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266 Cocrystals in Pharmaceutical Sciences
ere are two categories of “supramolecular synthon,” i.e., “homosynthon”
having the “same” functional group and “heterosynthon” having a “dier-
ent” functional group [33]. Combining more than two drugs in a single
dose has developed a popular drug-development approach and also in the
growth of cocrystals. Mixing more than two drugs in the preparation of
a cocrystal is called a drug-drug cocrystal [34]. In recent years, meloxi-
cam-aspirin, tramadol hydrochloride–celecoxib, metformin-glipizide, and
many more as drug-drug cocrystals have already been reported [33].
9.6.2 Amino Acid in Cocrystal to Enhance Solubility
It is considered that amino acids are the construction blocks of polypep-
tides and protein, which play crucial roles in food as well as tness. e
functions of the amino acid include “cell signaling,” osmolyte synthesis,
gene expression, regulation of hormone secretion, and protein synthesis.
ey are widely available in wheat, corn, rice, sorghum, etc. and they are
considered as commonly regarded as harmless compounds. Since, they
have a great propensity to develop a possible bond like “hydrogen bonds”
with several groups like pyridyl, phenolic hydroxyl, hydroxyl, and carboxyl.
In addition, they are known to have low toxicity [34]. For all those reasons,
the amino acid is used as a coformer in the formation of a cocrystal with
additional benets. Liquid-assisted grinding (LAG), SE, and neat grind-
ing are well-developed reported techniques for preparing cocrystals using
amino acids. Myricetin-proline cocrystals exhibited an enhanced drug
release when compared with the physical combination and pure myricetin
[35]. A similar study conducted to prepare a cocrystal of acetazolamide–
L-Proline exhibited higher solubility than pure acetazolamide with an
increasing value of pH [36]. Other studies also revealed improved solubil-
ity as well as dissolution in cocrystals of diclofenac sodium with L-proline
trihydrate as well as L-proline monohydrate [37]. LAG techniques were
also used in indomethacin [20], diclofenac with L-proline [38], and chlo-
rothiazide with a number of coformers [39], and all studies presented a
higher solubility than the pure drug. Overall, it can be explained that the
use of amino acid as a coformer is superior in developing a safer, simple,
environmentally friendly formulation for drug solubility enhancement.
9.6.3 Polymeric Eect on Cocrystallization
Polymeric excipients, which can improve drug delivery and act as pro-
gressive coformers rather than small molecules, have not been explored
Cocrystals for Solubility Enhancement 267
extensively previously. Nevertheless, in eorts to enhance the eectiveness
of poorly solvable medications, a range of polymers have been employed
in solid dispersion techniques. ese typically involve drug-polymer
systems comprising two components, with the molecularly dispersed drug
within an amorphous polymer matrix. In addition to these methods, lim-
ited instances of drug-polymer crystalline inclusion complexes have been
documented.
Until now, the majority of pharmaceutical cocrystals have consisted
of API paired with small molecules of coformers like saccharin, nicotin-
amide, and succinic acid. Conversely, instances of cocrystals among API
and polymers have been relatively limited, with examples such as hydroxy-
benzenes-PEG cocrystals [40, 41].
9.6.4 Cocrystals of Herbal Bioactive to Enhance Solubility
Herbal bioactives as the natural compounds sourced from plants are usu-
ally chosen widely because of their synergistic eect. Direct administra-
tion of these compounds comes across several problems like low water
solubility, least permeability through the membrane, and limited stabil-
ity leading to low bioavailability. To boost the aqueous solubility of herbal
bioactives like curcumin, naringenin, berberine, quercetin, resveratrol,
and baicalein, the cocrystallization technique was used in several previ-
ous studies [42]. Coformers like resorcinol and pyrogallol were used with
curcumin by using the LAG method and the study demonstrated 5- and
12-time increases in solubility with resorcinol and pyrogallol, respectively
[43]. Several other coformers like salicylic acid [44], N-acetylcysteine [45],
hydroxyquinoline [44], nicotinamide, tartaric acid, p-hydroxybenzoic acid
[46], ascorbic acid [47], hydroxyquinol, trimesic acid, succinic acid, parac-
etamol, salicylic acid, and folic acid dihydrate [47] were used, and in every
study, it exhibited enhanced solubility of curcumin.
In the case of quercetin, various coformers were used, including caf-
feine, isonicotinamide, isonicotinic acid, nicotinamide, theobromine
dihydrate, malonic acid, succinic acid, and picolinic acid. Various meth-
ods like slow evaporation, grinding, and LAG methods are used, and in
each study, the increased solubility was observed by several folds [48–54].
For instance, quercetin-caeine cocrystals enhanced (14 times) the sol-
ubility [48], and quercetin–picolinic acid cocrystals demonstrated a
10-time increase in solubility [51]. ere are several other herbal bioac-
tives where cocrystallization techniques were used to enhance the solu-
bility as listed in Table 9.1.
268 Cocrystals in Pharmaceutical Sciences
Table 9.1 Solubility enhancement of herbal drugs by cocrystallization technique.
