(509g) Preparation of API-Crystals in a Continuously Seeded Tubular Crystallizer

Particle shape and size have an influence on the solubility of an active pharmaceutical ingredient (API)-particle and hence on the bioavailability of the substance (1). Thus, bulk properties such as the crystal size and shape distribution (CSSD) are important quality attributes of powders. Moreover, downstream processes (e.g., filtering, washing, drying) and the handling abilities (e.g., flowability, tabletability) of the particles are positively affected by narrow crystal size distributions (CSDs). In order to obtain product crystals with desired features it is important to control numerous parameters during a crystallization process.

We present a continuously seeded tubular crystallizer system, which allows the crystallization of pharmaceutical substances under controlled conditions. An ethanolic suspension of acetylsalicylic acid (ASA)-seeds is fed into a tubular crystallizer, where it is mixed with a hot, slightly undersaturated ASA-EtOH solution. Supersaturation is created via cooling and the seeds grow to form the 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 (2-4) and to achieve narrow residence time distributions of the magma 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 CSDs can be obtained.

The effects of various process parameters on product characteristics have been investigated. The residence time of the suspension in the tubing has 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 as well as the cooling trajectories along the tubular crystallizer. All experiments clearly resulted in significant crystals growth despite the short residence times in the few minute range and crystal masses increased by a few g/min. Moreover steady-state conditions were obtained in less than 5 minutes. Suppression of nucleation events by avoiding rapid cooling, thus high levels of supersaturation allowed successful achievement of narrow CSDs. Additionally simulations regarding the temperature gradients and the crystal growth have been performed and the results were compared with the experiments.

(1) N. Variankaval, A. S. Cote, and M. F. Doherty. From form to Function: Crystallization of active pharmaceutical ingredients. Aiche Journal. 54, 2008, 1682-1688,

(2) R. J. P. Eder, S. Radl, E. Schmitt, S. Innerhofer, M. Maier, H. Gruber-Woelfler, J. G. Khinast. Continuously Seeded, Continuously Operated Tubular Crystallizer for the Production of Active Pharmaceutical Ingredients. Crystal Growth and Design. 10 (5), 2010, 2247-2257

(3) J. Schiewe and B. Zierenberg. Process and apparatus for producing inhalable medicaments. US Patent 2003/0015194 A1, 2003

(4) R. J. P. Eder, H. Gruber-Woelfler, J. Khinast. Kontinuierliche Kristallisation in einem Rohrkristallisator. Chemie Ingenieur Technik. 81, 2009