDEOFIDFTIRGCHPLCIRLC/MSNMRPEGPOSFCTEATHFTLC

Electron Capture DetectorEvaporative Light Scattering DetectorEthylene OxideFlame Ionization DetectorFourier Transform InfraredSpectroscopyGas ChromatographyHigh Performance LiquidChromatographyInfrared SpectroscopyLiquid Chromatography/MassSpectrometryNuclear Magnetic ResonanceSpectroscopyPolyethylene GlycolPropylene OxideSupercritical Fluid ChromatographyThermal Electron Analyzer

TetrahydrofuranThin Layer Chromatography

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4Principles of Emulsion FormationThomas FörsterChemical Research, Henkel KGaA, Düsseldorf, Germany

I. Basic Mechanisms to Produce Emulsion Droplets 105

A. Energy Scale for Droplet Break-up 106

B. Droplet Break-up under Shear 106

C. Droplet Break-up under High Pressure 108

D. Role of Surfactant: Droplet Size Reduction andStabilization 108

II. Phase Behavior and Structure of Emulsions 109

A. Representation of Phase Behavior by PhaseDiagrams 109

B. Properties of Microemulsions and Lamellar PhasesRelevant to Emulsion Formation 114

III. Phase-Inversion Emulsification 119

A. Balanced Surfactant Systems and OptimumFormulation 119

B. PIT Emulsification and Gel-Phase Emulsification 120

References 123

IBasic Mechanisms to Produce Emulsion Droplets

Emulsions are disperse systems in which twoor sometimes severalalmost insoluble liquidphases are intimately mixed. Except for special cases such as microemulsions or highinternal phase emulsions with a foam structure, the internal phase is contained in theexternal phase in the form of spherical droplets. Thus in the simplest case there is eitheran oil in water (o/w) or a water in oil (w/o) emulsion. However for cosmetic and technicalapplications, multiphase emulsions are also quite common; for example a water in oilemulsion can be dispersed in water to obtain a w/o/w emulsion.

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AEnergy Scale for Droplet Break-up

Because of their dispersed character, emulsions have a large internal surface, which isenergetically unfavorable. This has two basic consequences: first, energy is consumedduring emulsion preparation, and second, emulsions are thermodynamically unstablesince there is practically no entropic gain that would compensate the energy consumption(internal surface A · interfacial tension (go/w). An appreciable positive mixing entropy onlyresults in the case of colloidal mixing in a microemulsion. Therefore, apart from oil andwater, the preparation of emulsions also requires surfactants and energy.

The actual energy demand for the preparation of an emulsion is several orders ofmagnitude higher than the amount of energy stored in the emulsion in the form ofsurface energy because of the droplet break-up mechanism [1]. During the preparation ofan emulsion, large oil droplets are first deformed and then broken up. The Laplacepressure (p = 4 go/w/D, with droplet diameter D) acts against the droplet deformation. Fora w/o emulsion with a typical interfacial tension of approximately 2.5 mN/m and a dropletdiameter of 1 µm, a Laplace pressure of 10,000 Pa has to be overcome. In order to obtainsuch a pressure gradient over a length in the order of magnitude of the droplet diameter,a very high energy input is required, the greatest part of which dissipates as heat.

BDroplet Break-up under Shear

A large number of emulsifying processes are based on droplet break-up under shear [2].The break-up of a droplet is possible when the deforming force exceeds the interfacialforce that maintains the shape. This ratio is described by the Weber index. In the case oflaminar flowe.g., in the clearance of a colloid mill (see Fig. la)it is

Fig. 1Types of emulsifying

machines: (a) colloid mill

(b) stirrer

(c) homogenizer.(For detailed survey see Ref. 2.)

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t is the shear tension that results from the product of emulsion viscosity hE and shear ratev.

A droplet break-up is only possible up to a minimal diameter Dmin, which is characterizedby the critical Weber index Wecr [3,4]. Through individual droplet examinations underlaminar shear and emulsifying experiments in a colloid mill, Schubert and Armbrustershowed that the critical Weber index only depends upon the viscosity ratio between thedispersed phase and the emulsion hd / hE [5,6]. The critical Weber index passes a distinctminimum in the range 0.1 < hd / hE < 2 (see Fig. 2). Only in this range of minimal Weberindices can finely dispersed emulsions be produced under laminar shear. For Wecr = 1

With an emulsion viscosity hE of 0.1 Pa·s a shear rate v of 5000/s in the clearance of acolloid mill, and an interfacial tension go/w of 2.5 mN/m, a simple estimation yields aminimum droplet diameter of 10 µm.

One precondition for an effective emulsification in colloid mills is therefore a sufficientlyhigh emulsion viscosity. Furthermore, the viscosity ratio hd / hE is often too high for o/wemulsions. In this case, the oil droplets behave as hard spheres, i.e. they are notdeformed. Thus another emulsifying process must be applied, which is either not

Fig. 2Critical Weber number as a function of viscosity ratio for o/w emulsions

with C12E10 (laureth-10) and C12E20 (laureth-20) as emulsifier.(Reprinted from Ref. 5 by courtesy of VCH Verlagsgesellschaft.)

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based on laminar shear or utilizes an emulsion inversion to the type w/o (see below)during preparation.

During the process of stirring (see Fig. 1b), the droplets are broken up by pressuregradients in a turbulent flow. Instead of shear stress, now the Reynolds tension 1/2 Dv2 ·r, with the mean square velocity fluctuation Dv2 and the density r, must be used tocalculate the Weber index [5]. According to Kolmogorov, for the simplifying assumption ofa homogeneous, isotropic turbulence, the mean square velocity fluctuation Dv2 can becalculated from the product of power density P/V and droplet diameter D. The smallestdroplet size attainable with stirrers is [5,7].

CDroplet Break-up under High Pressure

In high pressure homogenizers the emulsion is forced through a homogenizing nozzle(radial gap in Fig. 1c). Here homogenizing pressures of 100 to 1000 bar are reached withvolume flows of up to 50,000 L/h [5]. Equation (3) can be used again for the calculationof the droplet size. The power P is calculated from the product of pressure drop p andvolume flow . Because of the high pressure drop and the short residence time of theemulsion in the homogenizing nozzle, very high power densities are achieved. In contrastto the colloid mill, the power density is independent of the emulsion viscosity and theviscosity ratio hd / hE . Therefore, high-pressure homogenizers are particularly effectivewhen finely dispersed low-viscosity emulsions are emulsified (e.g., homogenization ofmilk). A detailed comparison of the power densities of different emulsifying devices canbe found in Reference [7].

DRole of Surfactant:Droplet Size Reduction and Stabilization

During the preparation of an emulsion, droplets not only break up, but at the same timethey may recoalesce to larger droplets. Both phenomena are influenced decisively bysurfactants.

Surfactants reduce the interfacial tension between the oil and the water phase fromapproximately 25 to below 2.5 mN/m for w/o emulsions and below 0.25 mN/m for o/wemulsions, thus facilitating droplet break-up. In the colloid mill the theoreticallyattainable droplet diameter is 10 to 100 times smaller [see Eq. (2)]; in high-pressurehomogenization it is 4 to 16 times smaller with than without surfactant [see Eq. (3)].

However, these theoretically expected minimal droplet sizes are not achieved in practice.One important reason is recoalescence into larger droplets during the preparation of anemulsion [7,8]. Surfactants stabilize the droplets against coalescence as a result of a

''self-healing mechanism" that is known as the GibbsMarangoni effect (see Fig. 3) [9,10].

The surfaces of two emulsion droplets that have just been separated arebecause of thesudden surface increasecovered incompletely with surfactant molecules (Fig. 3, left).When these two droplets approach each other again, surfactant molecules from theexternal phase will adsorb unevenly at the droplet surface (Fig. 3, center). The adsorbedsurfactant quantity is smallest at the point where a thin film forms between the twoemulsion droplets. This results in a surfactant concentration and interfacial tension

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Fig. 3Scheme of the Gibbs-Marangoni effect.

gradient that causes the surfactant molecules to move from areas rich in surfactant to thecontact surface depleted of surfactant molecules (Fig. 3, right). The surfactants dragalong molecules of the external phase, and as a result, the droplets are separated, i.e.,recoalescence is prevented.

A precondition for the stabilizing GibbsMarangoni effect is a surfactant concentrationgradient in the droplet surface that develops due to the uneven adsorption of thesurfactant from the external phase. If the surfactant is dissolved in the interior of theemulsion droplets, the surfactant concentration gradient cannot develop, and coalescenceis not prevented. In this way the GibbsMarangoni effect also supplies the explanation forthe well-known Bancroft rule: The phase with the better surfactant solubility becomes theexternal phase in an emulsion [11]. Dispersed droplets that contain dissolved surfactantare not protected against recoalescence.

IIPhase Behavior and Structure of Emulsions

Simple o/w or w/o emulsions contain two phases (water and oil) whosethermodynamically unstable intimate mixture is stabilized with surfactants.

Due to their amphiphilic (hydrophilic and lipophilic) molecular structure, surfactants havea tendency to aggregate in aqueous or oily environments, e.g., to form micelles or liquidcrystals. These aggregates form thermodynamically stable phases that can also changethe macroscopic appearance of an emulsion.

ARepresentation of Phase Behavior by Phase Diagrams

The type of surfactant and oil, the mixing ratios, and the external conditions such astemperature and salt or solvent content determine which macroscopic phases can occurin a certain surfactant-oil-water system. These complex relationships can be representedgraphically in the form of phase diagrams, as shown for a simple three-componentsystem of C12E7 (dodecylpolyoxyethylene(7)glycol or laureth-7), decane, and water in thediagram in Fig. 4. In order to provide a clear overview, only single-phase areas arerepresented, not the different multiphase emulsion types.

In this emulsion system, there are three single-phase areas at 20°C: the cubic gel phase,the hexagonal phase, and the lamellar liquid-crystalline phase. In each corner, one of thethree components is present in its pure form. The composition of mixtures is read

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Fig. 4Ternary phase diagram of C12E7, decane, andwater at 20°C and liquid crystalline structures.

(Reprinted from Ref. 12 by courtesy of Steinkopff Verlag.)

with the aid of parallels to the three edges. A system of 10% decane, 60% water, and30% C12E7 therefore forms a transparent, high-viscosity cubic gel I, which could, forexample, be used as a basis for a sunscreen gel or a topical preparation (1315). Othercommon names for the cubic gel phase are transparent oil-water gel [16], microemulsiongel [17] orin the case of special acoustic propertiesringing gel [18].

In this simple case the cubic gel phase can be imagined as a crystal of closely packed oil-swollen surfactant micelles [12,18]. The curvature radius of the surfactant film is verylarge.

With an increasing surfactant/water ratio, the hydration and therefore thepolyoxyethylene head group area decline, and the curvature radius and the packingconditions in the liquid crystal change. A hexagonal liquid crystal HI results (where Iindicates that water is the external phase), which has a high viscosity because of its rod-like structure. The curvature radius decreases further during further exchange ofsurfactant for water, and a planar structure, the lamellar liquid crystal La, forms. Theplanar lamellar layers are easily movable, and as a result, the viscosity is distinctly lowerthan that in the hexagonal or cubic liquid crystal.

It is apparent from the phase diagram that the cubic phase exists only in a narrowconcentration range, while the hexagonal and the lamellar phases cover large areas.Lamellar and hexagonal liquid crystals in particular also occur in the oil-free system (foran overview of phase behavior of nonionic surfactant water systems see Reference 20).

Two-dimensional triangular diagrams usually show the influence of the mixing ratio

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of oil, water, and surfactant on the phase behavior of ternary systems. In the case offour-component systems the phase behavior must be represented in the form of three-dimensional phase tetrahedra [21,22]. As a rough approximation the four-componentsystems can be considered as so-called pseudo three-component systems in which twocomponentsin most cases the two emulsifying agentsare summed to form a pseudocomponent exhibiting a constant mixing ratio [23,24,27].

In order to represent the influence of process variables such as temperature or saltcontent on the phase behavior of a ternary system, a so-called phase prism is often used[25].

The schematical phase prism in Fig. 5 demonstrates the decisive influence of temperatureon the phase behavior of ternary oil-water-ethoxylated nonionic surfactant mixtures; inthis case the emulsion and microemulsion phases with a low surfactant content werestudied (in contrast to Fig. 4 where the single-phase liquid crystalline phases rich insurfactant were examined). Higher ethoxylated, nonionic surfactants form oil-swollenmicelles in water (wm) at low temperatures and stabilize o/w emulsions. With increasingtemperature, oil solubilization in the micelles increases and finally a third phase (D) witha high surfactant content forms. At low surfactant concentration, the system separatesinto three phases: an oil phase, a water phase poor in surfactant, and a middle phase richin surfactant, which solubilizes large quantities of water and oil (Winsor III). With afurther rise in temperature, the ethoxylated surfactant head groups are dehydrated evenmore, thus increasing the surfactant solubility in oil. Finally inverse, water-swollen

Fig. 5Phase prism, Winsor types, and dispersion structure of an emulsion composed of nonionic surfactant, oil, and water.

(Reprinted from Ref. 27 by courtesy of VCH Verlagsgesellschaft.)

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surfactant micelles are present in the oil (om), and w/o emulsions result. An increase intemperature therefore induces a phase inversion from an o/w into a w/o emulsion; in therange of the phase inversion temperature (PIT) the system passes through amicroemulsion phase.

Perpendicular cuts through the phase prism yield clear two-dimensional representations.The cutas indicatedthrough the surfactant corner with fixed o/w-ratio (often 1:1) showsthe dependence of the phase behavior of an emulsion system on temperature (on theordinate) and surfactant concentration (on the abscissa) (see Fig. 6). The phase inversiontemperature range in which a microemulsion exists appears as the well-known "Kahlweitfish" [25,27]. The body of the fish corresponds to the three-phase-microemulsion range(Winsor III), the tail of the fishat higher surfactant concentrationscorresponds to thesingle-phase microemulsion (Winsor IV) or the lamellar liquid crystal. The cusp of thesingle-phase microemulsion, where tail and body meet, specifies the minimum surfactantconcentration that suffices to solubilize the entire oil and water quantity in the D-phase,i.e. it is a measure of the solubilization capacity of the surfactant used. At lowtemperatures around 40°Cbelow the lamellar liquid crystal areathe single-phasemicroemulsion is water-continuous and consists of oil-swollen, strongly bent micelles[28]. The curvature radius of the surfactant layer decreases with increasing temperature,and a lamellar phase results in which the surfactants are packed in parallel, stiff layers[29]. The stiffness of the lamellar layers declines with a further rise in temperature whilethe mean curvature radius remains constant and a single-phase

Fig. 6"Kahlweit-fish" in the phase diagram of

C12E5, tetradecane, and water.(Reprinted from Ref. 27 by courtesy of VCH

Verlagsgesellschaft.)

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bicontinuous microemulsion forms [29,30]. Freeze fracture electron microscopy pictures ofdifferent microemulsion structures are shown in References 28 and 31.

Another common cut through the phase prism runs parallel to the oilwater axis with aconstant surfactant content. This representation (Fig. 7) demonstrates solubilizationlimits and cloud points [32]. On the ordinate, decisive formulation variables such astemperature (for ethoxylated nonionic surfactants [3234]), salt content (for ionicsurfactants [35]) or surfactant mixing ratios [32,34] are specified. The structure of themicroemulsion phase changes with the oil-water ratio [29,33,36]: The water-rich sideshows oil-swollen micellar droplets in water (wm), which are referred to as an o/wmicroemulsion. With an increasing o to w ratio the o/w microemulsion changes into athree-phase microemulsion (w + D + o) orin the case of higher surfactant contentinto abicontinuous microemulsion (D). On the oil-rich side, a w/o microemulsion (om) formswith droplet structure.

The third important representation type finally is the water content map, i.e., aperpendicular cut through the water corner with a constant oilemulsifier ratio (Fig. 8).This representation is particularly suitable for the planning of production processes, sincethe usual production methodpreparation of an oilemulsifier mixture, heating, and additionof watercan be taken into consideration [37]. At water contents in the range from 15 to80% o/w emulsions exist, which invert nearly constantly between 78 and 98°C. Atextreme water contents the phase inversion is no longer possible due to

Fig. 7Phase diagram of tetradecanewater emulsions containing 5% C12E5.

(Reprinted from Ref. 32 by courtesy of Steinkopff Verlag.)

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Fig. 8Temperaturewater-content map of an emulsion containing a fatty alcohol,

nonionic surfactant, and paraffin oil in a mixing ratio of 3/4/20.(Reprinted from Ref. 37 by courtesy of Allured Publishing.)

geometric reasons, and unstable w/o emulsions (w/o*) or o/w emulsions form at verylow or very high water contents, respectively. The temperaturewater-content map showswhich phases are passed through with certain production paths (see e.g. path 1 for aone-step hot process and path 2 for a two-stage hot-cold process, where an emulsionconcentrate with only 20% water is diluted at 85°C with cold water). In addition, Fig. 8contains information about the consistency of the systems at 25°C as a function of thewater content. At water contents below 40%, close packing of the oil droplets isapproached, resulting in a drastic increase in the viscosity and yield value.

BProperties of Microemulsions and Lamellar Phases Relevant to Emulsion Formation

Why are microemulsions interesting for the preparation of emulsions? Microemulsions arespecific systems in which the emulsifying agents are optimally adapted to the oil andwater phase and therefore show maximum interfacial activity. This is manifested inminimum interfacial tension and maximum solubilization [25,32,3840]. In the phasediagram in Fig. 7, the single-phase ranges wm and om specify the solubilization limits inthe case of extreme o to w ratios. Along the perpendicular line for an o to w ratio of 5:95at temperatures below 35°C an oil in water emulsion (o + wm) forms. As the phaseinversion temperature range is approached, oil solubilization increases, and in the phaseinversion temperature (PIT) range (36 to 41°C) the micelles can solubilize more than 5%

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oil, resulting in a single-phase range of oil-swollen micelles (wm), an o/w microemulsion.The micelles aggregate above the PIT range, and a phase with a high surfactant content(w + D) separates. Oil-swollen micelles are oil microdroplets with a radius between 2 and30 nm coated with a surfactant monolayer [40,41]. The surfactant/oil ratio determinesthe droplet radius [40,41].

Similar conditions prevail in the case of the reverse o to w ratio (95:5). In the phaseinversion range (50 to 55°C in Fig. 7) water-swollen inverse micelles in oil (om) form. Theradius of the water microdroplets lies in the range of 5 to 30 nm and is determined by thesurfactant/water ratio [41].

With a medium o to w ratio, a three-phase Winsor III microemulsion develops in thephase-inversion temperature range. Figure 9 shows the interfacial tension curve and thesolubilized oil and water volume fractions with increasing temperature along the line inFig. 7 with an o to w ratio of 1:1. When the phase inversion temperature range isapproached, the interfacial tension between the aqueous micellar solution (wm) and theoil phase decreases by several orders of magnitude while the oil solubilization in themicellar phase increases. In the phase inversion temperature range (45 to 50°C) amicroemulsion phase D, rich in surfactant, is present in addition to the almost surfactant-free oil and water phases [42]. The interfacial tension is minimal [25,40,4346] and thewater and oil solubilization in the surfactant phase D is maximal [25,32,38,39]. Since lowinterfacial tension facilitates the mechanical droplet break-up (see Eqs. [23]), formationof a microemulsion phase during the preparation of emulsions can improve the result.Above the phase-inversion temperature range the emulsion inverts into w + om, theinterfacial tension increases, and the water solubilization in the inverse micelles (om)declines.

During passage through the microemulsion range (Winsor I-Winsor III-Winsor II) theemulsion system inverts from o/w to w/o, because the distribution of the surfactantsbetween oil and water phase changes drastically (Bancroft rule).

At surfactant concentrations encountered in practice, the distribution of the surfactantbetween the oil and water phase is not determined by the monomer solubility but ratherby the critical micelle concentrations in oil and water [4750]: The surfactant accumulatesin the phase in which it first forms micelles, independent of whether the solubility of thesurfactant monomers is better in oil or in water. Thus, the Bancroft rule can bereformulated: The phase in which the surfactant forms micelles becomes the externalemulsion phase [50].

Generally in the phase-inversion range the major portion of surfactant is dissolved in oiland in the microemulsion phase [22,51,52]. The surfactant concentration in the water isnear the critical micelle concentration and is negligible. Surfactant distribution betweenoil and microemulsion phase depends on the hydrophilic/lipophilic balance of thesurfactant and the dissolving properties of the oil. For commercial surfactants and

surfactant mixtures of hydrophilic and lipophilic surfactants, the surfactant composition inthe microemulsion phase can deviate considerably from the weighed surfactantcomposition since the lipophilic surfactants accumulate preferably in oil [22,53]. As aconsequence, the surfactant mixture in the microemulsion phase becomes poorer in thelipophilic components, and the phase-inversion temperature increases. This depletioneffect is more pronounced at lower ratios of surfactant to oil. Thus for mixtures of high-and low-ethoxylated fatty alcohols the PIT declines with increasing overall surfactantconcentration (Fig. 10). As can be seen, the depletion effect is more strongly marked in

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Fig. 9Influence of temperature on volume fractions of water,

oil;and surfactant phases (schematic) and interfacialtension between phases in the system composed

of 5% C12E5, 47.5% water, and 47.5% tetradecane.(Reprinted from Ref. 32 by courtesy of Steinkopff

Verlag and with permission from Ref. 40,copyright American Chemical Society.)

the case of a higher portion of the lipophilic surfactant C12E4 in the surfactant mixture.Saturation of the lipophilic surfactant in oil is achieved only at high surfactant levels, andthe surfactant composition of the microemulsion phase then approaches the weighedsurfactant composition [22,5254].

The minimal interfacial tension attainable with microemulsions is the result of closesurfactant packing in the fluctuating, planar configuration of the bicontinuous D-phase.Another phase in which the surfactant molecules are closely packed in a planar config-

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Fig. 10Phase inversion temperature (PIT) as a function of mixed surfactant

concentration in an emulsion containing mixed fatty alcoholethoxylates, heptane, and water with a fixed-oil/water ratio of 1:1.

(Reprinted from Ref. 22 by courtesy of Academic Press.)

uration is the lamellar phase (see above, Fig. 6). Like the microemulsion phase, thelamellar liquid crystal also reduces the interfacial tension between the oil and waterphase [21,55]. Thus, after passing through a lamellar phase during the emulsionpreparation, finely dispersed emulsions are obtained. Furthermore, lamellar phasesunlikemicroemulsion phasescontribute considerably to emulsion stabilization.

On account of their amphiphilic character, droplets of the dispersed phase may becovered with lamellar layers. This viscous, lamellar film on the droplets is several layersthick and reduces the attraction potential between the droplets [21,56]. As a result, thelamellar layer acts as a barrier against coalescence.

At usual surfactant concentrations the volume proportion of the lamellar phase canbecome so large in the emulsion system that it not only covers the droplets as astabilizing film but forms a macroscopic phase in which the droplets are dispersed [57].Multi-phase emulsions of the type o/lc/w exist in which several oil droplets are trapped inone secondary liquid crystal (1c) droplet of the lamellar phase (Fig. 11). Cosmeticemulsions often contain self-bodying agents, which, when mixed with hydrophilicsurfactants, build a lamellar gel phase [44,5865]. The structure of the lamellar gel phaseresembles that of the lamellar liquid crystal [65]. Because of the portion of high-meltingself-bodying agents, e.g. cetostearyl alcohol or glycerol monostearate, the lamellar layersare solid at room temperature [44,59,60,62,64]. At still higher proportion of viscosity-contributing

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Fig. 11Structure of an oil/liquid crystal/water emulsion.

(Reprinted from Ref. 58.)

ingredients, crystals of this ingredient separate from the lamellar gel phase (for detailssee Chapter 7).

The formation of the lamellar gel phase leads to important changes in the macroscopicemulsion properties. In cosmetic applications changes of the rheological properties(viscosity and yield point) through the structural buildup in the emulsion [58,65,66] andthe increased water-bonding capacity of the lamellar gel phase [58,62,67] are mostimportant. Figure 12 shows the influence of the addition of cetostearyl alcohol on the

phase-inversion temperature and on the yield point (a measure of the consistency of theo/w emulsion). In a mixture with a fatty alcohol ethoxylate as hydrophilic emulsifier,cetostearyl alcohol acts as a lipophilic coemulsifier that reduces the phase-inversiontemperature from 85°C with 3% fatty alcohol to 65°C with 6%. In the range of 2 to 4%

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Fig. 12Phase inversion temperature and yield value as a function of fatty alcohol content in an o/w

emulsion containing 4% C16/18E12 and 20% paraffin oil.(Reprinted from Ref. 66 by courtesy of Chapman and Hall.)

cetostearyl alcohol, the yield point is zero and the emulsion viscosity is low. At higherconcentrations, the yield point increases linearly with the fatty alcohol content, resultingin o/w lotions or creams.

IIIPhase-Inversion Emulsification

ABalanced Surfactant Systems and Optimum Formulation

The formation of a lamellar phase or a microemulsion indicates that thehydrophilic/lipophilic properties of the surfactant mixture are balanced and exactlyadjusted to the water and oil phases, which can be seen from the minimal interfacialtension and phase inversion (see Fig. 13) [25,32,3840]. In such an optimum formulation,the different formulation variables [e.g. temperature, salt content, surfactantcomposition, ACN (alkane carbon number)] of the oil mixture, surfactant-to-oil ratio, andwater content follow specific rules [22,54,70,71]. Within the framework of the so-calledR-theory (ratio R of the interaction energies of the surfactant with the oil and the water)the influence of the different formulation variables as well as the surfactant molecularstructure on the phase behavior of microemulsions can be estimated semiquantitatively[72].

In practice these regularities are used in order to characterize surfactants and oils with aspecificity that reaches far beyond the long-known HLB system [73].

For ethoxylated nonionic surfactants there are characteristic HLB temperatures that canbe combined according to a linear mixing rule for the estimation of the emulsifyingproperties of surfactant mixtures [22,54,74]. A more general system, originally developedfor applications in tertiary oil recovery, is based on EACN (equivalent alkane carbonnumber) values for the characterization of the surfactants [7577]. Especially for

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Fig. 13Oil water interfacial tension (in mN/m) and macroemulsion type

(from electrical conductivity) against different formulation variables.(Reprinted from Ref. 47 by courtesy of Royal Society of Chemistry, from Ref. 68

by courtesy of Elsevier Science Publishers and with permission from Ref. 69,copyright American Chemical Society.)

cosmetic applications, the CAPICO (calculation of phase inversion in concentrates)concept was developed from these two systems (for further details see Chapter 9) [78].

BPIT Emulsification and Gel-Phase Emulsification

The relationship between microemulsion phase behavior and emulsions is most obviousin those emulsifying processes that use the optimum formulation in a phase inversion.The phase-inversion temperature (PIT) emulsification is based on a heatingcooling cyclein which the system passes through a microemulsion range (see Fig. 14). At increasedtemperatures o/w emulsions that are stabilized with ethoxylated nonionic surfactants caninvert into w/o emulsions. For surfactant mixtures with long-chain nonionic surfactantsand lipids commonly used in cosmetics, the phase-inversion temperature (PIT) can beadjusted to range between 60 and 100°C (see Fig. 14). In this PIT range thehydrophilic/lipophilic properties of the surfactant mixture are balanced, and amicroemulsion or a lamellar phase with minimal interfacial tension forms [44]. In thesubsequent cooling process to room temperature, very little mechanical energy isrequired to break up the oil phase into minute oil droplets [45,79]. As a result, a coarseo/w emulsion is converted into a finely dispersed bluish o/w emulsion throughtemperature-induced phase inversion (see Fig. 15); it is stable against sedimentationbecause of the small oil-droplet size (diameter approximately 120 nm) [66,7881].Concerning coalescence, PIT emulsions are generally considered to be stable if the

phase-inversion temperature is far higher than the storage temperature [45,78,80].Therefore, production temperatures (= PIT) are usually between 75 and 90°C [78].

In practice, the PIT emulsifying process is preferably applied as a hot-cold process thatallows considerable savings in energy and processing time [37,8284]. The temper-

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Fig. 14Principle of PIT emulsification: A course o/w emulsion is transformed into a blue

fine-disperse o/w emulsion by passing a microemulsionduring a heating-cooling cycle.

(Reprinted from Ref. 66 by courtesy of Chapman and Hall.)

Fig. 15Microscopic appearance of o/w emulsions at 25°C as a function of

preparationcourtesy temperature.(Reprinted from Ref. 66 by courtesy of Chapman and Hall.)

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aturewater-content map in Fig. 8 shows such a two-stage hotcold process. The single-step PIT process shown in Fig. 14 is marked as production path 1 in Fig. 8. The wholeemulsion with 7% mixed surfactant, 20% oil, and 73% water is heated to 85°C (to reachthe microemulsion range) and cooled down. In the two-stage process (path 2), only anemulsion concentrate with 20% water has to be heated to 85°C. In a second step the hotmicroemulsion concentrate is diluted with water of 40°C to reach the final concentrationwhile cooling. As a result, as with path 1, a finely dispersed and long-term stable o/wemulsion is obtained [37].

In gel-phase emulsification, a microemulsion or a lamellar gel phase is not inducedthrough temperature variation but through polyol addition [8587]. The gel phaseemulsification is also a two-stage process (see Fig. 16). In the first stepat roomtemperatureoil is dispersed in a lamellar phase of surfactant, glycerol, and a smallquantity of water so that a transparent o/lc gel emulsion is obtained. The surfactant canbe anionic [86] or an ethoxylated nonionic surfactant [85,87]. In the second step this o/lcgel emulsion is diluted with water to obtain the final formulation. An o/lc/w emulsionforms in which the lamellar liquid-crystalline phase protects the oil droplets againstcoalescence. The resulting oil droplet size depends primarily on the surfactant/oil ratioand can be adjusted in a wide range from over 1000 nm to less than 100 nm [86]. During

Fig. 16Principle of gel phase emulsification: (1) An o/lc gel

emulsion containing oil, monoarginine hexyldecyl phosphate,glycerol, and a minor amount of water is formed; and (2) The

o/lc gel emulsion is diluted with cold water.(Reprinted from Ref. 86 by courtesy of Academic Press.)

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the second dilution step, polyol concentration declines drastically. In the presence ofespecially suitable surfactants, the polyol concentration in the final formulation can belowered sufficiently to make this gel-phase emulsification suitable for the preparation ofcosmetic o/w emulsions. Both processes, the PIT emulsification as well as the gel-phaseemulsification, show that by utilizing the microemulsion phase behavior, finely dispersedo/w emulsions can be prepared by a simple emulsification procedure without the need forhighly sophisticated emulsifying equipment.

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36. J. F. Billman and E. W. Kaler, Langmuir 7:160917 (1991).

37. T. Förster and H. Tesmann, Cosmetics Toiletries 106 (12):4952 (1991).

38. K. Shinoda and S. Friberg, Adv. Colloid Interface Sci. 4:281300 (1975).

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64. T. de Vringer, J. G. H. Joosten, and H. Junginger, Colloid Polymer Sci. 264:691700(1986).

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5Emulsifier Selection/HLBDonald L. Courtney, SR.Emulsions REZ, Landenberg, Pennsylvania

I. Emulsifier Selection with the Aid of HLB 128

II. Required HLB of Blends of Lipids 131

III. Experimental Determination of Required HLB Number 131

IV. Published Data 132

V. Theoretical Validation of Griffin's HLB Values 132

A. J. T. Davies's Group Numbers 132

B. Alternate Determination of Required HLB 135

C. The PIT Method 135

VI. An Outstanding Pair of Emulsifiers 136

VII. Amount of Emulsifier 136

A. Required Stability 137

B. Difficulty of Ingredients to Be Emulsified 137

C. Amount of Oil Phase Ingredients 137

D. Efficiency of the Emulsifiers 137

E. Accuracy of the HLB Number Determination 137

F. Use of a Stabilizer 137

G. Preparation Method 137

References 138

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IEmulsifier Selection with the Aid of HLB

When formulating an emulsion, the formulator has numerous choices to make in selectingthe ingredients that will produce the desired qualities the formulator has been calledupon to develop. Many ingredients are quite predictable in their contribution to the finalproduct relative to viscosity, tactile qualities, appearance, rub-in, after-feel, irritation,odor, etc. An experienced formulator can generally select and formulate ingredients thatwill approximate the desired properties in a few days time. But selecting the system thatwill modify this complex mixture of ingredients into a stable, homogeneous, and elegantemulsion is usually the most elusive task of the entire process. Of course we are referringto those extremely complex chemical mixtures known as emulsifiers, and the search ismore difficult because a pair works better than one. Besides, there are thousands fromwhich the formulator can choose. Selection of the proper emulsifiers for a specific blend ofparticular ingredients can be a ponderous, confusing, and time-consuming process.

How does a formulator select emulsifiers for a brand new mixture of lipids? A popularmethod is to use those that have been used successfully in a past product. This is alogical step since the compounder knows the raw materials; they are in inventory;medical has approved them for use; and the supplier is a known and reliable source. Thedrawback is they probably won't work satisfactorily in this new system.

A resourceful formulator will read suppliers' literature, technical magazines, andtextbooks for alternate ideas. But what are the chances of finding an existing formulaidentical to his? If he did he would change his formula. However, he may come up withseveral new candidates that he tries with only modest success. Fortunately there is help.It is known simply as the HLB system.

In the 1940s, William C. Griffin pioneered the creation and manufacture of emulsifiers(surfactants). They were being generated so fast that he was faced with the dilemma ofdetermining their utility and how they related to each other. He was primarily concernedwith nonionics made from polyols (glycerin, propylene glycol, and sorbitol), fatty acidsand alcohols, and ethylene oxide adducts. At the time (1949) it was known that thegreater the amount of polyol or ethylene oxide (EO) in the molecule, the more hydrophilicor water soluble it would be. Conversely, the greater the proportion of fatty acid or fattyalcohol, the more lipophilic or oil soluble the emulsifier would be. Griffin was looking forsome way to classify or ''rate" these products, and he ultimately reasoned that comparingthe hydrophilic "strength" of each emulsifier would be a meaningful way to relate theirperformance. If three emulsifiers had the same percent hydrophilic content they shouldorient themselves in a micelle or on oil droplets in a similar fashion. Differences in thepolyols and lipid moieties would affect emulsifying efficiency, but performance should besimilar.

Since the hydrophilic portion of these products can readily be calculated and measured,

Griffin set out to evaluate his premise. To simplify the system he divided the weightpercent of the hydrophilic portion of the molecule by five and called the resulting numberthe HLB number of the surfactant. He derived the following formulas for the calculation[1].

where S is saponification number of the ester and A is acid number of the recovered acid.

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When the hydrophilic portion of the molecule consists only of ethylene oxide, thefollowing formula pertains [2].

where E is weight percent of oxyethylene content. The abbreviation HLB stands forHydrophile Lipophile Balance, and "Balance" refers to the relative portions of lipidic vs.hydrophilic segments.

Fortunately, this method of "rating" or classifying emulsifiers turned out to be quite usefuland meaningful. A system for organizing emulsifiers had been discovered and issummarized in Table 1.

The next step was to relate the HLB number of these emulsifiers to materials to beemulsifiedfats, oils, fatty acids, waxes, lipids, etc. Not surprisingly (in hindsight), eachmaterial to be emulsified has a required HLB number, i.e., each requires an emulsifier (oremulsifier blend) with a specific HLB number for optimum emulsification. This was anamazing and invaluable discovery! Use of an emulsifier with an HLB number identical tothe required HLB number of a lipid should yield a good emulsionor at least a better onethan any emulsifier with the same chemical components but a different HLB number. Forexample, cetyl alcohol has a required HLB number of 15.5. An ethoxylated stearyl alcohol(emulsifier) with 21 moles of ethylene oxide has an HLB of 15.5 and emulsifies cetylalcohol better than stearyl alcohol containing 16, 18, 20, 22, or 25 moles of ethyleneoxide.TABLE 1 HLB of Various Surfactants(ICI America Literature)Surfactant HLB valueSorbitan trioleate 1.8Glyceryl oleate 2.8Sorbitan oleate 4.3Sorbitan stearate 4.7Steareth-2 4.9Laureth-4 9.7PEG-8 Stearate 11.1Nonoxynol-5 10.0Nonoxynol-9 13.0PEG-4 Sorbitan peroleate 9.0PEG-25 Hydrogenated Castor Oil 10.8Triethanolamine Oleate (TEA oleate) 12.0Polysorbate 60 14.9Polysorbate 80 15.0PEG-40 Stearate 16.9PEG-100 Stearate 18.8Sodium Oleate 18.0Potassium Oleate 20.0

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Once the required HLB of a material to be emulsified and the HLB number of emulsifiersare known, producing a good emulsion can be accomplished easily and quickly. Theremaining task is to find the correct chemical type of emulsifier at the determined HLBvalue for the lipid to be emulsified. There is a best chemical type for each lipid.

What makes the HLB System even more useful to the formulator are its alligativerelationships. It is well established that a pair of emulsifiers makes a better emulsionthan a single emulsifier. If the formulator selects a pair of emulsifiers so that one has ahigher and the other a lower HLB number than the required HLB of the lipid to beemulsified, they can be blended to the exact required HLB number of the lipid.

The exact blend of the two emulsifiers is easily calculated since it is an arithmeticrelationship. For example, if emulsifier A has an HLB number of 5 and emulsifier B has anHLB number of 15, the 50/50 (weight) blend, has an HLB number of 10. The followingratios of this pair of surfactants produce the resulting HLB values shown in Table 2.

If the required HLB of the lipid is 8.5, the following formula allows a simple calculation:

Proof:

TABLE 2 HLB Values from Surfactant PairSurfactant A: HLB 5 Surfactant B: HLB 15 Resulting HLB of blend10% = 0.5 + 90% = 13.5 = 14.020% = 1.0 + 80% = 12.0 = 13.030% = 1.5 + 70% = 10.5 = 12.040% = 2.0 + 60% = 9.0 = 11.050% = 2.5 + 50% = 7.5 = 10.060% = 3.0 + 40% = 6.0 = 9.070% = 3.5 + 30% = 4.5 = 8.080% = 4.0 + 20% = 3.0 = 7.090% = 4.5 + 10% = 1.5 = 6.0

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The ability to blend emulsifiers to the correct required HLB is enormously important andvaluable for the following three reasons.

1. As stated earlier, two emulsifiers make a more stable emulsion than one, almostwithout exception. So it is desirable to use a pair of emulsifiers.

2. By blending emulsifiers one can achieve the exact HLB number required. Even thoughthere are thousands of emulsifiers available, the number providing a specific HLB numbercan be quite small or nonexistent. Without blending, the formulator would have to havean enormous number of emulsifier samples on hand for optimum emulsification of thenumerous lipids used in formulating.

3. The chemical composition of the emulsifier plays an important role in its efficiency forspecific lipids. For example, oleic acid derivatives are very good for emulsifying white oils(mineral oil). However, there may not be any available with the exact required HLB of agiven white oil.

For your convenience, a table of emulsifier HLBs (Table 1) is included herein.

IIRequired HLB of Blends of Lipids

Cosmetic formulators are noted for using a myriad of lipid components to produce thedesired elegance. So far we have dealt with the required HLB number of a single lipid.How does the HLB system cope with a combination of lipids? Quite simplythe combinationof the lipids, no matter how complex, has a required HLB! This can be calculated quitereadily, or better yet, determined experimentally. It is calculated as follows [3]:Calculation of Required HLB Number of a Complex MixtureIngredient Required HLB number % Oil phase HLB contributionA 12.0 × 30 = 3.6B 6.0 × 50 = 3.0C 15.0 × 20 = 3.0

Total 9.6

Thus 9.6 is the required HLB number of the blend.

IIIExperimental Determination of Required HLB Number

The following procedure is followed to determine the required HLB number of a singlelipid or complex mixture of lipids.

Any pair of emulsifiers can be used, but one should have a low HLB number (i.e. < 6) andthe other a high HLB number (i.e. > 14). For this illustration, the pair consisting ofSurfactant A and Surfactant B in Table 2 is selected. A series of emulsions is preparedwith each blend using a total of 2% surfactant, 20% lipid and 78% water. The surfactant

and the oil are blended in one container and water is added. Simple uniform shaking isadequate (at least ten shakes). If either the surfactant or lipid is a solid, it is melted andwarm water is used so that the system is liquid.

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Since the required HLB number is not known, emulsions are made with blends rangingfrom 10/90 (A/B) to 90/10 (A/B). The resulting emulsions are allowed to stand and areobserved over a period of several hours. Ideally most, if not all, will separate in varyingdegrees. The one with the least separation is the required HLB number; that is, if thebest emulsion is the 50/50 blend, the required HLB number is 10.0 [4].

If the required HLB had been known in advance to be somewhere around 10.0, one wouldonly have to make up five emulsionstwo with lower required HLB values (8 and 9) twowith higher (11 and 12) and one at 10.

If all the emulsions broke rapidly and equally, the process is repeated using 3%emulsifier or only 10% lipids. If the initial emulsions are creams, and thus hindered fromseparating, the procedure is repeated using reduced levels of lipids. If HLB 10 and HLB 11yield equally stable emulsions, one may assume that the required HLB number is 10.5.

Now one needs to find that optimum chemical type emulsifiers for the chosen lipid(s).(Reference 4 includes specific recommendations.) Surfactant types can be selected asdesired. Ordinarily, stearic acid derivatives and stearyl alcohol derivatives are superioremulsifiers and are good choices.

Pairs are chosen so that one has an HLB higher than 10 and one an HLB lower than 10.Each pair is blended to HLB (the required HLB number just determined), and emulsionsare made with each. This time a mechanical stirrer is used to make each system asconsistent as possible. The emulsion showing the least separation contains the chemicaltype to pursue.

It is only necessary to make one emulsion with each pair of emulsifiers, as each pairblended to HLB 10 should yield a better emulsion than any other blend. This is animportant, time-saving benefit of the HLB System. When the best pair of emulsifiers hasbeen identified, it would be judicious to finalize the system by comparing HLB 9, 10, and11 due to slight variations among chemical types. The HLB system is not as accurate astitrating an acid with a baseGriffin originally claimed an accuracy of ± 1 unit [1].

IVPublished Data

Fortunately, the required HLB numbers of many common lipids have been determinedand published [4]. Following is an excerpt of an extensive list of required HLB numbers ofwidely used ingredients (Table 3).

VTheoretical Validation of Griffin's HLB Values

The concept put forth by W. C. Griffin in 1949 has persisted so long for one reasonitworks! Many formulators can attest to this fact because of years of personal use. (The

author has had great success with it during thirty-five years of formulation work.)However, inquisitive theorists have scrutinized its concept from numerous approaches tovalidate it or to improve it. Validation has been successful, improvement is probablymarginal. Some of these efforts will be reviewed.

AJ. T. Davies's Group Numbers

Davies attempted to explain Griffin's HLB numbers (shown in Table 4) thermodynamicallyand by relating it to structural groups [6]. He produced the following equation to explainhis concept:

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TABLE 3 Required HLB Numbers for O/WEmulsionsMaterial Required HLBAcetylated lanolin 14Acid, isostearic 1516Acid, oleic 17Alcohol, cetyl 1516Alcohol, isohexadecyl 1112Alcohol, stearyl 1516Arlamol, C12C15 benzoate 13Arlamol E 7Beeswax 9Caprylic/Capric Triglyceride 5Carnauba wax 15Castor oil 14Cocoa butter 6Coconut oil 5Corn oil 6Cottonseed oil 56Dimethyl silicone 9d-Limonene (varies widely) 67Isopropyl myristate 1112Isopropyl palmitate 1112Jojoba oil 67Lanolin, anhydrous 9Mineral oil light (naphthenic) 1112Mineral oil light (paraffinic) 1011Mineral spirits 14Mink oil 5Nonyl phenol 14Paraffin wax 10Petrolatum 78Pine oil 16Silicone oil 5Silicone oil (volatile) 78Soybean oil 6Vitamin A plamitate 6Vitamin E 6Source: Ref. 1.

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TABLE 4 Davies's HLB Group NumbersHydrophilic group NumbersSO4Na 38.7COOK 21.1COONa 19.1N (tertiary amine) 9.4Ester (sorbitan ring) 6.8Ester (free) 2.4COOH 2.1OH 1.9O 1.3OH (sorbitan ring) 0.5Lipophilic GroupsCH 0.475s

Derived Group(CH2CH2O) 0.33

0.15

Becher notes, "Unfortunately, HLB values for ethoxylates calculated by this method areerroneous, since this method assumes that each additional EO group adds the sameincrement to the HLB." [6]

As Hans Schott commented, "Since Griffin validated his HLB scale for nonionic emulsifiersby measuring optimum emulsification for a wide variety of lipids with water it should bethe scale of choice. The Davies' scale seriously distorts the range of the experimental HLBvalues required for emulsifying lipids in water and vice versa. Therefore it is not suited toselect nonionic emulsifiers."[7]

Becher identified several alternate methods for HLB determination [6]:

Spreading coefficientPolarity indexPolarographyNMR and mass spectroscopyCalorimetryDielectric concept

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Partition coefficientHeat of (interfacial) adsorptionSolubility parameterPartial molar volumeMonolayer propertiesCritical micelle concentrationWater number, cloud pointPhase Inversion TemperaturePITInterfacial tensionFoaming

BAlternate Determination of Required HLB

Vaughan and Rice [8] have recently developed a method for determining the requiredHLB values of lipids based on their solubility parameters using the following equation:

The solubility parameter is derived from molecular weight, specific gravity, and boilingpoint, which are readily available for numerous compounds. This allows one to predict therequired HLB of lipids without experimentation.

Required HLB values calculated by this technique generally have surprisingly goodcorrelation with the Griffin method for linear emulsion ingredients. However, for chain-folded structures there is considerable deviation.

CThe PIT Method

The phase inversion temperature or HLB temperature has intrigued many physicalchemists interested in producing ultimate emulsions. It is based on the fact that o/wemulsions when heated reach a temperature at which they suddenly invert to w/oemulsionsthe PIT. This concept was announced by Shinoda and Arai in 1964. It is claimedthat an emulsion should be formed (phases mixed) at 24°C below the PIT. This allows ano/w emulsion to form initially yielding smaller particle sizes than if the emulsion is madeabove the PIT and inverts from w/o to o/w on cooling [9]. See Chap. 4, pages 120122, foradditional comments.

This property can also be used to assist in selecting the optimum chemical type ofemulsifier by making a series of emulsions with various emulsifiers and observing theviscosity changes as water is added to the oil and as the emulsion inverts from w/o too/w. If the system passes from a low viscosity w/o system through a viscoelastic gelstage while inverting to o/w and then to a fluid emulsion, the resulting emulsion shouldhave good stability [9]. It appears that PIT augments the HLB system and is used inconjunction with it.

The method involves a substantial amount of test work that may yield a more accurateHLB value for the emulsion. The method implies that the mixing temperature of thephases may play a more important role in the stability of an emulsion than previouslythought and that determination of the optimum emulsification temperature may be ofvalue. The author has not used this method as an adjunct to the HLB system as described

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earlier but has produced hundreds of excellent emulsions. It is his belief that PIT is notwidely used.

It has been noted that the phase inversion temperature is assigned to the particularemulsion system and accounts for oil type, electrolyte concentration in the aqueousphase and other factors which influence surfactant partitioning at the o/w interface,whereas HLB is assigned to the surfactant molecule. For homogeneous nonionicsurfactants (i.e. pure or single specie products) there is a linear relationship between HLBand PIT:

where Koil is approximately 17°C/HLB unit NHLB is Griffin HLB number, and Noil is the HLBvalue of the oil at THLB = 0°C [9].

VIAn Outstanding Pair of Emulsifiers

The author has had great success with a pair of emulsifiers for a wide variety of lipids andmixtures of lipids. The formulator is urged to evaluate this pair when trying to determinethe correct chemical type of emulsifier. This pair is steareth-2 (Brij 72) (HLB 4.9) andsteareth-21 (Brij 721) (HLB 15.5) [5]. For the sake of convenience the following blendsyield HLB values from 5 to 15.% Steareth-2 % Steareth-21 HLB100 0 590 10 680 20 770 30 860 40 950 50 1043 57 1133 67 1223 77 1315 85 14

5 95 15

VIIAmount of Emulsifier

The amount of emulsifier needed in a formula varies appreciably from formula to formulawith no hard and fast rules. The variable factors governing the amount to use include:

ARequired stability

BDifficulty of ingredients to be emulsified

CAmount of oil phase ingredients

DEfficiency of the emulsifiers

EAccuracy of the HLB number determination

FUse of a stabilizer

GPreparation method

Fortunately, guidelines can be followed to make a reasonable estimate of the amount,

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and actual determination is not a Herculean task. Some of the factors involved arereviewed below.

ARequired Stability

Very simply, the more severe the stability requirements of the formula the greater theamount of emulsifier needed; the less restrictive the requirements the lower is the levelof required emulsifier. Ordinarily manufacturers will require two to three years' stability ofa formula at room temperature. Ninety days' stability at 40°C is a reasonable high-temperature requirement. One must also consider the stability at 50°C since thistemperature is easily reached in the real world. A month's protection against separationshould be adequate; and some will accept less. Low-temperature stability is alsoimportant. Four or five freeze-thaw cycles are normal, and refrigerator temperatures arealso important.

BDifficulty of Ingredients to Be Emulsified

The difficulty of the lipid to be emulsified and the amount are very important, but efficientemulsifiers (previously discussed) should prevail.

CAmount of Oil Phase Ingredients

The amount of lipids used is directly related to the amount of emulsifier requiredalthough the relationship is not linear.

DEfficiency of the Emulsifiers

Emulsifiers can vary significantly in efficiency, i.e., the amount required to produce thedesired stability. Normally a formulator would want to use a highly efficient pair. Usuallystearic acid and stearyl alcohol derived emulsifiers are superior.

EAccuracy of the HLB Number Determination

The correct HLB number is very important as discussed above.

FUse of a Stabilizer

Sometimes emulsifiers alone will not yield the desired stability. With nonionic emulsifiers,Carbomer 934 at levels of 0.1% to 0.5% usually will help achieve the desired stability.

GPreparation Method

Good preparation would include adding the water phase to the oil phase (containing theemulsifiers) to provide inversion and, possibly homogenization. Having said this, aminimum of 2% emulsifier is probably required. It should be rare to exceed 5%, but thisis not unheard of. For example, if white oil is considered a benchmark, 3% oil couldprobably be emulsified with 2% emulsifier; 2050% white oil may require 45% emulsifier.The author has actually emulsified 70% oil with 7% emulsifier resulting in an extremelystable emulsion. Obviously, a straight-line relationship does

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not exist. A suggested procedure is to use 3 or 4% emulsifier with and without Carbomer934 for normal lipid levels. This assumes, of course, that very efficient emulsifiers areused.

In closing:If emulsion problems keep you awakeBecause of the speed with which they break,Say a prayer on bended knee,And quickly check your HLB!

References

1. The HLB System: A Time-Saving Guide to Emulsifier Selection, ICI Americas,Wilmington, DE, 1992, p. 19.

2. The HLB System: A Time-Saving Guide to Emulsifier Selection, ICI Americas,Wilmington, DE, 1992.

3. The HLB System: A Time-Saving Guide to Emulsifier Selection, ICI Americas,Wilmington, DE, 1992.

4. The HLB System, (51-0010-304), June 1990, ICI Americas, Wilmington, DE.

5. Brij 721 Polyoxyethylene 21 Stearyl Ether, (51-0001-228), Revised 1988, ICI Americas,Wilmington, DE.

6. J. Becher, J. Dispersion Science and Technology, 5:8196 (1984).

7. H. Schott, Journal of Pharmaceutical Science/87, 79:(1990).

8. Vaughan and Rice, J. Dispersion Science and Technology 11:8391 (1990).

9. M. Johnston, in Surfactant Technology, ICI Australia.

10. K. Shinoda and S. Friberg, Emulsions and Solubilizations, John Wiley, New York, 1986,pp. 6, 13032.

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6Multiple Emulsions in CosmeticsMonique Seiller and Francis PuisieuxPhysico-Chimie-Pharmacotechnie-Biopharmacie, Université de Paris-Sud, Châtenay-Malabry, France

J. L. GrossiordPhysique Pharmaceutique, Université de Paris-Sud, Châtenay-Malabry, France

I. Introduction 139

II. Structure and Composition 140

III. Preparative Method 141

IV. Characterization 144

A. Microscopic and Particle Size Analysis 144

B. Rheological Analyses 145

C. Titration of a Tracer or of an Active Substance 147

V. Stability 148

VI. Release of the Active Substance 149

VII. Dermatological Applications 150

VIII. Conclusions 153

References 153

IIntroduction

As a result of their structure, multiple emulsions, i.e., emulsions of emulsions, can containactive water-soluble and lipid-soluble substances in each of the three constituent phases.Although potentially advantageous as systems for application to the skin and mucousmembranes, multiple emulsions are not currently used as therapeutic dosage forms. Thisis due to the fact that such systemsinvestigated for only about ten yearsare new vesicularforms that are still not fully controllable in terms of formulation, manufacture,characterization, and performance after application to skin or mucous membranes.

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Yet there are reasons to believe that these limitations and stability problems may beovercome shortly and that considerable use will be made of this dosage form in thecoming years, particularly if its ability to prolong the release of active ingredients isconfirmed.

The use of multiple emulsions could become nearly as widespread as the use of simpleemulsions from which they are derived and may equal that of other similar vesicularsystems. One argument in their favor is that they exhibit approximately the sameproperties as these better known systems, and like simple emulsions, they can bedispensed directly to the skin because they are oily creams with the proper consistencyfor easy spreading.

IIStructure and Composition

Multiple emulsions are emulsions in which a dispersed phase contains another dispersedphase [1]. Thus a w/o/w emulsion is a system in which water globules are dispersed inoil globules, the latter being themselves dispersed in an aqueous phase (Fig. 1). Byanalogy, multiple emulsions of the o/w/o type exist, in which an internal oily phase isdispersed in the aqueous globules, which in turn are dispersed in an external oily phase.The emulsions described here are chiefly w/o/w emulsions with improved production andapplication properties for pharmaceuticals and cosmetics.

Multiple emulsions are sometimes called three-phase emulsions or triple-phaseemulsions. In fact, the term double emulsion would be more appropriate, because twoemulsions coexist in these systems: an emulsion with a continuous oily phase and anemulsion with a continuous aqueous phase. The term triple emulsion is nonethelessacceptable and sanctioned by custom. Yet it is not recommended, although often used,when it applies to miscellaneous preparations consisting, for example, of a gelled simpleemulsion or an emulsion containing microparticles in suspension, or even a simpleemulsion in which a different active substance is incorporated into each phase (e.g.,retinyl palmitate in the oily phase and urea and aloe extract in the aqueous phases).

Since multiple emulsions consist of at least two immiscible liquids, their preparationdemands the presence of emulsifiers, which are usually synthetic but sometimes are of

Fig. 1Oily globule in w/o/multiple emulsions.

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natural origin. At least two emulsifiers are used. They are called the primary surfactant(S1) and the secondary surfactant (S11). For multiple w/o/w emulsions, the molecules ofS1, with a lipophilic tendency, are oriented at the internal w/o interface and those of S11,with a hydrophilic tendency, at the w/o external interface. If the concentrations and thetypes of surfactants are properly adapted to that of the oily phase, they give rise to twomonomolecular films. The apolar parts of the emulsifiers are found in the oil, and thepolar parts are found in the internal (S1) or external (S11) aqueous phase. It follows thatthe emulsifiers exist in oriented layers, forming an actual envelope of the vesicle aroundthe oil.

Although some surfactants and oily phases are better adapted than others, all normalcomponents of simple emulsions can be used to obtain multiple emulsions. For thispurpose certain conditions must be satisfied concerning the ratio between theconcentration of S1 and S11 or of the maximum HLB of their mixture.

The oily phases most often used to form multiple w/o/w emulsions arein decreasing orderof usehydrocarbons such as liquid paraffin, triglycerides (mostly vegetable oils), followedby esters, fatty alcohols or acids, and silicones. Emulsifiers are primarily nonionicsurfactants. Among the most effective for S1 are esters of sorbitan with a longhydrocarbon chain, perfluoro derivatives, and, above all, polymeric surfactants such ascetyl dimethicone copolyol. For S11, the most effective are polyethoxylated esters ofsorbitan, copolymers of ethylene oxide and propylene oxide, highly ethoxylated fattyacids, and polyglyceryl condensates.

As in other vesicular systems, various additives are often introduced. At very lowconcentrations, they play the role of markers, making it possible to quantify the stabilityof the systems. They include electrolytes (NaCl), sugars (glucose), and fluorescentsubstances (carboxyfluorescein). In higher concentrations, some additives tend toincrease stability. They may include hydrophilic polymers (xanthan gum, alginates,cellulose derivatives, and carboxyvinyl compounds) incorporated into one of the aqueousphasesbut usually in the external aqueous phaseor lipophilic substances (waxes, fattyacids or alcohols, silicone derivatives) introduced into the intermediate oily phase.

The following is an example of the formula of a typical w/o/w multiple emulsion.

Primary emulsionalmond oilpurified soylecithinmagnesiumsulphatedeionized waterq.s.p.

24.0%5.0%0.7%

100.0%

Multiple emulsionPrimary emulsionpolysorbate 60polysorbate 80deionized waterq.s.p.

70.0%1.0%1.0%

100.0%

IIIPreparative Method

The procedure is crucial for obtaining a multiple emulsion and is even more importantthan that for a simple emulsion. Four main procedures can be applied.

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The two-step process, as shown in Fig. 2. The most common method. Note that, strictlyspeaking, this name is inaccurate, because the other processes also demand a doublemanufacturing step.

The phase inversion process, as shown in Fig. 3. This process is increasingly used. Thisname is also inappropriate because it does not involve a true phase inversion.

Lamellar phase dispersion process, as shown in Fig. 4. This method is very rarely used. Itis comparable to one of the processes employed to obtain vesicles with nonionicsurfactants.

The oily isotrope dispersion process. According to the authors, who recommend it, thisprocess is more appropriate for o/w/o type microemulsions.

These four methods are applied in a virtually identical manner.

Initially, a simple emulsion with an oily continuous phase (for the first two processes) orthe lamellar phase or the oily isotrope (for the latter two processes) is prepared at 70 to80°C. Whatever the system involved, the water, oil and emulsifiers, whose proportionsvary according to the method employed, are mixed using a standard turbine agitator forabout 30 min with high speed of about 103 rpm.

In the second phase, for the two-step procedure, the emulsion containing an oilycontinuous phase is slowly transferred into the aqueous phase. For the remaining threeprocesses, the water is gradually introduced, either into the emulsion with an oilycontinuous phase, into the lamellar phase, or into the oily isotrope. The seconddispersion is also performed with a turbine agitator, usually at ambient temperature forabout 30 min but at a lower spread of rotation of a few hundred rpm.

Each process obviously has its own advantages and drawbacks.

Fig. 2Two step emulsification method.

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Fig. 3Phase inversion method.

The main advantage of the two-step process is fully controlled application. It is possible,at least in theory, to control the quantity of internal water. Its disadvantage is that it isnot reproducible, if only because of the second emulsification is a critical step. In fact, theprimary w/o emulsion, which is highly viscous, is difficult to disperse. During this step,which requires intense shear forces, there is risk of breakage of some newly formed oilglobules, resulting in the mixing of part of the internal water with the external water.

The advantage of the phase-inversion process is that it is very easy to apply and providesa specific proportion of internal aqueous phase exactly as in the two-step process. Unlikethe latter, it is also reproducible. Yet it has the drawback of requiring two emulsificationsteps and, above all, of being difficult to implement. In fact, a very slight excess of watersuffices to transform the multiple emulsion into a simple emulsion of the aqueous type(w/o). On the other hand, excessively slow incorporation of water causes the formation ofa simple emulsion of the oily type (o/w).

Dispersion of a lamellar phase in water offers the advantage of requiring a singleemulsification step. The initial phase formed by a concentrated surfactant solution isthermodynamically stable and can be obtained rapidly. One limitation of this processstems from the fact that not all surfactants form a lamellar phase. If this phase exists,

Fig. 4Ternary phase diagram.

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the HLB of the surfactants is often high, which is disadvantageous for the stability of amultiple emulsion. The quantity of oil incorporated in the lamellar phase is always low,rarely higher than 10%.

The process by dispersion of an oily isotrope in water offers approximately the sameadvantages as the above process. Only one emulsification is required. The initial phase isa pure phase, stable and simple to obtain. The main drawback is the low level ofsolubilized water in the inverse micelles, which can be raised above 10% only withdifficulty.

The latter two processes also present common drawbacks resulting from the necessarilylarge quantities of surfactant employed. Water is added to the lamellar phase or to theoily isotrope, in which the initial water is not truly emulsified in the form of globules. Itthen is difficult to determine whether the specific quantity of water, to which thisdispersion gives rise, is still solubilized and to determine the total amount of this water inthe internal phase.

Also worth mentioning is another process recommended by Kavaliunas et al. [6]. It callsfor the mixing, in preset proportions, of an oily isotrope, an aqueous isotrope, and alamellar phase. While this process appears attractive, it is rarely applicable because itrequires constituents that can yield these three phases simultaneously.

IVCharacterization

It is difficult to include all available physicochemical analyses for the characterization ofmultiple emulsions; these analyses can be applied upstream to optimize formulation andmanufacture. This section, therefore, is limited to a discussion of methods forcharacterizing multiple emulsions from the time they are formed and during their aging.Most of the assays are microscopic, particle-size, and rheological analyses as well asanalytical determinations of tracers and of encapsulated active substances.

AMicroscopic and Particle Size Analysis [7,8]

Microscopic examination is the first test performed to identify the systems obtained. Italso offers an excellent means to observe the stability of these systems during aging.

Optical microscopy is a standard analytical method for checking the multiplicity of thesystems, as well as the particle size distribution. It allows direct measurement of the sizeof multiple globules greater than 0.5µm in diameter as well as an evaluation of the ratioof multiple globules to single globules. This method also provides an idea of the size ofthe internal aqueous globules, often about 1µm in size (Fig. 5). Before observation andmeasurement of the actual size of the globules, the multiple emulsion must beextensively diluted to yield a solution that is iso-osmotic with the internal aqueous phase.

This is required because the migration of water from the external phase to the internalphasein case of dilution with a solution of lower osmolaritymight cause swelling,sometimes followed by bursting of the oily globules. Conversely, dilution with a solutionof higher osmolarity might cause loss of internal water and hence a contraction of theinternal aqueous droplets.

Examination with polarized light under crossed Nicols sometimes helps to identify a

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Fig. 5Optical microscopy photograph of a multiple emulsion.

texture corresponding to a lamellar phase, which indicates the orientation assumed bythe two emulsifiers in the oily phase.

After freeze etching of the multiple emulsion, microscopy is sometimes used to visualizethe rupture of the oily globules (Fig. 6). Rather than attempting a direct estimation afterobservation, some authors prefer to take measurements from photographs in order todetermine the average particle-size distribution and the size dispersion on a sufficientlylarge sample. To obtain a still more accurate quantitative characterization of the sizes ofthe multiple oily globules, use is often made of particle-size analyses by particle countingor by the diffusion or diffraction of light. Observations of this type require high dilution ofthe multiple emulsions, whose osmolarity should be adjusted as closely as possible tothat of the internal aqueous phase to avoid disturbing the size of the globules.

BRheological Analyses [913]

The descriptive power and the versatility of rheological analyses are systematicallyemployed to characterize multiple emulsions. In fact, their wide scope makes it possibleto

identify the multiple emulsion by using nondestructive viscoelastic analysis (linearmicroshear regime), which gives an accurate signature of the structure at rest (Fig. 7);

simulate by oscillatory shear the conditions of skin application and to characterize itseffect over time;

cause accelerated aging by the application of intense shear forces and to identify anumber of changes in multiple emulsions (flocculation, fracture, phase inversion)

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Fig. 6Freeze etching photograph of a multiple emulsion.

the effects of skin application or artificial aging can be quantified by dynamicviscoelastic analysis (Fig. 7) or by the use of steady-state flow tests (Fig. 8); and

characterize the kinetics of swelling and subsequent breakdown of the oil globules.Recording the changes in viscosity over time and correlating swelling with the volumefraction of the dispersed phase (w/o primary emulsion), serves to quantify these kinetics(Fig. 9).

Fig. 7Oscillatory viscoelastic strain sweep.

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Fig. 8Examples of steady state flow rheograms without (a) and with (b) hysteresis loop.

CTitration of a Tracer or of an Active Substance

The titration of a compound (tracer or active substance), initially incorporated into theinternal aqueous phase, assesses the amount of the compound that remains in theinternal phase at the time of measurement by comparison to the theoretical quantity inthe encapsulated mass. This determination thus serves to

determine not only the encapsulation yield of production but also the analysis of thestability of the multiple emulsions over timeprovided the compound determined issufficiently water-soluble to prevent its diffusion across the oily membrane (for example,strong electrolytes); and

observe the kinetics of release of the compound by bursting of the oily globules and/or

Fig. 9Characterization of a swelling-breakdown kinetics by recording of the viscosity.

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by diffusion across the oily membrane (if permitted by the lipophilic character of thecompound).

The tracer is assayed either directly in the multiple emulsion (in the external aqueousphase after removal of the primary emulsion) or in the dialysis medium (after dialysis ofthe multiple emulsion).

Analysis of the Multiple Emulsion

Various ionized substances can be titrated in the multiple emulsion itself. Magdassi et al.[14], for example, used a sodium salt or an ephedrine salt. The chloride ions weredetermined by the mercuration method or by potentiometric titration directly in themultiple emulsion.

Analysis of the External Aqueous Phase

Davis et al. [15] encapsulated carboxyfluorescein in the internal aqueous phase. Theexternal aqueous phase was separated by filtration after creaming of the primaryemulsion. The marker was then detected in the clear external aqueous phase byfluorescence spectrophotometry.

Fukushima et al. [16] and Ratz and Cueman [17] used cytabarine and dextran blue orpolyporphyrin. After separating the external aqueous phase by sedimentation of the oilyglobules (with or without centrifugation of the multiple emulsion) the concentrations ofeach substance that passed into the external phase was measured by spectrophotometry.

Adeyeye and Price [18] used sodium salicylate. The multiple emulsion was diluted in thedispersant aqueous phase to which a small amount of hydrophilic surfactant had beenadded. The mixture was allowed to rest until the supernatant oily layer could beaspirated. The conductivity was then determined in the external phase, and its variationover time was measured at regular intervals.

Analysis of the Dialysis Medium

Matsumoto et al. [19] employed the encapsulation of glucose. A certain amount ofemulsion was dialysed against a volume of distilled water. The migrated glucose wasthen assayed by measuring its reducing power. Matsumoto et al. [20] also used sodiumchloride. It was titrated by conductimetric measurements in the dialysis medium.

Obviously, spectrophotometry continues to be the most common means of titration foridentifying the release of the encapsulated active substance after dialysis. Thus, forexample, Law et al. [21], using sulphane blue (C.I. No. 53430), Omotosho et al. [2224],using fluorouracil, methotrexate and chloroquine, and Fredo-Kumbaradzi et al. [25], usingsodium sulphacetamide, resorted to these types of titrations.

VStability

Since multiple emulsions are thermodynamically unstable systems, they unavoidablychange over time until they break. The first sources of instability of w/o/w multipleemulsions include those that are common to all dispersed systems: creaming, flocculationand coalescence of the oily globules, and phase inversion. In addition, multiple emulsionsmay also exhibit specific instability. Besides the coalescence of the internal aqueousglobules, it has already been pointed out that, in the presence of an osmotic gradient, anaqueous flow from the internal phase to the external phase or a reverse flow may occur,leading to the formation of a simple w/o or o/w emulsion.

At the present time, the use of high-performance polymeric surfactants, thickeners thatconsiderably increase the viscosity of the different phases, and cross-linking of the

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intermediate oily phase by various methods [26,27] has helped to retard thedestabilization of these systems. Stable multiple emulsions have actually been stored fortwo years at room temperature and for six months at 40°C without any change in theircharacteristics or in the release of the encapsulated substance [1].

VIRelease of the Active Substance

The release mechanisms of an active substance encapsulated in the internal aqueousphase are complex, difficult to control, and not fully understood. Two main mechanismsare usually considered. The first, which is the more likely after skin application, is mixingof the internal phaseand hence of the active substancewith the external phase, caused bythe breakage of the oily membrane separating them. The second is due to diffusion of theactive substance across this membrane.

It has already been stated that breakage of the intermediate membrane can occur underthe effect of an osmotic gradient between the two aqueous phases. This takes place afterthe globules attain a critical size due to swelling. This swelling is caused by the aqueousflow from the external phase to the internal phase, generated by the concentrationgradient of all the soluble species existing in the two phases. Breaking can also be causedby sufficiently intense shear, particularly during skin application.

The diffusion mechanism essentially concerns relatively lipid-soluble substances that havea significantly high oil/water partition coefficient. For this type of substance, diffusion ispassive and is governed by Fick's law. It is also possible to consider the diffusion of highlywater-soluble compounds due to the lipophilic surfactants present in the intermediate oilyphase, which could act as carriers. For example, inverse micelles could solubilize thewater and thus transport a part of the active substance from the internal phase to theexternal phase via facilitated diffusion. Activated diffusion does not appear to occur; sucha mechanism would require the action of carriers of different affinities at the twointerfaces.

The behavior of a multiple emulsion after application to the skin is a conjectural question.Two assumptions can be made. (1) The water evaporates before breaking or diffusionbecomes apparent. In this case, the partitioning of drugs between oil and skinpredominates, a behavior similar to that observed with simple emulsions. (2) Theevaporation takes place slowly enough to allow breakage or diffusion. Two principalmechanisms may be operative.

1. The encapsulated active substance displays virtually no diffusion across the oilymembrane. The active substance is then only released from the internal phase bybreaking of the multiple oil globules. This rupture takes place either by shearing of thepreparation or after swelling of the internal aqueous globules. Shear could be caused bymassage or by rubbing during the spreading of the cream.

Swelling could be caused by dilution of the multiple emulsion with water. In fact, duringadministration it is conceivable that the user is required to blend a given dose of themultiple emulsion in a certain volume of water just before application. This blendingcould even take place extemporaneously by means of dual compartment packaging. Dueto the osmotic gradient thus created or enhanced, and according to a mechanism alreadyanalyzed, an aqueous flow is then directed towards the internal

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phase, causing swelling of the internal water globules. When these globules reach theirmaximum size, they burst.

In both casesbreakage by shear or breakage after swellingthe active substance, which isnow present in the external aqueous phase, is immediately available. The multipleemulsion thus behaves as a simple emulsion with an aqueous continuous phase. In thiscase, the chief benefit of the multiple emulsion is to protect an active substance byencapsulation or to permit the introduction, in a single preparation, of active substancesthat will come into contact only when the cream is used.

2. The encapsulated active substance diffuses across the oily membrane, and when it isapplied to the skin the multiple emulsion preserves its multiple globules intact. Therelease of the active substance from the multiple emulsion is then no longer identical tothat of a simple emulsion. It is gradual and progressive and depends specifically on:

the type and thickness of the oily membrane,

the possible existence of paracrystalline phases in the interfacial film, especially lamellarphases obtained from surfactant bilayers,

the type and concentration of the surfactants,

the partition coefficient of the active substance and its diffusion rate across the oilymembrane, and

the particle size distribution of the oily globules.

The advantage of a multiple emulsion accordingly resides in its ability to delay therelease of the encapsulated active substance in comparison with simple emulsions.

VIIDermatological Applications

To date, dermatological applications of multiple emulsions for the administration of activesubstances have been considered only rarely and have been assessed infrequently. Atthis time, only a limited number of investigations have been published on the subject.

The first study employing the application of multiple emulsions by a localized method wasthat of Attia et al. in 1986 [28]. It concerned the release of pilocarpine hydrochloride as amyotic agent in eye infections. The active ingredient was added to water or to castoroilpossibly containing a sorbitan ester as a surfactantin o/w or w/o emulsions and inw/o/w and o/w/o multiple emulsions. Attia et al. conducted tests in vitro and in vivo.

For the in vitro tests, performed by dialysis, the authors showed that when the activeingredient was initially in the internal oily phase of the o/w/o emulsion, release wasapproximately as fast as that from the o/w primary emulsion but slower than that of theoily suspension containing the surfactant and that of the aqueous solution.

For the in vivo tests, based on the diameter of the pupil and the intraocular pressure, theauthors made the following observations: the shortest response times occur when theactive substance is contained in the aqueous solution. Conversely, the longest responsetimes occur when the active substance is included in the o/w/o emulsion and in the oilysuspension (1.5 times more for the myotic response and 3.5 times more for theintraocular pressure). The active substance must first cross the o/w interface and thenthe external oily phase before being released in the conjunctiva. According to theauthors, these results are caused either by a salting out effectprovoked by the presenceof sodium chloride in the emulsion, causing a precipitation of the active substanceor toprolonged

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contact of the emulsion with the corneal surfacecausing in situ sedimentation of theactive substance.

