Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques

ISSN No: 2321-8630, V 1, I 1, 2014
Journal Club for Pharmaceutical Sciences (JCPS)

Manuscript No: JCPS/RES/2014/4, Received On: 01/08/2014, Revised On: 04/08/2014, Accepted On: 07/08/2014
RESEARCH ARTICLE
Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques
Patel MV*, Patel DS, Patel NU, Patel KN, Patel PA
A-11, Shakuntal Bungalows, Opp. Kunjmall, Nikol Naroda road, Ahmedabad, India
ABSTRACT
Carbamazepine, structurally similar to dibenzine derivative is used in the treatment of Epilepsy and pain
associated with trigeminal neuralgia. The drug is practically insoluble in water, so the rate of dissolution
and bioavailability is less. In this investigation an attempt was made to enhance solubility of
carbamazepine by solubility enhancement techniques like Solid dispersion, Inclusion complexation and
Crystallization. For solid dispersion phase solubility studies were carried out using Mannitol, PEG 4000
and PVP K 30 and for Inclusion complexation Phase solubility studies were carried out using
Complexol-HPTM and HPMC E 3. The solid dispersions, Inclusion complexes and Crystals were
prepared by solvent evaporation method and characterized by FT-IR and differential scanning
calorimetry (DSC) and evaluated for different parameters. The highest percent cumulative drug release
was observed for CBI-2 batch of inclusion complex (97.38% in 60 min.)
KEYWORDS
Complexol-HPTM, Solvent Evaporation, Differential Scanning Calorimetry
INTRODUCTION
practically insoluble in water. CBZ is BCS
Carbamazepine (CBZ) is an anticonvulsant drug
class-II drug which shows dissolution dependent
with different crystalline forms1. All crystalline
oral bioavailability. Enhancement of solubility
forms have variable dissolution leading to
of
irregularand delayed absorption2. CBZ has an
complexation4
experimental log P value of 2.45 and is
effective way. Solid dispersion, which was
CBZ
by
Solid
and
dispersion3,
Inclusion
Crystallization5
is
an
introduced in 1970s6, is a multicomponent

*Address for Correspondence:
Patel MV
A-11, Shakuntal Bungalows, Opp. Kunjmall, Nikol
Naroda road, Ahmedabad, India
E-Mail Id: mickyvp11@gmail.com
Copyright reserved by Journals Club & Co.
system, having drug dispersed in hydrophilic

carrier. In has been used for many types of
poorly aqueous soluble drugs. Many hydrophilic

carriers have been investigated for improvement
pressure of 5 tons for 5 min in a hydraulic press.
of dissolution characteristics. Cyclodextrins are
Forty scans were obtained at a resolution of 4
used
cm-1, from 4000 to 600 cm-1.
to
increase
the
solubility
and
bioavailability of many water soluble drugs.
Preliminary
Cyclodextrin incorporation can influence the
Solubility of Solid Dispersion9
mechanisms by which drug is released.
Phase Solubility measurements were performed
So, they can enhance drug release by increasing
according to the method of Higuchi and
the concentration of diffusible species within the
Connors. Various aqueous solutions of Mannitol
matrix and they also enhance drug release by
(0%, 1%, 2%, 3% 4%, 5%, 6% w/v), PVP-K-30
acting as wicking agents.7 Polymorphism is
(0%, 0.4%, 0.6%, 0.8%, 1%, 1.2% and 1.5%
defined as the ability of a compound toassume
w/v) and PEG 4000 (0%, 0.4%, 0.6%, 0.8%,
more than one crystalline form.8
1%, 1.2% and 1.4% w/v) were prepared and 10
Trials
to
Determine
Phase
ml of each solution was taken into separate
MATERIALS & METHODS
conical flask. An excess amount of drug was
Materials
from Surya
added to these flasks. The flasks containing
organics and chemicals, Ankleshwar, Gujarat.
drugcarrier mixtures were shaken at 37 0.1
Complexol- HPTM was obtained from Gangwal
C for 24 hour in orbital bath shaker. After 24
Chemicals Private Limited, Mumbai. Mannitol,
hour, samples were filtered through 0.45-m
PVP- K 30 were obtained from West Coast
filter paper. The filtrate was suitably diluted
Pharmaceuticals Works Limited and PEG 4000
with corresponding polymer carrier solution and
was obtained from RFCL Limited. All the
analyzed
chemicals used in the study were of analytical
respective max (284.6 nm for Mannitol, 284.9
grade.
nm for PVP-K-30, 285.4 nm for PEG 4000)
Drug and Excipient Compatibility Study by
using a UV-Visible Spectrophotometer.
FT-IR
Preliminary Trials to Determine the Phase
Fourier-transform infrared (FT-IR) spectra were
Solubility of Inclusion Complex
obtained
spectrometer
Aqueous solutions were prepared containing
(Shimadzu 8400S, Japan). The samples (CBZ
Complexol-HPTM (025%, w/v) and HPMC-E-3
and Excipients) were previously ground and
(0, 0.1%, 0.15%, w/v). An excess amount of
mixed thoroughly with potassium bromide, an
drug
infrared transparent matrix, at 1:5 (Sample:
equilibrated at constant temperature in Orbital
KBr) ratio, respectively. The KBr discs were
laboratory bath shaker. After equilibrium, the
prepared by compressing the powders at a
suspensions were filtered and the solutions were
Carbamazepine
using
was
an
obtained
FT-IR
was
spectrophotometrically
added.
The
at
suspensions
their
were

