Prediction of Solid Solution Formation in a Family of Diastereomeric Salts. A Molecular Modeling Study

Abstract

The possibility of solid solution behavior of diastereomeric salts, containing multiple resolving agents of the same family (Dutch Resolution), is predicted by molecular modeling. Super-cells containing different ratios of resolving agents in the diastereomeric salt are constructed and optimized, and their lattice energy is computed. The energy difference between these "simulated solid solutions" and the native structures is related in an understandable fashion to the probability of solid solution formation. This procedure is applied to a family of diastereomeric salts of ephedrine and cyclic phosphoric acids, for which the ternary diagrams have been determined experimentally at 25 degrees C in ethanol. Good agreement between experimental and computational results indicates that this relatively simple and fast method could predict the stable character of solid solution behavior in binary systems.

Nucleation and growth of crystalline ribbons in diastereomeric ephedrine–cyclic phosphoric acid systems

“…Inam and Clinam are distributed throughout the crystal in a random manner. This result is consistent with the observed solubility behaviour of this system [10].…”

“…An ephedrine-cyclic phosphoric acid compound consists of a 1:1 mix of the two components to produce the compounds Inam (5), Clinam (6) and Aninam (7) ( Table 1). The crystal structures of these compounds are known [8][9][10].…”

“…Solutions were prepared to an initial supersaturation (b) of 1.5 or 2.0 (where b ¼ C initial =C equilibrium 25 C ) by weight. The solubility of the compounds in ethanol has been previously determined to be 9.5, 5.7 and 4.1 g per 100 g solution at 25 C for Inam, Clinam and Aninam, respectively [10]. For two-compound solutions, each compound had an individual initial supersaturation of 1.5 (we assumed there is no effect of compound B on the solubility of compound A and vice versa).…”

“…Similar to Clinam, growth is rapid once nucleation has occurred. The structure of the crystals collected from these solutions was the same as the Aninam crystal structure determined by Gervais et al [10].…”

How to Use Pasteur’s Tweezers

“…The salts contain a non-stoichiometric ratio of the resolving agents. For one well-investigated case, the salts are solid solutions indicative of the fact that the family members, probably owing to their structural similarity, do not recognise each other well [37]. This rather peculiar method of resolution has been subjected to extensive experimental test.…”