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Studies on charge transfer of enalapril maleate: from solid-state to molecular dynamics

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Abstract   

Introduction

Enalapril maleate is an antihypertensive ethyl ester pro-drug with two crystalline forms. A network of hydrogen bonds in both polymorphs plays an important role on solid-state stability, charge transfer process and degradation reactions (when exposed to high humidity, temperature and/or pH changes).

Computational Procedures

Supramolecular arrangement was proposed by Hirshfeld surface using the CrystalExplorer17 software and quantum theory of atoms in molecules. The electronic structure properties were calculated using the functional hybrid M06-2X with 6–311++G** base function employing diffuse and polarization functions to improve the description of hydrogen atoms on intermolecular interactions. Also, the H+ charge transfer between enalapril and maleate molecules was performed using Car-Parrinello molecular dynamics with the Verlet algorithm. In both simulations, the temperature of the ionic system was maintained around 300 K using the Nosé-Hoover thermostat and the electronic system evolved without the use of the thermostat.

Results

This work evaluates the effect of maleate on the structural stability of enalapril maleate solid state. The electronic structural analysis points out a partially covalent character for N1-H∙∙∙O7 interaction; and the molecular dynamic showed a decentralized hydrogen on maleate driving a decomposition by charge transfer process while a centered hydrogen driving the stabilization. The charge transfer process and the mobility of the proton (H+) between enalapril and maleate molecules was demonstrated using supramolecular modeling analyses and molecular dynamics calculations.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors are grateful to Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa de Goiás (FAPEG) and to Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for financial support. Also, the authors thank Prof. Dr. Ademir João Camargo of the Grupo de Química Teórica e Estrutural de Anápolis (Universidade Estadual de Goiás) for fruitful discussions. The data analysis to determine geometric parameters, RDF, MRT, among others, was performed through the GQTEA software, developed by him.

Funding

This work was supported by the Fundação de Amparo à Pesquisa do Estado de Goiás (FAPEG) and the Coordination for the Improvement of Higher Education Personnel (CAPES) through a scholarship for students and by the cluster of high-performance computers of the Grupo de Química Teórica e Estrutural de Anápolis.

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Authors and Affiliations

  1. Grupo de Química Teórica E Estrutural de Anápolis, Universidade Estadual de Goiás, Anápolis, GO, Brazil

    Ana Carolina M. Lourenço, Solemar S. Oliveira & Hamilton B. Napolitano

  2. Laboratório de Novos Materiais, Universidade Evangélica de Goiás, Anápolis, GO, Brazil

    Lauriane G. Santin, James O. Fajemiroye & Hamilton B. Napolitano

  3. Laboratório de Farmacologia de Produtos Naturais E Sintéticos, Instituto de Ciências Biológicas, Universidade Federal de Goiás, Goiânia, Brazil

    James O. Fajemiroye

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  1. Ana Carolina M. Lourenço
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  4. Solemar S. Oliveira
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Contributions

All authors contributed to the conception and design of the study and carried out the theoretical and analytical studies presented. The first version of the manuscript was written by Ana Carolina M. Lourenço, Lauriane G. Santin, James O. Fajemiroye, Solemar S. Oliveria, and Hamilton B. Napolitano. All authors commented and worked on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Hamilton B. Napolitano.

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Lourenço, A.C.M., Santin, L.G., Fajemiroye, J.O. et al. Studies on charge transfer of enalapril maleate: from solid-state to molecular dynamics. J Mol Model 29, 197 (2023). https://doi.org/10.1007/s00894-023-05597-2

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