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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5980_Библиотеки_им_академика_М_И_Перельмана.pdf
296 Cocrystals in Pharmaceutical Sciences
industrial scale [10]. Hot melt extrusion is a solvent-free process utilizing
elevated temperatures. ey enable continuous processing but are limited
by the thermal stability of components [11]. Mechanical activation tech-
niques like grinding, vibration-milling, ultrasound, and sonication utilize
mechanical energy for cocrystal formation [12]. While providing better
control, scale-up remains a challenge. Gas antisolvent techniques involve
rapid expansion of supercritical solutions or aerosol solvent extraction
employs high-pressure CO
2
-based processing [13]. However, specialized
equipment requirements limit widespread application.
A multitude of analytical techniques have been developed to character-
ize cocrystals and ascertain critical structure-property relationships. e
selection of appropriate techniques provides a comprehensive insight into
cocrystal composition, crystal structure, and phase identication. Solid-
state characterization of cocrystals involves powder X-ray diraction
(PXRD) which determines crystal structure and conrms phase purity.
It enables the identication of alternative polymorphs and hydrates [14].
Single crystal X-ray diraction (SCXRD) precisely denes molecular
Cocrystal
Preparation
PROBE
CO2
solvent
solvent
Supercritical fluid Method
Ultra Sonication Method
Liquid assisted grinding
API Coformer
Twin screw extrusion
Solvent Evaporation
Method
API Coformer
Anti-solvent Method
API Coformer
Anti-solvent
Freeze Dryer
Freeze drying Method
Figure 10.1 Cocrystal preparation methods. Various techniques are used for
the preparation of cocrystals. e most used methods include: (1) freeze-drying,
(2) antisolvent, (3) solvent evaporation, (4) twin-screw extrusion, (5) liquid-assisted
grinding, (6) ultrasonication, and (7) supercritical uid. 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 297
packing, conformation, and interactions through unit cell parameters.
However, it requires high-quality single crystals [15]. e solid-state NMR
spectroscopy can distinguish local environments when long-range order is
absent in PXRD. It aids in ambiguous structures [16].
Spectroscopic characterization of cocrystals involves fourier transform
infrared (FTIR) spectroscopy that identies functional group interactions
through peak shis. It conrms hydrogen bonding and salt formation [17].
Raman spectroscopy ngerprint regions characterize molecular arrange-
ments and complexation [18] and thermal methods like DSC (dierential
scanning calorimetry) and TGA (thermogravimetric analysis) quantify
endothermic and exothermic solid-state transitions and degradation
kinetics [19]. e morphology of cocrystals can be studied using micro-
scopic techniques such as scanning electron microscopy (SEM) visual-
izes crystal habits, defects, and particle morphology at micrometer scales
[20], and hot-stage microscopy monitors in situ phase changes and fusion
temperatures.
10.3 Enhancement of erapeutic Ecacy
with Cocrystals
Cocrystals have shown great potential in enhancing the therapeutic ecacy
of pharmaceutical drugs. One of the major ways in which cocrystals achieve
this is by improving the solubility and dissolution rate of poorly water-soluble
drug molecules. By incorporating such drugs into crystalline frameworks
together with suitable coformers, it is possible to modify the intermolecular
interactions and crystal packing of the drugs, which in turn improves their
hydrophilicity and wettability [1]. is allows for better and faster absorp-
tion of the drugs from the gastrointestinal tract aer oral administration.
Increased solubility and dissolution rate lead to higher concentrations of
drugs being absorbed systematically into the bloodstream [21]. is ensures
that therapeutically eective doses are achieved more eciently. In addition,
cocrystals have been found to possess properties like enhanced stability and
better owability and compressibility during formulation. All these advan-
tages of cocrystals ultimately help improve bioavailability and therapeutic
outcomes for many drugs that otherwise face delivery challenges due to poor
solubility and permeability [22, 23]. ere are several ways in which cocrys-
tals can enhance the therapeutic ecacy of drugs: Improving physicochem-
ical properties, enhancing stability and shelf life, improving bioavailability
and pharmacokinetics, combination therapy, and improving the targeted
298 Cocrystals in Pharmaceutical Sciences
delivery of drugs [24]. e role of cocrystals in enhancing therapeutic e-
cacy of drugs is summarized in Table 10.1.
