In Vitro Equivalence Studies and Comparative Assessment of Generic Metronidazole Tablets Commercially Available Under Biowaiver Conditions in Nigeria.
ABSTRACT
The aim of the present study was to investigate the physicochemical equivalence and compare the dissolution rate of thirteen brands of metronidazole tablets collected from retail pharmacies in Nigerian markets. This study sought to apply the BCS biowaiver requirements to assess the equivalence of commonly interchanged generic Metronidazole tablets with their innovator product in Nigeria.
Solubility of active pharmaceutical ingredients (API) has always been a concern for formulators, since poor aqueous solubility may hamper development of drugs and limit bioavailability of oral products. For drug products to be interchangeably used by healthcare providers, formulation characteristics, which reflect variation within brands, batches and lots examined via dissolution profile analysis, must not show high statistical discrepancies.
The quality and physicochemical equivalence of thirteen different brands of metronidazole tablets were assessed. The assessment included the evaluation of uniformity of weight, friability, breaking force /hardness test, disintegration and dissolution tests as well as chemical assay of the tablets.
TABLE OF CONTENTS
TITLE PAGE………………………………………………………………… i
CERTIFICATION…………………………………………………………….ii
DEDICATION………………………………………………………………. iii
ACKNOWLEDGEMENT…………………………………………………… iv
TABLE OF CONTENTS………………………………………..…………… v
ABSTRACT…………………………………………………………………. x
CHAPTER ONE
1.1 Introduction……………………………………………………………………………. 1
1.1.1 Generic drugs……………………………………………………………………….. 4
1.1.1.1 Nomenclature ……………………………………………………………………….5
1.1.1.2 Economics …………………………………………………………………,.,………6
1.1.1.3 Regulation …………………………………………………………………….…….7
1.1.1.4 Quality standards ……………………………………………………………………8
1.1.1.5 Litigation ……………………………………………………………………………9
1.1.2 Biowaiver conditions……………………………………………………………..….. 9
1.1.3 Definition of dissolution……………………………………………………………….10
1..1.3.1 In vitro Dissolution…………………………………………………………………11
1.1.3.2 Introduction to Dissolution………………………………………………………….12
1.1.3.3 History of dissolution Testing………………………………………….……………..12
1.1.3.2 History of dissolution testing………………………………………………….……..15
1.1.3.3 Back ground of dissolution……………………………………………………….…17
1.1.3.4 Uses of drug dissolution testing……………………………………………………..17
1.1.3.5 Background of Dissolution…………………………………………………………..18
1.1.3.5.1 Dissolution Mechanism…………………………………………………………….18
1.1.4 Drug dissolution theories………………………………………………………… 21
1.1.4.1 The Diffusion layer model………………………………………………………… 21
1.1.4.2 The Interfacial barrier model …………………………………………………… 23
1.1.4.3 The Danckwert’s model………………………………………………………… 23
1.1.5 Factor affecting dissolution process………………………………………………….25
1.1.5.1 Factors relating to the physicochemical properties of drug……………………..….25
1.1.5.2 Factors related to drug product formulation…………………………………………26
1.1.5.3 Factors related to dissolution testing device……………………………………..…29
1.1.5.4 Factors related to dissolution test parameters……………………………………….31
1.1.6 Table 1: Different types of dissolution apparatus………………………………….34
1.1.6.1 Rotating basket……………………………………………………………………….35
1.1.6.2 Drug Dissolution Apparatus II USP (Paddle)…………………..………….……….37
1.1.7 Comparative dissolution studies using similarity (f2) and difference (f1) factors…..39
1.7.1 Working examples of K8f1 and f2 factors……………………………………………42
1.1.7.2 Comparison of dissolution profiles using f1 and f2 factors …….………………….44
1.1.8 Solubility/ permeability……………………………………..………………………46
1.1.9 Biopharmaceutics classification system (BCS)…………………………………….47
1.1.9.1 BCS parameters for classifying drugs………………………………………………50
1.1.10. 5-nitroimidazole is an imidazole derivative……………………………… ………51
1.1.10.1 Synthesis of metronidazole………………………………………………………….53
1.1.10.2 Mechanism of action of metronidazole……………………………………………54
1.1.11 Significance of the study…………………………………………………………………………………55
CHAPTER TWO
MATERIALS AND METHOD…………………………………………….…….…….….56
2.1 Materials……………………………………………………………………………….…56
2.1.1 Preparation of standard curve and drug content determination ……………………..58
2.1.2 In vitro dissolution study………………………………………………….……….…58
2.2 Physicochemical properties of different brands of metronidazole tablets………………….65
2.2.1 Uniformity of weight ………………….………………………….……………………..65
2.2.2 Hardness ……………………,………………..…………………….………………….65
2.2.3 Friability…………………………………………………………….……….………….65
2.2.4 Disintegration Test …………….………………………………….………..………..…66
2.3 Statistical evaluation of dissolution data ……………………………………..…….,,,,,…66
2.3.1 ANOVA – based procedures ………………………………………………..……,,,,,…67
CHAPTER THREE
3.1 Results …………………………………………………………………………,,,.,….64
3.2Discussion…………………………………….…………………………….…,,…,,…..70
3.3Summary……………………………………………………………………..…,..,,…..75
3.4Conclusion…………………………………………………………….….……,,……….76
REFERENCES…………………………………………………………………………78
INTRODUCTION
The National agency for food and drug administration and control has laws governing the registration of pharmaceutical products, subject to the ability of these products to release the active pharmaceutical ingredient at the required time in accordance with provision of Decree 19 of 1993, amended into Decree 20, of the 1999 constitution of the Federal republic of Nigeria.
Thus generics of antibiotics to be marketed must have a recommendation governing their drug application, components and composition i.e. excipients composition, their manufacturing site, processes and equipment to ensure their in vitro equivalence with innovator products. The FDA in 1995 also issued a specific guidance on immediate release solid oral dosage forms to include scale up and post approval changes involving manufacturing and controls involving in vitro dissolution testing accompanied by in vivo bioequivalence documentation.
For drugs marketed with the same active constituent as an innovator drug product, dissolution profile similarity should be obtained in comparison with the innovator product. Different methods of assessing these similarities exist and because of the varying characteristics of excipients utilized by different manufacturers causing physicochemical and dissolution properties of these drugs to vary.
However if similarity or dissimilarity of the generic product is within specified limits in vivo bioequivalence testing which is usually expensive and time consuming can be waived. Statistical evaluation of dissolution profiles can be assessed via varying methods which include model independent methods which are characterized by pair wise approach procedures.
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Human Services.Committee for proprietary medicinal products (CPMP) ; 1999 Note for Guidance on quality
of modified release products.O’HaraT, Dunne A,Kinahan A, Cunningham S, Stark P, Devane J. ; 1997 Review of
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