Separation of propranolol hydrochloride enantiomers by preferential crystallization: Thermodynamic basis and experimental verification

Preferential crystallization is an attractive technology to separate racemic mixtures of conglomerates in the pure enantiomers; due to the advantage of obtaining directly a solid product and economic considerations. In case of racemic compound forming systems, a hybrid process may be performed consisting of an established separation technique capable of providing a certain enantiomeric enrichment and a subsequent preferential crystallization to produce the pure enantiomer(s). In previous work, the applicability of preferential crystallization in such a hybrid process was demonstrated for the example of mandelic acid. To evaluate the extensibility of the results to other pharmaceutically relevant systems, in this work propranolol hydrochloride is studied. Solubility and metastable zone width data determined in the ternary systems of (R)- and (S)-propranolol hydrochloride in water and methanol are shown and discussed. The eutectic composition of the enantiomers as an important characteristic value could be identified as similar to 45:55 and similar to 55:45, respectively. The potential of preferential crystallization to produce the pure enantiomer from partially resolved mixtures of (R)- and (S) propranolol hydrochloride in water is demonstrated.