Doris E. Braun

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.

Conformational polymorphism in aripiprazole: Preparation, stability and structure of five modifications

Five phase-pure modifications of the antipsychotic drug aripiprazole were prepared and characterized by thermal analysis, vibrational spectroscopy and X-ray diffractometry. All modifications can be produced from solvents, form I additionally by heating of form X degrees to approximately 120 degrees C (solid-solid transformation) and form III by crystallization from the melt. Thermodynamic relationships between the polymorphs were evaluated on the basis of thermochemical data and visualized in a semi-schematic energy/temperature diagram. At least six of the ten polymorphic pairs are enantiotropically and two monotropically related. Form X degrees is the thermodynamically stable modification at 20 degrees C, form II is stable in a window from about 62-77 degrees C, and form I above 80 degrees C (high-temperature form). Forms III and IV are triclinic (

Which, if any, hydrates will crystallise? Predicting hydrate formation of two dihydroxybenzoic acids

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Complex Polymorphic System of Gallic Acid—Five Monohydrates, Three Anhydrates, and over 20 Solvates

), I and X degrees are monoclinic (P2(1)) and form II orthorhombic (Pna2(1)). Each polymorph exhibits a distinct molecular conformation, and there are two fundamental N-H

The complexity of hydration of phloroglucinol: a comprehensive structural and thermodynamic characterization.

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Solid-state forms of β-resorcylic acid how exhaustive should a polymorph screen be?

O hydrogen bond synthons (catemers and dimers). Hirshfeld surface analysis was employed to display differences in intermolecular short contacts. A high kinetic stability was observed for three metastable polymorphs which can be categorized as suitable candidates for the development of solid dosage forms.

Simultaneous quantitative analysis of ternary mixtures of D-mannitol polymorphs by FT-Raman spectroscopy and multivariate calibration models.

A study of two dihydroxybenzoic acid isomers shows that computational methods can be used to predict hydrate formation, the compound:water ratio and hydrate crystal structures. The calculations also help identify a novel hydrate found in the solid form screening that validates this study.

Four Polymorphs of Methyl Paraben: Structural Relationships and Relative Energy Differences

We report the structure of the fifth monohydrate of gallic acid and two additional anhydrate polymorphs and evidence of at least 22 other solvates formed, many containing water and another solvent. This unprecedented number of monohydrate polymorphs and diversity of solid forms is consistent with the anhydrate and monohydrate crystal energy landscapes, showing both a wide range of packing motifs and also some structures differing only in proton positions. By aiding the solution of structures from powder X-ray diffraction data and guiding the screening, the computational studies help explain the complex polymorphism of gallic acid. This is industrially relevant, as the three anhydrates are stable at ambient conditions but hydration/dehydration behavior is very dependent on relative humidity and phase purity.

Packing polymorphism of a conformationally flexible molecule (aprepitant)

Hydrate formation is of great importance as the inclusion of water molecules affects many solid state properties and hence determines the required chemical processing, handling, and storage. Phloroglucinol is industrially important, and the observed differences in the morphology and diffuse scattering effects with growth conditions have been scientifically controversial. We have studied the anhydrate and dihydrate of phloroglucinol and their transformations by a unique combination of complementary experimental and computational techniques, namely, moisture sorption analysis, hot-stage microscopy, differential scanning calorimetry, thermogravimetry, isothermal calorimetry, single crystal and powder X-ray diffractometry, and crystal energy landscape calculations. The enthalpically stable dihydrate phase is unstable below 16% relative humidity (25 °C) and above 50 °C (ambient humidity), and the kinetics of hydration/dehydration are relatively rapid with a small hysteresis. A consistent atomistic picture of the thermodynamics of the hydrate/anhydrate transition was derived, consistent with the disordered single X-ray crystal structure and crystal energy landscape showing closely related low energy hydrate structures. These structures provide models for proton disorder and show stacking faults as intergrowth of different layers are possible. This indicates that the consequent variability in crystal surface features and diffuse scattering with growth conditions is not a practical concern.

Navigating the Waters of Unconventional Crystalline Hydrates

A combined experimental and computational study was undertaken to establish the solid-state forms of β-resorcylic acid (2,4-dihydroxybenzoic acid). The experimental search resulted in nine crystalline forms: two concomitantly crystallizing polymorphs, five novel solvates (with acetic acid, dimethyl sulfoxide, 1,4-dioxane, and two with N,N-dimethyl formamide), in addition to the known hemihydrate and a new monohydrate. Form II°, the thermodynamically stable polymorph at room temperature, was found to be the dominant crystallization product. A new, enantiotropically related polymorph (form I) was obtained by desolvation of certain solvates, sublimation experiments, and via a thermally induced solid−solid transformation of form II° above 150 °C. To establish their structural features, interconversions, and relative stability, all solid-state forms were characterized with thermal, spectroscopic, X-ray crystallographic methods, and moisture-sorption analysis. The hemihydrate is very stable, while the five solvates and the monohydrate are rather unstable phases that occur as crystallization intermediates. Complementary computational work confirmed that the two experimentally observed β-resorcylic acid forms I and II° are the most probable polymorphs and supported the experimental evidence for form I being disordered in the p-OH proton position. These consistent outcomes suggest that the most practically important features of β-resorcylic acid crystallization under ambient conditions have been established; however, it appears impractical to guarantee that no additional metastable solid-state form could be found.