Salt form selection and characterization of LY333531 mesylate monohydrate

LY333531 is a potent protein kinase C-beta (PKCbeta) inhibitor currently under development for the treatment of diabetic complications. Seven salts of LY333531 (hydrochloride, sulfate, mesylate, succinate, tartrate, acetate and phosphate) were evaluated during the early phase of development. Physical property screening techniques including microscopy, DSC, TGA, XRPD, hygroscopicity and solubility were utilized to narrow the selection to two salts: the mesylate and hydrochloride, Identification of the optimal salt form was based upon solubility, bioavailability, physical stability and purity. During the evaluation process three hydrated forms (anhydrate, monohydrate, and tetrahydrate) of the hydrochloride salt were identified. The mesylate salt was found to give only one, a monohydrate. Processing parameters (e.g. filtration rate, crystal form stability) demonstrated that the anhydrate was the preferred form of the hydrochloride salt. Bioavailability studies in dogs indicated that the C-max and area under the plasma concentration vs, time curve (AUC) for LY333531 and its active metabolite, LY338522, following administration of the mesylate salt were approximately 2.6 times those obtained after the LY333531 HCl dose. This difference was presumed to be due primarily to the fact that the mesylate was five times more soluble than the hydrochloride salt in water. These factors led to selection and development of LY333531 mesylate monohydrate as the active pharmaceutical ingredient for clinical evaluation. (C) 2000 published by Elsevier Science B.V. All rights reserved.