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Preparation, characterization and evaluation of cefixime ternary inclusion complexes formated by mechanochemical strategy

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Abstract

In an endeavor to ameliorate the solubility and subsequent oral bioavailability of Cefixime (CEF), a drug noted for its deficient water solubility, the formulation of ternary inclusion complexes was executed utilizing hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutylether-β-cyclodextrin (SBE-β-CD), in conjunction with N-methyl-D-glucaminet (MG). This development was realized through the application of a mechanochemistry technique, acknowledged for its “green” credentials. The complexes' physicochemical attributes were meticulously examined through various analytical techniques: Fourier-transform infrared spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC), Powder X-ray Diffractometry (XRD), and Scanning Electron Microscopy (SEM). Notably, the ternary complexes exhibited an uplift in apparent drug solubility, especially when juxtaposed with binary complexes. A prominent augmentation was perceived in the stability constant (Kc) and complexation efficiency (CE) when MG was integrated into the ternary complexes with HP-β-CD or SBE-β-CD. Further exploratory molecular docking and molecular dynamics studies underscored MG’s role in augmenting complex stability by serving as a bridge between CEF and cyclodextrins (CDs). The parallel artificial membrane permeability assay (PAMPA) indicated a conspicuous enhancement of CEF permeability in the ternary complexes relative to the control–free CEF. The particle size and zeta potential of the mechanochemically processed ternary complexes in liquid form were assessed using Dynamic Light Scattering (DLS). Moreover, in vivo evaluations revealed the ternary complexes to manifest notably superior oral bioavailability when compared to unadulterated CEF. Lastly, through the rapid storage assay, a heightened physicochemical stability was observed in the mechanochemically synthesized CEF ternary supramolecular inclusion complexes, compared to the pure drug, intimating a pioneering approach for the oral delivery of CEF, ensuring improved bioavailability.

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Abbreviations

CD:

Cyclodextrin

CEF:

Cefixime

CE:

Complexation efficiency

DLS:

Dynamic light scattering

DSC:

Differential scanning calorimetry

FT-IR:

Fourier-transform infrared spectroscopy

HP-β-CD:

Hydroxypropyl-β-cyclodextrin

Kc:

Stability constant

MD:

Molecular dynamics

MG:

N-methyl-d-glucaminet

PAMPA:

The parallel artificial membrane permeability assay

PDI:

Polydispersity index

PM:

Physical mixture

SBE-β-CD:

Sulfobutylether-β-cyclodextrin

SEM:

Scanning electron microscopy

XRD:

Powder X-ray diffractometry

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Acknowledgements

This research was supported by Natural Science Foundation of Jiangsu Food and Pharmaceutical Science College (Grant No. JSFP2019002), by grants HAB202240 from the Huai'an Municipal Science and Technology Bureau in Jiangsu, and the Major Basic Research Project of the Natural Science Foundation of the Jiangsu Higher Education Institutions (Grant No. 23KJA350001). We would like to thank Shuang Zheng (Jiangsu Food and Pharmaceutical Science College) for help with the bioavailability experiment.

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  1. College of Pharmaceutical Engineering, Jiangsu Food and Pharmaceutical Science College, Huaian, 223003, People’s Republic of China

    Rui** Kong, Lingwei Xu, Li Zhu & Yongrong Sun

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  1. Rui** Kong
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All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by RPK, LWX, LZ and YRS. The first draft of the manuscript was written by RPK, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Rui** Kong.

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Kong, R., Xu, L., Zhu, L. et al. Preparation, characterization and evaluation of cefixime ternary inclusion complexes formated by mechanochemical strategy. J Incl Phenom Macrocycl Chem 104, 51–71 (2024). https://doi.org/10.1007/s10847-023-01214-0

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