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Chapter-7 Carbamazepine

Department of Chemistry Dr. Hari Singh Gour Central University, Sagar (M.P.) 195

INTRODUCTION

Carbamazepine (CBZ) has been extensively used in the

treatment of epilepsy, as well as in the treatment of neuropathic pain

and affective disorders. The popularity of this drug is related to several

beneficial properties including proven efficacy in controlling different

types of seizures [1-2].

Structure

IUPAC name - 5H-Dibenz [b, f] azepine-5-carboxamide.

Formula - C15H12N2O

Solubility - Practically insoluble in water, soluble in

alcohol, acetone and propylene glycol [3].

Mol. Wt. - 236.26 g/mol

Brand name - Tegretol (C1), Carbatrol (C2), Carbadac (C3)

Identification - Identification of pure drug is performed by

FT-IR (Shimadzu 8400s) and compared with

standard one [4].

N

NH2O



Fig. 7.1: Reference IR Spectrum of CBZ

Table 7.1: Characteristics absorption frequencies for identification of

pure CBZ

S. No. Types of Vibrations Frequency (cm-1)

1. Ar. C – H Stretching 3020.63

2. C – H Bending 869.92

3. C – N Stretching 1307.78

4. C = O Stretching 1678.13

5. NH2 Stretching 3466.2

6. Ar. C = C Stretching 1604.83

Wave number (cm-1)

Tra

nsm

itta

nce



Fig

. 7.2

: IR

Spectr

um

of

pure

CB

Z



Bioavailability - 80%

Protein binding - 76%

Metabolism - Meinardi had published a review on CBZ in 1972 which

he discussed the determination, metabolism and pharmacology of the

drug. CBZ is readily absorbed from the gastrointestinal tract [5]. It is

believed to have a half life between 14-29 h [6]. Frigerio had isolated

carbamazepine-10-11-epoxide as a urinary metabolite from humans

following oral administration. The epoxide formation was confirmed by

the in vitro studies of the activity of the liver microsomal

monooxygenases [7].

Half life - 14-29 hrs.

Excretion - 2-3% excreted unchanged in urine.

History - CBZ was discovered by chemist Walter Schindler in 1953

[8]. Scgindler then synthesized the drug in 1960, before its anti-

epileptic properties had been discovered. CBZ was first marketed as a

drug to treat trigeminal neuralgia in 1962. It has been used as an

anticonvulsant in the UK since 1965, and has been approved in the

U.S. since 1974.

Adverse effects - Common adverse effects include drowsiness,

headaches and migraines, motor coordination impairment, and/or upset

stomach. CBZ preparations typically greatly decrease a person's alcohol

tolerance.

Bio–Analytical methods -

CBZ is widely prescribed as an anticonvulsant, antiepileptic

and antimanic drug [9-10]. In the body, CBZ is metabolized to an

active metabolite, CBZ-10, 11 Epoxide, which also displays

anticonvulsant properties similar to those of the parent compound

[11]. CBZ is poorly soluble in aqueous media and has a high oral

bioavailability in human [12].

http://en.wikipedia.org/wiki/Adverse_drug_reaction

http://en.wikipedia.org/wiki/Motor_coordination



Several methods have been reported for the determination of

CBZ standards and in pharmaceutical preparations.

Camara et al., have determined CBZ in human serum by UV-

spectroscopy and compared with reference methods [13].

Rezaei et al., have described a simultaneous spectrophotometric

method for the determination of CBZ and phenytoin in serum by PLS

regression and compared with HPLC [14].

Huang and co-workers have reported a flow injection photochemical

spectrofluorimetry for the determination of CBZ in pharmaceutical

preparations [15].

Fellenberg and co-workers have reported a rapid spectro-

photometric procedure for the simultaneous micro determination of

CBZ and 5, 5-diphenyl-hydantoin in blood [16].

Chen et al., have studied comparative analysis of antiepileptic

drugs by gas chromatography using capillary or packed columns and

by fluorescence polarization immunoassay [17].

Auer et al., have studied polymorphic forms in drug

formulations by near Infrared FT-Raman spectroscopy [18].

