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. 2020 Mar 16;25(6):1343.
doi: 10.3390/molecules25061343.

Improving Dissolution and Cytotoxicity by Forming Multidrug Crystals

Xufei Bian  1 , Lan Jiang  2 , Jing Zhou  1 , Xiaoshu Guan  1 , Jingyu Wang  1 , Peng Xiang  1 , Junyi Pan  1 , Xiangnan Hu  1
Affiliations

Improving Dissolution and Cytotoxicity by Forming Multidrug Crystals

Xufei Bian et al. Molecules. .

Abstract

Both rosiglitazone and metformin have effects on blood glucose regulation and the proliferation of liver cancer cells. Combination therapy with these two drugs is common and effective for the treatment of diabetes in the clinic, however, the application of these two drugs is influenced by the poor dissolution of rosiglitazone and the gastrointestinal side-effect of metformin resulting from a high solubility. The formation of a multidrug crystal form (Rsg-Met) by a solvent evaporation method can solve the solubility issue. Crystal structure data and intramolecular hydrogen bonds were detected by X-ray diffraction and infrared spectroscopy. Surprisingly, Rsg-Met shortens the time spent in solubility equilibrium and multiplies the dissolution rate of Rsg. Finally, we found that a low concentration of Rsg-Met enhanced the proliferation inhibition effect on liver cancer cells (HepG2, SK-hep1) compared with rosiglitazone, without affecting the human normal cell line LO2.

Keywords: Metformin; Rosiglitazone; crystal structure; cytotoxic effect; dissolution rate; multidrug crystal.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Chemical structures of the Rsg and Met with basic and acidic sites highlighted (*), respectively.
Figure 2
Figure 2
X-ray powder diffractograms of Rsg-Met, Met and Rsg.
Figure 3
Figure 3
Thermal ellipsoid figure for the Met ion and Rsg ion molecules drawn at 50% probability level.
Figure 4
Figure 4
Two dimensional layered structure connected by hydrogen bonds of Rsg-Met.
Figure 5
Figure 5
The FT-IR spectrum of Rsg, Met, and Rsg-Met.
Figure 6
Figure 6
Dissolution rate of Rsg and Rsg -Met in alkaline medium (pH = 6.8).
Figure 7
Figure 7
Detection of drug toxicity to (a) HepG2, (b) SK-hep1, and (c) LO2 cells by MTT assay treated with Rsg-Met, the mixture of Rsg and Met at the molar ratio of 1:1 and Rsg (* P < 0.05 and ** P < 0.01 versus the control group).
Figure 7
Figure 7
Detection of drug toxicity to (a) HepG2, (b) SK-hep1, and (c) LO2 cells by MTT assay treated with Rsg-Met, the mixture of Rsg and Met at the molar ratio of 1:1 and Rsg (* P < 0.05 and ** P < 0.01 versus the control group).
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