assayed spectrometrically at (288.3 nm for
The resultant mass was passed through sieve no.
Complexol-HPTM, 284.3 nm for HPMC-E-3 and
60 and stored in dessicator at room temperature
Complexol-HPTM
for further study
mixture).The
equilibrium
constants of the inclusion complex were
Preparation of Inclusion Complex
determined from the phase-solubility diagrams
The inclusion complexes were prepared by
according to Higuchi and Connors10. The slope
solvent
of the diagrams was evaluated from the phase
weighed drug and Complexol-HPTM were
solubility diagram. The apparent stability
dissolved separately in Ethanol, adding 0.1 %
constants (Ks) were then determined from
HPMC-E-3 and then mixed. The solvent was
following equation.
evaporated at 60 C and the resultant mass was
Stability constant K =
Slope
D (1 Slope)
Where, Slope = Slope of phase solubility

diagram
D0 = Solubility of drug without carrier
Preparation of Solid Dispersion
The solid dispersions were prepared by solvent
evaporation method. Accurately weighed drug
was taken in China dish, dissolved in Ethanol
and then carrier (PVP K 30) was added (weight
ratio). The solvent was evaporated at room
temperature and dried in hot air oven at 50C
for 4 hours.
Drug
(mg)
method.
Accurately
passed through sieve no. 60 and stored in

dessicator at room temperature for further study.
Table: 2 Formulation Batches of Inclusion
Complexes
Solid
Dispersion
Batches
Drug
(mg)
CBK-1
100
2.5
1:0.025
CBK-2
100
1:0.05
CBK-3
100
10
1:0.1
CBK-4
100
20
1:0.2
PVP K
30(mg)
Drug:Carrier
ratio
Crystallization Based Approach

Dichloromethane was used as solvents to obtain
Table: 1 Formulation Batches of Solid

Dispersion
Inclusion
complex
batches
evaporation
ComplexolHPTM (mg)
Drug:
Carrier
ratio
HPMC-E3 (%w/w)
crystals from pure drug. Accurately weighed

drug was dissolved in specified amount of
solvent. HPMC-E-3 was used as hydrophilic
carrier. Then they were allowed for air drying.
CBI-1
100
116.4
0.1
1:0.20
CBI-2
100
145.5
0.1
1:0.25
no. 60 and stored in dessicator at room
CBI-3
100
291.1
0.1
1:0.5
temperature for further study.
CBI-4
100
582.1
0.1
1:1
Evaluation Parameters for Solid Dispersions,
The prepared crystals were passed from sieve
Inclusion Complexes and Crystals11,12

FT-IR Spectroscopic Analysis

CBZ, Carrier, Solid dispersions/ Inclusion
into a measuring cylinder and note down the
complex/ Crystals were subjected for FTIR
value without tapping the cylinder.
CBZ, Carrier, Solid dispersions/ Inclusion

complex/ Crystals were subjected for FTIR
Angle of Repose
studies. Samples were prepared using KBrdisc
The maximum angle which is formed between
method and spectra were recorded over the
the surface of a pile of
range 400 cm-1 to 4000 cm-1. Spectra were
Table: 3 FormulationBatches of Crystals
analyzed for Drug-Carrier interactions and

functional groups involved in the process.
Differential
Scanning
Calorimetry
(DSC)
Analysis
Inclusion
Drug HPMCcomplex
(mg) E-3 (mg)
batches
Drug:Carrier
ratio
CBD-1
100
recorded using DSC-instrument. The samples
CBD-2
100
10
1:0.1
were hermetically sealed in aluminum pans and
CBD-3
100
20
1:0.2
heated over the temperature range 40 to 350C
CBD-4
100
30
1:0.3
DSC scans of the powdered samples were
at heating rate of 10C under inert nitrogen

dynamic atmosphere (100 ml/min).
Bulk Density =
powder and horizontal surface is called the

angle of repose.10 gm of drug were allowed to
flow by funnel from 4 cm of height from the
base. The height of pile and diameter of base
was measured and calculate the angle of repose
by following formula
M
V
Where, M0 = Initial mass of powder

