Department of Pharmaceutics, NIPER SAS Nagar, sector-67, Mohali 160062, Punjab, India.
Department of Pharmaceutics, NIPER SAS Nagar, sector-67, Mohali 160062, Punjab, India.
J Pharm Sci. 2019 Mar;108(3):1195-1202. doi: 10.1016/j.xphs.2018.10.020. Epub 2018 Oct 21.
The purpose of this study was to investigate the phase behavior of cyclophosphamide (CPA) during various stages of lyophilization, with special emphasis on obtaining crystalline CPA monohydrate (CPA-MH) in the lyophilized product. Subambient differential scanning calorimetry and low-temperature X-ray diffractometry (LTXRD) were used to study the phase behavior of CPA solution (3.7% w/v). In situ lyophilization in LTXRD chamber was used to monitor the phase transitions occurring during the drying stages. Finally, the implications of these findings were confirmed by freeze-drying the aqueous solution in a laboratory-scale freeze-dryer. The results suggested that CPA remains amorphous during freeze concentration, with a T' of -50°C. However, its crystallization as CPA-MH can be induced by annealing the frozen solution between -5°C and -10°C. In situ lyophilization in LTXRD showed that the CPA-MH crystallized during annealing, rapidly dehydrated during primary drying, thereby causing structural collapse. The dehydration of CPA-MH can be prevented by lowering the escaping tendency of water molecules from the crystal lattice of CPA-MH by maintaining the chamber pressure to 300, 400, or 500 mTorr. This study highlights the relationship of process parameters used during lyophilization with the solid form of lyophilized CPA.
本研究旨在探讨环磷酰胺（CPA）在冷冻干燥各个阶段的相行为，特别关注在冻干产品中获得结晶性的 CPA 一水合物（CPA-MH）。亚环境差示扫描量热法和低温 X 射线衍射法（LTXRD）用于研究 3.7% w/v 的 CPA 溶液的相行为。使用 LTXRD 腔室中的原位冷冻干燥来监测干燥阶段中发生的相转变。最后，通过在实验室规模的冷冻干燥器中冷冻干燥水溶液来证实这些发现的意义。结果表明，CPA 在冷冻浓缩过程中保持无定形，T'为-50°C。然而，通过在-5°C 和-10°C 之间退火冷冻溶液，可以诱导其结晶为 CPA-MH。LTXRD 中的原位冷冻干燥表明，在退火过程中，CPA-MH 结晶，在初级干燥过程中迅速脱水，从而导致结构坍塌。通过将腔室压力保持在 300、400 或 500 毫托，降低水分子从 CPA-MH 晶格逸出的趋势，可以防止 CPA-MH 的脱水。本研究强调了冷冻干燥过程中使用的工艺参数与冻干 CPA 的固体形式之间的关系。
