(727b) Diastereomeric Salt Crystallization Using Ternary Phase Diagram: A Ketoprofen Phenylethylamine Case Study

More than half of active pharmaceutical ingredients exhibit chirality, making enantioseparation a matter of significant interest for the pharmaceutical industry. In the case of racemic mixtures, typically only one enantiomer displays the desired therapeutic activity, while the other is considered an impurity constituting 50% of the mixture. This undesired enantiomer can lead to adverse side effects, as evidenced by the tragic thalidomide incident in the 1960s, where the R-enantiomer was found to cause physical birth defects, while the S-enantiomer was utilized to alleviate morning sickness in pregnant women.

One approach for isolating a high-purity enantiomer from a racemic mixture involves the formation of diastereomeric salts. This method entails reacting racemic acidic or basic target compounds with optically active compounds, such as enantiopure basic or acidic resolving agents, to produce a pair of diastereomeric salts. These salts can then be separated through fractional crystallization. Following this separation, the resulting salt undergoes a neutralization process to yield a pure enantiomer (Simon, M. et al, 2018).

The diastereomeric salt formation of S- ketoprofen-S- (1)-phenylethylamine (p-salt) and R- ketoprofen-S- (1)-phenylethylamine (n-salt) was systematically investigated by examining binary and ternary phase diagrams, utilizing a solvent consisting of 50:50 wt.% IPA: Heptane. The eutectic point for the salt composition occurs at approximately 56:44 wt.% n-salt: p salt. Subsequently, based on this finding, a crystallization procedure was developed to achieve enantiopure separation of the pure p-salt, utilizing information from the ternary phase diagram (Fig. 1).

Acknowledgements: The authors acknowledge the support of Enterprise Ireland under the Research, Development and Innovation Fund, Grant award 180753/RR.

Simon, M., Donnellan, P., Glennon, B. and Jones, R.C. 2018. Resolution via diastereomeric salt crystallization of ibuprofen lysine: ternary phase diagram studies. Chemical Engineering & Technology, 41(5), pp. 921-927.