Vol 4, Issue 1, 2022 (168-188)
http://journal.unpad.ac.id/idjp
*Corresponding author,
e-mail : : i.sopyan@unpad.ac.id (I. Sopyan)
https://doi.org/10.24198/idjp.v4i1.39321
© 2022 I. Sopyan et al
Review: Methods for Enhancing Solubility of Carvedilol
Iyan Sopyan1, Rania Talinta L1, Nurdiani Adiningsih1, Norisca Aliza Putriana1, Sandra
Megantara2
1Department Pharmaceutics and Technology of Pharmacy. Faculty of Pharmacy, Padjadjaran
University, Sumedang, West Java, Indonesia 45363
2Departmen Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas
Padjadjaran,Sumedang, West Jawa, Indonesia, 45363.
Corresponding Email : i.sopyan@unpad.ac.id
Submitted : 10/05/2022, Revised : 02/06/2022, Accepted : 14/06/2022, , Published 04/07/2022
Abstract
The oral route of administration is the most frequently used route of drug administration
and is generally the most convenient for patients. For an oral drug to be effective, a
therapeutic concentration in the blood must be achieved. Solubility in water and
permeability of active pharmaceutical ingredients are often used as the main conditions
for rapid and complete absorption and high bioavailability. Carvedilol is beta blockers
that works as an antihypertensive drug and included in biopharmaceutical classification
system (BCS) class II with high permeability but low solubility. Due to this, the goal of
this review is to go through a few different methods for increasing solubility of carvedilol.
Review article was done by searching the literature first, then the data extraction process
was carried out. Key words were arranged consisting of "carvedilol ", "increasing
solubility", and "dissolution" in the search column of the Science Direct database for last
10 years. dissolution, and bioavailability. Various solubility enhancement techniques
have been applied to carvedilol, including co-crystallization, liquidsolid technique,
cyclodextrin inclusion complex, nanoparticles, hydrotrophy, nanosuspension, solid
dispersion, nanoemulsion, and dendrimers. These techniques have been shown to increase
the solubility and dissolution rate of carvedilol thereby increasing its bioavailability.
Keywords: carvedilol, solubility enhancement, BCS class II
1. Introduction
The oral route of administration is the
most frequently used route of drug
administration and is generally the most
convenient for patients. For an oral drug to be
effective, a therapeutic concentration in the
blood must be achieved. This concentration is
largely dependent on its bioavailability, which
is strongly influenced by the rate and extent of
absorption [1]. More than 70% of the active
pharmaceutical ingredients (API) in the
formulation development are highly
hydrophobic and poorly soluble in water.
Solubility in water and permeability of API are
often used as the main conditions for rapid and
complete absorption and high bioavailability
[1,2].
Cardiovascular disease is said to be the
leading cause of death in the world where there
are reportedly at least 17.9 million people dying
from it [3].) Beta blockers are known to have
the ability to cope with some cardiovascular
diseases such as stable angina, heart failure,
arrhythmia, myocardial infraction, and also
hypertension. Carvedilol represents one of the
nonselective beta blockers that works by
blocking adrenergic receptors --1, β-1, and --2.
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169
Broadly speaking, carvedilol has been used to
treat long-term hypertension [3].
Compared to other beta blockers that
works as an antihypertensive drugs such as
atenolol and metoprolol, Carvedilol is known to
have better benefits against increased glucose,
lipid metabolism, and lipid peroxidase in
patients with diabetes and hypertension.
However, carvedilol is included in BCS class II
with high permeability but low solubility
(around <1 μg/ml at pH and 0, 23 μg/ml di pH
7, also around 100 μg/ml at pH in room
temperature, this condition led to slight
formulation development of carvedilol [4].
Low solubility results in low carvedilol
bioavailability (approximately 25% due to
hepatic first pass metabolism) and therefore,
repeated oral administration is required and it
may reduce patient compliance with drug
intake [3, 5, 6].
The low bioavailability of a drug
becomes a common obstacle in drug
development because in order to achieve
optimal therapeutic effects, a drug needs to
have high oral bioavailability. Low
bioavailability can be caused by several things
such as experiencing high first pass metabolism
and poor water solubility. Carvedilol has low
solubility and thus low bioavailability. In
addition, carvedilol has a half time of about 6-
8 hours. Therefore, low solubility with small
bioavailability becomes a major challenge in
the development of carvedilol formulations.
