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Development of continuous crystallisation processes of pharmaceutical compounds to achieve better control over final product attributes

Anna Jawor-Baczynska 1,  Alastair J. Florence 2,  Jan Sefcik 1

1. University of Strathclyde, Chemical and Process Engineering, 75 Montrose Street, Glasgow G11XJ, United Kingdom
2. University of Strathclyde, Strathclyde Institute for Pharmacy and Biomedical Sciences, 27 Taylor Street, Glasgow G40NR, United Kingdom

Abstract
Crystallisation form solution is an important separation and purification process commonly used for a broad range of solid products.  Many fine chemicals, such as dyes, explosive, and photographic materials, required crystallisation in their manufacture, as well as wide majority of active pharmaceutical ingredients and excipients1. Currently, pharmaceutical crystallisations are performed in batch mode which often leads to problems in achieving consistent product specifications, e.g. crystal form, particle shape and particle size distribution. Moving to continuous crystallisation technologies has the potential for huge increases the efficiency, flexibility and product quality1,2. However, the crystallisation process in continuous system is especially challenging due to lack of understanding particles nucleation and growth mechanism under flow conditions and challenges related to eliminate the crystal encrustation and fouling.

In this research we’ve designed and investigated an anti-solvent nucleation unit in order to continuously generate seeding suspensions for continuous crystal growth. We used two model compounds, paracetamol and DL-valine. The nucleator was constructed in such a way that warm solution is injected into cold antisolvent using a small diameter nozzle. The unit is composed of a jacketed vessel in which the temperature of the wall could be controlled to prevent the fouling problem; keeping the solution near the wall undersaturated. The encrustation problem was also eliminated by applying the ultrasound and effect of ultrasound on crystal size, crystal structures, morphology and yield was investigated. The control of crystal nucleation kinetics has been achieved by adjusting the mixing efficiency, solvent-antisolvent ratio, supersaturation level and residence time in the nucleator. Produced crystals may be used as a seeding suspension and be continuously introduced to a crystal growth unit (e.g. Oscillatory Baffled Crystalliser (OBC))3. Careful control of the crystal nucleation separated from subsequent crystal growth will allow a better control of the continuous crystallisation operation and production of the final product with desired properties.

1 Chen, J., Sarma, B., Evans, J. M. B. & Myerson, A. S. Pharmaceutical Crystallization. Crystal Growth & Design 11, 887-895, (2011).

2 Wong, S. Y., Tatusko, A. P., Trout, B. L. & Myerson, A. S. Development of Continuous Crystallization Processes Using a Single-Stage Mixed-Suspension, Mixed-Product Removal Crystallizer with Recycle. Crystal Growth & Design 12, (2012).

3 Mackley, M. R. & Ni, X. Experimental fluid dispersion measurements in periodic baffled tube arrays. Chemical Engineering Science 48, 3293-3305,(1993).

 

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Presentation: Invited oral at 17th International Conference on Crystal Growth and Epitaxy - ICCGE-17, General Session 4, by Anna Jawor-Baczynska
See On-line Journal of 17th International Conference on Crystal Growth and Epitaxy - ICCGE-17

Submitted: 2013-04-11 18:15
Revised:   2013-07-26 14:35