Review Article

Nutraceutical Cocrystals: An overview

ABSTRACT
Nutraceutical cocrystals are emerging as novel crystalline forms to modify physicochemical properties of pharmaceuticals. In general, various methods of cocrystal preparation including their applicability to nutraceutical are described. Crystal engineering of nutraceuticals can, produce cocrystals and is expected to be the effective way to enhance the solubility and bioavailability of the target flavonoid, herbal and vitamins molecules. Keywords: Nutraceuticals, cocrystals, flavonoids, vitamins

INTRODUCTION Nutraceuticals are natural bioactive, chemical compounds that have health promoting, disease preventing or medicinal properties and these includes a wide range of products such as polyphenols, vitamins, calcium fortified juices, theobromine from cacao tree, caffeine from coffee leaves etc.1 Nutraceuticals overlap with the other health products such as pharmaceuticals and herbals. Nutraceuticals have established safety record and are readily available under Good Manufacturing Practices (e.g. flavonoids), thereby, lowering preclinical burden, toxicity risk and speed to clinic. Many nutraceuticals (e.g. resveratrol) have major problems with low water solubility and bioavailability and in view of this; they can be used as targets for cocrystal formation to overcome those problems. On the other hand, highly water soluble nutraceuticals (e.g. citric acid), being safe, can serve as a cocrystal former for a less soluble active pharmaceutical ingredient (API) to improve its solubility. Further, improving bioavailability by synthesizing a nutraceutical cocrystal has a large intellectual property potential. Furthermore, nutraceutical cocrystals are patentable as they meet the criteria required
16

for patents. Moreover, nutraceuticals are available over the counter. Cocrystals are multi-component molecular crystals, a group that also contains solvates. Cocrystals refer mainly to crystals which contain compounds that are solids at standard conditions. Solvates are crystal forms that have molecules of solvent in the crystal lattice and these include hydrates as a special case in which the solvent is water. Cocrystals are considered unique solid dosage form which has many advantages over other traditionally known solid forms. Researchers demonstrated that through cocrystallization with different cocrystal formers, solubility of resveratrol could be greatly modified.2 It has been recognized that many substances may cocrystallize in a single continuous lattice structure, leading pharmaceutical scientists into new areas of crystal engineering.3 Cocrystals can be designed by utilizing reliable supramolecular synthons and these synthons are constructed from discrete neutral molecular species that are solids at ambient temperatures and where the cocrystal is a structurally homogeneous crystalline material.4 In case of cocrystals, many classes of compounds, including almost

Received Date : 18-03-2012 Revised Date : 21-05-2012 Accepted Date : 01-06-2012

DOI: 10.5530/rjps.2012.2.3 Address for correspondence Bhupinder Singh Sekhon PCTE Institute of Pharmacy Jhande, Near Baddowal Cantt (Ludhiana)-142 021 Punjab, India

www.rjps.in

RGUHS J Pharm Sci | Vol 2 | Issue 2 | AprJun, 2012

Bhupinder Singh Sekhon: Nutraceutical Cocrystals: An overview

any GRAS-listed substance, have the potential to form cocrystals with APIs.
Methods for cocrystal preparation/production and their limitations

Solution growth is one of the traditional methods for crystallization. Crystals growth occurs from the solution with a proper supersaturation degree. Several methods are used to produce supersaturation, such as cooling, evaporation, addition of a substance or solvent that lowers the solubility and chemical reaction. Among them, evaporation is the most popular way for preparing co-crystals. However, the successful rate of cocrystallization by solution growth is low.5 Seeding is a suitable way to improve the success rate of the solution based co-crystallization.6 Solvothermal and mechanical techniques are currently the most established methods for cocrystal formation.79 In solvothermal cocrystal synthesis, stoichiometric ratios of reactants are dissolved in a solvent of choice and supersaturation is achieved either through a temperature difference or through evaporation of the solvent. In mechanical cocrystal synthesis, stoichiometric ratios of reactants are mechanically agitated (e.g. by grinding in a mill) to induce phase transformations from a physical mixture into cocrystal. Similar to solvothermal techniques, mechanical techniques are also subject to empirically selected conditions (such as selection of solvent drop and grinding time), but the main challenges include process scalability, reactant stability during mechanically/thermally energetic processes, and extent of transformation.1013 Drops of solvent have been shown to influence the crystallization effect.1417 A detailed description of various methods for preparation of cocrystals that applies to nutraceuticals cocrystals synthesis is described below:
Slow evaporation (solution crystallisation)

grinding, cocrystal formers are ground together manually using a mortar and pestle, using a ball mill, or using a vibratory mill. Moreover, it could also be used to prepare novel pharmaceutical co-crystal materials which are not readily accessible by solution growth. The technique of adding small amounts of solvent during the grinding process has been shown to enhance the cocrystal formation.22,23 The solvent used performs a catalytic role and enable the formation of co-crystals not obtained by dry grinding. Moreover, the solvent molecules normally do not exist in the final product. Further, some co-crystals could be prepared by both dry grinding and liquid-assisted grinding, such as the co-crystals of some carboxylic acid with trimethoprim and pyrimethamine.24 Liquid-assisted grinding has advantages over dry grinding such as increased yield, ability to control polymorph production, better product crystallinity. Researchers have demonstrated that significant improvements in kinetics of co-crystal formation by grinding can be achieved by the addition of minor amounts of appropriate solvent.25 Recently, liquid-assisted grinding of pairs of enantiomeric cocrystals has been introduced as a novel technique of cocrystal-cocrystal grinding for the synthesis and dismantling of cocrystals.26 The methods and apparatus used for the formation of cocrystals viz: carbamazepine: saccharin (dry grinding), carbamazepine: saccharin (wet grinding), carbamazepine: nicotinamide (dry grinding), carbamazepine: nicotinamide (wet grinding), piracetum: gentisic (dry grinding), piracetum: gentisic (wet grinding) have been reported.27 Issues with scale-up, low purity yield, and requirements of high energy consumption are limitations of dry grinding. In case of liquid-assisted grinding, large volumes of solvent use are added to limitation mentioned for dry grinding. Additionally sealed heating method for cocrystal formation between trimethoprim and sulfamethoxazole has been reported.28
Crystallization from the melt

