PREFORMULATION STUDY: FOR SOLIDS Presented By:- Mr. BHANDARI UMESH M. 1 st yr M - Pharm. Department of Pharmaceutics. RCPIPER, SHIPUR 1
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PREFORMULATION STUDY:FOR SOLIDS
Presented By:-Mr. BHANDARI UMESH M.1st yr M - Pharm.Department of Pharmaceutics.RCPIPER, SHIPUR
05/01/2023
CONTENTS
INTRODUCTION OBJECTIVES PREFORMULATION STUDIES PHYSICOCHEMICAL
CHARACTERISATIONS ANALYTICAL MEASURES CONCLUSION REFERENCES
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INTRODUCTION
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Preformulation testing is the first step in the rational development of dosage forms.
If an organic compound shows sufficient desirable pharmacological activity, next step is
to incorporate the compound in dosage form.
Preformulation may be defined as phase of research and development where the
preformulation scientific charecterises the physical, chemical , mechanical and
medicinal properties of a new drug subject to in order to develop ,safer , and effective
dosage form.
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OBJECTIVES
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To develop the most stable , safe and effective dosage form with maximum bioavailability.
To confirms absence of barrier for the development of compound into safe and marketable drug
To study the physicochemical characterization of drug To select the most suitable excipients.
Establish its compatibility with common excipients
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WHY PREFORMULATION IS IMPORTANT ?
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It describes the process of optimizing the delivery of drug thorough determination of physical, chemical properties of new drug molecule that affect drug performance and development of an efficacious stable and safe dosage form.
Preformulation studies on a new drug molecule provide useful information for subsequent formulation of a physicochemically stable and Biopharmaceutically suitable dosage form.
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1. BULK CHARACTERIZATION : Bulk properties of the solid form such as crystallinity, polymorphism, particle size, powder flow property, and surface characteristics are likely to change during process development.
Crystallinity The crystal habit and internal structure of drug can affect the bulk and physicochemical properties, but sometime same internal structure but different habit.
Compounds have several different habits ( platy, equant, needle, bladed, and prismic etc.) eg. Novobiosin (antibiotic)
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PHYSICOCHEMICAL PROPERTIES
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POLYMORPHISM
When a substance exist in more than one crystaline species with a different internal structure thus various forms called as polymorphism
Formation of different polymorphs depends on solvents, temperature, pressure, rate of cooling, etc.
Polymorphic transitions can also occur during milling, granulating, drying and compressing operations
Two types of polymer• Enantiotropic eg. Sulphur • Monotropic eg. Glyceryl sterate
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Pseudo-polymorphism
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The molecular complex is incorporated in crystallizing solvents molecules, at specific site with in crystaline lattice and has steriometric number of solvent molecule complex
Two types• Hydrates incorporated solvent is water• Solvates incorporated solvent other than water
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Particle size
Study of particle size give an information about solubility, dissolution rate, absorption etc.
Smaller the particle size and greater surface area and faster the dissolution rate better will be the absorption rate and get higher bioavability of drug
eg. 1. Hydrophilic drug : Griseofulvin and spironolactone 2. Hydrophobic drug : Aspirin
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Powder flow property
The flow properties of a powder will determine the nature and quantity of excipients needed to prepare a compressed or a powder dosage form.
Most flow property significantly affected by change in partical size, density, shape , electrostatic charge and adsorbed moisture.
Flow property of powder is not good then weight variation hardness and thickness variation occur
Method for measurement of flow property• Angle of repose• Bulk density
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ANGLE OF REPOSE
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Angle of repose Flow property
<20 20-30 30-34 >40
Excellent Good PassableVery poor
Angle of repose of the granules was determined by the height cone method. A funnel was fixed to a desired height and granules were filled in it. They were allowed to flow down on a graph paper fixed on a horizontal surface’
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Bulk density
Carr’s index = ( tapped density – poured density) poured density
Hausner’s Ratio = tapped density poured density
A. Carr’s Index :
B. Hausner’s Ratio : X 100
X 100
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HYGROSCOPICITY
Many pharmaceutical materials have the tendency to adsorb atmospheric moisture (specially water soluble salt ) they called as hygroscopic and this phenomenon know as hygroscopicity
Hygroscopicity determine by Thermo gravimetric analysis Gas chromatography Karl Fischer titration
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1. INTRINSIC SOLUBILITY
It is equilibrium solubility of the free acids or free bases form of an ionisable compound at a pH where it fully unionised
Orally administered drug must dissolve in the aqueous fluid of the GIT prior to absorption.
Solubility can be improved by addition of cosolvents.
It can be determine by adding excess amount of drug to fixed volume of a solvent till saturation , and then filter then determine the concentration of drug
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SOLUBILITY ANALYSIS
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2. Drug pKa / Ionization at physiological pH
pKa is the dissociation constant of a drug.
The nonionized substances is lipid soluble thus dissolve in lipid material of the membrane and transported by passive diffusion.
Where as, the ionized substances is a lipid insoluble therefore permeation is slow.