Cry et al., described liquid chromatographic methods for assay

of CBZ, 10, 11-dihydrocarbamazepine and related compounds in CBZ

drug substance and tablets [19].

Mohammed et al., have described comparative LC-MS and HPLC

analysis of selected anti-epileptics and beta-blocking drugs [20].

Manoj has described separation and quantization of four

antiepileptic drugs [21].

Walker has described liquid chromatographic determination of

CBZ in tablets [22].



The rate of oral absorption of poorly soluble drugs is often

controlled by their dissolution rate in the gastrointestinal tract [23].

Thus solubility and dissolution rate are the key determinants of oral

bioavailability, which is the conducting point drawn for fate of oral

bioavailability [24-25]. CBZ belongs to the class II BCS, the

characteristics of which are low aqueous solubility, slow dissolution

and high membrane permeability [26]. Thus the main problem

associated with class II drugs is generally their bioavailability, due to

a slow dissolution rate. For improvement of solubility and dissolution

rate of poorly soluble drugs, numerous commercially available techniques

such as liquisolid, in which drug in solution state or dissolved drug is

adsorbed over insoluble carriers [27-29], in situ micronization [30-32],

solid dispersion [33-39] co-precipitation using anti-solvent [40] are

available. Surfactant can also use in formulations to improve

wettability and solubility of many lipophilic substances [41].

Determination of λmax of pure CBZ:

The pure form of CBZ was accurately weighed 10 mg and

dissolved in appropriate amount of methanol. The solution was

diluted with distilled water up to the mark in 100 mL standard flask

(100 g/mL). The stock solution was further diluted 1.0 mL in 10 mL

water to give a concentration of 10 g/mL the absorption spectra was

obtained with Elico 164 UV-visible Spectrophotometer a scan range of

200-400 nm and determine the maximum absorbance of drug

(Fig.7.3).



Fig. 7.3: Determination of λmax CBZ

Verification of Beer’s Lambert law:

The stock solution (100 g/mL) of CBZ was prepared by

dissolving 10 mg of CBZ in 10 mL of methanol in 100 ml volumetric

flask and made up to the mark with double distilled water.

Aliquots of 0.1 – 5.0 mL of the stock solution were pipetted out

into 10 mL volumetric flask .The volume was made up to the mark

with water. Beer’s law obeyed in the concentration range of 1.56 – 50

g/mL (Fig. 7.4).



Fig. 7.4: Verification of Beer’s Lambert law

Solubility measurements:

The solubility of CBZ was measured in different media such as

distilled water, PEG 400, PVP 44000, CTAB, SLS, PEG 4000 and PEG-

400/CTAB. An excess amount of drug (25 mg) was then added to 50

mL of each fluid in conical flask. The mixture was stirred on a

magnetic stirrer for half an h. 5.0 mL aliquot was withdrawn at 10

min. interval and filter immediately using a 0.45 μm syringe filter,

diluted with water and then assayed spectrophotometrically at 285

nm. Shaking continued until two consecutive estimations are the

same.



Table 7.2: Solubility of CBZ in different media

S. No.

Sample (each fluid at their

CMC values)

Wt. of drug (mg)

Overall volume

(mL)

Abs.

Solubility increase in fold

1. CBZ + Distilled water 25 50 0.096 1.00

2. CBZ + CTAB 25 50 0.523 5.44

3. CBZ + PEG 400 25 50 0.572 5.95

4. CBZ + PEG 4000 25 50 0.394 4.10

5. CBZ + PEG 400/CTAB 25 50 0.992 10.33

6. CBZ + PVP 44000 25 50 0.562 5.85

0

0.2

0.4

0.6

0.8

1

1.2

Distilled

water

CTAB PEG 400 PEG 4000 PEG

400/CTAB

PVP 44000

Different fluids

Fold

en

han

cem

en

t

Fig. 7.5: Solubility determination of CBZ in different fluids

In vitro Dissolution Study:

1. Apparatus: Electrolab TDT - 08L USP

2. Dissolution medium: PEG 400/CTAB (1 × 10-7 M)

3. Rotation speed: 75 rpm



4. Preparation of CBZ standard solution: 23mg CBZ was weighed

precisely and transferred in 100 mL volumetric flask and diluted

up to the mark with dissolution media. 1 mL of the above solution

is further diluted up to 10 mL with dissolution media.

