Effects of crystallization in the presence of the opposite enantiomer on the crystal properties of (ss)-( + )-pseudoephedrinium salicylate

Abstract

Previous work ( Int. J. Pharm., 94 (1993) 171–179) with (RS)-(-)-ephedrinium 2-naphthalenesulfonate, which forms a racemic compound with its opposite enantiomer, has shown that crystallization of the homochiral crystal (host) from aqueous solution containing traces of the opposite enantiomer (guest) leads to uptake of the guest with significant changes in various thermodynamic properties, including an increase in the intrinsic dissolution rate (IDR), perhaps through lattice disruption. The present work tests this possibility with a different but related chiral drug, (SS)-( + )-pseudoephedrinium salicylate, which forms a racemic conglomerate, instead of a racemic compound, with its opposite enantiomer. Increasing concentrations of the guest in the aqueous crystallization solution led to its increasing incorporation into the host crystals, corresponding to a segregation coefficient of 0.24. With increasing mole fraction, x 2, of the guest in the crystals, the IDR of the compacts increased to a maximum (12% increase at x 2 = 0.0076) and then decreased. Meanwhile, with increasing x 2, the enthalpy of fusion, ΔH f, entropy of fusion, ΔS f, and enthalpy of solution, ΔH s, decreased to minima (4–5% decreases at x 2 = 0.0028), suggesting disruption of the crystal lattice of the host and an increase in lattice strain, and then increased, suggesting a release of lattice strain. The water content (0.006 mole fraction) and melting point (405.2 ± 1.2 K) were not significantly affected. The change in the free energy of solution, estimated from the IDR, was approximately linearly related to the calorimetric ΔH s, suggesting enthalpy-entropy compensation. ΔS f and ΔS s decreased linearly with increasing ideal entropy of mixing, corresponding to values of 24.7 and 21.4, respectively, for the ‘disruption index’ ( Int. J. Pharm., 25 (1985) 57–72, 28 (1986) 103–112). These relatively high values indicate significant disruption of the crystal lattice of the host, suggesting potentiation of crystal defects by the incorporated guest.