Determination of the absolute configuration of organic molecules is essential in drug development and the subsequent approval process. We show that this determination is possible through electron diffraction using nanocrystalline material. Ab initio structure determination by electron diffraction has so far been limited to compounds that maintain their crystallinity after a dose of one electron per square angstrom or more. We present a complete structure analysis of a pharmaceutical cocrystal of sofosbuvir and l-proline, which is about one order of magnitude less stable. Data collection on multiple positions of a crystal and an advanced-intensity extraction procedure enabled us to solve the structure ab initio. We further show that dynamical diffraction effects are strong enough to permit unambiguous determination of the absolute structure of material composed of light scatterers.

A new approach is introduced for the comparison of molecular packing and the identification of identical crystal structure motifs. It has been tested on data sets for the solid forms of benzamide, cabergoline and trospium. In this approach, the packing similarity is calculated using a simple formula involving the distances between molecular centres and the relative orientations of molecular entities inside a finite molecular cluster. The approach is independent of the atomic labelling, the unit‐cell parameters, the space group setting and the number of molecules in the asymmetric part of the unit cell. Owing to its low sensitivity to volume changes, this approach allows the comparison of various solid forms (such as polymorphs, hydrates, solvates, co‐crystals or salts) of identical or similar molecular compounds. The method is also suitable for identifying similar results from direct space methods, which are often used in powder diffraction.

96 nano-crystallization trials can be done with just (sub)-milligram amounts of an organic salt to directly yield single crystal structures.

A search for new solid forms of an active pharmaceutical ingredient (API) is an integral part of the drug product development process. The studied compound, Ibrutinib, is a recently approved anticancer drug. The main aim of this study was to search for new solvates of Ibrutinib and to perform their structural characterization. To do so, we performed a tailor-made systematic solvate screening and tested several solution and slurry based methods in the solvate screening for their suitability and success rate. The phase composition of the screening samples was analyzed by Raman spectroscopy and powder X-ray diffraction. From the 11 tested solvents, eight solvates were prepared (with 4-hydroxy-4-methylpentan-2-on, dioxolane, α,α,α-trifluorotoluene, ortho-xylene, meta-xylene, para-xylene, anisole, and chlorobenzene). The crystal structures of all eight solvates were successfully solved from single-crystal X-ray diffraction data, and, to our best knowledge, this work is the first ever crystal structure study of Ibrutinib. The desolvation behavior of the prepared Ibrutinib solvates was studied by thermal methods (differential scanning calorimetry, thermogravimetric analysis, and hot-stage microscopy), and stability tests were performed to determine the strength of the API–solvent interaction. Dissolution experiments showed that the solvate formation can improve the dissolution rate by as much as 8.5 times, compared to the most stable nonsolvated form.