mp500334z_si_002.cif (140.71 kB)
Insights into Hydrate Formation and Stability of Morphinanes from a Combination of Experimental and Computational Approaches
dataset
posted on 2014-09-02, 00:00 authored by Doris E. Braun, Thomas Gelbrich, Volker Kahlenberg, Ulrich
J. GriesserMorphine, 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 compounds
except ethylmorphine (one anhydrate) and its hydrochloride salt (no
anhydrate). Morphine HCl forms a trihydrate and dihydrate. Differential
scanning and isothermal calorimetry were employed to estimate the
heat of the hydrate ↔ anhydrate phase transformations, indicating
an enthalpic stabilization of the respective hydrate of 5.7 to 25.6
kJ mol–1 relative to the most stable anhydrate.
These results are in qualitative agreement with static 0 K lattice
energy calculations for all systems except morphine hydrochloride,
showing the need for further improvements in quantitative thermodynamic
prediction of hydrates having water···water interactions.
Thus, the combination of a variety of experimental techniques, covering
temperature- and moisture-dependent stability, and computational modeling
allowed us to generate sufficient kinetic, thermodynamic and structural
information to understand the principles of hydrate formation of the
model compounds. This approach also led to the detection of several
new crystal forms of the investigated morphinanes.
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Hydrate Formationcrystal formsmoisture-dependent stabilityenthalpic stabilizationmorphine hydrochloride dihydratehydrate formationComputational Approaches Morphinedehydration modeling0 K lattice energy calculationsmorphine hydrochloridewater moleculeshydrochloride salts formanhydratestructure modelssalt structuresmorphinane formspowder X-ray diffraction patternsHydrate formation resultsDifferential scanningAnhydrous polymorphsMorphine HCl formsethylmorphinecrystal structuresinformationdrug compoundsspace group P 2 1 2 1 2 1hydrochloride salthumidity rangeCambridge Structural Databasephasemodel compoundsstate propertiescompounds exhibithydrogen bond networks