Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5702_Библиотеки_им_академика_М_И_Перельмана.pdf
156 Cocrystals in Pharmaceutical Sciences
Analogous to salt selection, which relies on pKa considerations for acid-
base pairs, cocrystals oer a method to concurrently approach many func-
tional areas within a pharmaceutical compound [14]. Unlike salts, which
typically target an individual basic or acidic functional group, cocrystals
can accommodate tertiary and quaternary combinations. Notably, cocrys-
tals enable tailored adjustments to the solubility and dissolution-pH
dependence of APIs, even for nonionizable molecules [15].
Dierentiating between solvates and cocrystals independently depends
on each component’s physical condition. Solvates, formed when a single
component is liquid at room temperature, are oen unstable due to sol-
vent loss during storage [16]. While solvates may enhance drug dissolution
rates, their instability, and potential toxicological concerns limit their reg-
ulatory acceptance. In contrast, cocrystals, typically a product of deliber-
ate design, oer greater stability as the cocrystallizing agents are solid at
room temperature. Although polymorphic cocrystals are rare, they present
a more controlled alternative to solvates. Cocrystals, distinct from solid
dispersions, provide a crystalline single-phase multicomponent system
[17]. ey are distinguished from solid dispersions by the interactions
between components. Solid dispersions, utilized to enhance drug dissolu-
tion rates and absorption, involve the active ingredients’ dispersion within
an inert carrier. However, solid dispersions may inadvertently form during
attempts for cocrystal preparation from solution [18].
Regarding polymorphism, while proving the absence of polymorphism
is challenging, preliminary evidence suggests that polymorphic substances
may serve as suitable candidates for cocrystallization [19]. For instance,
carbamazepine, with multiple well-characterized polymorphs, has demon-
strated diverse cocrystal formations, illustrating the potential to mitigate
polymorphism practically through cocrystals [20]. e key advantages of
cocrystallization lie in its versatility across dierent types of drug mole-
cules and the abundance of potential counter-molecules for synthesis. is
approach oers opportunities for the pharmaceutical industry to address
intellectual property concerns by revitalizing old APIs, thus extending
their life cycles [21]. To summarize, cocrystallization in the pharmaceu-
tical sector provides an eective means for modifying the characteristics
of therapeutic solids. In contrast to conventional methods like salt pro-
duction and solvates, it oers several advantages, like exibility, stability,
and the ability to minimize polymorphism [22]. Furthermore, cocrystalli-
zation is an eective strategy for pharmaceutical development because of
its broad spectrum of applications and intellectual property prospects [23].
Advancements and Applications of Herbal Cocrystals 157
6.1.3 Selection of Coformer
A pharmaceutical cocrystal comprises two neutral molecules, out of which
one serves as an API while the other as a coformer. e USFDA has cata-
loged an extensive list of thousands of compounds suitable to be employed
as coformers for medicinal cocrystals [24]. Preferably, the cocrystal should
be listed on the USFDA “Everything added to food in the United States”
(EAFUS) list, which includes over 3000 compounds recognized as accept-
able for use as food additives or have been approved as generally regarded
as safe (GRAS). e coformer utilized as a non-API constituent must be
safer for consumption and devoid of any adverse reactions [25]. Cocrystals
comprise multiple components that are bound together by supramolecular
synthons. e primary challenge in synthesizing cocrystals lies in selecting
coformers which compatible with specic APIs, necessitating the presence
of functional groups in both the API and coformer capable of form-
ing supramolecular hetero- or homosynthons [26]. Researchers employ
diverse knowledge-based methodologies to screen coformers, including
the following:
• In silico screening involves using computational tools to pre-
dict interactions between coformers and API. Coformers
selected for screening must have hydrogen donor or accep-
tor groups to form hydrogen bonds with the API. Molecular
docking simulations, using soware like Autodock4, Glide,
or GOLD, determine the most stable conformation and ori-
entation with the lowest energy interaction. e binding free
energy is calculated to identify coformers that can success-
fully form cocrystals with the API [27, 28].
