Combined cooling and antisolvent crystallization is a critical unit operation in pharmaceutical manufacturing, especially for heat-sensitive or poorly soluble active pharmaceutical ingredients. The model-based design of these systems relies on the accuracy of the underlying growth and nucleation kinetic parameters. Unlike temperature where these kinetic parameters are well-known to follow an Arrhenius relation, their dependency on solvent composition still remains unclear, especially in continuous mixed-suspension, mixed-product removal (MSMPR) systems. In this paper, we use population balance modeling coupled with nonlinear regression to estimate growth and nucleation parameters as a function of both temperature and solvent composition. As solvent composition increases from 44 vol % to 66 vol % solvent, both growth and nucleation rates were observed to decrease monotonically with their values reduced by almost one-third. It was also shown that, if the solvent dependency is ignored, the yield can be overpredicted or underpredicted by as much as 15%.

• Massachusetts Institute of Technology (MIT) (MIT)

• API
• Modeling

1. API
2. cooling & antisolvent crystallization
3. Growth & nucleation parameters
4. kinetic modelling
5. modeling
6. MSMPR
7. Research Article