Crystal Engineering of Green Tea Epigallocatechin-3-gallate (EGCg) Cocrystals and Pharmacokinetic Modulation in Rats

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.

Cocrystallization of Nutraceuticals

“…improving key physicochemical properties such as physical stability, 51,64,87,88,92,97,146 solubility 61,62,87,88,96,112 and bioavailability 96,112 of nutraceuticals, as well as of APIs. A summary of these studies is provided in Tables 4-5 and case studies discussed in more detail below.…”

Physical Stability Enhancement and Pharmacokinetics of a Lithium Ionic Cocrystal with Glucose

“…Different gavage vehicles are known produce PK changes for orally administered APIs. 46 Formulation can also drastically impact the oral PK of cocrystals and a recent study revealed that dosing of unformulated cocrystals might result in a perceived failure to produce accurate PK modulation. 9c 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 CrystEngComm.…”

Co-crystals and co-crystal hydrates of vanillic acid

“…[1][2][3] The supramolecular synthon approach where complementary functional groups pair up is key in the design of new crystal structures. [4][5][6] In particular the sythons involving carboxylic acid and nitrogen-containing functionalities have received much attention.…”