A Review on Freeze Drying of Drugs with tert-Butanol (TBA) + Water Systems: Characteristics, Advantages, Drawbacks

Abstract

Organic cosolvent systems have been evaluated for their potential and increasing use for freeze drying of solutions to produce stabilized powders of marketed pharmaceutical products. The formulations most often investigated include tert-butanol (TBA) + water mixtures. These organic cosolvent systems present many interesting advantages: high freezing temperatures, very short sublimation time, low sublimation enthalpies, high equilibrium vapor/solid pressure values, and low toxicity.

Thus, some main characteristics of water + TBA systems have been reviewed, especially regarding its interesting thermodynamic properties (sublimation enthalpy, equilibrium vapor pressure), impact of freezing conditions on morphological properties of frozen formulations (nucleation, crystal size and shape), influence of operating parameters (total pressure, temperature) on sublimation times, and organic cosolvent and water residual contents.

The crystal morphology of frozen formulations prepared with TBA revealed unexpected results compared with the results reported in the literature for water-based formulations in terms of the complex relationships between freezing rates, supercooling, nucleation temperatures, and solvent crystal morphology (size and shape).

It has been proved that optimum freeze-drying cycles are established by simultaneously taking into account the impact of formulation variables, especially the tert-butanol content, and classical freeze-drying variables during the freezing step (nucleation temperatures, freezing rates) and the sublimation step (shelf temperature, total pressure) to maximize the drying rates and to minimize the residual solvent levels while preserving the main quality attributes of the freeze-dried powder.

Keywords:

• Annealing
• Crystal morphology
• Freeze drying
• Residual solvent
• Sublimation enthalpy
• tert-Butanol
• Vapor pressure

Notes

Data from Daoussi et al.^{[ 9 , 15 ]}