The second study was a skin application conducted by Kundu Subhass in 1990 [29] withw/o/w and o/w/o types of multiple emulsions. These consisted of liquid paraffin andsorbitan esters and contained either sodium or methyl salicylate or salicylic acid astracers. These systems were investigated in vitro in a Franz cell equipped with asemipermeable membrance of cellulose acetate and in vivo after application to pigabdomens. The percentage of tracer passing into the receiving medium or into the bloodof the animals was measured by ultraviolet spectrophotometry.

In vitro, the author showed that the active substances are released more slowly frommultiple emulsions than from pure solutions containing the same substances. This releasewas even slower if thickenerssuch as silica, xanthan gum, or a carboxyvinyl polymerwereadded to the external phase of the w/o/w emulsions. This effect was especiallypronounced if their concentration is high. Similarly, if sodium choride was incorporated inthe internal aqueous phase, the release of the active substance was also modified. Therelease of the encapsulated tracer in the internal aqueous phase was characterized bythe existence of a linear relationship between the quantity released and the square rootof time. For the w/o/w emulsions investigated, the author concluded that the transport ofthe tracer across the external aqueous phase was the limiting factor.

In the case of o/w/o type of emulsions, the release of the active substances is alsodelayed if the carboxyvinyl derivative is introduced into the intermediate aqueous phase.In this type of system, the limiting factor appears to be the water/oil interface.

In vivo, the author showed that, regardless of the type of emulsion, no systemicpermeation of the active substances appeared after local application.

In order to create a skin cream and to understand the mechanism of formation of multipleemulsions, Raynal et al. [30] developed a multiple emulsion for the treatment of acne. Itcontained spironolactone in the intermediate oily phase, a chlorhexidine salt in theexternal aqueous phase, and sodium lactate in the internal aqueous phase. This multipleemulsion with three active substances was presumed to exert a threefold action: to treatthe acne with spironolactone, to fight the bacteria always present in this infection withchlorhexidine salt, and to moisturize the often dry skin by this treatment with sodiumlactate. Yet studies to evaluate the activity of this multiple emulsion after skin applicationstill remain to be performed.

The most important studies conducted on the behavior of multiple emulsions for cosmeticapplications are those of Ferreira et al. [3133]. In all these studies w/o/w emulsions werecompared with simple w/o and o/w emulsions. The originality of the work arises from thefact that these authors attempted to obtain significant comparative results and toexamine the influence of vesicles. They developed simple emulsions with an oilycontinuous phase (w/o), simple emulsions with an aqueous continuous phase (o/w), and

multiple w/o/w emulsions, each containing the same components in identical amounts.Different procedures were followed to obtain these three types of emulsion with the sameformula. The oil phase is a liquid paraffin, the primary surfactant a modified nonionicpolyester of the polymer type (Hypermer A60nd)* and the secondary surfactant acopolymer of ethylene oxide and propylene oxide (Poloxamer 407)*.

* I.C.I., 1 Avenue Newton, 92142 Clamart

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In the first study [31], Ferreira investigated the release of an antibacterial agent(metronidazole), which could be used topically. The tests, performed with the Franz cell,compared the behavior of the three types of emulsions. Different membranes were used:a hydrophilic cellulose membrane, a lipophilic silicone membrane, and biopsied rat skin.The three types of emulsion were applied in an infinite dose with occlusion. The activesubstance was determined by High Performance Liquid Chromatography.

The influence of the type of emulsion on the release of metronidazole was abundantlyclear when the emulsions were deposited on a membrane, like the cellulosic membrane,which offers only weak resistance to the passage of the hydrophilic active ingredient.With this membrane, release is fast and nonlinear for the multiple emulsions (w/o/w) andfor the simple o/w emulsion, but it is slow and linear for the simple w/o emulsion. Thetotal quantity of active substance released immediately after application is about 15times greater from the first two emulsions than from the w/o emulsion. After 5 h,however, the proportion of metronidazole released is much higher from the w/o emulsion.The authors believe that this is due to depletion of the active substance from the twoemulsions with an aqueous external phase. This is not the case with the w/o emulsion; infact, only 3% of the dose applied is released from this form. These results can beexplained on the basis of the partition coefficient of metronidazole, which is relatively lowand more favorable to water.

The influence of the type of emulsion on release is much less clear if the emulsions aredeposited on membranes that control diffusion kinetics of metronidazole: silicone andbiopsied skin. Nevertheless, due to hydration, the passage of the active substance fromaqueous emulsions appears to be much easier across the skin than through the siliconemembrane. Yet the active substance always appears to be released slowly from thew/o/w multiple emulsion, slightly more slowly from the o/w emulsion, but much fasterfrom the w/o emulsion. Thus, with a hydrophilic active ingredient exhibiting weak affinityfor oil, the behavior of the multiple w/o/w emulsion is always intermediatè between thatof the other two emulsions but closer to that of the o/w emulsion.

In a subsequent study [32], Ferreira et al. conducted the same protocol but replacedmetronidazole with glucose, an active substance that possesses a much lower partitioncoefficient into oil. The glucose was determined by radioactivity. The authors found thesame release profile from the three types of emulsions with glucose as withmetronidazole. The in vitro flux is high for the o/w emulsion, low for the w/o emulsion,and intermediate for the multiple emulsion, irrespective of the type of membrane. Thus,for example, absorption across hairless rat skin is equal to 72 µg/cm2 for the o/wemulsion, 0.8 µg/cm2 for the w/o emulsion, and 7.8 µg/cm2 for the w/o/w emulsion. Theauthors show that although the release profiles are identical for all three emulsions, thedifferences in flux are greater with glucose than with metronidazole. For example, releasethrough rat skin biopsy is practically identical for the o/w and the w/o/w emulsionsimmediately after application. After the first few hours (312 h), however, the o/w

emulsion exhibits a high flux and then reaches equilibrium after 12 h. These differencesbetween the emulsions are explained by the differences in the partition coefficient ofglucose, favoring water more than metronidazole. With such a strongly water-solublesubstance, the behavior of the multiple emulsion is, therefore, close to that of the w/oemulsion.

Thus the behavior of the different types of emulsion on the skin appears to dependequally on the physicochemical properties of the active ingredient and on the vehicleitself. The behavior of a multiple emulsion, while always intermediate between the other

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two types of emulsion, can vary considerably according to the type of active substanceencapsulated. This observation was confirmed by Ferreira et al. in a final studyconcerning moisturizing active substances [33]. The authors show that, irrespective of thetype of moisturizer, the occlusivity of the multiple w/o/w emulsion is always lower thanthat of a simple w/o emulsion. By contrast, it differs from the effect of a simple o/wemulsion. Thus, when non-film-forming moisturizers are included in the internal aqueousphase (sodium lactate, glycerol, urea, sodium pyrrolidone carboxylate), the occlusivity ofthe multiple emulsion is higher than that of the simple o/w emulsion. On the other hand,with film-forming moisturizers (chitosan, hydroxypropylcellulose), the occlusivity is lower.This can be explained as follows: in the multiple emulsion and the o/w emulsion, thesemoisturizers are in the internal and external aqueous phase respectively. Afterapplication, when the water evaporates, a network of polymers exhibiting someocclusivity is formed from the o/w emulsion, but such a network is lacking in the multipleemulsions.

VIIIConclusions

No therapeutic applications of multiple emulsions in new medicinal products have beenproposed so far. The rarely marketed multiple emulsions are designed for cosmeticapplication, with claims for refreshing, moisturizing, perfuming properties, and the like.And yet it is likely that multiple emulsions may soon achieve wide acceptance aspharmaceutical dosage forms for topical use.

Multiple emulsions for topical use can be compounded as creams of varying consistencyand can be used as soon as they are formed. Unlike other vesicular systems, it is notnecessary to disperse them in a gel or in a cream in order to obtain a suitable topicalform. Moreover, recent research has demonstrated that multiple w/o/w emulsions displaybetter performance than simple emulsions with an aqueous continuous phase and arealso more pleasant to use than simple emulsions with an oily continuous phase, becausethey are less oily to the touch.

Multiple w/o/w emulsions provide water and oil to the skin, just like simple emulsions,and may contain various hydrophilic and lipophilic components. They are easy toadminister and also offer excellent cosmetic qualities. Multiple emulsions represent a newand interesting form in several respects. For example, they offer protection forencapsulated active substances and their prolonged release. When formulated with theproper components, they could be identified as targeted dosage forms like other vesicularsystems.

References

1. M. De Luca, C. Vaution, A. Rabaron, and M. Seiller, STP Pharma 4:67987 (1988).

2. D. Attwood and A. T. Florence, Multiple Emulsions, Surfactant Systems, Their

Chemistry, Pharmacy and Biology, Chapman and Hall, London, 1983, pp. 50966.

3. S. Matsumoto, J. Colloid Interf. Sci. 94:36268 (1983).

4. M. Frenkel, R. Schwartz, and N. Garti, J. Colloid Interf. Sci. 94:17478 (1983).

5. A. T. Florence, and D. Whitehill, J. Colloid Interf. Sci. 79:24356 (1981).

6. D. R. Kavaliunas, and S. G. Franck, J. Colloid Interf. Sci. 66:58688 (1978).

7. S. S. Davis, and A. S. Burbage, in Particle Size Analysis (M. S. Groves, ed.), Heyden,London,1978, pp. 395410.

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8. S. S. Davis, and A. S. Burbage, J. Colloid Interf. Sci. 62:36162 (1977).

9. S. Matsumoto, I. Takeshi, K. Masanori, and T. Ota, J. Colloid Interf. Sci. 77:56465(1980).

10. Y. Kita, S. Matsumoto, and D. Yonezawa, J. Colloid Interf. Sci. 62:8794 (1977).

11. A. A. Elbary, S. A. Nour, and S. A. Ibrahim, Pharm. Ind. 52:35763 (1990).

12. J. L. Grossiord, M. Seiller, and F. Puisieux, Rheol. Acta 32:16880 (1993).

13. I. Terrisse, M. Seiller, A. Rabaron, A. Magnet, C. Le Hen-Ferrenbach, and J. L.Grossiord, Int. J. Cosm. Soc. 15:5362 (1993).

14. S. H. Magdassi, M. Frenkel, and N. Garti, J. Dispersion Sci. Technol. 5:4959 (1984).

15. S. S. Davis, and I. Walker, Int. J. Pharm. 17:20313 (1983).

16. S. Fukushima, M. Nishida, and M. Nakamo, Chem. Pharm. Bull. 35:337581 (1987).

17. J. I. Ratz, and G. H. Cueman, J. Soc. Cosm. Chem. 39:21122 (1988).

18. C. M. Adeyeye, and J. C. Price, Drug Dev. Ind. Pharm. 16:105378 (1990).

19. S. Matsumoto, T. Inoue, M. Kohdo, and K. Ikura, J. Colloid Interf. Sci. 77:55559(1980).

20. S. Matsumoto, Y. Kita, and D. Yonesawa, J. Colloid Interf. Sci. 57:35361 (1976).

21. T. K. Law, T. L. Whateley, and A. T. Florence, J. Controlled Release 3:27990 (1986).

22. J. A. Omotosho, T. L. Watheley, and A. T. Florence, Biopharm. Drug Dispos. 10:25768(1989).

23. J. A. Omotosho, T. L. Whateley, and A. T. Florence, J. Microencapsulation 6:18392(1989).

24. J. A. Omotosho, T. L. Watheley, and A. T. Florence, J. Pharm. Pharmacol. 38:86570(1986).

25. E. Fredo-Kumbaradzi, and A. Simov, Pharmazie 47:38889 (1992).

26. P. Oza, and S. G. Frank, J. Dispersion Sc. Technique 10:16385 (1989).

27. A. T. Florence, and D. Whitehill, Int. J. Pharm. 11:277308 (1982).

28. M. A. Attia, and F. S. Habib, STP Pharma 2:63640 (1986).

29. C. Kundu Subhass, Preparation and evaluation of multiple emulsions as controlledrelease topical drug, delivery systems. Thesis, St. John's University, USA, 1990.

30. S. Raynal, J. L. Grossiord, M. Seiller, and D. Clausse, J. of Controlled Release

26:12940 (1993).

31. L. Ferreira, M. Seiller, J. L. Grossiord, J. P. Marty, and J. Wepierre, Int. J.Pharmaceutics 109:25159 (1994).

32. L. Ferreira, M. Seiller, J. L. Grossiord, J. P. Marty, and J. Wepierre, J. ControlledRelease, accepted for publication, September 1994.

33. L. Ferreira, M. Seiller, J. L. Grossiord, C. Vaution, J. P. Marty, and J. Wepierre, VI èmeCongrès International de Technologie pharmaceutique, APGI, Paris, 1992.

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7Multiphase EmulsionsH. E. JungingerDepartment of Pharmaceutical Technology, Leiden/Amsterdam Center for Drug Research,Leiden, The Netherlands

I. Introduction 156

II. Structural Elements of O/W Creams As MultiphaseEmulsions 157

A. Creams with Ionic Surfactants 157

B. Colloidal Structures of Nonionic Hydrophilic Creams 163

C. Conclusions 167

III. Colloidal Structures of W/O Creams 168

IV. Colloidal Gel Structures of Amphiphilic Creams 169

V. Formation of Colloidal Crystalline Gel Phases duringManufacturing 171

A. Hydrophilic Ointment, DAB 10, and Water-Containing Hydrophilic Ointment DAB 10 173

B. Stearate Creams 175

C. Nonionic Hydrophilic Cream DAC 176

VI. PhysicoChemical Stability and Aging of ColloidalCrystalline Gel Structures 176

VII. Surfactant Systems Used in Cosmetic MultiphaseEmulsions 179

A. Consistency Increasing Agents 179

B. Nonionic O/W Systems 180

C. Nonionic O/W Systems (Alkylsulfates) 180

D. Nonionic O/W Systems (Soaps) 181

E. W/O Systems 181

References 181

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IIntroduction

For many centuries ointments and creams have been used to improve the healing ofwounds, to treat skin diseases in empirical ways, and, moreover, to retard the agingprocess of the skin and to preserve its natural beauty. Modern cosmetics anddermatological preparations are identified as semisolids [1] due to their unique propertyof being in the solid state under ambient conditions and being transformed to the liquidstate when mechanically stressed during application on the skin. This property allows thesystems to spread easily on the surface of the skin. This semisolid state is also the maindifference between fluid liquid emulsions (in cosmetics often named milks) and creams,although in modern cosmetic preparations the transition from a cream to an emulsionmay be gradual. This semisolid state is attributed to particular structural elements,namely crystallineand in some cases liquid crystalline gelstructures of colloidaldimensions that form a three-dimensional network within the system. They areresponsible for the consistency and stability of the creams, for their application propertiessuch as proper feel, spreadability, and cooling effects and their possible interactions withskin lipids. Furthermore, their formation during the manufacturing process requires specialattention and mixing speed, and shear stresses have to be adapted to not interfereadversely in the crystallisation process of these crystalline structures. Additionally, thecolloidal gel structures are primarily responsible for the physical aging of topicalpreparations. As a consequence these colloidal gel structures form the inherent networksof semisolid preparations, whereas they are absent in liquid emulsions. Because thesecolloidal gel structures form additional phases in semisolid systems, they may be definedas multiphase emulsions.

In general, colloidal gel structures may be defined as special systems, consisting of atleast two components, which by themselves consist of one or more phases. By applyingthe classical definition of a gel, given by Wolfgang Ostwald, semisolids may be describedas two-component lyogels: the first component, being in the solid state, builds up acoherent three-dimensional networkalso called matrix or texturein which a liquid, thesecond component, is immobilized as the other coherent medium. A typical gel may becompared with a water-soaked sponge. Since both phases completely interpenetrate (bi-coherent system), a differentiation between the inner and the outer phaseas is possiblefor liquid emulsions and suspensionscannot be made. This three-dimensional structure ofthe gel network is built up in semisolids by secondary valence forces, particularly by vander Waals forces and hydrogen bonds.

Creams as multiphase systems are defined as water-containing ointments and hence aredispersed systems, in which the dispersed phase is stabilized by such a gel structure.Depending on the type of cream, the continuous liquid phase is always part of the three-dimensional gel structure, i.e. in oil in water (o/w) creams the oily phase is the dispersedphase and water the continuous phase, both stabilized by colloidal structures. In water in

oil (w/o) creams the aqueous phase is the dispersed one, and the oily phase is thecoherent liquid phase of the colloidal gel structure. In amphiphilic creams special colloidalgel structures exist that allow either the transition to an o/w cream if water is added or toa w/o cream if the amount of the oily phase is increased.

If the colloidal structures of the different types of cosmetic creams are understood andknown, systematic development of creams with desirable properties becomes possible,and a basic understanding of these multiphase emulsions will be the key to modernformulation approaches. Most research dealing with characterization of the colloidal gel

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structures of semisolids as ointments and creams has been conducted withpharmaceutical formulations that will be described in the following paragraphs. However,the basic results obtained for special formulations (which are sometimes taken up asofficial monographs in pharmacopoeias) have general applicability and are also valid forcosmetic preparation because they contain either the same or similar ingredients. Hencethe colloidal gel structures of multiphase emulsions can be viewed as basic systems validfor both cosmetics and pharmaceutical preparations.

Generally, in pharmaceutical formulations, the oily phase of these systems consistsmainly of petrolatum or paraffinum sub- or perliquidum. The cosmetic properties,however, may be improved (resulting in a less occlusive effect) by using more skin-compatible emollients such as isopropyl myristate, oleyl oleate, and triglycerides withfatty acids of medium chain length. In the following structural models, these oilycomponents are regarded as inert, simple paraffins; although due to their weak polarity,these compounds may show some slight interference with the crystalline colloidal gelstructure. On the other hand, humectants such as glycerol, sorbitol, and naturalmoisturizing factors (NMF) in low concentrations are treated as belonging to the waterphases.

In this chapter the structural elements of multiphase emulsion as well as theirimplications on rational cream design and manufacture will be discussed.

IIStructural Elements of O/W Creams as Multiphase Emulsions

ACreams with Ionic Surfactants

1Colloidal Structures of Cetostearyl* Sulfate Creams

As a model system for cetostearyl creams (o/w creams), the Water ContainingHydrophilic Ointment DAB 10 (German Pharmacopoeia, 10th ed. Govi Verlag,Frankfurt/Main, 1992) will be discussed. Its formula is as follows:Emulsifying Wax 9.0% wt/wtLiquid Paraffins 10.5% wt/wtWhite Petrolatum 10.5% wt/wtWater 70.0% wt/wt

Emulsifying Wax (DAB 10) itself consists ofCetyl sulfate sodium 5% wt/wtStearyl sulfate sodium 5% wt/wtCetyl alcohol 45% wt/wtStearyl alcohol 45% wt/wt

Small angle X-ray diffraction (SAXD) and wide angle X-ray diffraction (WAXD) incombination with quantitative differential scanning calorimetry (DSC), thermogravime-

*The term cetostearyl is used here as shorthand for blends of C16 and C18 alkyl derivatives.

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Fig. 1Gel structures of the Water Containing Hydrophilic OintmentDAB 10. a: mixed crystal bilayer of cetostearyl alcohol andcetostearyl alcohol sulfates, b: interlamellarly fixed waterlayer, a + b: hydrophilic gel phase, c: lipophilic gel phase(cetostearyl alcohol semihydrate), d: bulk water phase,

e: lipophilic components (dispersed phase).(From Ref. 5.)

tric analysis (TGA), and polarization microscopical techniques led to the followingstructure of the Water Containing Hydrophilic Ointment DAB 10 [25]. It was found thatsuch o/w creams may be regarded as four-phase systems (Fig. 1). The dominant matricesare the hydrophilic and the lipophilic gel phases. Both gel phases consist of surfactantbilayers of colloidally sized mixed crystals. The surfactants in the bilayers are oriented insuch a way that the hydrocarbon tails are directed towards each other, as are the polargroups (Fig. 1, region a). The hydrophilic gel phase consists of cetostearyl alcohol and allof the ionic sodium n-alkylsulfates, which are randomly distributed between thecetostearyl alcohol molecules. The latter act as lateral spacers for the strong polarsodium n-alkylsulfate molecules. In the crystalline bilayer structure, therefore, stronghydrophilic moieties and hydrophobic cores counteract each other (Fig. 1, region a).

One part of the total water amount of the system is interlamellarly inserted between thepolar groups of the surfactant molecules (Fig. 1, region b). This part of the water isnamed interlamellarly fixed water. Regions a and b together form the hydrophilic gelphase. The water molecules interlamellarly fixed in the hydrophilic gel phases are inequilibium with water molecules in the other aqueous part, the bulk water phase (Fig. 1,region d). The bulk water phase is the liquid component of the gel structure, and the solidphase is the hydrophilic gel phase (although it contains part of the water interlamellarlybound). The bulk water is fixed within the network of the hydrophilic gel phase mainly bycapillary attraction forces. Furthermore, it is assumed that the interlamellarly fixed watermolecules exhibit physicochemical properties differing from those of the bulk waterphase.

The surplus of cetostearyl alcohol not incorporated in the hydrophilic gel phase builds upa separate matrix with lipophilic properties (Fig. 1, region c) called lipophilic gel phase.The inner or dispersed phase (Fig. 1, region e) is to a large degree immobilizedmechanically by this lipophilic gel phase. The lipophilic gel phase consisting of purecetostearyl alcohol is only able to form a semihydrate with water [3].

Freeze fracture electron microscopy (FFEM) has added a new dimension to the studies

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Fig. 2Freeze fracture micrograph of Emulsifying Wax DAB 10 (main structural component ofthe Water Containing Hydrophilic Ointment DAB 10) with 70% wt/wt of water. a: mixed

crystal bilayer, b: interlamellarly fixed water, a + b: hydrophilic gel phase, c: fractureedge of a lipophilic plane, d: bulk water phase. Magnification 48,000-fold.

(From Ref. 5.)

of colloidal o/w cream organization. This technique allows the visualizationat an ultra-structural levelof the previously mentioned structural elements [58]. From Fig. 2 thehydrophilic gel phase can be recognized very clearly. In this micrograph the alternatinglayers of the hydrophilic gel phase are nearly at right angles to the fracture plane.Together with areas of bulk water (d) entrapped in the hydrophilic gel phase, theinterlamellarly bound layers of water (b) and the bilayers of the surfactant molecules (a)are visible. Together, (a) and (b) form the hydrophilic gel phase.

Investigations into the swelling ability of the Emulsifying Wax DAB 10 (main surfactantcomponent of the Water Containing Hydrophilic Ointment DAB 10) with water show acharacteristic swelling behavior of the lamellar gel structure resulting in a straight line(Fig. 3), when the long spacings, as obtained from small angle X-ray diffraction (SAXD),are plotted versus the water/surfactant ratio (wt/wt) (see Fig. 3, where Ca is the weightfraction of surfactants; 1-Ca is the weight fraction of water). At a water content of 70%wt/wt the thickness of the interlamellar fixed water layer is about 15 nm (total longspacing minus long spacing of cetostearyl alcohol). For comparison, the molecular sizesfor the cetostearyl alcohol (lipophilic gel phase) as semihydrate and for the hydrophilicgel phase are given on the right-hand side of Fig. 3.

It must be emphasized that the degree of swelling of the hydrophilic gel phase dependson the total water content of the cream. Hence a dynamic equilibrium exists between thebulk water and the interlamellarly fixed water. The bulk water phase forms

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Fig. 3Swelling behavior of Emulsifying Wax DAB 10 with water.Ca: weight fraction of surfactant, 1-Ca: weight fraction of

water, : interplanar spacings of cetostearyl alcoholsemihydrate (lipophilic) gel, : interplanar

spacings of the hydrophilic gel phase.(From Ref. 3.)

the continuous phase of the system, but the interlamellar water fraction also contributesto this continuity. The capacity of the hydrophilic gel phase to incorporate interlamellarwater is high enough to obtain clearly defined melting and recrystallization peaksmeasured by DSC, which strongly vary from the water-free systems (see Sec. V.A.). At acertain water content of the system, maximum swelling of the interlamellar water layer isreached. Beyond this point the water molecules within the interlamellar layer possess thesame mobility as those of the bulk phase. Consequently, the colloidal structure of thehydrophilic gel phase breaks down, and the three-dimensional gel structure is lost. Thisphysical change represents the transition from the cream into the (unstable) state of asuspension (emulsion). As a result of this transition, the plastic flow behaviour propertiesof the cream are lost, and the system exhibits the pseudo-plastic flow behaviour of anemulsion or a suspension.

The lipophilic gel phase (Fig. 1, region c) can only form a semihydrate with water, whichis independent from the total water present in the system. After the transition from acream into an emulsion (suspension) state, the lipophilic gel phase still surrounds andstabilizes the dispersed inner phase (Fig. 1, region e).

To characterize these o/w creams further, a technique was sought that allows a more

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quantitative differentiation between the different types of water in these systems. It maybe speculated that the swelling capacity of the hydrophilic gel phase may influence thewater release to the skin and consequently the cooling efficiency of the creams. Bymeans of a dynamic thermogravimetric analysis (TGA), a method was developed thatenabled us to differentiate between interlamellarly fixed water and the bulk waterfraction [3,4]. The TGA results form the Water Containing Ointment DAB 10 with 70%water (wt/wt) and systems with lower water content are summarized in Fig. 4. The totalwater contents of the different creams are plotted against interlamellarly fixed waterfractions. At a total water amount of 70% wt/wt about 40% wt/wt is presentinterlamellarly in the hydrophilic gel phase and only 30% wt/wt belongs to the bulk waterphase. If the total water exceeds about 80% wt/wt the hydrophilic gel phase reaches asaturation state, in which the water molecules in the middle of the water layer betweenthe bilayers are found to have the same free energy as those of the bulk water moleculesat the same temperature. This superhydrated state of the hydrophilic gel phase by waterrepresents the transition from a cream into an emulsion. If this over-hydrated state isexceeded, the fraction of interlamellarly fixed water decreases markedly in favour of thefraction of the bulk water phase (Fig. 4 open symbols).

2Colloidal Structures of Stearate Creams

For stearate creams a formulation proposed by Tronnier and used in cosmeticformulations was chosen as a model system [9]. The stearate creams investigated hadthe following compositions:

Fig. 4Amount of interlamellarly fixed water in Water Containing

Hydrophilic Ointment DAB 10 depending on the total watercontent of the system ( = unstable systems).

(From Ref. 3.)

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Stearic acid 12% wt/wtPalmitic acid 12% wt/wtTriethanolamine 1.2% wt/wtGlycerin 13.5% wt/wtWater 1061.3% wt/wt

Addition of water to the water-free system that consists of stearic acid, palmitic acid, andtriethanolamine results in lamellar mixed crystals in which the water is incorporatedbetween the hydrophilic moieties of the lamellae. With increasing water concentrations(1061.3% wt/wt) the swelling capacity of this hydrophilic gel phase is enhanced (Fig. 5).The thickness of the interlamellar water layer is about 6.5 nm at a water content of 60%wt/wt (total long spacing equals 12.6 ± 0.2 nm) [5,10].

The results obtained by means of SAXD, DSC, and TGA led to a structure model forstearate creams as given in Fig. 6 [3,5,10]. The part of the lamellar mixed crystals thatconsists of free fatty acids and their triethanolamine salts is able to form the hydrophilicgel phase. Between the polar moieties of the mixed crystals (Fig. 6, region a) watermolecules are present (Fig. 6, region b). This water of the hydrophilic gel phase is inequilibrium with the bulk water of the continuous phase (Fig. 6, region d).

Fig. 5Swelling behavior of the gel forming components (triethanolamine stearate/palmitate)

of a stearate cream with water. Ca: weight fraction of surfactants, 1-Ca: weight fractionof water, : interplanar spacing of stearic/palmitic acid mixture (1:1 moles); lipophilic

gel phase, : interplanar spacing of triethanolamine stearate/palmitate (water free), :interplanar spacing of triethanolamine stearate/palmitate swollen with water

(hydrophilic gel phase of the stearate cream).(From Ref. 3.)

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Fig. 6Gel structures of stearate creams. a: mixed crystal

bilayer of triethanolamine stearate/palmitate, b:interlamellarly fixed water, a + b: hydrophilicgel phase, c: lipophilic gel phase (''stearate"),d: bulk water phase, e: isolated "stearate."

(From Ref. 3.)

The second part of the gel network, consisting of pure mixed crystals of palmitic andstearic acid, which cannot retain water interlamellarly, forms a lipophilic gelphase (Fig. 6,region c). If a dispersed (lipophilic) phase should be present in such a system, it would beessentially immobilized by the lipophilic gel phase. Stearate creams can show a specialpearl effect due to the crystallization of very small isolated platelets (Fig. 6, region e),depending on the amount of added triethanolamine and on the manufacturing conditions.Platelets are formed preferentially instead of a coherent lipophilic gel phase, especially inthe absence of a lipophilic phase.

The thermogravimetric results of the stearate cream are depicted in Fig. 7. It becomesapparent that at a high water content only one-third of the water is fixed interlamellarly,but two-thirds of the water is present as a bulk water phase, which is directly availablefor skin hydration. These facts may explain the results of Tronnier, who stated that theskin hydration rate by stearate creams is much higher in comparison to other o/w creams[9].

These facts could also be confirmed by isothermal TGA, comparing systems with differentratios of interlamellarly fixed water in their hydrophilic gel phases. At ambienttemperatures, stearate creams lost a substantial part of the incorporated water muchmore quickly than Water Containing Hydrophilic OIntment DAB 10 with a high amount ofinterlamellarly fixed water.

At a total water amount higher than 55%, these systems become unstable (Fig. 7), and atransition takes place from a cream with a coherent three-dimensional hydrophilic gelnetwork to an emulsion without these structural elements [4, 5].

BColloidal Structures of Nonionic Hydrophilic Creams

The o/w creams with crystalline gel structures in which nonionic emulsifiers are presentare widely used in topical and cosmetic preparations. This is easily explained by the factthat nonionic emulsifiers cause less irritation on sensitive skin compared to ionic

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Fig. 7Ratio of bulk and interlamellarly fixed water of a stearatecream, which depends on the total water amount of the

systems ( , = unstable systems).(From Ref. 3.)

emulsifiers. They tolerate addition of ionic compounds as active ingredients much better,and the stability of the system is not affected as severely as in the case of ionic creams.Last but not least, a large number of nonionic emulsifiers that meet all formulationrequirements are on the market today.

To exemplify an o/w cream with nonionic emulsifier a water-containing nonionichydrophilic ointment with the following formula is described:PEG-20 glyceryl stearate (PGM20) 7.5% wt/wtLiquid paraffin 7.5% wt/wtCetyl alcohol 5.0% wt/wtStearyl alcohol 5.0% wt/wtGlycerin 8.5% wt/wtWhite soft paraffin 17.5%

wt/wtWater 51.5%

wt/wt

This particular system is known as Unguentum Hydrophilicum Nonionicum Aquosum, DAC(Deutscher Arzneimittel Codex, 1979). Similar formulations appeared in the SwissPharmacopoeia, 6th edition, and in the Formulary of the Dutch Pharmacists (FNA).

Investigations using SAXD showed that mixtures of PGM20 and cetostearyl alcoholcrystallize as mixed crystals (Fig. 8). In the water and glycerin free system the diffractionpeaks of pure PGM20 and cetostearyl alcohol are also found.

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Fig. 8Swelling characteristics of cetostearyl alcohol, PEG-20 glyceryl stearate and water mixtures.In the water-free state two diffraction peaks are found for cetostearyl alcohol (4.7 nm) and

cetostearyl alcohol/PEG-20 glyceryl stearate mixed crystals (6.3 nm). Up to 25% wt/wtwater, irreproducible diffraction peaks are found due to insufficient hydration of thepolyoxyethylene groups. Between 2560% wt/wt water, continuous swelling of the

hydrophilic gel phase takes place. At a water content higher than 60% wt/wtthe hydrophilic gel phase becomes unstable and breaks down.

(From Ref. 3.)

With SAXD no reproducible repeating distances are found up to 25% wt/wt if water isadded to the water free system (Fig. 8). The samples remain solid-like, and polarizationmicroscopy shows anisotropic structures. At a water content of 25% wt/wt thepolyoxyethylene chains are just surrounded by the minimum of hydration water neededto build up a homogeneous lamellar structure. As a consequence, any reduction of thewater content leads to formation of mixed crystals containing partially hydrated orincompletely hydrated polyoxyethylene chains as well as cetostearyl alcohol and PGM 20.This picture (Fig. 8) is reinforced by the observation that samples containing less than25% wt/wt water show several endothermal peaks with DTA, and no electricalconductivity is observed. Thus, the coherency of the water layer has not been reached[11,12] due to insufficient hydration of the polyoxyethylene groups of PGM20.

Between 2560% (wt/wt) water, continuous swelling of the hydrophilic gel phase

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takes place (Fig. 8). In this system the nonionic surfactant PGM20 crystallizes withcetostearyl alcohol in the form of mixed crystals (Fig. 9, region a). The degree of swellingwith water depends on total water content. The length of the polyoxyethylene unitdetermines the maximum swelling capacity of the systems. Together with the waterbound to the polyoxyethylene units of the PGM20 molecules, the lamellar mixed crystalsbuild up the hydrophilic gel phase (Fig. 9, regions a and b) into which some bulk watermay also be incorporated. The hydrophilic gel phase together with (part of) the bulkwater (Fig. 9, region d) are the components of the three-dimensional gel network. Thesurplus of cetostearyl alcohol again forms the lipophilic gel phase (Fig. 9, region c), whichimmobilizes the lipophilic dispersed phase (Fig. 9, region e) consisting mainly of whitepetrolatum and liquid paraffins. As a result of these investigations it is concluded thatnonionic o/w creams may also be regarded as four-phase systems consisting of the samestructural elements as the ionic o/w creams [5,13]. Many nonionic surfactants withvarious PEG-chain-lengths are available. Thus it becomes possible to develop nonionico/w creams with any desired ratio of interlamellarly fixed water and bulk water fraction.Knowledge of these gel structures is of fundamental importance for developingformulations with desired properties such as controlled water release, especially in lightof the interactions between the vehicles and the skin [14,15].

Fig. 9Schematic presentation of the gel structures of nonionic hydrophiliccream (DAC 79). a: mixed crystal bilayer of cetostearyl alcohol and

PEG-20 glycerylmonostearate (PGM 20), b: interlamellarly fixedwater, a + b: hydrophilic gel phase, c: lipophilic gel phase(cetostearyl alcohol-semihydrate), d: bulk water phase, e:

lipophilic components (dispersed phase).(From Ref. 5.)

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CConclusions

The o/w creams with colloidally sized crystalline gel structures do not represent classicalo/w emulsions in which typical oil droplets, the inner phase, are stabilized by surfactantlayer(s). On the contrary, they form coherent colloidal networks with water filled pores. Alarge proportion of the water present in these creams is interlamellarly fixed.

The following conclusions may be drawn from the structure models for o/w creams withnonionic and ionic emulsifiers.

Interlamellarly Fixed Water

Interlamellar water, which is stabilized by interfacial forces, has different physicochemicalproperties than free water. During storage of the creams it has been shown (see Sec. V ofthis chapter) that there is a shift in the ratio of interlamellarly fixed water to bulk water infavor of the bulk water [15]. This may have some influence on the release of activesubstances and on the cooling effect of the creams.

Cooling Effect

The gel structures of the various o/w creams described here always contain a portion ofinterlamellarly fixed water in the hydrophilic gel phase, while another portion representsthe bulk water phase. An o/w cream is smoothly applied to the skin surface, but only thefree water (bulk water) may be readily available. In the above-mentioned stearate creamtwo-thirds of the total water is directly available for evaporation, while only one-third isinterlamellarly fixed. Therefore, such a stearate cream shows excellent coolingproperties. In o/w creams with nonionic emulsifiers the ratio of bulk water andinterlamellarly fixed water depends largely on the polyoxyethylene chain length: withincreasing chain length the interlamellarly fixed water increases, and the extent of thecooling effect can thus be simply determined by the chain length. It must be noted,however, that interlamellarly fixed water, which is expected to be released slowly, canhave a sustained release effect on the skin only as long as the colloidal structures are notdestroyed during application to the skin. By selecting the appropriate components of thehydrophilic gel phase, the interlamellarly fixed water amount and hence the cooling effectof the system can be varied to a certain extent.

Transition from Cream to a Liquid Emulsion

When a large amount of water is added, the hydrophilic gel phase swells until a thresholdvalue is reached. At this value the water molecules in the middle of the swollen layerhave the same free energy as the molecules of free, unfixed water (bulk water) at thesame temperature. In this transition state, the same high mobility of the water moleculesin the hydrophilic gel phase as that in the bulk water phase is reached, which causes thebreak-down of the hydrophilic gel phase.

The transition is characterized by the fact that the cream is transformed into a statewhich is described as a "liquid emulsion" or, in cosmetic terms, as a "milk." The plasticflow behavior properties of the cream (due to the gel structures) and the cream's yieldvalue are lost; the resulting system exhibits the pseudo-plastic flow behavior of anemulsion.

Improved Viscosity of O/W Creams

Fatty alcohols play an important role in the formation of the hydrophilic gel phase. Thesurplus of fatty alcohols, which is not integrated into the hydrophilic gel phase, forms thelipophilic gel phase. An increase in the proportion of fatty alcohols in such creams alwaysleads to increased formation of the lipophilic gel phase and is accompanied by anincrease in the viscosity of the entire system. This facilitates control of the viscosity ofo/w creams. A large proportion of a lipophilic gel phase can influence the interaction ofthe system with the skin. Systems

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with a very viscous lipid film have occlusive effects on the skin surface and may enhancetherapy. For example, users of a sun protection cream with a high sun protection factordo not like to have a white fat film residue on the skin, which has to be intensivelymassaged into the skin. In addition, the long-term efficacy of the sun protection cream isimproved.

Salt Intolerance

Addition of 2- or 3-valent ions to the hydrophilic gel phase of systems with ionicsurfactants that are stabilized via interfacial forces triggers a very sensitive reaction:when Ca2+, Mg2+, or Al3+ (as well as high concentrations of Na+ and K+ are added, thestabilizing interfacial forces of the hydrophilic gel phase are lost, and the interlamellarlyfixed water is released. An irreversible phase separation occurs. The fact that white spotsmay appear on the skin surface after the application of such a cream can be attributed tothis destabilization of the cream. If the salt content on the skin is too high (e.g. aftersevere sweating), phase separation of interlamellar water from the hydrophilic gel phasemay occur, and the fatty residues of the cream become visible as white spots. Creamswith nonionic emulsifiers in general, however, do not react as strongly to salt addition assystems with ionic emulsifiers.

IIIColloidal Structures of W/O Creams

By definition w/o creams are hydrophobic systems, the continuous phase of which islipophilic. A general formula of a w/o system (according to DAB 10) is as follows:Anhydrous lanolin (wool fat)* 3.00% wt/wtCetostearyl alcohol 0.25% wt/wtWhite petrolatum 46.75% wt/wtWater 50.00% wt/wt*with cholesterol as the most importantingredient.

A schematic presentation of w/o cream gel structures is given in Fig. 10. The w/osurfactants (cholesterol and other sterols as well as cetostearyl alcohol) accumulateprimarily at the interface between the water droplets and the oily phase of whitepetrolatum, forming a monomolecular mixed layer of surfactants at the water/oilinterface. Experimental work has proven that the water capacity strongly increases whenmixtures of fatty alcohols and sterols are used. It seems to be important to create a liquidcrystalline monolayer at the oil/water interface. Crystallization of the surfactant film atthe interface drastically reduces the system's capacity to take up water. As expected fromtheir solubilities the sterols and fatty alcohols are dissolved in the paraffin mixture (whitepetrolatum). A surplus of these o/w emulsifiers may cause separate crystallization in thelipophilic phase and may, in addition, strengthen the (para)crystalline gel structures ofwhite petrolatum [5].

The w/o creams represent classical w/o emulsions that are stabilized by a highly viscousgel of paraffins. The long-chain paraffins are able to build up a three-dimensional solidgel network in which the short-chain liquid paraffins are mainly immobilized bylysosorption [5].

In contrast to the o/w creams described in Sec. II, the crystalline gel structures of w/ocreams do not contain any water between the paraffin lamellae, nor does the crystalline

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Fig. 10Schematic presentation of the gel structures of a w/o cream: long paraffin chains

are forming the solid gel in which liquid paraffin chains are immobilized by lyosorption.Both cetostearyl alcohol ( ) and cholesterol (derivatives) ( ) accumulateat the waterparaffin interface, and both are molecularly dispersed in the paraffin

gel according to their solubilities: a surplus of cetostearyl alcohol maycrystallize as separate lamellar crystals.

(From Ref. 5.)

gel structure show swelling properties upon addition of the liquid component (short-chainliquid paraffins).

IVColloidal Gel Structures of Amphiphilic Creams

Amphiphilic creams are colloidal systems that transform by addition of an oily phase to aw/o cream and by water addition to an o/w cream. They therefore represent a specialtransition state between the other two cream types. A colloidal state is obligatory for theexistence of special gel structures in amphiphilic creams. Another prerequisite for theexistence of a cream with amphiphilic properties is the presence of lamellar mixedcrystals that exhibit only limited swelling upon water addition. Examples of suitablesurfactants fulfilling these requirements are glyceryl stearate and esters or ethers of PEGwith fatty alcohols or fatty acids. The degree of polymerization of the PEG should be lowwith

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n = 23. All these compounds are surfactants of the w/o type. The colloidal structure of anamphiphilic cream is illustrated with aid of the "basic cream" of DAC (DeutscherArzneimittel-Codex, Govi Verlag, Frankfurt/Main, 1986) having the following formulations:Glyceryl stearate 4.0% wt/wtCetyl alcohol 6.0% wt/wtMedium chain triglycerides 7.5% wt/wtWhite petrolatum 25.5%

wt/wtPEG-20 glyceryl-stearate(PGM20) 7.0% wt/wt

Propyleneglycol 10.0%wt/wt

Water 40.0%wt/wt

The limited swelling ability of glyceryl stearate is well documented in the literature[16,17]. Melted glyceryl stearate together with water swells continuously byinterlamellarly incorporating water molecules between the hydrophilic glycerin residueuntil a water content of 30% wt/wt is reached. At higher amounts of water the degree ofswelling remains constant, and the excess water is incorporated mechanically as droplets(bulk water phase) in the glyceryl stearate gel structure [5].

Conductance measurements of mixtures of glyceryl stearate, liquid paraffins, and waterwith a constant amount of glyceryl stearate of 30% wt/wt show no conductivity below awater content of 20% wt/wt (Fig. 11). Systems containing less than 20% wt/wt of waterexhibit w/o characteristics [5].

On the other hand, mixtures with a water content between 60 and 70% wt/wt show o/wcharacteristics. In the range between 2050% wt/wt water, the systems behave asamphiphilic systems, i.e., addition of water results in o/w systems, while addition of liquidparaffins generates w/o systems. However, none of these simple systems meet therequirements of well-developed creams for pharmaceutical or cosmetic use. The resultingo/w systems are generally unstable, and phase separation of the mechanically stabilizedbulk water phase occurs. Therefore, well-compounded formulations of these amphiphilicsystems contain added nonionic o/w emulsifiers with high water binding capacity. In theabove mentioned formulation of DAC, PGM 20 is added, which can form stable o/wcompounded creams at high water content, i.e. exceeding 50% wt/wt. Amphiphiliccreams commonly contain relatively high amounts of o/w and w/o surfactants, and the oiland water phases are approximately equal.

Amphiphilic creams are tri-coherent systems:

the dominant coherent gel phase is built up by glyceryl stearate lamellae,

the coherent continuous water phase consists mainly of interlamellarly bound waterbetween the glyceryl stearate lamellae, and

the lipophilic phase is also coherent.

The liquid paraffins are predominantly mechanically fixed by the glyceryl stearatelamellae. A schematic representation of the proposed gel structures of an amphiphiliccream and the transitions to a w/o system and o/w system are given in Fig. 12 A, B, andC, respectively.

Starting with the above described amphiphilic system (Fig. 12B), the degree of waterswelling of the glyceryl stearate lamellae is strongly reduced by addition of oil. Due to

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Fig. 11Conductivity of paraffinwater mixtures with a constantamount of glyceryl stearate (Tegin M) of 30% wt/wt.

(From Ref. 5.)

the favorable phasevolume ratio with respect to the lipophilic phase, a w/o cream resultsautomatically (Fig. 12A). On the other hand, an increase of the water level of theamphiphilic basic cream allows strong swelling of the PGM 20 surfactant-cetyl alcohollamellae, which additionally stabilize the bulk water phase (Fig. 12C). As a result, wateraddition yields a stable o/w cream.

VFormation of Colloidal Crystalline Gel Phases during Manufacturing

In the previous parts of this chapter it has been shown that lamellar mixed crystals ofcolloidal size form the most important structural elements of o/w creams: the hydrophilicand the lipophilic gel phases that are the solid parts of the gel structure of these systems.In amphiphilic creams a hydrophilic gel structure with limited swelling potential coexistswith precursors of hydrophilic and lipophilic gel phases, which may transform to thesecrystalline phases after addition of water or oil to the amphiphilic starting systems. Allsolid components of the gel structure in creams consist of lamellar crystals, which in thecase of hydrophilic gel phases, may be able to incorporate large amounts of waterbetween the lamellae.

During the manufacturing process these lamellar structures must recrystallize from

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Fig. 12Schematic presentation of gel structures existing during the transition from a w/o-cream(A) to an amphiphilic cream (B) and to a o/w-cream (C). a: Mixed crystals consisting of

PEG-20 glyceryl stearate and cetostearyl alcohol (A in the water-free state, B in the

partly swollen state, C in the swollen state). b: Mixed crystals of glycerol stearate andcetostearyl alcohol with limited swellability (A in the water-free state, B and C in the

state of limited swelling). c: Lipophilic phase (A as coherent continuous phase,B as coherent phase, C as dispersed inner phase).

(From Ref. 5.)

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the melted mixture of all components of the system, and care must be taken during thecooling part of the manufacturing process in order not to destroy these lamellae byexcessively high shear forces. As a matter of fact, in all the systems investigated,incorporation of water between the lamellae (hydrophilic gel phase) yields higher melting(recrystallization) peaksmeasured by differential scanning calorimetry, DSCby comparisonto the water free systems (lipophilic gel phase). Both hydrophilic and lipophilic gel phasesare present, and the different recrystallization temperatures of these gel phases must beconsidered during the manufacturing process. In the following paragraphs the formationof the crystalline gel phases is discussed.

AHydrophilic Ointment, DAB 10, and Water-Containing Hydrophilic Ointment DAB 10

Differential scanning calorimetry measurements of Hydrophilic Ointment DAB (i.e., theWater-Containing Hydrophilic Ointment in the absence of water (the formulationpresented in Sec. II.A.l. of this chapter)) have shown the following results (18).

The heating curve shows two distinct endothermic peak maxima at 23°C and 41°C,respectively (Fig. 13a). The first peak at 23°C represents the polymorphic phasetransition of the b0-modification to the a-modification of the mixed crystals consisting of90% wt/wt of cetostearyl alcohol and 10% wt/wt of sodium cetostearyl sulfate. The weakshoulder at 37°C represents the phase transition of the g4-polymorph to the a-modification. The broad peak with a peak maximum at 41°C represents melting of whitepetrolatum components and the phase transition from the a-modification to the liquidphase of cetostearyl alcohol (sulfate sodium). Upon cooling of the completely moltensystems, the correspondent peak for recrystallization and polymorphic phase transitionsare obtained (Fig. 13a).

After addition of 20% wt/wt of water, the Hydrophilic Ointment DAB 10 shows completelydifferent DSC scans (Fig. 13b): the polymorphic phase behavior of the fatty alcoholcomponents is shifted to lower temperatures. The melting point of the a-phase togetherwith the white petrolatum components is slightly increased from 41°C to 43°C, and a newpeak is seen at 68°C. Similar exothermic peak patterns are obtained during cooling of thesample.

The Water-Containing Hydrophilic Ointment DAB 10 with 70% wt/wt water shows thefollowing DSC scans (Fig. 13c). Upon heating, a very shallow peak in the temperaturerange of 28°C up to 42°C indicates melting of the white petrolatum components of thesystem. The peak at 54°C results from the melting of the cetostearyl alcohol(semihydrate), which is the lipophilic gel phase of the system. The peak at 72°C resultsfrom the melting of the hydrophilic gel phase of the systems. Note that the area underthe peaks is reduced due to the large amount of water added to the system [18].

Upon cooling of the molten system the hydrophilic gel phase recrystallizes at about 70°C,whereas the lipophilic gel phase solidifies at 54°C and the white petrolatum components

finally stiffen the system in the temperature range between 42°C and 28°C (Fig. 13c).

In the manufacturing process, the lipophilic components are heated to about 80°C, towhich water at the same temperature is added under vigorous stirring in order to achievehomogeneous mixing. At this temperature a w/o emulsion exists. At 75°C phase inversionto an o/w emulsion takes place, subsequently followed by recrystallization of thehydrophilic gel phase of the system. Below that temperature the shear stress applied tothe system must be reduced in order to ensure the interlamellar insertion

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Fig. 13DSC heating and cooling curves (heating and cooling rate: 2 K/min) of

a: water free formulation (Hydrophilic Ointment DAB 10), b: water ContainingHydrophilic Ointment with 20% wt/wt water, and c: water Containing

Hydrophilic Ointment of 70% wt/wt water. DAB 10 formula.(From Ref. 18.)

of water molecules between the mixed crystals of the hydrophilic gel phase. At about54°C the lipophilic gel phase crystallizes and stabilizes the dispersed lipophilic phase.During manufacturing, stirring should still be high enough to remove solidifying materialfrom the vessel's wall and distribute it homogeneously among the other (still liquid)material.

High speed and high shear processes, however, may lead to complete destruction of thecolloidal structures of such an o/w cream: whereas the ratio of interlamellarly fixed tobulk water in the Water Containing Hydrophilic Ointment DAB 10 is about 40 to 30%wt/wt as shown in Fig. 4 of this chapter, the ratio becomes 61 to 9% wt/wt when thecream is subjected to high shear stress (Ultra Turrax) during the complete cooling cycles[19]. Such treatment results in a completely inhomogeneous cream with phaseseparation of the water phase. If such a ''destroyed" cream is reheated to 80°C andcooled down with appropriate shear stress, a homogeneous o/w cream is obtained.

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BStearate Creams

Differential scanning calorimetry investigations of the water-free formulation (see Sec.II.A.2.) show a strong endothermic peak at 57°C [10] (results not shown). Polymorphicphase transitions are less pronounced in mixtures of fatty acids compared to thecorresponding fatty alcohols. When water is added in increasing amounts to the waterfreecomponents, DSC scans show two clearly distinguishable peaks at 57°C and 60°Crespectively (Fig. 14a, b, and c). They can be attributed to the melting of the lipophilicgel phase (57°C) and of the hydrophilic gel phase (60°C) of the stearate creams. Thecorresponding cooling curves in Fig. 14 show the same exothermic peaks even moreclearly, indicating crystallization of the hydrophilic gel phase at about 56°C andrecrystallization of the lipophilic gel phase at about 47°C. During manufacture, highmixing speed with high shear stress should be applied during the cooling process until60°C is reached. Then mixing with low shear stress should be continued untilcrystallization of all components of the stearate cream is complete [10].

Fig. 14DSC heating and cooling curves (heating and cooling rate: 2 K/min)

of a: water containing stearate cream with 20% wt/wt water, b: watercontaining stearate cream with 30% wt/wt water, and c: water

containing stearate cream with 50% wt/wt water.(From Ref. 10.)

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CNonionic Hydrophilic Cream DAC

The water-free formulation of the Nonionic Hydrophilic Cream DAC (See Sec. II.B. of thischapter) shows three distinct endothermic peaks at 32°C, 40°C, and 51°C, as depicted inFig. 15 [12]. The peak at 51°C denotes the melting of cetostearyl alcohol. The otherpeaks belong to the b-to-a transition of cetostearyl alcohol, to melting of cetostearylalcohol and PGM20, and possibly to melting of separated PGM 20. The latter threeprocesses overlap [12]. In Fig. 16 the heat flow scan of a sample containing 42.1%(wt/wt) water is given. The endothermal heat effect at 61°C is due to the transition ofthe hydrocarbon chains in the lipophilic bilayers from the a-modification to the liquidstate. Notice the weak shoulder at the low-temperature side of the peak. The shoulder ispresumably connected with regions of hydrated cetostearyl alcohol in which no PGM20 isincorporated (melting point 56°C). This peak represents the lipophilic gel phase, whereasthe very sharp peak at 61°C is connected with the melting of the hydrophilic gel phase[12,20]. Complementary DSC peaks are obtained when the molten cream is cooled down.Also in the case of the Nonionic Hydrophilic Cream DAC, high-shear mixing could beapplied during the cooling process until a temperature of 61°C is reached. Thereafter low-shear mixing should be applied to obtain a cream with the desired properties.

It is concluded from this discussion that the hydrophilic gel phases crystallize at relativelyhigh temperatures (72°C59°C). For the manufacture of large-scale batches, in-processcontrol of the mixing speed at temperatures above the crystallizing temperatures of thehydrophilic gel phases is required (at high-shear rates). After recrystallization of the gelstructures, low-shear stress should be maintained in order to obtain proper colloidalcrystals of the most important hydrophilic gel phases of these o/w creams.

VIPhysicoChemical Stability and Aging of Colloidal Crystalline Gel Structures

Little information is currently available about the physico-chemical stability and the agingprocesses of colloidal crystalline gel structures in o/w creams. The dominant effect

Fig. 15DSC heating curve of a mixture containing cetyl alcohol,

stearyl alcohol, and PGM 20. Heating rate: 5 K/min.

(From Ref. 12.)

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Fig. 16DSC heating curve of Nonionic Hydrophilic Cream

containing 42.1% wt/wt water. Heating rate: 5 K/min.(From Ref. 12.)

described for both Water Containing Hydrophilic Ointment [21] and Nonionic HydrophilicCream DAC [14] is continuous repair of crystal defects of the lamellar sheets duringstorage. In both systems cetostearyl alcohol is present in excess with respect to theformation of an "ideal" hydrophilic gel phase. The excess of cetostearyl alcohol results inthe formation of the lipophilic gel phase: see Sec. II.A.1. and II.B. of this chapter. Duringmanufacture, stirring causes shear stresses. As has been described in the previous sectionof this chapter, the crystallization process of the hydrophilic gel phase is rapid, and hencemixed crystals with a nonideal stochastic distribution of cetostearyl alcohol molecules andtheir sodium sulfate esters (Water Containing Hydrophilic Ointment DAB 10 or PGM20(Nonionic Hydrophilic Cream DAC) are formed. The stochastic distribution of bothcomponents will be different from that of the most stable (ideal) arrangements of bothcomponents in these primary crystals and will contain numerous crystal defects.Physicochemical aging processes in such systems mean predominantly healing processesof these crystals. As a consequence of these aging processes the ratio of interlamellarlyfixed water to bulk water is shifted in favor of the amount of bulk water. Measurementsemploying SAXD clearly show a decrease of the long spacings of hydrophilic gel phases ofthese systems. Upon heating and melting of the o/w creams and subsequent cooling, themaximum insertion of water molecules between the lamellar mixed crystals is againobtained.

De Vringer et al. [15] have described in detail the two extreme situations (depicted inFig. 17). The already mentioned excess of cetostearyl alcohol can be distributed amongthe bilayers in two possible situations. Three types of water are distinguished: F standsfor free water, that is, water inside or outside the lamellae into which no polyoxyethylenechains are incorporated; H stands for water bound to the hydroxyl groups of cetylstearylalcohol; and O represents water in an aqueous polyoxyethylene solution. In situation 1(Fig. 17) the excess of cetostearyl alcohol is distributed inhomogeneously. In fact, twophases coexist. Small patches of hydrated cetostearyl alcohol, into which no PGM 20 isincorporated, alternate with gel patches in which cetostearyl alcohol and PGM 20 arepresent in the ideal ratio. It has been shown that only a one-molecule-thick water layer

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can be incorporated between the hydroxyl groups of pure cetostearyl alcohol [12]. Sincein this case the patches of swollen cetostearyl alcohol do not collapse, it is likely that theyare small and are stabilized by the surrounding gel patches.

In situation 2 (Fig. 17) the hydrocarbon tails of the PGM20 molecules are distributedhomogeneously among the cetostearyl alcohol molecules in the lipophilic bilayers.Consequently, the polyoxyethylene chains are also distributed homogeneously among thehydrophilic layers. Obviously, the two situations described here are the extremes. In fact,a mixture of all intermediate situations could exist.

If we consider only the hydrocarbon bilayers, situations 1 and 2 are equal. For this reasonwe cannot differentiate situation 1 from situation 2 by means of DSC heating experimentsor with WAXD experiments. Both methods yield information about the lipophilic sheets,Still, this information is very valuable. Since the WAXD reflection and the meltingenthalpies of the hydrocarbon sheets of old samples resemble the data obtained fromfreshly prepared samples, we can conclude that the structure of the hydrocarbon sheetsdoes not change on aging [14]. In SAXD experiments, we notice, however, that the longspacings decrease on aging. Since the structure of the lipophilic sheets does not change,the decrease must be related to changes of the hydrophilic layer. Experiments onPGM20/water mixtures with DSC [15] showed that two water molecules are tightly boundto the ether oxygens of the polyoxyethylene unit, and although excess water stillcontributes to the hydration of the polymer chain, further addition of water does not leadto an increase in the fraction of nonfreezing water. For this reason, and because thehydration of polyoxyethylene is stronger at ambient temperature than at the elevatedpreparation temperature, it was expected that on aging, the nonfreezing water fraction,which equals the minimum amount of water required to retain the gel structure, shouldremain unchanged. Indeed, DSC cooling experiments showed that in both old and freshlyprepared samples, two water molecules per oxyethylene unit did not freeze [15].

In order to gain more insight into the mechanism involved in the aging processes, spin-lattice relaxation experiments have been performed [15] with Nonionic Hydrophilic CreamDAC containing 60.1% wt/wt D2O. In fact these measurements prove that theinhomogeneous distribution of the polyoxyethylene chain in the mixed crystals isbecoming more homogeneous. The change of the distribution is caused by thetemperature dependency of the hydration of polyoxyethylene. At the preparationtemperature, the

Fig. 17Possible distributions of cetylstearyl alcohol among the lipophilic

sheets. 1 = inhomogeneous situation; 2 = homogeneous situation;F, H, and O represent free water, water bound to the

lipophilic-hydrophilic interface (////), and water in an aqueouspolyoxyethylene solution, respectively.

(From Ref. 15.)

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TABLE 1 distribution of Water in Colloid Crystalline GelsAge of the samples = 8 days Age of the samples = 185 days

Totalwater, %wt/wt

Bulkwater, %

wt/wt

Interlamellarlyfixed water, %

wt/wt

Totalwater, %

wt/wt

Bulkwater, %

wt/wt

Interlamellarlyfixed water, %

wt/wt63 21 42 63 30 3370 33 47 70 31 3977 25 52 77 28 4780 27 53 80 38 42

hydration is relatively weak, and the hydrated polyoxyethylene chains form clusters.These clusters are fixed at the moment the lipophilic chains of PGM20, which stick in thehydrocarbon sheets, solidify. At room temperature, the hydration of polyoxyethylene isstronger, and hydration forces tend to separate the polyoxyethylene chains. However,this separation is only possible if the hydrocarbon chains of PGM20, which are tied up inthe lipophilic sheets, also part. Because of the crystalline character of the lipophilicsheets, lateral diffusion of the hydrocarbon tails is very slow. Consequently, the agingprocess is also slow [15]. Within 190 days the thickness of the interlamellarly fixed waterinserted between the lamellae decreased about 50%. With thermogravimetric analysis(TGA) similar results have been obtained with different amounts of water, as depicted inTable 1 [19].

During physicochemical aging studies of these creams, no macroscopic change of thesystems is observed. Hence the "primary" quality of the creams is not affected. The"secondary" quality, however, may be affected in such a way that the shift to a higheramount of bulk water may change the desired application properties of the o/w creams tosome extent. However, it should be stressed that during skin application most of theircolloidal structures are either mechanically destroyed or changed by quick waterevaporation because the thickness of the creams is only about 20 µm on the skin surface[22].

VIISurfactant Systems Used in Cosmetic Multiphase Emulsions

Surfactant systems currently used in cosmetics as ingredients for multiphase emulsionsare mostly complex multicomponent formulations. Division into the following categories ispossible: consistency increasing agents, nonionic o/w systems, anionic o/w systems(alkylsulfates), anionic o/w systems (soaps), and w/o systems. Some examples are listedbelow.

AConsistency Increasing AgentsCFTA designation CompositionCetyl Palmitate Cetyl palmitate

(table continued on next page)

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(table continued from previous page)CFTA designation CompositionGlyceryl Stearate Glycerine monostearate

Glyceryl StearatesMixture of mono-, di-, andtriglycerides of palmitic and stearicacid

Glyceryl Stearate (and) Cetearyl Alcohol(and) Cetyl Esters (and) Coco-GlyceridesSorbitan Stearate Sorbitan monostearateCetearyl AlcoholMyristyl AlcoholCetyl AlcoholStearyl Alcohol

BNonionic O/W SystemsCFTA designation Composition

PEG-20 Glyceryl Stearate

Polyoxyethyleneglycerinemonostearatewith approx. 20moles EO

Cetearyl Alcohol (and) Ceteareth-20Cetearyl Isononanoate (and) Glyceryl Stearate (and) PEG-20 Glyceryl Stearate (and) Cetearyl Alcohol (and)Ceteareth-20 (and) Cetyl PalmitateGlyceryl Stearate (and) Ceteareth-20 (and) Ceteareth-12(and) Cetearyl Alcohol(and) Cetyl PalmitateCetearyl alcohol (and) Cetearyl GlucosideCeteareth-12Ceteareth-20Ceteareth-30PEG-40 Hydrogenated Castor OilPEG-60 Hydrogenated Castor Oil

Polysorbate 20Polyoxyethylenesorbitanmonolaurate

Polysorbate 60Polyoxyethylenesorbitanmonostearate

Polyglyceryl-2-PEG-4 Stearate Polyoxyethylenepolyglyceryl stearate

CNonionic O/W Systems (Alkylsulfates)CFTA designationGlyceryl Stearate (and) Sodium Cetearyl SulfateCetearyl Alcohol (and) PEG-40 Castor Oil (and) Sodium Cetearyl Sulfate

Cetearyl Alcohol (and) Sodium LaurylSulfate

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DNonionic O/W Systems (Soaps)CFTA designation Composition

Glyceryl Stearate SE Self-emulsifying combination of glycerin mono/distearateand potassium stearate

Palmitic Acid (and)Stearic Acid

EW/O SystemsCFTA designation CompositionDicocoyl Pentaerythrityl DistearylCitrate (and) Sorbitan Sesquioleate(and)Beeswax (and) Aluminum Stearate

A mixed ester consisting ofpentaerythritol, fatty alcohol, fatty acid,and citric acid

Dicocoyl Pentaerythrityl DistearylCitrate (and) Microcrystalline Wax(and)Glyceryl Oleate (and) AluminiumStearate (and) Propylene Glycol

A mixture of high-molecular weight fattyacids, fatty acid salts, and oil bindingadditive

PEG-7 Hydrogenated Castor Oil Hydrogenated Castor Oil with 7 moles EOSorbitan Stearate Sorbitan monostearateSorbitan Laurate Sorbitan monolaurateSoya Sterol Refined soya sterolPEG-5 Soya Sterol Ethoxylated soya sterolPolyglyceryl-3 Diisostearate Triglycerol diisostearateGlyceryl Oleate Oleic acid monoglyceride, molecular-

distilled

References

1. K. Münzel, Pharm. Acta Helv. 28:32036 (1953).

2. H. E. Junginger, C. Führer, J. Ziegenmeyer, and S. E. Friberg, J. Soc. Cosmet. Chem.30:923 (1979).

3. H. E. Junginger, Pharm. Weekbl. Sci. Ed. 6:14149 (1984).

4. H. E. Junginger, A. A. M. D. Ackermans, and W. Heering, J. Soc. Cosmet. Chem.35:4547 (1984).

5. H. E. Junginger, in Dermatika (R. Niedner and J. Ziegenmeyer eds.), WissenschaftlicheVerlagsgesellschaft, Stuttgart, 1992, pp. 475515.

6. H. E. Junginger, W. Heering, C. Führer, and I. Geffers, Coll. Polym. Sci. 259:56167(1981).

7. H. E. Junginger and W. Heering, Acta Pharm. Technol. 29:8596 (1983).

8. H. E. Junginger and W. Heering, Dtsch. Apoth. Ztg. 130:68485 (1990).9. H. Tronnier, in Über die Wirkungsweise indifferenter Salben- und Emulsionssysteme ander Haut in Abhängigkeit von ihrer Zusammensetzung, (H. Tronnier ed.) Editio Cantor,Aulendorf, 1964.

10. H. E. Junginger, Pharm. Ind. 46:75862 (1984).

11. T. de Vringer, J. G. H. Joosten, and H. E. Junginger, Coll. Polym. Sci. 262:5660(1984).

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12. T. de Vringer, J. G. H. Joosten, and H. E. Junginger, Coll. Polym. Sci. 264:691700(1986).

13. T. de Vringer, J. G. H. Joosten, and H. E. Junginger, Coll. Polym. Sci. 265:16779(1987).

14. H. E. Boddé, T. de Vringer, and H. E. Junginger, Coll. Polym. Sci. 72:3742 (1986).

15. T. de Vringer, J. G. H. Joosten, and H. E. Junginger, Coll. Polym. Sci. 265:44857(1987).

16. K. Larsson, Z. Phys. Chem. (Neue Folge) 56:17398 (1967).

17. N. Krog and A. P. Borup, J. Sci Food Agric. 24:691701 (1973).

18. H. E. Junginger, C. Führer, A. Beer, and J. Ziegenmeyer, Pharm. Ind. 41:38085(1979).

19. H. E. Junginger, unpublished results.

20. T. de Vringer, Physicochemical Aspects of Lamellar Gel Structures in Nonionic O/WCreams, Ph.D. thesis, Leiden University, The Netherlands, 1987.

21. W. Heering, Die Struktur des Gelgerüsts der Wassererhaltigen Hydrophilen Salbe DAB8, Ph.D. thesis, Technical University Braunschweig, Germany, 1984.

22. G. L. Flynn and N. D. Weiner, in Dermal and Transdermal Drug Delivery (R. Gurny andA. Teubner eds.), APV Paperback Vol. 31, Wissenschaftliche Verlagsgesellschaft,Stuttgart, 1993, pp. 3365.

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8Stability of EmulsionsChristopher D. VaughanSPF Consulting Labs, Inc., Ft. Lauderdale, Florida

I. Theory and Practice 184

II. What Happens during Aging? 185

A. Reactions 185

B. Solvent Effects 187

C. Interactions 188

D. Hildebrand's Solubility Parameter 190

III. Applying Cohesive Theory to Specific Systems 191

A. Amphiphiles 191

B. Sticky Molecules 191

C. Cohesive Behavior 192

D. Limits to Possible Interactions 193

IV. Instability 195

A. The Instability Mechanism 195

B. Methods to Reduce Instability 196

C. Modifying Emulsifiers to Stabilize an Emulsion 196

D. Modifying Oil and Water Phases to StabilizeEmulsions 198

V. Current Standards to Evaluate Stability 199

A. New 1995 FDA Guidelines for Drug Stability Testing 201

B. Choosing Test Procedures 201

C. Successful Predictions 203

VI. The Future of Stability Projection 203

References 204

Page 184

ITheory and Practice

Every stability study presents a wonderful example of the interaction between practicaltechnology (we know it works, but we don't know why) and theoretical science (thisshould work, but it doesn't always). Both approaches combine to provide improvedpredictions of the effect of time on the uniformity of a mixture. In many cases thecommercial success of formulated products depends on the ''shelf life" of the mixedingredients as much as on the performance of the mixture as it is used. Either way,interactions between ingredients control the stability and the delivery of the mixture.Successful stability testing must account for these interactions. This chapter reviewshistorical methods to predict "stability," and presents a practical strategy to improve yourchances of success for predicting the useful life of mixtures.

Predicting stability of a chemical mixture has been a slow and risky process at best.However, many recent advances in colloid science provide improvement to methods forbalancing fluid systems. New theory provides mechanisms that can explain observedphenomena. Awareness of probable interactions helps narrow our choice of remedies tobalance an unstable system. Statistical approaches are now being widely adopted to helpus measure variability and evaluate the chances that our stability predictions will beaccurate [1]. Moreover, improved analytical techniques such as small angle neutronscattering (SANS) [2], scanning tunneling microscopy (STM) [3], atomic force microscopy(AFM), and x-ray photoelectron spectroscopy (XPS) [4] allow us to peer into theinteractions of mixtures, to measure them, and to understand better why some changewhile some do not. Finally, new polymeric and branched surfactants are changing theface (interface) of emulsion droplets.

Pragmatic technologists are less concerned with the why of systems; rather, they applythe practical techniques that they believe are effective. The only trouble they encounteris when "tried and true" techniques are applied to new and untried systems. But, such ismost always the case in stress accelerated stability tests, when new mixtures areevaluated to see if they will be stable in use. It is not enough to "have seen thetechnique work before," but one must understand the system through its components,specifically the reactivity and the cohesion between components. This key is the mostpowerful new advance of all, because it can link new techniques to old methods.

Statistical analyses of testing error specifically identify the need for combining precisetest methods with mechanistically based theory. When applied to stability studies ofmixtures, good theoretical reasons for appropriate test methods can save us from beingfooled by system specific variables. These include phase transitions that may occur whenone of our mixed components melts, or reactions triggered when available energyexceeds the activation point of an unexpected reaction, or some other sudden systemchange. Therefore it is risky to rely solely on the blind extrapolation of empirical methods.

Stability projection requires a combination of resources from both empirical and physicalchemistry. Statisticians find that Type I and Type II errors signify either weakness in testprecision or theoretical foundation respectively; Type I error fails to accept the truth. Thisskeptical error is most often the result of small sampling, inadequate repetitions, andimprecise methodology. We call this a test sensitive error, and it is caused by sloppylogical input, which results in overlap of the input data, making test vs. control resultsdifficult to discern with confidence. Conversely, Type II error includes cause and effect(fails to adopt the null hypothesis), and results from a faulty understanding of the

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theoretical mechanics behind the connection we are trying to measure. This theorysensitive error often occurs from improper choice of statistical analysis method or fromcomparing variables unrelated to one another. One error is an input and measurementerror, while the other is an output and theory error. The statisticians teach us that bothcontributions to testing have measured value, and often, when we review testing thatprovided bad predictions, the type of error will help narrow our search for ways toimprove the test.

The blending of art and theory applied to stability prediction must peer deeply into theworks of our chemical formulations. This chapter provides keys to reduce Type II (theorysensitive) error by providing new ways to apply mechanistic foundations to time-honoredtest methods.

Our review of practical and theoretical approaches to measure stability concentrates onapplications to emulsions, but the principles apply to all systems of mixtures. It shouldprovide an understanding of what works, what doesn't work, and all the "whys" we knowso far. The ultimate goal of the following review is to help you choose tests wisely whenyou are facing both time constraints, financial limitations, and the uncertainty of newmaterial combinations.

All new endeavors are at best imperfect. A well-conceived stability test provides the bestsolution for meeting the unknown risk of functional product success or failure in themarketplace.

IIWhat Happens during Aging?

When we get old, our reactions slow down, while our interactions become more stable.The same thing happens to all chemical systems. Antioxidants, like vitamin E or BHA, areclaimed to extend animal life as well as the lifetime of reactive products. These reactivelives are only temporarily extended, eventually giving way to the relentless tenacity ofoxidation.

Although reactions tend to move to completion, structural energy often fails to dissipateas time's arrow moves all systems toward the disarray of entropy. In the condensedmatter of our earth's gravitational field, molecules are compressed to sufficient proximityfor intermolecular structures to form and remain held in place by their cohesive energy.Thus mineral crystals (and even mold spores) formed millions of years ago can be foundintact today. Even the DNA of prehistoric creatures can be analyzed now as a result of itsstructural cohesion. It is this same cohesive energy that we can use to predict theoutcome of shorter term aging.

Several specific changes can occur in colloidal systems as they age. Reactions canproceed to completion. The reaction products can alter the interactions such as solubilityor structure of the other materials. Changes in viscosity, color, odor, and emulsification

can result. In most cases such changes are detrimental to the stability and effectivenessof the colloidal system.

AReactions

Reactions and interactions compete in all systems over a period of time. Eventually allreactions reach an end, leaving only the interactions to establish the structure. Reactions,however, are driven by much higher energies than interactions. Therefore they are easier

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to see, measure, and predict. Reactive forces are so strong that they force electrons tomove from one molecule to another. Oxidation and reduction, decomposition, andcombining reactions are all the result of these strong forces.

The energy level needed for a reaction to occur is termed the activation energy. This isthe energy needed to raise the rate of an interminably slow reaction to the range of "realtime." Thus, it appears to start a self-sustaining reaction. Like overcoming the initialfriction energy of a block as it begins to slide down a slope, the activation energy includesthe pushing force needed to start the movement. This force varies with the slope, butalways includes the cohesive forces holding the block to the surface. When thoseadhesions are overwhelmed by an equal and opposite force (your push), the block beginsto slide. Very often cohesive energies can indicate the energy of activation needed toovercome the equal and opposing stabilizing structural energy.

