Eliška Skořepová

Systematic solvate screening of trospium chloride: discovering hydrates of a long-established pharmaceutical

The ability of the antispasmodic agent trospium chloride (TCl) to form solvates was investigated by applying conventional solvate screening methods on 20 solvents. According to the solubility of TCl, different approaches were considered (slow evaporation, slurrying and anti-solvent addition). Five solvates, with the solvents methanol, acetonitrile, propionitrile, N,N-dimethylformamide, nitromethane and dihydrate, were identified and characterized by various analytical techniques. Moreover, a solvate with isopropyl alcohol and TCl sesquihydrate was prepared circumstantially outside the systematic screening. The structures of all the solvates were determined by single crystal X-ray diffraction. The reproducible forms were further characterized by powder X-ray diffraction and desolvation behaviour was observed by thermoanalytical (TGA/DSC) methods. Structural features of novel solvates and of previously described polymorphs and cocrystals of TCl were compared, presented by a tree diagram which classifies the structures according to their molecular packing.

Iodine salts of the pharmaceutical compound agomelatine: the effect of the symmetric H-bond on amide protonation

The search for new solid forms of an active pharmaceutical ingredient (API) is an important step in drug development. Often, an API has low water solubility, which then leads to low oral bioavailability. The problem can be solved by salt formation. One such API is agomelatine (AG), a melatonergic antidepressant. The aim of this work is to prepare iodide(s) of this compound. Three structurally different iodides of agomelatine were synthesized: agomelatine hydriodide trihydrate (AGI), agomelatine hemitriiodide (AG2I3) and agomelatine hemitriiodide iodine (AGI2). Their structures were solved from single-crystal X-ray diffraction data. In all of the structures, the agomelatine molecule was positively charged. Specifically, the amide oxygen was protonated, and in two of the structures (AG2I3 and AGI2), a symmetric hydrogen bond was formed. However, agomelatine is an amidic compound, and since amides are generally considered as neutral, in addition to SXRD, we present data from solid state NMR and the ΔpKa calculation to support the proton transfer and the salt formation.

CrystalCMP: an easy-to-use tool for fast comparison of molecular packing

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.

Studies on the crystal structure and arrangement of water in sitagliptin l-tartrate hydrates

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 non-stoichiometric 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.

Correction: Studies on the crystal structure and arrangement of water in sitagliptin L-tartrate hydrates

Correction for ‘Studies on the crystal structure and arrangement of water in sitagliptin L-tartrate hydrates’ by Eszter Tieger et al., CrystEngComm, 2016, 18, 3819–3831.

CCDC 1495585: Experimental Crystal Structure Determination

Related Article: Eszter Tieger, Violetta Kiss, Gyorgy Pokol, Zoltan Finta, Jan Rohlicek, Eliska Skořepova, Michal Dusek||CrystEngComm|||doi:10.1039/C6CE01834C