**3. Components of nutraceutical co-crystals**

Essentially, a nutraceutical co-crystal is made up of naturally occurring API and the conformer required to induce co-crystallization. In **Figure 2** we have illustrated the composition of a typical nutraceutical co-crystal. Nutraceuticals are strong candidates for co-crystallization [24]. The term nutraceutical was coined by conjoining

**Figure 2.** *Components of nutraceutical co-crystals.*

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

two terms "nutrition" and "pharmaceutics." It was originally described by DeFelice in 1989 as food (or component of a food) that gives medicinal or health benefits, including the prevention and/or treatment of an illness [25]. Since the definition appeared to be extremely generalized, a definition citing differences between dietary supplements, nutraceuticals, and functional foods were stated [26]. In the light of this, nutraceuticals were defined to included compounds obtained from minerals, vitamins, amino acids, therapeutic herbs or other botanicals, dietary substances, concentrates, metabolites, isolates, extricates, or any combinations of the aforementioned. Subsequently, nutraceuticals became an umbrella term for naturally occurring molecules that are employed for both their nutritional value as well as therapeutic efficacy [27]. Currently, a vast number of nutraceuticals are used for their therapeutic and prophylactic properties in both allopathic as well as alternative systems of medicine [28]. The major impediment in active use of APIs of natural origin is the lack the characteristics essential for viable drug formulation. Nutraceuticals are often observed to have diminished aqueous solubility, decreased dissolution rate, poor permeation, and low absorption through biological membranes [29].

Co-crystals can overcome the absorption and bioavailability issue associated with nutraceutical API. However, formation of co-crystals depends in large on the co-former employed for the co-crystallization. The co-former of appropriate choice is preferably selected by in accordance with the GRAS list. GRAS or generally regarded as safe, is a list issued by the USFDA. It consists of more than 3000 co-formers such as succinic acid, benzoic acid, nicotinamide, isonicotinamide, picolinic acid, betaine, saccharin, maleic acid, and proline [30]. The choice of appropriate co-formers is of extreme importance. Several reasons, including but not limited to lack of complementarity in hydrogen bonding, preferred packing patterns, conformational flexibility, molecular shape and size, and stability can impede binding of the co-former with the API. However, if the co-former exhibits strong intermolecular interactions with the nutraceutical even systems seemingly immiscible in nature can form cocrystals. Nonetheless, miscibility of the components is considered as an advantage in formulation of co-crystals. Consequently, it is of immense importance that a lot of experimental effort is put into the selection of an appropriate co-former [31].

To select the correct co-former, as well as to characterize the nutraceutical cocrystals, information-based systems are employed. Examples of these systems include hydrogen-bonding penchant, synthonic building, supramolecular compatibility test, Cambridge Structure Database (CSD), pKa-based models, Fabian's strategy, Cross section vitality calculation, the conductor-like screening show for genuine solvents (COSMO-RS), Hansen dissolvability parameter, virtual co-crystal screening (based upon atomic electrostatic potential surfaces-MEPS), warm investigation, measuring immersion temperature, Kofler contact strategy and coordinating [32].

For example, the PKa based tool utilizes the difference between pKa of nutraceutical and its co-former to predicts co-crystallization. If the difference between the co-crystal components i.e. δpKa < 1 flawless formation of co-crystal takes place. If δpKa >1 the system will lead tend to form salts [33]. Cambridge structural database is used to predict the intermolecular hydrogen bonding between co-crystal starting materials. Also, single crystal X-ray crystallography can be used to characterize the crystal structure of a compound [34]. Hansen solubility parameter is used to assess the miscibility between cocrystal components based on the difference in solubility parameters. Usually, the difference in solubility parameters of components <7 MPa1/2 predicts co-crystal formation [35]. Supramolecular synthon approach is yet another tool screening co-formers for co-crystallizaion. It is classified into supramolecular

homosynthon and supramolecular heterosynthon approaches. Supramolecular homosynthon approach is observed between similar functional group while the heterosynthon approach is observed between different functional groups [36]. The binary and ternary phase diagrams are used for evaluating the ease of solubility between drug and co-former, and between the drug, co-former, and solvent respectively. It has been observed that typically the 'W' shaped phase diagram preludes co-crystal formation and a 'V' shaped diagram predicts the formation of eutectic mixture [37]. Conductorlike screening model for real solvents or CSMO-RS is a computational screening technique which works on the difference in enthalpy between co-crystal components. For co-crystal formation to be favored, enthalpy of the drug-co-former complex must be more than the enthalpy of the parent components [38].
