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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.)
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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
Copyright reserved by Journals Club & Co. 1
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
Carbamazepine (CBZ) is an anticonvulsant drug
with different crystalline forms1. All crystalline
forms have variable dissolution leading to
irregularand delayed absorption2. CBZ has an
experimental log P value of 2.45 and is
practically insoluble in water. CBZ is BCS
class-II drug which shows dissolution dependent
oral bioavailability. Enhancement of solubility
of CBZ by Solid dispersion3, Inclusion
complexation4 and Crystallization5 is an
effective way. Solid dispersion, which was
introduced in 1970s6, is a multicomponent
system, having drug dispersed in hydrophilic
carrier. In has been used for many types of
poorly aqueous soluble drugs. Many hydrophilic
*Address for Correspondence: Patel MV A-11, Shakuntal Bungalows, Opp. Kunjmall, Nikol Naroda road, Ahmedabad, India E-Mail Id: [email protected]
Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques
Copyright reserved by Journals Club & Co. 2
carriers have been investigated for improvement
of dissolution characteristics. Cyclodextrins are
used to increase the solubility and
bioavailability of many water soluble drugs.
Cyclodextrin incorporation can influence the
mechanisms by which drug is released.
So, they can enhance drug release by increasing
the concentration of diffusible species within the
matrix and they also enhance drug release by
acting as wicking agents.7 Polymorphism is
defined as the ability of a compound toassume
more than one crystalline form.8
MATERIALS & METHODS Materials
Carbamazepine was obtained from Surya
organics and chemicals, Ankleshwar, Gujarat.
Complexol- HPTM was obtained from Gangwal
Chemicals Private Limited, Mumbai. Mannitol,
PVP- K 30 were obtained from West Coast
Pharmaceuticals Works Limited and PEG 4000
was obtained from RFCL Limited. All the
chemicals used in the study were of analytical
grade.
Drug and Excipient Compatibility Study by
FT-IR
Fourier-transform infrared (FT-IR) spectra were
obtained using an FT-IR spectrometer
(Shimadzu 8400S, Japan). The samples (CBZ
and Excipients) were previously ground and
mixed thoroughly with potassium bromide, an
infrared transparent matrix, at 1:5 (Sample:
KBr) ratio, respectively. The KBr discs were
prepared by compressing the powders at a
pressure of 5 tons for 5 min in a hydraulic press.
Forty scans were obtained at a resolution of 4
cm-1, from 4000 to 600 cm-1.
Preliminary Trials to Determine Phase
Solubility of Solid Dispersion9
Phase Solubility measurements were performed
according to the method of Higuchi and
Connors. Various aqueous solutions of Mannitol
(0%, 1%, 2%, 3% 4%, 5%, 6% w/v), PVP-K-30
(0%, 0.4%, 0.6%, 0.8%, 1%, 1.2% and 1.5%
w/v) and PEG 4000 (0%, 0.4%, 0.6%, 0.8%,
1%, 1.2% and 1.4% w/v) were prepared and 10
ml of each solution was taken into separate
conical flask. An excess amount of drug was
added to these flasks. The flasks containing
drugcarrier mixtures were shaken at 37 0.1
C for 24 hour in orbital bath shaker. After 24
hour, samples were filtered through 0.45-m
filter paper. The filtrate was suitably diluted
with corresponding polymer carrier solution and
analyzed spectrophotometrically at their
respective max (284.6 nm for Mannitol, 284.9
nm for PVP-K-30, 285.4 nm for PEG 4000)
using a UV-Visible Spectrophotometer.
Preliminary Trials to Determine the Phase
Solubility of Inclusion Complex
Aqueous solutions were prepared containing
Complexol-HPTM (025%, w/v) and HPMC-E-3
(0, 0.1%, 0.15%, w/v). An excess amount of
drug was added. The suspensions were
equilibrated at constant temperature in Orbital
laboratory bath shaker. After equilibrium, the
suspensions were filtered and the solutions were
Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques
Copyright reserved by Journals Club & Co. 3
assayed spectrometrically at (288.3 nm for
Complexol-HPTM, 284.3 nm for HPMC-E-3 and
Complexol-HPTM mixture).The equilibrium
constants of the inclusion complex were
determined from the phase-solubility diagrams
according to Higuchi and Connors10. The slope
of the diagrams was evaluated from the phase
solubility diagram. The apparent stability
constants (Ks) were then determined from
following equation. Stability constant K = SlopeD (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.
