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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5980_Библиотеки_им_академика_М_И_Перельмана.pdf
106 Cocrystals in Pharmaceutical Sciences
Table 4.1 Various techniques employed for cocrystal synthesis. (Continued)
Methods Drugs Coformer Conclusion Reference
Liquid-assisting
grinding
Indomethacin Nicotinamide Enhance solubility [67]
5-Fluorouracil Phenolic acid
Nnutraceutical
ferulic acid + water
1.64-fold increase in
solubility
[68]
Acyclovir Tartaric acid Higher saturated
solubility
[68]
Aceclofenac Dimethyl urea 3.43-fold increase in
solubility
[69]
Naproxen L-alanine 1.4-fold increase in
solubility
[70]
Didanosin Benzoic acid and
salicylic acid
Didanosine-benzoic
acid cocrystal and
didanosine-salicylic
acid cocrystal
successfully formed
[71]
Rebamipide Oxalic acid
Citric acid
3,4-dihydroxybenzoic
acid
7.29-fold increase in
solubility
[72]
Telmisartan 3,5-dihydroxy
benzoic acid
reefold increase in
solubility
[72]
Bergenin Isonicotinamide 1.57- to 2.87-fold increase
in solubility
[73]
Axitinib Fumaric acid
Suberic acid
Trans-cinnamic acid
11.7-, 5.5-, 1.9-fold
increase in solubility
respectively
[74]
Neat grinding Aceclofenac Dimethyl urea Acyclovir-glutaric acid
cocrystal showed a
similar solubility with
pure drug, meanwhile
acyclovir-fumaric acid
cocrystal has a higher
solubility compared to
pure acyclovir
[69]
Ipragliozin L-prolin Stability against hydrate
formation
[75]
(Continued)
Preparation Techniques of Pharmaceutical Cocrystals 107
Table 4.1 Various techniques employed for cocrystal synthesis. (Continued)
Methods Drugs Coformer Conclusion Reference
Aceclofenac Salicylic acid Sevenfold increase in
solubility
[76]
Acyclovir Fumaric Acid and
glutaric Acid
Cocrystals of acyclovir-
fumaric acid have a
higher solubility as
compared to pure drug
[77]
Piroxicam Piroxicam
Sodium acetate
Improved the solubility
and dissolution rate
[78]
Antisolvent
crystallization
Diacerein β-Resorcylic acid 2.3- to 2.8-fold increase in
solubility
[79]
Paracetamol Caeine Enhance dissolution rate [80]
Supercritical uid Indomethacin Saccharin Dierences in
morphology
and particle size
distribution
[81]
Hot-melt
extrusion
Aripiprazole Adipic acid Enhanced solubility and
dissolution rate
[82]
Mechanochemical
method
5-Fluorouracil 3,4-dihydroxybenzoic
4-aminopyridine
and gentisic acid
Improve permeability and
bioavailability
[83]
Dimethylglyoxime Acridine,
phenanthroline
monohydrate, and
acetamide
Improve solubility and
bioavailability
[84]
Chrysin Cytosine and
thiamine
hydrochloride
Enhanced dissolution
and solubility prole
with improved
bioavailability
parameters
[85]
Solvent-assisted
grinding and
Solvent ultrasonic
method
Dipuzine Benzoic acid Enhance apparent
solubility and
dissolution rate
[86]
Slurry method Quercetin Caeine:methanol
Isonicotinamide
eobromine
dihydrate
Improved solubility and
oral bioavailability
[87]
(Continued)
108 Cocrystals in Pharmaceutical Sciences
4.3 Optimization Parameters for Cocrystal
Formation
4.3.1 Choice of Coformer
Selecting a coformer consistent with an API is a vital phase in novel solid
form design, though it presents a signicant challenge during the cocrystal
formation process. e USFDA has compiled an inventory of thousands of
substances that might potentially serve as coformers for novel solid forms.
e coformer, which is the non-API constituent, must be non-toxic and
free of side eects. Ideally, non-API should hold generally regarded as safe
(GRAS) status. Various techniques, such as lattice energy calculations,
thermal analysis, the Koer contact method, the Cambridge structure
database (CSD), and synthon engineering, can be employed to choose an
appropriate coformer for synthesizing the novel solid form (cocrystals).
