title: Rational coformer or solvent selection for pharmaceutical cocrystallization or desolvation.
abstract: It is demonstrated that the fluid-phase thermodynamics theory conductor-like screening model for real solvents (COSMO-RS) as implemented in the COSMOtherm software can be used for accurate and efficient screening of coformers for active pharmaceutical ingredient (API) cocrystallization. The excess enthalpy, H(ex) , between an API-coformer mixture relative to the pure components reflects the tendency of those two compounds to cocrystallize. Thus, predictive calculations may be performed with decent effort on a large set of molecular data in order to identify potentially new cocrystal systems. In addition, it is demonstrated that COSMO-RS theory allows reasonable ranking of coformers for API solubility improvement. As a result, experiments may be focused on those coformers, which have an increased probability of cocrystallization, leading to the largest improvement of the API solubility. In a similar way as potential coformers are identified for cocrystallization, solvents that do not tend to form solvates may be determined based on the highest H(ex) s with the API. The approach was successfully tested on tyrosine kinase inhibitor axitinib, which has a propensity to form relatively stable solvated structures with the majority of common solvents, as well as on thiophanate-methyl and thiophanate-ethyl benzimidazole fungicides, which form channel solvates.
authors: Pfizer Global Research and Development, Groton, Connecticut, USA. yuriy.a.abramov@pfizer.com
authors: Yuriy A
authors: YA
authors: Abramov
authors: Christoph
authors: C
authors: Loschen
authors: Andreas
authors: A
authors: Klamt
mesh_terms: D000077784:Axitinib; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization / Q000379:methods*; D007093:Imidazoles / Q000737:chemistry; D007191:Indazoles / Q000737:chemistry; D008956:Models, Chemical; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D012995:Solubility; D012997:Solvents / Q000737:chemistry*; D013816:Thermodynamics; D013875:Thiophanate / Q000737:chemistry
chemical_list: D007093:Imidazoles; D007191:Indazoles; D004364:Pharmaceutical Preparations; D047428:Protein Kinase Inhibitors; D012997:Solvents; D013875:Thiophanate; D000077784:Axitinib