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

Priya Verma,Anubha Srivastava,Karnica Srivastava,Poonam Tandon,Manishkumar R Shimpi

doi:10.3389/fchem.2021.708538

Abstract

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).

Highlights

Pharmaceutical cocrystals (Aakeröy and Sinha, 2018; Duggirala et al, 2016) have received interest in recent years from a variety of disciplines including chemical, material and pharmaceutical sciences
The ground state optimized structures of charge transfer interaction from unit 1 (CAF), CA, monomer and dimer model of CAF-CA cocrystal are shown in Supplementary Figures S4, S5, S6 and Figure 2, respectively
The spectral features confirmed the presence of intermolecular hydrogen bonding interactions (C51 O52···H40-O39), (C38 O41···H89-O88) and (O26-H27···N24-C22) in dimer model of cocrystal, resulting the red shift in C O mode of CAF; C O and O-H groups of CA along with elongation in bond lengths

Summary

INTRODUCTION

Pharmaceutical cocrystals (Aakeröy and Sinha, 2018; Duggirala et al, 2016) have received interest in recent years from a variety of disciplines including chemical, material and pharmaceutical sciences. In continuation to our previous work (Verma et al, 2019; Shukla et al, 2019), the present study includes the quantum chemical methods and spectroscopic techniques (Infrared, Raman spectra) to determine the vibrational spectroscopic signatures of monomer and dimer model of CAF-CA cocrystal. The density functional theory (DFT) methods (Geerlings et al, 2014) with Becke’s three parameters (Lee-Yang-Parr; B3LYP) (Lee et al, 1988; Becke, 1993; Parr, 1980) and standard 6–311++G (d, p) basis set (Andersson and Uvdal, 2005) were used to obtain the ground state optimized geometries of CAF, CA, monomer and dimer model of CAF-CA cocrystal by using Gaussian 09 program package (Frisch, 2009). The global quantum chemical indices; electronegativity (χ), chemical potential (μ), hardness (η), electrophilicity index (ω) and softness (S) are obtained by energies of HOMO, LUMO (EHOMO, ELUMO) and can be calculated by the equations as (Parr and Pearson, 1983; Geerlings et al, 2003; Chattaraj and Roy, 2007), χ

S 2η ω μ2 2η

RESULTS AND DISCUSSION

CONCLUSION

DATA AVAILABILITY STATEMENT