V0 = Initial volume of powder
Tapped Density
Tapped density was achieved by tapping a
measuring cylinder containing a powder sample.
Cylinder containing 5 gm of powder was then
= tan
Where,
= Angle of Repose
h = Height of the pile of powder
tapped 100 times on flat surface. The volume of

powder was noted down.
Tapped density =
r = Radius of the pile of powder

Bulk Density
M
V
Where, M0 = Initial mass of powder

Vt= Tapped volume of powder
Bulk density was determined by measuring the
Carrs Index
volume of known mass of powder sample that
It is also known as compressibility ratio of
has been passing through a screen in to a
powder and calculated by following formula
graduate cylinder. 5 gm of powder was poured

V V
complexes equivalent to 100 mg of drug was
% Carr s index = 100
V
taken. Percent drug released should be
Hausners Ratio
determined by taking an aliquot of 5 ml at
The Hausners ratio is a number that is
different time intervals. An equal volume of
correlated to the flowability of a powder or
fresh dissolution medium was replaced to
granular material. It is expressed by following
maintain the original volume. The samples were
formula
diluted for estimating percent released by UVHausner s Ratio =
--
Visible Spectrophotometer.
Where tapped = Tapped density
Dissolution Parameter
bulk= Bulk density
Medium: 1% SLS
Volume: 900ml
Saturated Solubility Study of Prepared Solid
Apparatus: USP type II
Dispersions, Inclusion complexes and Crystals
RPM: 75 rpm
Solubility studies were performed according to
Time point: 5, 10, 15, 22, 25, 30, 35, 40, 45,
the method reported by Higuchi and Connors.10
50, 60 minutes
CBZ solid dispersions/ Inclusion complexes/
Temperature: 37C 0.5C
Crystals in amounts that exceeded its solubility,
max: 287 nm
were transferred to conical flasks containing 10
RESULT AND DISCUSSION
ml distilled water (1% SLS). The contents were
Drug Excipient Compatibility Study by FT- IR
stirred in laboratory orbital shaker at 370.1C
The FT-IR spectra of carbamazepine with
for 24 hrs. After 24 hours, the samples were
carriers and is shown in figure 1. There was no
filtered through a 0.45-m Whatman filter
disappearance of any characteristic peak in any
paper, suitably diluted with distilled water (1%
of the mixture. So, there was no drug and
SLS) and analyzed for drug content at the 287
excipient
nm using a UV-Visible spectrophotometer.
excipient.
In-vitroDissolution Study as per USP13
compatibility between drug and
Preliminary trials for Phase solubility study of

solid dispersion
In-vitro drug release was determined using USP
To investigate effect of different carriers on the
(United
dissolution
solubility of CBZ, the saturated solubilities of
at 75 rpm
CBZ were determined in different solutions. As
maintained at 370.5 C in 900 ml of 1% SLS
seen, with the increase in carrier (Mannitol,
as dissolution media. Amount of prepared
PVP K 30, PEG 4000)
States
Pharmacopeia)
apparatus II of paddle type

Fig. 1 Comparative FT-IR spectra of sample A- CBZ, Sample F- CBZ and Mannitol, Sample J- CBZ and
PEG 4000, Sample H- CBZ and PVP K 30, Sample N- CBZ and Complexol-HPTM
Fig 2: Comparative phase Solubility Study of CBZ and Carriers of Solid Dispersion
CBZ Concentration
(mmol/L)
0.054
CBZ and Mannitol
CBZ and PEG 4000
CBZ and PVP K 30
0.052
0.05
0.048
0.046
0.044
0.042
0.04
% w/v of Carrier
Fig3: Comparative phase solubility study of CBZ, Complexol-HPTM and HPMC E 3
CBZ Concentration (mmol/L)
0.6
0.5
0.4
0% HPMC
0.3
0.1 % HPMC
0.2
0.15 % HPMC
0.1
0
0
10
15
20
25
% w/v of Complexol-HPTM

