(744e) Precise Tailoring of the Crystal Size Distribution by Optimal Seeding Time Profiles

For active pharmaceutical ingredients (APIs), a major challenge has been in the development of a systematic engineering approach to design crystallization processes to produce a desired crystal size distribution to satisfy the API's bioavailability requirements. In this work, we explore the possibility to precisely achieve target crystal size distributions through the addition of seed crystals at various weights into an aging vessel for crystal growth for various times. In other words, this strategy optimizes a seeding time profile based on the target distribution, using seeds of narrow distribution, for the operation of a batch crystallizer. To simplify the formulation, a constant growth rate was used; experimentally, this can be easily achieved by constant supersaturation control [1, 2], which is optimal or near optimal for most crystallizers [3]. The optimal weights as a function of the drop time was derived using a nonlinear least-squares optimization solver, and appears as a ?flipped? version of the target crystal size distribution. This approach has the capability of tailoring any crystal size distribution of any shape, for example, the flat-top and multi-modal distributions as demonstrated in this work, as long as the target size distributions do not have characteristics narrower than the narrowest size distribution of the seed crystals. Succinic acid was used as the model compound in this study; the nucleation, growth, and dissolution kinetics have been reported previously [4, 5].

References

1. Fujiwara, M.; Chow, P. S.; Ma, D. L.; Braatz, R. D. Crystal Growth & Design 2002, 2, 363-370.

2. Zhou, G. X.; Fujiwara, M.; Woo, X. Y.; Rusli, E.; Tung, H. H.; Starbuck, C.; Davidson, O.; Ge, Z.; Braatz, R. D. Crystal Growth & Design 2006, 6, 892-898.

3. Jones, A. G.; Mullin, J. W. Chemical Engineering Science 1974, 29 (1), 105.

4. Qiu, Y.; Rasmuson, A. C. AIChE Journal 1990, 36 (5), 665-676.

5. Qiu, Y.; Rasmuson, A. C. AIChE Journal 1991, 37 (9), 1293-1304.