APPLICATION OF ISOTHERMAL MICROCALORIMETRY IN PREFORMULATION .1. HYGROSCOPICITY OF DRUG SUBSTANCES

Isothermal microcalorimetry was evaluated for the determination of the critical relative humidity (cRH) for three drug substances possessing different hygroscopic properties. Two extremely water-soluble substan ces (flupentixol,2HCl and Lu 25-109, water solubility over 1000 mg/ml) and a hydrophobic substance (sertindole, approximately 10 mu g/ml) we re examined. The technique was evaluated with respect to sample size, duration of exposure time and temperature for the substance Lu 25-109, and further tested with the other compounds. The cRH values determine d by isothermal microcalorimetry showed results similar to various wei ghing methods. This, together with the high sensitivity of the techniq ue, which will enable a determination within hours, and the small samp le amount needed, makes isothermal microcalorimetry a valuable screeni ng technique for new drug candidates. The temperature effects on the c RH for Lu 25-109 showed a linear van't Hoff plot, but with a heat of i nteraction with water differing from the enthalpy of water condensatio n, however. By results obtained from solution calorimetry, this deviat ion was accounted for by the heat of formation of a saturated solution in the water layer surrounding the solid particles. (C) 1997 Elsevier Science B.V.