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316 Cocrystals in Pharmaceutical Sciences
10.3.4 Combination erapy
Cocrystals have emerged as a promising strategy for combination drug
therapy [60]. A cocrystal is a multicomponent crystal consisting of two
or more molecules generally in a stoichiometric ratio [1]. Cocrystals dif-
fer from traditional pharmaceutical salts and solvates in that the compo-
nent molecules are in their neutral/parent form. is property allows for
combining two drug molecules without altering their intrinsic properties
or pharmacology. Cocrystals oer several advantages for combination
therapies. First, cocrystallization allows multiple drug components to be
eectively delivered in a single dosage form at predened stoichiometric
ratios. is can help ensure consistent and predictable pharmacokinetics
compared to physical mixtures or co-administration of separate dosage
forms [21].
To date, over a dozen cocrystal-based drug products have received
market approval from regulatory agencies. Clinical studies have demon-
strated the ecacy and safety of these cocrystal combinations for various
therapeutic indications. Entresto
®
is a pharmaceutical cocrystal approved
for the treatment of chronic heart failure. It consists of a 1:1 cocrystal of
valsartan and sacubitril, targeting both the renin-angiotensin-aldoste-
rone system (RAAS) and neprilysin pathways. In clinical trials, Entresto
®
demonstrated reduced cardiovascular death and hospitalization compared
to enalapril, an ACE inhibitor. is improved ecacy is attributed to the
cocrystal’s ability to deliver both actives simultaneously at their optimal
1:1 ratio [7].
Tramadol-celecoxib cocrystal (CTC) is a 1:1 cocrystal of tramadol hydro-
chloride and celecoxib that has been extensively studied by Almansa et al.
e experimental studies have revealed several key ndings about CTC.
Dissolution studies have shown that the IDR of celecoxib is increased in
CTC, while tramadol hydrochloride is released at a slower rate compared to
when the drugs are administered individually. In terms of pharmacokinet-
ics, clinical studies have found that tramadol is absorbed more slowly from
CTC, resulting in a reduction in peak plasma concentration. On the other
hand, celecoxib is absorbed faster from CTC compared to its single-entity
form. Moreover, phase II clinical trials have demonstrated that CTC has a
superior analgesic eect for moderate-severe acute post-surgical pain man-
agement when compared to tramadol, celecoxib alone, and their combina-
tion. e mechanism of action underlying these ndings is believed to be
the optimized dissolution properties of CTC, which positively modify the
pharmacokinetic prole of both drugs. Tramadol’s slower release reduces
its peak plasma concentration, while celecoxib’s faster release increases
Cocrystals for Enhancing Therapeutic Efficacy 317
its bioavailability. is synchronized plasma concentration-time prole is
hypothesized to produce the enhanced analgesic synergy observed clin-
ically. In conclusion, the experimental evidence suggests that CTC, with
its modulation of the dissolution and absorption properties of tramadol
and celecoxib, oers clinically relevant advantages in terms of pharmaco-
kinetics and ecacy over conventional combination or single-drug formu-
lations [55].
Meloxicam and aspirin both have anti-inammatory eects, but they
dier in their selectivity for COX enzymes. Meloxicam primarily targets
COX-2, whereas aspirin inhibits both COX-1 and COX-2. Cheney et al.
have reported a 1:1 cocrystal of meloxicam and aspirin (MA) in their study.
e experimental studies shed light on the combined therapeutic eect of
MA. Solubility experiments using phosphate buer have shown that MA
exhibits a 44-fold increase in solubility at pH 7.4 compared to meloxi-
cam alone. is increased solubility is expected to enhance the dissolu-
tion rate as well, potentially leading to the complete absorption of drugs.
Pharmacokinetic studies in rats have demonstrated that MA has approx-
imately 4 times higher oral bioavailability compared to meloxicam alone,
which correlates with its improved solubility. is enhanced bioavailability
suggests that the cocrystallization of MA allows for a greater concentration
of the drugs to be absorbed and available systemically, potentially enhanc-
ing their therapeutic eectiveness [52].
