title: 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.
authors.affiliation: Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, USF Health College of Medicine, University of South Florida, Tampa, Florida, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Smith
authors.forename: Padmini
authors.initials: P
authors.lastname: Kavuru
authors.forename: Lukasz
authors.initials: L
authors.lastname: Wojtas
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Zaworotko
authors.forename: R Douglas
authors.initials: RD
authors.lastname: Shytle
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism*; D002110:Caffeine / Q000737:chemistry; D002152:Calorimetry, Differential Scanning; D055598:Chemical Phenomena; D018360:Crystallography, X-Ray; D019587:Dietary Supplements / Q000032:analysis*; D006207:Half-Life; D007408:Intestinal Absorption; D008297:Male; D000432:Methanol / Q000737:chemistry; D008968:Molecular Conformation; D009536:Niacinamide / Q000737:chemistry; D033362:Powder Diffraction; D011794:Quercetin / Q000097:blood / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013805:Theobromine / Q000737:chemistry
chemical_list: D000975:Antioxidants; D009536:Niacinamide; D002110:Caffeine; C027681:isonicotinamide; D011794:Quercetin; D013805:Theobromine; D000432:Methanol