• Hydrogen bonding is crucial in cocrystal formation, driv-
ing molecular arrangements through noncovalent interac-
tions like π–π stacking and van der Waals forces. Eective
hydrogen bond formation follows guidelines that prioritize
six-membered ring interactions. Using the Cambridge struc-
ture database, hydrogen bond propensity values (0 to 1) pre-
dict bond formation. is approach quantitatively evaluates
interactions, aiding in the ecient screening and selection of
drug-coformer systems for cocrystal development [29, 30].
• e Cambridge structure database is essential for analyz-
ing intramolecular interactions in crystals. It aids in iden-
tifying packing motifs and functional groups, supporting
158 Cocrystals in Pharmaceutical Sciences
drug discovery by generating coformer collections for spe-
cic APIs, streamlining research, and reducing resource
use [31, 32].
• e pKa approach predicts herbal cocrystals or salt forma-
tion by assessing proton transfer between an acid and base.
It calculates ΔpKa by subtracting the acid pKa from the base.
A ΔpKa over 2 to 3 suggests salt formation, while a negative
value indicates cocrystals. e value between 0.3 creates a
continuum, not clearly distinguishing between cocrystals
and salts [29, 33].
• e Hansen solubility parameter assesses molecular com-
patibility based on solubility it calculates Δδt, the dierence
in solubility parameters between an API and a coformer, to
predict cocrystal formation. Values below 7MPO suggest
higher cocrystal likelihood, though practical results oen
deviate from predictions [34, 35].
• COSMO-RS (conductor-like screening model for real sol-
vents) accurately predicts the thermodynamic properties
of liquids. Using the COSMOtherm program, it evaluated
conformer feasibility in the supercooled liquid phase for
APIs. COSMO-RS, based on statistical physics, quanties
interaction energies, including polar and hydrogen bonds. It
calculates excess enthalpy for stoichiometric mixtures, dis-
tinguishing hydrogen bonding from overall enthalpic con-
tributions [36, 37].
• In 1995, Desiraju introduced “supramolecular synthon”
to describe the organization of crystalline structures in
supramolecules formed through specic intramolecular
interactions. Crystal engineering leverages supramolecular
chemistry principles, focusing on noncovalent interactions
to create new entities. Originally introduced by Corey in
organic chemistry, synthons are structural units in supra-
molecules [38, 39].
6.1.4 Methods of Cocrystal Synthesis
ese are various methods are utilized for cocrystal production including
the solid-state method and green-production method as demonstrated in
Figure 6.2.
Advancements and Applications of Herbal Cocrystals 159
6.1.4.1 Solid-State Methods
Neat (Dry) Grinding: In this method, pressure is applied on a solid com-
bination of coformers and APIs to facilitate cocrystal formation. A mortar
and pestle can be utilized for manual mixing, while a vibratory or ball mill
can be utilized for mechanical mixing [40]. e amount of time spent on
grinding, which typically takes 30 to 60 min, is controlled to maximize
the quality of the nal product. is technique’s disadvantage lies in the
comparatively poor eectiveness of cocrystal formation, yet it ensures sta-
bility simply by doing the requirement for solvents [41]. A portion of the
product could turn amorphous aer dry mixing, adding contaminants that
require further removal.
Wet (Liquid-Assisted) Grinding: In this approach, solid powders are ini-
tially milled with a small amount of liquid added. Various solvents such as
water, ethanol, or toluene can be used, requiring just a couple of droplets or
microliters. Also known as solvent-drop grinding, this approach enhances
Methods to
formulate co-
crystals
Solid-state
Methods
Neat (Dry)
Grinding
Methods
Wet (Liquid-
assisted) Grinding
Solvent-based
methods
Solvent
Evaporation
method
Ultrasound-
assisted
Ultrasonic Probe
Ultrasonic bath
Microwave-
assisted
Green-Production
Methods
Figure 6.2 Various methods of production of cocrystals.
160 Cocrystals in Pharmaceutical Sciences
cocrystal formation by acting as a solid powder binder rather than a dis-
solution medium [42]. Its advantages include simplicity, eectiveness,
environmental friendliness, cost-eectiveness, and higher cocrystal purity
compared to other methods. Additionally, it improves the yield percentage
compared to dry grinding [43].