Table 10.1 Role of cocrystals in enhancing therapeutic ecacy of drugs.
Properties
of drug
improved Drug Coformer
Observed
improvement Reference
Improving physicochemical properties
Melting point Propofol Isonicotinamide Increased
melting point
(from 18°C
to 68°C),
enabling
conversion to
a stable solid
form
[26]
Lithium chloride Glucose Modestly
improved
hygroscopic
stability under
40% RH
compared
to the drug
substance
alone
[29]
Metoclopramide Oxalic Acid Eectively
inhibited
hydration,
improving
stability
[30]
S-Oxiracetam Gallic Acid Less hygroscopic
than
S-oxiracetam
alone or
the racemic
parent drug
when stored at
25°C/60% RH
for 12 months
[31]
(Continued)
Cocrystals for Enhancing Therapeutic Efficacy 299
Table 10.1 Role of cocrystals in enhancing therapeutic ecacy of drugs.
(Continued)
Properties
of drug
improved Drug Coformer
Observed
improvement Reference
eophylline Flavonoids Greater
resistance to
hydration than
theophylline
alone when
subjected
to humidity
cycling
[32]
Solubility and
dissolution
Naproxen eophylline Approximately
twofold higher
dissolution
rates
compared
to naproxen
alone
[35]
Sulfadimidine
4-Aminosalicylic
Acid
~80% dissolution
within 5 min,
compared to
only ~30% for
sulfadimidine
alone
[36]
Isoniazid Curcumin Provided a
controlled
release of
isoniazid
over 48 hours
due to the
incorporation
of the
insoluble
curcumin
[34]
(Continued)
300 Cocrystals in Pharmaceutical Sciences
Table 10.1 Role of cocrystals in enhancing therapeutic ecacy of drugs.
(Continued)
Properties
of drug
improved Drug Coformer
Observed
improvement Reference
Enhancing bioavailability and pharmacokinetics
Permeability Acyclovir Fumaric acid
and glutaric
acid
Increased
permeability
across rat
skin by 2.8-
and 4-fold,
respectively,
compared to
acyclovir alone
[56]
Furosemide Anthranilamide Increased
cumulative
permeation
and ux across
a cellulose
membrane
compared to
furosemide
alone
[57]
Indomethacin Saccharine Enhanced
permeability
across
intestinal
epithelial
cells without
cellular
damage
[58]
(Continued)
Cocrystals for Enhancing Therapeutic Efficacy 301
Table 10.1 Role of cocrystals in enhancing therapeutic ecacy of drugs.
(Continued)
Properties
of drug
improved Drug Coformer
Observed
improvement Reference
Absorption
and
distribution
Baicalein Caeine 4.1-fold
higher oral
bioavailability
(AUC)
compared
to baicalein
alone,
attributed to
inhibition of
degradation.
[59]
Celecoxib-
tramadol
hydrochloride
Modulated the
release kinetics
of both drugs,
improving
bioavailability
and safety
[54, 55]
Increasing stability of drug molecules
Improving
stability
Lithium chloride Glucose Modestly
improved
hygroscopic
stability under
40% RH
compared
to the drug
substance
alone
[29]
Metoclopramide Oxalic acid Eectively
inhibited
hydration,
improving
stability
[30]
(Continued)
302 Cocrystals in Pharmaceutical Sciences
10.3.1 Improving the Physicochemical Properties of Drugs
e addition of coformers into the APIs crystal lattice, the cocrystals allow
for tuning various physicochemical properties such as solubility, dissolu-
tion rate, melting point, hygroscopicity, and mechanical behavior [25]. e
cocrystallization process and dierent factors aecting the solubility and
stability of cocrystals are summarized in Figure 10.2.
