CHAPTER 11

DIACEREIN

286

11.1. DRUG PROFILE

Diacerein, also known as diacetylrhein, is a (4, 5- diacetoxy-9, 10-dihydro9, 10

di-oxo-2 anthracene carboxylic acid) is a new anti-inflammatory, analgesic and

antipyretic drug used in the treatment of osteoarthritis. A 2005 Cochrane review found

Diacerein to be slightly, but significantly, more effective than placebo in Diacerein has a

small effect in improving pain and slowing the progress of osteoarthritis (in the hip).[1]

Figure: 11.A: Structure of Diacerein

Systematic (IUPAC) name : 4, 5-diacetyloxy-9, 10-dioxo-anthracene-2 carboxylic acid

Formula : C19H12O8

Mol. Mass : 368.294 g/mol

Routes : Oral

Excretion : Renal (30%)

It has a novel mode of action that differentiates it from NSAIDs and other

conventional form of drug therapy [2]

. Clinical trials have shown that Diacerein is highly

effective in relieving the symptoms of osteoarthritis. It also significantly reduces severity

of pathological changes of osteoarthritis compared to placebo and increases the

expression of transforming growth factor (TGF) - beta 1and TGF-beta 2, with, potential

cartilage repairing properties. Diacerein does not alter renal or platelet cyclo-oxygenase

287

activity and may therefore be tolerated by patients with prostaglandin-dependent renal

function.

In addition to effect on macrophage migration and phagocytosis, it also inhibits

superoxide production, chemotaxis and phagocytic activity of neutrophils [3, 4]

. However,

Diacerein lacks cyclooxygenase inhibitory activity and hence shows no effect on

prostaglandin synthesis [5,6]

. Therefore, it has been considered as a slow-acting

antiarthritic drug not belonging to the NSAIDs that may interfere with the pathological

course of osteoarthritis [7].

The most common side effects of Diacerein treatment are

gastrointestinal, such as diarrhea. [8]

List of brand names of Diacerien

S.No. BRAND

NAME

FORMULATION COMBINATION AVAILABLE

STRENGTH

(mg)

MANUFACTURER

1 ARTIFIT Cap 50 FDC

2 BICERIN Cap 50 OCTANE BIOTECH

3 CARTIDIN Cap 50 RANBAXY

4 CEDIA-50 Tab 50 INVISION

5 DASHING Cap 50 GENETIC PHARMA

6 DASHING-

GM

Tab glucosamine

sulphate

800 GENETIC PHARMA

7 DIACER Cap 50 CADILA

8 DIASOL Cap 50 IPCA

9 DIOSTEO Tab 50 INDOCO

10 DIPAIN Tab 50 WELBE LIFE

11 DISERAMI

NE

Cap 50 STALLION LABS

288

12 DYCERIN Cap 50 INTEGRACE

(GLENMARK)

13 GEMCERIN Tab glucosamine

sulphate, methyl

sulphonyl methane

50 ALKEM

14 GUDCERIN Cap 50 MANKIND

15 HILIN Cap 50 DR. REDDY'S LABS

16 ICERIN-50 Cap 50 INTRA LABS

17 JOINCERIN Cap 50 TORRENT (VISTA)

18 LEFAX Cap 50 ADLEY FORM.

19 NETREAT Cap 50 MERIDIAN

20 NETREAT-

G

Tab glucosamine 800 MERIDIAN

21 ONISRIN

cap

Cap 50 SYNTONIC LIFE

SCIENCES

22 ONISRIN G Tab glucosamine

sulphate

800 SYNTONIC LIFE

SCIENCES

23 ONISRIN

GSM

Tab glucosamine

sulphate

MSM

1100 SYNTONIC LIFE

SCIENCES

24 TOPCERIN Cap Diacerein 50mg 50 ENDEAVOUR

Table: 11.1

289

11.2. LITREATURE SURVEY

Several analytical methods have been reported for the determination of Diacerein in

pure drug, pharmaceutical dosage forms and in biological samples using

spcetrophotometry, liquid chromatography, electro kinetic chromatography high

performance thin layer chromatography either in single or in combined forms.

