Investigation of optimal manufacturing process for freeze-dried formulations: Observation of frozen solutions by low temperature X-ray diffraction measurements

Investigation of optimal manufacturing process for freeze-dried formulations: Observation of frozen solutions by low temperature X-ray diffraction measurements
Hiroaki Egawa, Etsuo Yonemochi and Katsuhide Terada, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
Thermochimica Acta, In Press, Corrected Proof, Available online 10 May 2005,
Received 4 November 2004; revised 13 January 2005; accepted 25 January 2005. Available online 26 February 2005.
You can view the abstract online. A subscription is required to view the full text or it can be purchased online.
Freeze-drying is used for the production of sterile injections in the pharmaceutical industry. However, most pharmaceutical compounds are obtained as less stable amorphous form. Freeze crystallization by annealing is an effective method for pharmaceutical compounds that fail to crystallize in the freeze-drying process. Crystallization occurs in the frozen solution during the thermal treatment. In order to establish suitable annealing conditions efficiently, it is important to observe the crystallization process directly in the frozen solution. Recently, low temperature X-ray diffraction has been used to observe frozen solutions. In order to investigate the crystallization process kinetically, the temperature of the low temperature X-ray diffraction instrument must be accurately controlled.
We calibrated the temperature of X-ray diffraction instrument by measuring eutectic temperatures of solutions for a series of compounds. Each eutectic crystal was observed in frozen solution with ice crystal below the eutectic temperature. Eutectic temperatures were detected by the decrease in diffraction intensity associated with heating from below the eutectic temperature. Good correlation was obtained between values in the literature and experimental values.