Study On Concomitant Polymorphism Of Furosemide-4,4’-Bipyridine Cocrystals

Pharmaceutical cocrystals are crystalline solids composed of the active pharmaceutical ingredient(API)and the cocrystal former in a stoichiometric ratio,and can enhance the solubility,dissolution rate and bioavailability of APIs.Pharmaceutical cocrystals exhibit different physicochemical and pharmacokinetic properties in polymorphs,which would affect their therapeutic effect.The study on concomitant polymorphism of cocrystals contribute to understanding and controlling the cocrystallization process of desired polymorphic products.Furosemide(FS)is a sulfonylamide loop diuretic,commonly used in the treatment of edema and arterial hypertension.4,4’-Bipyridine(4BPY)is a frequently used conformer in cocrystallization with the API.In this study,FS-4BPY cocrystals were selected as a model system,and their thermodynamic behaviors and concomitant polymorphic cocrystallization process in solution were studied systematically.First,methods for bulk preparation of different forms of FS-4BPY cocrystals were developed.Cooling crystallization and slurry crystallization gave needle-like pale yellow form I and block-like bright yellow form II,respectively.Both polymorphs were characterized by optical microscopy,powder X-ray diffraction,fourier transform infrared spectroscopy,differential scanning calorimetry,and thermogravimetric analysis.Dissolution behaviors of FS-4BPY cocrystals in organic solvents were investigated.Solubilities of form I and form II were determined by the gravimetric method,revealing the relative stability of the two forms.The experimental solubility data were correlated by the modified Apelblat model,the CNIBS/R–K model,the Jouyban–Acree model,and the NRTL model.All models give satisfactory correlations.The apparent dissolution thermodynamic properties,including the dissolution Gibbs energy,the dissolution enthalpy and the dissolution entropy,were calculated based on the NRTL model.Finally,concomitant cocrystallization process of polymorphic FS-4BPY cocrystals was investigated.The effect of initial supersaturation on the formation of polymorphs was determined,and the concomitant cocrystallization zone was measured.Based on the solubility data and the induction time,the mechanism of nucleation and growth of cocrystallization process was analyzed,and concomitant polymorphism of FS-4BPY cocrystals was discussed from thermodynamics and kinetic aspects.