Can We Identify the Salt–Cocrystal Continuum State Using XPS?

Abstract

X-ray photoelectron spectroscopy (XPS) is used to understand the nature of acid–base crystalline solids, to know whether the product is a salt (proton transfer, O–···H–N+) or a cocrystal (neutral adduct, O–H···N). The present study was carried out to explore if intermediate states of proton transfer from COOH to nitrogen (the proton resides between hydrogen bonded to O and N, O···H···N, quasi state) can be differentiated from a salt (complete proton transfer, N+–H··· O–) and cocrystal (no proton transfer, O–H···N) using N 1s XPS spectroscopy. The intermediate states of proton transfer arise when the pK a difference between the acid and the conjugate base is between −1 and 4, −1 < ΔpK a < 4, a situation common with COOH and pyridine functional groups present in drug molecules and pharmaceutically acceptable coformers. Complexes of pyridine N bases with aromatic COOH molecules in nine salts/cocrystals were cocrystallized, and their N 1s core binding energies in XPS spectra were measured. The proton state was analyzed by single-crystal X-ray diffraction for confirmation. Three new complexes were crystallized and analyzed by XPS spectra (without knowledge of their X-ray structures), to assess the predictive ability of XPS spectra in differentiating salt–cocrystal intermediate states against the extremities. The XPS results were subsequently confirmed by single-crystal X-ray data. Complexes of 3,5-dinitrobenzoic acid and isonicotinamide in 1:1 and 1:2 ratios exist as a salt and a salt–cocrystal continuum, respectively, as shown by the N 1s core binding energies. The proton states of the crystalline solids by XPS are in good agreement with the corresponding crystal structures. Other complexes, such as those of 3,5-dinitrobenzoic acid with 1,2-bis­(4-pyridyl)­ethylene, exhibit a salt–cocrystal continuum, maleic acids with 1,2-bis­(4-pyridyl)­ethylene and acridine are salts, 2-hydroxybenzoic acid and acridine is a salt, and the complex of 3,5-dinitrobenzoic acid and 3-hydroxypyridine is a salt and salt–cocrystal continuum, while fumaric acids with 1,2-bis­(4-pyridyl)­ethylene and acridine are cocrystals. Furthermore, three new acid–base complexes of 3,5-dinitrobenzoic acid with phenazine, 4-hydroxypyridine, and 4-cyanopyridine were studied initially by XPS and then confirmed by X-ray diffraction. In summary, since the N 1s binding energies cluster in a narrow range as cocrystals (398.7–398.9 eV) and salts (400.1–401.1 eV), it is clearly possible to differentiate between cocrystals and salts, but the salt–cocrystal continuum values in XPS spectra are clustered in an intermediate range of cocrystals and salts but overlap with those of cocrystal or salt binding energies.

Recent Advances in Pharmaceutical Cocrystals: From Bench to Market

“…Srinu et al studied the possibility of differentiating salt–cocrystal continuum from salt and cocrystal by using XPS. They found that it is not possible to differentiate between the salt–cocrystal continuum from salt and cocrystal because of the lack of clear distinction between intermediate binding energies and salt–cocrystal binding energy values ( Tothadi et al, 2021 ). Hence, it can be concluded that every technique has some characteristic features which are different from others, and to characterize a cocrystal sample, every technique can bring conclusive information about cocrystals.…”

Unexpected Salt/Cocrystal Polymorphism of the Ketoprofen–Lysine System: Discovery of a New Ketoprofen–l-Lysine Salt Polymorph with Different Physicochemical and Pharmacokinetic Properties

“…Contrary to salts, however, in which the molecules within the crystal lattice predominantly interact through ion pairing [4], in cocrystals, the components are combined via other noncovalent interactions (e.g., hydrogen bonds, van der Waals forces, π-stacking, and electrostatic interactions) in a definite stoichiometric ratio [5,6]. Thus, particularly when hydrogen bonds (HBs) are involved, cocrystals can be distinguished from salts because, in the latter, a complete proton transfer occurs along the axis of the HB interaction between the API and the molecular partner, whereas, in cocrystals, a neutral adduct is formed by the components [7].…”

Cocrystals Based on 4,4’-bipyridine: Influence of Crystal Packing on Melting Point

“…In fact, there is a rule of thumb that dictates, depending on the ∆pKa value (∆pKa = pKa[protonated base] -pKa[acid]), the proton will remain in the acid (∆pKa < 0) resulting in a cocrystal, or it will be placed in the base (∆pKa > 3.75) obtaining a salt [17][18][19]. In addition, there are intermediate cases where ∆pKa is between 0 and 3.75 and the pKa rule cannot be applied successfully, since the location of the proton is sometimes challenging because it is between the acid and the base forming a salt-cocrystal continuum [20,21].…”

“…, x FOR PEER REVIEW 2 of 16 < 0) resulting in a cocrystal, or it will be placed in the base (ΔpKa > 3.75) obtaining a salt [17][18][19]. In addition, there are intermediate cases where ΔpKa is between 0 and 3.75 and the pKa rule cannot be applied successfully, since the location of the proton is sometimes challenging because it is between the acid and the base forming a salt-cocrystal continuum [20,21]. Among all cocrystals, those containing carboxylic acids are widely studied because they are commonly found in APIs [22][23][24].…”