Reevaluation of solubility of tolbutamide and polymorphic transformation from Form I to unknown crystal form

Thermodynamic stability order of tolbutamide between polymorphs was evaluated using calorimetry and spectroscopic analysis. The heat of solution (Delta H) of Forms I-III measurements were carried out in dimethylsulfoxide between 298.2 K and 319.2 K. It was found that the Delta H of Forms II and III was increased nearly parallel with a temperature rise. However, change of the Delta H of Form I with a temperature rise was not in correspondence with that of other forms. Solubility data confirmed the change in Delta H of Form I around 308.2 K. XRD-DSC measurement of Form I detected a polymorphic transformation (Form I-L -> unknown form) at 311 K. Obtained data suggested that the new crystal form (Form I-H) would exist above 311 K, and the order of thermodynamic stability was Form III < Form I-L < Form II below the transition temperature. on the other hand, the order was changed in Form I-L and Form I-H < Form III < Form II above the transition temperature. The crystal structure of Form I-H was determined by measurement of PXRD pattern on BL19B2 at SPring-8, and the change in the solid-state NMR spectrum confirmed the transformation of the crystal structure of Form I-L. (C) 2008 Elsevier B.V. All rights reserved.