Characterization of solvatomorphs of methotrexate using thermoanalytical and other techniques

Identification and characterization of different forms of methotrexate were carried out by crystallization from different solvents. Five different forms of the drug were obtained. Appearance of a desolvation endotherm in the DSC accompanied by mass loss in TGA for forms I, II, IV and V showed these forms to be acetonitrile solvate hydrate (form I), trihydrate (forms II and IV) and dimethylformamide solvate (form V), respectively. However, the desolvation peak was absent in form III (obtained from methanol) indicating the absence of any solvent of crystallization. This form was found to be partially crystalline by its XRPD pattern. Solution calorimetry was further used to differentiate between the forms as they differ in lattice energy, resulting in different enthalpies of solution. The dissolution and solubility profiles were correlated with the enthalpy of solution and subsequently with crystallinity of all the forms; the least endothermic form (form III) had the highest dissolution rate.