Rational Coformer or Solvent Selection for Pharmaceutical Cocrystallization or Desolvation

• Published in: Journal of pharmaceutical sciences Vol. 101; no. 10; pp. 3687 - 3697
• Main Authors: Abramov, Yuriy A., Loschen, Christoph, Klamt, Andreas
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.10.2012; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association; Elsevier Limited
• Subjects: Biological and medical sciences; Chemistry, Pharmaceutical - methods; cocrystals; COSMO-RS; crystal engineering; crystallization; Crystallization - methods; desolvation; excess enthalpy; General pharmacology; Imidazoles - chemistry; in silico modeling; Indazoles - chemistry; Medical sciences; Models, Chemical; Pharmaceutical Preparations - chemistry; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Protein Kinase Inhibitors - chemistry; Solubility; solvates; Solvents - chemistry; Thermodynamics; Thiophanate - chemistry; excess enthalpy; in silico modeling; solvates; desolvation; crystallization; solubility; cocrystals; COSMO-RS; crystal engineering; Pharmaceutical technology; Crystallization; Solubility; Cocrystallization; Modeling; In silico; Solvent; Physicochemical properties
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.23227

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, Hex, 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 Hexs 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.