Crystals of Organic Acid-Bases Complexes Defy the pKa Rule Under Compression

Abstract

Crystals of organic acid-base adducts are major components in the active pharmaceutical ingredients (API). These 1:1 adducts either form a co-crystal with a hydrogen-bonded motif or a salt by transfer of proton from the acid to the base. As a rule of thumb if the difference in pKa between the protonated base and the acid (ΔpKa) is ≤ 1, a co-crystal is expected while ΔpKa > 3 leads to a salt. The preferred crystalline form for 1:1 adducts of pyridine, pyridazine, pyrazine and furan with formic acid are elucidated using genetic algorithm assisted first-principles crystal structure predictions (CSP). In agreement with the ΔpKa rule, all the adducts stabilize as H-bonded co-crystals 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 co-crystal – salt equilibrium. The critical pressure (Pc) required to induce co-crystal → salt conversion for formic acid… pyridine/pyridazine/pyrazine is 3 GPa, 5 GPa 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 co-crystals. Violating the ΔpKa rule, Pc overcomes the free-energy required for the proton-transfer (ΔGPT) to stabilize the salts. The very high ΔGPT = 177.9 kcal/mol for the furan…formic acid adduct prevents salt formation even at 30 GPa. Apart from the thermodynamic and kinetic control during crystallization, pressure acts as a key control for organic acid-base adducts.