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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5702_Библиотеки_им_академика_М_И_Перельмана.pdf
196 Cocrystals in Pharmaceutical Sciences
and polymer-assisted grinding. Additionally, microwave-assisted cocrys-
tallization, freeze drying, electrospraying, laser irradiation, and resonant
acoustic mixing form the miscellaneous techniques used in DDC produc-
tion [27]. e dierent miscellaneous methods, i.e., the newer methods are
used in large-scale manufacturing of DDC as compared with the conven-
tional methods. Conventional methods are used for small-scale develop-
ment of DDC. e dierent strategies for preparing cocrystals are given
below [28, 29].
ere are some critical process parameters in the preparation of
DDCs. e process parameters and input variables validate the Critical
Quality Attributes (CQAs) that dene the desired properties of the nal
product [30]. It is crucial to consider the ability of DDC to withstand dif-
ferent storage conditions. Cocrystals tend to break down when exposed
to higher temperatures and high humidity levels during storage, primar-
ily due to the partial dissolution of the acids used as coformers. e speed
and arrangement of the screw are crucial factors, especially in processes
such as hot-melt extrusion [31, 32]. e quality target product prole
(QTPP) outlines essential quality characteristics for DDC, encompassing
factors such as solubility, stability, particle size, appearance, permeability,
dissolution rate, as well as the pharmacokinetic and therapeutic behavior
of cocrystals [33]. Critical Quality Attributes (CQAs) represent specic
subsets of the QTPP that must adhere to dened ranges, limits, or dis-
tributions to ensure the desired quality traits of cocrystal. ese attri-
butes encompass the physical, chemical, biological, and microbiological
properties of the nal product [34]. Newer techniques such as hot-melt
extrusion and screw melt extrusion have started swapping traditional
solvent-based methods [35]. ese new processes oer easier scalability,
reduced development time, increased energy transfer rates, minimized
plant space requirements, reduced waste production and energy usage,
improved specicity, and consistent development conditions to pre-
vent the buildup of harmful substances, all contributing to a more cost-
eective manufacturing process [14].
7.1.2 Characterization of DDCS
Currently, there are various evaluation tests available for MDC; they are
based on knowledge-based approaches. Some of the methods include syn-
thon engineering, molecular complementarity, hydrogen bonding propen-
sity, Hansen solubility parameter, pKa-based lattice energy calculations,
Drug-Drug Cocrystals: Advancements and Applications 197
and phase diagrams based on solubility and melting. ese screening
methods are being widely used for DDC systems [36]. Prashant et al. used
a synthon-based retrosynthetic strategy to develop an MDC of lamivudine
and zidovudine [23].
Table 7.2 Various instrumental techniques for characterization of DDCs.
Instrument Working principle
Single-crystal XRD Constructive interference is supported by the
interaction between the monochromatic X-rays
and the crystalline sample.
Powder XRD Because the wavelength of X-rays and the
interatomic spacing in crystals are comparable,
X-rays are diracted by cocrystals.
Raman spectroscopy,
FTIR
Provide details regarding the stretching and
vibration of molecules, atoms, or lattices.
Hirshfeld surface
analysis
Investigation of the interactions between
molecules within a crystal structure.
Terahertz spectroscopy
(THz)
It uses electromagnetic elds that spin at a
frequency ranging from several hundred
gigahertz to several terahertz in order to
examine the vibrations occurring both within
and between molecules in molecular solids.
Solid-state nuclear
magnetic resonance
Examining the structural characteristics based
on the nucleus’s spin, which produces the
magnetic eld.
Hot-stage microscopy Examining materials at dierent times and
temperatures utilizing both thermal analysis
and microscopy.
Dierential scanning
calorimetry
e measurement of enthalpy changes caused
by changes in a substance’s physical and
chemical properties over time or at dierent
temperatures.
ermogravimetric
analysis
It is predicated on the composition and thermal
stability of the substance being measured.
Scanning electron
microscopy
SEM scans the surface of the sample using a
focused electron beam.
198 Cocrystals in Pharmaceutical Sciences
e characterization techniques for DDCs are similar to those used for
common cocrystals. e analytical methods include microscopy, single-
crystal x-ray diraction, powder x-ray diraction, solid-state nuclear
magnetic resonance, infrared spectroscopy, Raman spectroscopy, ther-
mogravimetric analysis, dierential scanning calorimetry, dynamic vapor
sorption, dierential scanning calorimetry, thermogravimetric analysis,
among others [37]. e analysis of compositions containing cocrystals
is essential to evaluate their interactions with excipients and instabilities
due to changes in temperature, pH, and dissociation [38, 39]. e various
instrumentations and physicochemicals for characterization of DDCs are
listed below in Tables 7.2 and 7.3.
