Statistical Design of Experiment on Contact Secondary Nucleation as a Means of Creating Seed Crystals for Continuous Tubular Crystallizers

In the pharmaceutical industry, it is often desired to produce seed crystals with an appropriate narrow size distribution of the desired polymorph. This study describes a system that generates such crystals continuously in a small-scale tubular crystallizer at low supersaturation via contact secondary nucleation. A response surface model was constructed by conducting a statistical design of experiment that models the nucleation rate as a function of contact force, area, and frequency. This model reveals that within a certain range the nucleation rate is linearly related to all three factors in this system. A combination of in-line video analysis and off-line microscope image analysis was used to determine the particle size distribution of seed crystals obtained in this system, and the majority of the crystals were found to be under 20 μm. This seems to be a feature of contact secondary nuclei in general and does not vary significantly with contact force, area, and frequency. Furthermore, the seed crystals...