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206 Cocrystals in Pharmaceutical Sciences
of 2.78 times that of 5-FU alone. Moreover, the cocrystals demonstrated
greater cytotoxic activity against 4T1 mouse breast cancer cells [65]. In
another study, a slurry liquid-assisted grinding and solvent evaporation
approach was utilized to fabricate the cocrystals of rucaparib (Ruc)-
theophylline monohydrate (TPMH), Ruc-ethyl maltol, and Ruc-maltol. All
prepared cocrystals dissolved more rapidly than Ruc-camsylate salt at pH
2 and 4.5, with Ruc-TPMH having the maximum apparent solubility at pH
4.5 and 6.8. Pharmacokinetic studies on rats found that Ruc-TPMH had
2.4 times the C
max
and 1.4 times the AUC
0-24h
at a single dosage compared
to Ruc-Cam [66]. George and coworkers designed cocrystals of olaparib
(OLA) and kaempferol (KAE) for sustained release. Intrinsic dissolution
rate (IDR) tests indicated that OLA-KAE cocrystals had 0.40 times higher
IDR values than pure OLA. Dissolution tests lowered the dissolution rate
to 21.4% of the original drugs. Aer 3 months of accelerated conditions,
OLA-KAE cocrystals demonstrated improved physical stability. OLA-KAE
cocrystals inhibited ovarian cancer cells more eectively than OLA alone.
e OLA-KAE cocrystals were observed to be a viable strategy for gener-
ating prolonged-release formulations with increased pharmacological e-
cacy [67]. Yin and colleagues formulated cocrystals of oxaliplatin (OXA)
by employing baicalein and naringenin as cocrystal formers. Compared
to OXA, both cocrystals displayed a slower release rate and prolonged
hydrolysis. Cell toxicity was investigated utilizing the CCK-8 assay, which
established that OXA-naringenin was safer, while OXA-baicalein had
more substantial eects on suppressing cancer cells [68]. Table 7.5 lists the
reported cocrystals of anticancer drugs along with a method of prepara-
tions and key ndings. erefore, cocrystals are an eective strategy for
elevating both the ecacy and safety proles of anticancer drugs, includ-
ing potential enrichment in solubility, dissolution rates, bioavailability,
and, ultimately, therapeutic results.
7.4 Reported Drug-Drug Cocrystals
for Antituberculosis Drugs
Tuberculosis (TB) is a contagious disorder triggered by Mycobacterium
Tuberculosis (MTB), predominantly aects the lungs and is character-
ized by symptoms such as chronic coughing, fever, and chest pain [82].
It has emerged as a major global health concern in the previous few years
because development of multidrug resistance strains and rising poverty
[83]. For the management of TB, DDCs are gaining interest as they oer a
Drug-Drug Cocrystals: Advancements and Applications 207
promising, cost-eective strategy for developing enhanced drug delivery
with minimal risk. ese cocrystals have the potential to enhance both
physicochemical and biopharmaceutical properties without chemical
alterations [84]. In this context, Liu et al. fabricated isoniazid (INH)-QCT
cocrystals to address the severe hepatotoxicity associated with the isoni-
azid. e study outcomes revealed that the dissolution rate of QCT sig-
nicantly increased by 51.67 times. Furthermore, oral bioavailability in
rats was enhanced by 28.91 times. e INH-QCT cocrystals substantially
decreased hepatotoxicity related to INH. e ndings highlight potential
routes for reducing the toxicity of anti-TB drugs using the crystallization
process [85]. Similarly, Yadav et al. developed cocrystals of INH with hepa-
toprotective coformers such as syringic acid and QCT to tackle hepatotoxic-
ity. e investigation indicated elevated levels of alanine aminotransferase,
aspartate aminotransferase, and alkaline phosphatase enzymes among the
INH-treated group, while the levels found in the INH-synergic acid and
INH-QCT cocrystal–treated groups were similar to those in the untreated
group. Research showed favorable evidence for the ecacy of nutraceu-
tical coformers in alleviating hepatotoxicity linked with diverse drugs
[86]. Salem et al. fabricated cocrystals of 4-aminosalicylic acid and sulfa-
methazine via high-power ultrasound and high-pressure homogenization
(HPH). Both procedures yielded grade I cocrystals and exhibited high
crystallinity. HPH generated nanosized cocrystals, whereas high-power
ultrasound established microsized. At higher pressures, HPH resulted in
smaller, narrow-sized cocrystals with restricted distribution. HPH cocrys-
tals seemed needle-like, whereas high-power ultrasound showed a distinct
morphology. Both nano- and microsized cocrystals improved the sulfa-
methazine dissolution rate of both drugs [87]. Simultaneously, Sakamoto
et al. synthesized two cocrystals of quabodepistat, one with 2,5-dihy-
droxybenzoic acid (2,5-DHBA) and another with 2-hydroxybenzoic acid
(2-HBA). e prepared cocrystals had higher bioavailability in beagle
dogs, while the 2-HBA cocrystals had 1.4 times higher bioavailability.
