Insights into Hydrate Formation and Stability of Morphinanesfrom a Combination of Experimental and Computational Approaches

摘要

Morphine, codeine, and ethylmorphine are important drug compounds whose free bases and hydrochloride salts form stable hydrates. These compounds were used to systematically investigate the influence of the type of functional groups, the role of water molecules, and the Cl^– counterion on molecular aggregation and solid state properties. Five new crystal structures have been determined. Additionally, structure models for anhydrous ethylmorphine and morphine hydrochloride dihydrate, two phases existing only in a very limited humidity range, are proposed on the basis of computational dehydration modeling. These match the experimental powder X-ray diffraction patterns and the structural information derived from infrared spectroscopy. All 12 structurally characterized morphinane forms (including structures from the Cambridge Structural Database) crystallize in the orthorhombic space group P212121. Hydrate formation results in higher dimensional hydrogen bond networks. The salt structures of the different compounds exhibit only little structural variation. Anhydrous polymorphs were detected for all compoundsexcept ethylmorphine (one anhydrate) and its hydrochloride salt (noanhydrate). Morphine HCl forms a trihydrate and dihydrate. Differentialscanning and isothermal calorimetry were employed to estimate theheat of the hydrate ↔ anhydrate phase transformations, indicatingan enthalpic stabilization of the respective hydrate of 5.7 to 25.6kJ mol^–1 relative to the most stable anhydrate.These results are in qualitative agreement with static 0 K latticeenergy calculations for all systems except morphine hydrochloride,showing the need for further improvements in quantitative thermodynamicprediction of hydrates having water···water interactions.Thus, the combination of a variety of experimental techniques, coveringtemperature- and moisture-dependent stability, and computational modelingallowed us to generate sufficient kinetic, thermodynamic and structuralinformation to understand the principles of hydrate formation of themodel compounds. This approach also led to the detection of severalnew crystal forms of the investigated morphinanes.