In a chemical reaction both the static and dynamic forces are affected by thetemperature, and these vary with the system of the solvent and reactants. As such theactivation energy is an empirical value usually determined from the results of a kineticstudy, and stability studies are typically kinetic studies. Activation energies have beenestablished for numerous drug materials [5]; however published activation energies arenot always the same as those that may occur in your system!

Activation energy is an important result of the Arrhenius treatment of accelerated stabilitytesting. This critical and often misunderstood concept controls the stability projection of asystem under test, but must be determined empirically. (See Table 1.)

In 1889 Svante Arrhenius showed that reaction rates increase exponentially withtemperature. With the aid of the Arrhenius equation and by using data of time studies attwo different temperatures (thermally accelerated data), we can find the activationenergy for any changing parameter that we are measuring [6]. Alternately, we candetermine the change over time of a physical parameter given the activation energy. Fora first-order (linear/one variable) reaction the Arrhenius rate relationship [7] is asfollows:

TABLE 1 EnergyRequirementsHeats of activationCompound Kcal/molAscorbic acid 1623Aspirin 1318Benzocaine 19Yellow 6 and red 33 20Folic Acid 1727Glucose 3132Hydrocortisone 720Morphine 23

Prednisolone 11Thiamine 1329Vitamin A 1523

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where E is the Activation Energy (in electron volts), k is the Boltzmann constant = 8.617× 105 electron volts/degree C or 1.318 × 1016 erg/degree C, T is temperature in Kelvin(absolute) degrees, and A¢ is a characteristic ("preexponential") constant related toreaction mechanism, concentrations, and test conditions.

While atomic force microscopy, and x-ray photoelectron spectroscopy studies often quotemolecular interaction energy in electron volts, many pharmaceutical and chemicalstability studies use calories instead of electron volts and the gas constant (R) instead ofthe Boltzmann constant. It is helpful to convert to like terms for comparison of theory andtest results.

therefore the Arrhenius equation becomes:

where the rate of reaction has the units liters/mole sec, and R is the gas constant, 1.987cal/deg mole.

Runesson and Gustavii [8] present a good example in their study of the hydrolysis ofparaben preservative by polyols. They determined the energy required to produce achange in the ingredient over timethe activation energy E. They found the E of thereaction of paraben with polyols at pH 7.3 to be 21.8 kcal/mole. From this, they predicteda half-life of 11 months for methylparaben in 30% sorbitol and 17 months in 15%sorbitol, compared to 39 months with no polyol at all. Actual measurements verifiedthese predictions.

Materials with similar cohesive energies interact most strongly, and the solubilityparameter is a useful measure of the cohesion. Cohesion of two reactants can increasetheir reaction probability, as it does in the polyolparaben transesterification investigatedby Runesson and Gustavii. Sorbitol's solubility parameter (18.65) is about twice as closeto the solubility parameter of methylparaben (11.98) as is the solubility parameter ofwater (23.4). In this chapter we will show how solubility parameters can be used topredict interactions. Had Runesson known beforehand that sorbitol interacts twice asstrongly with methylparaben as does water, he would have expected the observeddoubled hydrolysis rate.

BSolvent Effects

The interactions within a system can often increase (or decrease) the rate of a reactionand its activation energy [9]. This effect is called solvation. In simple terms, anyinteracting molecule (solvent) can change the orientation or electromagnetic balance of a

solute primarily through cohesive attraction. Brink and Tramper [10] found that the bestsingle indicator of solvative effects by organic solvent on biocatalysis is the solubilityparameter. About the same time, Taft, Kamlet, and Abraham developed a"solvatochromic" equation that modifies the solubility parameter to precisely predictsolute reactivity [11]. If a neighboring molecule has a strong attraction to the reactivespecies, the solvative effect can be either remarkably catalytic or protective. Honig and

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Nicholls recently clarified this apparent conundrum with respect to proteins: "Indeed, inmany cases electrostatic interactions between groups of opposite charge actually opposebinding. The effect may be understood from the fact that formation of, for example, anion pair at an interface between two macromolecules involves the removal of the chargedmoieties from water. The desolvation costs associated with this process appear, ingeneral, to be larger than the pairwise coulombic interaction" [12]. In lipid bilayers thesame destabilizing effect was first recognized by Parseghian [13], who observed that thecohesive competition for the ion pair by the solvent (water) was greater than thepositive-to-negative charge attraction that would be formed within the lipid bilayer! Anyfree energy analysis of system stability requires that we consider all contributingcohesions, not just charge centers.

Photodecomposition of dyes and UV absorbers [14] is another situation in which solvationcan be either constructive or destructive. Photodecomposition rates vary with the polarityof the solvent. Thus, it is instructive to show that greater solvolytic interaction cansometimes prevent reaction activation [15] by "bleeding-off" the absorbed energy beforeit can build up to an activation level. In other systems solvative attachment byneighboring cohesive fields can help promote electron rearrangements resulting insolvolysis. For example, we [16] have shown that most UVB chromophores exhibit thesame polarity in the excited p* state [10.5 (cal/cc)1/2]. A vehicle with the same solventpolarity will have maximum cohesive contact and intermolecular energy transfer (bleedoff) from the excited chromophore thereby stabilizing it against photodecomposition.Conversely, good contact with titanium dioxide will increase its photocatalytic effect,where the energy absorbed by the mineral and then transferred is sufficient to producecatalyzed SN1 scission of esters and amines.

CInteractions

Interactions are the result of cohesive attraction between two molecules. The cohesiveenergy appears to come primarily from the atomic nucleus where it is shielded by thecharge of the electron cloud [17]. For example, fluorine with seven valence electronsexhibits relatively little cohesive energy while zinc with only two active electrons (evenwith full shells) exhibits much more attractive (cohesive) energy. (See Fig. 1) Whencombined in molecules, the cohesive energy fields of atoms are only slightly modified byadjacent atoms within the molecule. Together they combine to form the cohesive energyof the molecule, expressed as the solubility parameter. London showed, however, thatthe cohesive energy fields from different atoms vary significantly not only in strength butalso in the way they interact [18]. Therefore, the van der Waals attraction was brokendown into the sum of three basic cohesive components in order of increasing strength:London dispersion energy, Dipole-dipole energy and Hydrogen bonding energy.

Each of the three interactive cohesive energies behaves differently and combines toestablish the permanent balance of forces between molecules, aggregates, and phases.

London cohesion is uncharged and symmetrical, while dipole interaction is charged andunsymmetrical. Hydrogen bonding (and acid/base interaction, which follows the samedynamics) is flexible, reaching out to an acceptor if one is nearby. (See Fig. 2)

When viewed on a large scale, the combined interactions between molecules produce the"colligative" physical properties of mixtures. Better understanding of these cohesiveinteractions is catalyzing a revolution in both chemistry and biology. Control of physical

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Fig. 1Source of cohesive energy. Shielding the nuclearattraction: electron density vs. cohesive energy.

(From Ref. 17.)

properties permits improvements in product function. The weak interactive forces are thegrist of the materials science revolution. Though they have been poorly understood in thepast, these "weak" forces are responsible for properties ranging from viscosity, adhesion[19], and membrane penetration [20] to the coiling of DNA and the transcription ofgenetic code. Interactions produce the real chemistry of chemistry. To the consumer, thisrevolution means new and better products.

Fig. 2Three types of cohesive fields.

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DHildebrand's Solubility Parameter

In general conversation the term chemistry has come to mean interaction, when appliedto markets, social groups, and businesses. Until recently the science of chemistry hasmainly been a science of reaction dynamics. The understanding of cohesive energy is but40 years old. Although Sugden [21], early in the twentieth century recognized aconsistency between the "colligative" properties of materials, it was not until 1950 whenJoel H. Hildebrand [22] published his treatise on the solubility of nonelectrolytes thatcohesive energy became an effective tool. Hildebrand called his measurement of cohesiveenergy the solubility parameter because it relates well to solubility. Since that time,scientists have found many other properties to which it is related. All are properties, suchas stability, resulting from interactions.

The solubility parameter is a measure of the strength or density of cohesive energyexpressed in (cal/cc)1/2. The square root allows linear averaging to get the grosssolubility parameter of mixtures. (See Table 2).

What a strange paradox it is that physical characteristics which seem most obvious to thenonscientist are controlled by forces so weak that scientists until recently found themvery difficult to measure.

Weak cohesive forces pull organic molecules together with energies ranging from 25 toabout 500 cal/cc. Water (inorganic), with a solubility parameter of 23.4 (cal/cc)1/2, isbound by 548 cal/cc (23.4 × 23.4), yet cohesive energy can be as dense as severalthousand cal/cc for some minerals. The cohesive energy between organic molecules isnot strong enough to cause changes in them, only in their orientation. The orientation ofmolecules is what we see! Just as the orientation of any construction material is what wesee. In a building we see a house, or a store, or an office, rather than just a pile of bricks.Molecules are building blocks, too. But they are the very building blocks of life andeverything around us. Now perhaps it is clear why their orientation is more importantTABLE 2 Solubility Parameters of SomeCommon MaterialsSolubility parameter (cohesive energy)Materials SP

(cal/cc)1/2Dimethicone 5.92Mineral oil 7.09Isopropyl myristate 8.02Isocetyl alcohol 8.71Octylmethoxycinnamatea 9.10

Caprylic acid 9.35Polyvinyl choride 9.70Stratum corneum (porc.) 9.80Polyvinylidene Cl (Saran) 10.29

Butoxyethanol 10.53aFedor's Method

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and more obvious than their substance. As in life, what you do with what you've got ismore important than how much you have!

The most important contribution of the solubility parameter is that it is a precisemeasurement of a relative "character" of materials. In the past chemists have looselyreferred to the character of interacting materials as "polar" or "nonpolar," often ignoringthat many noncharged molecules vary greatly in their interactive behavior. Now it ispossible to quantify such a loose term as "polar" molecular character using total cohesiveenergies. Once armed with knowledge of the caliber of the cohesive field source (a wholeor part molecule) one only needs to know the nature of the impact to use this weaponeffectively.

IIIApplying Cohesive Theory to Specific Systems

AAmphiphiles

Very few molecules are symmetrical, and even fewer systems are really homogeneous.Thus the use of solubility parameters with most practical chemical materials mustovercome three hurdles affecting precise applications:

1. Nonsymmetrical molecules may express different cohesive strength at different ends.

2. Very few materials are totally pure and impurities can often reduce self-cohesion andimprove miscibility.

3. Poor interaction with neighbors can induce folding or coiling of long chains, furtherreducing miscibility.

As a result, it is sometimes necessary to calculate the cohesive energy density ofmolecular parts or extend the proximity of expected interaction from the usual ± 2solubility parameter units to three or even four solubility units.

We have applied Fedors's method [23] to determine the solubility parameter of a numberof lipophiles and now also to hydrophiles commonly found in surfactants.

The more closely the cohesive energy of the hydrophilic group matches the energy of thephase into which it extends, the greater the attractive force to that phase. Hydrophilictails that approach 23.4 (cal/cc)1/2 (the cohesive power of water) will display the mostinteraction with the water phase. It is interesting to note that longer ethoxyl chains wouldappear to exert ever weaker (but longer and more complex) interactions with the waterphase. (See Table 3.)

BSticky Molecules

An important key to the nature of the cohesive bond is the sticky nature it imparts to allmolecular surfaces. Van der Waals discovered that compressed gases shrank more underpressure than predicted by PV = nRT the Universal Gas Law. From this, he determinedthe cohesive nature of molecules and measured the strength of the cohesive field. Hefound that it was not at all like the best known electromagnetic fields, which dissipate bythe inverse of the square of the distance from the source (the inverse square law).Instead the cohesive field died away much more rapidly. It followed an inverse power law(1/r6). Thus van der Waals's cohesive field measurements described what we canrecognize as a sticky surface, one which goes from very weak to very strong in a veryshort distance. Either adjacent molecules are in it (stuck) or they are not (unstuck). So,

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TABLE 3 Cohesive Energy ofHydrophilic TailsHydrophilic grouppart

Solubilityparameter

HO(CH2CH2O)2- 12.7 (cal/cc)1/2HO(CH2CH2O)6- 10.7 (cal/cc)1/2HO(CH2CH2O)12- 9.1 (cal/cc)1/2COOH 15.2 (cal/cc)1/2COONa+ 19.6 (cal/cc)1/2CONH2 23.4 (cal/cc)1/2

the interactions between cohesive fields can be viewed as molecular surfaces stucktogether, presumably in some energetically favorable orientation. The contact pointsbetween molecules may be easily dislodged by physical pressure, heat energy, or evenlight. The recent sticky-sphere models [24,25] have been very successful in predictingsolubility. Those of us who are trying to imagine the possible interactions controlling (orfailing to control) an unstable mixture can see the delicate nature of the interactions asthe molecules stick and break apart and stick again as the mixture is stirred. Nonionicsurfactants trying to stick their ethoxylated tails into the water phase are only weaklyinteracting. No wonder a little heat energy can shake the hydrophilic ends loose from thewater. This is what happens at the cloud point. In fact, some silicone and fluoridesurfactant emulsions can even be physically shaken to temporary clarity.

When one molecule sticks to the next and the nextlike a string of magnets, or a house ofcardsthe tiny weak molecular forces combine to produce something on a scale we cansee. So, when we manipulate these cohesive forces, we can then control their visibleeffects in combination. More importantly, though, we can construct structures that opposeinstability, as if we were "molecular contractors." Teflon, for example, is a polymer thatcontains lots of fluorine, so it is a very "nonpolar," large building block. It has very weakcohesion. With molecular cross-links as tie rods, we can spread this material to constructweakly attaching but extensive films. This is why Teflon is a material of choice fornonstick surfaces.

CCohesive Behavior

The cohesive energy of mixed ingredients controls properties such as viscosity, adhesion,miscibility, and even the boiling point. This cohesive energy is simply the attractive forcewithin the atoms that form the molecules of all ingredients. Some molecules have morecohesive energy, like water, and some have less, like oil.

Chemists have consistently called highly cohesive ingredients like water or ammonia"polar," and those that are less cohesive oily or "nonpolar," when, in fact, classicalpolarity or charge separation provides a poor indicator of interaction since it is but one ofthree contributors to molecular cohesion.

For example, many scientific journals apply the term "polarity" to elution ofchromatography solvents (Table 4), and to amino acid character in proteins, or to theblock or

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TABLE 4 Elutropic Values on AluminaSolubility parameter vs. dielectric constantCompound e° Alumina Dielectric constant SPPentane 0.00 1.80 7.10Hexane 0.01 1.89 7.28Cyclohexane 0.04 2.02 7.30Cyclopentane 0.05 1.96 8.11Carbon tetrachloride 0.18 2.24 8.61O-xylene 0.26 2.57 9.01Toluene 0.29 2.38 8.94Benzene 0.32 2.28 9.08Ethyl ether 0.38 4.34 7.27Chloroform 0.40 4.81 9.05MIBK 0.43 13.11 8.76Tetrahydrofuran 0.45 7.58 9.16Ethylene dichloride 0.49 4.60 9.80MEK 0.51 18.50 9.43Acetone 0.56 20.70 9.87Pyridine 0.65 33.00 11.70Propanol 0.71 12.40 10.30Isopropanol 0.82 19.92 11.24Methanol 0.95 37.70 14.33Correlation Coeff. 1.00 0.77 0.89Linear Regression SP = 5.62 e° + 6.99Linear Regression Dielectric = 28.46 e° + 2.72

graft character of polymers. We too, find ourselves using the term "polarity" loosely todescribe cohesive differences while acknowledging that there is confusion about theprecise effect of (charge) polarity and unfamiliarity with the term cohesive energy.

DLimits to Possible Interactions

If one's goal is to make a stability-testing program appear difficult and complex forwhatever reason, one might say "I have 17 different ingredients that could interact,resulting in 216 possible problems, and that only considers one-to-one interactions! Whatabout when 3 ingredients can interact?"

These 64,000 possibilities are enough to confuse even the molecules themselves.Chemists who understand interaction mechanics can't be so easily fooled. They know thatmolecules form significant interactions only with other molecules that have closesolubility parameters, within 2 or 3 (cal/cc)1/2 units at most, although this varies with thetype of interaction. So for most systems, material A interacts preferentially with B, B withC, C with D, and so onreducing the 64,000 possibilities back to maybe 20 or 30, even ifone includes the usually ignored interactions with air [26] and the container wall. Thesolubility parameter approach to analyzing a mixture's stability will identify most

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potential interactions. But, as in any simplification, there are some occasionalcomplications which cannot be ignored but are usually not very common.

Solubility parameters of molecular parts are useful for evaluating the interactions ofamphiphiles, ''coupling" agents, and block copolymers, specifically (see Fig. 3). Twoparameters are useful for some materials that exist as cis or trans isomers or as keto-enol tautomers, such as alpha hydroxy acids. Intermolecular hydrogen bonding or foldingof long chains in poor solvents reduces their cohesion usually 1 or 2 (cal/cc)1/2. If they arein your system, these should be considered.

Fig. 3Interactions in a system.

Illustrated by showing how the rate of softening of polystyrene dependson solubility parameter.

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The most significant aspect of this rational simplification is that it provides the key toremedy insufficient interactions (and resultant lack of stabilizing structure) in anyunstable mixture.

IVInstability

Stability is both an unattainable absolute and our stated goal, but we know fromexperience that instability is the real challenge we meet and overcome. Instability is likepornography: It is very difficult to describe but easy to recognize. This is becauseinstability and stability are relative terms, rather than absolute terms. The Second Law ofThermodynamics assures us that nothing is stable and all systems drift toward disarray.However some drift faster than others!

Stability testing is supposed to predict a functional lifetime. But "what is acceptable" is anever changing paradigm. It is affected by technological competition, market acceptability,and legal constraints. Very often improvements in stability provide opportunities forquality and value competition in the marketplace. Konica Corp recently introducedphotographic color print paper with improved dye couplers whose color quality is claimedto endure for 100 years [27]. Obviously this claim must be based on accelerated stabilitytesting. Likewise, long wear of paint, cosmetic product creaminess, drug shelflife/expiration, and the "fresh" flavor of foods are competitive quality features that havethe potential to provide economic success as surely as the reliability of Japanese carsresulted in a dominant market share in the 1970s. Indeed, the mixed chemical systemswe are examining are surely less complex than the reliable cars from Japan.

There is actually a simple answer to seemingly complex and ever changing qualitystandards: Always run your stability tests side-by-side with the market leaders in yourcategory! The competitive edge may be rapidly changing, so you must keep your eye onthe competition.

As competitive requirements become more demanding, a systematic approach combiningboth current theory and practical knowledge will provide the keys to improving the stateof the art. Use the information in this chapter. Also use your practical knowledge fromwhat you have seen. But most of all try to understand what is going on within the newsystem. You will see that although your mixture may be new and unknown, the reactiveand cohesive energies of the components can be known, and in the end the cohesiveenergies dominate the system. Later in this chapter you will find some standards andmethods described for drug and cosmetic stability that may be effective when applied tofood, paint, and adhesive coatings. These methods however are always being changed,so we concentrate here on providing an understanding of what is happening during agingand on the tests that attempt to duplicate it.

A

The Instability MechanismIn the mechanics of interaction, strong cohesive fields are attracted selectively to otherstrong cohesive fields. The mutual attraction is the product of the two cohesive energiescombined:

where SPa and SPb are solubility parameters and Eintab is the interaction energy.

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For example, water with a solubility parameter of 23.4 (cal/cc)1/2 can interact with itself,producing the interaction (23.4 × 23.4) [(cal/cc)1/2]2 = 547 cal/cc.

This means that in a polar medium like water (which is strongly cohesive), one polarwater molecule pulls towards the next water molecule so strongly that other materialsare squeezed out of the way. Therefore, the maximum attraction is between like strongfields over weaker (less polar) neighbors. Meanwhile the weaker (less polar) neighborsare selectively attracted to themselves. This explains the ancient empirical observation:like dissolves like.

Commonly, this describes the mechanics of oil separating from water, as it does for allunlike materials. Only, now we can know how much alike materials really are and judgehow well they will mix or separate by their solubility parameter.

Many examples have been published depicting how precise this approach is [2830], andtabulations of solubility parameters of numerous materials are available in the literature[31,32]. They are an important key to understanding the forces driving stability andseparation in mixtures.

BMethods to Reduce Instability

In theory all systems are eventually unstable. However for all systems there exists sometime frame of acceptable life expectancy. In fact, lifespan is the prime measure ofacceptability of most systems. For humans, 100 years is surely an acceptable period ofstability. For goods, shelf-life, service-life, career span, or repair frequency are likewisevalued, measured, and depreciated by their effective time frame.

The effective life of mixtures of all types has been the subject of art becoming science(technology) developed over many centuries. Long ago mixtures of all sorts were firstformulated through trial and error into forerunners of products that we know today.Simple mixtures of a few inert ingredients were created with limited understanding. Inmodem mixtures, the number of ingredients, their reactive stability, and the complexityof the mixture provide keys to reducing the risk of failure to obtain an "acceptablefunctional lifetime."

CModifying Emulsifiers to Stabilize an Emulsion

Emulsifiers are the molecular cement that stabilizes emulsions. In the 1950s Griffindeveloped a practical scheme for classifying emulsifiers that he called Hydrophilic-Lipophilic Balance (HLB)[33]. The HLB value classifies emulsifiers by the weight ratio ofthe water soluble molecular end (head) to the oil soluble molecular part (tail). (See Fig.4.) Actual application of Griffin's HLB toward solving emulsion stability problems shows itssimplicity. Although it delivers limited precision, it provides qualitative direction to the

task of reducing emulsion instability. Thus, it has been widely adopted by practitioners inthe field.

An initial emulsion formulation attempt often fails in practical stability testing. Eitherwater or oil may separate from the emulsion. The HLB system can be used to choose thetype of emulsifier (oil soluble or water soluble) with which to make adjustments. Griffinprovided an important tool for the arsenal of formulation practitioners.

Sometimes the HLB system does not work, or works poorly. You might adjust theemulsifier HLB back and forth, but stability never reaches the "acceptable" level. Maybethe acceptable level has inched ever higher, or maybe the emulsifier is just an ineffective

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Fig. 4Cohesive structures. Illustrated withthe aid of solubility parameters in an

emulsified oil drop system.

bridger. Guessing about the cause of a failure is usually unproductive. Instead, areexamination of why the HLB system works when it does can usually yield usefuldirection. Here's what's happening when HLB works and when you have created thewanted interactions.

1. Surfactants form a wall between immiscible phases. This wall serves as a barrier toblock coalescence of the internal phase with other nearby similar droplets. The wall isgenerally held in place by the attraction of an oil-like phase to one side of the wall, whilea water-like phase is attracted to the other side. Thus, the interfacial wall functions bestwhen its oil-soluble part matches the oil-like phase and the water-soluble part matchesthe water-like phase. This pair of interactions is the strongest key to emulsion stability.

2. Surfactants form bridges (sometimes). Those bridges are often stabilizing structuresacross phase interfaces. Other times they can contribute to coalescence if they branchthrough adjacent interphases into the internal phase. Bridges must be constructed withcare when using long polymeric surfactants.

3. Surfactants can sometimes also work by interfering with the structure of a phase.Hydrotropes and water-soluble surfactant tails (hydrotropic hydrophiles) for example canbe so strongly attracted to the water that they compete with water-water self-attraction.Then the water structure is disturbed, and its ability to squeeze out solutes is diminished.Hydrotropes do this.

Beerbower [34] applied Hildebrand's solubility parameter values to emulsifiers in anattempt to more precisely match the emulsifier to the oil phase and overcome anomaliesin the HLB system. He compared the cohesive energy of the hydrophilic head group withthe cohesive energy of the oil soluble tail to give a more precise cohesive energy ratio(CER) based on the strength of the interactions of the two ends, rather than aHydrophile/Lipophile Balance (HLB) based on the ratio of molecular weights of the ends.

We further developed this concept [35] to precisely match the energy of the lipophilic tailto the oil phase "polarity." This was done by calculating the solubility parameters of onlythe oil soluble part of the molecule similar to the calculations shown in Table 3 for thecohesive energy of the hydrophilic (water soluble) tails.

The match between the emulsifier tails and the phases into which they extend is the

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primary interaction that controls stability of most two-phase emulsified systems [36]. Onecan achieve better energetic matches by changing the polarity of the oil phase, the waterphase, or the emulsifier segments.

DModifying Oil and Water Phases to Stabilize Emulsions

The HLB adjustment has been the principal tool of the chemist trying to improve thestability of an unacceptably unstable system. If oil is separating, a lower HLB emulsifier isrequired. Or if water is separating, the HLB must be raised. This is very effective, but it isnot the only way, and sometimes you may not want to change the emulsifier.

If you have not already matched the lipophilic tail of the emulsifier to the oil phase, thiscan be done by adjusting the oil phase materials. An oil phase adjustment to increase thepolarity of that phase can increase the cohesive pull on surfactant tails extending intothat phase. This has the same effect as lowering the HLB of the emulsifier but withincreased stabilizing structure. Recently Gersappe et al. reported yet another new way toadjust an oil phase containing incompatible polymers such as poly(ethylacrylate) (PEA)and poly(methyl methacrylate) (PMMA) [37]. A graft copolymer with PEA and PMMAsections has been shown to remedy such incompatibilities and contribute to uniform filmapplication. This combination is useful for nail enamel or hair spray resin formulation.

Similarly, a water phase adjustment, such as adding propylene glycol, can reduce thecohesion of the hydrophile to the water giving a lowered HLB effect. For example, in arecent experiment, Papoutsi et al. [38] added polyethylene glycols (PEGs) to the waterphase of a sodium dodecyl sulfate (SDS), pentanol, cyclohexane w/o microemulsion.Conductivity (a measure of w/o emulsion structure) decreased significantly from 0.02microsiemens to almost zero with a very small addition of the hydrophilic polymer. Andthe effect was more marked with higher molecular weight PEGs. Apparently the PEGassists the water-soluble headgroups of the SDS and pentanol in making cohesive bridgeswith the water phase. But most importantly, this represents an example of thefundamental principle of stability: structure equals stability.

Longer PEGs provide greater structure, therefore their stabilizing effect is greater.

Surfactant Helpers

Materials such as proteins or hydrophilic polymers, can change the effective HLB of theemulsifier system and impart viscosity to the water phase. Goddard [39] has broadlyinvestigated the interactions of polymers with surfactants. Interactions betweencarboxymethylcellulose (CMC) and the hydrophilic emulsifier heads can produce an effecton the phase interface equivalent to raising the HLB. Very small amounts of theseinteracting molecules are extremely potent. We calculated the effect of adding CMC inone system and it acted as if it had an HLB of 145.

Liquid CrystalsLiquid crystalline structures most widely studied by Friberg have the ability to providestructure across the external phase in the emulsion. These are highly stabilizingstructures and can be created with simple ingredients like cetyl alcohol. More recently,Menger [40] has investigated stabilizing cationic (CTAB) emulsified systems with anionicbridges formed from micelle to micelle by two-tailed anionic (Gemini) surfactants at uselevels well below the amount needed to produce aggregation. (See Fig. 5.)

These most interesting new additives, two-tailed and two-headed gemini surfactants, areclaimed to have remarkably high surface activity and low critical micelle concentrations[41]. They can form bridges and other lyotropic and thermotropic structures [42].

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Fig. 5Gemini bridges schematic of cross-linked

micelles as postulated by Menger.(From Ref. 40.)

Once again they represent an example of greater structure giving greater stability.Indeed, Rosen has reported that the most efficient gemini structures are those with rigid(rather than flexible) links tying the conventional surfactant structures together.

Capped Surfactants

Capped surfactants like gemini structures exhibit high efficiencies and form bridges. Withtwo hydrophilic heads and a lipophilic middle (or vice versa), capped surfactants providehigh detergency and low foaming. None of these new stabilizers are well defined by HLBespecially since their effects sometimes vary depending on the extent of interaction withconventional surfactants. Their structure-forming abilities can better be identified byevaluating the cohesive polarity of the various amphiphilic parts of the molecules.

VCurrent Standards to Evaluate Stability

Accepted protocols for most chemical and physical testing such as stability testing varyfrom country to country. Currently, the most stringent regulatory requirements for testingdrug stability emanate from Germany (EEC), Japan, and the United States.

In October 1992 two international pharmaceutical organizations, the Arbeitsgemeinschaftfur Pharmazeutische Verfahrenstechnik (the APV) and The Federation InternationalePharmaceutique (the FIP) met jointly to instigate unification and harmonization ofregulatory requirements across the world drug market [43]. Despite the expectedeconomic and political jousting in this arena, remarkable progress has been achieved.The FDA has now issued new guidelines for stability testing [44] incorporating manychanges to adapt to internationally accepted scientific standards. These standards andhow they

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evolved reach beyond the scope of this book. However, it is an example of the blend oftheory and practice that defines the level of quality to which accepted methods mustconform.

What is acceptable is becoming less and less subjective a determination. Everywhereprecision and accuracy are the first criteria for any test method. It is the test methods,the instruments, and the skill of the operators that limit the precision of laboratory testingused to generate stability evaluations. If precise tests are used, results can be projectedaccurately, but if the test methods are sloppy, the projections may be unacceptable dueto their inherent variability.

Standards of precision and test methodology have been established independently nowby many scientific and pseudoregulatory organizations, including

The US Pharmacopeial Convention (USP)The British Pharmacopeia (BP)The Food and Chemical Codex (FCC)International Federation of Societies of Cosmetic Chemists (IFSCC)Cosmetics, Toiletries, and Fragrance Association (CTFA)American Society of Testing Methods (ASTM)International Standards Organization (ISO)

These organizations publish books (compendia) of test methods and guidelines for testingprotocols.

Standard-setting organizations compete for prestige through a balance of quality, ease,and practicality of test application. This competition has resulted in continually improvingstandards of quality in all forms of testing. Improving standards of testing affect bothstability projections and evaluations. But the principles of stability control and evaluationapply equally well to a myriad of other fields where products compete for marketleadership. The largest market for stability testing is the 60-billion-dollar automotivefield. Engine alloys, oil additives, plastics, bearings, tires, glass, and even interiorupholstery are evaluated for wear and fatigue. The next largest market is food ($22billion). These industries have adopted ever-advancing quality-control measures primarilyin response to competition, insurance requirements, and the massive growth in litigation.This motivation suggests that the legal aspects of quality control are substantial. In truth,it is our legal system that has defined the precision requirements for acceptable data.

In the recent landmark US Supreme Court case Daubert vs. Merrell Dow Pharmaceuticals(the Bendectin Case) [45], the plaintiff's scientific testimony was denied because themethods were not widely or generally accepted among scientists, nor had they beenpublished in peer-reviewed journals. This standard, is known as the "Frye Standard"based on a 1923 case. The Supreme Court ruled that the lower courts were wrong, andthat Frye had been superseded by the 1975 Federal Rules of Evidence, specifically rule702, which governs expert testimony. It states: "If scientific, technical, or other

specialized knowledge will assist the trier of fact to understand the evidence or determinea fact at issue, a witness qualified by knowledge, skill, experience, training, or educationmay testify thereto in the form of an opinion or otherwise." Unlike any other witness, theexpert witness may present hearsay and opinion as evidence. The US Supreme Court'sruling placed responsibility on judges to individually evaluate such evidence foradmissibility. Therefore publication and generally accepted methodology still remainvaluable criteria for acceptance of evidence, but, they are not the exclusive requirementsfor evidence.

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ANew 1995 FDA Guidelines for Drug Stability Testing

In a move toward global harmonization of pharmaceutical test methods and criteria, theFDA has begun to revise its guidelines for stability testing. This document provides avaluable reference point for understanding the practical, current state of what isacceptable and why it is accepted. This exceptional window of understanding, as providedby the US regulatory process, results from the public interaction before and during theestablishment of regulations (the regulatory process).

The Pharmaceutical Manufacturers Association (PMA) also recommends guidance forroom temperature stability studies [46]. These guidelines reflect some of the standardstorage conditions being adopted by international agreement. Room temperature isagreed to end at 30°C, but the lower limit still varies by country (Japan 10°C; US 15°C)but 25° to 30°C is generally accepted.

Extrapolation of the Arrhenius equation is also widely agreed as the acceptable methodfor predictions of (chemical) shelf life. Climate zones for shelf-life labeling have beenadopted by EEC and Japan and are favored by the US PMA committee. Such labelingrequires alternative test criteria for products marketed in different climates. NorthAmerica and Japan for example span climate zones 1 and 2. Therefore, long-term testconditions of 25°C at 60% relative humidity will support a room temperature labelstorage statement for these climate conditions.

BChoosing Test Procedures

The choice of the appropriate test procedure for any surfactant-containing system underdevelopment is best determined on an individual basis. It should primarily measure theproduct performance or attribute for which it is being sold. For drug and cosmeticproducts, assays of active or functional ingredients may be the most important criterion ofthe stability test. For example the hydrocortisone remaining in a topical creamformulation would be the primary criterion for this drug product's stability, or thedihydroxyacetone (DHA) content of a cosmetic sunless tanning creme would indicate itssuitability for use. For hair spray, the holding power and spray pattern are likely primarystability criteria. Often the primary criterion (potency) is affected by other physicalparameters.

1Viscosity

In many instances viscosity is really a secondary criterion, except in lubricants where it issynonymous with the product function. Nevertheless, viscosity is widely used, easy tomeasure, and a superb indicator of whether something of functional importance is goingwrong. Rheological (viscosity) relationships to emulsion stability have been widely

studied and are considered to be the most significant general test procedure that can beapplied to mixed systems whose stability is maintained by the strength of structuresgenerated within the liquid phase. Such structures are produced by surfactants andemulsifiers, as well as by hydrocolloids, gums, and clays. The analysis of rheologicalrelationships to physical drug stability by Zografi [47] was instrumental in establishing theFDA requirement for viscosity testing of all fluid drug products in its guidelines for stabilitytesting. Viscosity is truly a significant indicator of system stability. Since viscosity is areflection of the gross interactions in the system, any change in any ingredient will oftenupset the interactive system and its rheology. Changes in viscosity are acceptable duringdrug stability studies; however, they may not alter the dose delivery

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or uniformity of the (emulsion/suspension/solution) formulation. Rheological stability isoften an indicator that some nonprimary function such as cosmetic cream consistency or"mouthfeel" of a toothpaste or mouthwash may be unacceptable. Often applicationcharacteristics are actually as much primary criteria for acceptance as are the functionalattributes. Depending on the amount of "quality" one is presenting, many criteria canconstitute critical defects. Viscosity is the best all around indicator of product quality andit is almost universally used in stability testing of all fluid systems. Rieger [48] hasrecently reviewed stability test methods for emulsions [49] with some good emphasis onthe work of Zografi.

2pH

Chemical systems with changing pH are usually systems in which a reaction is takingplace. One interesting exception has to do with solid or insoluble acids or bases that inviscous systems may take months to equilibrate with liquid counterions. Fumed silica isknown for this rather innocuous but alarming behavior. Again, pH is easy to test, so it iswidely used in stability testing.

3Color, Odor, and Appearance

These methods may be old but they are far from obsolete. Often they are really sensitiveto changes in formulation. Sometimes they sound an alarm long before the emulsionbleeds or a reacting ingredient finally generates enough acid to overcome the buffering ofthe other ingredients. These three obvious attributes often indicate trouble withpreservative, package interaction, or a myriad of potential problems. Then again a smallchange here could mean nothing. Human sensory perception is still more sensitive insome aspects than our most sophisticated instrumentation.

The five parameters, viscosity, pH, color, odor, and appearance, are standard tests forthe stability of emulsified or surfactant-containing systems in cosmetics. All othermethods are less widely accepted and usually specific to the product type. Some of theseother methods are worth noting.

4Other Methods

Many methods fit into the category called acid tests by chemists or elephant tests byengineers. These are tests that are overkill and therefore failure to survive such testing isnot an indication that a product will lack function or appearance and not be marketable.The main value of such tests is that if a product survives them, it is a good indicator thatit's safe to build the pilot plant, run the advertisements, and print the labels. Extremestress testing generates great confidence. However, I would never rely solely on theelephant or acid tests since they do not simulate actual usage. Sometimes the extreme

conditions obscure a product flaw. For example, high-temperature stability may hide thefact that an ingredient could crystallize. Yet an understanding of solubility principlespresented here might more accurately identify this potential problem.

Among the largest elephants (if they step on the thing and it survives . . .) is thecentrifuge. Most centrifuges apply far more gravity to a system than it would ever faceunder use conditions and can exceed yield values that would never be approached inactual life. Of course if the product survives a good spin, then you can say "it is not toobad" or "the test is looking good." Unfortunately that's about as specific as one can get.

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But maybe a recheck should be done on the product to see whether it will still pour out ofthe bottle.

This problem exemplifies the main challenge in stress testing and, in fact, most testing ingeneral. Very often the testing itself changes the system.

One very useful other test that is often overlooked, especially at small labs, is the shiptest. Just ship your product the way you were planning to distribute it and then test it.The unusual combination of temperature changes, vibrations, and pressure changesexperienced during shipping cannot be duplicated (or even imagined) in the laboratory.The ship test is one of the most successful qualifiers for marketability of any product, butremember to make at least six separate shipments.

CSuccessful Predictions

Every successful test program depends on three important aspects:

1. quality data;

2. effective application of theory; and

3. duplication of effort.

All the factors for successful predictions combine within the concept of validation. This isthe concept of showing your results are valid or true. In principle nothing can really betested for validity. Only infinite testing under all conditions could accomplish that.Therefore, a statistical treatment is normally required to show how high a probability ofaccuracy (approaching truth) your test has achieved. A 99.5% probability is generallyacceptable for most purposes [50] and probabilities as low as 95% are admissible incourt.

Good data depends on skill and precision. Precision is only limited by the quality of themeasuring instrument combined with the skill of the user. A basic precision and accuracy(P & A) assessment of any test is the first step toward validation. Validation of testprotocols is required for drug product testing throughout the world, however the "V-word"(validation) is a source of panic among cosmetic formulators, organic chemists, and otherempirical practitioners. It needn't be so, for soon initiatives like ISO 9000 certification willforce validation on everyone. It is no secret that validating work such as the P & A studyis boring, time consuming, and costly, but it changes a common "test result" into a truemeasure of quality. Accuracy, above all, requires that a precise test be applied tomeasure logically related variables.

VIThe Future of Stability Projection

We have seen that molecules are sticky and that the solubility parameter provides a

precise measure of that stickiness. Moreover we have seen that this stickiness varies instrength or cohesive energy density over the surfaces of most molecules. This anisotropyallows most molecules to orient into structures which can contribute to stability of mixedsystems. Surfactants and emulsifiers are excellent examples of amphiphilic structureformers. The causes of success or failure in their use might simply be attributed toreactions and interactions, but such is not the case. To avoid the errors of false-positivetest results or true-negative results of practical testing, it is useful to understand thenature or ideal behavior of the materials that form the system under test. But we shouldbe aware of more factors important to the success of stability projection. Errors exist inpublished

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physical constants and properties of materials found in the literature. Use of theseerroneous data can result in incorrect solubility parameter values. Many systems are socomplex that their tertiary folding and aggregation confound a uniform treatment. Proteinfolding and DNA structure projection still primarily rely on empirical databases of knownprotein segment folds and nucleotide helices. Eventually even the most complex systemwill be simplified by the ever increasing computational power of the computer.

References

1. F. Langenbucher, Drug Dev. and Ind. Pharmacy 17:16581 (1991).

2. I. Bergenholtz, A. A. Romagnoli, and N. J. Wagner, Langmuir 11:155970 (1995).

3. A. Stabel, L. Desaradhi, D. O'Hagan, and J. P. Rabe, Langmuir 11:142730 (1995).

4. L. Nick, A. Lippitz, W. Unger, A. Kindermann, and J. Fuhrmann, Langmuir 11:191216(1995).

5. L. Kennon, J. Pharm. Sci. 53:816 (1964).

6. K. Laidlaw, J. Chem. Ed. 1597 (1972).

7. W. Nelson, Accelerated Testing, Wiley Intersci. Publ., New York, 1990.

8. B. Runesson and K. Gustavii, Acta Pharm. Suec. 23:15162 (1986).

9. W. P. Kierstead, K. R. Wilson, and J. T. Hynes, J. Chem. Phys. 95:5256 (1991).

10. L. E. S. Brink and J. Tramper, Biotechnol. and Bioengineering 28:125869 (1985).

11. M. J. Kamlet, J. M. Abboud, M. H. Abraham, and R. T. Taft, J. Org. Chem. 48:287787(1983).

12. B. Honig and A. Nicholls, Science 268:114449 (1995).

13. V. Parseghian, Nature 221:884 (1969).

14. N. A. Shaath, H. M. Fares, and K. Klein, Cosmet. and Toil. 105:4111 (1990).

15. US Patent 5208011, 1993.

16. C. D. Vaughan, Florida Sunscreen Symposium, Sanibel, FL, 1989.

17. L. Pauling, The Nature of The Chemical Bond, 3rd ed., Cornell Univ. Press, Ithaca,1960.

18. F. London, Trans. Faraday Soc. 33:8 (1937).

19. S. Paul, J. Coatings Technol. 54:5965 (1982).

20. E. R. Cooper, J. Pharm. Sci. 73:11536 (1984).

21. Sugden, The Parachor.22. J. H. Hildebrand and R. L. Scott, The Solubility of Nonelectrolytes, Dover Publ. Inc.,New York, 1964.

23. R. F. Fedors, J. Polym. Engr. and Sci. 14:1478154 (1974).

24. W. C. T. Kranendonk and D. Frenkel, Mol. Phys. 63:40324 (1988).

25. J. Zhu and J. C. Rasaiah, J. Chem. Phys. 92:755464 (1990).

26. M. Rieger, Cosmet and Toil. 106:5766 (1991).

27. Chemical and Engr. News: Dec. 10 p32 (1984).

28. C. D. Vaughan, J. Soc. Cosmet. Chem. 36:319 (1985).

29. C. D. Vaughan, Cosmet. and Toil. 103:3242 (1988).

30. C. D. Vaughan, Cosmet. and Toil. 108:5764 (1993).

31. A. F. Barton, Handbook of Solubility Parameters and Other Cohesion Parameters,Chem. Rubber Publ., Boca Raton, 1988.

32. The Cosmetic Bench Reference (N. Allured, ed.), Allured Publ. Carol Stream.

33. W. C. Griffin, H. J. Renauto, and A. D. Adams, Am. Perf. and Cosmet. 81:18 (1966).

34. A. F. Beerbower and M. Hill, Am. Cosmet. and Perf. 87:85 (1972).

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35. C. D. Vaughan and D. A. Rice, J. Disp. Sci. and Technol. 11:8391 (1990).

36. H. Schott, J. Pharm. Sci. 73:79092 (1984).

37. D. Gersappe, D. Irvine, A. Balazs, Y. Liu, J. Sokolov, M. Rafailovitch, S. Schwarz, andD. G. Pfeiffer, Science 265:1013 (1995).

38. D. Papoutsi, P. Lianos, and W. Brown, Langmuir 10:34025 (1994).

39. E. D. Goddard, J. Soc. Cosmet. Chem. 41:2349 (1990).

40. F. M. Menger and A. V. Eliseev, Langmuir 11:185557 (1995).

41. L. D. Song and M. J. Rosen, Langmuir 12:114953 (1996).

42. S. Fuller, N. Shinde, and J. T. Tiddy, Langmuir 12:111723 (1996).

43. Drug Masters Files-Global Harmonization of Quality Standards (Moeller and Oesser,eds.), Wissenshaftliche Verlagsgesselschaft mbH, Stuttgart, 1992.

44. Federal Register, FDA Int'l. Conference on Harmonization; Stability Testing of NewDrug Substances and Products; Guideline Availability; Notice., Sept. 22, 1994, p. 487549.

45. Phantom Risk: Scientific Inference and the Law (K. R. Foster, D. E. Bernstein, and P.W. Huber, eds.), MIT Press, Cambridge, MA, 1993.

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50. Validation of Compendial Methods, section 1225, USP XXII, 1990, pp. 17102.

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9Phase Inversion in Emulsions:CAPICOConcept and ApplicationArmin WadleProduct Development Skin CareCOSPHA, Henkel KGaA, Düsseldorf, Germany

Holger TesmannCFTCOSPHA, Henkel KGaA, Düsseldorf, Germany

Mark LeonardCOSPHA, Henkel Organics, Belvedere, Kent, England

Thomas FörsterChemical Research, Henkel KGaA, Düsseldorf, Germany

I. Introduction 207

II. Principles of Phase Behavior in Emulsions 208

A. PIT and Phase Behavior with EthoxylatedEmulsifiers 208

B. PIT and Phase Behavior with Ionic Emulsifiers 209

C. The Effect of Additives on the PIT 210

D. Comparison between PIT and HLB 211

E. Phase Behavior and Emulsification Properties 212

III. PIT-Emulsification 212

IV. PIT and Stability of O/W Emulsions 215

V. CAPICO Concept 217

A. Characterization of Cosmetic Ingredients 217

B. Formulation of Cosmetic O/W Emulsions 221

References 223

IIntroduction

The cosmetic industry is constantly searching for a straightforward approach to the

development of emulsions. A concept that gave a significant reduction in developmenttime by an appropriate selection of emulsifiers and oils, together with economic use ofboth raw materials and equipment, would be of particular interest. Existing formulationconcepts offer quantitative and/or qualitative criteria based on either the sensory aspects[13] or the emulsification process. Amongst the various concepts to be considered basedon the emulsification process are the HLB concept of Griffin [4,5], the EIP (emulsificationinversion point) of Marszall et al. [68], the HLB temperature or PIT (phase

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inversion temperature) of Shinoda et al. [9,10] and the CAPICO-concept (calculation ofphase inversion in concentrated emulsions) of Wadle et al. [3,11,38].

The HLB system by Griffin is the most widely known but is limited in its use forformulating cosmetic emulsions. This is due to the fact that the HLB values describe theemulsifier molecules solely by their structural modifications, without referring to theiractual state at the oil/water interface during emulsification. Furthermore, the influence oftemperature on their hydrophilic/lipophilic properties is neglected. In contrast to theselimitations, the HLB temperature or PIT and the CAPICO-concept take into account theeffects of several variable parameters of emulsion preparation. In addition to thestructural aspects of emulsifiers, co-emulsifiers or consistency-enhancing agents and oils,temperature is also considered. Temperature serves as one of the most usefulparameters that can be used to influence the emulsification process.

Within the scope of the CAPICO-concept (of which a detailed explanation follows) theemulsifiers, co-emulsifiers, and oily components are designated by characteristic values,derived from the PIT in trial o/w emulsions. From these values, optimized blends ofchosen emulsifiers can be calculated for a given mixture of oils. Thus, the CAPICO-concept offers the opportunity to start the formulation work for a defined cosmeticemulsion type with well selected and suited raw materials.

IIPrinciples of Phase Behavior in Emulsions

APIT and Phase Behavior with Ethoxylated Emulsifiers

In order to evaluate the aspects of emulsion formation in a systematic manner, a deeperinsight into the principles of phase behavior is necessary. Many research groups haveshown that the phase behavior of a ternary system consisting of water, oil, and emulsifiercan be completely represented in a phase prism [1217]. A two-dimensional cut at aconstant oil/water ratio (Fig. 1) shows the effect of temperature on emulsion phasesstabilized with ethoxylated emulsifiers [18]. This phase behavior is a general feature ofo/w-emulsions based on ethoxylated emulsifiers. This unique phase change due to risingtemperature happens only with ethoxylated emulsifiers and can be regarded as essentialto their application properties.

The example illustrates that the hydrophilic/lipophilic properties of ethoxylatedemulsifiers are strongly temperature dependent, as is shown by the dependence ofemulsion type on temperature. In the lower temperature range a two-phase oil-in-water(2j; o/w) emulsion is formed. With increased temperature, inversion of the inner andouter phase takes place, and a two-phase water-in-oil (2j; w/o) emulsion is formed. As acharacteristic property of these emulsion systems, in a certain temperature range thehydrophilic/lipophilic properties of the ethoxylated emulsifier are just balanced and a

three-phase (3j) or one-phase (1j) microemulsion appears. For the given emulsionsystem this is achieved in the temperature range between 80 and 90°C. Furthermore, inthe one-phase region, an isotropic area with a liquid crystalline range (La) exists. Themedian temperature of the inversion range is considered as the PIT of the emulsion. Inthe temperature range below 60°C the fatty-alcohol-containing emulsion shows thetypical sequence of different microcrystalline structures. The regular liquid-crystalstructure observed in the melting range of the fatty alcohol changes to the viscosity-enhancing gel structure at lower temperatures.

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Fig. 1Phase diagram of a four-component emulsion with theethoxylated emulsifier C16/18-12EO. Ratio between

water/paraffin oil/ C16/18-OH = 70/20/3.(From Ref. 8.)

The PIT phenomenon is caused by the temperature dependent change of the hydrationforces between the ethoxylated part of the emulsifier and water. The hydration forces arestronger below the PIT, and the emulsifier is hydrophilic. Above the PIT the hydrationforces diminish, and the emulsifier becomes more oil soluble or lipophilic.

The existence of a phase inversion indicates significant changes at the oil/waterinterface, which are determined by various factors. Those of major importance are thekind of emulsifier and oil, the mixing ratio of the components, and the temperature. Theinfluences of different kinds of ethoxylated emulsifiers and oils on the PIT are illustratedin Fig. 2 [13,19]. It is evident from Fig. 2 that changing the oily component of anemulsion has a pronounced effect on the PIT. For nonpolar hydrocarbons and differentethoxylated emulsifiers it is shown that the PIT increases with increasing carbon number(ACN, Alkane Carbon Number) or molecular weight. Furthermore, the PIT increases withthe hydrophilicity of the emulsifiers. In general, this is done by increasing the ethoxylatedmoiety (C8Ej with j = 3,4,5) or by decreasing the alkyl chain length. These correlationsmake it obvious that the PIT depends on both the hydrophilicity of the emulsifiers and thehydrophobicity of the oily components.

BPIT and Phase Behavior with Ionic Emulsifiers

In contrast to the temperature sensitivity of ethoxylated emulsifiers, thehydrophilic/lipophilic balance of ionic emulsifiers is almost independent of temperature.For ionic emulsifiers the critical variable is the salt content of the emulsion, whichinfluences the respective phase behavior to a far greater extent compared to its influencein emulsions

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Fig. 2Relation between PIT of emulsions and the hydrophilic and

hydrophobic properties of emulsifiers and oils(ACN = Alkane Carbon Number).

(From Ref. 13.)

with ethoxylated emulsifiers [17,20,21]. Accordingly, the salt effect in emulsions withionic emulsifiers is equivalent to the temperature influence shown in emulsions withethoxylated emulsifiers.

Another pronounced difference between ionic and ethoxylated emulsifiers is due to thefact that their water solubilities are reversed with temperature. With increasingtemperature the solubility of ethoxylated emulsifiers in water decreases, while itincreases for ionic emulsifiers. Generally, an o/w emulsion is formed using an ionicemulsifier due to its high hydrophilicity. With a given salinity and the addition of ahydrophobic co-emulsifier, the hydrophilic property of the emulsifier mixture issuppressed, and the phase behavior can be changed. This reversed phase behavior canbe exploited by using a blend of an ionic emulsifier and of a nonionic co-emulsifier. Thephase behavior of the emulsion now becomes almost temperature independent [22]. Thisis shown in Fig. 3 with the ionic emulsifier C16H33SO4Na and the nonionic co-emulsifierglyceryl mono(2-ethylhexyl)ether. With this balanced emulsifier mixture a microemulsion(Wm) is formed, which stays stable over a wide temperature range. With more hydrophilicor hydrophobic emulsifier mixtures, two-phase o/w-(Wm + O) or w/o-(D + W) emulsions,which are also temperature independent, are formed.

CThe Effect of Additives on the PIT

Various additives common to cosmetic emulsions are effective at the oil/water interfaceand consequently influence the hydrophilic/lipophilic balance of the emulsifiers or the PITof the emulsion. For cosmetic emulsions the effect of salinity, fatty acids, andconsistency-giving agents, e.g. long chain fatty alcohols, are of main interest. Inemulsions using ethoxylated emulsifiers, these additives decrease the PIT to different

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Fig. 3Temperature dependent phase behavior of an emulsion composed of 9/1 weight ratio

aqueous NaCl (1 wt%) solution/liquid paraffin emulsified with 5 wt% mixtureof C16H33SO4Na/glycerol mono(2-ethylhexyl)ether.

(From Ref. 22.)

degrees. Compared to long-chain alcohols and fatty acids, the effect of adding salt is notvery pronounced [23] and can be disregarded in common cosmetic emulsions.

The effect of fatty acids and long-chain fatty alcohols is shown in Fig. 4 [24]. Thedecrease in the PIT shows that these additives are effective at the oil/water interface andthereby influence the hydrophilic/lipophilic balance. Fatty acids and consistency agents ofthe fatty-alcohol or fatty-acid monoglyceride type must, therefore, be regarded as co-emulsifiers and have to be taken into account when the emulsifying components of o/wemulsions are characterized. In the case of fatty acids and long-chain fatty alcohols Fig. 4shows that the shift in PIT is proportional to the concentration but is relativelyindependent of the actual chain length.

DComparison between PIT and HLB

The PIT of an o/w emulsion is determined by characteristic features of the emulsifiermixtures and oily components and reflects their interaction at the oil/water interface.Thus, the PIT concept describes an emulsion as a complex unit, which is significantlydifferent from the HLB concept. By considering additional variables of emulsiontechnology, Shinoda compared the PIT concept and the HLB numbers on the basis of theinformation available from both concepts (Table 1, Ref. 24). From this comparison it is

evident that the PIT is a more suitable parameter than the HLB to describe the complexinteractions between the emulsifiers, oils, and additives during emulsification.

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Fig. 4The effect of added fatty acids and alcohols on the PIT in an

emulsion composed of 1/1 weight ratio liquid paraffin andwater emulsified with 3 wt% C12-6,3EO.

(From Ref. 24.)

EPhase Behavior and Emulsification Properties

Within the PIT range, formation of a microemulsion phase (ME) is observed. Themicroemulsion phase is formed at extremely low interfacial tensions (< 104 mN/m)between the oil and water phases (Fig. 5), which provides ideal emulsification properties[2530].

The advantage of minimum interfacial tension for emulsification purposes is expressed inEq. (1).

where E is energy consumption, g is interfacial tension between water and oil phase, andDA is newly created internal surface.

During emulsification, new internal surfaces are created. The droplet size of the internaloil phase of an o/w emulsion is determined by the energy consumption and the interfacialtension (cf. Chapter 4). At low interfacial tension the oil droplets are easily deformable bystirring, and droplet break-up is possible even with a low energy input. Taking intoaccount that energy is mainly dissipated during heating/cooling cycles or homogenizationsteps [31], a minimal interfacial tension at the emulsification temperature is mosteffective for emulsification purposes. Thus, the PIT range provides ideal conditions toreach a very fine oil droplet size with minimal energy input.

IIIPIT-Emulsification

Commercial cosmetic emulsions are usually manufactured by a two-step batch process.

The oil and water phases are heated in separate vessels in order to melt the ingredientsand to provide optimal emulsification conditions. Subsequently, the phases are combined,forming an emulsion with stirring. In addition, a homogenization step is often used. To

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TABLE 1 Comparison Between PIT and HLB withRegard to Information Available on Both ConceptsFactors PIT HLB NumberHydrophile-lipophilebalance of surfactantTypes of hydrophilic moietyof surfactantTypes of lipophilic moietyof surfactantTypes of oilsAdditives in waterand/or oil phaseConcentration of emulsifierPhase volumeTemperatureEmulsion typesCorrelation with theother propertiesIn the case of ionic surfactant

, Accurate information is available , Lessaccurate information is available , Crudeinformation is available , Almost no information isavailable , Information is available in thepresence of salt and cosurfactantSource: Ref. 24.

Fig. 5Influence of the temperature on the interfacial tension between the aqueous and

oily phase in the quaternary system composed of C16/18-12EO = 6,3 wt%,C16/18-OH = 4,7 wt%, mineral oil = 19.8 wt%, and water = 69.2 wt%.

(After Ref. 27.)

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benefit from PIT conditions (Section II.D.) the microemulsion phase must be passedthrough during the emulsification process [2730]. This requirement can be controlled byusing a temperature/water content diagram (water phase map), where the specific phasebehavior is given as a function of the water content. A water phase map can be built upby observing the phase behavior as the water content is varied but the oil/emulsifier ratiois kept constant. Following this procedure, water phase maps can be utilized to showwhich phases are passed during the emulsification process.

In Fig. 6 the water phase map is given for an emulsion with ethoxylated emulsifiers,covering the whole water level. For most cosmetic emulsions the PIT stays almostconstant over a wide water-content range but, depending on the type of oils andemulsifiers, disappears in highly diluted systems. A significant feature at low water levelsis the appearance of a microemulsion phase, which is utilized for the PIT-emulsification. Amore complicated phase behavior arises if the emulsifier content is considerably reduced[24].

According to the water phase map in Fig. 6 [30] the effect of water content on the PIT isinsignificant within a wide range from concentrated to diluted o/w emulsions. Therefore,the water phase map or the phase behavior of o/w emulsions can be predicted bymeasuring the PIT of a concentrated o/w emulsion. For the preparation of finelydispersed o/w emulsions, different emulsification routes were investigated, utilizing thewater phase map. The emulsification via route 1 (emulsification of an emulsionconcentrate at 80°C and dilution with cold water) or route 2 (one-step emulsification ofall components at 80°C), using respectively a microemulsion and a lamellar liquidcrystalline phase with the minimum oil/water-interfacial tension, yields very small oildroplets,

Fig. 6Water phase map for PIT-emulsification of the oily component cetearyl isononanoate.

The ratios C16/18-12EO/glycerol monostearate = 2/1 and cetearylisononanoate/mixed emulsifier = 4,5/1 are kept constant.

(After Ref. 30.)

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indicating a high emulsification capability. If these preferred routes 1 and 2 are notfollowed, with the same formula only a coarse emulsion is reached at the emulsificationtemperature, below the microemulsion phase (route 3). The mean droplet sizes aresummarized in Table 2.

Based on these results, an efficient commercial two-step process of emulsification can beachieved (PIT-emulsification): (1) by adjusting the PIT to the emulsification temperatureusing a suitable emulsifier and co-emulsifier blend and (2) by diluting the oil/emulsifierphase with the water phase, going through an initial microemulsion phase [25,30].

An energy and time-saving emulsification process can be designed [11] by producing afinely dispersed emulsion concentrate, using only a part of the water phase, as the firststep. In the second step this emulsion concentrate can be diluted with the remainder ofthe cold-water phase. By this means, time-consuming cooling cycles can be minimized.

Figure 7 [33] illustrates the characteristic dimensions of the dispersed oil droplets thatare accessible by PIT-emulsification compared to conventional macro- and micro-emulsions. The PIT emulsions or fine macroemulsions usually appear in the dropletdiameter range of 0.1 to 1 µm and can be considered as the link between a macro- andmicroemulsion. Due to these typical dimensions, the PIT emulsions show a bluishappearance when viewed perpendicular to scattered light.

IVPIT and Stability of O/W Emulsions

The stability of emulsions is usually examined in terms of creaming and coalescence [34].It has been shown that the storage temperature, type of hydrophilic emulsifier orlipophilic co-emulsifier, and content of the emulsifier blend have a significant influence onemulsion stability.

Emulsion stability must be discussed first with reference to the storage temperature.Temperature elevation, particular beyond the melting point of the high-melting co-emulsifiers, promotes coalescence. Generally the temperature stability of emulsions withfatty-acid monoglycerides or long-chain fatty alcohols is restricted to the temperaturerange of below 40 to 50°C.TABLE 2 Mean Droplet Size of theDispersed Oil Phase CetearylIsononanoate Achieved by DifferentEmulsification Conditions (cf. Fig. 6)Emulsification

routeMean oil droplet size

[nm]1 104 ± 282 114 ± 533 1400 ± 1300

Source: Ref. 30.

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Fig. 7Characteristics dimensions of the dispersed oil phase in

different emulsion types.(After Ref. 33.)

The emulsion stability in the PIT range is determined by the emulsifier concentration,because it determines whether a three- or a one-phase microemulsion will be present (cf.Sec. II.A. above and Fig. 1). At low emulsifier content a very unstable three-phasemicroemulsion is built up, which is subject to phase separation. When such an emulsion isstored at its PIT, rapid phase separation occurs [34].

Cosmetic emulsions are usually formulated with a water content higher than 70%.Therefore, during temperature elevation, phase inversion does not generally occur, dueto the volumetric ratios of the phases [35,36]. Nevertheless, the stability at higherstorage temperature is limited by the degree of coalescence that results from the changeof interfacial tension when the PIT range is approached. It is reported that emulsionstability increases when the PIT of the emulsions is at least 3060°C above the actualstorage temperature [34].

Phase separation or creaming of the oil phase is due to the density difference betweenthe oil and water phase. This phenomenon is counterbalanced by the Brownian motion ofthe oil droplets, which is most effective at a small oil droplet size. In the absence ofcoalescence, PIT emulsions can be considered to be stable against creaming due to theoil droplet size in the range of 100 nm.

A very small oil droplet size is not the only criterion for stable o/w emulsions as far ascoalescence of the oil droplets and phase separation are concerned. Stability againstcoalescence depends mainly on emulsifier composition. The long-term emulsion stability

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TABLE 3 Effect of Emulsifier Mixture on Storage Stability ofan O/W Emulsion Composed of 20 wt% Di-n-octyl ether and73.8% wt% Water

mean oil droplet size [nm]emulsifier mixturewt% PIT

[°C]after

productionafter storage (4

weeks)C16/18-12 EO 3.8 73 305 450glycerolmonostearate 2.4

C16/18-12 EO 2.7 74 350 3500C12/14-4 EO 3.5Source: Ref. 37.

is improved when coalescence is prevented by adjusting emulsifier and co-emulsifiermixtures appropriately (Table 3) [37]. The storage stability was examined bymeasurement of ultrasonic velocity and mean oil droplet size. Despite initially havingnearly the same mean oil droplet size and PIT, the difference in the long-term stability isobvious. After several days phase separation occurs only with the emulsifiers C16/18-12EOand C12/14-4EO. Coalescence is diminished if lipophilic and high-melting co-emulsifiers,like glyceryl stearate, are used in combination with hydrophilic emulsifiers, like C16/18-12EO. These emulsifier components reportedly build up a lamellar gel around the oildroplets, which shields the droplets against coalescence. This stability mechanism will beabsent if only water soluble emulsifiers like C16/18-12EO or C12/14-4EO are used.

VCAPICO Concept

The PIT approach has proved to be a specific and precise tool for describing the complexinteractions in a multicomponent system, like a cosmetic emulsion. Based on the phasebehavior presented above, the CAPICO concept (Calculation of Phase Inversion inConcentrated Emulsions) was developed for formulating cosmetically acceptable andstable o/w emulsions in a straightforward approach [3,11,38]. Within the scope of theCAPICO-concept, commercially available emulsifiers and oily components used incosmetics have been experimentally evaluated and assigned numbers that correlate withtheir properties in emulsions. With these numbers, optimized emulsifier and oil mixturescan be calculated to find optimal conditions for the PIT emulsification process.

ACharacterization of Cosmetic Ingredients

To evaluate the influence of cosmetic ingredients on the PIT of an emulsion in asystematic way, a reference o/w emulsion is defined, using the emulsifier ceteth-6 NRE(narrow range ethoxylate). Choosing an appropriate oil/emulsifier ratio of 4.5/1 ensuresthat during phase inversion the one phase microemulsion is passed through and the PITis approximately independent of emulsifier concentration. In Fig. 8 the respective PITs

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Fig. 8Calibration curve for the determination of ACN values of

different types of oils.

with different types of oils are shown. In this approach the linear hydrocarbons rangingfrom decane to hexadecane are defined according to their alkyl chain length, the alkanecarbon number (ACN).

As discussed in Sec. II.A. above, a linear correlation between the PIT and the ACN exists.The PIT increases progressively with increasing ACN. By substituting the hydrocarbonswith cosmetic lipids, their respective characteristic ACN numbers can easily bedetermined by projecting the observed PIT onto the ACN scale. This is shown for coco-caprylate/caprate and dicaprylyl ether in Fig. 8. This method allows one to comparechemically different cosmetic oils, e.g. of esters or of paraffin types, in a unified referenceframe. Generally, higher ACN values indicate an increase of the lipophilic character of theoil. For comparison Table 4 lists some experimentally derived ACN values for differentkinds of cosmetic oils.

Through use of the ACN values, cosmetic oils can be judged on the basis of their influenceon the PIT emulsion without considering criteria like chemical structure or polarity; e.g.,emulsions containing any oils with high ACN values will also show high PIT values.Without changing the PIT of the emulsion, an oil with a medium ACN value can be easilysubstituted by a balanced mixture of oils with lower and higher ACN values.

For the characterization of an emulsifier, the same reference o/w emulsion was used, butceteth-6 NRE was substituted with the respective cosmetic emulsifier. Figure 9 illustratesthe basic emulsifier properties affecting the PIT of an emulsion.

Extending the lipophilic chain length of an emulsifier lowers the PIT (compare laureth-6NRE and ceteth-6 NRE). An opposite effect results from extending the hydrophilic moiety(compare laureth-4 NRE and laureth-6 NRE). By comparison to the linear relationshipbetween the PIT and the ACN of the linear hydrocarbons, the emulsifiers arecharacterized by the slope SF, the sensitivity factor, and the intercept,

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TABLE 4 Experimentally DeterminedACN Values of Commercially AvailableCosmetic OilsOily component (INCI Name) ACNIsopropyl Myristate 13Dicaprylyl Ether 14Coco-Caprylate/Caprate 17Dioctylcyclohexane 17Cetearyl Isononanoate 18Octyl Stearate 19Decyl Oleate 20

PIT0. Using this method, characteristic and experimentally evaluated numbers are derivedthat are specific for each emulsifier. The PIT0 denotes the PIT of an emulsion with thespecific emulsifier and a hypothetical oil with ACN equal to zero. It can be regarded as ameasure of the emulsifier's basic hydrophilicity. The slope SF takes into consideration thespecific interaction between emulsifiers and oils, which is a distinct difference from theHLB concept. Use of emulsifiers with small SF values changes the

Fig. 9Characterization of emulsifier from the linear dependence of the

PIT on the alkane carbon number (ACN); (C12-6 EO =laureth-6; C16-6 EO = ceteth-6; C12-4 EO =

laureth-4).

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hydrophilic/lipophilic balance, or the PIT, of an emulsion only to a minor degree wheneveroily components are changed or added. Use of emulsifiers with high SF values has apronounced influence on the PIT when the oily components are changed.

Figure 9 also shows that the characterization of the emulsification properties by the PIT-method is more accurate than that by the HLB approach. Despite having almost equalHLB-values, the emulsifiers laureth-4 NRE (HLB = 10.7) and ceteth-6 NRE (HLB = 11.1)show different emulsification properties. These are indicated by the course of therespective PIT. At 25°C an emulsion with the oily component dodecane (ACN = 12) andthe emulsifier laureth-4 NRE is of the w/o type, whereas the emulsifier ceteth-6 NREcreates a o/w emulsion under the same conditions. For comparison, Table 5 lists theexperimental results for ethoxylated emulsifiers and lipophilic co-emulsifiers like fattyalcohols and acyl glycerides. Strongly hydrophilic or lipophilic emulsifiers and co-emulsifiers, which do not produce a phase inversion of an emulsion, are useful in mixtureswith a characterized ethoxylated emulsifier.

The CAPICO-concept uses the demonstrated linear relationship to describe thehydrophilic/lipophilic characteristics of an emulsion quantitatively and to calculate therespective PIT. As illustrated in Figs. 8 and 9 the PIT follows the linear equation

From this, the CAPICO equation for a multicomponent emulsion is derived

The lipophilicity of the oil mixture is given by the mean <ACN> = SL yL ACNL. Thecomponents of the emulsion are described by their characteristic numbers where thesubscript L denotes the oil and the subscript K the emulsifier and co-emulsifier systemrespectively. The relative content of the different phases is given by the weight fractionxK and yL. By this approach the PIT and <ACN> are balanced by the weight of theemulsifiers and oils. Using emulsions containing hydrocarbons and different emulsifiers,the self-consistency of the linear mixing rules for the PIT was confirmed [11].TABLE 5 Experimentally Determined PIT0 and SFValues of Commercially Available Emulsifiers and Co-emulsifiersEmulsifier (INCI Name) PIT0 [°C] SF [°C]Ceteareth-30 255 4.3Ceteareth-20 162 4.0PEG-20 Glyceryl Stearate 97 3.0Ceteareth-12 77 3.0Cetearyl Alcohol 48 1.4Glyceryl Stearate -32 1.1

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The CAPICO-concept can be used in various ways. For a given emulsification task suitableemulsifiers and oils may be selected. Furthermore, the CAPICO-equation serves as aneffective tool for selecting the preferred PIT-emulsification conditions by bringing the PITof an emulsion and the emulsification temperature into line. The CAPICO-concept allowsadjustment and calculation of emulsifier mixtures that are most suitable for emulsifying agiven blend of cosmetic oils by phase inversion emulsification.

BFormulation of Cosmetic O/W Emulsions

The formulation of a cosmetic emulsion by the CAPICO-method is performed in a fewworking steps that are summarized in Fig. 10. At the beginning there will be a givenproduct profile with raw materials selected according to different cosmetic requirements.Starting with these limiting conditions, a basic formula with high probability of exhibitinga phase inversion is calculated by the CAPICO-equation [Eq. 3]. In order to get amarketable formulation, the initial emulsion must be evaluated with respect to the givenproduct profile and, if necessary, empirically optimized [11].

The composition of a typical cosmetic formulation (Tables 6 and 7) was calculated fromthe CAPICO values shown in Tables 4 and 5. It fulfills the market requirements forstorage and temperature stability. Emulsified by the PIT-emulsification method, thisemulsion possesses a very finely dispersed oil phase, as proven by the blue appearanceof the scattered light. This example shows that with use of the calculated emulsifiermixture as a starting point, o/w emulsions can be developed that are within a few stepsof optimum. These emulsions may range from high-viscous to very low-viscous creamsand sprayable emulsions.

Fig. 10Product development by the

CAPICO-concept.

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TABLE 6 CAPICO Calculation of a SprayableO/W EmulsionProduct profile: Moisturizing spraySelection of components(c.f. Table 4 and 5)Emulsifier:Coemulsifier:Oily component:

Cutina E 24Cutina GMSCetiol SN

CAPICO-Calculation(c.f. Eq. 3)Emulsification temperature (PIT)Total emulsifier content:× (Cutina E 24):× (Cutina GMS):

85°C8.9 wt%0.6 (5.3 wt%)0.4 (3.6 wt%)

TABLE 7 Sprayable O/W Emulsion Calculated by theCAPICO Conceptcomponents wt% functionCutina GMS (1)(Glyceryl Stearate) 3.6 coemulsifierCutina E 24 (1)(PEG-20 Glyceryl Stearate) 5.3 emulsifierCetiol SN (1)(Cetearyl Isononanoate) 20.0 oily componentWater, preservative 71.1Viscosity:(Brookfield RVF, 23°C,Spindel 2, 10 Upm)

approx20 mPa·s

(1) Fa. Henkel KGaA

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References

1. M. M. Breuer, in Encyclopedia of Emulsion Technology, vol. 2, Marcel Dekker, NewYork, 1985, p. 386.

2. U. Zeidler, Fette, Seifen, Anstrichm. 87:403 (1985).

3. A. Ansmann, R. Kawa, E. Prat, and A. Wadle, Seifen, Öle, Fette, Wachse, 120:158(1994).

4. W. C. Griffin, J. Soc. Cosmet. Chem. 1:311 (1949).

5. W. C. Griffin, J. Soc. Cosmet. Chem. 5:249 (1954).

6. L. Marszall, Cosmet. Toiletries 90:37 (1975).

7. L. Marszall, Cosmet. Toiletries 92:32 (1977).

8. L. Marszall, Fette, Seifen, Anstrichm. 80:289 (1978).

9. H. Kunieda and K. Shinoda, J. Colloid Interface Sci. 107:107 (1985).

10. K. Shinoda and H. Sagitani, J. Colloid Interface Sci. 64:68 (1978).

11. Th. Förster, H. Tesmann, and A. Wadle, Proceedings of 17. IFSCC Congress,Yokohama, 1992.

12. M. Kahlweit, R. Strey, D. Haase, H. Kunieda, et al., J. Colloid Interface Sci. 118:436(1987).

13. M. Kahlweit, R. Stray, and G. Busse, J. Phys. Chem., 94:3881 (1990).

14. A. M. Bellocq, J. Biais, P. Bothorel, B. Clin, G. Fourche, P. Lalanne, B. Lemaire, B.Lemanceau, and D. Rouse, Adv. Colloid Interface Sci. 20:167 (1984).

