CHANGES IN SOLID-STATE STRUCTURE OF CYCLOPHOSPHAMIDE MONOHYDRATE INDUCED BY MECHANICAL TREATMENT AND STORAGE

The effects of mechanical treatment and various storage conditions on the structure of cyclophosphamide monohydrate were evaluated by therma l and X-ray analyses and molecular modeling. The monohydrate form of c yclophosphamide was found to convert to the anhydrous form through a m etastable phase. Metastable forms were produced by mechanical treatmen t and by desiccation. These forms could be detected in differential sc anning calometric thermograms as endothermic peaks, at approximately 3 9 degrees C, and X-ray powder diffractometric analysis, e.g.; by a cha racteristic reflection at 15.3 degrees (2 theta). Molecular modeling w as used to study molecular interactions and putative metastable struct ures. The dehydration enthalpies of the cyclophosphamide monohydrate o btained from quantum chemical calculations and DSC analysis were 51.6 and 36.1 J/g, respectively. In a unit cell of the stable monohydrate, a water molecule is held by O(7) of the cyclophosphamide molecule and N(6)H of a neighboring cyclophosphamide molecule, with hydrogen bonds enabling existence of a water tunnel. The metastable form of cyclophos phamide is detected when a sterically formed block in the possible tun nel is removed, and the water molecules are allowed to leave the syste m one by one.