Effect of the opposite enantiomer on the physicochemical properties of ( - ) -ephedrinium 2-naphthalenesulfonate crystals

Abstract

During the growth of optically active crystals (host), trace quantities of the opposite enantiomer (guest) present in the solution may be taken up by the host. However, the enantiomeric guest, due to its opposite chirality, may distort the crystal lattice of the host. Thus, the incorporation of the guest may lead to changes in the pharmaceutically important properties of the host, such as dissolution rate and thermodynamic properties, perhaps through lattice disruption. This hypothesis was tested by growing crystals of a model compound, ( - )-ephedrinium 2-naphthalenesulfonate, from aqueous crystallization media containing various trace quantities of its opposite enantiomer. A Stereoselective HPLC method was developed to determine the trace amounts of the opposite enantiomer within and on the surface of the homochiral host crystals. Increasing concentrations of the guest in solution led to its increasing incorporation into the host crystals and to increasing intrinsic dissolution rate of the host. The enthalpy and entropy of fusion of the host decreased with increasing incorporation of the guest, suggesting the disruption of the crystal lattice of the host and an increase in its lattice strain. The water content and the melting point were not significantly affected. At higher levels of the incorporated guest, the enthalpy and entropy of fusion increased, suggesting a relaxation of the lattice strain, and subsequently reached a plateau value. A value of 20.6 was obtained for the ‘disruption index’, which is defined as the rate of change of the difference between the entropy of the solid and that of the liquid, with respect to the ideal entropy of mixing of the host with the guest (York and Grant, Int. J. Pharm., 25 (1985) 57–72). This relatively high disruption index indicates significant disruption of the crystal lattice of the host by the incorporated guest, suggesting changes in the nature and concentration of the crystal defects.