| Abstract
| - 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. Thesolvent used was acetone, and the antisolvent was carbon dioxide (CO2). The GAS technique was chosen forits ability to produce micrometer-sized particles of uniform size. A better understanding of how the GASprocess affects the CSDs of BDP is desirable to optimize the GAS experimental conditions for the productionof inhalable powders for next-generation dry-powder portable inhalers (DPIs). To describe the pressurizationduring the GAS process, a mass balance and a phase equilibrium model were required. A predictive relativepartial molar volume fraction (RPMVF) equilibrium model was used in the absence of existing phase datafor 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 phenanthrene−toluene−CO2 model system, the naphthalene−toluene−CO2 model system, and the more complex cholesterol−acetone−CO2 model system before being used to predict the BDP−acetone−CO2 system. A population balancewas then used to model experimentally determined particle size distributions. Two models for secondarynucleation were used independently: (i) an empirical equation that is commonly used to model secondarynucleation, and (ii) a theory-based equation. The crystallization model was able to give good estimates of thecumulative volume (mass)-weighted size distributions metrics dp(10%), dp(50%), and dp(90%) of theexperimental CSDs.
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