concentration in the solution, the saturated
solubility of CBZ was increased as increase in
solubility of CBZ increased, indicating that
the concentration of Complexol-HPTM with the
making solid dispersion with carriers is the
slope 1, indicating that 1:1 stoichiometry
effective way to increase the solubility of
complex formation16. The solubility constant
CBZ14.
solubility
was calculated, which was 395.97mol-1 for
diagrams were presented in Fig 2. With the
Complexol-HPTM in absence of HPMC-E-3,
increase in the concentration of carrier, CBZ
438.03 mol-1 for Complexol-HPTM 0.1% HPMC
concentration
linear
E 3 and 405.85 mol-1 for Complexol-HPTM in
relationship upto some concentration. The
presence of 0.15% HPMC E-3. So, Complexol-
stability constant was calculated, which was
HPTM with 0.1% HPMC-E-3 was selected for
134.82 mol-1 for Mannitol, 197.73 mol-1 for
further study.
The
comparative
increased
phase
with
PVP-K-30 and 37.30 mol-1 for PEG4000. So,

PVP-K 30 was selected as a carrier to be used
Evaluation of Solid Dispersion
for the preparation of solid dispersion.
Characterization of Solid Dispersion by FT-IR
Preliminary Trials for Phase Solubility of

Inclusion Complex
FT-IR spectra of pure Carbamazepine, carrier

PVP-K-30,
solid
dispersion
and
physical
mixture are shown in figure indicating no

To investigate effect of Complexol-HPTM on
significant evidence of chemical interaction
the solubility of CBZ, the saturated solubilities

of CBZ were determined in the absence or
presence of water soluble polymer HPMC-E-3.
With
the
increase
in
Complexol-HPTM
concentration in the solution, the saturated

solubility of CBZ increased, indicating that
between drug and carrier. Characteristic bands

of Form III were observer at 3473.3 and 3163.8
cm-1 17. The spectra of solid dispersion confirm
the stability of drug with its solid dispersion. In
physical mixture there is just the overlapping of
both spectra. N-H stretching of aromatic amine
complexation is the effective way to increase
increased to 3474.3 cm-1, N-H stretching of
the solubility of CBZ. The comparative phase
aliphatic amine decreased to 3163.8 cm-1, C=O
solubility diagrams were presented in Fig.
stretching of CONH2
3.When complexation is carried out with

HPMC-E-3, the solubility of CBZ increased
upto 0.1% concentration due to interaction of
Complexol-HPTM and
HPMC
E-315.
The
increased to 1673.9 cm-1, C=C stretching of

benzene ring decreased to 1593.8 cm-1, C-N
stretching of aromatic ring increased to 1384.2

cm-1 and C-N stretching of aliphatic amine
Fig. 5 shows the DSC spectra of CBZ, PVP K
increased to 1112.1 cm-1.
30 and solid dispersion prepared by solvent
Characterization of Solid Dispersion by DSC
evaporation method.
Fig. 4: Comparative FT-IR spectra of sample A- CBZ, Sample B- PVP-K-30, Sample E- Solid
dispersion of CBZ and PVP-K-30, Sample H- Physical mixture of CBZ and PVP-K 30
Fig 5 : Comparative DSC of solid dispersion Sample A- CBZ, Sample B- PVP-K 30, Sample CSolid dispersion of CBZ and PVP-K 30

DSC
spectra
of
pure
CBZ
show
In
Fig.
5A,
the
endotherm
at
177.17
polymorphictransition with two endotherms at
Corresponds to the melting of Form III,
around
CBZ
followed by immediate recrystallization to Form
exhibitsenantiotropic polymorphism, i.e. there
I and subsequent melting of Form I at 191 C. In
exista transition temperature below the melting
DSC spectra of PVP K30, a broad endotherm
point of either of polymorphs at which both
ranging from 90 to 140 C was observed
177.17
and
194.16
C.
18
these forms have the same free energy .Above
indicating the loss of water due to extremely
the transition temperature, the higher melting,
hygroscopic nature of PVP polymers
Form I has the lower free energy and is more

stable.
Below
the
transition
temperature,
however, thelower melting, Form III is more

stable since it has lower free energy. Hence at
The thermo grams of solid dispersion also

showed similar broad endotherm, but no
endotherms were observed around the melting
point of both forms of CBZ
room temperature, Form III is more stable.
Table 4: Micromeritic properties of prepared solid dispersion