15. K. Shinoda and S. Friberg, Adv. Colloid Interface Sci. 4:281 (1975).

16. M. Kahlweit, R. Strey, P. Firmann, D. Haase, J. Jen, and R. Schomäcker, Langmuir4:499 (1988).

17. M. Kahlweit, R. Strey, R. Schomäcker, and D. Haase, Langmuir 5:305 (1989).

18. F. Schambil, F. Jost, and M. J. Schwuger, Progr. Colloid and Polymer Sci. 73:37(1987).

19. M. Kahlweit, R. Strey, and P. Firman, J. Phys. Chem. 90:671 (1986).

20. K. Shinoda and Y. Shibata, Colloids and Surfaces 19:185 (1985).

21. R. E. Anton and J. L. Salanger, J. Colloid and Interface Sci. 140:75 (1990).

22. K. Shinoda, H. Kunieda, T. Arai, and H. Saijo, J. Phys. Chem. 88:5126 (1984).

23. M. Bourrel, J. L. Salanger, R. S. Schechter, and W. H. Wade, J. Colloid Interface Sci.75:451 (1980).

24. K. Shinoda and S. Friberg, Emulsions and Solubilization, Wiley, New York, (1986).

25. T. J. Lin, J. Soc. Cosm. Chem. 29:117 (1978).

26. T. J. Lin, J. Soc. Cosm. Chem. 29:745 (1978).

27. Th. Förster, F. Schambil, and W. von Rybinski, J. Dispersion Sci. Technol. 13:183(1992).

28. Th. Förster, F. Schambil, H. Tesmann, Int. J. Cosm. Sci. 12:217 (1990).

29. Th. Förster and H. Tesmann, Cosmetics & Toiletries 106:49 (1991).

30. A. Wadle, Th. Förster, and W. von Rybinski, Colloid Surfaces A 76:51 (1993).

31. P. Walstra, in Encyclopedia of Emulsion Technology, vol. 1, Marcel Dekker, New York,1983, p. 57.

32. H. Rai and K. Shinoda, J. Colloid Interface Sci. 25:396 (1967).

33. B. W. Davis, in Encyclopedia of Emulsion Technology, vol. 3, Marcel Dekker, NewYork, 1988, p. 307.

34. K. Shinoda and H. Saito, J. Colloid Interface Sci. 30:258 (1969).

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35. J. L. Salanger, M. Minana-Pérez, M. Pérez-Sánchez, M. Ramirez-Gouveia, and C. I.Rojas, J. Dispersion Science and Technology 4:313 (1983).

36. R. E. Antón, P. Castillo, and J. L. Salanger, J. Dispersion Sci. Technol. 7:319 (1986).

37. Th. Engels, Th. Förster, and W. von Rybinski, to be published.

38. Th. Förster, W. von Rybinski, H. Tesmann, and A. Wadle, Int. J. Cosm. Sci. 16:84(1994).

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10Solubilization in Cosmetic SystemsStig E. FribergDepartment of Chemistry, Clarkson University, Potsdam, New York

Jiang YangSurfactants and Specialties North America, Rhône-Poulenc, Inc., Cranbury, New Jersey

I. Introduction 225

II. Microemulsions, Liquid Crystals, and Liposomes 226

III. Cosmetic Applications 229

IV. Solubilization into Stratum Corneum Lipids 229

V. Formulations 230

VI. Microemulsions 232

References 236

IIntroduction

Solubilization is a term denoting the tendency of a substance to dissolve in the dispersedpart in a colloidal system. The emphasis on the dispersed part is essential: dissolving awater soluble substance in the continuous part of a colloidal system, such as a salt in theaqueous part of an oil-in-water (o/w) microemulsion, is not solubilization, but dissolvingan oil-soluble compound in the oil droplets in the same microemulsion is. To a largeextent cosmetic preparations are colloidal structures, and solubilization is essential forproduct esthetics and performance. As a consequence, the number of solubilized systemsis very high, and in this chapter no attempt is made to cover many of these systems. Thechapter is instead organized around a few illustrative systems for which the fundamentalfactors are analyzed.

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Before this analysis is undertaken, a few general comments will be made about colloidalsystems of interest for cosmetic preparations.

IIMicroemulsions, Liquid Crystals, and Liposomes

Hydrocarbon or fatty oils are not soluble in water nor is water significantly soluble inthem. The oil and water may be dispersed in each other mechanically, formingmacroemulsions (emulsions). These, in their simplest form, are micron-sized droplets ofoil in water (o/w) or of water in oil. They are stabilized by surfactants or polymersadsorbed at the interface (see Fig. 1). The oil and/or the water may be a micellarsolution or may contain liposomes, but emulsions, as such, only show transient colloidalstructures during the coalescence and are not treated in this chapter. They have recentlybeen dealt with in an excellent and useful review article [1]. A special, but rathercommon, class of emulsions contains a separate phase of colloidal structure; that classwill be described later in this article.

The lower limit of drop size for the emulsions formed by mechanical means isapproximately a radius of 0.15 µm. If smaller size is needed, microemulsions areprepared. Microemulsions commonly have droplet radii in the range of 25500 Å; inexceptional cases values up to 0.15 µm may be found. The dimensions of the drops arenow a few percent of the wavelength of visible light and the microemulsions are seen astransparent (see Fig. 2). Contrary to the case of emulsions, in which droplet size isdetermined by the mechanical action, in the microemulsion [2,3] the droplet size isdetermined by the surfactant; its arrangement at the interface limits the droplet radii(see Fig. 1). The size of the droplet is, hence, determined by the surfactant, theformation of the microemulsion is spontaneous, and any mechanical actionused to reachthe final state fasteris insignificant. It is usually sufficient to pour the componentstogether. If intentional efforts are made to add the components in an order that delaysspontaneous mixing as long as possible, months or years may pass [4,5] before theprocess is finished, but the process will lead to a final microemulsion state. A simpleshake will at any time immediately result in a transparent microemulsion.

Microemulsions exhibit three main structures:

Fig. 1In an emulsion droplet the length of the

surfactant is small compared to the droplet radius.

In a microemulsion droplet they are of thesame magnitude.

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Fig. 2An emulsion (left) is turbid because the size of the

droplets exceeds the wavelength of visible light, while ina microemulsion (right) the droplet size is far less and

the liquid is transparent.

1. Isolated droplets of oil in water,

2. Isolated droplets of water in oil, and

3. Bicontinuous structures.

In some systems, depending on the water-to-oil ratio, a continuous change takes placefrom o/w, to bicontinuous, to w/o without a phase change. Figure 3 shows how such adevelopment may be envisioned. Microemulsions are very efficient in solubilizinghydrocarbon oils in water and vice versa. Fatty oils are solubilized with more difficulty,but in exceptional cases solubilization levels of 1015% have been achieved [6].

Microemulsions contain aggregates of limited dimensions, actually of colloidal size, whichare dispersed in a liquid. Their shape depends on the ratio, , between two volumes:that of the surfactant hydrocarbon chain, v, (obtained from the density of thecorresponding hydrocarbon vmolecule = 1.66 M/r where v is volume per molecule of thehydrocarbon chain, Å3/molecule, M is molecular weight, and r is its density in g/cm3) andthat of the volume formed by a body with the area occupied by the head group, a, andthe length of the hydrocarbon chain . If R is less than one third, spheres will be formedwhen the critical concentration is exceeded. However, if R is in the range between onehalf and one, lamellar structures are geometrically the only acceptable association

Fig. 3In a water continuous (o/w) microemulsion (left) the oil (black)exists as isolated droplets; while in the oil continuous system

(w/o) the water is in the form of isolated droplets (white, right).In some microemulsions a continuous change from o/w to w/o

passes through bicontinuous structures (middle).

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Fig. 4In a lamellar liquid crystal three regions are found. A = aqueous or polar

solvent layer, B = hydrocarbon chains, commonly methylene groups, andC = terminal methyl group layers.

forms. This means that instead of forming a closed sphere, which remains dispersed inthe solution as a micelle or a microemulsion droplet, the parallel assoication of thesurfactnat has no limit. Hence, the association structure becomes ''infinite," it separatesas a distinct phase outside the solution, and a lamellar liquid crystal is obtained (see Fig.4). The liquid crystal may also consist of close-packed cylinders (see Fig. 5), and otherforms also exist.

With this view, the lamellar liquid crystal structure may be perceived as a means to avoidthe contact between the hydrophobic chains and water. This goal is achieved in adifferent manner when a lamellar liquid crystal is mechanically dispersed in a solutionwith which it is in equilibrium. The mechanical action disperses the liquid crystal and thecontact between water and the chains is avoided by the formation of spherical shells ofsurfactant (see Fig. 6), a vesicle, or liposome [7,8]. In fact, a w/w emulsion has beenformed, stabilized by a bilayer or multilayer of surfactant.

Fig. 5In another liquid crystal the surfactants are organized in

close-packed cylinders with water between them.

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Fig. 6In a unilamellar vesicle (a liposome) the interior water isseparated from the surrounding water by the bilayer.

IIICosmetic Applications

All of these structures mentioned are essential for cosmetic preparations and even anapproximately complete description would be too large for a chapter of this size, and onlysome of them will be treated in this chapter. However, the most important phenomenonfrom a cosmetic point of view is the fact that the stratum corneum lipids are organizedinto a lamellar structure [9,10]. The debate about details of this structure has sometimesbeen tense, but the lamellar structure has been retained through all the discussions.

IVSolubilization into Stratum Corneum Lipids

The lamellar structure lends itself very well to model investigations [11], which provideinformation about the location of added compounds. Retinoic acid [12, 13] was used in astudy in which low-angle X-ray diffraction [14] and nuclear magnetic resonance [15] werecombined to find both the location of and the local perturbation by the acid within thestratum corneum lipids [16]. The results were given the following interpretation. The low-angle X-ray diffraction data showed a strong reduction of interlayer spacing when the acidis added. Such a result combined with the knowledge of the acid structure (Fig. 7) revealsthat the location of the acid is at B, Fig. 4. Its chain is intermingled with the hydrocarbonchains of the stratum corneum lipids and the acid polar group may be anchored at theinterface B/A, Fig. 4.

To find the perturbation of the stratum corneum lipid molecule, the palmitic acid

Fig. 7The structure of retinoic acid.

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Fig. 8A deuterated palmitic acid in a lamellar liquid crystal shows a nuclear magnetic resonancespectrum of a series of doublet signals, one from each methylene group of the chain.

component of the stratum corneum lipids was deuteriated, and the order parameters ofits methylene and methyl groups were calculated from the splitting of the nuclearmagnetic resonance (NMR) signal, Fig. 8. The results, Fig. 9, showed an intense increaseof disorder at methylene groups 9 and 10 of the palmitic acid. The location of thesepositions correspond to that of the cyclohexenyl group of the retinoic acid, Fig. 7, and theconclusion that the acid carboxylic group is anchored at the interface A/B, Fig. 4 iscorrect.

VFormulations

Cosmetic formulations are commonly made in the form of emulsions [1], which in thecase of simple two-phase emulsions are not of interest for solubilization. However, anumber of emulsions actually contain three phases. In addition to the two isotropic waterand oil phases, they also contain a liquid crystal [17, 18]. The presence of the liquidcrystal may not seem to influence solubilization very much from the beginning, but itssolubilization is of decisive importance for the action of the additive in quesiton.

An illustrative example is given by vitamin E acetate [19]. Part of its phase diagram withwater and the common emulsifier lecithin [20], Fig. 10, at first indicates that

solubilization is not a feature to attract interest; as a matter of fact vitamin E acetate isnot solubilized at all in the lamellar liquid crystal and very little is soluble in the water. Areasonable emulsion (90% water, 3% vitamin E acetate and 7% lecithin) consists ofvitamin E acetate droplets and liquid crystal particles dispersed in water (LLC + VE)/W,

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Fig. 9Addition of retinoic acid to a lamellar liquid crystal with deuterated

palmitic acid causes enhanced disorder of the deuterated acid at aposition corresponding to the hexyl ring, Fig. 7. = 2.5%

retinoic acid; = 5% retinoic acid; and = 10%retinoic acid.

Fig. 11A (LLC = lamellar liquid crystal, VE = vitamin E acetate, W = water). Afterapplicaiton, the water evaporates and the emulsion changes from (LLC + VE)/W to (W +VE)/LLC, Figure 11A and B. When 60% of the water is evaporated, Fig. 10, point C, Fig.11C, no water droplets remain and the emulsion is now continuous layer of liquid crystalwith droplets of vitamin E acetate in it.

So far during the evaporation process no solubilization has taken place and thecomposition of the liquid crystal and of the vitamin E acetate remains constant. Howeverwith the next 14% of water evaporating, Figure 10 C ® D, the situation is drasticallychanged. All the vitamin E acetate is now solubilized into the liquid-crystalline phaseaccording to the phase diagram. This is a rather sensational phenomention; evaporationof a small amount of water causes, the vitamin E acetate droplets to be spontaneouslysolubilized into the liquid crystalline phase and experimental confirmation of thepredictions from the phase diagram is certainly in order. As a matter of fact, the processcan be followed in the optical microscope. Figure 12AC, show the gradual solubilization ofthe vitamin E acetate droplet into the liquid crystal. (The black central spot is the dyeused to enhance to contrast of the vitamin E acetate droplet.) It should be emphasizedthat the only reason for the solubilization of the vitamin E acetate is the evaporation ofwater; the amounts of lecithin and vitamin E remain E remain completely unchanged.

The changes are essential from a cosmetic science point of view because the

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Fig. 10Part of the phase diagram for water (H2O), lecithin (Lec), andvitamin E acetate (vitamin). LLC = lamellar liquid crystal, and

A ® F = evaporation route.

Evaporation induced change from C to D, Fig. 10, means that a lotion remaining on theskin is changed from a liquid crystal layer with a spotty presence of vitamin E acetatedroplets to a layer in which the vitamin compound is evenly distributed in the layer.

Even more important is the fact that continued evaporation-induced change from DE, Fig.10 leads to an increase of the chemical potential of the vitamin E acetate within the liquidcrystal. As a matter of fact, with less water than at F, Fig. 10, the vitamin E acetate hasas great a tendency to leave the liquid crystal to enter the skinas if the pure vitamincompound were present on the skin. Hence, a layer containing approximately 10% ofvitamin E acetate gives the same effect as if the skin were covered with the vitamin, butwihtout the oily feeling.

VIMicroemulsions

As indicated earlier, solubilization per se in microemulsions is outside the scope of thischapter, but two examples demonstrating the rather pronounced influence of thepresence of active components on the stability of microemulsion systems will be given.The first example is well known sunscreen molecule p-aminobenzoic acid, PABA [21]. Themodel system of water, pentanol, and sodium dodecylsulfate is not useful for cosmeticpurposes because both amphiphiles are irritants, but the results are an illustration of thepotential influence PABA may have.

The basic system, Fig. 13, shows the w/o microemulsion base area, I, the o/wmicroemulsion base area, II, and a narrow region, III, of a bicontinuous structure.Addition of 10% PABA to the pentanol shows the most drastic change in the solubilityregions. The w/o region is completely wiped out, and the o/w microemulsion region is allthat is left. It should be observed that in the portion of the o/w region with maximum

pentanol/PABA solubility only 5% by weight of PABA is present.

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Fig. 11An emulsion at A, Fig. 10, contains droplets of

liquid crystal (white) and vitamin E acetate (grey)in water (A).

Evaporation to B, Fig. 10, results in water andvitamin droplets in the liquid crystal (B).

After evaporation from A to C, Fig. 10, the water hasdisappeared and the vitamin is now dispersed in a

continuous liquid-crystalline layer (C).

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Fig. 12Evaporation from C to D, Fig. 10, causes the droplet of vitamin E acetate to

disperse spontaneously into the liquid crystal (left to right). (The black ring andcentral spot are from a dye used to obtain better contrast).

Fig. 13The microemulsion base region (solid line) in the water system (H2O),

sodium dodecylsulfate (SDS), and pentanol (S) was significantly changed afteraddition of PABA to pentanol in a weight ratio C5OH/PABA = 90/10 (dashed

line). I = water-in-oil (w/o) microemulsion; II = oil-in-water (o/w) microemulsion;and III = bicontinuous.

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Fig. 14The microemulsion base region (solid line) in the system water (H2O), sodiumdodecylsulfate (SDS), and pentanol (S) was significantly changed after addition

of triethylcitrate (TEC) to pentanol in a weight ratio C5OH/TEC = 75/25 (S)(dashed line). w/o = water-in-oil microemulsion; o/w = oil-in-water

microemulsion; and LLC = lamellar liquid crystal.

The second example is a fragrance. Fragrances are usually sold as solutions in ethanol,but concerns about organic solvents have resulted in the introduction of microemulsionformulations [22]. Hence, the influence by typical fragrance molecules on microemulsionregions is of interest.

As model compound, triethylcitrate, TEC was chosen [23], because it is frequently usedand because it has a potential for reducting bodily malodors [3, 14]. Its action on themicroemulsion system is less pronounced that of PABA, but it is significant (see Fig. 14).A Mixture of 25% TEC in pentanol does not annihilate the w/o microemulsion region, butit is significantly narrowed. For higher ratios of TEC, the o/w region still remains, but itsextent is limited [23].

It is obvious that both sunscreens and fragrances pose new problems in solvent freeformulations and that systematic research in this area is needed to provide the basis fornew, safe, and reliable formulations.

Acknowledgment

This research was supported by a grant from Penreco Co., The Woodlands, Texas and bythe New York State Commission of Science and Technology at the Center for AdvancedMaterials Processing at Clarkson University, Potsdam, New York.

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References

1. R. Lochhead, Cosmetics & Toiletries 109:93 (1994).

2. Microemulsions: Structure and Dynamics (S. E. Friberg and P. Bothorel, eds.), CRCPress, Boca Raton, FL, 1987.

3. K. Stickdorn, M. J. Schwuger, and R. Schomacher, Tenside 31:4 (1994).

4. S. E. Friberg, M. Podzimek, and P. Neogi, J. Disp. Sci. Techn. 7:57 (1986).

5. Z. Ma, S. E. Friberg, and P. Neogi, Colloids Surf 33:249 (1988).

6. S. E. Friberg and L. Rydhag, J. Am. Oil Chem. Soc. 48:113 (1971).

7. T. Kaneko and H. Sagitani, Colloids Surf 69:125 (1992).

8. E. Schonfelder and H. Hoffman, Ber. Bunsenges. Phys. Chem. 98:842 (1994).

9. P. M. Elias, J. Invest. Dermatol. 80:44 (1983).

10. D. C. Swartzendruber, P. W. Wertz, K. C. Madison, and D. T. Downing, J. Invest.Dermatol. 88:709 (1987).

11. S. E. Friberg, D. W. Osborne, and T. L. Tombridge, J. Soc. Cosmet. Chem. 36:349(1985).

12. D. F. Birt, Proc. Soc. Exp. Biol. Med. 183:311 (1986).

13. J. S. Weiss, C. N. Ellis, J. T. Headington, T. Tincof, T. A. Hamilton, and J. J. Voorhees,J. Am. Med. Assoc. 259:527 (1988).

14. K. Fontell, in Liquid Crystals and Plastic Crystals, vol. 2 (G. W. Gray and P. A. Winsor,eds.), Ellis Horwood, Chichester, 1974, p. 80.

15. H. Wennerström and B. Lindman, Physics Reports 52:1 (1979).

16. S. E. Friberg, I. Kayali, A. J. I. Ward, T. Suhery, F. A. Simion, and L. D. Rhein, J.Dermal Clinical Evaluation Soc. 2:7 (1991).

17. S. E. Friberg, Langmuir 8:8 (1992).

18. S. E. Friberg, M. L. Hilton, and L. B. Goldsmith, Cosmetics & Toiletries 102:87 (1987).

19. V. E. Kagan, E. H. Witt, R. Goldman, G. Scita, and L. Packer, Free Radical Res. Comm.16:51 (1992).

20. S. E. Friberg, T. Moaddel, and A. J. Brin, J. Soc. Cosmetics Chem (submitted).

21. Sunscreens, Development, Evaluation, and Regulatory Aspects, (N. J. Lowe and N. A.Shaath, eds.), Marcel Dekker, New York, 1990.

22. Y. Tokuoka, H. Uchiyama, and M. Abe, Colloid Polym Sci. 272:317 (1994).23. S. E. Friberg and S. Vona, Soaps, Cosmetics, Chem. Specialties 32 (August 1994).

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11Selection of SolubilizersFrancesc ComellesSurfactant Technology, Centro de Investigación y Desarrollo, Barcelona, Spain

Carles TrullásResearch Department, Laboratorios Isdin, Barcelona, Spain

I. Introduction 237

A. What Does Solubilization Mean? 238

B. Preformulation Aspects of Solubilization 239

C. Selection of Ingredients 239

II. Application of Phase Diagrams 240

A. Solubilization in Micellar Solution 241

B. Solubilization in Reverse Micellar Solution 244

C. Solubilization in Microemulsions 244

D. Solubilization in Liquid Crystals 247

III. Effect of the Solubilizate on the Final Formulation 250

A. General Commentary 250

B. Influence of the Stability of the Formulation 251

C. Impact on Efficacy 252

D. Influence of Physical and Physico-ChemicalCharacteristics 254

IV. Summary 256

References 257

IIntroduction

The incorporation of lipophilic components into water-based cosmetic formulations is animportant requirement for the use of diverse active ingredients. Such formulations exist ina wide range of compositions with textural and physico-chemical properties and are of

much more interest for cosmetic use than simple aqueous solutions. Any cosmetic productis ultimately applied to the human body, a delicate substrate. Aggressive or

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irritative interactions with the living organism cannot be tolerated. In fact, the twoprimary purposes of cosmetic formulations, skin care and decoration, must always providephysiological benefits and create the image of well-being.

The safety limits for cosmetic applications to substancessingularly and incombinationsmust be carefully studied in basic research. Ingredients (e.g., solubilizers,cosurfactants, and hydrocarbons) and use conditions must be carefully selected to avoidor minimize any adverse toxicological or dermatological effects.

The literature dealing with the practical application of solubilization in cosmetics issomewhat out of balance. The number of basic-research publications exceeds thatdealing with practical applications. Despite the existence of a great number of patentscovering applied research carried out by cosmetic companies it is rare to find fullysatisfactory application references in journals.

Solubilization of a specific ingredient should be planned very carefully using teachingsfrom various published studies. Although these studies are usually performed with otheringredients, this information can provide a useful general background. In addition, oneshould attempt to adapt this knowledge to the ingredients and the conditions of interest.This chapter deals with

Different types of cosmetic solubilization;Illustrations of products, with several examples;Methodologies for the study of solubilization; andExamination of the influence of the solubilizate on the final formulation.

AWhat Does Solubilization Mean?

The classic definition of solubilization of McBain and Hutchinson [1]dispersion of aninsoluble substance in a given medium as a colloidal solutiondescribes a very simplesystem: a predominant solvent, usually water, includes a surfactant at a concentrationabove its critical micelle concentration (CMC), in which the insoluble component isincorporated into micelles. In cosmetics the concept of micellar solubilization is limited totonics, lotions, and colognes. Other cosmetic systems are usually much more complexand contain a relatively high number of ingredients. The physical characteristics ofproducts in the market today tend more towards gels, creams, ointments, and the like,with heavier textures and with more complex structures than simple micellar solutions.Finally, consumers equate more viscous formulations with higher concentrations andbetter efficacy and prefer their ease of application and their more attractive nature.

To meet these requirements, there exists a wider concept of solubilization that includesinaddition to micellesother transparent monophasic structures. In these systems thesurfactants may associate (depending on their concentration and on the solvent) aslyotropic liquid crystals or microemulsions, into which the active ingredients can be

formulated at higher concentrations than those achievable in micellar solutions. A cleardistinction exists between these special compositions and those based on emulsification.As defined, solubilization involves monophasic, transparent, and sometimesthermodynamically stable formulations, while emulsification results in a biphasic systemin which one phase is dispersed in the other and stabilized by the action of a surfactant.In this discussion, solubilization must meet two requirements: (1) achievement ofmonophasic compositions combining the basic ingredients of the system, such as water,surfactants,

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oils, cosolvents, etc., and (2) incorporation of the active ingredients into these basiccompositions that act as support or transport media. Incorporation is not performed aposteriori, but the active ingredients, depending on their lipophilic or hydrophiliccharacteristics, are included in the basic ingredients making up the final formulation.

BPreformulation Aspects of Solubilization

Several issues should be borne in mind before starting the preparation of a formulationwith a solubilized active ingredient.

1. Specifications for performance, e.g., moisturizing, humectancy, cleansing, UV-protection, or deodorant properties, help in the selection of the most appropriate activeingredients.

2. The concentration of the active ingredient in the final product frequently controlsformulation characteristics; for example, if a lipophilic active ingredient must besolubilized at very low concentration, the simplest approach is micellar solubilization, inwhich this agent is the only lipophilic ingredient. However, if a more viscous presentation,e.g., a gel, is preferred and if the amount of the active ingredient is insufficient, anadditional oily compound may be required to provide a more structured system, such as aliquid crystal.

3. The type of formulation desired (aqueous, oily, or gelled) may necessitate inclusion ofadditional ingredients and control of their ratios. In the final product this can result inmicellar solubilization, in solubilization in the oily phase, in microemulsification, or inliquid-crystal formation.

CSelection of Ingredients

Ingredients used to prepare solubilized formulations should have general acceptance. Themost widely used substances [2] include the following.

1. Surfactants as solubilizers.

Anionics may include alkali or alkanol amine salts of fatty acids, alkyl sulfates, alkylether sulfates and phosphates, monoglyceride sulfates, alkylamido ether sulfates, alkylsulfonates, a-olefin sulfonates, and sulfosuccinates.

Nonionics may include polyoxyethylene alkyl ethers, polyoxyethylene alkylphenolethers, polyoxyethylene fatty acid esters, polyoxyethylene castor oil, polyoxyethylenesorbitan fatty acid esters, glyceryl fatty acid esters, polyglyceryl esters,polyoxyethylene fatty acid monoglycerides, alkyl polyglucosides, polyoxyethylene-polyoxypropylene block polymers, fatty acid alkanol amides, polyoxyethylene fatty acidalkanol amides, and fatty amine oxides.

Cationics may include quaternary ammonium salts and amido amines.Amphoterics may include alkyl amido betaines, alkyl sulfobetaines, alkyl betaines, andalkyl imidazolinium betaines.

2. Cosurfactants may include polyoxyethylene ethers with low ethylene oxide (EO)content, fatty acid alkanol amides, polyoxyethylene fatty-acid alkanol amides, fatty amineoxides, and alkylglyceryl ethers.

3. Lipophilic ingredients may include mineral oils (hydrocarbons or silicones), animal

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oils (squalane or mink), vegetable oils (almond, avocado, jojoba, mint), fatty acid esters,fatty acids, fatty alcohols, and triglycerides.

4. Cosolvents may include polyethylene glycols, glycerol, polyglycerols, sorbitol, and thelike.

5. Active ingredients are required to fulfill the specific action of the cosmetic formulation.

IIApplication of Phase Diagrams

For many years, the construction of phase diagrams has been a common practice in thestudy of ternary systems [composed of water (W), lipophilic component (O), andsurfactant (S)], which allows delineation of the diverse phases at equilibrium (Fig. 1).

Phase diagrams graphically identify the realms of the different monophasic compositions.They provide (1) information on the appropriate ratio of ingredients to obtain a specificcomposition, and (2) opportunity to predict the composition of the formulation resultingfrom various ratios of the ingredients.

For the cosmetic formulator, phase diagrams provide an especially attractivemethodology. However, in most of the published diagrams the aim is basic research.Thus, the surfactants are specially purified, the ''oils" are well defined (generally singlehydrocarbons), and medium chain alcohols (C4C5) are used as cosurfactants, and theutility of phase diagrams in cosmetics is seriously limited. It is logical, nevertheless, for afirst approximation, to examine simple systems in which the main ingredients, e.g., thesurfactant and the lipophilic components, are replaced by more appropriate cosmeticingredients and to identify the preferred homogeneous phases in the diagrams.

When the systems are formed by four components, they can be represented by means ofa regular tetrahedron with different ingredients located on the vertices. To facilite thestudy, a pseudoternary phase diagram can be prepared by combining two of theingredients on the same vertex. Logically, it is preferable for these ingredients to be

Fig. 1Typical phase diagrams: (a) of a systemcontaining water (W), anionic surfactant

(S), and cosurfactant (Co-S)

(b) of a system of water (W), nonionicsurfactant (S), and hydrocarbon (O) at the

hydrophilic-lipophilic balance (HLB)temperature [T(HLB)].

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mutually compatible, so that they can be treated as a single phase once their ratio ofcombination has been established.

Cosmetic systems usually comprise more than just three or four ingredients. The questionthen arises on how one adapts a cosmetic composition system to a ternary diagramrepresentation. The usual strategy is to group different ingredients according to theirfunctional characteristics (hydrophilics, lipophilics, and amphiphilics) and label these tocorrespond to the more general ingredients, water (W), oil (O), or surfactant (S), of aclassical ternary system. Obviously, the assignment of two or even more components toone vertex requires selection of the ratios in which these components must be combined.In this process, the desired characteristics of the formulations as well as the maximumand minimum acceptable levels of active ingredients for a topical application must beconsidered. Examination of a tetrahedral system may provide alternate possibilities forcombining ingredients for the most appropriate pseudoternary diagram.

In Fig. 2, different possibilities for incorporating an active lipophilic agent into amulticomponent system formed by a surfactant (or a combination of surfactants), an oil(or several oils properly blended), and a polar phase (constituted by water and anhydrophilic cosolvent), are shown. Alternate possibilities of solubilization are exhibited bydifferent systems. A review of solubilization in isotropic liquid media (micellar solutionsand microemulsions) as well as in lyotropic liquid crystals can then be made.

ASolubilization in Micellar Solution

Micellar solubilization is the classic approach to solubilization of a water-insolubleingredient in an aqueous solution of a surfactant above its CMC. Much has been writtenon micelle formation, factors affecting the CMC, shape and size of the micelles, and onmicellar solubilization of several lipophilic ingredients, such as hydrocarbons, alcohols,phenols, ethers, vitamins, and drugs [36]. In micellar solubilization, the amount ofsolubilized material is very low. The active ingredient usually is the only lipophiliccomponent that can be represented in a classic W/O/S diagram, and the solubilizationrealm is located near the water corner.

Any plan for micellar solubilization requires consideration of additional important factors.The surfactant must be water soluble (high hydrophilic-lipophilic balance, HLB) within therange of use temperatures. In the case of an anionic surfactant the Kraft temperature(the temperature in which the solubility of the surfactant reaches a critical value formicelle formation and at which the solubility curve starts to increase rapidly) must bebelow the use-temperature range. For a nonionic surfactant, the cloud point (thetemperature above which its aqueous solution becomes heterogeneous because of achange from water solubility to oil solubility) must be above the maximum usetemperature.

Since formation of micelles is an essential condition, the CMC of the selected surfactant

should be known. This value can be determined experimentally either by establishedmethods, (e.g., variation of the surface tension or conductivity with the concentration) orfrom the published data [7]. Nonionic surfactants have lower CMCs than ionic surfactants.This is advantageous since less of the nonionic surfactant is needed for solubilization; thisfact and the better skin tolerance of nonionic surfactants combine to reduce the incidenceof contact dermatitis from ionic surfactants in solubilizates.

Another important parameter controlling the ability of a surfactant to act as a

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Fig. 2Possibilities for incorporating lipophilic active

ingredient (LAI) in a system of water (W), oil (O),and surfactant (S), modeled by a regular tetrahedron.

Selection of pseudoternary phase diagrams:(a) for an invariate content of active ingredient (LAI)

(b) for an invariate content of the activeingredient at different initial combinations of

O and S for dilution with water

(c) for an invariate ratio of O to LAI

(d) for an invariate ratio of O to S.

solubilizer is structure. An increase in the hydrocarbon chain length enlarges the volumeof the internal hydrophobic portion of the micelle and consequently enhances thesolubilization of nonpolar lipophilic compounds [8].

The maximum concentration of an active lipophilic ingredient which can be solubilized(MAC) by different levels of an aqueous surfactant can be determined. This fixes theminimal surfactant concentration required for solubilizing the desired amount of acompound. The determination can be made by several methods. It is common practice toprepare solutions of the surfactant at a fixed concentration containing different levels ofthe lipophilic component or at different concentrations of the surfactant at a fixed contentof lipophilic ingredient. After equilibration of the mixture with stirring for several hours,one can easily determine the surfactant-to-lipophilic ingredient ratio that leads to micellarsolubilization.

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In the phase diagrams, the incorporation of a lipophilic component into an aqueoussolution of a surfactant corresponds to a titration with "O" at compositions of "W" plus "S"within the micellar zone until the initial transparency is lost. Another possibility is titrationwith water (or with the polar phase) of different combinations of the lipophilic agent andthe surfactant until the appearance of a transparent micellar phase.

In light of the critical influence of temperature on solubility, nonionic surfactantsoccasionally yield cloudy preparations as a result of a decrease in the cloud point causedby the solubilizate. It is, therefore, proper to determine the "new" cloud point in thepresence of the desired concentration of the lipophilic ingredient to identify the highesttemperature at which it is possible to generate an isotropic solution.

During formulation it is customary to use mixtures of surfactants either from the samefamily (i.e. nonionic surfactants with different degrees of ethoxylation to obtain a givenHLB) or from different families (usually anionics with nonionics or amphoterics). Suchcombinations may yield synergistic effects on surface tension and CMC [9,10] and mayalter detergency, wettability, and cutaneous compatibility.

The influence of mixed micelles on solubilization may result in an increase or a decreasein the MAC by comparison to the single surfactant. In binary systems, in which two kindsof micelles may coexist [11], an increase in the MAC by comparison to each of thesurfactants has been described. Other investigators consider solubilization a result of thenonideality of the mixed solutions of surfactants and associate negative synergism withreduced solubilization and positive synergism with higher solubilization [12]. Thechemical structure of the lipophilic ingredient determines the site of solubilization withinthe same micellar system [13]. Generally, nonpolar lipophilic ingredients are solubilizedto a limited extent in the inner core of the micelle because of the compactness of themixed micelle, whereas more polar lipophilic ingredients are solubilized in the palisadelayer of the micelle. Surfactant structure also contributes to micelle formation andsolubilization: in binary systems of an anionic and a nonionic, a high level of ethoxylationgenerally leads to increased solubilization. It is interesting to review the recent literatureon mixed surfactants systems that discusses the different possibilities for solubilizingvitamins, dyes, sunscreens, and perfumes [1418].

Another important factor to be borne in mind is the action of cosolvents on thesolubilization of a lipophilic ingredient. The use of aliphatic alcohols, glycerol, glycols,polyglycols, and glycol ethers in mixtures with water as the polar phase of the system iscommon. The presence of the cosolvent facilitates clear solubilization when use of wateralone might require higher surfactant levels.

Some examples of cosmetic micellar solubilizates are tonics, lotions, and colognes(especially when limited by alcohol content). These formulations are aqueous orhydroalcoholic, colorless or colored transparent solutions. They may contain cosolventssuch as alcohol, glycerol, or glycols, and include one or more lipophilic ingredients, such

as fragrances, vitamins, UV filters, and the like. A typical formulation of a micellarsolubilizate might contain 5% (oily) perfume, 22% (nonionic) surfactant, and 73% water.It is noteworthy that a higher amount of surfactant than lipophilic ingredient is requiredto achieve solubilization.

The use of phase diagrams to study the solubilization of different synthetic perfumes (d-limonene, a-hexylcinnamaldehyde, a-ionone, benzylacetate, linalool, and eugenol) isillustrated in a recent study [19]. Increased hydrophilicity of the perfume oil

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extends the normal and reverse micellar regions in micellized systems containing ceteth-10 and water.

The solubilization of vitamins has been widely studied. Solubilization of vitamin Apalmitate in aqueous solutions of polysorbate-20, -40 and -60 has been reported [20],with increasing solubilization resulting from increased lengths of the surfactanthydrocarbon chain. These data confirm the general rule that solubilization of lipophilicingredients is favored by increasing the size of the micelle.

BSolubilization in Reverse Micellar Solution

Another system for obtaining an isotropic solution is reverse micellar solubilization ofwater or other hydrophilic components in an oily medium. In this case, the surfactantselected must have lipophilic characteristics (low HLB) and good compatibility with theoil.

Whenever nonionic surfactants are used, the temperature has an important effect onsolubilization because their solubility in water decreases with increasing temperature.Similar characteristics are shown by the hydrocarbon phase and the surfactant phase(microemulsion) when the temperature exceeds the HLB-temperature; coalescence of thetwo phases causes maximal water solubilization. It is difficult, therefore, to distinguishbetween reverse micellar solutions and W/O microemulsions [21]. From the applicationpoint of view, the fact that maximum water solubilization appears within such a narrowtemperature range can be inconvenient because the amount of solubilized water must bereduced to an acceptable level to cover the whole range of use temperature.

The first step in the experimental study of possible solubilization in an oily medium is theprogressive incorporation of water (or of a polar phase) at different ratios of oil tosurfactant to ascertain the possibility of obtaining an isotropic solution. The ratiosbetween the oil and the surfactant that allow water solubilization depend on thestructures of these components. The isotropic solution is not always limited to the vicinityof the vertex of the lipophilic component in the ternary phase diagram, which can becompared to systems with anionic surfactants and cosurfactants (Fig. 1a). Sometimes,the range of solubility includes several ratios between the lipophilic ingredient and thesurfactant (Fig. 1b) or may even originate near the surfactant vertex. A high content ofthe surfactant component is not suitable for cosmetic applications unless extensivedilution is possible.

The incorporation of water by the titration method must be performed at temperaturescovering the range of interest. On the basis of such studies, the amounts of surfactantand water required to create a homogeneous transparent system in the oil can beselected.

When an anionic surfactant of very high hydrophility is used, a cosurfactant is required to

create a reverse micellar solution. Incorporation of oil or hydrocarbon over a wide rangeof concentrations can lead to microemulsion formation. As will be further discussed undermicroemulsions below, the critical factor is the need for an alternative to the conventionalmedium chain length alcohol (usually pentanol), which is not suitable for cosmeticapplication.

CSolubilization in Microemulsions

Interest in the characteristics and properties of microemulsions is fully documented by theextensive literature describing these compositions [2226]. These systems have amicrostructure consisting of microdroplets ranging from approximately 10 to 200 nm.They can be either o/w or w/o type and in some cases bicontinuous. They may be

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stabilized by a nonionic surfactant, by a combination of an ionic surfactant and acosurfactant, or by a single anionic surfactant with enough hydrophobicity, such as dioctylsodium sulfosuccinate [27].

The concept of microemulsion remains controversial because of the difficulty indifferentiating between reverse micellar solutions and microemulsions. The latter mayarise from the former and have been identified as swollen micelles or colloidal micellarsolutions. It is, nevertheless, instructive to examine different concepts of microemulsions[28,29].

In principle, microemulsions are identified as homogeneous, transparent, isotropic liquids.They are obtained spontaneously when the ingredients are brought into contact and arethermodynamically stable. They can simultaneously solubilize significant amounts ofeither water or hydrocarbon at low levels of a surfactant, sometimes in the presence of acosurfactant (Fig. 1b). However, these appealing characteristics are severely limited incosmetic applications. Medium chain-length alcoholsalways required for solubilization byanionic surfactantsinterfere with the use of these extensively studied systems. Referencesto microemulsions from anionic surfactants are scarce except to those formed by pentanol(or butanol) and sodium dodecyl sulfate (SDS). Some attempts have been made tosubstitute these cosurfactants by other compounds, e.g., glycolic derivatives, lanolinderivatives, or amines [3032]. Especially interesting is the use of nonionic surfactantswith low EO content for microemulsification that depends on the number of EO groups,the nature of the hydrocarbon, and the presence of electrolytes [33]. However, theselection of an adequate cosurfactant remains an unsettled problem for most systems.

If a nonionic surfactant is used in a microemulsion, the critical influence of temperatureon the system becomes a problem, in light of the narrow range of temperatures (HLBtemperature or phase inversion temperature, PIT) within which microemulsion formationcan be shown. This may cause phase separation due to variations in storage orapplication temperature.

However, the word "microemulsion" persists in cosmetics, although it may have moresemantic than structural connotations. A study of these compositions shows that theycommonly exhibit dissimilar ratios of ingredients. Thus, microemulsion compositionsdescribed, for example, as 70% W, 5% O, and 25% S, or as 5% W, 70% O, and 25% S,could also be identified correctly as micellar or reverse micellar solubilizates respectively.The absence of a clear differentiation between microemulsions and micellar solutionsforces one to consider any transparent, isotropic, liquid composition of a systemcontaining water (or polar phase), oil, and surfactant (and possibly a cosurfactant) as amicroemulsion.

It is important to note, however, that by broadening the concept of microemulsion toinclude the above compositions, the ratio of water to oil is no longer close to unity, one ofthe attractive features of "classic" microemulsions. At times the amount of surfactant (or

surfactant plus cosurfactant) may exceed 4070% of the formulation, which does notconform to the fundamental principle of microemulsion. Moreover, the termmicroemulsion covers other types of formulations, e.g., some transparent gels(microemulsion gels) requiring expenditure of mechanical and thermal energy. Formationof these gels depends on the order of addition of the ingredients. In some cases they areanisotropic and do not retain the characteristics of original microemulsions. In thischapter transparent gels are included in the section addressing liquid crystals, becausethey commonly include such structures.

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How are cosmetic microemulsions formulated? According to the most orthodoxmicroemulsion approach, the level of the hydrophobic ingredient to be solubilized by anonionic surfactant is selected first. If this level is sufficiently high to form amicroemulsion when it is combined with an equal (or similar) amount of a polar phase inthe presence of a reasonable amount of surfactant, further study is warranted. A series ofcompositions is prepared with increasing amounts of surfactant while the approximately1:1 ratio between the lipophilic ingredient and the polar phase is maintained.Examination of the phases formed at equilibrium at different temperatures (Fig. 3)provides information on the range of temperatures within which a microemulsion can beobtained at minimal surfactant content (HLB or PIT temperatures).

The HLB temperature is a characteristic of the binary combinations of surfactant andlipophilic ingredients. Once the level of this oily ingredient is established, a surfactant (ormixture of surfactants) is selected that has an HLB temperature in the use range. For agiven lipophilic ingredient, an increase of the hydrophility of the surfactant (by increasingthe EO content or by shortening the hydrocarbon chain length) raises the HLBtemperature. On the other hand, at a fixed surfactant level, a decrease of thehydrophobicity of the oil reduces the HLB temperature. Based on this information, aselection of the surfactant and of the lipophilic component can be made to achieve anHLB temperature close to room temperature. It is important, however, to considerseasonal or regional variations of temperatures that may drastically alter the phasecharacteristics of the system and could lead to phase separation (especially since humanskin is not at the same temperature as its environment).

If the percentage of the lipophilic active agent to be solubilized is too low to form amicroemulsion, it can be combined with another lipophilic ingredient. In that case it canbe said that the active ingredient has been added to a vehicle to form a microemulsion.Many references describing improved efficacy or reactivity of active ingredients solubilizedin microemulsions exist [3436].

Cosmetic microemulsions cannot always be formed under the rigid conditions estab-

Fig. 3Influence of temperature on the phase behavior

of a system of a nonionic surfactant (S) containing

water (W) and oil (O) in a ratio of 1:1 as afunction of surfactant concentration.

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lished for ingredients. As mentioned before, other compositions (with different ratiosbetween components) are identified as microemulsions. From the application point ofview the only important question is selection of the solubility regions from the diagrams,without concern for the structure of these so called microemulsions.

The selection of the solubility regions in a given system is generally carried out byprogressive addition of the polar phase via a titration method and by use of differentcombinations of the surfactant and the lipophilic ingredient, unless a fixed level of activeingredient is desired in the diluted vehicle.

Among the numerous microemulsions with cosmetic ingredients reported, we mention thefollowing.

Those formed by alkyl glucosides combined with alkylglycerol ethers, which yield isotropiccompositions with water and hydrocarbons [37].

Polysorbate-80 (or -60 or -40) and sorbitol in a ratio of 1:1.5, with isopropyl myristateand water [38].

A mixture of PEG-4 sorbitan laurate and polysorbate-80 in a ratio of 9:1, together withcetearyl octanoate and water for solubilizing an antiinflammatory agent [39].

The same combination of surfactants with isopropyl myristate and water for solubilizingantiaging agents [40].

Combinations of sorbitan laurate and PEG-4 sorbitan laurate with isopropyl myristate andwater for solubilizing lidocaine [41].

Combinations of dioctyl sodium sulfosuccinate and sorbitan laurate in a ratio of 60:40with hexadecane and water [42].

Combinations of a blend of glyceryl caprylate/caprate and PEG-8 caprylate/caprate,polyglyceryl isostearate with isopropyl palmitate (or isopropyl myristate orisohexadecane), and water [43].

Sucrose esters (oleate, myristate, monolaurate, dilaurate) with cetearyl octanoate,aliphatic alcohols and water [44].

Several microemulsion patents for hair treatments and solubilization of perfumes exist[4547] as well as papers on properties and structures of microemulsions [4851].

DSolubilization in Liquid Crystals

Raising the concentration of a surfactant in a micellar solution causes enlargement of themicellar size (aggregation number), which occurs before liquid crystal structures arereached. No continuous medium exists in liquid crystals, and no disperse particles occuras in a micellar solution; instead, the structure is ordered. Among the lyotropic liquid

crystals formed by an amphiphilic compound and a solvent (generally water), one maydistinguish lamellar, hexagonal (direct and reverse), and cubic forms, each of which hasbeen carefully characterized and described [52,53].

A lamellar liquid crystal consists of bimolecular layers of the amphiphilic compoundalternating with layers of water. This phase exhibits a semiliquid consistency, istransparent or slightly translucent, shows anisotropy when observed through crossed lightpolarizers, and is readily identified by polarized microscopy because of its typical mosaicappearance. Although this lamellar phase appears in binary systems of surfactant andwater at very high surfactant concentrations (more than 50%), it can still incorporateboth lipophilic and amphiphilic ingredients. The area of existence of lamellar phases inthe

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phase diagrams can be extended both to the center and to the water vertex, which helpsto lower surfactant concentration to a more acceptable level (Fig. 1a).

In a hexagonal liquid crystal phase, the amphiphilic molecules are assembled intocylinders (with the hydrophobic groups oriented inward and the polar groups outward).The cylinders are packed into a hexagonal array in a continuous aqueous medium. Thephysical characteristics of this phase are transparency and anisotropy. It presents acharacteristic fan-like texture under polarized microscopic observation and exhibits higherviscosity than the lamellar phase. In the binary system, water plus surfactant, hexagonalliquid crystals appear at concentrations higher than those of micellar aqueous solutions.When a lipophilic ingredient is incorporated, the range of existence of this liquid crystalincreases moderately towards the lipophilic vertex in the phase diagram, without raisingthe level of incorporated water (Fig. 1a). The reverse hexagonal structure, in which thesurfactant is oriented with the hydrophobic groups to the external part of the cylinders,can also exist.

The cubic mesophase consists of spherical units arranged in a body-centered structure,with symmetry in three directions. Cubic liquid crystals are transparent and very viscousphases with isotropy and consequently not visible in polarized light. They have beendetected in several systems, occupying different positions in the diagrams, and requirethe presence of a certain amount of lipophilic component.

The most interesting aspect of these liquid crystals is their ability to incorporate bothlipophilic and hydrophilic agents into the corresponding lipophilic and hydrophilic regionsof their structures. Logically, the incorporation of active ingredients, such as vitamins,sunscreens, antiinflammatories, drugs, etc., is one of the main objectives in cosmeticsand pharmacy [5457]. However, several principles must be remembered: a liquid crystalis very easily obtained; only water and a surfactant at high concentration are required;and solubilization of a moderate amount of a lipophilic compound in a liquid crystal is notvery difficult. Therefore, the high number of papers dealing with solubilization of activeingredients in lyotropic liquid crystals is not surprising. However, the high concentration ofsurfactant used in some of these liquid crystals reduces their cosmetic utility.

Some examples of systems that yield various types of liquid crystals [58,59] are oleth-10and water, which solubilizes different oils and oleth-2; potassium caprylate and water,which solubilizes decanol; and sodium caprylate and water, which solubilizes caprylicacid. Liquid crystals have been identified in systems such as siloxane surfactants andwater [60]; lecithin and water [61]; monoglycerides and water [62]; oleic acid,triethanolamine, and water [63]; combinations of glyceryl caprylate/caprate and PEG-8carpylate/caprate and polyglyceryl isostearate with fatty acid esters and water; and PEG -7, -9, -11, -20, C13-15 alkyl ethers and water [64]. An interesting lamellar liquid crystal isthe makeup remover consisting of steareth-20, trioctanoin, and water [65]. Other liquidcrystals are obtained from combinations of sodium lauryl sulfate with various commercialnonionic surfactants, water, and an aliphatic lipid [66]. Solubilization of synthetic

perfumes in liquid crystals (which can, of course, be achieved by micellar solutions asmentioned earlier) can take place in systems formed by ceteth-10 and water or sodiumlauryl sulfate and water [67].

Cubic liquid crystals, which form attractive transparent gels, are of great interest. Aspecial kind of transparent gel, the so-called microemulsion gels [68], exhibitingapplication advantages and disadvantages have been reviewed [69], and theirrheological characteristics (as viscoelastic fluids) have been described by severalinvestigators [7072].

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The Comelles et al. papers demonstrate a rational approach for the solubilization ofactive ingredients with the aid of phase diagrams. The first study of this system [73] wasinitiated to identify the composition of an attractive transparent gel. The aim was todetermine the limits of existence of the gel phase as a function of the ratios ofingredients (Fig. 4a). Because the number of ingredients is more than three, thesurfactants were blended in a 1:1 ratio and occupy the vertex corresponding to S; thepolar ingredients, water and 1,3-butylene glycol, were combined in a 3:1 ratio and occupythe W vertex; the third vertex, O, was assigned to mineral oil. This pseudoternary phasediagram revealed a transparent gel realm at oil-to-surfactant ratios ranging from 40:60 toapproximately 60:40. The 1:1 ratio was the one that allowed the highest dilution with thepolar phase.

The incorporation of 4.8% octyl methoxycinnamate as a sunscreen agent [74] increasedthe transparent gel area (Fig. 4b) over that formed by mineral oil alone, due to a changein the lipophilicity of the system. A more complex system, formed by incorporatingsimultaneously different active ingredients, both hydrophilics (urea) and lipophilics (octylmethoxycinnamate, BHT, vitamin A palmitate, vitamin C palmitate, and vitamin Eacetate) was subsequently examined [75]. In this case, the system was represented by aregular tetrahedron, with mineral oil (O) as one vertex, the combination of surfactants(S1 plus S2) as another, and the combination of the sunscreen (SS) and avitamin/antioxidant complex (VT) in a third vertex. The fourth vertex represents the polarphase, comprising water, 1,3-butylene glycol, and urea (Fig. 5). The procedure forforming the transparent gel is dilution with the polar phase of some selected lipophilicbasic compositions situated in the base of the tetrahedron (Fig. 5) to create the finalcompositions containing adequate levels of active ingredients for topical application.

Another approach for incorporating octyl methoxycinnamate into a transparent gel

Fig. 4Transparent gel regions: (left) before and (right) after incorporation of the sunscreenagent 4.8% octyl methoxycinnamate (SS) to a multicomponent system. W = water;

BG = 1,3-butylene glycol; O = mineral oil; S1 = oleth-3; S2 = oleth-3 phosphate.(From Ref. 74, with permission.)

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Fig. 5Transparent gel formation by dilution of selected lipophilic compositions

containing different active ingredients (shown in the base of the tetrahedron)with an optimized polar phase. W = water, BG = 1,3-butylene glycol;

U = urea; O = mineral oil; S1 = oleth-3; S2 = oleth-3 phosphate;SS = sunscreen (octyl methoxycinnamate); VT = combination of

vitamins A, C and E, and BHT as antioxidant.(From Ref. 75, with permission.)

formulation is the use of a system consisting of PEG-20 castor oil, isopropyl palmitate,propylene glycol as polar cosolvent and water [76] according to the scheme shown in Fig.2. The conclusion was that, regardless of the selected approach, the limiting factor forobtaining a gel is a sufficiently high initial concentration of surfactant in the primarylipophilic combination, i.e., before diluting with 35% polar phase. It is possible to blendthe remaining isopropyl palmitate and sunscreen in different ratios according to the levelof sunscreen (27) desired in the final formulation.

IIIEffect of the Solubilizate on the Final Formulation

AGeneral Commentary

So far, only approaches for incorporating active ingredients into different kinds ofmonophasic formulations (micelles, microemulsions and liquid crystals) have beenconsidered. The emphasis must now shift to the effect of the final solubilizate on stability,efficacy, and physical and physico-chemical characteristics.

The focus of this chapter is application to complex systems, but the number of

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references to multicomponent formulations is limited. Most of the cited literatureconcerns simple systems and addresses conclusions from diverse interactions ofsurfactants with active ingredients, with preservatives, and with skin. In multicomponentformulations complex interactions between ingredients cause effects not predictable fromsimple systems and complicate generalizations. The large number of ingredients incosmetic use and their many possible combinations require specific examination. In thefollowing segment, some aspects of the interactions between the solubilized componentsand other ingredients, as well as interactions between the skin and the product, arebriefly described.

BInfluence on the Stability of the Formulation

1Effect of Solubilizate Concentration

The first problem is the effect of the solubilized active ingredient on the stability of theformulation. In any phase-diagram study of a solubilized system, one can delineateregions of solubility and determine whether a given formulation can maintain its clarity.In micellar solutions, the incorporation of the solubilizate may cause an increase in thesize and shape of the micelle and may modify the CMC. For example, the incorporation ofurea leads to an increase in the CMC due to its disruptive effect on water structure. Theincorporation of short-chain alcohols into ionic surfactants lowers the CMC, whichbecomes more pronounced as the hydrophobicity of the alcohol increases. The CMC of anonionic surfactant may be increased or decreased, depending on the length of thealcohol chain. An increase in the CMC may initiate destabilization of the system, makingmicellar solubilization of the lipophilic ingredient impossible.

2Effect of Temperature

Another parameter influencing the stability of micellar solutions is the cloud point, thetemperature at which a separation into two phases may occur. Some solubilizatesdecrease this temperature, e.g., (long-chain alcohols and phenols), resulting informulation stability only at low temperatures. On the other hand, in nonionic-surfactant-based microemulsions in which the critical influence of the temperature is well known, theinfluence of the solubilizate must be evaluated to confirm the stability of themicroemulsion within the anticipated use temperature range.

3Effect of Bacterial Action and Oxidation

The requirement of biodegradability of surfactants in water to avoid possible ecologicalproblems makes the commercially used surfactants more susceptible to microbial attack.However, microbial spoilage of cosmetic formulations containing such surfactants is not

acceptable. Consequently, preservation against microbiological contamination is neededfor most cosmetics.

Although the solution, incorporating an antimicrobial agent, seems easy, the complexityof the formulations can cause interactions between the preservative and otheringredients, e.g., the surfactant. In dilute formulations containing soaps or surfactants,the preservative may be solubilized in the micelle, with consequent loss of activity.Nonionic surfactants are especially likely to inactivate phenolic preservatives: in additionto solubilization they may form complexes between the ether oxygens of thepolyoxyethylene chains and the phenolic hydroxyl groups [77,78]. In the presence of a

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surfactant, it may be necessary to increase the preservative concentration or toincorporate substances that enhance their water solubility (e.g., propylene glycol,butylene glycol, hexylene glycol, or glycerol) to compensate for losses due tosolubilization. Numerous aspects of the action of the preservatives on cosmeticformulations have been reviewed in the literature [79,80].

Apart from individual ingredients in a given formulation, their combinations can enhanceor lower bacterial attack. In general, bacteria cannot grow in oily media and requirewater, causing aqueous solutions to be especially prone to bacterial attack. In w/omicroemulsions, however, despite the presence of water, the small droplet size does notprovide sufficient medium for the bacteria to grow. Regardless of the structuralcharacteristics of microemulsions, they are incompatible with the lamellar structure ofmicrobial membranes [81] and preservatives may not be necessary.

Oxidizable components (such as lipids with unsaturated fatty acids, some activeingredients, and vitamins) can destabilize formulations. For example, vitamin A is morestable when solubilized in the hydrophobic region of a micelle in aqueous media than inoily solutions because it is protected from air (oxygen) in the micelle. The incorporationof an antioxidant is another way to prevent oxidative degradation [82].

CImpact on Efficacy

Solubilization of an active ingredient can alter its topical bioavailability and modify itsefficacy. Thus, selection of the vehicle is very important for two reasons: the solventeffect on active ingredient and the interaction with skin.

1Interactions of Surfactants with Active Ingredients

It is not surprising that the properties of surfactants, especially their solubilizing action,facilitate interactions with active ingredients. Some studies of solubilized systemsdescribe an increase, some a decrease, and some no effect on the activity of differentpharmacologically active ingredients and on their transfer through biological membranes[83]. The presence of surfactant levels above the CMC could be expected to reduce theconcentration of the active ingredient in the medium (by uptake into micelles) and tolower partitioning into the skin. Some active ingredients exhibit amphiphilic propertiesand can interact directly with a surfactant-forming mixed micelle. An example is thealready mentioned interaction between nonionic surfactants and a preservative, whichreduces the efficacy of a solubilized active ingredient.

2Interaction of Surfactant with Epidermis

The epidermis is the substrate for the action of cosmetics, either on its surface or by

penetrating across it. The composition and physical characteristics of epidermis havebeen well described [84], with special attention to the stratum corneum, the top layer ofthe skin. Its main functions are the barrier effect (protecting the body from externalaggressions and agents), and maintenance of hydration (by avoiding excessivetransepidermal water loss). The interaction between an active ingredient and stratumcorneum may not depend exclusively on these two features. This is especially true if theactive ingredient is solubilized in a formulation that includes a blend of ingredientsselected to yield a specific structure. The efficacy of an active ingredient cannot bedissociated from the action of the accompanying ingredients, especially so-called''penetration enhancers,"

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e.g., surfactants, solvents, or humectants, that alter the barrier formed by the epitheliallipids and increase permeability [8587].

Several models have been proposed describing this intercellular bilayer structure of themajor lipid components of the stratum corneum as consisting of ceramides, cholesterol,and fatty acids [8890]. In a series of papers [9193] it was reported that partialneutralization of the fatty acids close to the pH of skinin the presence of at least 33% inwaterleads to formation of a lamellar liquid crystal structure that can integrate other skinconstituents. At lower levels of hydration, solidification of the lipids in these liquid crystalsmay occur. The change from a liquid crystal to a solid crystal is reminiscent of the changefrom hydrated to dry skin, confirming the importance of hydration for healthy skin [9496].The effect of humectants, such as glycerol, has been studied [97]; it seems that its actionon skin lipid structure can prevent crystallization of lipids and helps to maintain the liquidcrystal structure even at low water content.

The action on skin of surfactants as key formulation components for solubilization ofactive ingredients has been exhaustively studied [98,99]. The effect can be beneficial,depending on the chemical structure and/or concentration, because the surfactants canfacilitate the penetration of active ingredients applied to the skin. By contrast, this actioncan also be detrimental when, as a consequence of cutaneous barrier damage,penetration of other potentially undesirable agents is enhanced. Excessive transepidermalwater loss and skin roughness and dryness may result. Soaps and anionic and cationicsurfactants are the most aggressive and reportedly can solubilize and elute lipid and lowmolecular weight nitrogenous components from the epidermis. The latter are believedresponsible for binding of water to stratum corneum, improving the elasticity andflexibility of the skin. Nonionic surfactants exhibit better compatibility with proteins andare favored for use in cosmetic formulations. Commonly employed combinations ofanionic with nonionic or with amphoteric surfactants can reduce the irritative potential ofthe former. Surfactants are not the only agents that can modify the structure of stratumcorneum; other ingredients, such as solvents and humectants (e.g. urea and glycerol),exert similar action. Consequently, the efficacy of an active ingredient is a complexmosaic of interactions of the structure of the stratum corneum, of its water level, and ofthe presence of penetration enhancers. The study of these relationships is one of themain challenges in dermatocosmetology.

In conclusion, a surfactant's effect on increasing or decreasing active penetration dependson the ability of the surfactant to interact with the skin and on the physico-chemicalcharacteristics of the active compound.

3Influence of Product Structure

Besides the individual activity of each ingredient, the structure of the final product canalso modify the efficacy of active ingredients [100,101]. Micellar solutions in aqueous

media are rarely used in cosmetics, because of their simplistic composition and lowsolubilizate content. More complex solubilization systems, such as microemulsions andliquid crystals, are more common. In light of their high capacity for solubilization (of bothhydrophilic and lipophilic ingredients), their special microstructure (of very smalldroplets), and their thermodynamic stability, microemulsions have been widely studied astransport media of active ingredients to the epidermal surface. Several papers describeimproved efficacy and sustained release of active ingredients in microemulsions bycomparison to other formulations such as solutions or emulsions [102].

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Liquid crystals can solubilize significant quantities of active ingredients into their polar ornonpolar regions. The major advantages are differing levels of viscosity between lamellarliquid crystals and gelled cubic liquid crystals and the resulting modifications of therelease of active ingredients [103,104]. In addition, due to their structure, liquid crystalsdo not disrupt natural lamellar lipid structures within the stratum corneum and do notenhance crystallization of skin lipids even at water levels below the critical value.

Generally, comparisons of the efficacy or reactivity of an active ingredient solubilized indifferent formulations must be made with caution. Differences of formulation structureare the result of ingredient concentration, which makes a sound comparison not alwayspossible. For example, the amount of surfactant necessary to form a given microemulsionmay be ten times higher than that necessary to form an emulsion, and the amount maybe higher still to form a liquid crystal.

DInfluence of Physical and Physico-Chemical Characteristics

1Viscosity

Two principal conditions can account for modifications of viscosity as a consequence ofsolubilization:

One in which solubilization causes a structural change, andOne in which solubilization occurs within the same structure.

The first case occurs when the amount of solubilizate varies widely. A system consistingof different amounts of water, lipophilic ingredient, and surfactant (as shown in Figure 1)can exhibit varying structures (i.e. changes from liquid crystal to microemulsion or frommicellar solution to liquid crystal), each exhibiting different rheological behavior.Generally, low viscosity Newtonian behavior is typical for both micellar solutions andmicroemulsions with globular structures. Liquid crystals, however, show complexrheological behavior in which the viscosity depends on the shear rate and the shear time.The behaviors range from the fluid lamellar liquid crystal to the very viscous cubic liquidcrystal. Moreover, liquid crystals frequently possess thixotropic and visco-elasticcharacteristics.

In the second case, even when solubilization of a given ingredient does not affect astructural change, viscosity can still be modified, sometimes significantly. In micellarsolutions solubilization of nonpolar molecules alters micellar size and shape fromspherical micelles with Newtonian behavior to oblate micelles. In the latter, viscosityincreases due to restriction on free movement, with attendant loss of Newtonianbehavior. An example of the action of solubilizates on viscosity is the study of theinfluence of several perfumes in shampoos based on 10% sodium lauryl ether sulfate:citronellol, for example, increases the viscosity beyond that normally generated by

sodium chloride [105]. In microemulsions prepared at a fixed ratio of surfactant tocosurfactant, increase in the viscosity depends on the weight fraction of water [106].However, the change in viscosity of micelles and microemulsions is generally limited andhardly noticed by consumers.

A more drastic effect occurs in liquid crystals. For example, the system formed by water,1,3-butyleneglycol, mineral oil, oleth-3 and oleth-3 phosphate, yields transparent gelswith liquid crystal structures and the rheological behavior of plastic fluids [107]. Figure 6shows the variation of yield values in these gels by two different approaches.

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Fig. 6Variation of yield values; (a) dilution of a fixed combination of O to S (50:50)

with variable polar phases (W plus BG)

(b) dilution of variable combinations of O to S with a fixed polar phase of W plus BG (75:25);W water; BG = 1,3-butylene glycol; O = mineral oil; S = mixture of oleth-3

and oleth-3 phosphate in 1:1 ratio.

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In a, an initial composition at a fixed ratio of O to S of 50:50 is diluted with different polarphases including 1,3-butylene glycol (BG) in several ratios of W to BG. In b, differentinitial ratios of O:S are diluted with a W to BG polar phase at a ratio of 75:25. It isapparent in (a) that the higher the ratio of W to BG the higher the yield value, which inaddition is reached at lower dilution. Thus, the presence of BG lowers both the yield valueand the viscosity. In (b) the preferred ratio of O to S of 50:50 extends the gel realm andproduces a higher yield value.

2Transparency

The incorporation of some cosolvents into the polar phase, (e.g., ethanol, sorbitol,glycerol, or polyglycols) improves the transparency of the formulation. The use ofhydroalcoholic solutions for solubilization of fragrances is well known. In the systemdescribed in Fig. 6, transparent gel formation does not occur when the 50:50 O to S blendis diluted only with water. A minimal amount of BG in the polar phase is requiredthatwhich results in a W to BG ratio of about 95:5 and ranges from 91:9 to 75:25, the bestratios for extending the range and for improving the clarity of the gel [107]. On the otherhand, the presence of cosolvents acting as cosolubilizers sometimes permits reduction ofthe surfactant content required to solubilize a given ingredient.

3Odor of the Fragrance

When a perfume is incorporated into a formulation, the fragrance is frequently altered notonly in intensity (due to dilution) but also in its quality [108,109]. It has been establishedthat odor and intensity can be quite different at identical perfume concentration,depending on the kind of formulation used for solubilization. The reasons might beinteractions between some of the perfume components and other formulationingredients, such as surfactants or active ingredients [110]. A typical example occurswhen thioglycolates in hair preparations react either with perfumes or hair, yieldingunpleasant odors.

The perception of a fragrance is determined by passage from the perfume's normal liquidstate to the vapor phase. The volatility of a fragrance component determines both theintensity and the quality of the perceived odor. In micellar solutions, the amount ofperfume in the aqueous phase seems to account for more of the odor than the amountsolubilized in the micelles. Thus, in a lauryl ether sulfate solution, an increase in theconcentration of the surfactant decreases the intensity of the odor [111]. Anothercriterion that can affect the intensity of the perfume is viscosity. In the same system itwas shown that an increase in the viscosity by addition of sodium chloride can result in adecrease in odor intensity [111].

IV

SummaryIncorporation of active oily components into cosmetic formulations is complicatedbecause of their lipophilic characteristics. Although emulsification is the most commonprocedure for incorporating lipophilic compounds, solubilization into transparenthomogeneous phases is an especially attractive possibility.

Liquids (micellar solutions and microemulsions) and differently textured gels (liquidcrystals) act as transport media of the active ingredients to the skin surface. Since theseformulations are applied to the human body, a choice of compatible ingredients isrequired in advance to avoid any possible adverse reactions.

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The study of transparent cosmetic systems by means of phase diagrams is illustrated withseveral examples.

Finally, the possible influence of the solubilizate on the physico-chemical properties aswell as on efficacy and stability of the final formulation is considered.

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12Liposomes and NiosomesDaniel D. LasicConsultant, Drug and Gene Delivery Consultations, Newark, California

I. Introduction 264

A. Definition 264

B. Rationale 265

II. Interaction of Liposomes with Skin 267

A. Structure and Composition of Skin 267

B. Penetration of Liposomes in the Skin 270

III. Liposomes and Niosomes 271

A. Chemical Composition 271

B. Liposome Preparation 273

C. Properties and Characterization of Liposomes 275

D. Stability 275

E. Other Lipid Colloidal Particles 276

F. Mixtures of Other Amphiphilic Colloidal Particles withLiposomes 277

IV. Liposome Formulations and Applications 278

A. Pharmaceutical Applications 278

B. Cosmetic Applications 279

References 281

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IIntroduction

Many diverse substances of natural or synthetic origin are known to exhibit beneficialeffects on human health and appearance. Amongst the most important concerns for thecosmetic and pharmaceutical industries are not only the physical, chemical, and biologicalproperties of these active substances and their actions but also ways to formulate, apply,and deliver them. Although these substances are often water incompatible, nature as wellas humankind has found ways to blend immiscible oily and watery substances.

The structure of many biological systems is the result of a delicate balance betweenaqueous systems and nonpolar molecules. There is general agreement that the so-calledhydrophobic effect determines the structure and function of biological systems. The bestknown examples are natural biomembranes and their artificial counterpartsliposomes [1].While fundamental understanding of the hydrophobic effect [2,3], especially itsmechanisms and driving force [4,5], is still lacking, extensive experimental data provide asuitable basis for a scientific approach to formulation. Thus, difficult-to-dissolvesubstances can be used to treat various disorders and to improve appearance andcomplexion.

In cosmetic practice the important problem of incorporating water-incompatiblesubstances has generally been solved by using amphiphilic colloidal systems. Suchcosmetic systems include mostly gels, ointments, creams, emulsions, tinctures, andlotions. As a result of continuing developments in surfactant science, microemulsionswere introduced, and in the late 80s, following an explosion in liposome research inmedical applications, liposomes were also introduced into cosmetic formulations [6,7].

There is, however, an important distinction between microemulsions on one side andliposomes on the other. In contrast to the former, the latter are not systems atthermodynamic equilibrium. This has a profound effect on their properties and directly ontheir preparation and application. While thermodynamically stable systems are relativelyeasy to prepare, tend to remain stable, and are reproducible from batch to batch, thekinetically stabilized (suspension) systems are more difficult to prepare reproducibly andmight exhibit instability [1]. However, after application, microemulsion droplets veryrapidly change their phase, while liposomes remain stable due to the fact that they arekinetically trapped into their state, and energy is needed to open or break them. Forexample, surfactant micelles dissolve and microemulsion droplets aggregate upondilution, while liposomes are stable and do not change. This stability upon applicationdemonstrates their superior potential for microencapsulation and delivery of activesubstances [1].

Despite the fact that theoretical understanding of these phenomena is beginning toemerge only now, practice has already produced many successful formulations. Trial anderror methods have generated extensive empirical knowledge, while in the last few years

more rational design of active-ingredient carrier systems has emerged.

ADefinition

Liposomes are hollow colloidal particles in which phospholipid bilayers encapsulate part ofthe medium into their interior. Their size ranges from 0.01 to 100 µm, while the thicknessof their walls is normally around 4050 nm. The membrane is most frequently composed oflipid bilayers made from natural or synthetic polar lipids. When such

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vesicles are formed from nonionic surfactants they are referred to as nonionic surfactantliposomes or niosomes.

Due to their structure, chemical composition, and colloidal size, vesicles have severalpotentially very useful properties. With respect to the structure and morphology onedistinguishes large (L) or small (S) unilamellar (U) or multilamellar (ML) vesicles (V) thatcan be prepared from natural or synthetic amphiphilic lipids. Figure 1 shows liposomes aswell as several other colloidal lyotropic systems. Recently lipid tubules, i.e. long, thin,open cylinders composed of some synthetic lipids, have found interesting applications ascontrolled-release systems [8], and some cosmetic applications are likely.

To understand the rich variety of aggregate shapes, several theoretical concepts wereintroduced. Interactions due to various energy and entropy contributions can yieldthermodynamically stable aggregates (lamellar, cubic, or hexagonal phases) in excesswater. By contrast, in kinetically trapped systems, such as liposomes or tubularaggregates, the introduction of curvature provides improved understanding of the stabilityand structure of aggregates. The low-energy state of most bilayers is the planarconfiguration. Therefore, in principle, liposomes are at a relatively high-energy state dueto their curvature [1]. For nonspherical shapes, two curvatures can be defined, Cx and Cy.Curvature energy is proportional to , with the Rs being the principal radii (inverse ofcurvatures, C = R-1) in the plane. For spherical symmetry, the stress relaxes to 2/R, whilefor more rigid bilayers that cannot curve into spherical structures (such as crystallinesheets or sheets with tilted molecules as in smectic C phases) the stress may be relaxedby elimination of one curvature, for instance Cy = 0 at Ry = ¥. The molecular origin of therigidity of the bilayer is due to the chemical structure of the lipids and the composition ofthe bilayer. A phospholipid analogue of the open cylindrical structure is that of cochleatecylinders, which are in fact bilayers rolled into cigar-like structures [1].

Natural surface-active lipids include phospholipids, glycolipids, and sphingolipids, whilesynthetics are mostly nonionic surfactants (Fig. 2). Most of the formulations usecholesterol to stabilize bilayers, as will be discussed below when various cosmeticliposome formulations are presented. In addition to conventional phospholipid liposomes[911] and sphingosomes [12], liposomes made from ''skin-lipids" [13,14] and nonionicsurfactant vesicles (Niosomes [6,15], Novasomes [16], and many others) are used.

BRationale

The rationale for the use of liposomes as a delivery system for active ingredients incosmetics is similar to the use of liposomes in drug delivery. In addition, as we shall showlater, the vehicles themselves may have beneficial effects in cosmetic applications andcan therefore exhibit double action.

