Context <p>Cocrystal screening is an important stage in pharmaceutical research for improving the physical characteristics of active pharmaceutical ingredient (API). This work offers the selection of potential conformers by computational tools rather than expensive experimental methods. The cocrystal screening results provide the vital information about the stability of the interaction between coformer and API. In this study, the screening of cocrystals of APIs riparin (I-III) has been performed with the six coformers that contain a carboxylic group, such as maleic acid, malonic acid, oxalic acid, salicylic acid, benzoic acid and succinic acid. The pairing energy for the intermolecular hydrogen bonding interaction O–H…O is found to be significant as compared to the N–H…O interaction from the electrostatic potential surface analysis. As recommended by the ESP analysis, the cocrystal of riparins (I–III) is created with the selected coformers via intermolecular hydrogen bonding O–H…O. The interaction energy is derived from the ground state energy of the optimized geometry, and the strength of the hydrogen bond interaction is also evaluated. The riparin (I-III) maleic acid cocrystals have higher interaction energy and exhibit the strongest hydrogen bond as compared to other cocrystals. The riparin III-maleic acid cocrystal shows enhanced chemical reactivity due to the lowest energy gap of the frontier molecular orbitals.</p> Method <p>The coformers, active pharmaceutical ingredients (APIs), and cocrystals were optimized by employing density functional theory in the Gaussian 16 software package. We have utilized the B3LYP exchange and correlation functional along with the 6–311 + + G(d,p) basis set. The interaction's pairing energy was evaluated by taking the product of the hydrogen bond donor (<InlineEquation ID="IEq1"> <EquationSource Format="TEX">${\alpha }_{max}$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mi>α</mi> <mrow> <mi mathvariant="italic">max</mi> </mrow> </msub> </math></EquationSource> </InlineEquation>) and acceptor (<InlineEquation ID="IEq2"> <EquationSource Format="TEX">${\beta }_{max}$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mi>β</mi> <mrow> <mi mathvariant="italic">max</mi> </mrow> </msub> </math></EquationSource> </InlineEquation>) parameters associated with the global maximum and minimum electrostatic potential, which were mapped onto the molecular surface. This data was obtained from the Multiwfn 8.0 and VMD 1.9.1 software packages. The interaction energy in the cocrystal formation was obtained by subtracting the ground state energy of the conformer and API from that of the cocrystal. The strength of intermolecular hydrogen bonding and the stabilization energy associated with cocrystal formation were assessed using the quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis. GaussView 06 software was utilized to visualize the optimized structures and frontier molecular orbitals.</p>

Hydrogen bond strength for riparins (I-III) cocrystals with carboxylic acid group coformers: ESP, QTAIM, and NBO analytical screening

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发表日期：

2025年12月3日

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Tirth Raj Paneru,
Poonam Tandon,
Bhawani Datt Joshi

摘要

Context

Cocrystal screening is an important stage in pharmaceutical research for improving the physical characteristics of active pharmaceutical ingredient (API). This work offers the selection of potential conformers by computational tools rather than expensive experimental methods. The cocrystal screening results provide the vital information about the stability of the interaction between coformer and API. In this study, the screening of cocrystals of APIs riparin (I-III) has been performed with the six coformers that contain a carboxylic group, such as maleic acid, malonic acid, oxalic acid, salicylic acid, benzoic acid and succinic acid. The pairing energy for the intermolecular hydrogen bonding interaction O–H…O is found to be significant as compared to the N–H…O interaction from the electrostatic potential surface analysis. As recommended by the ESP analysis, the cocrystal of riparins (I–III) is created with the selected coformers via intermolecular hydrogen bonding O–H…O. The interaction energy is derived from the ground state energy of the optimized geometry, and the strength of the hydrogen bond interaction is also evaluated. The riparin (I-III) maleic acid cocrystals have higher interaction energy and exhibit the strongest hydrogen bond as compared to other cocrystals. The riparin III-maleic acid cocrystal shows enhanced chemical reactivity due to the lowest energy gap of the frontier molecular orbitals.

Method

The coformers, active pharmaceutical ingredients (APIs), and cocrystals were optimized by employing density functional theory in the Gaussian 16 software package. We have utilized the B3LYP exchange and correlation functional along with the 6–311 + + G(d,p) basis set. The interaction's pairing energy was evaluated by taking the product of the hydrogen bond donor ( ${\alpha }_{max}$ $α_{\max}$ ) and acceptor ( ${\beta }_{max}$ $β_{\max}$ ) parameters associated with the global maximum and minimum electrostatic potential, which were mapped onto the molecular surface. This data was obtained from the Multiwfn 8.0 and VMD 1.9.1 software packages. The interaction energy in the cocrystal formation was obtained by subtracting the ground state energy of the conformer and API from that of the cocrystal. The strength of intermolecular hydrogen bonding and the stabilization energy associated with cocrystal formation were assessed using the quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis. GaussView 06 software was utilized to visualize the optimized structures and frontier molecular orbitals.