A novel open tubular continuous crystalliser: design and evaluation

The ability to continuously manufacture products can be of huge benefit to industry as it can reduce waste and capital expenditure. Continuous crystallisation has received tepid interest for many years but has come to the fore recently as it holds the potential for a radical transformation in the way crystalline products are manufactured, leading to the development method being embraced by major industries such as pharmaceuticals. In addition to the financial benefits offered by continuous crystallisation over conventional batch methods, a higher level of control over the crystallisation process can also be achieved - allowing improved, more consistent particle attributes to be obtained in the crystallisation process. This control is in part a consequence of the smaller volumes involved in continuous crystallisation, which also has the advantage of reducing any hazards associated with the materials being processed. By using smaller volumes, the mixing efficacy is inherently increased which reduces any disparity between local environments, thereby allowing kinetics to dictate the nature of the products. The EPSRC Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation (CMAC [1]) in the UK is a collaborative national initiative to further the knowledge base and understanding of all aspects relating to continuous crystallisation and its use in the manufacturing of crystalline particulate products. In this work we present the design and construction of a novel continuous crystalliser and its evaluation using various model systems such as calcium carbonate (polymorph control [2]) and Bourne reactions (mixing efficacy [3]). The crystalliser will then be used in the co-crystallisation of agrichemical and pharmaceutical compounds with co-formers in an effort to optimise the solid-state properties of these materials such as solubility. Various aspects of the evaluation of the design of the new crystalliser will be presented with reference to these trials, and assessed critically with respect to evolution of this design and potential implementation in manufacturing processes.

Tetraphenylphosphonium Salts for Small Molecule Capture

Tetraphenylphosphonium salts are useful tools for capturing (and crystallizing) small molecules. The packing of the cations in such salts leads to channels or cavities suitable for trapping of the small molecule by the anion. For example, we have prepared the complex salts [PPh4][SO2X] (X = Cl, Br, I) through the exposure of solutions of [PPh4]X to an atmosphere of SO2. Churakov et al. have reported the preparation of [PPh4]X·nH2O2 (X = Cl, Br; n = 0.98-1.90) after trapping hydrogen peroxide using the precursor halide salts (1). Envisioning a similar result, a concentrated solution of [PPh4]CN·xH2O was exposed to an atmosphere of CO2. Colourless crystals were isolated and characterised as [PPh4][NCCO2] using crystallographic and spectroscopic techniques. The packing of the ions in the product, in the tetragonal space group I-4, is similar to that observed in many other simple [PPh4]X salts, where X = Br, I, SCN, OCN, N(CN)2, etc. Solution of the crystal structure was complicated by the high symmetry and disorder in the anion, with only three unique atoms being necessary for its characterization. Thus the utility of our chosen cation can also become a hindrance. Crystals can usually be grown and data obtained but structure solution is not a certainty. For example, the structures of [PPh4]CN·xH2O have not been reported, likely because of the rapid spinning of the anions in the cation framework, even though they are hydrogen bonded to the water which is clearly visible. Similarly, we have data collected for the products from a number of related reactions, [PPh4][CN]·xH2O + PhC(O)F, [PPh4]F + SO2, [PPh4]X (X = Cl, Br, I, CN, N3) + CS2, and can clearly identify the cation in the unit cell. However, elucidation of the structures of the anions has not been possible. It is hoped that this presentation will engender discussion of possible solutions to the observed disorder problems.