Beneficial effects of liposomes and encapsulated ingredients may be classified intoseveral different categories:

1. Improved dispersion of difficult-to-solubilize compounds;

2. Microencapsulation in a vehicle that may enhance penetration into the skin;

3. Improved adhesion on the surface and sustained release;

4. Beneficial properties of the carrier itself; and

5. Reduced skin toxicity/irritation of the carrier/solubilizer system.

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Fig. 1Schematic representations of various types of liposomes and other

lyotrophic particles. Micelles in two-component systems, liposomes of differentmorphologies, and liquid crystalline phases generally exist. Micelles can be spherical,

prolate, oblate, or inverse. Of the wide variety of liquid-crystalline phases, both hexagonal andlamellar phases are shown. Emulsion and microemulsion droplets are similar to liposomeswith one monolayer encapsulating the nonpolar phase (oil-in-water) or inverse monolayer

encapsulating the polar phase (water-in-oil). A microemulsion can be formed by the swellingof micelles or by mixing appropriate amounts of surfactant, cosurfactant (which reduces bending

elasticity), and solvent phases. Such a system spontaneously transforms into a translucentmicroemulsion after incubation at the appropriate temperature. Stable noncolloidal structures,

such as lamellar, hexagonal, cubic, ribbon-like, or inverse phases, can sometimes be dispersedmechanically to form relatively stable colloidal suspensions. The same is true for cochleate cylinders,

spiral rolls of bilayer fragments (which look like cigars), lipid tubules (cylindrical structures ofself-closed bilayers with two open ends, normally 0.51 µm in diameter and 5100 µm in

length), and several other particles (formed by the diverse phasebehavior of various amphiphiles in mixtures with water).

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As stated above, hydrophobia substances are often difficult to disperse or dissolveuniformly. Nonliposomal systems depend on alcohols, detergents, and/or oils fordispersion, and this frequently can lead to skin irritation and allergy. On the other side,liposomes can create dispersed aqueous systems with the aid of natural, biocompatible,and biodegradable molecules. Microencapsulation can protect encapsulated molecules,provide a sustained release system, and enhance penetration into the skin. In somecases formation of the protective film on the surface of the skin is needed, and theliposome surface can be tailored to improve adhesion. The same is true in ophthalmicapplications of liposomes [17].

In contrast to many carrier systems, which may exhibit irritative potential or toxicity,liposomes per se can provide beneficial effects. If properly selected, lipids themselves canmoisturize the skin. They may contain fatty acids, especially linoleic acid, which areessential for healthy skin. Therefore, some skin treatments can include empty liposomes.Simple formulations with potentially beneficial effects are liposomes containing a-tocopherol (vitamin E) as an antioxidant and lipids with a large fraction of linoleic chains.Care has to be taken in the selection of lipids because it has been shown that somelipids, such as phosphatidylethanolamine, can actually dehydrate skin [18].

IIInteraction of Liposomes with Skin

Skin forms a very tight barrier and, in general, compounds cannot permeate through skinor penetrate into it. Pharmaceutical applications use mechanical, electrical, and chemicalmeans to improve drug delivery through the skin. Obviously, the usage of thesetechniques is not desired in cosmetic applications, and a carrier that could improve skinpermeation is still being sought. On the other hand, many researchers believe thatliposomes may meet this requirement.

AStructure and Composition of Skin

Because skin is our protection against the external environment it forms a veryimpermeable and complex barrier. It is from 0.5 to 4 mm thick and, if not damaged, iswater and germ proof.

The structure of the skin is shown in Fig. 3. It consists of three layers: stratum corneum,epidermis, and dermis. The upper horny layer (stratum corneum) is composed of 1525layers of dead, nonmetabolizing cells. These keratinized cells form a layer approximately10 µm thick. Intercellular spaces contain bilayer laminate structures of various lipids. Apictorial description of skin as a protective wall might describe cells as bricks and lipid asmortar. The continuous structure is disrupted by sweat pores and hair shafts. Epidermis,which is approximately 50 µm thick, is composed of living cells (keratinocytes), which areconstantly transformed into corneocytes to form the stratum corneum. Vascularization of

the skin begins about 0.10.2 mm below in the epidermis in an aqueous phase containingthe extracellular matrix formed from collagen fibers and elastin embedded intomucopolysaccharides. This dermis rests on a layer of fat cells (subcutis) that separatesskin from the musculature and contains blood vessels, hair shafts ending in follicles, andsebaceous and sweat glands with ducts, which end on the surface in pores.

As already mentioned, skin is a very impermeable barrier. The most impermeable part isthe stratum corneum. In a first mechanism, the transepidermal transport of various

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Fig. 2Structures of some lipids used in the production of liposomes and niosomes.

substances can be shunted via sweat glands, hair follicles (shafts), and sebaceous pores.Alternately, the penetration into skin may occur transcellularly or by an intercellularroute. This second mechanism is the main pathway for the penetration of water, active

ingredients, and carrier molecules into skin as exemplified by colloidal systems such ascreams, ointments, emulsions, and gels as well as liposomes.

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Fig. 2Continued

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Fig. 3Schematic representation of the skin.

BPenetration of Liposomes in the Skin

Due to its simplicity the transdermal administration route is attractive for pharmaceuticalapplications and is practically the only way for cosmetic applications. Modern cosmeticformulations, however, are intended not only to provide a protective film on the surfaceof the skin but also to supply water, humectants, and other active ingredients deeper intothe skin. In order to achieve this difficult goal, some pharmaceutical applications oftenrequire cosmetically unacceptable means to improve permeation.

Classic chemical penetration enhancers depend on either skin occlusion or skin softeningto increase permeability. Upon occlusion with a nonpermeant coating, such as silicone,skin softens because water cannot exit. The increasing water level effects swelling of theskin strata. However, this type of intervention decreases vital epidermal functions,resulting in skin irritation. Another approach is temporary dissolution of barriers byalcohols, fatty acids, dimethylsulfoxide, and solvent-type penetration enhancers. Needlessto say, these treatments may result in skin damage.

The first initial reports of liposome diffusion into skin and the concomitant hypothesis ofthe penetration of intact liposomes into the skin [19] were not supported by subsequentexperiments. A geometrical equivalent would be to push a basketball through a chain-linkfence [20]actually through a stack of them. Subsequent research showed someimprovement in the penetration of both liposome lipids and encapsulated hydrophilic andhydrophobic molecules into the skin [21,22]. It was postulated that liposomes canincrease hydration of the skin (lecithin can contain 23 water molecules bound to its polarhead) as well as fuse with lamellar bodies to fluidize natural lipid bilayers, resulting inincreased transport through the skin [23]. For this purpose, active ingredients need notbe encapsulated into liposomes, but liposomes may act as natural moisturizers for the

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skin. Better miscibility with the stratum corneum lipids was claimed in the case ofliposomes, especially those prepared from so-called skin lipids.

Several methods to measure liposome permeation through skin exist. They includestandard techniques such as radioactive tracers, chamber models, electron microscopy,adhesive tape stripping methods [19,24,25], several novel imaging techniques, and someothers [17]. The strip method (consisting of gluing and stripping adhesive tape [Selotape]and analyzing each strip) has shown, for instance a 510 fold increased accumulation ofcortisol in liposomal form (as compared to an emulsion) in epidermis and dermis,respectively [26]. Two- to eight-fold improvements of biodisposition of triamcinolone,econazole, minoxidil, and retinoic acid in epidermis and dermis as compared to controls(ointments, creams, gels, solutions) have been reported [27]. Parallel uptake ofradiolabeled lipid ([3H]cholesterol) and of an encapsulated aqueous marker ([14C]inulin)was observed in studies that were designed to reveal the mechanism of permeation [25].Strong dependence on the type of the skin and liposome composition was observed, asshown by studies of the structure of the upper layer(s) of skin [2830].

A valuable new technique to study the penetration into the skin is 1-dimensional EPRimaging [31]. This method showed, for instance, that the diffusion coefficient ofliposomes into the skin, as measured via the entrapped spin label, can vary from 0 forMLV (or larger liposomes made from rigid lipids) to 1.2 and 2.5 10-6 cm2/s for SUV andLUV (made from fluid lipids). Despite almost two decades of work it is still not clearwhether liposomes improve penetration substantially enough to warrant commercialtherapeutic applications.

Currently, the majority of cosmetic researchers believe that some improvement in skinpenetration and/or its hydration may occur due to a still unkonwn transport mechanism.As in the case of medical applications of liposomes, investigators include everyone fromskeptics to optimists. For more information the interested reader should consult thereferences cited above.

IIILiposomes and Niosomes

The morphological, physico-chemical, and biological properties of liposomes andniosomes are very similar. There are, however, significant differences due to varyingsurface properties (charge, presence of hydrophilic groups), reactivity and interactioncharacteristics, physical and chemical stability, and membrane permeability. Liposomescan be neutral, negatively, positively charged, or zwitterionic, while niosomes are bydefinition neutral. Of course, charged amphiphiles can be dissolved in their bilayers.

AChemical Composition

For topical applications liposomes are normally prepared from either phospholipids (egg

or soy lecithins), sphingolipids (ceramides), "skin-lipid" (cerebroside, cholesterol, fattyacid(s), cholesterol sulfate), or nonionics (in niosomes). Of course, many other lipidcompositions may be used in so-called rational liposome design.

Liposomes were originally prepared from lecithin and its mixtures with cholesterol [32].Later formulations included charged lipids, such as phosphatidylserine,phospatidylglycerol, or dicetyl phosphate (which impose negative charge) andstearylamine or some synthetic diacyl-lipids (to impose positive charge). The majorcomponents of

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bilayers, however, are neutral, i.e., zwitterionic phospholipids such as phosphatidylcholineor, to a smaller extent, phosphatidyl ethanolamine [33]. Charge on the bilayers increasesliposome stability and improves encapsulation efficiency. Despite differences in thecomposition of fatty acids, several different phosphatidylcholines are normally employed.Most frequently lecithins extracted from hen eggs or soya beans are used [34]. Due tothe variability in fatty acid composition and the high degree of unsaturation, they providerather fluid membranes, while the use of hydrogenated lecithins increases rigidity of themembrane and significantly decreases the oxidative damage to liposomes. Lecithins withmonodisperse fatty-acid chains are more expensive and therefore are rarely used inlarge-scale preparations. Cholesterol acts as a plasticizer, which alloys and strengthensthe bilayer. In other words, mechanical toughness (the elastic stretching modulus of thebilayers) increases; this is reflected in improved mechanical stability and reducedpermeability of the liposome. Soy lecithin is preferred due to higher chain unsaturationand absence of possible off odor and yellowish shade.

Instead of lecithin, some sphingolipids, such as sphingomyelina plant analogue oflecithincan be used [12,17,34]. (See Fig. 2.) Skin lipids, the name given to stratumcorneum lipids (roughly 40% sphingomyelin + cerebroside + ceramides; 25%cholesterol; 25% fatty acids; and 10% cholesterol esters and cholesterol sulfate) havealso been used. Liposomes with such lipid compositions or those prepared from skin lipidextracts are thought to improve skin permeation in view of their compatability with skin[35].

Stratum corneum liposomes contain no phosphorus, thus eliminating a potential problemof microbial growth with phospholipid liposomes which, during repeated administrations,provide a source of phosphorus, normally a rate-limiting nutrient for the growth ofmicrobes [17].

All these lipids are biocompatible and biodegradable natural products; many of them arepermitted for parenteral administration into humans. For topical formulations, however,other lipids can be used. Primarily nonionic detergents are used, but some amine-typebasic cationic surfactants may be included. They can be single, double, or in fewexamples, even triple chained.

Since nonionic surfactant vesicles, or niosomes, were first introduced, a number ofdifferent nonionic surfactants have been used to prepare liposomes for variousapplications. Figure 2 shows some of the most common surfactants. In general, single-chain surfactants require the presence of cholesterol to form liposomes, while double-chain surfactants can form liposomes on their own. Nevertheless, cholesterol is normallyadded to improve stability and bilayer cohesivity and to reduce leakage. The most widelyused surfactant molecules are mono- and dialkyl polyglyceryl ethers or polyoxyethyleneglycols. A few years ago the so-called Novasome vesicles (or simply Novasomes) wereintroduced into veterinary medicine and cosmetics. Most frequently they are preparedfrom single tailed polyoxyethylene fatty acid esters, cholesterol, and free fatty acids at

various ratios, normally 74/22/4. These surfactants can be made more resistant tooxidation of the chain by using saturated fatty-acid chains and more stable to hydrolysisby linking them to the polar head via ether bonds instead of hydrolyzable ester bonds[16]. Recently, fluorocarbon lipids were introduced in emulsion and liposome technology,mostly as potential blood substitutes [36]. Their cosmetic utility has not been exploitedas yet.

Another novel concept is the idea of very flexible liposomes that can creep into the

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channels in the skin and thus penetrate into the skin [37]. Such liposomes were calledtransfersomes, but more work will be needed to prove the validity of this concept.

Continuing development in lipid chemistry and organic synthesis and understanding ofliposome behavior, skin structure, and liposome/skin interactions are constant sources forthe introduction of novel liposome preparations.

Current developments in intravenous drug therapy resulted in sterically stabilized(stealth) liposomes as promising drug carriers in anticancer therapy [38,39]. Theseliposomes contain polymers, most frequently polyethylene oxide (with a degree ofpolymerization between 45 to 125) attached to the polar heads on the surface. Thisresults in improved stability. Due to the inertness of polymer coating they are also lessadhesive and less adsorptive than the nonpolymer coated analogues. Their potential intopical application to increase penetration into the skin has not yet been assessed, buttheir performance may still offer some other dermatological benefits. Preliminary datashow that these liposomes are not taken up to a large extent by the cells of the body'simmune system upon intravenous administration. It seems, instead, that they end up inthe skin and, therefore, may be used to deliver appropriate drugs to the dermis via aparenteral route of administration.

Recent advances in cationic liposomes as transfection systems for gene delivery into cellsgive rise to a variety of less toxic and less irritating liposome compositions for topicalapplications [1]. These may include various sticky formulations for localized (ophthalmic,topical, intranasal, or pulmonary) drug delivery and for water-resistant cosmetic films.More sophisticated attachments to appropriate surface groups may result frompolymerization, specific interaction, hydrogen bonding, or chemical bond formation. Inaddition to ligand-bearing liposomes one can use lipids with attached lysine, which cancrosslink with the lysine groups on the horny layer of the skin upon addition oflysyloxidase. Cationic liposomes may also provide better vehicles for negatively chargeddrugs, antisense DNA (oligomers), and active agents. However, the behavior cannot besimply predicted from the opposing charges, i.e., anionic liposomes and cationic drugs.Cationic liposomes may be less stable than anionic ones due to the generally highervalues of critical micelle concentration of diacyl cationic surfactants. Their behavior maydepend on conditions in the solution, such as the nature of counterions present, to amuch larger extent than that of anionic liposomes, due to their influence on effectivesurface charge and/or their interaction with polar heads.

BLiposome Preparation

Liposomes and niosomes are prepared by similar procedures. In general, the methodsconsist of mixing membrane-forming lipids in an organic phase (chloroform, methanol,ethanol, tert-butanol), drying, and subsequent hydration of the lipids (Fig. 4)[1,17,3234,40]. This results in the formation of large multilamellar liposomes that are

sized down by different mechanical treatments, such as sonication, extrusion,homogenization, and the like. Homogenization is especially suitable for large-scalepreparation of liposomes with less strictly defined size distribution. Some of the lipids canbe hydrated simply by mixing lyophilized cakes, spray dried powders, ground mixtures,dry powders, or melts with the aqueous phase during (vigorous) agitation. Typicalexamples are niosomes and Novasomes, which can be prepared by vigorous mixing of theaqueous phase upon injection of melted surfactant.

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Fig. 4Schematic representatio of the preparation of liposomes: (a) The mixture of appropriate lipid(s)is weighed or pipetted in an organic solution into round bottom glass flask. During rotation the

organic solvent is evaporated in a rotovap, followed by thorough vacuum drying. The dry lipid film isredispersed in the appropriate aqueous solution (a,b) and upon agitation (shaking) large, heterogeneous

liposomes are formed (c). If an active water soluble substance is present in the hydrating medium itmay be passively entrapped into the liposomes. Water-insoluble active substances can be deposited fromorganic phase in (a). If smaller, less lamellar liposomes are desired they can be down-sized by a varietyof techniques such as sonication, extrusion, or homogenization (d). Nonencapsulated active molecules

can be removed by dialysis, gel filtration, or diafiltration (e). Less demanding liposome applications can make use of heterogeneous MLV (c), which frequently can be prepared directly by mixing

appropriate compounds in water and ethanol solutions without drying of the organic phase. However,if cholesterol is needed, it must be mixed with lipids in the organic phase.

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Cosmetics can be formulated to less demanding and less strict specifications than thoserequired for pharmaceutical use. Therefore such products can be prepared with relativeease. This applies to liposome size and size distribution, as well as to lamellarity, sterility,and leakage of the entrapped agent, and finally to the selection of raw materials.

High quality liposomal products require well-controlled preparative procedures, whichnormally involve extrusion of larger liposomes through well-defined pores of filters withgiven pore size. Preparation of, for example, 0.1-µm liposomes normally requiresextrusions through 0.4-, 0.2-, and 0.1-µm filters. Most frequently, polycarbonate filters areused. Increased flow rates and reduced pressures can be achieved by the use of ceramicor inorganic (aluminum oxide with electro-etched pores at very high density) filters. Onthe other hand, most types of homogenizers produce nonhomogeneous vesicle-sizedistributions, a fact commonly ignored even in medical applications. As a rule, additionalsteps, such as centrifugation, filtration, or simple extrusion must be performed to removesample heterogeneity whenever required.

CProperties and Characterization of Liposomes

Size distribution, lamellarity, encapsulation efficiency, and stability of liposomes can bemonitored by many different physico-chemical techniques. Size is normally measured byvarious microscopic, hydrodynamic, spectroscopic, and diffraction techniques includingultracentrifugation, gel filtration, magnetic resonance methods, or light scattering [1].

Encapsulation efficiency is assessed after separation of liposomes from nonencapsulatedmolecules by gel filtration, dialysis, or centrifugation with the aid of standard analyticaltechniques, such as electronic adsorption, fluorescence spectroscopy, chromatography(HPLC), or radioactive labeling [1].

DStability

In medical applications stability represented one of the major challenges. People oftenreferred to it, along with sterility and scale up, as one of the ''triple S" problems ofcommercial liposome applications. Nowadays, these problems are to a large extentsolved.

Liposome stability is a complex interaction problem in which several featurescooperatively destabilize the product [41]. These include physical/colloidal stability andchemical stability of the components, as well as shelf-life stability, which is a sum and aproduct of the above two stabilities.

1. Physical and colloidal stability refers to the constancy of size distribution, lamellarity,and encapsulation efficacy. These can be enhanced by proper mechanical andthermodynamic selection of the bilayer properties as well as surface characteristics [1].

One of the most frequent mechanisms for liposome instability is aggregation followed byfusion. Aggregation can be strongly suppressed by electric, steric, or electrostaticstabilization of the particles. The presence of charged groups or of inert and bulky surfacegroups on the liposome surface enhances steric repulsion. Repulsion can be achieved bypreparing liposomes from charged lipids and from lipids containing bulky or polymericpolar heads such as polymers (polyoxyethylene), polysaccharides or the like, or byattaching (covalently or by adsorption) polyelectrolytes on the surface.

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Another important growth mechanism is Ostwald ripening, which has to be considered inthe case of many nonionic and charged surfactants (especially single chain) that possessa high critical micelle concentration (CMC) [1]. Particles with higher curvatures havehigher values of the CMC, and larger liposomes therefore grow at the expense of smallerones ("the rich get richer and the poor get poorer").

2. Chemical stability is enhanced by proper lipid selection, treatment, and preparation.Oxidative damage is reduced by the addition of antioxidants, such as vitamin E orbutylated hydroxytoluene, and the use of lipids with saturated fatty-acid chains.Hydrolysis is minimized by selection of the optimal pH (normally around 6). For long termstability the rate of destabilizing reactions can be reduced to practically zero bylyophilization. It was shown, for example, that in the presence of some cryoprotectants,liposomes can be freeze dried and rehydrated without change in their size distribution orleakage of the encapsulated material [1].

3. Biological stability, which primarily deals with the survival of liposomes exposed to thedestructive environment of biological fluids, is not very important for topical applications.Briefly, liposome stability in vitro can be improved by using very cohesive, mechanicallystrong bilayers. For increased in vivo stability, where the presence of cells and the body'sdefense systems actively clear or passivate all foreign surfaces, the most feasible solutionappears to be coating liposomes with inert polymers [1].

4. Shelf-life stability of liposomes is undoubtedly increased by freeze- and spray-drying orsimply by freezing. Shelf-life of liquid preparations requires optimization of severalfactors, including composition, additives such as antioxidants and chelators, pH, ionicstrength, and avoidance of light. In the case of some cosmetic preparations preservationagainst microbiological degradation can be achieved simply by keeping the liposomalsystem in 1520% ethanol or propanol, a common cosmetic ingredient, which reducesgrowth of microorganisms [17]. Many cosmetic preparations include synthetic lipids,which are chemically more stable due to ether linkages between hydrophobic andhydrophilic parts, saturated chains, and/or more stable polar heads. Very often theselipids have high CMC values, and the size growth due to Ostwald ripening may occur inliquid and semi-liquid formulations. The benefits resulting from semi-solid formulationsare reduced mobility and reduced oxygen diffusion, leading to improved stability.

EOther Lipid Colloidal Particles

This discussion deals primarily with aqueous solutions or dispersions. Liposomes can beformulated into creams, gels, aerosols, dry powders, and some other phases as well assome nonaqueous solvents [1]. The isotropic viscous state is not necessarily obtainedonly by high lipid concentrations. In many cases strong repulsive forces betweenliposomes (highly charged bilayers in low ionic-strength media or sterically stabilizedliposomes) can form rather viscous preparations. Addition of polymers that can bridge

liposomes and/or form a network also improves firmness of the sample. Other amphiphilicsubmicron particles can also be formulated into a variety of colloidal suspensionsinvolving solid, fluid, and gaseous states of matter dispersed one in another.

Several other lipid-based particulate colloidal systems can be used for the delivery of

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active agents to the skin. Emulsions, mixtures of polar and nonpolar solutions kineticallystabilized with the help of surfactants (and cosurfactants), are rather ill-defined colloidalsuspensions that may contain oil in water (o/w) or water in oil droplets (w/o), vesicles,and mixed micelles. Better defined are simple and mixed micelles and microemulsions.Microemulsionsonly o/w systems are mentioned herecan serve as excellent solubilizingsystems. However, immediately upon application they are modified from their chemicalequilibrium, and phases segregate and disintegrate, that is, follow a path determined bytheir phase diagrams. The same is true for micelles [1].

Kinetically stabilized oil droplets in water coated with (monolayers of) surfactants areoften referred to as nano- and microparticles. Although they may be topologicallyidentical to microemulsions, several important differences exist. In contrast tomicroemulsions, which form spontaneously after mixing appropriate compounds, they areprepared in a process that requires energy input into the system. Similar to liposomes,they are kinetically trapped into a higher energy state, mostly due to the imposition ofcurvature, and are, therefore, more stable upon dilution and application thanmicroemulsions. Typical systems are reportedly formed by high-energy treatment ofmixtures of water, oil, and lecithin. Often no cosurfactant is mentioned. However,possible changes in the lipid composition after prolonged sonication or homogenizationhave not been reported. It is very likely that (small) fractions of lecithin moleculeshydrolyze and produce lysolecithin and fatty acid, which can both act as cosurfactants [1].

Other important colloidal systems, described elsewhere in this volume, are foams andmousses. There is no intent to discuss these rather important systems, but a personalobservation is added. Work with liposomes very often creates some foam on the surface.During work with PEG-lipid containing liposomes it was observed, for example, thatmixtures containing 510 mol% of polyethoxylated lipids produce extremely stable foamswith bubbles in the sub-mm range [41]. While normal foams above liposomes (commonlyabout 210% of the liposome height in a container) disintegrate in minutes, after vigorousagitation or high pressure extrusion, these foams were stable for months.

FMixtures of Other Amphiphilic Colloidal Particles with Liposomes

Practically all cosmetic liposomes containing active ingredients are formulated into gels,creams, or ointments; for dermatological purposes the last two are preferred becausethey reportedly cause less irritation [17].

All the above mentioned particles can be mixed with liposomes. However, there is no clueas to whether or not the liposomes can retain their properties after mixing. Very oftenmixtures of MLV, LUV, SUV, o/w emulsion droplets, and nano- or macroparticles can berather stable if they are a product of a single preparatory process. However, mixing ofliposomes with such systems causes reequilibration, which may alter the liposomes. Asimple case is the mixing of liposomes with micelles or microemulsions. In the first case

liposomes can dissolve a portion of the micelle-forming surfactant until they becamesaturated. Initially, this may increase their colloidal stability and strongly decrease theirpermeability barrier. Continuation of detergent addition results in the dissolution ofliposomes and formation of mixed micelles. Mixing of liposomes with microemulsionsnormally causes aggregation, particle size growth, and possibly phase disproportionationof the system.

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Mixing of liposomes with nano- or microparticles can result in a more stable suspensiondue to the fact that all components are kinetically trapped into their structures. In manycases, as stated before, high encapsulation ratios may not be required because theimproved penetration into the skin can be due to swelling and fluidization of lamellarsheets in intercellular sites of the stratum corneum.

One can conclude that many liposomal cosmetic products are in reality mixtures of thevarious particles described above.

IVLiposome Formulations and Applications

Liposomes with active ingredients were first employed in drug delivery. However, despitethe publication of more than 10,000 papers there are only a few formulations whichpassed all the rigorous in vitro and in vivo tests [1]. Currently, after several decades ofresearch, there is only one commercially available liposomal drug (Amphotericin B againstsystemic fungal infections), and another one is expected to be available in 1994(anticancer agent doxorubicin in long-circulating liposomes, which avoid rapid clearanceby the immune system after intravenous administration). Development in dermatologyand cosmetics was much quicker. A topical antifungal cream, Prevaryl [42], was launchedin 1987, a year after several cosmetic companies introduced their antiaging liposomalcreams, which contained humectants as well as additional more complex ingredients[43].

APharmaceutical Applications

Simultaneously with developments in pharmaceutics and cosmetics, liposomes were alsostudied as carrier systems in topical therapy. Because it is often difficult to distinguishbetween a sophisticated cosmetic preparation and a topical therapeutic agent, such as ananti-acne cream, some of these applications shall be very briefly mentioned.

1. Dermatological liposome formulations [1,17,27,44,45] may contain corticosteroids(such as triamcinolone), nonsteroidal antiinflammatory drugs, topical antifungals (such aseconazole), hair growth promoters (such as minoxidil), compounds slowing hair loss (suchas coleus extracts), local anesthetics (such as tetracaine, lidocaine, and dibucaine),retinoids to cure acne and skin disorders, enzymes for DNA repair, agents such asantimicrobials and fungicides, antimetabolites (such as methotrexate and interferon), andtobramycin and other antibiotics. Despite some promising reports, most of theseapplications, however, have not been critically evaluated yet.

2. Ophthalmological liposomes reportedly can improve disposition and penetration ofocular drugs and can provide sustained drug release, as well reduce irritation. Drugs suchas idoxiuridine, pilocarpin, steroids, tobramycin, inulin, vitamin E, dexamethasone,atropine, trifluorothymidine, and fluorouracil have been applied in liposome formulations

either topically, intravitreally, or intracorneally [17].

3. Oral liposomes represent a controversial field. They will not be described in detail, buta few applications with cosmetic effects will be mentioned. Mucoadhesive ointmentscontaining mucoadhesive liposomes with triamcinolone acetonide and similarcorticosteroids were used to treat ulcers in the oral cavity. Phosphatidylinositol containingliposomes are known to adhere to the surface of bacteria, and liposomes loaded withantibiotics and agents against caries have been tested already. Liposomes

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containing vaccines against caries were used orally either directly in mouthwashes orindirectly via adsorption from Peyer's patch in intestines. Liposomes containingphosphatidylserine increase serum titer against antigens, such as bovine serum albumin,up to ten-fold. To increase the titer in saliva is, however, more difficult. Liposomes canalso be formulated into dentifrices.

BCosmetic Applications

Cosmetic applications of liposomes may include simple and advanced formulations.Simple cosmetics provide only temporary effect, such as skin protection (sunscreens) orfragrances. Modern cosmetic products are designed to achieve more: consumers mayprefer that products, such as fragrances, provide more than just an agreeable smell. Theymay demand active ingredients intended to slow down or even reverse some trends, suchas skin aging or hair loss, or to provide some other pharmacological benefit.

The most popular approach nowadays is do-it-yourself cosmetic formulations. In additionto mixing various extracts and oils, fragrances and the like, some manufacturers offerliposomes, o/w emulsions, w/o emulsions, or their mixtures as a vehicle for variousingredients.

Dehydration of the skin is commonly believed to be an important cause for its aging. Dryskin tends to crack, and various environmental agents can enter and cause damage. Dryskin also loses its elasticity and flexibility. Free radicals and damaged connective tissueare further causes of deleterious effects. Improved hydration is claimed for liposomallyentrapped humectants and moisturizers, such as glycerol, hyaluronic acid,polysaccharides, polymers, and some other molecules. Addition of free radical scavengerssuch as vitamin E and butylated hydroxytoluene, of enzymes such as superoxidedismutase, of antibiotics such as tobramycin, or of antifungals are cosmetic approachesused to combat aging of the skin and other deleterious effects.

The deficiency in essential fatty acids, most notably n-6 linoleic acid, results in symptomslike eczema, psoriasis, ichthyosis, and scaling, and in general poor skin, hair, and nailconditions. Topical addition of linoleic acid can reverse the trend. In order to deliver suchfatty acids to the skin, novel lipids were developed. One of them resembles normallecithin with reversed arrangement of the phosphate and quaternary ammonium group(Fig. 2). In the case of two chains the lipid is positively charged and, while compatiblewith anionic bilayer-forming lipids, it binds better to proteinaceous substrates.Furthermore, it is claimed that although it is nontoxic and mild to the skin, it exhibitspotent antimicrobial activity [46].

Other ingredients include various extracts for wound healing and, as claimed,regeneration of burned skin. Less pharmaceutical and more beautifying formulations arethe protective agents in sunscreens, pigments, and skin-whitening creams as well asface-, body-, and hair-care products. Liposomes are also used in perfumes, lipsticks, liquid

makeups and the like.

The most recently formulated anti-aging creams contain alpha hydroxy acids. They werefound to reverse the effect of photoaging because these molecules can exfoliate deadskin cells from the epidermal layer. This results in younger looking and healthierappearing skin.

More complex formulations include elastin, collagen peptides, and regeneration peptides,which were shown to stimulate cell growth in skin cell cultures.

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TABLE 1 Some Cosmetic Applications of Liposomes and Lipid Based ColloidalSystemsProduct Marketer Liposomes and key ingredientsCapture Christian Dior Liposomes in gel with ingredientsPlenitude L'OréalEffect du Soleil L'Oréal Tanning agents in liposomesNiosomes Lancôme (L'Oréal) Glyceropolyether with

moisturizersNactosomes Lancôme (L'Oréal) Vitamins, retinolacetateEsprit de Soleil Lancôme (L'Oréal) Nonionic lipid

Formule Liposomes Gel Payot (FerdinandMuehlens) Thymoxin, hyaluronic acid

Fundamental Care Perfums Givenchy Liposome gel

Future Perfect Skin Gel Estee LauderTMF, Vitamin A palmitate,vitamin E, cerebroside,ceramide, phospholipid

Emulsion Nrl ComplexeLiposome FRE Chanel Feproteins, trace elem.

minerals, vitam.Gel Lissant Contour desYeux Payot Ammonium liquid, democalmin

Heliotrop LiposomeActiv-Pflege

Elektrobio (Ernst KunzeGmbH)

Aloe vera extract, rose water,soya phospholipid

Intensive Redicer Anti-Cellulit Gel Helena Rubinstein Proteoglycan

Inovita Pharm/Apotheke Thymus extract, hyaluronicacid, vitamin E

Kao Sofina EmolielCream and MoistureEssence

Kao Sofina Cosmetic(Parfumerien Dr.Lenartz GmbH)

Glycolipid PSL, Sphingolipid E

La Myrell Contour andLiposomes Repair GelKonzentrat

Cosmetics MargotZimmer GmbHh

BRF System, Repair Factor,thymus extract

Liposome Aktions Gel Madame NanetteBiocosmetic Aloe vera, thymus extract

Liposome Skin VitalComplex

Shulton (AmericanCyanamid) 20% liposome

Micro 2000 ComplexeAnti-Stress Elizabeth Arden Hydrospheres

Saneo 2 LiposomeAmpule

Gabriele WyethKosmetik Fibrostimulin

Sympathik 2000 Biopharm GmbH Thymus extract, vitamin A,palmitate, soya phospholipid

Liosen Geymonat Chestnut extract, hyalur. acid

TMH-Ampulle Gerthard Klapp Mucopolysaccharide, hyaluronicacid, liposome

Natipide II Nattermann PL Liposomal gel for do-it-yourselfcosmetic

Eye Perfector Avon, NY soothing cream to reduce eyepuffiness

Source: Ref. 1.

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A still more sophisticated formulation, for instance, uses recombinant proteins againstsunburn damage to the cells [47]. The idea is to quickly remove DNA photoproducts(pyrimidine dimers), which are caused by ultraviolet light and presumably are initiators ofskin cancer. These degraded photoproducts can be excised and removed by repairenzymes (T4 endonuclease V). This is followed by quick resynthesis of DNA. In vitrostudies have shown enhanced removal of photoproducts, lowering of damaged patchsizes, and reduction of UV-induced mutagenesis. In test animals the incidence of skincancer was reduced 30% [46]. Despite that and despite the sound logical basis of themolecular mechanism, the in vivo applicability of this and similar formulations remainsquestionable. In light of the questions concerning liposome permeation and of theknowledge that these substances must be endocytosed by the appropriate cells deep inthe "inaccessible tissue," one must view the efficacy of such treatments with skepticism.

As already mentioned, some experts consider liposomes only as the least harmful andeasy removable substrate for active ingredients and/or, as some advertisementsproclaim, as a means for achieving "superior cosmetic pleasurability" and smooth, coolapplication qualities.

Today, cosmetic liposome formulations produced by several hundred large and smallenterprises include antiaging creams, "elasticity increasing and wrinkles combating"formulations, fragrances for prolonged and lasting effects in body lotions, aftershaves,skin-whitening formulations, tanning agents and water-resistant sunscreens, dentifrices,perfumes, makeups, shampoos, and some others. Fragrances as well as various herbalextracts are formulated into liposomes and are later mixed with appropriate carriers.Skin-whitening formulations may include liposomes containing vitamin E or retinoic acid,which may reduce the oxidation rate of ascorbic acid. Perfumes are normally formulatedin ethanol, but liposomes offer the means of preparing water-based perfumes. In contrastto the normally clear solutions, these perfumes are generally milky. Upon application,according to some studies, they provide a smooth skin finish [17,48]. Table 1 showssome of the liposome-containing cosmetic products on the market.

A recent trend in the cosmetic industry is the production of transparent creams. This isnot readily achievable with semi-solid liposome formulations. The first transparent(translucent) liposomal product could, nevertheless, reach the market soon because thisis not an excessively difficult task for an experienced liposome formulator.

After 15 years of intensive work, it is apparent that the number of cosmetic applicationsof liposomes currently exceeds that of pharmaceutical interest. Continuing research anddevelopment indicates that cosmetic liposomes will show further growth. On the otherhand, the use of liposomes in drugs is also expected to accelerate rapidly.

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41. D. D. Lasic, Angew. Chemie 106:176579 (1994); An. Ch. Int. Ed. Eng. 33:16751786(1994).

42. R. W. Kriftner, in Liposome Dermatics (O. Braun-Falco, H. C. Korting, and H. I.Maibach, eds.), Springer Verlag, 1992, pp. 91100.

43. A. Meybeck, in Liposome Dermatics (O. Braun-Falco, H. C. Korting, and H. I. Maibach,eds.), Springer Verlag, 1992, pp. 341345.

44. M. S. Korting, H. C. Korting, and O. Braun-Falco, J. Am. Acad. Dermat. 21:12715(1989).

45. S. Sveninsson and W. Holbrook, Int. J. Pharm. 95:1059 (1993).

46. D. Fost, Multifunctional biomimetic phospholipids: chemistry, performance andapplications in personal care, Mona Industries, NJ, personal communication.

47. D. B. Yarosh, J. Tsimis, and V. Yee, J. Soc. Cosm. Chem. 41:85 (1990).

48. H. Lautenschlager, Seifen-Ole-Fette-Wachse 18:7617 (1988).

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13Surfactants for Skin CleansersPaul ThauTechnology Surveillance, Cosmair, Inc., Clark, New Jersey

I. Introduction 285

II. Biochemical and Safety Considerations in the Selectionof Skin Cleansers 286

A. Biochemical and Physico-Chemical Measurements 287

B. Recently Developed In-Vitro Test Methodologies forSurfactants 287

C. Topical Safety Testing 288

III. Anionic Surfactants 288

IV. Amphoterics 297

V. Nonionic Surfactants 300

VI. Formulating Skin Cleansers to Enhance Mildness 302

VII. Recent Skin Cleanser Formulation Trends 303

References 304

IIntroduction

Articles for effective skin cleansing have evolved in parallel with the development ofhigher civilizations. Soap, the forerunner of modern-day skin cleansers, originated in theancient civilizations bordering the Mediterranean. The Phoenicians were certainly familiarwith the use of soap as early as 600 B.C. They carried it to the South of France, and fromthere its use spread to Spain, Italy and Germany [1].

The importance of adequate skin cleansing to health was clearly proved after thesoapmaker's art was lost with the fall of the Roman empire. The soapless centuries

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between 500 A.D. and 1500 A.D. were notorious for the devastating plagues that nearlydepopulated an unhygienic Western Europe.

Soap remained a rare commodity until about 1791 when the French surgeon NicholasLeblanc discovered an inexpensive method of obtaining alkali from sodium chloride.Within a decade, soap making techniques became available to all, and soap became anitem of daily use. Soap continued and still is the primary personal cleanser, even thougha variety of synthetic detergents became commercially available after World War II.

Skin cleansers act upon the skin surface by dispersing, emulsifying, and removing alltypes of surface soil. This includes grime and oil, body secretions, skin-cell debris,microorganisms, and a variety of externally applied items, such as cosmetics, toiletries,and medicaments. Washing with an effective cleanser removes the substrates for and theend products of organic decomposition (acids, amines, and sulfur compounds) that weassociate with putrefaction and uncleanliness [2].

Washing is a societal dictate. Dermatologists suggest that frequency and vigor of washingshould be adjusted to conform to the environment and the several stages of agingthrough which every skin advances: infancy, preteen, puberty, adulthood, and aging skin.In general, washing once a day is adequate; skin type (normal, oily, dry) may alter thisfrequency. Washing the entire skin only every two or three days is often quite adequatefor small children and older adults [3].

Environmental conditions, such as wind, cold, sunlight, central heating, and airconditioning, all intensify the potential for skin dryness from excessive use of skincleansers. As a result, some modification in frequency of use or in concentration of skincleanser products is often necessary under extreme conditions. In the absence of rationalguidelines, most individuals find it necessary to select a skin cleanser with a trial anderror approach [4].

The simplest and still most commonly used cleanser is water. It is cheap, ubiquitous,nontoxic, and harmless to normal skin. However, as a modern cosmetic, it has certainbasic shortcomings. Pure water wets skin keratin poorly. Washing with pure waterrequires a comparatively long contact period and intensive mechanical action to effectintimate contact with the skin surface. Penetration of skin folds and follicle orifices bypure water is inefficient [2]. Penetration of skin surface lipid by water is incomplete, anddirt and bacteria embedded in skin fat are, therefore, not removed by water alone.Bacteria and most types of dirt are not water soluble, and therefore, require largeamounts of water for removal from the skin. Part of the dirt and grime is redeposited onthe skin if only a limited quantity of water is used. The final result of washing with onlywater is mere redistribution of dirt and not its removal.

To counteract these failings, surfactants are used to facilitate wetting of skin and preventredeposition of dirt particles by emulsifying, solubilizing, and dispersing them. Numeroussurfactants have been developed in recent years. However, the primary concern is the

selection of those agents that will perform effectively and have no or minimal undesirableside effects on the skin.

IIBiochemical and Safety Considerations in the Selection of Skin Cleaners

In addition to the techniques discussed in Chapter 11 of the first edition of this book(listed below), a significant number of additional methodologies have been developed

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with the intention of replacing animal-test procedures. Correlations of these in vitromethodologies with previously available animal-test results are limited. Much moreremains to be done to select a combination of in vitro methodologies that will predict skintolerance and mildness after human use testing.

ABiochemical and Physico-Chemical Measurements

1. Determination of sulfhydryl groups (SH) liberated from human callus by treatment withsurfactant solution [5]

2. Extraction of water-soluble materials from stratum corneum by solutions [6]

3. Percutaneous absorption of 14C labeled surfactants through guinea pig skin in vivo [7]

4. Histamine release from mast cells by surfactants [8]

5. Inhibition of enzyme systems in skin [9]

6. Interaction between bovine serum albumin and surfactants [10]

7. Loss of lipid from cell walls [6]

8. Zein solubilization by surfactants [11]

9. Influence of surfactant washing on the capacity of human skin to neutralize alkalicompounds [9]

BRecently Developed In-Vitro Test Methodologies for Surfactants*

1. Hemoglobin degeneration test. This test, which is a proposed alternative for the Draizerabbit eye irritation test (ocular mucous membrane), measures the protein degenerationcapacity of various agents by treating hemoglobin with particular surfactants andobserving the effect [12].

2. CAM test. The purpose of this procedure is to evaluate the potential toxicity of a testproduct or surfactant as measured by the degree of damage caused to vascularizedchicken egg chorioallantoic membrane [13].

3. Prediction of surfactant irritation from the swelling response of collagen film [14]

4. Eye tex. Biochemical method to assess eye irritation [15].

5. Skin tex. Biochemical method to assess skin irritation [16].

6. Neutral Red. Potential toxicity of a test product is measured by reduction of neutral reduptake in cultures of normal human epidermal keratinocytes [17].

A recent publication from ColgatePalmolive R & D demonstrated the use of three in vitro

screening tests (collagen swelling [14]), pH rise [9], and zein solubilization [11] topredict in vivo clinical results. The collagen swelling test and the pH rise test showed thebest individual correlations between the in vitro and in vivo ranking. The use ofappropriate multidimensional testing will provide information that most closely mimicshuman test results [18].

*Microbiological Associates, Inc., Technical Literature, (IFSCC, Preprint Poster Session).

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CTopical Safety Testing

With the discontinuation of animal testing during the past ten years, the use of individualhuman test methods in a stepwise approach to systematically optimize mild surfactantpreparations has assumed increased importance [19].

The dermatological effects of surfactants on the skin are attributed to the following basicmechanisms:

1. Adsorption on the skin's surface,

2. Penetration into the lower dermal layers,

3. Elution of individual compounds, and

4. Irritation caused by cytotoxic effects on the living skin cells.

Since topical safety testing of surfactants will be described in detail in Chapters 19 and25, only a brief outline of current methodologies is provided in this chapter [19].

1. Burckhart test (single, brief application) [73]

2. Duhring chamber test (single, lengthy occlusive application) [31]

3. Arm flex wash test (exaggerated washing of the sensitive skin on the elbow)

4. Consumer use test (repeated application under normal use conditions)

The arm flex test combined with below-identified physical measurement methods permitsdifferentiations in many cases that cannot be obtained with the Duhring chamber testalone. This technique also has utility to record any negative sensorial responses, e.g.,feelings of tightness, burning, and itching.

1. The experimenter can assess the influence of the formulation on the barrier function ofthe skin by measuring transepidermal water loss.

2. The direct-light microscope is useful for the precise differentiation and visualization ofeffects on the surface of the skin.

3. The profilometer can measure the skin surface relief.

A sensible combination of subjective and objective methods is recommended to provide areliable and reproducible safety assessment of a product.

IIIAnionic Surfactants

1Alkyl Sulfates

Alkyl Sulfates ( ) are produced commercially either from coconut alcohol or fromlinear synthetic alcohols. In contrast to soap, alkyl sulfates and most other syntheticdetergents retain their excellent foaming properties in hard water [20]. Lauryl sulfate hasbeen found to yield the best foam and best solubility characteristics. Longer chain alcoholderivatives, such as sodium cetyl/stearyl sulfate, are better tolerated by skin but are lesswater soluble and foam less copiously.

The harshness of sodium lauryl sulfate (SLS) is often moderated in formulations byrational combinations with other surfactants, such as ethoxylated alkyl sulfates andsulfosuccinates, or inclusion of appropriate superfatting agents. Substantiation forbenefits from these respective combinations will be presented under the individualheadings.

Combinations of higher fatty-alcohol sulfates with amphoteric surfactants have been

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reported in the patent literature to produce bars with good milling and physicalcharacteristics. These compositions are also described as imparting a skin-conditioningeffect and a lowered degree of irritation potential [21]. The swelling of collagen film byanionic surfactants has been shown to correlate well with their skin irritation potential[14,25]. This in vitro technique demonstrated that alkyl sulfates produced greatercollagen swelling than alkyl ether sulfates. The irritation potential of a series ofsurfactants were ranked as follows by this technique:

The effect of cocamidopropyl betaine on alkyl sulfate induced swelling was studied withthis technique. Collagen swelling due to alkyl sulfate was reduced by as much as 45% bycertain combinations of SLS with betaine.

2Ethoxylated Alkyl Sulfates

The advantages of ethoxylated alkyl sulfates [ ] compared to alkyl sulfatesare greater water solubility and better foam stability in the presence of electrolytes, hardwater, and protein [22]. These benefits are counterbalanced by a slight reduction in foamvolume and foam density. Fatty alcohol ether sulfates have also been found to be slightlymilder to skin than lauryl sulfates in most biological tests, but neither is classified as aprimary irritant. Irritation due to the ether sulfate evidently does not increase significantlywith increasing concentration as reported by Brandau [23].

Skin-cleansing gel and lotion formulations generally contain ethoxylated alkyl sulfates incombination with other surfactants, (e.g., amphoterics) and/or conditioning agents (e.g.,fatty acid esters or polymeric additives) to achieve a desirable balance between cleansingand mildness. The label declaration of a commercial cleansing gel product illustrates theutility of a blend of various surfactants in combination with conditioning additives,colorant, antibacterial agent, and fragrance [24]:Ammonium lauryl sulfate Citric acidSodium laureth sulfate FragranceLauramide DEA DMDM hydantoinGlyerin Tetrasodium

EDTAIsostearamidopropyl-morpholine lactate FD&C yellow #5Disodium ricinoleamido MEAsulfosuccinate FD&C red #4Triclosan

Numerous in-vitro studies have shown that combining ethoxylated alkyl sulfate with alkylsulfates often results in less denaturation of stratum corneum. This irritation reductionhas been confirmed in a human skin irritation response study with this combination ofsurfactants. Results demonstrated a significant reduction in erythema compared to theuse of alkyl sulfate alone. This improved skin compatibility is theorized to be produced by

alterations in the micellar properties of alkyl sulfates upon the addition of ethoxylatedalkyl sulfates [25].

3Sulfosuccinate Esters

Two types of sulfosuccinate esters exist; of these the sulfosuccinate monoester (halfsulfosuccinate ester) [ ], is used more frequently in skin

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cleansers than the diester [ ] type. Sulfosuccinate surfactants combineboth carboxylate and sulfonate groups in the same molecule. The monoesters areunsymmetrical, are poor wetting agents, and are deficient in flash foam and suds volumeproperties when used alone. In spite of these limitations, this broad range of compoundsis used in skin cleaners, bubble baths, and shampoos because of their inherent skincompatibility and unusual capacity to act as anti-irritants when blended with othersurfactants, such as alkyl sulfates and sulfonates. Half ester sulfosuccinates also exhibitsynergistic foaming properties when blended with alkyl sulfate or alkyl ether sulfates[23,26].

Since this surfactant category is very diverse, a listing of some compounds by INCI namesfollows in Table 1.

The exceptional mildness to skin of sulfosuccinate surfactants has been substantiated bypatch tests (primary irritation), repeat patch tests, saccharase enzyme inhibition tests, aswell as by numerous other dermatological test procedures [5,27,28]. A summary of somerabbit skin primary irritation indices of some sulfosuccinate surfactants and a few otherskin cleanser surfactants is presented in Table 2.

Another experiment that clearly demonstrates the capacity of most sulfosuccinatemonoesters to reduce skin irritancy potential significantly when combined with othersurfactants was conducted by Wood and Bettley [5]. Their investigation demonstratedthe diminished denaturing action of 0.04 M sodium dodecylbenzenesulfonate (SDBS) incombination with 0.004 M disodium lauramide MIPA sulfosuccinate (IL/3). This reduceddenaturation was measured by the iodoacetamide method for titratable thiol groups inskin. Although the actual mechanism for this protective action has not been clarified, itcould be produced by the lowering of available SDBS monomer or by an initial binding ofthe sulfosuccinate to the skin protein which is thereby protected from attack by SDBS.This finding is illustrated in Fig. 1.

4Isethionates

These esters of isethionic acid (RCOOC2H4SO3H) are derived either from coconut, oleic, ormyristic acid [29]. They are commercially available as either sodium or ammonium salts.The prime differentiation is that sodium cocoyl isethionate has limited water solubility,whereas ammonium cocoyl isethionate is highly water soluble and lends itself to theformulation of clear liquid products.

Isethionate cleansers are characterized by their mildness to skin, compatibility with hardwater, and high foam. The foaming and lathering properties of the isethionates inTABLE 1 Typical SulfosuccinateSurfactantsINCI namesDisodium oleamido PEG-2 sulfosuccinate

Disodium laureth sulfosuccinateDisodium undecylenamido MEA-sulfosuccinateDisodium ricinoleamido MEA-sulfosuccinateDioctyl sodium sulfosuccinate

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TABLE 2 Primary Irritation Index of Surfactant Solutionsa% Active and product tested Primary irritation index10% Sodium lauryl sulfate 3.310% Sodium laureth sulfate 2.320% Sodium laureth sulfate 2.810% TEA-lauryl sulfate 3.010% Ammonium lauryl sulfate 5.110% Sodium alkylbenzenesulfonate (LAS) 5.020% Disodium oleamido PEG-2 sulfosuccinate 1.320% TEA-oleamido PEG-2 sulfosuccinate 1.6aA primary irritation index of over five means that the test material is ratedas a primary irritant; a score of 25 means moderately irritating, but not aprimary irritant; a 02 score qualifies as only mildly irritating; 0 signifies thatthere is no observable irritation to rabbit skin at the concentration andconditions of the test. The figures given are for the average of the totalscore (edema plus erythema) of multiple rabbit tests.

Fig. 1Diminution of denaturing action of SDBS on skin when 0.004 M

sulfosuccinate (IL/3) is added.

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hard or soft water resemble those of soap in soft water. Moreover, the foam ofisethionate surfactants is additive to that of soap when the surfactant is used incombination with soap. Isethionates have general usefulness in sudsing lotions andcreams, cleansing bars, and combination syndet/soap bars. The commercial isethionatesare soluble in neutral, acidic, alkaline, soft, and salt water.

A series of studies [8,6,30] provides strong documentation for the excellent tolerance ofskin for isethionates. The collective data shows that cleansing products containingisethionates have less effect on skin moisture retention properties than productscontaining either sodium lauryl sulfate or conventional soap. A study of Frosch andKligman [31] utilizing a chamber test for assessing the comparative irritancy of soaps andsyndet bars on a susceptible human test panel has shown that a syndet bar containingsodium cocoyl isethionate as the major surfactant is significantly milder than all soap barstested, including many specialty dermatological bars.

An illustrative mild facial wash formula from supplier literature that shows the use ofsodium cocoyl isethionate in combination with sodium methyl cocoyl taurate anddisodium oleamide MIPA sulfossuccinate is shown below [32].Mild facial wash 96-109-2Ingredients (INCI)

% by wtA.Distilled water 50.0

Propylene glycol 3.0Methylparaben 0.1Propylparaben 0.1Sodium cycoyl isethionate and stearic acid (65%) 21.0Sodium methyl cocoyl taurate (30%) 10.0Diosodium oleamido MIPA sulfosuccinate (35%) 5.0PEG-150 distearate 0.5BHT 0.1

B.Magnesium aluminum silicate, 5% dispersion 10.0Tetrasodium EDTA 0.2

C.Preservative q.s.D.Perfume q.s.

Procedure. Heat water to 6570ºC and begin adding (A) ingredients in order, allowingeach to mix well. Begin cooling to 45ºC, add (C), and continue cooling to 35ºC. At 35ºCadd fragrance (D), mix well, and package.

5N-Acyltaurine Surfactants

The amide structure of the N-acyltaurine surfactants ( ) stabilizesthese derivatives of fatty acids against hydrolysis under acid and alkaline conditions, evenat high temperatures. In contrast, the ester-type isethionates are stable in solution onlyat essentially neutral conditions (pH 6 to pH 8.0) at room temperature [33].

In terms of skin and eye tolerance, the sulfoalkyl esters are significantly milder than

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the sulfoalkyl amide surfactants. Thus the skin irritation index of sodium myristoylisethionate (56% active) is only 0.13, while that of sodium methyl myristoyl taurate(24% active) is 3.04 [34].

The taurates (e.g., sodium methyl cocoyl taurate) are high flash-foam, mild surfactantsthat are useful in all personal care products regardless of pH. Their foaming andtoxicological properties make them useful in a wide range of bath and showerformulations. They are used as primary surfactants in both transparent and opaquesystems [34].

6Sodium Lauryl Sulfoacetate

Sodium lauryl sulfoacetate can be prepared by esterification of sulfoacetic acid or fromthe chlorester [35]. Sodium lauryl sulfoacetate has a pH close to neutral and exhibitsexcellent foaming, wetting, emulsifying, and detersive properties. It is effective inreducing the surface tension of aqueous solutions and displays excellent stability to waterhardness [35]. Sodium lauryl sulfoacetate is claimed to be milder to the skin than manyother anionic surfactants including most alcohol sulfates and ethoxylated alcohol sulfates,and sodium lauryl sulfoacetate has been incorporated into many proprietary products inplace of soap for use by individuals whose skin is sensitive to soap.

The surfactant is used at concentrations up to 25% as an ingredient in luxury-type drybath foams because of its profuse foaming power. This type of formulation exhibits hightolerance for soap with minimal deterioration of foam. It reportedly has little potential toproduce urinary tract irritation, particularly by comparison to alkyl aryl sulfonates [36].

7Sarcosinates

Sarcosinate surfactants [RCON(CH3)CH2COO-M+] exhibit some physical and chemicalsimilarities to fatty acid soaps and are sometimes referred to as ''interrupted" soaps. Thepresence of the N-methyl amido group [CON(CH3)] in the carbon chain exerts aconsiderable influence on physical and chemical properties [37,38]:

1. Sarcosinates are more soluble in water and are less affected by hard water thancommon soaps.

2. In contrast to soap, they may be incorporated into formulations as low as pH 4 withexcellent results. At this stage, they are used as a blend of the free acid and its salts.

Sarcosinates offer desirable properties for the formulation of skin cleansers because theyproduce copious soap-like foam, exhibit skin gentleness, and are remarkably compatiblewith a variety of surfactants, including cationics [37]. They also have the distinctiveproperty of being strongly absorbed on various protein substrates, such as hair, skin, andwool, at pH 47 [39]. Sarcosinates exist in equilibrium with quantities of the free N-acyl

sarcosinic acid in the pH range 47. While being almost completely and clearly solubilized,the minor amount of free sarcosinic acid exhibits strong affinity for skin [39]. This featurecan be utilized advantageously within a simple sarcosinate formulation in combinationwith other mild surfactants, such as sodium cocoyl isethionate, to produce a skin cleanserthat can impart a distinctively smooth and soft residual skin feel.

The following facial cleanser formulation from the patent literature [40] illustrates theuse of a triethanolamine salt of an acylated sarcosine as the "primary active detergentwhich effectively removes the oil on the skin without excessively drying the skin."

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TEA-lauroyl sarcosinate,40% 15.00%PVP 1.00%Hydrolyzed collagen 1.00%Lauramide DEA 2.00%EDTA 0.10%Methylparaben 0.15%Water q.s. to 100.00%

This formulation is claimed to possess superior skin cleansing properties and exhibitexcellent skin tolerance with minimal tendency to produce skin dryness. Thus it isunnecessary to incorporate any oil ingredients to replace natural lipids removed by moreconventional formulations.

8Fatty AcidPolypeptide Condensates

This surfactant category was one of the earliest synthetic detergents and was originallyintroduced during the early 1930s in Germany under the name of Lamepons. The fattyacid-polypeptide condensates are N-fatty acyl derivatives of amino acids and peptidesderived from leather scraps and other easily hydrolyzable proteinaceous materials. Theycan be regarded as modified soaps into which a polypeptide chain has been insertedbetween the alkyl chain and the polar end group (RCONH[polypeptide]COO-M+). They areavailable commercially as potassium or triethanolammonium salts [41].

Fatty acidpolypeptide condensation products are noted for their mild yet efficientcleansing action on skin. Their low skin irritation potential and excellent skin compatibilityrating have been well documented [9]. The mildness feature of these surfactants can beattributed in part to their limited tendency to defat or alter the pH of skin [42] and thusto minimize swelling of the skin as compared to that produced by soaps [43]. The fattyacid polypeptide condensate surfactants are desirable for use in skin cleansers since theyare more resistant to hard water than typical soaps and do not defat the skin as much asthe sulfated and sulfonated surfactants [44]. Cleansers based upon these surfactantshave also been reported to have been well tolerated by individuals with intolerance tosoap [43].

A cosmetic cleanser patented by Powers and Barnett [44] is based on a combination ofan oleic acid-polypeptide condensate and an acyl isethionate prepared from coconut fattyacids. It is claimed that the poor-foaming oleic acid-polypeptide detergent is synergisticwith the coconut acyl isethionate in respect to sudsings, emulsifying, and cleansingaction. An example from the patent literature is [44]Liquid skin cleanserSodium cocoyl isethionate (64%) 30.00%Potassium cocoyl-hydrolyzed collagen(35%) 25.00%Glycol stearate 5.00%

Water 40.00%Perfume, color q.s.

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9Acylglutamate

Acylglutamates are amides derived from L-glutamic acid and natural higher fatty acids[45]. Some of the features of acylglutamates include

1. Moderate foaming power and good detergency.

2. Good compatibility with hard water.

3. A pH of 57 for aqueous solutions of monobasic salts, similar to the pH of human skin.The dibasic salts exhibit a pH of 89.

4. A comfortable and soft feeling to the skin during and after use.

5. Good skin and eye toxicity profile.

Acylglutamate derivatives are recommended for numerous skin cleanser applications,including toilet bars, bubble baths, and body shampoos. A suggested body shampoocomposition is shown below [45]:TEA-cocoyl glutamate 15.0%Sodium laureth sulfate 16.0%Cocamide DEA 4.5%Sodium PCA 1.0%Preservative and fragrance q.s.Water 63.5%

10Linear Alkylaryl Sulfonates (LAS)

This category of surfactant displays excellent cleansing and degreasing properties.Members of this class are not affected by hard water because their calcium andmagnesium salts are water-soluble. The triethanolamine salts find applications incosmetic and toiletry formulations. The primary disadvantage of LAS surfactants is theirtendency to irritate the skin unless their high denaturing capacity is moderated by othercomponents of specific formulations.

Table 2 shows the high primary irritation index of LAS compared to that of othersurfactants [23]. An example of possible means for reducing the skin irritation potential isshown in Fig. 1. The use of sodium dodecylbenzenesulfonate at a 10:1 ratio with asulfosuccinate surfactant appears to produce a reduction in skin irritation potential asmeasured by the iodoacetamide methd of titratable thiol groups from skin.

Until about twenty years ago, LAS surfactants were used extensively in high foamingbubble bath formulations. However, since the surfactant was thought to be implicated toa high incidence of vaginal and urinary tract infections in children, the frequency of thisapplication has diminished drastically [36]. The primary cosmetic category for which LAS

surfactants continue to be used is that of an effective cleanser for oily skin. Thesurfactant TEA-dodecylbenzenesulfonate, which has a history of use for this application, isavailable in the United States as a 60% active liquid and is claimed to have specific utilityfor cosmetic applications because it is a product of cold sulfonation, which produces apurer and milder product [46]. A related derivative is sodium octoxynol-2-ethanesulfonate, which has a use history as a skin cleanser. This ethoxylated LAS is the primarysurfactant in a commercial skin cleansing product [47]. The cleansing properties

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of this type of formula are moderated by the inclusion of lanolin, cholesterol, andpetrolatum, which are claimed to deposit a fine film of oil on the skin during the washingprocess and, thereby, help protect against excessive dryness. Cleansers such as this arerecommended for use by individuals whose skin may be irritated by the use of soap orother alkaline cleansers. The products are claimed to contain an effective detergent forremoval of soil and oil from the skin and are recommended by dermatologists as anadjunct in the treatment of acne.

11Alpha-Olefin Sulfonate Surfactants (AOS)

The AOS surfactants are produced by the direct reaction of olefins with strong sulfonatingagents, such as sulfur trioxide. This leads to the formation of surface-active anionicmixtures containing both alkene sulfonates and hydroxyalkane sulfonates. Thesesurfactants may be used in place of linear alkyl benzene sulfonates in many formulas withresulting improvements in biodegradability, mildness to skin, foaming, and detergency. Inaddition, AOS surfactants are stable over a much broader pH range than alkyl sulfates,alkyl ether sulfates, and ester-type surfactants [48]. They also exhibit excellent foamingand detergency in hard water. The INCI name of the primary AOS of commerce is sodiumC14-16 olefin sulfonate.

Irritation studies on AOS have been conducted on the backs of ten human volunteers,using the closed patch technique with daily applications of 2.5% aqueous solution (seeTable 3). At the end of ten applications, it was shown that irritation was comparable tothat produced by soap [50].

The AOS surfactants have been used successfully in the formulation of a variety of skin-cleansing products, including toilet bars and bubble bath compositions. A sug-TABLE 3 Primary Skin Irritation Indices andClassificationa of AOS and LAS at VariousConcentrationsConcentration Material (Draize

score) ClassificationAOS LAS

1% 0.2 0.2 Nonirritant2% 0.0 0.0 Nonirritant5% 0.3 0.4 Nonirritant10% 0.5 0.8 Mild irritant20% 2.9 3.7 Moderate

irritant36.8% 4.5 4.9 Moderate

irritantaDermal irritation data of irritancy versusconcentration by Federal Hazardous SubstancesLaboratory Procedure [49]. For descriptivepurposes, Draize scores of 0.00.04 are callednonirritating; 0.51.9 are called mildly irritating;2.04.9 are called moderately irritating; and

5.08.0 are severely irritating.

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gested liquid bubble bath formulation containing sodium alpha-olefin sulfonate is listedbelow [51]:Sodium C14-16 olefin sulfonate,40% 30.0%Cocamide DEA 5.0%TEA-lauryl sulfate, 40% 10.0%Sodium chloride 2.0%Formaldehyde solution 0.1%Phosphoric acid q.s. to pH 6.87.2Perfume and colorWater Balance to

100%

The trend in the cosmetic market to use liquid hand cleansers in place of bar soapcontinues to be strong [48]. As a result of their relative mildness, cleansing efficiency,outstanding lathering properties, and favorable cost, AOS surfactants have gainedpopularity for this use.

12Monoalkyl Phosphates (MAP)

An example of the MAP type of surfactants, that have been developed by Kao Corporationand which are utilized in a number of commercial skin-cleanser products, is TEA-laurylphosphate. This class of anionic surfactant possesses excellent foaming and cleansingproperties. These surfactants are claimed to be mild to skin and to provide a distinctive,nontightening skin feel after rinsing [52].

A publication by Kawai [53] et al. reported on the relationship between surfactantstructure and the sensation of tightness that ordinarily occurs on facial skin a few minutesafter face washing. Most anionic surfactants were shown to cause various degrees of skintightness, the order found in this study was TEA-lauryl phosphate < potassium myristate= TEA-cocoyl glutamate < sodium laureth-2 sulfate < sodium lauryl sulfate. The degreeof tightness was shown to be related to both the lipid removal and the degree of residualsurfactant absorption on skin after rinsing.

IVAmphoterics

1N-Alkyl-2-Amino Monopropionates and Dipropionates

These surfactants are synthesized by the condensation of fatty primary amines andacrylic monomers [54]. This reaction can be controlled to give two types of products: N-alkyl aminopropionates and N-alkyl iminodipropionates. A variety of long-chain saturatedand unsaturated alkyl groups (C10 to C18 and mixtures) is commercially available.

Amphoteric surfactants characteristically contain both basic and acidic functional groups.Within these surfactants, the basic center is either a secondary or tertiary amine group,depending upon whether the molecule is a mono- or dipropionate. The acid propertiesare provided by the carboxylate group or groups. In acidic solution, the surfactant is acationic amine salt; in alkaline solution, it is an anionic carboxylate salt. In the isoelectricrange the zwitterion, which is both positive and negative, predominates.

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The different molecule charges that can develop in a typical b-aminopropionate derivativeas a result of changes in pH are illustrated below:

An equilibrium mixture of all three forms exists at all except the most extreme conditionsof acidity and basicity [55]. The zwitterion has limited solubility. As a consequence, thesesurfactants exhibit minimum solubility at the isoelectric point, and properties such asfoaming, detergency, wetting, etc. also pass through a minimum at the isoelectric point.

Typical pH levels and isoelectric range pH levels of two derivatives that have potentialutility in cosmetic compositions are shown below:

Isolectric Concentrations (w/w inwater)

TypicalpH

Isolectric rangepH

Sodiumlauriminodipropionate 30% 7 2.44.2Lauraminopropionic acid 50% 6 3.84.9

Tests of sodium lauriminodipropionate and lauraminopropionic acid for acute oral toxicity,primary skin irritation, skin sensitization, and eye irritation have shown them to have afavorable safety profile [54]. The N-alkyl-2-amino monopropionates and dipropionatesare compatible with nonionic, anionic, and cationic surfactants within defined ratios andalso have the capacity to solubilize many organic and inorganic additives in surfactantapplications.

2Betaines

Betaine surfactants are internally compensated quaternary ammonium compounds thatdiffer from quaternary ammonium salts in that they do not have a mobile anion. Betainesretain their positive molecular charge and cationic character in both acidic and alkalinemedia. Since these surfactants do not acquire positive or negative charges according tothe pH of their aqueous solution, it has been reasoned that it is incorrect to classifybetaines as amphoteric surfactants [56]. The contention is that betaines should rightfullybe classified as cationics. Despite these strong arguments, most betaine supplierscontinue to categorize them as amphoterics or as ampholytes. In the isoelectric rangesurface-active betaines exist in the zwitterionic structure: RN+ (CH3)2CH2COO.

Betaines are not affected by water hardness and produce excellent foam with goodstability in soft and hard water. They are generally compatible with both anionic andcationic surfactants, with the exception of anionics at low pH. Excellent viscosity buildingis obtained from combinations of betaines with anionic surfactants [56]. Thecocamidopropyl betaine derivative has superior compatibility with anionics at higher useconcentration than coco-betaines.

Extensive animal safety testing has shown the betaines to have very low eye- and skin-irritation potential. These agents have also been found to be effective in reducing theirritation potential of alkyl sulfates, alkyl ether sulfates, and soaps [57]. A possiblemechanism for this anti-irritant action is the significant lowering of the total monomer

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concentrations by the formation of hydrophobic complexes between the anionic andamphoteric surfactants [58].

3Hydroxysultaines (Sulfobetaines)

These substances also exhibit compatibility in surfactant systems based on cationic,anionic, or nonionic surfactants. This compatibility exists over a broad pH range. Forexample cocamidopropylhydroxysultaine is more effective in the removal of sebum thancocamidopropyl betaine and also has the ability to reduce the irritation potential offormulations based on alkyl sulfates, alkyl ether sulfates, and other anionic surfactants[59]. The hydroxysultaine retains both its positive and negative charge across the pHspectrum because the sulfonate ion is more strongly anionic than the correspondingcarboxylate ion in the betaine. Sulfobetaines are very substantive materials as exhibitedby excellent performance in cationic dye uptake tests [55,60].

4Acyl Derivatives of Ethylene Diamine

A wide variety of these compounds, formerly classified as imidazoline derivatives, areavailable from various commercial sources. The group includes monocarboxylates,dicarboxylates, and sulfonates, differing primarily in their fatty side chain. Some of thefeatures of this category of surfactants that make them useful for skin-cleanserapplications are summarized below [61]:

1. Mildness to skin and eye

2. Minimum or no eye sting

3. Good foaming and foam stability

4. Complete foam compatibility with soap and soap foam

5. Hard-water resistance

6. Compatibility with quaternary germicides

7. Compatibility with cationic, anionic, and nonionic agents in all preparations

8. Biodegradability

9. Ability to complex with anionic surfactants, which reduces the latters' tendency toproduce eye irritations, without interfering with foaming properties [60].

These desirable features depend upon the pH of the finished product, which normallyshould be between 6.5 and 7.5.

A representative listing of available acyl derivatives of ethylene diamines is shown below:

CTFA names Fatty radical (s)Hydrophilic groups (s)Disodium cocamphodiacetate Coconut DicarboxylateSodium cocoamphoacetate Coconut MonocarboxylateDisodium lauroamphodiacetate99% Lauric DicarboxylateSodium lauroamphoacetate 99% Lauric Monocarboxylate

The composition of a "nondegreasing" foaming facial wash containing disodiumlauroamphodiacetate is shown below [62]:

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Nondegreasing foaming facial wash% w/w

Disodium lauroamphodiacetate 35.0Sodium laureth sulfate, 25% 15.0Sodium lauroyl sarcosinate 10.0Oleth-10 phosphate 2.0Water 38.0Preservative, fragrance q.s.Adjust to pH 7 with hydrochloric acid

VNonionic Surfactants

1Polyoxypropylene/Polyoxyethylene Block Polymers

These nonionic surfactants are formed by the condensation of propylene oxide onto apropylene glycol nucleus followed by the condensation of ethylene oxide onto both endsof the polyoxypropylene base. The polyoxyethylene hydrophilic groups on the ends of themolecule are controlled in length to constitute anywhere from 10% to 80% of the weightof the final molecule. This extensive series of surfactants may be represented empiricallyby the formula [63,64]: HO(CH2CH2O)x(CH[CH3]CH2O)y(CH2CH2O)zH. The INCInomenclature identifies these substances as poloxamers.

The properties of the individual members of the series vary with the molecular weights ofthe polyoxypropylene and polyoxyethylene moieties of the molecule and with their ratio.The entire series of more than 32 different polyols has been described by the "Grid"system [64], and commercial products possess HLB numbers from 1.0 to 30.5. Thesepolyols are considered low- to moderate-foaming surfactants. They are more soluble incold water than hot because of hydrogen bonding of water to the many ether oxygenatoms. An interesting property of some members of the surfactant family is their ability toform clear gels. Poloxamer 407, the most efficient gel former in the series, shows thisproperty at a concentration of 20% in water.

One of the primary reasons for the use of these surfactants in skin-cleansing products istheir well-documented safety, particularly their excellent skin and eye tolerance. Theseproperties make these polyol surfactants especially desirable for products designed foruse as facial cleansers and eye makeup removers.

A suggested formulation for a facial cleanser lotion is given below. Its effectiveness is dueto the use of a combination of poloxamer 407 with a surfactant blend to provide goodskin-cleansing action for removal of facial makeup and facial grime [64].Facial cleanserPoloxamer 407 10.0%Proprietary blend of sodium cocoamphodiacetate, sodium lauryl sulfate,sodium laureth sulfate, and propylene glycol 10.0%

Propylene glycol 2.0%PPG-26 oleate 2.0%Proprietary blend of polysorbate 80, cetyl acetate, and acetylatedlanolin alcohol 2.0%

(table continued on next page)

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(table continued from previous page)Water 74.0%Preservative q.s.

A patented composition [65] covers the use of 3050 percent poloxamer 407 incombination with 3050 percent sodium cocoyl isethionate and excipients to produce acomposition useful in the manufacture of nonalkaline detergent bars with excellentcleansing action and good skin compatibility.

2Amine Oxides

Amine oxides, RN(CH3)2® 0, are prepared generally by the reaction of a tertiary aminewith hydrogen peroxide under controlled conditions. Other oxides, such as those derivedfrom alkylamidopropyl dimethylamines (e.g., cocamidopropylamine oxide,RCONH(CH2)3N(CH3)2® O) or from alkylbishydroxyethylamines (e.g., dihydroxyethylcocamine oxide, RN(CH2CH2OH)2® O) also have similar commercial utility. Theproperties of the amine oxide surfactant will vary with pH of their aqueous media. Theyexist as uncharged nonionics in alkaline solutions but gain positive charges and exhibitcationic activity in acidic solutions. At pH levels below 3, the amine oxides possessessentially cationic activity [56]. The molecule adds a proton in the presence of anionicsurfactants to form the cationic conjugate acid. The conjugate acid forms 1:1 salts withanionics that are much more surface-active than either the anionic or the amine oxide[66].

3Alkyl Glucosides

Alkyl glucosides, also known as alky polyglucosides, have only become commerciallyavailable within the past five years; although glucoside chemistry was originally describedby Emile Fischer in the early 1900s [67,68]. These surfactants are synthesized by reactingcorn starch glucose with a fatty alcohol. The resultant unique nonionic surfactant hasmuch greater tolerance for electrolytes than conventional ethylene-oxide-based nonionicsand also does not display inverse solubility (cloud point) at elevated temperatures. It hasbeen shown that alkyl glucoside surfactants can lower both surface and interfacial tensioneffectively.

