Review Article
Nutraceutical Cocrystals: An overview
Bhupinder Singh Sekhon
PCTE Institute of Pharmacy, Jhande, Near Baddowal Cantt (Ludhiana)-142 021, Punjab, India
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 | Apr–Jun, 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. Crystal’s 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.7–9 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.10–13
Drops of solvent have been shown to influence the
crystallization effect.14–17 A detailed description of various
methods for preparation of cocrystals that applies to
nutraceuticals cocrystals synthesis is described below:
Slow evaporation (solution crystallisation)
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.
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
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
Mechanochemical methods
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
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
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 | Apr–Jun, 2012
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 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
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
Supercritical fluids
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.
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
η, the ratio of solvent volume to sample weight. The
formation of the cocrystal was observed in all standard
LAG experiments when η = 0.25 µL mg−1. Cocrystal
formation by neat grinding was observed only for
the cocrystal of theophylline and L-malic acid. LAG
experiments at very low η values (below 0.5 µL mg−1)
revealed that the rate of cocrystal formation depended on
the choice of the liquid and increases with η. SonicSlurry
experiments performed at higher η values of 2, 6 and
12 µL mg−1 provided three different outcomes: the pure
cocrystal, a mixture of the cocrystal with a cocrystal
component, or a single cocrystal component. LAG
experiments at η = 10 µL mg−1 produced results consistent
with the SonicSlurry experiments at η = 12 µL mg−1.
Solvent free co-crystallisation
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
RGUHS J Pharm Sci | Vol 2 | Issue 2 | Apr–Jun, 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
O
OH
Nutraceuticals cocrystallization
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 | Apr–Jun, 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
H3C
O
OH
HO
O
CH3
A
OH
B
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 2.5× lower
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 γ-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 (160 °C) 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 acid–imidazole
heteromeric synthon; however, one polymorph also
has a hydroxyl–carbonyl synthon (Form I), while in
the other a hydroxyl–imidazole 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
(COOH···N).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.
Curcumin–resorcinol (1:1) and curcumin–pyrogallol
(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 O–H···O 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
curcumin–resorcinol and curcumin–pyrogallol in 40%
EtOH–water 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 | Apr–Jun, 2012
Bhupinder Singh Sekhon: Nutraceutical Cocrystals: An overview
O
OH
OH
HO
OCH3
OCH3
Figure 3: Structure of Curcumin.
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 C–OH 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, 3’4, 4’, 5–7-pentahydroxyflavone, Figure 4)
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 (68 mg)
and caffeine (38 mg) in methanol (5 ml) 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 | Apr–Jun, 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 (67.6 mg) and isonicotinamide (24.6 mg) in methanol (5 ml) 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, CO…OH and NH…OH supramolecular
heterosynthons and OH…OH supramolecular homosynthons. One of the two hydrogen atoms in the amino
OHe
OHd
OHa
O
A
B
C
OHc
OHb
O
Figure 4: Structure of quercetin.
21
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 NH…CO and NH…OH
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 CO…OH and N atom …OH 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 (60 mg) and isonicotinamide
(24.6 mg) in ethanol (5 ml) 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 (QUETBR·2H2O) were
OHc
OCH3
OHa
O
A
B
C
OHc
OHb
O
Figure 5: Structure of hesperetin.
22
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 QUECAF·MeOH
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
(10.635 g) and NCT (5.497 g) were added to 500 ml of a
round-bottom flask attached to a condenser containing
200 ml of 70:30% (v/v) ethanol/methanol mixture using
solution cooling crystallization method. Solids dissolved
in the solvent were heated at 65°C and refluxed for 1 h
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 20 ml of ethanol, and
vacuum oven-dried at 30°C for 48 h. Dried cocrystals
obtained were crushed and passed through a sieve
60 ASTM. In cryomilling method, an equimolar ratio of
CBZ (1.181 g) and NCT (0.611 g) 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 2 min before
the milling operation using liquid nitrogen as coolant.
The cryomill was operated for three cycles at 10 rpm/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 | Apr–Jun, 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 100–200 mg 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 C1–8 carboxylic acid or C1–8 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 C1–8 carboxylic acid or C1–8 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 | Apr–Jun, 2012
NH2
HO
NH
CH3
O
O
Figure 6: Structure of theanine.
equilibrium solubility of 10 mg/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.
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