Effect of Pulverization on Dehydration Behavior of Crystals of GK-128, a Serotonin3 Receptor Antagonist

Abstract

The effect of pulverization on the dehydration behavior of 2-[(2-methylimidazol-1-yl)methyl]benzo[f]thiochromen-1-one monohydro-chloride hemihydrate (GK-128), a newly developed serotonin3 receptor antagonist, was studied using powder X-ray diffraction analysis, thermo-gravimetry (TG), and differential scanning calorimetry (DSC). The crystalline forms of GK-128 obtained by pulverizing with a jet mill and an agate mortar were each confirmed to be the same as that of intact GK-128, since the powder X-ray diffraction patterns of the two prepared samples were identical with that of intact GK-128. However, after pulverization by jet mill, the dehydration temperature of GK-128 was markedly lowered and the DSC endothermic peak due to dehydration disappeared. The activation energy for dehydration, calculated by the Ozawa method using TG data, decreased with decreasing particle size and/or crystallinity of GK-128 crystals, e.g., the activation energies for dehydration of intact and jet-milled GK-128 were 128.1 and 75.9 kJ/mol, respectively. The results of comparison of powder X-ray diffraction patterns of pulverized GK-128 and intact GK-128 and of determination of the crystal structure of GK-128 suggested that water molecules could be removed easily along the c-axis of GK-128 crystals.