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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5702_Библиотеки_им_академика_М_И_Перельмана.pdf
336 Cocrystals in Pharmaceutical Sciences
Table 11.1 Reported cocrystals for improving tabletability.
S. no. Drug Coformer Technique Inference Ref.
1 Resveratrol 4-aminobenzamide Liquid-assisted
grinding (LAG)
e tabletability of the formulation is
signicantly improved as a result of
cocrystal formation, which leads to
an enhancement in bonding strength
among the particles, which concludes
in improved compression and cohesion
during the tablet manufacturing process.
[65]
2 Isoniazid 4-aminobenzamide Rapid solvent
removal methods
Improved tensile strength as compared to
pure drug.
[66]
3 Nebivolol
hydrochloride
4-hydroxybenzoic
acid
Liquid-assisted
grinding
and solvent
evaporation
method.
e development of cocrystals of nebivolol
hydrochloride with 4-hydroxybenzoic
acid elevated tabletability.
[55]
(Continued)
Cocrystals and Physicomechanical Properties 337
Table 11.1 Reported cocrystals for improving tabletability. (Continued)
S. no. Drug Coformer Technique Inference Ref.
4 Flufenamic acid Nicotinamide Solvent Evaporation It has been demonstrated that using
cocrystals to increase tabletability works
well.
[67]
5 Ibuprofen Nicotinamide Rapid solvent
removal using
rotary evaporation
Mechanical characteristics are enhanced
by cocrystallization of nicotinamide and
ibuprofen.
[11]
6 Flurbiprofen Nicotinamide Rapid solvent
removal using
rotary evaporation
e formation of cocrystal/cocrystallization
of urbiprofen with nicotinamide improved
tabletability.
[11]
7 Nicorandil
(NCR)
Fumaric acid Slow evaporation e tabletability of the drug was improved
by the cocrystallization approach.
[24]
Suberic acid
8 Rivaroxaban Malonic acid Slow solvent
evaporation
Cocrystallization managed to modify
crystallographic features as compared
to the parent constituents leading to the
formation of a new multicomponent
crystal phase, which results in enhanced
tabletability.
[29]
(Continued)
338 Cocrystals in Pharmaceutical Sciences
Table 11.1 Reported cocrystals for improving tabletability. (Continued)
S. no. Drug Coformer Technique Inference Ref.
9 Chlorzoxazone Picolinic acid Supercritical uid
method
Tabletability test results showed improved
powder compaction behavior.
[14]
10 Ligustrazine Salicylic acid (SA) Solution
cocrystallization
Ligustrazine suers from over-compression
at high pressures and SA has low
plasticity which provides additional
mechanical strength to the drug.
[68]
11 Palbociclib Kakaempferol Antisolvent
cocrystallization
Cocrystals proved to be an eective
approach for increasing tabletability.
[69]
12 Telmisartan Oxalic acid Ultrasound-assisted
cocrystallization
from solution
(USSC) methods
Results showed
enhanced tensile strength; hence, tablets
can be easily formed at any compaction
force.
[70]
13 Olaparib Fumaric acid Solvent evaporation Improved tabletability as compared to pure
drug and the most increased AUC0-24h
and Cmax values that were 6.1 and 11.6
times of free OLA, respectively, have
great potential to be advanced into the
enhanced solid preparations of OLA.
[71]
(Continued)
Cocrystals and Physicomechanical Properties 339
Table 11.1 Reported cocrystals for improving tabletability. (Continued)
S. no. Drug Coformer Technique Inference Ref.
14 Vanillin 6-chloro-2,4-
dinitroaniline
Slow evaporation
method
e cocrystal approach successfully
modies brittle crystals hence
strengthening its mechanical properties.
[28]
Ethylvanillin
Iso-vanillin
Ortho-vanillin
Ethylene
diamine
15
Caeine Methyl gallate Slurry method Improved tensile strength and powder
compaction as the drug faces over
compaction with severe lamination.
[72]
16 Paracetamol
form II
Oxalic acid Cocrystallization
from solution
e layered structure of cocrystals improves
their ability to form tablets more
eectively.
[75]
eophylline
Naphthalene
Phenazine
17 eophylline Methyl gallate Solvent evaporation
method
Enhanced elastic modulus, indentation
values, and crystal slip planes which led
to providing the required tabletability
performance.