Dissolution studies indicated similar dissolution proles for both cocrys-
tals, although the 2-HBA cocrystals dissolved more slowly at pH 1.2. e
ndings suggest its potential for improving the quabodepistat oral bio-
availability [88]. Likewise, Li and coworkers synthesized the cocrystals of
ethionamide and nutraceutical chrysin to reduce the hepatotoxic eect.
e research found that chrysin had an excellent hepatoprotective eect,
nearly eradicating the liver toxicity of ETA. is could boost ETA’s thera-
peutic ecacy, potentially alleviating the TB epidemic [89]. Additionally,
Table 7.6 outlined the identied cocrystals of antituberculosis drugs and
their key consequences.
208 Cocrystals in Pharmaceutical Sciences
Table 7.6 Cocrystals of anti-TB drugs and their enhanced properties.
Drug Coformers
Synthesis
method Salient outcomes Ref.
Prothionamide Salicylic and
fumaric acid
Neat/solvent-
drop
grinding
and slow
evaporation
Fivefold increased
aqueous solubility
compared to the
crystalline form of
prothionamide.
[90]
Isoniazid Glutaric acid Solid-state
and
solvent-
assisted
grinding
Isoniazid-Glutaric
acid
Enhanced solubility
in dierent pH
environments and
in Pyrazinamide-
glutaric acid
improved
solubility in
dierent pH
environments.
[91]
Pyrazinamide Diunisal Liquid-
assisted
grinding
Improved the
physicochemical
properties and
therapeutic
activity of a drug
[92]
Rifampicin +
pyrazinamide
+ ethambutol
dihydrochloride
Isoniazid-caeic
and vanillic
acids
--- Enhanced stability of
drugs
[93]
4-aminosalicylic
acid
Isonicotinamide
and caeine
Solvent-drop
grinding
Improved solubility
and stability
[94]
Isoniazid Curcumin Rapid solvent
evaporation
Sustained release of
isoniazid
[95]
Isoniazid Protocatechuic
acid
Slow
evaporation
Enhanced stability
but reduced
solubility at pH 7.2
[96]
(Continued)
Drug-Drug Cocrystals: Advancements and Applications 209
erefore, cocrystals of anti-TB drugs represent a promising method,
oering improved drug properties as well as reduced associated side eects.
7.5 Reported Drug-Drug Cocrystals for Diuretics
Diuretics are drugs designed to promote urine production, commonly
employed in the management of disorders such as edema, hypertension,
and heart failure [100]. Diuretics with limited aqueous solubility and per-
meability have led to the development of cocrystals for improving their
properties. Zhang et al. synthesized two novel solid forms of acetazolamide
(ACZ) to elevate its solubility and permeability. ese forms include a salt
containing piperazine and a crystal having theophylline. According to dis-
solution and in vitro permeation assays, the ACZ solubility and permea-
bility were improved by cocrystal and salt. In conclusion, salt production
was more helpful in enhancing solubility while cocrystallization might
dramatically enhance the permeability [101]. Likewise, Acebedo-Martinez
et al. developed cocrystals using furosemide and two popular NSAIDs,
ethenzamide and piroxicam. e prepared samples were subjected to XRD,
infrared spectroscopy, solubility, thermal analysis, and stability. e phys-
icochemical properties were assessed, and the nding showed that the sol-
ubility improved in NSAIDs but not in furosemide. Additional research is
needed to assess drug-drug interaction in these unique multicomponent
Table 7.6 Cocrystals of anti-TB drugs and their enhanced properties.
(Continued)
Drug Coformers
Synthesis
method Salient outcomes Ref.
Piperazine-ferulate Pyrazinamide Liquid-
assisted
grinding
Reduced dissolution
and solubility rate
and sustained
drug release
[97]
Isoniazid Resveratrol --- Decreased skin
permeation by
reducing solubility
[98]
5-uorocytosine Isoniazid Slow
evaporation
Improved stability
of drug without
impairing
solubility of drugs
[99]
210 Cocrystals in Pharmaceutical Sciences
solids [102]. In another study, Narala et al. fabricated hydrochlorothia-
zide (HCT) cocrystals by using resorcinol (RSL), nicotinamide (NIC),
and catechol (CAT) as coformer via liquid-assisted grinding and hot-melt
extrusion approach. Drug-coformer interactions resulted in greater sol-
ubility and higher diusion/permeability for HCT-CAT and HCT-RSL.
