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246 Cocrystals in Pharmaceutical Sciences
solubility and the minimum solidication zone width (MSZW). Another
PAT utilized in the crystallization process is particle vision and mea-
surement (PVM), which allows for the observation and preservation of
high-quality microscopy photographs of crystals, particles, and droplets
as they naturally occur in the dynamic and real process concentration.
It validates the information obtained from FBRM by oering real-time
photos and also provides further understanding of the crystal structure,
shape, production of secondary liquid or oiling out, monitoring of dier-
ent crystal forms, and other aspects related to the process of crystallization
[44]. Apart from crystal size and morphology monitoring, attenuated total
reectance−Fourier transform infrared (ATR-FTIR), ultraviolet/visible
spectroscopy (ATR-UV/vis), Fourier transform infrared (FTIR) spectros-
copy, and NIR spectroscopy can be used for monitoring the solution com-
position during the cocrystallization process [12].
8.6 Commercial Opportunities for Cocrystals
e prevalence of drug candidates with low solubility in water is increasing
across the pharmaceutical industry. According to Takagi (2006), around
40% of the immediate-release oral products that are commercially avail-
able are classied as practically insoluble. Approximately 70% of the newly
identied chemical entities (NCE) by combinatorial screening programs
are estimated to be water-insoluble. is has led to the introduction of
cocrystal technology in the pharmaceutical industry for commercial pur-
poses. According to a report by Grand View Research Inc., the market size
for cocrystal technology is estimated to be around US$200 million by 2025
[54]. e growth of this market is expected to be driven by the increasing
demand for new and improved drug delivery systems, as well as the rising
prevalence of chronic diseases. e examples of cocrystal drugs that are
currently on the market are presented in Table 8.3.
8.7 Future Directions and Outlook
8.7.1 Machine Learning and AI
Various computational modeling techniques will be implemented in the
development of cocrystal products, including lattice energy minimization,
supramolecular recognition modeling, and machine learning techniques.
Scaling Up Pharmaceutical Cocrystals 247
Computational models have the capability to evaluate potential coformers,
thereby aiding researchers in the selection of coformers that can generate
a robust and stable cocrystal structure and forecast cocrystal formation
and properties. is, consequently, can accelerate the process of cocrystal
discovery and design. In a study by Mswahili and the team, they extracted
descriptor values from the simplied molecular input line entry system of
compounds and compared various machine learning models using data
Table 8.3 Examples of cocrystal drugs that are currently on the market.
Commercial
name Indication API Coformer
Benet of
cocrystallization
Entresto
®
Chronic heart
failure
Valsartan Sacubitril Enhance
bioavailability of
valsartan
Tecdera
®
Multiple
sclerosis
Dimethyl
fumarate
Nicotinamide Improve
thermodynamic
stability,
solubility, and
dissolution
prole
Suglat
®
Type 2
diabetes
Ipragliozin L-Proline Enhance the
stability of
anhydrous form
Steglatro
®
Type 2
diabetes
Ertugliozin Z-pyroglutamic
acid
Improve stability
Depakote
®
Acute bipolar
mania and
epilepsy
Valproic acid Valproate
sodium
Solid phase
stability and less
hygroscopicity
Lexapro
®
Depression
and anxiety
Escitalopram Oxalate Improve stability of
API
Beta-Chlor
®
Diagnosis or
treatment
of arthritis,
allergic
disorders,
and atopic
dermatitis
Chloral
hydrate
Betaine Improve thermal
stability
248 Cocrystals in Pharmaceutical Sciences
from 1476 instances. e results showed that the articial neural network
exhibited the highest accuracy, sensitivity, and F1 score. Additionally, the
model performed comparably with only half of the descriptors selected
through feature selection algorithms. ese ndings suggest that this
approach can lead to faster and more accurate cocrystal development,
enhancing the eciency of the process [55].
8.7.2 Advanced Process Analytical Technology (PAT)
e primary application of PATs in product manufacturing has been the
design, analysis, and control of diverse functional processes. ese tech-
nologies are employed to provide essential data regarding a multitude of
parameters that have the potential to substantially impact distinct CQA.
e crystallization of pharmaceutical active ingredients involves an exten-
sive series of processes. Such severe conditions may result in product failure.
