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Absolute Structure Determination

The physicochemical properties of a compound is closely related to its structure and often can be predicted from its structure. Single crystal X-ray data collection and structure elucidation is one of the best techniques to obtain the 3-dimentional structural information, including bond connectivity, chirality, solvate/water participation etc.

The single crystal structure will unambiguously prove the connectivity of the molecule. There can be a small level of uncertainty in the connectivity of a structure if determined by solution NMR and/or mass spec. Particularly with hetero-aromatic fused ring systems. If the project advances, the data would be included in the proof of structure section of the NDA.

Single Crystal X-ray Diffraction (SCXRD)

For many years, single-crystal X-ray diffraction for many years was reserved primarily as a tool for discovery medicinal chemists seeking to establish molecular structure, conformation, and absolute configuration. Its application has expanded to the hands of material scientists in pharmaceutical development who seek to optimize the physical properties of the active pharmaceutical ingredient (API), discovering new salt forms, polymorphic forms, cocrystals, and solvates.

With the advancements in the brilliance of lab X-ray sources, the increased sensitivity, reduced noise, and increased size of area detectors allow complete datasets to be collected in a matter of minutes to hours, which were once required days to complete. Crystal-size requirements have been reduced by an order of magnitude, where a crystal's smallest dimension need only be 20-30 µm. The primary issue has now become whether you can crystallize a substance and crystal quality.

For the discovery chemist, absolute stereochemistry once required a heavy atom to be present in its structure. Now, absolute structure can often be determined with reasonable statistical certainty on high-quality crystals composed of relatively light atoms and with a very high degree of certainty for crystals that contain Cl or S in their lattice.

The technique's role has expanded in the material scientist's lab as well. The knowledge of a crystal structure enables one to immediately know a crystal's content, reducing the need for Ion chromatography or solution NMR to identify other constituents in the lattice. As a result of this information, one can readily determine if the newly discovered material is a true polymorph, a co-crystal, or a solvate.

An understanding of the crystallographic packing enables prediction of important material properties that influence the ease of processing of an API, such as true density, morphology, and the dehydration behavior of hydrates. In particular, the material scientist is readily able to calculate the theoretical X-ray powder diffraction pattern. This allows one to unravel complicated powder diffraction patterns composed of mixtures of phases and for one to definitively establish phase purity of crystalline powders that are analyzed using the simpler method of X-ray powder diffraction. From the structural model and a theoretical X-ray powder diffraction pattern calculated from it, one can relate crystal morphology, preferred orientation, and its influence on the relative intensities that are observed in an experimental X-ray powder diffraction pattern.

Thankfully, just as NMR and Mass Spectrometry technologies continue to advance, so, too, does X-ray crystallography. In many ways, structures that not too long ago required a synchrotron to determine can now be collected in minutes to hours using the common laboratory diffractometer.

Absolute Structure Determination

Bruker D8 Venture

Absolute Structure Determination

Absolute Structure Determination

Experimental Powder Diffraction Pattern (top) Compared to Calculated Powder (bottom). Pronounced preferred orientation is noted and is associated with the most prominent faces along {001}, as shown and explained by the claculated crystal morphology. All peaks accounted for by its indexation and space group with no "extra" peaks observed that would indicate and extraneous phase impurity.

Absolute Structure Determination

Theoretical Bravais-Friedel-Donnay-Harker model of the morphology of Sucrose based on its Crystal Structure, displaying its most prominent faces {001}.

Absolute Structure Determination

Conformational and Concomitant Polymorphism of the crystal system ROY directly related to the molecular conformation and extended conjugation and their similarity of packing energy.


Microcrystal Electron Diffraction (MicroED) uses a beam of electrons to obtain a diffraction pattern from the sample of interest. Through continuous tilting/rotation of the sample stage, the diffraction patterns will be collected from several orientations to provide three-dimensional structural information.

Absolute Structure Determination

Resources of Absolute Structure Determination

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