Stabilization of the maleate salt of a basic drug by adjustment of microenvironmental pH in solid dosage form

Tablet formulations of the maleate salt of a basic drug (I) showed a major loss in potency and a lack of mass balance upon storage under accelerated stability testing conditions. No such stability issues were observed in capsules that were compositionally similar, and even the tablet was stable when it was encapsulated in capsule shell. It was identified that the salt converts to its free base form in the microenvironment of the tablet formulation. Studies using radiolabeled drug substance showed that the free base formed in the tablet volatilized under test conditions used and was absorbed in the wall of plastic container. No mass loss was observed with encapsulated tablets since the capsule shell either protected the drug substance from volatilization or trapped any drug substance that volatilized. The conversion of the salt to free base could be related to the pH-solubility profile of the compound where the pH(max) (pH of maximum solubility) was 3.3-3.6, above which the salt would convert to base while no such conversion would occur below this pH. The microenvironmental pH of the tablet was found to be 4.3, favoring the salt-to-base conversion. A stable tablet formulation with shelf-life >3 years was successfully developed by lowering the microenvironemental pH of tablet from 4.3 to <3.0 by adding citric acid to the formulation.