New crystalline berberine salt characterized by spectroscopy and quantum chemistry

Researchers have synthesized and characterized a new crystalline salt of berberine and 2-sulfobenzoate, finding that the two components crystallize in a 1:1 ratio and are held together through an unusual combination of weak and strong intermolecular hydrogen bonds. The laboratory study combined hydrothermal screening, crystal-structure analysis, powder X-ray diffraction, differential scanning calorimetry and vibrational spectroscopy. Its quantum-chemical component used density functional theory, quantum theory of atoms in molecules, reduced-gradient density analysis, natural bond orbital analysis and molecular-descriptor calculations to examine how formation of the salt changes molecular interactions and predicted chemical behavior.

The crystal-engineering strategy was intended to produce a new crystalline phase of berberine, a natural-product medicine associated with antimicrobial properties. Hydrothermal screening experiments yielded the berberine–2-sulfobenzoate salt, and diffraction and thermal analysis supported successful formation of the intended material. The structural investigation found no classic hydrogen bonds within the reported salt system.

Instead, weak C–H···O contacts stabilize the interaction between berberine and 2-sulfobenzoate, while a strong dimeric intermolecular hydrogen bond forms between two 2-sulfobenzoate molecules. Spectroscopic observations showed that vibrational modes in the berberine–2-sulfobenzoate salt shifted relative to the modes of the individual components, with the change evident in the Raman spectra. The researchers interpreted these shifts in conjunction with the crystal structure and computational results, showing that salt formation alters the molecular environment experienced by berberine and 2-sulfobenzoate.

For the density functional calculations, they selected a 1:2 berberine–2-sulfobenzoate system so that the model would cover a larger number of intermolecular hydrogen bonds. The modeled system was examined with quantum theory of atoms in molecules and reduced-gradient density analysis to interpret the strength and type of the molecular interactions, while natural bond orbital analysis was used to assess the stability of the system. The calculations also produced molecular electrostatic potential surfaces for berberine, 2-sulfobenzoate and the salt system, identifying regions associated with electrophilic, nucleophilic and neutral behavior.

Frontier molecular orbital and global-descriptor calculations indicated that the modeled berberine–2-sulfobenzoate salt was more chemically reactive than berberine alone. Molar refractivity was used to characterize drug-likeness behavior, and the authors described the combined evidence as confirmation of a new berberine salt with improved physicochemical properties. These reactivity and drug-likeness results are properties predicted or modeled computationally; the study does not establish clinical advantages for the salt.

The research is a laboratory synthesis and solid-state characterization of a crystalline material rather than a clinical investigation of its effects in people.

Subject of Research: Experimental and quantum-chemical characterization of a crystalline berberine–2-sulfobenzoate salt

Article Title: Synthesis, crystal structure, and characterization of a new crystalline berberine–2-sulfobenzoate salt, integrating vibrational spectroscopy and quantum chemical investigation

Article References: Srivastava, D. A., Prajapati, P., Shimpi, M. R., & Tandon, P. (2026). Synthesis, Crystal Structure and Characterization of a New Crystalline Berberine-2-Sulfobenzoate Salt, Integrating Vibrational Spectroscopy and Quantum Chemical Investigation. Frontiers in Chemistry, 14, 1971429. https://doi.org/10.3389/fchem.2026.1971429

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DOI: 10.3389/fchem.2026.1971429

Keywords: berberine, 2-sulfobenzoate, crystal synthesis, hydrogen bonding, vibrational spectroscopy, Raman spectroscopy, density functional theory, quantum chemistry, molecular reactivity, physicochemical properties, Synthesis, crystal