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

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).

Synthesis and structural characteristic of pyridine carboxylic acid adducts with squaric acid

“…These values are derived from HOMO and LUMO orbital energies. [60][61][62][63] A small orbital energy gap in a molecule refers to a soft molecule and is associated with high chemical reactivity, while a large orbital energy gap is related to low chemical reactivity and is connected with a hard molecule. The chemical potential (μ) of the molecule is equal to one-half of (E LUMO + E HOMO ), chemical hardness (η) is onehalf of the energy gap, global softness (σ) and electrophilicity (ω) are calculated by the formulas σ = 1/2η and ω = μ 2 /2η, respectively.…”

Multicomponent Crystals of Clozapine with Improved Solubility: A Combined Theoretical and Experimental Strategy on Coformer Screening and Structure–Property

“…Finally, the weak interactions in solid state substances, such as the numerical values of intermolecular hydrogen bonding interaction energy, were analyzed based on the quantum theory of atoms in molecules (QTAIM), 28−31 which can further understand the reasons for the formation of multicomponent crystal systems. 32 From the electrostatic potential surfaces, 33−37 not only the respective electrophilic and nucleophilic characteristics of CLZ and coformer can be observed but also the interaction modes between CLZ and coformer in multicomponent crystals can be explored. These variations in solubility, stability, and hygroscopicity are further justified in terms of their crystal structure and intermolecular interactions.…”

Experimental and Quantum Chemical Studies of Nicotinamide-Oxalic Acid Salt: Hydrogen Bonding, AIM and NBO Analysis

“…Oxalic acid (OXA) belongs to the family of carboxylic acid and is hydrophilic in nature, which can be produced by animals, plants, bacteria, and fungi ( Hodgkinson and Zarembski, 1968 ). In the carboxylic acid (COOH) functional group, both donor (OH) and acceptor (C═O) moieties are present and have a tendency of forming strong hydrogen bonds with heteroaromatic rings of a nitrogen atom ( Childs and Hardcastle, 2007 ; Verma et al, 2021 ). The structural analysis of nicotinamide–OXA (NIC–OXA) salt revealed the layered structure in which two NIC cations and one oxalate ion interact via strong and weak hydrogen bonds N + –H⋯O − and C–H⋯O, respectively ( Shimpi et al, 2017 ).…”