Crystal Landscape of Chiral Drug Chlorphenesin and Its Structural Analogues: Polymorphism of Racemic and Enantiopure Samples, Metastable and Stable Racemic Conglomerates, Diverse in Unity Crystal Motifs

The phase behavior of chiral API Chlorphenesin 1 and its structural analogues 2 and 3 was investigated by DSC and PXRD methods. For the entire family of compounds 1 – 3, many crystalline modifications have been found for the first time. It has been shown that both racemic and enantiopure samples 1 form stable and metastable phases; racemic meta -derivative 2, along with stable and metastable racemic compounds, is capable of forming a metastable racemic conglomerate. In the case of the ortho -derivative 3, metastable crystalline racemic compounds were not detected, while both stable and metastable homochiral forms are capable of forming racemic conglomerates. For compounds 1 – 3, the free energies of metastable forms were estimated experimentally relative to the thermodynamically most stable racemic compounds. All racemic compounds of chloro- and methyl-substituted chlorphenesin analogues, studied by X-ray diffraction analysis, form a common supramolecular motif, while three different crystal organizations have been identified for enantiopure forms. In 7 cases out of the 9 studied, the crystal packing is formed with the participation of two symmetry independent molecules. Apparently, both the unusual diversity of the crystalline landscape and the increased frequency of Z ′ > 1 cases in the series under study have a common reason and reflect the variety of ways for intermolecular hydrogen bond formation in the crystals of aryl glycerol ethers.