Crystal engineering of green tea epigallocatechin-3-gallate (EGCg) cocrystals and pharmacokinetic modulation in rats

Adam J Smith, Padmini Kavuru, Kapildev K Arora, Sheshanka Kesani, Jun Tan, Michael J Zaworotko, R Douglas Shytle, Adam J Smith, Padmini Kavuru, Kapildev K Arora, Sheshanka Kesani, Jun Tan, Michael J Zaworotko, R Douglas Shytle

Abstract

The most abundant polyphenol in green tea, epigallocatechin-3-gallate (EGCg), has recently received considerable attention due to the discovery of numerous health-promoting bioactivities. Despite reports of its poor oral bioavailability, EGCg has been included in many dietary supplement formulations. Conventional preformulation methods have been employed to improve the bioavailability of EGCg. However, these methods have limitations that hinder the development of EGCg as an effective therapeutic agent. In this study, we have utilized the basic concepts of crystal engineering and several crystallization techniques to screen for various solid crystalline forms of EGCg and evaluated the efficacy of crystal engineering for modulating the pharmacokinetics of EGCg. We synthesized and characterized seven previously undescribed crystal forms of EGCg including the pure crystal structure of EGCg. The aqueous solubility profiles of four new EGCg cocrystals were determined. These cocrystals were subsequently dosed at 100 mg EGCg per kg body weight in rats, and the plasma levels were monitored over the course of eight hours following the single oral dose. Two of the EGCg cocrystals were found to exhibit modest improvements in relative bioavailability. Further, cocrystallization resulted in marked effects on pharmacokinetic parameters including Cmax, Tmax, area under curve, relative bioavailability, and apparent terminal half-life. Our findings suggest that modulation of the pharmacokinetic profile of EGCg is possible using cocrystallization and that it offers certain opportunities that could be useful during its development as a therapeutic agent.

Figures

Figure 1
Figure 1
Graphical representation of the new EGCg crystal forms.
Figure 2
Figure 2
(a) EGCg molecules in Form II forming sheets with channels. (b) A typical channel being occupied by solvent molecules in Form II.
Figure 3
Figure 3
(a) Illustration of a representative sheet formed by EGCg and water molecules in Form III. (b) Nitrobenzene molecule sandwiched between sheets of EGCg and water molecules in Form III.
Figure 4
Figure 4
(a) Crystal packing of Form IV; crinkled sheets with cavities were created via several O–H···O H-bonds. (b) Self-interpenetrated 3D structure of Form IV.
Figure 5
Figure 5
Intermolecular H-bonding between EGCg and INM molecules. Water molecules are removed for clarity.
Figure 6
Figure 6
(a) Asymmetric unit of EGCgNIC·9H2O cocrystal. (b) H-bonding between EGCg and NIC molecules.
Figure 7
Figure 7
Crystal packing in EGCg·INA·3H2O.
Figure 8
Figure 8
Illustration hydrogen bonding between EGCg and NAC molecules in EGCgNAC·xH2O cocrystal (water molecules are not shown in the figure for clarity).
Figure 9
Figure 9
Dissolution profiles of (a) EGCg and its cocrystals and (b) the cocrystals alone in water.
Figure 10
Figure 10
Pharmacokinetic profiles (mean plasma concentration + SEM versus time). The solid line in each panel represents the indicated EGCg cocrystal. The dashed lines are the EGCg control. There were three rats per group (n = 3). ★P < 0.05.

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