M. Jagadeeswaran et al [9]

has developed a simple reverse phase high-performance

liquid chromatographic method for the simultaneous determination of Diacerein and

aceclofenac in tablets. Chromatographic separations of the two drugs were analyzed on a

Phenomenex C18 column (250 × 4.60 mm, 5 µ). The mobile phase constituted of 0.01 M

potassium dihydrogen phosphate and acetonitrile 60:40 (v/v) and pH adjusted to 4.5 using

glacial acetic acid was delivered at the flow rate 2.0 mL min-1. Detection was performed

at 280 nm. The retention time of Diacerein and aceclofenac was 3.61 and 6.28 min,

respectively. Calibration curves were linear with coefficient correlation between 0.99 to

1.0 over a concentration range of 80-120 µg mL-1 of Diacerein and aceclofenac. The

relative standard deviation (R.S.D) was found to be < 2.0%.

Sarika Narade et al [10]

has been developed a simple, sensitive, rapid, accurate and

precise spectrophotometric method for the estimation of Diacerein in bulk and

pharmaceutical dosage forms. Diacerein shows maximum absorbance at 258.5 nm with

molar absorptivity of 4.2258×104

l/mol/cm. Beer’s law was obeyed in the concentration

range of 1-10 µg/ml. The limit of detection (LOD) and limit of quantification (LOQ)

were found to be 0.02 µg/ml and 0.07 µg/ml respectively. The results of recovery studies

(98.68-101.11%) indicated that proposed method is accurate and precise for the

determination of Diacerein in capsules.

N. Kannappan et al [11]

described the analytical method suitable for validation of

Diacerein by reversed Phase high performance liquid chromatography (RP-HPLC)

method. The method utilized RP-HPLC (Water Alliance 2695 with PDA UV detector)

model, a column Zorbax CN, the Analytical balance Shimadzu Libror and a pH meter

Control Dynamics. The mobile phases were comprised of A and B of Acetonitrile and

Buffer pH-|3.5|. Validation experiments were performed to demonstrate system

suitability, specificity, precision, linearity and range, accuracy study, stability of

analytical solution and robustness. The method was linear over the concentration range of

290

25-150 g/ml. The method showed good recoveries (80.30% - 118.14%) and the relative

standard deviations of intra and inter-day assay were ± 0.6030 and result were 101.26%

respectively. The method can be used for quality control assay of Diacerein.

Janhavi Rao et al [12]

has developed and validated a stability-indicating HPLC

method for the quantitative determination of Diacerein in capsule dosage forms. An

isocratic separation was achieved using a perfectsil target ODS-3, 250×4.6 mm i.d., and 5

µm particle size columns with a flow rate of 1 ml/min and using a UV detector to monitor

the eluate at 254 nm. The mobile phase consisted of phosphate buffer: acetonitrile (40:60,

v/v) with pH 4.0 adjusted with phosphoric acid. The drug was subjected to oxidation,

hydrolysis, photolysis and thermal degradation. Diacerein was found to degrade in acidic,

basic, and oxidative stress and also under neutral condition. Complete separation of

degraded products was achieved from the parent compound. All degradation products in

an overall analytical run time of approximately 10 min with the parent compound

Diacerein eluting at approximately 4.9 min. The method was linear over the

concentration range of 1-10 µg/ml (r2 = 0.9996) with a limit of detection and quantitation

of 0.01 and 0.05 µg/ml respectively. The method has the requisite accuracy, selectivity,

sensitivity, precision and robustness to assay Diacerein in capsules. Degradation products

resulting from the stress studies did not interfere with the detection of Diacerein and the

assay is thus stability-indicating.

