Purpose. To monitor the phase transitions during freeze-drying of cefazolin sodium (I) as a function of process and formulation variables. Methods. Aqueous solutions of I were frozen under controlled conditions in the sample chamber of a variable temperature X-ray powder diffractometer (XRD). The instrument was modified so that the chamber could be evacuated and the samples dried under reduced pressures. Thus, the entire freeze-drying process was carried out in the XRD holder with real time monitoring of the phase transitions during the different stages of freeze-drying. Results. When aqueous solutions of cefazolin sodium (10% w/w) were cooled to -40°C, the XRD pattern revealed only the crystallization of ice. Annealing the frozen sample led to the crystallization of I as the pentahydrate. Differential scanning calorimetry revealed that the presence of isopropyl alcohol (IPA) (5% w/w) led to a decrease in the Tg', the glass transition temperature of the system, and lowered the temperature of crystallization. The crystallization was studied at -8 and at -15°C in the XRD, and, as expected, more rapid crystallization was observed at the higher temperature. Primary, drying at -8°C led to the dehydration of the pentahydrate, resulting in a poorly crystalline product. Again, XRD permitted real time monitoring of the decrease in intensities of some characteristic peaks of the pentahydrate. The in situ XRD technique also enabled us to study the effects of processing conditions (different primary and secondary drying temperatures) and crystalline bulking agents on the solid-state of I in the lyophile. When I was lyophilized using mannitol or glycine as an additive, without an annealing step, the drug was X-ray amorphous although the additive crystallized. When annealed and freeze-dried, I remained crystalline in the presence of glycine but not in the presence of mannitol. Conclusions. The in situ XRD technique has enabled us to characterize the phase transitions during freeze-drying of cefazolin sodium in multicomponent systems.
Bibliographical noteFunding Information:
Partial financial support from the Parenteral Drug Association Foundation for Pharmaceutical Sciences is gratefully acknowledged. AP was partially supported by the ISWOP, University of Minnesota. We thank James Roemer for his technical help and Dr. Rahul Surana for his valuable comments.
- Cefazolin sodium
- Differential scanning calorimetry
- X-ray powder diffractometry