There are several techniques performed to
address the problem of poor solubility of
carvedilol including physical and chemical
modifications of the drug, such as increasing
particle size, increasing porosity and
wettability, and changing shape from crystal to
amorph. Furthermore, there are methods used
to improve the solubility of carvedilol which
are nanosuspension, nanoemulsion,
dendrimers, solid dispersion, hydrotropy,
cocrystallization, liquidsolid technique,
cyclodextrin complexation, and nanoparticle.
arr[1,7–12].
2. METHOD
The writing of this review article was
done by searching the literature first, then the
data extraction process was carried out. Key
words were arranged consisting of "carvedilol
", "increasing solubility", and "dissolution" in
the search column of the Science Direct
database. The literature was selected according
to the inclusion criteria, namely literature that
discusses the drug colon delivery system,
evaluations carried out, polymers used, various
approaches taken, and articles with a maximum
year of publication in the last 10 years. The
exclusion criteria are articles that are not in
accordance with the topic of discussion and
which cannot be fully accessed.
The selection of articles is presented in the flowchart image below
Figure 1: Flow chart or selection of articles
TECHNIQUES TO INCREASE SOLUBILITY OF CARVEDILOL
The method of developing the solubility enhancement of carvedilol which will be discussed in this
review is as shown in the flow chart below :
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170
Figure 2. Solubility development methods of carvedilol
2.1 Co-crystallization
Cocrystallization is a technique of crystal
engineering through the application of the
concept of supramolecules in the
pharmaceutical industry. In a chemical
supramolecular compound, a supramolecular
compound is defined as a compound arranged
on two or more components which are mutually
bonded or interacted through hydrogen bonds,
electrostatic bonds, van der Waals force, pi-pi
stacking, as well as other forms of non-covalent
bonds. Of all the types of bonds that occur,
hydrogen bonds are the most important
interaction due to their considerable strength
levels [13].
In the formation of a cocrystal, function group
which can form a supramolecular synthon bond
i.e., a supramolecular heterosynthon and a
supramolecular homosynthon are required.
Supramolecular heterosynthons are a type of
interaction that occurs in two or more different
compounds but has the same functional group.
Homosynthon supramolecular is an interaction
between the same functional group [14].
Cocrystallization methods are already
frequently used to improve the solubility of
BCS class II drugs such as nifedipine (Reetu et
al., 2019), glimepiride [15], Atorvastatin
calcium [16], phenofibrate [17], and Carvedilol
[5,8]. In the cocrystallization technique, it is
necessary to add another compound or known
as a coformer to form a crystal lattice with
carvedilol. There are several coformers
reported to have been used in increased
carvedilol solubility through cocrystallization
namely hydtocholorothiazide [5], nicotinamide
[18], fumarate acid, succinic acid, and oxalic
acid [8].
Broadly speaking, the multicomponent crystal
can be formed using two methods namely
solution-based method and solid-based
method. Solution-based method comprises 5
methods i.e., solvent evaporation (solvent
evaporation), antisolvent method, cooling
crystallization, reaction cocrystallization, and
slurry conversion. Whereas, the solid-based
method comprises contact cocrystallization,
neat grinding, liquid-assisted grinding, and
mell crystallization [19]. Each technique will
be described bellow in brief.
a. Solvent evaporation
This method represents a simple
method by dissolving an active
substance and a coformer in a solvent
until it dissolves perfectly. Then, the
solution is evaporated until the solvent
evaporates and a crystal is formed. The
selection of solvents on this method is
critical because when neither the
pharmaceutically active material nor
the crystal forming component is very
soluble, some components will
precipitate which causes the failure of
the formation of the cocrystal [20].
b. Antisolvent method
A method carried out by adding
antisolvent so that there is a retardation
of the cocrystal until it reaches a
saturated passing state and deposition
occurs [21].
c. Cooling crystallization
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This method involves a cooling process
against the mixed solution of the active
pharmaceutical ingredient with the
coformer [20].
d. Slurry conversion
This method constitutes the formation
of a cocrystal by adding an excess
cocrystal component to the solvent
used. In the method, each component is
to be slowly dissolved which forms a
complex that causes the formation of a
cocrystal [20].
e. Solid-state grinding
Formation of the cocrystal through
grinding using a machine such as ball
milling (Liquid assisted grinding) or
manually (neat grinding) [20].
f. Melt crystallization
This method utilizes high temperature and
pressure so that melt is formed on the active
pharmaceutical ingridient and coformer [22].