Herbal
bioactive Description Coformer Method used Result Reference
Berberine Isoquinoline alkaloid;
biological activities
like antibacterial,
anti-inammatory,
anticarcinoma,
and antidiabetic;
poor oral
absorption and low
bioavailability
Fumaric acid Recrystallization and slurry
method
e dissolution rate
increased by three
times
[55]
Citric acid Physical mixture Enhanced solubility [56]
Myricetin and
dihydromyricetin
SE Enhanced solubility for
both the cocrystal
[57]
L (+)-lactic acid Physical mixing Increased solubility [58]
Pimelic acid, adipic acid,
succinic acid, and
glutaric acid
Slow-evaporation technique Improved solubility,
cocrystal with pimelic
acid showed maximum
dissolution prole
[59]
3-methylcinnamic acid SE Solubility enhanced by
13.9, 1.5, 4.7, and
15.8 times in water,
methanol, ethanol,
and isopropanol,
respectively
[60]
(Continued)
Cocrystals for Solubility Enhancement 269
Table 9.1 Solubility enhancement of herbal drugs by cocrystallization technique. (Continued)
Herbal
bioactive Description Coformer Method used Result Reference
Resveratrol Polyphenolic
stilbenoid; activity
as antiviral,
antimicrobial,
cardioprotective,
estrogenic,
immunoprotective,
and
neuroprotective;
low solubility and
<1% bioavailability
Isoniazid and
nicotinamide
Gas antisolvent technique Enhanced dissolution
prole
[61]
Isoniazid and
4-aminobenzamide
LAG and SE Increased solubility and
tabletability
[62]
Ascorbic acid Evaporation method Bioavailability enhanced
by 3.73-folds and
increased AUC, C
max
[63]
L-proline Recrystallization method 15.8% increase in
solubility and
dissolution
[64]
Naringenin Flavonoids; possess
anticancer,
anti-bacterial,
antioxidant,
antiviral, anti-
inammatory, and
cardioprotective
activity
Isonicotinamide, picolinic
acid, and betaine
Evaporation technique Improved solubility and
dissolution rate
[65]
(Continued)
270 Cocrystals in Pharmaceutical Sciences
Table 9.1 Solubility enhancement of herbal drugs by cocrystallization technique. (Continued)
Herbal
bioactive Description Coformer Method used Result Reference
Baicalein Flavonoids; have
activities like
anti-inammatory,
antitumor,
antioxidant, and
cardioprotective
Nicotinamide High-pressure
homogenization
2.17 times increased
solubility
[66]
Myricetin Flavonoids; have
anticancer,
antioxidant, and
anti-inammatory
activity
Caeine SE 17-time increase in
dissolution prole
[67]
eobromine Bitter alkaloid;
antioxidant, anti-
inammatory
activity
“2,3-dihydroxybenzoic
acid,
3,4-dihydroxybenzoic
acid,
2,5-dihydroxybenzoic
acid,
2,4-dihydroxybenzoic
acid,
2,6-dihydroxybenzoic
acid, 3,5-
dihydroxybenzoic acid”
LAG and slow evaporation
technique
4.4 to 26 times enhanced
solubility
[68]
(Continued)
Cocrystals for Solubility Enhancement 271
Table 9.1 Solubility enhancement of herbal drugs by cocrystallization technique. (Continued)
Herbal
bioactive Description Coformer Method used Result Reference
Chrysin Flavone compound;
activity against
inammation,
erectile
dysfunction, gout,
anxiety
iamine and cytosine Solvent-drop grinding
method
Enhanced solubility by
means of three to four
times
[69]
Fisetin Flavonoid,
active against
inammation and
cancer
Caeine and
nicotinamide
Cooling crystallization Twofold increase in
solubility
[70]
Piperine Alkaloid-based
compound
Saccharin SE Enhanced dissolution [71]
Hesperetin Flavonoids found
in citrus fruits;
activity against
tumors, and
inammation,
and act as an
antioxidant
Picolinic acid, caeine,
and nicotinamide
Solvent-drop grinding Four- to vefolds
solubility enhanced
[72]
272 Cocrystals in Pharmaceutical Sciences
9.6.5 Solubility Enhancement of Anticancer Drug
via Cocrystallization
Because of the huge global concern for public health, solubility enhance-
ment of anticancer drugs is very important. Approximately 19 million new
cases and 10 million cases of death were reported in 2020 according to the
Global Cancer Observatory (GCO). In this conict on cancer, it has been
projected that, possibly, there will be 16 million death cases reported in the
next decade. Over the past few decades, it has been noticed that science
and technology trying to ll the gaps related to cancer drug delivery and
most treatments are solely through the parenteral route. However, paren-
teral routes are easy to administer, but looking at the frequency and patient
compliance, the “oral” administration involves a lot of friendly consider-
ation and delivers the drug conveniently due to its comfort and safety, as
well as acceptance. However, lower water-solubility, low permeability, rst-
pass metabolism, and higher eux ratio hamper the bioavailability, par-
ticularly the chemotherapeutic compound. Previously, many eorts have
been applied like nano-formulations, complexation, crystal engineering,
and lipid-based systems to overcome the solubility problem and improve
the properties of the drug compound. Physiological parameters like sol-
ubility, hygroscopicity, dissolution, and stability can aect a compound’s
therapeutic eectiveness. To escape from this issue, cocrystallization is
best suited for preparing a stable form of any drug without changing the
chemical form at the molecular level. Most anticancer APIs are weakly
basic or acidic and have similar pKa values which is an advantage for
choosing coformers such as amides, carboxylic amides, polyphenols, and
carboxylic acid. Very few anticancer drugs are zwitterion like paclitaxel.
