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The physical properties of organic solids are altered when hydrated (and, more generally, when solvated) and this is of particular significance for pharmaceuticals in application; for instance, the solubility of a hydrate is less than that of its parent. The effective volumes of waters of crystallization for non-ionic pharmaceuticals (where the `effective' volume is the difference per water molecule between the hydrate volume and the volume of the anhydrous parent) are here examined. This investigation contrasts with our earlier study of effective volumes of waters of crystallization for ionic materials where the coulombic forces are paramount. Volumetric properties are significant since they correlate strongly with many thermodynamic properties. Twenty-nine hydrate/parent systems have been identified, and their volumetric properties are reported and analysed (apart from aspartame and ephedrine for which the structural data are inconsistent). Among these systems, the data for paracetamol are extensive and it is possible to differentiate among the volumetric properties of its three polymorphs and to quantify the effect of temperature on their volumes. The effective volumes in both ionic and non-ionic systems are similar, with a median effective volume of 22.8 Å3 for the non-ionic systems compared with 24.2 Å3 for the ionic systems, and both are smaller than the molecular volume of 30 Å3 of ambient liquid water – which appears to be an upper limit to the effective volumes of waters of crystallization under ambient conditions. These results will be supportive in checking and confirmation of hydrated crystal structures and in assessing their thermodynamic properties.

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Tables S1-S4. Volume data and chemical structures

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