Table: 1 Formulation Batches of Solid Dispersion
The resultant mass was passed through sieve no.
60 and stored in dessicator at room temperature
for further study
Preparation of Inclusion Complex
The inclusion complexes were prepared by
solvent evaporation method. Accurately
weighed drug and Complexol-HPTM were
dissolved separately in Ethanol, adding 0.1 %
HPMC-E-3 and then mixed. The solvent was
evaporated at 60 C and the resultant mass was
passed through sieve no. 60 and stored in
dessicator at room temperature for further study.
Table: 2 Formulation Batches of Inclusion Complexes
Crystallization Based Approach
Dichloromethane was used as solvents to obtain
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.
The prepared crystals were passed from sieve
no. 60 and stored in dessicator at room
temperature for further study.
Evaluation Parameters for Solid Dispersions,
Inclusion Complexes and Crystals11,12
FT-IR Spectroscopic Analysis
Solid Dispersion
Batches
Drug (mg)
PVP K 30(mg)
Drug:Carrier ratio
CBK-1 100 2.5 1:0.025
CBK-2 100 5 1:0.05
CBK-3 100 10 1:0.1
CBK-4 100 20 1:0.2
Inclusion complex batches
Drug (mg)
Complexol-HPTM (mg)
HPMC-E-3 (%w/w)
Drug: Carrier
ratio
CBI-1 100 116.4 0.1 1:0.20
CBI-2 100 145.5 0.1 1:0.25
CBI-3 100 291.1 0.1 1:0.5
CBI-4 100 582.1 0.1 1:1
Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques
Copyright reserved by Journals Club & Co. 4
CBZ, Carrier, Solid dispersions/ Inclusion
complex/ Crystals were subjected for FTIR
CBZ, Carrier, Solid dispersions/ Inclusion
complex/ Crystals were subjected for FTIR
studies. Samples were prepared using KBrdisc
method and spectra were recorded over the
range 400 cm-1 to 4000 cm-1. Spectra were
analyzed for Drug-Carrier interactions and
functional groups involved in the process.
Differential Scanning Calorimetry (DSC)
Analysis
DSC scans of the powdered samples were
recorded using DSC-instrument. The samples
were hermetically sealed in aluminum pans and
heated over the temperature range 40 to 350C
at heating rate of 10C under inert nitrogen
dynamic atmosphere (100 ml/min).
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
= tan
Where,
= Angle of Repose
h = Height of the pile of powder
r = Radius of the pile of powder
Bulk Density
Bulk density was determined by measuring the
volume of known mass of powder sample that
has been passing through a screen in to a
graduate cylinder. 5 gm of powder was poured
into a measuring cylinder and note down the
value without tapping the cylinder.
Angle of Repose
The maximum angle which is formed between
the surface of a pile of
Table: 3 FormulationBatches of Crystals
Bulk Density = MV 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
tapped 100 times on flat surface. The volume of
powder was noted down. Tapped density = MV Where, M0 = Initial mass of powder
Vt= Tapped volume of powder
Carrs Index
It is also known as compressibility ratio of
powder and calculated by following formula
Inclusion complex batches
Drug (mg)
HPMC-E-3 (mg)
Drug:Carrier ratio
CBD-1 100 - -
CBD-2 100 10 1:0.1
CBD-3 100 20 1:0.2
CBD-4 100 30 1:0.3
Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques
Copyright reserved by Journals Club & Co. 5
% Carr s index = 100 V VV Hausners Ratio
The Hausners ratio is a number that is
correlated to the flowability of a powder or
granular material. It is expressed by following
formula Hausner s Ratio = --
Where tapped = Tapped density
bulk= Bulk density
Saturated Solubility Study of Prepared Solid
Dispersions, Inclusion complexes and Crystals
Solubility studies were performed according to
the method reported by Higuchi and Connors.10
CBZ solid dispersions/ Inclusion complexes/
Crystals in amounts that exceeded its solubility,
were transferred to conical flasks containing 10
ml distilled water (1% SLS). The contents were
stirred in laboratory orbital shaker at 370.1C
for 24 hrs. After 24 hours, the samples were
filtered through a 0.45-m Whatman filter
paper, suitably diluted with distilled water (1%
SLS) and analyzed for drug content at the 287
nm using a UV-Visible spectrophotometer.