While both andrographolide and salicylic acid exhibit anti-inammatory
properties, they exert their eects through dierent molecular mecha-
nisms. Andrographolide targets multiple signaling pathways involved
in inammation, immunomodulation, and oxidative stress, while sali-
cylic acid primarily acts as a COX inhibitor to reduce inammation and
pain. In their study, Suresh et al. reported the successful development of
a 1:1 cocrystal of andrographolide and salicylic acid (AS). Notably, AS
demonstrated a remarkable 12-fold increase in solubility compared to
andrographolide alone, as evidenced by saturation solubility experiments.
Furthermore, in vitro dissolution studies revealed that the dissolution rate
of AS was approximately 3 times faster than that of andrographolide alone.
e relative drug release of AS was estimated to be approximately 2 times
higher than andrographolide, as observed in dynamic dissolution studies.
Importantly, AS exhibited complete inhibition of the chemical transfor-
mation of andrographolide to its inactive sulfate metabolite, as conrmed
analytically. ese experimental ndings collectively demonstrate that
cocrystallization between andrographolide and salicylic acid eectively
modulated the physiochemical properties of andrographolide. is modu-
lation was achieved through molecular-level interactions between the two
318 Cocrystals in Pharmaceutical Sciences
components, without any chemical modication to andrographolide. e
signicant enhancement in solubility, dissolution rate, and drug release
observed in the AS cocrystal provides valuable insights into the potential
of this combination therapy approach [61].
While isoniazid primarily targets cell wall synthesis, pyrazinamide acts
on the intracellular environment of Mycobacterium tuberculosis. e com-
bination of these two drugs in tuberculosis treatment is synergistic, as they
target dierent aspects of bacterial metabolism and provide a more com-
prehensive approach to eradicating the infection. In their study, Yan et al.
reported the synthesis of a drug-bridge-drug ternary cocrystal composed
of isoniazid, pyrazinamide, and fumaric acid. e physicochemical char-
acterizations revealed that the ternary cocrystal exhibited an optimized
formulation capacity, displaying favorable compressibility and tableting
properties. Dissolution studies demonstrated signicantly enhanced disso-
lution rates of isoniazid and pyrazinamide from the ternary cocrystal com-
pared to physical mixtures. Furthermore, pharmacokinetic experiments
conducted in rats revealed synergistic eects between the three compo-
nents of the ternary cocrystal, leading to improved bioavailability when
compared to physical mixtures. e mechanism of action involves the for-
mation of a cocrystalline network through multiple molecular interactions
between isoniazid, pyrazinamide, and the bridging fumaric acid moiety.
is cocrystalline network eectively modulates the formulation capacity
and optimizes dissolution behavior in vitro, resulting in enhanced bio-
availabilities of isoniazid and pyrazinamide in vivo. ese ndings provide
a new rationale for the design of eective anti-tuberculosis combination
therapies, highlighting the potential of the isoniazid-pyrazinamide-fumaric
acid cocrystal in achieving synergistic anti-tuberculosis eects compared
to simple physical mixtures [62].
10.3.5 Improving the Targeted Delivery of Drugs
Nano-cocrystals are a novel class of drug delivery system that combines the
advantages of nano-crystals and cocrystals. By reducing the particle size of
cocrystals into the nanoscale range, nano-cocrystals are able to exploit the
benets associated with both technologies for targeted drug therapy. As
successors to nano-crystals, nan-ococrystals have the potential for supe-
rior targeting capabilities over either nano-crystals or cocrystals alone.
Being nanoparticles, nano-cocrystals are able to utilize mechanisms like
the enhanced permeability and retention eect to passively accumulate in
pathological sites like tumor tissues for targeted action. In addition, the
large surface area of nano-cocrystals allows for opportunities to selectively
Cocrystals for Enhancing Therapeutic Efficacy 319
functionalize their surface with targeting ligands. is enables active tar-
geting abilities for improved localization and intracellular delivery of ther-
apeutic payloads. Moreover, the nanoscale size range of nano-cocrystals
serves to extend their plasma circulation time, improving the proportion
of drug accumulated at target sites. e combined properties of nano-
cocrystals thus present promising prospects for achieving the ecient,
specic release of pharmaceutical actives directly at the site of intended
therapy [63].
