Modelling solution speciation to predict pH and supersaturation for design of batch and continuous organic salt crystallisation processes

Organic salt crystallisation is of great importance to the pharmaceutical industry as the majority of pharmaceutical products are marketed as salts. In this study a solution speciation model was developed and experimentally validated to predict pH and supersaturation during organic salt crystallisation processes when only the overall solution composition is known. By solving a particular system of equations simultaneously the full speciation and pH of the solution is calculated. Simply with knowledge of only the overall solution composition, dissociation constants and solubility products this model can be used to generate the design space for organic salt crystallisation and gain deeper understanding of the salt crystallisation process. In particular, the model can be used to calculate the maximum theoretical crystallisation yield and the corresponding mother liquor pH which would be impossible to determine otherwise without performing experiments. The case study used in this work is the polymorphic organic salt ethylenediammonium 3,5-dinitrobenzoate (EDNB) which is the 2:1 salt of 3,5-dinitrobenzoic acid (3,5-DNBA) with ethylenediamine. In this system three solid forms can be produced: EDNB monoclinic, EDNB triclinic and/or the 3,5-dinitrobenzoic acid (3,5-DNBA) starting material. The solution speciation model was used to investigate the crystallisation process for each solid form and test different feed molar ratios and different solution addition/mixing approaches for semi-batch and continuous processes.