Methodology for phase selection of a weak basic drug candidate, utilizing kinetic solubility profiles in bio-relevant media

Abstract

We aimed to develop a phase selection methodology for a weak basic active pharmaceutical ingredient (API) that would require less than 10 mg of the API and monitor the real-time kinetic solubility of the API in two bio-relevant media. Three sets of kinetic solubility measurements were conducted for free form I and the disulfate salt of an API (compound A) in order to determine the better API phase for further development of the compound. Tests consisted of solid API dissolution in both simulated gastric fluid (SGF) and fasted-state intestinal fluid (FaSSIF), and precipitation kinetics by injection of liquid state API into FaSSIF. All dissolution tests were conducted above the saturated concentrations in order to determine the compounds’ thermodynamic and kinetic solubility to trace the API’s phase transitions during dissolution. The pharmacokinetic profiles of compound A following oral administration of two API phases were evaluated in dogs. Results of the three sets of kinetic solubility measurements showed different kinetic solubility profiles for the two API phases under gastrointestinal conditions, indicating that the disulfate salt is preferred over free form I due to its superior kinetic solubility profile. This conclusion is consistent with the bioavailability results obtained in dogs.