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
136 Cocrystals in Pharmaceutical Sciences
Table 5.1 e details regarding the characterization of pharmaceutical cocrystals
by DSC, FTIR, and solubility. (Continued)
Sr. no. Analytes Conformers
DSC
[°C] FTIR
Solubility
[mg/mL] Ref.
Saccharin - - -
16. Febuxostat Isonicotinamide 166.8 3299 cm
-1
(N-H
stretch)
2968 cm
-1
(O-H
stretch)
2221 cm
-1
(C≡N
stretch)
1694 cm
-1
(carboxylic
C=O stretch)
13.1 mg/mL [73]
Arginine 199.3 3368 cm
-1
(N-H
stretch)
2963 cm
-1
(O-H
stretch)
2229 cm
-1
(C≡N
stretch)
1644 cm
-1
(carboxylic
C=O stretch)
570.8 mg/
mL
17. Carbamazepine Nicotinamide - - 1.95 [74]
Saccharin - - 0.99
Succinic Acid - - 0.55
fumaric acid - - 1.24
18. Ivabradine
hydrochloride
(S)-mandelic acid 160.2 3500 cm
-1
(secondary
alcohol)
2500 cm
-1
(N–
H+ functional
group)
- [77]
(R)-mandelic acid 131.5 1450 cm
-1
(C-H
deformation
vibrations)
-
(Continued)
Characterization of Pharmaceutical Cocrystals 137
Table 5.1 e details regarding the characterization of pharmaceutical cocrystals
by DSC, FTIR, and solubility. (Continued)
Sr. no. Analytes Conformers
DSC
[°C] FTIR
Solubility
[mg/mL] Ref.
19. Ticagrelor Nicotinamide 122.4 1704 cm
-1
(C=O
band
stretching)
1094 cm
−1
(hydrogen
bond
interaction
N–H…O)
pH 2 acidic
medium
signicant
solubliity
[79]
Nicotinamide hydrate 120.5
20. Sulfaguanidine thiobarbutaric acid 170 3340 cm
-1
(NH2)
stretching
1176 cm
-1
sulfonyl group
3191 cm
-1
NH-O
interaction
- [80]
1,10-phenanthroline 217 3340 cm
-1
(NH2)
stretching
1231 cm
-1
sulfonyl group
1420 cm
-1
(C=N)
1620
cm
-1
(C=C)
-
21. Zonisamide 179caeine 179 - 0.7418 mg/
mL
[81]
5-methyl-2-pyridone 148.2 -
L-proline 157.7 0.2758 mg/
mL
catechol 107 0.7924 mg/
mL
22. Ketoconazole oxalic acid 186 1686 cm
-1
(C=O)
22.34 mg/
mL
[82]
fumaric acid 174 1730.80 cm
-1
(C=O)
43.92 mg/
mL
nicotinamide 136 1626 cm
-1
(C=O) 33.42 mg/
mL
(Continued)
138 Cocrystals in Pharmaceutical Sciences
Table 5.1 e details regarding the characterization of pharmaceutical cocrystals
by DSC, FTIR, and solubility. (Continued)
Sr. no. Analytes Conformers
DSC
[°C] FTIR
Solubility
[mg/mL] Ref.
23. Dapsone caeine 176.6 3372 and 3356
cm
-1
(Aromatic
Amino group)
1283, 1136, and
1099 cm
-1
(sulfonyl group)
506.5 µg/mL [83]
24. Indole-3-acetic
acid
2-aminopyrimidine 122-126 3318 cm
-1
(NH)
stretching
3173 cm
-1
(O-H)
stretching
1687 cm
-1
(C=O)
stretching
- [84]
2-amino-4,6-
dimethylpyrimidine
151-153 3319 cm
-1
(NH)
stretching
3142 cm
-1
(O-H)
stretching
1664 cm
-1
(C=O)
stretching
--
2,4,6-triaminopyrimidine 249-251 1631 cm
-1
(carboxylate
group)
1334 cm
-1
(proton
transfer
x-ray crystal
structure)
-
25. Indole-3-butyric
acid
2-amino-4,6-
dimethylpyrimidine
151-153 3340 cm
-1
(NH)
stretching
3164 cm
-1
(O-H)
stretching
1671 cm
-1
(C=O)
stretching
-
26. Riluzole ferulic acid 159.4 3279 cm
-1
(N-H)
stretching
1606.5 cm
-1
(N-H)
bending
- [85]
(Continued)
Characterization of Pharmaceutical Cocrystals 139
Table 5.1 e details regarding the characterization of pharmaceutical cocrystals
by DSC, FTIR, and solubility. (Continued)
Sr. no. Analytes Conformers
DSC
[°C] FTIR
Solubility
[mg/mL] Ref.