Table 7.3 Various physicochemical techniques for characterization of DDCs.
Name Description
Hansen solubility study (HSS) is is an essential tool for predicting how
well coformers and medications will work
together throughout the crystallization
process.
Hygroscopicity It might change a drug’s physiochemical
characteristics, including its solubility,
rate of dissolution, mechanical attributes,
stability, and bioavailability.
Melting point Drug cocrystallization may change the
drugs’ melting points and improve their
thermal stability.
Stability e cocrystals should be exposed to
dierent stability conditions, including
temperatures and humidity.
Photostability For evaluating the photodegradation of the
cocrystals and ensuring suitable storage,
handling, and transportation conditions.
Tabletability Evaluated for over-countering the scale-up
issues, improved mechanical properties,
and reducing tablet defects.
Drug-Drug Cocrystals: Advancements and Applications 199
7.2 Reported Drug-Drug Cocrystals for Non-Steroidal
Anti-Inammatory Drugs (NSAIDs)
NSAIDs have been utilized for alleviating pain, reducing fever, and man-
aging various inammatory conditions [40]. e Biopharmaceutical
Classication System (BCS) categorizes NSAIDs as class II, distinguished
by having low solubility in aqueous solutions [41]. For increasing the sol-
ubility of drugs, cocrystals emerge as an innovative approach. In this con-
text, Bhatia et al. synthesized cocrystals of ketoprofen-p-aminobenzoic
acid (KP-PABA) through the solvent evaporation method employing a
central composite experimental design. e cocrystals were evaluated for
their analgesic and anti-inammatory properties. e study found that
KP-PABA cocrystals had a solubility of 60.11 µg/ml and a drug release rate
of 93.45%. e optimized formulation had a lower IC
50
value of 248.79 µg/
ml compared to a pure drug (524.40 µg/ml), suggesting greater protec-
tion against protein denaturation compared to ketoprofen alone. In vivo
studies revealed that cocrystals signicantly reduced paw edema vol-
ume in Wistar rats, indicating a promising drug delivery system for anti-
inammatory activity [14]. Likewise, Charoenchaitrakool et al. fabricated
cocrystals of mefenamic acid, nicotinamide, and paracetamol utilizing
the gas anti-solvent technique. Box-Behnken design was implemented
to assess the eect of process factors on the mefenamic acid dissolving
rate and determine the ideal environment for preparing cocrystals with
the extreme mefenamic acid dissolution rate. Findings indicated that the
quickest dissolving time of cocrystals was 4.19 min while utilizing a pre-
cipitation temperature of 25°C. Prepared cocrystals had a dissolving rate
16.40 times higher than unprocessed mefenamic acid. erefore, outcomes
showed that the cocrystal can accelerate mefenamic acid’s dissolution rate
[42]. Similarly, Ma et al. synthesized meloxicam (MLX)-salicylic acid (SA)
cocrystals using SA as the coformer. e dissolving curve demonstrated
that the MLX-SA cocrystals increased the dissolution rate and solubility of
MLX. Moreover, the gel was developed, which improved the transdermal
penetration without inuencing the in vitro release of MLX. e MLX-SA
cocrystals incorporated gel successfully treated rheumatoid arthritis in rats
[43]. In another study, Aramini et al. employed a slurry approach for pro-
ducing the ketoprofen lysin salt (KLS) and gabapentin (GABA) cocrys-
tals. KLS-GABA cocrystals enhanced KLS solubility and permeability in
the gastrointestinal tract, as indicated by phytochemical, biodistribution,
and pharmacokinetic studies. In vivo, the study revealed that KLS-GABA
cocrystal improved systemic absorption of KLS as compared to KLS alone
200 Cocrystals in Pharmaceutical Sciences
or combined with GABA. e prepared cocrystals produced the synergis-
tic eect of KLS and GABA. In the inammatory and neuropathic pain
rat model, the KLS-GABA cocrystal alleviated pain and spinal neuroin-
ammation. e ndings highlighted that KLS-GABA cocrystals were an
eective strategy for chronic pain treatment [44]. Chen et al. utilized a
melt crystallization technique to prepare celecoxib-carbamazepine cocrys-
tals. Single-crystal X-ray diraction (XRD) was used to examine cocrystal
structure and growth dynamics with the aim of optimizing circumstances
for the hot-melt extrusion method. e synthesized cocrystals altered the
intrinsic dissolving rate of the celecoxib drug and showed a synchronized
release pattern. is study unveiled that melt crystallization was a feasi-
ble technique for generating DDCs on a large scale [28]. Nechhaipadappu
and associates synthesized cocrystals of ufenamic acid (FFA) containing
2-chloro-4-nitrobenzoid acid (CNB) and ethenzamide (ETZ) as coform-
ers. e cocrystals were prepared by utilizing solvent evaporation and
solvent-drop–assisted grinding techniques. In the FFA-CNB cocrystal,
FFA’s solubility doubled, while there was no rise in the FFA-ETZ cocrystals.