A common way to synthesize cocrystals is through slow evaporation of a solution that involves two or more molecules in stoichiometric amounts and they have the possibility to form hydrogen bonds with each other. In this case, the cocrystal is likely to be thermodynamically favoured. Limitation of slow evaporation method relates to issues with scale-up and use of large volumes of solvent.
Mechanochemical methods

Cocrystal formation by simply melting two cocrystal formers together, followed by cooling has been reported. In case of no cocrystal formation from a melt, a seed from a melt may be employed in a crystallization solution in order to afford a cocrystal.29
Slurry crystallisation

Mechanochemical reactions influenced by milling or grinding as well as dependent on molecular recognition has emerged as an excellent experimental approach to rapidly and efficiently screen for and synthesise pharmaceutical cocrystals.18,19
Dry grinding and liquid-assisted (wet) grinding

Dry and liquid-assisted grinding approaches to cocrystal formation have been extensively followed.20,21 In dry
RGUHS J Pharm Sci | Vol 2 | Issue 2 | AprJun, 2012

Another method to synthesize cocrystals is through slurry crystallization.30 Slurry crystallization performed simply by adding crystallization solvents to solid mixtures of cocrystals components (stanolone and mestanolone) which had been prepared using lyophilization of their dimethyl sulfoxide solution with 11 pharmaceutically acceptable guest acids has been reported.31 Based on the physical stability treatment for hydrates/solvates to co-crystals with solid co-crystal formers, a suspension/slurry
17

Bhupinder Singh Sekhon: Nutraceutical Cocrystals: An overview

screening technique was successfully demonstrated in sixteen pharmaceutical co-crystal systems.32 A slurry technique based on the thermodynamics of the physical stabilities of cocrystals was demonstrated for a 1:1 cocrystal of caffeine and 2-hydroxy-1-naphthoic acid.33 Cocrystallization was achieved simply by adding distilled water as solvent to equimolar binary mixture of powder trimethoprim and sulfamethoxazole using slurry technique.34 Grinding techniques suffers such as dissociation of cocrystal during crystallization and cost and time required for slurry and co-grinding methods. To overcome these issues, novel high-throughput cocrystal slurry screening was developed.35 Large volumes of solvent are limitation of slurry crystallisation.
Solvent free co-crystallisation

Solvent free co-crystallisation were found scalable (producing kg-scale preclinical co-crystal product currently), solvent free (lowers cost and time, and avoids the presence of residual solvents), continuous, singlestep process (avoids batch variability), high co-crystal yield and low processing losses, and meets regulatory and industry demand for quality by design and process analytical technology.36
Supercritical fluids

Further, liquid-assisted extrusion has also been demonstrated and the addition of small amounts of benign liquids adds another processing dimension to the extrusion process, thereby, allowing for further flexibility in optimizing cocrystal production using TSE. Liquid-assisted extrusion offers advantage of promoting cocrystal formation at lower temperatures. Unlike other mechanical mixing procedures, TSE is a continuous process and lends itself to practical scalability. Thus, extrusion can be considered an efficient, scalable, and environmentally friendly process for the manufacture of cocrystals which provides a viable alternative to solution crystallization processes.40 Carbamazepine-nicotinamide cocrystal solid dispersions preparation with polymer carriers by melting method (and/or hot melt extrusion) has been reported.41 During solvent free continuous cocrystallization, drug and co-former gravimetrically fed into a heated co-rotating twin screw extruder formed cocrystals. An increased conversion of the mixture into cocrystal occurred with increase in barrel temperature and screw mixing intensity. A decrease in screw rotation speed also provided improved cocrystal yield due to the material experiencing longer residence times within the process.42
Sonochemical method for cocrystals synthesis

Different supercritical fluid techniques are used to produce cocrystals by taking advantage of different supercritical fluid properties (solvent, anti-solvent or atomization enhancement), bringing additional advan tages compared to the classical cocrystal production methods. Supercritical fluid technology allows a single-step generation of cocrystals that are difficult or even impossible to obtain by traditional techniques. The potential of supercritical fluids as media for the co-crystallization of APIs has been addressed by some workers.37,38 And screening for pharmaceutical co-crystals using the supercritical fluid enhanced atomization process might of help for production of multi-API co-crystals.39 Issues with scale-up, low purity yield are limitation of supercritical fluids for cocrystal formation.
Twin screw extrusion

The application of twin screw extrusion (TSE) in the continuous production of cocrystals has been demonstrated for four model cocrystal-forming systems. Moreover, extrusion was found to be an effective method to make cocrystals, whether or not the mechanism of formation involved eutectic formation. TSE provides highly efficient mixing and close material packing of components which in turn lead to improved surface contact between components, thereby, facilitating cocrystal formation without the use of solvents.
18

Researchers have demonstrated a convenient sonochemical method to prepare organic cocrystals of nano-and micrometer-sized dimensions.43,44 Scientists demonstrated the utility of sonochemical method to synthesize pharmaceutical nano-cocrystals.45 Ultrasound assisted solution cocrystallization offered pure caffeine/maleic acid 2:1 cocrystal product.46 Mechanochemical liquid-assisted grinding (LAG) and sonochemical (SonicSlurry) techniques comparison to synthesize pharmaceutical cocrystals involving theophylline and caffeine as pharmaceutical ingredients and L-malic or L-tartaric acid as pharmaceutical cocrystal formers have been reported. For these model systems, the results are interpreted using the parameter , the ratio of solvent volume to sample weight. The formation of the cocrystal was observed in all standard LAG experiments when = 0.25L mg1. Cocrystal formation by neat grinding was observed only for the cocrystal of theophylline and L-malic acid. LAG experiments at very low values (below 0.5L mg1) revealed that the rate of cocrystal formation depended on the choice of the liquid and increases with . SonicSlurry experiments performed at higher values of 2, 6 and 12 L mg1 provided three different outcomes: the pure cocrystal, a mixture of the cocrystal with a cocrystal component, or a single cocrystal component. LAG experiments at =10Lmg1 produced results consistent with the SonicSlurry experiments at =12Lmg1.
RGUHS J Pharm Sci | Vol 2 | Issue 2 | AprJun, 2012

