(145b) Reactive Crystallization of Pharmaceuticals

Crystallization process design in the pharmaceutical industry frequently targets controlled small mean particle size materials to meet formulation, clinical and regulatory needs. In order to produce particles of small mean size directly, isolation techniques and equipment configurations producing uniformly high supersaturation, i.e. high rates of nucleation are needed. Reactive crystallization is known to produce very high levels of supersaturation. We have previously developed and characterized an opposed-jet Y-mixer for use in precipitations. In this work, we apply this device to further describe kinetic processes occurring in reactive precipitations.

We applied the Y-mixer to the reactive precipitations of benzoic acid, tyrosine and voriconazole over a range of supersaturation. Three techniques for monitoring particle formation processes were used: turbidity monitoring, direct microscopic observation, and quenched particle size analysis. Turbidity monitoring during flow is used to measure induction times less than 300 ms. At lower supersaturation, the number of particles can be tracked after flow has stopped to describe induction times longer than 100 ms. Finally, the quenched particle size distributions employing a double-Y tube allow for monitoring the time evolution of the particle size distribution.

Experimental induction times and nucleation rates agree reasonably well with the classical theory which predicts a high supersaturation dependence. The quenched particle size distributions suggest some secondary nucleation effects based on the shape of the quenched distributions. Induction times are significantly shorter under increased reactant concentration ratios. This result when analyzed in terms of a simplified diffusion-reaction model suggests that diffusion-induced interfacial gradients on a length scale smaller that of eddies are important in reactive precipitation.