6.1.4.2 Solvent-Based Methods
ese procedures rely on the inclusion of a signicant solvent amount in
which APIs and coformers dissolve. e selection of solvent is critical, with
adjustments in solvent type and temperature aimed at achieving optimal
cocrystal characteristics [44]. Compound crystallization from solution
develops in solvent-dependent cocrystallization when the solvent becomes
supersaturated by the cocrystal. e rate-limiting step for solvent-based
methods occurs when the rate of cocrystallization is greater than the degree
of solvent unsaturation. Various techniques fall under solvent-based meth-
ods, including solvent evaporation, slurring, active cocrystallization, and
the antisolvent method, with solvent evaporation being the most common.
6.1.4.3 Solvent Evaporation Method
is prevalent approach involves mixing equimolar amounts of API and
coformer through solvent or solvent mixture. e solvent promotes bond
formation and molecular interaction, with subsequent evaporation reveal-
ing a developed cocrystal. Careful monitoring of the evaporation rate is
crucial; rapid evaporation typically yields numerous small cocrystals,
whereas slow evaporation produces fewer, larger cocrystals [45]. Solvent
evaporation can occur spontaneously at room temperature or through
accelerated techniques involving increased temperature and/or decreased
pressure, like rotary evaporators as well as ltration by vacuum [46].
6.1.4.4 Miscellaneous Methods
Spray-drying represents a widely acknowledged approach employed for
converting emulsions, liquids, and suspensions into dry powder [47].
Employing advanced equipment enables precise regulation of atmospheric
conditions and the application of hot steam air to rapidly evaporate the
solvent. is approach signicantly outpaces previous solution cocrystal-
lization procedures in the context of speed and purity of cocrystal man-
ufacturing. Electrospray technology entails the utilization of an electric
eld to generate a ne spray of charged droplets. is approach involves
Advancements and Applications of Herbal Cocrystals 161
the application of electrical impulses to disintegrate the liquid into minute
droplets [48]. e uid is expelled through a narrow nozzle subjected to
elevated electric potential, thereby leading to dispersion into a thin mist
of highly charged droplets. Following the completion of the drying pro-
cess, the resultant particles are collected employing an electrostatic pow-
der collector. Acoustic resonant mixing (RAM) involves the utilization of
sound waves to homogenously blend the API and coformer formed in the
presence of a solvent, facilitating the formation of a cocrystal without the
requirement of a grinding medium. Acoustic power is imparted to a moist
powdered combination, which ensures a thorough amalgamation of all the
components [49].
Nano-cocrystallization in the pharmaceutical holds promise for improv-
ing the dispensability of poorly soluble drugs, a longstanding challenge for
the pharmaceutical industry. e research in this domain centers on the
manufacturing of nanococrystals which possess signicant commercial
worth. Scalable production of nanocrystals can be achieved through meth-
ods like media grinding, precipitation, and high-pressure homogenization
[50]. Nanocrystals exhibit notable eectiveness for therapy when adminis-
tered intravenously, orally, or via the pulmonary route. Furthermore, they
oer targeted delivery capabilities [51]. e production process typically
employs a top-down ow process using a ball grinding technique to induce
shear stresses, generating uniform nanosized particles. Precipitation, a
bottom-up growth process, is also commonly employed. Freeze-drying,
which is also referred to as lyophilization, is a widely adopted preserva-
tion method for various materials, including pharmaceuticals. e pro-
cess involves subjecting the material solution to a regulated and reduced
surrounding pressure, inducing sublimation of frozen water within the
materials [52]. is approach also holds the potential for creation of the
solid-state cocrystal structures.
6.1.5 Characterization Techniques
Cocrystal characterization techniques include structural methods like
single-crystal X-ray crystallography, powder X-ray diraction, and infra-
red spectroscopy, as well as physical property analyses like melting point
determination, dierential scanning calorimetry (DSC), and thermogravi-
metric analysis (TGA) as described in Figure 6.3 [53]. It has been demon-
strated that near-infrared (NIR) spectroscopy may be used for cocrystal
screening, with Raman spectroscopy acting as a comparison technique.
