Packing Interactions and Physicochemical Properties of Novel Multicomponent Crystal Forms of the Anti-Inflammatory Azelaic Acid Studied by X-ray and Solid-State NMR

Abstract

The reactivity of the active pharmaceutical ingredient azelaic acid (AA) with carboxylic acid, alcohol, amine, and amide based co-formers was screened. Five new multicomponent crystal forms of AA were obtained by liquid assisted grinding and conventional solution methods. The obtained forms: (i) a co-crystal with 4,4′-bipyridine (AA:BIP, 1), (ii) an anhydrous and an hydrated molecular salt with piperazine (AA:PIP, 2 and 3), and (iii) two anhydrous molecular salts with morpholine (AA:MORPH, 4) and 1,4-diazobicyclo­[2.2.2]­octane (AA:DABCO, 5), were fully characterized by X-ray diffraction and solid-state (SS) NMR. In all new forms the carboxylic-carboxylic R 2 2(8) homosynthon present in AA is broken, and NH2···OCOOH or +NH2···OCOO- hydrogen bonds (HBs) become the fundamental pillars in the new supramolecular arrangements. The X-ray structure of 4 exhibits a static disorder in the hydrogen atoms engaged in an HB between two COOH moieties of AA. Density functional theory geometry optimization of the hydrogen positions followed by GIPAW-DFT calculations of 1H chemical shifts showed that such disordered atoms refer to O···H···O hydrogens, roughly equidistant from both proton acceptor and donor atoms. 1H SSNMR detected unusually strong HBs associated with such disordered hydrogens through the presence of 1H resonances shifted to very high frequencies (up to ca. 20.1 ppm). These results clearly show the advantageous use of both X-ray diffraction and SSNMR techniques for structural elucidation. We concluded that the hydrated piperazine salt 3 readily converted to 2 at ambient RH and that their thermal behavior is strongly determined by both the supramolecular arrangement and strength of HB network. Piperazine salt 2 presents an improved aqueous solubility bestowing a promising opportunity to avoid the use of alcoholic solutions in the final formulations.

Hydrogen bonding networks in gabapentin protic pharmaceutical salts: NMR and in silico studies

“…In both systems, the 1 H resonance ascribed to + NH 3(GBP) ⋯ − O (METHA/ETHA) HB is observed at 7.7 and 7.2 ppm (Figure ), typical of protonated amines, suggesting proton transfer between GBP and METHA/ETHA molecules. Moreover, the 13 C CPMAS NMR spectra of GBP:METHA and GBP:ETHA (Figure ) exhibit resonances at 179.7 and 173.7 ppm, respectively, typical of carbonyl carbons of carboxylic acid groups . Overall, the results seem to indicate the amine groups are protonated by the strong Brønsted acids provided by the METHA and ETHA sulfonic group.…”

Periodic DFT Calculations—Review of Applications in the Pharmaceutical Sciences

“…Already, a term, "NMR crystallography", has been created [197][198][199] to describe an approach which combines performing experimental NMR and generating spectra with a DFT-based software in order to confirm or create the crystal structure of the studied system. It has been already proven that a research constructed in this way delivers more accurate data, compared to the separate application of these two techniques [200][201][202]. In some cases it is plainly stated that the proper designation of the hydrogen positions would not be possible at all, unless the combination of DFT and ssNMR had been used [203].…”

The Lisbon Supramolecular Green Story: Mechanochemistry towards New Forms of Pharmaceuticals

“…To tackle this issue, we decided to study some co-crystals and salts with the two techniques that allow their full characterization: X-ray diffraction and solid-state NMR (SSNMR). The latter, well established in pharma science, has been used as a complementary technique to probe the short-range local structure, helping the positioning of light atoms, such as hydrogens [60][61][62][63], and in particular to study packing interactions, such as hydrogen bonds (HBs), and even establish their relative strength [62,64].…”