ABSTRACT
We aimed to develop a phase selection methodology for a weak basic active pharmaceutical ingredient (API) that would require less than 10mg 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.
Subject(s)
Body Fluids/metabolism , Chemistry, Pharmaceutical/methods , Pharmaceutical Preparations/chemistry , Pharmaceutical Preparations/metabolism , Administration, Oral , Animals , Biological Availability , Body Fluids/chemistry , Dogs , Hydrogen-Ion Concentration , Kinetics , Phase Transition , SolubilityABSTRACT
High performance liquid chromatography (HPLC) is frequently used for quantifying drugs in gelatin capsules. Gelatin has a strong UV absorption that often overlaps with drug absorbances. Therefore, the gelatin capsules must be removed manually before analysis. This study describes a novel extraction method named collagenase-assisted extraction (CAE), which uses collagenase to degrade gelatin into fragments with reduced hydrophobicity, allowing gelatin-related peaks to elute immediately, eliminating interference with the drug peak and enabling use of whole gelatin capsules during drug quantification. Use of CAE eliminates powder loss when opening a gelatin capsule, allows extraction of drugs from the capsule, reduces analytical time, and extends HPLC column life.
