Abstract
In this work, the mechanism of solvent-mediated desolvation transformation of lenvatinib mesylate (LM) was investigated. Two new solid forms of LM, a dimethyl sulfoxide (DMSO) solvate and an unsolvated form defined as form D, were discovered and characterized using powder X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, polarized light microscopy and Raman spectroscopy. To investigate the thermodynamic mechanism of solvent-mediated desolvation transformation (SMDT) from LM DMSO solvate to form D, solubilities of LM DMSO solvate and form D in binary solvent mixtures of DMSO and water at different water volume fractions and temperatures (293.15-323.15 K) were measured and correlated by non-random two liquids model. The solubility data were used to evaluate the thermodynamic driving force of the SMDT process from DMSO solvate to form D and the effect of the activities of water and DMSO on the transformation process. Raman spectroscopy was used to monitor in situ the solid phase compositions during the SMDT process from LM DMSO solvate to form D while the solution concentration was measured by the gravimetric method. The overall desolvation transformation experiments demonstrated that the SMDT process was controlled by the nucleation and growth of form D. Moreover, effects of operating factors on the SMDT process were studied and the results illustrated that water activity in solution was the paramount parameter in the SMDT process. Finally, a new SMDT mechanism was suggested and discussed.
Highlights
Nowadays, screening new solid forms of an active pharmaceutical ingredient (API) is an indispensable step in the development and production of drugs
It can be found that the Powder X-ray diffraction (PXRD) data of dimethyl sulfoxide (DMSO) solvate and form D are different from reported forms of lenvatinib mesylate (LM)
Polarized light microscopy (PLM) was used to observe the morphology of DMSO solvate and form D of LM and the results are shown in supporting information (Fig. S3)
Summary
Nowadays, screening new solid forms of an active pharmaceutical ingredient (API) is an indispensable step in the development and production of drugs. The physical properties of different solid forms of the same compound, such as melting point, solubility, dissolution rate, physical and chemical stability, etc., may vary significantly. These properties will further affect the bioavailability, fluidity and efficacy of the final products (Scholl et al, 2006; Llinas & Goodman, 2008; Be"rzinsˇ et al, 2017; Brittain, 2009; Bond, 2009). Methyl cholate has eight unsolvated forms and 27 solvates (Be"rzinsˇ et al, 2017).
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