As a cosurfactant in skin cleansers, glucosides provide mildness, good detergencycompatibility with all other surfactant types, and performance synergy in combinationwith anionic surfactants.

In addition to the advantage of commercial availability from renewable, vegetablesourcedraw materials, alkyl glucosides display a very high degree of biodegradability. Laurylglucoside and decyl glucoside demonstrate application advantages when used as mild

cosurfactants in combination with anionic surfactants. These nonionic surfactants can becombined up to a ratio of 1:1 with fatty alcohol ether sulfate without foam depression. Inmixtures with anionic surfactants, alkyl glucosides also provide a foam-stabilization effectand improve foam volume in hard water and in the presence of sebum.

The efficacy of alkyl glucosides as mildness increasing additives is clearly shown in thefollowing arm-flex wash test results shown in Fig. 2.

A prototype facial cleanser for sensitive skin containing a combination of lauryl glucosideand sodium laureth sulfate is shown below [66]:

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Fig. 2Arm-flex wash test with SLS and decyl glucoside.

Facial cleanser for sensitive skinIngredients % w/wLauryl glucoside and sodium laureth sulfate 19.20Lauramide DEA 2.00Potassium cocoyl hydrolyzed collagen 7.60PEG-7 glyceryl cocoate (1) 1.00Methylchloroisothiazolinone (and) methylisothiazolinone 0.05Water 70.15

VIFormulating Skin Cleansers to Enhance Mildness

A major challenge in developing a commercially acceptable skin cleanser composition isto achieve a good balance between foaming and cleansing efficacy with skin mildnessand pleasant skin feel [69]. Liquid cleansers for special skin care needs are often basedupon a mixture of various types of synthetic detergents to achieve flexibility offormulation attributes. It is common to blend primary anionic surfactants together withsmaller amounts of amophoteric and nonionic surfactants to produce synergisticenhancement of foaming and mildness [70]. A suggested approach to formulate an "extramild" liquid soap formulation is a combination of sodium tridecth sulfate, PEG-80 sorbitanlaurate, cocamidopropyl hydroxy betaine, and sodium lauramphodiacetate [69].

Various refatting/emollient type additives are frequently added to liquid cleanserformulations to counteract excessive sebum removal during the skin cleansing process,which could produce skin dryness and tightness. Two examples of this type additive areoctylhydroxystearate and PEG-7 glyceryl cocate. These materials, when used at lowconcentrations, can be solubilized by the surfactant system and act to "tame" thecleansing efficiency of the composition. Various types of polymeric additives also have

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been used effectively to help condition, moisturize, and in some instances augmentmildness of skin cleansers. Some examples are polyquaternium 7, polyquaternium 10,and the sodium salt of polyacrylamidomethylpropane sulfonate. The cationic polymershave been shown to be substantive to skin. Some measurable parameters used to assessa skin cleanser's overall performance and consumer acceptability are itemized below[71,72]:

1. Foaming and lather texture

2. Cleansing efficacy

3. Rinsability

4. Viscosity

5. Mildness to skin

6. Skin feel during use

7. Skin feel after use

8. Fragrance acceptability

VIIRecent Skin Cleanser Formulation Trends

Two skin cleanser review articles [69,72] have surveyed recent innovative productintroductions and new technology trends. A foremost goal is the continuing endeavor todevelop skin cleanser compositions with enhanced mildness without sacrificing desirablecosmetic attributes. With the advent of refined in vitro and in vivo biological screeningprocedures, the opportunity to develop skin cleanser compositions that have only a minoreffect on skin physiology exists. Synergistic performance properties between existing andnew surfactants offers an important approach. Examples of recent surfactantintroductions that possess good skin compatibility profiles are alkyl glucosides, monoalkylphosphates, and acylglutamates.

The development of two-in-one skin cleansing products that combine two chemicallyopposing processes, cleansing and conditioning, has presented formulators with arigorous technical challenge. The inclusion of emollient and conditioning additives insurfactant blends has required systematic raw-material screening and selection ofappropriate combinations to overcome potential problems of instability, foam suppressionand excess residual skin feel. These shortcomings are claimed to have been minimized inthe following prototype formulation [72].Two-in-one shower gel (emulsion)A. Cetyl dimethicone copolyol 5.00%

C1214 hydrogentated vegetable triglycerides 5.00%B. Deionized water 25.00%

Glycerin 3.00%Sodium citrate 2.00%C. Deionized water q.s. to 100.00%

Sodium laureth sulfate, 70% 27.00%Disodium Cocamphodiacetate 16.00%Polyquaternium 39 2.50%

D.Fragrance q.s.Preservative q.s.

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Other recent skin-cleanser formulation trends are as follows:

1. Products with environmentally friendly surfactants have been in growing demand byconsumers. Additives, such as botanical extracts, are frequently included in theseformulas.

2. Skin cleansers containing moisturizing beads, (emollient oils and conditioning agentsthat have been encapsulated in gelatin or alginate) which are suspended in surfactantvehicles with appropriate rheological properties are in demand. These beads break openwhen rubbed onto the skin to provide skin conditioning. This approach eliminates theneed for additional emulsifiers to stabilize the hydrophobic materials in the surfactantbase.

3. A trend to formulate skin cleansers specifically for individuals with sensitive skin hasalso become evident within the past few years.

References

1. Chemical Technology: An Encyclopedia Treatment, Vol. 5, Natural Organic Materialsand Related Synthetic Products, Harper and Row, New York, 1972.

2. J. S. Jellinek, Formulations and Function of Cosmetics, Wiley Interscience, New York,1970, pp. 2067.

3. J. A. Parrish, B. A. Gilchrest, and T. B. Fitzpatric, in Between You and Me, Little Brown,Boston, 1978, pp. 4044.

4. E. W. Brauer, The Use and Abuse of Soap, American Medical Association, Chicago,1970.

5. D. G. Wood and F. R. Bettley, Br. J. Dermatol 84:320 (1971).

6. J. D. Middleton, J. Soc. Cosmet. Chem. 20:339412 (1969).

7. F. R. Bettley, Trans. St. John's Hospital of Dermatol Soc. 58:65 (1972).

8. C. Prottey and T. Ferguson, in Congress Int. Fed. Soc. Cosmet Chem., vol. 8, London,1974, p. 15.

9. H. Tronnier, G. Schuster, and H. Modde, Arch. Klin Exp. Dermatol. 231:3 (1965).

10. G. Imokowa, K. Sumura, and M. Katsumi, J. Am. Oil Chem. Soc. 52:4903 (1975).

11. F. Balaguer, J. G. Domingues, J. L. Parva, and C. M. Pelejero, in Congress Intl. Fed.Soc. Cosmet. Chem., vol. 8, 1974, pp. 329.

12. Technical Bulletin Hemoglobin Degeneration Test, Ajinomoto U.S.A. Inc.

13. J. Leighton et al, In Vitro Toxicology, vol. 2, 1983, pp. 16377.

14. J. C. Blake Haskins, et al, J. Soc. Cosmet. Chem. 37:199210 (1986).15. A. M. Goldberg et al, In Vitro Toxicology, Tenth Anniversary Symposium, Liebert,1993, p. 236.

16. A. M. Goldberg et al, In Vitro Toxicology, Tenth Anniversary Symposium, Liebert,1993, p. 210.

17. A. M. Goldberg et al, Lens and Eye Toxicity Research, 9:16292 (1992).

18. B. M. Morrison et al, 18th Int. I.F.S.C.C. Congress, Preprints, Poster Session, 1995, pp.61115.

19. B. Jackwert et al, Parfumerie and Kosmetik, 74:14248, 1993.

20. S. Shore and I. R. Bergen, in Anionic Surfactants, part I (W. M. Linfield, ed.), MarcelDekker, New York, 1976, pp. 13637.

21. Duveen Chemical Co., Brooklyn, NY, Private Communications, 1977.

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22. M. J. Rosen, Surfactants and Interfacial Phenomena, 2nd ed., John Wiley, New York,1989.

23. R. B. Brandau, Detergent Age, (Jan. 1967).

24. Dial Liquid Antibacterial Soap, original formula.

25. L. D. Rhein et al, J. Soc. Cosmet. Chem. 37:125139 (1986).

26. G. Barker, Cosmet Parfun. 90:6975 (1975).

27. B. Idson, J. Pharm Sci. 57:1 (1968).

28. Rewo Chemical Group, Rewopol SBFA-30, Sternau, West Germany.

29. PPG Mazer Jordapon Technical Bulletin, 1991.

30. E. J. Singer and L. J. Vinson, Proc. Sci. Sect. Toilet Goods Assoc. 46:29 (1966).

31. P. J. Frosch and A. M. Kligman, J. Am. Acad. Dermatol. 1:3541 (1979).

32. Finetex Technical Data Sheet, Nov. 1994.

33. New Anionics for Cosmetics and Toiletries, GAF, Bulletin, 1975.

34. Cosmetics & Personal Care Products Index1994, Finetex Inc.

35. A. J. Stirton and J. K. Weill, in Anionic Surfactants, part II (W. M. Linfield, ed.), MarcelDekker, New York, 1976, pp. 38284.

36. Lathanol LAL Bulletin, Stepan Chemical Co., Norfield, IL.

37. J. R. Hart, Cosmet. Technol. 2:4044 (1980).

38. J. R. Hart, Cosmet. Toil. 94:74 (1979).

39. M. F. Nelson, Jr. and S. Stewart,, J. Soc. Cosmet. Chem. 7:12231 (1956).

40. U.S. Patent 4,147,782 to W. H. Rorer, Inc. (1979).

41. C. Fox in Emulsions and Emulsion Technology, part III (K. J. Lissant, ed.), MarcelDekker, New York, 1974, p. 77.

42. Product Profiles, Inolex Chemical Co., 1995.

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45. Acylglutamate Bulletin, Ajinomoto Co. Inc., 1991.

46. Calsoft T-60 Data Sheet, Pilot Chemical Co., 1992.

47. Physicians Desk Reference, 48th ed., Medical Economics, Oradell, NJ, 1994, p. 2112.

48. Bioterge Alpha Olefin Sulfonate Bulletin, Stepan Chemical Co., Northfield, IL.

49. Commuinique, Toxicity Studies on Alpha Olefin Sulfonate, Ethyl Corporation, BatonRouge, La., May 24, 1979.

50. G. Barker, Cosmet. Parfum. 90:70 (1975).

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52. Kao Prioly B-300 Technical Buletin, Kao Corp., Aug. 1994.

53. M. Kawai and G. Imokowa, J. Soc. Cosmetic Chem. 35:14756 (1984).

54. Deriphat Amphoteric Surfactants, Henkel Inc., Minneapolis, MN.

55. A. J. O'Lenick, Jr., et al, Happi, 7074 (Nov. 1986).

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57. Lonzaine Amphoteric surfactants, Lonza, Inc.

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61. Surfactant Specialties, Miranol Products Technical Literature, Rhône-Poulenc.

62. Technical and Product Development Data, The Miranol Co., Inc., 1979.

63. Pluronic Polyols, Toxicity Information Data, BASF Wyandotte.

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64. I. R. Schmolka, Cosmet Perfum. 89:63 (1974).

65. P. R. Bossman, U.S. Patent 3,766,097 (1973).

66. M. J. Rosen, Surfactants and Interfacial Phenomena, Wiley Interscience, New York,1978, p. 169.

67. Henkel APG Technical Bulletin.

68. B. Salka, Cosm & Toil. 108:89 (1993).

69. L. Lundmark, Cosm. & Toil. 107:4953, (1992).

70. T. Schoenberg, Soap Cosm. Chem. Spec. 59:34A (1983).

71. N. Brassard, Cosm. & Toil. 104:5359 (1989).

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14Cleansing Bars for Face and Body:In Search of MildnessRichard I. MurahataClinical and Appraisal Science, Unilever Research U.S., Edgewater, New Jersey

M. P. AronsonPersonal Washing Research, Unilever Research Laboratory Port Sunlight, Merseyside,United Kingdom

Paul T. Sharko and Alan P. GreenePersonal Washing Product Development, Lever Brothers Company, Edgewater, NewJersey

I. The History of Soap Production 307

A. Preindustrial Soap Making 307

B. Industrialization of the Soap Making Process 309

C. The Development of Diversification 309

II. Formulation of Mild Bars 311

A. General Features of Personal Washing Bars 311

B. Formulation of Mild Bars 314

C. Sensory Signals and Skin Mildness 321

III. Modern Process Engineering of Cleansing Bars 322

A. Introduction 322

B. Soap Manufacture and Processing 322

C. Exploitation of Mild Synthetic Surfactants 325

IV. Conclusion 327

References 327

IThe History of Soap Production

A

Preindustrial Soap MakingThe desire for cleanliness and other cosmetic benefits (fragrance, beauty, skin care) hasbeen part of the human condition since early written history. Modern cleansers are basedon fats, oils, and their derivatives, which have been utilized for cleansing in various formsfor over two millennia (Fig. 1). Soap, generally defined as the alkali salt of a fatty acid, isa member of the general class of compounds called surfactants (surface-active agents).These molecules are characterized by having a hydrophilic head group and a hydrophobic

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Fig. 1Schematic representation of the familytree of personal washing products. Thecommon roots are fats and oils. Some

were made into soaps and otherrinse-off products; others were appliedand scraped off. The soap segment

currently represents the largest marketwith mild, beauty, and deodorant assignificant categories. Syndets are animportant market in the United States

and growing around the world. Asmaller, but still important market is

the combars.

tail. Synthetic detergents (or syndets) are another class of surfactant with similarstructure and mechanisms of soil removal. However other key propertiesfor example,lather, bar feel, and sensitivity to water hardnesscan be quite different.

While it is not clear when the first true ''soap" was developed and used, the cleansingproperties of alkaline solutions obtained by extracting wood ashes or deposits of naturalsoda or borax have certainly been known from the earliest recorded histories. Clay tabletsfrom Sumeria refer to soap-like washing materials as early as 2500 B.C. [1]. The Egyptiansused a combination of animal and vegetable oils together with alkaline salts for treatingskin disease as well as for cleansing. Although early Greeks did not use soap, theycleansed themselves by applying oils and abrasive materials that were then scraped off.

According to a Roman legend, the term soap was derived from Mt. Sapo where animalswere sacrificed. Rain washed a mixture of melted animal fats and ashes into the clayalong the banks of the Tiber River. Local women found that the clay made clotheswashing easier [2]. The word soap was alternatively been attributed to the Celts, whoproduced a material called "saipo" from animal fats and plant ashes [3]. Others contendthat Phoenicians who settled Gaul around 600 B.C. were the inventors of soap. Galen, in the2nd century A.D. refers to the use of German and Gallic soap as both an emollient and acleanser for the body and clothes [4].

In the 8th century, soap making was an art known to the Phoenicians, Arabs, Turks,Vikings, and Celts, and by 800 A.D., European soap making was centered in Marseilles

(France), Savona (Italy), and Castilla (Spain), followed a few centuries later by Bristol(England). At that time bathing with soap was a luxury that only the wealthy could afford.

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BIndustrialization of the Soap Making Process

Several important discoveries are credited with transforming soap making from the realmof art to a manufacturing science. Trachenius, Geoffroy, Scheele, Lavoisier, Chevreul, andLeBlanc all made significant contributions to the understanding of the chemistry and,consequently, the manufacture of soap. The basic chemistry of soap had changed little inthe intervening centuries; it was not until the late 19th century that its manufacture wasconsidered to have reached "scientific character" [5].

The basic stamped soap bar is one of the most common and easily recognizedmanufactured products in the world today. The first American manufacture of soap stockby rendering fats occurred in 1806. Soap in "cake" form was introduced around 1830 [4],and this innovation was improved upon in England with introduction of individuallywrapped and branded bars in 1884.

CThe Development of Diversification

Mass production and the development of branded products provided the means andimpetus for the diversification of soap products that we see in the market today. As thesoap market diversified it was common to classify products according to methods ofmanufacture, appearance, intended use, and special additives [48]. Special additivesinclude not only those used at high enough concentrations to achieve a clearlydemonstrable benefit, (e.g. superfatting, mercury salts, phenol, peroxide, sulfur,antimicrobial agents, and moisturizers) but also those for which true benefit has beenmore difficult to appreciate (vitamins, botanical extracts, etc.) Cleansing, the primarybenefit of washing bars, was certainly delivered even by preindustrial products and wasnot a point of general distinction among soap brands. For over a century, soapmanufacturers have competed by providing products with distinct consumer-perceivableproperties such as lather, skin feel, and bar appearance and by delivering added benefits.These distinctions have been provided by judicious selection of the fat/oil blend, the useof additives, and advances in processing technology. As discussed below, today's marketcan be divided into several major categories.

1Deodorant Soaps

"Medicated soaps" first made their appearance around 1885 when several Europeandermatologists indicated that ingredients such as salicylic acid or mercuric chloride were avaluable therapeutic additive to soap. This hypothesis was supported by the results ofmicrobiological studies demonstrating the antibacterial properties of soap solutions [4].The first widely popular bars with added ingredients for hygiene were based on the workof British surgeon Joseph Lister, who used carbolic acid (phenol) as a presurgicaldisinfectant. In 1887 a bar soap that contained phenol to enhance its germicidal

properties was introduced in Britain and subsequently in the United States in 1895.Gradually the capability of germicidal soaps to inhibit both perspiration odor and bodyodors was recognized and promoted. A deodorant positioning was introduced in 1896,which started a new category of personal washing products.

The use of antibacterial ingredients to inhibit the growth of odor-producing microbes isnow a commonly used method of formulating deodorant soaps. The antibacterialingredient hexachlorophene, was introduced in a bar in 1948, and unlike the phenol-containing bars, it had a very pleasant fragrance. A number of other antimicrobial actives

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(e.g., salicylanilides) have been used since. However, in the United States there are onlytwo antibacterial agents currently in general use as soap additives, trichlorocarbanilide(TCC) and triclosan. The second basic approach currently used to achieve longer lastingdeodorant protection is based on deofragrance technology. The latest innovation in thisdeodorant bar category is the development of products combining deodorancy with skin-care benefits.

2Beauty Soaps

While deodorant soaps grew from the desire for a health benefit, the beauty soapcategory developed from a desire for sensory properties and mildness. Propertiesconsidered to be important were bar hardness, lathering properties, color, fragrance, andmildness to the skin [9]. The selection of a particular fat/oil blend, as well as certainprocessing techniques, are factors in achieving these desired properties. Early tallowsoaps cleaned well, were hard and long lasting, while coconut oil soaps produced a latherthat was much creamier and voluminous than that from tallow. However, it was notedearly on that soap derived from coconut oil had greater skin-irritation potential than thatderived from tallow [7]. Beauty soaps were born from an attempt to blend soft vegetablesoap with harder animal-derived soap to achieve a balance of consumer properties. Theability to provide predictable benefit through formulation changes has grown with theincreasing knowledge base of soap chemistry and physical structure. For example, theeffect of superfatting on mildness, a property recognized as early as 1939 [10], may wellbe due as much to its ability to alter the bar's phase structure as to its chemical effects.The beauty category eventually became dominated by superfatted soap bars. An earlybeauty bar was also the first popular floating bar, and, over time, this bar's purity claimbecame understood as a statement of mildness and identified the potential for a newcategory of mild bars.

3Mild Bars

While many soap bars have been positioned on a mildness platform, the inherent irritancyof the soap molecule precludes wide variations in mildness between bars for which soapis the primary surfactant. The potential for developing bars with easily demonstrablemildness benefits was made possible by the introduction of bars based on non-soapsurfactants, known as synthetic detergents or syndets. Over the last fifty years, thestandard for mild cleansers has been set by synthetic-detergent-based bars, whichprovide superior skin care benefits as well as distinct sensory cues. In 1948, the firstsynthetic detergent bar was introduced in the United States. Another bar, based on adifferent surfactant system, was launched in Germany around the same time. The leadingbar in the category today utilizes fatty acid isethionate as its principal surfactant. Othersynthetic detergents that have been tried are anionics such as alkylglycerol ethersulfonate (AGES) and monoalkyl phosphates (MAPS). Some bars also contain amphoteric

(betaines) and nonionic detergents (alkyl glucosides), although no widely distributedproduct uses them as the primary surfactant.

As we have seen, the composition and processing of bars have undergone a gradualevolution to make the bars widely affordable, and these bars have properties with appealto a wide range of people that comprise the global market [7]. All technical advances arefundamentally driven by consumer desire for a greater variety of benefits to be deliveredfrom the products they use. One component of their performance that has become

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Fig. 2Although all personal washing products are towards the mild

end on a global scale of irritancy, there are significantdifferences within the category. These differences can bereadily demonstrated by clinical tests and are consumerperceivable. Within this category, soaps are significantlyless mild than isethionate based syndets. Modifications

discussed can move soap towards isethionates andisethionates even further towards mild, but they cannottotally override the inherent properties of the primary

surfactant.

increasingly important over the last half century is mildness to skin. While allcommercially available cleansing bars are basically safe and found acceptable by nearlyall consumers, there are clinically demonstrable and consumer-perceivable differences inmildness among the products. Soap is inherently less mild than isethionate-basedcleansers. This difference can be reduced, but not eliminated by modification of thecomposition (Fig. 2). The mild-bar segment has steadily grown in value attesting toappreciation by consumers, especially women, of the benefits these compositions offer inoverall skin care. Interestingly, it is still newsworthy that consumers are seeking benefitsthat go beyond simple cleansing, especially functional benefit with mildness [11]. Thechanges in available chemistry and processing technology have helped accommodate thisconsumer desire and are the focus of this chapter. This trend is also mirrored in the liquidcleanser category, which is outside the scope of the work.

IIFormulation of Mild Bars

AGeneral Features of Personal Washing Bars

As we have seen, since their mass market introduction in the late 19th century, personalwashing bars are now widely used throughout the world to clean the skin. Theircomposition and processing have undergone a gradual evolution to make them widelyaffordable, and mild bars have properties that appeal to a wide range of people thatcomprise the global market [11]. One component of their performance that has becomeincreasingly important over the last quarter of this century is mildness to skin. The mild

bar segment has steadily grown in value attesting to appreciation by consumers,especially women, of the benefits these compositions offer in overall skin care.

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In this section we highlight some of the key formulation technologies that have beendeveloped for mild bars based primarily on a review of the patent literature. Since thepatent literature on skin-cleansing systems is extensive, we will emphasize developmentsthat are related to mildness and have had wide commercial relevance to bars. Beforemoving to formulation specifics, some general requirements that bar compositions mustsatisfy will be discussed.

1Consumer Expectations

Showering, bathing, and hand washing are very common experiences of everyday life.Toilet bars have two primary functions in these processes: they facilitate the removal ofsoil, and they help make the cleaning process more pleasurable. Soil, in the context ofpersonal hygiene, encompasses a range of materials that include exogenous debris, (i.e.,"dirt"), various body soils, dead skin, and germs. The cleaning function of toilet bars,though often taken for granted, is important in contributing to general health, especiallyin densely populated societies [12].

Personal washing bars must also provide a number of in-use sensory properties orattributes that consumers appreciate and have come to expect. Although the requiredquality of the attribute may vary according to individual and cultural preference, the keyattributes are shown in Table 1. They include lather (amount and texture), fragrance(intensity and note), rinsability, skin feel during and following washing, and bar feel. It isthe combination of these attributes in a given bar composition that defines the overallsensory experience and determines how pleasant the bar will be to use.

Cleansing-bar manufacturers have developed a range of evaluation methods to quantifythe various sensory properties of personal washing bars shown in Table 1. Thesemethods include relatively simple lab screening tests [13], sophisticated instrumentaltechniques [14,15], and quite often, both naive and expert panel evaluations [13,16] tocapture the range of human experience that current machines cannot yet measure. Avariety of test methods is disclosed in the patent literature (see for example References1618), and some of these have been standardized by ASTM (see Reference 18).

Now available to consumers are a variety of bars whose attribute qualities cover a rangeof combinations. A review of bars that have been marketed has been provided recently bySpitz [1].

In addition to their in-use sensory attributes, personal washing bars must also possesscertain physical or material properties that make them suitable for everyday use. ThebarsTABLE 1 Sensory Properties of Personal Washing BarsAttribute QualityBar feel Hard, firm, creamyLather Amount, texture, appearance

Fragrance Note, intensity, substantivityWet-skin feelSqueaky clean, oily, conditonedRinsability Fast, slow, residueDry-skin feel Tight, tingle, soft, smooth, moisturized, conditioned

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should not crack during use, should not easily fracture when dropped, should dry rapidlyafter use, should wear away at a uniform and acceptable rate, and should not formundesirable grit or sand (perceivable insoluble particles) during use. Furthermore, drasticchanges in the composition of the bar during its lifetime should be minimized to ensureconsistent performance. Again, there is a variety of methods available to quantify thesebar properties [19,20]. Judging from the number of patents disclosing formulation andprocess routes to control and optimize these properties, these parameters have been thesubject of considerable research by manufacturers as well as their raw-material suppliers.

2Manufacturing Constraints

The processing of mild bars will be covered in detail in a subsequent section. Here wenote a few general features of bar manufacture that introduce additional constraints onbar compositions.

There is a variety of manufacturing processes by which personal washing bars can bemade. These range from simple melt-casting to milling and multistep extrusionprocesses. Some processes are only suitable for the manufacture of specialty soaps [21],while others are practiced on a very large scale [22]. Many of these processes stem fromsoap making while others have been developed more recently.

Regardless of the exact process employed, the methods for fabrication of all personalwashing bars have three steps in common: (1) the synthesis of the raw materials,especially the surfactant(s) that comprise the bar; (2) the formation of a mixture; and (3)the transformation of the mixture into a solid having the desired shape, hardness, andphysical properties of a bar. These steps are often integrated, especially in high-volumemanufacture.

The ability to efficiently manufacture bars on a large scale places a number of constraintson types of materials that can be used in mild personal-washing bars. The ingredientsmust be capable of forming uniform and stable mixtures or dispersions that solidifyrapidly to form stable cohesive solids that are not too soft or sticky. Furthermore theingredients must have reasonable chemical stability under the conditions experienced inbar making, which in some processes can be severe.

Although numerous ingredients that satisfy the above requirements are available tomanufacturers, many ingredients that potentially can confer desirable properties to mildskin-cleansing compositions do not. To overcome such limitations, a variety of processand bar-forming aids has been developed, for example, internal lubricants, plasticizers,and structurants. Such materials further extend the range of ingredients that can beemployed in the formulation of personal washing bars.

3Mildness

As discussed recently by Rieger [23] the interactions of surfactants with the skin havebeen the subject of considerable study and debate [2329]. Most studies have focused onthe changes that surfactants induce in the stratum corneumthe skin's primary protectivebarrier. It is clear that surfactants can induce structural changes in keratin proteins[25,3032], extract or disrupt lipids [33,34] and natural moisturizing factors [28], andinterfere with the normal desquamation process [34]. These changes to the stratumcorneum degrade its water-holding ability, alter its optical properties, and compromise itsbarrier function. The net result is that harsh surfacants can add to environmental damageand lead to dry, flaky, and rough skin. In addition to biophysical changes in the

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superficial layer of the skin, surfactants can also initiate a cascade of biochemicalresponses that result in irritation. The reactions are complex and involve a variety ofmediators [35].

There is probably no single property that controls the mildness of surfactants towardsskin. However there is growing evidence that surfactants that have a low potential tointeract with and unfold keratin and membrane proteins tend to be mild [28,32,36,37].Protein/surfactant interactions are thought to be strongest for charged surfactants(particularly anionics with compact head groups) and are cooperative in nature[27,32,3638]. Thus milder surfactants tend to have large, highly diffuse polar headgroups and are more nonionic in character [27,28,32].

There are two broad and quite general approaches to the formulation of mild cleansingsystems: (1) selection of surfactants that are intrinsically mild, e.g., those with largehighly diffuse polar head groups and (2) the use of coactives or additives to moderate theinteractions of harsher surfactants with the skin. The use of additives, especiallycosurfactants, is not just a dilution effect. For example, it is known that cooperativeproteinsurfactant interactions are modulated by monomer activity [25,3639]. Surfactantblends can minimize the monomer activity of the most protein-interactive species throughmixed micelle formation [36,37].

BFormulation of Mild Bars

A large number of surfactants and surfactant mixtures that have been disclosed in the artare purported to be mild to skin. However, only a subset of these compositions has beendisclosed as suitable for the formulation of mild personal washing bars. The number ofthese disclosed compositions that have actually been exploited on a significantcommercial scale is still smaller.

Two broad approaches have been taken in the formulation of mild bars. The first is toemploy common fatty acid soap as the primary active ingredient and increase mildnessthrough formulation with additives and various cosurfactants. The second approach is toemploy milder nonsoap surfactants as the primary active. These approaches arediscussed below.

Regardless of which approach is taken, the bar formulation must be optimized to achieveacceptable sensory properties, efficient manufacture on an adequate scale, and mildnessto the skin. Thus, the challenge for the formulator and process engineer is to isolatecompositions and process parameters within the window depicted in Fig. 3.

1Soap-Based Bars

The phase behavior of soap is ideally suited to its use in personal washing bars. Its Krafft

point at high water dilution can be manipulated so that it readily dissolves at normalwashing temperatures [40,41]. Furthermore, soap forms a number of liquid-crystalphases at low water content that allow it to flow under high shear [40,41]. Thesecoexistent liquid-crystal phases thus act as both plasticizer and binder. This is theunderlying reason why bars consisting of essentially pure soap can be readilymanufactured on a large scale. These physical properties, coupled with favorableeconomics and availability, have made soap by far the most widely used surfactant forthe formulation of personal washing bars. However, depending on chain lengths, soapscan be quite harsh to the skin. A number of routes have been disclosed to improve themildness of soap-based compositions. These

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Fig. 3The consumer

properties/manufacturing/mildnessbalance.

include chain length optimization, addition of fatty acid, use of polymeric and otheradditives, and coactives. These approaches are illustrated below.

It is well known that the irritation potential of soap depends on its chain length andreaches a maximum at about C12 [28,42]. Longer chain soaps, especially those formedfrom saturated fatty acids, are significantly milder to skin. However, these longer chainsoaps are much less water soluble (too high a Krafft temperature), do not lather well[13], and thus form bars with poor in-use properties.

Moroney et al. disclose specific blends of short- and long-chain saturated and unsaturatedsoaps having a mixture of potassium and sodium counterions. Bars made from thesecompositions are purported to have a good balance between high lather and improvedmildness [43].

A different approach was taken by Fromont who utilized a triethanolamine-neutralizedsalt of stearic acid in combination with a mixture of sodium soaps. The mixture wasadjusted to a near-neutral pH [44]. Sodium soaps would normally precipitate as the acidsoap at this pH. However, the Krafft point of TEA soaps is low, and even longer chainsoaps have adequate solubility to lather well.

It should be recognized that the interaction of alkyl carboxylates with skin is not onlygoverned by their absolute chain length but also by their solubility. This point isillustrated in Fig. 4 where the binding isotherms of triethanolammonium laurate andoleate to stratum corneum are compared with those of several synthetic surfactants.Relative zein solubilization, which gives a measure of mildness [45,46], is also included inthe inset. It is clear that the C18:1 soap interacts strongly with the corneum in this case.Thus there is a limit to mildness/solubility balance that can be achieved with soap.

Reduction of active via dilution with solvent or inert fillers (e.g., starch) has also beenused to reduce the irritation potential of the composition. However, it is often difficult toovercome the inherent irritancy of the surfactant system without affecting desirableconsumer properties. The basic problem is that significant skin/surfactant interactions

already take place to a significant extent at a relatively low concentration in the vicinityof the critical micelle concentration, CMC.

Using a variant of the forearm-wash method, Visscher et al. demonstrated a small butdetectable benefit on dryness reduction due to the addition of an unspecified

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Fig. 4Binding of several surfactants to human stratum corneum after1 minute contact time at 25ºC. Inset is zein protein solubilization

(1 hr, 40 mM, 25ºC). SDS = sodium dodecyl sulfate,SLI = sodium lauroyl isethionate.

amount of fatty acid to plain soap bars [4749]. The underlying basis for this observationwas presented in a series of experiments by Murahata and Aronson, who showed that theeffect can be explained by the formation of insoluble "acid soap" related to a decrease inpH [50].

There are, however, limitations to this approach. The incorporation of small amounts offatty acid, i.e., "superfatting," up to about 510%, is a well-known way to boost lather andimprove in-use properties [13]. However addition of higher levels of fatty acid, theequivalent of a reduction in pH to below about 8.5, leads to a rapid reduction in latheringability. The surfactant properties of long-chain acid soaps are limited because of theirinsolubility. Furthermore, free fatty acids, especially long-chain variants such as stearicand palmitic acids, are effective antifoam materials as discussed by Aronson [51].

The incorporation of synthetic detergents has been explored by several groups as a routeto enhance the mildness of soap-based formulations. These actives include anionic,nonionic, and amphoteric surfactants. Combinations of soap with nonionic surfactants ofthe alcohol ethoxylate type are disclosed by Chambers et al. [52] and others [53,54].Homologs having relatively long ethoxylate chain lengths are often employed since theseare quite mild to the skin andimportantlyexist as solids at ambient temperatures.Soap/alcohol ethoxylate blends have also been used to make translucent bars [55]. Othernonionic surfactants that have been used with soap include fatty acid sorbitan esters,ethoxylated sorbitan esters, and alkanolamides [56,57].

Various compositions containing synthetic anionic surfactants with soap have beendisclosed. These include alkyl sulfates [58,59], alkyl glycerylether sulfonates [60], acylisethionates [61], fatty amidoethanolamide sulfosuccinates [62], and alkyl citrates [63].Another class of compounds that has been studied extensively as mildness enhancers iscationic polymers. Goddard and his coworkers [64] observed that modified cellulose

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ethers having a low level of hydrophobic substitution interact strongly with anionicsurfactants. This complexation can dramatically alter the solution and surface propertiesof the anionic surfactant. Goddard also recognized that these polymers also appeared toreduce the interaction of both a synthetic anionic surfactant, for example, sodium dodecylsulfate and fatty acid soaps [65], with the skin.

Since these early observations, a variety of modified natural polymers and syntheticcationic polymers has been investigated in soap bars as mildness enhancers [66,67]. Thiswork has also been extended to bars based on synthetic surfactants (see below). One ofthe properties of water-soluble high-molecular-weight polymers that can limit theireffectiveness in personal washing bar formulations is their often slow dissolution rate.Polymers often form a tacky gel phase that retards water uptake and complete hydration.This is obviously not desirable for bar formulations since the mildness enhancement isbased on complexation between the polymer and surfactant molecules. Medcalf et al.[68] discovered that this problem could be overcome by prehydrating the polymer withwater before incorporation into the bar.

Although cationic polymers may alter the skin-feel attributes of soap bars, large effectson clinical mildness have not been observed in several carefully controlled publishedstudies. Strube et al. [69] used a modified soap-chamber test and the flex-washmethodology to compare a bar containing soap, sodium cocoglyceryl ether sulfonate, andpolyquaternium-7 with a bar containing soap and sodium cocoyl isethionate. The irritationproduced by these formulations was not significantly different in the chamber test, andthe soap/cocoyl isethionate formulation was actually judged to be significantly milder inthe flex wash than the cationic polymer-containing bar [69]. Sharko et al. [70] comparedthe same formulations utilizing a less aggressive arm-wash methodology. Again thesoap/cocoyl isethionate composition exhibited significantly less erythema than thepolymer-containing bar and a lower level of barrier damage as measured bytransepidermal water loss.

The mildness exhibited by the soap/cocoyl isethionate formulation used in the clinicalstudies described above is related, in part, to the level of sodium isethionate present inthis composition. Indeed, Caswell et al. [61] discovered that the incorporation of sodiumisethionate at a level of 215 wt% into a soap/synthetic detergent bar provided aconsistent enhancement in the clinical mildness of the formulation.

Another additive that has been reported to provide skin-care benefits in personal washingbars is glycerin. Dahlgren et al. [71] have reported that glycerin incorporated at levels ³10 wt% provided a skin-smoothing effect. The origin of this effect is unclear at thepresent time, since as Dahlgren et al. showed, the amount of glycerin left on the skinfrom a cleansing bar is quite small [71].

Although many soap/syndet/additive bar compositions are known in the art, only two ofthese compositions to date have achieved high commercial impact. These compositions

are given in Table 2. Bar A is positioned on a high-rinsability platform while Bar B ispositioned as a mild deodorant composition. Both bars contain significant levels of mildsynthetic surfactants.

The clinical mildness of these compositions was compared using the arm-wash protocolas specified by Sharko et al. [70]. Expert grading as well as instrumental analysis wereemployed. Between 30 and 40 panelists were employed. The results, collected in Table 3,indicate that Bar B, the soap/acyl isethionate/sodium isethionate bar is a significantlymilder and less drying composition and leads to less barrier damage than

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TABLE 2 Compositions of Soap/Syndet BarsMajor ingredients

BarA

Soap (sodium and magnesium tallowate, cocoate or palm kernel types),sodium cocoglyceryl ether sulfonate, coconut or palm kernel fatty acids,nonionic surfactant, sodium chloride and sulfate, trichlorocarbanilide, water

BarB

Sodium tallowate, sodium cocoyl isethionate, sodium cocoate, water, stearicacid, sodium isethionate, sodium chloride, triclosan, tetrasodium EDTA,disodium phosphate, trisodium etidronate, BHT

TABLE 3 Comparison of Soap/Syndet Bars in the Arm-WashTestA. Wilcoxon matched-pairs test results (products as describedin Table 1)Parameter Ties Za PClinical Assessment

Dryness 17 1.8671 0.0292Erythema 3 4.2513 0.0001

Self-Assessment 0 3.4613 0.0004B. Paired T-Test Results (products are as described in Table 1)Parameter Mean score ± STD DEV t PTEWL Bar Ab 18.19 ± 6.05 4.1180.0003TEWL Bar B 13.19 ± 4.78SKICON Bar Ac 30.11 ± 8.93 1.30 N.S.SKICON Bar B 20.14 ± 9.47a* Bar Ad 8.74 ± 2.00 2.9300.0035a* Bar B 7.92 ± 1.37Ue Bar Ae 21.61 ± 6.44 0.31 N.S.Ue Bar B 21.25 ± 6.64Ur Bar A 14.39 ± 6.37 1.23 N.S.Ur Bar B 13.21 ± 4.02aZ = normal deviate value used to calculate significancebTEWL = transepidermal water loss in g/m2/hr measured using anServomed Evaporimeter Model Ep-1.cSKICON = skin conductance in micromhos measured with an I.B.S.Skicon 200.da* = color balance between red (positive values) and green (negativevalues) using the L*a*b system recommended by the CIE (CommissionInternationale de l'Eclairage). Color measurements obtained with a MinoltaChromameter CR-200.eUe = extension/Ur = recoil. Both measures of elastic properties obtainedwith a Diastron Dermal Torque Meter.

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Bar A. These bars were also evaluated for self-perceived mildness. It is clear from theresults in Table 3 that a higher level of clinical mildness was perceived by the panelists.Self-perceived mildness will be discussed in more detail below.

Several authors have discussed a method to quantify the rinsability of cleansing barcompositions by an assay that measures residual fluorescein left on the skin fromaqueous bar slurries spiked with this probe [21,72]. The validity and relevance of this testmethod are highly questionable. In addition to the rinsing regime being highlyexaggerated, fluorescein does not track anionic surfactants, and its intrinsic interactionwith the skin is highly pH dependent [73].

The connection between mildness and rinsability must be approached with caution,regardless of whether issues exist with a specific test method. The results presented inTable 3 indicate that clinical mildness is not necessarily correlated with a claimed ease ofrinsing, and the two may well be distinct phenomena. A good correlation is expectedbetween mildness and the level of surfactant bound to the relevant proteins of the skin.However, modern mild bars are often formulated with ingredients designed to conditionand moisturize the skin, for example, fatty acids, bath oils, and polymers. Such materialsdeposited in small amounts on the skin may be beneficial to the appearance and textureof the skin and some are claimed to enhance mildness in their own right (see below).

2Synthetic-Detergent-Based Bars

Of the many mild synthetic surfactants that are available, sodium acyl isethionates (SAI)have by far the most commercial significance for mild personal washing bars. They arethe main surfactant used in several major brands in the ''beauty bar" segment. Thesurfactant SAI is made on an industrial scale for bars by the direct esterification of a fattyacid with the sodium salt of 2-hydroxyethane sulfonate [74]. The resulting ester is ideallysuited to bar manufacture and, in part, accounts for the popularity of SAI.

Acyl isethionates have a balance of intrinsic properties that make them very suitable forthe formulation of mild bars. They have good water solubility yet form a hardnonhygroscopic solid. They are relatively high-foaming surfactants yet are much milder tothe skin than soap. The ionization of the sulfonate head group is essentially independentof pH and thus SAIs can be used to formulate bars at neutral pH.

The binding isotherm of sodium lauroyl isethionate (SLI) to human stratum corneum isshown in Fig. 4. As expected, because of its extended polar head group, SLI binds to thekeratin proteins by about a factor of 23 less strongly than either SDS or laurate soap atconcentrations well above the CMC, e.g., 70 mM. Utilizing a competitive binding probe,Mukherjee et al. [75] have shown that because of the weaker interactions of SAI withkeratin proteins, it is not retained on the skin to the same extent as soap after rinsing.Thus SAI has a far lower intrinsic potential to induce structural changes in the stratumcorneum [76] than the corresponding soaps.

Acyl isethionate does not exhibit the same phase behavior as soap when mixed withwater. In particular, it does not have the broad coexistence of liquid crystal and solidphases as does soap [40]. Thus SAI by itself does not possess the suitable thermoplasticproperties that would allow it to be readily formed into bars by extrusion and requires abinder systems. As discussed below in connection with processing, considerable researchhas been undertaken to develop various binder systems for SAI. Not only does the choiceof binder system allow efficient bar manufacture, but it also influences the in-use sensoryproperties of the composition.

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An important binder system for acyl isethionate bars is based on long-chain fatty acidssuch as stearic acid. Such compositions are described, for example, in the seminal work ofGeitz et al. [77]. In addition to serving as a process aid, binder systems based on long-chain fatty acids have several additional functions in the bar. One of these functions isrelated to enhanced mildness. Massaro [49] has shown that mixtures of stearic acid andsodium cocoyl isethionate exhibit significantly lower zein solubilization than theisethionate by itself. This indicates that stearic acid has the potential to enhance theclinical mildness of isethionates, as it does in soap-based systems [47,48], since it is wellknown that zein solubilization correlates with clinical measures of mildness such as theflex wash [45]. In addition to mildness enhancement, long-chain fatty acids also can, ifformulated correctly, improve the sensory properties of the formulation and provide skin-conditioning benefits, i.e., moisturization.

Unlike soaps, acyl isethionates, can be formulated with significant amounts of stearic acid(>> 10%) and still lather quite well [77]. Furthermore the type of lather produced isquite different from that of normal soap, being more creamy in texture. In one of the fewstudies of bar lathering reported in the literature, Mukherjee and Wiedersich have shownthat SAI/stearic acid bars form lathers that have a much smaller bubble-size distributionand different viscoelastic properties than soap bars [14]. These differences were relatedto the lower dynamic surface tensions exhibited by the liquors from the isethionate-basedbar [14]. The creamy lather of these beauty-bar compositions is highly appreciated byconsumers and no doubt contributes to their success in the marketplace.

Stearate creams are widely used vehicles for cosmetic and pharmaceutical skin-carepreparations [78]. It is therefore not surprising that cleansing-bar formulationsincorporating stearic acid and related ingredients in the correct form could provide amoisturizing effect to the skin. Ananthapadmanabhan et al. [79] have measured theamount of stearic acid deposited on the skin from an SAI/stearate-based moisturizing bar.Although the level deposited is small in absolute value, it is significant relative to theamount of stearic acid present in the barrier lipids of the stratum corneum [28,33] andcritical to its normal function.

There are a several routes that can be taken to further improve the mildness of acylisethionates. Many of these are quite similar to those discussed above in connection withsoap-based formulations. We have already mentioned the incorporation of fatty acids.Rys et al. showed that the mildness of isethionate compositions can be increased bylimiting the level of soap and C14 and shorter chain-length isethionates, and by employingspecific coactives [80]. The effect of coactives was further studied by Rys-Cicciari et al.[81]. They disclosed bar compositions based on a ternary mixture of betaines (e.g.,cocamidopropyl betaine), amido sulfosuccinates (e.g., disodium cocamido MEA-sulfosuccinate), and acyl isethionate (cocoyl isethionate) that have improved mildness tothe skin. By carefully considering all the ingredients in the formulation it was possiblewith this ternary system to achieve a significant improvement in clinical and consumer-

perceivable mildness without compromising the desirable sensory properties of the bar.

Although acyl isethionates are the most widely used surfactants to formulate mild bars, anumber of other surfactants and their combinations have been disclosed in the art. Theseinclude alkyl glyceryl ether sulfonates (commonly known as AGES [82]), acyl sarcosinates[8083], olefin sulfonates [84], acyl taurates [66,85], alkane sulfonates [86],

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alcohol ethoxy glyceryl sulfonates [86], alkyl ethoxy sulfates [84], and long-chain alkylsulfates [87].

Polymers, especially the cationic polymers discussed above in connection with soap bars[66,67] and widely used in cosmetic products, have been reported to be usefulcomponents of ultramild bars. Small et al. [66] utilized cationic cellulosic, cationic guar,and several synthetic cationic polymers, e.g., poly(dimethyldiallyl) ammonium chloride(cf. polyquaternium 22), as "skin-feel and skin-mildness aids." These workers found thatthe selected polymers in combination with soap, a moisturizer, and specific syntheticsurfactants yield compositions that were as mild or milder than water in the exaggeratedmildness tests employed.

Jorden et al. [67] make the distinction between mildness-enhancing polymers and "lowslipperiness polymeric skin-feel aids." According to these workers, effective polymericmildness-enhancing polymers have the ability to complex with anionic surfactants. Thiscomplexation can in turn alter the interaction of the surfactant with substrates such asskin. This argument was used previously by Goddard and coworkers [64] to explain thesorption behavior of sodium dodecyl sulfate in the presence of a cationic modifiedcellulose. In contrast, skin-feel modifiers have a high charge density and interact directlywith the skin surface to alter its rinsing characteristics. Jorden et al. report thatcombinations of these two types of polymers provided a dual benefit [67]. It remains tobe seen whether polymers of this type will actually provide the level of clinical andsensory benefits required to be successful in the marketplace.

CSensory Signals and Skin Mildness

We have seen that a number of test methodologies has been used to demonstrate theskin-interaction properties of mild products. In many of these tests, the subject's skincondition is monitored subsequent to a period of exaggerated use. Exaggerated use isgenerally required to elicit a significant and observable response from the skin so thatdifferences in response between products can be either scored visually or quantifiedinstrumentally. While testing of this type is widely recognized for its contribution to thesupport of advertising and patent claims, the relevance of these tests to consumerperception has not always been appreciated. A recent study has tested a wide variety ofcleansing bars by several different test methods [88,89].

Celleno et al. [89] used the soap-chamber test recommended by Frosch and Kligman [42]to test a series of cleansing bars. All products caused significant skin responses, and itwas possible to rank the products in terms of irritancy and to divide the products intoseveral groups. The ranking obtained from the soap-chamber test agreed with theranking yielded by a flex-wash test.

In addition to the exaggerated-use tests, Celleno performed a test in which subjects wereasked to wash their faces at home, twice a day and in a normal fashion [88]. Subjects

kept a log in which they recorded the incidence of either positive signals (hydration,softness, smoothness) or negative signals (dryness, tension, roughness). By this meansthe frequency of various sensory signals following a normal wash could be compared tothe irritation potential predicted by an exaggerated test. The results of this test made itclear that those products that were ranked with a relatively low irritation potential in theexaggerated tests were also more likely to elicit positive sensory signals and unlikely toelicit negative sensory signals.

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IIIModern Process Engineering of Cleansing Bars

AIntroduction

Soap-making technology, gradually emerging from a craftman's art and a bit of "blackmagic," has only recently evolved into a science based on chemical engineering principlesand practice. Much of this evolution has been driven by market demands for superiorproducts that do more than simply lather and clean. Having the capability for inventingbars with an ever-increasing complexity in formulation, the industry is faced with theproblem of producing such products in a technically practical manner. In order to achievemildness or other valuable properties, the bars may contain materials other than soap(such as emollients, moisturizers, antimicrobial agents, etc.), all of which disturb therheological behavior of the bar formula during the final finishing step. Indeed, the mostsophisticated products in the marketplace are the so-called "syndets," based not on soapbut on synthetic surfactants, which do not generally exhibit the rather civilized processingbehavior of soap.

That the soap production process is so well refined is a result of long years of experiencerather than an intimate understanding of the material properties of soap. In fact, it hasonly rather recently been understood that soap has a complex physical microstructureconsisting of domains of solid, liquid, and liquid-crystalline phases. This structurefacilitates the extrusion and molding of soap into its ultimate, familiar form. The finalmicrostructure is established both by the judicious blending of the fats and oils fromwhich the bar is made as well as by carefully controlled processing. A successfulexecution of the soap-production process delivers to the consumer a bar of desirable userproperties, such as a voluminous and creamy lather, low degree of water uptake, goodwear rate, etc.

The addition of synthetic surfactants to the formulations of cleansing bars is responsiblefor many of the recent technological advances in the field, without which the processengineering of cleansing products would be a rather staid and boring activity. Mostsurfactants are easily dispersed or dissolved in a liquid form, much simpler for the processengineer to produce. However, most people, especially in the United States, have grownup with the habit of using a cleansing bar, and old washing habits die hard. Despiterecent market penetration by shower and bath liquids, bars continue on a global basis tobe the predominant form for cleansing in the bath and shower. Thus, the need to improveprocess technology continues.

BSoap Manufacture and Processing

In this section, we will review the basics of soap making, illustrating the processes

employed to produce several different types of soap. We start with the so-called "hardsoaps," followed by superfatted soaps, transparent soaps, and finally aerated or floatingsoaps.

1Hard Soaps

The most common type of soap, hard soap, is produced from a blend of fats and oils.Typically the starting material is a blend of a higher molecular weight fat, most oftentallow-based, with lower molecular weight oil, most often coconut. Many other fats andoils can be used, and it is not unusual to find palm oil substituted for tallow, and palm

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kernel oil substituted for coconut. The object of blending dissimilar oils is to achieve theproper balance of structural and consumer properties. The higher molecular weight fatsprovide structural components that ensure firmness and plasticity of the bar. Lowermolecular weight oils provide lather and cleaning power.

In practice, the ratio of tallow to coconut oil is generally set at about 4:1. Ratios withhigher coconut oil content are sometimes used for the sake of voluminous lather, butthere is an attendant loss of mildness as well as a cost upcharge, since coconut oil hashistorically been a more costly material than tallow. Processability is also impacted, sincethe high-coconut-oil containing bars will tend to be sticky and more difficult to finish.

A review of formulations from around the globe will disclose many exotic substitutes foreither tallow or coconut oil, such as fish oil. Many indigenous vegetable oils are alsosubstituted, a practice prevalent in third world countries in which high import penaltiesprovide incentive to maximize use of locally grown materials. Odor and color, as well asgeneral processability often suffer, but soaps of remarkably high quality can often bemade from blends of poor quality oils, helped by the ingenuity of the local engineers andformulators.

The basic batch kettle saponification process, developed in the 19th century, is stillcommonly used. In this process, a solution of caustic soda is dosed into the oil blend in asteel kettle. The triglycerides are split and neutralized, yielding soap and glycerin. Mixingand heating are supplied by open steam coils. The mixture is boiled for several hoursuntil the reaction is complete. Salt is then added to aid separation of the glycerin, whichis a by-product of the triglyceride splitting. The crude glycerin is then drawn off from thebottom. The remaining crude soap is then treated with additional caustic in a so-calledwashing process to neutralize any residual fatty acids and to help with the dissolution andremoval of residual glycerin and other unsaponifiable materials. Additional water and saltare added to the contents of the kettle which, upon settling, separates into three layers.The uppermost layer is pure, neat soap; the middle layer consists of both soap andimpurities; and the lowest is an alkaline solution. The soap is then pumped off from thekettle. Generally, the batch process as described takes one week to complete.

Many more modern continuous saponification processes have been developed to achievethe same result using continuous high-energy in-line jet saponification reactors,continuous countercurrent washing columns, and centrifuges for the final separation. Inthese processes pure soap will be delivered within a few hours of the startup of the plant.

The modern process generally recognized to be the most effective is the fatty acidprocess. In this, the splitting and neutralization reactions of the fats and oils are carriedout separately. The fats and oils are split or hydrolyzed in a high-pressure columnoperated at a temperature of about 500ºF, and at a pressure of 700 psig, necessary tomaintain the mixture in a liquid state. The process is catalyzed by the use of metallicoxide catalysts and can be operated as either a batch or continuous process. Next the

glycerin is separated from the fatty acid and recovered. This is followed by fractionaldistillation to purify the fatty acids, as well as to separate specific 'cuts' of fatty acids forspecialized uses prior to further processing. Crystallization, such as in the Emersol process[90] can also be used to separate high molecular weight fatty acids from lower weightmaterials. Suitable blends of fatty acids can then be used for soap making by the additionof alkali in a suitable mixing device, such as a crutcher, or for the manufacture ofnumerous other derivatives, including synthetic detergents.

The final purified neat soap is a thick paste consisting of about 34% water. Preserva-

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tives and other additives are dosed to the neat soap either continuously by calibrateddosing pumps, or in a batch mixer such as a crutcher, and the neat soap is then dried.Generally, continuous vacuum dryers are used, although continuous-belt tunnel dryers ordrum dryers can also be used. The final soap chip contains about 10% water. Subsequentto drying, additional additives, such as colorants, perfume, and antimicrobial agents areblended with the chips in an amalgamator, which can be run either batchwise orcontinuously. Subsequent to mixing of the final ingredients, the material is either milled,or is passed through a refining stage in an extruder wherein the mix attains homogeneity.This soap stock is then 'plodded' via a vacuum extruder into logs, which are cut and thenstamped into the final bar shape.

2Superfatting and Other Performance Additives

Superfatting of the bar, which is generally achieved by the addition of excess fatty acid, iscarried out prior to the drying stage, either by continuously dosing the fatty acid prior tothe dryer, or by mixing in the crutcher. The superfatting process, which greatly enhancesthe lather quality of the bar, is generally used in bars which contain relatively highconcentrations of coconut fatty acids. This combination leads to a relatively sticky anddifficult to handle material when extruded. Careful temperature control of the extrudate isnecessary for superfatted soap. Cooling tunnels can be used to surface cool the material.Processing aids, such as starch and talc [91] can also be added to the soap stock toharden the material.

Emollients, moisturizers, and other sensory or performance additives can also be addedduring the final mixing stage. It is not uncommon to find glycerin, cocoa butter, lanolin,vitamins, fatty esters, or other additives blended into the final bar in support of"moisturization" claims and other skin benefits. Since these materials are mostly liquids,they have the potential for greatly disrupting the structure of the base material, resultingin a soft and unworkable mixture. Consequently the concentration at which they can beincluded is limited by the base formula's ability to absorb them without unacceptablyraising the proportion of the bar that consists of liquid or liquid-crystalline phases. As aresult, the final concentration of the specialized ingredients is held to generally no morethan 13 % of the final formula.

3Floating Soap

Floating soap was originally conceived and manufactured in the late 19th century. Asoriginally made, the soap was aerated in the crutcher prior to the soap drying stage. Morerecently a continuous process for the manufacture of an aerated bar has been described[92]. In this so-called 'freezer bar' process a soap mixture is first dried, then aerated, andfinally cooled in a single stage in a scraped-wall heat exchanger. The cooled material isthen extruded into plugs, which are then conditioned prior to stamping. Aerated bars can

also be made using a cast or framing process, although it would be expected that themore desirable route would be the extrusion method. Further improvements to thisprocess are described by Tanerai et al. [93], in which sucrose is used to structure theextrudate and eliminate the need for a drying step.

4Transparent Soap

Transparent soaps have been manufactured since the 18th century. The simplesttransparent soaps are manufactured by the standard saponification process. The object ofthe

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transparency process is to avoid the generation of large soap crystals that interfere withlight transmission through the soap mass and cause the mass to become opaque. Onemust add materials that will tend to act as solvents for the soap to interfere withcrystallization. Glycerin is very effective at disrupting the formation of soap crystals. Thus,a common approach to the production of transparent soaps calls for retaining the glycerinin the soap mass rather than separating it. This approach has led to the common term'glycerin soap' in reference to transparent soaps. Other materials, such as rosin, sugars,polyols, and alcohol can be added to help create a noncrystalline gel state. Fromont [44]discovered that the use of triethanolamine as a reactant for the soap in the presence ofexcess triethanolamine as well as glycerin led to a transparent soap. Many discoveriesand improvements followed, particularly as related to user performance, clarity, andpreservation of color [94].

The original processes required a batch process in which bars were cast or framed.However, Jungermann et al. [95] developed a continuous process in which the rawmaterials are continuously mixed and passed into molds that are then passed through acooling tunnel.

CExploitation of Mild Synthetic Surfactants

1Nomenclature

The nomenclature for combinations of soap and synthetic surfactants is not uniform. Thereader will undoubtedly recognize that the market contains a continuum of formulations,designed to meet the manufacturers' desired technical and consumer objectives. Weconsider products consisting primarily of synthetic surfactants as "syndet" bars, evenwhen they contain a small amount of soap. While it may be argued that "syndets" shouldcontain no soap whatsoever, this definition seems too restrictive in view of thepredominance of well-known ''syndet" bars, which contain a low concentration of soap forpurposes of process or lather performance. We will use the term "combar" to describe abar which consists mainly of soap with the addition of some synthetic surfactant.

2Combars

The development of combars dates to World War II when Hoyt [96] disclosed a barformulated with soap and alkyl benzene sulfonate, making use of corn starch as a binder.In 1952, a combar based on a blend of soap and primary alcohol sulfate wascommercialized. This blend was effective in reducing calcium soap deposits, but it wasrelatively harsh to the skin. This product evolved over the years to the use of laurethsulfate, a blend of laureth sulfate plus lauryl glyceryl ether sulfonate (LGES), and finallysimply soap and LGES. This lead progressively to a less harsh formulation. Positioning ofthe product to the consumer also evolved as Americans turned to showers, resulting in a

shift in consumer focus from bathtub ring to rinsability in the shower.

More recently, a number of inventions related to the combination of soap and fattyisethionates has been disclosed. Caswell et al. [61] disclosed cleaning compositions withskin protection agents, the object of which is to provide a combar of enhanced mildness.Simion et al. [54] disclosed a process for preparing a combar consisting of soap and anethoxylated surfactant. In this invention neat soap at about 200ºF is blended with anethoxylated alcohol sulfate, to which a cellulose ether or synthetic silica is added toreduce final bar tackiness. This mix is then dried to less than 5% moisture content,

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followed by two milling stages and conventional extrusion and stamping. For the mostpart, the disclosed art suggests that combar bars are generally processed usingconventional means, albeit with some difficulty as evidenced by the use of processingaids in the formulation.

3Syndet Bars

During the late 1940s and early 1950s the use of synthetic detergents became prevalentin fabric and dish cleaning. Synthetic detergents first found a raison d'être in personalcleansing bars as a way to reduce the appearance of bathtub "ring," the unsightly calciumsoap deposits left after the water is drained from the bathtub. The year 1948 saw thefirst market introduction of a bar designed for this purpose. It was a syndet barformulated with cocomonoglyceride sulfate and designed to deliver a clean bath tub aswell as mildness to the skin. The formulators directed much of their early effort to theissue of purity and cost of the synthetic detergent.

In 1955, a patented formula [76] based on the use of sodium cocoyl isethionate wasintroduced. Initially conceived as a response to the bathtub ring phenomena, it becameevident to the marketers and formulators that this formulation satisfied a consumer needfor milder products. This lead to an advertising platform based on mildness andnondrying, which was reinforced by the ingredient claim, "1/4 Cold Cream." The claimwas eventually changed to "1/4 Moisturizing Cream" in response to the decline of coldcream use. A second variant of this basic formula was launched on a platform thatfocused on its sensory aspects. This platform emphasized softness and smoothness of theskin with an advertising campaign based on the sensuality of the bar.

The active for these first isethionate syndets was made via an acyl chloride route, whichleft a high concentration of electrolytes and other unreacted materials in the bar, and wasrelatively costly. The search for a cleaner, lower cost route led to the development of aprocess for directly esterifying a fatty acid with isethionate, to yield a mixture of fattyisethionate and fatty acid [97]. This process known as DEFI (directly esterified fattyisethionate) was followed by further refinements of the process and modifications of thebasic chemistry of the reaction.

Unlike soap, which enjoys a physical structure enabling it to be easily extruded andstamped, most synthetic surfactants lack the plasticity requisite for processing in thismanner. A key element of syndet bar formulations is the incorporation of fatty extendersthat can bind the synthetic detergent and provide plasticity during the molding process.Even though bars containing these extenders may be fairly soft when stamped, they oftenharden as they cool and become conditioned. Soap and fatty acid are commonly used asfatty extenders for this purpose. Other materials that have been used include fattyalcohol or other waxy materials, such as paraffins. Fillers such as starch and dextrin [98]are used to structure the bar, as well as to improve user performance. The use of high-

molecular-weight surfactants to help structure the bars has also been disclosed [80].

Redd et al. [99], disclosed two mixing processes. In the first, the synthetic surfactant,which in this instance is alkyl glyceryl sulfonate, is added to a crutcher at 150ºF alongwith water and electrolyte. Fatty acid and a neutralizer solution of Mg(OH)2 are thenadded to form soap. At this point, additional cosurfactant and various structurants areadded to the crutcher and the mixing process continues at about 185ºF for another 20 to40 minutes. Finally, an excess of fatty acid is added and the mixing is continued foranother 10 minutes. Subsequent to crutching, the mix is dried and cooled using a flash

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chamber and chilled to final temperature using either a chill roll or belt. The flakes thusmade are then processed in a conventional manner to manufacture the final bar. Thealternative method disclosed calls for the use of MgCl2 as an ion-exchange agent for themaking of the soap.

For some formulations, the material remains soft and sticky even when cooled. For theseit is desirable to condition the extrudates prior to stamping. Conventional cooling of thedie members is also widely employed. Another approach to the issue of bar formation isthe elimination of the extrusion and stamping process entirely. Processes in which thefinished bars are framed or cast are common and harken back to the early days of soapmaking.

IVConclusion

As we have seen, significant progress has been made in the last few decades to bringscience and technology to the "art" of manufacturing personal washing bars. Theseadvances have helped satisfy the consumer driven need for increased mildness anddelivery of subsidiary benefits, while maintaining the other sensory properties demandedby an increasingly sophisticated consumer. The desire for skin mildness is apparent in allmarkets ranging from those currently dominated by soap based products to those inwhich significant inroads have been made by combar and syndet technologies. Recentadvances in the understanding of surfactant/skin interactions, surfactant chemistry, andprocess engineering have resulted in further market dislocations, which may be theharbinger of even better products to come. This rapid progress is even more remarkablewhen the inherent constraints imposed by the final form, a bar, are taken intoconsideration. There remain many opportunities for improving personal washing barsutilizing emerging technologies in the various global markets. The consumer will be theultimate judge and beneficiary of the success of these efforts.

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15Topical Antibacterial Wash ProductsBoyce M. Morrison, JR. and Diana D. ScalaSkin Clinical Investigations, Colgate-Palmolive Company, Piscataway, New Jersey

George E. FischlerAnalytical Sciences/Microbiology, Colgate-Palmolive Company, Piscataway, New Jersey

I. Introduction to Antibacterial Wash Products 331

II. Regulatory and Safety Issues 334

A. History of FDA Guidelines 334

B. Antibacterial Ingredients 336

III. Antibacterial Efficacy Testing 337

A. In Vitro Methodology 337

B. In Vivo Methodology 342

IV. Surfactants in Antibacterial Cleansers 349

A. Mildness of Antibacterial Cleansing Systems 350

B. Liquid Cleansing Products 351

C. Bar Cleansing Products 351

D. Other Cleansers 351

V. Summary 353

References 353

IIntroduction to Antibacterial Wash Products

Antibacterial wash products, i.e., soaps, have been developed with the dual purpose ofreducing bacterial flora on the skin as well as cleansing the skin. These products areclassified as over-the-counter (OTC) drugs by the Food and Drug Administration (FDA).Drugs have been defined by the FDA as "articles intended for use in the diagnosis, cure,mitigation, treatment, or prevention of disease in man . . . and articles (other than food)intended to affect the structure or any function of the body of man . . . " [1]. Theseantibacterial wash products are designed for use on the hands and on the rest of the

body.

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Antibacterial soaps are marketed in two forms: liquids and bars. There are alsoantibacterial creams and towelettes, but these represent only a small fraction of productsin this category. As of September 1995, antibacterial liquid soaps had a 63% volumeshare of the U.S. liquid soap market and represent total Food/Drug/Mass Combined salesof over $173,000,000 [2]. Similarly, antibacterial bar soaps have a 48% volume share ofthe U.S. bar-soap market on total Food/Drug/Mass Combined sales of over $693,000,000[3].

Bar soaps containing an active ingredient such as triclocarban or triclosan were originallydeveloped and sold as deodorant soaps but more recently have been marketed for theirantibacterial benefits. According to Schubert [4], antibacterial/deodorant soaps havebeen around since the turn of the century. More recently, all of the major U.S. soapcompaniesColgate-Palmolive, Dial, Procter & Gamble, and Lever Brothershave marketedantibacterial/deodorant soap bars. These bar soaps have been designed to be effectiveagainst odor-causing bacteria, an effect which results in a reduction of body odor. Most ofthe antibacterial bar soaps use triclocarban as the bacteriostat. An exception is Lever2000, which is marketed by Lever Brothers Company1 and uses triclosan as its activeingredient. Table 1 lists the leading U.S. brands of antibacterial/deodorant bar soaps.

The primary purpose of liquid antibacterial handsoaps is the degerming of the hands toprovide both immediate removal of bacteria and effective protection against the regrowthof microorganisms. These liquid soaps are designed for either consumer use or forspecialized use such as by health-care personnel. The first liquid soaps were introduced inthe 1940s [5]. These formulations were based on potassium soaps and were positionedfor the industrial market. More recently, liquid soaps have been formulated as detergent-based systems. Some of the surfactants used in today's liquid soaps are mentioned laterin this chapter (Sec. IV.B.). It was not until the late 1970s that Minnetonka, Inc.introduced a liquid soap for the mass market under the trademark Softsoap.2 Softsoapwas the leader in the liquid soap category for 10 years until Liquid Dial was introduced.3Liquid Dial was an antibacterial version of a mild liquid cleanser, with triclosan as theactive ingredient. The Colgate-Palmolive Company purchased Softsoap from Minnetonkaand developed a product called Softsoap Antibacterial Moisturizing Soap in 1989 tocompete with the Liquid Dial product. The active ingredient in this product was para-chloro-meta-xylenol (PCMX). A few years later triclosan replaced PCMX in Softsoap.Today, virtually all of the liquid soaps in the mass market, including those from Colgate-Palmolive, Dial, Procter & Gamble, Lever Brothers, and Jergens use triclosan as the activeingredient. Table 2 lists the leading U.S. brands of antibacterial liquid soaps.

This chapter discusses (1) the U.S. regulation of antibacterial wash products; (2) the invitro and in vivo efficacy testing of those products; and (3) the use of surfactants inantibacterial wash products.

1 Lever 2000 is a registered trademark of Conopco, Inc.2 Softsoap is a registered trademark of Softsoap Enterprises Inc.

3 Liquid Dial is a trademark of the Dial Corporation.

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TABLE 1 Leading U.S. Antibacterial/Deodorant Bar SoapsBrand ManufactureaIrish Spring Colgate-Palmolive CompanyPalmolive GoldColgate-Palmolive CompanySafeguard Procter & Gamble CompanyZest Procter & Gamble CompanyDial Dial CorporationSpirit Dial CorporationLever 2000 Lever Brothers CompanyLifebuoy Lever Brothers CompanyaIrish Spring is a registered trademark andPalmolive Gold is a trademark of theColgate-Palmolive Company. Safeguardand Zest are registered trademarks of theProcter & Gamble Company. Dial and Spiritare registered trademarks of the DialCorporation. Lever 2000 and Lifebuoy areregistered trademarks of Conopco, Inc.Source: Ref. 3.

TABLE 2 Leading U.S. Antibacterial Liquid SoapsBrand ManufactureraSoftsoap Colgate-Palmolive CompanyIrish Spring Colgate-Palmolive CompanyLiquid Dial Dial CorporationJergens The Andrew Jergens CompanyLever 2000 Lever Brothers CompanySafeguard Procter & Gamble CompanyClean & Smooth Benckiser Consumer Products, Inc.aSoftsoap is a registered trademark of SoftsoapEnterprises, Inc. Irish Spring is a registered trademarkof the Colgate-Palmolive Company. Liquid Dial is atrademark of Dial Corporation. Jergens is a registeredtrademark of Kao Kabushiki Kaisha. Lever 2000 is aregistered trademark of Conopco, Inc. Safeguard is aregistered trademark of the Procter & GambleCompany. Clean & Smooth is a registered trademark ofJoh. A. Benckiser GMBH.Source: Ref. 2.

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IIRegulatory and Safety Issues

AHistory of FDA Guidelines

The Food and Drug Administration (FDA) has attempted to regulate topical antimicrobial4products for OTC use in a series of tentative final monographs (TFM) that extend overtwenty years. The initial document was published on September 13,1974 [6]. Thisdocument was based on a series of meetings during the previous year of an advisoryreview panel for antimicrobial ingredients. In this document, the FDA listed severalcategories of topical antimicrobial products. These included antimicrobial soap, health-care personnel handwash, patient preoperative skin preparation, skin antiseptic, skin-wound cleanser, skin-wound protectant, and surgical hand soap. The document statedthat "not all antimicrobial products are used for the same purpose nor should therequirements for effectiveness be the same . . . [O]ne of the important conceptsconsidered in the development of definitions is the distinction between the determinationof effectiveness in preventing or combating clinical infection (sepsis) and the reduction ofresident or transient microorganisms on the skin" [6]. Unfortunately this belief has notbeen carried forward to the TFM issued in 1994.

The first OTC Topical Antimicrobial Products TFM was issued on January 6, 1978 [7]. Inthis TFM, the original seven categories and their definitions remained virtually intact. Therationale for the seven separate product categories is detailed in the TFM as follows:"The Commissioner notes that products in the category of 'health-care personnelhandwashes' are intended to serve a different purpose than products in the category'antimicrobial soaps.' 'Health-care personnel handwashes' are intended to be used asoften as 50 to 100 times daily by a single user. They are also intended for use in ahospital setting by health-care personnel who understand the need for almost constantremoval of transient flora to prevent cross-infection between patients. . . . By contrast,antimicrobial soaps are intended to be used by the general public . . . in non-hospitalsettings. . . . The different circumstances of use require different labeling for these twotypes of products" [7]. The 1978 TFM gives a detailed explanation of the differencesbetween antimicrobial soap and health-care personnel handwashes by using thesupporting rationales of labeling clarity and safety concerns. Antimicrobial soap productsdiffer from other antimicrobial products in terms of

their target user group (average consumers versus health-care personnel);their use location (home versus health-care setting); andtheir frequency of application (a few times versus 50 to 100 times per day).

As stated above, one of the accepted preparations is that of an antimicrobial soap, whichwas defined in the 1978 TFM as "a soap containing an active ingredient with both in vivoand in vitro activity against skin microorganisms" [7]. Furthermore, an active ingredient

was defined "as a compound or substance that kills microorganisms or prevents or4 Whereas the scope of this chapter is limited to antibacterial wash products, the FDA uses the term antimicrobial.Antimicrobial is a broader term that not only encompasses bacteria but fungi and other microorganisms as well.

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inhibits their growth and reproduction and contributes to the claimed effects of theproduct in which it is included'' [7].

A TFM was issued on July 22, 1991 for first-aid antiseptic drug products [8]. In thismonograph, the FDA removed three of the product categories: skin antiseptic, skin-woundcleanser, and skin-wound protectant, from the 1978 TFM and placed them in a new TFMfor first-aid products. This left the remaining four categoriesantimicrobial soap, health-care personnel handwashes, surgical scrubs, and patient preoperative skin preparationstobe regulated in a subsequent TFM.

The most recent TFM was issued on June 17, 1994 [9]. As a result of this TFM, the FDAno longer maintains antimicrobial soap as a separate product category. In fact, the 1994TFM states that "[t]he agency sees no reason to continue to include 'antimicrobial soap'as a separate product category. Soap is considered to be a dosage form, and specificdosage forms are not .being included in this monograph unless there is a particular safetyor efficacy reason for doing so. Antimicrobial ingredients may be formulated as soaps forsome of the uses discussed in this document, e.g., handwash; however, the designation'antimicrobial soap' is no longer being proposed for inclusion in the monograph" [9]. Thisis a departure from the approach taken for antimicrobial soaps over the past twentyyears. The most logical of the proposed categories for consumer products is "antiseptichandwash/health-care personnel handwash." This category is proposed as only ahandwash category, and there is no suggestion in the TFM that these products areintended for full-body use. Furthermore, the proposed labeling and efficacy requirementsof this category fail to address any use of these products on the entire body. Finally, thetesting requirements are more suited for a health-care product than for a consumerproduct. It is conceivable that many current products would not meet the more stringentrequirements of a health-care handwash (Table 3) and could no longer be marketed.

