Comparative in-vitro equivalence studies of some locally manufactured and imported generic BCS Class III drug products against their comparator counter products
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Date
2023
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Addis Ababa University
Abstract
According to the Biopharmaceutical classification system (BCS), active pharmaceutical
ingratiate (API) classified into four classes (BCS Class I-IV) based on aqueous solubility
and intestinal permeability. BCS Class III medications are highly soluble and poorly
permeable, and they are among the drug products that require documented evidence of
bioequivalence study. In addition to the permeability problems, there may be differences
between generic and innovator products in terms of the type, source, and quantity of
ingredients, manufacturing method and process, and machinery used for production, and
these factors can bring major differences in dissolution and bioavailability. The objective
of this study was therefore to compare the in vitro equivalence of four locally
manufactured and imported BCS Class III drug products, namely, Metoclopramide
hydrochloride 10 mg tablets, Cloxacillin sodium 500 mg capsules, Metformin
hydrochloride 500 mg tablets, and Enalapril maleate 5 mg tablets against their
comparator counter products (MTF3, CLX3, MCP3, and ENA3), respectively. The
selected drug products and their comparator counter products were purchased from retail
pharmacies found in Addis Ababa, Ethiopia. For each drug product, physical properties
such as weight uniformity, hardness, thickness, diameter, and friability were determined
using appropriate equipment as per the USP monograph. The assay content and content
uniformity for each drug product were also determined as per their respective procedures
in the USP monograph and validated methods. In vitro dissolution profiles were
performed according to monograph methods and validated methods, and in vitro drug
release tests were also done to assess equivalence of the products investigated. The
results of weight variation content uniformity, and assay content indicated that all the
investigated drug products were within the pharmacopeia requirements. Similarly, all
products investigated complied disintegration time tests (i.e., ≤ 30 min) of immediate-
release drug products. Except for two generic products of metformin hydrochloride
tablets MTF2 (62.66%±9.74), and MTF4 (78.71%±6.86), all the drug products included
in this study fulfilled the acceptance criteria for dissolution (i.e., Q ≥ 80% at 30 min).
The in-vitro equivalence of these products was assessed by statistical, model-
independent, and mode-dependent methods. One generic products of metformin
hydrochloride (MTF2) and all generic products of metoclopramide hydrochloride
showed significant difference (p < 0.05) in dissolution profiles with comparator
II
products. Of the five generic products of metformin hydrochloride film coated
tablets [MTF2 (32.88), MTF4 (39.80) and MTF6 (49.94)] and generic products of
metoclopramide hydrochloride [MCP1 (37.04) and MCP2 (41.56)] failed to meet the f2
acceptance criteria. This means that these products are not interchangeable. However,
cloxacillin sodium capsules and enalapril maleate tablets complied with the f2 > 50
acceptance criteria. In conclusion, this study showed that all the generic products of
metformin hydrochloride tablets, metoclopramide hydrochloride tablets, enalapril
maleate tablets, and cloxacillin sodium capsules complied the quality specifications of
weight uniformity, hardness, friability, disintegration, and assay. Three generic products
brands of metformin hydrochloride MTF2, MTF4, and MTF6, and both generic products
brands of metoclopramide hydrochloride (MCP1 and MCP2) did not show in-vitro
equivalence with their comparator products. All generic products of cloxacillin sodium
capsules and enalapril maleate tablets included in this study met model independent
fitting factor specifications, were statistically insignificant (P>0.05) in dissolution
profiles and can be considered equivalent to their comparator counter product.
Description
Keywords
BCS Class III drugs, Generic products, Comparator pharmaceutical products, In-vitro dissolution, In-vitro equivalence, Bioequivalence