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

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 R22(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.