Vol 4, Issue 2, 2023 (255-266)
http://journal.unpad.ac.id/idjp
*Corresponding author,
e-mail : nadiyah19002@mail.unpad.ac.id (N.S. Athaya)
https://doi.org/10.24198/idjp.v4i2.44137
2022 N.S. Athaya et al
Review: Solubility And Bioavailability Enhancement Of Carvedilol Using
Multicomponent Crystal Method
Nadiyah Salma Athaya*, Iyan Sopyan
Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy
Universitas Padjadjaran Jl. Raya Bandung Sumedang KM. 21, Jatinangor, 45363
Submitted : 31/12/2023, Revised : 10/01/2023, Accepted : 24/01/2023, Published : 03/16/2023
Abstract
Carvedilol is included in the BCS class 2 classification, drugs that have low
solubility and high permeability. Drugs with low solubility pose a major challenge
for oral drugs in achieving the desired systemic circulation. Moreover, carvedilol is
indicated for the treatment of cardiovascular disease and hypertension which
requires a rapid pharmacological response. A way to increase drug solubility is by
forming multicomponent crystals, including solvates, cocrystals, and salts.
Cocrystal and salt formation methods are the most frequently used methods in the
pharmaceutical field. The multicomponent crystal approach is a process of
combining active drug ingredients with other compounds known as coformers
which then interact through molecular bonds. Multicomponent crystals provide
benefits to improve the physicochemical properties of drugs without affecting their
pharmacological properties. In this review, we discuss the multicomponent crystal
approach as an effort to increase the solubility and bioavailability of carvedilol. The
main reference data used in this review are research journals published in the last
10 years (2012-2022) using the keywords carvedilol, multicomponent crystal,
solubility, bioavailability, and using Google Scholar as a database. There is also a
discussion on regulation of cocrystals, methods for forming multicomponent
crystals, and characterization of multicomponent crystals. The multicomponent
crystal approach has promising benefits in increasing the solubility and
bioavailability of carvedilol in the body.
Keywords: Carvedilol, multicomponent crystal, solubility, bioavailability
1. Introduction
Carvedilol is a drug for the
treatment of cardiovascular disease, that is
mild to moderate congestive heart failure
and hypertension. Carvedilol is taken orally
in twice-daily doses for therapy in the
immediate-release form or once-daily in
controlled-release form. Dosage is
individualized based on blood pressure and
heart rate response, even when used in heart
failure. The dosage range used was from
3.125 mg twice daily to 25 mg twice daily
(1). Carvedilol is included in the BCS class
2 classification which has low solubility
and high permeability (2). The oral
N.S. Athaya et al / Indo J Pharm 4 (2022) 255-266
256
bioavailability of carvedilol is 20%,
because carvedilol has a first past effect
metabolism in the liver with a short half-life
(t½), which is about 6 hours. This causes
the frequency of using oral carvedilol to
become more frequent, so it is required to
increase the use of oral doses which will
certainly affect patient comfort and
compliance in taking the drug (3,4).
To achieve the desired
pharmacological response in systemic
circulation using oral carvedilol, it is
necessary to make efforts to increase the
solubility and bioavailability of carvedilol
by modifying the physico-chemical
properties through a multicomponent
crystal approach (5). Multicomponent
crystals are classified into salts, cocrystals
and solvates. In the pharmaceutical field,
the formation of salts and cocrystals is the
most commonly used method and is proven
to increase the solubility of active
pharmaceutical ingredients (6).
2. Method
The writing of article review begins
with a literature search on Research Gate
and Science Direct with the keywords
"carvedilol", "multicomponent crystal",
"solubility", and "bioavailability"
published in various international journals
and national. The literature obtained was
then re-selected according to the inclusion
criteria, they are articles and reviews with
the last 10 years of publication (2012-
2022), articles discussing the increase in
solubility and dissolution rate of the drug
carvedilol using the multicomponent
crystal method approach, and also the
characterization of multicomponent
crystals. And the exclusion criteria are
opinions and publications that are not in
accordance with the topic of discussion.
Table 1. Methods performed for review
3. Result and Discussion
3.1 Carvedilol
β - blocker drug which is
indicated for the treatment of
cardiovascular disease, that is congestive
heart failure and hypertension. Carvedilol's
ability to lower blood pressure is the result
of inhibition of β-adrenergic receptors and
vasodilation which causes α -adrenergic
inhibitory activity . Carvedilol has
antioxidant activity because it is the only β-
blocker class of drugs that has a carbazole
group (3,7).
Based on the Biopharmaceutical
Classification System (BCS), carvedilol is
classified as BCS class II, it is drugs that
have low solubility and high permeability.
