Modeling of the gas-antisolvent (GAS) process for crystallization of beclomethasone dipropionate using carbon dioxide

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 beclomethasone-17,21-dipropionate (BDP), which is an anti-inflammatory corticosteroid commonly used to treat asthma. The solvent used was acetone, and the antisolvent was carbon dioxide (CO2). 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-CO2 system. This model uses the binary two-phase solvent/CO2 phase equilibrium, and then relates it to the solid concentration. The model was tested successfully with the phenanthrenetoluene-CO2 model system, the naphthalene-toluene-CO2 model system, and the more complex cholesterolacetone-CO2 model system before being used to predict the BDP-acetone-CO2 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..