Vol 4, Issue 2, 2023 (255-266)

http://journal.unpad.ac.id/idjp

*Corresponding author,

e-mail : [email protected] (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

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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

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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).

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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

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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

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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

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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

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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.

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