The solubility of carvedilol in water is
known to be only 0.093 mg/mL. It has been
reported that drug molecule solubility
below 100 g/mL indicates limited
absorption dissolution and may require
increased dose to maintain effective
therapeutic concentration (bioavailability).
There are more than 70% of newly
developed active pharmaceutical
ingredients (API) and 40% of drugs that
have been marketed belonging to BCS class
II compounds, which is carvedilol. This can
have an impact on the performance of drugs
administered orally (8–10).
Figure 1. Carvedilol Moecular Structure (11)
3.2 Multicomponent Crystal
Multicomponent crystals are one
of the crystal engineering techniques that
have been proven to be able to improve
physicochemical properties such as
solubility, stability, and bioavailability of
N.S. Athaya et al / Indo J Pharm 4 (2022) 255-266
257
drugs that are less soluble in water which
are then applied in the concept of
supramolecular synthone (12).
Multicomponent crystals consist of two or
more compounds that interact via
molecular bonds (hydrogen bonds,
electrostatics, van der Waals forces, π - π
stacking, and other forms of non-covalent
bonds) with each compound in the form of
atoms, ions or molecules. Among these
interactions, hydrogen bonding is the most
important interaction in the formation of
supramolecular compounds because it has
high strength (6,13,14).
Figure 2. Hydrogen bonds in the formation of multicomponent crystals (15)
Generally, multicomponent crystals are
classified into 3 main classes, these are
solvates and their polymorphs, salts,
cocrystals. However, based on the type of
compound composition, multicomponent
crystals are divided into 7 subclasses,
among them are solvates, salts, cocrystals,
solvate salts, solvate cocrystals, salt
cocrystals, and solvate salt cocrystals
(13,16). In applications in the
pharmaceutical field, salt and cocrystal
formation methods are potential methods
and have been widely applied to increase
the solubility of active drug ingredients (6).
Figure 3. Classification of Multicomponent Crystal (16)
The difference between
cocrystal and salt lies in the
transfer of protons. The
formation of salts requires the
transfer of protons from
components of acidic
compounds to components of
basic compounds, which can
also be predicted from the
difference in the pKa of the two
components of the compound,
where the difference in pKa ≥ 3
will produce a salt form (17,18)
3.2.1 Solvates and hydrates
Solvates and hydrates are
additional products from multicomponent
crystalline solid molecules that are formed
when the main molecule (API/excipient) is
added to an additional molecule
(water/hydrate) or another solvent (solvate)
which is incorporated in a crystal lattice
structure. Commonly known as the pseudo
polymorphic form (19). Pseudo-
polymorphism resulting in the formation of
a crystalline solid addition with the solvent
is often called pseudopolymorphism,
whereas a group of solvates with different
stoichiometry of the same solvent and
compound is often called a "pseudo-
polymorph". Solvates may form when
pharmaceutical solids are processed or
stored in solvents during periods of
crystallization, reflux, wet granulation, or
storage. Exposure to solvent vapors can
also cause solvate formation (20).
3.2.2 Salt
Pharmaceutical salts are defined as
components formed from active
pharmaceutical ingredients (API) which
can be ionized (can be anionic, cationic or
switterion molecules) with counter ions to
form neutral complexes. The counter ions
used can be molecular, such as mesylate or
acetate, or atomic, such as bromium or
sodium. In addition to increasing solubility,
other physicochemical properties that are
affected by salt formation include flow
properties, particle size, crystallinity,
hygroscopicity, and melting point (18,21).
Salt formation can produce a product that is
more stable and easier to recrystallize, so
that components with high purity can be
obtained. Modification of compounds by
forming salts has the advantage of
producing compatibility with excipients,
easy production, and safer use of API.
However, because salt formation can only
be carried out for ionized active
pharmaceutical ingredients, its application
is quite limited compared to cocrystal
formation (17,18).
N.S. Athaya et al / Indo J Pharm 4 (2022) 255-266
258
The formation of salts of pharmaceutical
active ingredients with benzoic acid
coformers has been produced one of them
through desloratadine-benzoic acid,
because it is known that benzoic acid is in
anionic form. This means that a proton (H +
) is transferred via the carboxyl group of
benzoic acid to the N atom of piperidine
loratadine. The difference in the pKa values
of the two components is quite large, which
is greater than 3. Desloratadine-benzoic
acid salt can increase its solubility in water
by 51 times, and increase the dissolution
rate by 10 times than pure desloratadine
(22).
3.2.3 Cocrystal
Cocrystal is a crystalline phase formed
from two or more neutral molecules
(coformer compounds) bonded in a crystal
lattice through non-covalent interactions in
a certain stoichiometric ratio. Non-covalent
interactions that occur in cocrystals are
mainly hydrogen bonds, but can also occur
through electrostatic interactions, van der
Waals forces, and π - π stacking (18).