When a coformer possesses complementary functional groups, it can bond
with the API through supramolecular synthons using intermolecular inter-
actions identied via the CSD [46]. is strategy helps prevent undesirable
polymorphs, which can have adverse eects on drug performance. Strong
hydrogen bond cocrystals have been shown by the Cambridge structure
database. ese synthons serve as structural units within supermolecules
and are assembled through known or potential synthetic processes involv-
ing intermolecular interactions. While hydrogen bonds are commonly
involved in other intermolecular forces, including halogen bonds, van der
Waals forces, π-π interactions in aromatic compounds, and others, because
of their intensity and directionality, stacking interactions also contribute
signicantly to the crystallization process and play an important role in
newly solid forms. Strong hydrogen bonds commonly observed in solid
materials like cocrystals include N–H•••O, O–H•••N and O–H•••O.
Weaker hydrogen bonds involve interactions such as N–H•••
π, C–H
•••N
Table 4.1 Various techniques employed for cocrystal synthesis. (Continued)
Methods Drugs Coformer Conclusion Reference
Naringenin Isonicotinamide,
Picolinic acid
Betaine
Improved dissolution rate [88]
Simvastatin Aspartame Improved dissolution rate [89]
Tadalal Malonic acid Enhance solubility and
dissolution rate
[90]
Preparation Techniques of Pharmaceutical Cocrystals 109
and C–H•••O. van der Waals forces, which arise from inductive and dis-
persive attractions between molecules, contribute to the production of
solid dispersions [47]. Halogen-containing molecules, i.e., those with u-
orine, tend to create halogen connections throughout the process of self-
assembly. Desiraju and the research team describe a halogen bond as a
net attractive connection that occurs between a nucleophilic region in one
molecule or within the same molecule with the electrophilic portion of a
halogen atom in another molecule. e therapeutic eects of the drugs
are of interest to solid-state chemists, as cocrystallizing them with APIs
can improve solubility, physical and chemical properties, stability, and bio-
availability. is approach produces valuable, reasonably priced, and easily
obtainable synergistic hybrids. Together with their complementary bene-
ts, nutraceutical-API combos may help connect APIs within a multidrug
crystal lattice. Flavonoids and vitamins have been explored as potential
nutraceutical candidates for cocrystals to improve their physicochemical
properties and bioavailability. e selection of coformers typically follows
a supramolecular strategy [48].
4.3.2 Kinetics of Cocrystallization
e exploration of nucleation and growth in cocrystals formed through the
combination of dierent stoichiometric ratios of coformers is a fundamen-
tal characteristic of cocrystallization. When coformers in solution reach
supersaturation, the nucleation of numerous cocrystals competes with the
formation of the novel solid form, i.e., cocrystals. e solubility of coform-
ers and cocrystals, along with their metastable regions, inuences the rel-
ative nucleation rates and growth, which can shi the order of nucleation
based on how fast supersaturation occurs. Although TPDs oer data about
stable crystal forms, the cocrystallization process is primarily governed by
the kinetics of nucleation and growth [27]. Understanding these factors is
crucial for controlling cocrystal production and achieving the desired dis-
persion of sizes. e bare minimum of time needed for batch or residence
for pure cocrystal production depends on both growth and dissolution
kinetics. Furthermore, adjusting coformer concentrations can aect the
growing rate of dierent crystal faces, which in turn inuences crystal mor-
phology. Techniques like heteronuclei or ultrasound can be integrated into
cocrystallization processes due to their impact on nucleation kinetics [49].
Understanding the kinetics of both nucleation and growth of cocrystal and
conformer crystal is crucial for ecient large-scale production. Although
small-scale manufacturing of novel cocrystals can be achieved through a
variety of solid-state or solution-based methods, large-scale production
110 Cocrystals in Pharmaceutical Sciences
calls for a thorough grasp of these kinetics to optimize the process. For
example, producing a pure 1:2 cocrystal (such as maleic acid with caeine)
in many solvents is challenging, as both 1:1 and 1:2 forms tend to nucleate
simultaneously, resulting in an impure mixture that eventually transitions
to the 1:1 form. As a result, most attempts to obtain a pure 1:2 cocrystal
focus on rapid kinetic methods. However, recognizing the thermodynamic
and kinetic hurdles has led to the development of specialized conditions or
steps to produce the metastable cocrystal form. Croker et al. investigated
the nucleation behavior of p-toluenesulfonamide with triphenylphosphine
oxide cocrystals at dierent stoichiometric proportions throughout a cool-
ing cocrystallization process. By cooling mixes in the area of the stable
cocrystal, as predicted by a TPD, they successfully produced a novel solid
form. However, in the mixed-phase region, one cocrystal form nucleated
rst, followed by the other. e proportions of cocrystals in the mixture
changed over time, suggesting that either the nucleation did not occur
simultaneously or their growth rates varied depending on the coformer
combination. us, the nucleation sequence is determined by kinetic fac-
tors rather than the stability as shown by the phase diagram [50].
