Polymorph and Particle Size Control of PPAR Compounds PF00287586 and AG035029

Abstract

Development of polymorph control procedures for PF00287586 and AG035029 is described herein. For PF00287586, investigations were undertaken to control formation of both identified polymorphs, Form A and Form B. Solvent screening methodology was employed to find a solvent system that inhibited the solvent-mediated transformation of A to B so that the thermodynamically less stable Form A could be generated. For Form B, meta-stable zone width (MSZW) determination was performed and used to devise a controlled crystallization protocol to furnish Form B with improved flow and physical characteristics. For AG035029, both seeded crystallization and solvent-mediated transformation methods to generate Form B were investigated. During the development of the seeded crystallization, challenges arose when a ring of spontaneously nucleated Form A would form above the liquid level in the vessel during the cooling phase. Extraneous seeding from this “beard” invariably resulted in crystallization of Form A. A solution was developed by modification of the solvent system. Finally, optimization of the solvent-mediated transformation is presented.