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

Abstract

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.

Crystallisation of a salt hydrate with a complex solid form landscape

“…Further details can be found in a previous work. 5 It is of practical importance to determine whether a system is monotropic or enantiotropic to enable the choice of and control over the desired form. 13 Extensive efforts were made to evaluate the thermodynamic stability relationships using various approaches.…”

“…14), therefore concomitant crystallisation was frequently observed. The conformation of Phase 1 and Phase 2 is identical, 5 which corresponds to the small difference in the chemical potential between the polymorphs resulting in similar solubility profiles. 39 According to Fig.…”

“…SLT hemihydrates Phase 1, 8 Phase 2 9 and Phase 3 10 are claimed by Zentiva, while the fourth modification is described in a patent application filed by Merck, 11 referred to as a hemihydrate, therefore this phase is labeled Phase M. Phase 1 and Phase 2 -and probably Phase M as well -are packing polymorphs, 5 and their IR spectra are very similar, while Phase 3 is easily distinguishable (see the ESI †). As the forms are closely related, concomitant crystallisation was frequently observed.…”

“…To date, four polymorphs of SLT hemihydrate as well as one tetrahydrate have been identified, 5 but no anhydrous form or solvate has been discovered. The hemihydrate forms possess the same stoichiometry (water content) and as polymorphism denotes systems with the same chemical composition, 6,7 these forms are considered true polymorphs.…”

Structural variety of heterosynthons in linezolid cocrystals with modified thermal properties

“…All distances are given in Å . such non-stoichiometric hydrates are channel hydrates, in which water molecules may be loosely bound and as a result they are easily removable (Braun & Griesser, 2018;Tieger et al, 2016;Dudek et al, 2016). This however is not the case of LIN:3,4-DHBA:H 2 O cocrystal.…”