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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5702_Библиотеки_им_академика_М_И_Перельмана.pdf
166 Cocrystals in Pharmaceutical Sciences
manufacturing protocols can provide a consistent production of pharma-
ceutical cocrystals and formulations that meet the desired quality stan-
dards [78]. Control measures may vary depending on whether cocrystals
are employed for a specic formation or distributed as raw materials for
many generic formulations. Designating cocrystals as APIs and providing
active substance master les can facilitate their distribution for formula-
tion manufacture. Clarifying terminology about the quality of medicinal
cocrystals would facilitate their utilization.
6.3.4 Regulatory Considerations
Crystal engineering of pharmaceutical cocrystals oers a promising
approach to improving solubility. Regulatory agencies like the FDA and
EMA have issued guidelines for herbal cocrystals as intermediates, simi-
lar to API-excipient complexes; the EMA aligns this documentation with
salts. Regulatory approval requires demonstrating stability, dissolution,
and safety of coformers. Both agencies emphasize that cocrystals enhance
drug development but require strict compliance with manufacturing and
characterization standards [12, 44, 79].
6.4 Reported Herbal Cocrystals
e description of herbal cocrystals and conformers with their method-
ology of formation and characteristic features is mentioned in Table 6.1.
6.5 Future Perspectives and Trends
6.5.1 Advances in Cocrystal Technology
New developments in the eld of pharmaceutical materials science have
expanded our understanding of the relationship between the functional
capabilities of APIs and their molecular and crystal structures. e inten-
tional creation of medicinal materials has become possible as a result of
this increased understanding. e inuence of APIs’ solid-state and physi-
cochemical features on the eectiveness of pharmaceutical formulations is
becoming more well-acknowledged [102]. Cocrystals, consisting of several
coformers and APIs, have shown promise in customizing the characteris-
tics of solid dosage forms [103].
Advancements and Applications of Herbal Cocrystals 167
Table 6.1 Description of herbal cocrystals and conformers with their
methodology of formation and characteristic features.
Sr.
no.
Herba l
cocrystals
(API) Coformer Method Inference References
1. Berberine
chloride
Citric acid Manual grinding
using an agate
mortar
• Enhanced thermal
stability, along
with resistance
toward changes in
the humidity, was
noted.
• Furthermore,
enhancement
in tablet ability,
solubility, and
dissolving rates.
[80]
2. Berberine
chloride
Fumaric acid Recrystallization
and slurry
method
• A notable
improvement in the
speed at which the
substance dissolves
was observed.
• Enhanced
durability when
exposed to high
levels of humidity
and temperature.
[81]
3. Berberine
chloride
Myricetin and
dihydromyricetin
Slurry method • Improvement in
water solubility
was observed
with the use of
myricetin, resulting
in synergistic
anticancer actions
for the HT-29
cell line in both
cocrystals.
[67]
4. Chrysin Berberine Ball mill
• Almost 1.7-
times increase in
bioavailability was
observed in rats in
comparison to that
of the pure form.
[82]
(Continued)
168 Cocrystals in Pharmaceutical Sciences
Table 6.1 Description of herbal cocrystals and conformers with their
methodology of formation and characteristic features. (Continued)
Sr.
no.
Herba l
cocrystals
(API) Coformer Method Inference References
5. Apigenin 4,4’-bipyridine Solvent-drop
grinding
• Improvement
in the solubility
prole, followed
by increased
ecacy and lower
toxicity, were seen,
thereby resulting
in a signicantly
enhanced anti-
inammatory
impact.
[83]
6. Baicalein Isoniazid,
isonicotinamide,
caeine,
theophylline,
and theophylline
trihydrate
Reaction
crystallization
and liquid
diusion
• e greatest
improvement in the
rate of dissolution
was observed with
caeine.
• 4.1-factor increase
in the values of
the area under the
curve and better
bioavailability.
[84]
7. Chrysin Cytosine and
thiamine
hydrochloride
Solvent-drop
grinding
• Achieved a three-
to fourfold increase
in the dissolution
and solubility rate.
