Combined virtual and experimental screening of multicomponent crystals of 2,4-dichlorophenoxyacetic acid

Abstract

2,4-Dichlorophenoxyacetic acid (2,4-D) is an herbicide and plant growth regulator that is widely applied in crop production. New multicomponent crystals of 2,4-D have been discovered by a combined virtual and experimental cocrystal screening to modify its physicochemical properties. In the virtual screening step, only the candidate compounds (coformers) simultaneously satisfying both criteria of conductor-like screening model for real solvents (COSMO-RS) and molecular complementarity (MC) analysis were screened out, and then, 25 out of the 53 coformers were successfully identified. In the following experimental screening step, 2,4-D was proven to generate 20 new solid phases with the respective coformer by liquid-assisted grinding (LAG). Six new multicomponent crystals of 2,4-D were synthesized and characterized, including five salts with piperazine (PZ), 2-benzimidazole (BZ), 3-aminobenzoic acid (ABA), p-phenylenediamine (PPD) and o-phenylenediamine (OPD), and one cocrystal with 2-ethoxybenzamide (EB). Their aqueous solubility and accelerated stability were also investigated. Overall, this work introduced a protocol that combines virtual screening tools based on COSMO-RS and MC analysis with the experimental LAG approach to screen solid forms of target compounds. The feasibility of this protocol was confirmed in the case of 2,4-D.