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A multi-kinase inhibitor, pazopanib (PAZ) is cocrystallized with cyclooxygenase (COX) inhibitors fenamic acids to investigate the dissolution rate and inhibition of cell migration in VEGF-triggered HUVEC cells to test the efficacy of stoichiometric drug-drug combinations. Crystallization experiments at sub-milligram level in acetonitrile-methanol mixture yielded two drug-drug salt forms of PAZ with flufenamic acid (FFA) and niflumic acid (NFA) as PAZ+∙FFA‒∙ACN (an acetonitrile solvate named as form I) and PAZ+∙NFA‒. Structure of crystal forms were characterized by single crystal X-ray diffraction (SC-XRD) method. Crystal structures revealed that the presence of 2-aminopyrimidine group in PAZ is a strong partner for the carboxyl group in all solid forms which formed the acid⋯pyrimidine heterosynthon with COX inhibitor fenamic acids. To perform the dissolution experiments and cell line analysis, scale-up of both salt forms were done in acetonitrile-methanol mixture through crystallization that showed a polymorphic transformation in the case of PAZ+∙FFA‒∙ACN (an acetonitrile solvate named form II). The thermodynamic stability of PAZ+∙FFA‒∙ACN (form II) and PAZ+∙NFA‒ were analysed using slurry experiment under ambient condition in pH 1.2 (0.1 N HCl) buffer medium and residual solid phase was characterized by powder XRD which showed that PAZ+∙FFA‒∙ACN (form II) was a metastable solid form while PAZ+∙NFA‒ was a stable solid form. The dissolution experiments at gastric pH 1.2 showed that the rate of dissolution of PAZ+∙FFA‒∙ACN was 10 times higher than PAZ+∙NFA‒. The cell migration assay suggested that PAZ+·FFA‒·ACN inhibited ~25% and PAZ+·NFA‒ inhibited ~20% migration of HUVEC cells compared to PAZ alone. These investigations suggested that the drug-drug salts PAZ+·FFA‒ and PAZ+·NFA‒ would be potential combo drug candidates for the clinical trials.
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