[73]
(Continued)
340 Cocrystals in Pharmaceutical Sciences
Table 11.1 Reported cocrystals for improving tabletability. (Continued)
S. no. Drug Coformer Technique Inference Ref.
18 Paracetamol Trimethyl glycine Slurry method Enhanced compression characteristics
due to structural stability and improved
crystal face
[74]
19 Sulfadimidine 4-aminosalicylic
acid
Cocrystallization
from solution
Crystal habit engineering of cocrystals leads
to enhanced ow characteristics.
[75]
20 Adefovir
dipivoxil
Stearic acid Hot-melt extrusion
method
e tabletability is improved due to the
changed crystal habit introduced via the
coformer.
[76]
21 Paracetamol 5-nitroisophthalic
acid
Solvent evaporation
method
Superior tabletability of cocrystal than the
xenobiotics.
[77]
22 Voriconazole Fumaric acid Slurry method Hardness is enhanced by the development
of cocrystals as compared to its original
form.
[78]
Oxalate salt
4-aminobenzoic
acid
4-hydroxybenzoic
acid
Cocrystals and Physicomechanical Properties 341
11.3 Pharmaceutical Cocrystals Improving Stability
Cocrystals (CCs) are dened as crystalline materials consisting of two or
more diverse compounds that form a denite crystal lattice, oen enhancing
the stability, dissolution, hygroscopicity, tensile strength, solubility, tablet-
ability, mechanical strength, and performance of xenobiotics [33]. One of the
advantages of cocrystals is that they can upgrade stability against moisture,
which is the utmost requirement for preventing degradation and maintain-
ing the ecacy of hygroscopic drugs. Moreover, it can cocrystal improve also
physical and chemical studies, and results have shown that cocrystals can
exhibit reduced hygroscopicity compared to pure APIs, leading to enhanced
resistance to moisture uptake and, consequently, improved formulation
stability. One example is phenazopyridine which has a highly hygroscopic
nature, due to which it is very dicult to form dosage form and also has a
low therapeutic eect due to which manufacturing and ecacy are poor so to
overcome this issue the cocrystal of phenazopyridine was synthesized using
dierent coformers which are Benzoic acid, 4-hydroxyphenyl acetic acid,
and saccharin. e CC was prepared via solvent evaporation technique. e
CC showed improved solubility, but cocrystal with 4-hydroxyphenyl acetic
acid showed higher solubility among all 3 CCs. Moreover, the hygroscopicity
of phenazopyridine was also reduced and CC with saccharin was found to
be least hygroscopic at 85% and 98% RH [33]. Another example is palmat-
ine chloride which is hygroscopic. For improving hygroscopicity palmatine
chloride (PMTCl) use of an unreported salt cocrystal of palmatine chloride
combined with gallic acid (GA) has been designed and synthesized through
the solvent evaporation method. Data of structure analysis demonstrates that
the asymmetric unit of PMTCl-GA includes two PMT cations, two chloride
anions, a GA-neutral molecule, and two methanol molecules. In the process
of self-assembly of salt cocrystal GA neutral molecules and methanol par-
ticipate which inhabit binding sites among chloride anions through strong
hydration capability and external water molecules which reduces the bind-
ing ability of PMTCl-GA with external water molecules. e hygroscopic
strength of PMTCl-GA showed signicant enhancement when compared to
that of PMTCl [34]. Additionally, cocrystals can improve strength, but they
may also introduce new challenges associated with the solubility and bio-
availability of the xenobiotic, necessitating careful evaluation of their phys-
icochemical properties. While cocrystals present a promising approach to
enhancing drug formulations, ongoing research is essential to address these
challenges and optimize their use in pharmaceutical applications.