This method has been shown to improve the
solubility of carvedilolin several reseraches.
One of them was reported in a study conducted
by Thenge et al, 2020 that cocrystal formation
of carvedilol using solvent evaporation with
several different coformers such as fumarate
acid, oxalic acid, and succinic acid can
enchance the solubility and the rate of
dissolution significantly compared to pure
carvedilol. The results of the characterization of
SEM, FT-IR, DSC, and XRD also supported
the statement and confirmed that new solid-
phase formation occurred. The graph of the
increase in solubility and dissolution rate as
well as the characterization results can be seen
in Figure. 1, Figure. 2, Figure. 3, Figure. 4,
Figure. 5, and Figure. 6 respectively.
Figure 3: Dissolution profile of pure carvedilol dan Co-crystals
Figure. 4: Solubility studies of pure carvedilol and Co-crystals
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Figure. 5: SEM of pure carvedilol (a), CAR-SA Co-crystal (b), CAR-FA Co-crystal (c), and CAR-
OA Co-crystal (d)
Figure. 6: FT-IR spectra of pure carvedilol (a), CAR-SA Co-crystal (b), CAR-FA Co-crystal
(c), and CAR-OA Co-crystal (d)
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Figure. 7: DSC Thermogram of pure carvedilol (a), CAR-SA Co-crystal (b), CAR-FA Co-crystal (c),
and CAR-OA Co-crystal (d)
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Figure.8: XRD spectra of pure carvedilol (a), CAR-SA Co-crystal (b), CAR-FA Co-crystal (c), and
CAR-OA Co-crystal (d)
2.2 Liquidsolid technique
The technique comprises changing liquid
lipophilic drugs or suspension or water-
insoluble drug solutions in non-volatile
solvents into dry, nonadherent, powder-ready
compressible through mixing with carrier agent
or coating agent. As for the concept of this
technique, when a drug soluble in a carrier
solution is incorporated into a carrier having
pore or textured fiber as cellulose then
absorption and adsorption will occur (Bhavsar
and Anand, 2017)
The following are the preparations performed
on this technique:
a. Liquid formulation: Obtaining the liquid
medicine (drug dispersion in a non-
volatile solvent) and then added with a
carrier material, a disintegrating/coating
agent so that a liquid system is formed
b. Pelletization process: Performed by
addition granulating agent into the liquid-
solid system and then carried out the
excretion-spheronization stage and put
into fluid bed drying so that pellets are
produced for further analysis (Bhavsar
and Anand, 2017)
In a study conducted by Bhavsar and Anand,
2017. the pellet formulation concsits of
carvedilol, crosspovidone (coating agent and
disintegrating agent), PEG 400 as a nonvolatile
solvent, copovidone (wetting agent), and
microcrystalline cellulose/avicle (carrier
material). Through this study, it was proved
that through the technique of liquidsolid with
PEG400 as a non-volatile solvent can improve
the solubility and dissolution rate of carvedilol.
The drug release profile in Figure. 7 showed
that pellets of the liquid system had a higher
dissolution percentage (96.51%) compared to
market carvedilol drugs (79,36%).
This might happened because in the pellet of
the liquid system, the drug is already in the
form of a solution in PEG400 and at the same
time, it is carried by the microcrystalline
cellulose, thus increasing the dissolution rate
due to the increasing of wettability and surface
avaibility against the dissolution medium.
SEM results on Figure. 8 indicates that the
particle in pellet exhibits the shape of a sphere
with a smooth surface and the formation of
several agglomerates.
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Figure 9: SEM of liquidsolid pellets
XRDP results (Figure.9) indicate that there are
several missing peaks or a decrease in peak
intensity in the liquid pellets of carvedilol
compared to pure carvedilol. Therefore, it is
concluded that the carvedilol liquid pellet has
an amorphous shape.
Figure. 10: Difractogram of pure carvedilol (a) and liquidsolid pellets (b)
2.3 Cyclodextrin inclusion complex
Cyclodextrin is a cyclic (1-1,4)-
oligosaccharide of cider d-D-glucopyranose,
which is relatively hydrophobic at its center and
has the hydrophilic outer surface. sik-
cyclodextrin is used to denote the solubility of
the drug by formation of an inclusion complex
[9]. ---cyclodextrin and its derivatives (2-
hydroxypropyl- ---cyclodextrin or HP hp-CD
and sulfobutyl ether- cyclodextrin or SBcd-
CD) constitute are the most commonly used
compounds in inclusion complications
[23](Wang et al., 2011; Xu et al., 2014; Wang
et al., 2014).
