methylcellulose and biphenylylacetic-acid

There are few studies of alkalising pH-modifiers in HPMC hydrophilic matrices. These agents may be incorporated to provide microenvironmental buffering and facilitate pH-independent release of weak acid drugs. This study compared tris(hydroxylmethyl) aminomethane (THAM, TRIS, tromethamine, trometamol) with sodium citrate as internal buffering agents for HPMC (4000 cps) 2208 and 2910 matrices containing felbinac, a weak acid drug which exhibits pH-dependent solubility. Drug release at pH 1.2 and 7.5 was accelerated by both buffers, but THAM-buffered matrices provided extended, diffusion-based release kinetics, without loss of matrix integrity at high buffer concentrations. Release kinetics appeared to be independent of media pH. THAM did not depress the sol-gel transition temperature or suppress HPMC particle swelling, and had minimal effects on gel layer formation. Sodium citrate promoted greater thickness of the early gel layer than THAM. Measurements of internal gel layer pH showed that both buffers produced a rapid alkalisation of the gel layer which was progressively lost. As result of its higher pK(a) and molar ratio on a percent weight basis, THAM provided a higher internal pH and a greater longevity of pH modification. It is concluded that THAM offers a useful buffering option for weak acid drugs in HPMC-based systems.

Topics: Buffers; Chemistry, Pharmaceutical; Citrates; Diffusion; Excipients; Gels; Hydrogen-Ion Concentration; Hypromellose Derivatives; Methylcellulose; Phenylacetates; Sodium Citrate; Solubility; Tablets; Transition Temperature; Tromethamine

Few studies report the effects of alkalizing buffers in HPMC matrices. These agents are incorporated to provide micro-environmental buffering, protection of acid-labile ingredients, or pH-independent release of weak acid drugs. In this study, the influence of sodium citrate on the release kinetics, gel layer formation, internal gel pH and drug release mechanism was investigated in HPMC 2910 and 2208 (Methocel E4M and K4M) matrices containing 10% felbinac 39% HPMC, dextrose and sodium citrate. Matrix dissolution at pH 1.2 and pH 7.5 resulted in complex release profiles. HPMC 2910 matrices exhibited biphasic release, with citrate increasing the immediate release phase (<60min) and reducing the extended release. HPMC 2208 matrices were accelerated, but without the loss of extended release characteristics. Studies of early gel layer formation suggested gel barrier disruption and enhanced liquid penetration. pH modification of the gel layer was transitory (<2h) and corresponded temporally with the immediate release phase. Results suggest that in HPMC 2910 matrices, high initial citrate concentrations within the gel layer suppress particle swelling, interfere with diffusion barrier integrity, but are lost rapidly whereupon drug solubility reduces and the diffusion barrier recovers. These Hofmeister or osmotic-mediated effects are better resisted by the less methoxylated HPMC 2208.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Buffers; Chemistry, Pharmaceutical; Citrates; Delayed-Action Preparations; Drug Carriers; Drug Compounding; Excipients; Gels; Hydrogen-Ion Concentration; Kinetics; Lactose; Methylcellulose; Models, Chemical; Phenylacetates; Sodium Citrate; Solubility; Tablets; Technology, Pharmaceutical