Similar to the formation of salts, cocrystals
can improve the physicochemical
properties of active pharmaceutical
ingredients without affecting their
pharmacological effects which include
solubility, stability, bioavailability and
mechanical properties. However, cocrystals
have advantages that cannot be carried out
by salt-making methods, that is cocrystals
can be made on pharmaceutical active
ingredients that have weak or no ionization
capabilities (14,23). The drawback is in
terms of procedures that require additional
procedures in the process of synthesizing
drug compounds (24). The term
pharmaceutical cocrystal refers to
cocrystals formed from pharmaceutical
active ingredients with the appropriate
coformer (18).
3.3 Co-crystal Regulation
Regulations on the formation of cocrystals
and their formulations influence the
development strategy and quality control.
According to the FDA which was the first
agency to provide guidance on the
arrangement classification of
pharmaceutical cocrystals, cocrystals are
defined as "Solids which are crystalline
materials consisting of two or more
molecules in the same crystal lattice".
Cocrystal is classified as a Drug Product
Intermediate (DPI) which is expected to
improve the physicochemical properties of
a drug. According to the FDA, cocrystal is
classified as a new polymorph form of the
active ingredient so it is not considered a
new API (16,25).
In 2015, the European Medicine Agency
(EMA) published a reflection paper on the
use of cocrystals from active ingredients in
health products. EMA classifies co-crystals
as novel active substances and defines them
as “salts, esters, ethers, isomers, mixtures of
isomers, complexes or derivatives of a
different active substance shall be
considered to be the same active substance,
unless their properties differ significantly
with respect to with safety". However,
dual-phase materials obtained by
precipitation or physical mixing are not
considered cocrystals by EMA (26).
Parameter comparison based on FDA and
EMA cocrystal regulatory status is shown
in Table 2.
Table 2. Parameter comparison based on FDA and EMA regulatory status of cocrystal (25,26)
3.2 Methods for Forming
Multicomponent Crystals
Common methods in the
preparation of multicomponent crystals are
divided into 2, that is the solution-based
method and the solid-based method . The
solution-based method requires high
solvent to dissolve the multicomponent
crystal constituents, and may affect the
results of cocrystallization because it can
change the intermolecular interactions of
the active pharmaceutical ingredients and
N.S. Athaya et al / Indo J Pharm 4 (2022) 255-266
259
the coformer. Meanwhile , the solid-based
method does not require or requires little solvent in the formation of multicomponent
crystals (27).
Figure 4. Multicomponent crystal formation method (27)
Figure 5. Illustration of the formation of a multicomponent crystal system (28)
3.4.1 Solution -based method
a. Solvent Evaporation
Solvent evaporation is the most
commonly used method for the formation
of multicomponent crystals. This method is
carried out by dissolving a number of active
drug substances and coformers in a
common solvent. The solvent used must be
able to completely dissolve the active drug
substance and the coformer, because if
there are substances that are not dissolved,
components will be found that precipitate
so that crystal formation fails. Ideally,
solvent evaporation is carried out from
three ratios, the ratio of active
substances:coformer (1:1; 1:2; and 2:1)
(27,29). Solvent evaporation has a simple
and effective procedure for screening and
laboratory scale (30).
b. Anti-solvent method
The anti-solvent method is an
effective approach to control the quality,
particle size and properties of cocrystals
with a continuous cocrystallization process.
The addition of anti-solvent will reduce the
solubility of a solute and form crystals
quickly. The choice of solvent combination
in this method is a critical point where the
resulting cocrystal must have low solubility
with the use of a small amount of solvent.
Examples of solvent:anti-solvent mixtures
used to produce cocrystals are
ethanol:water, ethanol:acetonitrile and
ethanol:ethyl acetate (27,30).
c. Cooling crystallization
The cooling crystallization method
is generally used for the formation of large-
scale pure multicomponent crystals. This
method is based on temperature variations
and usually uses a reactor to mix the
components and solvent. The reactor
system is then heated to achieve dissolution
of the two components, then saturation is
achieved by lowering the temperature
(27,30).
d. Reaction cocrystallization
The reaction cocrystallization
method is used when there are 2
components having different solubility, in
which reactants with nonstoichiometric
concentrations are mixed to produce a
saturated solution of cocrystals to form a
cocrystal precipitate. In this method, the
formation of cocrystals is controlled by the
ability of the reactants to reduce the
solubility of the cocrystals (30).
e. Slurry conversion
The slurry conversion method is a
method for forming multicomponent
crystals in which excess cocrystalline
components are added to the solvent.