• Along with the
improvement in the
in vivo and in vitro
characteristics such
as antihemolytic,
antioxidant, and
anti-inammatory
properties.
[85]
(Continued)
Advancements and Applications of Herbal Cocrystals 169
Table 6.1 Description of herbal cocrystals and conformers with their
methodology of formation and characteristic features. (Continued)
Sr.
no.
Herba l
cocrystals
(API) Coformer Method Inference References
8. Curcumin Resorcinol, catechol,
hydroxyquinol,
hydroquinone,
and pyrogallol
Rapid solvent
evaporation
• Compound stability
was strengthened
when exposed to
high humidity
conditions.
• e compound’s
tablet-forming
ability improved
compared to its
pure form.
• e rate of
dissolution
increased by
a factor of 7
when it was in a
cocrystal form with
hydroxyquinol.
[86]
9. Genistein 4,4’-bipyridine Solution
evaporation
• Enhanced
antibacterial
ecacy, along with
increased solubility
when compared to
the pure form was
observed.
[63]
10. Hesperetin Picolinic acid,
nicotinamide,
and caeine
Liquid-assisted
grinding
• Achieved an
increase of 4
to 5 factors in
dissolution prole.
• ereby, resulting
in increased
safety against
inammation
because of
enhanced
antioxidant and
antihemolytic
characteristics.
[64]
(Continued)
170 Cocrystals in Pharmaceutical Sciences
Table 6.1 Description of herbal cocrystals and conformers with their
methodology of formation and characteristic features. (Continued)
Sr.
no.
Herba l
cocrystals
(API) Coformer Method Inference References
11. Isoniazid Quercetin Ball milling
• e dissolution
rate was enhanced
by 51.67 times,
resulting in
signicant
improvements.
• e bioavailability
was boosted by
a factor of 28.91,
leading to increased
eectiveness.
• Additionally,
enhancement in the
hepatoprotective
activity of quercetin
was also seen.
[65]
12. Curcumin Ascorbic acid Solvent
evaporation
• Signicant rise in
aqueous solubility
of the substance, by
an increase of 576
times concluded.
• erefore, better
ability of the
substance to
dissolve also led to
improvement in
biological eects.
[66]
13. Emodin Berberine chloride
dihydrate
Stirring • Enhancements
in the maximum
concentration
(Cmax), along with
area under the
curve (AUC) values
when comparing it
to pure emodin.
[67]
(Continued)
Advancements and Applications of Herbal Cocrystals 171
Table 6.1 Description of herbal cocrystals and conformers with their
methodology of formation and characteristic features. (Continued)
Sr.
no.
Herba l
cocrystals
(API) Coformer Method Inference References
14. Berberine 3-methyl cinnamic
acid
Solvent
evaporation
• Observation of
increased solubility
in several polar
solvents was noted.
• A 7.7-fold increase
in absorption was
found.
[68]
15. Luteolin Caeine and
isoniazid
Liquid-assisted
grinding
method
• Increased solubility
by a factor of 3
was reported when
isoniazid was
combined.
• Both coformers
showed a spike
in AUC by 2.7-
and 1.4-fold,
respectively.
[69]
16. Quercetin Nicotinamide Gas antisolvent
process
• Superior
dissolution
performance at pH
levels of 1.2 and 6.8
compared to a pure
drug, achieving at
least twice times
that of pure drug
release.
[87]
17. Quercetin Pentoxifylline,
betaine,
theophylline, and
L-pyrroline
Solvent-drop
grinding
• Enhanced the
dissolution rate of
quercetin compared
to raw quercetin
• In Sprague-Dawley
rats, the oral
bioavailability of
quercetin increased
by 64, 27, 10, and 7
times by quercetin
designed with
pentoxifylline,
betaine,
theophylline, and
L-pyrroline
[88]
(Continued)
172 Cocrystals in Pharmaceutical Sciences
Table 6.1 Description of herbal cocrystals and conformers with their
methodology of formation and characteristic features. (Continued)
Sr.
no.