Batch
B.D. (gm/ml)
CBK-1
CBK-2
CBK-3
CBK-4
% Carrs index
Hausners ratio
0.5030.006
0.5200.017
0.5100.010
T.D.
(gm/ml)
0.5930.015
0.6370.021
0.6330.012
15.1190.984
18.3080.116
19.4720.788
1.1790.041
1.2250.031
1.2420.012
Angle of
repose
260.044
240.394
280.235
0.5530.032
0.6350.025
12.8830.332
1.1550.105
270.287
(*All values are expressed as mean SD, n=3)
Thisindicates that CBZ might be in amorphous
MicromeriticProperties
state. PVP inhibitscrystallization of drugs in
Dispersion
solid dispersions resultingin amorphous form of
All the solid dispersions were evaluated for
the drug in the solid dispersions.Crystallization
different Micromeritic properties. Bulk density
inhibition
ranged from 0.5030.006 to 0.5530.032 tapped
is
attributed
to
two
effects:interactions, such as hydrogen bonding

17
between thedrug and the polymer .
density
ranged
0.6370.021,
of
from
Carrs
Prepared
0.5930.015
index
ranged
Solid
to
from
12.8830.332 to 19.4720.788, Hausners ratio


ranged from 1.1550.105 to 1.2420.012, Angle
of repose ranged from 240.394 to 280.235.
Saturated solubilty study of solid dispersions
17.32
Solubility (mg/100 ml)
18
12.94
13.55
CBK-1
CBK-2
12.53
13
8
4.59
3
-2
CBZ
CBK-3
CBK-4
Fig 6 : Saturated Solubility Study of CBZ and Solid Dispersion
Saturated Solubility Study of Prepared Solid
dissolution of pure drug could be poor
Dispersions
wettability. It was found that drug release was
Results of the saturated solubility study are
increased by the preparation of solid dispersion
shown in Fig. 6. Solubility of CBZ was found to
with PVP-K30. From Fig. 7 it can be seen that
be 4.59 mg/100ml while improvement in
dissolution
solubility was observed with all the solid
dispersions increase with increase in PVP-K-30
dispersions. This difference in solubility can be
upto 1:0.1 ratio of CBZ:PVP-K-30. This
explained by the different physicochemical
increase in the dissolution rate may be due to
properties of the solid dispersions.
increase in drug wettability by carrier2
of
carbamazepine
in
solid
After this particular ratio with further increase

Saturated solubility study data suggest that the
solid dispersion of Batch CBK-3 has highest
solubility than other solid dispersions.
in the amount of PVP-K-30, the dissolution was

decreased. The decrease in the dissolution may
be due to binding effect of PVP-K-30. So, it can
In Vitro Dissolution Study of Prepared Solid
be concluded that the dissolution rate of
Dispersions
carbamazepine increased by preparing solid
The dissolution rate of pure carbamazepine was
dispersion with PVP-K
very poor and during 60 min maximum 30% of
Characterization of Inclusion complex
the drug was released. The reason for the poor
FTIR analysis of prepared Inclusion complex
10

FT-IR spectra of pure Carbamazepine, carrier
Complexol HPTM, HPMC E 3, Inclusion
Comparative study of CBZ and PVP K 30 solid dispersion

100
90
80
% CDR
70
60
CBK-1
50
CBK-2
40
CBK-3
30
CBK-4
20
CBZ
10
0
0
10
15
20
25
30
Time (min)
35
40
45
50
60
complex and physical

Fig 7: Comparative %CDR of CBZ and solid dispersion batches
Fig 8 : Comparative FT-IR spectra of sample A-CBZ, Sample K Complexol HPTM, Sample MInclusion complex of CBZ and Complexol HPTM, Sample N- Physical mixture of CBZ and
Complexol HPTM, Sample L-HPMC E
Fig 9 : Comparative DSC of inclusion complex, Sample D- CBZ, Sample E- HPMC E 3, Sample FComplexol-HPTM, Sample G- Inclusion complex of CBZ, HPMC E 3 and Complexol-HPTM
11
mixture are shown in figure indicating no
thermogram of Complexol -HPTM showed a
significant evidence of chemical interaction
large endothermic band ranging between 48 C
between drug and carrier in case of Inclusion
and 100 C and at 250 C which could
complex which confirms the stability of drug
correspond to the loss of water molecules from
with its Inclusion complex. In physical mixture
thecyclodextrin cavity, and the thermogram
there is just the overlapping of both spectra. N-
ofHPMC-E-3 also showed a largeend othermic
H stretching of aromatic amine decreasedto
band ranging between 65 C and 120C. The
2935.8 cm-1, N-H stretching of aliphatic amine
thermogram of CBZ, Complexol-HPTM and
disappeared due to complexation with OH
HPMC-E-3 showed disappearance of peaks of
group of Complexol HPTM 21, C=O stretching of
CBZ. These thermal behavior changes indicate
CONH2 increased to 1683.5 cm-1, C=C
the formation of theinclusion complex through
stretching of benzene ring decreased to 1593.8
molecular interactions between the CBZ and
cm-1, C-N stretching of aromatic ring increased
Complexol-HPTM, resulting in the amorphous
to 1394.6 cm-1 and C-N stretching of aliphatic
dispersed form of CBZ22.
amine disappeared due to complexation with

