Abstract
Objective: To characterize the dissolution behaviour of carbamazepine generic suspensions using the USP Dissolution Apparatus 2 and the flow-through cell method with simulated gastrointestinal fluids as dissolution media.Methods: Tegretol® suspension and two generic formulations were tested. Dissolution studies were performed using the USP Apparatus 2 (75 rpm and 900 ml of dissolution medium) and the flow-through cell method (laminar flow at 16 ml/min). Simulated gastric fluid (SGF) (with and without pepsin) and simulated intestinal fluid (SIF) (without pancreatin) at 37.0±0.5 °C, was used as dissolution media. The quantity of dissolved carbamazepine was determined at 5 min intervals until reaching 60 min, at 285 nm. Percentage dissolved at 60 min, mean dissolution time, dissolution efficiency values (model-independent parameters), as well as t50% and t63.2% were calculated (model-dependent parameters). Values for all parameters were compared between the reference and generic formulations using one-way analysis of variance (ANOVA) following a Dunnett’s multiple comparison test. Dissolution data were also fitted to different fit models.Results: Since the first sampling time, the reference product had reached 100% of drug dissolved, which was determined using USP Apparatus 2. Nevertheless, significant differences in the three model-independent parameters of generic products were found (*P<0.05). Dissolution data obtained with the paddle apparatus were fitted to different kinetic equations; however, using the flow-through cell method and SIF without pancreatin, the three drug products were fitted to the same kinetic model (Gompertz). With ANOVA-based comparisons and the flow-through cell method, significant differences were found in dissolution data of generic product A versus reference at all sampling times (*P<0.05). The flow-through cell method and SGF with pepsin were the best options to discriminate among dissolution profiles.Conclusion: The flow-through cell method seems to be an adequate dissolution apparatus to characterize in vitrodissolution performance of Class II drugs manufactured as suspensions. For carbamazepine suspensions, SGF and laminar flow at 16 ml/min were the most appropriate conditions to discriminate among generic formulations. Given the physicochemical characteristics of carbamazepine and the environment in which the drug products were tested, these differences could be of clinical relevance.
Highlights
In vitro dissolution studies are useful to assess the lot-to-lot quality of pharmaceutical formulations, changes in their manufacturing process and prediction of in vivo performance of some drugs
The flow-through cell method seems to be an adequate dissolution apparatus to characterize in vitro dissolution performance of Class II drugs manufactured as suspensions
Simulated gastric fluid (SGF) and laminar flow at 16 ml/min were the most appropriate conditions to discriminate among generic formulations
Summary
In vitro dissolution studies are useful to assess the lot-to-lot quality of pharmaceutical formulations, changes in their manufacturing process and prediction of in vivo performance of some drugs. These studies are currently performed with the United States Pharmacopeia (USP) basket (USP Apparatus 1) or paddle apparatus (USP Apparatus 2). In vitro dissolution studies can contribute to establishing the interchangeability of generic formulations [2]. Some authors have been concerned about the safe interchangeability between reference products and their generic counterparts or even among generic formulations [3, 4]
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