The effects of mechanical treatment and various storage conditions on the structure of cyclophosphamide monohydrate were evaluated by thermal and X-ray analyses and molecular modeling. The monohydrate form of cyclophosphamide was found to convert to the anhydrous form through a metastable phase. Metastable forms were produced by mechanical treatment and by desiccation. These forms could be detected in differential scanning calometric thermograms as endothermic peaks, at approximately 39 degrees C, and X-ray powder diffractometric analysis, e.g.; by a characteristic reflection at 15.3 degrees (2 theta). Molecular modeling was used to study molecular interactions and putative metastable structures. The dehydration enthalpies of the cyclophosphamide monohydrate obtained 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 cyclophosphamide is detected when a sterically formed block in the possible tunnel is removed, and the water molecules are allowed to leave the system one by one.
The quantitative x-ray diffraction analysis offers often an exact and practical technique to determine the relative amounts of the phases of the solid in question. The sample may contain only one amorphous phase.The purpose of this paper is to estimate the suitability of this technique to quantify the phase fractions of pharmaceutical substances. Three different method were used to determine the relative amounts of phases. Methods were compared and the major sources of error were estimated. The measurements and calculations are carried out using selegilin hydrochloride, mannitol and modified starch as an example. The results show that the amount of about 2 % of selegilin hydrochloride can be observed reliably from among the mannitol (crystalline substance) or modified starch (amorphous substance). During the work it became obvious that the accuracy of these calculations can essentially be improved planning the measurements carefully.
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