Complexol HPT 3
Micromeritic Properties of Prepared Inclusion

Complexes
Bulk density ranged from 0.5270.015 to
Differential Scanning Calorimetry (DSC) of

Prepared Inclusion Complexe
0.5410.030, tapped density ranged from
Fig. 9 illustrates the DSC profile of pure CBZ,
0.6200.010 to 0.6530.040, Carrs index
Complexol-HPTM, HPMC-E-3 and complex.
ranged from 12.9140.294 to 19.2770.698,
The DSC thermo gram of CBZ characterized by
Hausners ratio ranged from 1.1500.040 to
a sharp melting peak at 194.16Cwas of typical
1.1740.041, Angle of repose ranged from
pure,
anhydrous
substance,
while
the
210.264 to 250.237.
12

Table 5: Micromeritic Properties of Prepared Inclusion Complex
Batch
B.D. (gm/ml)
T.D.
(gm/ml)
% Carrs
index
Hausners
ratio
Angle of repose
CBI-1
0.5400.036
0.6270.012
13.7600.961
1.1650.058
220.156
CBI-2
0.5410.030
0.6200.010
12.9140.294
1.1500.040
210.264
CBI-3
0.5370.006
0.6300.017
14.7630.952
1.1740.041
230.110
CBI-4
0.5270.015
0.6530.040
19.2770.698
1.2400.093
250.237
(*All values are expressed as mean SD,n=3)

Table 6: Micromeritic Properties of Prepared Crystals
Batch
B.D.
T.D.
% Carrs
Hausners
Angle of
(gm/ml)
(gm/ml)
index
ratio
repose
CBD-1
0.5270.015 0.6930.015
23.9820.852
1.3180.068
350.287
CBD-2
0.5370.031 0.6500.030
17.1750.541
1.2160.123
330.179
CBD-3
0.5260.014 0.6270.021
16.0470.390
1.1910.020
310.170
CBD-4
0.5240.056 0.6430.045
15.6750.532
1.1540.075
320/271
(*All values are expressed as mean SD, n=3)
Saturated Solubility Study of Prepared
In vitro Drug Release of Complexes
Inclusion Complexes
The dissolution rate of pure carbamazepine was
very poor and during 60 min maximum 30% of
shown in Fig. 10. Solubility of CBZ was found
the drug was released. The reason for the poor
to be 4.59 mg/100ml while improvement in
dissolution of pure drug could be poor
solubility was observed with all the inclusion
wettability. It was found that drug release was
complexes.This difference in solubility can be
increased by complexation of drug with
explained by the different physicochemical
Complexol-HPTM.
properties of the inclusion complexes. Saturated

solubility study data suggest that the inclusion
complex of Batch CBI-3 has highest solubility
than other inclusion complexes.
13

Fig. 10: Saturated solubility study of inclusion complex
(Solubility (mg/100 ml)
Saturated solubility study of Inclusion complexes

20
18
16
14
12
10
8
6
4
2
0
19.26
18.30
17.99
15.94
4.59
CBZ
CBI-1
CBI-2
CBI-3
CBI-4
Fig 11: Comparative % CDR of CBZ and Inclusion Complex Batches Evaluation
From the release profiles, it can be seen that
carrier.After this particular ratio with further
dissolution of carbamazepine in inclusion
increase in the amount of Complexol-HPTM, the
complexes increase with increase in Complexol-
dissolution was decreased. So, it can be
HPTMupto 1:0.25 ratio of CBZ:Complexol-
concluded
HPTM. This increase in the dissolution rate may
carbamazepine increased by preparing solid
be due to increase in drug wettability by
dispersion withComplexol-HPTM.
that
the
dissolution
rate
14
of