Although this method is solution based, it
does not require preparation of a clear (fully
dissolved) initial solution (27,29).
3.4.2 Solid- based method (Solution
based method)
a. Contact cocrystallization
The contact cocryztallization
method is based on the interaction between
the active pharmaceutical ingredients and
the coformer spontaneously after the
mixing process with the raw material .
Higher humidity and temperature, as well
as smaller raw material particle sizes can
affect the formation of cocrystals with this
method (27,31).
b. Neat grinding
Neat grinding or solid state grinding
is carried out by mixing the cocrystal
components stoichiometrically in the solid
state and grinding them manually with a
mortar pestle. This method is
environmentally friendly and can avoid
sulphate formation, but in terms of its
efficacy it is considered less for the
N.S. Athaya et al / Indo J Pharm 4 (2022) 255-266
260
formation of cocrystals in large quantities
(30).
c. Liquid-assisted grinding
The liquid-assisted grinding method
is accomplished by liquid-assisted grinding
which involves adding a solvent, usually in
very small amounts to a dry solid before
grinding begins. The solvent acts as a
catalytic to help form cocrystals (29). This
method produces cocrystals with high
crystallinity compared to neat grinding
(27).
d. Melt crystallisation
Melt crystallization method is a
technique for forming pharmaceutical
cocrystals that does not require a solvent,
but attention should be paid to the heat
stability of the active pharmaceutical
ingredients and the coformers used. High
temperature and pressure are required to
form a melt from the active ingredient and
coformer using an extruder (30,32).
3.1 Coformer
Coformer is a cocrystal forming
substance that functions to increase the
solubility and bioavailability of active
pharmaceutical ingredients. The selection
of coformers for the formation of multi-
component crystals is limited, only those
defined and registered by the Food and
Drug Administration (FDA) as Generally
Recognized as Safe (GRAS) (33,34). The
criteria that must be met in selecting a
coformer are that it must be non-toxic, able
to bind non-covalent with the active
substance, can increase the solubility of the
active substance in water, and be
compatible with the active substance (35).
3.2 Solubility and Bioavailability
Solubility is one of the important
parameters for achieving the desired drug
concentration in the systemic circulation to
achieve a pharmacological response. Drugs
that have poor water solubility will be
released inherently at a slow rate due to
their limited solubility in the
gastrointestinal tract, which causes a
decrease in bioavailability in the body. Low
bioavailability results in administration of
higher doses in order to achieve therapeutic
concentrations. The parameter that often
determines the rate of drug absorption is the
dissolution rate (3,36). This is in line with
carvedilol which has a poor solubility in
water, that is only 0.093 mg/mL and is
practically insoluble in water (37), so it is
linear with low bioavailability, which is
only around 20% (3).
In general studies, several
methods can be used to increase the
solubility of BCS class II drugs such as
Carvedilol using the multicomponent
crystal method, solid dispersion, liquid-
solid technique, emulsification, and nano-
crystal methods. Here the several studies
that proven can increase the solubility and
dissolution rate of carvedilol significantly
by various methods of multicomponent
crystal approach using various coformers
and solvents, the data of which is listed in
table 3.
Table 3. Carvedilol solubility and bioavailability Enhancement using the Multicomponent
Crystal Approach Method
The results of increasing the dissolution
rate of multicomponent carvedilol crystals
with pure carvedilol can be seen in the
examples in Figures 6 and 7. In Figure 6,
Fernandes et al., (2018), showed that pure
carvedilol has a lower dissolution rate than
the carvedilol-nicotinamide cocrystal. The
dissolution rate of pure carvedilol at pH 1.2
was 18,35% at 60 minutes, while the
dissolution rate of the carvedilol-
nicotinamide cocrystal at the same pH and
minutes increased significantly to 88%. The
solubility of cocrystal carvedilol-
nicotinamide (1:2) was also increased by 15
times. The solubility of pure carvedilol in
0.1 N HCl pH 1.2 was found to be 0.093
N.S. Athaya et al / Indo J Pharm 4 (2022) 255-266
261
mg/mL, while the carvedilol-nicotinamide
cocrystal showed a dynamic solubility of
1.41 mg/ml in 0.1 N HCl after 48 hours
(39).
The use of pH medium is important in
conducting dissolution tests to improve the
dissolution rate of the drugs (44). Because
in the ionized form, the solubility of
carvedilol depends on the pH of the
medium, where carvedilol, which is a
weakly basic molecule, will be more
soluble at increasingly acidic pH conditions
(decreasing pH). The increase in carvedilol-
nicotinamide solubility may also be due to
cocrystal formation or due to the additive
effect of carvedilol and nicotinamide as
both have nitrogen in their parent ring
which can be protonated at acidic pH.
