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 P2 1 2 1 2 1 , although the crystal packings are quite different. Naloxone anhydrate crystallizes in the monoclinic space group P2 1 . 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.

The (pseudo)polymorphism of ethinyl estradiol was investigated via extensive crystallization experiments. Four new crystal structures of ethinyl estradiol solvates that resulted from this study are presented. They contain dioxane, nitromethane, ethanol, or dimethylformamide. The crystal structures of the hemihydrate, methanolate, and acetonitrile solvate were redetermined to obtain the accurate hydrogen atom positions. The structural details of the different solvates of ethinyl estradiol were investigated in order to understand the scope of the solvate formation of ethinyl estradiol. Ethinyl estradiol forms many solvates, mostly with solvents having H-bond accepting or both accepting and donating propensity. Despite our rather comprehensive study, no true polymorph of ethinyl estradiol anhydrate was found.

Aspartame has three pseudo-polymorphic forms, two hydrates and a hemi-hydrate, for which crystal structures were determined from single-crystal diffraction data. This paper presents the crystal structure of the anhydrate, which was obtained by dehydrating the hemi-hydrate. The crystal structure of aspartame anhydrate, l-aspartyl-l-phenylalanine methyl ester, was determined from X-ray powder diffraction data. Aspartame anhydrate crystallizes in the monoclinic system with space group P21 and cell parameters:  a = 19.4078(10) Å, b = 4.9605(2) Å, c = 15.6547(9) Å, β = 94.876(2)°, V = 1501.65(14) Å3. Final Rietveld refinement resulted in R wp = 2.26 and a GOOF of 2.30. Comparing the hydrates of aspartame and using molecular modeling provide a complete and clear picture of the dehydration behavior of aspartame at the molecular level.

For the chemically and structurally related antagonists naltrexone and naloxone, hydrate and anhydrate forms exist for the hydrochloride salts, the generic forms that are on the market. The hydration/dehydration behavior of these salts was studied by applying hot-humidity stage X-ray powder diffraction, microscopy, differential scanning calorimetry, thermogravimetric analysis, and solid-state NMR. The combination of these techniques shows consistent results and yields a detailed conversion scheme. A new crystal structure, determined from X-ray powder diffraction data, for naltrexone hydrochloride anhydrate is presented. The structure was solved by the DASH program and was refined with TOPAS. This new structure, together with the already known structures of naltrexone and naloxone hydrochloride, enabled us to investigate the influence of the subtle molecular differences between the two antagonists and the role of water on structural properties in the solid state. All known hydrate and anhydrate forms of naltrexone and naloxone hydrochloride crystallize in the orthorhombic space group P2 1 2 1 2 1 , although the crystal packings show clear differences. Dehydration causes in both cases no breaking of the symmetry, but the change in unit cell for naltrexone is profoundly different from that of naloxone. Dehydration of naltrexone hydrochloride tetrahydrate takes place with shrinkage of the volume of the unit cell, whereas dehydration of naloxone hydrochloride dihydrate results in an expansion of the unit cell. The H-bonding patterns corresponding to the two opioids seem to be footprints for the crystal structures and for the hydration/dehydration behavior of the two antagonists. Despite naltrexone and naloxone hydrochloride are chemically and structurally related and show similarities in their biological behavior, the overall hydration and dehydration process is fundamentally different.

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