A STUDY OF PHASE TRANSITIONS IN FROZEN SOLUTIONS OF MANNITOL, CEFAZOLIN SODIUM, CEPHALOTHIN SODIUM, AND NAFCILLIN SODIUM.

摘要

The increasing application of freeze-drying has revealed problems of discoloration, meltback, puffing, and collapse of a number of products, thus necessitating their rejection based on esthetic or stability considerations. These problems are related to phase transitions which occur in the frozen solution. Experiments were done to identify and characterize phase transitions occurring in frozen solutions of mannitol, cefazolin sodium, cephalothin sodium, and nafcillin sodium.; Data obtained with differential scanning calorimetry (DSC) showed that the solute remained in an amorphous physical state when the solution was frozen and maintained below the glass transition temperature. The DSC thermograms obtained from warming the frozen solutions of mannitol, cefazolin sodium, and nafcillin sodium showed glass transitions, exotherms, and melting endotherms. Glass transitions occurred at -65(DEGREES)C, -20(DEGREES)C, and -10(DEGREES)C and exotherms were observed at -30(DEGREES)C, -10(DEGREES)C, and -5(DEGREES)C for the three compounds, respectively. Energies calculated from the exotherms of the thermograms, for mannitol (4.7 Kcal per mole) and cefazolin sodium (11.4 Kcal per mole), showed fair correlation to the compounds' heat of solution as reported in the literature (4.4 and 7.8 Kcal per mole, respectively). This result indicated the exotherm was due to crystallization of the drug. This was confirmed using scanning electron microscopy and x-ray powder diffraction techniques. The DSC thermogram from warming a frozen cephalothin sodium solution showed a glass transition at -22(DEGREES)C and a melting endotherm, however, a crystallization exotherm was not observed. Glass transition and crystallization exotherm temperatures for the compounds studied were concentration independent which indicated the phases were of constant composition. The melting temperature, which is a colligative property, was concentration dependent. Non-isothermal kinetic studies of mannitol and cefazolin sodium crystallization in frozen solutions showed the process to be highly temperature dependent having activation energies of 80 and 62 Kcal per mole, respectively. Isothermal kinetic data for cefazolin sodium were described using a zero-order model and by the Johnson-Mehl-Avrami (JMA) equation which describes processes where nucleation and crystal growth occur simultaneously. Activation energies for the zero-order model and JMA equation were calculated from Arrhenius plots yielding 71 and 75 Kcal per mole, respectively.; This high temperature dependence of crystallization and also of solution melting is important in the storage of frozen solutions and the freeze-drying processing, since the phases present in the frozen solution influence the product stability and an acceptable freeze-drying temperature. Partial melting would allow drug degradation to occur in the liquid phase of a frozen product and collapse and puffing in a product during freeze-drying. Crystallization could increase drug stability. A non-uniform temperature within a freezer or freeze-drying chamber could lead to non-uniform product batches.; This work identified the phase transitions occurring in frozen solutions of selected compounds and related the phases to problems observed in the storage of frozen solutions and in the freeze-drying process. It is expected that the results can be extrapolated to other compounds.