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

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]



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



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



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



% 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)



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



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



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



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



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



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



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.



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



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



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.



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



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



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.

REFERENCES 1. Beach, S., Latham, D., Sidgwick, C., Hanna,

M., & York, P. (1999). Control of the

physical form of salmeterol xinafoate.

Organic Process Research & Development,

3(5), 370-376.

2. Behme, R. J., & Brooke, D. (1991). Heat of

fusion measurement of a low melting

polymorph of carbamazepine that undergoes

multiplephase changes during differential

scanning calorimetry analysis. Journal of

pharmaceutical sciences, 80(10), 986-990.

3. Prajapati, S. T., Gohel, M. C., & Patel, L. D.

(2007). Studies to enhance dissolution

properties of carbamazepine. Indian journal

of pharmaceutical sciences, 69(3), 427.

4. Choudhury, S., & Nelson, K. F. (1992).

Improvement of oral bioavailability of

carbamazepine by inclusion in 2-

hydroxypropyl--cyclodextrin. International

journal of pharmaceutics, 85(1), 175-180.

5. Nokhodchi, A., Bolourtchian, N., &

Dinarvand, R. (2005). Dissolution and

mechanical behaviors of recrystallized

carbamazepine from alcohol solution in the

presence of additives. Journal of crystal

growth, 274(3), 573-584.

6. Zerrouk, N., Chemtob, C., Arnaud, P.,

Toscani, S., & Dugue, J. (2001). In vitro and

in vivo evaluation of carbamazepine-PEG

6000 solid dispersions. International journal

of pharmaceutics, 225(1), 49-62.

7. Koester, L. S., Xavier, C. R., Mayorga, P.,

& Bassani, V. L. (2003). Influence of -

cyclodextrin complexation on

carbamazepine release from hydroxypropyl

methylcellulose matrix tablets. European

journal of pharmaceutics and

biopharmaceutics, 55(1), 85-91.

8. Getsoian, A., Lodaya, R. M., & Blackburn,

A. C. (2008). One-solvent polymorph screen

of carbamazepine. International journal of

pharmaceutics, 348(1), 3-9.

9. Sethia, S., & Squillante, E. (2004). Solid

dispersion of carbamazepine in PVP K30 by

conventional solvent evaporation and

supercritical methods. International Journal

of Pharmaceutics, 272(1), 1-10.

10. Rong, L.(2008). Water insoluble drug

formulation,(2nd ed.).CRC Press, pp 138-

139.



11. Cooper, J., Gun, C. (1986). Powder Flow

and Compaction. Inc Carter SJ, Eds.

Tutorial Pharmacy. New Delhi, Hidix CBS

Publishers and Distributors, pp 211-33.

12. Aulton, M. E., & Wells, T. I. (1998).

Pharmaceutics: The Science of Dosage

Form Design. London, England, Churchill

Livingston, 247.

13. Higuchi, T., & Connors, K. A. (1965).

Phase-solubility techniques. Adv. Anal.

Chem. Instrum, 4(2), 117-212.

14. USP NF. (2004). Asian edition, United

States, pharmacopoeial convention, 322-

325.

15. Sethia, S., & Squillante, E. (2002).

Physicochemical characterization of solid

dispersions of carbamazepine formulated by

supercritical carbon dioxide and

conventional solvent evaporation method.

Journal of pharmaceutical sciences, 91(9),

1948-1957.

16. Katzhendler, I., Azoury, R., & Friedman, M.

(1998). Crystalline properties of

carbamazepine in sustained release

hydrophilic matrix tablets based on

hydroxypropyl methylcellulose. Journal of

controlled release, 54(1), 69-85.

17. Hoshino, T., Uekama, K., & Pitha, J. (1993).

Increase in temperature enhances solubility

of drugs in aqueous solutions of

hydroxypropylcyclodextrins. International

journal of pharmaceutics, 98(1), 239-242.

18. Rustichelli, C., Gamberini, G., Ferioli, V.,

Gamberini, M. C., Ficarra, R., &

Tommasini, S. (2000). Solid-state study of

polymorphic drugs: carbamazepine. Journal

of pharmaceutical and biomedical analysis,

23(1), 41-54.







20. Van den Mooter, G., Wuyts, M., Blaton, N.,

Busson, R., Grobet, P., Augustijns, P., &

Kinget, R. (2001). Physical stabilisation of

amorphous ketoconazole in solid dispersions

with polyvinylpyrrolidone K25. European

journal of pharmaceutical sciences, 12(3),

261-269.

21. Leuner, C., & Dressman, J. (2000).

Improving drug solubility for oral delivery

using solid dispersions. European journal of

pharmaceutics and biopharmaceutics, 50(1),

47-60.

22. Choudhary, S., & Nelson, K. F.(1992).

Improvement of oral bioavailability of

carbamazepine by inclusion in 2-

hydroxypropyl--cyclodextrin.Int. J.

Pharm,85, 175-180.

23. Kou, W., Cai, C., Xu, S., Wang, H., Liu, J.,

Yang, D., & Zhang, T. (2011). In vitro and

in vivo evaluation of novel immediate



release carbamazepine tablets:

Complexation with hydroxypropyl--

cyclodextrin in the presence of HPMC.

International journal of pharmaceutics,

409(1), 75-80.

24. Kobayashi, Y., Ito, S., Itai, S., &

Yamamoto, K. (2000). Physicochemical

properties and bioavailability of

carbamazepine polymorphs and dihydrate.

International journal of pharmaceutics,

193(2), 137-146.







26. Nokhodchi, A., Bolourtchian, N., &

Dinarvand, R. (2005). Dissolution and

mechanical behaviors of recrystallized

carbamazepine from alcohol solution in the

presence of additives. Journal of crystal

growth, 274(3), 573-584.

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.

solubility enhancement of carbamazepine by using various solubility enhancement techniques

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