5. Test preparation: The dissolution of CBZ from commercial

formulations was studied in 900 mL of dissolution medium using a

1 (Basket method) USP-29 at Electro lab TDT – 08L dissolution rate

test apparatus. Dissolution medium (900 mL) was maintain at

37°C ± 0.5°C and agitated at a speed of 75 rpm under sink

condition. 1 mL aliquot was withdrawn at predetermined time

intervals of 5, 10, 20, 30, 40, 50 min. and the same volume of

dissolution medium was added to the medium to compensate for

each sample taken. Samples were filtered through a filter paper

and the dissolved drug was assayed by a spectrophotometer at 285

nm.

6. Time point: Dissolution amount was measured separately at 5,

10, 20, 30, 40 and 50 minutes.

claim Lable

100

100

potency

dilution Test

dilution Std.

Std. of Absorbance

Sample of Absorbance

Table 7.3: Sample absorbance at different time intervals

S. No. Time

(min)

Absorbance

C1 C2 C3

1. 5 0.034 0.026 0.065

2. 10 0.197 0.19 0.197

3. 20 0.301 0.27 0.311

4. 30 0.404 0.38 0.398

5. 40 0.607 0.545 0.526

6. 50 0.674 0.632 0.608

Standard Abs. 0.693



Table 7.4: % drug release of various formulations in PEG 400/ CTAB (at their CMCs values) at different time

S. No. Time

(min)

% Drug release

C1 C2 C3

1. 5 5.07 3.88 6.57

2. 10 29.42 28.37 29.42

3. 20 44.95 40.32 46.44

4. 30 60.33 56.75 59.44

5. 40 90.65 81.39 80.00

6. 50 97.67 94.38 90.80

Table 7.5: log time, square root of time and log % of drug release

S. No.

Time

(min) log time

Square root

of time

log % drug release

C1 C2 C3

1. 5 0.69 2.23 0.70 0.58 0.81

2. 10 1.00 3.16 1.46 1.45 1.46

3. 20 1.30 4.47 1.65 1.60 1.66

4. 30 1.47 5.47 1.78 1.75 1.77

5. 40 1.60 6.32 1.95 1.91 1.90

6. 50 1.69 7.07 1.98 1.97 1.95



Fig. 7.6: Dissolution profile (n=3) of three commercial products of

CBZ in polymeric micellar media (Zero order plot)

Fig. 7.7: Regression plot for zero order



Fig.7.8: First order plot

Fig.7.9: Regression plot for first order



Fig.7.10: Korsmeyer Plot

Fig. 7.11: Regression plot for Korsmeyer model



Fig. 7.12: Higuchi plot

Fig. 7.13: Regression plot for Higuchi model



Table 7.6: Kinetic parameters for C1

S. No. Time

(min)

Rate Constant (k)

First order Korsmeyer Higuchi Zero order

1. 5 0.46 7.64 ×10-3 0 0

2. 10 0.24 1.94 × 10-2 7.70 2.43

3. 20 0.13 1.30 ×10-2 8.92 1.99

4. 30 0.09 1.07 ×10-2 10.10 1.84

5. 40 0.13 1.15 ×10-2 13.54 2.13

6. 50 0 1.0 ×10-2 13.09 1.85

r2 0.737 0.917 0.976 0.968

Slope (n) 1.19


S. No. Time

(min)

Rate Constant (k)


1. 5 0.46 5.49 ×10-3 0 0

2. 10 0.2 1.69 ×10-2 7.75 2.44

3. 20 0.13 1.01 ×10-2 8.152 1.82

4. 30 0.09 8.56 ×10-3 9.66 1.76

5. 40 0.10 8.57 ×10-3 12.26 1.93

6. 50 0 7.52 ×10-3 12.80 1.81

r2 0.716 0.899 0.977 0.976

Slope (n) 1.25




S. No. Time

(min)