Figure 6. Dissolution profile of pure CVD and CVD-nicotinamide multicomponent crystal at
pH 1.2 (39)
In Figure 7, Zhang et al, (2021)
proved that the dissolution
rate of carvedilol
multicomponent crystals was
higher than pure carvedilol at
an alkaline pH in water
distilled medium. Pure
carvedilol (S-CAR-XR),
carvedilol-phosphate
multicomponent crystal (P-S-
CAR-XR), and carvedilol-
hydrochloride multicomponent
crystal (H-S-CAR-XR) have the
same FBE (free base equivalent)
of carvedilol, but the release
of carvedilol with
modification of the
multicomponent crystal form
was faster than free base in
water distilled medium. These
findings indicate that the
release rate of pure carvedilol
is limited by its low solubility
in the intestinal environment
(pH 5−7). The intestine is the
main site of absorption of ost
drugs, so the prolonged and
effective release of pure
carvedilol is difficult to
achieve in vivo. The
multicomponent carvedilol
crystals have a higher rate of
drug release compared to the
free base, but the rate of
release may still be limited by
alkaline counterions in the
intestinal environment.
Figure 7. Dissolution profile of pure CVD and CVD-phosphoric acid, CVD-sulfuric acid
multicomponent crystal at water distilled medium (41)
3.7 Multicomponent Crystal
Characterization
In the formation of multicomponent
crystals, it is necessary to evaluate to
ensure the quality of the drug being made.
Evaluations carried out on cocrystals
include FTIR spectroscopy, X-ray
Diffraction (XRD), and Differential
Scanning Calorimetry ( DSC) (45).
3.7.1 Fourier Transform Infrared
Spectrophotometer (FTIR)
FTIR is a characterization technique that
can record the IR spectrum where there is a
process of absorption of radiation that
corresponds to the transition energy in the
bond vibrating by the molecule being
analyzed. The absorption process will occur
when the IR frequency is the same as the
vibrational frequency and quantitative
information about the absorbed energy will
be seen when the light is transmitted (46).
Characterization using FTIR aims to
confirm the interaction between the active
ingredient and the coformer used. For
example, seeing the presence of hydrogen
bonds is characterized by a shift in group
peaks, a decrease in peak intensity, and the
N.S. Athaya et al / Indo J Pharm 4 (2022) 255-266
262
emergence of new peaks where these are
the parameters that will be seen (47). FT-IR
analysis is also used to differentiate salt
formation compared to other multi-
component crystals (cocrystals), as
differentiated by the location of the protons
between the acid and the base.
Hata et al., (2020), proved that in the
formation of salt species, there is a typical
carboxylate anion that has a carbonyl
stretching band (a strong asymmetric band
below 1600 cm−1), and the
appearance of a shoulder
between 1505 cm−1 and 1610
cm−1 where it can be observed that ionized
carboxyl groups are absent in the spectrum
of the individual components. On the other
hand, when the frequency of the carbonyl
group in the carboxylic acid shifts to a
higher energy (approximate frequency
range 1700-1730 cm-1), then cocrystalline
species are formed. Figure 9 shows that
examination of the FT-IR spectrum shows
proton transfer from the salt form to the
CVD, confirming the salt formation
between CVD and DL-MA.
Figure 8. FTIR spectrum analysis of DL-Mandelic Acid, CVD, and CVD-DL Mandelate
Acid (40)
3.7.2 X-Ray Diffractometer (XRD)
XRD is a method used to obtain structural
information from its constituent
components via a diftracogram (31). XRD
analysis of multicomponent crystals aims to
identify the formation of new crystalline
phases where each crystalline phase of the
compound has its own diffractogram
characteristics so that XRD analysis can be
used to differentiate the multicomponent
crystalline products formed (38).
Hiendrawan et al., (2016) proved that the
result of CVD/MDA from the method of
multicomponent crystals are forms I and II.
The results of the PXRD analysis showed
that form I was more stable than form II
under ambient conditions. Then, the new
CVD multicomponent crystal shows a
PXRD pattern with different peak positions
compared to CVD and coformer. Based on
these results, it was explained that the new
CVD multicomponent crystal has a
different internal crystal structure
compared to the initial components. And it
is proved that during the desolvation
process, the intermolecular interactions
between the solvent and the CVD-coformer
molecules are broken. The XRD analysis
between CVD and CVD multicomponent
crystal showed in figure 9.
Figure 9. XRD analysis of pure CVD and CVD multicomponent crystal (38)
3.7.3 Differential Scanning
Calorimetry (DSC)
DSC is a thermal analysis procedure to
measure how the physical properties of a
compound sample change with temperature
over time in the form of a thermogram (48).