Bhupinder Singh Sekhon: Nutraceutical Cocrystals: An overview

Further, measuring approximate solubilities of individual cocrystal components revealed that product formation depends on saturation levels of reactants. In general, cocrystal formation should occur under conditions in which all cocrystal components remain saturated.14 Cocrystals isolation can be previewed by means of a number of high-throughput screening methods.47
Nutraceuticals cocrystallization

OH

Pharmaceutical cocrystallization has allured a lot of attention by means of altering the physicochemical properties of API such as solubility, stability and bioavailability. Generally, a coformer hydrogen bonds with the target molecule forming a cocrystal. Within the pharmaceutical industry, coformers are typically selected from the same list of pharmaceutically accepted salt formers, generally regarded as safe (GRAS) and/or everything added to food in the United States (EAFUS) lists, due to previous occurrence of these molecules in FDA approved drug or food products. An additional group of molecules to be considered as possible coformers are nutraceuticals. Crystal engineering seeks to rationally design new materials with desired properties. Nutraceuticals cocrystals belong to the class of compounds which are little studied. Nutraceuticals show a range of therapeutic applications; however, they are not regulated and tested as tightly as pharmaceutical drugs. Crystal engineering based on intensive Cambridge Structural Database analysis was used to predict and design new cocrystals of targeted nutraceuticals. Nutraceuticals such as flavonoids and vitamins have been investigated as candidates for crystal engineering studies to improve the physical properties such as solubility which may improve their bioavailability.48 Flavonoids are natural products found in most parts of plants and are often studied because of their potent antioxidant and free radical scavenging activities. Researchers have observed from the cocrystallization of flavonoids with 1,4-diazobicyclo[2.2.2] octane (DABCO) that the complexity of these extended structures increased as the number of substituents on the flavonoid backbone increased. The preparation and properties of flavonoid interactions to the formation of cocrystals with active pharmaceutical ingredients were reported.49 Polyphenols, a major class of nutraceuticals and potential disease preventing agents, are the appropriate targets to exploit and establish the importance of nutraceutical cocrystallization and its use. Protocatechuic acid (3,4-dihydroxybenzoic acid, Figure 1) is a phenolic acid in the broad class of polyphenols of the nutraceuticals. It is widely available in oil, vegetables, fruits and tea. In this context, novel 1:1 cocrystals of protocatechuic acid (strong antioxidant) with pharamaceutically accepted
RGUHS J Pharm Sci | Vol 2 | Issue 2 | AprJun, 2012

OH OH
Figure1: Structure of protocatechuic acid.

molecules (cocrystal formers) such as caprolactam, isonicotinamide, isonicotinic acid, theophylline, nicotinamide and theobromine have been obtained by slow evaporation of stoichiometric amounts of starting materials in an appropriate solvent and they were removed from their mother liquors before complete evaporation of the solvent. Cocrystallization via grinding and slurry conversion was also successful to produce 1:1 cocrystals of protocatechuic acid with caprolactam, isonicotinamide, isonicotinic acid, theophylline, nicotinamide and theobromine. The resultant cocrystals were characterized by FTIR, DSC, PXRD, single crystal x-ray diffraction and TGA (Thermo Gravimetric Analysis).50 Cocrystal of quercetin, isonicotinic acid and water (1:1:1) and cocrystal of quercetin, theobromine and water (1:1:2) were obtained through cocrystallization via solution crystallization and cocrystallization via grinding and slurry conversion. Quercetin theobromine dihydrate cocrystal resulted in 1.5 fold increase in solubility of quercetin.50 Pterostilbene has been characterized as a nutraceutical, and is found in nature in a number of tree barks and a variety of berries, including grapes, as well as plants commonly used in traditional folk medicine. Pterostilbene (Figure 2A) and resveratrol (Figure 2B) act synergistically in protecting human erythrocytes from damage due to oxidative stress. Pterostilbene have been reported to exhibit a range of biological activities including anti-cancer, antioxidant, anti-inflammatory and other potential health benefits. Cocrystals of pterostilbene include: pterostilbene: caffeine cocrystal, pterostilbene: carbamazepine cocrystal, pteros tilbene: glutaric acid cocrystal, and pterostilbene: piperazine cocrystal. Three cocrystals of a 1:1 stoichiometric molar ratio of pterostilbene with caffeine (two polymorphs, Form I and Form II) and carbamazepine were prepared
19

Bhupinder Singh Sekhon: Nutraceutical Cocrystals: An overview

OH O HO

OH

H3C

CH3

OH

Figure 2: A: Pterostilbene; B: Resveratrol.

