A Mathematically Simplified Solid-Solid-Liquid Ternary Phase Diagram with Tie-Lines for Early Process Development Validated by Chiral Resolution of Racemic Ibuprofen

Predictions of the purity and yield of a solid product by solid-liquid separation, such as reaction crystallization and extraction, can accurately be captured if the solid-solid-liquid ternary phase diagram of the product-impurity-solvent system is available. However, constructing the phase diagram with tie-lines experimentally is tedious, time-consuming, and unsuitable for solvent selection during early process development. In this work, a mathematical model for predicting the purity and yield of a given solvent was developed without the need to establish the full phase diagram. Just by determining a few vital points in the ternary phase diagram, we can rapidly predict the outcome for a given setting by computation, which can speed up the assessment of suitable solvent candidates for early process development significantly. This approach has been validated against the case of chiral resolution of racemic ibuprofen by diastereomeric salt formation with (S)-1-phenylethylamine.