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Improved Pharmaceutical Properties of Honokiol via Salification with Meglumine: an Exception to Oft-quoted ∆pKa Rule

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Abstract

Honokiol (HK), a BCS class II drug with a wide range of pharmacological activities, has poor solubility and low oral bioavailability, severely limiting its clinical application. In the current study, incorporating a water-soluble meglumine (MEG) into the crystal lattice of HK molecule was performed to improve its physicochemical properties. The binary mixture of HK and MEG was obtained by anti-solvent method and characterized by TGA, DSC, FTIR, and PXRD. The SCXRD analysis showed that two HK− molecules and two MEG+ molecules were coupled in each unit cell via the ionic interaction along with intermolecular hydrogen bonds, suggesting the formation of a salt, which was further confirmed by the XPS measurements. However, the ∆pKa value between HK and MEG was found to be less than 1, which did not follow the oft-quoted ∆pKa rule for salt formation. After salification with MEG, the solubility and dissolution rate of HK exhibited 3.50 and 25.33 times improvement than crystalline HK, respectively. Simultaneously, the powder flowability, tabletability and stability of HK-MEG salt was also significantly enhanced, and the salt was not more hygroscopic, and that salt formation did not compromise processability in that regard. Further, in vivo pharmacokinetic study showed that Cmax and AUC0-t of HK-MEG salt were enhanced by 2.92-fold and 2.01-fold compared to those of HK, respectively, indicating a considerable improvement in HK oral bioavailability.

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Abbreviations

APIs:

Active pharmaceutical ingredients

BCS:

Biopharmaceutics classification system

CCDC:

Cambridge Crystallographic Data Centre

CMC-Na:

Sodium carboxymethyl cellulose

DSC:

Differential scanning calorimetry

FTIR:

Fourier transform infrared spectroscopy

HK:

Honokiol

IDR:

Intrinsic dissolution rate

IS:

Internal standard

MEG:

Meglumine

PXRD:

Powder X-ray diffraction

SCXRD:

Single crystal X-ray diffraction

SVS:

Static vapor sorption

TGA:

Thermogravimetric analysis

XPS:

X-ray photoelectron spectroscopy

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Acknowledgements

This research was supported by National Natural Science Foundation of China (81873012, 82074029, 82104401), “Double First-Class” University Plan (CPU2018GY11, CPU2018GY27, 3342100010, 2632021ZD15), Natural Science Foundation of Jiangsu Province (SBK2020042291), China Postdoctoral Science Foundation (2020M671665, 2021M693517), Postdoctoral Research Grant of Jiangsu Province.

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  1. Xiaoshuang He and Yuanfeng Wei contributed equally to the experimental work.

Authors and Affiliations

  1. School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, People’s Republic of China

    Xiaoshuang He, Yuanfeng Wei, Shiru Wang, Yuan Gao, Shuai Qian, Zunting Pang & Weili Heng

  2. School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People’s Republic of China

    Jianjun Zhang

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Contributions

Xiaoshuang He: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; Drafting the work or revising it critically for important intellectual content.

Yuanfeng Wei: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; Drafting the work or revising it critically for important intellectual content.

Shiru Wang: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work.

Jianjun Zhang: Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published.

Yuan Gao: Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published.

Shuai Qian: Final approval of the version to be published; Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Zunting Pang: Final approval of the version to be published; Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Weili Heng: Final approval of the version to be published; Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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He, X., Wei, Y., Wang, S. et al. Improved Pharmaceutical Properties of Honokiol via Salification with Meglumine: an Exception to Oft-quoted ∆pKa Rule. Pharm Res 39, 2263–2276 (2022). https://doi.org/10.1007/s11095-022-03335-6

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