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 (Δ H) of Forms I–III measurements were carried out in dimethylsulfoxide between 298.2 K and 319.2 K. It was found that the Δ H of Forms II and III was increased nearly parallel with a temperature rise. However, change of the Δ H of Form I with a temperature rise was not in correspondence with that of other forms. Solubility data confirmed the change in Δ 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.