As a result of the 1994 TFM, the consumer products industry joined with the Soap andDetergent Association (SDA) and with the Cosmetic, Toiletry, and Fragrance Asso-TABLE 3 Efficacy Criteria for HCPHW* and General Handwash Tests

Method TargetPopulation

Number ofwashes

Efficacy criteria(log10 reduction from baseline after xth

contamination/wash cycle)log red'n x

HCPHW-1994 TFM

Healthprofessionals 10 2

3110

HCPHW-SDA/CTFA

Healthprofessionals 10 1.5

2110

Generalhandwash

Generalpublic 5 1

1.515

*Health Care Personal Hand Wash.Source: Refs. 9 and 10.

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ciation (CTFA) to form a task force to address the 1994 TFM and propose alternativescenarios, where appropriate. This group met with the FDA at a public feedback meetingon March 29, 1995. During this meeting, three new categories were proposed by the taskforce within the context of a healthcare continuum model to bring the total number ofantimicrobial categories to six. The six categories are preoperative skin preparation,surgical scrubs, health-care personnel handwash, food-handler handwash, antimicrobialhandwash, and antimicrobial bodywash. These categories are defined in terms of usepatterns and of the health risks involved. The health-care continuum model states thatthe size of the population that typically uses a product in each of these categories isinversely proportional to the severity of the risk of infection from not using the product.That is, the population that uses surgical scrub products is rather small but the health riskfrom not using these products is large. At the other end of the spectrum, the populationthat uses consumer antimicrobial bodywash products is very large; however, the healthrisk from not using these products is small. This group also submitted comments on the1994 TFM in support of the healthcare continuum model to the FDA in a June 1995 letter[10].

BAntibacterial Ingredients

The 1978 TFM discussed at length some of the active ingredients used in antimicrobialsoaps, including triclocarban and triclosan. Both of these ingredients were classified asCategory III for use in these types of products, which means that the available data wereinsufficient to allow the FDA to categorize the substances as either Category I (generallyrecognized as safe and effective) or Category II (not generally recognized as safe andeffective and would result in misbranding).

The 1978 TFM also raised concerns about the toxic effects that triclosan and itsmetabolities could have in humans and recommended that more studies be performed.The TFM recommended that bar soaps containing triclosan be limited to a concentrationof 1% and that antimicrobial bar soaps containing triclosan have a label warning "Do notuse this product on infants under 6 months of age" [7]. The most recent monographstates that the FDA has been in contact with the manufacturer of triclosan about the needfor additional data in the form of a chronic-exposure study in order for the agency toassess the safety of triclosan when used for the long term [9]. As such triclosan remainsCategory III for safety. However it should be noted that the agency has alreadyconcluded that triclosan (in concentrations up to 1.0%) is safe for short-term use as afirst-aid antiseptic [8]. No mention was made in the 1994 TFM of restricting the use oftriclosan in infants under 6 months of age.

The 1978 TFM also discussed the safety of triclocarban. The TFM stated that "theavailable evidence does not indicate that the use of triclocarban in bar soaps presentsany known hazard to the general public . . . and does not appear to be as toxic ashexachlorophene" [7]. Furthermore, since triclocarban can decompose at elevated

temperatures in aqueous solutions to yield the very toxic chloroanilines, the 1978 TFMstated that soap products containing triclocarban should not be heated and then used onhumans. The upper limit for triclocarban in bar soaps should be 1.5% and thechloroaniline content should be less than 100 ppm [7]. The 1994 TFM reiterated itsstatement on the safety of triclocarban when used for OTC daily topical use at aconcentration of 1.5 percent [9].

Only alcohol (6095%) and povidone-iodine (510%) were classified as Category I for dailytopical use in the 1994 TFM. All other ingredients, including triclosan,

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triclocarban, PCMX, quaternary ammonium compounds, and isopropyl alcohol (7091.3%)were classified as Category III [9]. Some were classified because of safety reasons, somebecause of efficacy reasons, and some because of both.

In addition to establishing the safety of some of these antibacterial ingredients, theirefficacyalone and in formulationsneeds to be established using in vitro and in vivomethods. These efficacy issues are addressed in the next section.

IIIAntibacterial Efficacy Testing

The 1994 TFM has proposed that in vitro and in vivo efficacy testing be performed tocharacterize the effectiveness of antibacterial products [9]. In vitro testing should beperformed on the ingredient, the vehicle, and the finished product. The agency goes on topropose appropriate methodologies including minimum inhibitory concentration (MIC)testing and time-kill studies using large numbers of test organisms. Furthermore in vivotesting should be performed using tests that approximate the use condition of theproduct. In the case of the categories proposed in the 1994 TFM, this test would be theStandard Method for the Evaluation of Health Care Handwash Formulation, ASTM(American Society for Testing and Materials) E 1174-87 [11]. In their comments on theTFM, the SDA and CTFA have indicated that this testing is quite onerous and is costprohibitive. They estimated the in vitro testing could cost as much as $5,000,000 performulation [10] and have proposed alternative testing that is more appropriate andmore suited to each of the six categories. The proposed tests for the antimicrobialhandwash and antimicrobial bodywash categories are similar to tests that are currentlyperformed by consumer product companies. Some of these tests are ASTM standards;others have been proposed as standards. The next sections detail these in vitro and invivo tests.

AIn Vitro Methodology

Basic information about the antibacterial activity or spectrum of a particular chemical isan essential element when formulating antibacterial products. It is also possible that anyparticular compound that gives a positive antibacterial indication in vitro, may not exhibitsignificant activity when formulated into a product and used topically. The activity of anyactive ingredient may be affected by ingredient interaction, solubility, or partitioncoefficient when in contact with the skin. In the past, in vitro testing has been extensivelyused when formulating topical antibacterial products. This over reliance on in vitro datahas been questioned in recent years, and more emphasis has been placed on in vivo andex vivo methods. The results of any in vitro tests must be correlated to actual useconditions and to the specific areas of the body where the products are to be used. It ismore appropriate to utilize in vitro data to determine that an ingredient or product canpotentially be considered antibacterial and to show its range of activity. This should then

be followed by in vivo tests in order to establish the efficacy of the product under actualuse conditions.

The FDA has outlined a series of basic in vitro and in vivo tests to be followed in order toestablish the antibacterial efficacy of either an ingredient or product [6,7,9]. The in vitromethods to be followed include the MIC test and other standard methods such as theKelseySykes method and the phenol coefficient test. The latter two tests are methodsoriginally designed for the testing of disinfectants. Their usefulness in determining theefficacy of topical products is questionable, particularly the phenol coefficient

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method. While these two methods have subsequently been replaced in the 1994 TFM, abrief discussion of them is necessary. In 1994, the FDA replaced the previous in vitrotesting recommendations by a requirement for MIC testing of active ingredient, formulavehicle, and finished formula along with a time-kill test methodology to be performed atseveral points over a period of thirty minutes [9]. Time-kill methods will be described inthis section along with a Zone of Inhibition Diffusion Method and MIC techniques.

1Phenol Coefficient Test

The phenol coefficient test has primarily been utilized for the testing of chemicaldisinfectants [12]. It has long been utilized in this area, but has minimal relevance to thetesting of topical drug products. Detailed discussions of the method can be found in manytexts [12,13] and will not be discussed here. In brief, the activity of an antibacterialingredient or product is directly compared to that of a standard phenol solution against astandard organism, and the ratio of the activity between the phenol and test material iscalculated. In order to compare favorably to phenol in this method, the test material mustbe rapidly bactericidal at use concentration. Many successful antibacterial compoundsused in topical products today are inhibitory in nature and may not act rapidly. In usethey may be substantive to the skin and continue to exert an inhibitory effect over a longperiod of time.

2KelseySykes Method

The KelseySykes method was developed in order to overcome deficiencies recognized inother standard disinfectant methodologies such as the RidealWalker, or ChickMartin tests[14]. These latter methods continued to link the activity of chemical disinfectants tophenol. In their method, Kelsey and Sykes substituted standard dilutions of thedisinfectant to be tested against a range of microorganisms. A brief description of themethod follows.

A range of disinfectant dilutions should be tested, including use concentration anddilutions above and below the recommended use level. Test organisms should includeStaphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, or any others deemednecessary. Use standard American Type Culture Collection (ATCC) strains. Prepareorganisms for testing by growing them over night in standard media and suspending 108cfu/mL in media, serum, or yeast suspension for use as an inoculum (where cfu stands forcolony-forming unit). Add 1 mL of the appropriate bacterial inoculum to 3 mL of eachdilution of disinfectant. After 8 minutes remove one drop of the mixture and transfer toeach of five broth recovery tubes containing appropriate neutralizers. Two minutes later(10 minutes after initial inoculation), reinoculate the disinfectant solutions with anadditional 1 mL of bacterial suspension, and 8 minutes later subculture as before. Repeatthis procedure 2 minutes later, i.e. 20 minutes after initial inoculation. Recovery broth

tubes are incubated at 32°C for 48 hours. A satisfactory result is obtained from a dilutionwhere there is no growth in 40% or more of the total number of tubes after the secondinoculation [15].

The use of this method for determining the antibacterial efficacy of topical products is notideal. The interaction of the bacterial-suspending solution with the active ingredient beingtested limits its usefulness in testing topical products. The semiquantitative nature of theresults also require subjective interpretation, which may not translate to in vivo or in-useclinical efficacy.

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3Minimum Inhibitory Concentration Test

This procedure can be used to supply basic information about an antibacterial compoundunder investigation, i.e. spectrum of activity and useful range of activity. Dilutionsusceptibility methods determine the minimum concentration of an antibacterial agentrequired to inhibit a microorganism, expressed as micrograms per milliliter, or parts permillion. This method can be either agar- or broth-based. Active ingredients are usuallytested at twofold serial dilutions, and the lowest concentration that inhibits visible growthis recorded as the MIC value. It is important to remember that the reported MIC value isnot an absolute value. The true MIC of a compound that supports the growth of anorganism at a concentration of 2µg/mL, but inhibits it at 4µg/mL, is not 4µg/mL but somevalue between the two. One of the major advantages of this methodology is flexibility.Many standard test media may be utilized depending on choice of test organism. Becauseof the relative ease with which this test can be performed, many compounds andorganisms may be screened in a comparatively short period of time. There are numerousdescriptions and variations of the MIC test; the descriptions given here are taken from theNCCLS (National Committee for Clinical Laboratory Standards) approved standard forMethods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically[16].

(a)Agar Dilution Method

In this technique, the antibacterial agent is incorporated into an agar medium with eachplate containing a different concentration of the ingredient. The plates are inoculated onthe surface using a standard inoculum replicator, which can transfer many inocula to eachplate. When testing antibiotic compounds, the agar medium of choice is MuellerHintonagar. This is because of its ability to support a wide variety of aerobic and facultativelyaerobic organisms while containing few antibiotic inhibitors. The actual choice of mediashould be based on its ability to nutritionally support the growth of the test organismwhile minimizing any chemical interference with the test compound. Appropriate dilutionsof the antibacterial agent should be incorporated into molten agar, which has beenallowed to cool to 4648°C, by combining the ingredients and pouring them into petridishes while allowing the mixture to solidify. It is recommended that a standard ratio ofone part antibacterial dilution solution be added to nine parts agar. Prior to use, allow theplates to come to room temperature if they have been refrigerated; this is to ensure thatthe surface of the agar is dry. Variations in inoculum size may substantially affect the MICendpoint. It is therefore necessary to standardize the inoculum concentration as well asaccurately control the inoculum amount. The inoculum should be prepared by selecting 4or 5 colonies from an agar plate or slant and inoculating them into suitable brothmedium. Incubate this suspension until visibly turbid and adjust the density by comparingit to a 0.5 McFarland standard or by spectrophotometric means. For agar-plate

methodology, the NCCLS recommends an inoculum of 12 µL containing approximately 107cfu/mL [16]. This will deliver about 104 organisms/spot inoculation. A viability controlconsisting of a plate without any antibacterial agent should be included. After incubatingthe inoculated plates at the appropriate temperature, one should determine the MIC byfinding the lowest concentration of antibacterial agent that completely inhibits growth.Agar dilution methods have both advantages and disadvantages over broth techniques.The simultaneous testing of many isolates on a single plate is possible, and it is easier todetect contamination than when using broth methods. The preparation of theantibacterial dilutions and agar plates is much more labor

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intensive. This is especially truecompared to broth methodologyif many chemicalcompounds are to be screened.

(b)Broth Dilution Method

Broth dilution tests may use either a macro-dilution method, in which the volume of brothused is > 1.0 mL/tube, or a micro dilution method, which utilizes 0.050.1 mL brothvolumes in microtiter plates. As in agar methodology, MuellerHinton medium is thestandard when testing antibiotics. The actual choice of broth again depends on thecompound being tested. The preparation of the bacterial inoculum is the same as in theagar technique. A final inoculum concentration of 15 × 105 cfu/mL per tube or microtiterwell is recommended. The volume of inoculum to broth can vary as long as it isstandardized throughout testing so that final antibacterial solution dilutions aremaintained, and the resulting organism concentration is kept at the recommended level.A single stock solution of the antibacterial compound is prepared at twice the strength ofthe highest concentration to be tested. This solution is then serially diluted twofold inbroth through a series of 1012 macro- or micro-dilution tubes. Viability controls consistingof broth tubes or wells that do not contain any antibacterial agent should be included.After inoculation the tubes or microtiter plates should be incubated at the appropriatetemperature. The MIC value is determined from the lowest concentration tube or wellwhere microorganism growth is not detected [16].

4Zone of Inhibition Diffusion Method

A method for determining the susceptibility or resistance of bacteria to antibiotics orantibacterial compounds is the agar (disc) diffusion method [17]. Antibacterial agents atdifferent concentrations are applied to a substrate disc, such as paper, or directly onto anagar plate that has been previously seeded with bacteria. The antibacterial agent thendiffuses through the agar medium. This results in a gradually changing gradient of drugconcentration in the agar surrounding the disc. Bacterial growth occurs concurrently withthe diffusion of the antibacterial agent. An area of no growth occurs where theconcentration of the drug is sufficient to inhibit the growth of the microorganisms. Ingeneral the more susceptible the organism, the larger the zone of inhibition. There aremany factors that will influence the outcome of this procedure. For that reason, it shouldbe considered semiquantitative at best.

The position of the edge of the inhibitory zone is usually determined within the first fewhours of incubation. Organisms that have greatly varying growth lag phases, or longgeneration times, may appear to be more susceptible than they are in vivo, because theantibacterial agent will have more time to diffuse before log phase growth begins. Thesize of the zone is also influenced by the rate of diffusion of the drug compound throughthe agar. Different antibacterials will diffuse at different rates. The zone sizes obtained

from testing one ingredient cannot be directly compared to another which diffuses at adifferent rate. When antibacterial ingredients are applied to a disc substrate other thanpaper, e.g. gelatin, the inhibitory zone will also depend on the interaction of the drugwith the disc and its rate of release from the substrate. The incorporation of antibacterialagents into complex formulations, rather than as simple solutions, will further complicatethe interpretation of zone size. The diameter of the zone of inhibition has a linearrelationship to the MIC value of a compound as measured by a dilution technique. Theprocedure currently used in clinical laboratories for determining the susceptibility ofantibiotics and recommended by the FDA and NCCLS is a modification of the KirbyBauerdilution technique [18].

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When the technique is used as a screening method for antibacterial ingredients to beused in topical products, either direct agar inoculation or paper or gelatin discimpregnation can be utilized. As with MIC dilution techniques, the choice of agar mediumshould be based on the ability of the medium to support the growth of the organism,while minimizing chemical interferences. Organisms may be inoculated directly onto thesurface of the agar, or they may be incorporated into a molten agar that is then used tooverlay an already solidified agar plate. In either case the inoculum should bestandardized to contain 5 × 1071 × 108 cfu/mL of a log phase broth culture. Once plateshave been prepared with organisms, no more than 15 minutes should elapse before theantibacterial ingredient is applied either by disc placement or by direct application. Careshould be taken to ensure that there is complete contact of the disc with the agarsurface. The plates can then be inverted and incubated at an appropriate temperature.The diameter of the zone of inhibition can then be read using special calipers or a zonereader. Zone sizes are typically reported as diameter of the zone, rather than as zonefrom the edge of the disc.

5Time-Kill Suspension Test

The use of suspension tests to determine both the kill kinetics and spectrum of activity ofantibacterial formulations is a common practice. It has its origins in the phenol coefficientmethod [12,13] and the KelseySykes tests [14] described previously. A major differencebetween the methodologies is that the KelseySykes methods are essentiallynonquantitative as they measure the capacity of an antibacterial formulation to maintainactivity upon repeated challenge with microorganisms. The time-kill suspensionmethodology can be either quantitative or qualitative in nature. When used for evaluatingantibacterial wash products, the quantitative method is utilized. Valuable information onkilling rate can thereby be assessed. The D-value, the time to kill 90% (1 log10) of thetest organism population, can be determined using this methodology [19]. While there iscurrently no single standardized method for performing this type of test, all the methodscurrently use an appropriate volume and concentration of bacterial inoculum. Thisinoculum is added to the antibacterial formulation at sufficient concentration so thatwhen combined with the test solution, the final organism/test solution concentration issimilar to the use concentration of the formulation. After a predetermined exposureperiod, an aliquot of the mixture is removed to a neutralizing broth or diluent, appropriatedilutions are made, and surviving organisms enumerated on solid media. Due to thesimple nature of the method, many variables or factors can be examined. Severalconcentrations of the antibacterial formulation, various exposure times, and theinteraction of formulation components with the active ingredient are some parametersthat can be measured.

Several detailed time-kill suspension tests are currently in use around the world,particularly in Europe. In the Netherlands, the Dutch Standard Suspension Test, known as

the 5-5-5 Suspension Test Method is used [15]. In this procedure, a washed bacterial cellsuspension with an inoculum concentration of 105 cells/mL is combined with the testmaterial in the presence of an interfering substance, such as serum or albumin, for 5minutes. The mixture is neutralized and plated on solid media to enumerate survivors.The lowest concentration that reduces the organisms by 5 log10 is considered acceptable.The organisms and interfering substance are selected based on the nature of theantibacterial test formulation. Products used in the food, hospital, and veterinaryindustries are tested against organisms that have the most significance in thoseindustries [15].

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In France, the Association Française de Normalisation (AFNOR) has published severaltime-kill suspension methods that are used for determining the suitability of watermiscible, neutralizable antibacterial compounds [20]. The methods differ as to whether ornot interfering substances are used and whether organism recovery and enumeration areperformed by using the standard pour plate methodology or by the membrane filtrationtechnique. In the latter, following the contact period, the test suspension is vacuumfiltered through a bacterial retention membrane filter and rinsed with a suitableneutralizer. The filter is then placed on a solid medium for enumeration of survivingmicroorganisms. The utility of the membrane filter technique is dependent on the specificantibacterial ingredient, as some surface-active agents may be difficult to neutralize inthis manner.

A European suspension test draft standard for hand wash products, prEN 1276, has beenprepared by the European Normalization Technical Committee 216 [21]. The proposedmethodology is expected to be very similar to the AFNOR methods already discussed.

In the United States, the FDA requested, as part of comments to be submitted to the1994 TFM, a proposal for a standard time-kill method to be used to study both thespectrum of activity of antibacterial ingredients and the kill kinetics for them [9]. Inresponse to this request, a proposed method is currently under consideration by theASTM E 35.15 Subcommittee on Antimicrobial Agents. The methodology wouldincorporate many of the standard techniques previously discussed. Standardized organisminocula, based on the end use of the antibacterial formulation, would be used. Contacttimes, as well as neutralizers and media, would be specified [22].

BIn Vivo Methodology

The efficacies of antibacterial wash products have been assessed using a variety ofprocedures. Some are assessed against normal skin microflora while others are assessedagainst exogenously acquired bacteria. In order to assess the efficacy of antibacterialwash products against exogenously acquired bacteria, skin is exposed to representativelaboratory strains of bacteria. This section will describe some of the methods used toexamine the efficacy of antibacterial wash products against normal and exogenouslyacquired microflora.

1Normal Flora

In 1938, Price explained that bacteria found on the skin are comprised of "transient" and"resident" bacteria. He distinguished the transients from the residents by their ease ofremoval and by their ability to survive on or colonize the skin. He described transientbacteria as those which are "loosely attached to the skin and are easily removed viamechanical means such as by washing with soap and water, rubbing the skin againstclothing, etc." These organisms are found on the skin temporarily and usually do not

survive dry skin conditions [23]. Resident skin bacteria, on the other hand, are wellestablished on the skin and are more tenacious and more difficult to eliminate. Wheneverthe resident flora are decreased in number due to scrubbing or by application ofgermicides, the population is usually reestablished, mainly due to multiplication of thebacteria left behind.

In 1974, Noble and Somerville proposed a third type of skin flora"temporary

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residents." Temporary residents are transient microflora that multiply and persist on theskin for short periods [24].

Several methods have been devised to examine the effect of washing the skin on theremoval of normal flora. In addition, some of these methods have been modified todemonstrate the residual efficacy of antibacterial wash products against transientmicroorganisms using artificially contaminated skin.

(a)Hands

The hands are a major route of transmission of bacteria [2533]. Due to the high risk oftransmitting bacteria and disease in the medical profession, much of the scientificliterature in this area originated in the medical and health communities. Some of thesestudies were conducted to determine the effectiveness of hospital products to control thespread of microbes due to continuous patient/health-care professional contact. Thesemethods may find application in evaluating the efficacy of antibacterial wash productsused for personal hygiene.

PriceCade Handwash

Price developed a handwashing method in order to better understand the normal skinflora of the hands [23]. Using his handwash procedure, Price found that when hands werewashed in a basin of sterile water, a large number of bacteria were removed. Withcontinued washing, the number of bacteria recovered from the hands progressivelydecreased until a steady state was reached. This method was later used and modified byCade [34] to examine the antibacterial efficacy of hexachlorophene against transient aswell as resident skin bacteria. The method is summarized here and the reader is referredto Cade's original paper for the details.

Panelists wash their hands in a prescribed and supervised manner for ten consecutivedays. The wash water is collected in basins at specific points, and the number of bacteriain the water is determined. Each wash cycle consists of five consecutive washes. The firstbasin containing the microflora collected during the first wash represents the looselybound microflora as well as some of the residents. The fifth basin, containing themicroflora collected during the fifth wash, represents the more tightly bound residentmicroflora. Bacteria were enumerated using routine serial dilution techniques with aneutralizer in the diluent. Using this method. Cade estimated that a 2% hexachlorophenesoap had a 94% overall degerming action, a 90% reduction against resident flora, and an88% reduction against transient-resident flora [34].

This method was adapted by Williams et al. to evaluate longer term effects (up to sixmonths) of antibacterial soaps on normal skin flora [35]. The study included a one-monthperiod during which the subjects used a placebo soap to establish a baseline, followed byfive consecutive months of exclusive use of the test antibacterial soap. The hands were

sampled at the end of each month using a modification of the Cade procedure [34]. Theyfound that the use of the test antibacterial soaps reduced bacteria on the subjects' handsrelative to the placebo soap at the 2% significance level after one month of use. Efficacyremained relatively constant after two months of usage but the variability increased asthe test progressed. Between two and five months' use of the test antibacterial soaps,the authors continued to observe a decreasing trend in the number of bacteria on thesubjects' hands, but the variability in the results increased [35]. The reason for this wasunclear but may have been related to subject compliance with exclusively using the testsoaps during the five-month test.

Williams et al. identified staphylococci, comprising about 80% of the isolates, as themajor inhabitant of the skin of the hands. Micrococci accounted for 8%, and the

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remainder was comprised of diphtheroids, yeasts, and Gram-negative cocci and bacilli. Atthe end of the five-month antibacterial soap usage period, they did not find a significantchange in the microbial ecology of the hands [35].

Glove Juice Method

In order to simplify bacterial collection from hands, several investigators have used theglove juice method instead of the basin method originally described by Price [23]. Theglove juice method has also been called a "broth rinse method" and a "hygienic handdisinfection method" [3639].

The subject's hand is placed in a large glove or plastic bag containing stripping orsampling fluid. Microorganisms on the hands are removed using sampling fluid containinga neutralizer and some physical action such as massaging the hand in the glove or bag.In the case of multiple samplings, the neutralizer is not added until the last collection soas not to interfere with the antibacterial efficacy of the test product. The hand is removedfrom the glove or bag, and the number of organisms in the sampling fluid is determined.

Other investigators [25,26] have used modifications of this method to study the route ofcross contamination of E. coli and Klebsiella spp. in hospital wards. Salzman et al. [25]sampled the bacteria on the hands of hospital personnel by having them rinse one handin 90 mL of sterile water contained in an 8-inch by 16-inch autoclavable bag. The handwas agitated vigorously for twenty to thirty seconds in the bag and then the other handwas rinsed in the same bag using the same procedure. Casewell and Phillips [26] used amethod wherein the hand was placed inside a sterile extra-large glove. Fifty milliliters ofsterile, quarter-strength Ringer's solution was poured into the glove. The gloved fingerswere then rubbed together for thirty seconds.

Using variations of the glove juice method as described above [25,26], hospital personnelwere identified as potential vectors in the transmission of organisms obtained throughpatient contact. Salzman et al. found that more than half of the sampled hands ofhospital personnel showed coliform (such as E. coli) contamination with 20% carryingantibiotic resistant coliforms on their hands [25]. Casewell and Phillips found that handsof 17% of the staff of an intensive care ward were contaminated with klebsiella. In 36%of the cases, the klebsiellae found on the nurses' hands were probably obtained throughpatient contact since those serotypes matched those of patients in the ward [26].

Sprunt et al. used a similar method to determine the effectiveness of routine handwashing employed by nursery personnel in removing patient-acquired bacteria [40].Nurses and infant-care technicians were asked to use their normal washing procedurewith various test products, as needed, for the specified amount of time. Bacteria from thehands were sampled by having the subjects rinse their hands in 10 mL of Trypticase soybroth5 in a sterile polyethylene bag. Bacteria were collected by clenching and opening thehand five times in the sampling fluid at the bottom of the bag. Aliquots of the samplingfluid were spread onto blood agar plates, and the numbers of bacteria comprising major

morphological types were recorded. They found that the routine quick hand washesemployed by busy aides and nurses are effective in removing patient-acquired organismsregardless of the wash product used.

More recently, McGinley et al. [41] and Leyden et al. [42] have demonstrated that thesubungual spaces of the hand contain large populations of bacteria and that thesebacteria

5 Trypticase is a trademark of BBL-Becton Dickinson Microbiology Systems.

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contribute significantly to the number of bacteria recovered by the glove juice method.They found a 4 log10 reduction in bacteria on hands washed with 4% chlorhexidine or10% povidone-iodine when the subungual region was sealed. However, when thesubungual region was not sealed, they found the same products elicited only a 1 log10bacterial reduction.

The investigators suggested that the glove juice method may be more appropriate forassessing the efficacy of surgical wash products since surgeons' hands are potentiallyinside gloves for long periods of time [41, 42]. Prolonged exposure of the hands insidethe glove may allow the subungual bacteria to find their way into the glove andpotentially to the patient. On the other hand, the efficacy of antibacterial products maybe better examined by other methods or by a modified glove juice method with thesubungual region sealed with cyanoacrylate glue.

Imprint methods. Sprunt et al. [40] also used a finger imprint method to quantify andidentify the types of organisms found on the hands of nurses and infant-care techniciansin nursery wards. Fingers and a part of the palm of the dominant hand were lightlypressed on a 150-mm × 20-mm blood agar plate for a few seconds. As the hand wasremoved, it was rolled forward to allow contact of the tips of the fingers with the agar,They found this method only somewhat suitable compared to a broth rinse method(similar to a glove juice method). In certain cases, when the bacterial load on the handwas heavy, the numbers of organisms transferred onto the plates were too numerous tocount.

Leyden et al. have described a method in which the whole hand is used [43]. Theycollected and compared bacteria from twenty subjects using the glove juice method andfull hand imprint plates. The number of bacteria recovered using the glove juice methodwas expressed as log10 cfu per cm2. The number of bacteria recovered using the full handimprint plate was quantified using image analysis and expressed as pixel gray intensityper cm2. The image analysis pixel intensity values had a significant correlation to log10cfu. Using the full hand imprint method, they demonstrated that washing for thirtyseconds with a plain detergent resulted in a nonsignificant reduction from baseline(21.9%); 1% triclosan or 7.5% povidone-iodine wash preparations producedintermediate reductions of 48.4% and 50.2% respectively; and a 4% chlorhexidinegluconate antibacterial wash product produced the largest reduction (92.6%).

(b)Other Body Sites

Noble and Somerville have previously reviewed methods of sampling various body sites[24]. These include (1) the use of direct contact with agar on Rodac plates, petri dishes,or metal bottle caps; (2) the use of sterile velvet pads, tape stripping, or cotton oralginate swabs; and (3) the use of biopsy methods. The detergent scrub (or cup scrub)and the Thran Spray Gun methods are commonly used sampling techniques [10] and are

discussed in more detail below.

Cup Scrub Method

Williamson et al. optimized the cup scrub method by determining the effect of surfactantcontent and pH of the stripping or sampling fluid on the recovery of normal skin flora[44]. A surfactant is needed in the sampling fluid to help reduce water surface tensionand to help disperse the collected bacteria since bacteria grow in aggregates. Theyinvestigated the use of several nonionic surfactants to disperse bacterial aggregates.They eliminated cationic surfactants since some quaternary ammonium compounds havesignificant antibacterial properties. They also excluded anionic surfactants since mostwere too toxic to the bacteria. Dispersal efficiency was defined as the number of cfusobtained from a dilution of a bacterial suspension treated with the

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surfactant (A) relative to the number of cfu from a bacterial suspension treated with awater control (B). The greater the A/B ratio, the greater the dispersal efficiency. Theyidentified Triton X-1006 as the best nonionic since it had one of the highest dispersalefficiencies and showed the most consistent results. They also found that the number ofbacteria recovered on the skin is dependent on the pH of the sampling fluid. A pH around7.9 provided for maximum recovery.

The cup scrub method as described by Williamson et al. [44] and variations thereof havebeen used to either quantify the normal level of microflora or evaluate the efficacies ofantibacterial products on the forearm [45,46], axilla [47], and forehead [48].

Thran Spray Gun Method

The axilla is an area of special interest to underarm deodorant and antibacterial soapmanufacturers since axillary bacteria have been implicated in causing underarm malodor[49,50]. As a result, antibacterial soaps have been used to reduce the number of odor-causing microflora on the axilla.

In 1983, Theiler et al. reported a novel technique for sampling the axilla [47]. They useda sampling device called the Thran Spray gun. This device used a gentle pressurizedspray of sampling fluid to wash a small section (1.77 cm2) of the axillary vault. Thesampling fluid contacted the skin and was immediately delivered into a sterile collectionreceptable. The skin was in contact for sixty-five seconds with a total of 100 mL ofsampling fluid.

Theiler et al. compared the Thran Spray gun technique to a cup scrub technique [47].They found the Thran Spray gun technique to provide reproducible results and themethod induced less irritation than the more vigorous mechanical scrub method.However, the Thran Spray gun technique extracted five times less bacteria than amechanical scrub technique. This was presumably due to the difference in physicalpressure using the two methods. Due to the gentler action of the Thran Spray gun, onlysurface bacteria were removed. The mechanical scrub technique involved more vigorousaction and resulted in greater removal of surface and embedded bacteria. This finding isimportant and should be kept in mind when comparing the number of bacteria from theskin obtained by different methods.

Using this technique, Theiler et al. demonstrated that an antibacterial/deodorant soapcontaining triclocarban was significantly better (p < 0.025) than a placebo soap ininhibiting the growth of axillary aerobic bacteria [47].

2Exogenously Applied Flora

Handwashing with soap and water has been suggested to reduce the risk of infection-causing bacterial transmission from the hands [27,28,51,52]. Studies determining the

advantages of handwashing with an antibacterial soap over that of a plain soap havebeen contradictory. Some have shown that washing with soap and water [40] is aseffective as washing with antibacterial wash products while others [45,5355] have shownthat the antibacterial soaps are more efficacious than a nonmedicated soap againstbacteria. Differences in results are probably dependent on many factors including theantibacterial agent used, product formulation, the method of assessing efficacy, and theduration of efficacy. Ehrenkranz also pointed out that the number of bacteriacontaminating the hands

6 Triton X-100 is a trademark of Union Carbide Corporation.

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may also be a factor in assessing the advantage of washing with an antibacterial washproduct compared to washing with a nonmedicated or bland soap [56].

Several studies [45,46,54] have demonstrated that an advantage of washing with anantibacterial soap over a plain soap is the residual or persistent efficacy of theantibacterial ingredient deposited on the skin after washing and rinsing. The extent of theresidual efficacy is probably related to the chemical structure of the active ingredient,which influences its percutaneous penetration into the skin as well as its rinsibility. Thesefactors can also influence the duration of efficacy of the product. The following are somemethods that describe the use of exogenously applied bacteria to demonstrate residual orpersistent efficacy of antibacterial soaps.

(a)Health Care Personnel Handwash (HCPHW)

This method was originally designed to determine the reduction of transient bacteria byhand-wash products used by health professionals [7]. Since health professionals come incontact with many patients within a given day, the method tried to simulate this bymeasuring efficacy between several contamination/wash cycles as described below. The1994 TFM states that this method can be used to measure residual or persistent activityof the product by comparing the efficacy after a single contamination/wash cycle to theefficacy after the tenth contamination/wash cycle [9].

Hands that have been prewashed with a plain soap are artificially contaminated with aknown quantity of a laboratory strain of bacteria. The most commonly used organism inthis method is Serratia marcescens [9,11] although E. coli [57] has also been used. Thenumber of organisms on the hands is determined using the glove juice method toestablish a baseline count. Artificial hand contamination is repeated after which the handsare washed with the test product under a prescribed manner (contamination/wash cycle).The contamination/wash cycle is repeated consecutively up to twenty-five times. Thenumber of organisms on the hands after a specified number of contamination/wash cyclesis determined using the glove juice method.

The ASTM has recently issued E 1174-94 as a standard procedure for the HCPHW methodusing ten contamination/wash cycles [58]. Efficacy is measured after the first, third, fifth,seventh, and tenth contamination/wash cycles. In 1994, the FDA recommended that aproduct is efficacious if it met the criteria in Table 3 [9].

Paulson used the ASTM method to compare the efficacy of several hand cleansers usedby foodhandlers [59]. These products included a nonantibacterial lotion soap, anantibacterial lotion soap containing 0.6% para-chloro-meta xylenol (PCMX), and a lotionsoap containing 2.5% PCMX. Although he used only five subjects per product, he foundthat the residual or persistent antibacterial activity of an antibacterial lotion soapcontaining PCMX was greater than that of a nonantibacterial lotion soap. He also showedthat persistent activity increased as the level of PCMX increased from 0.6% to 2.5%. As

the HCPHW method was designed for rinse-off skin cleansing products, the method maynot be as useful for leave-on cleansing products. The efficacy of a leave-on alcoholic gelpreparation (62% ethanol) rubbed onto the hands was determined by Paulson using amodification of this method [59].

The 1995 SDA/CTFA submission to the FDA [10] proposed a variation of the ASTMmethod to measure the efficacy of handwashes for general consumer use (GeneralHandwash Test). Presumably, during the course of a typical day, the general populationdoes not wash their hands as frequently as health professionals. The General Handwash

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Test is conducted in a similar fashion as the HCPHW except that efficacy is determinedafter the first and fifth contamination/wash cycles only. Another difference between theGeneral Handwash Test and the HCPHW is the criterion for efficacy (Table 3).

A variation of the HCPHW method was introduced by Bartzokas et al. in 1983 [57]. Theydescribed a method in which the hands were contaminated by dipping both hands up tothe middle of the palms in a container containing 2 liters of bacterial inoculum. After 2minutes of immersion, the hands were removed and air-dried by rotating the hands andfingers to avoid accumulation of bacteria on a small area. To recover the bacteria,subjects place their hands over a sterile petri dish containing 10 mL of sampling fluid andknead their fingers for a specified time. The number of bacteria recovered in the samplingfluid was enumerated using routine serial dilution techniques.

Bartzokas' results showed that an alcoholic preparation containing 0.5% triclosan wasmore effective than two chlorhexidine products (one alcoholic preparation and the other adetergent preparation) and the control formulations (60% isopropyl alcohol).

(b)Cup Scrub Method

Aly and Maibach described the use of a cup scrub procedure for determining the efficacyof topical antibacterial ingredients in vivo against exogenously applied bacteria [60]. Thismethod was later modified by Finkey et al. [45] for antibacterial soaps. Soap solutionswere applied to the skin several times. Laboratory strains of bacteria were then appliedto the treated sites and occluded with a plastic weigh boat and adhesive surgical dressingfor five hours. After the occlusion period, the bacteria were harvested using a cup scrubtechnique, plated, incubated, and counted. Further modifications were made by ourlaboratory in order to more closely simulate bar-soap use and to be able to compare upto four products simultaneously [46]. This modified method entailed dividing the forearminto two sections and washing each section with a different bar soap rather than a soapsolution. Bacterial application and harvesting were as described above. For a givenorganism, this method was reproducible within and between laboratories. Preliminarystudies have also shown that this method can also be used after a single wash(unpublished data). This method showed that skin washed with a soap bar containingtriclocarban is more effective than placebo washed skin in inhibiting the growth of thetest organism (Fig. 1).

(c)Agar Patch Test

Yackovich et al. have reported an ex vivo technique for evaluating the residualbacteriostatic activity of soaps containing triclocarban [54]. This method was amodification of the method of Eigen et al. [61]. It involves placing agar plates, surfacestreaked with bacteria, against forearms that have been washed with the test soaps for aspecified amount of time. The plates are then removed, incubated, and the number of

surviving bacteria counted. In Eigen's method, the bacteria were within an agar seedlayer and not on the surface. Therefore, in order to achieve activity, the antibacterialingredient had to diffuse into the medium to prevent bacterial growth. Surface-streakingof the bacteria eliminated this problem. Using this method, Yackovich et al. demonstratedthat skin washed with soap containing triclocarban provided significantly better residualantibacterial activity than skin washed with a placebo soap [54]. In another study,Yackovich et al. demonstrated that the agar patch method was also useful for liquidsoaps containing triclosan [62].

(d)Finger/Hand Imprint Methods

Vinson et al. first described the use of the calf-skin halo (disc diffusion) test in 1961 [63].Yackovich et al. modified this test to examine the

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Fig. 1Antibacterial efficacy as represented by log10 bacterial counts

per square centimeter. The efficacy is measured againstS. aureus (ATCC Strain 27217).

(From Ref. 46.)

residual efficacy of antibacterial wash products in vivo. Subjects washed one hand with atriclosan soap while the other hand was washed with a placebo soap. The fingers wereplaced gently on the surface of agar plates surface streaked with the test bacteria. Theplates were incubated overnight, and the area of bacterial clearing was evaluated thenext day [62].

They demonstrated that the efficacy of soaps containing triclocarban was poorly detectedin this test. This was presumably due to the low water solubility and poor diffusibility oftriclocarban in agar. However, this method was better able to detect the efficacy of soapscontaining triclosan [54] since triclosan is more water soluble than triclocarban.

IVSurfactants in Antibacterial Cleansers

The choice of surfactants in antibacterial cleansing products is very important.Formulators must consider several factors in selecting which surfactants to use in theirantibacterial products. These include, but are not limited to, mildness, the solubility ofantibacterial ingredient in liquid formulas, and the compatibility of the surfactant systemwith the antibacterial ingredient.

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AMildness of Antibacterial Cleansing Systems

The mildness of antibacterial cleansing products is very important. Consumers oftenrequire products that are mild and suitable for people with sensitive skin as evidenced bythe increasing number of mild cleansing products in the marketplace. Health professionalsalso seek mild cleansing products. Hospital personnel wash their hands frequently andoften complain of irritated hands [64]. As a result, hospital personnel do not wash theirhands as frequently as they should [65]. It has also been suggested that dermatitic skinharbors more bacteria than does normal skin [51,66]. Therefore, hospital personnel andconsumers in general will be more apt to use a mild antibacterial skin cleansing productthan a harsh one.

Over the years, manufacturers of consumer handwashes and bodywashes haverecognized the need to develop mild and efficacious products. The most commonly usedanionic surfactants in liquid antibacterial cleansing products are the alkyl sulfates, such aslauryl sulfate. Sodium or ammonium salts of lauryl sulfate are relatively harshcomponents of these wash products. However, their harshness can often be moderatedby modifying their structure by adding one or more ethoxyl groups in the carbon chain[67,68]. Nonionic surfactants are very mild to the skin; however, they provide for verypoor foaming of the formulation.

Since the development of mild synthetic surfactants, antibacterial skin cleansing productscan be formulated to be as mild or milder than most ordinary soaps. Morrison and Payehave examined the irritation potential of several liquid skin cleansers using in vitroscreening methods and confirmed their mildness on humans using a soap chamber test[69]. The results of these studies showed that two antibacterial liquid soap formulationscontaining triclosan were milder than a commercially available, mild, nonantibacterialsynthetic detergent bar.

Comparative skin irritation studies have also been conducted in humans. Strube et al.examined the irritation potential of a number of commercial soaps using a flex arm washtest [70]. Included in the test products were three soaps that contained triclocarban ortriclosan. One of the test soaps containing triclocarban induced the same level of meantotal erythema score as two other nonantibacterial bar soaps. The two test antibacterialsoaps containing triclocarban induced statistically more erythema at endpoint than thetest antibacterial soap containing triclosan.

In an exaggerated face wash study, Finkey and Crowe [71] demonstrated that a soapwith an antibacterial ingredient was milder than a plain soap as evidenced by visualobservation of erythema and biophysical measurement of the barrier function of the skin(transepidermal water loss). Thus, exaggerated use tests have demonstrated thatantibacterial wash products can be formulated to be as mild or milder than ordinary skincleansers. The mildness of these products can be manipulated by varying their surfactant

systems (See Chapters 13 and 14).

There has been at least one report of an in-use study that has examined the mildness ofan antibacterial soap on infant skin [72]. This study compared a nonmedicated bar soapwith one that contained 1.5% triclocarban. Both products were tested on 100 infants in ablind cross-over study. Each phase of the study lasted four weeks. The results of thestudy showed that there were no differences in mildness between the two groups.Furthermore there was no evidence of irritation that could be attributed to either soap.

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The authors concluded that both products were equally mild. Thus, it is possible forantibacterial skin cleansers to be as mild as ordinary skin cleansers in normal-use tests.

As was mentioned earlier, manufacturers of personal care products have recognized theneed to develop mild and efficacious products. Antibacterial skin-cleansing products havebeen developed that are as mild or milder than some nonantibacterial products. Thus, theaddition of triclosan or triclocarban, the two most frequently used ingredients, does notnecessarily adversely affect the irritation potential of skin-cleansing products.

BLiquid Cleansing Products

The first antibacterial liquid soap for personal hand-cleansing use was introduced in theUnited States in 1987 [5]. The types of surfactants currently used in liquid antibacterialcleansers are varied. One must be careful in the types of surfactants used in liquidantibacterial cleansing products as they may inactivate the antibacterial agent. Nonionicsurfactants such as polysorbate-80 (Tween 807) are commonly used in liquid cleansersand have been used to neutralize triclosan [42,73]. The ASTM E 1054-91 [74] can beused to determine whether or not nonionic surfactants inactivate the antibacterialingredient.

Examples of surfactants currently used in antibacterial liquid hand-cleansing formulationsinclude alkyl olefin sulfonates, alcohol sulfates and their ethoxylated analogs,monoethanolamine sulfosuccinates, cocamidopropyl betaine, and alkyl glucosides.

CBar Cleansing Products

Most soap bars in the United States containing an antibacterial ingredient are positionedas deodorant soaps. In addition to their deodorant efficacy due to the fragrance, thesesoaps presumably reduce and inhibit the number of axillary bacteria often implicated inmalodor.

Bar cleansing products, including antibacterial soaps, most often use soap as the majoringredient. Combination bars (combars) make up a small segment of the bar-cleansingmarket. In combars, up to 25% of the soap is replaced by a synthetic surfactant. Mostantibacterial/deodorant soaps sold in the United States are true soap bars. Currentlythere is only one antibacterial/deodorant combar in the marketplace. The surfactant usedin this combar is sodium cocoyl isethionate. Alkyl glyceryl ether sulfonates have also beenused in antimicrobial cleansing bars [70].

DOther Cleansers

This section gives examples of other forms of antibacterial skin-cleansing productscurrently present in the marketplace. However, there is less information about these

products than the antibacterial bar and liquid products.

1Gels

Leave-on antibacterial products are generally classified as hand rubs. These productsinclude gels, creams, and lotions and are generally used by people who cannot readily

7 Tween 80 is a trademark of ICI Americas, Inc.

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wash their hands and need quick degerming of the hands. In vivo methods to evaluatethe antibacterial activity of these products are less well known than those for rinse-offproducts. The use of multiple application/bacterial collection as in a HCPHW method maynot be suitable for leave-on products [59]. A single application/bacterial collection maybe more appropriate. Paulson found that a gel sanitizer containing 62% ethanol elicitedmore bacterial reduction than any of the antibacterial soaps tested after a singlecontamination/product application cycle in a HCPHW test. The ASTM is currentlydeveloping a standard method for hand rubs [22].

Some antibacterial gels contain ethanol as the active ingredient. Alcohol has beenrecognized as a Category I ingredient for safety and efficacy as a First Aid Antiseptic DrugProduct [8], as an Antiseptic Handwash or Healthcare Personnel Handwash, as a PatientPreoperative Skin Preparation, and as a Surgical Hand Scrub [9]. However, alcohol-containing products are perceived to be drying to the skin. To mitigate these dryingeffects, antibacterial gel formulations are formulated with emollients.

In 1990, Newman et al. examined the effect of an alcoholic gel preparation afterhandwashing with a soap [75]. The gel preparation contained 60% (w/w) ethyl alcoholwith glycerin and silicone as emollients. Subjects washed their hands ten times a day forfive days with a bar soap. Between washings, one hand was treated with the gel whilethe other hand was untreated. At the end of the study, they found that the gel treatmentmitigated the symptoms of soap-induced dry skin such as cracking and scaling. The gel-treated hands also showed less irritation (erythema) than the untreated hands. As part ofthe HCPHW method, Paulson [59] examined the irritation (erythema, edema, rash,dryness) potential of an alcohol gel sanitizer containing 62% ethanol. He found that thegel did not induce significant irritation over the course of the twenty-five consecutiveapplications. Therefore, it is possible to formulate alcohol containing gel preparationswhich are mild to the skin.

2Towelettes

Towelettes provide a convenient means of cleansing the skin especially when water is notavailable. Richter [76] has a patent on tissues for hand cleansing impregnated withiodophors that reduce bacterial counts on the skin more than Ivory soap and plain soaptissues. The composition of his invention isIngredient Example %Anionic surfactants Sodium methyl cocoyl taurate 26

sodium cocoyl isethionate 5Nonionic surfactants Poloxamer 18Iodine 2.6Sodium iodide 1.5Citric acid 0.2Water and perfume balance

Morita et al. [77] described a composition for a wet tissue to cleanse, deodorize, andsterilize the hands and skin. The tissue is prepared by impregnating a paper or unwoven

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cloth with an aqueous solution containing chitosan salts or quaternized chitosan salts(87% deacylated chitosan lactate, molecular weight 7000). The tissue is claimed to benonirritating and to have long-lasting antibacterial activity.

VSummary

Antibacterial wash products are designed to clean the skin as well as reduce the numberof bacteria on the skin. There are two primary forms of antibacterial wash products thatare available in the market: bars and liquids. These products are typically formulated witheither triclocarban or triclosan as the active antibacterial agent. The efficacy of theseingredients and products has been established by numerous in vitro and in vivo testingmethods. These methods are in the process of becoming industry standards and havebeen submitted to the FDA as part of industry's comments on the 1994 TFM.

Furthermore, today's consumer demands milder products than have been previouslyavailable. Many of the marketed formulations are based on a mild surfactant system thatimparts an added consumer benefit to these products. As milder and more efficaciousantibacterial wash products are developed, it is anticipated that consumers will shift theirpurchase practices from bar and liquid soaps to these value-added wash products.

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30. G. Reybrouck, Journal of Hospital Infection. 8:523 (1986).31. H. W. Hill and H. M. Matthews, Public Health Journal. 17:34752 (1926).

32. D. Gould, J. Adv. Nurs. 16:121625 (1991).

33. M. E. Stiles and A. Z. Sheena, Journal of Food Protection. 50:28995 (1987).

34. A. R. Cade. Evaluation of Soaps and Detergents. Special Technical Publication No.115. ASTM, 1952.

35. J. B. Williams, J. Brown, and E. Jungerman, Industrial Microbiology, vol. 17,Proceedings of the 32nd General Meeting of the Society for Industrial Microbiology, 1975,American Institute of Biological Sciences, Washington, DC. 1976, pp. 185191.

36. R. N. Michaud, M. B. McGrath, and W. A. Goss, J. Clin. Microbiol. 3:40613 (1976).

37. M. Rotter, W. Koller, G. Wewalka, H. P. Werner, G. A. J. Ayliffe, and J. R. Babb, J.Hyg., Camb. 96:2737 (1986).

38. G. A. J. Ayliffe, J. R. Babb, and A. H. Quoraisha, J. Clin. Path. 31:92328 (1978).

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39. M. W. Casewell, M. M. Law, and N. Desai, Journal of Hospital Infection. 12:16375(1988).

40. K. Sprunt, W. Redman, and G. Leidy, Pediatrics. 52:26471 (1973).

41. K. J. McGinley, E. L. Larson, and J. J. Leyden, J. Clin. Microbiol. 26:95053 (1988).

42. J. J. Leyden, K. J. McGinley, S. G. Kates, and K. B. Myung, Epidemiol. 10:45154(1989).

43. J. J. Leyden, K. J. McGinley, M. S. Kaminaer, J. Bakel, S. Nishijima, M. J. Grove, and G.L. Grove, Journal of Hospital Infection. 18(Suppl. B):1322 (1991).

44. P. Williamson and A. M. Kligman, J. Invest. Derm. 45:498503 (1965).

45. M. B. Finkey, N. C. Corbin, L. B. Aust, R. Aly, and H. I. Maibach, J. Soc. Cos. Chem.35:35155 (1984).

46. D. D. Scala, G. E. Fischler, B. M. Morrison, Jr., R. Aly, and H. I. Maibach, AnnualMeeting of the American Academy of Dermatology, Washington, DC, 1994.

47. R. F. Theiler, C. L. Schmit, and J. R. Rogeim, J. Soc. Cos. Chem. 34:35159 (1983).

48. K. J. McGinley, G. F. Webster, and J. J. Leyden, Br. J. Derm. 102:43741 (1980).

49. N. H. Shehadeh and A. M. Kligman, J. Invest. Derm. 40:61 (1963).

50. J. J. Leyden, in Antiperspirants and Deodorants (K. Laden and C. Felger, eds.) MarcelDekker, New York, 1988, pp. 311320.

51. A. C. Steere and G. F. Mallison, Ann Internal Med. 83:68390 (1975).

52. U. M. Kahn, Trans. Royal Soc. Trop. Med. Hyg. 72:16468 (1982).

53. G. A. Ayliffe, J. R. Babb, K. Bridges, H. A. Lilly, E. J. Lowbury, J. Varney, and M. D.Wilkins, J. Hyg., Camb. 75:25974 (1975).

54. P. Yackovich and J. E. Heinze, J. Soc. Cos. Chem. 36:23136 (1985).

55. J. Ojajarvi, J. Hyg., Camb. 85:193203 (1980).

56. N. J. Ehrenkranz, Infect. Control Hosp. Epidemiol. 13:299301 (1992).

57. C. A. Bartzokas, M. F. Gibson, R. Graham, and D. C. Pinder, Journal Hospital Infection4:24555 (1983).

58. American Society for Testing and Materials (ASTM). E 1174-94. Standard Test Methodfor Evaluation of Health Care Personnel Handwash Formulation. Annual Book of ASTMStandards 11.05:478480 (1995).

59. D. S. Paulson, Dairy, Food, and Environmental Sanitation 14:52428 (1994).

60. R. Aly and H. I. Maibach, J. Soc. Cos. Chem. 32:31723 (1981).

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62. F. Yackovich, C. A. Wagner, and J. E. Heinze, J. Soc. Cos. Chem. 40:26571 (1989).

63. L. J. Vinson, E. L. Ambye, A. G. Bennett, W. C. Schneider, and J. J. Travers, J. Pharm.Sci. 50:82730 (1961).

64. J. C. Seitz and J. L. Newman, American Journal of Infection Control 16:46 (1988).

65. E. Larson and M. Killien, American Journal of Infection Control 10:9399 (1982).

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67. L. D. Rhein, C. R. Robbins, K. Fernee, and R. Cantore, J. Soc. Cos. Chem. 37:12539(1986).

68. J. C. Blake-Haskins, D. Scala, L. D. Rhein, and C. R. Robbins, J. Soc. Cos. Chem.37:199210 (1986).

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71. M. B. Finkey and D. M. Crowe, Bioeng. Skin. 4:31121 (1988).

72. V. Kadar and R. A. Osbourn, Current Therapeutic Research 16:45256 (1974).

73. C. A. Bartzokas, J. E. Corkill, and T. Makin, Infect. Control 8:16367 (1987).

74. American Society for Testing and Materials (ASTM). E 1054-91. Standard Practices forEvaluating Inactivators of Antimicrobial Agents Used in Disinfectant, Sanitizer, Antiseptic,or Preserved Products. Annual Book of ASTM Standards 11.05:406407 (1995).

75. J. L. Newman and J. C. Seitz, American Journal of Infection Control 18:194200 (1990).

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16Hair CleansersCharles ReichAdvanced Technology/Hair Care, Colgate-Palmolive Company, Piscataway, New Jersey

I. Introduction 358

II. Surfactants in Shampoos 358

A. Anionics 358

B. Nonionics and Amphoterics 361

C. Cationics 362

III. Hair-Cleaning Mechanism 362

A. The Nature of the Substrate 362

B. Cleaning of Particulate Soil 364

C. Cleaning of Oily Soil 366

IV. Efficacy of Soil Removal by Hair Cleansers 369

A. Cleaning of Sebum 370

B. Cleaning of Quaternium Compounds fromConditioner-Treated Hair 372

C. Cleaning of Cationic Polymers 376

D. Cleaning of Fixative Residues 378

E. Cleaning of Dimethicone Residues 379

F. Conclusions 380

References 381

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IIntroduction

The primary function of a hair cleanser, or shampoo, is to clean the hair: a process thatcan be defined as the removal of unwanted material from the hair substrate. Insofar asthis purpose is common to the cleaning of virtually any substrate, there is much that canbe learned about the cleaning of hair from the results of detergency investigations ingeneral, and those on fabric laundering in particular. Several excellent reviews on thesetopics exist [15].

There are many particulars of the hair-cleaning process, however, that are different fromthose applying to fabrics and other substrates, and these differences must be consideredin choosing and evaluating the efficacy of surfactants for hair cleansers. When cleaninghair

Short cleaning times, on the order of only a few minutes, are employed;

The water temperatures are low, generally 2045°C;

The concentrations of the detergents in shampoos are high, ranging between 820%;

The ingredients in the shampoo must exhibit low toxicity and low skin and eye irritation;

The shampoo must have a sufficiently high viscosity to easily remain in the hand, butmust spread easily over the hair; and

The shampoo must develop a rich, stable lather that rinses easily.

In the following sections, the effects of the above and other parameters on detergentchoice, efficacy, and cleaning mechanism are considered. The first section will brieflysurvey the most common surfactants employed in shampoos today. Following this, thenature of the hair substrate and the different mechanisms for soil removal will bepresented. Finally, the cleaning efficacy of hair cleansers for the most common hair soils,including those deposited by shampoos and styling products, will be presented.

IISurfactants in Shampoos

The primary detergent in early shampoos was soap, mainly the potassium andammonium salts of oleic and coconut fatty acids [6]. These soap formulas performedadequately in soft water, producing a rich, luxurious foam. In hard water, however, theylathered poorly as a result of formation of insoluble Ca2+ and Mg2+ salts that, in addition,precipitated out on the hair, causing dramatic dulling [79]. As a result, soap waseventually replaced as a primary surfactant by synthetic detergents that are far moreresistant to precipitation in hard water.

These synthetic detergents can be classified according to whether or not their hydrophilic

group is charged and also the sign of any charge. Primary detergents in current use arealmost exclusively anionic, with other types of surfactants generally used in a secondarycapacity.

AAnionics

1Alkyl and Alkyl Ether Sulfates

The most common primary detergents used today are the lauryl and lauryl ether (laureth)sulfates. These were introduced into the U.S. market more than fifty years ago [10] andsince that time, the lauryl (ammonium, sodium, triethanolamine, and diethanolamine)

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and laureth (sodium and ammonium) sulfates, have dominated the market. Alone or incombination, these surfactants are the primary detergents in the overwhelming majorityof current shampoos. In the United States, ammonium lauryl sulfate (ALS) is most oftenemployed, while in many other countries, sodium or ammonium laureth sulfates (with anaverage of 2 or 3 moles of ethylene oxide) are preferred [11].

The lauryl sulfates are prepared by sulfation of a mixture of synthetically prepared C12C14fatty alcohols or a mixture of coconut fatty alcohols (approximately 50% C12). Dependingon the manufacturer, then, commercial lauryl and laureth sulfates will contain differentmixes of mostly C12 and C14 surfactants. This is done to improve the foam and surfaceactivity of the species.

The lauryl and laureth sulfates are used so extensively as hair cleansers because theirproperties represent an excellent balance of the often conflicting requirements for anideal shampoo. Thus the solubilities of the commonly used alkyl surfactants, especiallythe ammonium (ALS) and triethanolamine (TEALS) salts, are high, while the solubilities ofthe calcium and magnesium salts are sufficient to eliminate the precipitation problemsoccurring with soap use in hard water.

Addition of ethylene oxide groups to the alkyl surfactants increases solubility, thusreducing the tendency for precipitation and decreased foam volume exhibited by thesesurfactants in the presence of Ca2+ and Mg2+ ions. Use of laureth sulfates is particularlyattractive in hard water areas. Schwuger [12] has discussed the effect of ether groups onthe solubility, surface properties, and detergency of alkyl ether sulfates.

An important attribute for consumer acceptability of a shampoo is a sufficiently highviscosity, usually between 20005000 cp. This range and higher viscosities are easilyattained for alkyl and alkyl ether sulfates through the use of various additives, the mostcommon being alkanol amides and inorganic salts. Lauramide DEA (diethanolamide),cocamide MEA (monoethanolamide), and cocamide DEA are the alkanol amides mostoften used. The major constituent in these species is the amide,

where R is a hydrocarbon chain that, in the case of the lauramides, for example, wouldcontain eleven carbon atoms. The monoethanol amides are generally reported to bemore effective viscosity enhancers than the corresponding diethanol amides [13,14].

The viscosity-building effect of the long-chain amides is a result of the building of orderedstructures between detergent and amide molecules. This effect is aided, in part, by thelinear alkyl chain in the detergent, which lines up easily to form ordered arrangements[10]. Increased structure is also the reason shampoos are thickened by organic salts

[12,15]; this effect is increased in the presence of amides [15].

The development of a rich, copious lather is important to consumers and may be crucialto a product's acceptance. In use, lauryl and laureth sulfate surfactants produce abundantlathers. These lathers are often rather loose, however, and foam quality generallydecreases in the presence of sebum [16]. Most shampoos therefore employcocamidopropyl betaine or one of the above alkanol amides as foam boosters. These

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additives are very effective in stabilizing and modifying the foam of the lauryl and laurethsulfates, changing the lacy structure to one composed of dense small bubbles. Thisprovides a thicker, creamier, lather with a rich, luxurious feel that is very desirable toconsumers [16,17].

The alkanol amides are effective lather modifiers for much the same reason that they areeffective as viscosity enhancers: they form complexes with the surfactant molecules thatmaximize intermolecular attractive forces in the surface film and increase film viscosity[10,18]. Again, this effect is aided, in part, by the linear alkyl chain in the detergent.Another reason for the foam stability of the alkyl and alkyl ether surfactants is theelectrostatic repulsion between the two sides of the foam film caused by the negativecharge on these molecules [19].

Cocamidopropyl betaine works as a lather modifier in the same manner as the alkanolamides; it should therefore not be surprising that it can also be used as a viscosityenhancer.

Minimal irritation is another necessary property for a hair cleanser. Studies on skinirritation of surfactants show that irritation is generally not a problem with the long-chainalkyl sulfates including those commonly used in shampoos, although within this groupirritation is at a maximum for alkyl sulfates with a C12 hydrocarbon chain [2024]. Thisirritation is decreased for laureth sulfate surfactants.

The sulfate group is attached to the lauryl and laureth surfactants through an esterlinkage. These detergents are therefore subject to hydrolysis at low or high pH levels,and as a result, shampoos containing them are generally formulated with pH between 5and 9.

2a-Olefin Sulfonates

The alpha olefin sulfonates (AOS), as a class, rank second behind the alkyl and alkylether sulfates in frequency of use in shampoos. Because of the predominance of the lattertwo surfactants, however, this translates to only limited use in nonpremium shampoos.

The detergent is actually a mix of surfactants that can be represented by the followingstructures:

Commercial surfactants are a mix of C14 and C16 materials, so that R in the abovestructures represents a C10 or C12 hydrocarbon.

The SO3 attachment in a-olefin sulfonates does not involve an ester linkage, so that AOS

exhibits excellent stability at low pH levels where the alkyl and alkyl ether sulfates wouldbe completely hydrolyzed. This surfactant is also less expensive than the latter twosurfactants and is more soluble in hard water than sodium lauryl sulfate (SLS) [25].

Foaming of AOS has been reported to be equal to SLS and SLES (sodium laureth sulfate)under various conditions [26]. Buildup of viscosity can be accomplished with the sametypes of material as with alkyl ether sulfates, including monoalkanol amides and salt[25,27]. Viscosity building with AOS is more difficult than with alkyl sulfates

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[27,28], however, and the detergent has been reported to leave a harsher feel on thehair than the latter surfactants [28].

3Miscellaneous Anionics

A very large number of different anionic detergents are available from manufacturers foruse in shampoos [7,29]. In general these surfactants have one or more shortcomings,such as inadequate foaming or high cost, that prevents their wide use as primarydetergents, although they may find use as secondary surfactants or in specialty products.

Examples of the above are the disodium alkyl sulfosuccinates that produce excellentfoams that, unfortunately, are unstable in the presence of lipids. They can, however, becombined with alkyl sulfates to yield low irritation products with light conditioningproperties and improved lather [30,31].

The linear alkylbenzene sulfonates (LAS) are another class of anionics that have beenemployed in shampoos. This class of surfactants is used extensively in laundry detergentsand is quite inexpensive. The detergent tends to form light, airy foams, however, andleaves a dry feel on the hair [32]; it has therefore found only marginal use as a secondarysurfactant in a very few inexpensive shampoos [33].

Other anionic surfactant classes that have been suggested for use in shampoos are N-acylglutamates, N-acyl methyltaurates, N-acyl sarcosinates, alkyl ether phosphates, andlauroyl isethionates. Because of high expense or poor solubilities, especially in hardwater, these surfactants have found only limited use.

BNonionics and Amphoterics

The detergency of nonionic surfactants is equal to, and in many cases better than, that ofanionic detergents [34,35]. Nevertheless, nonionic detergents have not found use asprimary hair cleansers because of poor foam and poor foam stability. This is probably aresult of the large surface area per molecule and the lack of charge on the surface filmsof these materials [36].

Certain nonionics have found use as cosurfactants in shampoos because they have beenfound to reduce eye irritation without affecting shampoo foam. An example is polysorbate20, which is the monoester of lauric acid and anhydrosorbitol condensed withapproximately 20 moles of ethylene oxide. This surfactant has been used widely in babyshampoos. Another example is PEG-80 sorbitan laurate, an ethoxylated sorbitanmonoester of lauric acid with an average of 80 moles of ethylene oxide.

Amphoteric surfactants have been included in this section because they also impartmildness to shampoo formulations and are often used in conjunction with nonionics inbaby shampoos. Among the most frequently used are the amphoteric glycinates [37], an

example of which is sodium lauroamphoacetate.

Another group of commonly used compounds are the long-chain betaines, an importantexample of which is cocamidopropyl betaine,

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These compounds, in conjunction with other anionics, have low ocular irritation propertiesand, as was stated previously, are effective foam boosters and thickeners for manyanionic surfactants.

CCationics

Because of their positive charge, cationic surfactants are not effective as detergents inshampoos. This is because, as will be discussed later, the hair surface is negativelycharged at common shampoo pH. As a result, the cationics bind too strongly to the hairfiber and are not effectively removed in the rinsing process.

In addition, because cationic surfactants bind to hair with their hydrophilic heads at thesurface and their hydrophobic tails extending out, they render the hair surface morehydrophobic [38]. This increases the attraction of the hair surface for oily (hydrophobic)dirt, making it harder to remove such soil from the hair and increasing the tendency forresoiling.

IIIHair-Cleaning Mechanism

The previous sections surveyed some of the most important surfactants used inshampoos along with several properties important to consumer acceptance such as foamquality and viscosity building. The basic function of these surfactants, cleaning the hair,was touched on only briefly, however. In order to understand this function and therelative strengths and weaknesses of various detergents in cleaning different soils, it isnecessary to consider the different detergency mechanisms that can operate during theshampooing process. In the following sections, these cleaning mechanisms will beexamined along with some of the variables affecting their relative importance in the hair-cleaning process.

AThe Nature of the Substrate

Before examining specific cleaning mechanisms, it is necessary to consider the nature ofthe hair surface, the substrate from which soil must be removed. The chemicalconstitution and morphology of this surface are important parameters affecting both theease of removal of different types of dirt and the tendency to attract new soil.

Figure 1 shows an SEM micrograph of the root end of a typical, virgin hair fiber. The fiber

consists of a hydrophilic central portion, termed the cortex, surrounded by a covering of810 overlapping cells called the cuticle [39,40]. Compared to the cortex, the cuticle ishighly crosslinked as a result of a high cystine content. In addition, the outer covering ofthe cuticle, termed the epicuticle, has a high content of fatty acids covalently bound tothe epicuticle protein [41,42]. The presence of these lipids results in the epicuticle, andthus the hair surface, having a hydrophobic nature [4043].

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Fig. 1Scanning electron micrograph (SEM) of a typical root section of a virgin hair fiber.

At the same time, untreated hair has an isoelectric point near pH 3.67 [44] so that at theusual pH levels of shampoos (58), the surface also contains negatively chargedhydrophilic sites. This mix of hydrophobicity and hydrophilicity, of course, affects thenature of the soils attracted to and retained by the hair surface.

The situation is further complicated by the fact that the hydrophobicity of the hair surfaceis not constant. Thus, it has been shown [45,46] that the number of negatively chargedsites on hair increases as one moves from the root section to the tip. This is mainlycaused by oxidation of cystine in the hair to cystine S-sulfonate and cysteic acid as aresult of exposure to the UV portion of sunlight. This makes the tips of the hair lesshydrophobic than the roots. Chemical bleaching also oxidizes cystine in hair to cysteicacid, producing a greater effect than that caused by exposure to sunlight. This results in asignificant increase in surface hydrophilicity [43].

Consideration of the physical condition of the hair surface, in addition to its surfaceenergetics, is helpful in understanding cleaning effects. Figure 2 shows an SEM photo ofthe tip region of a hair fiber. Note that weathering and grooming effects have caused

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Fig. 2An SEM photo of the same fiber as Fig. 1, taken near the tip section. Note the

ragged and uplifted edges of the scales.

the scale edges to be slightly raised, making it possible for soil to be entrapped in thedamaged areas.

Figure 3 shows a hair fiber that has been abraded to the point that the cuticle has splitand exposed the hydrophilic cortex. In this case, in addition to particulate entrapment,the damaged areas could also strongly adsorb hydrophilic soils that would not stronglybind to the intact hydrophobic cuticle.

BCleaning of Particulate Soil

For detergency purposes, the soils found on hair can generally be divided into two types:solid particulates and liquid or oily soil. Solid soils can come from hair-care products suchas polymeric hair-spray resins or from the environment. These latter soils include clays,carbon particles in the form of soot, abraded rubber from automobile tires, etc. [47,48].

Solid particles generally adhere to the hair surface through van der Waals or ionic

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Fig. 3An SEM photo of a split end. Note the exposed fiber cortex.

forces [4951]. In water, the free-energy change per unit area involved in removing anadhered solid particle from a fiber surface is termed the work of adhesion, Wa, and isgiven by the equation,

where gAB represents the interfacial tension between any two phases A and B, where A orB can be P, W, or F: P represents the soil particle, W represents water, and F representsthe fiber [52].

Since interfacial tensions between water and hydrophobic surfaces are high, Eq. (1)indicates that hydrophobic particles are quite difficult to remove from the hydrophobichair surface since such a system results in large values for Wa.

Anionic or nonionic surfactants in a shampoo can reduce the work necessary to removesolid particles because they tend to adsorb to hair with their hydrophobic portions incontact with the fiber surface and their hydrophilic heads oriented towards the bath. Thishas the effect of reducing gFW and, thus Wa. Adsorption of surfactant onto hydrophobicsoil would further decrease the work of adhesion by decreasing gPW.

A more important mechanism than the above, however, for removal of particulates is theincrease of negative potentials of both soil and hair surface through the adsorption ofanionic surfactants. This increases the mutual repulsion between the particle and the

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hair fiber, thus facilitating soil removal. This mechanism, of course, does not work fornonionics (although the hydrophilic polyoxyethylene heads do provide stearic barriersbetween fiber and particle), and, in general, these surfactants do not remove solidparticulates from hair as effectively as do anionics [53].

The ease with which any particular solid particle is removed from the hair surface isdependent on its size. The reason for this is that as particle size decreases, the surfacearea per gram, and consequently the area of true contact per gram between particle andsubstrate, increases. A result of this is that more force per unit area is required to removesmaller particles [54]. At the same time, mechanical forces (e.g., flexing and rubbing ofhair) operate less efficiently on small particles [54,55], making these forces less availablefor particle removal. In practice, normal cleaning processes cannot remove particles lessthan 0.1 µm in size from fibrous substrates [56].

CCleaning of Oily Soil

The second general class of soils found on hair are oily or liquid soils. These arehydrophobic deposits that are generally liquid or that can be made liquid at cleaningtemperatures. Examples include sebum deposits from the scalp (solid at roomtemperature, but almost completely molten at body temperatures [57] ), lipids from skincells; and oils, waxes, and silicones from hair-care products.

The detergency mechanisms most important in cleaning the above fatty materials aregenerally different from those of solid particulates. These include roll-back, emulsification,mesophase formation, and solubilization. In the following sections, a discussion of thesemechanisms, along with their relative importance in the hair-cleaning process, will bepresented.

1Roll-Back Mechanism

Figure 4 shows an oil droplet adsorbed to a solid substrate. The equilibrium contact angleformed by the droplet is governed by Young's equation, which in water can be written

where g is the interfacial tension between two phases, O represents the oil phase, W isthe water phase, F is the fiber, and q is the contact angle (Fig. 4) [58].

Examination of Eq. (2) shows that adsorption of a surfactant to the fiber surface (orientedwith the hydrophilic head pointing towards the aqueous phase) will increase the contactangle, q, since it causes a decrease in gFW. If the decrease in gFW is sufficiently large, thecontact angle will increase to 180°, and the oil droplet will spontaneously separate fromthe fiber surface (Fig. 4).

Fig. 4Different stages of the roll-back process. Note increases in

contact angle as the oil droplet is rolled back from the substrate.

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In effect what has happened in the above case is that the surfactant has increased theaffinity of the fiber surface for water to such an extent that the water can displace the oildroplet and simply rolls it up. This process was first described by Adam [59] and by Kling[60] and is termed roll-back.

The roll-back process is the most important mechanism in fabric laundering for cleaningoily soils. Equation (1) applies to this process, so that, as with particulates, oily(hydrophobic) soil is generally more difficult to remove from hydrophobic substrates likehair than is more polar soil. Many examples of this have been reported for cases in whichonly roll-back occurs and for cases where multiple detergency mechanisms are inoperation [6166].

In practice, oily soil will deposit on hair with a contact angle having a low value. It is notunusual for oils to have a contact angle of zero, in fact, in which case the soil forms a thinfilm on the hair fiber. Because of their substantivity, it may not be possible for asurfactant to completely roll back very hydrophobic, oily soils without the application ofmechanical work such as flexing and rubbing of wet hair during the shampoo process.This procedure tends to completely remove any soil whose contact angle has beenincreased to greater than 90° by detergent adsorption. Oil droplets rolled back to lessthan 90°, on the other hand, may be incompletely removed, leaving behind a smalldroplet [58].