This method is known to have several benefits
such as improved solubility, bioavailability,
stability, and preventing incompatibility.
Formation of cyclodextrin complexes can be
performed by several methods such as spray
drying, kneading, grinding, solvent
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evaporation, co-precipitation, microwave
irradiation, and freeze drying [24]. Each
technique will be described bellow.
a. Spray drying
This method is also known as
atomization which will form dry
powder from liquid with the help of
hot gas.
b. Freeze drying
This approach creates porous
amorphous powders with a high
degree of drug-cyclodextrin
interaction. The drug and cyclodextrin
are added to the solvent and then
freeze-dried in this technique. At the
start of the freezing process, the
solvent system will be removed, and
drying will occur when the pressure is
reduced. This technique is frequently
used as a substitute for solvent
evaporation.
c. Kneading
A method is performed by forming a
cyclodextrin paste through the
addition of water or hydroalcoholic
solution and then followed by the
addition of a pharmaceutical active
ingredient which is then kneaded. The
kneaded products will be sieved to
obtain fine powder (Ünlüsayin et al.,
2015).
d. Grinding
The active ingredients of the drug and
cyclodextrin will go through a
grinding process to obtain a fine
mixed powder. The product will be
stored in a container at room
temperature.
e. Co-precipitation
This method is performed by adding
the drug to the cyclodextrin solution
slowly accompanied by continuous
magnetic agitation. The complex will
precipitate, then be filtered and dried
at room temperature.
f. Microwave irradiation
Because it saves time, this technology
is most commonly utilized in
industrial environments. The drug and
cyclodextrin will be dissolved in a
solution of water and an organic
solvent, then microwaved at 60
degrees Celsius to react. The
remaining solvent mixture will be
added once the reaction is finished to
remove uncomplexed drugs and
cyclodextrin, and the sediment will be
filtered and dried.
g. Solvent evaporation
This method represents a simple
method by dissolving active
substances and cyclodextrin in a
solvent until it is perfectly soluble.
Then, the solution is evaporated until
the solvent evaporates and a complex
is formed [20].
Research by Zoghbi et al., 2017 showed a
significant increase in solubility by
approximately 22 to 70-fold in inclusion
complexes using hydroxypropyl---cyclodextrin
(HPcdCD) with solid dispersion using two
carriers: polyoxamer 188 (PLX) and
Polyvinylpyrrolidone K-30 (PVASI)
preparation (PVASI) [9].
2.4 Nanoparticles
Nanotechnology drug delivery system is one of
the drug administration system that is
considered effective, especially for lipophilic
drugs. Nanoparticles are a drug delivery system
that is considered to increase the oral
bioavailability of carvedilol [25].
Micronization of drug crystals by various
mechanisms to a lower size can increase drug
dissolution. According to the Noyes-Whitney
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equation, the dissolution rate increases with an
increase in the specific surface area. According
to the Ostwald-Freundlich equation, solubility
increases with decreasing particle size. The
preparation of nanoparticles can be carried out
as follows:
a. Ionic gelation
b. Polymerization of monomers seperti
emulsion, microemulsion, dan
miniemulsion
c. Dispersion of performed polymer
The methods included in this preparation are
evaporation solvent, diffusion solvent, salting
out, nanoprecipitation, supercritical fluid
technology, and dialysis [18,25,26].
Research by Sharma et al., 2019, showed that
carvedilol-chitosan nanoparticles with sodium
tripolyphosphate as a cross-linking agent using
ionic gelatin methods can increase in vivo
bioavailability compared to market drugs.
Carvedilol-chitosan nanoparticles are
characterized for particle size, morphology,
zeta potential, FTIR, encapsulation efficiency,
In vitro drug release studies, pharmacokinetic
studies, gastric mucosa irritation tests, drug
entrapment efficiency tests, and stability tests.
The zeta potential of the carvedilol-chitosan
nanoparticles shows +32 mV 2 2 mV which
showed physical stability and mucoadhesive
where the higher the value then the stability
will also increase and it’s prevents aggregation
of the particles [26].