According to the study, hot-melt extrusion is an attractive method for syn-
thesizing cocrystals within industrial scale-up [103]. Furosemide (FSM)
is an eective diuretic prescribed for the management of congestive heart
failure and edema, but it has low oral bioavailability. To tackle this issue,
researchers synthesized salt and cocrystals of FSM with imidazole (IMZ)
and 5-uorocytosine (5-FCN) coformers. e new solid form’s structural
properties were examined through XRD, FTIR, and NMR spectroscopy.
FSM-IMZ and FSM–5-FCN cocrystals showed substantial improvement in
solubility, intrinsic dissolution, and permeability when compared to FSM
alone. ese ndings suggest a potential approach to enhance FSM bio-
availability [15]. e HCT molecular cocrystals by Sanphui and coworkers
were produced utilizing nicotinic acid, nicotinamide-aminobenzoic acid,
succinamide, resorcinol, and pyrogallol as coformer. Solubility and stabil-
ity tests were carried out in water under ambient conditions. e cocrystal
with p-aminobenzoic acid had a sixfold improvement in solubility over
HCT and was stable in an aqueous solution for 24 hours. e cocrystals
containing resorcinol, nicotinamide, and pyrogallol had a 1.5- to 2-fold
rise in solubility and converted into HCT within 1 hour of dissolution
[104]. Similarly, Ranjan and associates utilized a cocrystallization approach
to fabricate the HCT cocrystals with water-soluble coformers phenazine
(PHEN), 4-dimethylaminopyridine (DMAP), and picolinamide (PICA). It
was found that HCT-DMAP and HCT-PHEN cocrystals were 4 and 1.4
times more soluble than the free drug. e study suggests the choice of
coformer with considerable eect on the physicochemical characteris-
tics of HCT. Additionally, it recommends cocrystallization as an attrac-
tive strategy for enhancing the solubility of the HCT in water [105]. Table
7.7 summarizes the cocrystal formulation of diuretics along with salient
outcomes.
In summary, cocrystals of diuretics represent a signicant advancement
in pharmaceutical sciences, to revolutionize treatment paradigms by oer-
ing optimized therapeutic formulations with enhanced ecacy and safety
proles.
Drug-Drug Cocrystals: Advancements and Applications 211
Table 7.7 Enhanced therapeutic ecacy of diuretics with cocrystals.
Drug Coformers Synthesis method Salient outcomes Ref.
ACZ eophylline Liquid-assisted
grinding
and solvent
evaporation
Enhanced
solubility and
permeability
[101]
Ethenzamide +
Piroxicam
Furosemide Mechanochemical Improved
solubility of
ethenzamide
and piroxicam
[102]
HCT Nicotinamide Hot-melt extrusion Improved the
twofold
solubility of
HCT
[103]
Spironolactone Tryptophan --- reefold
enhancement
in the
dissolution
rate in
comparison to
the pure drug
spironolactone
[106]
Acetazolamide 4,4-bipyridine-
N,N-dioxide
--- Increased
solubility and
permeability.
[107]
HCT Metformin
hydrochloride
Mechanochemical Increased 1.21-
fold solubility
of HCT.
[108]
FSM Cytosine Liquid-assisted
grinding
11-fold higher
solubility than
pure FSM.
[109]
FSM Nicotinamide Slurry High stability at
25
°
C
[110]
(Continued)
212 Cocrystals in Pharmaceutical Sciences
7.6 Reported Drug-Drug Cocrystals
for Miscellaneous Drugs
Various DDCs have been developed for a wide range of drugs beyond
those mentioned above. erefore, miscellaneous DDCs are summarized
in Table 7.8.
Overall, the aforementioned investigations indicated that DDCs are an
eective strategy for enhancing the performance of diverse drugs, with
Table 7.7 Enhanced therapeutic ecacy of diuretics with cocrystals. (Continued)
Drug Coformers Synthesis method Salient outcomes Ref.
FSM Piperazine Liquid-assisted
grinding
ree times
higher
solubility as
compared
to FZM-
piperazine salt.
[111]
FSM Isnicotinamide Solvent-assisted
mechanochemical
FSM-is
nicotinamide
has higher
apparent
solubility than
FSM.
[112]
Table 7.8 Cocrystals of various drugs for the management of numerous
disorders.