In-vitroDissolution Study as per USP13
In-vitro drug release was determined using USP
(United States Pharmacopeia) dissolution
apparatus II of paddle type at 75 rpm
maintained at 370.5 C in 900 ml of 1% SLS
as dissolution media. Amount of prepared
complexes equivalent to 100 mg of drug was
taken. Percent drug released should be
determined by taking an aliquot of 5 ml at
different time intervals. An equal volume of
fresh dissolution medium was replaced to
maintain the original volume. The samples were
diluted for estimating percent released by UV-
Visible Spectrophotometer.
Dissolution Parameter
Medium: 1% SLS Volume: 900ml Apparatus: USP type II RPM: 75 rpm Time point: 5, 10, 15, 22, 25, 30, 35, 40, 45,
50, 60 minutes
Temperature: 37C 0.5C max: 287 nm
RESULT AND DISCUSSION Drug Excipient Compatibility Study by FT- IR
The FT-IR spectra of carbamazepine with
carriers and is shown in figure 1. There was no
disappearance of any characteristic peak in any
of the mixture. So, there was no drug and
excipient compatibility between drug and
excipient.
Preliminary trials for Phase solubility study of
solid dispersion
To investigate effect of different carriers on the
solubility of CBZ, the saturated solubilities of
CBZ were determined in different solutions. As
seen, with the increase in carrier (Mannitol,
PVP K 30, PEG 4000)
Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques
Copyright reserved by Journals Club & Co. 6
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
Fig3: Comparative phase solubility study of CBZ, Complexol-HPTM and HPMC E 3
0
0.1
0.2
0.3
0.4
0.5
0.6
0 5 10 15 20 25
CBZ
Conc
entr
atio
n (m
mol
/L)
% w/v of Complexol-HPTM
0% HPMC
0.1 % HPMC
0.15 % HPMC
0.04
0.042
0.044
0.046
0.048
0.05
0.052
0.054
CBZ
Con
cent
ratio
n (m
mol
/L)
% w/v of Carrier
CBZ and Mannitol CBZ and PEG 4000 CBZ and PVP K 30
Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques
Copyright reserved by Journals Club & Co. 7
concentration in the solution, the saturated
solubility of CBZ increased, indicating that
making solid dispersion with carriers is the
effective way to increase the solubility of
CBZ14. The comparative phase solubility
diagrams were presented in Fig 2. With the
increase in the concentration of carrier, CBZ
concentration increased with a linear
relationship upto some concentration. The
stability constant was calculated, which was
134.82 mol-1 for Mannitol, 197.73 mol-1 for
PVP-K-30 and 37.30 mol-1 for PEG4000. So,
PVP-K 30 was selected as a carrier to be used
for the preparation of solid dispersion.
Preliminary Trials for Phase Solubility of
Inclusion Complex
To investigate effect of Complexol-HPTM on
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
complexation is the effective way to increase
the solubility of CBZ. The comparative phase
solubility diagrams were presented in Fig.
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
solubility of CBZ was increased as increase in
the concentration of Complexol-HPTM with the
slope 1, indicating that 1:1 stoichiometry
complex formation16. The solubility constant
was calculated, which was 395.97mol-1 for
Complexol-HPTM in absence of HPMC-E-3,
438.03 mol-1 for Complexol-HPTM 0.1% HPMC
E 3 and 405.85 mol-1for Complexol-HPTM in
presence of 0.15% HPMC E-3. So, Complexol-
HPTM with 0.1% HPMC-E-3 was selected for
further study.