In addition, studies by Khan et al., 2016 also
showed an increase in the solubility and
dissolution rate in carvedilol preparation
nanoparticles using poly lacetic co glycolic
acid (PLGA), polyethylene glycol 8000 (PEG
8000), and ethyl cellulose in differential ratio
(1:1, 1:2.5). Carvedilol nanoparticles are
characterized for particle size, entrapment
efficiency, zeta potential, polydispersity index,
and percent drug loading. Based on research
results, it showed that increasing particle size
will increase polymer concentration also where
the highest is on carvedilol-PLGA-PEG
(Figure. 10).
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Figure.11: Particle size (a) and zeta potensial of nanoparticles (b)
Carvedilol-PLGA-PEG showed the highest
potential zeta yield so it was concluded that
there was an increase in colloidal stability. The
results of the in vitro dissolution test in
Figure.11 showed maximum drug release of
95% in 24 hours on nanoparticles using ethyl
cellulose, 85% for PEG nanoparticles, and 65%
for PLGA-PEG nanoparticles [10].
2.5 Hydrotrophy
Hydrotropy is a technique that was first
introduced by Neubeurg (1916) in which a
large amount of the second solute is dissolved
into the first solute so that it will increase the
solubility of the first solute [26]. In this
technique, a hydrotrope, which is an ionic
organic salt of various types of organic acids
such as urea and sodium acetate, is used.
Hydrotrope has two sides in its structure,
namely an anion group that plays a role in
increasing solubility in water and an aromatic
ring group. The mechanism of action of
hydrotrope is to involve the interaction between
lipophilic drugs and hydrotropic agents such as
nicotinamide, urea, and sodium alginate
[18,27].
Chikhle et al., 2016 conducted a study to
increase solubility using this technique to
increase the solubility of carvedilol in which
the hydrotropic dispersion method used sodium
benzoate, nicotinamide, and sodium citrate in a
ratio of 20:15:5 dissolved in water. The results
of this study showed that the dissolution rate of
the hydrotropic solid dispersion product of
carvedilol (99%) was increased compared to
market carvedilol.
2.6 Nanosuspension
Nanosuspension is a method in which a
dispersion solution containing a
pharmaceutical active ingredient or drug is
stabilized with a surfactant or polymer. There
are several methods used to form
nanosuspensions, namely high-pressure
homogenization, melt emulsification where the
drug is dispersed in an aqueous solution and
stabilizer then goes through a heating and
cooling process, emulsion diffusion method
where the drug is dispersed in an organic
solvent and homogenized to form an emulsion,
and media milling [28].
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Figure. 12: SEM micrographs of pure carvedilol (a) and nanosuspensions (b)
Carvedilol nanosuspension studies were
conducted on four formulations where the
carvedilol nanosuspension showed the highest
dissolution profile of 90% for 60 minutes
compared to pure carvedylol which was 40% at
pH 1 [28].
Studies on intestinal absorption performed in
situ in wister rats and in vivo in beagle dogs
showed an increase in carvedilol
nanosuspension compared to pure carvedilol.
This study concluded that the formation of
carvedilol nanosuspension may improve the
profile of dissolution and oral absorption.
Figure. 13: In situ absorption (a) and Pharmacokinetics study (b)
2.7 Solid Dispersion
Solid dispersions can be defined as solid
products in which the hydrophobic drug is
dispersed in a hydrophilic matrix, either in an
amorphous, and/or molecularly
microcrystalline form. The hydrophilic matrix,
also known as the carrier, affects the
characteristics of the solid dispersion
formulation. Solid dispersion techniques have
been widely used to increase the solubility of
drugs that are poorly soluble in water so as to
increase the dissolution rate, absorption and
therapeutic efficacy of drugs in oral dosage
forms. In this technique, the drug is completely
dispersed in a hydrophilic carrier by various
methods [29,30].
The following are some of the advantages of
solid dispersion techniques:
a. In solid dispersion, the particle size of
the drug is reduced to a smaller size
thereby increasing the surface area
which can increase the solubility and
dissolution rate of the drug.
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b. The form of the drug is changed from
a crystalline form to an amorphous
form which has a higher energy level
so that it is more soluble.
c. The wettability of the drug particles is
increased by the dissolved carrier so
that it will increase the solubility of the
drug.
d. Solid dispersion can increase the
porosity of drug particles depending
on the nature of the carrier so as to
increase the drug release ability.
e. The interaction between the drug and
the carrier can reduce aggregation and
agglomeration as well as the release of
drug particles in a saturated state so as
to produce rapid absorption and can
increase drug bioavailability.