Witika et al. produced lamivudine-zidovudine nano-cocrystals using a
sonochemical synthesis method in the presence of surfactants and poly-
mers. eir goal was to stabilize the nano-sized cocrystals and control their
critical quality attributes such as particle size, polydispersity index, and
zeta potential. ey characterized the nano-cocrystals using techniques
such as X-ray powder diraction, Raman spectroscopy, FTIR spectroscopy,
and dierential scanning calorimetry. is conrmed the cocrystalline
nature of the lamivudine-zidovudine nanoparticles. ey then tested the
cytotoxicity of the nano-cocrystals versus a physical mixture of the APIs
in HeLa cells. Interestingly, the experimental results showed signicantly
lower cytotoxicity for the nano-cocrystals compared to the mixture, with
cell viability remaining over 80% even at high concentrations of 100 μM.
is demonstrates the ability of the nano-cocrystals to safely release the
drugs aer cellular absorption. In a follow-up study, Witika et al. further
optimized the sonochemical synthesis using a quality-by-design approach
to producing nano-cocrystals with predened properties for drug delivery
applications [64].
10.4 Regulatory Considerations for Cocrystal
Approval
e cocrystal drug product development workow is shown in Figure 10.4.
It requires addressing certain regulatory aspects. Both the US Food and
Drug Administration (FDA) and the European Medicines Agency (EMA)
have provided guidance on the regulatory classication and development
of cocrystals [65]. In 2013, the FDA issued a guidance document titled
“Regulatory Classication of Pharmaceutical Cocrystals” which dened
cocrystals as “crystalline materials composed of two or more molecules
within the same crystal lattice.” e guidance explains that cocrystals con-
stitute drug product intermediates and not new active pharmaceutical
ingredients (APIs). FDA classies cocrystals as a special case of solvates or
320 Cocrystals in Pharmaceutical Sciences
hydrates, recognizing their potential to modify dierent properties asso-
ciated with therapeutic ecacy without altering the active moiety [66].
e EMA reection paper from 2014 denes cocrystals as “homogeneous
(single phase) crystalline structures made up of two or more components
in a specic stoichiometric ratio where the arrangement in the crystal lat-
tice is not based on ionic bonds.” us, EMA views cocrystals similarly to
salts, considering them eligible for regulatory approval as new substances
if shown to impact ecacy, safety, or pharmacokinetics compared to the
reference drug [67]. Some key regulatory considerations for developing
cocrystals include:
– Demonstrating equivalence to the reference listed drug in
terms of pharmacokinetic parameters like rate and extent of
API
Coformers
Coformer selection &
Cocrystal Discovery
Optimum cocrystal
Drug product Formulation
Solid state
Characterisation
Pre-formulation
Scale upRegulatory
Cocrystals
SXRD
PXRD
FTIR
DSC
TGA
SEM
Figure 10.4 From discovery to delivery: e workow of coformer selection and
cocrystal drug product development. e cocrystallization process starts with the
selection of the API and the coformer. e cocrystal discovery is based on screening
methods and solubility studies to identify the most promising cocrystal candidates.
e solid-state characterization of the cocrystals is performed using various analytical
techniques. e preformulation studies are carried out to optimize the cocrystal
formulation and to assess its stability. e scale-up process involves optimizing the
manufacturing process and scale-up of the cocrystal. e regulatory approval is required
before the cocrystal product can be commercialized. e gure is adapted from (Singh
et al., 2023; https://doi.org/10.3390/pharmaceutics15041161) published under a CC4
license.
Cocrystals for Enhancing Therapeutic Efficacy 321
absorption. Studies may be needed to show the dissociation
of cocrystal components.
– Establishing stability of the cocrystal form under intended
storage and processing conditions as per ICH guidelines.
– Characterizing the cocrystal components and ensuring
quality, stability, and cGMP compliance.
– Demonstrating process validation and manufacturing
reproducibility for the cocrystal product.
– Providing scientic rationale for the selection of pharmaceu-
tically acceptable and non-toxic excipients and coformers.
– Addressing any potential patent issues related to the cocrys-
tal compositions.
