Structural Investigations of Hydrate, Anhydrate, Free Base, and Hydrochloride Forms of Morphine and Naloxone

For the structurally related agonist morphine and the antagonist naloxone, hydrates and anhydrates exist for both the free bases and the hydrochloride salts. We present five new crystal structures, determined from X-ray powder diffraction data, for morphine and naloxone: four anhydrates and one hydr...

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Bibliographic Details
Published in:	Crystal growth & design Vol. 8; no. 11; pp. 4150 - 4158
Main Authors:	Guguta, C, Peters, Th. P. J, de Gelder, R
Format:	Journal Article
Language:	English
Published:	Washington,DC American Chemical Society 05-11-2008
Subjects:	Condensed matter: structure, mechanical and thermal properties Crystalline state (including molecular motions in solids) Crystallographic databases Exact sciences and technology Physics Single-crystal and powder diffraction Structure of solids and liquids; crystallography Structure of specific crystalline solids Theory of crystal structure, crystal symmetry; calculations and modeling X-ray diffraction and scattering Dimensionality Space groups Symmetry property Stacking sequence Chlorine XRD Shrinkage Monoclinic lattices Unit cell Hydrogen bonds Anisotropy Hydrochlorides Chlorides Database Counterions Orthorhombic lattices Hydrates Crystal structure
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Summary:	For the structurally related agonist morphine and the antagonist naloxone, hydrates and anhydrates exist for both the free bases and the hydrochloride salts. We present five new crystal structures, determined from X-ray powder diffraction data, for morphine and naloxone: four anhydrates and one hydrate. The structures were solved by the DASH and FIDDLE programs and were refined with TOPAS. These new structures, together with already known structures from the Cambridge Structural Database, enabled us to investigate the influence of the subtle molecular differences between these agonists and antagonists, the role of water, and the effect of the chloride counterion on structural properties of morphine and naloxone in the solid state. All structures, except one, crystallize in the orthorhombic space group P212121, although the crystal packings are quite different. Naloxone anhydrate crystallizes in the monoclinic space group P21. In all cases dehydration causes an anisotropic shrinkage of the unit cell but only for the free base of naloxone this also induces a breaking of the symmetry. For morphine dehydration causes a lowering of the dimensionality of the hydrogen-bonding network, but for naloxone this is not the case since the dimensionality of the network is not dominated by the water molecules. When comparing the structures of the free bases and the hydrochloride salts, it is clear that the chloride ion always takes part in the hydrogen bonding networks and that it prefers to bridge to water instead of nitrogen. These results suggest that the introduction of water or counterions such as chlorine generate structures with higher dimensional hydrogen bonding networks than the corresponding anhydrate or free base structures.
ISSN:	1528-7483 1528-7505
DOI:	10.1021/cg800622m