Rate Constant (k)


1. 5 0.46 1.33 ×10-2 - -

2. 10 0.24 2.88 ×10-2 7.23 2.28

3. 20 0.13 2.20 ×10-2 8.91 1.99

4. 30 0.098 1.84 ×10-2 9.66 1.76

5. 40 0.10 1.83 ×10-2 11.61 1.83

6. 50 0 1.64 ×10-2 11.91 1.68

r2 0.745 0.926 0.989 0.969

Slope (n) 1.05

PREPARATION OF NANOPARTICLES

In this method, 0.1% w/v CBZ was dissolved in 100 mL of

media. Hydroxy propyly methyl cellulose added to the above solution

which acts as stabilisers. The mixtures was stirred for 24 hrs,

centrifuges the solution after centrifugation. Nano crystal are found

nanoparticles suspension is then purified to removed various

stabilizers and surfactants employed for polymerization by

ultracentrifugation and to produce small particle size, often a high-

speed ultrasonication was be employed. The primary role of stabilizers

and surfactant is to inhibit excessive crystal growth or particle

aggregation/agglomeration in the solution. This technique has been

reported for making polybutylcyanoacrylate or poly (alkylcyano-

acrylate) nanoparticles. Nanocapsule formation and their particle size

depend on the concentration of the surfactant and stabilizers used.



Fig. 7.14: Size distribution of CBZ



RESULTS AND DISCUSSION

Table 7.2 summarizes the experimentally determined solubility

of CBZ in pure water, SLS, CTAB, PVP 44000, PEG 400, PEG 4000

and PEG 400/CTAB (at their CMC’s values). When PEG 400 and

CTAB were used separately, no significant solubility was increased.

However, when PEG 400/CTAB was used as a mixed surfactant

system, the solubility of CBZ was increased by 10.33 folds. Among

other polymeric micelle, micelles prepared from conjugates of PEG 400

and CTAB, have demonstrated high stability and low toxicity. The very

low CMC value of PEG 400/CTAB surfactant system (1×10-7) indicates

that PEG/CTAB micelles can preserve their integrity even upon the

dilution in the blood pool during the supposed therapeutic

application.

In order to determine, if an increased dissolution rate can

improve the power of a dissolution profiles of drug products,

dissolution tests were conducted using three marketed products. My

results show that the dissolution profiles of poorly soluble drug is

influenced by the class of surfactant added to the dissolution medium.

The mixed surfactant system, PEG 400/CTAB, most efficiently

enhanced the dissolution rate of CBZ.

From the data and graphs obtained, it was concluded that the

formulation brand-A release 97.67 % release of CBZ in 50 min. was

selected as the best formulations among PEG 400/CTAB media

formulations. Each formulation was subjected to model fitting

analysis to know the mechanism of drug release. The data was treated

according to zero order (% cumulative amount of drug release versus

time).

The values of release exponent (n), kinetic constant (k)

calculated from different kinetics models i.e., zero- order, first- order,



Higuchi model and Korsmeyer- Peppas model are presented in tables

7.6, 7.7, 7.8. As observed from the table, correlation coefficient (r2) of

all formulation was high enough to evaluate the drug dissolution

behavior using equations.

In most of the cases it was revealed that the release kinetics

CBZ from the tablet appeared to follow mixed release kinetics of

Higuchi order (r2 > 0.976-0.989) as well as zero order release kinetics

(r2 > 0.968-0.976) but Higuchi order release kinetics predominates.

Particle size, charge determination and morphology of final

dissolute drug were examined by Zeta sizer (Fig. 7.14), SEM and TEM.

The morphological evaluation of nanoparticles was performed by

Scanning Electron Microscopy as shown in Fig. 7.15.

Among the tested compositions, round and smooth “high

quality” nano-particle were found when the model drugs were present.

The size of particles in drug was settled in the drug was found to be

330 nm.

Finally, I would like to point out that unfortunately, some

doubts still remain on the real use of these powerful tools apart from

the academic environment.