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The percentage of ionization can be calculated by Henderson Hasselbalch equation … For Acidic compounds:
For Basic compounds:
Degree of ionization depends up on the pH.for acidic drugs pKa ranges from 3-7.5.
for basic drugs pKa ranges from 7-11.
pH = pKa + log(unionized drug/ionized drug)
pH = pKa + log(ionized drug/unionized drug)
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3. PARTITION COEFFICIENT
Partition coefficient is a ratio of equilibrium concentration of drug in oil phase to equilibrium concentration of drug in aqueous phase .
where, Co-organic phase concentration
Cw-aqueous phase concentration
It useful for the measuring liphophilic charecter of drug.
K=Co/Cw
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• Eg. n- octanol • Chloroform• Ether etc.
various organic solvents used
4. SOLUBILITY ENHANCEMENT solubility of poorly water soluble drug can be enhanced by one of the following method.
• Co-solvency eg. Ethanol, PEG, glycerin• Solubilisation eg. Tween, SLS
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5. DISSOLUTION
To know the gastrointestinal absorption & other physicochemical properties.
The intrinsic dissolution rate is determined by the rotating disc method.
The dissolution rate is described by Noyes-Whiteny equation.
=
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dc DA dt = h (Cs – C)
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DRUG STABILITY In this study includes both solutions and solid-state experiments under various conditions for handling, formulation, storage, and in vivo administration.
Stability is important part of drug development program
Acid sensitive drugs protected from highly acidic environment of the stomach by coating it with suitable polymers.
Solid phase stability depends on several factors like temperature, pH, humidity, hydrolysis, oxidation, etc…
STABILITY ANALYSIS
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COMPATIBILITY
Compatibility test play a very important role in the preformulation studies of oral dosage forms.
Problems arise because of the interaction with other drug substances and with preservatives, stabilizers, dyes, and flavors.
It is important for the formulator of a new drug substance to know with which excipients he can work and which he cannot.
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DRUG- EXCIPIENT COMPATIBILITY STUDY
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ANALYTICAL MEASURES
Various analytical techniques are available for the investigation of the physicochemical properties and determination of impurity of new drug molecules. These includes:
1. Microscopy 2. Spectroscopy3. Chromatography4. Thermal method
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A. MICROSCOPY In this technique substances are examined under the microscope. It gives information about shape, thickness, particle size, etc. of drug molecules.
By this method we can study crystal morphology, difference between polymorphic character of molecule. Following microscopic tech
Electron microscopeOptical microscope SEM TEM
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B. SPECTROSCOPY1.UV and Visible Spectrophotometry
When organic molecules in solution, or as liquid, are exposed to light in the visible and ultraviolet light regions of spectrum, they absorb light of particular wavelengths depending on the type of electronic transition that is associated with the absorption.
The electronic transitions depends on the electron bonding with in the molecule.
Detection of impurity.
UV study of compounds gives information regarding unsaturation of compounds.
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2. IR Spectroscopy
The study of the interaction of electromagnetic radiation with vibrational and rotational resonances within a molecular structure is termed as IR Spectroscopy. Gives an information regarding functional group present in new drug molecule.
FT-IR use for both qualitative and quantitative analysis of sample.
IR has the ability to differentiate isomers groups such as Cis-trans double bond compound.
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3. X-RAY DIFFRACTION
When a beam of non homogenous x-rays is allowed to pass through a sample the x-ray beam is diffracted & it is recorded by means of photographic plates .
Single Crystal X-ray provides the most complete information about the solid state.
It is used to differentiate the amophous and crystalline forms.
This method is tedious, time consuming & hence unsuitable for routine use.
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C. CHROMATOGRAPHY
In the preformulation studies, chromatographic techniques such as
• TLC• HPTLC • HPLC• GC • FLASH CHROMATOGRAPH
The major advantages are direct analysis of aqueous samples, high sensitivity, and specific determination of drug concentration, separation of drug from impurities or degradation products.
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Analytical data from TLC may be required to precisely determine the kinetics of decomposition.
HPLC and GC are useful for solubility measurements.
GC has strong separation power.
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D. THERMAL ANALYSIS
In the preformulation studies, Thermal analysis techniques such AS
• DTA• DSC• TGA
These following method are particularly useful in preformulation studies including purity, polymorphism, solvation, degradation, and excipient compatibility.
It measures physical or chemical changes of drug molecule
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CONCLUSION
Preformulation studies on a new drug molecule provide useful information for subsequent formulation of a Physicochemically stable and Biopharmaceutically suitable dosage form.
Thorough Preformulation work is the foundation of developing effective and economical formulations.
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1) Leon Lachman, Herbert A.L, The theory and practice of industrial pharmacy, special Indian edition 2009: CBS publishers and distributors. Pg no.. 171- 196
2) Banker GS, Rhodes CT., Modern pharmaceutics, 4th ed. New York: Marcel Dekker; 2002. p.167-184
3) Alfred Martin., Physical pharmacy. 4th ed. New York: Lippincott Williams & Wilkins; 2001. p. 77-100
4) Michael E. Aulton, Aulton’s pharmaceutics, 3rd ed Elsevier Ltd 2007, page no. 336-370
REFERENCES
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5) D.A. Skoog, F.J Holler, S.R. Crouch, Instrumental analysis Indian edition New Delhi, 2011, page no.191,836,865-867,893-896,976-988
6) A.H. Nathani, Ready retrive, Pharmaceutical formulation, 1st ed Carrier publication Nashik, page no. 1-22
7) Chatwal G.R, Anand S.K, Instrumental method of chemical analysis, 5th ed Himalaya publication, Mumbai 2013, page no. 2.177,
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