Characterization of polymorphs and hydrates of GK-128, a serotonin 3 receptor antagonist

Abstract

The polymorphic and pseudopolymorphic forms of GK-128, a newly developed benzothiochromenone derivative, were characterized by powder X-ray diffractometry, thermal analysis, infrared spectroscopy, near-infrared spectrometry and hot-stage microscopy. The intrinsic dissolution rates at various temperatures were measured using the static disk method. GK-128 was found to have at least two hydrates (hemihydrate and monohydrate) and two anhydrates (anhydrate I and anhydrate II). When each form was stored at 25°C with a range of 0 to 97% relative humidity (RH), anhydrate I and anhydrate II were transformed to hemihydrate and monohydrate at above 90% RH and above 70% RH, respectively, while the crystalline forms of hydrates did not change after storage for 4 weeks. Intrinsic dissolution tests indicated that monohydrate was the most stable of these forms, since its dissolution rate was the slowest and no crystal transformation was observed during the dissolution tests. On the basis of the intrinsic dissolution rate of each form and the solubility of monohydrate, the solubilities of other metastable forms were calculated in order to estimate the transition temperature and the heats of dissolution. The transition temperature of hemihydrate and monohydrate was found to be 47°C, and the heats of dissolution of anhydrate I and anhydrate II were 16.5 and 14.7 kJ/mol, respectively.