Effects of excess enantiomer on the crystal properties of a racemic compound: ephedrinium 2-naphthalenesulfonate

Abstract

A small enantiomeric excess in the crystallization medium during the crystal growth of the racemic compound, (±)-ephedrinium 2-naphthalenesulfonate, (±)-EN, is found to become partially incorporated into the racemic crystals. The small enantiomeric excess (guest) in a racemic compound (host) may disrupt the crystal lattice, leading to changes in the thermodynamic properties and intrinsic dissolution rate of the host crystals. This hypothesis was tested by growing crystals of (±)-EN from aqueous media containing various excess quantities of either enantiomer and the resulting crystals were analyzed by a stereoselective HPLC method. The melting point phase diagram of (±)-EN was determined and the extent of solid solution formation was 0.029 mole fraction of either enantiomer of EN in the racemic compound of EN at 25°C. The segregation coefficient was found to be about 0.078, lower than 0.15 for a homochiral host (Duddu, S.P. et al., Int. J. Pharm., 94 (1994) 171–179), suggesting that (±)-EN with higher symmetric packing has a lower tendency to take up excess enantiomer into its host crystals. The melting point and the heat of fusion of the crystals were measured by differential scanning calorimetry. Increasing amounts (0–5%) of guest incorporated into the host gave approximately linear decreases in the melting point, enthalpy of fusion and entropy of fusion. The disruption index was on the order of 5, which is comparable with that for non-isomeric doping of organic crystals, but much lower than that of 20 for doping (− )-EN with ( + )-EN (Duddu, S.P. et al., Int. J. Pharm., 94 (1994) 171–179). The intrinsic dissolution rate reached a maximum value at low levels (0.015–0.03 mole fraction) of doping corresponding to solid solution formation, and then decreased to the original value at higher levels of doping corresponding to the formation of a separate phase. Thus, a small excess of either enantiomer in the racemic compound significantly changes the thermodynamic properties and the intrinsic dissolution rate of (±)-EN. These results may have implications for other racemic drugs.