IN VITRO EQUIVALENCE STUDIES AND COMPARATIVE ASSESSMENT OF GENERIC METRONIDAZOLE TABLETS COMMERCIALLY AVAILABLE UNDER BIOWAIVER CONDITIONS IN NIGERIA.

CHAPTER ONE

1.1 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 ¹. 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 ^{2, 3}.

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 ⁴. 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 ⁵. These include the difference and similarity factors (f¹and f²) and   Rescigno indices.

ƒ² = 50 log {[1 + (1/m)   Wj(Rj − Tj)(Rj − Tj) ]-0.5 100}   Equation 1

ƒ¹ = {[[Rj – Tj] / Σ Rj  ].100}                                                  Equation 2

Where m, reflects the number of time points utilized

Rj, the cumulative percent of the reference product dissolved at specifically selected time points.

Tj, the cumulative percent of the generic brand dissolved at specifically selected time points ^{6, 7, 8.}

They provide a remarkably easy descriptive and comparative analysis of dissolution data where the percent error between two respective curves across determining point is measured by the f¹ factor. Model dependent methods have been utilized extensively to define drug release from varying polymeric matrices where the value of the release constant characterizes specific release properties synonymous with the incorporated excipients and other process variables utilized in drug formulation ^5,9,10. These data provide regulatory authorities with information regarding product performance via equivalence dissolution profile testing, ensuring that large differences at any time point doesn’t affect the sensitivity of the model used^{9, 10, and 11}

Metronidazole (1 β -hydroxyethyl-2- methyl 5 nitroimidazole) an antiprotozoal, antibacterial and amebicide¹² is a BCS class I drug (Fig. 1), being highly permeable and highly soluble across biological membrane, thus drug  absorption depends on the ability of the drug to go into solvation/dissolution after  oral  administration, and then be able to permeate the biological membrane of the gastrointestinal tract^13. Thus the dissolution process is critical in prediction of in vivo events of a drug ^{14, 15}

Formulation factors arising from varying impaction forces utilized in tablet production which comprises of insufficient compression forces as a result of equipment inconsistencies, variations arising from excipient sources, ratios/techniques via which these excipients are combined (i.e. binders and disintegrant ratios) have been known to give rise to friable tablets which may negatively impact on tablet quality. ^16,17,18,19.

The study of dissolution in vitro is considered a fundamental requirement in the pharmaceutical industry in order to assure the quality of solid pharmaceutical dosage forms for oral use, guarantee the quality from batch to batch, orientate the development of new formulations and secure the uniformity in quality and performance of the drug even after modifications ¹⁹. On a parallel basis, this allows formulation optimization in the development phase and, in the same way, it allows stability studies, manufacturing process monitoring, and the establishment of in vivo/in vitro correlations ^20,21,22,23.