Preparation of stock solution of pure CBZ drug:

Stock solution of CBZ was prepared by dissolving 236 mg in 3:1

acetic acid and water (v/v) and made up to the mark in 100 mL

volumetric flask.

Preparation of different solutions for calibration curve in presence of

V(V):

An aliquot of the sample solution containing 0.08 – 8 mL of CBZ

was transferred into a series of 10 mL volumetric flasks. The acid

concentration was adjusted up to 1 M. 0.1 mL of V(V), 0.7 mL of PEG

400/CTAB were added respectively. The contents of each flask were

diluted with distilled water up to the mark and mixed well. The

mixtures were poured for 10 minutes. The absorbance was measured

at 365 nm against the regent blank prepared without drug similarly.

Fig. 7.17: Absorption maxima of V(V) and V(IV)



Fig. 7.18: Calibration curve of pure drug in presence of V(V)

Table 7.9: Reaction mixture

Sample

Concentration (M)

Stock solution (M) Required (M)

[CBZ] 0.001 8 × 10-6 – 8 × 10-4

[V(V)] 0.01 0.0001

[H+] 18 1

[PEG/CTAB 400] 0.00001 1 × 10-7

Overall volume 10 mL



Table 7.10: Absorbance of standard solution of pure drug at

different concentrations in presence of V(V)

S. No. Concentration(M) Absorbance (at 365 nm)

1. 0.000008 0.054

2. 0.00002 0.062

3. 0.00004 0.076

4. 0.00006 0.086

5. 0.00008 0.099

6. 0.0001 0.112

7. 0.0004 0.201

8. 0.0006 0.280

9. 0.0008 0.330

Preparation of sample solution:

Twenty tablets were accurately weighed and finely powdered in

a mortar. An amount of tablet mass equivalent to 23 mg (to obtain

0.001 M) was transferred to a 100 mL volumetric flask and dispersed

in acetic acid and water (3:1). The flask was placed in magnetic stirrer

for 20 min. The resulting suspension was diluted with same solution

and then filtered. 0.8, 1.0, 4.0 mL of solution were pipette in 10 mL of

volumetric flask and prepared these solution applying the procedure

as for pure drug.



Table 7.11: Absorbance of sample solutions of different marketed

brands at three concentrations

S. No. Concentration

[M]

Absorbance (365 nm)

Pure drug C1 C2 C3

1. 0.00008 0.099 0.101 0.098 0.103

2. 0.0001 0.112 0.113 0.111 0.114

3. 0.0004 0.201 0.202 0.203 0.201

Table 7.12: Recovery Study

S. No. Label claim in mg Amount of drug found (%)

C1 C2 C3

1. 200 102.02 98.98 103.03

2. 200 100.89 99.10 100.00

3. 200 100.49 100.99 100.99

Average Recovery (%) 101.13 99.69 101.34

Standard Deviation 0.79 1.12 1.54

RESULTS AND DISCUSSION

Spectral studies:

The oxidation study of CBZ was conducted in presence of V(V)

in presence of polymeric micellar media. Surfactant used to catalyze

the reaction and as a solubilizing agent. 1M sulphuric acid producing

the greenish blue colored complex which indicates the reduction of

V(V) into V(IV). The colored complex showed a new characteristic peak

at 365 nm. All spectral study was done at 365 nm.



Linearity:

The linearity range was observed between 1.89 – 190 μg/mL.

The plot clearly showed a straight line passing through origin.

Application of the method to tablets:

The statistical analysis of data obtained for the calibration curve

in pure solution indicated a high level of precision for the proposed

method. The correlation coefficient was highly significant. In order to

determine the accuracy of the proposed method, the oxidation of CBZ

was carried out in presence of various commonly used excipients at

the lower concentration level.

Table 7.13: Quality Control Parameters

S. No. Parameters CBZ

1. max (nm) 365

2. Beer’s Range ( g/mL) 1.89 – 190

3. Molar Absorbtivity (L mol-1 cm-1) 5.07 × 103

4. Sandell’s Sensitivity (µg cm-2) 0.041

5. Correlation Coefficient 0.9919

6. Intercept 0.063

7. Slope 0.0015

8. Limit of Detection (μg/mL) 2.02 × 102

9. Limit of Quantization (μg/mL) 6.75 × 102

10. Standard Deviation of calibration line 0.101



PROPOSED MECHANISM

As literature reveals that it is extensively metabolized by oxidative

enzymes present in the liver, hence in the present study metabolic

conversion of CBZ is studied with V(V) as an oxidant.

