Experimental Design for the Efficient Determination of the Crystallization Kinetics of a Polymorphic System in Combined Cooling and Antisolvent Crystallization

In this work, the polymorphic transformation of a dimorphic model compound, ortho-aminobenzoic acid (OABA), is investigated using experimental characterization in combination with population balance modeling. A novel experimental design is proposed to estimate the crystallization kinetic parameters of the polymorphic system in a combined cooling and antisolvent crystallization (CCAC) process with a minimum number of experiments, which can reduce the resources and time required to obtain kinetic information, which is of great importance in the drug substance development stage. The modeling studies revealed that the growth rates of the two polymorphs depend on the solvent composition. At a particular temperature and supersaturation, the form I growth rate increased as the solvent content proportion increased, whereas the form II growth rate decreased as the solvent content increased. The identified kinetic parameters of the nucleation and growth rate expressions of the two polymorphs were validated for different solvent compositions and temperatures. The validated model was then used to perform in silico design of experiments to develop a design space that can be used to identify operating conditions to achieve the desired crystal size and polymorphic form.