**6. Applications of co-crystallization in improving nutraceutical solubility and bioavailability**

Nutraceutical APIs are of vital importance in all areas of modern drug development. Pharmacophores of natural origin not only improve drug development but can also be conjugated to enhance the physicochemical properties of already approved

#### *Co-Crystallization Techniques for Improving Nutraceutical Absorption and Bioavailability DOI: http://dx.doi.org/10.5772/intechopen.109340*

drugs. However, a relatively large percentage of nutraceuticals of therapeutic value exhibit poor water solubility and bioavailability [56]. Literary evidence cites numerous examples of nutraceuticals such as flavonoids and other essential nutrients as candidates for co-crystallization studies. For example, on formulating as a co-crystal, absorption and bioavailability of Protocatechuic acid a nutraceutical antioxidant was found to significantly enhance. This was achieved by employing pharmaceutical grade co-formers. Examples of pharmaceutical co-formers include caprolactam, isonicotinamide, isonicotinic acid, theophylline, nicotinamide, and theobromine. The process employed for co-crystallization of Protocatechuic acid was accomplished by gradually evaporating stoichiometric amounts of the nutraceutical and a co-former in a suitable solvent. Following which the co-crystals were extracted out from the mother liquors prior to evaporation of the entire solvent [57].

Another extensively envisaged class of nutraceuticals is the Flavonoid family. Of which quercetin is an important member. It is known to possess potent therapeutic properties. Quercetin is documented for its properties of free radical scavenging, enzyme inhibition (ornithine carboxylase, protein kinase, calmodulin), vasodilatation and platelet disaggregation. Despite having significant therapeutic priviledge, quercetin fails to achieve its required in vivo potency. Mostly because, in pure form quercetin is limited by, primarily due to its low solubility and consequent poor absorption in the gut and diminished bioavailability [58]. Also it was observed that on forming co-crystals with succinic acid, solubility and dissolution profile of quercetin was found to improve significantly [59]. The nutraceutical compound Hesperetin, is a well acclaimed antioxidant, antiallergic, antimutagenic, and anti-cancer agent [60]. Co-crystallization of hesperitin to improve its bio-efficacy is an extensively documented endeavor. Hesperetin was co-crystallized using pharmaceutically acceptable co-formers such as isonicotinamide and nicotinic acid. Co-crystallization of hesperetin with isonicotinamide forms a supramolecular synthon wherein isonicotinamide binds with the hesperitin nutraceutical by forming an OH---N hydrogen bond. Crystallization of hesperetin with nicotinic acid results in two 1:1 cocrystals in which the nicotinic acid exists as a zwitterionic state [61].

The nutraceutical molecule Pterostilbene is a popular component of traditional system of medicine. It is found expressed in several tree barks and a variety of berries, such as grapes. The physical stability and in-turn pharmaceutical viability of Pterostilbene can be significantly improved by co-crystallizing it with either caffeine or carbamazepine [62]. The co-crystals thus formed were of a 1:1 stoichiometric molar ratio. For characterization crystallographic (XRPD, single crystal) and thermoanalytical (TGA, DSC) techniques were used. Physical stability of the reported nutraceutical co-crystals with respect to relative humidity was also established [62].

Efficacy of the nutraceutical compound P-coumaric acid was improved by co-crystallizing it with nicotinamide. The co-former is a member of the vitamin B complex family. The consequent 2:1 (p-coumaric acid-nicotinamide) co-crystals were characterized by X-ray powder diffraction, thermal analyses, and spectroscopic techniques [63]. Derived from *Curcuma longa*, curcumin, is a pharmaceutically viable nutraceutical with excellent therapeutic attributes. However, as in context of most nutraceuticals, curcumin also suffers from poor water solubility, which limits its bioavailability. Co-crystallization of curcumin have been reported as excellent means of improving the molecules aqueous solubility. For the purpose salicylic acid and hydroxyquinol were employed as co-formers. It was observed that the curcuminsalicylic acid system forms an eutectic mixture, whereas the curcumin-hydroxyquinol system forms cocrystals. The reason for this predicament was attributed to the weak

intramolecular hydrogen bonding interactions in salicylic acid and strong hydrogen bonding interactions between hydroxyl ∙OH groups present in hydroxyquinol molecule and curcumin molecule. However, both curcumin-salicylic acid eutectic as well as curcumin-hydroxyquinol cocrystals demonstrated improved powder dissolution, absorption and bioavailability rates than parent curcumin [64].

Citric acid is an alpha acid that is naturally found concentrated in citrus fruits. Citric acid is commonly used as a food additive to provide acidity and sour taste to foods and beverages. It is also employed as prophylaxic for kidney stones by making urine more alkaline. Because of its excellent aqueous solubility, it is used as a co-former in pharmaceutical co-crystallization [65]. Many examples of citric acid has been cited in literature. For example, citric acid improves the solubility and dissolution profile of the poorly water-soluble drug, simvastatin [66]. Synthesis of atorvastatin calcium co-crystals for solubility enhancement was also achieved by employing citric acid and nicotinamide as co-formers [67]. Gossypol is a natural product occurring as biphenolic compound derived from the cotton plant (genus *Gossypium*). It is extensively envisaged for its pharmacological applications such as anticancer, antimicrobial, and antiviral properties. The nutraceutical is however limited because of high toxicity. This adverse effect of gossypol can be avoided by increasing the bioavailability of the compound so that the desired therapeutic effect can be achieved in a smaller dose. For the purpose, (−)-gossypol co-crystals with a C1–8 carboxylic acid or C1–8 sulfonic acid which are inhibitors of anti-apoptotic Bcl-2 family proteins have been created [68]. In recent years nutraceutical co-crystallization has achieved new heights. In a study, it was reported that conjugating cardiotonic drug milrinone with nutraceuticals such as syringic acid and gallic acid improves the *in-vitro* and *in-vivo* performances of cardiotonic drug milrinone [69].