As describes in the literature survey, CBZ is extensively

metabolized through several pathways. In accordance with the

observed experimental data, the mechanism for the oxidation of CBZ

involves an electrophilic attack of protonated V(V) at 10, 11- double

bond of azepine ring. The principle pathway of CBZ metabolism

involves the formation of the chemically stable 10, 11 –epoxide. The O-

glucuronide of 10,11-dihydo-10-hydroxy-CBZ has been found only as

a bio-transformation product, which is confirmed by LC-MS analysis.

Fig. 7.19: LC/MS spectrum of standard CBZ and CBZ+V(V)



VO2+ + H

3O V(OH)3

2+

V(OH)32++ HSO4

[V(OH)3HSO4]+-

[A]

+ [A]

N

O NH2

N

O NH2

O

OH V OHSO3

OH

+

[B]

Intermediate complex

[B] + Dn[B] Dn

fast

epoxidation

N

O NH2

O

N

O NH2

OH OH

Hydrolysis

CBZ 10, 11- epoxide 10, 11- dibydro - 10 - hydroxy CBZ

adduct

At low acidity

CBZ

(m/z 271)

+



CONCLUSION

1. The critical micelles concentration (CMC) for the PEG/CTAB was

also studied and it was found at 1 × 10-7 M concentration of

surfactant. When all the reactions are studied at the CMC of

surfactant it shows acceleration of the reaction rate. The reaction

shows that mixed surfactants and H+ both favored the metabolic

conversion of CBZ.

2. The drug CBZ shows the good interaction with metal ion i.e. V(V)

as it was taken as a oxidant in the present study. The drug follows

the Beer’s law 1.89 – 190 g/mL and from the liner equation

Molar absorptivity, Sandell’s sensitivity also calculated (Table

7.13).

3. The proposed method advantageous over other reported UV-visible

spectrophotometric method with respect to their higher sensitivity

with permits of the determination of up to microgram level.

4. Simplicity, reproducibility, precision, accuracy and stability of

colored species for a week noted advantages.

5. No interference from associated excipients, additives and degraded

products were observed.



REFERENCES

1. F. G. Campbell, J. G. Graham, K. J. Zilkha, J. Neuro Neurosurg.

Psychiat, 1966, 29, 265-267.

2. J. M. Killian, G. H. Fromm, Arch. Neurol. 1968, 19, 129-136.

3. Merck Index, Merck and Co., Inc., N. J. Rahaway, U.S.A., 9th ed.

1976, 226.

4. K. Florey, “Analytical Profiles of Drug Substances” Elsevier,

Academic Press, New York, 1980, 9, 87-106.

5. H. Meinardi, “Antiepileptic Drugs” edited by D. M. Woodbury, M.

Dixon, Raven press New York, 1972, 487.

6. Martindale, “The Extra Pharmacopeia” edited by A. Wade, The

pharmaceutical press, London, 27th ed., 1977, 1236.

7. A. Frigerio, R. Fanelli, P. Biandrate, G. Passerint, P. L. Morselli,

S. Garattini, J. Pharm. Sci., 1972, 61, 1144.

8. W. Schindler, F. Hafliger, Helvetica Chimica Acta, 1954, 37, 472-

483.

9. M. K. Bradley, H. Rane, R. R. Levy, R. Matson, B. Meldrum, J. K.

Penry, F. E. Dreifuss (Eds.), “Carbamazepine and Carbamazepine

Epoxide, Antiepileptic Drugs” Raven press, New York, 3rd Ed.,

1989, 505-517.