At 75% relative humidity, the cocrystals remained stable for six months
at room temperature without exhibiting any hygroscopic behavior [45].
Table 7.4 Salient outcomes of NSAID-based cocrystals.
Drug Coformers
Method of
preparation Salient outcomes Ref.
Diclofenac Ciprooxacin Mechanochemical 20.8 times higher
solubility of
diclofenac
without aecting
the antibacterial
ecacy of
ciprooxacin,
reduced dose and
side eects of
parent drugs
[47]
Etodolac Glutaric acid Cooling
crystallization
Increased two to
three times the
solubility of
etodolac than
pure drug
[48]
(Continued)
Drug-Drug Cocrystals: Advancements and Applications 201
Table 7.4 Salient outcomes of NSAID-based cocrystals. (Continued)
Drug Coformers
Method of
preparation Salient outcomes Ref.
Etodolac Isonicotinamide Mechanical
grinding
Enhanced
dissolution rate,
solubility, and
permeability
[49]
Naproxen Caprolactam Liquid-assisted
grinding
11.9 times increased
solubility of
naproxen and
caprolactam
[50]
Niumic acid Caeine Mechanochemical Improved the
solubility and
stability of the
drug, reduced
dose, and
sustained drug
release
[51]
Naproxen L-alanine Liquid-assisted
grinding
Improved
dissolution
rate and oral
bioavailability
[52]
Piroxicam Febuxostat --- Piroxicam solubility
was improved
2.8-fold
compared to pure
drug
[53]
Ibuprofen Nicotinamide Slow evaporation Enhanced solubility
and analgesic
activity
[54]
Niumic acid Caprolactam Liquid-assisted
grinding
Increased 1.4 times
solubility and 2
times dissolution
rate
[55]
(Continued)
202 Cocrystals in Pharmaceutical Sciences
Devi and colleagues developed KP cocrystals with fumaric acid as a
coformer. e cocrystals were prepared using a solvent-assisted grinding
method. e formulation substantially improved solubility and dissolu-
tion rate, with IC
50
values of 327.33 μg/ml and 556.11 μg/ml, respectively.
Compared to the pure drugs, the cocrystal formulation demonstrated
greater resistance to protein denaturation. In vivo experiments demon-
strated that the cocrystal formulation produced a faster pharmacological
eect in Wistar rats and albino mice than the standard drugs [46]. A list of
recent DDCs of NSAIDs is represented in Table 7.4.
erefore, cocrystals present a novel method to improve therapeutic
ecacy and overcome the delivery challenges associated with NSAIDs.
7.3 Reported Drug-Drug Cocrystals for Anticancer
Drugs
Cancer represents a signicant global cause of mortality, and for the
management of this, many anticancer drugs are used, but these have low
solubility and bioavailability, which reduces their therapeutic eciency.
e current research focuses on enhancing oral absorption of these low-
solubility drugs [59, 60]. To address these challenges, cocrystals emerge as
a novel therapeutic strategy. Duan et al. prepared cocrystals of palbociclib
with orcinol or resorcinol. e fabricated cocrystals were studied using a
Table 7.4 Salient outcomes of NSAID-based cocrystals. (Continued)
Drug Coformers
Method of
preparation Salient outcomes Ref.
Tramadol
hydrochloride
Celecoxib Wet grinding Celecoxib released
faster, while
tramadol released
more slowly from
cocrystals
[56]
Naproxen Nicotinamide --- High dissolution
rate
[57]
Tramadol Celecoxib --- Improved
pharmacokinetic
prole and
analgesic activity
[58]
Drug-Drug Cocrystals: Advancements and Applications 203
variety of methods, including XRD and thermogravimetric analysis. e
cocrystals of palbociclib exhibited improved dissolution rates under pH
conditions of 1.0 and 6.8, and increased solubility two to three times while
maintaining high stability. e palbociclib-resorcinol cocrystals elevated
relative bioavailability in rats by 1.24 times compared to palbociclib alone.