Evaluation of Solid Dispersion
Characterization of Solid Dispersion by FT-IR
FT-IR spectra of pure Carbamazepine, carrier
PVP-K-30, solid dispersion and physical
mixture are shown in figure indicating no
significant evidence of chemical interaction
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
increased to 3474.3 cm-1, N-H stretching of
aliphatic amine decreased to 3163.8 cm-1, C=O
stretching of CONH2
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
Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques
Copyright reserved by Journals Club & Co. 8
cm-1 and C-N stretching of aliphatic amine
increased to 1112.1 cm-1.
Characterization of Solid Dispersion by DSC
Fig. 5 shows the DSC spectra of CBZ, PVP K
30 and solid dispersion prepared by solvent
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 C-
Solid dispersion of CBZ and PVP-K 30
Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques
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DSC spectra of pure CBZ show a
polymorphictransition with two endotherms at
around 177.17 and 194.16 C. CBZ
exhibitsenantiotropic polymorphism, i.e. there
exista transition temperature below the melting
point of either of polymorphs at which both
these forms have the same free energy18.Above
the transition temperature, the higher melting,
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
room temperature, Form III is more stable.
In Fig. 5A, the endotherm at 177.17
Corresponds to the melting of Form III,
followed by immediate recrystallization to Form
I and subsequent melting of Form I at 191 C. In
DSC spectra of PVP K30, a broad endotherm
ranging from 90 to 140 C was observed
indicating the loss of water due to extremely
hygroscopic nature of PVP polymers
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
Table 4: Micromeritic properties of prepared solid dispersion
(*All values are expressed as mean SD, n=3)
Thisindicates that CBZ might be in amorphous
state. PVP inhibitscrystallization of drugs in
solid dispersions resultingin amorphous form of
the drug in the solid dispersions.Crystallization
inhibition is attributed to two
effects:interactions, such as hydrogen bonding
between thedrug and the polymer17.
MicromeriticProperties of Prepared Solid
Dispersion
All the solid dispersions were evaluated for
different Micromeritic properties. Bulk density
ranged from 0.5030.006 to 0.5530.032 tapped
density ranged from 0.5930.015 to
0.6370.021, Carrs index ranged from
12.8830.332 to 19.4720.788, Hausners ratio
Batch B.D. (gm/ml) T.D. (gm/ml)
% Carrs index Hausners ratio Angle of repose
CBK-1 0.5030.006 0.5930.015 15.1190.984 1.1790.041 260.044 CBK-2 0.5200.017 0.6370.021 18.3080.116 1.2250.031 240.394 CBK-3 0.5100.010 0.6330.012 19.4720.788 1.2420.012 280.235
CBK-4 0.5530.032 0.6350.025 12.8830.332 1.1550.105 270.287
Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques
Copyright reserved by Journals Club & Co. 10
ranged from 1.1550.105 to 1.2420.012, Angle
of repose ranged from 240.394 to 280.235.
Fig 6 : Saturated Solubility Study of CBZ and Solid Dispersion
Saturated Solubility Study of Prepared Solid
Dispersions
Results of the saturated solubility study are
shown in Fig. 6. Solubility of CBZ was found to
be 4.59 mg/100ml while improvement in
solubility was observed with all the solid
dispersions. This difference in solubility can be
explained by the different physicochemical
properties of the solid dispersions.
Saturated solubility study data suggest that the
solid dispersion of Batch CBK-3 has highest
solubility than other solid dispersions.
