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306 Cocrystals in Pharmaceutical Sciences
planes, and weakened API-API interactions to reduce punch sticking [38].
e mechanical properties of chlorzoxazone-picolinic acid cocrystals were
assessed through compaction analysis. Tablets produced with the cocrys-
tals achieved tensile strengths of about 1.6 MPa at 250 MPa compaction
pressure without tablet defects (capping or lamination). e formation of
cocrystal-based tablets of chlorzoxazone improved the mechanical prop-
erties which were just 0.8 MPa at compaction pressure 50 MPa, reecting
enhanced plastic deformation and bonding ability due to the cocrystal’s
denser packing structure [39]. Nanoindentation experiments revealed that
caeine-glutaric acid cocrystal polymorphs exhibited anisotropic mechan-
ical responses depending on the crystalline face, with form I being soer
and form II harder due to dierences in intermolecular interactions and
potential slip planes [37].
As shown in the case studies, cocrystals of caeine-glutaric acid, celecoxib–
L-proline, and chlorzoxazone-picolinic acid exhibited enhanced plastic
deformation, reduced punch sticking propensity, and improved tablet ten-
sile strength compared to the respective parent drugs. ese improvements
in mechanical behavior are crucial for the successful development and
manufacturing of solid dosage forms, as they enable better compaction,
reduced processing issues, and more robust nal products. Ultimately, the
ability to engineer cocrystals with optimized mechanical properties can
lead to more consistent drug delivery and improved therapeutic outcomes
for patients.
10.3.1.5 Optical Properties
Cocrystallization can modify the colors and uorescence of pharmaceuti-
cal actives by tuning intermolecular pi-pi stacking, hydrogen bonding, and
charge transfer interactions in the crystal lattice [1]. Cocrystal form I of
furosemide and 4,4-bipyridine appeared pale yellow while form II appeared
orange. It was proposed that the dierent p-stacking patterns and hydrogen
bonding interactions in the two polymorphic structures led to their distinct
colors [40]. Menadione is known to undergo [2+2] photodimerization upon
exposure to sunlight. However, cocrystals of menadione with 1-hydroxy-
2-naphthoic acid, 6-hydroxy-2-naphthoic acid, and sulfamerazine did not
show any noticeable color change or degradation aer illumination for 5 days,
whereas menadione alone changed color noticeably. It was proposed that
the enhanced pi-pi stacking between menadione and the coformers acted
to block menadione molecules from approaching each other to undergo
photocyclization [41]. Phloretin cocrystals with nicotinamide showed
strong yellowish-green uorescence under UV light, whereas the phloretin-
Cocrystals for Enhancing Therapeutic Efficacy 307
isonicotinamide cocrystal did not uoresce. e distinct luminescent prop-
erties were attributed to dierences in packing arrangement and intermolec-
ular interactions between the molecules in the two cocrystals [42].
As demonstrated, cocrystals exhibited distinct color variations and
luminescent behavior compared to pure drug substances, attributed to
altered intermolecular interactions and packing arrangements. Such modi-
cations in optical characteristics may provide insights into the underlying
structural changes that can impact the stability, solubility, and therapeutic
ecacy of the drug.
10.3.2 Enhancing Stability and Shelf Life
Improving the stability of drugs during manufacturing, storage, and trans-
portation is essential for pharmaceutical applications. Drug stability is
impacted by various degradation pathways such as hydrolysis, oxidation,
isomerization, and dimerization that can occur in the solid state [43].
Cocrystal engineering has been shown to eectively enhance the stability of
drug molecules through the manipulation of crystal-packing interactions
[27]. When a drug is incorporated into a crystalline lattice with a coformer,
its molecular environment is altered in a way that can inhibit degradation
reactions (Figure 10.3). For example, cocrystallization can increase the
distance between reactive sites on drug molecules, prevent close contacts
that catalyze degradation, or place the drug in a microenvironment with
Drug Coformer Hydrogen bond Functional group
H
2
O
H
2
O
Enhanced chemical
stability
Coformer forms bond with
those functional groups
Functional group
prone to hydrolysis
Chemical stability
Isomerization
Coformer inhibit
molecular motion
Coformer
Unstable
coformer
Stable coformer
with enhance
chemical stability
Hydration
Hydrogen bond
interaction
Figure 10.3 Coformer-drug interactions are the key to enhancing drug stability.
