Synergistic Control of Nonlinear Growth Kinetics and Nucleation Kinetics in the Concomitant Crystallization of Aripiprazole as Reflected by the Ostwald Ratio

Some polycrystalline drugs are subject to concomitant polymorphism during the manufacturing process, resulting in large batch-to-batch variation and reduced drug bioavailability. Most existing studies on concomitant polymorphism have focused only on differences in nucleation kinetics and lacked analysis of the role of growth processes in polymorph control. Herein, we conducted a systematic study on the concomitant crystallization of aripiprazole Form III and Form V under the influence of thermodynamic and kinetic factors employing thermal analysis with the Ostwald ratio as a medium. It shows that the nucleation and growth rates of both forms cross over with increasing supersaturation. The comparison between the polymorph composition computed by the Ostwald ratio and the experiments highlights the considerable influence of crystal growth on the formation of concomitant polymorphism. The effect of crystal growth at lower supersaturation is indeed minimal due to the large difference in nucleation rates, but as the supersaturation increases, the difference in nucleation rates becomes smaller and the growth rate ratio gradually becomes a key factor. The images plotted with initial concentration and crystallization temperature further demonstrate that the introduction of actual nonlinear growth kinetics can lead to improved computation accuracy of the Ostwald ratio. This work provides evidence for the application of the Ostwald ratio in the design of batch crystallization for a concomitant system.