Effects of crystallization in the presence of the diastereomer on the crystal properties of (SS)-(+)-pseudoephedrine hydrochloride.

Abstract

The formation and separation of diastereomers is widely used to resolve enantiomers. However, during crystallization of a chiral compound from a solution containing its diastereomer, the diastereomer may be incorporated as an impurity into the host 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 (SS)-(+)-pseudoephedrine hydrochloride (+PC) from aqueous solution containing various amounts of (RS)-(-)-ephedrine hydrochloride (-EC). Although the melting phase diagram of these two solid compounds, determined by differential scanning calorimetry (DSC), shows eutectic behavior, 0.034-2.4 mol% of -EC was incorporated into the crystal lattice of +PC during crystallization to form terminal solid solutions with a segregation coefficient of 0.31. In a single batch, the larger crystals contain more incorporated impurities than smaller crystals. The enthalpy and entropy of fusion measured by DSC decrease with increasing incorporation of the guest molecules into the host, indicating increases in the enthalpy and entropy of the solid. The disruption index, which indicates the disruptive effect of guest molecules in the host crystal lattice, is 60 at < or = 0.084 mol% of -EC in +PC crystals, but is only 5 at higher levels of -EC. The greater disruptive effect at lower levels of impurity incorporation may be explained by the formation of substitutional solid solutions in which the impurity molecules disrupt the hydrogen bonding network in the host crystals, whereas additional incorporated impurity may be adsorbed onto the surfaces of the mosaic blocks with reduced effect on the crystal lattice. The average intrinsic dissolution rate of impure crystals in 2-propanol is 15.8% lower than that of pure host crystals, suggesting the formation of stable solid solutions.