syringic acid 142.4 -
fumaric acid, 163.1 -
cinnamic acid 145.5 -
2,4- dihydroxy benzoic
acid
157.3 -
proline 206.9 -
vanillic acid 139.7 -
27. Tadalal Malonic Acid 192.7 - [86]
28. Zoledronic Acid DL-tartaric acid
Cocrystal-I
Cocrystal-II
Cocrystal-III
130.40
121.14
118.83
1739 cm
-1
(C=O)
ketone
3574.10 cm
-1
(-OH)
6.74 mg/mL
8.03 mg/mL
29.06 mg/
mL
[87]
nicotinamide 131.76 1681.93 cm
-1
(C=O) amide
group
3574.10 cm
-1
(-OH)
97.19 mg/
mL
29. Salicylic acid 3-Nitrobenzamide 114.5
115.6
- - [88]
30. Valsartan succinic acid 93.63 2922.24 cm
-1
(C-H)
stretching
1552.28 cm
-1
(C-N)
stratching
1733.94 cm
-1
(C=O)
stretching
1472.80 cm
-1
(C=C)
stretching
472.58 ± 0.25
µg/mL
[89]
Fumaric acid 94.84 383.11 ± 0.23
µg/mL
Oxalic acid 95.05 355.35 ± 0.24
µg/mL
(Continued)
140 Cocrystals in Pharmaceutical Sciences
e authors, Ali Samie et al., made several new salts with three essential
medicine chemical components for an antidiabetic medicament (gliclazide,
glipizide, and tolbutamide). e salts were based on CAC (catechol), REC
(resorcinol), piperazine (PPZ), and p-toluenesulfonic acid (PTSA). e nd-
ings established that PPZ’s salt generated had remarkable solubility [58]. us,
in the work of enge et al., the design and characterization of the diacerein
cocrystals with molecules such as urea and tartaric acid were carried out, and
the conformer form was established. e expert team noticed that their com-
pound had a phenomenon of rapid degradation, which was more than the typ-
ical compound [59]. Ionic cocrystals (ICCs) were prepared by Shemchuk et al.
using grinding and mixing in a solution. ese crystals included L-histidine,
DL-histidine, and calcium salts such as calcium chloride, bromide, and iodide.
X-ray diraction techniques using either powder or single-crystal analysis
were used to characterize the structure. For data collection and structure solu-
tion utilizing SCXRD, ICCs produced by solvent evaporation worked well; in
Table 5.1 e details regarding the characterization of pharmaceutical cocrystals
by DSC, FTIR, and solubility. (Continued)
Sr. no. Analytes Conformers
DSC
[°C] FTIR
Solubility
[mg/mL] Ref.
31. Meloxicam salicylic acid 207 1653 cm
-1
(C=O)
stretching
absent
3290 cm
-1
(N-H)
stretching
absent
SO
2
change
from
1263 cm-
1
to
1277 cm
-1
Similar
solubility
like drug
[90]
fumaric acid 243 1662 cm
-1
(C=O)
stretching
3290 cm
-1
(N-H)
stretching
higher
solubility
malic acid 211
226
3290 cm
-1
(O-H)
absent from
drug
3442 cm
-1
(O-H)
absent from
conformers
Similar
solubility
like drug
*Dierential Scanning Calorimetry: DSC, ermal Gravimetric Analysis: TGA, Fourier
Transform Infra-Red Spectroscopy: FTIR, Powder X-Ray Diraction: Single Crystal X-ray
Diraction: PXRD Single Crystal X-ray Diraction: SCXRD, hydrochloric acid: HCl.
Characterization of Pharmaceutical Cocrystals 141
all other cases, PXRD structure solution was successfully used [64]. A novel
cocrystal involving aripiprazole (ARI) with orcinol as a coformer was synthe-
sized, characterized, and compared to other ARI cocrystals using dihydroxy-
and trihydroxy-benzene coformers (catechol, resorcinol, and phloroglucinol)
were made by Cho et al. e exact structure of the ARI-ORC cocrystal was
gured out using a method called SCXRD. Surprisingly, the cocrystal powder
exhibited no detectable degradation aer exposure to a temperature of 80°C
and 98% (relative humidity) for 1 week. It matches with its relatively high melt-
ing point [67]. In the present study, conducted by researchers Pan et al., two
polymorphs (α and β forms) of azelnidipine (AZD) were developed.
