Cambridge Structural Database hydrate structures

Gillon, A.L. Feeder, N. Davey, R.J. Storey, R. Hydration in molecular crystals—a Cambridge structural database analysis. Cryst. Growth Des. 2003, 3, 663-673. 

Gillon AL, Feeder N, Davey ly, and Storey R, Hydration in Molecular Crystals-A Cambridge Structural Database Analysis. Cryst Growth Des 2003 3 663-673. 

A number of statistical analyses of the literature have been carried out in an attempt to estimate the extent of polymorphism. A search of the Cambridge Structural Database on the keywords polymorph , form , modification and phase indicates that about 3.5% of the -350 000 entries fall into this category. Approximately 25 % of the entries are either solvates or hydrates. At the other end of the spectrum, Byrn has reported that of the >150 compounds submitted for crystal form screening and analysis to SSCI, Inc. 85 % exhibit more than one crystal form, 37% are solvates and 31 % are hydrates [40]. Other studies based on different selection criteria reveal results falling somewhere between these two extremes [41]. For instance, Griesser and Burger have collected information on about 600 polymorphic forms and solvates (including hydrates) pharmaceutical compounds that are solid at 25 °C [41c],... 

The arguments just provided detail the potential issues around hydrates in the development process. The other consideration is the frequency with which hydrates are encountered in real life. Focusing on active drug substances, it is estimated that approximately one-third of the pharmaceutical actives are capable of forming crystalline hydrates [3]. A search of the Cambridge Structural Database (CSD) shows that approximately 11% of all the reported crystal structures contain molecular water [4]. This represents over 16,000 compounds. If organometallic compounds are excluded, this number drops to approximately 6,000 (3.8%), and the breakdown of these according to hydration number is shown in Fig. 1. This shows the expected trend in which monohydrates are most frequently encountered, and where the frequency decreases almost exponentially as the hydration number increases. The hemihydrate stoichiometry occurs approximately as frequently as the trihydrate, which should serve as a caution to explore fully the occurrence of fractional hydration. That is, an apparent stoichiometry of 0.6 water molecules could be a partially dehydrated monohydrate, or it... 

J. van de Streek and W. D. S. Motherwell, New software for searching the Cambridge Structural Database for solvated and unsolvated crystal structures applied to hydrates, CrystEngComm, 9, 55-64 (2007). 

An analysis of all crystal structures available in the Cambridge Structural Database for hydrates of /8-lactams reveals that the water molecules in the crystal structures are not in sufficient proximity (within the sum of van der Waals distance) to the reactive center on the /8-lactam core to bring about reaction. For cases where water molecules are in close proximity to the reactive centre, further rationalization can be made in terms of the relative orientation of reactants and the steric hindrance of the initial approach of the water, or the low degree of conformational flexibility in the crystal. This type of calculation on cefadroxil monohydrate (reaction scheme shown in Figure 3.6) which contains a water molecule within van der Waals distance of the reactive /8-lactam carbonyl group, has shown that several atoms would lie outside of the molecular surface formed by the rest of the crystal, indicating steric clashes. 

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