The stability of cyclophosphamide in lyophilized cakes.

摘要

The influences of excipients and residual moisture on the solid-state stability of cyclophosphamide in lyophilized products were investigated. Seven commonly used excipients were chosen for study. They were mannitol, lactose, sorbitol, sodium bicarbonate, urea, polyvinylpyrrolidone (PVP), and dextran.;Studies on the melting characteristics of frozen solutions of cyclophosphamide alone and in the presence of the seven excipients revealed that cyclophosphamide does not crystallize out during freezing. It was anticipated that freeze-drying these solutions would result in the formation of amorphous cyclophosphamide.;Lyophilized products containing cyclophosphamide and the excipients were prepared. All of the products were well-formed cakes with the exception of the one containing cyclophosphamide and sorbitol, which was a collapsed mass.;Cyclophosphamide in the well-formed cakes was found to undergo rapid degradation in the solid state, regardless of the excipient used. Powder X-ray diffraction and differential scanning calorimetry (DSC) showed that cyclophosphamide was amorphous in these products.;A simple method was developed which permits introduction of measured quantities of water vapor into the lyophilized cake.;In the cakes containing mannitol, sodium bicarbonate, or urea as excipients, X-ray diffraction and DSC showed that cyclophosphamide was converted from the amorphous to the monohydrate form when exposed to moisture, and exhibited improved stability.;Introduction of moisture into the lactose-, PVP-, or dextran-containing products does not result in improved stability of the cyclophosphamide. X-ray diffraction and DSC reveal that cyclophosphamide remains in the amorphous form in these cakes.