Effect of gastrointestinal transit on micro-environmental pH inside HPMC matrix tablets - in vitro study

Abstract

A commonly used approach to enhance the dissolution of drugs with pH-dependent solubility is the incorporation of pH modifiers. The aim of this study was to evaluate the duration and extent of pH modifying effect on the micro-environmental pH in HPMC matrix by applying two mechanistic approaches regarding hydrodynamic stress on the tested formulation (i.e. static dissolution apparatuses (USP2) and dynamic approaches including the Advanced gastric simulator (AGS) and the Intestinal model for simulation of peristaltic action (IMSPA)). Moreover, the aim of our research was also the preparation of sustained-release matrix systems with improved - enhanced drug dissolution. In our study, the occurrence of a pH gradient in the gel layer of the HPMC tablets was observed during simulation of their passage along different compartments of the GIT. The pH gradient was affected by the media composition and duration of tablet exposure to the surrounding media. Both dissolution methods were also used to evaluate the influence of the mechanical stress on the drug release kinetics. Micro-environmental pH (pH_M) was evaluated, using two methods: the cryostatic method with a surface pH electrode, and with the incorporation of a pH sensitive dye (methyl orange) into the matrix tablets. Our study demonstrates a significantly higher dissolution rate due to mechanical stress during the bio-relevant simulation of GIT transit of the mechanically sensitive HPMC tablets with poorly soluble drugs. A considerably higher release rate was also observed from tablets with the weakly basic drugs dipyridamole and propranolol hydrochloride containing pH modifier in case of mechanically bio-relevant dissolution models compared to the USP2 apparatus. For the assessment of the pH_M, the incorporation of a pH indicator dye in the HPMC tablet proved to be more suitable, while the cryostatic method was found to be useful only for a rough pH_M estimation.

Keywords: Gastrointestinal transit; HPMC matrix tablet; Mechanically bio-relevant dissolution models; micro-environmental pH; pH dependent solubility.