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(286d) Continuous Reactive Crystallisation for Control of Salt Formation Processes

Authors: 
McGinty, J., EPSRC Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation, University of Strathclyde
Sefcik, J., University of Strathclyde
Price, C., University of Strathclyde
Salt crystallisation is of great importance to the pharmaceutical industry (majority of pharmaceutical products are marketed as salts) but it is often not a well-controlled process. This is because salt formation via a pH shift can be highly sensitive to mixing, and under batch or semi-batch conditions this can lead to severe issues with reproducibility and consistency of quantitative particle attributes, including solid form, crystal size distribution and crystal habit. The salt crystallisation process typically takes the form of a batch titration where the basic drug is dissolved in a solvent before the acid is slowly added. The issue with this procedure is that when the two solutions first come into contact the local supersaturation will build up very quickly and uncontrolled nucleation may occur leading to an undesired salt stoichiometry or crystal size distribution. For this reason, greater control over mixing to achieve greater control over the supersaturation build up is required to improve the consistency of the process and the quality of the particulate product. The aim of this research is to develop a quantitative reactive crystallisation model including a solution speciation model, a mixing model and a population balance model to guide the operation of continuous reactive crystallisation processes. We show the development of this quantitative reactive crystallisation model and how it is used to select operating conditions for the continuous crystallisation of the example 2:1 salt of 3,5-dinitrobenzoic acid and ethylenediamine. By doing this we can control which of the two polymorphic forms (monoclinic & triclinic) is crystallised, the crystal habit and the crystal size distribution.