Herbal-derived puerarin-berberine cocrystal: Computational insights into mechanisms driving simultaneous enhanced...

Ge-Gen-Huang-Lian Decoction (GGHLD) is a traditional Chinese herbal formula with diverse pharmacological effects, primarily attributed to puerarin (PUE, from Pueraria lobata) and berberine (BER, from Coptidis rhizoma). However, the limited solubility and bioavailability of PUE and BER restrict their clinical efficacy.

To address these limitations, a novel PUE-BER cocrystal was engineered to enhance solubility, dissolution rate, phase stability, and in vivo bioavailability, with structural mechanisms elucidated through combined experimental and computational approaches.

A multidisciplinary comparative study integrating crystal engineering, physicochemical characterization, in vitro dissolution/stability testing, in vivo pharmacokinetics in rats, and computational lattice analysis.

The PUE-BER cocrystal was synthesized via crystal engineering and characterized by single crystal X-ray diffraction (SCXRD). Phase stability was evaluated by powder X-ray diffraction (PXRD) in water and pH 1.2/6.8 buffers. Equilibrium solubility and intrinsic dissolution rate (IDR) were determined for PUE and BER. Pharmacokinetics were assessed in Sprague-Dawley rats (n = 8/group) after oral administration of the cocrystal, pure compounds, and simulated GGHLD; plasma levels were quantified by UPLC-MS/MS, and pharmacokinetic parameters (C_max, AUC_0-24, T_max) calculated via non-compartmental analysis. Computational modeling included lattice energy, packing efficiency, hydrogen bond density, and channel dimensions using SCXRD data.

SCXRD revealed a low-density orthorhombic P 2₁ 2₁ 2₁ lattice (1.502 g/cm³) with 65 % packing efficiency, a dense hydrogen bond network (0.25 H-bonds/atom), and tubular solvent channels (7.655 Å interlayer spacing). In vitro, PUE solubility increased 2.0-fold in water, 1.5-fold in pH 1.2 buffer, and 1.3-fold in pH 6.8 buffer versus pure PUE, with significantly higher IDR; BER solubility was moderately reduced. PXRD confirmed phase stability across all media. In vivo, the cocrystal increased PUE C_max by 1.8-fold (104.1 ± 18.1 μg/L vs. 57.2 ± 7.2 μg/L), AUC_0-24 by 3.0-fold (384.4 ± 20.5 μg/L.h vs. 127.6 ± 10.8 μg/L.h), and prolonged T_max (1.4 ± 0.1 h vs. 1.1 ± 0.1 h), with secondary peaks indicating enterohepatic recirculation. For BER, C_max increased 1.2-fold (10.2 ± 0.9 μg/L vs. 8.8 ± 1.6 μg/L) and AUC_0-24 1.4-fold (55.3 ± 3.7 μg/L.h vs. 40.2 ± 2.8 μg/L.h). Compared with simulated GGHLD, the cocrystal markedly enhanced PUE bioavailability and modestly improved BER. Computational modeling predicted IDR enhancement due to reduced dissolution energy barriers facilitated by solvent accessible channels.

The PUE-BER cocrystal significantly improves PUE solubility, IDR, and oral bioavailability while maintaining stability and modestly enhancing BER exposure. Computational insights link these enhancements to optimized lattice architecture and solvent channels, establishing the cocrystal as a promising formulation strategy for GGHLD derived therapeutics.