and characterized by crystallographic (XRPD, singlecrystal) and thermoanalytical (TGA, DSC) techniques. Physical stability of the reported cocrystals with respect to relative humidity was found to be significantly improved in relationship to caffeine or carbamazepine. The carbamazepine: pterostilbene cocrystal was stable upon slurrying in water for 3 days and its solubility was 7 lower than carbamazepine dihydrate and 2.5lower than pterostilbene.51,52 Gas anti-solvent method of supercritical fluid process was used to prepare cocrystals of carbamazepine (CBZ) and nicotinamide (NCT) and inclusion complexes of these cocrystals with -cyclodextrin (CD). The dissolution studies showed a 2.5 fold increase in dissolution rate in the case of co-crystals and a 40 fold increase when cocrystals were complexed with CD. A lower melting point (160C) was observed in the case of co-crystals and the exothermic peaks were missing for pure CBZ and co-crystals when they were complexed with CD. The absence of the melting peaks indicated complete complexation. X-ray powder diffraction patterns of co-crystals and inclusion complexes were distinct from the starting materials and the shift in peaks of 1H-NMR confirmed intermolecular hydrogen bonding and complexation.53 Four cocrystals of p-coumaric acid (a phytochemical and nutraceutical compound) with caffeine (1:1 and 1:2 stoichiometric ratios) and theophylline (two 1:1 polymorphs, Form I and Form II) were prepared and their structural determination was carried out by singlecrystal X-ray crystallography. The two theophylline cocrystals displayed synthon polymorphism, where both structures possess a carboxylic acidimidazole heteromeric synthon; however, one polymorph also has a hydroxylcarbonyl synthon (Form I), while in the other a hydroxylimidazole synthon (Form II) was observed.54
20

Cocrystals of a 2:1 and 1:1 stoichiometric molar ratio of pterostilbene with piperazine or glutaric acid were synthesized on a multigram scale and fully characterized by single-crystal X-ray diffraction. The aqueous concentration of pterostilbene measured over five hours from dissolution of the pterostilbene-piperazine cocrystal was six times higher than the solubility of the single-component pterostilbene.55 Cocrystal formation between nicotinamide and five fenamic acid derivative drugs was achieved using solution-based and solid-state preparation methods. All cocrystals formed utilized one of the most predictable supramolecular synthons (COOHN).56 Curcumin (Figure 3) (the principal curcuminoid of turmeric) application as a drug is severely limited by poor aqueous solubility. Novel cocrystals of curcumin with resorcinol and pyrogallol were obtained by liquid-assisted grinding. Curcuminresorcinol (1:1) and curcuminpyrogallol (1:1) were characterized by X-ray diffraction, thermal analysis, FT-IR, FT-Raman, and solid-state 13C NMR spectroscopy. The 1:1 cocrystal stoichiometry has been sustained by OHO hydrogen bonds between the phenolic OH groups of the coformers to the carbonyl group of curcumin. The melting point of the cocrystals was observed in between that of curcumin and the coformer and the lower melting cocrystal was more soluble than higher melting. The dissolution rates of curcuminresorcinol and curcuminpyrogallol in 40% EtOHwater are ~5 and ~12 times faster than that for curcumin.57 The aqueous solubility of the pterostilbene-carbamazepine cocrystal was estimated to be less than half of that for pterostilbene. By comparison, pterostilbene-caffeine was measured to have an aqueous concentration 27 times higher than pterostilbene and the increased concen tration was maintained for approximately five hours.
RGUHS J Pharm Sci | Vol 2 | Issue 2 | AprJun, 2012

Bhupinder Singh Sekhon: Nutraceutical Cocrystals: An overview

OH

HO OCH3
Figure 3: Structure of Curcumin.

OH OCH3

Such studies demonstrated that the aqueous concentration of a nutraceutical compound can be increased through the formation of cocrystals.58 Cocrystal formation in stoichiometric mixtures of citric acid with paracetamol was reported. Changes in intensities of the vibrational modes associated with the amide and the carboxylic acid groups were observed upon cocrystal formation. Several new vibrational bands were identified in the cocrystal which were not manifest in the raw material and could be used as diagnostic features of cocrystal formation. The results showed that paracetamol: citric acid 2:1 cocrystals were obtained. The asymmetric unit of the crystal contains two paracetamol molecules hydrogen-bonded to the citric acid; one of these acts as a phenolic-OH hydrogen bond donor to the carbonyl of a carboxylic acid arm of citric acid. In contrast, the other phenolic-OH acts as a hydrogen bond acceptor from the quaternary COH of citric acid.59 Flavonoids, naturally occurring polyphenolic com pounds are widely known for their antioxidant activity. However, they have limited bioavailability and poor water solubility. Crystal engineering is considered to be effective way to enhance the solubility and bioavailability of the target flavonoid molecules.60 Quercetin (3, 34, 4, 57-pentahydroxyflavone, Figure4) is a bioflavonoid which is widely distributed in the plant kingdom. It is also present in medicinal botanicals like Ginkgo biloba, Hypericum perforatum, Sambuscus Canadensis and many others.61 Quercetin-caffeine-methanol cocrystal solvate was prepared by dissolving quercetin dehydrate (68mg) and caffeine (38mg) in methanol (5ml) and heated until a clear solution was obtained. Slow evaporation of this solution in refrigerator resulted in 1:1 crystals after 3 days.60 The crystal structure of single crystal of quercetin-caffeine-methanol cocrystal solvate (Cocrystal I)
RGUHS J Pharm Sci | Vol 2 | Issue 2 | AprJun, 2012

revealed that the imide group and the aromatic nitrogen of caffeine interacts with the hydroxyl groups of quercetin. Caffeine molecules interact with quercetin molecules via the formation of OHc.Natom and OHa.CO supramolecular heterosynthons. The former supramolecular heterosynthon was formed by the interaction of OHc quercetin and the aromatic nitrogen of the imidazole ring in caffeine and the latter results due to the hydrogen bonding between OHa of quercetin and the CO moiety of the imide group of caffeine. The carbonyl in the caffeine molecule hydrogen bonds to the methanol molecule.60 Quercetin-isonicotinamide cocrystal was prepared by dissolving quercetin dehydrate (67.6mg) and isonicotinamide (24.6mg) in methanol (5ml) and heated until a clear solution was obtained. Slow evaporation of this solution in refrigerator resulted in 1:1 crystals after 2 days.60 Isonicotinamide molecules interact with quercetin molecules via, COOH and NHOH supramolecular heterosynthons and OHOH supramolecular homosynthons. One of the two hydrogen atoms in the amino

OHe OHd OHa O

A
OHb

C
OHc O

Figure 4: Structure of quercetin.

