Elucidating the Dehydration Mechanism of Ondansetron Hydrochloride Dihydrate with a Crystal Structure

In drug development, evaluating the stability of the hydrate is particularly important because changes in the hydration state could cause alterations of the physicochemical properties. In this study, it was found that ondansetron hydrochloride dihydrate, a competitive serotonin type 3 receptor antagonist, dehydrated to anhydrate in two steps with a hemihydrate form as an intermediate. The crystal structures of the unstable hemihydrate and anhydrate forms were successfully analyzed through the structure determination from powder diffraction data technique using high-temperature synchrotron X-ray diffraction data. Comparison of the crystal structures of the dihydrate and hemihydrate revealed that in the first dehydration step the water molecule hydrogen-bonded to the imidazole ring was removed. In the second step, the remaining water molecule that was closely bound to the chloride anions was removed to form a void. Moreover, the dehydration was examined through analysis of the intermolecular interactions. Furthermore, the hygroscopic properties of the hydration and dehydration were investigated. These phase transitions triggered by dry and high temperature conditions are common in drug development. Therefore, the crystal structure and physicochemical properties of all phases of hydrates and anhydrates should be characterized.