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Pure Appl. Chem., 2005, Vol. 77, No. 3, pp. 581-591

Thermodynamic stability and transformation of pharmaceutical polymorphs

Mitsutaka Kitamura

Department of Mechanical and System Engineering, University of Hyogo, 2167 Shosha, Himeji 671-2201, Japan

Abstract: The thermodynamic stability and transformation of pharmaceutical polymorphs was investigated, especially those of the thiazole derivative pharmaceutical, 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (BPT). The influence of methanol compositions in solvents and temperature on the solubility and the transformation behavior of BPT was clarified. The transformation behavior was explained by the chemical potential difference between the stable and metastable forms. It was shown that a specific solute–solvent interaction contributes to the preferential nucleation and growth of the stable or metastable forms and influences the transformation behaviors. The solubility of BPT of the solvated crystals is much more influenced by the solvent compositions than the true polymorphs. The solubility ratio of the solvated crystals depends on the solvent composition, whereas the solubility ratio of the true polymorphs is considered to be independent of the solvents. The crystallization behavior was also investigated. The transformation rate after crystallization appeared to depend on the initial concentration of BPT and the addition rate of the antisolvent. The cause of this phenomenon was presumed to be a slight inclusion of the stable form in the metastable form.