Following the interest generated by two previous blind tests of crystal structure prediction (CSP1999 and CSP2001), a third such collaborative project (CSP2004) was hosted by the Cambridge Crystallographic Data Centre. A range of methodologies used in searching for and ranking the likelihood of predicted crystal structures is represented amongst the 18 participating research groups, although most are based on the global minimization of the lattice energy. Initially the participants were given molecular diagrams of three molecules and asked to submit three predictions for the most likely crystal structure of each. Unlike earlier blind tests, no restriction was placed on the possible space group of the target crystal structures. Furthermore, Z' = 2 structures were allowed. Part-way through the test, a partial structure report was discovered for one of the molecules, which could no longer be considered a blind test. Hence, a second molecule from the same category (small, rigid with common atom types) was offered to the participants as a replacement. Success rates within the three submitted predictions were lower than in the previous tests - there was only one successful prediction for any of the three ;blind' molecules. For the ;simplest' rigid molecule, this lack of success is partly due to the observed structure crystallizing with two molecules in the asymmetric unit. As in the 2001 blind test, there was no success in predicting the structure of the flexible molecule. The results highlight the necessity for better energy models, capable of simultaneously describing conformational and packing energies with high accuracy. There is also a need for improvements in search procedures for crystals with more than one independent molecule, as well as for molecules with conformational flexibility. These are necessary requirements for the prediction of possible thermodynamically favoured polymorphs. Which of these are actually realised is also influenced by as yet insufficiently understood processes of nucleation and crystal growth.

An experimental study of barbituric acid found a new P2 1 /c polymorph with two conformations of barbituric acid in the asymmetric unit, one molecule adopting an envelope conformation and the other refining as planar. The new Form ii involves different hydrogen bond acceptors to Form i. An ab initio conformational analysis study found that barbituric acid can change its envelope conformation by over 20°from planar with a small energy change that can be compensated for by packing forces, so that the new Form ii is predicted to have a lower lattice energy than Form i. A computational search for minima in the lattice energy found many hypothetical structures of barbituric acid within the energy range of possible polymorphism, with a variety of hydrogen bonding acceptors and motifs. The search was found to be very sensitive to the assumed molecular structure of barbituric acid, so further plausible low energy variations in the molecular conformation would produce even more low energy crystal structures. Thus, the combined experimental and theoretical studies show that barbituric acid can pack in such a variety of low energy structures that further polymorphs seem possible.

A survey of the molecules which have been used in crystal structure prediction studies is presented. The results of these studies have been analysed in terms of whether the experimentally observed crystal structures are found at or near the global minimum in the lattice energy. The results suggest that whilst some crystal structures can be predicted just on the basis of lattice energy searches, there is yet insufficient experience to judge for which molecules this energetic criterion is sufficient, within the limitations of current force-field accuracy. The molecules chosen to test crystal structure prediction methods appear to be biased away from the types that would be expected to be readily predictable and suitable for crystal engineering. The survey highlights the need for more theoretical and experimental collaboration to understand what determines whether a molecule's crystal structure will be so favourable that other polymorphs are unlikely.

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