Sharmarke Mohamed

Towards crystal structure prediction of complex organic compounds – a report on the fifth blind test

The results of the fifth blind test of crystal structure prediction, which show important success with more challenging large and flexible molecules, are presented and discussed.

Report on the sixth blind test of organic crystal structure prediction methods

The results of the sixth blind test of organic crystal structure prediction methods are presented and discussed, highlighting progress for salts, hydrates and bulky flexible molecules, as well as on-going challenges.

Computational prediction of salt and cocrystal structures--does a proton position matter?

The lattice energy landscape is calculated for three pyridinium carboxylate salts and the corresponding pyridine·carboxylic acid cocrystals. Experimentally, one system crystallizes as a salt, another as a cocrystal and the acidic proton in the third is disordered across the N(arom)...O hydrogen bond vector. A novel structure of a 1:1 4-cyanopyridine·4-fluorobenzoic acid cocrystal (I) was characterized to provide the cocrystal as a system with an isolated carboxylic acid-pyridine heterosynthon. By contrast, the 4-dimethylaminopyridinium maleate salt (GUKVUE) shows the effects of an internal hydrogen bond, and the proton-disordered pyridine·isophthalic acid crystal (IYUPEX) shows the effects of competing intermolecular hydrogen bonds. All three crystal structures were found low in energy on the lattice energy landscape for the correct proton connectivity. For all three systems, comparing the salt and cocrystal energy landscapes shows the importance of the proton position for the relative stabilities of structures, despite the expected similarities between the ionized and neutral forms of the carboxylic acid-pyridine heterosynthon. The systems with additional hydrogen bonds have some hydrogen bonding motifs that are only favourable for the salt or for the cocrystal. This illustrates the sensitivity of the range of thermodynamically plausible crystal structures to whether the molecules are assumed to be ionized or neutral.

Discovery of three polymorphs of 7-fluoroisatin reveals challenges in using computational crystal structure prediction as a complement to experimental screening

A combined computational and experimental polymorph search was undertaken to establish the crystal forms of 7-fluoroisatin, a simple molecule with no reported crystal structures, to evaluate the value of crystal structure prediction studies as an aid to solid form discovery. Three polymorphs were found in a manual crystallisation screen, as well as two solvates. Form I (P21/c, Z′ = 1), found from the majority of solvent evaporation experiments, corresponded to the most stable form in the computational search of Z′ = 1 structures. Form III (P21/a, Z′ = 2) is probably a metastable form, which was only found concomitantly with form I, and has the same dimeric R22(8) hydrogen bonding motif as form I and the majority of the computed low energy structures. However, the most thermodynamically stable polymorph, form II (P, Z′ = 2), has an expanded four molecule R44(18) hydrogen bonding motif, which could not have been found within the routine computational study. The computed relative energies of the three forms are not in accord with experimental results. Thus, the experimental finding of three crystalline polymorphs of 7-fluoroisatin illustrates the many challenges for computational screening to be a tool for the experimental crystal engineer, in contrast to the results for an analogous investigation of 5-fluoroisatin.

Screening for cocrystals of succinic acid and 4-aminobenzoic acid

The ability of the pharmaceutically acceptable cocrystallising agents, succinic acid and 4-aminobenzoic acid, to form cocrystals with ten small organic molecules with hydrogen bonding acceptors but no donors, was investigated by grinding, hot-stage microscopy and solution based crystallisation experiments. The reproducible results obtained by different methods showed that only six cocrystals formed. The crystal structures of the four novel cocrystals, succinic acid·2,2′-bipyridine (1 : 1, P21/c, I), succinic acid·diphenylcyclopropenone (1 : 2, P21/c, II), 4-aminobenzoic acid·antipyrine (1 : 1, P21, III) and 4-aminobenzoic acid·phenazine (1 : 2, P, IV), are reported. The computed crystal energy landscapes of the cocrystals and their components show why succinic acid·1,4-dicyanobenzene did not form a cocrystal as well as predicting the observed structure of succinic acid·2,2′-bipyridine as the most stable. The most stable hypothetical structures of a 1 : 1 succinic acid·1,4-dicyanobenzene cocrystal are closely related to those of the components. The results demonstrate that cocrystal formation requires both hydrogen bonding and close packing, and so markedly non-planar pharmaceuticals will be quite specific in the steric and hydrogen bonding disposition requirement of coformers.

Commercial prospects for genomic sequencing technologies

This article analyses the evolution of the market for genomic sequencing technologies in the light of major reductions in sequencing costs and time, and the growth in potential pharmacogenomics applications.

7-Fluoroisatin–1,4-dioxane (1/1)

The title 1,4-dioxane solvate, C 8H4FNO2 center dot C4H8O2, was isolated during a manual crystallization screen on 7-fluoroisatin (7-fluoroindoline-2,3-dione). The 7-fluoroisatin molecule occupies a general position and each of the independent molecules of 1,4-dioxane is disposed about a centre of inversion, with half of each in the asymmetric unit. Hydrogen-bonded ribbons of 7-fluoroisatin are linked by 1,4-dioxane to form sheets parallel to (30 (1) over bar). Whilst one solvent molecule has an active role in the sheet formation, the other simply fills the cavity formed within the sheet.

7-Fluoroisatin-dimethyl sulfoxide (1/1)

The title dimethyl sulfoxide (DMSO) solvate, C8H4FNO2 center dot C2H6OS, was isolated during a manual crystallization screen on 7-fluoroisatin (7-fluoroindoline-2,3-dione). Molecules of 7-fluoroisatin are linked via C-H center dot center dot center dot O interactions to form chains parallel to the a direction, from which N-H center dot center dot center dot O hydrogen-bonded molecules of DMSO protrude.

Solvent inclusion in the crystal structure of bis­[(adamantan-1-yl)methanaminium chloride] 1,4-dioxane hemisolvate monohydrate explained using the computed crystal energy landscape

Energy computations on the title salt show a clear preference for solvated structures, which correlates with the most effective formation of hydrogen bonds.

5-Fluoroisatin–dimethyl sufoxide (1/1)

The title dimethyl sulfoxide (DMSO) solvate, C8H4FNO2 center dot-C2H6OS, was isolated during a manual crystallization screen on 5-fluoroisatin (5-fluoroindoline-2,3-dione). Molecules of 5-fluoroisatin are linked via C-H center dot center dot center dot O interactions to form chains parallel to (0 (1) over bar1) from which N-H center dot center dot center dot O hydrogen-bonded DMSO molecules protrude.