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New pharmaceutical cocrystal forms of flurbiprofen: structural, physicochemical and thermodynamic characterization

DOI: 10.1021/acs.cgd.9b00781 DOI Help

Authors: Artem O. Surov (G.A. Krestov Institute of Solution Chemistry of the Russian Academy of Sciences) , Alex N. Manin (G.A. Krestov Institute of Solution Chemistry of the Russian Academy of Sciences) , Alexander P. Voronin (G.A. Krestov Institute of Solution Chemistry of the Russian Academy of Sciences) , Denis Boycov (G.A. Krestov Institute of Solution Chemistry of the Russian Academy of Sciences) , Oxana V. Magdysyuk (Diamond Light Source) , German L. Perlovich (G.A. Krestov Institute of Solution Chemistry of the Russian Academy of Sciences)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Crystal Growth & Design

State: Published (Approved)
Published: August 2019

Abstract: In this work, three new cocrystals of the nonsteroidal anti-inflammatory drug flurbiprofen with salicylamide, benzamide and picolinamide have been discovered using thermodynamic analysis of solid-liquid binary phase diagrams, and their crystal structures have been determined from the high-resolution synchrotron powder diffraction data. Solid state DFT calculations have been carried out to gain additional insight into energy differences between the cocrystal structures. The pH-solubility behavior and solubility advantage of the cocrystals have been examined via eutectic concentrations of the components, and the thermodynamic stability relationships between different solid phases have been rationalized in terms of Gibbs energies of the formation reactions. In addition, a new model has been proposed for estimating the solubility product (Ksp) of a cocrystal, based on the experimental intrinsic solubility of the drug and coformer complemented by calculated physicochemical HYBOT descriptors. The applicability of the molecular volume of cocrystal formation as a reliable parameter for clarifying the relationship between the driving force of the cocrystallization process and the structural features of participating solids has been also discussed.

Subject Areas: Chemistry, Medicine


Instruments: I12-JEEP: Joint Engineering, Environmental and Processing