Abstract

Liquisolid compact is a novel dosage form in which a liquid medication is converted to

a dry free flowing powder and compressed. Liquid medication may a liquid drug, drug solution
or dispersion in a non volatile solvent or solvent system. Objective of the study was formulation
development of liquisolid compacts of clopidogril and its characterization. The present study was
carried out in different phases involving pre formulation studies, formulation development of
liquisolid compacts containing clopidogril and evaluation of the developed formulations. Pre
formulation studies comprised of development and validation of UV-visible spectrophotmeteric
method of analysis for glimepiride

Various formulations of liquisolid compacts were developed using different types of

carrier material. All the developed formulations were evaluated before and after compression.
Before compression the powder blend was evaluated for bulk density, tapped density, angle of
repose, Hausner ratio, Carr’s Index, flowability and moisture content. While compressed
liquisolid compacts were evaluated for physical parameters (weight variation, tablet thickness,
wetting time, drug content and moisture content), mechanical strength of tablets (crushing
strength, tensile strength, specific crushing strength and friability), disintegration behavior
(disintegration time and oral disintegration time) and dissolution rate.

Clopidogril is a poor water soluble drug. It exhibited better solubility in methanol and
analytical grade methanol was used as solvent for development of UV-visible
spectrophotometric method of analysis. UV visible spectrophotometric method of analysis was
accurate and specific for glimepiride. Methods of analysis was quiet linear, having r2 values of
0.998 and regression equation as Y = 0.0391X. The presence of excipients had no effect on the
response and drug solution in methanol remained stable for three days.

Physically tablets from all the formulations had smooth and shiny physical appearance,
without any sticking and picking. There were no visible signs of the presence of non volatile
solvent system. Crushing strength of the liquisolid compacts was in the range of 2 – 12 kg and
friability was below 1%, indicating their better mechanical strength. Liquisolid compacts of
clopidogril showed good disintegration behavior and disintegration time was within the official
limits. Drug release from liquisolid compacts was governed by the nature of the carrier material.

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Starch and micro crystalline cellulose resulted in faster dissolution rate while inclusion of
hydroxyl propylmethyl cellulose (HPMC) resulted in sustained release for longer period of time.
It was concluded that liquisolid compacts can be prepared for clopidogril, with modified release
characteristics using carrier material of different nature.

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 Acknowledgement

First of all many thanks to Almighty Allah, for uncountable blessings to accomplish the

study.

I would like to thank my research supervisor Dr. Amjad Khan, Pharm-D, PhD, from the

core of my heart for his guidance, encouragement, critical evaluation and confidence that he gave

me throughout the study.

I am grateful to Dr. Roohullah (Chairman Department of Pharmacy) for his moral

support.

BEENISH ALI

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 DEDICATED

To

My Family
FOR THEIR PRAYERS AND SUPPORT

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 Table of Contents

1. INTRODUCTION ……………………………………………………………………. 1
2. BACKGROUND (LITERATURE SURVEY) ……………………………………... 2
2.1 Clopidogrel 2
2.2 Physico-chemical characteristics of clopidogrel 2
2.3 Mechanism of Action 4
2.4 Pharmacodynamics 5
2.5 Pharmacokinetics 6
2.5.1 Absorption 6
2.5.2 Metabolism 7
2.5.3 Distribution 8
2.5.4 Excretion or Elimination 10
2.6 Dose and administration of Clopidogrel 10
2.6.1. Metabolism 11
2.6.2. Elimination 12
2.6.3. Indications 12
2.6.4. Contraindications 12
2.6.5. Drug Interaction 12
2.6.6. Special Populations 12
2.6.7. Adverse drug reactions 12
2.7. Limitation of Oral Drug Administration 14
2.8. Enhancement of Oral Bioavailability 15
2.8.1 Solubility and Dissolution rate enhancement: 15
2.8.1.1 Physical Modification 15
2.8.1.2 Chemical modifications 17
2.9 Liquisolid Compacts 18
2.9.1 Advantages and Limitations of Liquisolid Compacts 20
2.9.2 Applications 21
2.10 Aims and Objective 23

