Nonequimolar Mixture of Organic Acids and Bases: An Exception to the Rule of Thumb for Salt or Cocrystal

Abstract

Formation of salt and/or cocrystal from organic acid-base mixtures has significant consequences in the pharmaceutical industry and its related intellectual property rights (IPR). On the basis of calculations using periodic dispersion corrected DFT (DFT-D2) on formic acid-pyridine adduct, we have demonstrated that an equimolar stoichiometric ratio (1:1) exists as a neutral cocrystal. On the other hand, the nonequimolar stoichiometry (4:1) readily forms an ionic salt. While the former result is in agreement with the ΔpKa rule between the base and the acid, the latter is not. Calculations reveal that, within the equimolar manifold (n:n; n = 1-4), the mixture exists as a hydrogen bonded complex in a cocrystal-like environment. However, the nonequimolar mixture in a ratio of 5:1 and above readily forms salt-like structures. Because of the cooperative nature of hydrogen bonding, the strength of the O-H···N hydrogen bond increases and eventually transforms into O(-)···H-N(+) (complete proton transfer) as the ratio of formic acid increases and forms salt as experimentally observed. Clearly, an enhanced polarization of formic acid on aggregation increases its acidity and, hence, facilitates its transfer to pyridine. Motion of the proton from formic acid to pyridine is shown to follow a relay mechanism wherein the proton that is far away from pyridine is ionized and is subsequently transferred to pyridine via hopping across the neutral formic acid molecules (Grotthuss type pathway). The dynamic nature of protons in the condensed phase is also evident for cocrystals as the barrier of intramolecular proton migration in formic acid (leading to tautomerism), ΔH(⧧)tautomer = 17.1 kcal/mol in the presence of pyridine is half of that in free formic acid (cf. ΔH(⧧)tautomer = 34.2 kcal/mol). We show that an acid-base reaction can be altered in the solid state to selectively form a cocrystal or salt depending on the strength and nature of aggregation.

Co-crystals, Salts, and Ionic Co-crystals of Ethanol and Ammonia

“…These results highlight the likely importance of the stoichiometry and the local chemical environment over simple rules based on pKa differences between the acidic and basic components. [72][73][74][75] I and others have predicted the occurrence of similar complete and partial proton transfer reactions in ammonia hydrates, [76][77][78] including the transformation of ammonia monohydrate (AMH)…”

Lithium fluoride recovery from cathode material of spent lithium-ion battery

“…These phenomena can be interpreted as follows: when HCOOH was increased, sufficient ionized H + species were generated to react with LiCoO 2 powder in the solid/liquid interphase, and when the interfacial H + concentration was reduced, the additional ionized H + species could diffuse outward. [23][24][25] Fig. 2 shows that the theoretical LiCoO 2 /HCOOH reactive ratio was 1 : 3.…”

The Challenge for Engineering Pharmaceutical Crystalline Solids: Scientific and Regulatory Affairs Perspectives for Crystal Structure Design and Prediction

“…The principle of cocrystallization refers to supramolecular chemistry phenomena of setup noncovalent intermolecular interactions (mainly all type of H-bonding, π•••π stacking) that, either based on the homomeric molecular recognition between the same molecules, or heteromeric recognitions between different ones, such as API, conformer and solvent, lead to formation the basic structural units, known as synthons that are exist as homosynthons and heterosynthons when in the former the identical functional groups (moieties) interact by H-bonds and in later when H-bonding is occurred between different, but complementary proton donor-acceptor functional groups. (17)(18)(19) Referring to the nature of H-bond as electron donoracceptor interactions (20) the charge distribution and the extent of its transfer indicate to its significant partial distribution in some molecular crystals that overlap across both PCCs and PSs, representing cocrystal-salt continuum. In order to avoid overlapping across the PCs, PSs and Solvates, performed analyzes of the entries in the Cambridge Structural Database (CSD), based on the distinguishing charge location in salts from neutral conformers and solvents, and the number of cocrystallized component per asymmetric crystal cell (Z), impact the definitions for three classes of PCCs, PSs and Solvates to be expanded to additional four classes, that are in total seven mutually exclusive subclasses: true salt, true solvate, true cocrystal (binary systems, Z R = 2), salt solvate, cocrystal solvate, cocrystal salts where naural API cocrystallize with ionic conformer or salt form of API is cocrystallized with neutral coformer (ternary systems, Z R = 3), and cocrystal salt solvate (quaternary systems, Z R = 4), all relevant in terms of frequency of occurrence.…”