A Study of the Phase Transitions in Frozen Antibiotic Solutions by Differential Scanning Calorimetry

Abstract

Phase transitions which occur in frozen antibiotic solutions were monitored with use of differential scanning calorimetry (DSC), microscopic analysis, scanning electron microscopy, and x-ray diffraction. It was shown three selected antibiotics all froze as the amorphous form and unless thermally treated before drying remained in the lessdesirable hygroscopic amorphous form. Conversion to the crystalline form at various sub-zero temperatures was determined; for cefazolin sodium, the conversion temperature was between –20 and –10 °C; for nafcillin, it was between –10 to –4 °C; and for cephalothin sodium, the thermal event was so slow that scanning rates as low as 0.625° per minute were too fast to detect its location by DSC. For the latter, crystallization was more effectively achieved by alternate means such as crystal seeding or by humidifying the freeze-dried material. From the DSC thermograms, phase diagrams were constructed and the phase changes identified. Such information is valuable in the design and control offreeze-drying cycles and also can permit the freeze-drying of products often believed to be poor candidates for the process.