**4. Mechanism of co-crystallization**

Co-crystallization of nutraceuticals defines the incorporation of a nutraceutical API and a co-former inside the same crystal lamella. Of essential importance is the nature of the solvent used for co-crystallization. Also, to be noted is the stoichiometric proportion in which the co-former will interact with the nutraceutical API to form non-covalent bond. For inducing co-crystallization, the co-former must have a certain degree of melt miscibility with the nutraceutical. Both the constituents of the co-crystal must exhibit similar repeat unit chemistry and similar crystal unit cell lattice [39]. Besides factors including temperature, blending and pH are also compelling parameters instrumental to the biomechanics of co-crystallization [40]. The rules of hydrogen holding, synthons, and chart sets are included in planning co-crystal frameworks. Co-crystallization is an empirical and multistage process [41]. **Figure 3** shows the schematic of the co-crystal formation. As observed in certain, cases for example in co-crystals containing naphthalene, the diffusion of solids and vapor is also an essential factor in defining cocrystallization parameters. As opposed to it, in heavier aromatic hydrocarbons, surface diffusion is of much importance in staging the co-crystal arrangement [42].

By employing an intermediate liquid at ambient temperature, formation of solid co-crystals in the liquid phase can be achieved. Eutectic formation in co-crystal synthesis is also an increasingly significant mechanism in co-crystal formation. The co-crystal formation at the interface of two colorless crystals of diphenylamine and

**Figure 3.** *Mechanism of co-crystallization.*

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

benzophenone was revealed by microscopic observation, where the contact surface was converted into liquid [43]. Furthermore, eutectic-mediated co-crystallization in conjugation with grinding increases the fresh reactant surfaces for the eutectic formation while improving the co-crystal nucleation in the eutectic phase [44].

For instances with no conceivable mass exchange, for example in fluid or gaseous stage, co-crystallization occurs through the arrangement of amorphous intermediates. This is mostly observed when molecular solids with strong intermolecular hydrogen bonding undergoes co-crystallization. Even the choice of appropriate co-formers relies on the functional groups inclined to form complementary hydrogen bonding with the nutraceutical API. Owing to their directional interactions, hydrogen bonds most emphatically impact molecular recognition [45]. To further emphasize the significance of hydrogen bonding in co-crystallization, certain guidelines have been created to anticipate the consequences of hydrogen bond interactions in cocrystallization. These guidelines include: (1) the hydrogen bonding in any crystal structure will include all acidic hydrogen atoms, (2) all good hydrogen bond acceptors will participate in hydrogen bonding if there is an adequate supply of hydrogen bond donors, (3) hydrogen bonds will preferentially form between the best proton donor and acceptor, and (4) intramolecular hydrogen bonds in a six-membered ring will form in preference to intermolecular hydrogen bonds [46].

Apart from hydrogen bonding, the stereochemistry and competing interactions between molecules are also required to be taken into consideration. Electrostatic energies and free volume of the co-crystal are important constraints in the biomechanics of co-crystallization. For a stable co-crystal to form it is important to maintain a low level of electrostatic energies and free volume inside the crystal [47]. Furthermore, temperatures of co-crystallization are yet another factor of consequence. Below the glass transition temperature of the reactants results in amorphous phase formation; however, higher than glass temperature results in metastable polymorphic forms [48]. For liquid-assisted grinding, it is yet not possible to correctly define the mechanism of co-crystal formation. However, in some instances, it is observed that the liquid phase acts as a lubricating medium to induce molecular diffusion [49]. The co-crystals resulting from both heat and liquid-assisted grinding are thermodynamically stable. Therefore, it can be stated that the low solvent fraction used in the process of liquidassisted grinding is not a sole reliant in controlling the outcome of the process. The same is also true for slurry co-crystallization. Moreover, the nature of the liquid phase used in grinding can be significantly influential during mechanochemical co-crystallization. The mentioned mechanisms are the ones mostly involved with mechanochemical synthesis of co-crystals [50].
