Diastereomeric salt precipitation based resolution of ibuprofen by gas antisolvent method

•Efficient optical resolution of ibuprofen by gas antisolvent precipitation.•Selectivity is maximal at minimal pressure needed for precipitation.•Crystal habits can be controlled by carbon dioxide–organic solvent molar ratio.

We investigated the resolution and crystallization of ibuprofen with (R)-phenylethylamine based on diastereomeric salt formation using the supercritical gas antisolvent (GAS) method. Our goal was to study the effects of the operational parameters (pressure, temperature and the carbon dioxide–organic solvent ratio) during an antisolvent resolution. The diastereomeric purity of the crystalline diastereomer salt (70–80% in a single step) was not affected by either parameter in the range investigated. However, yields, and thus selectivity (a product of yield and diastereomeric purity) was strongly affected by pressure and the carbon dioxide–organic solvent ratio. Using methanol and ethanol, yield curves as a function of the molar carbon dioxide–organic solvent ratio are the same for both solvents. By selecting appropriate parameters, the crystal habit (average crystal size and crystal size distribution) can be influenced. Some crystals formed thin fibers with diameters in the micrometer range (1–3 μm), but certain parameters yielded shorter and thicker bladed crystals. At the optimal settings (10 MPa, 35 °C, 12.3 mol/mol carbon dioxide–methanol ratio) the resolvability (0.444) slightly exceeded previously reported values using supercritical carbon dioxide, with a significant reduction in operating time.

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