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3. EXPERIMENTAL …………………………………………………………………….24
3.1 Materials 24
3.2 Instrumentation 24
3.3 Study Design 25
3.4 Development and Validation of Method of Analysis 27
3.4.1 Preparation of Stock Solution 27
3.4.2 Selection of Wave Length of Maximum Absorbance (λ max) 27
3.4.3 Validation of UV Visible Spectrophotometric Method of Analysis 27
3.4.3.1 Linearity of the Method 27
3.4.3.2 Specificity and Selectivity of the Method 28
3.4.3.3 Precision of the Method 28
3.4.3.4 Stability of solutions 28
3.5 Determination of Solubility of Clopidogrel 29
3.6 Stability of Solution 30
3.7 Design of Liqui-solid Compact 30
3.7.1 Liquid load factor 30
3.7.2 Excipients ratio 31
3.8 Preparation of Liqui-solid Compacts 32
3.9 Evaluation of Liqui-solid Compacts 33
3.9.1 Pre Compression Evaluation of Liquisolid Formulations 33
3.9.1 Bulk Density 33
3.9.2 Tapped Density 33
3.9.3 Carr’s Index 34
3.9.4 Hausner Ratio 34
3.9.5 Angle of repose 35
3.9.2 Post Compression Evaluation of Liquid-solid Compacts 36
3.9.2.1 Physical Characteristics of Liqui-solid Compacts 36
Weight and Weight Variation of Liqui-solid Compacts 36
Thickness of Liqui-solid Compacts 37
Drug content of Liqui-solid Compacts 37
3.9.2.2 Mechanical strength of the tablets 37

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 Crushing strength 38
Tensile strength of the tablet 38
Specific crushing strength 38
Friability 39
3.9.2.3 Disintegration Time 39
3.9.2.4 In vitro drug release (Dissolution test) 40
3.9.2.5 Kinetics of drug release 40
3.9.2.5 Comparison of dissolution profile 41
4. RESULTS AND DISCUSSION ……………………………………………………… 43
4.1 Development of UV-visible Spectrophotometric Method of Analysis 43
4.1.1 Selection of Solvent 43
4.1.2 Preparation of stock solution 43
4.1.3 Selection of Wavelength of Maximum Absorbance 43
4.2 Validation of UV-visible Spectrophotometric Method of Analysis 44
4.2.1 Linearity 44
4.2.2 Stability of the Solution 46
4.2.3 Specificity and Selectivity 46
4.2.4 Precession of Analytical Method 46
4.3 Solubility of Clopidogrel 48
4.4 Pre Compression Evaluations of Liquisolid Compacts 48
4.5 Post Compression Evaluation of Liquisolid Compacts 50
4.5.1 Physical Characteristics of Liquisolid Compacts of Clopidogrel 50
4.5.2 Mechanical Strength of Liquisolid Compacts 52
3.5.3 Disintegration Behavior of Liquisolid Compacts 53
4.6 Comparison of Dissolution Profile of Liqui-solid Compacts 54
5. CONCLUSION ………………………………………………………………………... 55
6. REFERENCES ………………………………………………………………………... 56

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 List of Figures and Tables

Figure-2.1: Structural Formula of Clopidogrel

Figure 2.1: Mechanism of platlet aggregation and thrombosis
Figure-2.2: Schematic Presentation of the preparation of liquisolid compacts
Figure-3.1: Schematic presentation of Study Design
Table-3.1: Composition of Various Formulations of Liquisolid Compacts, Containing
Clopidogrel
Table-4.1: Validation Parameters of UV Visible Spectrophotmetric Method of Analysis of
Clopidgrel
Table-4.2: Intra Day and Inter Day studies of UV Visible Spectrophotmetric Method of Analysis
of Clopidogrel
Table-4.3: Pre Compression Evaluation of Liquisolid Compacts Containing Clopidogrel
Table-4.4: Physical Parameters of Liquisolid Compacts
Table-4.5: Mechanical Strength of Liquisolid Compacts of Clopidogrel
Figure-4.1: Disintegration time of liquisolid compacts of Clopidogrel
Figure-4.2: Dissolution Profile of Liqui-solid Compacts

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 Abbreviations

API Active Pharmaceutical Ingredient

CLP Clopidogril
BPCS Bio Pharmaceutical Classification System
AUC Area Under Curve
Cmax Peak Plasma Concentration
Fig Figure
GIT Gastro Intestinal Tract
H Hour
i.e. That is
ICH International Conference on Harmonisation
IUPAC International Union of Pure and Applied Chemistry
IVIVC In-vitro, In vivo Correlation
LLOD Lower Limit of Detection
LLOQ Lower Limit of Quantification
Min Minutes
mL Milliliter
ODTs Oro Dispersible Tablets
Rpm Revolution Per Minute
RSD Relative Standard Deviation
S.D. Standard Deviation
USP United States Pharmacopoeia

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