J. Ketolainen et al., CHANGES IN SOLID-STATE STRUCTURE OF CYCLOPHOSPHAMIDE MONOHYDRATE INDUCED BY MECHANICAL TREATMENT AND STORAGE, Pharmaceutical research, 12(2), 1995, pp. 299-304
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.