Drug Coformers Diseases
Preparation
methods Key ndings Ref.
Genistein Piperazine Diabetes, tumors,
cardiovascular
diseases, and
menopausal
symptoms
Grinding-
assisted and
solvent-
based
Enhanced solubility
and bioavailability
[113]
Ibrutinib Ketoconazole Lymphoproliferative Liquid-assisted
grinding
Elevated dissolution
rate, solubility, and
oral bioavailability
of both drugs
[114]
(Continued)
Drug-Drug Cocrystals: Advancements and Applications 213
Table 7.8 Cocrystals of various drugs for the management of numerous
disorders. (Continued)
Drug Coformers Diseases
Preparation
methods Key ndings Ref.
Favipiravir eophylline Respiratory viral
infections
Rotary
evaporation
and spray
drying
Enhanced dissolution
rate
[115]
Apixaban Quercetin rombosis Slurry Improved solubility,
bioavailability, and
stability
[116]
Azithromycin Paracetamol Microbial infection Slow solvent
evaporation
Increased solubility
and antimicrobial
activity
[117]
Metaxalone Nicotinamide Muscle pain --- Elevated solubility,
bioavailability,
and mitigated side
eects
[118]
Nitrofurantoin Trimethoprim Urinary infection --- Increased antibacterial
activity against
gram-negative
at minimum
concentration
[119]
Levooxacin Metacetamol Bacterial infection Grinding Improved
photostability
and reduced
hygroscopicity of
levooxacin
[120]
Milrinone Ferulic acid Cardiovascular
diseases
--- Improved solubility
and permeability,
extended half-life,
and bioavailability
of drugs
[121]
Nicorandil Suberic acid Angina pectoris --- Increased solubility
and dissolution rate
[122]
Levooxacin Metacetamol Bacterial infection Liquid-assisted
grinding
Improved
photostability of
levooxacin
[123]
Efavirenz Nevirapine Viral infection Solvent-
assisted
grinding
Showed a synergistic
eect
[124]
214 Cocrystals in Pharmaceutical Sciences
potential advantages including increased solubility, stability, and bioavail-
ability. Continued research and development in the eld have the potential
to generate advanced pharmaceutical formulations that improve patient
health.
7.7 Patent Perspectives
DDCs are being developed to improve the pharmacokinetic and pharma-
codynamic characteristics of drugs for the successful treatment of numer-
ous disorders. Cocrystals have shown a wide range of benets including
improved dissolution, solubility, bioavailability, and stability. As a result, to
accomplish the advantages mentioned above, there has been a progressive
rise in patent lings for cocrystals, as seen in Table 7.9.
Table 7.9 Patents related to drug-drug cocrystals.
Patent table
S. no.
Patent no./
application no.
Title Description Reference
1 US20120258170A1 Pharmaceutical
cocrystals.
Improved solubility, IDR,
stability, and great
therapeutic potential
were obtained. Its
composition comprises
quercetin and
metformin.
[125]
2 EP1608339B1 Pharmaceutical
cocrystal of celecoxib-
nicotinamide.
Increased aqueous
solubility and
stability. It consists
of a combination
of celecoxib and
nicotinamide.
[126]
3 WO2017191539
A1
Process for the
preparation of
dl-proline cocrystal of
dapagliozin.
Enhanced bioavailability,
enhanced galenic
properties, or higher
purity and used in the
treatment of patients
with type 2 diabetes.
[127]
(Continued
)
Drug-Drug Cocrystals: Advancements and Applications 215
Table 7.9 Patents related to drug-drug cocrystals. (Continued)
Patent table
S. no.
Patent no./
application no.
Title Description Reference
4 US8124603B2 In vivo studies of
crystalline forms of
meloxicam.
Improved bioavailability
enhanced the rate of
dissolution and shorter
time to Cmax in blood,
as compared to pure
meloxicam.
[128]
5 US6001996A Complexes of
cephalosporins and
carbacephalosporins
with parabens
Maximize overall
yield. is invention
relates to novel
cephalosporin and
carbacephalosporin/
paraben complexes.
[129]
6 US7625910B2 Cocrystal Less needs to control
in the manufacturing
process. Useful in
the treatment of
hyperproliferative
diseases such as cancer.
[130]
7 EP3210975 A1 Cocrystals of lorcaserin
Promote weight loss
through satiety. Its
composition consists
of (R)-lorcaserin
hydrochloride with
(+)-di-p-toluoyl-
D-tartaric.
[131]
8 WO2017172811
A1
Novel cocrystals e pharmaceutical
composition is in the
form of an injectable
depot for extended
release.
[132]
(Continued
)