However, in addition to the
advantages of solid dispersion, there are also
some disadvantages of solid dispersion
techniques:
a. Physical instability.
b. Solid dispersions showed a change in
crystallinity and decreased dissolution
rate with the length of storage time.
c. Thermodynamic instability so that the
solid dispersion is sensitive to humidity
and temperature during storage which
can cause phase separation and
crystallization.
d. The instability of the solid dispersion
during storage time can have an impact
on drug quality and treatment
effectiveness [31,32].
Solid dispersions can be prepared by
various methods, including:
a. Melting/fusion method
This method involves directly heating a
drug and a hydrophilic carrier until they
melt at a temperature slightly over their
eutectic temperature, resulting in a
physical combination. The melt is then
cooled and rapidly solidified in an ice
bath while being stirred. The resulting
solid mass is crushed and sieved
(Pankaj and Prakash, 2013; R. Sharma
et al., 2013).
b. Solvent evaporation method
The solvent evaporation method is a
typical method for producing solid
dispersions in the pharmaceutical
industry, in which the drug and carrier
are dissolved in a volatile solvent. The
solvent was then evaporated while
being constantly agitated. After that, the
solid dispersion was crushed and sieved
(Pankaj and Prakash, 2013; R. Sharma
et al., 2013).
c. Melt evaporation
This method is a combination of
melting and solvent evaporation
methods. The principle of this method is
that the drug is dissolved in a suitable
solvent and then introduced into the
carrier melt. The mixture is then
evaporated to dryness [31,32].
d. Melt agglomeration process
In this method the binder acts as a
carrier. There are two ways of making
solid dispersions, the first is by spraying
the drug dispersion on the melted
binder. The second method is that the
drug, binder and other excipients are
heated above the melting temperature of
the binder used to form agglomerates
[31,33].
e. Hot-melt extrusion method
The HME method is carried out by a
combination of smelting and extruder
methods, in which a homogeneous
mixture of drugs, polymers, and
plasticizers is melted and then extruded.
The shape of the product can be
controlled in the extruder so that it does
not require milling in the final step [32].
f. Freeze-drying
In this method the drug and carrier are
dissolved in a common solvent then the
solution is frozen and sublimated in
liquid nitrogen to form a lyophilized
molecular dispersion [34].
g. Electrospinning method
This method is a combination of solid
dispersion and nanotechnology. In this
method, solid fibers are produced from
a stream of polymer liquid or melt
delivered through a millimeter-scale
nozzle [32,33].
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h. Co-precipitation
In this method, the carrier is dissolved
in a solvent then the drug is introduced
into the solution with stirring to form a
homogeneous mixture. Then, water is
added dropwise to the homogeneous
mixture to induce precipitation. The
precipitate formed is then filtered and
dried [32].
i. Supercritical fluid technology
The drug and carrier are dissolved in a
supercritical solvent (e.g., CO2) and
sprayed through a nozzle into a lower-
pressure expansion vessel. The fast
expansion causes the drug and solute
carrier to nucleate quickly, resulting in
the creation of solid dispersion particles
with the required size distribution in a
short amount of time [32].
j. Spray-drying method
To prepare the feed solution, the drug is
dissolved in a suitable solvent and the
carrier is dissolved in water. The two
solutions are then blended together
using sonication or another suitable
process until the solution is transparent.
The feed solution is sprayed into fine
droplets in a drying chamber using a
high-pressure nozzle during the
procedure. Droplets of drying fluid (hot
gas) are generated, forming nano or
micro-sized particles [32,33].
k. Kneading method
The carrier is dispersed in water or an
organic solvent and processed into a
paste in this procedure. Then it's mixed
with the drug and kneaded until it is
completely homogenous. The uniform
mixture is next dried and, if necessary,
sifted [32,33].
l. Co-grinding method
In this procedure, the drug powder and
carrier are precisely weighed and then
blended for a period of time at a specific
speed in a blender. The slurry is then put
into the grinding chamber of a vibrating
ball mill (Pankaj and Prakash, 2013).
This solid dispersion technique has
been widely used in an effort to increase the
solubility of a drug, especially carvedilol. For
example, a study conducted by Yuvaraja and
Jasmina (2014) showed an increase in water
solubility up to 353 times in the ionized solid
dispersion of carvedilol: HPꞵCD: tartaric acid
(1:3:0.75) when compared to pure carvedilol.
The increase in solubility also occurred in other
solid dispersions with CD, PVP K-30,
HPꞵCD, PLX-407, and tartaric acid as carriers
at various mass ratios. In addition to the
increase in solubility in water, this study also
showed an increase in the solubility of
carvedilol in various pH variations, namely at
pH 1.2, 6.8, and 7.4, which can be seen in
Figure. 15.