In Vitro Dissolution Study of Prepared Solid Dispersions
The dissolution rate of pure carbamazepine was
very poor and during 60 min maximum 30% of
the drug was released. The reason for the poor
dissolution of pure drug could be poor
wettability. It was found that drug release was
increased by the preparation of solid dispersion
with PVP-K30. From Fig. 7 it can be seen that
dissolution of carbamazepine in solid
dispersions increase with increase in PVP-K-30
upto 1:0.1 ratio of CBZ:PVP-K-30. This
increase in the dissolution rate may be due to
increase in drug wettability by carrier2
After this particular ratio with further increase
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
be concluded that the dissolution rate of
carbamazepine increased by preparing solid
dispersion with PVP-K
Characterization of Inclusion complex
FTIR analysis of prepared Inclusion complex
4.59
12.94 13.55
17.32
12.53
-2
3
8
13
18
CBZ CBK-1 CBK-2 CBK-3 CBK-4
Solu
bilit
y (m
g/10
0 m
l)
Saturated solubilty study of solid dispersions
Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques
Copyright reserved by Journals Club & Co. 11
FT-IR spectra of pure Carbamazepine, carrier Complexol HPTM, HPMC E 3, Inclusion
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 M- Inclusion 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 F-
Complexol-HPTM, Sample G- Inclusion complex of CBZ, HPMC E 3 and Complexol-HPTM
0102030405060708090
100
0 5 10 15 20 25 30 35 40 45 50 60
% C
DR
Time (min)
Comparative study of CBZ and PVP K 30 solid dispersion
CBK-1
CBK-2
CBK-3
CBK-4
CBZ
Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques
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mixture are shown in figure indicating no
significant evidence of chemical interaction
between drug and carrier in case of Inclusion
complex which confirms the stability of drug
with its Inclusion complex. In physical mixture
there is just the overlapping of both spectra. N-
H stretching of aromatic amine decreasedto
2935.8 cm-1, N-H stretching of aliphatic amine
disappeared due to complexation with OH
group of Complexol HPTM 21, C=O stretching of
CONH2 increased to 1683.5 cm-1, C=C
stretching of benzene ring decreased to 1593.8
cm-1, C-N stretching of aromatic ring increased
to 1394.6 cm-1 and C-N stretching of aliphatic
amine disappeared due to complexation with
Complexol HPT 3
Differential Scanning Calorimetry (DSC) of Prepared Inclusion Complexe Fig. 9 illustrates the DSC profile of pure CBZ,
Complexol-HPTM, HPMC-E-3 and complex.
The DSC thermo gram of CBZ characterized by
a sharp melting peak at 194.16Cwas of typical
pure, anhydrous substance, while the
thermogram of Complexol -HPTM showed a
large endothermic band ranging between 48 C
and 100 C and at 250 C which could
correspond to the loss of water molecules from
thecyclodextrin cavity, and the thermogram
ofHPMC-E-3 also showed a largeend othermic
band ranging between 65 C and 120C. The
thermogram of CBZ, Complexol-HPTM and
HPMC-E-3 showed disappearance of peaks of
CBZ. These thermal behavior changes indicate
the formation of theinclusion complex through
molecular interactions between the CBZ and
Complexol-HPTM, resulting in the amorphous
dispersed form of CBZ22.
Micromeritic Properties of Prepared Inclusion Complexes Bulk density ranged from 0.5270.015 to
0.5410.030, tapped density ranged from
0.6200.010 to 0.6530.040, Carrs index
ranged from 12.9140.294 to 19.2770.698,
Hausners ratio ranged from 1.1500.040 to
1.1740.041, Angle of repose ranged from
210.264 to 250.237.
Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques
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Table 5: Micromeritic Properties of Prepared Inclusion Complex
(*All values are expressed as mean SD,n=3) Table 6: Micromeritic Properties of Prepared Crystals
Batch B.D.
(gm/ml)
T.D.
(gm/ml)
% Carrs
index
Hausners
ratio
Angle of
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
Inclusion Complexes
Results of the saturated solubility study are
shown in Fig. 10. Solubility of CBZ was found
to be 4.59 mg/100ml while improvement in
solubility was observed with all the inclusion
complexes.This difference in solubility can be
explained by the different physicochemical
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.
In vitro Drug Release of Complexes
The dissolution rate of pure carbamazepine was
very poor and during 60 min maximum 30% of
the drug was released. The reason for the poor
dissolution of pure drug could be poor
wettability. It was found that drug release was
increased by complexation of drug with
Complexol-HPTM.