Additionally, it displayed a higher IC
50
value for healthy cells, indicating a
better biosafety prole. So, cocrystallization might be an eective technique
for enhancing palbociclib’s physicochemical characteristics and pharmaco-
kinetics prole [61]. Liu et al. developed a DDC hydrate by mixing dihydro-
myricetin (slightly water-soluble) with pentoxifylline (very water-soluble)
in a 1:1 ratio. e cocrystals were produced through hydrogen bonding
interactions between hydroxyl groups of dihydromyricetin and acceptor
groups of pentoxifylline. e dihydromyricetin-pentoxifylline cocrystals
decreased the hydrophilicity and solubility gap between these drugs and
released simultaneously and continuously. At 100 µM dosage, the cocrys-
tals had a synergistic anticancer eect on HepG2 cells. erefore, the study
identied cocrystallization as an appropriate strategy for the prolonged
release of drugs with varied water solubility [62]. Yin et al. fabricated
cocrystals of lobaplatin using avonoids like setin, quercetin (QCT),
naringenin myricetin, and luteolin as coformers. e anticancer activity
of all prepared cocrystals was assessed through the CCK-8 assay. e out-
comes unveiled that the cocrystals of lobaplatin-myricetin monohydrate,
lobaplatin-luteolin monohydrate, and lobaplatin-setin monohydrate had
higher ecacy than lobaplatin alone. ese advancements may provide an
appropriate solution for the overwhelming limitations of the parent drugs
[63]. In another study, Yu et al. prepared 5-uorouracil (5-FU)–L-proline
zwitterionic cocrystals. Additionally, the prepared cocrystals were incorpo-
rated into carriers composed of poly(ethylene glycol)-poly(caprolactone)
to form cocrystal micelles. Research ndings demonstrated a substantial
improvement in 4.6 times the solubility and 3.89 times the permeability
of the pure 5-FU drug. Moreover, the drug loading and entrapment e-
ciency of 5-FU cocrystal micelles showed enhancement of 2.39 times and
1.74 times, respectively, in comparison to the FU micelles without cocrys-
tals. Both the cocrystals and their micelles demonstrated outstanding
antineoplastic activity with the cocrystal micelles exhibiting even more
pronounced improvements. e ndings suggest the potential utility of
cocrystal-based formulations in cancer therapy [64]. Hao et al. synthesized
cocrystals of gallic acid and 5-FU to improve the antitumor and syner-
gistic action. e dissolution rate and solubility of the 5-FU–gallic acid
cocrystals were less compared to pure 5-FU, but membrane permeability
was improved. It signicantly enhanced oral absorption, with an AUC
0-t
204 Cocrystals in Pharmaceutical Sciences
Table 7.5 Anticancer drug–based cocrystals for the management of various cancers.
Drug Coformers Preparation method In vivo model Key ndings Ref.
Panobinostat Dabrafenib Mechanochemical
BRAF
V600E
Improved dissolution rate
and decreased survival
rate of cancer cells.
[69]
5-FU Trimethoprim --- SW480,
MDA-MB-231,
and H1299
Increased aqueous solubility,
eectively inhibited breast
cancer cells and low
toxicity.
[70]
Phenylahistin Microtubule inhibitor --- BALB/c mice Improved pharmacokinetic
prole, reduced toxicity
[71]
Lenvatinib Salicylic acid and
sulfamerazine
Slow solvent
evaporation
Hep G2 Lenvatinib-salicylic acid CC
showed 120 times higher
solubility than lenvatinib
alone.
Exhibited 2.25 times more
aqueous solubility
compared to lenvatinib
alone
[72]
Nandrolone Salicylic acid Grinding HeLa cell Enhanced anticancer activity [73]
Curcumin Ascorbic acid Solvent evaporation --- Increased dissolution rate
and aqueous solubility
[74]
(Continued)
Drug-Drug Cocrystals: Advancements and Applications 205
Table 7.5 Anticancer drug–based cocrystals for the management of various cancers. (Continued)
Drug Coformers Preparation method In vivo model Key ndings Ref.
Luteolin monohydrate Caeine and isoniazid Liquid-assisted
grinding and rapid
solvent removal
Male Sprague-
Dawley rats
Improved solubility and
bioavailability
[75]
Niclosamide Nicotinamide Spray drying A549 Enhanced bioavailability and
reduced dose
[76]
Flucytosine Sinapic acid and
syringic acid
--- DU145 Upregulated the apoptotic
pathway, ucytosine
repurposed for anticancer
activities
[77]
Curcumin Trimesic acid --- MDA-MB-231 Increased dissolution rate
and bioavailability of
curcumin
[78]
Berberine chloride Myricetin and
dihydromyricetin
Slurry HT-29 Showed a synergistic eect [79]
Palbociclib Adipic acid Slurry --- Palbociclib solubility
was improved 56-fold
compared to pure drug
[80]
Getinib iosemicarbazide Recrystallization A549 and H1299 Improved physiochemical
and biopharmaceutical
performance of getinib.
[81]