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. 2021 Apr 14;13(4):546.
doi: 10.3390/pharmaceutics13040546.

Improving the Solubility, Dissolution, and Bioavailability of Metronidazole via Cocrystallization with Ethyl Gallate

Jinhui Li  1 , Xinghui Hao  1 , Chenguang Wang  2 , Haiyan Liu  3 , Lianchao Liu  1 , Xin He  1 , Changquan Calvin Sun  2
Affiliations

Improving the Solubility, Dissolution, and Bioavailability of Metronidazole via Cocrystallization with Ethyl Gallate

Jinhui Li et al. Pharmaceutics. .

Abstract

Metronidazole (MTZ) is an antibacterial drug widely used for the treatment of protozoan and anaerobic infections in humans and animals. However, its low bioavailability necessitates the frequent administration of a high dose to attain an effective plasma concentration profile for therapy. To reduce the dose of MTZ, we have prepared a new cocrystal between MTZ and ethyl gallate (EG). The solid-state properties of MTZ-EG were characterized using complimentary techniques, including thermal, spectroscopic, microscopic, and X-ray crystallographic methods. The MTZ-EG cocrystal exhibits a higher solubility and faster dissolution than MTZ. The bioavailability of MTZ in rats was increased by 36% when MTZ-EG was used.

Keywords: cocrystal; dissolution; ethyl gallate; metronidazole; pharmacokinetics; solubility.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Chemical structures of (a) metronidazole (MTZ, MW= 171.15 g/mol) and (b) ethyl gallate (EG, MW= 198.17 g/mol).
Figure 1
Figure 1
Photographs of powders of (a) MTZ, (b) EG and (c) MTZ-EG. The color change after the two starting powders were grinded together is evident.
Figure 2
Figure 2
(a) PXRD patterns and (b) FT-IR spectra of MTZ-EG, MTZ and EG.
Figure 3
Figure 3
(a) Asymmetric unit, (b) hydrogen bonds between the two pairs, (c) 1D chain and (d) 3D packing of MTZ-EG viewed along the a axis (a 2D layer is highlighted).
Figure 4
Figure 4
(a) DSC and (b) TG curves of MTZ-EG, MTZ and EG.
Figure 5
Figure 5
The hot-stage image of MTZ-EG at different temperatures.
Figure 6
Figure 6
SEM images of (a) MTZ (×1000), (b) EG (×2000) and (c) MTZ-EG (×30).
Figure 7
Figure 7
(a) Powder dissolution rate and (b) IDR of MTZ-EG and MTZ.
Figure 8
Figure 8
Mean plasma concentration–time profiles of the MTZ and MTZ-EG after oral administration to rats (n = 5).
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