Addressing these regulatory aspects helps establish a cocrystal product
as a therapeutic equivalent to the reference drug, facilitating its approval
and market access. e story of sacubitril-valsartan’s evolution from a scien-
tic concept into the approved heart failure treatment Entresto
®
was a long
yet fruitful journey guided by rigorous clinical research [7]. Its beginnings
trace back to discoveries regarding neprilysin’s role in degrading peptides
vital to cardiovascular homeostasis. Researchers recognized inhibiting this
enzyme’s activity could help manage heart failure symptoms by allowing
therapeutic peptides’ increased circulation. is realization spurred sacu-
bitril’s early development as a neprilysin inhibitor. Initial studies explored
its blood pressure-lowering and cardiac function-improving capabilities,
yielding promising results. ey set the stage for sacubitril’s pairing with
valsartan, an angiotensin receptor blocker, into a novel combination ther-
apy. Its rst clinical trial testing sacubitril/valsartan’s safety and ecacy
marked the beginning of a trial-guided odyssey [68].
e landmark PARADIGM-HF trial would prove most pivotal, compar-
ing the combination to enalapril, the standard treatment. Its overwhelming
success in preventing cardiovascular deaths and hospitalizations stopped
the trial early. Presented to regulators, the FDA granted priority review
and conditional approval on July 7, 2015, recognizing sacubitril/valsartan’s
life-saving potential as Entresto [69].
Post-approval commitments further reinforced Entresto’s benets,
expanding indications based on thorough investigations. Today, it exem-
plies cocrystals’ potential for progressing medicine by rening treatments
at the molecular level. Sacubitril/valsartan’s pioneering approval sets the
stage for future innovation in applying multifaceted drug research. Most
importantly, it underscores cocrystals’ life-saving power through transla-
tional eorts linking discovery to real-world care.
322 Cocrystals in Pharmaceutical Sciences
10.5 Conclusion and Future Aspects
Cocrystallization is emerging as an important approach in pharmaceutical
sciences for modulating the physiochemical and performance properties
of drugs. Signicant advances have been made in the past two decades
towards understanding cocrystal formation and characterization. e
fundamental principles of supramolecular synthon-mediated interactions
between API and coformer provide a scientic basis for the rational design
of cocrystals. Considerable research eorts have demonstrated the abil-
ity of cocrystals to improve the solubility, dissolution, permeability, bio-
availability, and stability proles of numerous drugs. is in turn enhances
their therapeutic ecacy by enabling complete and consistent absorp-
tion of intended drug concentrations in vivo. Regulatory guidelines have
accepted cocrystals as eligible for approval provided their clinical equiva-
lence to reference products is demonstrated. Several real-world examples
of marketed cocrystal products validated the technology. However, further
exploration of multicomponent systems, advanced formulations, targeted
delivery, and combination therapies hold promise to fully realize cocrys-
tals’ potential. Addressing challenges like scalable manufacturing and
understanding long-term behavior also requires ongoing investigation.
Looking ahead, cocrystallization represents a versatile means to rene
early and clinical-stage drug candidates. Strategic application of compu-
tational and high-throughput methodologies could aid the discovery of
optimized crystal forms. Continued evaluation in well-designed clinical
trials will strengthen understanding of structure-activity relationships and
true patient impact. With diligent research linking discovery to practice,
cocrystals are positioned to advance medicinal care by enabling the deliv-
ery of novel and improved medicines to benet public health worldwide.
e future of cocrystal research is promising with many opportuni-
ties yet to be explored. Areas of focus include developing multicomponent
frameworks incorporating two or more active pharmaceutical ingredients
to generate new combination therapies. Long-acting controlled-release
cocrystal platforms integrated with biocompatible polymers could improve
adherence and pharmacokinetics. Engineering targeted delivery through
functionalizing porous cocrystal surfaces with antibodies or ligands may
enhance ecacy. Exploring non-oral routes such as pulmonary cocrystal
designs may unlock new administration pathways. Application of Quality
by Design and process analytical technologies can facilitate scalable and
reproducible manufacturing. Uncovering excipient cocrystals may con-
fer benets like improved stability and compression properties. Innovative
Cocrystals for Enhancing Therapeutic Efficacy 323
crystallization processes leveraging mechanochemistry, 3D printing, or
emerging technologies present opportunities. Further elucidating structure-
property relationships through computational modeling may provide valu-
able insights. Additional clinical evaluations of existing and new cocrystal
products hold promise to expand therapeutic applications into new disease
areas. With consistent progress in these areas, cocrystals have signicant
potential to transform drug development strategies and enhance outcomes
for patients worldwide.
Acknowledgment
e authors are very thankful to Guru Nanak Institute of Pharmaceutical
Science and Technology for providing library and infrastructure facilities.
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