**2. Need for co-crystallization of nutraceuticals**

Evolutionary biomechanics have helped to create a vast reservoir of naturally occurring therapeutic compounds. Alkaloids, flavonoids, terpenoids, and steroids are principal categories of nutraceuticals having a wide range of pharmacological

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

properties [ 11 ]. Natural pharmacophores have rigid confirmations, complex molecular architecture, and well-defined stereochemistry. These in turn aid the nutraceuticals to bind with a variety of physiological targets and thereby increase their bio-efficacy [ 12 ]. Nevertheless, because of poor solubility and dissolution characteristics leading to limited gastro-intestinal absorption and restrictive bioavailability, the bio-efficacy of a nutraceutical scafold is significantly compromised ( **Figure 1** ) [ 13 ]. Furthermore, nutraceuticals are often annotated with functional groups that allow them to bind with a variety of biological targets. But these very groups are also often responsible for the undesirable solubility and stability characteristics of the nutraceutical pharmacophores. Consequently, even though natural products are endowed with an amazingly wide therapeutic window, they have taken a back seat in active clinical use [ 14 ].

 Naturally occurring therapeutic molecules are essentially cost-effective. Also, in comparison to synthetic drugs, nutraceuticals are way less likely to cause toxic manifestations in systemic physiology. That being so, currently the major focus of the pharmaceutical industry is to explore various means of improving the absorption and bioavailability of nutraceuticals for the purpose of producing effective pharmaceutical formulations [ 7 ]. The energetics in crystalline solids dictates that the atoms in a standalone crystal on attaining minimum potential energy will attain maximum stability [ 15 ]. Therefore, by converting into their crystalline form, nutraceutical APIs can be made more stable soluble, absorbable and consequently more bioavailable [ 16 ].

 Crystallization procedures are widely employed by the pharmaceutical industry for the extraction, separation, and purification of drug leads from natural resources [ 17 ]. By crystallizing nutraceuticals, they can be converted into a more thermodynamically stable and highly soluble molecule with much greater percentage purity than their amorphous counterparts [ 18 ]. Solubility, bioavailability, as well as the

#### **Figure 1.**

 *Schematic representation of relation between solubility, GI (gastrointestinal) absorption, bioavailability and bio-efficacy of nutraceuticals.* 

shelf-life of an API are all influenced by the purity, size, and shape distribution of the crystal lattice. Pharmaceutical crystallization has evolved a lot since its inception [19]. Currently, polymorphs, salts, hydrates, solvates, and co-crystals are some of the commonly envisaged pharmaceutically crystals. Polymorphs are diverse crystalline shapes of the same atom or molecules. On the other hand, in conjugation with the drug molecule, either an organic solvent, or water and/or a crystalline co-former is required for producing solvates, hydrates, and co-crystals respectively. However, each crystal form has its own limitations. For example, isolated chemical hydrates and solvates eventually lose stability due to the loss of the solvent or water molecule [20]. Besides, using an appropriate co-former, co-crystals of both synthetic as well as nutraceutical APIs can be efficiently created. For this reason, procuring palatable formulations of challenging molecules can be achieved by employing the strategy of co-crystallization. Pharmaceutical co-crystals can also produce salts and display polymorphism and solvatomorphism, which broadens the range of solid-state forms for a particular API. Pharmaceutically acceptable components and nutraceutical API are combined in co-crystals in a stoichiometric ratio through non-covalent interactions like hydrogen bonds, van der Waals forces, and stacking interactions [21].

Since it was realized that by using co-crystal engineering one may be able to improve the physicochemical properties of nutraceuticals, a significant number of studies highlighting the use of crystal engineering and supramolecular synthons as excellent means for designing pharmaceutical-based co-crystals have been archived. This has further encouraged the development of the co-crystal approach to improve the performance of nutraceuticals [22]. As co-crystal research has grown, a wide range of application areas for co-crystal creation to manipulate physical properties have become available. Furthermore, co-crystallization is suitable for changing the permeability of candidate molecules across cell membranes as well as for increasing the dissolving characteristics of nutraceutical API [23]. The scope of the current chapter is dedicated to improving nutraceutical absorption and bioavailability by means of co-crystallization. Herein the authors, have attempted to state all the plausible factors pertaining to the application of co-crystallization in mitigating poor gastrointestinal absorption and bioavailability of nutraceuticals.
