(105d) Development of Continuous Antisolvent Nucleation Processes to Achieve Better Control over Crystalline Particle Attributes

Crystallisation from solution is an important separation and purification process commonly used in manufacturing of a broad range of solid products, including fine chemicals, such as dyes, pigments and explosives, as well as active pharmaceutical ingredients and excipients. Consistent crystalline particle attributes, such as solid form, particle shape and size distribution are desirable for optimising downstream processing steps as well as for uniform dissolution time and good bioavailability for drug delivery. Currently, crystallisation of fine chemical and pharmaceuticals is typically performed in a batch mode which can often lead to problems in achieving consistent product specifications, such as crystalline form and particle size distribution.  Moving to continuous crystallisation technologies has the potential for significant increases in efficiency, flexibility and product quality, while aiming to obtain required particle attributes directly without a need for subsequent size reduction. However, development of continuous crystallisation processes requires reliable control over crystal nucleation as well as suitable management of possible encrustation and fouling issues.  

We have designed and investigated a continuous antisolvent nucleation unit (a nucleator) in order to generate seeding suspensions for subsequent crystallisation steps. The control of crystal nucleation kinetics was achieved by adjusting the mixing efficiency, solvent-antisolvent ratio, supersaturation and residence time in the nucleator. Crystal suspensions produced in the nucleator were continuously introduced to a cascade of continuous stirred crystallisers or a continuous oscillatory baffled crystalliser, where seed crystals were further grown by cooling crystallisation. Careful control of the crystal seed formation separated from subsequent crystal growth allowed for development of more flexible continuous crystallisation operations and improved ability to obtain desirable final particulate products.