Crystallization Features of the Chiral Drug Timolol Precursor: The Rare Case of Conglomerate with Partial Solid Solutions

• Published in: Crystal growth & design 2014-04, Vol.14 (4), p.1676-1683
• Main Authors: Bredikhin, Alexander A, Zakharychev, Dmitry V, Gubaidullin, Aidar T, Fayzullin, Robert R, Pashagin, Alexander V, Bredikhina, Zemfira A
• Format: Article
• Language: English
• ISSN: 1528-7483; 1528-7505
• DOI: 10.1021/cg4017905

A synthetic precursor of the chiral drug timolol, 4-[4-(oxiran-2-ylmethoxy)-1,2,5-thiadiazol-3-yl]-morpholine (2) represents a rare case of conglomerate with partial solid solution. This fact was established by inspection of an original solubility test, by the originally developed IR spectra analysis, and by construction of a binary phase diagram which is totally based on thermochemical measurements. The special procedure was developed for quantitative analysis of complex differential scanning calorimetry traces for incongruently melting samples of intermediate enantiomeric composition. The X-ray analyses were performed on a single crystal of 2 grown from the enantiopure feed material and on a single crystal picked out from the racemic polycrystalline sample. The structure of the enantiopure crystal was solved and refined in the P212121 space group with the only symmetry independent molecule in the unit cell. The structure of the crystal picked out from the racemic 2 sample was solved and refined in the P1 space group with four symmetry independent molecules in the unit cell. The epoxy moieties of the independent molecules in this crystal were found to be disordered over two positions with almost equal relative occupancies of opposite enantiomers for all the molecules. The quantitative characteristics of the disorder, 0.78(0.02):0.22(0.02), are close to those found by an independent method of the Tammann diagram.