Bhupinder Singh Sekhon: Nutraceutical Cocrystals: An overview

moiety of the isonicotinamide hydrogen bonds to the carbonyl group of adjacent quercetin molecules and the other hydrogen atom interacts with OHd of a different quercetin molecule giving rise to NHCO and NHOH supramolecular heterosynthons, respectively. The carbonyl of the amide moiety hydrogen bonds to OHe quercetin molecules whereas the Natom of the isonicotinamide molecule interacts with OHa of quercetin molecules and thereby generates COOH and N atomOH supramolecular heterosynthons respectively.60 Hesperetin (RS-2,3-dihydro-5,7-dihydroxy-2-(3-hydroxy4-methoxyphenyl)-4H-1-benzopyran-4-one, Figure 5), the aglycone form of hesperedin has very good antiinflammatory properties. It is a phenolic antioxidant, antiallergic, antimutagenic and in vitro studies have shown that hesperetin has some anti cancer activity.60 Hesperetin-isonicotinamide cocrystal was prepared by dissolving hesperetin (60mg) and isonicotinamide (24.6mg) in ethanol (5ml) and heated until a clear solution was obtained. Slow evaporation of this solution in refrigerator resulted in 1:1 crystals after 5 days.60 Crystallization of hesperetin with isonicotinamide resulted in a 1:1 cocrystal. The supramolecular synthon formed in the cocrystal includes OH---N hydrogen bond between the nitrogen atom of isonicotinamide and the OHa of the adjacent hesperetin molecule. Crystallization of hesperetin with nicotinic acid results in two 1:1 cocrystals in which the nicotinic acid exists as a zwitterionic state. Crystal engineering has lead to the generation novel cocrystals of hesperetin with pharmaceutically acceptable molecules such as isonicotinamide and nicotinic acid.61 Four cocrystals of quercetin (QUE): quercetin: caffeine (QUECAF), quercetin: caffeine: methanol (QUECAF MeOH), quercetin: isonicotinamide (QUEINM), and quercetin: theobromine dihydrate (QUETBR2H2O) were

OHc OCH3 OHa O

A
OHb

C
OHc O

Figure 5: Structure of hesperetin.

prepared by slow evaporation (solution crystallisation) method and each of these cocrystals exhibited pharmacokinetic properties that are superior to those of quercetin alone. The QUECAF and QUECAFMeOH cocrystals increased the solubility of QUE by 14-and 8-fold when compared to QUE dihydrate. Further, the cocrystals outperformed QUE dihydrate with increases in bioavailability up to nearly 10-fold.62 The cocrystal of carbamazepine (CBZ) was prepared using nicotinamide (NCT) as a conformer by alteration of the reported solution cooling crystallization method,63 solvent evaporation, and modified melting64 and cryomilling methods. Equimolar weights of CBZ (10.635g) and NCT (5.497g) were added to 500ml of a round-bottom flask attached to a condenser containing 200ml of 70:30% (v/v) ethanol/methanol mixture using solution cooling crystallization method. Solids dissolved in the solvent were heated at 65C and refluxed for 1h while stirring. The cocrystals of CBZ and NCT appeared in the reaction vessel during the cooling period to room temperature. Filtration was used to obtain the cocrystals, which were washed twice with 20ml of ethanol, and vacuum oven-dried at 30C for 48h. Dried cocrystals obtained were crushed and passed through a sieve 60 ASTM. In cryomilling method, an equimolar ratio of CBZ (1.181g) and NCT (0.611g) was co-grounded in the cryomill (SPEX Sample Prep 6770 Freezer/Mill, SPEX CertiPrep, Metuchen, NJ, USA) with a polycarbonate vial and stainless steel rod, which acted as an impactor for grinding.65 Liquid nitrogen was used as coolant for the mill. The sample was precooled for 2min before the milling operation using liquid nitrogen as coolant. The cryomill was operated for three cycles at 10rpm/min with 10-min grinding time for each cycle and 2-min cooling period between the cycles. The vial was then transferred to a desiccator after cryogrinding to prevent moisture condensation on the sample due to extremely low temperature They were characterized for solubility, intrinsic dissolution rate, chemical identification by Fourier transform infrared spectroscopy, crystallinity by differential scanning calorimetry, powder X-ray diffraction, and morphology by scanning electron microscopy. The preformulation profile of the cocrystals was similar to CBZ, except that it had an advantageous resistance to hydrate transformation.66 Researchers reported a composition comprising a cocrystal of a neutraceutical and a cocrystal former wherein the neutraceutical and the cocrystal former are hydrogen bonded to each other. In this context, the nutraceutical was selected from the group consisting of vitamin B2 (riboflavin), glucosamine HCl, chlorogenic acid, lipoic acid, catechin hydrate, creatine, acetyl-L-carnitine HCl, vitamin B6, pyridoxine, caffeic acid, naringenin, vitamin B1 (thiamine HCl), baicalein, luteolin, hesperedin, rosmarinic
RGUHS J Pharm Sci | Vol 2 | Issue 2 | AprJun, 2012