Figure. 14: Solubility enhancement factor of carvedilol in formulation at different pH [33]
An increase in the dissolution rate at various pH
variations was also observed (Figure. 16). In
this study, evaluations were also carried out in
the form of FTIR, XRD, DSC and SEM tests.
The FTIR spectrum (Figure. 17) showed a
significantly different intensity and band shape
in the solid dispersion when compared to pure
carvedilol and the physical mixture, these
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182
results allow physical interaction (physical
association) between carvedilol and
cyclodextrin. Diffractograms of solid
dispersions CV:HPꞵCD:TA:PVP K-30
(1:3:0.75:0.03) and CV: HPꞵCD:TA
(1:3:0.75) (Figure. 18) showed that carvedilol
is no longer present as a crystalline substance,
and drug molecules are molecularly scattered in
carrier domains, with solid complexes existing
in an amorphous state, as indicated by a halo
with an amorphous appearance. It suggested the
establishment of a CV-HPꞵCD inclusion
complex.
Figure. 15: Carvedilol dissolution in various pH mediums from various formulations [33]
Figure. 16: FTIR spectrum of carvedilol (A), PVP K-30 (B), tartaric acid (C), HPꞵCD (D), physical
mixture of CV:HPꞵCD:TA:PVP K-30 (E), physical mixture of ionized CV: HPꞵCD:TA (F), solid
I. Sopyan et al / Indo J Pharm 4 (2022) 168-188
183
dispersion of CV:HPꞵCD:TA:PVP K-30 (G), and solid dispersion of ionized CV: HPꞵCD:TA (H)
[33]
Figure. 17: XRD of carvedilol (A), PVP K-30 (B), tartaric acid (C), HPꞵCD (D), physical mixture of
CV:HPꞵCD:TA:PVP K-30 (E), physical mixture of ionized CV: HPꞵCD:TA (F), solid dispersion of
CV:HPꞵCD:TA:PVP K-30 (G), and solid dispersion of ionized CV: HPꞵCD:TA (H) [34]
The removal of the endothermic peak of
carvedilol corresponding to its melting point
was seen in thermograms of solid dispersion
systems (Figure. 17). It could be because of its
perfect homogenous dispersion within the
carrier and amorphization caused by
overcoming crystal lattice energy, followed by
hydrogen bond binding within the amorphous
carrier HPꞵCD. This fact showed that an
amorphous inclusion complex had formed. The
amorphization of the drug, as indicated by
FTIR, XRD, and DSC tests, is an indicator of
its amorphization and creation of an amorphous
inclusion complex between carvedilol and
carriers, resulting in an increase in the drug's
solubility. Thus, the change of the drug's
crystalline state to an amorphous state may be
responsible for the improved solubility of
poorly soluble carvedilol. The SEM results of
the solid dispersion (Figure. 18) appear as a
uniform mass and homogeneously mixed with
a wrinkled surface. This may be due to the
homogeneous dispersion of the drug in the
carrier.
Figure. 18: DSC of carvedilol (A), PVP K-30 (B), tartaric acid (C), HPꞵCD (D), physical mixture of
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CV:HPꞵCD:TA:PVP K-30 (E), physical mixture of ionized CV: HPꞵCD:TA (F), solid dispersion of
CV:HPꞵCD:TA:PVP K-30 (G), and solid dispersion of ionized CV: HPꞵCD:TA (H) [34]
Figure. 19: SEM of HPꞵCD:TA (A), carvedilol (B), physical mixture of ionized CV: HPꞵCD:TA
(C), solid dispersion of ionized CV: HPꞵCD:TA (D) [34]
2.8 Nanoemulsion
The name 'Nanoemulsions' refers to emulsions
with internal phase droplets ranging in size
from 50 to 1000 nanometers1. Nanoemulsions
are nanodispersed systems that can be a safe
choice for the creation of new pharmaceutical
and cosmetic formulations due to their
relatively high physical stability and acceptable
aesthetic appeal. They are made up of an oil
phase, an aqueous phase, a surfactant, and a
cosurfactant in the proper proportions. The
particles can exist in two forms: water in oil and
oil in water, with the core of the particle being
either water or oil. Low interfacial tension is
accomplished by adding a co-surfactant to
nanoemulsions, resulting in the spontaneous
production of a thermodynamically stable
nanoemulsion. Nanoemulsions, with their high
kinetic stability, low viscosity, and
transparency/translucency, are ideal for a
variety of industrial applications, including
drug administration [35].
