Tuning the Pharmacokinetic Performance of Quercetin by Cocrystallization

Abstract

Quercetin (QUE) is a widely studied nutraceutical with a number of potential therapeutic properties. Although QUE is abundant in the plant kingdom, its poor solubility (≤20 μg/mL) and poor oral bioavailability have impeded its potential utility and clinical development. In this context, cocrystallization has emerged as a useful method for improving the physicochemical properties of biologically active molecules. We herein report a novel cocrystal of the nutraceutical quercetin (QUE) with the coformer pentoxifylline (PTF) and a solvate of a previously reported structure between QUE and betaine (BET). We also report the outcomes of in vitro and in vivo studies of QUE release and absorption from a panel of QUE cocrystals: betaine (BET), theophylline (THP), l-proline (PRO), and novel QUEPTF. All cocrystals were found to exhibit an improvement in the dissolution rate of QUE. Further, the QUE plasma levels in Sprague–Dawley rats showed a 64-, 27-, 10- and 7-fold increase in oral bioavailability for QUEBET·MeOH, QUEPTF, QUEPRO, and QUETHP, respectively, compared to QUE anhydrate. We rationalize our in vivo and in vitro findings as the result of dissolution–supersaturation–precipitation behavior.

Cocrystal of Naringenin and Norfloxacin: Crystal Transformation, Solubility, and Antibacterial and Anticancer Activities

“…1,2 In recent years, drug cocrystals have made great progress in modifying drug properties, such as improving the properties, stability, and solubility of drugs without affecting their pharmacological properties. 3,4 Since the first ionic cocrystal drug "sacubitril + valsartan" for the treatment of heart failure was approved by the FDA in 2015, cocrystals such as tramadol Hydrochloride− Celecoxib and egliptin-L-pyroglutamic acid have been discovered. The drug cocrystal of tramadol hydrochloride and celecoxib reduces the toxic and addictive properties of tramadol hydrochloride and enhances the analgesic effect of celecoxib.…”

“…Pharmaceutical cocrystals are novel solid forms based on the principles of crystal engineering and supramolecular chemistry, which consist of active pharmaceutical ingredients (APIs) and cocrystal formers (CCFs) bonded in a certain ratio within a crystal lattice through noncovalent bonds. , In recent years, drug cocrystals have made great progress in modifying drug properties, such as improving the properties, stability, and solubility of drugs without affecting their pharmacological properties. , Since the first ionic cocrystal drug “sacubitril + valsartan” for the treatment of heart failure was approved by the FDA in 2015, cocrystals such as tramadol Hydrochloride–Celecoxib and egliptin- l -pyroglutamic acid have been discovered. The drug cocrystal of tramadol hydrochloride and celecoxib reduces the toxic and addictive properties of tramadol hydrochloride and enhances the analgesic effect of celecoxib. , A drug cocrystal not only significantly improves the deficiencies in the physicochemical properties of two drugs but also realizes the concept of combined medicine with better efficacy, which makes it more promising and valuable in the pharmaceutical market.…”

Unraveling a Unique Metastable Phase of a Proxyphylline Cocrystal Exclusively Produced by Compressed Carbon Dioxide

“…Beyond the fact that cocrystals are solid forms different from the solid reactants they originate, literature also lately reported several examples of polymorphic cocrystals − and solvate cocrystals. − These are mostly produced by conventional methods. Though the potentiality of scCO 2 -based techniques to control polymorphism has been addressed for homocrystals, − only few articles reported polymorphism of cocrystals, , one for the production of a solvate, and none has ever reported the obtention of a cocrystal solvate.…”