Characterisation of a reactive crystallization

Abstract

Pharmaceutical synthesis involves work up, reaction, crystallization, filtration and further downstream processes. This thesis project focuses on a reactive crystallization in order to gain scientific understanding of how reaction kinetics and parameters could affect targeted crystal specifications. Paracetamol synthesis is chosen as the model reactive crystallization process because it is significant in pharmaceutical industry and can be operated under simple conditions with 4-aminophenol and acetic anhydride as reactants. To maximize yield, the solubility for crystallization was optimized first, from which suitable reagent concentrations were determined. As in a single process, solubility for crystallization in the reactive crystallization of paracetamol was controlled by the solvent compositions that were directly produced in the reaction step. The effects of reaction temperature and water content on reaction kinetics and mechanism as well as product quality were jointly investigated for the first time. Higher reaction rate constants for paracetamol synthesis were obtained for higher temperatures. Form I crystals with high purity were obtained with the presence of water, and 4'- acetoxyacetanilide without water. It has demonstrated that the reagents and solvents from the reaction step are the means for controlling and delivering required crystal properties in an oscillatory baffled reactor (OBR). Finally, the reactive seeded cooling crystallization of paracetamol was carried out in a continuous oscillatory baffled reactor (COBR) based on the learnings from its batch counterpart. Effects of mixing intensity on crystal properties were discussed, crystals size reduced with the increase of oscillatory Reynolds number (Reo). The seeding strategy was investigated at a fixed seed size and various seed masses, smooth and encrustation free runs were undertaken with the crystallization path close to the solubility curve. Both temporal and spatial steady states in concentration and size were attained by analysing the concentrations and crystal sizes at two locations along the COBR. Particle products of polymorphic form I were continuously generated with an average purity of 99.96 %.