Andrea Johnston

Solving molecular crystal structures from laboratory X-ray powder diffraction data with DASH: the state of the art and challenges

The crystal structures of 35 molecular compounds have been redetermined from laboratory monochromatic capillary transmission X-ray powder diffraction data using the simulated-annealing approach embodied within the DASH structure solution package. The compounds represent industrially relevant areas (pharmaceuticals; metal coordination compounds; nonlinear optical materials; dyes) in which the research groups in this multi-centre study are active. The molecules were specifically selected to form a series within which the degree of structural complexity (i.e. degrees of freedom in the global optimization) increased systematically, the degrees of freedom increasing with increasing number of optimizable torsion angles in the structural model and with the inclusion of positional disorder or multiple fragments (counterions; crystallization solvent; Z′ > 1). At the lower end of the complexity scale, the structure was solved with excellent reproducibility and high accuracy. At the opposite end of the scale, the more complex search space offered a significant challenge to the global optimization procedure and it was demonstrated that the inclusion of modal torsional constraints, derived from the Cambridge Structural Database, offered significant benefits in terms of increasing the frequency of successful structure solution by restricting the magnitude of the search space in the global optimization.

Control and prediction of packing motifs: a rare occurrence of carbamazepine in a catemeric configuration

A predicted orthorhombic crystal structure of carbamazepine is isostructural with an experimentally determined dihydrocarbamazepine crystal structure, providing a rationale for synthesising a novel 1 : 1 solid solution that has carbamazepine in a rare catemeric configuration.

Targeted crystallisation of novel carbamazepine solvates based on a retrospective Random Forest classification

Three novel crystalline solvates of the antiepileptic compound carbamazepine were obtained by targeted crystallisation from solvents identified by a Random Forest classification of solvent properties, experimental conditions and known crystallisation outcomes.

An automated platform for parallel crystallization of small organic molecules

An automated platform for parallel crystallization of small organic molecules from solution is described. The principal gain over manual crystallization lies in the automated sequencing of crystallization steps, including computer-controlled dosing of liquids and solids. The platform is designed to conduct 32 crystallizations per day, from solution volumes up to 10 ml, allowing a search for physical forms to be conducted over a finer grid than might be accessible manually and thereby increasing the probability of success.

A catemer-to-dimer structural transformation in cyheptamide

A catemeric crystal structure of cyheptamide undergoes a transformation in the solid-state upon heating to produce a dimer-based form whose structure has been determined from laboratory X-ray powder diffraction (XRPD) data, thereby providing the first conclusive evidence of a carbamazepine analogue crystallising in both hydrogen bonded motifs.

Hirshfeld surface analysis of two bendroflumethiazide solvates.

Bendroflumethiazide, or 3-benzyl-6-(trifluoromethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, is reported to crystallize as 1:1 solvates with acetone, C(15)H(14)F(3)N(3)O(4)S(2).C(3)H(6)O, and N,N-dimethylformamide, C(15)H(14)F(3)N(3)O(4)S(2).C(3)H(7)NO. A detailed investigation of the crystal packing and intermolecular interactions is presented by means of Hirshfeld surface analysis. This analysis confirms the atomic positions of methyl H atoms of the solvent molecules that were inferred from the X-ray data and provides a useful tool for structure validation.

Structure and stability of two polymorphs of creatine and its monohydrate

An experimental search for crystalline forms of creatine including a variable temperature X-ray powder diffraction study has produced three polymorphs and a formic acid solvate. The crystal structures of creatine forms I and II were determined from X-ray powder diffraction data plus the creatine formic acid (1 : 1) solvate structure was obtained by single crystal X-ray diffraction methods. Evidence of a third polymorphic form of creatine obtained by rapid desolvation of creatine monohydrate is also presented. The results highlight the role of automated parallel crystallisation, slurry experiments and VT-XRPD as powerful techniques for effective physical form screening. They also highlight the importance of various complementary analytical techniques in structural characterisation and in achieving better understanding of the relationship between various solid-state forms. The structural relationships between various solid-state forms of creatine using the XPac method provided a rationale for the different relative stabilities of forms I and II of creatine with respect to the monohydrate form.

A random forest model for predicting the crystallisability of organic molecules

A random forest model has for the first time enabled the prediction of the crystallisability (crystals vs. no crystals) of organic molecules with ~70% accuracy. The predictive model is based on calculated molecular descriptors and published experimental crystallisation propensities of a library of substituted acylanilides.

Carbamazepine trifluoroacetic acid solvate

Carbamazepine forms a 1:1 solvate with trifluoroacetic acid (systematic name: 5H-dibenzo[b,f] azepine-5-carboxamide trifluoroacetic acid solvate), C(15)H(12)N(2)O center dot C(2)HF(3)O(2). The compound crystallizes with one molecule of carbamazepine and one of trifluoroacetic acid in the asymmetric unit to form an R(2)(2)(8) motif. The solvent molecule is disordered over two sites, with site-occupancy factors 0.53 (1) and 0.47 (1).

Chloro­thia­zide–pyridine (1/3)

In the title compound, C7H6ClN3O4S2·3C5H5N, (systematic name: 6-chloro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide pyridine trisolvate), chlorothiazide forms a 1:3 solvate with pyridine. The crystal structure is stabilized by strong intermolecular N—H⋯N hydrogen bonds.