A critical review on thermodynamic and hydrodynamic modeling and simulation of liquid antisolvent crystallization of pharmaceutical compounds

[Display omitted] •System thermodynamics of the antisolvent crystallization is discussed.•Supersaturation, MSZW, induction time, crystallization kinetics are critically analysed.•Hydrodynamic modeling and CFD-based approach for LASC are critically reviewed.•A complete outlook of LASC is presented.•Modeling based LASC scale-up guidelines and challenges are discussed. Fine particles are in great demand in the pharmaceutical industry due to their versatile applications. Liquid antisolvent crystallization (LASC) is one of the promising approaches to prepare fine particles without requiring high energy. The interdependence of system thermodynamics, mass transfer kinetics, and the multi-phase hydrodynamics in the liquid antisolvent crystallization process is not well understood. In this review, the different modeling aspects of LASC are described from a fundamental perspective. The system thermodynamics of LASC is discussed and several models used in literature to predict the solubility in pure solvents and binary solvent mixtures are summarized. A detailed description of supersaturation, metastable zone width and induction time in antisolvent crystallization are presented and critically analyzed. The nucleation and growth kinetics are discussed and interpreted in terms of process variables. The hydrodynamic aspect of LASC which involves the mixing at different length scales is discussed and analyzed in detail. The CFD simulation-based approach to describe the interaction among different phenomena is critically reviewed. The crystallization scale-up, which is a major challenge in the LASC process, is discussed. A guideline for crystallization scale-up using the CFD-based modeling approach is presented which will be helpful to prospective researchers.