Cocrystals of Quercetin with Improved Solubility and Oral Bioavailability

Abstract

Flavonoids have been studied extensively due to the observation that diets rich in these compounds are associated with lower incidences of many diseases. One of the most studied flavonoids, quercetin, is also the most abundant of these compounds in the plant kingdom. Numerous therapeutic bioactivities have been identified in vitro. However, its in vivo efficacy in pure form is limited by poor bioavailability, primarily due to its low solubility and consequent low absorption in the gut. Cocrystallization has gained attention recently as a means for improving the physicochemical characteristics of a compound. Here, we synthesized and evaluated four new cocrystals of quercetin (QUE): quercetin:caffeine (QUECAF), quercetin:caffeine:methanol (QUECAF·MeOH), quercetin:isonicotinamide (QUEINM), and quercetin:theobromine dihydrate (QUETBR · 2H(2)O). Each of these cocrystals exhibited pharmacokinetic properties that are vastly superior to those of quercetin alone. Cocrystallization was able to overcome the water insolubility of quercetin, with all four cocrystals exhibiting some degree of solubility. The QUECAF and QUECAF·MeOH cocrystals increased the solubility of QUE by 14- and 8-fold when compared to QUE dihydrate. We hypothesized that this improved solubility would translate into enhanced systemic absorption of QUE. This hypothesis was supported in our pharmacokinetic study. The cocrystals outperformed QUE dihydrate with increases in bioavailability up to nearly 10-fold.

Physicochemical Characterization and <i>In Vitro</i> Dissolution Test of Quercetin-Succinic Acid Co-crystals Prepared Using Solvent Evaporation

“…8,9 It has been demonstrated that the formation of co-crystals can improve several properties of APIs, such as bioavailability, stability, hygroscopic properties, compressibility, and flowability. 5 Smith et al 10 successfully produced the 1:1 molar ratio cocrystal of Q-caffeine. Moreover, the co-crystals enhanced solubility up to 14-fold and up to 10-fold compared with those of Q and Q dihydrate, respectively.…”

Quercetin postconditioning attenuates myocardial ischemia/reperfusion injury in rats through the PI3K/Akt pathway

“…Therefore, agents that confer cardioprotection at the onset of reperfusion after myocardial ischemia provide a promising approach to attenuate myocardial I/R injury. Que is a member of the flavonoid family and is widely present in the plant kingdom (7). Que manifests a wide range of beneficial biological activites and can mediate cardioprotective effects (7,23).…”

“…Que is a member of the flavonoid family and is widely present in the plant kingdom (7). Que manifests a wide range of beneficial biological activites and can mediate cardioprotective effects (7,23). For example, an increased intake of Que has been suggested to reduce risk of cardiovascular diseases (23).…”

“…Quercetin (Que; 3,3′,4′,5,7-pentahydroxyflavone) is an important member of the flavonoid family that is present in plants and red wine (7). It is nontoxic and has a broad range of pharmacological and biological activities including antioxidative, anticarcinogenic, vasoprotective, anti-inflammatory, antidiabetic, and antiplatelet effects (8-11).…”

Nanobiotechnology Solutions againstAedes aegypti

“…However, the synthesis of four types of co-crystals led to an improvement in physicochemical and pharmacokinetic characteristics in comparison with free quercetin. 53 Other reports have described the use of cellulose nanocrystals (CNCs) as viral inhibitors. The first approach was carried out with unmodified CNCs derived from tunicates in a single model, and a decrease in phage infection of host E. coli was observed.…”