308 Cocrystals in Pharmaceutical Sciences
opposing properties that shield it from degradation [1]. Several stabili-
ty-enhanced cocrystals have demonstrated improved long-term stability
and resistance to degradation under stress conditions like heat, light, and
humidity. By improving drug stability through cocrystallization, the shelf
life of pharmaceutical products can be prolonged, allowing for extended
expiration dates that facilitate manufacturing, distribution, and patient
usage of medicines [27]. Major ways in which cocrystals can enhance the
stability and shelf life of pharmaceutical products:
Coformers interact with drug molecules through various forces, such
as hydrogen bonding, electrostatic interactions, and Van der Waals
forces. is helps stabilize the drug molecule and prevent its degradation.
Coformers can also protect the drug molecule from the eects of the envi-
ronment, such as moisture and light. e overall eect of these interactions
is to enhance the chemical stability of the drug molecule and improve its
therapeutic ecacy. e gure is adapted from (Singh et al., 2023; https://
doi.org/10.3390/pharmaceutics15041161) published under a CC4 license.
10.3.2.1 Changing the Reaction Cavity/Environment
Cocrystallization can increase the distance between reactive sites on drug
molecules that undergo degradation reactions like hydrolysis, preventing
close contacts that can catalyze the reactions [1]. is enlarges the reac-
tion cavity and sterically hinders degradation. is is demonstrated in the
case of nicorandil (NCD). NCD is an anti-anginal drug that readily under-
goes degradation under humid, heat, and mechanical stress conditions
through a cyclic degradation pathway. In the crystal structure of NCD,
the distance between the nitrogen atom (N1) of the pyridine ring and the
carbon atom (C8) of the ethyl group is 3.367 Å, which is shorter than the
sum of van der Waals radii of C and N. is close contact between N1
and C8 facilitates the degradation process by stabilizing the carbocation
(C8+) intermediate. Guo et al. developed NCD cocrystals with coformers
like 1-hydroxy-2-naphthoic acid and salicylic acid. e X-ray crystal struc-
tures of these cocrystals revealed that the distances between N1 and C8
were elongated and exceeded the van der Waals radii sum. As a result, the
C8+ carbocation in the degradation intermediate cannot be stabilized by
N1, inhibiting the catalyzed eect on NCD decomposition. Consequently,
all NCD cocrystals exhibited signicantly enhanced hydrothermal stabil-
ity compared to NCD alone. is case study illustrates how cocrystalli-
zation with suitable coformers can enlarge reaction cavities and increase
distances between reactive sites, sterically hindering degradation reactions
Cocrystals for Enhancing Therapeutic Efficacy 309
from occurring. is imparts greater stability to labile drug molecules like
NCD [44].
10.3.2.2 Alteration of Solid-State Properties
Properties like crystallinity, density, and polymorphic form inuence
molecular mobility and packing interactions in crystals. Cocrystals can
modify these properties in a way that restricts molecular movement and
interactions leading to degradation. Epalrestat (EPR) is susceptible to
Photoisomerization upon exposure to light. It readily undergoes an E,Z to
Z,Z photoisomerization that aects its pharmacological properties. Putra
et al. reported that, when EPR was cocrystallized with betaine (BET), the
resultant cocrystal showed no color change or degradation aer illumina-
tion for 24 hours, unlike EPR alone which changed color. e X-ray crystal
structures revealed that EPR-BET cocrystals possess strong intermolecular
interactions and a reduced photoisomerization reaction cavity compared
to the EPR form. is decreases molecular mobility and restricts the orien-
tation that EPR molecules can adopt when exposed to light. As a result, the
photoisomerization is suppressed [45].