4.3.3 Application of Modeling and Process Analytical
Technology
e quality-by-design (QbD) technique emphasizes the development of
formulations and manufacturing processes to conrm that products meet
predened quality standards. QbD emphasizes the creation of a highly
ecient manufacturing process, enabling constant, instantaneous assur-
ance of product worth through comprehensive process comprehension
and management. is methodology utilizes thorough knowledge of the
process and its variables to ensure that batches consistently meet speci-
cations, minimizing the need for extensive post-production testing and
allowing for real-time batch release. Formulations that combine drugs or
drugs with coformers to create cocrystals, solid-state co-amorphous for-
mations, crystalline solid dispersions, or amorphous solid dispersions, are
increasingly being explored [51]. While these combination strategies oer
several benets, they also present challenges related to physical stability,
requiring more rigorous process controls to ensure that the drug remains
in its intended solid-state form. Recent advancements have been made in
process analytical technology (PAT) modeling, simulation, and applica-
tion for innovative cocrystallization methods. ese advancements allow
for the real-time monitoring of essential quality parameters throughout
Preparation Techniques of Pharmaceutical Cocrystals 111
production, promoting consistency and improved product quality. Using
PAT modeling also facilitates the application of QbD principles in indus-
trial crystallization. Yu et al. created the method of moments that was used
to solve a mathematical model for the batch-cooling crystallization of a
cocrystal of caeine and glutaric acid. ree basic equations that addressed
the cooling trajectory, one-dimensional population balance, and mass bal-
ance were included in the model [52]. Among the presumptions were a
growth rate that is independent of size, agglomeration, no nucleation or
breakage, and ideal mixing conditions. e model aimed to maintain poly-
morphic purity by controlling supersaturation. Experimental data were
used to estimate growth rates and crystal growth order. Simulations and
experiments optimized seeding parameters such as timing, seed loading,
size, and cooling prole to prevent unwanted polymorph formation. PATs,
like ATR-FTIR for solute concentration and videography for monitoring
cocrystal morphology, were employed. Monte Carlo simulations were used
to assess model parameter uncertainty and process variability, and experi-
mental data were used to validate the model. It was also scaled from a 1-L
vessel to a 10-L crystallizer, demonstrating successful validation at both
scales [53].
While modeling aids in understanding and designing processes, ongo-
ing observation of crucial process parameters and crucial quality traits is
necessary for eective quality control, which is fundamental to the imple-
mentation of QbD. In crystallization, the most frequently monitored attri-
butes include solution composition, solid form morphology, and particle
size [54]. Tools such as near-infrared FTIR measurement, ATR-UV/Vis
spectroscopy, and ATR-FTIR are utilized for monitoring the composition
of the solution. Raman analysis, turbidity measurements, particle vision
microscopy (PVM), and FBRM help observe the production and charac-
teristics of the solid form. In a study by Powel et al., batch and semibatch
crystallizers were used to study the p-toluenesulfonamide with triphen-
ylphosphine oxide cocrystal in acetonitrile. Using PAT technologies to
support a control plan for real-time process monitoring resulted in the suc-
cessful production of pure 1:1 and 3:2 novel solid forms. Even in mixed-
phase regions, the desired crystal form was obtained through the use of
thermal cycling and Raman spectroscopy. is demonstrates the critical
role of PAT tools in monitoring and controlling crystal transformations
during the cocrystallization process. Huang et al. utilized Raman spec-
troscopy to investigate the eects of coformer concentration and tempera-
ture on the cocrystallization of theophylline with benzoic acid cocrystals
through cooling and slurry crystallization methods. e real-time data
112 Cocrystals in Pharmaceutical Sciences
obtained from the study also enabled the identication of the nucleation
temperature and the cooling process endpoint [55].