Whether in single crystal or powder form, X-ray diraction detects X-ray
162 Cocrystals in Pharmaceutical Sciences
pattern changes relative to the original material pattern, which gives a clear
indicator of new cocrystal formation [54].
Modications in the material’s vibrational mode brought on by light
scattering can reveal the existence of cocrystals, which makes Raman spec-
troscopy an invaluable diagnostic tool [55]. FTIR spectroscopy represents
functional groups as peaks within certain ranges, providing a distinct “n-
gerprint” for every chemical [56]. Further research to conrm cocrystal
formation may be necessary if FTIR detects any new bands or changes in
previously identied peaks that may indicate the establishment of hydro-
gen bonds. When choosing appropriate coformers from a range of chemi-
cals for cocrystal building, FTIR is very useful.
e thermal analysis method depends on variations in the enthalpy and
melting temperatures of cocrystals, as well as on the physical mixes of these
cocrystal constituents (active medicinal substances and coformers) [57].
TGA and DSC are the two methods used in this analysis. Cocrystal for-
mation in DSC is indicated by the existence of an endothermic peak at a
temperature that is lower or intermediate than the melting temperatures
of the raw components [58]. DSC measures phase changes like melting,
polymorphism, and the loss of volatile components in cocrystals. It tracks
power changes with temperature [59].
Characterization of
Cocrystals
Infrared
Spectroscopy
Thermogravimetric
analysis
Differential
Scanning
Calorimetry
Melting Point
determination
X-Ray
Crystallography
Powder X-ray
diffraction
Figure 6.3 Characterization method of cocrystals.
Advancements and Applications of Herbal Cocrystals 163
On the other hand, TGA measures mass loss with temperature and
is eective in identifying the precise temperature at which the cocrystal
begins to decompose and lose its volatile component. e amount of mass
loss in TGA oers conrmed information about the stoichiometric ratio of
the starting materials in the cocrystal [60]. Unique cocrystals, such as a sta-
ble salt-cocrystal of tiotropium fumarate with fumaric acid, were character-
ized, revealing their distinct structures and properties [61]. Investigations
into the thermodynamic stability of cocrystals and their component forms
provided valuable insights into cocrystal formation processes [62].
6.2 Benets and Applications of Herbal Cocrystals
6.2.1 Enhanced Solubility and Bioavailability
e Biopharmaceutics Classication System (BCS) categorizes drugs into
four classes based on their solubility and permeability, revealing that approx-
imately 40% of marketed drugs have poor solubility [63]. Researchers have
concentrated on enhancing the solubility of such drugs using various meth-
ods, including cocrystal formulation. Shimpi et al. developed a cocrystal of
tadalal, a phosphodiesterase inhibitor, with malonic acid. is cocrystal
exhibited a signicantly higher aqueous solubility across a wide pH range
compared to the drug alone. Additionally, a eutectic mixture of tadalal
with a coformer demonstrated a notable increase in solubility compared to
pure tadalal [64]. Similarly, Chen et al. successfully prepared a cocrystal
of the blood coagulation inhibitor, apixaban, with oxalic acid. ey discov-
ered that this cocrystal signicantly raised the intrinsic dissolving rate and
solubility in buer solution, which improved the pharmacokinetic char-
acteristics in Beagle dogs [65]. Additionally, McNamara et al. combined
glutaric acid with a class II low water-soluble sodium channel blocker API,
a derivative of pyrimidine-4-carboxamide. Dogs’ in vivo plasma concen-
tration studies showed that this cocrystal greatly increased solubility and
intrinsic dissolution rate [66].
Furthermore, ezetimibe, an antihyperlipidemic drug, was investigated
by Sugandha and colleagues as a cocrystal with methylparaben. When
compared to free ezetimibe, cocrystals made using various techniques
showed more solubility, which improved dissolution and bioavailability
[67]. To overcome the restricted solubility, dissolution, and bioavailability
of piperine, a secondary metabolite generated from plants, Zaini and asso-
ciates synthesized it as a cocrystal with succinic acid. is new cocrystal
was shown to have a notable rise in solubility along with enhancements
164 Cocrystals in Pharmaceutical Sciences
in dissolution and bioavailability. It is believed that the water-soluble
coformer succinic acid enabled the development of channels between pip-
erine molecules [68].