Herba l
cocrystals
(API) Coformer Method Inference References
18. Quercetin
and
apixaban
Acetonitrile and
ethyl acetate
Solution
crystallization
• Enhanced the
dissolution rates
due to the presence
of solvents
• Remained stable at
high temperatures
and illumination
conditions
[89]
19. Curcumin
and
resveratrol
CO
2
and acetone Cocrystallization
with
Supercritical
solvent
• Antioxidant activity
and dissolution rate
were enhanced
• Solubility of
curcumin and
resveratrol
ameliorated by 1.5
and 2 times
• Behavioral tests
in mice model
indicated an
increase in
antinociceptive and
anti-inammatory
potency
[90]
20. Curcumin N-acetylcysteine Antisolvent gas
technique
• Demonstrated
greater solubility in
acidic and neutral
pH environments
compared to pure
drug
• Inhibit neutrophil
chemotaxis showed
in in vitro testing.
• In vivo tests
revealed enhanced
antinociceptive and
anti-inammatory
eects compared to
pure curcumin.
[91]
(Continued)
Advancements and Applications of Herbal Cocrystals 173
Table 6.1 Description of herbal cocrystals and conformers with their
methodology of formation and characteristic features. (Continued)
Sr.
no.
Herba l
cocrystals
(API) Coformer Method Inference References
21. Curcumin 4,4-bipyridine -
• e powder
dissolution
experiment
demonstrated a
notable spring
eect and achieved
approximately
seven times the
apparent solubility
of raw curcumin.
[92]
22. Curcumin Pyrogallol Liquid-assisted
grinding
• e wound was
treated with
cocrystals closed by
day 12 aer surgery.
• Notably, by 15 days
post-injury, showed
a minimal scar
range.
• Additionally,
histopathological
assessments,
including
inammation,
granulation
tissue formation,
re-epithelialization,
and collagen
deposition,
highlighted the
signicantly
superior wound-
healing capability.
[93]
(Continued)
174 Cocrystals in Pharmaceutical Sciences
Table 6.1 Description of herbal cocrystals and conformers with their
methodology of formation and characteristic features. (Continued)
Sr.
no.
Herba l
cocrystals
(API) Coformer Method Inference References
23. Curcumin L-pyrroline and
piperine
Solvent
evaporation
technique
• Aer 8 hours, the
cumulative drug
release was 20%
for pure curcumin,
whereas cocrystals
achieved a
remarkable 71%.
• In a permeability
study at pH 6.8,
curcumin showed
a permeability of
less than 0.05 mg/
ml, while cocrystals
demonstrated a
vefold increase,
reaching 0.2545
mg/ml.
[94]
24. Curcumin Isonicotinamide Solvent
evaporation
technique
• e solubility of
cocrystals in water
was 73.1 µg/ml,
marking a 14-fold
increase compared
to the pure drug.
• e cocrystals
demonstrated 130%
greater potency in
inhibiting edema in
mice compared to
the pure drug.
[95]
25. Curcumin L-carnitine Liquid-assisted
grinding
• Demonstrated
faster dissolution
rates compared to
pure drugs.
• Pharmacokinetics
studies showed
that AUC
0-t
was 6.3
times higher and a
C
max
that was 10.7
times higher than
the pure drug.
[96]
(Continued)
Advancements and Applications of Herbal Cocrystals 175
Table 6.1 Description of herbal cocrystals and conformers with their
methodology of formation and characteristic features. (Continued)
Sr.
no.
Herba l
cocrystals
(API) Coformer Method Inference References
26. Hesperidin L-arginine -
• Signicantly
improved solubility
and dissolution rate
compared to pure
drug.
• Enhanced the
in vitro anti-
inammatory and
antioxidant activity
of hesperidin
compared to pure
drugs.
[97]
27. Hesperetin Piperine - • Solubility
experiment
conducted on the
powder cocrystals
in simulated
gastrointestinal
uid demonstrated
that they
signicantly
enhanced the
dissolution
behavior of the
drug.
• e bioavailability
of the drug in
cocrystals was
found to be six
times greater
than that of the
unprocessed drug.
[98]
(Continued)