Toward Biorelevant Dissolution: Application of a Biphasic Dissolution Model as a Discriminating Tool for HPMC Matrices Containing a Model BCS Class II Drug

Abstract

The potential of a biphasic dissolution system to assist with the analysis of controlled-release (CR), Biopharmaceutics Classification System (BCS) Class II pharmaceutical products has been investigated. Use of a biphasic dissolution medium (aqueous/octanol) provided sink conditions and afforded complete dissolution of nifedipine formulated in a CR matrix tablet while maintaining the dosage form in an aqueous environment. This was not possible in a monophasic (aqueousonly) dissolution medium. Consequently, the biphasic model allowed the discrimination of three formulations containing different HPMC loadings while the monophasic medium did not. The performance of the formulations in conventional dissolution media incorporating the inorganic salt dibasic sodium phosphate, the surfactant sodium dodecyl sulfate (SDS), and ethanol as solubility modifiers was assessed. The addition of the salt and surfactant failed to produce complete discrimination in a predictive manner. The use of a hydroalcoholic medium comprising water and ethanol enabled the statistical discrimination of the three formulations but not as effectively as the biphasic medium.

Overcoming sink limitations in dissolution testing: a review of traditional methods and the potential utility of biphasic systems

“…To assess the superiority of this system over some of the other methods used to maintain sink conditions, we have assessed the performance of the formulations in conventional dissolution media incorporating the inorganic salt dibasic sodium phosphate (10 or 150 mm), the surfactant SDS (5%) and ethanol as solubility modifiers. [72] Dissolution in either 10 mm or 150 mm sodium phosphate (Figure 9a, c) failed to provide sink conditions. The addition of 5% SDS to these media (Figure 9b Discrimination between tablets formulated to release the drug at different rates ('fast', 10% HPMC; 'medium', 20% HPMC and 'slow', 40% HPMC) was possible in a biphasic (water-octanol) system yet not so in a monophasic (water-only) system.…”

“…To assess the superiority of this system over some of the other methods used to maintain sink conditions, we have assessed the performance of the formulations in conventional dissolution media incorporating the inorganic salt dibasic sodium phosphate (10 or 150 m m ), the surfactant SDS (5%) and ethanol as solubility modifiers [72] . Dissolution in either 10 m m or 150 m m sodium phosphate (Figure 9a, c) failed to provide sink conditions.…”

“… Dissolution performance of nifedipine‐containing controlled‐release matrix tablets in (a) 10 m m phosphate buffer, (b) 10 m m phosphate buffer + 5% sodium dodecyl sulfate (SDS), (c) 150 m m phosphate buffer and (d) 150 m m phosphate buffer + 5% SDS. Although slight discrimination between tablets formulated to release the drug at different rates (‘fast’, 10% HPMC; ‘medium’, 20% HPMC and ‘slow’, 40% HPMC) was possible in a surfactant‐containing system, the biphasic (water–octanol) system achieved this more effectively [72] …”

“…Our group has recently focused on the potential implementation of a biphasic dissolution model as a formulation development tool to assist with the analysis of CR, BCS Class II pharmaceutical products. [72] Studies on nifedipine showed a biphasic dissolution medium (distilled water-octanol) to successfully promote sink conditions, and afford complete dissolution of the drug formulated in a CR matrix tablet, while maintaining the dosage form in an aqueous environment. This observation was not possible in a monophasic (water only) dissolution medium, where a maximum of 28% label claim was observed.…”

Evolution of a mini-scale biphasic dissolution model: Impact of model parameters on partitioning of dissolved API and modelling of in vivo-relevant kinetics

“…Various biphasic dissolution models are described in the literature [10][11][12] which are regarded as advantageous as they implement sink conditions by introducing a partitioning process of the non-protonated base into a second lipophilic phase [13]. The implementation of a lipophilic phase mimics the absorption step, which is an alternative process to precipitation of a weak base at elevated pH in the GIT, showing superior predictive power for APIs with dissolution-limited absorption [14].…”