10.3.1.1 Melting Point
Cocrystallization can be utilized for increasing the melting point of APIs and
converting liquid drugs into solid dosage forms [1]. McKellar et al. imple-
mented a cocrystal approach for obtaining the solid form of propofol utilizing
iso-nicotinamide as the coformer. e obtained cocrystal was found to exhibit
an increased melting point (approximately 50°C higher than pure drug) and
was a stable solid at room temperature. Experimental thermal analysis data
revealed that propofol has a melting endotherm at 18°C, whereas the cocrystal
Table 10.1 Role of cocrystals in enhancing therapeutic ecacy of drugs.
(Continued)
Properties
of drug
improved Drug Coformer
Observed
improvement Reference
S-Oxiracetam Gallic acid Less hygroscopic
than
S-oxiracetam
alone or
the racemic
parent drug
when stored at
25°C/60% RH
for 12 months
[31]
eophylline Flavonoids Greater
resistance to
hydration than
theophylline
alone when
subjected
to humidity
cycling
[32]
Cocrystals for Enhancing Therapeutic Efficacy 303
showed a distinct melting endotherm at 68°C, representing over a 50°C increase
in melting point. is cocrystal formation allowed the conversion of liquid
propofol into a thermodynamically stable crystalline solid suitable for man-
ufacturing as oral or other solid dosage forms. e increased melting point
addresses issues with instability, pain during injection, and hyperlipidemia
associated with the liquid propofol formulation [26].
10.3.1.2 Hygroscopicity
Cocrystallization can quantitatively improve the hygroscopic stability of
APIs by inhibiting crystalline water formation through tighter hydrogen
bonding networks and blocking hydration sites during pharmacy man-
ufacturing and storage conditions [27]. Lithium chloride is used to treat
neuropsychiatric disorders but is extremely hygroscopic. e lithium chloride-
glucose cocrystal showed lower hygroscopicity under 40% RH com-
pared to the drug substance alone, as assessed by equilibrium moisture
content testing [28]. Metoclopramide is prone to crystallize water during
manufacturing, triggering an ion-exchange reaction with excipients. e
metoclopramide-oxalic acid cocrystal eectively inhibited hydration,
improving stability [29]. Oxiracetam is a racemic drug containing the
more pharmacologically active S-enantiomer which has higher hygroscop-
icity. Hygroscopic testing showed the S-oxiracetam-gallic acid cocrystal
was less hygroscopic than S-oxiracetam alone or the racemic parent drug
when stored at 25°C/60% RH for 12 months [30]. eophylline-avonoid
cocrystals showed improved resistance to moisture than theophylline alone
when subjected to humidity cycling between 25°C/30% RH and 40°C/75%
RH for 7 days [31].
ese case studies demonstrated how cocrystallization can be an eec-
tive strategy to address the challenge of drug hygroscopicity. By judiciously
selecting coformers that can form robust hydrogen bonding networks and
restrict water uptake within the crystal lattice, cocrystals of compounds like
lithium chloride, metoclopramide, oxiracetam, and theophylline exhibited
markedly improved resistance to hydration compared to the respective
parent drugs. is enhanced hygroscopic stability is expected to translate
into improved shelf life, processing characteristics, and ultimately, more
consistent therapeutic outcomes for patients.
10.3.1.3 Solubility and Dissolution
Cocrystallization can enhance the dissolution behavior and rates of poorly
soluble drugs through the formation of new supramolecular structures
304 Cocrystals in Pharmaceutical Sciences
between APIs and coformers [32]. Controlled-release proles can also
be achieved by incorporating insoluble excipients into cocrystal lattices
[33]. Naproxen-theophylline cocrystals produced by solvent-drop grind-
ing exhibited around 2-fold higher dissolution rates than naproxen alone
when evaluated using a USP Type II paddle apparatus at 50 rpm in 0.1 N
HCl [34]. Cocrystals of sulfadimidine-4-aminosalicylic acid demonstrated
enhanced dissolution behavior compared to the drug substance alone, with
~80% dissolution within 5 minutes for the cocrystal versus only ~30% for
sulfadimidine on its own, as assessed by a USP Type I basket method [35].
