Abstract
Dexketoprofen trometamol is the tromethamine salt of dexketoprofen [(2S)-2-(3-benzoylphenyl)propanoic acid-2-amino-2-(hydroxymethyl)propane-1,3-diol], a nonsteroidal anti-inflammatory drug (NSAID) used for the treatment of moderate- to strong-intensity acute pain. The crystal structure of the hitherto sole known hydrate phase of dexketoprofen trometamol (DK-T_2H2O), as determined by single-crystal X-ray diffraction, is presented. The water molecules are arranged in dimers included in isolated sites and sandwiched between piles of trometamol cations. The molecular and crystal structures of DK-T_2H2O are analyzed and compared to those of the parent anhydrous crystal form DK-T_A. In both the crystal structures, all the potential H-bond donors and acceptor of the dexketoprofen and trometamol ions are engaged, and both the species crystallize in the P21 space group. However, during the DK-T_A➔DK-T_2H2O hydration process, the unique symmetry axis is not conserved, i.e., the ions are arranged in a different way with respect to the screw axis, even if the two crystal structures maintain structural blocks of DK anions and T cations. Quantum mechanical solid-state calculations provide some hints for the possible intermediate structure during the crystalline–crystalline hydration/dehydration process.
Highlights
Upon crystallization, a large number of active pharmaceutical ingredients (APIs) incorporate solvent molecules into their crystal lattice [1]
When a 1:2 Dexketoprofen trometamol (DK-T):H2 O molar ratio mixture was used, no visible changes take place, as provided by the photos reported in Figure S1; the X-ray Powder Diffraction (XRPD) pattern collected after 1 minute from the mixing shows that the hydrate form was formed (Figure S2, Supplementary Materials)
From visual analysis the 48 that thethe water molecules arefor sandwiched between columns of atrometamol cationsofparallel hydrate/anhydrous pairs, we found that in only cases, the overall molecular packing is comparable to the c axis direction, it should be expected that the hydration/dehydration process occurs along between and anhydrous crystals and the water molecules do not disrupt theanions molecular the c axis.the
Summary
A large number of active pharmaceutical ingredients (APIs) incorporate solvent molecules into their crystal lattice [1]. The solvate of a drug molecule usually presents different physical, chemical and mechanical properties with respect to its unsolvated species, which obviously has a significant impact on the stability, solubility and performance of the API, as well as on the related regulatory issues. For this phenomenon, i.e., the possibility for a given substance to exist in different crystal forms, with each one having a different elemental composition as a result of the inclusion of Crystals 2020, 10, 659; doi:10.3390/cryst10080659 www.mdpi.com/journal/crystals inclusion of one or more solvent molecules, several authors have used the terms “pseudopolymorphism” [2] or “solvatomorphism” [3].
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