The crystal form named in advance

Given the diagram of a new organic molecule and the conditions under which a crystal of it was grown, one predicted crystal structure matches the single-crystal X-ray structure that has been withheld.

The crystal form decides solubility, stability, and whether a tablet or a formulation can be made twice. Companies still find late polymorphs after years of screening. A method that names the form actually grown, before it sees the diffraction, would let a solid-state group decide which experiment to run and would give a sharp test of energy models that today return long lists.

The standing blinded comparison is the seventh crystal-structure-prediction blind test, run by the Cambridge Crystallographic Data Centre from 2020 to 2022 and published in 2024.

In the structure-generation half, a match was a 30-molecule overlay, hydrogens omitted, distance and angle tolerances of 35 percent, and a root-mean-square deviation below 1.0 Å. Lists ran to about 1,500 structures. For the agrochemical XXXI, which has three rotatable bonds, 10 of 17 groups generated form A and 9 of 17 generated form B somewhere in the list. For the drug candidate XXXII, which has eleven rotatable bonds, 3 of 13 groups generated form A and 2 of 13 generated form B (Hunnisett and co-workers, Acta Crystallographica B, 2024, 80, 517–547, doi:10.1107/S2052520624007492 (opens in a new tab)).

In the ranking half, periodic dispersion-corrected density-functional methods were the most consistent. For XXXII they agreed with each other and placed the experimental forms more than 4 kJ/mol above the predicted global minimum, at low temperature and at ambient temperature (Hunnisett and co-workers, Acta Crystallographica B, 2024, 80, 548–574, doi:10.1107/S2052520624008679 (opens in a new tab)). Finding a packing inside a long list, and naming that packing as the form to expect, are different outcomes. The second paper’s result on XXXII is that the experimental forms were not ranked first.

An open doubt: target XXVIII in the same test was published by an outside group while the test was running, so that target is not evidence about a blind prediction. This problem uses the generation paper’s overlay rule and asks for one structure, on molecules flexible enough that the seventh test did not rank the experimental form first.

The laboratory holds six unpublished single-crystal structures. Each molecule contains only C, H, N, O, S, F, and Cl, has a molecular weight between 250 and 550, has at least eight rotatable bonds, and has one molecule in the asymmetric unit. The structure has no unresolved disorder. On the morning the diagrams are released, none of the six is in the Cambridge Structural Database; the laboratory records the search. A molecule that fails one of these checks is replaced before release.

The laboratory releases, for each molecule, the constitutional diagram with relative stereochemistry, the crystallization solvent, the temperature, and the method (evaporation, cooling, or vapor diffusion). It does not release cell parameters, a powder pattern, a photograph, or a space group. The attempt has seven days to submit one crystallographic information file per molecule: the single structure it expects under those conditions. A list is not a submission for the full grade.

Grading uses the withheld single-crystal structure. The structures match when a 30-molecule overlay, hydrogens omitted, with distance and angle tolerances of 35 percent, fits all 30 molecules with a root-mean-square deviation below 1.0 Å. That match rule is the one used in the seventh blind test, adopted here so two laboratories will call the same pair a match. The laboratory archives the overlay.

At least 4 of the 6 submitted structures match the withheld experimental structures under the overlay rule above.

Four of six, the eight-rotatable-bond minimum, the seven-day clock, and the decision to submit one file are pass marks defined here. The 1.0 Å and 30-molecule criteria are taken from the generation paper cited above. Eight rotatable bonds is a selection rule aimed at the unsolved end of that test: three rotatable bonds were often generated somewhere in a long list, and eleven were not placed first by the ranking methods.

Before release, a second crystallographer overlays the experimental structure on itself with the same rule and confirms a match. A structure that fails this self-match is replaced.

The attempt does not receive the diffraction frames, the solved structure, or a powder pattern until after the six files are archived. The grader compares files, not narratives. If the overlay program returns a match and a visual check shows a different packing, the visual check wins and the target fails. The disagreement is archived.

Any energy model, search, or machine-learning potential. Any amount of computation during the seven days. Use of the Cambridge Structural Database for other molecules. Prediction of disorder is allowed only if the major component still meets the overlay rule; the targets themselves are ordered.

A powder pattern, a cell, or a space group of the target. A list of structures from which the closest is chosen after grading. A submission filed after any diffraction of that batch has been shown to the attempt. A molecule already in the Cambridge Structural Database. Changing the submitted file after the deadline. Counting a match to a different polymorph from the one grown under the stated conditions.

At least 4 of the 6 experimental structures appear in a list of at most 50 structures submitted, under the same deadline and the same overlay rule. Fifty and 4 of 6 are pass marks for this lesser bar. Partial success shows that the packing was generated. It is not a solution, because the form was not named.

The overlay rule (30 molecules, 35 percent tolerances, root-mean-square deviation below 1.0 Å) is taken from Hunnisett et al., Acta Crystallographica Section B, 2024, 80, 517–547, doi:10.1107/S2052520624007492 (opens in a new tab). Table 3 of that paper is the source for the generation counts: XXXI, 10 of 17 and 9 of 17; XXXII, 3 of 13 and 2 of 13. The ranking result, experimental forms of XXXII more than 4 kJ/mol above the global minimum, is from Hunnisett et al., Acta Crystallographica Section B, 2024, 80, 548–574, doi:10.1107/S2052520624008679 (opens in a new tab).

Four of six, eight rotatable bonds, one submitted structure, the list of 50, and the seven-day clock are pass marks defined here.