Additionally, 12 complexes of AZD with oxalic acid became synthesized
with AZD with oxalic acid molar ratios of 2:1, 1:1, and 1:2. e conr-
mation of the formation of 2 cocrystals and 10 co-amorphous structures
was achieved through XRD, TMDSC, and DSC-TG. Further insights into
intermolecular connections were explored using NMR and FTIR. In dier-
ent media, the solubility and the dissolution rate in 0.1 mol·
L-1
HCl of the
complexes were also investigated as part of the study [70]. Almansa et al.
prepared a new kind of cocrystal by mixing rac-tramadol hydrochloride
and celecoxib in equal amounts. is cocrystal, showcasing four distinct
mechanisms of analgesic action, maintains a 1:1 molecular ratio corre-
sponding to a 1:1.27 weight ratio, ensuring that a dose (100 mg) comprised
of rac-tramadol hydrochloride (44 mg) and celecoxib (56 mg), aligning
with typical clinical doses. e developed ionic cocrystal was thoroughly
characterized, revealing a well-structured DSC prole and a supramolec-
ular 3D structure. e three components were associated with hydrogen
bonding, with chloride ions forming a crucial intermolecular interaction
with proximal drug molecules [71] and Mohammad Khairool Azizul and
colleagues investigated the metastable zone width and nucleation order
of carbamazepine–saccharin cocrystals through slow cooling crystalliza-
tion. eir study employed the Kashchiev–Borissova–Hammond–Roberts
method to determine kinetic parameters, including induction time, critical
nucleus radius, and the interfacial energy of the cocrystals [75].
Andrea Perrin et al. investigated various cocrystals formed from
bis(2-pyrrolidone) and ε-caprolactam in combination with boric acid and
1,4-phenylenediboronic acid. e substantial polarity of the lactam car-
bonyl group demonstrated a marked anity for the hydrogen bond donor
properties of boronic acid. ese cocrystals exhibited cyclic boronic acid
tape motifs, with an uncommon donor-donor pattern dened by the robust
perpendicular interaction with lactam attributes. Notably, all cocrystals
can serve as contributors to boric or boronic acid cross-linkers in the pro-
cess of guar gelation [76].
142 Cocrystals in Pharmaceutical Sciences
e researchers tested how helpful multivariate statistical techniques
were in detecting cocrystal formation, using indomethacin with saccha-
rin and furosemide with p-aminobenzoic acid as examples. ese samples
were made at dierent ratios of the API and the coformer (1:1, 2:1, and
1:2). e researchers used data from DSC curves, FTIR, and Raman spec-
troscopy to analyze cocrystals (CA and PCA). ey found that comparing
cocrystals with physical mixtures gave a clearer picture of how cocrystal-
lization works compared to only looking at the drug molecule with the
coformer or the drug molecule with physical mixtures alone. ey also
observed that the results of these analyses could dier depending on the
instrument used, and the calculation method employed [78]. Aitipamula
et al. developed four cocrystals of zonisamide, an antiepileptic drug. ey
used dierent conformers (L-proline, catechol, 5-methyl-2-pyridone, and
caeine), and cocrystal screening was conducted using solvent-evaporation
and solid-state grinding techniques. Initial characterization with DSC and
TGA showed no weight loss, indicating the solid surface’s absence of sol-
vates/hydrates or solvent/moisture absorption.
Further analysis with PXRD conrmed the presence of unique peaks,
conrming cocrystal formation. e powder obtained from grinding was
used for subsequent experiments. e drug-drug cocrystal with caeine
exhibited promise for developing a sustained-release formulation of zoni-
samide. It demonstrated stability under various conditions and presented
a lower dissolution rate and solubility than the original zonisamide [81].
L.H. do Amaral et al. developed the cocrystal of dapsone with caeine
[83]. Here, the cocrystals were prepared using large-scale preparation tech-
niques, which were explored for oral inhaled powder form with postulated
cocrystals. A (1:1) M cocrystal ratio could be obtained by slow evaporation
from acetone and ethyl acetate. A range of mixtures, including acetone,
ethyl acetate, and ethanol, possessed cocrystals using the said methods.
e samples prepared were characterized utilizing XPRD, DSC, TGA, and
FTIR. e median particle sizes (D50) obtained through laser diraction
analysis for spray-dried powders made with acetone, ethanol, and ethyl
acetate were 5.4 ± 0.7, 5.2 ± 0.1, and 5.1 ± 0.0 m, correspondingly, making
them suitable for use with dry powder inhalers for pulmonary delivery.