342 Cocrystals in Pharmaceutical Sciences
When a solid is exposed to a certain amount of water vapor at a particular
temperature and relative humidity, a phenomenon known as hygroscopicity
takes place. rough noncovalent interactions, primarily hydrogen bonding,
the solid’s surface and bulk properties are aected” [35, 36]. Hydroscopic
active pharmaceutical ingredients (APIs) may absorb water at any point
during processing (lyophilization, compaction, wet granulation, spray dry-
ing), storage, and transportation [36]. Highly hygroscopic solids can be
described as “water-loving” because they have polar functional groups or
water-attracting binding sites that allow them to form hydrogen bonds with
water [37]. Moisture absorption is characteristically ruled by the following
ve factors: the solid’s reactivity to water; the temperature of the surrounding
air; the solid’s exposed surface area; the velocity of the moist air; and the dif-
ference between the solid’s equilibrium moisture concentration and the par-
tial vapor pressure of the surrounding water [38]. In addition, the presence of
polar groups, such as hydrogen bonding sites could also contribute to hygro-
scopicity which depends upon the drug’s surface area, chemical composition,
crystal structure orientation, and presence of any disorganized structure
[35]. Physicochemical characteristics of drugs such as stability, crystallinity
(both chemical and physical), solubility, dissolving behavior, wettability, bio-
availability, powder ow property, powder compatibility, and hardness, can
be hampered by hygroscopic behavior. e physicochemical properties of
highly hygroscopic nutraceutical and pharmaceutical solids can be signi-
cantly altered by chemical degradation and/or solid-state that in turn aect
their therapeutic ecacy and shelf life [39]. Moisture could have a major
impact on the pharmacological properties of solid dosage forms as it favors
chemical processes like hydrolysis, decreasing glass transition temperatures
[40], and handling and formulation development [41]. Preventive measures
can be used during formulation to prevent and/or minimize the hygroscop-
icity of active components, rather than depending on the modication of
storage and manufacturing conditions to ensure the stability of hygroscopic
compounds. Cocrystal appears to be one of the most guaranteed approaches
for enhancing the stability of APIs [42]. Utilizing hydrophobic coform-
ers, encapsulating drug molecules, adjusting crystal packing arrangement,
encouraging hydrogen bonding interactions, and reducing solvent content
through desolvation eects, cocrystals present a viable approach to decreas-
ing the hygroscopicity of drugs [12, 43]. Yokoyama and colleagues reported
the progress of a series of multiple-component crystals of 3-aminopyridine,
a hygroscopic compound [44]. is is one of the initial case studies on phys-
ical stability enhancement concerning atmospheric humidity. Researchers
found out that for up to 45 days, moisture held at 100% RH is not absorbed
by the fatty acid cocrystals.
Cocrystals and Physicomechanical Properties 343
Hydrogen bonds between water molecules and exposed functional
groups on the crystal surface are the primary means of interaction [45].
e majority of research has suggested that the mechanism underlying the
cocrystal formation-induced modication of hygroscopicity is hydrogen
bond creation between the coformer and the API. e hydrophilic func-
tional groups of the API appear to be interacting with the coformer mol-
ecules, preventing these groups from interacting with water molecules.
Metoclopramide hydrochloride and berberine chloride have shown suc-
cess with this approach. According to Lue and colleagues, the cocrystalliza-
tion of citric acid with berberine chloride, a highly hygroscopic chemical,
results in increased stability against moisture. According to DVS isotherms,
berberine chloride can absorb water at a very low RH of 10%. At 70% RH,
it changes into berberine chloride dihydrate, resulting in a weight gain of
around 10%. However, with the cocrystal approach, less than 2% of mois-
ture got absorbed at up to 70% RH [46]. According to a dierent study,
oxymatrine has an excellent capacity to create hydrogen bonds with mol-
ecules of water, which makes it extremely hygroscopic. In cocrystals, urea
and oxymatrine form hydrogen bonds that occupy oxymatrine’s hydro-
gen bond site, lowering hygroscopicity [47]. Using acesulfame (AceH) as
a coformer, Aitipamula et al. employed the cocrystallization method to
enhance the physicochemical characteristics of griseofulvin (GF). While
amorphous GF transformed to crystalline form under high humidity con-
ditions in less than a day, the synthesized cocrystal (GF)2·Ace-H mono-
hydrate exhibits higher physical strength [48]. Another study showed that
lithium chloride (LIC), which is used to treat neuropsychiatric disorders,
has a high hygroscopicity and rapidly deliquees, even at 11.30% relative
humidity which constrains the drug’s potential development. e develop-
ment of LIC and glucose cocrystals showed improvement in hygroscopic
stability under 40% relative humidity [49].