Bhupinder Singh Sekhon: Nutraceutical Cocrystals: An overview

acid, epicatechin gallate, epigallocatechin, vitamin B9 (folic), genistein, methylvanillin, ethylvanillin, silibinin, diadzein, melatonin, rutin hydrate, vitamin A, retinol, vitamin D2 (ergocalciferol), vitamin E (tocopherol), diosmin, menadione (K3), vitamin D3 (caholecalciferol), phloretin, indole-3-carbinol, fisetin, glycitein, chrysin, gallocatechin, vitamin B4 (adenine), vitamin B5 (pantothenic acid), vitamin B7 (biotin), theobromine, quercetin, ferulic acid, ellagic acid, hesperitin, and pro tocatechuic acid; and a cocrystal former selected from the group consisting of pharmaceutically acceptable carbohydrates, amines, amides, sulfonamides, carboxylic acids, sulfonic acids, phenols, polyphenols, aromatic heterocycles, xanthines and alcohols.67 A dissolution study on the 1:1 metronidazole: gallic acid cocrystal indicated that the cocrystal dissolved at a rate of about 22% of metronidazole. This difference in dissolution rate may be used to develop a drug product comprising a cocrystal of metronidazole: gallic acid to delivers a slower release dose profile of metronidazole than metronidazole as currently used.68 Curcumin, a substance found in the spice turmeric, has long been used in Asian medicine to treat a variety of maladies. However, curcumin has extremely poor water solubility and bioavailability. Cocrystals of curcumin with a biologically inert or beneficial compound improved its physical properties.69 Four major polyphenolic catechins are found in green tea and include (_)-epicatechin (EC), 3 (_)-epicatechin 3-gallate (ECG), (_)-epigallocatechin (EGC), and (_)-epigallocatechin 3-gallate (EGCG). A cup of green tea may contain 100200mg of EGCG. Several inves tigators have reported that green tea exerts cancer preventive activity at a variety of organ sites, including skin, lung, oral cavity, esophagus, stomach, small intestine, colon, pancreas, and mammary gland.67,70 Gossypol is a natural product derived from the cotton plant (genus Gossypium). Researchers reported results relating to compositions comprising co-crystals of (-)-gossypol with a C18 carboxylic acid or C18 sulfonic acid which are useful as inhibitors of Bcl-2 family proteins. The invention also relates to the use of co-crystals of (-)-gossypol with a C18 carboxylic acid or C18 sulfonic acid for inducing apoptosis in cells and for sensitizing cells to the induction of apoptotic cell death.71 Theanine (Figure 6) also gamma-glutamylethylamide or 5-N-ethyl-glutamine is an amino acid which is present in tea plant (camellia sinensis). Green tea, black tea and oolong tea contains theanine. Cocrystal system formed by aspirin (acetylsalicylic acid) and (L)-theanine ((L)-5-N-ethyl-glutamine) adequately demonstrated the potential advantages that can be achieved. The equilibrium solubility of aspirin is rather low, however, its cocrystal with theanine exhibited an
RGUHS J Pharm Sci | Vol 2 | Issue 2 | AprJun, 2012

NH2 HO O O
Figure 6: Structure of theanine.

NH

CH3

equilibrium solubility of 10mg/mL. This enhanced solubility is considered sufficient for formulations of aspirin that can be administered intravenously.72 CONCLUSIONS Cocrystallization has gained attention recently as a means for improving the physicochemical characteristics of a compound. The applications of concepts of supramolecular synthesis and crystal engineering to the development of nutraceutical cocrystals offer many opportunities for the drug development and delivery. Experts are of the opinion that sooner or later nutraceutical cocrystals will gain a broader grip in drug formulation. REFERENCES
1. Lockwood B. Nutraceuticals, Pharmaceutical Press: London, UK, 2007. 2. Aboarayes DA. Crystal engineering of nutraceutical cocrystals, 2009. Theses and Dissertations. Paper 1820. http://scholarcommons.usf.edu/ etd/1820. 3. Sekhon BS. Pharmaceutical co-crystals - a review. Ars Pharmaceutica 2009;50:99117. 4. Aakery CB, Salmon DJ. Building co-crystals with molecular sense and supramolecular sensibility. Cryst Eng Comm. 2005;7:439448. 5. Zhang S. Physical properties and crystallization of theophylline co-crystals. Licentiate Thesis in Chemical Engineering, KTH, Royal Institute of Technology, Stockholm Sweden, 2010. 6. Trask AV. Achieving polymorphic and stoichiometric diversity in cocrystal Formation: Importance of solid-state grinding, Powder X-ray structure determination, and seeding. Cryst Growth Des. 2005;5:22332241. 7. Brittain HG. Cocrystal systems of pharmaceutical interest. Cryst Growth Des. 2012;12(2):10461054. 8. Aakery CB, Chopade PD. Cocrystals: Synthesis, structure, and applications. In: Supramolecular chemistry: From molecules to nanomaterials (Steed JW, Gale PA, eds.). John Wiley & Sons, Ltd., 2012;6: 29752992. 9. Yadav AV, Shete AS, Dabke AP, Kulkarni PV, Sakhare SS. Co-Crystals: A novel approach to modify physicochemical properties of active pharmaceutical ingredients. Indian J Pharm Sci. 2009;71(4):359370. 10. Weyna DR, Shattock T, Vishweshwar P, Zaworotko MJ. Synthesis and structural characterization of cocrystals and pharmaceutical cocrystals: Mechanochemistry vs slow evaporation from solution. Cryst Growth Des. 2009;9(2):11061123. 11. Braga D, Curzi M, Dichiarante E, et al. Making crystals from crystals: A solid-state route to the engineering of crystalline materials, polymorphs, solvates and co-crystals; considerations on the future of crystal engineering. Eng Crystall. Mater Prop. 2008:131156.

