Energetic Competition in the Complexation Affinity of Paracetamol with Water and Oxalic Acid

The intermolecular interactions of active pharmaceutical ingredients (APIs) are the driving forces of API molecular activity in solid crystal structure and stability, in vivo receptor binding, and in environmental transport and persistence. In API manufacturing, complexation of the API with another molecule (cocrystal conformer) to create stable crystalline structures can be a useful tool, but the possibility of more energetically stable complexes forming instead of the target conformation can lead to undesired changes to the properties of the final product. Natural complexation of the API to cocrystal conformers in the environment can cause undesirable accumulation of the API. Using Density Functional Theory (DFT), the paracetamol and oxalic acid (PCA-OXA) cocrystal was studied to determine how hydrogen bonding dictates complex formation. Five different functionals were employed: B3LYP-D3, B3LYP-D3-BJ, M06-2X, M06-2X-D3, and B97-XD in combination with the aug-cc-pVDZ Dunning basis set. The hydrogen bonding sites of PCA-OXA were investigated to determine strength and overall contribution/competition of H-bonding formation during the initial stages of the nucleation process by relaxing the geometries and evaluating structural and energetic changes. Complexation and configuration energies were calculated for 1:1 PCA-OXA, PCA-Water, and OXA-Water complexes. Calculations were performed both in vacuum and in water environment (explicit and implicit solvation). Results showed significant shortening of the hydrogen bonds within the PCA-OXA complex with large changes in energy during complexation of oxalic acid with paracetamol. An overall analysis of all of the results collected for the PCA-OXA complexes indicates that sites 2 and 4 play the largest roles in the initial steps of the nucleation process with position 2 showing the most stable intermolecular interactions. It is expected that in an aqueous environment, there would be little to no energetic competition for PCA to form hydrogen bonds with other molecules.