Density and stability differences between enantiopure and racemic salts: construction and structural analysis of a systematic series of crystalline salt forms of methylephedrine

Alan R. Kennedy, Catriona A. Morrison, Naomi E. B. Briggs, William Arbuckle

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17 Citations (Scopus)


A data set of systematically related solid-state structures of pharmaceutical relevance has been created and used to investigate structural impact on physical propeities in 20 pairs of enantiopure and racemic methylephedrinium. salts. The structures are described and compared through graph-set analysis and the crystal packing similarity features of Mercury CSD 2.3. The commonest graph-set motif, C-2(2) (9), was found to be present in 22 of the 37 independent structures and was flexible enough to include both carboxylate and sulfonate functionalities. An equivalent C-2(1) (7) motif was present in all six halide structures investigated. Analysis of molecular structure found three common methylephedrinium cation conformations, while analysis of cation packing found six isostructural groups, each containing at least two salt structures and based on one of three common cation packing motifs. Melting points and crystallographically obtained densities were examined in detail for the 13 enantiopure and racemic structural pairs found to be chemically identical to each other. While average densities conform to Wallach's rule, 6 of the 13 individual pairings do not This does not support the structural justification normally given for Wallach's rule. One of the three observed common cation packing motifs is highly associated with failure of Wallach's rule, as are significant differences in hydrogen bonding between the enantiopure and racemic structures.

Original languageEnglish
Pages (from-to)1821-1834
Number of pages14
JournalCrystal Growth and Design
Issue number5
Publication statusPublished - May 2011


  • chiral drugs
  • solubility
  • ephedrine

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