Crystals of Organic Acid–Base Complexes Defy the ΔpKa Rule Under Compression

Abstract

Crystals of organic acid–base adducts are major components in active pharmaceutical ingredients. These 1:1 adducts either form a cocrystal with a hydrogen-bonded motif or a salt by transfer of a proton from the acid to the base. As a rule of thumb, if the difference in pK_a between the protonated base and the acid (ΔpK_a) is < −1, a cocrystal is expected, while ΔpK_a > 4 leads to a salt, and in the intermediate zone (−1 ≤ ΔpK_a ≤ 4) both cocrystal and salt are observed. The preferred crystalline form for 1:1 adducts of pyridine, pyridazine, pyrazine, and furan with formic acid is elucidated using genetic algorithm-assisted first-principles crystal structure predictions. In agreement with the ΔpK_a rule, all the adducts stabilize as H-bonded cocrystals under ambient pressure. However, under isotropic pressure, formic acid transfers the protons to the three nitrogenous bases, forming salts of pyridinium formate, pyridazinium formate, and pyrazinium formate. External pressure is found to dictate the cocrystal–salt equilibrium. Critical pressure (P_c) required to induce cocrystal → salt conversion for formic acid··· pyridine/pyridazine/pyrazine is 3, 5, and 15 GPa, respectively. Compression is shown to enhance the electrostatic interactions between the molecules, leading to additional stabilization of the ionic configurations, namely, N⁺-H···O^– in salts vis-à-vis the neutral N–H···O motifs in the cocrystals. Violating the ΔpK_a rule, P_c overcomes the free energy required for the proton transfer (ΔG_PT) to stabilize the salts. The very high ΔG_PT = 177.9 kcal/mol for the furan···formic acid adduct prevents salt formation even at 30 GPa. Apart from thermodynamic and kinetic control during crystallization, pressure acts as a key control for organic acid–base adducts.