Department of Pharmaceutics, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, 603203, India.
AAPS PharmSciTech. 2024 Aug 28;25(7):200. doi: 10.1208/s12249-024-02920-9.
To ensure product stability, it is critical to maintain the monohydrate state of cyclophosphamide following lyophilization, as this is the most stable solid form of the Cyclophosphamide. On the other hand, because of their limited aqueous solubility and stability, non-aqueous solvents are preferred for determining the composition and stability of bulk solutions. Hence, the purpose of this study was to use non-aqueous solvents for determining the composition and stability of bulk solutions, and to shorten the lyophilization process by retaining the cyclophosphamide monohydrate. Furthermore, prior to selecting the solvent for the bulk solution consisting of 90:10 tertiary butyl alcohol (TBA) and acetonitrile (ACN), various factors were taken into account, including the freezing point, vapor pressure of solvents, solubility, and stability of cyclophosphamide monohydrate. The concentration of the bulk solution was adjusted to 200 mg/mL in order to optimize the fill volume, enhance sublimation rates at lower temperatures during primary drying, and eliminate the need for secondary drying. The differential scanning calorimetry (DSC) measurements of bulk solution were used to improve the lyophilization cycle. The lyophilization cycle opted was freezing at a temperature of -55 °C with annealing step at -22 °C by which the reconstitution time was significantly reduced. The drying was performed at below - 25 °C while maintaining a chamber pressure of 300 mTorr. The complete removal of non-aqueous solvents was achieved by retaining water within the system. The presence of cyclophosphamide monohydrate was confirmed using X-ray diffraction (XRD). The reduction of lyophilization process time was established by conducting mass transfer tests and evaluating the physicochemical properties of the pharmaceutical product. Using non-aqueous solvents for freeze-drying cyclophosphamide is a viable option, and this study provides significant knowledge for the advancement of future generic pharmaceuticals.
为确保产品稳定性，在冷冻干燥后保持环磷酰胺一水合物状态至关重要，因为这是环磷酰胺最稳定的固体形式。另一方面，由于其有限的水溶解度和稳定性，非水溶剂更适合用于确定大量溶液的组成和稳定性。因此，本研究旨在使用非水溶剂来确定大量溶液的组成和稳定性，并通过保留环磷酰胺一水合物来缩短冷冻干燥过程。此外，在选择由 90:10 叔丁醇（TBA）和乙腈（ACN）组成的大量溶液的溶剂之前，考虑了各种因素，包括溶剂的冰点、蒸汽压、溶解度和环磷酰胺一水合物的稳定性。将大量溶液的浓度调节至 200mg/mL，以优化填充量、在初级干燥过程中在较低温度下提高升华速率，并消除对二次干燥的需求。大量溶液的差示扫描量热法（DSC）测量用于改进冷冻干燥循环。选择的冷冻干燥循环是在-55°C下冷冻，并在-22°C下进行退火步骤，这显著缩短了重配时间。在低于-25°C的温度下进行干燥，同时保持腔室压力为 300 毫托。通过在系统内保留水来完全去除非水溶剂。使用 X 射线衍射（XRD）确认环磷酰胺一水合物的存在。通过进行传质测试和评估药物产品的物理化学性质，确定了缩短冷冻干燥过程时间的方法。使用非水溶剂进行冷冻干燥环磷酰胺是一种可行的选择，本研究为未来仿制药的发展提供了重要的知识。