6.2.2 Improved Stability and Shelf Life
e use of cocrystals in the formulation of several medications has been
shown to signicantly increase stability. For instance, ufenamic acid, a
nonsteroidal anti-inammatory medication, was combined with nitroben-
zoic acid and ethenzamide to generate cocrystals. Weak halogen bonds
were used in this formulation to stabilize the ufenamic acid for more
than 6 months under ambient settings. Yang et al. produced berberine, a
naturally occurring isoquinoline alkaloid extract with a variety of phar-
macological properties, as a cocrystal with fumaric acid. Even at high tem-
peratures and humidity, this cocrystal demonstrated improved solubility
and stability. e dynamic vapor sorption (DVS) analysis and stress testing
were part of the stability evaluation [69].
6.3 Challenges and Limitations of Herbal Cocrystals,
Solubility Issues, and Incompatibilities
Herbal cocrystals, despite their broad applicability, face challenges in
commercial-scale production, limiting their market presence. eir devel-
opment requires precision, as creating a commercially viable, stable form is
guaranteed. Key obstacles include determining accurate drug dosage and
selecting suitable coformers from many potential options, necessitating
eective screening tools. Current methods like hydrogen bond propensity
and pKa rules aid in coformer identication, but more ecient screening
techniques are needed. Additionally, issues with polymorphism, solubil-
ity, and scaling up remain signicant. Nonetheless, herbal cocrystals hold
promise for enhancing drug properties and oer a cost-eective approach
to new pharmaceutical developments [12, 70].
6.3.1 Scale-Up and Manufacturing Challenges
e FDA denes a batch as a specic quantity of drug produced with con-
sistent quality, while a “lot” refers to part of a batch with similar consis-
tency. e pharmaceutical industry, traditionally using batch production
can benet from adopting, energy eciency, and improved quality control.
Advancements and Applications of Herbal Cocrystals 165
Continuous processes enable real-time monitoring and produce more
consistent outcomes, though they involve complex technology and higher
transition costs compared to batch methods [49, 71].
6.3.2 Safety Concerns
e development of herbal cocrystals represents an emerging area of
research. However, this necessitates caution owing to its limited knowledge
surrounding its safety prole. Here are numerous incompatibilities linked
to safety that must be kept in mind, which include the following: inade-
quate scientic research has been conducted to determine the safety of the
majority of herbal cocrystals [72]. Also, choosing a cocrystal possibility is
the safety of the coformer, which is another crucial consideration as this
can result in added regulatory requirements. e safety of both the inactive
along inactive components in a pharmaceutical product is a necessity for
obtaining market approval [50]. e coformer employed for the selected
cocrystal for the development of the product must be nontoxic and safer
to use when administered in the required amount for therapeutic doses
of the medicine [73, 74]. Before formulating a cocrystal for any medica-
tion, it is crucial to carefully evaluate the safety of the coformer and deter-
mine the appropriate quantity to be used in the cocrystal product. ereby,
employing excipients that are already recorded in the inactive ingredient
database (IID) as coformers could be used as it would necessitate a less
thorough regulatory evaluation as their safety in a specic quantity for cer-
tain methods of administration and dosage type may have previously been
veried [29, 75].
6.3.3 Quality Control
Quality control is an essential aspect of pharmaceutical cocrystal produc-
tion. ese cocrystals are manufactured employing unit procedures com-
monly used for producing APIs and their formulations [76]. Crystallization
from solutions is expected to yield high-quality solids, allowing for thor-
ough characterization of the cocrystals, as outlined in the recommenda-
tions provided by the European Medicines Agency. However, cocrystals
produced utilizing conventional formulation methods, including grinding
and spray-drying, may have smaller dimensions, lower purity, and con-
tamination, making it challenging to fully analyze them [77].
To ensure consistent production meeting quality standards, a tailored
control strategy aligned with the properties of the product and manu-
facturing processes is necessary. Integrating this approach with eective