e investigation carried out by Zhou et al. revealed a rare type of cocrys-
tal involving salicylic acid and 3-nitrobenzamide (SA-3NBZ which is formed
by thermal means). Calculations based on the theory were carried out to
explain the examined structure. e DSC and hot-stage microscopy were
utilized to identify polymorphic cocrystals of salicylic acid and 3-nitro-
benzamide in 1:1:2 molar ratios observed by SCXRD and their conrma-
tion. e ability to stabilize the energy of the polymorphic cocrystals of the
Characterization of Pharmaceutical Cocrystals 143
salicylic acid was studied experimentally using the density functional theory
with the dispersion correction. A weak stabilization eect was observed in
both 1:1 and 2:2 cocrystals, resulting in an energy decline (-0.01 and -0.05 eV
per molecule), correspondingly, compared to the initial materials.
Furthermore, analysis of the noncovalent interactions index also suggested
that these weak interactions were inuenced by intralayer hydrogen bonds
and van der Waals forces [88]. Similarly, three new ethenzamide cocrystals
with glutaric, maleic, and malonic acids were synthesized by A. Kozak et al.
e main goal was to analyze changes in the ethenzamide molecule geom-
etry and interactions induced by dierent acids in its crystalline state and
correlate these with the physicochemical properties of pure ethenzamide
[91]. Wang et al. showed an advanced approach in their research. ey used
both Raman and terahertz time-domain spectroscopic approaches to ana-
lyze the structure and vibrational modes of a pharmaceutical cocrystal made
of acetazolamide and 4-hydroxybenzoic acid. Both spectra provided unique
ngerprinting information for the cocrystal and its parent materials. e
experiment observations showed distinct peaks (absorption) at 0.82, 1.16,
1.28, and 1.64 THz, which were dierent from the prime substances, within
the frequency range of 0.2 to 1.8 THz. ese dierences were also evident in
Raman vibrational spectra. Using density functional theory, three theoret-
ical cocrystal forms were simulated, and the form with C(N)NH⋯HOOC
interactions demonstrated a higher consistency with investigational conse-
quences. is study highlights the eectiveness of proposed methodologies
in elucidating intermolecular hydrogen bonding interactions crucial for
pharmaceutical cocrystallization [92].
5.4 Conclusion
Understanding how drug molecules pack together (their structure) is crit-
ical to unlocking valuable information about their behavior. is includes
forms like crystals (polymorphs, solvates, and cocrystals) or formless sol-
ids (amorphous). To achieve a complete picture, scientists need to combine
various analytical tools. Existing methods eectively analyze cocrystals,
revealing detailed information about their structure, stability, and how
they behave as drugs. e future holds promise for even deeper insights.
e development of in situ and real-time characterization techniques
is crucial. Current methods typically analyze samples post-formation.
Techniques that monitor the cocrystal formation and transformation in
real time will oer deeper insights into the mechanisms and enable better
process optimization.
144 Cocrystals in Pharmaceutical Sciences
Data science and machine learning can also analyze vast datasets to pre-
dict successful cocrystal formation and accelerate discovery. Furthermore,
researchers are exploring new types of cocrystal formers to create cocrys-
tals with even more desirable properties. However, there are still knowl-
edge gaps to address. We need a clearer understanding of how a cocrystal’s
structure directly aects its performance, such as how easily it dissolves.
Predicting a cocrystal’s long-term stability is also crucial for its use as a
drug. Finally, scaling up cocrystal production from research labs to com-
mercial manufacturing requires further development of ecient methods.
Hence, scaling up production for commercial use of cocrystal remains
challenging. Developing scalable and cost-eective processes is essential
for broader pharmaceutical applications. By tackling these challenges,
scientists can unlock the full potential of cocrystals and deliver improved
pharmaceutical products.
Acknowledgment
Our sincere thanks to the principal of RCPIPER, Shirpur, India, for sup-
port in providing library resources.
References
1. Pindelska, E., Sokal, A., Kolodziejski, W., Pharmaceutical cocrystals, salts
and polymorphs: Advanced characterization techniques. Adv. Drug Deliv.
Rev., 117, 111–146, 2017.
2. Vioglio, P.C., Chierotti, M.R., Gobetto, R., Pharmaceutical aspects of salt and
cocrystal forms of APIs and characterization challenges. Adv. Drug Deliv.
Rev., 117, 86–110, 2017.
3. Rathi, R. and Singh. Multicomponent crystal compromising dasatinib, I., and
selected co-crystals formers: a patent evaluation of EP2861589B1. Pharm.
