Development of discriminatory and biopredictive bicarbonate buffer based dissolution method to screen delayed release formulations

Abstract

Objective- To develop a novel, discriminatory and biopredictive bicarbonate buffer (BB)-based dissolution method to understand the behaviour of oral delayed release (DR) formulations containing Mesalamine.Significance- Conventional dissolutions have limitations in obtaining discrimination and predictive in-vivo behaviour for various DR formulations, as it doesn’t mimic the physiological buffering. For DR formulations, functional coat opening time plays a crucial role in determining the initial drug release. BB are dynamic systems and have natural ability to gradually increase the pH due to evaporation of CO2. This was considered as an advantage to discriminate pH sensitive DR coatings.Methods- USP-III BB dissolution condition with 10 DPM agitation was developed. Design of experiments (DoE) approach was used to study the impact of agitation and bicarbonate molarity on rate of pH change of BB. A relation of In-vitro onset of release with in-vivo onset of drug absorption and Cmax was established to predict the in-vivo formulation behaviour.Results- Developed dissolution showed differences in onset of drug release for all formulations. DoE showed that agitation had significant impact on rate of pH change of BB irrespective of molarity. A strong linear correlation was obtained for in-vitro drug release onset with in-vivo onset of drug absorption and Cmax (R2 > 0.99) at 10 DPM agitation. The % prediction error of <10 for in-vivo onset of release and <4 for Cmax was observed.Conclusions- This work demonstrates that dissolution in BB is more discriminatory and biopredictive than conventional dissolutions in predicting onset of release and Cmax for Mesalamine DR formulations.