Open access peer-reviewed chapter
Abstract
Nutraceuticals is an umbrella term for therapeutic leads derived from plants, animals and/or microbial species. Being synthesized in nature’s own laboratory a nutraceuticals have structural and functional features for interacting with an array of physiological targets. However, because of this very structural complexity and diversified nature, nutraceuticals often suffer from diminished gastrointestinal (GI) absorption and limited systemic bioavailability. Thus, in-spite of having an obvious edge over synthetic molecules, pharmaceutical applicability of nutraceuticals play second fiddle in the present pharmaceutical prospective. In this regard, co-crystallization of nutraceuticals have evolved as an attractive prospect. Co-crystallization causes stoichiometric non-covalent binding between nutraceutical API (active pharmaceutical ingredient) and a pharmaceutically acceptable co-former creating a single-phase crystalline material. Nutraceutical co-crystals thus created possess excellent absorption and bioavailability attributes. The principal aim of the current chapter is to highlight co-crystallization as the means of nutraceutical ascendancy over toxic synthetic drugs currently dominating the pharmaceutical market. In the current chapter the authors provide a detail exposition on the methods and application of co-crystallization in context of nutraceutical absorption and bioavailability. Herein, we discuss in detail about the constituents, characteristics, mechanism of action and protocol for preparation of nutraceutical co-crystals with relevant references from current and past studies.
Keywords
- co-crystals
- bioavailability
- absorption
- stability
- solubility
- nutraceutical
- nano co-crystals
1. Introduction
Nature is the ultimate chemist; it houses a vast repertoire of medicinal molecules. Most of the works done by early physicians are based on the principle of
Widely used OTC (over the counter) aspirin is a popular analgesic obtained from bark of willow tree, vincristine and vinblastine are potent anticancer agents isolated from rosy periwinkle [3], aggrastat a highly recommended anticoagulant is extracted from an afrotropic native the saw-scaled viper [4], these are some of the popular examples of drugs culminated from the nature’s repertoire. Nevertheless, despite holding cure to the most intractable of human maladies [5], a very low percentage of marketed medicine is formulated using nutraceutical pharmacophores [6].
Poor absorption from the GI (gastrointestinal) tract and the consequent limitation in systemic bioavailability are predominant roadblocks in pharmaceutical use of nutraceuticals. A fact that is also supported by restrictive solubility profile of nutraceutical molecules. Irrespective of its source of origin, the major contributors of unsuccessful pharmaceutical formulations, are diminished gastro-intestinal (GI) absorption and less than the required systemic bioavailability [7]. The definition of bioavailability defines the fraction of dose following administration that reaches the systemic circulation. It is also a representation of the bio-efficacy or in other words the therapeutic utility of any medicinal compounds [8]. Factors responsible for low bioavailability include molecular instability, poor aqueous solubility and pitiable rate of dissolution and absorption in systemic physiology. Therefore, for exploiting the efficacy of nutraceuticals in active pharmaceutical use, we must concentrate on improving their GI absorption and bioavailability [9]. Several strategies targeting to improve, GI absorption and bioavailability of the therapeutic lead have although been developed, drug modification via co-crystallization is presently the rage of the hour. Like co-crystals of synthetic molecules, nutraceutical co-crystals are crystalline solid composed of a nutraceutical API and a pharmaceutically acceptable excipient also known as the co-former non-covalently bonded in a stoichiometric ratio [10].
The cardinal imperative of the current chapter is to provide an overview of the concept of co-crystallization in modulating the absorption and bioavailability of nutraceutical ligands. Since the ascendency of crystal engineering, co-crystallization has proven to be of immense use in modifying the physicochemical attributes of APIs. The principal advantage of employing co-crystallization strategies is that co-crystals improve the solubility and absorption characteristics of the target API without alternating in any way the intrinsic pharmacological activity of the molecule. In subsequent sections of the current chapter a lot of interesting insights can be gained regarding the properties, strategies, advancement and prospects of co-crystallization in accentuating the use of nutraceuticals in pharmaceutical drug designing.
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 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].
Figure 1.
Schematic representation of relation between solubility, GI (gastrointestinal) absorption, bioavailability and bio-efficacy of nutraceuticals.
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 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.
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 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].
Figure 2.
Components of nutraceutical co-crystals.
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 co-crystals. 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 co-crystals, 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]. Conductor-like 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].
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 co-crystallization parameters. As opposed to it, in heavier aromatic hydrocarbons, surface diffusion is of much importance in staging the co-crystal arrangement [42].
Figure 3.
Mechanism of co-crystallization.
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 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 co-crystallization. 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 liquid-assisted 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].
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 co-crystallizing 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].
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 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
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
7. Conclusions
Co-crystallization is a promising approach for improving the physicochemical properties of APIs. For years the research fraternity has worked tirelessly to develop numerous methodologies for the preparation of pharmaceutically acceptable co-crystals. The co-crystallization protocol includes lab-scale synthetic methodology as well as large-scale production methods. In the current chapter, we have aimed to provide standard descriptions and various examples of established and emerging co-crystal preparations in context of nutraceutical co-crystals. Also in the chapter, we have provided detailed insight into the proposed mechanisms of co-crystallization in different techniques. As co-crystals continue to gain interest and prove their value, the range of demonstrated co-crystal application areas continues to expand. The current chapter also highlights the increasing application of pharmaceutical co-crystals. It is anticipated that co-crystals will become more and more routine in pharmaceutical development as their benefits continue to be demonstrated and routine routes of manufacturing are proven. Since the early 2000s, it was realized that cocrystal engineering may be a potential approach to improve the physicochemical properties of pharmaceuticals, which was contributed to several representative pharmaceutical cocrystal publications. In conclusion, the current chapter emphasizes the role of crystal engineering in pharmaceutical-based cocrystal design. Also by virtue of the current chapter the authors encourage researchers to explore the possibility of creating novel nutraceutical co-crystal for bringing naturally occurring molecules to the forefront of drug designing and development paradigms.
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