Prof. Jinling Fan, Henan University of Science and Technology, et al.: Preparation and properties of photoglycyrrhizidine/cyclodextrin solid complex

2.
Analysis of the adclation rate, drug load and saturated solubility of GLD/2-SBE-β-CD solid clathrates

Effect of preparation method on GLD/2-SBE-β-CD solid complex

When the ratio of GLD to 2-SBE-β-CD is 1:1, the GLD/2-SBE-β-CD solid clathrate obtained by dry preparation and three wet preparation methods is shown in
Figure 2.

It can be seen from Table 3 that the inclusion rate and drug load of the clathrate obtained by the four preparation methods are not significant, the inclusion rate is 93.
33%~97.
68%, and the drug load is 11.
19%~11.
89%.
The clathrates prepared by different drying methods can significantly improve the saturated solubility of GLD (7 μg/mL of GLD without encapsulation) because CD has a hydrophilic surface structure, and its cavity inner wall is composed of carbon chain bone structure, which exhibits hydrophobicity, so it can form clathrates with poorly soluble compounds through van der Waals force or hydrogen bonding, thereby improving the solubility
of poorly soluble compounds 。 Except for the saturated solubility of the clathrate prepared by co-evaporation method that was significantly lower than that of the spray drying method, the saturated solubility of the clathrate prepared by the other three preparation methods (freeze drying method, spray drying method and kneading method) was not significantly different, all of which were greater than 83 mg/mL
.

Effect of feeding ratio on GLD/2-SBE-β-CD solid clathrates

It can be seen from Table 4 that the ratio of GLD to 2-SBE-β-CD substances increased, the inclusion rate decreased and the drug load increased
.
When the ratio of GLD to 2-SBE-β-CD substance was 1.
5:1, the inclusion rate was 86.
09% and the drug load was 22.
39%, compared with the volume ratio of GLD and 2-SBE-β-CD substances of 1:1 and 1:1.
5, the inclusion rate decreased by 7.
75% and 8.
58%, and the drug load increased by 88.
31% and 141.
14%,
respectively.

The above results show that different preparation methods have no significant effect on the cladding rate and drug load of GLD/2-SBE-β-CD solid complexes, but have a certain effect
on the water solubility of the clathrates.
Appropriately increase the ratio of GLD to 2-SBE-β-CD substances, although the inclusion rate decreases to a certain extent, but can significantly increase the drug load
.

3.
Characterization of GLD/2-SBE-β-CD solid clathrates

SEM results analysis

As shown in Figure 3, 2-SBE-β-CD is a spherical structure of different sizes, smooth surface and depression, which is consistent with the literature report.
GLD has a columnar crystal structure with a clear outline; Both spherical 2-SBE-β-CD and columnar GLD can be observed in the GLD/2-SBE-β-CD physical mixture, indicating a simple mixture
of the two 。 The morphological characteristics of GLD/2-SBE-β-CD clathrates are significantly different from physical mixtures, indicating that there is an interaction between host and guest molecules.
The external morphology of the clathrate is quite different depending on the preparation method: the clathrate prepared by freeze-drying method has a sheet structure with sharp edges; The clathrates prepared by kneading and co-evaporation are irregular block structures.
The clathrates prepared by spray drying method are spherical particles (less than 10 μm) with smooth surface and small particle size, and the particle size is significantly smaller than that prepared by freeze drying, kneading and co-evaporation
.

DSC results analysis

As shown in Figure 4, GLD has a sharp melting peak at 233 °C, which is the melting point
of the crystal.
2-SBE-β-CD has two peaks, and a short and wide endothermic peak appears at 40~160 °C, which is the endothermic peak released by water in its cavity.
There is an endothermic peak at 270 °C, which represents 2-SBE-β-CD decomposition, which is consistent with
the results reported in the literature.
The GLD/2-SBE-β-CD physical mixture had endothermic peaks at 233 °C and 270 °C, which was reflected in the simple superposition of GLD and 2-SBE-β-CD endothermic peaks, indicating that GLD still exhibited crystal characteristics
in the physical mixture.
There was no significant difference in the DSC diagram of GLD/2-SBE-β-CD solid clathrate prepared by freeze drying, spray drying, kneading and co-evaporation (the d curve in the figure was prepared and measured by freeze drying, and the rest was omitted).

。 Compared with 2-SBE-β-CD, the peak intensity of the first peak of the GLD/2-SBE-β-CD solid clathrate is reduced and shifted, indicating that the insertion of GLD into the cavity causes the migration of water molecules, and the shift is speculated to be the formation of an interacting hydrogen bond between GLD and 2-SBE-β-CD.
The second peak shifted to 276 °C, corresponding to the decomposition of 2-SBE-β-CD in GLD/2-SBE-β-CD solid complexes.
The absence of melting peaks of GLD in the DSC curve of the clathrate indicates that the crystalline GLD transitions to an amorphous state
due to the formation of GLD/2-SBE-β-CD solid clathrates.
These results all indicate that 2-SBE-β-CD has encapsulated GLD in the cavity to form a solid clathrate
.

Analysis of FTIR results

As shown in Figure 5, in the spectrum of GLD, a strong and wide peak appears at the 3 346 ^cm-1 wavenumber, which is the telescopic vibration of O—H; 1 518, 1 464 ^cm-1 wavenumber is the telescopic vibration of the aromatic ring C=C; The absorption peak
of -CH3 at the wavenumber of 2 964 and 2 920 ^cm-1 is -CH3.
In the spectrum of 2-SBE-β-CD, the characteristic band related to O—H telescopic vibration was exhibited before and after the 3 430 ^cm-1 wavenumber.
2 935 ^cm-1 wavenumber is the telescopic vibration of C-H; 1 653 ^cm-1 wavenumber is the bending vibration of water molecules; 1 163, 1 039 ^cm-1 wavenumber is the telescopic vibration
of C—O.
In the spectra of the GLD/2-SBE-β-CD physical mixture, the characteristic absorption peaks of GLD and 2-SBE-β-CD still existed, indicating that the physical mixture was a simple superposition of host and guest molecules, and that there was no or only weak interaction
between GLD and 2-SBE-β-CD.
There was no significant difference in the FTIR plots of GLD/2-SBE-β-CD solid complexes prepared by different methods (the d curve in the figure was prepared and measured by freeze-drying method, and the rest was omitted).

Analysis of GLD and 2-SBE-β-CD molecules

As shown in Figure 6, GLD molecules are able to enter the cavity of 2-SBE-β-CD intact
.
GLD and 2-SBE-β-CD molecules form two hydrogen bonds: the oxygen of the C2 sulfonic acid group in two adjacent glucose units of 2-SBE-β-CD forms a hydrogen bond with the hydrogen at the C2 position and C3 position O—H on the B ring of the GLD molecule, respectively; The hydrogen bonding distances are 2.
1 and 2.
3 Å
, respectively.
It was shown that hydrogen bonding is one of
the main forces of GLD interaction with 2-SBE-β-CD.

4.
GLD/2-SBE-β-CD solid clathrate analysis in simulated gastrointestinal fluid