In the case of the tyrosine kinase inhibitor, dasatinib, the forma-
tion of cocrystals with various carboxylic acid coformers, such as
4-hydroxybenzoic acid, 4-chlorobenzoic acid, and sorbic acid, has
Drug molecule Coformer molecule Cohesive intermolecular
interaction
Adhesive intermolecular
interaction
Coformer of high solubility
Cocrystallization
2
Cocrystal
structure
Metastable drug
structure
Stable drug
structure
Poor leaching of
drug molecules
Cocrystallization
Coformer of intermediate
solubility
Drug conc.
Slow leaching
of coformer
Cocrystal structure
Amorphous drug structure
Amorphous drug
structure
Parent drug
behaviour
Time
3
1
2
3
1
Weaker intermolecular
interaction
Formation layered
structure
Formation of less stable
crystal structure
Formation higher polarity
cocrystal
Figure 10.2 Schematic representation of the cocrystallization process and the dierent
factors aecting the solubility and stability of cocrystals. e drug molecule in stable
crystalline form has poor water solubility due to cohesive intermolecular interaction
(1) Upon cocrystallization with coformers of higher solubility, a new crystal is formed.
Upon addition of solvent, the conformer molecules get dissolved rapidly resulting in
an amorphous state of drug molecule that may be converted into a stable form (2) or
metastable form with better solubility (3) Spring parachute eect: e solubility of the
drug in the amorphous cocrystal is higher than that of the pure drug, and the dissolution
rate is faster. e drug molecules are released faster from the amorphous cocrystal into the
solution, and the concentration of the drug in the solution increases rapidly. is is known
as the “spring parachute eect.” 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 305
demonstrated signicant improvements in solubility and dissolution char-
acteristics [36]. e cocrystallization process facilitated the development
of new crystalline forms of dasatinib, which exhibited solubility enhance-
ments up to 6-fold higher than the pure drug. is substantial increase
in solubility is attributed to the formation of strong intermolecular inter-
actions, such as hydrogen bonding and π-π stacking, between dasatinib
and the coformers, as revealed by detailed spectroscopic and computa-
tional analyses. e improved solubility and dissolution properties of the
dasatinib cocrystals have the potential to enhance the drug’s bioavailability
and therapeutic ecacy, ultimately leading to improved patient outcomes.
Isoniazid-curcumin cocrystals were synthesized to achieve sustained
release of isoniazid. Dissolution tests in pH 1.2 buer showed only 28% of
isoniazid was dissolved from the cocrystals aer 15 minutes, whereas iso-
niazid from a physical mixture was fully dissolved. is demonstrated the
cocrystal aorded controlled release over 48 hours due to the integration
of the insoluble curcumin in the crystal lattice [33].
ese enhancements in solubility and dissolution are crucial for enabling
complete and consistent absorption of the active pharmaceutical ingredients,
thereby ensuring that therapeutically eective concentrations are achieved at
the site of action. Improved bioavailability translates to better therapeutic
outcomes for patients, particularly for drugs that suer from poor solubility
and permeability issues. Furthermore, the ability to modulate drug release
proles through cocrystal design oers opportunities to optimize pharma-
cokinetics and tailor drug delivery to specic clinical needs.
10.3.1.4 Mechanical Behavior
Cocrystallization can modify the mechanical properties of drugs for
improved solid dosage form manufacturing by tuning plasticity, slip plane
activity, intermolecular forces, and packing arrangements [1]. e compac-
tion behavior and mechanical properties of caeine-glutaric acid cocrystal
polymorphs were tested using a hardness tester and analysis of powder
Brillouin light scattering spectra. e caeine-3-nitrobenzoic acid cocrys-
tal form I was found to exhibit better plastic deformation ability than form
II due to the presence of more slip planes in its 2D layered crystal structure.
is improved plasticity allows for better compaction properties during
tablet manufacturing [37].
In comparison to pure celecoxib, the celecoxib–L-proline cocrystals
presented lower punch sticking propensity when evaluated using a single
punch tableting machine at compaction pressures 100 and 250 MPa. e
cocrystal formation enhanced interlayer bonding energies, deactivated slip