Through DSC, it can be seen whether or not
the formation of multicomponent crystals is
based on changes in the melting point
which is usually at the melting point of the
constituent components, that is the active
ingredient and the coformer used. Mixtures
that form multicomponent crystals will
show endothermic and exothermic peaks,
while mixtures that do not form
multicomponent crystals will only show
endothermic peaks (49).
Figure 10. DCS thermogram analysis a) pure CVD, b) HCT, c) multicomponent crystal
CVD-HCT (50)
4. Conclusion
Modification of carvedilol through a
crystalline multicomponent approach can
be a promising option for increasing
solubility and bioavailability in the body,
especially when it is to be used for oral
administration. Many coformers have been
studied to form carvedilol multicomponent
crystals, such as carboxylic acid groups,
nicotinamide, and others. There are several
methods for forming multicomponent
crystals that can be selected according to
N.S. Athaya et al / Indo J Pharm 4 (2022) 255-266
263
the criteria for active substances,
coformers, both for small-scale synthesis
methods in the laboratory and for large-
scale production methods in industry.
Acknowledgements
The author of this article would like to
thank the supervising lecturers who have
supported and assisted in providing data
and information for the purposes of this
research.
References
1. Okamoto H, Hori M, Matsuzaki M,
Tsutsui H, Yamazaki T, Nagai R, et
al. Minimal dose for effective
clinical outcome and predictive
factors for responsiveness to
carvedilol: Japanese chronic heart
failure (J-CHF) study. Int J Cardiol
[Internet]. 2013;164(2):238–44.
Available from:
http://dx.doi.org/10.1016/j.ijcard.2
012.11.051
2. Hairunnisa H, Sopyan I, Gozali D.
Ko-Kristal: Nikotinamid Sebagai
Koformer. J Ilm Farm Bahari.
2019;10(2):113.
3. Ramadhani U., Djajadisastra J,
Iskandarsyah. Pengaruh Polimer
dan Peningkat Penetrasi Terhadap
Karakter Penetrasi Matriks Sediaan
Patch Transdermal Karvedilol. J
Ilmu Kefarmasian Indones.
2017;15(2):120–7.
4. Jhaveri M, Nair AB, Shah J, Jacob
S, Patel V, Mehta T. Improvement
of oral bioavailability of carvedilol
by liquisolid compact: optimization
and pharmacokinetic study. Drug
Deliv Transl Res. 2020;10(4):975–
85.
5. Desiraju GR. Crystal engineering:
From molecule to crystal. J Am
Chem Soc. 2013;135(27):9952–67.
6. Cai L, Jiang L, Li C, Guan X, Zhang
L, Hu X. Multicomponent crystal of
metformin and barbital: Design,
crystal structure analysis and
characterization. Molecules.
2021;26(14).
7. Prado LD, Rocha HVA, Resende
JALC, Ferreira GB, De Figuereido
Teixeira AMR. An insight into
carvedilol solid forms: Effect of
supramolecular interactions on the
dissolution profiles.
CrystEngComm.
2014;16(15):3168–79.
8. Fernandes GJ, Kumar L, Sharma K,
Tunge R, Rathnanand M. A Review
on Solubility Enhancement of
Carvedilol—a BCS Class II Drug. J
Pharm Innov. 2018;13(3):197–212.
9. Halder S, Ahmed F, Shuma ML,
Azad MAK, Kabir ER. Impact of
drying on dissolution behavior of
carvedilol-loaded sustained release
solid dispersion: development and
characterization. Heliyon [Internet].
2020;6(9):e05026. Available from:
https://doi.org/10.1016/j.heliyon.20
20.e05026
10. Aronow W. Update of treatment of
heart failure with reduction of left
ventricular ejection fraction. Arch
Med Sci – Atheroscler Dis.
2016;1(1):106–16.
11. Kemenkes RI. Farmakope
Indonesia edisi VI. Departemen
Kesehatan Republik Indonesia.
2020. 2371 p.
12. Gunnam A, Nangia AK. High-
Solubility Salts of the Multiple
Sclerosis Drug Teriflunomide.
Cryst Growth Des.
2019;19(9):5407–17.
13. Grothe E, Meekes H, Vlieg E, Ter
Horst JH, De Gelder R. Solvates,
Salts, and Cocrystals: A Proposal
for a Feasible Classification
System. Cryst Growth Des.
2016;16(6):3237–43.
14. Karagianni A, Malamatari M,
Kachrimanis K. Pharmaceutical
cocrystals: New solid phase
modification approaches for the
N.S. Athaya et al / Indo J Pharm 4 (2022) 255-266
264
formulation of APIs.
