Structural and Computational Insights into Cocrystal Interactions: A Case on Cocrystals of Antipyrine and Aminophenazone

Abstract

This study aimed to gain insight into cocrystal interactions through solid-state characterization and theoretical computation. We formulated four novel cocrystalline phases of antipyrine (AN) and aminophenazone (AM) with coformer fumaric acid (FA) and saccharin (SA), respectively. The cocrystals were prepared by solvent-assisted grinding and slow evaporation. Solid-state characterization was conducted through differential scanning calorimetry, powder X-ray diffraction, and single-crystal X-ray diffraction. Crystal structure analysis showed that AN and SA created a 1:1 cocrystal. However, the proton transfer reaction caused AM and SA to produce a 1:1 salt through charge-assisted strong hydrogen-bonding interactions between the quaternary ammonium cationic group and the carbonyl group. As expected, the presence of two carboxyl groups with the same property in FA indicated that AN and AM formed 2:1 cocrystals with FA. Density functional calculations indicated that H bond interactions in cocrystals mainly involved pairwise interactions in the global maxima and minima sites on molecular electrostatic potential surfaces, but this rule did not apply to the salt. In addition, the H-bond interaction was further explained by using the highest occupied molecular orbital, lowest unoccupied molecular orbital, Hirshfeld surface, and mutual penetration distances of the van der Waals surface.

Improving Solubility and Avoiding Hygroscopicity of Tetrahydropalmatine by Forming a Pharmaceutical Salt Cocrystal via CAHBs

“…By calculating the Hirshfeld surface and two‐dimensional fingerprint of molecules, according to the size and color of spots near atoms, the intermolecular interaction can be revealed intuitively, and the size and proportion of different forces in crystal cells can be distinguished, So to further understand the role of hydrogen bonding and CAHBs in the crystal packing of THP‐SSA, the Hirshfeld surface and 2D fingerprints were predicted for each component using CrystalExplorer 3.1 software. [ 28–30 ] The charge‐assisted hydrogen bonds N + ‐H···O ‐ and hydrogen bonds C‐H···O formed between the N atom on the piperidine ring in THP and the oxygen atom in the sulfonic acid group on SSA have been mapped. On the surface of d norm and shown as bright red areas ( Figure ), this means that these interactions are closer than other contacts.…”

Experimental and Theoretical Investigation of Hydrogen-Bonding Interactions in Cocrystals of Sulfaguanidine

“…As the formation of hydrogen bonds is primarily driven by electrostatic interactions, molecular electrostatic potential surfaces (MEPSs) can illustrate electrostatic interactions by visualizing the potential hydrogen donor and acceptor sites. 21,22 Sarkar et al synthesized eight cocrystals of thiophene-based compounds and conducted MEPS calculations, indicating that the prediction of the homomeric and heteromeric synthons matched the experimental cocrystallization studies in seven out of eight cases. 23 In addition, QTAIM (quantum theory of atoms in molecules) analysis has been applied in the decoding of weak interactions in cocrystals, providing a pathway for comparing the experimental with the theoretically derived electron density based on the topological properties of the electron density (ρ).…”

Pharmaceutical Salts of Piroxicam and Meloxicam with Organic Counterions

“…Hirshfeld surface analyses and two-dimensional (2D) fingerprint plots were obtained using the CrystalExplorer 21.5 program . Density functional theory calculations using the Gaussian 09 program package employing the RB3LYP functional with the 6-31G (d, p) basis set were performed on PRM, MEL, and the six obtained crystals without conducting structural optimization. , The molecular orbitals were viewed using the Multiwfn 3.8 program and plotted using VMD. , …”