Insights from a Thermodynamic Study and its Implications on the Freeze-Drying of Pharmaceutical Solutions Containing Water and Tert-Butyl Alcohol as a Cosolvent

Abstract

In the production of several anticancer drugs, tert-butyl alcohol (TBA) is present as a co-solvent in the aqueous drug solution. In order to ascertain if TBA should be removed beforehand or if it could be retained to facilitate the freeze-drying of the drug solution, it is important to acquire both qualitative and quantitative knowledge of the variations occurring with respect to time in heat and mass transfer during the freeze-drying process. In this work, a thermodynamic model employing the UNIFAC (Dortmund) method was developed to determine the values of the currently experimentally unavailable partial vapor pressures of the binary gas mixture of water and TBA in equilibrium with their frozen solid mixtures. The results agree satisfactorily with relevant experimental measurements and indicate that TBA vapor has constantly higher pressures than water vapor and also promotes the vapor pressure of water during sublimation. The responses of the partial pressures of water and TBA vapors are found, through the analysis of their partial and total differentials, to be increasingly more sensitive to temperature change at elevated temperatures and to compositional change when the mole fraction of water in a frozen binary mixture approaches zero. The increased vapor pressures due to TBA lead to higher total pressures at the moving interface separating the dried and frozen layers, resulting in larger total pressure gradients and convective mass transfer rates in the dried layer during primary drying. But the higher total pressures reduce the magnitude of the bulk diffusivity of the gas mixture, and combined with the smaller Knudsen diffusivity of TBA, the pressures could significantly affect the competing mass transfer mechanisms during freeze-drying. The approach presented in this work could provide a general thermodynamic modeling approach for predicting the vapor pressures of multicomponent vapor mixtures in equilibrium with their multicomponent solid frozen mixtures.

Department(s)

Chemical and Biochemical Engineering

Keywords and Phrases

Bulk diffusion; Convective flow; Freeze-drying; Knudsen diffusion; Partial vapor pressures; Tert-butyl alcohol (TBA); Thermodynamic modeling; UNIFAC (Dortmund); Water

International Standard Serial Number (ISSN)

1079-7440

Document Type

Article - Journal

Document Version

Citation

File Type

text

Language(s)

English

Rights

© 2019 Parenteral Drug Association Inc., All rights reserved.

Publication Date

01 May 2019

PubMed ID

30651336

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