Molecular Structure, Spectral Investigations, Hydrogen Bonding Interactions and Reactivity-Property Relationship of Caffeine-Citric Acid Cocrystal by Experimental and DFT Approach.

The pharmaceutical cocrystal of caffeine-citric acid (CAF-CA, Form II) has been studied to explore the presence of hydrogen bonding interactions and structure-reactivity-property relationship between the two constituents CAF and Citric acid. The cocrystal was prepared by slurry crystallization. Powder X-ray diffraction (PXRD) analysis was done to characterize CAF-CA cocrystal. Also, differential scanning calorimetry (DSC) confirmed the existence of CAF-CA cocrystal. The vibrational spectroscopic (FT-IR and FT-Raman) signatures and quantum chemical approach have been used as a strategy to get insights into structural and spectral features of CAF-CA cocrystal. There was a good correlation among the experimental and theoretical results of dimer of cocrystal, as this model is capable of covering all nearest possible interactions present in the crystal structure of cocrystal. The spectroscopic results confirmed that (O33-H34) mode forms an intramolecular (C25 = O28∙∙∙H34-O33), while (O26-H27) (O39-H40) and (O43-H44) groups form intermolecular hydrogen bonding (O26-H27∙∙∙N24-C22, O39-H40∙∙∙O52 = C51 and O43-H44∙∙∙O86 = C83) in cocrystal due to red shifting and increment in bond length. The quantum theory of atoms in molecules (QTAIM) analysis revealed (O88-H89∙∙∙O41) as strongest intermolecular hydrogen bonding interaction with interaction energy -12.4247 kcal mol-1 in CAF-CA cocrystal. The natural bond orbital analysis of the second-order theory of the Fock matrix highlighted the presence of strong interactions (N∙∙∙H and O∙∙∙H) in cocrystal. The HOMO-LUMO energy gap value shows that the CAF-CA cocrystal is more reactive, less stable and softer than CAF active pharmaceutical ingredients. The electrophilic and nucleophilic reactivities of atomic sites involved in intermolecular hydrogen bond interactions in cocrystal have been demonstrated by mapping electron density isosurfaces over electrostatic potential i.e. plotting molecular electrostatic potential (MESP) map. The molar refractivity value of cocrystal lies within the set range by Lipinski and hence it may be used as orally active form. The results show that the physicochemical properties of CAF-CA cocrystal are enhanced in comparison to CAF (API).

Study of molecular structure and hydrogen bond interactions in dipfluzine-benzoic acid (DIP-BEN) cocrystal using spectroscopic and quantum chemical method.

The purpose of this article is to predict the molecular structure of the cocrystal of dipfluzine-benzoic acid (DIP-BEN) through computational approach (DFT calculations) and validate it using vibrational spectroscopic studies. The molecular structure of the DIP-BEN cocrystal has been predicted by forming models on the basis of the active sites available to form H-bonds between dipfluzine (DIP) and benzoic acid (BEN). Conformational study has been performed and potential energy surface scans are plotted around the flexible bonds of the cocrystal molecule and three stable conformers have been obtained. Quantum theory of atoms in molecules (QTAIM) explains that all the interactions are medium and partially covalent in nature. Natural bond orbital analysis of the second order perturbation theory of the Fock matrix suggests that interactions LP (2) O2 → σ*(O74H75) and LP (2) F1 → σ* (O89H90) are responsible for the stabilization of the molecule. The HOMO and LUMO energies and electronic charge transfer (ECT) confirms that charge flows from BEN to DIP. Global reactivity descriptor parameters suggest that DIP-BEN cocrystal is softer, thus more reactive in comparison to DIP. Local reactivity descriptor parameter is used to predict reactive sites of the cocrystal. The experimental and theoretical results support the formation of cocrystal through strong hydrogen bond (O89H90⋯F1 and O74H75⋯O2) interactions present in cocrystal.