Chidi et al., 2017 used an aqueous phase
titration method to make carvedilol
nanoemulsion. The solubility of carvedilol in
various oils (capryol 90, isopropyl myristate,
oleic acid, olive oil, sunflower oil, clove oil,
linseed oil) was used to choose the oil with the
highest solubility, while percentage
transparency and ease of emulsification were
used to choose the surfactant (tween 20 and
tween 80) and cosurfactant (transcutol P,
propylene glycol, PEG 400, and glycerol).
After extensive testing, clove oil, tween 20, and
PEG 400 were chosen as the oil, surfactant, and
cosurfactant, respectively. The research was
conducted with various formulation of the Smix
ratio as can be seen in table 1. Characterization
which includes centrifugation test, freezing-
thawing test, heating-cooling test, particle size
and zeta potential (ZP) measurement, poly
dispersity index (PDI) assay, determination of
pH, refractive index, viscosity, drug content, in
vitro drug release studies, kinetic models and
drug release mechanism, and statistical analysis
were carried out on nanoparticles. The
carvedilol nanoemulsion formulation of batch
NEC4 (Smix Ratio 1:3) was proven to be the best
formulation based on several in-vitro release
studies (Figure. 20). Low particle size, low
viscosity, and high percentage transmittance
were all found in the optimized formulation.
The present investigation clearly demonstrated
the utility of nanoemulsion in improving
carvedilol solubility, dissolving rate, and, as a
result, oral bioavailability.
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Figure 20. In vitro dissolution profiles of carvedilol nanoemulsion formulations [35]
2.9 Dendrimers
Dendrimers first introduced by Vogtle in 1978,
are an unique and efficient nanotechnology
platform for drug delivery. Dendrimers range in
size between 1 and 100 nm with three distinct
domains: (i) a core, which is centrally located
containing atoms or molecules with at least two
identical chemical functions; (ii) branches,
which are repeating units in a geometric series
leading to radially concentric layers known as
"generations"; and (iii) a terminal functional
group, on the surface which determines the
nature of the dendrimer. Dendrimers are highly
branched, well-organized nanoscopic
macromolecules (typically 5000‑500,000
g/mol), have a low polydispersity index and
have shown an important role in the emerging
field of nanomedicine. Dendrimers have
garnered a lot of attention in biological
applications due to their high water solubility,
biocompatibility, polyvalence, and precise
molecular weight. Because of these properties,
it's a great medication delivery and targeting
vehicle. Solubility is influenced by dendrimer
concentration, pH, generation size, core,
terminal functionality, and temperature.
Different types of dendrimers are available
based on different polymers such as
polyamidoamine (PAMAM), polyamines,
polyamides (polypeptides), poly(aryl ethers),
polyesters, carbohydrates, and DNA [36–38].
In a study conducted by Zheng et al (2013)
effectively synthesized carvedilol PAMAM-
multiwalled carbon nanotubes using the
divergent growth technique for dendrimer
assembly. Carvedilol was incorporated into the
dendrimer using three ways: fusion, incipient
wetness impregnation, and solvent approaches.
The dissolving results revealed that the samples
created using the fusion approach disintegrated
faster than those created using the incipient
wetness impregnation method. Additionally,
the items made with the solvent technique had
the slowest drug release. However, all of the
samples created with PAMAM-MWNTs
significantly increased the solubility of
carvedilol. From the molecular form, the
physicochemical characterization revealed the
distribution of carvedilol inside and outside the
PAMAM-MWNTs. On poorly water-soluble
medicines, the new drug delivery system may
provide a potential advantage in terms of
improved dissolution and drug-loading
capacity.
3. CONCLUSION
The low bioavailability of a drug becomes a
common obstacle in drug development because
in order to achieve optimal therapeutic effects,
a drug needs to have high oral bioavailability.
Carvedilol has low solubility and thus low
bioavailability. Various solubility enhancement
techniques have been applied to carvedilol,
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including co-crystallization, liquidsolid
technique, cyclodextrin inclusion complex,
nanoparticles, hydrotrophy, nanosuspension,
solid dispersion, nanoemulsion, and
dendrimers. These techniques have been shown
to increase the solubility and dissolution rate of
carvedilol thereby increasing its
bioavailability.
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