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Crystallization and resolution of cis-permethric acid (cPA) with (1R)-1-phenylethanamine (PhEA) as a resolving agent was investigated by means of gas antisolvent (GAS) and supercritical antisolvent (SAS) methods. A significant pressure effect on both the yields and diastereomeric excesses of the crystallized cPA-PhEA salts was observed in a defined pressure range. The pressure effect was found to be related to the structure and dissociation of the salts. Both methods yielded diastereomeric salts with excellent diastereoselectivity, compared to data reported in literature, and a fibrous structure of uniform fiber diameter.

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Solubility parameters are widely used in the polymer industry and are often applied in the high pressure field as well as they give the possibility of combining the effects of all operational parameters on solubility in a single term. We demonstrate a statistical methodology to apply solubility parameters in constructing a model to describe antisolvent fractionation based chiral resolution, which is a complex process including a chemical equilibrium, precipitation and extraction as well. The solubility parameter used in this article, is the Hansen parameter. The evaluation of experimental results of resolution and crystallization of ibuprofen with (R)-phenylethylamine based on diastereomeric salt formation by gas antisolvent fractionation method was carried out. Two sets of experiments were performed, one with methanol as organic solvent in an undesigned experiment and one with ethanol in a designed experiment. The utilization of D-optimal design in order to decrease the necessary number of experiments and to overcome the problem of constrained design space was demonstrated. Linear models including dependence of pressure, temperature and the solubility parameter were appropriate to describe the selectivity of the GASF optical resolution method in both sets of experiments.

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Chiral molecules, especially enantiomers and diastereomers of purity > 99 %, present a significant market share within the chemical, pharmaceutical, and flavor industries. Antisolvent precipitations, both batch and semicontinuous operations to serve the current trends in flow chemistry were demonstrated to be environmentally benign and efficient tools in achieving high optical purities. Although salts are known to be insoluble in supercritical CO 2 , instabilities of the nascent salts were detected and applied for increasing efficiency. Diastereomeric excess values of the crystalline products exceeded 99 % in maximum of three consecutive steps both by repeated resolution with half molar equivalent of the amine to the acid and by direct recrystallization of the salts.

Three new, successful resolving agents, namely (S)-2-phenylglycinol, (R)-1-phenylethanaminium (R)-(1-phenylethyl) carbamate and (S)-2-hydroxy-1-phenylethanaminium (S)-(2-hydroxy-1-phenylethyl) carbamate of ibuprofen are presented. The carbamate salts are stable white crystals, they can be easily stored and handled. All salt forming resolution were performed in supercritical carbon dioxide as the only solvent. The enantioseparations were efficient (approx. 50 % enantiomeric purities, > 90 % yields in the crystalline phase) and robust. Unlike previous experiences with primary amine resolving agents, the diastereomeric salt formations and resolutions were competed in short times, even within one hour suggesting that the carbamates are intermediates of the salt formation reaction.