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STUDIES ON MULTICOMPONENT COATING SYSTEMS IN RELATION phd. STUDIES ON MULTICOMPONENT COATING SYSTEMS

Aug 06, 2018

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  • SEMMELWEIS UNIVERSITY

    DOCTORAL SCHOOL OF PHARMACEUTICAL AND PHARMACOLOGICAL SCIENCES

    STUDIES ON MULTICOMPONENT COATING

    SYSTEMS IN RELATION TO PELLETS

    Ph.D. THESIS

    DM ORBN

    Research Tutor: Prof. Dr. Istvn Rcz, Ph.D., D.Sc.

    Semmelweis University Department of Pharmaceutic and Gedeon Richter Ltd.

    Budapest, 2002.

  • I

    CONTENTS A INTRODUCTION 1 B OBJECTIVES 2 C LITERATURE REVIEW 3 C.1. The pellet 3

    C.1.1 Pellet as a pharmaceutical dosage form 3 C.1.2 The possibilities of pellet manufacturing 7 C.1.3 Coating 17

    C.2. Coating systems 18 C.2.1 Coating solution formulation 18

    C.2.1.1 Polymers 18 C.2.1.1.1 Physicochemical characteristics of latexes 20 C.2.1.1.2 Minimum film-forming temperature (MFT) 20

    C.2.1.2 Plasticizers 21 C.2.1.3 Colouring systems 23

    C.2.2 Glass Transition Temperature of Polymers (Tg) 25 C.2.3 Enthalpy relaxation of glassy polymers 25 C.2.4 Film coat quality 28 C.2.5 Release mechanisms and control of 31

    drug release of coated dosage forms C.2.5.1 Factors influencing drug release 36

    D. MATERIALS AND METHODS 38 D.1 Materials 38 D.2 Sample preparation 38

    D.2.1 Preparation of free polymer films 38 D.2.2 Preparation of pellets 38

    D.2.2.1. Preparation of pellets in Stephan UMC-5 apparatus 38 D.2.2.2. Preparation of pellets in Pharmex 35T-Spheromat 39

    extrusion-spheronization equipment D.2.2.3. Preparation of pellets with rotofluidization equipment 39

    D.2.3 Granulometric examination of pellets 40 D.2.3.1 Study of flowability of pellets 40 D.2.3.2 Study of the particle size distribution of pellets 40 D.2.3.3. Determination of the tapped and loose density of pellets 40

    D.2.4 Coating of the prepared pellets in Kugelcoater HKC-5 40 coating equipment

    D.2.5 Coating of the prepared pellets in Aeromatic Strea-1 43 coating equipment

    D.2.6 Coating of the prepared pellets in rotofluidization equipment 44 D.3 Examination of the coating dispersions 44

    D.3.1 Determination of the Refractive Index of Polymer Dispersions 44 D.3.2 Calculation of the Molar Refraction by the Lorenz-Lorenz Equation 44 D.3.3 Dynamic surface tension measurements 45 D.3.4 Determination of the white point of dispersions 45 D.3.5 Thermoosmometric study of polymer dispersions 46

    D.4 Examination of the polymer free films 46 D.4.1 X-Ray Diffraction (XRD) Measurements 46

  • II

    D.4.2 Determination of the Glass Transition Temperature of cast polymer films by Differential Scanning Calorimetry 47

    D.4.3 Determination the enthalpy relaxation of polymer films at the glass 47 transition temperature

    D.4.4 Microscopic examination of coating with FT-IR microscope 48 D.4.5 Positron lifetime measurements of free films 48 D.5 Examination of the coated pellets 50

    D.5.1 Examination of the particle size distribution of coated pellets 50 D.5.2 Friability test of the coated pellets 50 D.5.3 Scanning electron microscopy studies 50 D.5.4 Recording diffuse reflectance spectra 50 D.5.5 In vitro dissolution study 50 D.5.6 Analysis of the results of dissolution studies 51 D.5.7 Determination of dissolution of drugs in vitro by means of the

    Sartorius Dissolution Simulator type SM 167 51 51 E. RESULTS AND DISCUSSION 52 E.1 Effect of the Concentration of the Water Soluble Plasticizer on the

    Dissolution Characteristics of Eudragit Coated Metoprolol Pellets 52 E.2 Effect of the Concentration of the Water Insoluble Plasticizer on the

    Dissolution Characteristics of Eudragit Coated Theophylline Pellets 56 E.3 Polymer-Plasticizer Interactions: Comparison of

    Experimental Data with Theoretical Results 57 E.4 Coating Polymer-Plasticizer Interaction in relation to the