Pat. Anal., 11, 1, 15–21, 2021.
4. Yadav, A.V., Shete, A.S., Dabke, A.P., Kulkarni, P.V., Sakhare, S.S., Cocrystals:
a novel approach to modify physicochemical properties of active pharma-
ceutical ingredients. Indian J. Pharm. Sci., 71, 4, 359, 2009.
5. Lin, S.Y., Simultaneous screening, and detection of pharmaceutical cocrys-
tals by the one-step DSC–FTIR microspectroscopic technique. Drug Discov.
Today, 22, 4, 718–728, 2017.
6. Rathi, R., Kaur, S., Singh, I., A Review on Co-crystals of Herbal Bioactives
for Solubility Enhancement: Preparation Methods and Characterization
Techniques. Cryst. Growth. Des., 22, 3, 2023–42, 2022.
Characterization of Pharmaceutical Cocrystals 145
7. Kalepu, S. and Nekkanti, V., Insoluble drug delivery strategies: review of
recent advances and business prospects. Acta Pharm. Sin. B., 5, 5, 442–453,
2015.
8. Serajuddin, A.T., Salt formation to improve drug solubility. Adv. Drug Deliv.
Rev., 59, 7, 603–616, 2007.
9. Rathi, R. and Sanshita, I.S., Hot Melt Extrusion Technique for Developing
Pharmaceutical Co-crystals: A Review. Drug Deliv. Lett., 14, 2, 97–108, 2024.
10. Izutsu, K.I., Koide, T., Takata, N., Ikeda, Y., Ono, M., Inoue, M., Fukami,
T., Yonemochi, E., Characterization and quality control of pharmaceutical
cocrystals. Chem. Pharm. Bull., 64, 10, 1421–1430, 2016.
11. Das, R., Ali, E., Abd Hamid, S.B., Current applications of x-ray powder dif-
fraction-a review. Rev. Adv. Mater. Sci., 38, 2, 95, 2014.
12. Bunaciu, A.A., UdriŞTioiu, E.G., Aboul-Enein, H.Y., X-ray diraction:
instrumentation and applications. Crit. Rev. Anal. Chem., 45, 4, 289–299,
2015.
13. Otsuka, Y. and Goto, S., Dry and wet mechanochemical synthesis of piroxi-
cam and saccharin cocrystals and evaluation by powder X-ray diraction,
thermal analysis and mid-and near-infrared spectroscopy. J. Pharm. Sci.,
111, 1, 88–94, 2022.
14. Imanto, T.E.G.U.H., Wikantyasning, E.R., Nurwaini, S.E.T.Y.O., Amalia,
M.O.N.I.C.A., Sambudi, N.S., Harun, N.Y., Preparation and Solid-State
Characterization of Ketoprofen-Succinic Acid-Saccharin cocrystal with
Improved Solubility. Int. J. Appl. Pharm., 16, 1, 275–279, 2024.
15. Budziak-Wieczorek, I. and Maciołek, U., Synthesis and Characterization
of a (–)-Epicatechin and Barbituric Acid Cocrystal: Single-Crystal X-ray
Diraction and Vibrational Spectroscopic Studies. ACS Omega, 6, 12, 8199–
8209, 2021.
16. Boa Ballaran, T., Kurnosov, A., Trots, D., Single-crystal X-ray diraction at
extreme conditions: a review. High Pressure Res., 33, 3, 453–465, 2013.
17. Rathi, R., Kushwaha, R., Goyal, A., Singh, I., Oxaliplatin-avone pharmaceu-
tical co-crystal-CN111205332A: patent spotlight. Pharm. Pat. Anal., 11, 5,
147–154, 2022.
18. Gründer, Y. and Lucas, C.A., Surface X-ray diraction studies of single crys-
tal electrocatalysts. Nano Energy, 29, 378–393, 2016.
19. Pauchet, M., Gervais, C., Courvoisier, L., Coquerel, G., Successful applica-
tion of the derived crystal packing (DCP) model in resolving the crystal
structure of a metastable polymorph of (±) modanil. Cryst. Growth Des., 4,
6, 1143–1151, 2004.
20. Zerrouki, K., Bouchene, R., Tüzün, B., Retailleau, P., Novel supramolecular
cocrystal of 8-hydroxyquinoline with acetone-(2, 4-dinitrophenyl) hydra-
zone: One pot synthesis, structural characterization, Hirshfeld surface and
energy framework analysis, computational investigation and molecular
docking study. J. Mol. Struct., 1300, 137290, 2024.