Microenvironmental pH modulation based release enhancement of a weakly basic drug from hydrophilic matrices

For weakly basic drugs, pH‐dependent solubility characteristics can translate into low and incomplete release of these drugs from sustained release formulations. The objective of this study was to quantitatively analyze the relationship between microenvironmental pH modulation and release enhancement of a weakly basic drug in the free base form. A prototype matrix system primarily consisting of trimethoprim (pKa 6.6), hydroxypropyl methylcellulose (HPMC), and a polymeric or nonpolymeric pH modulator was used. Incorporation of the methacrylic acid polymer, Eudragit® L100‐55 resulted in marginal release enhancement as the pH modulation effected by this polymer was attenuated by the basicity of the drug. Water uptake and scanning electron microscopy (SEM) studies suggested that Eudragit® L100‐55 incorporation also resulted in reduced water uptake and matrix permeability. The effect of nonpolymeric pH modulators on release enhancement was also studied. The lowering in microenvironmental pH by malic acid was sufficiently high and persistent to result in pH‐independent release. A correlation plot between the experimentally determined microenvironmental pH, effected by the polymeric and nonpolymeric pH modulators, and percent drug release, exhibited good linearity with a correlation coefficient of 0.83; thereby, indicating that drug diffusion across the gel barrier is the predominating mechanism of release. © 2006 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 95: 1459–1468, 2006