title: Development of a targeted polymorph screening approach for a complex polymorphic and highly solvating API.
abstract: Elucidation of the most stable form of an active pharmaceutical ingredient (API) is a critical step in the development process. Polymorph screening for an API with a complex polymorphic profile can present a significant challenge. The presented case illustrates an extensively polymorphic compound with an additional propensity for forming stable solvates. In all, 5 anhydrous forms and 66 solvated forms have been discovered. After early polymorph screening using common techniques yielded mostly solvates and failed to uncover several key anhydrous forms, it became necessary to devise new approaches based on an advanced understanding of crystal structure and conformational relationships between forms. With the aid of this analysis, two screening approaches were devised which targeted high-temperature desolvation as a means to increase conformational populations and enhance overall probability of anhydrous form production. Application of these targeted approaches, comprising over 100 experiments, produced only the known anhydrous forms, without appearance of any new forms. The development of these screens was a critical and alternative approach to circumvent solvation issues associated with more conventional screening methods. The results provided confidence that the current development form was the most stable polymorph, with a low likelihood for the existence of a more-stable anhydrous form.
authors.affiliation: Pharmaceutical Sciences, Pfizer Global Research & Development, Groton, Connecticut 06340, USA. anthony.m.campeta@pfizer.com
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Campeta
authors.forename: Brian P
authors.initials: BP
authors.lastname: Chekal
authors.forename: Yuriy A
authors.initials: YA
authors.lastname: Abramov
authors.forename: Paul A
authors.initials: PA
authors.lastname: Meenan
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Henson
authors.forename: Bing
authors.initials: B
authors.lastname: Shi
authors.forename: Robert A
authors.initials: RA
authors.lastname: Singer
authors.forename: Keith R
authors.initials: KR
authors.lastname: Horspool
mesh_terms: D000077784:Axitinib; D003198:Computer Simulation; D003460:Crystallization / Q000379:methods*; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000737:chemistry; D007191:Indazoles / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D004364:Pharmaceutical Preparations / Q000737:chemistry*
chemical_list: D007093:Imidazoles; D007191:Indazoles; D004364:Pharmaceutical Preparations; D000077784:Axitinib