This study highlights the improved biopharmaceutical properties of quercetin with therapeutically active coformers: picolinic acid and nicotinamide, using cocrystallization, well supported by antioxidant, antihaemolytic and pharmacokinetic activities.

Cocrystallization by the solvent drop grinding technique has been employed successfully to generate highly water-soluble cocrystals of a poorly soluble nutraceutical hesperetin with different coformers, picolinic acid, nicotinamide, and caffeine. The miniscule amount of solvent (ethanol here), added during grinding, expectedly imparts high molecular mobility and efficiency to the method. On the basis of preliminary indication of the phase transformation by differential scanning calorimetry, these cocrystals were further characterized by Fourier transform-infrared and solid state NMR spectroscopy. However, the final structural confirmation of these distinct cocrystalline forms was provided by either single crystal X-ray diffraction (XRD) for HESP-PICO or powder XRD data in Material Studio software to generate the crystal structure of HESP-NICO and HESP-CAFF. The data revealed the existence of supramolecular synthons established by novel hydrogen bonds between hydroxyl groups of hesperetin with acid or amide carbonyl (CO), and/or amidic NH 2 , and/or pyridine/aromatic nitrogen (N aromatic ) of coformers. Dissolution studies of cocrystals in aqueous buffer showed maximum concentration of hesperetin to be nearly 4−5 times higher than the pure substance. This has led to optimized pharmacokinetics as exhibited by improved relative bioavailability (HESP-PICO:1.36, HESP-NICO:1.57, HESP-CAFF:1.60). Furthermore, the enhanced antioxidant and antihemolytic effect, coupled with the protective action against inflammation, signifies the development of a clinically useful and a pharmaceutically acceptable form of hesperetin.

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The present study involves the contribution of cocrystallization towards the modification of the biopharmaceutical parameters of poorly watersoluble plant-originated isoflavone, daidzein (DAID). The cocrystals were prepared with GRAS status coformers i.e., isonicotinamide, theobromine and cytosine using mechanochemical grinding and characterized by various analytical techniques (DSC, FT-IR, PXRD and solid-state NMR). Crystal structures were obtained from PXRD data using BIOVIA Materials Studio software and compared in terms of supramolecular motifs. An additional qualitative and quantitative insight into interactions between both components of the cocrystal illustrated the presence of OH⋯N and OH⋯O=C heterosynthons and revealed a stabilizing role of hydrogen bonding. The cocrystals were further evaluated for their solubility, intrinsic dissolution and in vivo profile. Solubility and dissolution studies of pure daidzein and its cocrystals, namely daidzein-isonicotinamide (DIS), daidzein-cytosine (DCYT) and daidzein-theobromine (DTB) exhibited an almost 2-fold improvement. Evaluation of maximum concentration (Cmax) of cocrystals reveals that the DIS cocrystal shows the highest Cmax of 1848.7 ng/ml followed by DCYT cocrystal (1614.9 ng/ml) and DTB cocrystal (1326.0 ng/ml) in comparison to DAID which has a Cmax 870.5 ng/ml. Each of these cocrystals showed significant enhancement in in vivo and in vitro activities in comparison to daidzein. Thus, this report suggests cocrystallization as a viable approach to resolve the solubility and bioavailability issues that circumvent the use of a therapeutically potential isoflavone, daidzein.