Research Article: The mechanism of solvent-mediated desolvation transformation of lenvatinib mesylate from di­methyl sulfoxide solvate to form D

Date Published: June 01, 2020

Publisher: International Union of Crystallography

Author(s): Zhixin Zheng, Baohong Hou, Xiaowei Cheng, Wanying Liu, Xin Huang, Ying Bao, Ting Wang, Zhao Wang, Hongxun Hao.


The solvent-mediated desolvation process of newly discovered lenvatinib DMSO solvate to form II at different water volume fractions and temperatures was investigated. It is confirmed that the activity of water is the most important factor affecting the desolvation process: the desolvation process only occurs when the activity of water is greater than the activity of DMSO, and one new mechanism of solvent-mediated desolvation process was proposed.

Partial Text

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 (Schöll et al., 2006 ▸; Llinàs & Goodman, 2008 ▸; Bērziņš et al., 2017 ▸; Brittain, 2009 ▸; Bond, 2009 ▸). Different crystal forms of multifarious drugs have been screened by controlling various factors influencing the crystallization process, such as temperature, solvent, humidity, solid loading, stirring rate, additives and template materials (Jiang et al., 2015 ▸; Hao et al., 2010 ▸, 2012 ▸; Guo et al., 2018 ▸; Barbas et al., 2018 ▸; Shi et al., 2015 ▸; Zong et al., 2017 ▸; Yang et al., 2013 ▸, 2012 ▸; Ouyang et al., 2014 ▸). In fact, many substances have far more solvated forms than the unsolvated form. For example, methyl cholate has eight unsolvated forms and 27 solvates (Bērziņš et al., 2017 ▸). Sulfa­thia­zole has more than 100 solvates but only five unsolvated forms (Anwar et al., 1989 ▸; Apperley et al., 1999 ▸; Bingham et al., 2001 ▸). Therefore, the study of solvates should be of great concern.

Two new solid forms of LM were obtained and characterized by PXRD, TGA, DSC, PLM and Raman spectroscopy for the first time. To investigate the transformation behaviors from DMSO solvate to form D, the PXRD calibration curve was established to quantify the mass fraction of the two solid forms in a mixture. The solubility data of DMSO solvate and form D in DMSO–water mixed solvents were measured and correlated using NRTL equation. The solubility data were used to evaluate the thermodynamic driving force of the SMDT process from DMSO solvate to form D. It was found that a turning point at Vw = 0.225 existed. When Vw was relatively high, DMSO solvate would desolvate and transform to form D while the desolvation transformation process would not take place at lower Vw. Through further investigations, it was found that the activity of water was the most important parameter that determined whether or not the SMDT process could happen. Moreover, Raman and solution concentration data displayed that the SMDT process was controlled by nucleation and growth of form D. Furthermore, the affecting mechanism of water activity and temperature on the SMDT process were investigated. The results demonstrated that the increase in temperature slowed down the SMDT process because of the decreasing thermodynamic driving force and the obstruction of forming new hydrogen bonds between LMs and water molecules. One new SMDT mechanism was suggested and discussed according to the experimental results and the mechanism was verified by cooling crystallization experiments.




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