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.

Polymorphic studies of active pharmaceutical ingredients are of great importance for academic researchers as well as pharmaceutical industries, as each polymorph exhibits different physicochemical properties. In this study, vibrational ball milling was used to investigate the polymorphic transformations of sofosbuvir, a drug that is used for the treatment of hepatitis C, under different experimental conditions. We observed that by changing the type of liquid additive, the starting form 1 after 30 min of milling transformed mainly to an amorphous phase or form A, which is the most thermodynamically stable form at room temperature. Furthermore, by exploring different time periods of milling we discovered that, depending on the nature of the liquid additive, the transformation toward the most stable form can occur through different intermediate forms. Additionally, we observed that different amounts of liquid additive can control the time scale of a transformation, allowing a detailed observation of all the stages of the transformations. Finally, via ball milling we had access to several polymorphs of sofosbuvir and we present here for the first time the crystal structures for three of them, forms A, B, and 1.

Crystallization of bosutinib from a wide variety of solvents resulted in many distinct structures, and displayed difficulties to crystallize without solvent incorporation. We have prepared 23 solvated/hydrated and one anhydrous solid form and for 11 of them solved the crystal structures. With the goal of rationalizing the high propensity to solvate formation and exploring the stability relationships between the phases, the solid forms were characterized by different experimental and computational methods. Their stability was compared theoretically by calculating the packing efficiency in the crystal structures and the binding energy of the solvent in the crystal lattice using differential scanning calorimetry. Experimental studies were completed by analysing the forms' physical stability in solid state and in suspension and their intrinsic dissolution rate. The survey conducted on the inclusion compounds has resulted in basic understanding of the underlying factors affecting discriminative solvate formation: the solvents are utilised to satisfy previously unused hydrogen bonding capabilities in the host molecule.

The thermodynamic properties, phase behavior, and kinetics of polymorphic transformations of racemic (DL-) and enantiopure (L-) menthol were studied using a combination of advanced experimental techniques, including static vapor pressure measurements, adiabatic calorimetry, Tian-Calvet calorimetry, differential scanning calorimetry (DSC), and variable-temperature X-ray powder diffraction. Several concomitant polymorphs (α, β, γ, and δ forms) were observed and studied. A continuous transformation to the stable α form was detected by DSC and monitored in detail using X-ray powder diffraction. A long-term coexistence of the stable crystalline form with the liquid phase was observed. The vapor pressure measurements of both compounds were performed using two static apparatus over a temperature range from 274 K to 363 K. Condensedphase heat capacities were measured by adiabatic and Tian-Calvet calorimetry in the wide temperature interval from 5 K to 368 K. Experimental data of Land DL-menthol are compared mutually as well as with available literature results. The thermodynamic functions of crystalline and liquid L-menthol between 0 K and 370 K were calculated from the calorimetric results. The thermodynamic properties in the ideal-gas state were obtained by combining statistical thermodynamics and quantum chemical calculations based on a thorough conformational analysis. Calculated ideal-gas heat capacities and experimental data on vapor pressure and condensed-phase heat capacity were treated simultaneously to obtain a consistent thermodynamic description. Based on the obtained results, the phase diagrams of L-menthol and DL-menthol were suggested.

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.

The hydration/dehydration behavior of four distinct channel hydrates of sitagliptin L-tartrate (SLT) was investigated by thermoanalytical methods, dynamic vapour sorption analysis and variable humidity X-ray powder diffraction. The crystal structures were determined from single crystal and powder X-ray diffraction data. A survey of the forms revealed that SLT hydrates exhibit both stoichiometric and nonstoichiometric features demonstrating that the characterization of channel hydrates can be challenging as their behavior is not inevitably unambiguous. Upon dehydration, the parent hydrates retain their structures, and the lattices do not collapse; isostructural dehydrates are formed. The solved crystal structures of the packing polymorphs SLT phase 1 and phase 2 provide an effective basis to rationalize the observed hydration/dehydration pathways. The structures are dominated by infinite sheets formed by hydrogen tartrate anions, linked by hydrogen bonds. These layers separate the parallel, infinite chains of water molecules. The water molecules stabilize the structures by providing additional hydrogen bonds between the cation and the anion. This interaction substantiates the high affinity of water molecules to the API framework and explains the stoichiometric characteristics observed by solid state analytical methods. On the other hand, their non-stoichiometric character is evidenced by the non-destructive dehydration processes.

Effective desymmetrization in copper-catalyzed intramolecular C–H insertion reactions of α-diazo-β-oxosulfones in the formation of fused thiopyran dioxides is described for the first time. The use of a copper–bis­(oxazoline)–NaBARF catalyst complex system leads to formation of the major thiopyran dioxide stereoisomer with up to 98:2 dr and up to 98% ee. The effect of varying the bis­(oxazoline) ligand, copper salt, and site of C–H insertion on both diastereo- and enantioselectivities of these intramolecular C–H insertion reactions has been investigated. Similarly, desymmetrization in the formation of a fused cyclopentanone proceeds with up to 64% ee. These results represent the highest enantioselectivity reported to date in a copper-mediated desymmetrization through C–H insertion.

This article describes new developments in the CrystalCMP software. In particular, an automatic procedure for comparison of molecular packing is presented. The key components are an automated procedure for fragment selection and the replacement of the angle calculation by root-mean-square deviation of atomic positions. The procedure was tested on a large data set taken from the Cambridge Structural Database (CSD) and the results of all the comparisons were saved as an HTML page, which is freely available on the web. The analysis of the results allowed estimation of the threshold for identification of identical packing and allowed duplicates and entries with potentially incorrect space groups to be found in the CSD. computer programs 842 Rohlíček and Skořepová CrystalCMP: automatic comparison of molecular structures J. Appl. Cryst. (2020). 53, 841-847 Figure 1Graphical description of the method. Left: two crystal structures are represented by two molecular clusters of seven molecules (red and blue). The light-red points represent mass centers of molecules. Right: overlaid molecular clusters according to the central molecule. D c represents the average distance of centroids of the closest molecules in red and blue clusters and A d is the average angle of rotation between them.