A major factor opposing the roll-back process is high soil viscosity. Increased soil removalin this case can, again, be obtained by application of mechanical work or by increasingthe temperature, a step that reduces viscosity and increases rates of diffusion andsurfactant adsorption.

2Solubilization

Above a certain concentration, termed the critical micelle concentration (CMC),surfactants tend to form colloidal-sized association structures, or micelles, in which thehydrophobic portions of the surfactants are pointed towards the micelle interior and thehydrophilic heads are directed outwards towards the solvent [67].

Micelles are important in cleaning because they can solubilize insoluble soils byincorporating them into the micellar structure [68,69]. Nonpolar soils, such ashydrocarbons, are incorporated deep in the interior of the micelle, while more polarmaterials are found closer to the hydrophilic heads.

The kinetics and mechanism by which micelles solubilize a soil have been described as(1) adsorption of micelles on the soil surface; (2) incorporation of soil into the micelle;and (3) desorption of the soil-containing micelle. Diffusion of micelles to and away fromthe soil surface precede and end this solubilization process [70,71].

In laundering, solubilization is generally not an important mechanism, at least foranionics, because the concentrations of these surfactants in the washing machine (about0.0065%) are below the CMC (about 0.01%) under normal conditions [72]. Thus noanionic micelles are available for soil incorporation. Nonionics have a lower CMC thananionic detergents, but even in this case, the number of micelles formed is too low tosolubilize much of the soil present.

In the case of shampooing, the above is not true. Based upon typical shampoo detergentconcentrations of 1520%, Barker [73] has estimated that the final surfactantconcentration in the lather during shampooing is 12%, a value that is 5 to 10 times theCMC of SLS. The possibility thus exists that solubilization plays a major role in thedetergency of shampoos. This is an especially important consideration in light of reports

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[74,75] that maximum detergency in cleaning of various fats and oils occurs, for severalsurfactants, at 6 to 10 times the CMC.

In the above reports, SLS was one of the surfactants found to exhibit increaseddetergency above the CMC; the total amount of cleaning, however, was low compared tononionic surfactants. This is presumably because anionic surfactants, like SLS, form smallspherical micelles (71 monomer units at room temperature [76]) that have little room forpolar compounds near their hydrophilic heads and even less for nonpolar materials in themicelle interior [77,78].

Despite the SLS behavior discussed above, it is still possible for SLS to solubilize relativelylarge amounts of fats and oils in shampoos. One reason is that soils on hair are mixturesof polar and nonpolar soils and incorporation of one type of soil in the micelle increasesthe micellar capacity for the other type [79]. Thus incorporation of hydrocarbons in themicelle interior causes the micelle to swell, making it possible for more polar soil to beincorporated near the micelle exterior. Conversely, incorporation of more polar material,such as long-chain fatty acids or alcohols, increases the capacity of the micelle forhydrocarbons.

Another reason for increased solubilization of soils by SLS in shampoos is the presence ofother ingredients in the products, including inorganic salts, foam boosters, viscosityenhancers, and long-chain alcohols, all of which can potentially change the size andshape of the SLS micelles. Inorganic salts, for example, are routinely added to mostshampoos to increase viscosity. The presence of these electrolytes has the effect ofdecreasing repulsion between the charged head groups of ionic surfactants in a micelle bycompressing the electrical double layer surrounding these hydrophilic groups. Thispermits closer packing of the heads, resulting in a larger aggregation number.

Thus, for SLS micelles, addition of NaCl can increase the average number of units in theaggregate from 71 in pure water [76] to 100 after addition of 0.03 M salt [80], to 1630 at0.80 M salt [81]. These salt concentrations, which are not at all unusual for commercialproducts, result in larger aggregates that potentially have more room to solubilizehydrocarbons and long-chain polar materials that are incorporated well into the micelleinterior. Above 0.4 M salt, the shape of the micelles is also changed, from spherical torod-shaped [82,83]. Such a shape change increases the volume of the inner core withrespect to the exterior, thus further increasing the extent of incorporation of nonpolarmaterials.

Other additives in shampoos, such as long chain amides and betaines, increase micellesize by forming mixed micelles with the anionic detergent. This has the effect of reducingrepulsion between ionic head groups leading, as with salt addition, to larger micelles withmore solubilizing capacity. Long-chain fatty alcohols, which are often found in commercialanionics as a result of incomplete sulfation, also have the same effect.

In addition to particular additives, solubilization of polar soils can often be increased

through the use of lauryl ether sulfates. For example, Tokiwa [84] found that the nonionicdodecylpolyoxyethylene ethers (DPOE) had 10 times the solubilizing power of sodiumdodecyl sulfate (SDS) for the insoluble dye Yellow OB. Although the dye can beincorporated in the interior of the micelle, much more of it can be solubilized in the regionnear the ethylene oxide groups of the nonionic surfactant. Lauryl or dodecyl ether sulfatesalso contain ethylene oxide groups and it was found that use of a variant with

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one ethylene oxide group (SDES-1) increased solubilization 3-fold over SDS, while 5 timesas much Yellow OB was solubilized by SDES-3.

As was the case with roll-back, soil removal by solubilization is aided greatly byincreasing temperature [85] and application of mechanical work through rubbing andflexing of hair and through rinsing. More work needs to be done to determine the exactcontribution of solubilization to the cleaning of various soils; however, solubilization isundoubtedly a highly significant cleaning mechanism and, quite likely, is the mostimportant means by which shampoos remove soils from human hair.

3Penetration, Emulsification, and Mesophase Formation

Emulsification and mesophase formation are two important mechanisms by whichdetergents effect removal of soils from substrates. Emulsification involves breaking alarge oily mass into smaller particles that can form a stable suspension in the aqueouscleaning medium. Such a process, which requires mechanical work, is greatly aided by thepresence of amphiphilic compounds in the oily soil such as fatty acids or fatty alcoholsthat can interact with the shampoo detergent to cause spontaneous emulsification of thesoil [8688]. Since the shampooing process takes only a few minutes, emulsified soil hasto remain suspended in the surrounding aqueous medium for only a short period of time.Interaction with the detergent acting as an emulsifying agent is helpful in this regard, asis suspension of soil particles in the shampoo lather [89].

Fatty alcohols or acids, and oily soils containing amphiphiles of this type, can also oftenbe removed from substrates as a result of liquid crystal or mesophase formation betweenthe amphiphile and a detergent. Thus Lawrence [9092] found that surfactants couldpenetrate mineral oil containing 1020% of a fatty acid or alcohol to produce liquid crystalphases that could be broken up by subsequent osmotic penetration by water. Dispersionhas also been reported as a result of formation of myelinic figures, or tubes, penetratinginto the aqueous phase [93].

Increasing temperature can increase the rate at which solid soils are removed fromsubstrates by formation of mesomorphic phases. This effect, which presumably is dueatleast in partto increased penetration of the soils at higher temperatures, was reported byScott for stearyl alcohol [94] and by Chan and Shaeiwitz for lauric, palmitic, and stearicacids [70,71]. Removal of solid soils by penetration without mesophase formation hasbeen reported for tripalmitin [94] and for octadecane and tristearin [64,95]. In thesecases, cracks and dislocations in the soils served as sites for penetration and ''chipdislodgment" by the detergent.

One final means of cleaning oily soils containing large amounts of fatty acids involvesconversion of the acids to the corresponding soluble soap [1]. This process, which resultsin emulsification of the oily soil, is important in fabric washing. It is not important in haircleansing, however, since shampoos are generally not sufficiently alkaline to effect

neutralization of fatty-acid soils.

IVEfficacy of Soil Removal by Hair Cleansers

The preceding sections described the most important mechanisms by which hair cleansersremove soils from the hair surface. In the following sections the cleaning efficiencies ofthese cleansers for the most common hair soils will be presented.

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ACleaning of Sebum

Sebum is a lipid material that is found deposited on human hair as a result of secretiononto the scalp by the sebaceous glands [96,97]. It is a mixture of several lipophiliccompounds (Table 1) and is distributed more or less uniformly over the hair surface as aresult of contact with sebum-filled follicles by hair fibers [98], followed by mechanicalactions such as grooming and rubbing against pillows.

Sebum is probably the single most important soil found on human hair. Hair that has toomuch sebum on the surface becomes limp and clumped together and is perceived bypanelists as dull and dirty. In addition, the presence of the lipid contributes to furthersoiling because it is sticky and retains airborne particles and other materials with which itcomes into contact [99103]. It can also act as a binder, cementing many soil particlestogether [104].

Most surface lipid on hair is sebum; internal lipid also exists, which is partly structural andpartly extractable material [105]. Much of the latter seems to have originated from thesebaceous glands [106]. Robbins [105] has reported that the total extractable lipid canbe as much as 9% of the total weight of hair that has not been shampooed for a week.The external and internal lipid are divided roughly equally among this extractablematerial.

Detergents in shampoos do not penetrate the hair fiber to any great extent in the timerequired for shampooing. Thus shampoos clean only surface lipid. Internal lipids do notcontribute appreciably, however, to consumer-perceivable effects such as soiling, dulling,and feel of hair. Robbins [105], for example, found that the same quantity of internal lipidcould be extracted from oily hair as from dry, implying that the surface lipid was entirelyresponsible for the oily state of the hair. It is the removal of these surface deposits,therefore, that one must be concerned with when evaluating cleaning of hair.

An examination of the nature of lipids deposited on hair surfaces indicates that this soilmay be cleaned from hair by any of several different detergency mechanisms. Thus, thepresence in sebum of roughly 25% free fatty acids means, as discussed in Sec. III.C.3,that it is subject to cleaning by emulsification and mesophase formation. In addition,since this soil is almost completely molten at body temperatures [57], it is also subject toremoval by the roll-back mechanism. Finally, since the detergents in shampoos are atconcentrations well above their CMC values, sebum can also be cleaned from hair byTABLE 1 Average Composition of Sebum inAdultsIngredient Percent of totalCholesterol 8.65Free fatty acids 23.39Triglycerides 32.71Wax and cholesterol esters 19.53

Squalene 10.31Paraffins 5.42Source: Ref. 99.

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solubilization, with the various components listed in Table 1 distributing themselveseither deep in the micelle interior or closer to the hydrophilic surface.

The relative importance of the above mechanisms in actual cleaning of sebum is acomplicated function of detergency kinetics, temperature, age and consistency of thesebum, nature of the other soils on the hair surface, time allotted to shampooing,whether the hair is chemically processed or damaged, etc. How these factors play out inany particular set of circumstances is not well known, but more than one detergencymechanism can certainly operate simultaneously [61,70,71]. It seems likely therefore,that, given the multiplicity of cleaning mechanisms, major portions of the surface lipidfound on hair can be removed by the shampooing process.

The above assertion is supported by much of the literature: a number of studies onsebum cleaning have concluded that, at normal shampoo concentrations, anionicsurfactants perform an adequate job of cleaning surface lipids [66,105,107109]. Thus,Shaw [107] cited scanning electron microscopy results to support his conclusion thatanionic surfactants could remove virtually all surface lipid from hair in a single application.Robbins reached much the same conclusion for two applications [105] based onextractions of wool swatches and hair clippings.

The results of Thompson [108] and Clarke and coworkers [66,109] on the relativecleaning of the various components of an artificial sebum illustrate many of thedetergency principles presented in Sec. III. Both of these groups used gaschromatography techniques to show that the most nonpolar fractions of sebum, such asparaffin, were more difficult to remove from hair than the more polar fractions such asfree fatty acids. Table 2 lists some of the results from Thompson's work. These data canbe understood in terms of the discussion on work of adhesion in Sec. III.C.1: hydrophobicsoils such as paraffin have a greater affinity for the (hydrophobic) hair surface and arethus harder to remove. Another reason is that the cleaning solutions in the two groups'work contained only detergent with no additives; the micelles were therefore small andspherical (Sec. III.C.2) with more room for polar compounds near the hydrophilic outerportions than for nonpolar materials incorporated deep in the micelle interior.

Table 2 shows that sodium laureth-2 sulfate (SLES-2) is superior to ammonium laurylsulfate (ALS) in cleaning sebum, a finding that was also corroborated by Clarke's work.One reason for this is that SLES-2 has a lower CMC than ALS [4,109a] and, under thesame conditions, its micelles have a higher aggregation number. Thus at a givenTABLE 2 Detergent Cleaning of Sebum FractionsSebum fraction ALS percent

removalSLES-2 percent

removalTriglycerides 94.6 94.7Free fatty acids 97.1 96.2Paraffin 80.8 95.2Squalene 87.6 98.4Spermaceti wax 84.6 96.9

Average of allfractions

85.9 95.9Source: Ref. 108.

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concentration (above the CMC), a solution of SLES-2 is likely to solubilize more sebumthan a solution of ALS simply because more of its molecules are involved in micelleformation and it contains larger micelles. In addition, as was discussed in Sec. III.C.2,certain molecules are better solubilized in the region near the ethylene oxide groups ofSLES-2. (Note that ammonium salts of alkyl sulfates have a lower CMC and a highermicellar aggregation number than the corresponding sodium salts (4,109a), and ALSwould therefore be expected to be a better detergent than SLS.)

Schwuger [12] showed that below the CMC, addition of ethylene oxide groups to SLSleads to increased surfactant adsorption at the aqueous solution/air interface and alsoonto activated carbon. If SLES-2 adsorption is also greater for the case of ALS, suchincreased adsorption onto hair could lead to increased removal of sebum by the roll-backmechanism [110], thus explaining the superior cleaning by SLES-2 observed by Clarke atconcentrations below the CMC.

Most of the work on sebum cleaning reported in the literature has employed simplesurfactant solutions rather than fully formulated shampoos. In the latter case, additivesthat are also effective detergents, such as betaines, are present and, as was discussedpreviously, the micelles are likely to be large and nonspherical with increased capacity forsolubilizing nonpolar materials. Under these conditions it is very likely that the adequatesebum cleaning differences between different surfactants would be reduced. It istherefore expected that any of the typical commercial shampoos currently availablewould be effective in cleaning sebum from hair.

It should be noted that the sebum-cleaning results reported above were generallyobtained for virgin hair samples with hydrophobic surfaces. Bleached hair, on the otherhand, has a much more hydrophilic surface than virgin hair [38,46] and, therefore, shouldhave a much lower affinity (Eq. 1) for lipids, making soils such as sebum much easier toremove. This increased ease of removal is likely to play a large role in the observationthat people with chemically treated hair (permed, straightened, bleached, etc.)experience increased dryness in their hair. The greater degree of negative charge andthus decreased hydrophobicity at the tips of virgin hair [45,46] may also help explain theincreased need for conditioning reported by consumers for this portion of the hair fiber.

BCleaning of Quaternium Compounds from Conditioner-Treated Hair

Conditioners are used to increase combing ease in hair, to reduce fly-away, and toimprove the feel of hair. The primary ingredient in most conditioners is a long chainquaternium compound or monofunctional cationic. These cationics are generallycombined with lipid additives such as long-chain fatty alcohols. Typical cationics arecetyltrimonium chloride (CTAC) and stearalkonium chloride (SAC).

Other conditioner active ingredients include steartrimonium chloride and distearyl-

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dimonium and tristearylmonium chlorides. Typical lipid additives include cetyl and stearylalcohols. Cationic concentrations in conditioners are generally on the order of 12% whilethe lipid concentrations are usually equal to or greater than those of the cationics.

Conditioners are generally used at pH levels above the isoelectric point of hair (3.67)[44], so that the cationic surfactant in the conditioner binds to hair with its cationic headclose to the negatively charged sites on the fiber surface and its hydrophobic tail orientedoutwards. The result is a fiber surface with a hydrophobic coating that is soft and easilycombed [38].

The binding of quaternium surfactants to keratin surfaces has been studied by severalresearchers [111114] and shown to be a function of chain length, with increasing bindingobserved with increase in the length of the hydrophobic chain. Binding is, of course, alsodriven by the number of negative binding sites on the hair. This is shown in Table 3,which lists the results of radiotracer experiments measuring the amount of radiolabeledSAC bound to virgin and bleached hair [115]. Bleached hair has many more negativebinding sites than virgin hair, and the amount of SAC binding to the bleached substratewas 2.5 times that binding to the virgin surface. As was stated previously, the tips ofvirgin hair also contain more negative sites than the roots, and here again more SAC wasobserved binding to the former areas than to the latter. Based on the discussion at theend of the previous section, it can be said that the SAC conditioner binds most to areas ofthe hair where it is most needed. Of course one must also consider that it may be moredifficult to remove the SAC from these sites.

Removal of quaternary compounds (quats) such as CTAC and SAC from hair can beexpected to be more difficult than the cleaning of sebum. The reason for this is that theformer compounds tend to deposit in the form of positively charged films having a strongelectrostatic attraction for the hair surface. Because of the solid nature of these films, theroll-back mechanism of cleaning does not apply, while the positive charge on the quatsinterferes with the mechanism of cleaning described in Section III.B: the introduction ofmutual repulsion between soil and substrate as a result of adsorption of anionicsurfactant.

Solubilization of quats by anionic surfactants can still occur, but work by Reich andcoworkers [116,117] has shown that, at least for CTAC and SAC, solubilization by lauryland laureth sulfates (1 to 5EO) is ineffective. Thus, using radiotracers, light scattering,TABLE 3 Binding of Radiolabeled Stearalkonium Chloride to Human HairaHair type SAC bound/gram hair (mg)

root areabSAC bound/gram hair (mg)

tip areabAlbino virgin hair 0.789 0.649Albino bleachedhair 1.62 1.83aTest procedure: 0.67 g of 1% [14C]SAC (30% ethanol:water) wasapplied to a 2-g tress and rubbed into the hair for 1 minute. Tresseswere then rinsed in a beaker of tap water for 45 seconds, followed by

rinsing in a second beaker for 15 seconds, and finally rinsed underrunning 100ºF tap water for 1 minute. Portions of hair taken fromdifferent parts of the tress were then dissolved in 2 M NaOH at 80°C,oxidized with H2O2, then mixed with Aquasol-2 LSC cocktail and perchloricacid and counted.bEach number represents an average of 5 replicates.

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and dye-binding experiments, it was shown that washing SAC and CTAC with lauryl orlaureth sulfate detergents resulted in formation on the hair of insoluble complexes thatwere dulling to the hair surface and difficult to remove with any lauryl or laureth sulfate-based surfactant. This is shown in Table 4 where it is seen that washing deposited SACwith 5% ALS resulted in only 31% removal of the cationic. At the same time, as a resultof SAC:ALS complex formation, more than twice the amount of ALS was found bound tothe wool after washing SAC treated swatches as was found after washing clean swatches.Adjusting quantities to take into account the amount of ALS bound to clean wool, onecalculates that 6.73 mg of total material was left deposited after washing a swatchinitially containing 6.68 mg of SAC, a net result of no cleaning. Similar results wereobserved for SLES detergents.

Table 4 shows the same effects as the above for CTAC treated swatches: only 40% of theCTAC was removed after washing with 20% ALS, while washing with 5% ALS resulted innet deposition of detergent as a result of CTAC:ALS complex formation.

Reducing the hydrophobic chain lengthy of the detergents results in conditioner:detergentcomplexes that are more soluble and can therefore be removed more easily from the hairsurface by shampooing. Thus it can be seen in Table 4 that washing SAC-treatedswatches with 5% sodium deceth-2 sulfate (SDES-2) resulted in removal of more than62% of the conditioner. At the same time, within experimental error, the same amount ofSDES-2 was observed bound to clean swatches as to SAC-treated wool, thus indicatingthat insoluble SAC:SDES complexes were not formed on the wool surface. Similar resultswere observed with CTAC so that one can conclude, at least for the two conditionerstested, that SDES-2 is superior to the lauryl and laureth sulfates for removing conditioneractive ingredients.

Experiments with a fully formulated SAC conditioner (Cond. A), containing ceteth-2 as thelipid additive, yielded different results from the above. Table 5 shows that unlike the casewith conditioner active ingredients, lauryl sulfate-based detergents can removeTABLE 4 Deposition from Detergent Cleaning of SAC and CTACa,bTreatment Cationic bound/g wool

(mg)cDetergent bound/g wool

(mg)c1% SAC 6.685% ALS 1.941% SAC/5% ALS 4.58 4.091.7% CTAC 7.131.7% CTAC/20% ALS 4.251.7% CTAC/5% ALS 4.305% SDES-2 1.861% SAC/5% SDES-2 2.52 2.121.7% CTAC/20%SDES-2 2.881.7% CTAC/5% SDES-2 1.47aSource: Ref. 116.bRadiotracers were [14C]SAC, [35S]ALS, and [35S]SDES-2. Treatments were

rubbed into wool for 1 minute; total rinsing duration was 2 minutes.cEach number represents an average of 5 replicates.

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TABLE 5 Deposition from Detergent Cleaning of Commercial Conditionera,bTreatment SAC bound/g wool (mg)cDetergent bound/g wool (mg)cCond. A 4.275% ALS 1.18Cond. A/5% ALS 1.67 3.57Cond. A/5% SODSd 1.835% SDES-3 1.08Cond. A/5% SDES-3 1.11aSource: Ref. 116.bRadiotracers were [14C]SAC, [35S]ALS, and [35S]SDES-2. Treatmentswere rubbed into wool for 1 minute; total rinsing duration was 2 minutes.cEach number represents an average of 5 replicates.dSODS is a mixture of 45% sodium octeth-1 sulfate and 55% sodiumdeceth-1 sulfate.

as much of a fully formulated conditioner as can shorter chain surfactants. Thus, washingCond. A treated swatches resulted in the same degree of removal of SAC, about 60%, byboth ALS and SODS (a mixture of sodium octeth-1 and deceth-1 sulfates that behavessimilarly to SDES-2 in cleaning cationics). In addition, performing twoconditioner/washing cycles did not result in buildup of the conditioner soil [116]. Thesedifferences from the conditioner active ingredient experiments may be the result ofcoating of the deposited SAC with ceteth-2. As was seen in the preceding section, lipidslike ceteth-2 are more easily cleaned than SAC and, if this lipid were interposed betweenthe cationic and the substrate, it might also increase the ease of removal of theconditioner active ingredient.

Despite the fact that buildup of the conditioner soil was not observed with fullyformulated conditioners, buildup of detergent on top of deposited conditioner was stillobserved to occur. Thus, in Table 5 it is seen that washing Cond. A treated swatches withALS resulted in a 3-fold increase in deposited detergent, presumably as a result ofcomplex formation with the 40% of the initial SAC that remained on the wool afterwashing. Continued Cond. A/ALS treatments resulted in still further ALS buildup; after 3cycles, the deposited detergent was observed to increase a further 30% [116]. Thisincrease, of course, results in reduced cleaning when total deposits are considered. Thusin an experiment with Cond. A and a commercial shampoo containing TEALS(triethanolamine lauryl sulfate), washing swatches containing 3.17 mg of deposited SACresulted in a total deposit after shampooing of 3.28 mg, an outcome, again, of no netcleaning [116].

Examination of Table 5 shows that washing Cond. A treated swatches with SDES-3resulted in no detergent buildup. This was true even after 3 Cond. A/SDES-3 cycles [116].This, again, was because of the increased solubility of SDES/SAC association complexes.On the basis of these experiments, therefore, one can conclude, at least for CTAC andSAC, that washing of conditioner soil with lauryl or laureth sulfates results in poorcleaning as a result of buildup of the detergent on top of the conditioner. Shortening of

the surfactant hydrophobic chain length to 10 carbons eliminated this buildup, leading toimproved cleaning of these cationic soils.

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CCleaning of Cationic Polymers

Many cationic polymers exhibit conditioning effects on hair and are frequently used inhair-care products, including shampoos, for this purpose. Important examples of thesepolymers include polyquaternium-10, a polymer having a quaternized hydroxyethylcellulose structure, and polyquaternium-7, a copolymer of dimethyldiallylammoniumchloride (DMDAAC) and acrylamide.

Polyquaternium-10, also known as Polymer JR, has a moderately low positive chargedensity of 670 [118] (residue weight per unit of charge) and a molecular weight of250,000, 400,000, or 600,000, depending upon the version used. Many studies on itsbinding to hair have been performed utilizing a variety of techniques including radiotracermethods, ESCA, and streaming potential measurements [118122]. These studies indicatethe Polymer JR is quite substantive to hair and cannot be completely removed by SLS,even after an exposure time of 30 minutes.

Polyquaternium-7, also known as Merquat 550, has a positive charge density of 197[123], more than 3 times the density of Polymer JR, and a molecular weight of about500,000. Fewer adsorption studies have been published for this polymer than for PolymerJR; Goddard and Harris, however, reported ESCA results on hair [120], while Sykes andHammes [124] described adsorption of Merquat 550 from solutions of different anionicand amphoteric surfactants.

Most of the studies of Polymer JR binding to keratin have involved immersion of thesubstrate in Polymer JR solutions for periods as long as several days. These studies arenot ideal models for actual consumer usage for several reasons. First, the treatmentdurations of days are much longer than the normal consumer usage and treatment timesof only minutes. In addition, the modes of application have been passive, not utilizing themechanical work of rubbing treatment solutions and shampoos into the hair that, again,is involved in normal consumer use. Finally, exposing keratin fibers to Polymer JRsolutions for long periods of time leads to considerable diffusion of the polymer into theinterior of the fiber [118,120], while only surface adsorption occurs during the normal,short exposure times to actual products.

In order to correct the above deficiencies, radiotracer experiments were carried out in ourlaboratories by mechanically rubbing treatment solutions into substrates for limiteddurations of only one minute, a procedure that more closely modeled normal consumerusage.

Table 6 presents the binding of Polymer JR to bleached and virgin hair from a 1.76%aqueous solution. As a result of a greater number of negative binding sites on the formerhair, the binding measured for the cationic Polymer JR was 2.3 times greater for bleachedhair than for virgin fibers.

Table 7 tabulates the results of binding and cleaning experiments on wool swatches. It isseen that Polymer JR is quite substantive to keratin surfaces; only 43% of thepolycationic could be removed in a single SLS washing. Washing experiments were alsoperformed with Polymer LR, a polymer similar in structure to JR, but having a lowercharge density. In this case, because of the lower degree of positive charge, 75% of thepolycationic was removed in a single washing.

Cleaning experiments were also performed with Merquat 550. Although this polymer hasa higher charge density than Polymer JR and was at a slightly higher concentration in thetreatment solutions, deposition of Merquat 550 was somewhat lower than Polymer

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TABLE 6 Binding of Radiolabeled PolymerJR 400 to HairaSubstrate Mg JR bound/gram hairbVirgin hair 0.424Bleached hair 0.962aTest procedure: 0.67 g of 1.76%[14C]Polymer JR in water was applied to a2-g tress and rubbed into the hair for 1minute. Tresses were then rinsed in abeaker of tap water for 45 seconds,followed by rinsing in a second beaker for15 seconds, and finally rinsed underrunning 100°F tap water for 1 minute.Protions of hair taken from the tress werethen dissolved in 2 M NaOH at 80°C,oxidized with H2O2, then mixed withAquasol-2 LSC cock-tail and perchloric acidand counted.bEach number represents an average of 5replicates.

JR, while the percent removal from wool was essentially equal to that of the lattermaterial. The reason Merquat 550 is no harder to remove from wool than Polymer JR,despite its higher charge density, is unclear; there may be steric reasons and it may berelated to the finding of Goddard and Harris [120] that treating hair fibers with equalconcentrations of Polymer JR and Merquat 550 resulted in 25% surface coverage by theformer polymer and only 10% coverage by the latter.

Cleaning experiments were also performed with radiolabeled SLS to determineTABLE 7 Deposition and Cleaning of Polycationic ConditionersaTreatment Mg Polymer bound/g woolb % Cleaning1.76% Polymer JR 5.771.76% Polymer JR/5% SLS 3.27 431.5% Polymer LR 4.631.5% Polymer LR/5% SLS 1.16 752.5% Merquat 550 4.782.5% Merquat 550/5% SLS 2.81 41aTest Procedure: 0.15 ml of [14C] polymer solution in water wasrubbed into 0.15 gram wool swatch for one minute, followed byrinsing in a beaker of tap water for 45 seconds, another rinse in asecond beaker for 15 seconds, and a final rinse under running 100ºFtap water for 1 minute. The same procedure was followed with SLS.Following this swatches were dissolved in 2 M NaOH at 80ºC, thenmixed with Aquasol-2 LSC cocktail and perchloric acid and counted.b Each number represents an average of 5 replicates.

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whether the same type of surfactant buildup occurred with the above polymers as wasobserved with CTAC and SAC. The amount of SLS binding to polymer-treated wool afterwashing was no greater than that observed from washing clean swatches. In addition,performing cycles of polymer/SLS treatments did not result in significant increases insurfactant binding.

It is therefore concluded that the lauryl sulfate detergents do not build up on any of theabove polymers and that the difficulty in cleaning Polymer JR and Merquat 550 is not aresult of formation on the wool surface of the type of conditioner:detergent complexesdiscussed in the preceding section. The difficulty in cleaning these polymers is, instead,probably related to the multiple electrostatic points of attachment between the polymersand the keratin surface. In order to effect polymer removal, it is necessary to overcomeall of these attachment points at the same time, a much more difficult proposition thaneliminating the single point of attachment between a small molecule and the hair surface.

The binding experiments tabulated in Table 7 were all performed using simple solutionsof polymers in water. In the presence of typical anionic detergents in shampoos, bindingof Polymer JR and Merquat 550 to hair has been reported to be greatly decreased [121,124] as a result of formation of association complexes between the polymer and thedetergent. Despite decreased deposition, however, Hannah [122] has reported thatassociation complexes deposited in the presence of excess SLS resist removal from hair.Similar findings were reported by Reich and Robbins [7], who observed formation ofcomplexes between sodium myristate and Polymer JR when a Polymer JR-containingshampoo was used to wash hair that had previously been washed with a shampoocontaining sodium myristate. These complexes were found to cause considerable dullingof hair and to also be resistant to removal from the fiber surface.

DCleaning of Fixative Residues

The polymeric resins found in fixatives such as hair sprays, mousses, and setting lotionsare the ingredients responsible for the holding properties of these products. Thesepolymers are generally neutral or anionic in order to facilitate removal from hair. Typicalpolymers in use today include the copolymer of vinyl acetate and crotonic acid, thecopolymer of polyvinyl pyrrolidone and vinyl acetate (PVP/VA), the ethyl ester of thecopolymer of polyvinyl methyl ether and maleic anhydride (PVM/MA), and the copolymerof octylacrylamide/acrylates/butylaminoethyl methacrylate (Amphomer).

Very few studies have been published on the cleaning of hair-spray resins from hair. Onesuch study by Sendelbach and coworkers [125] employed gravimetric studies and a novelconductivity method based on electrodes coated with hair-spray resins, to measure thecleaning of a series of fixative polymers. These included Amphomer (neutralized 80%with aminomethylpropanol); PVP/VA; the copolymer of carboxylated polyvinyl acetate,vinyl propionate, and crotonic acid (CAP); and shellac. Washing of these resins with a

lauryl ether sulfate solution resulted in removal of roughly 80% of CAP, more than 90%of PVP/VA, 50% of the shellac, and only 20% of the Amphomer.

Shellac, which was used in hair sprays before the development of synthetic resins, is wellknown to be difficult to remove from hair and is therefore no longer in general use. Inview of this, the cleaning level reported for Amphomer, a popular fixative resin, seemstoo low. The recommended degree of neutralization for Amphomer, 90% or greater, is

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higher than the 80% used by Sendelbach; at higher neutralization levels, the polymerwould be more soluble in water and should be cleaned much more easily.

More work needs to be done to determine the extent of cleaning of hair-spray resins. Itseems likely, however, that with the proper degree of neutralization, significant cleaningof commercial fixative polymers should be achievable. This was certainly found to be truein our laboratories for a radiotagged sample of the ethyl ester of PVM/MA. Table 8 showsthat when wool swatches were treated with a commercial hair spray containing theradiolabeled polymer, 89% of the resin was removed with a single washing with 10%ALS.

ECleaning of Dimethicone Residues

In recent years, 2-in-1 shampoos have come on the market that provide much greaterlevels of conditioning than previous generations of conditioning shampoos. Improvedconditioning from these products is provided by deposition from the shampoo of thehydrophobic silicone polymer, dimethicone,

Rushton and coworkers [126] have studied dimethicone buildup and cleaning. Their ESCAmeasurements indicated that after 5 washings with a commercial 2-in-1 shampoo,dimethicone deposits on virgin hair had increased roughly 35% compared to a singlewashing. Between 5 and 60 washes, however, no further deposition was observed.Rushton also reported, on the basis of atomic absorption measurements, that a singlewash with commercial shampoos could remove more than 90% of deposited dimethicone.These latter measurements were made on solvent extracts of treated hair; however,TABLE 8 Deposition and Cleaning of Hair Spray ResinaTreatment Mg Resin bound/g woolb % CleaningHair spray A 33.6Hair spray A/10% ALS 3.69 89aTest Procedure: 0.15 ml of commercial hair spray A containingthe ethyl ester of [14C]PVM/MA was applied to each 0.15 gramwool swatch. Swatches were then dried overnight and eitherprocessed or washed by rubbing with 0.15 ml of ALS solution forone minute, followed by rinsing in a beaker of tap water for 45seconds, another rinse in a second beaker for 15 seconds, and afinal rinse under runing 100°F tap water for 1 minute. Subsequentprocessing was carried out by dissolving swatches in 2 M NaOH at80°C, then mixing with Aquasol-2 LSC cocktail and perchloric acid,followed by counting.bEach number represents an average of 5 replicates.

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no evidence was presented to show that all of the deposited dimethicone could beretrieved in this manner. More work needs to be done to unequivocally determine theease of cleaning of dimethicone deposits.

FConclusions

The extent of cleaning of soils commonly found on human hair is dependent upon thenature of the soils. There are a number of cleaning mechanisms to which lipid soils,including sebum, are subject, and the bulk of the evidence indicates that greater than90% removal of lipid soil from hair can be achieved with a single wash with commercialshampoos.

Cleaning of monofunctional cationic conditioners is more difficult than the above. Thesematerials bind to hair electrostatically as well as by hydrophobic bonding, and as a result,sodium deceth sulfates, the best detergents for these soils, were observed to removeonly 60% cationic from wool swatches in a single washing. Similar results [115] wereobtained on hair. Detergents with 12 carbons in their hydrophobic chains, i.e., lauryl andlaureth sulfates, remove even less cationic because they interact with these conditioners(at least for CTAC and SAC) to form insoluble precipitates on hair that are difficult toremove. Cationics from fully formulated conditioners are easier to remove with SLS; aswith SDES, 60% can be removed in a single washing. The SLS interacts with theconditioners in this case too, however, building up on these cationics, so that the netwashing is greatly reduced.

Except for the specific problems encountered in cleaning CTAC and SAC with C12detergents, the most difficult of the preceding materials to remove from keratinsubstrates were the polycationic conditioners. Washing of these polymers with SLSresulted in only 43% removal. This is a result of the strong electrostatic bonds betweenthese polymers and the hair surface, coupled with the fact that multiple bonds areformed, all of which must be broken at about the same time in order to effect removalfrom the keratin substrate.

Less information is available concerning cleaning of dimethicone and hair spray resinsthan for the above lipids and cationics. The available evidence indicates, however, thatthe degree of difficulty in removing these materials from hair is closer to that of lipidsthan of cationics.

Cleaning of each of the above soils was considered on a more or less individual basis.These soils are not present on hair in isolation, however, but are found combinedtogether as a mixed solid/liquid soil. The effect of the presence of other soils on cleaningof a particular deposit is difficult to predict. A solid soil of interest may be in direct contactwith the fiber surface (solid-soilsubstrate attachment), or it may be coated with an oilysoil (liquid-soilsubstrate and solid-soilliquid-soil attachments). The presence of other soilsmay make cleaning of a particular soil easier or more difficult depending on the particular

nature and configuration of the accompanying deposits.

The observation that cleaning of SAC was easier in the presence of a lipid soil, ceteth-2,is one example of an added soil making a second soil easier to remove from a substrate.Similar observations have been reported [127]. Sebum, which is a lipid soil, is present toa varying degree on all human hair. It may be that cationics coated with this soil wouldbe easier to remove from hair than uncoated samples, while particles easier

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to remove from hair than sebum would be rendered more difficult to clean by thepresence of a lipid coating. More work needs to be done to elucidate these interactions.

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109a. Frank Bala, Colgate-Palmolive, unpublished results.

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17Surfactants in Dental ProductsMorton Pader*Consumer Products Development Resources, Inc., Teaneck, New Jersey

I. Introduction 385

II. Antiplaque Activity 386

III. The Use of Surface-Active Agents in Oral HygieneProducts 389

IV. Interactions of Surface-Active Agents with Bacteria 390

V. Safety and Performance 391

VI. Physical-Chemical Properties of Surfactants GenerallyUsed in Oral Care Products 392

VII. Formulation and Manufacture 394

VIII. Final Remarks 395

References 395

IIntroduction

The term surfactant, as used in this chapter, refers to anionic, cationic, and nonionicchemicals which are active by virtue of their ability to affect the surface of theirsubstrates. It is not limited to agents that act simply by separating a soil from itssubstrate.

Surface-active agents (detergents) have been used in oral care products for manydecades. Despite this, some aspects of their use are still contentious, especially theirroles beyond creating foams in toothpaste use and solubilizing flavors in oral rinses. The

*Deceased.

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purposes of this chapter are to review the current applications of surfactants in oral careformulation and to explore the role of these surfactants in areas beyond simpleformulation concerns.

''A clean tooth is a healthy tooth." This statement, or the equivalent can be traced to veryearly dental literature. The validity of the statement revolves around the definition of theword "clean." Views expressed by dental authorities a century ago, and confirmed byresearch over the intervening decades, have established that "clean" in the dental sensemeans freedom from bacteria (especially pathogenic bacteria), bacterial accretions, andextrinsic stain. It was also established that cleansing of the teeth with even powerfuldetergents was not sufficient of itself to assure the health or even cleanliness of a tooth.(One major company failed disastrously in an attempt to market a simple solution ofanionic detergent as a replacement for a fully formulated toothpaste.)

The development of new surfactants and surfactant applications for oral care has beenalmost stagnant over the past few decades. First, the surfactant is only a minor part oforal care compositions, and the relevance to oral care of certain detergents has still notbeen defined convincingly. Hence the surfactant has been considered of lesserimportance in the total arena of product function and formulation. Second, certainsurfactants have established niches in oral care products that are not likely to be filled byalternatives in the short term. A selection of surfactant materials for use in dentalproducts has been fine-tuned over the century, and the total number of operablesurfactants has been whittled down to a few strong, efficient standbys (e.g. sodium laurylsulfate in dentifrices). And third, the advances made in total product performance (suchas anticaries and other drug/cosmetic toothpastes) were accomplished at great expense.Naturally, there is strong reluctance to make any changes in excipients, such as thedetergent, which could jeopardize that performance. In reality, the past years have beena consolidation of surfactants for oral care, not an expansion.

IIAntiplaque Activity

Writing the section on dentifrices in the first edition of Surfactants in Cosmetics waspreceded by an intense interest by the dental profession in controlling dental plaque. Itwas recognized that dental plaque comprised a mass of bacteria. As a consequence, awide range of plaque control agents based on antiseptics and detergents wasinvestigated, including anionic, nonionic, and cationic detergents. Antiplaque activity wasidentified with a host of detergents. Cationics, in particular, showed antiplaque activity,which was attributed to their ability to kill plaque microorganisms without necessarilyremoving them from the oral cavity. One, chlorhexidine, was shown to be especiallyeffective and even today is used professionally for plaque control. Others were foundwanting as plaque control agents and for that or other reasons (e.g. oral side effects)were never employed in marketed oral care products. Of the many detergents discussed

in the first edition, only a few (chlorhexidine, sodium lauryl sulfate, and cetyl pyridiniumchloride [CPC]) are in mass-marketed oral products currently. (Oral rinse supplementedwith domiphen bromide uses CPC.)

Time has nurtured a better understanding of how surfactants operate in oral-careproducts, but one would be premature to say that a consensus exists. It is not within thescope of this chapter to discuss in depth the different attitudes of dental researchers overtime towards the value of and justification of detergents in some oral hygiene products.

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There is still debate. What is coming to the fore is the selectivity of detergents ininfluencing various oral hygiene conditions.

Few studies have been published on detergent systems designed to remove or reducedental plaque according to classical principles of soil removal. Yet detergent cleaning ofteeth and the oral cavity must, at an appropriate level, be not dissimilar from cleaningsoiled household substrates according to classic concepts of detergency. Schwartz [1]observed that cleaning a solid object (the substrate) consists in removing unwantedforeign matter (soil) from its surface, and that "detergency" is a term referring to thecleaning effect in systems with the following characteristics:

(1) The cleaning is accomplished by a liquid medium, the bath. (2) The cleaning action of the bath is not dueprimarily to a dissolving action of the soil, although such dissolving action may take place on certain of the soilconstituents. Nor is the cleaning action effected simply by shearing of the bath against the soiled substrate. (3)The cleaning effect is caused primarily by interracial forces acting among substrate, soil and bath. These forcesoperate to loosen the soilsubstrate bond and thereby facilitate soil removal. Although pure water is a surprisinglyeffective bath for separating some soilsubstrate combinations, the bath in most practical detersive systemscontains a special solute (or mixture of solutes), the detergent, that enhances the cleaning effect. In mostdetersive systems the bath is aqueous.

The cleaning process generally consists of (1) application of a liberal amount of the bathto the soiled substrate by immersion, brushing, spraying, etc., (2) working of the bathover the soiled surface by mechanical or hydraulic means (the beginning of soil removal);and (3) separation of substrate from the bath.

It is apparent that the classic concept of detersive cleaning, studied so intensely for thecleaning of fabrics and hard surfaces, is not unlike the operations involved in dental tissuecleansing. Classic theories of removal of soils (oils, solid particles, etc.) are applicable toall phases of dental cleaning. In the case of cationic detergent cleaning, it is probablethat the affected microorganisms are killed during submersion in the bath by chemicalinteraction of the cationic with the microorganisms, and that a residue of the cationic mayremain associated with the substrate, providing a prolonged release mechanism.Detergent cleaning in the oral cavity can be predicted, at least at some reasonable levelof confidence, by assessing the nature of the soil and substrate, the nature of the bathand its mode of application, and the physical forces involved in the process.

Before proceeding further, it should be pointed out that many dental investigators do notaccept the view that detergency without bacterial kill can be an important route to dentalcleanliness. Being schooled in pharmaceutics, they take the stance that elimination orreduction of dental soils can be achieved only by chemical means, such as chemicaldestruction of bacteria. Even if the chemical is a detergent, its major mode of action isexerted through its chemical properties.

First, let us define the soils to be removed by oral care products. Within minutes or hoursfollowing a dental prophylaxis the teeth become coated with a filmthe pelliclederivedfrom saliva [2]. This film is very tenacious, much too tenacious to be removed by adetergent bath alone. The best, most effective means for removing it is application of an

abrasive with a strong shearing force (the toothbrush). The pellicle should be removedbecause it can absorb stains (e.g. from cigarette smoke) and it can be the base

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to which oral bacteria can readily attach to the tooth and develop into dental plaqueswith a variety of undesirable properties.

Dental plaque is very complex. It undergoes multiple changes in structure and propertiesas it develops over time [2]. Initially, plaque tends to be a soft, relatively looseaccumulation of oral bacteria and debris. It can be removed virtually completely at thisstage by careful and diligent use of a toothbrush (probably better along with a dentifrice).By using popular measures to quantitate plaque (for example, visualizing it with a dye), itmight be concluded that a certain small amount of the plaque mass can be removed byrinsing with plain water, and better, with a detergent bath [3]. For most persons,however, a sufficient degree of plaque removal requires use of a toothbrush or similarmechanical device, and stain control requires an abrasive cleanser with or without asurface-active agent. A detergent is advantageous in the bath, at a minimum because theconsumer enjoys the foam.

Bacterial plaque must be controlled because it harbors pathogenic microorganisms, whichcan cause caries, gingivitis, and more destructive types of oral disease. Secondarily, it isimportant because it can develop into dental calculus (tartar), it can take on an unsightlyappearance, and it can harbor microorganisms responsible for oral malodor.

Most dental investigators of plaque inhibitors appear to be content to consider plaque asa homogeneous structure. They tend to disregard the possibility that differentagents/processes might exhibit greater or lesser efficacy depending on the degree ofplaque maturation. The softer, newer layers of plaque may well respond to removal bysimple detergent baths and mechanical forces, while removal of the older, calcifiedplaque layers requires more powerful tools. Apparent inconsistencies among studiesmeasuring plaque removal or inhibition can be traced to disregard of this fact.

Studies of the structure of dental plaque have revealed a variety of mechanisms wherebyits integrity is maintained, including intermolecular calcium bridges, van der Waals forces,hydrogen bonding, the elaboration by the bacteria of structurally specific polysaccharide"glues," etc. Not unexpectedly, then, attempts to combat dental plaque have taken avariety of approaches, from search for a "magic bullet" to a combination of agents eachcapable of interrupting some phase of plaque production.

Unfortunately, practically no studies on removal of oral bacteria, plaque in particular,have addressed the problem from the point of view of the surface chemist. Many dentalinvestigators have been content to accept two premises: (1) destruction of oralmicroorganisms by direct chemical kill is equated with removal of those microorganisms,and (2) surfactants in oral care products are of little value beyond their ability togenerate a foam, solubilize flavors, and perform other nonbiological functions. Thesituation closest to the truth is that surfactants in oral-care products can operate alongseveral separate paths simultaneously, which can make use of biological and purelyphysical features of the surfactant. Thinking along the lines of bacterial control by

surfactant systems, many features of oral-care products, which heretofore were acceptedwithout experimental support, can be addressed. For example, does the toothpaste"bath" play a role in plaque removal? Does the surfactant in toothpaste or oral rinse helpprevent redeposition of soil removed from a dental surface?

The evidence is limited, but it must be concluded that dental plaque, and/or elementsthereof, is labile to removal by detergent systems.

The relatively recent introduction to the market of an oral rinse containing sodium laurylsulfate (SLS) with antiplaque claims generated a strong debate on the antiplaque

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value of SLS. This debate involved many investigations of the antiplaque efficacy of SLSand cationics. This chapter is not a proper forum for describing the conclusions reached,because they are deduced from negative findings relevant to detergents and plaque. It isgenerally agreed that accumulation of plaque along the gingival margin can lead to thedevelopment of gingivitis, and some opine that there is a correlation between plaqueamount and intensity of gingivitis deriving therefrom. Study of an SLS-containingprebrushing oral rinse, however, showed that the rinse reduced plaque accumulationsignificantly, but there was no corresponding reduction in gingivitis [4]. Two separateevents, plaque reduction and change in disease (gingivitis) status appeared not to berelated. At least in this one case, plaque reduction per se did not appear to be anecessary precursor to improvement in gingival health. A clear, quantitative relationbetween plaque reduction and reduction of gingivitis incidence has been contended byseveral investigators. So far, lack of such a correlation appears to have beendemonstrated, especially for SLS, and less so for CPC. In the meantime, the lack of aclear-cut correlation has led some researchers to lean towards the view that maintenanceof a healthy dentition is more a function of overall good oral hygiene than of plaquecontrol specifically. (The definition of "overall good oral hygiene" can be the foundation ofimportant research studies.)

"Bad breath" is generated by organisms lodged in numerous sites in the oral cavity. Theelimination of bad breath is a prime reason for the use of toothpastes and mouth rinses.There is clear evidence that an (anionic) detergent-based oral rinse can effectivelyremove oral bacteria (as found on buccal tissue) and be as effective in control of thosebacteria as well as a germicidal rinse [5,6].

IIIThe Use of Surface-Active Agents in Oral Hygiene Products

Most common, active oral-care agents are delivered from pastes (dentifrices) and oralrinses. Products for denture cleansing (which will be discussed here only briefly) may bedelivered from liquids, tablets, or pastes. Some surface-active agents have foundcommercial use in all delivery forms, some in only specific forms. Table 1 depicts alimited picture of the application of detergents in major oral hygiene products on today'smarket. To be in accord with current views, the detergents are characterized as functionalor antimicrobial or both, and the products are representative of those most popular in theU.S. market.

Table 1 shows that surfactants, as used today in oral care products, can play passivephysical roles or roles intimately connected with oral microorganisms and sometimesboth. A few anionic surfactants have played multiple roles. It is virtually impossible toquantitate the individual contributions of the factors involved. Sodium lauryl sulfate is agood example. Sodium lauryl sulfate (at an appropriate concentration in the bath) hasbeen shown to be capable of

destroying or removing some oral microorganisms in vivo [3],helping to remove dental plaque [3],enhancing foam during product use,assisting the solubilization of certain flavors in oral rinses [5,6], anddemonstrating an increase in activity when supplemented with detergent builders [4,5,6].

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TABLE 1 Role of Detergents in Oral Hygiene ProductsDetergenttype Examples Product

type Roles Comment

Cationic Cetylpyridiniumchloride Oral rinses Antimicrobial

Chlorhexidine Oral rinses Antimicrobial By prescription onlyin the United States

Anionic Sodium laurylsulfate

DentifriceOral rinsePrebrushingrinseDenturecleanser

Foaming aid FlavorstabilizerAntimicrobialCleanser

In prebrushing rinseto facilitate removalof plaque

Nonionic Polaxamer 407Oral rinse Flavor solubilizerNo importantchemical germicidaleffect

IVInteractions of Surface-Active Agents with Bacteria

Classically, as already noted, dental investigators have preferred to reduce bacteriaresident in the oral cavity by attacking them with detergents (germicides) at low, buteffective, concentration, and this approach has resisted change. Even while admittingthat detergents without strong germicidal properties can reduce bacterial populations bywashing bacteria away, investigators take the view that direct chemical kill is necessaryto produce a major reduction in oral plaque bacteria. There is too little publishedinformation to generate a cohesive picture of the potential for detergency (soil removal)to reduce oral microbial populations and thereby counter that view. Extrapolating fromthe total literature on detergent effects on microorganisms, one can infer the following.

Nonionic surfactants will have relatively little effect, at use concentrations in oral-careproducts, on the survival of oral microorganisms. (There are exceptions, such as glycerylmonolaurate [7], which exhibits activity against specific organisms.) Nonionics can exhibitpowerful detersive action in appropriate formulations. Their capacity to remove oralbacteria or their secrections in current over-the-counter (O-T-C) products remainsunexplored.

Cationic surfactants kill oral microbes primarily by direct chemical action. The mosteffective in common use is chlorhexidine. Cationic surfactants derive their activity throughnumerous mechanisms [8]. For example, in the case of chlorhexidine it has beenproposed that mechanisms include adsorption of the chemical to negative groups on themicrobial surface, thereby preventing bacterial adhesion to the negative tooth pelliclesurface; displacement of calcium from plaque, thereby disrupting the plaque structure;and binding to the oral mucosa and releasing slowly therefrom, thus providing asustained-release effect. Rather than act as a detergent in the classic soil-removal sense,chlorhexidine (and other cationics) may cause staining of the teeth.

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Anionic detergents, such as SLS have been established convincingly to have effects onbacteria. These effects logically should carry over to at least some oral bacteria. Lysis ofbacteria has been proposed to follow the sequence of (1) adsorption of the agent to thecell wall and penetration thereof; (2) interaction with cellular components anddisorganization of the membrane; (3) leakage of low molecular weight metabolities, suchas amino acids, (4) degradation of proteins and nucleic acids, and (5) lysis of the cell walldue to wall-degrading autolytic enzymes [5]. The ability of certain anionic surfactants toproduce lysis of certain oral bacteria has been demonstrated [9].

There is enough data in the literature to allow one to speculate that different detergentsaffect specific oral bacteria in specific modes. Sodium lauryl sulfate reduces bacteriaresident in buccal tissue to about the same extent as cetylpyridinium chloride [5].Nonetheless, the latter has shown greater consistency in plaque control among differentlaboratories. And chlorhexidine certainly exerts some effects on oral bacteria that neitherSLS nor CPC can. For example, it has consistently demonstrated ability to reducegingivitis, whereas the other two surfactants have not.

VSafety and Performance

The generally recognized as safe (GRAS) surfactants are preferred for products used inthe oral cavity. Years of validation and wide-spread use have narrowed the number ofdetergent active ingredients used in today's oral products to a very small one.

Anionic detergents, past and present, were limited mainly to SLS and N-lauroylsarcosinate. The anionic surfactants are preferred in dentifrices for a variety of reasons.Among these are high foaming capacity, high detersive activity, good solubility in leansolvent systems, safety at use concentrations, ability to prepare them essentially free ofoff-flavors, and availability. Indeed, virtually every anionic detergent devised has beenrecommended in one instance or another for use in dentifrices. Specialty surfactants wereused from time to time for perceived superiority (e.g., sodium cocomonoglyceridesulfonate). The surfactant N-lauroyl sarcosinate was used for its antimicrobial propertiesbut was temporarily removed from the market because of excess complaints about thegeneration of mucosal lesions. It is now in a marketed dentifrice in the United States.Anionic detergents, such as SLS, may be primary irritants, but are quite innocuous at useconcentrations considered safe for oral treatment.

Cationic surfactants may exhibit undesirable side effects. There have been reports, forexample, that chlorhexidine can stain the teeth. Cationic detergents are used at lowlevels for their specific antimicrobial effects, however, and present no major esthetic orother problems in O-T-C products.

The nonionic surfactants are used in oral rinses primarily to solubilize and stabilize theflavor. Their foaming is weak. Their detersive properties in oral rinses have not been

assessed to any depth. The polysorbates and poloxamers are used almost exclusively inthe U.S. market, e.g. polysorbate 80 and poloxamer 407.

The nonionics generally are compatible with cationics. This feature has been exploited inseveral formulations, especially those in which it is advantageous to incorporate anantibacterial cationic in a foaming product, e.g. oral rinse. Attempts to obtain a foamingtoothpaste with nonionics have not been successful, at least commercially. Inadequatefoam is obtained even thoug amounts of nonionic are added.

The various surfactans generally are used as mixtures for optimal efficacy.

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VIPhysical-Chemical Properties of Surfactants Generally Used in Oral Care Products

1Sodium Lauryl Sulfate

Sodium lauryl sulfate is the detergent used most in dentifrice formulation. It is preferredto others in the United States and elsewhere, although it has no significant clearlydefined functional superiority compared to some other detergents, such as N-lauroylsarcosinate. Key reasons for its popularity in dentifrices include the following: (1) SLSfoams very well in the presence of oral materials, such as saliva; (2) SLS, although aprimary irritant, has been shown to be safe in laboratory experiments and decades of usein marketed dentifrices; (3) SLS is readily available in dental "grades," i.e. as a surfactantvirtually free of soapy flavor, relatively pure, almost colorless, and reproducible incharacteristics; (4) SLS is compatible with the commonly used active ingredients indentifrices, e.g. fluoride, and excipients used in some oral-rinse compositions; and (5)SLS is relatively stable for long periods of time in finished products.

The surfactant SLS has been implicated in the exhibition of the "orange juice" effect,namely, development of an astringent flavor following ingestion of certain foods,especially orange juice. This plaint is rarely, if ever, heard today. Either it had nofoundation in fact originally or was the result of impurities in the SLS of earlier days.

Studies have shown that SLS can remove dental plaque. One or more mechanisms ofaction can be involved, including pure detersive removal action and chemical destruction[3]. Sodium lauryl sulfate has been selected for use in oral care products because of itsability (like that of anionic detergents in general) to exhibit strong detersive activity inthe presence of saliva and other oral fluids. Not unexpectedly, detersive activity of SLS inan oral rinse is enhanced significantly by the presence of detergent builders, such assoluble pyrophosphate [6]. (The effect of the presence of builders on SLS's effect onbacterial cell walls has not been investigated in oral care.)

Sodium lauryl sulfate is marketed mostly as a mixture of C12 and C14 fatty-alcohol chainlengths, as would be obtained from coconut oil. It has only limited solubility in water andis formulated in oral rinses along with excipients (mainly nonionic surfactants), which notonly enhances the solubility of the SLS per se, but makes the SLS more effective as aflavor stabilizer [5].

Schwartz has prepared an excellent discourse on solid particle removal [1]. All of theelements of that type of operationdetergent bath, substrate, and agitationare found inboth brushing and rinsing with an SLS solution. Despite its high detersive power, SLS atconcentrations safe for use in the human mouth is still too weak to provide a bath thatcan operate successfully without some major mechanical support, such as a toothbrush.

2

Sodium Lauroyl SarcosinateThis compound was used as the surfactant in a prominent toothpaste and is in atoothpaste marketed today. It has virtually all the good features of SLShigh foamingcapacity, freedom from off-flavor, etc. Additionally, evidence was offered that itsantimicrobial activity could reduce the incidence of dental caries. The sarcosinate wasremoved from dentifrices, however, because of reports of excessive oral mucosal irritationby users of the dentifrice. Sodium lauroyl sarcosinate has recently been reintroduced into(another) marketed dentifrice, albeit one with a radically different formula from theoriginal and

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including SLS. (This supports the widely held view that safety of total product, not of asingle ingredient, must be assessed.)

3Sodium Dodecyl Benzene Sulfonate

This detergent is one of the most popular for general home and industrial cleaning. It hasbeen used in dentifrice in a purified form in countries other than the United States, buthas been practically supplanted by SLS around the world in accordance with themarketing and formulation directions that dentifrices have taken.

4Other Anionic Surfactants

Virtually every anionic detergent ever brought to market or disclosed in the patentliterature has been recommended as a surfactant for toothpaste. Apparently, none couldbe justified as replacement for SLS. The successful use of SLS in a variety of functionaltoothpastes, pastes which have been exposed to broad consumer and clinical populationsand shown to be safe and effective, makes it unlikely that a new detergent will supplantSLS in the foreseeable future.

5Polyoxyethylene Derivatives of Sorbitan Fatty Acid Esters

These materials are used mainly in oral rinses to disperse flavoring oils and maintainthem in dispersion. They also can provide a weak, open foam during rinsing. Theirapplication is primarily in the formulation of oral rinses that may or may not containalcohol. Polysorbate 20 is useful for this purpose.

The nonionics cited here (polyoxyethylene derivatives of sorbitan fatty acid esters andpolyoxyethylenepolyoxypropylene block polymer, see below) are used for stabilizing andfoaming. Whether or not they could be effective antimicrobial/antiplaque agents by virtueof their detergent action cannot be determined from published studies in the dentalliterature because their efficacy was assessed only in terms of ability to cause chemicalkill of microorganisms [10].

6Poly(oxyethylene)Poly(oxypropylene) Block Copolymers

These materials (poloxamers) are used in oral rinses to solubilize aromatics. On onehand, they probably have no substantial influence on the biological effect of the total oralrinse. On the other hand, their ability to remove bacteria has not really been studied.Poloxamers 188, 338 and 407 have been recommended for application in oral rinses.

7Cationics

Cationics have been discussed above in some detail. Their level in oral rinses is low, e.g.0.10.2% chlorhexidine, 0.05% CPC. They generally are compatible with nonionicsurfactants. But mixtures must be used with caution; there are reports that nonionics caninhibit the antimicrobiol activity of cationics [5]. It is improbable, because of cationicflavor, that enough cationic could be incorporated into a toothpaste or oral rinse toprovide detergency in the classic sense of separation of soil from substrate.

8Other Detergent Systems

Few studies have been published in recent years based on the use of new surfactants inoral care. Studies show some surfactants can inhibit the adhesion of bacteria to surfaces.There has been little interest in exploring this phenomenon in depth. The detergentC31G, a combination of alkyldimethyl glycine and alkyldimethyl amine oxide, is apotential

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antiplaque agent that gave positive results in several screening tests [11]. It has notbeen used in a commercial product.

VIIFormulation and Manufacture

1Dentifrices

There are two major types of dentifrice formulation, both comprising lean solventsystems, i.e. an aqueous phase with low proportion of water, usually substantially lessthan 50%. The abrasive amounts to 1525% in one type, about 50% in the other. Thesedentifrices contain about 0.52% surfactant. The surfactant in most dentifrices is SLS,which, at the indicated level, provides acceptable foam during tooth brushing.

Dentifrices contain polymers (gums and resins) to establish certain dentifrice rheologicalproperties. The detergent and polymer should interact predictably. The polymerspredominantly used in dentifrices provide structure by forming a three-dimensionalnetwork. The dentifrice ingredients are immobilized (more or less) within this network. Afew of the polymers are prepared as tightly packed structures that give little structurethree-dimensionally until they are solvated. The rate and extent of the solvation can beinfluenced by surfactants, e.g. by hastening solvation of the polymer. Not much has beenpublished on the effect of surfactants on polymers such as used in toothpaste, andsurprises can be encountered in toothpaste manufacture. The surfactant/polymer systemshould be understood thoroughly before venturing into toothpaste manufacture.

The character of the foam generated during toothbrushing is determined by many factors.There is no way at this time to accurately predict what it will be from examination of atotal toothpaste formulation because too many nondetergent features are involvedtheproperties of the abrasive, humectant, and polymer all play important roles. Many are noteven controllable by the dentifrice manufacturer, such as type of toothbrush, diligence onthe part of the brusher, whether or not the brusher prewets the toothbrush, whether thebrush is mechanically or electrically driven, etc.

Toothpowders are not popular. Virtually every dentifrice today contains fluoride andconsistent dosage of fluoride from a toothpowder is difficult to accomplish. Toothpowdersare essentially toothpastes without a liquid humectant system, and SLS can be used as asource of foaming. Toothpowders can be mixed in conventional powder-mixingequipment. Powdered SLS is available for this purpose.

2Oral Rinses

With perhaps the exception of products containing SLS for antiplaque activity, O-T-C oralrinses serve little or no known role in cleansing the mouth in the classic sense. As already

noted, surface-active agents are used to solubilize the flavors and keep them dispersedduring storage. The most widely used are the polyoxyethylene derivatives of sorbitanfatty acid esters and the polyoxyethylenepolyoxypropylene block copolymers. Thesematerials frequently are used in admixture. Proportion and concentration are dependenton the amount and type of flavor, e.g. mint or cinnamon. The literature suggests thatabout 0.05 to 0.20% surfactant is adequate.

3Denture Cleansers

The market is covered by two types of product, one not dissimilar from regular toothpasteand one which is an effervescent powder or tablet. (Formulation of the tablets is a fine

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art, and will not be discussed here.) The tablet may contain about 1% SLS to enhanceeffervescence, but bleaching action of an oxygenating agent released from the tablet isthe primary route towards cleansing. The SLS assists in creating and stabilizing the foam.Classic detergency theory (as discussed above) would predict that cleaner dentures canbe obtained with the paste compared to the effervescent powder. The paste provides allthe elements of a good dental cleanerabrasive, detergent bath, mechanical action, etc.The effervescent powder lacks some of these elements, and cleaning is dependent mostlyon chemical action.

VIIIFinal Remarks

The oral-care research and marketing worlds have paid little heed to surfactants in oral-care products. It is necessary to elucidate the roles of classic detergency (separation ofsoil from substrate) and bacterial kill as separate entities in the oral-care product arena.Resistance to do this could close the door to fruitful research, and possibly lead toincreased confusion on the processes involved in cleansing of teeth. This confusion couldpromote invalid advertising themes such as the inference that small bubbles generatedbetween the teeth can be as effective in removing bacteria and other debris as atoothbrush bristle applied to the interdental spaces.

References

1. A. M. Schwartz in Surface and Colloid Science (E. Matijevic, ed.), Wiley Interscience,New York, 1972, vol. 5, pp. 196241.

2. M. Pader in Oral Hygiene Products and Practice, Marcel Dekker, New York, 1988, chap.4.

3. L. Bailey, Clin. Prev. Dent. 11:21 (1989).

4. T. Schiff and L. C. Borden, J. Clin. Dent. 4:107 (1994).

5. M. Pader in Surfactants in Cosmetics (M. M. Rieger, ed.), Marcel Dekker, New York, vol.16, chap. 10.

6. M. Pader and C. T. Elton, U.S. Patent 4,150,151, Lever Bros. Co., 1979.

7. J. J. Kabara, P. Lynch, K. Krohn and R. Schemmel, in The Pharmacological Effect ofLipids (J. J. Kabara, ed.), The American Oil Chemists' Society, Champaign, IL, 1978, chap.3.

8. M. Pader in Oral Hygiene Products and Practice, Marcel Dekker, New York, 1988, chap.10.

9. M. R. J. Salton, J. Gen. Physiol. 52:227S (1968).

10. J. K. Lim, S. Smith, J. McGlothlin and V. R. Gerenser, Caries Res. 16:440 (1982).11. A. M. Corner, V. J. Brightman, S. Cooper, S. L. Yankell and D. Malamud, J. Clin. Dent.2:34 (1990).

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18In Vitro Interactions:Biochemical and Biophysical Effects of Surfactants on SkinLinda D. RheinWorld Wide Therapeutic Skin Care, Johnson & Johnson Consumer Products, Skillman, NewJersey

I. Introduction 397

II. Surfactant Action on Stratum Corneum Proteins 398

A. Binding 398

B. Membrane Swelling 399

C. Role of the Critical Micelle Concentration 402

III. Surfactant Interactions That Counter Skin Irritation 405

IV. Effect of pH on SurfactantInduced Swelling andIrritation 407

V. Surfactant Action on Stratum Corneum Lipids 410

A. Extraction of Stratum Corneum Lipids by Surfactants 410

B. Surfactant Effects on Physical Chemical Behavior ofSkin Lipid 414

VI. Action of Surfactants on Living Epidermis 421

References 424

IIntroduction

Surfactants can interact with skin in a multiplicity of ways. They first act on the surface ofthe stratum corneum, then penetrate this layer and perhaps beyond it. Within thestratum corneum, potential target sites of action are intercellular lipid, keratin incorneocytes, and desomsomal intercorneocyte connections. If stratum corneum has beenpermeated, surfactants can affect living-cell metabolism in the epidermis or even elicit acytotoxic action. Penetration past the living epidermis into the dermis can elicit aninflammatory response. The surfactant may not even have to act directly on the dermis.Communication via production of cytokines that can elicit a response from dermal

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components also occurs. This chapter focuses on action of surfactants on stratumcorneum and epidermis, reviews studies that used various in vitro approaches to profiletheir interactions, and explores in depth the role of surfactant solution phenomenon incontrolling the action of surfactants on stratum corneum.

IISurfactant Action on Stratum Corneum Proteins

Certain surfactants have been known for decades to denature the secondary structure ofproteins [1]. Some investigators have studied the interaction of surfactants with intactstratum corneum. Since 70% of the dry weight of stratum corneum is proteinaceous, onetherefore might foresee the opportunity for considerable interaction with sites on theprotein. Two parameters were studied (1) binding to the membrane and (2) membraneswelling.

ABinding

The binding of alkyl sulfate-type surfactants to human callus was investigated byImokawa and Mishima [2]. Figure 1 shows the adsorption isotherms for the homologous

Fig. 1Adsorption isotherms for alkyl sulfates with isolated calluspowder in vitro. Experimental conditions were as follows:callus, 48 to 80 mesh, pH 7.0, 6-h incubation at 40°C.

(From Ref. 2. Reproduced with kind permission of MunksgardInternational Publishers Ltd., Copenhagen, Denmark.)

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series of alkyl sulfates to callus measured in vitro. It is apparent that they followLangmuir's model, suggesting a limited number of saturable binding sites. However, itwas further noted that the apparent saturation of the isotherms occurs at approximatelythe critical micelle concentration (CMC) for each surfactant. Because the concentration ofsurfactant monomers becomes constant above the CMC, this would limit the number ofmonomers (or submicellar species) available to bind to the callus. Thus the apparentsaturation at the CMC may not be attributed to saturation of binding sites, but rather tothe availability of a fixed dose of monomer above the CMC. These data are alsoconsistent with the hypothesis that the surfactant monomer rather than the micelle is thespecies that interacts with the skin. Thus the saturation phenomenon observed in theisotherm may be related to this particular solution property of the surfactants. One canthen speculate that the greater the surfactant binding to keratin, the greater the extendof denaturation of keratin protein; once these events occur extensively, the surfactant willpenetrate through the stratum corneum into the living tissue. In the living tissue, theirdenaturing activity continues, but this time an inflammatory reaction sets in to repair thedamage.

Faucher and Goddard [3] have also studied the binding of detergents to keratinaceoussubstrates. They reported for sodium lauryl sulfate (SLS) that binding increased overtime. It followed a linear dependence on the square root of time, consistent with adiffusion process. The slopes of the uptake versus square root of time lines can beregarded as a measure of rate of sorption. Again the rate function for surfactant uptakeversus concentration at 1 hour is biphasic and intersects at the CMC of SLS.

These authors also examined binding of sodium lauryl ether sulfates containing differentlevels of ethoxylation to bleached human hair. They found that increasing the degree ofethoxylation concomitantly decreased binding. Various explanations are possible for thisphenomenon. As ethoxylation increases the molecular size increases making it moredifficult to penetrate the keratin matrix. Additionally the CMC decreases and thus thesurfactant monomer level decreases, rendering less surfactant available to interact withthe substrate, if the monomer is the interactive species. The relationship of CMC to skinreactivity of surfactants will be addressed in detail in a later section.

BMembrane Swelling

Another in vitro response of stratum corneum to surfactantsmembrane swellinghas beenprobed in depth. Putterman and coworkers [4] and Rhein et al. [5] have shown thatexposure of isolated stratum corneum to anionic surfactants induces continuous swellingof the membrane. The swelling occurs in all dimensions, but is substantially greater in thethickness dimension. The extent of swelling induced by various surfactants parallels theirpropensity to elicit clinical erythema (Table 1); that is, more irritating surfactants causedmore swelling. Associated with the swelling reaction was curling and twisting of isolatedstratum corneum, which dramatically decreased the width of the treated strip [6]. This

curling phenomenon and stratum-corneum swelling respond similarly to varioussurfactants, and they both directly parallel the clinical irritation potential of variousanionic surfactants; that is, the greater the twisting, the more the swelling, the greaterthe irritation potential [6]. Other authors used an alternative membrane, cross-linkedcollagen (Helitrex Corporation), to track swelling. This membrane behaved surprisinglysimilar to stratum corneum [7].

Rhein et al. [5] found that surfactant-induced stratum corneum swelling was (1)

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Table 1 Relationship Between Surfactants' Clinical Irritation Potential and TheirAbility to Cause Stratum Corneum to SwellSurfactant Skin irritation in vivoa Stratum corneum swellingb (%

change in length)Dodecylbenzenesulfonate Severe within 1 day 10.0

Sodium lauryl sulfateSevere within 1 day 11.8

AEOS-3EOc Mild to moderate within5 days 4.0

AEOS-6EOc Mild to moderate within5 days 1.5

AEOS-12EOc None after 5 days 1.5Polysorbate-20 None after 5 days 0.2aFrom Blake-Haskins et al. Ref. 7; human subjects, 10% concentration, pH 7,Duhring chambers.bMethodology is given in Ref. 5. Results shown are summarized from this work.Concentration was approximately 75 mM.cAEOS is ethoxylated alcohol sulfate with 3, 6, or 12 ethoxylate units.

dependent on surfactant concentration, (2) increased with increased incubation time, and(3) reversible under conditions of low concentration (1%) and shorter incubation times (1to 6 h). Because swelling is reversible, it probably results from interactions of surfactantswith stratum corneum proteins rather than lipids. Indeed, Putterman et al. (4) showedthat pretreatment with lipid solvents would potentiate surfactant-induced stratumcorneum swelling, probably by exposing more binding sites on the protein. The reversibletwisting and curling of the stratum corneum may also be caused by conformationalchanges in proteins resulting from their denaturation.

When stratum corneum swelling was measured as a function of anionic surfactantconcentration, the swelling induced appeared to saturate at the CMC [5]. Again, thissuggests that the surfactant monomer rather than the micelle is the species that interactswith the proteins and that the surfactant solution properties probably control the reaction.Systematic structural studies of the surfactant-induced swelling reaction also verify thatstratum corneum swelling parallels the known irritation potential of structurally relatedsurfactants. Maximum swelling was induced by surfactants with C12 or C14 alkyl chainlengths in homologous series of several anionic surfactants, for example, alkyl benzenesulfonates, alphaolefin sulfonates, alkyl sulfates, and paraffin sulfonates (see Fig. 2). Thisparallels their known in vivo clinical irritation, which is maximal at C12 (see review, Ref.8). Ethoxylation of alkyl sulfates reduces the swelling response (see Table 1 and Ref. 5),which also parallels the known reduced irritation of these ethoxylated variants [6,7]. Thepresence of divalent cations reduces or inhibits the swelling response to anionicsurfactants. Schrader's in vivo clinical results [9] suggest that magnesium lauryl sulfate isalso clinically less irritating than the sodium salt. Cationic surfactants have an even moreinteresting effect. Alkyl trimethylammonium bromides, which are clinically irritating [10],inhibit stratum corneum [5] and collagen [7] swelling. Positive charges obviously changethe nature of the interaction of the surfactants with the skin surface. This will be

discussed later.

The reason for the maximum activity (whether quantified as swelling, protein denaturingpotency, induction of skin roughness, or clinical irritation) usually occurring

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Fig. 2Dependence of swelling of human stratum corneum on alkyl chain length for various surfactants.