Another example is ambrisentan (AMT), an antihypertensive drug prone
to hydrolysis degradation. Its cocrystal with glycylglycine (GG) connected
AMT molecules via carbonyl⋅⋅⋅OH hydrogen bonds and OH⋅⋅⋅π interac-
tions. ese strong intermolecular interactions within the lattice stabilize
AMT, enhancing its hydrolytic stability compared to pure AMT [46]. In
both examples, judicious cocrystallization with coformers optimized the
solid-state packing and reduced molecular mobility through enhanced
intermolecular interactions. As demonstrated, carefully designed cocrys-
tals can restrict molecular mobility and interactions within the crystal
lattice, thereby suppressing degradation pathways that would otherwise
compromise the drug’s potency and consistency of therapeutic eect. ese
improvements in chemical stability directly translate to better preservation
of the active pharmaceutical ingredient’s pharmacological activity during
manufacturing, storage, and in vivo administration. By mitigating the risk
of drug degradation, the cocrystal approach helps ensure the reliable deliv-
ery of the intended therapeutic dose to the patient, ultimately enhancing
the overall ecacy and safety of the treatment.
10.3.2.3 Manipulation of Hydrogen Bonding Pattern
Strong and strategic hydrogen bonds formed between the drug and
coformer disrupt the formation of hydrogen bonding motifs that can
310 Cocrystals in Pharmaceutical Sciences
catalyze degradation reactions. is shields reactive functional groups
on drug molecules. Adefovir dipivoxil is an oral prodrug of the antiviral
drug adefovir [47], but it suers from poor chemical stability due to two
degradation pathways—hydrolysis of the pivaloyloxymethyl moiety and
dimerization of the adenine ring. Gao et al. designed cocrystals of ade-
fovir dipivoxil with the weakly acidic coformer saccharin and the basic
coformer nicotinamide. ey found that the hydrolytic stability of adefo-
vir dipivoxil followed the order: Adefovir dipivoxil-saccharin cocrystal <
Adefovir dipivoxil < Adefovir dipivoxil-nicotinamide cocrystal. Aer 30
days of chemical stability testing, the adefovir dipivoxil-saccharin cocrys-
tal showed the lowest content of degradation product among the three
forms. e researchers attributed this to saccharin’s weakly acidic nature.
rough hydrogen bonding interactions, saccharin generates a weakly
acidic microenvironment around the adefovir dipivoxil molecule in the
cocrystal. is weak acidity inhibits the hydrolysis degradation pathway of
adefovir dipivoxil. In contrast, nicotinamide provides a basic environment
that accelerates hydrolysis [48]. So, in this example, judiciously selecting
saccharin as the coformer manipulated the hydrogen bonding network to
place adefovir dipivoxil in a weakly acidic crystal environment. is hin-
dered its hydrolytic degradation pathway and enhanced the chemical sta-
bility of the cocrystal.
us, the strategic formation of strong hydrogen bonds between
drug molecules and coformers has emerged as an eective approach for
improving the chemical stability of pharmaceuticals and, consequently,
their therapeutic ecacy. By disrupting the hydrogen bonding motifs that
can catalyze degradation pathways, cocrystallization creates a protective
microenvironment around the drug substance. is enhanced stability
translated to better preservation of the drug’s pharmacological potency,
enabling more consistent and reliable delivery of the intended therapeu-
tic dose. Continued exploration of hydrogen bonding-driven cocrystal
design will further expand the utility of this approach in developing robust,
high-ecacy drug formulations.
10.3.2.4 Inuencing Solid-State Microenvironment
Some coformers are selected such that they provide an acidic/basic/redox
microenvironment unfavorable for degradation pathways like oxidation
to occur. is chemically stabilizes the drug molecule. EPR is unstable
to photoisomerization upon light exposure. e XRD structure of EPR
showed a large reaction cavity, allowing high molecular mobility and sus-
ceptibility to isomerization. EPR was cocrystallized with betaine (BET).