Cocrystals of nitrofurantoin with, p-hydroxybenzoic acid (PHBA),
p-aminobenzoic acid (PABA), urea, and L-arginine were described by
Vangala et al. and Cherukuvada et al. Among the cocrystals prepared
by Cherukuvada et al., only the nitrofurantoin−PABA cocrystal showed
enhanced stability toward hydration [50, 51]. In contrast, anhydrous nitro-
furantoin changes to its monohydrate within 7 weeks under the same
circumstances. Nitrofurantoin−PHBA cocrystals exhibited high physical
stability under 24 °C and 97% RH on prolonged storage (up to 13 weeks).
Metoclopramide (MCP), a common antiemetic medication sold as meto-
clopramide hydrochloride (MCP HCl) salt98, is another example of a
cocrystal that is stable in water. During the production process, crystal-
lized water in the monohydrate form may accelerate the Maillard reaction
344 Cocrystals in Pharmaceutical Sciences
with lactose and cause an ion exchange reaction with KBr98. e use of an
oxalic acid cocrystal successfully reduced the hydration of MCP HCl. e
enhanced stability against moisture can be attributed to the participation
of all hydrogen bond donor and acceptor sites of MCP in the cocrystal for-
mation [52]. An inhibitor of 5-lipoxygenase called zileuton (ZIL) is used
to treat asthma. ZIL is available as a racemic combination in its anhydrous
form. When exposed to high humidity, the moderately hygroscopic anhy-
drous form of ZIL (form A) changes into a monohydrate (form H). e
cocrystallization method was used by Chen et al. to solve the hydration
stability problem. Nicotinamide (ZIL−NIC) and isonicotinamide (ZIL−
ISO) were used to create its cocrystals. When examined under controlled
circumstances, it was discovered that both cocrystals were comparatively
stable and did not experience phase transformation or disintegration for
up to 4 weeks [53]. So, Cocrystal formation has shown that the decrease
in hygroscopicity was caused by the development of hydrogen bonds amid
the compounds that make up crystals, which decreased the amount of
hydrogen bonding spots that could interact with water. More examples of
dierent drugs whose stability is enhanced by the formation of cocrystals
are enumerated below in Table 11.2.
11.4 Conclusion and Future Prospective
e future of cocrystals in enhancing the stability and mechanical prop-
erties of drugs holds signicant promise for the pharmaceutical industry.
As researchers continue to explore the potential of cocrystal technology,
innovative strategies are emerging to address the persistent challenges of
drug formulation. One key area of focus is the selection of novel coformers
that can not only stabilize APIs but also tailor their mechanical proper-
ties to meet specic formulation requirements. Advances in computational
chemistry and molecular modeling are enabling the design of bespoke
cocrystals with optimized solubility and stability proles, allowing for
more eective drug delivery systems.
Moreover, the increasing interest in personalized medicine is likely to
drive the development of cocrystals tailored to individual patient needs,
enhancing therapeutic ecacy. Additionally, regulatory frameworks are
gradually adapting to accommodate cocrystal formulations, which could
streamline the approval process for these innovative products. As analyt-
ical techniques improve, the characterization of cocrystals will become
more sophisticated, allowing for better prediction of performance in var-
ied conditions. Furthermore, the integration of cocrystal technology with
Cocrystals and Physicomechanical Properties 345
Table 11.2 Reported cocrystals for improving stability.
S. no. Drug Coformer Technique Inference Reference
1 Palmatine
chloride
Gallic acid Solvent evaporation
method
Since Palmatine chloride is a hygroscopic
drug, the cocrystal of palmatine
chloride was formulated with gallic
acid. e cocrystal showed increased
hygroscopicity of palmatine chloride.
[34]
2 L-carnitine(LC) Myricetin (MYR) Slurry method e stability of LC was improved via the
cocrystal formation approach as 16-fold
lower hygroscopicity was observed.
[54]
3 Ibuprofen Nicotinamide Rotary evaporation e formation of cocrystal/cocrystallization
of ibuprofen with nicotinamide improved
hygroscopicity and tabletability.
[11]
4 Flurbiprofen Nicotinamide Rapid solvent
evaporation
using rotary
evaporation
e formation of cocrystal/cocrystallization
of urbiprofen with nicotinamide
improved hygroscopicity and tabletability.
[11]
(Continued)