23

Bhupinder Singh Sekhon: Nutraceutical Cocrystals: An overview

12. Friscic T, Jones W. Recent advances in understanding the mechanism of cocrystal formation via grinding. Cryst Growth Des. 2009;9(3):16211637. 13. Karki S, Friscic T, Jones W, Motherwell WDS. Screening for pharmaceutical cocrystal hydrates via neat and liquid-assisted grinding. Mol Pharmaceut. 2007;4(3):347354. 14. Friscic T, Childs SL, Rizvi SAA, Jones W. The role of solvent in mechanochemical and sonochemical cocrystal formation: a solubilitybased approach for predicting cocrystallisation outcome. Cryst Eng Comm. 2009;11(3):418426. 15. Braga D, Giaffreda SL, Grepioni F, et al. Solvent effect in a solvent free reaction. Cryst Eng Comm. 2007;9:879881. 16. Trask AV, Jones W. Crystal engineering of organic cocrystals by the solidstate grinding approach. Organic Solid State Reactions. 2005; 254:4170. 17. Trask AV, Motherwell WDS, Jones W. Solvent-drop grinding: green polymorph control of cocrystallisation. Chem Commun. 2004;890891. 18. Frii T . Supramolecular concepts and new techniques in mechanochemistry: cocrystals, cages, rotaxanes, open metalorganic frameworks. Chem Soc Rev. 2012;41:34933510. 19. Delori A, Frii T, Jones W. The role of mechanochemistry and supramolecular design in the development of pharmaceutical materials. Cryst Eng Comm. 2012;14: 23502362. 20. Etter MC, Reutzel SM, Choo CG. Self-organization of adenine and thymine in the solid state. J Am Chem Soc. 1993;115:44114412. 21. Kuroda R, Imai Y, Tajima N. Generation of a co-crystal phase with novel coloristic properties via solid state grinding procedures. Chem Comm. 2002;28482849. 22. Rehder S, Klukkert M, Lbmann KAM, et al. Investigation of the formation process of two piracetam cocrystals during grinding. Pharmaceutics. 2011;3(4):706722. 23. Jones W. Pharmaceutical cocrystals: An emerging approach to physical property enhancement. MRS Bulletin. 2006;31:875879. 24. Trask AV. Screening for crystalline salts via mechanochemistry. Chem Comm. 2006;5153. 25. Shan N, Toda F, Jones W. Mechanochemistry and co-crystal formation: effect of solvent on reaction kinetics. Chem Comm. 2002;23722373. 26. Frii T, Fbin L, Burley JC, Jones W, Motherwell WDS. Exploring cocrystalcocrystal reactivity via liquid-assisted grinding: the assembling of racemic and dismantling of enantiomeric cocrystals. Chem Commun. 2006;50095111. 27. Gonazalez Zugasti J, Kane N, Oliveira M, Peterson M. Methods and systems for cocrystal synthesis. Patent No US7763 112B2, July 27, 2010. 28. Zaini E, Sumirtapura YC, Soewandhi SN, Halim A. Cocrystal formation between trimethoprim and sulfamethoxazole by sealed heating method. Acta Crystallography 2008;A64:C490. 29. Braga D, Grepioni F, Maini L, Polito M. Crystal polymorphism and multiple crystal forms. Struct Bond. 2009;132:2550. 30. Vishweshwar P, McMahon JA, Bis JA, Zaworotko M.J. Pharmaceutical co-crystals. J Pharm Sci. 2006;95:499516. 31. Takata N, Shiraki K, Takano R, Hayashi Y, Terada K. Cocrystal screening of stanolone and mestanolone using slurry crystallization. Cryst Growth Des. 2008;8(8):30323037. 32. Zhang GGZ, Henry RF, Borchardt TB, Lou X. Efficient co-crystal screening using solution-mediated phase transformation. J Pharm Sci. 2007;96 (5):990995. 33. Buar DK, Henry RF, Duerst RW, Lou X, MacGillivray LR, Zhang GGZ. A 1:1 cocrystal of caffeine and 2-hydroxy-1-naphthoic acid obtained via a slurry screening method. J Chem Crystallogr. 2010;40(11):933939. 34. Zaini E, Sumirtapura YC, Soewandhi SN, Halim A, Uekusa H, Fujii K. Cocrystalline phase transformation of binary mixture of trimethoprim and sulfamethoxazole by slurry technique. Asian J Pharm Clin Res. 2010;3(4):2629. 35. Kojima T, Tsutsumi S, Yamamoto K, Ikeda Y, Moriwaki T. High-throughput cocrystal slurry screening by use of in situ Raman microscopy and multi-well plate. Int J Pharm. 2010;399(12):5259. 36. World Pharmaceutical Frontiers 3436. www.worldpharmaceuticals.34.net http://www.worldpharmaceuticals.net/editorials/21/Crystal%20clear.pdf 37. Padrela L, Rodrigues MA, Velaga SP, Matos HA, Azevedo EG. Formation of indomethacin-saccharin cocrystals using supercritical fluid Technology. Eur J Pharm Sci. 2009;38:917. 38. Padrela L, Rodrigues MA, Velaga SP, Fernandes AC, Matos HA, Azevedo EG. Screening for pharmaceutical cocrystals using the supercritical fluid enhanced atomization process. J Supercrit Fluids. 2010;53:156164.

