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The transition temperature for enantiotropic polymorphs of pharmaceutical drugs was estimated by measuring the heat of solution and solubility at 25 °C. Instead of the conventional estimation method using van’t Hoff plots, a thermodynamic formula was derived with the heat of solution and solubility as variables for calculating the temperature at which the Gibbs free energy difference between two polymorphs in enantiotropic system become zero. The transition temperatures of polymorphic pairs for five model compounds (seratrodast, mefenamic acid, sulfathiazole, acetazolamide, and carbamazepine) calculated by the formula were in good agreement with previous studies. Since this formula requires solubility data at only one arbitrary temperature other than the heat of solution data for both polymorphs in a polymorphic pair, the proposed method is much faster than the conventional method, requiring solubility data at five or more different temperatures for preparing van’t Hoff plots.

The feasibility of a simple Fourier transform (FT) Raman spectroscopic method for the quantitative determination of unexpected active drug polymorphs or amorphous in drug products was explored. In this study, calibration samples were prepared by physically mixing drug substances with their polymorphs or amorphous, without using excipients. A partial least-squares (PLS) method was applied to the quantitative analysis of the FT Raman spectra obtained. As model drug products, compound A drug substances (form a) containing several ratios of polymorph, (form b), were physically mixed with excipients to prepare powder samples corresponding to compound A tablets (30 and 120 mg). The mixture of compound B, form I and amorphous, were also mixed with excipients to mimic powdered compound B tablets (32 mg). Satisfactory relationships between the theoretical contents of polymorph or amorphous and determined contents were obtained; quantitation limits were 5-10％. In the case of powder samples corresponding to compound A tablets (30 mg) and compound B tablets (32 mg), diŠerentiating the FT Raman spectra prior to PLS analysis was required to improve the precision of the determinations.

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