To implement PAT, each critical phase and parameter (whether in-line or
out-of-line processing) can therefore be utilized to closely monitor crystal
formation and development. is technology has emerged as an innovative
instrument, and there are currently a multitude of academic and industrial
investigations underway. e objective of PAT is to ensure superior qual-
ity by conducting accurate and timely assessments of crucial performance
and quality of basic materials, in-process materials, and nished goods.
PAT application entails the integration of scientically grounded process
design and optimization, suitable sensor technologies, information and
statistical tools (chemometrics), and feedback process control strategies—
all of which collaborate harmoniously to ensure the production of excel-
lent products. A variety of in situ analytical techniques combined with che-
mometric instruments for the analysis of multivariate process information
will serve as the foundation for future advancements in crystallization pro-
cess modeling, simulation, and control [56–58].
8.7.3 Green Chemistry
Pharmaceutical cocrystallization is increasingly recognized for enhancing
the solubility and bioavailability of poorly soluble drugs without altering
their chemical identity or therapeutic eect. Scaling up the production of
cocrystal products has traditionally required a high amount of solvent.
erefore, green and convenient techniques have been introduced and
developed to minimize synthetic steps and solvent use. Recent studies have
explored various methods to manufacture cocrystal drug products using
green chemistry approaches, further promoting environmentally friendly
Scaling Up Pharmaceutical Cocrystals 249
and ecient drug development processes [59]. For example, Duarte and
team used spray congealing for the large-scale production of cocrystals.
e obtained cocrystal particles were compact and spherical consisting of
aggregates of individual cocrystals entangled or adhered with each other.
By varying atomization and cooling eciency, cocrystal particle properties
can be real time adjusted [60].
Furthermore, the utilization of PAT allows for accurate regulation of
reaction parameters, immediate access to analytical data, and sophis-
ticated data analysis techniques to promote sustainability objectives by
comprehensively comprehending reaction kinetics, thermodynamics,
and the direct impact of process variables on yield and waste production
[61]. Merck scientists are developing biocatalytic-based syntheses for
pharmaceutical intermediates, emphasizing fewer reaction steps, milder
conditions, and better sustainability compared to classical methods. ey
successfully applied biocatalysis in the production of Belzutifan, address-
ing challenges with PAT tools to ensure precise control and overcome ana-
lytical diculties in handling dense slurries and reaction monitoring [62].
Another approach to reduce solvent use is ow chemistry. Purdue
University chemists and engineers modied the continuous ow process
for lomustine to use green solvents, 2-MeTHF, and acetic acid, replac-
ing dichloromethane. is new approach improved solubility, yield, and
productivity while maintaining the process’s environmental friendliness,
demonstrating the importance of reactant solubility and reactor congu-
ration in optimizing continuous ow processes [63].
8.8 Conclusion
Based on the preceding explanation, it can be inferred that cocrystalliza-
tion is a superior option compared to conventional approaches such as salt
production, solvates, and polymorphs for enhancing the physicochemical
and processability properties of APIs. e utilization of solvates, salt, and
polymorphs for producing pharmaceutically acceptable forms of APIs is
limited due to a naturally restricted number of solvates and polymorphs,
as well as the absence of ionizable groups in some APIs. Research con-
ducted in the past decade has signicantly advanced multiple aspects of
cocrystallization, including screening, development, characterization, pro-
duction, and formulations of cocrystals. e guidelines provided by reg-
ulatory agencies such as the US FDA and EMA conrm the recognized
signicance of pharmaceutical cocrystals in the advancement of better
candidates with enhanced properties. However, this technology has not
250 Cocrystals in Pharmaceutical Sciences
yet become a standard procedure for the manufacturing of medications. In
order to eectively utilize cocrystals in the pharmaceutical industry, it is
crucial to concentrate research eorts on establishing consistent synthetic
procedures for cocrystals, determining and enhancing the factors that
impact the quality of cocrystals (such as purity, yield, and reproducibility),
and integrating cocrystal screening and development into the drug devel-
opment process.
Acknowledgment
e authors wish to extend sincere gratitude to Rangsit University and
Burapha University for providing access to the Journals database.
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