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
Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques
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Fig. 10: Saturated solubility study of inclusion complex
Fig 11: Comparative % CDR of CBZ and Inclusion Complex Batches Evaluation
From the release profiles, it can be seen that
dissolution of carbamazepine in inclusion
complexes increase with increase in Complexol-
HPTMupto 1:0.25 ratio of CBZ:Complexol-
HPTM. This increase in the dissolution rate may
be due to increase in drug wettability by
carrier.After this particular ratio with further
increase in the amount of Complexol-HPTM, the
dissolution was decreased. So, it can be
concluded that the dissolution rate of
carbamazepine increased by preparing solid
dispersion withComplexol-HPTM.
4.59
15.9418.30 19.26 17.99
02468
101214161820
CBZ CBI-1 CBI-2 CBI-3 CBI-4
(Sol
ubili
ty (m
g/10
0 m
l)
Saturated solubility study of Inclusion complexes
Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques
Copyright reserved by Journals Club & Co. 15
Parameters of Prepared Crystals FTIR Analysis of Prepared Crystals Results of the DSC thermograms are shown in
fig. 13. DSC thermograms of CBZ form I (Pure
Drug) showed no transformation and melts
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 a 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
187C, significantly higher than thetransition
temperatures of forms II or III. This isfollowed
by further crystallization to produce amaterial
that then melts between 190 and 192C.
Differential Scanning Calorimetry (DSC) of prepared crystals Differential scanning calorimetry results showed
thatpure CBZ has a polymorphic transition with
two endotherms at around 176C and 194C. It
is well-known that CBZ exhibits enantiotropic
polymorphism, i.e. there exists a transition
temperature below themelting point of either of
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
lower free energy. The transition temperature of
CBZ enantiotropic forms has been reported to
be around 71 C24. Henceat room temperature,
Form III is the most stable formand is the one
possessed by most commerciallyavailable CBZ.
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 from 0.6270.021 to
0.6930.015, Carrs index ranged 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.
Saturated Solubility Study of Carbamazepine Crystals Results of the saturated solubility study are
shown in Fig. 14. Solubility of CBZ was found
to be 4.59 mg/100ml while improvement in
solubility was observed with all type of crystals
and highest in CBD-1 batch. This difference in
solubility can be explained by the different
physicochemical properties of the crystals.
Saturated solubility study data suggest that the
crystals of CBD-1 batch had a highest solubility
than any other type of crystals
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.
Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques
Copyright reserved by Journals Club & Co. 16
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
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
4.59
19.38
16.65
14.34
11.99
02468
101214161820
CBZ CBD-1 CBD-2 CBD-3 CBD-4
Solu
bilit
y (m
g/10
0 m
l)Saturated solubility study of crystals
Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques
Copyright reserved by Journals Club & Co. 17
Fig 14 : Comparative Saturated Solubility Study of Carbamazepine Crystals
Fig 15 : Comparative study of In vitro drug release of crystals
The highest dissolution rate was observed forthe
crystals recrystallized from Dichloromethane
and HPMC E 3 and that was 90.70% at 60 min.
The solubility of recrystallized CBZ was
increased in presence of hydrophilic additive
like HPMC E 32.
The solubility of all the batches of
Dichloromethane crystalswas found to be higher
almost double whencompared to the pure drug.
Since the bioavailabilityof carbamazepine is
limited only by its dissolutionrate, even a small
0102030405060708090
100
0 5 10 15 20 25 30 35 40 45 50 60
% C
DR
Time (min)
Comparative study of Carbamazepine Crystals
CBD-1
CBD-2
CBD-3
CBD-4
CBZ
Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques
Copyright reserved by Journals Club & Co. 18
increase in dissolution will resultin a large
increase in its bioavailability.
SUMMARY AND CONCLUSION The present study was undertaken with an aim
to enhance the solubility of CBZ and compare
the techniques. The solid dispersion batch CBK-
3(1:0.1) showed 93.36% drug release at 60 min.
The inclusion complex batch CBI-2(1:0.25)
showed 97.38 at 60 min. The crystal batch
CBD-2 showed 90.70% drug release at 60 min.
Inclusion complex batch showed maximum
drug release at 60 min. So, inclusion
complexation was effective way to enhance the
CBZ solubility.
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Solubility Enhancement of Carbamazepine by Using Various Solubility Enhancement Techniques
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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.