Freeze -drying of tertiary butyl alcohol /water cosolvent systems
Abstract
The objective of this study was to identify significant formulation and processing variables affecting levels of tert-butyl alcohol (TBA) and isopropyl alcohol (IPA) in freeze-dried solids prepared from TBA/water cosolvent systems. The TBA concentration above which eutectic crystallization takes place was determined by differential scanning calorimetry. Model formulations were subjected to extremes of freezing rate by either dipping in liquid nitrogen or by slowly freezing on the shelf of a freeze-dryer. On the basis of these studies, the most important determinant of residual TBA level is the physical state of the solute. For freeze-dried sucrose, residual TBA levels were approximately 2 orders of magnitude higher than freeze-dried glycine and were significantly affected by initial TBA concentration and freezing rate. For the sucrose/TBA/water system, relatively low residual TBA levels were obtained when the initial TBA level was above the threshold concentration for eutectic crystallization of TBA, whereas samples freeze-dried from solution containing TBA concentrations below this threshold contained significantly higher levels of TBA. Formulations of sucrose/TBA/water which were frozen rapidly contained residual TBA levels which were approximately twice those measured in the same formulation after slow freezing and drying under the same conditions. For the sucrose/TBA/water system, the temperature and time of secondary drying had only minimal influence on residual TBA in the freeze-dried solid. At low initial TBA concentrations (2%), residual TBA increases with increased cake thickness, perhaps because of the influence of depth of fill on effective freezing rate. In addition, the feasibility of preparing freeze-dried solids of tobramycin base and tobramycin sulfate that readily break apart to form powders which can be poured from the vial was investigated by incorporating TBA as a cosolvent into the formulation. Frozen solutions of tobramycin base and tobramycin sulfate in water and in various concentration of t-butanol (TBA) were characterized by thermal analysis and freeze dry microscopy, and trial batches were prepared. For tobramycin base, rehumidification of freeze-dried solids, followed by additional secondary drying results in crystallization of tobramycin base, which results in residual TBA levels well below 1%. For tobramycin sulfate, TBA/water eutectic crystallization is critical to minimize residual TBA in the freeze-dried solids. Formulations containing tobramycin sulfate allow the TBA/water eutectic mixture to crystallize readily as compared to tobramycin base, which promotes TBA removal during primary drying. Annealing at −20°C after the initial freezing process was shown to result in significantly lower residual TBA levels and significantly less vial-to-vial variability in residual TBA than without annealing by promoting eutectic crystallization of the TBA/water mixture.
Degree
Ph.D.
Advisors
Nail, Purdue University.
Subject Area
Pharmaceuticals
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