Parameters of Prepared Crystals
lower free energy. The transition temperature of
FTIR Analysis of Prepared Crystals
CBZ enantiotropic forms has been reported to
Results of the DSC thermograms are shown in
be around 71 C24. Henceat room temperature,
fig. 13. DSC thermograms of CBZ form I (Pure
Form III is the most stable formand is the one
Drug) showed no transformation and melts
possessed by most commerciallyavailable CBZ.
between 177.17 and 194.15C. Form II does not

melt, but a transformationoccurs between 135
and 170C and the new phase then melts
between 188 and 192C. Form III meltsand
crystallizes
to
new
form
nearly
simultaneouslybetween 162 and 175C. The

new form subsequentlymelts between 189 and
193C. Form IV showsmelting and partial
crystallization to a new form between 178 and
Micromeritic Properties of Prepared Crystals

All the crystals were evaluated for different
Micromeritic properties. Bulk density ranged
from 0.5240.056 to 0.5370.031, Tapped
density
ranged
0.6930.015,
from
Carrs
0.6270.021
index
ranged
to
from
15.6750.532 to 23.9820.852, Hausners ratio

ranged from 1.2160.123 to 1.3180.068, Angle
of repose ranged from 310.170 to 350.287.
187C, significantly higher than thetransition

temperatures of forms II or III. This isfollowed
Saturated Solubility Study of Carbamazepine

Crystals
by further crystallization to produce amaterial
that then melts between 190 and 192C.
shown in Fig. 14. Solubility of CBZ was found
Differential Scanning Calorimetry (DSC) of

prepared crystals
to be 4.59 mg/100ml while improvement in
Differential scanning calorimetry results showed
and highest in CBD-1 batch. This difference in
thatpure CBZ has a polymorphic transition with
solubility can be explained by the different
two endotherms at around 176C and 194C. It
physicochemical properties of the crystals.
is well-known that CBZ exhibits enantiotropic
Saturated solubility study data suggest that the
polymorphism, i.e. there exists a transition
crystals of CBD-1 batch had a highest solubility
temperature below themelting point of either of
than any other type of crystals
solubility was observed with all type of crystals
polymorphs at which both these forms have the

same free energy23. Above the transition
temperature, the higher melting Form I has the
lower free energy and is more stable. Below the
transition temperature, however, the lower
melting Form III is more stable since it has
In vitro Drug Release of Prepared Crystals

The results of the In vitro dissolution study
showed a marked differencein dissolution
behavior of the crystals and pure drug. Results
showed that the amount of CBZ dissolved from
Dichloromethane crystals and HPMC E 3 was
considerably higher than others.
15

Fig 12 : Comparative FT-IR spectra of sample A-Carbamazepine, Sample O - Crystals obtained from
Dichloromethane, Sample P - Crystals obtained from Dichloromethane and HPMC E
Saturated solubility study of crystals

19.38
20
Solubility (mg/100 ml)
18
16.65
16
14.34
14
11.99
12
10
8
6
4.59
4
2
0
CBZ
CBD-1
CBD-2
CBD-3
CBD-4
Fig 13: Comparative DSC of crystals, Sample H- CBZ, Sample I- HPMC E 3, Sample J-Crystals
prepared from Dichloromethane, Sample K- Crystals prepared from Dichloromethane and
HPMC E
16

Fig 14 : Comparative Saturated Solubility Study of Carbamazepine Crystals
Fig 15 : Comparative study of In vitro drug release of crystals

Comparative study of Carbamazepine Crystals
% CDR
100
90
80
CBD-1
CBD-2
70
60
50
CBD-3
CBD-4
40
30
20
10
0
CBZ
10
15
20
25
30
Time (min)
35
40
solubility
45
of
50
all
60
The highest dissolution rate was observed forthe
The
the
batches
crystals recrystallized from Dichloromethane
Dichloromethane crystalswas found to be higher
and HPMC E 3 and that was 90.70% at 60 min.
almost double whencompared to the pure drug.
The solubility of recrystallized CBZ was
Since the bioavailabilityof carbamazepine is
increased in presence of hydrophilic additive
limited only by its dissolutionrate, even a small
like HPMC E 32.
17
of

increase in dissolution will resultin a large
carbamazepine
by
inclusion
in
2-
increase in its bioavailability.
hydroxypropyl--cyclodextrin. International
journal of pharmaceutics, 85(1), 175-180.
SUMMARY AND CONCLUSION

