Tuning the Pharmacokinetic Performance of Quercetin by Cocrystallization.

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.

Crystal Engineering of a Chiral Crystalline Sponge That Enables Absolute Structure Determination and Enantiomeric Separation.

Chiral metal-organic materials (CMOMs), can offer molecular binding sites that mimic the enantioselectivity exhibited by biomolecules and are amenable to systematic fine-tuning of structure and properties. Herein, we report that the reaction of Ni(NO3)2, S-indoline-2-carboxylic acid (S-IDECH), and 4,4'-bipyridine (bipy) afforded a homochiral cationic diamondoid, dia, network, [Ni(S-IDEC)(bipy)(H2O)][NO3], CMOM-5. Composed of rod building blocks (RBBs) cross-linked by bipy linkers, the activated form of CMOM-5 adapted its pore structure to bind four guest molecules, 1-phenyl-1-butanol (1P1B), 4-phenyl-2-butanol (4P2B), 1-(4-methoxyphenyl)ethanol (MPE), and methyl mandelate (MM), making it an example of a chiral crystalline sponge (CCS). Chiral resolution experiments revealed enantiomeric excess, ee, values of 36.2-93.5%. The structural adaptability of CMOM-5 enabled eight enantiomer@CMOM-5 crystal structures to be determined. The five ordered crystal structures revealed that host-guest hydrogen-bonding interactions are behind the observed enantioselectivity, three of which represent the first crystal structures determined of the ambient liquids R-4P2B, S-4P2B, and R-MPE.

Crystal engineering of ionic cocrystals comprising Na/K salts of hesperetin with hesperetin molecules and solubility modulation.

Hesperetin (HES) is a weakly acidic flavonoid of topical interest owing to its antiviral properties. Despite the presence of HES in many dietary supplements, its bioavailability is hindered by poor aqueous solubility (1.35 µg ml-1) and rapid first-pass metabolism. Cocrystallization has evolved as a promising approach to generate novel crystal forms of biologically active compounds and enhance the physicochemical properties without covalent modification. In this work, crystal engineering principles were employed to prepare and characterize various crystal forms of HES. Specifically, two salts and six new ionic cocrystals (ICCs) of HES involving sodium or potassium salts of HES were studied using single-crystal X-ray diffraction (SCXRD) or powder X-ray diffraction and thermal measurements. Structures of seven of the new crystalline forms were elucidated by SCXRD, which revealed two families of isostructural ICCs in terms of their crystal packing and confirmed the presence of phenol...phenolate (PhOH...PhO-) supramolecular heterosynthons. Diverse HES conformations were observed amongst these structures, including unfolded and folded (previously unreported) conformations. One ICC, HES with the sodium salt of HES (NESNAH), was scalable to the gram scale and found to be stable after accelerated stability testing (exposure to elevated heat and humidity). HESNAH reached Cmax after 10 min in PBS buffer 6.8 compared with 240 min in pure HES. In addition, relative solubility was observed to be 5.5 times greater, offering the possibility of improved HES bioavailability.

Conformational Trimorphism in an Ionic Cocrystal of Hesperetin.

We report the existence of conformational polymorphism in an ionic cocrystal (ICC) of the nutraceutical compound hesperetin (HES) in which its tetraethylammonium (TEA+) salt serves as a coformer. Three polymorphs, HESTEA-α, HESTEA-ß and HESTEA-γ, were characterized by single-crystal X-ray diffraction (SCXRD). Each polymorph was found to be sustained by phenol···phenolate supramolecular heterosynthons that self-assemble with phenol···phenol supramolecular homosynthons into C 3 2(7) H-bonded motifs. Conformational variability in HES moieties and different relative orientations of the H-bonded motifs resulted in distinct crystal packing patterns: HESTEA-α and HESTEA-ß exhibit H-bonded sheets; HESTEA-γ is sustained by bilayers of H-bonded tapes. All three polymorphs were found to be stable upon exposure to humidity under accelerated stability conditions for 2 weeks. Under competitive slurry conditions, HESTEA-α was observed to transform to the ß or γ forms. Solvent selection impacted the relationship between HESTEA-ß (favored in EtOH) and HESTEA-γ (favored in MeOH). A mixture of the ß and γ forms was found to be present following H2O slurry.

Supramolecular Synthon Promiscuity in Phosphoric Acid-Dihydrogen Phosphate Ionic Cocrystals.

Approximately 80% of active pharmaceutical ingredients (APIs) studied as lead candidates in drug development exhibit low aqueous solubility, which typically results in such APIs being poorly absorbed and exhibiting low bioavailability. Salts of ionizable APIs and, more recently, pharmaceutical cocrystals can address low solubility and other relevant physicochemical properties. Pharmaceutical cocrystals are amenable to design through crystal engineering because supramolecular synthons, especially those sustained by hydrogen bonds, can be anticipated through computational modeling or Cambridge Structural Database (CSD) mining. In this contribution, we report a combined experimental and CSD study on a class of cocrystals that, although present in approved drug substances, remains understudied from a crystal engineering perspective: ionic cocrystals composed of dihydrogen phosphate (DHP) salts and phosphoric acid (PA). Ten novel DHP:PA ionic cocrystals were prepared from nine organic bases (4,4'-bipyridine, 5-aminoquinoline, 4,4'-azopyridine, 1,4-diazabicyclo[2.2.2]octane, piperazine, 1,2-bis(4-pyridyl)ethane, 1,2-bis(4-pyridyl)xylene, 1,2-di(4-pyridyl)-1,2-ethanediol, and isoquinoline-5-carboxylic acid) and one anticonvulsant API, lamotrigine. From the resulting crystal structures and a CSD search of previously reported DHP:PA ionic cocrystals, 46 distinct hydrogen bonding motifs (HBMs) have been identified between DHP anions, PA molecules, and, in some cases, water molecules. Our results indicate that although DHP:PA ionic cocrystals are a challenge from a crystal engineering perspective, they are formed reliably and, given that phosphoric acid is a pharmaceutically acceptable coformer, this makes them relevant to pharmaceutical science.

Screening and Preparation of Cocrystals: A Comparative Study of Mechanochemistry vs Slurry Methods.

Cocrystals of biologically active molecular compounds have potential utility in drug products thanks to their effect upon physicochemical properties such as aqueous solubility. The fact that control of cocrystallization can be more challenging than crystallization of single-component crystals means that systematic studies that address the methodology of cocrystal screening, production, and purification are a topical subject. We previously reported a comparison of slow evaporation vs mechanochemistry for a library of 25 molecular cocrystals. Herein, we compare the previously reported mechanochemistry results (solvent-drop grinding (SDG) with eight solvents) with new results obtained from slurrying in five preferred solvents using the same library of 25 cocrystals. Overall, both methods were found to be effective with slurrying and SDG being 94 and 78.5% successful, respectively. Importantly, 96% of the cocrystals formed via slurrying were observed to be free of starting materials (coformers) according to powder X-ray diffraction (PXRD), whereas this was the case for only 72% of the cocrystals prepared by SDG. Slurrying therefore compared favorably with mechanochemistry, which tends to leave small amounts of unreacted coformer(s) as byproducts, and solution crystallization, which often affords crystals of the least soluble coformer because it can be difficult to control the saturation of three or more solids. Perhaps the most interesting and surprising result of this study was that water slurrying proved to be highly effective, even for low-solubility coformers. Indeed, water slurrying was found to be effective for 21 of the 25 cocrystals studied.