Early View e202400591
Research Article

Theoretical Study on Intramolecular Hydrogen Bonds of Flavonoid Cocrystals

Lisha Zhang

Lisha Zhang

Key Laboratory of Electrochemical Energy Storage and Energy Conversion of Hainan Province, Hainan Normal University, Haikou, 571158 P. R. China

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Wei Gao

Wei Gao

School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006 P. R. China

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Li Su

Li Su

Haikou Customs Technology Center, Haikou, 570311 P. R. China

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Wenying He

Wenying He

Key Laboratory of Electrochemical Energy Storage and Energy Conversion of Hainan Province, Hainan Normal University, Haikou, 571158 P. R. China

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Yize Wang

Yize Wang

Key Laboratory of Electrochemical Energy Storage and Energy Conversion of Hainan Province, Hainan Normal University, Haikou, 571158 P. R. China

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Minghui Hu

Minghui Hu

Key Laboratory of Electrochemical Energy Storage and Energy Conversion of Hainan Province, Hainan Normal University, Haikou, 571158 P. R. China

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Zixi Liu

Zixi Liu

Key Laboratory of Electrochemical Energy Storage and Energy Conversion of Hainan Province, Hainan Normal University, Haikou, 571158 P. R. China

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Yanling Liu

Yanling Liu

Key Laboratory of Electrochemical Energy Storage and Energy Conversion of Hainan Province, Hainan Normal University, Haikou, 571158 P. R. China

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Huajie Feng

Corresponding Author

Huajie Feng

Key Laboratory of Electrochemical Energy Storage and Energy Conversion of Hainan Province, Hainan Normal University, Haikou, 571158 P. R. China

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First published: 01 October 2024

Graphical Abstract

Disruption of intramolecular hydrogen bonds in flavonoids significantly increases the complexity of interactions–like hydrogen bonding and π-π stacking–between flavonoid active pharmaceutical ingredients and cocrystal formers, and among the flavonoid molecules themselves.

Abstract

This study investigates the role of intramolecular hydrogen bonds in the formation of cocrystals involving flavonoid molecules, focusing on three active pharmaceutical ingredients (APIs): chrysin (CHR), isoliquiritigenin (ISO), and kaempferol (KAE). These APIs form cocrystals with different cocrystal formers (CCFs) through intramolecular hydrogen bonding. We found that disruption of these intramolecular hydrogen bonds leads to decreased stability compared to molecules with intact bonds. The extrema of molecular electrostatic potential surfaces (MEPS) show that flavonoid molecules with disrupted intramolecular hydrogen bonds have stronger hydrogen bond donors and acceptors than those with intact bonds. Using the artificial bee colony algorithm, dimeric structures of these flavonoid molecules were explored, representing early-stage structures in cocrystal formation, including API-API, API-CCF, and CCF-CCF dimers. It was observed that the number and strength of dimeric interactions significantly increased, and the types of interactions changed when intramolecular hydrogen bonds were disrupted. These findings suggest that disrupting intramolecular hydrogen bonds generally hinders the formation of cocrystals. This theoretical study provides deeper insight into the role of intramolecular hydrogen bonds in the cocrystal formation of flavonoids.

Conflict of Interests

The authors declare no conflict of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.