    Enthalpy Relaxation of Polymer 74 E.5 Comparative Evaluation of Coated Pellets Produced by Different Fluidized

    Bed Equipments 83 SUMMARY 90 REFERENCES 92 ACKNOWLEDGEMENT 100 BIBLIOGRAPHY 101

  • 1

    A INTRODUCTION

    For historical reasons, sugar coating has been the most extensively employed

    method but is at present being superseded by film coating techniques. Film coating of

    tablets in contrast is a relatively new technology dating back to the 1950s (Abbott

    Laboratories). Most newly developed coated products are film coated and water is now

    the first choice solvent for new film coated formulations (tablets, microcapsules,

    pellets). The major reasons for coating can be summarized as follows:

    1. Protection of active ingredients

    from the environment, particularly light and moisture.

    2. Safety/Identification

    Patients may be taking several medications and colour is a useful

    identification of the correct compound.

    3. Taste/Odour barrier

    Many active substances have a bitter taste or an unpleasant odour. By

    placing an isolating barrier around the tablet, these factors can be reduced

    or eliminated thus improving patient compliance.

    4. Improved appearance

    The granular nature of some formulations can be covered by an opaque

    coating giving a more homogeneous appearance.

    5. Brand identity

    Many pharmaceutical companies are rightly proud of their reputations

    and a company brand appearance enforces this pedigree.

  • 2

    6. Improved handling on high speed automatic filling and packaging

    equipment

    Very often coating confers an added mechanical strength to the

    tablet core. Crosscontamination is also reduced in the

    manufacturing plant as "dusting" is eliminated by coating.

    7. Functional coatings

    These methods are used to impart enteric or controlled release

    properties to the coated dosage forms [1].

    B OBJECTIVES

    In the literature review of my thesis I intend to summarize those references which are in

    close connection with my experimental research work. I will give an overview of those

    methods further developed by myself in the course of the industrial coating of solid

    dosage forms.

    The purposes of the literature part of my thesis were to study:

    the different methods applied for pelletization and coating

    the commonly applied film coating materials, among them with the

    two key excipients of coating, with the coating polymer and plasticizer,

    the physico-chemical characterisation of coating systems,

    different modified release dosage forms and the methods applied for their

    characterisation.

  • 3

    The objectives of the experimental part of my thesis were:

    to formulate pellets for the coating procedure from commonly applied active

    ingredients

    to prepare and characterize differently coated pellets

    to characterize the coating systems and

    the free films of coating systems by different physico-chemical methods

    to evaluate qualitatively and quantitatively the possible interactions between

    the two key ingredients of coating systems, those of the polymer and

    plasticizer.

    C LITERATURE REVIEW

    C.1. The pellet

    C.1.1 Pellet as a pharmaceutical dosage form

    Although the basic meaning of the word 'pellet' is 'a small ball or tube-shaped piece of

    any substance', in the different branches of industry and agriculture this term is used to

    indicate particles or piles of particles of various shape, size and scale, which are

    produced by granulation, extrudation, pelletisation, drop-frosting 2.

    Henceforward - according to pharmaceutical requirements and specialisation - the term

    'pellet' is to refer to granuled pharmaceutical dosage form for peroral usage, which is

    characterised by 10-3 - 10-4 m in size, near-spherical form, slightly uneven surface and

    compactness approximate to that of agglomerated materials (low porosity). Thus the

  • 4

    advantages of the pellet as a pharmaceutical dosage form are implied in the above given

    definition 2-4.

    Good coating properties: The minimum scale of surface/capacity (volume) relatively

    even surface and small degree of porosity from the point of view of coating - especially

    filmcoating - is optimal both technologically (low powder formation, quick drying,

    reduced proneness to agglutination) and because of the relative quantity of the coating

    material; e.g. fluidisation - granules produced by spraying process - the structure of

    which can be compared to that of breadcrumbs' - are practically impossible to abrupt

    with reasonable quantity of coating material. In connection with good coating properties

    fraction toughness and abrasion hardness derived from the shape and form of the

    granules, and the almost identical specific surface of the particles from successive

    batches can also be mentioned.

    Adjustable active ingredient transmission: The definite specific surface derived from the

    near-spherical shape (form) which can reliably influenced by modifying the size of the

    particles, and the good coating properties ensure almost infinitely adjustable active

    ingredient transmission and planable active ingredient transmission profile.

    Regarding the latter we should think - for example - that the 'small balls' can be covered

    by coating different in quality and thickness, and these can be arbitrarily blended

    together before filling capsules or compression. In this way the ingestion of the initial

    and the maintaining dose can happen simultaneously and safely, alongside with the

  • 5

    elimination of the side-effects cau