Cocrystals for Enhancing Therapeutic Efficacy 311
e BET-EPR cocrystal XRD structure showed smaller and more crowded
reaction cavities compared to EPR alone, due to hydrogen bonding inter-
actions with BET restricting molecular mobility. When exposed to light,
EPR powder changed color signicantly, while the BET-EPR cocrystal
remained unchanged. e cocrystal microenvironment suppressed isom-
erization by limiting molecular motion within the dense crystal structure
[45].
us, by incorporating coformers that provide an unfavorable microen-
vironment for the degradation pathways of drugs, cocrystals can eectively
shield the drug molecule. ese stability improvements directly translate to
better preservation of the drug’s pharmacological potency, enabling more
reliable and consistent delivery of the intended therapeutic dose.
10.3.2.5 Increased ermal Stability
Stronger and denser packing of molecules in the lattice and higher lattice
energies of cocrystals can impart greater thermal stability by elevating melt-
ing points and raising the energy requirement for degradation reactions.
PFD-fumaric acid and PFD-trimesic acid cocrystals were found to have
increased heat of fusion compared to PFD alone, as measured through sol-
ubility experiments. e heat of fusion is a thermal property, representing
the amount of energy required to melt a substance. A higher heat of fusion
indicates stronger interactions holding the solid structure together. e
authors attributed the increased heat of fusion in the cocrystals to stron-
ger intermolecular forces arising from hydrogen bonding interactions
between PFD and the coformers in the crystalline lattice. ese stronger
interactions lead to higher thermal lattices and binding energies. While
thermal stability/degradation experiments are not reported, the implica-
tion is that by requiring more energy to disrupt the crystalline structure
through melting, the cocrystals may have improved stability against ther-
mal decomposition compared to PFD alone. e stronger interactions
make the cocrystal structure more robust [49].
us, cocrystallization has demonstrated the ability to enhance the
thermal stability of drug substances, which is crucial for ensuring the
therapeutic ecacy and safety of pharmaceutical products. e enhanced
thermal stability directly translates to improved resistance against degra-
dation, helping maintain the potency and consistency of the therapeutic
eect. Continued research into the thermodynamic properties of cocrys-
tals will further elucidate the mechanisms by which they can be leveraged
to develop more stable and ecacious drug formulations.
312 Cocrystals in Pharmaceutical Sciences
10.3.3 Improving Bioavailability and Pharmacokinetics
Pharmacokinetics refers to the study of how drugs are absorbed, distrib-
uted, metabolized, and eliminated by the body. Cocrystals can inuence
these processes by altering the drug’s physicochemical properties, such as
its stability, permeability, and rate of metabolism [50]. e bioavailability
of a drug refers to its ability to reach the systemic circulation and produce
the desired therapeutic eect. However, many drugs face challenges in
achieving sucient bioavailability due to their poor solubility in biological
uids. Cocrystals provide a solution to this problem by forming new crys-
talline structures that enhance drug solubility [23].
Low aqueous solubility oen translates to poor and erratic oral absorp-
tion, which can signicantly impact the ecacy of some drugs. By mod-
ifying a drug’s physicochemical properties through cocrystallization, it is
possible to improve solubility and dissolution rates. Enhanced dissolution
leads to higher drug concentration levels in the gastrointestinal uid, allow-
ing for more complete absorption. Several studies have demonstrated that
cocrystals can remarkably increase a drug’s exposure in the body (AUC)
and maximum observed drug concentration (Cmax) aer oral admin-
istration [46, 51]. e ability of cocrystals to modify release proles and
potentially bypass rst-pass liver metabolism also aects absorption and
distribution characteristics [23]. ese pharmacokinetic advantages can
translate to clinically meaningful outcomes such as higher ecacy, fewer
required doses, and a better safety prole.
10.3.3.1 e Mechanism for Enhancing the Bioavailability
and Improve Pharmacokinetics of Drugs
10.3.3.1.1 Increased Solubility and Dissolution Rate
By forming cocrystals, the aqueous solubility and dissolution rate of poorly
water-soluble drugs can be signicantly improved. is leads to higher
absorption in the gastrointestinal tract and increased bioavailability [1].
Cheney et al. prepared 12 meloxicam cocrystals with aromatic/aliphatic car-
boxylic acid coformers. Non-sink dissolution studies showed the cocrystals
underwent solvent-mediated phase transformation to meloxicam. To study
the impact on oral absorption, a single-dose PK study in rats was conducted.