Pharmaceutics. 2018;10(1).
15. Peltonen L. Practical guidelines for
the characterization and quality
control of pure drug nanoparticles
and nano-cocrystals in the
pharmaceutical industry. Adv Drug
Deliv Rev [Internet].
2018;131:101–15. Available from:
https://doi.org/10.1016/j.addr.2018.
06.009
16. Aitipamula S, Banerjee R, Bansal
AK, Biradha K, Cheney ML,
Choudhury AR, et al. Polymorphs,
salts, and cocrystals: What’s in a
name? Cryst Growth Des.
2012;12(5):2147–52.
17. Clarke HD. Crystal Engineering of
Multi-Component Crystal Forms:
The Opportunities and Challenges
in Design. ProQuest Diss Theses.
2012;(January):153.
18. Setyawan D, Paramita DP. Strategi
Peningkatan Kelarutan Bahan Aktif
Farmasi. Surabaya: Airlangga
University Press; 2019.
19. Healy AM, Worku ZA, Kumar D,
Madi AM. Pharmaceutical solvates,
hydrates and amorphous forms: A
special emphasis on cocrystals. Adv
Drug Deliv Rev [Internet].
2017;117:25–46. Available from:
https://doi.org/10.1016/j.addr.2017.
03.002
20. Boothroyd S, Kerridge A, Broo A,
Buttar D, Anwar J. Why Do Some
Molecules Form Hydrates or
Solvates? Cryst Growth Des.
2018;18(3):1903–8.
21. Elder DP, Holm R, De Diego HL.
Use of pharmaceutical salts and
cocrystals to address the issue of
poor solubility. Int J Pharm
[Internet]. 2013;453(1):88–100.
Available from:
http://dx.doi.org/10.1016/j.ijpharm.
2012.11.028
22. Ainurofiq A, Mauludin R,
Mudhakir D, Soewandhi S.
Synthesis, characterization, and
stability study of desloratadine
multicomponent crystal formation.
Res Pharm Sci. 2018;13(2):93–102.
23. Thakuria R, Sarma B. Drug-drug
and drug-nutraceutical
cocrystal/salt as alternative
medicine for combination therapy:
A crystal engineering approach.
Crystals. 2018;8(2).
24. Bolla G, Nangia A. Pharmaceutical
cocrystals: Walking the talk. Chem
Commun. 2016;52(54):8342–60.
25. Food and Drug Administration.
Regulatory classification of
pharmaceutical co-crystals,
guidance for industry. US Dep Heal
Hum Serv [Internet].
2018;(February):1–4. Available
from:
http://www.fda.gov/Drugs/Guidanc
eComplianceRegulatoryInformatio
n/Guidances/default.htm%0Ahttps:
//www.fda.gov/media/81824/downl
oad
26. EMA. Reflection paper on the use
of cocrystals and other solid state
forms of active substances in
medicinal products. Eur Med
Agency [Internet].
2015;44(May):1–10. Available
from:
http://www.ema.europa.eu/docs/en
_GB/document_library/Scientific_
guideline/2015/07/WC500189927.
pdf
27. Guo M, Sun X, Chen J, Cai T.
Pharmaceutical cocrystals: A
review of preparations,
physicochemical properties and
applications. Acta Pharm Sin B
[Internet]. 2021;11(8):2537–64.
Available from:
https://doi.org/10.1016/j.apsb.2021
.03.030
28. Vieira EF, Soares C, Machado S,
Correia M, Ramalhosa MJ, Oliva-
teles MT, et al. Seaweeds from the
Portuguese coast as a source of
proteinaceous material: Total and
free amino acid composition
N.S. Athaya et al / Indo J Pharm 4 (2022) 255-266
265
profile. Food Chem [Internet].
2018;269(April):264–75. Available
from:
https://doi.org/10.1016/j.foodchem.
2018.06.145
29. Buddhadev SS, Garala KC.
Pharmaceutical Cocrystals—A
Review. 2021;14.
30. Rodrigues M, Baptista B, Lopes JA,
Sarraguça MC. Pharmaceutical
cocrystallization techniques.
Advances and challenges. Int J
Pharm [Internet]. 2018;547(1–
2):404–20. Available from:
https://doi.org/10.1016/j.ijpharm.2
018.06.024
31. Karimi-Jafari M, Padrela L, Walker
GM, Croker DM. Creating
cocrystals: A review of
pharmaceutical cocrystal
preparation routes and applications.
Cryst Growth Des.
2018;18(10):6370–87.
32. Yan Y, Chen JM, Lu TB.
Thermodynamics and preliminary
pharmaceutical characterization of
a melatonin-pimelic acid cocrystal
prepared by a melt crystallization
method. CrystEngComm.