39. Dhumal RS, Kelly AL, York P, Coates PD, Para A. Cocrystalization and simultaneous agglomeration using hot melt extrusion. Pharm Res. 2010; 27(12):27252733. 40. Daurio D, Medina C, Saw R, Nagapudi K, Alvarez-Nez F. Application of twin screw extrusion in the manufacture of cocrystals, Part I: Four case studies. Pharmaceutics 2011;3:582600. 41. Liu X, Lu M, Guo Z, Huang L, Feng X, Wu C. Improving the chemical stability of amorphous solid dispersion with cocrystal technique by hot melt extrusion. Pharm Res. 2012;29(3):806817. 42. Kelly AL, Gough T, Dhumal RS, Halsey SA, Paradkar A. Monitoring ibuprofennicotinamide cocrystal formation during solvent free continuous cocrystallization (SFCC) using near infrared spectroscopy as a PAT tool. Int J Pharm. 2012;426(12):1520. 43. Ruecroft G, Hipkiss D, Ly T, Maxted N, Cains PW. Sonocrystallization: the use of ultrasound for improved industrial crystallization. Org Process Res Dev. 2005;9:923932. 44. Bucar DK, MacGillivray LR. Preparation and reactivity of nanocrystalline cocrystals formed via sonocrystallization. J Am Chem Soc. 2007;129: 3233. 45. Sander JRG, Bucar DK, Henry RF, Zhang GGZ, MacGillivray LR. Pharmaceutical nano-cocrystals: sonochemical synthesis by solvent selection and use of a surfactant. Angew Chem Int Ed Engl. 2010; 49(40):72847288. 46. Aher S, Dhumal R, Mahadik K, Paradkar A, York P. Ultrasound assisted cocrystallization from solution (USSC) containing a non-congruently soluble cocrystal component pair: Caffeine/maleic acid. Eur J Pharm Sci. 2010;41(5):597602. 47. Bis J, Brittain H. Science and Technology Showcase: Cocrystals. AAPS Preformulation Focus Group Newsletter, August 2011, Issue 3; http://www.aaps.org/uploadedFiles/Content/Sections_and_Groups/ Focus_Groups/PFGnewsltrAug2011.pdf 48. http://www.linkedin.com/pub/kapildev-arora/11/943/96b 49. Timmons DJ, Bernas AA, Pacheco MR, Fricke KA. Crystal engineering with flavonoids; The 235th ACS National Meeting, New Orleans, LA, April 610, 2008; http://oasys2.confex.com/acs/235nm/techprogram/ P1163554.HTM 50. Pujari TA. Cocrystals of nutraceuticals: Protocatechuic acid and quercetin, 2009. Theses and Dissertations. Paper 2156; http://scholarcommons. usf.edu/etd/2156 51. Schultheiss NC, Bethune SJ. Pterostilbene cocrystals . United States Patent Application 20110189277, 08/04/2011; http://www.freepatents online.com/y2011/0189277.html 52. Schultheiss N,Bethune S, Henck JO. Nutraceutical cocrystals: utilizing pterostilbene as a cocrystal former. Cryst Eng Comm. 2010;12: 24362442. 53. Shikhar A, Bommana MM, Gupta SS, Squillante E. Formulation development of CarbamazepineNicotinamide co-crystals complexed with -cyclodextrin using supercritical fluid process. J Supercrit Fluids. 2011;55(3):10701078. 54. Schultheiss N, Roe M, Boerrigter SXM. Cocrystals of nutraceutical p-coumaric acid with caffeine and theophylline: polymorphism and solid-state stability explored in detail using their crystal graphs. Cryst Eng Comm. 2011;13:611619. 55. Bethune SJ, Schultheiss N, Henck JO. Improving the poor aqueous solubility of nutraceutical compound pterostilbene through cocrystal formation. Cryst Growth Des. 2011;11(7):28172823. 56. Fabian L, Hamill N, Eccles KS, et al. Cocrystals of fenamic acids with nicotinamide. Cryst Growth Des. 2011;11(8);35223528. 57. Sanphui P, Goud NR, Khandavilli UBR, Nangia A. Fast dissolving curcumin cocrystals. Cryst Growth Des. 2011;11(9):41354145. 58. Bethune SJ, Schultheiss N, Henck JO. Aqueous solubility of nutraceutical cocrystals. http://www.aapsj.org/abstracts/AM_2010/T3181.pdf 59. Elbagerma MA , Edwards HGM, Munshi T, Scowen IJ. Identification of a new cocrystal of citric acid and paracetamol of pharmaceutical relevance. Cryst Eng Comm. 2011;13:18771884. 60. Kavuru P. Crystal engineering of flavonoids , Master of Science, Department of Chemistry, College of Arts and Sciences, University of South Florida; http://purl.fcla.edu/usf/dc/et/SFE0002463 http://scholar commons.usf.edu/etd/325/ 61. Jin GZ, Yamagata Y, Tomita K. Structure of naringin hexahemihydrate. Acta Cryst. 1990;C46:310313. 62. Smith AJ, Kavuru P, Wojtas L, Zaworotko MJ, Shytle RD. Cocrystals of quercetin with improved solubility and oral bioavailability. Mol Pharmaceut. 2011;8(5):18671876.

24

RGUHS J Pharm Sci | Vol 2 | Issue 2 | AprJun, 2012

Bhupinder Singh Sekhon: Nutraceutical Cocrystals: An overview

63. Rodriguez-Hornedo N, Nehm SJ, Seefeldt KF, Falkiewicz CF. Reaction crystallization of pharmaceutical molecular complexes. Mol Pharm. 2006;3:362367. 64. Seefeldt K, Miller J, Alvarez-Nunez F, Rodriguez-Hornedo N. Crystallization pathways and kinetics of carbamazepinenicotinamide cocrystals from the amorphous state by in situ thermomicroscopy, spectroscopy and calorimetry studies. J Pharm Sci. 2007;96:11471158, 65. Chieng N, Hubert M, Saville D, Rades T, Aaltonen J. Formation kinetics and stability of carbamazepinenicotinamide cocrystals prepared by mechanical activation. Cryst Growth Des. 2009;9:23772386. 66. Rahman Z, Agarabi C, Zidan AS, Khan SR, Khan MA. Physicomechanical and stability evaluation of carbamazepine cocrystal with nicotinamide. AAPS PharmSciTech. 2011;12(2):693704. 67. Zaworotko M, Clarke H, Kapildev A, et al. Nutraceutical co-crystal compositions. US 2010/0204204, August 12, 2010.

68. 69.

70.

71. 72.

Childs SL. A cocrystal of metronidazole and gallic acid. US 2009/0258859, 10/15/2009; http://www.google.com/patents/US20090258859 Schultz DA. Crystal engineering of cocrystals of curcumin. http://chem web.rc.usf.edu/castle/view_abstract/df92dc2f8ea3d606aa8f98469a 4e6806/ Shim JH, Choi HS, Pugliese A, et al. ()-Epigallocatechin gallate regulates CD3-mediated T cell receptor signaling in leukemia through the inhibition of ZAP-70 kinase. J Biol Chem. 2008;283(42):28370 28379. Wang S, Chen J. Gossypol co-crystals and the use there of. 03/26/2009, Patent application number:20090082445. Brittain HG, Felice PV. Intravenous formulation with water-soluble cocrystals of acetylsalicylic acid and theanine, United States Patent Application US/2010-0286099, published November 11, 2010; http:// www.faqs.org/patents/app/20100286099#ixzz1pQeVOWst

RGUHS J Pharm Sci | Vol 2 | Issue 2 | AprJun, 2012

25