Robert W. Lancaster

Over one hundred solvates of sulfathiazole

The sulfadrug sulfathiazole forms an extensive family of solvates and adducts, the crystal structures of which show a large variety of hydrogen-bonded frameworks.

Disappearing Polymorphs Revisited

Nearly twenty years ago, Dunitz and Bernstein described a selection of intriguing cases of polymorphs that disappear. The inability to obtain a crystal form that has previously been prepared is indeed a frustrating and potentially serious problem for solid-state scientists. This Review discusses recent occurrences and examples of disappearing polymorphs (as well as the emergence of elusive crystal forms) to demonstrate the enduring relevance of this troublesome, but always captivating, phenomenon in solid-state research. A number of these instances have been central issues in patent litigations. This Review, therefore, also highlights the complex relationship between crystal chemistry and the law.

A comparative spectroscopic investigation of three pseudopolymorphs of testosterone using solid-state i.r. and high-resolution solid-state NMR

Abstract Three pseudopolymorphic forms of testosterone have been examined by i.r. and CP/MAS NMR spectroscopies. The transmittance i.r. data clearly distinguish the forms. The NMR work also provides clear distinctions and shows crystallographic splittings for the α form only, in accordance with the X-ray data. The NMR spectra are fully assigned. The effect of crystallisation procedure on the NMR spectra was explored. NMR can be used to quantitatively assess mixtures of the β and δ forms.

Tunable recognition of the steroid α-face by adjacent π-electron density

We report a previously unknown recognition motif between the α-face of the steroid hydrocarbon backbone and π-electron-rich aromatic substrates. Our study is based on a systematic and comparative analysis of the solid-state complexation of four steroids with 24 aromatic molecules. By using the solid state as a medium for complexation, we circumvent solubility and solvent competition problems that are inherent to the liquid phase. Characterization is performed using powder and single crystal X-ray diffraction, infrared solid-state spectroscopy and is complemented by a comprehensive cocrystal structure prediction methodology that surpasses earlier computational approaches in terms of realism and complexity. Our combined experimental and theoretical approach reveals that the α⋯π stacking is of electrostatic origin and is highly dependent on the steroid backbone’s unsaturated and conjugated character. We demonstrate that the α⋯π stacking interaction can drive the assembly of molecules, in particular progesterone, into solid-state complexes without the need for additional strong interactions. It results in a marked difference in the solid-state complexation propensities of different steroids with aromatic molecules, suggesting a strong dependence of the steroid-binding affinity and even physicochemical properties on the steroid’s A-ring structure. Hence, the hydrocarbon part of the steroid is a potentially important variable in structure-activity relationships for establishing the binding and signaling properties of steroids, and in the manufacture of pharmaceutical cocrystals.

Structure determination of a steroid directly from powder diffraction data

We report the determination of the crystal structure of a new polymorph of the pharmaceutical material fluticasone propionate, which is obtained as a microcrystalline powder by a supercritical crystallization procedure; the structure was solved directly from powder diffraction data using our Genetic Algorithm technique (in which a population of trial structures evolves through well-defined procedures for mating, mutation and natural selection) and refined using Rietveld refinement techniques.

Cross-polarization/magic-angle spinning NMR studies of polymorphism: Cortisone acetate

Abstract 13C CPMAS spectra have been recorded for nine samples of cortisone acetate (21-acetoxy-17α-hydroxy-4-pregnene-3,11,20-trione, C23H30O6) and the observed resonances are attributed to six crystalline forms. Two of these forms are novel. The spectra of all six are entirely distinct. The resonances are assigned to individual carbon atoms on the basis of previously-determined solution-state spectra together with dipolar dephasing experiments and observations of shielding anisotropies as reflected in spinning sideband manifolds. The results are interpreted in relation to known crystal structures. The value of solid-state NMR for analysis of polymorph mixtures is emphasized.

Fifty-year old samples of progesterone demonstrate the complex role of synthetic impurities in stabilizing a metastable polymorph

We describe a unique experiment whereby analysis of fifty-year old samples of progesterone shows that a metastable, ‘disappearing’ polymorph contains several impurities that are not found in the stable form.

‘Polymorphism’ in a novel anti-viral agent: Lamivudine

Two modifications of Lamivudine have been studied. One has a highly symmetrical crystal lattice and the other, unusually, an asymmetric unit containing five non-equivalent molecules (with some disorder). The latter contains one molecule of water for every five of Lamivudine. Solid-state NMR spectra reflect these dramatic differences and the technique has been used to predict the extent of the asymmetry in the latter form. X-Ray diffraction studies confirm the differences in symmetry between the two polymorphs, which have also been characterised by IR spectroscopy and differential scanning calorimetry.

Cross-polarization/magic-angle spinning NMR studies of polymorphism: androstanolone

Abstract Carbon-13 CPMAS spectra have been recorded for anhydrous and monohydrate forms of androstanolone. The results are discussed in relation to crystallography. The anhydrous form gives crystallographic splittings in the spectra arising from non-equivalent molecules in the unit cell. The spectra are assigned by comparison with solution-state data.

A comparative spectroscopic investigation of two polymorphs of 4′-methyl-2′-nitroacetanilide using solid-state infrared and high-resolution solid-state nuclear magnetic resonance spectroscopy

The low-temperature i.r. and high-resolution solid-state 13C n.m.r. spectra of two polymorphs of 4′-methyl-2′-nitroacetanilide are presented and discussed with reference to their structures as determined by X-ray crystallography.