Chiral co-crystal solid solution: structures, melting point phase diagram, and chiral enrichment of (ibuprofen)2(4,4-dipyridyl)

Abstract

Crystal engineering of pharmaceuticals through co-crystallization provides a new strategy for altering the physical and chemical properties of solid forms of active pharmaceutical ingredients (APIs). The understanding of structure–property relationship of co-crystals containing chiral pharmaceutical agent (PA) and co-crystal former (CCF) is of great importance to the application of co-crystallization strategy in chiral pharmaceuticals. We report here the first example of solid solutions formed between the co-crystals of opposite enantiomers: (ibuprofen)2(4,4′-dipyridyl) (1) co-crystals. We discovered that enantiomeric mixtures of (1) exist as a Roozeboom type II solid solution. The crystal structures of the (ibuprofen)2(4,4′-dipyridyl) (1) solid solutions are very similar to those of their corresponding enantiomorph and racemic compound, featured with the presence of pseudo-inversion centers. (Ibuprofen)2(4,4′-dipyridyl) (1) co-crystals have significantly higher melting temperatures and greater melting enthalpies than their parent ibuprofen chiral crystals. The parent ibuprofen is a strong racemic compound former. Co-crystallization with 4,4′-dipyridyl, however, has altered the system and produced solid solutions, where chiral enrichment was achieved upon crystallizing the enantiomeric mixtures of (ibuprofen)2(4,4′-dipyridyl) (1) co-crystals. Co-crystallization, therefore, provides new opportunities for the chiral resolution of previously known racemic compound-forming systems.