Most cocrystals exhibited higher intestinal absorption than meloxicam, as
evidenced by higher mean serum concentrations at matched time points.
Linear regression analysis correlated mean in vitro dissolution proles to
mean serum concentration data, indicating cocrystals with higher dissolu-
tion rates likely yield better bioavailability through enhanced release [52].
Cocrystals for Enhancing Therapeutic Efficacy 313
Cocrystals oen exhibit supersaturation behavior during dissolution
due to higher energy crystalline forms. However, bioavailability may not
be realized if precipitation occurs rapidly [1]. Dihydromyricetin (DMY)
is a class IV drug with low solubility and permeability. DMY-caeine and
DMY-urea cocrystals were prepared. In vitro dissolution showed this main-
tained supersaturation initially but rapidly precipitated DMY dihydrate.
Various polymers and surfactants were screened as crystallization inhib-
itors. Polyvinylpyrrolidone K30 (PVP K30) most eectively stabilized the
supersaturated solutions, maintaining 6-fold higher concentrations than
DMY for over 300 minutes. Rats were dosed with the cocrystals suspended
in 0.5% sodium carboxymethylcellulose (NaCMC) or 2% PVP K30. DMY-
urea with NaCMC failed to improve bioavailability versus DMY alone,
attributed to rapid (<10 min) precipitation in vivo. However, DMY-urea
with PVP K30 achieved a 4.9-fold higher AUC than DMY due to PVP K30
stabilizing supersaturation. DMY-caeine alone provided 3.9-fold higher
AUC than DMY through maintaining supersaturation longer (~30 min).
With PVP K30, a further improvement to 5.3-fold was seen [53].
10.3.3.1.2 Modied Release Properties
Some cocrystals exhibit modied release behavior compared to their par-
ent drugs. is includes sustained or delayed release, which can improve
pharmacokinetic proles [1]. Celecoxib has a low solubility of 7 μg/mL and
belongs to BCS class II. However, rapid absorption of tramadol (BCS class I)
is associated with a higher incidence of adverse eects likely due to peak
concentrations. CTC was formulated to modify the PK proles of both
drugs [54]. Intrinsic dissolution rate (IDR) studies showed CTC decreased
tramadol IDR 7-fold while increasing celecoxib IDR 3-fold compared to
drugs alone. is suggested CTC could provide sustained release of trama-
dol for safety while improving celecoxib dissolution [54, 55].
Beagle dog PK studies were then performed comparing CTC tablets,
commercial tramadol, and celecoxib products. CTC exhibited higher cele-
coxib Cmax and AUC than Celebrex, demonstrating it enhanced celecoxib
bioavailability through modied dissolution. Meanwhile, CTC resulted
in lower tramadol peak concentration and AUC relative to the commer-
cial product. Human PK studies found CTC also reduced tramadol Cmax
and AUC versus immediate-release tramadol, maintaining similar overall
exposure. us, CTC was successful in modulating the release of each drug
to enable improved bioavailability of celecoxib while potentially enhancing
tramadol’s safety prole [54, 55].
314 Cocrystals in Pharmaceutical Sciences
10.3.3.1.3 Enhanced Permeability
e permeation of drugs across biological membranes aects the rate and
extent of absorption. Cocrystals may improve permeability through their
interactions with membrane transporters or altered solid-state properties.
Acyclovir is a BCS class III drug with good solubility but low permeabil-
ity. Yan et al. synthesized acyclovir-fumaric acid and acyclovir-glutaric
acid cocrystals. Permeability studies across rat skin showed the cocrystals
increased the permeated amount of acyclovir by 2.8 and 4-fold respectively,
compared to pure acyclovir [56]. is demonstrated cocrystals can improve
the bioavailability of low-permeable drugs by enhancing permeability.
Furosemide is a BCS class IV drug with both low solubility and per-
meability. Banik et al. prepared different cocrystals and found that
furosemide-anthranilamide cocrystals exhibited higher cumulative perme-
ated amount/ux across a cellulose membrane compared to pure furosemide
or other cocrystals [57]. is provided direct evidence that cocrystallization
can simultaneously improve solubility and permeability for class IV drugs.