The present study was undertaken with an aim
5. Nokhodchi,
A.,
Bolourtchian,
N.,
&
to enhance the solubility of CBZ and compare
Dinarvand, R. (2005). Dissolution and
the techniques. The solid dispersion batch CBK-
mechanical
3(1:0.1) showed 93.36% drug release at 60 min.
carbamazepine from alcohol solution in the
The inclusion complex batch CBI-2(1:0.25)
presence of additives. Journal of crystal
showed 97.38 at 60 min. The crystal batch
growth, 274(3), 573-584.
behaviors
of
recrystallized
CBD-2 showed 90.70% drug release at 60 min.
6. Zerrouk, N., Chemtob, C., Arnaud, P.,
Inclusion complex batch showed maximum
Toscani, S., & Dugue, J. (2001). In vitro and
drug
inclusion
in vivo evaluation of carbamazepine-PEG
complexation was effective way to enhance the
6000 solid dispersions. International journal
CBZ solubility.
of pharmaceutics, 225(1), 49-62.
release
at
60
min.
So,
7. Koester, L. S., Xavier, C. R., Mayorga, P.,

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Bolourtchian,
N.,
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193(2), 137-146.
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HOW TO CITE THIS ARTICLE

Patel, M.V., Patel, D.S., Patel, N.U., Patel, K.N., Patel, P.A. (2014). Solubility Enhancement of
Carbamazepine by Using Various Solubility Enhancement Techniques. Journal Club for
Pharmaceutical Sciences, 1(I), 1-20.
20

Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques

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ISSN No: 2321-8630, V 1, I 1, 2014

Journal Club for Pharmaceutical Sciences (JCPS)

practically insoluble in water. CBZ is BCS

Carbamazepine (CBZ) is an anticonvulsant drug

class-II drug which shows dissolution dependent

with different crystalline forms1. All crystalline

oral bioavailability. Enhancement of solubility

forms have variable dissolution leading to

irregularand delayed absorption2. CBZ has an

experimental log P value of 2.45 and is

effective way. Solid dispersion, which was

introduced in 1970s6, is a multicomponent

Copyright reserved by Journals Club & Co.

system, having drug dispersed in hydrophilic

Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques

pressure of 5 tons for 5 min in a hydraulic press.

of dissolution characteristics. Cyclodextrins are

Forty scans were obtained at a resolution of 4

cm-1, from 4000 to 600 cm-1.

bioavailability of many water soluble drugs.

Cyclodextrin incorporation can influence the

Solubility of Solid Dispersion9

mechanisms by which drug is released.

Phase Solubility measurements were performed

So, they can enhance drug release by increasing

according to the method of Higuchi and

the concentration of diffusible species within the

Connors. Various aqueous solutions of Mannitol

matrix and they also enhance drug release by

(0%, 1%, 2%, 3% 4%, 5%, 6% w/v), PVP-K-30

acting as wicking agents.7 Polymorphism is

(0%, 0.4%, 0.6%, 0.8%, 1%, 1.2% and 1.5%

defined as the ability of a compound toassume

w/v) and PEG 4000 (0%, 0.4%, 0.6%, 0.8%,

more than one crystalline form.8

1%, 1.2% and 1.4% w/v) were prepared and 10

ml of each solution was taken into separate

MATERIALS & METHODS

conical flask. An excess amount of drug was

added to these flasks. The flasks containing

organics and chemicals, Ankleshwar, Gujarat.

drugcarrier mixtures were shaken at 37 0.1

Complexol- HPTM was obtained from Gangwal

C for 24 hour in orbital bath shaker. After 24

Chemicals Private Limited, Mumbai. Mannitol,

hour, samples were filtered through 0.45-m

PVP- K 30 were obtained from West Coast

filter paper. The filtrate was suitably diluted

Pharmaceuticals Works Limited and PEG 4000

with corresponding polymer carrier solution and

was obtained from RFCL Limited. All the

chemicals used in the study were of analytical

respective max (284.6 nm for Mannitol, 284.9

nm for PVP-K-30, 285.4 nm for PEG 4000)

Drug and Excipient Compatibility Study by

using a UV-Visible Spectrophotometer.

Preliminary Trials to Determine the Phase

Fourier-transform infrared (FT-IR) spectra were

Solubility of Inclusion Complex

Aqueous solutions were prepared containing

(Shimadzu 8400S, Japan). The samples (CBZ

Complexol-HPTM (025%, w/v) and HPMC-E-3

and Excipients) were previously ground and

(0, 0.1%, 0.15%, w/v). An excess amount of