2015;17(3):612–20.
33. FDA. CFR - Code of Federal
Regulations Title 21 [Internet].
2022. Available from:
https://www.accessdata.fda.gov/scr
ipts/cdrh/cfdocs/cfcfr/CFRSearch.c
fm?fr=184.1021&SearchTerm=ben
zoic acid
34. Rowe RC, Sheskey PJ, Quinn ME.
Handbook of Pharmaceutical
Excipients. Washington: The
Science and Practice of Pharmacy;
2020.
35. Ferdiansyah R, Ardiansyah S,
Rachmaniar R, Yuniar I. Review :
The Effect Of Cocrystal Formation
Using Carboxylic Acid Coformer
With Solvent Evaporation and
Solvent Drop Grinding Methods On
Bioavailability Of Active
Substances. J Ilm Farm Bahari.
2021;12(1):28–38.
36. Arun RR, Harindran J.
Enhancement of Bioavailability of
Carvedilol Using Solvent
Deposition Techniques. Int J Pharm
Sci Res. 2017;8(8):3391–401.
37. Hamed R, Awadallah A, Sunoqrot
S, Tarawneh O, Nazzal S,
AlBaraghthi T, et al. pH-Dependent
Solubility and Dissolution Behavior
of Carvedilol—Case Example of a
Weakly Basic BCS Class II Drug.
AAPS PharmSciTech.
2016;17(2):418–26.
38. Hiendrawan S, Widjojokusumo E,
Veriansyah B, Tjandrawinata RR.
Pharmaceutical Salts of Carvedilol:
Polymorphism and
Physicochemical Properties. AAPS
PharmSciTech [Internet].
2017;18(4):1417–25. Available
from:
http://dx.doi.org/10.1208/s12249-
016-0616-x
39. Fernandes GJ, Rathnanand M,
Kulkarni V. Mechanochemical
Synthesis of Carvedilol Cocrystals
Utilizing Hot Melt Extrusion
Technology. J Pharm Innov.
2019;14(4):373–81.
40. Hata N, Furuishi T, Tamboli MI,
Ishizaki M, Umeda D, Fukuzawa K,
et al. Crystal structural analysis of
dl-mandelate salt of carvedilol and
its correlation with
physicochemical properties.
Crystals. 2020;10(1):1–14.
41. Zhang Q, Huang B, Xue H, Lin Z,
Zhao J, Cai Z. Preparation,
Characterization, and Selection of
Optimal Forms of (S)-Carvedilol
Salts for the Development of
Extended-Release Formulation.
Mol Pharm. 2021;18(6):2298–310.
42. Thenge R, Patel R, Kayande N,
Mahajan N. Co-crystals of
carvedilol: Preparation,
characterization and evaluation. Int
J Appl Pharm. 2020;12(1):42–9.
N.S. Athaya et al / Indo J Pharm 4 (2022) 255-266
266
43. Eesam S, Bhandaru JS, Naliganti C,
Bobbala RK, Akkinepally RR.
Solubility enhancement of
carvedilol usingdrug–drug
cocrystallization
withhydrochlorothiazide. Futur J
Pharm Sci. 2020;6(77):1–13.
44. Csicsak D, Borbas E, Ka S, Pataki
H, Taka K, Vo G. Towards more
accurate solubility measurements
with real time monitoring : a
carvedilol case study †.
2021;11618–25.
45. Kumar S, Nanda A. Pharmaceutical
cocrystals: An overview. Indian J
Pharm Sci. 2017;79(6):858–71.
46. Qiao N, Li M, Schlindwein W,
Malek N, Davies A, Trappitt G.
Pharmaceutical cocrystals: An
overview. Int J Pharm [Internet].
2011;419(1–2):1–11. Available
from:
http://dx.doi.org/10.1016/j.ijpharm.
2011.07.037
47. Najih YA, Widjaja B, Riwanti P,
Mu’alim AI. Characterization of
Meloxicam and Malonic Acid
Cocrystal Prepared With Slurry
Method. J Islam Pharm.
2018;3(2):51.
48. Stoler E, Warner JC. Non-Covalent
derivatives: Cocrystals and
eutectics. Molecules.
2015;20(8):14833–48.
49. Yamashita H, Hirakura Y, Yuda M,
Teramura T, Terada K. Detection of
cocrystal formation based on binary
phase diagrams using thermal
analysis. Pharm Res.
2013;30(1):70–80.
50. Eesam S, Bhandaru JS, Naliganti C,
Bobbala RK. Solubility
enhancement of carvedilol using
drug – drug cocrystallization with
hydrochlorothiazide. 2020;5.
Refbacks
- There are currently no refbacks.