In Caco-2 cellular studies, Ferretti et al
. found that the indomethacin-
saccharine cocrystal enhanced the apparent permeability of Indomethacin
without aecting cellular integrity [58]. is suggests cocrystals can enhance
permeability even at the level of the intestinal epithelium, possibly via
drug-coformer interactions in solution-altering membrane diusion.
ese case studies elucidate dierent mechanisms like increased mem-
brane ux, synergistic eects with permeability-enhancing coformers, and the
absence of toxicity that underlie permeability enhancement of cocrystals—
a key advantage for bioavailability improvement of BCS class III and IV
drugs. Proper selection of coformers is important to manifest this poten-
tial of cocrystals. One case study analyzed was indomethacin cocrystals.
Ferretti et al. studied the permeability of Indomethacin cocrystals across
intestinal epithelial NCM460 cell monolayers. Cocrystal 1 containing
2-hydroxy-4-methyl-pyridine damaged cellular integrity and increased
Indomethacin apparent permeability compared to pure Indomethacin.
Conversely, physical mixture 1 did not aect cells. Cocrystal 3 containing
saccharine improved Indomethacin permeability without cellular damage
[58]. is demonstrated that cocrystals can modulate membrane permea-
bility dierently than physical mixtures.
ese case studies signify how cocrystals can alter the intestinal/skin
permeation of drugs in addition to solubility enhancement. By simultane-
ously improving solubility and membrane permeability, cocrystals repre-
sent a promising strategy for enhancing the bioavailability of BCS class III
and IV drugs with poor solubility and/or permeability characteristics. e
Cocrystals for Enhancing Therapeutic Efficacy 315
ability of cocrystals to modify diusion/release rates through biological
membranes expands their applications in improving oral drug delivery.
10.3.3.1.4 Modied Degradation
Drug stability inuences bioavailability. Cocrystals can alter the degrada-
tion pathways of unstable drugs through interactions or modied micro-
environments, increasing the fraction absorbed. One of the ways cocrystals
can improve bioavailability is by protecting the drug from degradation
in the gastrointestinal (GI) tract. Baicalein is a natural avonoid with
low solubility and permeability (BCS class IV). Zhu et al. synthesized a
baicalein-caeine cocrystal and conducted pharmacokinetic experiments
in rats. ey found that the cocrystal showed a 4.1-fold higher AUC
0-24h
compared to pure baicalein, which was attributed to the higher dissolution
rate of the cocrystal. Interestingly, the physical mixture of baicalein and
caeine also improved AUC
0-24h
by 2-fold compared to pure baicalein. is
improvement was explained by the synergic eect of caeine on baicalein
absorption by increasing intestinal blood ow [59].
Caeine is known to inhibit the metabolism of some drugs like acet-
aminophen and ergotamine tartrate when co-administered, leading to
higher plasma concentrations. It is proposed that caeine may protect
baicalein from degradation and rst-pass metabolism in a similar way,
allowing more baicalein to absorb into the systemic circulation. While the
exact mechanism was not investigated, this case study demonstrates how
a coformer like caeine can potentially improve bioavailability by mod-
ifying drug degradation kinetics in the GI tract through metabolic inhi-
bition eects [59]. Another example is celecoxib-tramadol hydrochloride
cocrystal (CTC) discussed for the treatment of acute pain. Animal and
human pharmacokinetic studies found that CTC exhibited a potential to
simultaneously improve the bioavailability of celecoxib while improving
the safety of tramadol hydrochloride by modifying its release kinetics. is
suggests the cocrystal form protected both drugs from early degradation
in the GI tract, allowing their plasma concentrations to increase in a con-
trolled manner [54].
ese case studies provide evidence that cocrystals can enhance bio-
availability by modifying drug degradation pathways through coformer-
drug interactions like metabolic inhibition, thereby protecting more drugs
from degradation so they can successfully permeate and distribute in the
body. Careful selection of appropriate coformers is important from a safety
perspective as well.