A thermodynamic-based approach to analyzing a highly solvating polymorphic system: the desolvation window method.
There are two major challenges in developing a solid form: (1) identifying the thermodynamically stable form and (2) determining the method used to crystallize that form. Often experiments performed to address these challenges have different objectives and use separate experimental techniques. The thermodynamically stable form is usually found on small scale, utilizing slurries or crystallizations. Subsequently, a crystallization process is developed to purge impurities and to increase yield and these experiments are typically conducted on medium to large scale (greater than 10  g). Axitinib, a research compound for the treatment of cancer, forms solvates in most solvents to which it is exposed, presenting a problem in discovering and making a desirable anhydrous phase. A method has been developed that will give the best chance of making a thermodynamic stable form of the anhydrous material, necessarily not a desolvated form. This approach relies on solvent mediated transformation (thermodynamic control), rather than crystallization or solid-to-solid phase desolvation (generally kinetic control). Experimental conditions (a desolvation window) to produce an anhydrous solid form for this compound that shows predominance for solvate formation is detailed.
Samas
Brian
B
Pfizer Global Research & Development, Pharmaceutical Sciences, Groton, Connecticut, USA. brian.samas@pfizer.com
Seadeek
Christopher
C
Campeta
Anthony M
AM
Chekal
Brian P
BP
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000302:isolation & purification; D000077784:Axitinib; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D007093:Imidazoles / Q000737:chemistry* / Q000302:isolation & purification; D007191:Indazoles / Q000737:chemistry* / Q000302:isolation & purification; D007536:Isomerism; D007700:Kinetics; D044367:Phase Transition; D010879:Piperazines / Q000737:chemistry; D033362:Powder Diffraction; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013678:Technology, Pharmaceutical; D013696:Temperature; D013816:Thermodynamics; D013844:Thiazoles / Q000737:chemistry; D044366:Transition Temperature; D014867:Water / Q000032:analysis
D000970:Antineoplastic Agents; D007093:Imidazoles; D007191:Indazoles; D010879:Piperazines; D012997:Solvents; D013844:Thiazoles; D014867:Water; C092292:ziprasidone; D000077784:Axitinib