IN VITRO EQUIVALENCE STUDY OF DIFFERENT DOSES OF CARBAMAZEPINE REFERENCE TABLETS USING USP APPARATUSES 2 AND 4 Original Article JOSE RAUL MEDINA-LOPEZ * Departamento Sistemas Biológicos, Universidad Autónoma Metropolitana-Xochimilco, Mexico City, Mexico Email: rmlopez@correo.xoc.uam.mx , LUIS ANTONIO CEDILLO-DÍAZ, MARCELA HURTADO Received: 21 Mar 2019, Revised and Accepted: 24 May 2019 ABSTRACT Objective: To perform an in vitro equivalence study of two doses of carbamazepine reference tablets sold in the local market under hydrodynamic conditions of USP Apparatus 4, a dissolution apparatus that better simulates the human gastrointestinal tract. Results were compared with dissolution official conditions using USP Apparatus 2. Methods: Dissolution profiles of both formulations were carried out with an automated USP Apparatus 2 at 75 rpm and 900 ml of dissolution medium. USP Apparatus 4 with laminar flow at 16 ml/min and 22.6 mm cells were used. 1% lauryl sulfate aqueous solution at 37.0±0.5 °C was used as dissolution medium. Spectrophotometric determination of drug at 285 nm was carried out during 60 min. Dissolution profiles were compared with model-independent and-dependent approaches. Results: When comparing dissolution profiles of low vs. high dose similar profiles were found (f 2 Conclusion: Equivalent dissolution performance of two doses of carbamazepine reference tablets were found in each USP dissolution apparatus. >50) in each dissolution apparatus, however, when the same dose was compared, USP 2 vs. USP 4, opposite results were obtained. Comparison of mean dissolution time and dissolution efficiency data corroborates these results. Weibull function was the best mathematical model that described the in vitro dissolution performance of carbamazepine. No significant differences were found in Td values (low vs. high dose) but opposite results were also found with USP 2 vs. USP 4. The main problem identified in this comparative study is the low dissolution rate and extent found with USP Apparatus 4. More research on this field is necessary for all available doses of reference drug products since the quality of generic formulations depends on the quality of references Keywords: Carbamazepine, Flow-through cell method, Reference drug products, USP Apparatus 4 . © 2019 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) DOI: http://dx.doi.org/10.22159/ijap.2019v11i4.33174 INTRODUCTION Dissolution test is an important tool to ensure lot-to-lot good quality and after some manufacture, changes as well as for determination of interchangeability among generic formulations. These formulations have the same pharmacological effect with the benefit of lower costs for patients and hospitals. Generic drug products should demonstrate the same in vitro dissolution performance of reference drug products so, quality of generic drug products depends of the quality of references. Due to the high cost of bioequivalence studies and information of Biopharmaceutics Classification System (BCS) about solubility and permeability of some drugs, Guidelines for Industry-based on BCS have established criteria by which bioequivalence studies can be replaced by in vitro dissolution studies [1]. This waiver is based mainly on the fulfillment of f 2 similarity factor between dissolution profiles of test and reference (f 2 >50) using dissolution media with pH of physiological relevance as well as compliance with related criteria to the excipients used in the formulation manufacture [2]. Some biowaiver monographs have been published for class I and III drugs (high solubility drugs) [3] but for its physicochemical and clinical characteristics, no biowaiver monograph has been published for carbamazepine. Fig. 1: Molecular structure of carbamazepine Carbamazepine is a poorly soluble drug with a narrow therapeutic window used to treat epilepsy and other neurological disorders as trigeminal neuralgia [4]. Molecular structure of carbamazepine is shown in fig. 1. The drug is available as generic drug products and Mexican health authorities request bioequivalence studies to approve the marketing of these formulations. Considering BCS criteria carbamazepine has been classified as a class II drug (low solubility/high permeability) and for its low solubility, dissolution problems of two different doses in the same volume of dissolution medium could be observed. Class II drugs are expected to have a dissolution-limited absorption and a significant in vitro/in vivo correlation (IVIVC) should be expected using a well-designed in vitro dissolution test. Official d For multiple strengths of immediate-release products with linear kinetics, the bioequivalence study may be performed at the highest strength and waivers of in vivo studies may be granted on lower strengths, based on an adequate dissolution test, provided the lower strengths are proportionately similar in composition [5]. It is possible that this assertion does not apply to carbamazepine however, it is important to investigate the in vitro dissolution performance of two doses of carbamazepine reference tablets under hydrodynamic environments generated by commonly used dissolution apparatuses with the aim of gather information to suggest a biowaiver mechanism for carbamazepine drug products, starting at least, with the available doses of reference and pharmacopeial conditions. issolution test for carbamazepine tablets is described in United States Pharmacopoeia (USP) [6]. The method indicates the use of USP Apparatus 2 (paddle) at 75 rpm and 900 ml of 1% sodium lauryl sulfate aqueous solution at 37.0±0.5 °C as dissolution medium. Under these conditions and for carbamazepine immediate-release tablets labeled as 200-mg there are two tests with the following times and tolerances: TEST 2 between 45 and 75% of the labeled amount of carbamazepine is dissolved in 15 min; not less than 75% (Q) of the labeled amount of carbamazepine is dissolved in 60 min and TEST 3 between 60 and 85% of the labeled amount of carbamazepine is dissolved in 15 min; not less than 75% (Q) of the International Journal of Applied Pharmaceutics ISSN- 0975-7058 Vol 11, Issue 4, 2019