e most commonly used coformer is nicotinamide and its derivative
for the cocrystallization of anticancer drugs. Having pyridine and amide
groups, they act like primary synthons [73]. Most of the studies focused
on the improvement of solubility of any poorly water-soluble compound
by using various techniques of cocrystallization. Even though solubility is
the rate-limiting factor in oral bioavailability, metabolism may be a signif-
icant factor in a drug’s bioavailability. Sometimes, cocrystal preparation
increases the dissolution prole rather than improving solubility. Faster
dissolution enhances the faster absorption in the GI tract by decreasing
Tmax.
Apatinib cocrystallization (low oral bioavailability) with three vari-
ous coformers, i.e., sebacic, mandelic, and adipic acid, in a recent report,
improved both solubility and bioavailability [74]. is study suggested that
apatinib–sebacic acid cocrystals give a 7.5-fold increase in solubility along
Cocrystals for Solubility Enhancement 273
Table 9.2 Cocrystallization of the anticancer drug for improved activity.
Anticancer drug Coformers Method used Result References
Ethylene
bipyridine
Flavone compounds Vaporization of solvent Increased solubility and also enhanced
eect against HCT-8 and Caco-2
cancer cells
[74]
5-Fluorouracil
(5-FU)
Urea, thiourea, and
pyrazinamide
Supercritical antisolvent
(for crystallization)
and supercritical
solvent (for
co-crystallization)
Improved solubility and anticancer
activity
[75]
Acetanilide, thiourea,
urea, aspirin
Solid-state grinding,
non-grinding method
Enhanced solubility and percent growth
inhibition were observed through MTT
assay against HCT 116 colorectal cell
line study by all the cocrystals
[76]
3,4-dihydroxybenzoic
acid, gentisic acid,
4-aminopyridine,
solution crystallization
and solvent-assisted
grinding
Enhanced permeation and 2-3-folds
improved in relative bioavailability
studied in rat skin, cell viability
dropped by cocrystals in MCF-7, Hela,
and Caco-2 cell line which indicate
improved antitumor activity
[77]
(Continued)
274 Cocrystals in Pharmaceutical Sciences
Table 9.2 Cocrystallization of the anticancer drug for improved activity. (Continued)
Anticancer drug Coformers Method used Result References
2,5- Dihydroxybenzoic
acid (25DHBA),
34DHBA, 35DHBA
Slurry and liquid
assisted grinding
method
5FU-34DHBA and 5FU-34DHBA.2H
2
O
showed increased solubility (34%
and 11%), while 5FU-35DHBA and
5FU-25DHBA resulted in decreased
solubility (27% and 51%). e
pharmacokinetic parameters, including
Cmax, tmax, and t
1/2
, were also altered
in vivo pharmacokinetic study
[78]
Mercaptopurine Zinc triate SE Enhanced the ability to be dissolved in
aqueous solvent
[79]
Axitinib Cinnamic acid and
fumaric acid
Slurry method and LAG Improved solubility and dissolution
without compromising stability
[80]
Glutaric acid Slurry method Enhanced solubility and stability [81]
Betulinic acid Ascorbic acid Slow evaporation
technique
Rise in solubility and bioavailability and
showed superior cytotoxic activity on
tumor cell lines, i.e., HaCat, B164A5,
B16F0, MCF7, and MDA-MB-231
[82]
Baicalein Nicotinamide Slurry method Improved dissolution, solubility, and
bioavailability
[66]
(Continued)
Cocrystals for Solubility Enhancement 275
Table 9.2 Cocrystallization of the anticancer drug for improved activity. (Continued)
Anticancer drug Coformers Method used Result References
Artemisinin Acetylene dicarboxylic
acid
Co-grinding without
solvent
Enhancement of solubility [83]
Ceritinib Quercitin and
nicotinamide
Neat grinding Improved solubility and stability [84]
Dasatinib Vanillin, ethyl gallate,
methyl gallate, propyl
gallate, nicotinamide,
and N-methyl-4-
hydroxybenzoate
SE Better solubility, bioavailability, and
stability
[85]
Doxorubicin Maraviroc Slow SE technique Solubility improved [86]
Docetaxel Nicotinamide Slow SE technique Rise in dissolution, solubility, and
penetration properties
[87]
Emodin Nicotinamide SE Oral absorption, improved solubility, and
bioavailability
[88]
(Continued)