**5. Impact of co-crystallization on gastro-intestinal absorption and bioavailability of nutraceuticals**

Nutraceuticals have also held special significance in drug discovery and design. Despite having developmentally evolved structural and physicochemical properties those very properties also impedes their bench-to-beside translation. Molecular complexity, poor aqueous solubility, functional group reactivity, and general instability are the cardinal constraints in achieving viable nutraceutical formulation [51]. For these reasons nutraceuticals do not make it to the frontline in active therapy.

The low absorption of nutraceuticals from gastro-intestinal tract is because of inherent impairment in aqueous solubility and permeability. Consequently,

nutraceuticals in therapeutic use are needed to be administered frequently and in large doses [52]. Gastro-intestinal absorption defines the amount of drug that gets absorbed from the gastro-intestinal tract post oral administration of a drug molecule. Bioavailability on the other hand is the concentration of administered dose that reaches the systemic circulation. Gastrointestinal absorption and bioavailability are interdependent phenomenon. After oral administration, the lead compound gets disintegrated and dissolved in the gastric fluid. For effective absorption, API needs to be present in an aqueous solution at the site of absorption. Thus, for increasing GI absorption, it is of utmost importance that the aqueous solubility of the nutraceutical API must be improved [53].

By far the most prolific utility of co-crystals to date has been to improve the solubility of the starting material, particularly when that starting material is an active pharmaceutical ingredient. Low aqueous solubility is a barrier to satisfactory drug delivery and, as such, often prevents a medicine from being fit for its purpose. Inherently, a co-crystal will have a different solubility than that of the starting materials due to the altered underlying crystal structure. The solubility alteration can be in either direction. Enhanced solubility is desirable, as it will improve the bioavailability of the drug, but excessive enhancement can be problematic as it can lead to undesirable precipitation of the starting material due to the generation of a supersaturated solution. This has been characterized for co-crystal materials as a "spring and parachute" effect [44].

A 'spring' can be a formulation of the API of thermodynamical higher energy providing faster dissolution and thus a higher rate and extent of absorption. However, a limiting factor of this improved dissolution profile can be rapid recrystallization of a more stable and less soluble form. Thus, an excipient or co-former or a process which retards the rate of recrystallization is needed. This is called the 'parachute'. For every poorly water-soluble drug an individual concept combining the benefits of 'spring and parachute' is needed to accomplish a supersaturated solution of the drug [54].

Thus, co-crystals bear the potential to enhance the delivery and clinical performance of drug products by modulating drug solubility, pharmacokinetics, and bioavailability. Particularly, using cocrystals to improve oral drug absorption of BCS class II and IV drugs has been a strong focus of several case studies published in the literature. Stanton et al. have compared the improvement on the solubility and pharmacokinetics of AMG 517, a potent and selective transient receptor vanilliod 1 (TRPV1) antagonist, when cocrystallizing this drug with carboxylic acid (cinnamic acid and benzoic acid and amide co-formers are used). All four AMG517 cocrystals showed faster intrinsic and powder dissolution rates in fasted simulated intestinal fluid than the free base of AMG 517. The results on the pharmacokinetics showed a 2.4- to 7.1-fold increase in the area under the concentration-time curve in rat PK investigations, which highlights the improvement in bioavailability of AMG 517 when in a cocrystalline form. Other studies have demonstrated the efficiency of cocrystallization in improving the solubility and bioavailability of poorly soluble APIs such as indomethacin, baicalein and quercetin [55].