Due to its resemblance to conventional crystallization, solution
cocrystallization can employ the same PAT tools typically used for
single-component crystallization. However, cocrystallization introduces
the challenge of dierentiating and managing the production of various
concurrent solid forms. is means the models of processes and control
techniques for cocrystallization may dier signicantly. Further research
is needed to develop strong models for cocrystallization, focusing on
characteristics of the product and process factors that can be monitored
using the current PAT tools. Continuous cocrystallization techniques,
with close monitoring and real-time adjustments through PAT tools, are
expected to be more eective than batch processes in maintaining the
quality of the goods. With the creation of accurate models, active control,
and real-time monitoring, ongoing cocrystallization could progress toward
a quality-by-control (QbC) approach, oering enhanced process eciency
and reliability [56].
4.4 Future Perspectives and Challenges
Investigating cocrystals represents a sustainable and eco-friendly approach,
as it avoids complex reactions and minimizes the need for excessive sol-
vent use. Cocrystals, also referred to as multi-component crystals, can be
developed using simple methods like grinding, aligning with the green
chemistry approach. ese structures, consisting of two or more molecu-
lar constituents bound by non-covalent interactions, oer unique proper-
ties and superior performance compared to their individual constituents.
Cocrystals hold signicant promise across various sectors, though they
also present certain challenges. In the pharmaceutical industry, cocrystals
have the potential to enhance drug stability, solubility, and bioavailability,
leading to more eective medications with fewer side eects. ey can also
aid in extending patent protection for drugs by oering novel formula-
tions. In materials science, cocrystals exhibit enhanced physicochemical
properties, opening novel possibilities in areas like catalysis, electronics,
and energy storage. ey could signicantly impact technologies like bat-
teries, where better performance and stability are critical.
e preparation and optimization of novel solid forms involve spe-
cialized approaches and skills, and scaling up production for industrial
Preparation Techniques of Pharmaceutical Cocrystals 113
use remains a key hurdle. Moreover, the regulatory framework for novel
solid forms in the pharmaceutical sector is still evolving, necessitating
clear evaluation and approval guidelines. Further research is also needed
to understand the principles governing novel solid forms’ development
and stability. Predictive models and computational tools could assist in
designing cocrystals with desirable properties. In conclusion, novel solid
forms hold vast potential in industries like materials science and pharma-
ceuticals. Overcoming obstacles related to preparation, production, regu-
lation, and fundamental understanding will be essential to harness their
capabilities fully. Continued research and cooperation between engineers,
scientists, and regulatory bodies will drive the development and practical
application of novel solid forms in the future. e future of novel solid
form development is set to advance through the adoption of cutting-edge
technologies that improve both the eciency and functionality of cocrys-
tallization. Green chemistry techniques, such as using supercritical CO₂
or eco-friendly solvents, oer more sustainable approaches to cocrystal
synthesis. Innovations like high-throughput screening and automation
are expected to accelerate the discovery of new cocrystals by streamlin-
ing the process of identifying suitable coformers and crystallization condi-
tions. e articial intelligence and integration of machine learning could
also revolutionize cocrystal design, predicting molecular interactions and
crystallization outcomes, thus reducing reliance on experimental trial and
error. ere is increasing interest in combining cocrystals with advanced
drug delivery systems, such as nanoparticles and polymers, to improve the
bioavailability and therapeutic eects of poorly soluble drugs. Regulatory
pathways for cocrystals are becoming more dened, facilitating smoother
transitions from discovery to market. ese advancements promise to
expand the use of novel solid forms in pharmaceutical formulations, pav-
ing the way for more ecient, targeted, and patient-friendly treatments.
Acknowledgments
I would like to acknowledge the support and resource guidance provided
by Chitkara College of Pharmacy, Chitkara University, Rajpura/Chitkara
University School of Pharmacy, Chitkara University, Himachal Pradesh,
and University Institute of Pharmaceutical Sciences, Panjab University,
Chandigarh by for the completion of this book chapter.
114 Cocrystals in Pharmaceutical Sciences
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