Modeling of the Gas-Antisolvent (GAS) process for crystallization of beclomethasone dipropionate using carbon dioxide

Shawn Dodds, Jeffery A. Wood, Paul A. Charpentier*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

24 Citations (Scopus)


The purpose of this work was to develop a mathematical model to describe the crystal size distributions (CSDs) produced from the gas-antisolvent (GAS) technique on the crystallization of beclomethasone17,21-dipropionate (BDP), which is an anti-inflammatory corticosteroid commonly used to treat asthma. The solvent used was acetone, and the antisolvent was carbon dioxide (CO 2). The GAS technique was chosen for its ability to produce micrometer-sized particles of uniform size. A better understanding of how the GAS process affects the CSDs of BDP is desirable to optimize the GAS experimental conditions for the production of inhalable powders for next-generation dry-powder portable inhalers (DPIs). To describe the pressurization during the GAS process, a mass balance and a phase equilibrium model were required. A predictive relative partial molar volume fraction (RPMVF) equilibrium model was used in the absence of existing phase data for the BDP-acetone-CO 2 system. This model uses the binary two-phase solvent/CO 2 phase equilibrium, and then relates it to the solid concentration. The model was tested successfully with the phenanthrenetoluene- CO 2 model system, the naphthalene-toluene-CO2 model system, and the more complex cholesterolacetone-CO 2 model system before being used to predict the BDP- acetone-CO 2 system. A population balance was then used to model experimentally determined particle size distributions. Two models for secondary nucleation were used independently: (i) an empirical equation that is commonly used to model secondary nucleation, and (ii) a theory-based equation. The crystallization model was able to give good estimates of the cumulative volume (mass)-weighted size distributions metrics d p(10%), d p(50%), and d p(90%) of the experimental CSDs.

Original languageEnglish
Pages (from-to)8009-8017
Number of pages9
JournalIndustrial & engineering chemistry research
Issue number24
Publication statusPublished - 21 Nov 2007
Externally publishedYes


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