Zwitterionic Cocrystals of Flavonoids and Proline: Solid-State Characterization, Pharmaceutical Properties, and Pharmacokinetic Performance

Abstract

We utilized the concepts of crystal engineering to acquire cocrystals of D/L-proline with a variety of flavonoids and further evaluated the impact on solubility and pharmacokinetic of flavonoids. We have synthesized and characterized six D/Lproline cocrystals with flavonoids and their single crystal structures were revealed. The powder dissolution profiles were determined and the pharmacokinetic properties for Kae-L-Pro were analyzed and compared with the corresponding physical mixture. D/L-Proline was found to be a suitable coformer for a variety of structural similar flavonoids. This study may offer an alternative approach for the development of these widely used flavonoids.

Flavonoids with Glutathione Antioxidant Synergy: Influence of Free Radicals Inflow

“…These flavonoids are well-known natural antioxidants whose potential health benefits have attracted a great deal of interest in their studies as prospective drugs [ 7 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. Thus, a large and growing body of literature has been devoted to the modification of their biopharmaceutical and physicochemical properties, such as antioxidant activity and bioavailability, by crystal engineering [ 40 , 41 , 42 , 43 , 44 ], obtaining solid dispersions [ 45 , 46 , 47 , 48 , 49 ], and the development of new polymorphic forms [ 50 , 51 , 52 , 53 , 54 ]. This report is in line with the abovementioned works and aims to study the possible alteration of the antioxidant activity of flavonoids by combining them with other natural antioxidants.…”

Zwitterionic cocrystal of diclofenac and l-proline: Structure determination, solubility, kinetics of cocrystallization, and stability study

“…Cocrystal engineering is a method for developing the most desirable physicochemical properties of drugs. It is used to optimize drug solubility, dissolution, and absorption (Bhandaru et al, 2015;He et al, 2016). Most cocrystals of medicinal compounds that have been studied are either molecular or ionic (Duggirala et al, 2016).…”

“…The zwitterion co-former selected for use in this study was L-proline (PRO), which is a GRAS (Generally Regarded as Safe) compound and a popular amino acid used in cocrystal research (Tilborg et al, 2013;Othman et al, 2016;He et al, 2016;Liu et al, 2016). It is reported that the 5-membered ring "lateral chain" in PRO renders the molecular structure restricted and rigid (Tilborg et al, 2014).…”

“…It is reported that the 5-membered ring "lateral chain" in PRO renders the molecular structure restricted and rigid (Tilborg et al, 2014). Cocrystals of the following drugs and L-proline have been formulated and studied by single-crystal X-ray diffraction (SCXRD): naproxen (Tilborg et al, 2013), flurbiprofen (Silva et al, 2016), quercetin (He et al, 2016), and nitrofurantoin (He et al, 2016). The chemical structures of diclofenac acid (DFA) and L-proline (PRO) are presented in Fig.…”

Syntheses and crystal structures of hydrated and anhydrous 1:2 cocrystals of oxyresveratrol and zwitterionic proline

“…PRO has been used as a cocrystal former in various drugs and pharmacological active compounds because of its molecular rigidity and high solubility in water (Chesna et al, 2017;Surov et al, 2018;Tilborg et al, 2014). According to previous studies, the phenolic hydroxyl groups of flavonoids are able to form charge-assisted hydrogen bonds with the carboxylate moiety of PRO (He et al, 2016). Moreover, PRO could form a cocrystal with resveratrol [(E)-5-(4-hydroxystyryl)benzene-1,3-diol; RES; C 14 H 12 O 3 ], which is a close analogue of OXY…”