Comparison of experimental methods and theoretical calculations on crystalenergies of 'isoenergetic' polymorphs of cimetidine

The thermodynamic energy relationship between two crystal modifications of cimetidine was investigated and compared with differences in their processi ng properties with respect to transformation from one modification to the o ther. The crystal energies of the two modifications A and D were found to be almo st identical and therefore the polymorphs are regarded as virtually isoener getic crystals. This statement is based on DSC measurements of the melting points and of the enthalpies of fusion for the two crystal forms, which ena ble the calculation of the Gibbs free energy functions. Furthermore, the st atement is supported by measurements of the enthalpies of solution in two d ifferent solvents. Both DSC and solution experiments reveal a slightly high er stability of the D modification with respect to the A form. In addition, tribomechanical treatment also indicates modification D to be the more sta ble one, as well as the higher density of the D form. No transformation dur ing DSC at low heating rate was found which could be used in a stability co nsideration. As the explicit crystal structures of the two modifications are resolved, i t was possible to calculate crystal energies theoretically as well. The the oretical results showed a remarkable difference in the crystal energies at zero degree Kelvin. Furthermore, they were just contradicting experimental findings by stating A being more stable than D. Possible reasons for this d iscrepancy and the feasibility of today's calculation methods with respect to prediction of stability properties are discussed.