THE MECHANISM OF DEHYDRATION AND REHYDRATION OF CYCLOPHOSPHAMIDE MONOHYDRATE (HYDRATES, SOLID-STATE)

DEBRA NOBUMI SHIOZAWA, Purdue University

Abstract

Physical properties pertinent to the solid phase of the monohydrate and anhydrate forms of cyclophosphamide were determined. Cyclophosphamide monohydrate had a transition temperature of 47.9(DEGREES)C and a (DELTA)H(,fusion) of 6.30 kcal/mol. The anhydrate form, which was different crystallographically from the monohydrate form, had a transition temperature of 51.9(DEGREES)C and a (DELTA)H(,fusion) of 5.39 kcal/mol.^ The dissociation pressure obtained from the dehydration isotherms at 21(DEGREES)C, 25(DEGREES)C, 30(DEGREES)C and 35(DEGREES)C gave a calculated (DELTA)H(,dissociation) of 13.0 kcal/mol. The (DELTA)H(,association) was calculated as -12.0 kcal/mol. The hysteresis effect suggested that the mechanisms of dehydration and rehydration were different.^ Analysis of DSC thermograms of samples from the dehydration process of cyclophosphamide monohydrate indicated that a simple eutectic mixture (melting point 41(DEGREES)C) was present. The solid-liquid phase diagram showed a eutectic point at 0.34 mole fraction of the monohydrate. The solid-liquid phase diagram constructed from the analysis of samples from the rehydration process of cyclophosphamide anhydrate showed similar results.^ At a 21(DEGREES)C and 0% relative humidity, the kinetics of the dehydration of cyclophosphamide monohydrate followed Fickian diffusion. At 25(DEGREES)C and above, the mechanism of dehydration changed because the temperature was approaching the melting point of the eutectic mixture. An increasing amount of atomic movement within the crystalline lattice at higher temperatures caused a greater escaping tendency of the water of crystallization.^ Two mechanisms of rehydration for cyclophosphamide anhydrate were proposed. The first mechanism of rehydration involved the condensation of water onto the surface of the solid at higher humidity environments. Dissolution of the solid into the liquid was followed by the recrystallization of the monohydrate from solution. The second mechanism occurred in the absence of condensed water. Interaction of water molecules with cyclophosphamide molecules on the surface of the solid resulted in the conversion of crystalline form of anhydrate to the monohydrate. The lag time in the rehydration kinetics indicated that rehydration may have been initiated through a nucleation process. The extent of water penetration into the anhydrate solid was controlled by the rate of crystalline conversion to the monohydrate form from the anhydrate. ^

Degree

Ph.D.

Subject Area

Chemistry, Pharmaceutical

Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server
.

Share

COinS