10. M. Olling, T. T. Mensinga, D. M. Barends, C. Groen, O. A. Lake,

J. Meulenbent, Biopharm. Drug Dispos., 1999, 20, 19-28.

11. H. Jung, R. C. Milan, M. E. Girard, F. Leon, M. A. Montoya, Int.

J. Pharm., 1997, 152, 37-44.

12. F. Demirkaya, Y. Kadioglu, FABAD J. Pharm. Sci., 2005, 30, 78-82.

13. M. S. Camara, C. Mastandrea, H. C. Goicoechea, J. Biochem.

Biophys. Methods, 2005, 64, 153-166.



14. Z. Rezaei, B. Hemmateenejad, S. Khabnadideh, M. Gorgin,

Talanta, 2005, 65, 21-28.

15. C. Huang, Q. He, H. Chen, J. Pharm. Biomed. Anal., 2002, 22,

59-65.

16. A. J. Fellenberg, A. C. Pollard, Clin. Chim Acta, 1976, 69, 429-

431.

17. K. Chen, H. K. Bashi, Anal. Toxicol., 1991, 15, 82-85.

18. M. E. Auer, U. S. Griesser, J. Sawatzki, J. Mol. Structure, 2003,

661, 307-317.

19. T. D. Cry, F. Matsui, R. W. Sears, N. M. Curran, E. G. Lovering,

Anal. Chem., 1987, 70, 836-840.

20. E. A. H. Mohammed, II Farmaco, 2000, 55, 136-145.

21. M. K. Manoj Babu, J. Pharm. Biomed. Anal., 2004, 34, 315-324.

22. E. S. Walker, J. Assoc. Off. Anal. Chem., 1988, 71, 523-525.

23. R. Lobenberg, G. L. Amidon, Eur. J. Pharm. Biopharm., 2000, 50,

3-12.

24. K. G. H. Desai, A. R. Kulkarni, T. M. Aminbhavi, J. Chem. Eng.

Data, 2003, 48, 942-945.

25. S. Rawat, S. K. Jain, Pharmazie, 2003, 58, 639-641.

26. E. Rinaki, G. Valsami, P. Macheras, Pharm. Res., 2003, 20,

1917-1925.

27. A. Nokhodchi, Y. Javadzadeh, M. R. Siahi-Shadbad, M. Barzegar-

Jalali, J. Pharm. Pharm. Sci., 2005, 8, 18-25.

28. S. Spireas, C. L. Jarowski, D. I. Rohera, Pharm. Res., 1992, 9,

1351-1368.

29. Y. Javadzadeh, M. R. Siahi-shadbad, M. Barzegar-Jalali, A.

Nokhodchi, Farmaco, 2005, 60, 361-365.



30. N. Rasenack, H. Hartenhauer, B. Muller, Int. J. Pharm., 2003,

254, 137-145.

31. N. Rasenack, B. P. R. Muller, Pharm. Res., 2002, 19, 1894-1900.

32. G. Sertsou, J. Butler, A. Scott, J. Hempenstall, T. Rades, Int. J.

Pharm., 2002, 245, 99-108.

33. Y. Rane, R. Mashru, M. Sankalia, J. Sankalia, AAPS

PharmaSciTech., 2007, 8, 1-17.

34. W. L. Chiou, S. Reigelman, J. Pharm. Sci., 1971, 60, 1281-1302.

35. C. Leuner, J. B. Dressman, Eur. J. Pharm. Biopharm., 2000, 50,

47-60.

36. J. L. Ford, Pharm. Acta Helv., 1986, 61, 69-88.

37. A. H. Goldberg, M. Gibaldi, J. L. Kanig, J. Pharm. Sci., 1966, 55,

581-583.

38. H. El-Zein, L. Riad, A. A. El-Bary, Int. J. Pharm., 1998, 168, 209-

220.

39. A. S. Narang, A. K. Srivastava, Drug Dev. Ind. Pharm., 2002, 28,

1001-1013.

40. V. Bakatselou, R. C. Oppenheim, J. B. Dressman, Pharm. Res.,

1991, 8, 1461-1469.

41. H. Valizadeh, A. Nokhodchi, N. Qarakhani, Drug Dev. Ind.

Pharm., 2004, 30, 303-317.

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