Ephedrine is a drug that is commonly used as a stimulant or decongestant. The compound is usually marketed in the sulfate or hydrochloride salt forms. Pseudo-ephedrine (a diastereomer) has similar biochemical properties to ephedrine itself. Both ephedrine and pseudo-ephedrine form salts with a number of different counterions. This study shows how the Solid Form module (Macrae et al. 2008) can be used to analyse the packing similarity of a family of salt structures. For this analysis, 20 salt structures containing ephedrine or pseudo-ephedrine were obtained from the Cambridge Structural Database (CSD, Allen et al. 2002) which contain only two components and a counterion smaller than the drug compound.




Two main conformations of ephedrine occur in the solid state, these are labelled as "extended" (see image on the left below) and "folded" (image on the right). The labels refer to the relative position of the bottom methyl group attached to the secondary ammonium nitrogen. In the "folded" conformation, this methyl group is pointing towards the hydroxyl group thus producing a more compact intramolecular geometry, whereas in the "extended" conformation the methyl groups points away from the hydroxyl group. A previous theoretical study (Leusen et al. 1991) found that the energy barrier between the two conformations is less than 4.2 kJ/mol, so the molecules could easily change conformation during the processes of crystal nucleation and growth.


In order to analyse the packing of the 20 salt structures, the Crystal Packing Similarity tool in the Solid Form module was used to determine geometrically similar clusters of molecules using clusters of size 2, 3, 4, 6, 8, 12 & 15. For the purposes of this study, only the packing of the drug molecules was considered for analysis and the counterions in each structure were ignored. Using the results of each level of cluster analysis, the structures were formed into groups containing consistent clusters - in this way a tree diagram was obtained where each node on the diagram (see figure below) represents a group of structures with a similar cluster of molecules. The numbers down the side of the diagram indicate the size of the cluster used for that particular similarity grouping. As we progress down the diagram, the nodes indicate larger regions of packing similarity and the nodes on the bottom line (cluster of 15 molecules) indicate pseudo-isostructural groups. The colours of the nodes on the tree diagram are intended to simply highlight the separation in structural similarity between different branches of the tree.

The packing similarity tree diagram shows that there are three structures that exhibit no packing similarity with the remainder of the dataset (13, 16 & 17) - these contain larger or more unusual counterions (e.g. saccharinate & diethyl phosphorothioate). The orange branch of the diagram indicates a group of four structures that have similar packing, which in this case is based on methyl to phenyl contacts. These four structures are all pseudo-ephedrine salts and there were no similar clusters found between ephedrine and pseudo-ephedrine salt structures. The remaining structures (shown in various shades of blue) all contain a similar molecular shape-based stack of ephedrine moieties.

Moving further down the blue branch it is clear to see that the structures split into two distinct sets (dark blue and light blue). These two sets indicate the differences in packing caused by the conformation of ephedrine - the dark blue group contains the extended conformation and the light blue group exhibits the folded intramolecular geometry. On the final level of the diagram (cluster size of 15) there are two nodes that indicate two distinct sets of pseudo-isostructural salts - these correspond to hydrogen-bonded bi-layer structures of ephedrine formed by the "extended" and "folded" conformations respectively. Interestingly the two pseudo-isostructural sets exhibit very distinct and different crystal morphologies with the extended bi-layer salts forming needle-like crystals and the folded bi-layer salts forming plate-like crystals (Collier et al. 2006).
The salts that form into the "folded" layer structures (the light blue branch, structures 5, 6, 10, & 12) each contain counterions that exhibit either a sulfonate group (5, 6, & 12) or nitrate (10), both of which present a similar arrangement of three hydrogen-bond acceptors. All three of the acceptors in this group are used by hydrogen bond donors in the ephedrine layer, so the counterion is fixed in position by this network. In the "extended" layer structures (1, 8 & 9), on the other hand, only two hydrogen bond acceptors are required to link the counterion to an ephedrine layer so different counterions are observed.
In conclusion, the packing similarity analysis has quickly identified two distinct bi-layer types formed by the two observed conformations of ephedrine. Substantial changes to crystal habit are seen to occur due to the bi-layer type chosen (needles and plates). Two pseudo-isostructural groups of salt structures have been identified using this analysis and there is the potential for designing new salt structures with a chosen morphology based on this information. Finally, it is observed that the structures of the pseudo-ephedrine salts have no packing similarity in common with ephedrine due to the small differences in molecular shape. The packing of these structures is clearly separated from the ephedrine salts in the tree diagram and the packing is based on methyl to phenyl contacts which are not observed in any of the other structures.


  • Allen, F. H. (2002). Acta Cryst. B58, 380-388.
  • Collier, E. A., Davey, R. J., Black, S. N., Roberts, R. J. (2006). Acta Cryst. B62, 498-505.
  • Leusen, F. J. J., Bruins Slot, H. J., Noordik, J. H., van der Haest, A. D., Wynberg, H. & Bruggink, A. (1991). Recl. Trav. Chim. Pays-Bas, 110, 013-018.
  • Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst., 41, 466-470.