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In this paper, a model-based optimal strategy is presented for the control of particle size in antisolvent crystallization. Size is controlled on demand by dynamic optimization using a population balance based model. Knowledge of the ternary solute-solvent-antisolvent equilibrium and crystallization kinetics is crucial in this strategy, and these are thus incorporated in the model. The optimization is capable of determining the optimal antisolvent feed profile that achieves a desired particle size. Experimental validation of the strategy is carried out and presented herein. Such a strategy stands as a key solution to antisolvent operations ubiquitous in the pharmaceutical and fine chemicals industries.

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Aspirin, which is used as a pain killer and is recommended to cure diseases such as arthritis, was precipitated using the gas-antisolvent (GAS) process. The objective of this study was to investigate the effects of four operating parametersnamely, antisolvent addition, process temperature, solute concentration, and solvent type (methanol and acetone)on the final product particle size distribution, morphology, and crystallinity. In accordance to particle size analysis and scanning electron microscopy (SEM), it was observed that the increment of antisolvent addition rate reduced the mean size of precipitated particles and the size distributions became narrower. Furthermore, the process temperature and the solute concentration had a reverse effect on the precipitated aspirin particle size. The crystallized particles had a mean size between 48 μm and 124 μm. In contrast, particles precipitated from methanol solution had smaller mean size than from acetone. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) showed that particles produced from acetone had more crystalline structure in comparison with the samples produced from methanol and also the unprocessed purchased aspirin. This can be explained through reduced involvement of methanol into the crystalline structure. The results proved the capability of GAS process for the production of aspirin for the therapeutic applications.