(149e) API-Crystal Preparation In A Continuously Seeded Tubular Crystallizer

We present a continuously seeded tubular crystallizer system, which allows the crystallization of pharmaceutical substances under controlled conditions (1-5). Ethanolic suspensions of acetylsalicylic acid, ibuprofen as well as acetaminophen seeds are fed into a tubular crystallizer, where they are mixed with hot, highly concentrated ethanolic solutions of the corresponding model-substances. Cooling generates supersaturation upon which the seeds grow to form product crystals while being conveyed through the tubing. Due to the tubular appearance and the small inner dimensions of the crystallizer in the few millimeter range it is possible to adjust the temperatures along the tubing according to the needs of the crystallization and to achieve narrow residence time distributions of the crystal slurry in the pipe. Hence, the seeds entering the feed end simultaneously grow in a similar environment (concentration, temperature etc.) and have approximately the same amount of time for growth. Thus, narrow product crystal size distributions (CSDs) can be obtained.

The effects of various critical process parameters on product characteristics have been investigated. Residence times of the suspensions in the tubing have been changed by altering the length of the crystallizer or the flow rates respectively. Further parameters that have been varied independently were the seed loading, seed properties as well as the cooling trajectories along the tubular crystallizer. Moreover, the spatial orientation of the tubular crystallizer coils were subject to variations (horizontal or vertical) in order to assess if particle segregation phenomena lead to different results regarding the crystal size distribution. Furthermore, a segmented flow of slurry and air-bubbles was implemented to completely rule out particle size segregation phenomena and to reduce the residence time distribution of the crystals to a minimum. All experiments clearly resulted in significant crystals growth despite the short residence times in the few minute range. Moreover, crystal masses increased by a few g/min and steady-state conditions were obtained instantaneously. Suppression of nucleation events by avoiding rapid cooling, thus high levels of supersaturation together with narrow residence time distributions of the slurry in the tubing allowed successful achievement of narrow CSDs.

Furthermore, simulations regarding the temperature gradients and the crystal growth have been performed in order to get a better understanding of the process. Modelled and experimental results were compared to each other and calculations where foundation for process improvements.

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