Sarika Narade et al [13]

has developed a simple, rapid, accurate and precise UV

spectrophotometric method for the simultaneous determination of Diacerein (DCN) and

aceclofenac (ACF) in tablet dosage forms. The method involved solving simultaneous

equations based on measurement of absorbance at two wavelengths, 258 nm and 274 nm,

max of Diacerein and aceclofenac respectively. The linearity for both Diacerein and

aceclofenac was in the range of 1-10 µg/ml and 5-40 µg/ml respectively. The % recovery

was found to be 99-101 % and 99-100 % for Diacerein and aceclofenac respectively

indicating proposed method is accurate and precise for simultaneous estimation of DCN

and ACF in tablets.

Keddal G. Lalitha et al [14]

has been developed a simple, economic, accurate reverse

phase isocratic RP-HPLC method for the quatitation of Diacerein in tablet dosage form.

The quantitation was carried out using Zorbax CN column. The mobile phase was

291

ammonium acetate buffer (pH adjusted to 3.5): Acetonitrile [53:47]. The LOD and LOQ

are found to be 3.952 µg mL-1 and 11.97 µg mL-1 respectively. The flow rate was

1mL/min with UV detection at 254 nm. The method has been validated and proved to be

accurate, precise, linear, rugged, robust, simple and rapid. The calibration curve was

linear in the concentration range 25-150 µg mL-1 with coefficient of correlation 0.99942.

The percentage recovery of Diacerein was found to be 101.60%.The method is useful in

the quality for the estimation of Diacerein in tablet dosage form.

R. Siva kumar et al [15]

has been developed a new simple, accurate, precise and

reproducible RP-HPLC method for the simultaneous estimation of Aceclofenac and

Diacerein in tablet dosage forms using C column (Phenomenex, 250 x 4.6 mm, 5 µm) in

isocratic mode. The mobile phase consisted of 0.02 M phosphate buffer: acetonitrile with

5 ml of 0.4% triethylamine in ration of (35:65 v/v) and adjusted to pH 4. The detection

wavelength was carried out at 254 nm. The method was linear over the concentration

range for Aceclofenac 5-25 µg/ml and for Diacerein 2-10 µg/ml. The recoveries of

aceclofenac and Diacerein were found to be in the range of 99.23-100.98% and 99.45-

100.61% respectively. The validation of method was carried out using ICH-guidelines.

The described HPLC method was successfully employed for the analysis of

pharmaceutical formulations containing combined dosage form.

Useni Reddy Mallu et al [16]

developed a simple, specific, sensitive, and rapid high

performance liquid chromatography (HPLC) method for the determination of

Glucosamine sulphate and Diacerein for assay. Glucosamine and Diacerein were baseline

separated and quantitated on C18 reversed phase column (4.6×250mm, 5.0µm), using a

mobile phase composed of a phosphate buffer-acetonitrile (55:45v/v, pH 3.0) delivered at

a flow rate of 0.6mL/min, and with UV detection (lamda excitation 195nm). The method

was proven to be linear over a Glucosamine concentration range of 84 to 504µg/mL with

a mean correlation coefficient of 0.9999 and a Diacerein concentration range of 5.6 to

33.6µg/mL with a mean correlation coefficient of 0.9998.

Ashwini Ojha et al [17]

has describes a simple HPLC method with UV detection for

simultaneous determination of rhein (the immediate metabolite of Diacerein) and

aceclofenac from human plasma samples. Sample preparation was accomplished through

292

liquid–liquid extraction with ethyl acetate and chromatographic separation was

performed on a reversed-phase ODS column. Mobile phase consisted of a mixture of

acetate buffer and acetonitrile run under gradient at flow rate of 1.0 ml/min. Wavelength

was set at 258 nm. The method was validated for linearity, accuracy, precision and

stability. The calibration was linear over the range of 0.1–7.0 μg/ml for rhein and 0.5–

20 μg/ml for aceclofenac using 500 μl plasma samples. Extraction recoveries were 85%

for rhein and 70% for aceclofenac. The method can easily be adopted for high-throughput

clinical and pharmacokinetic studies of above two-drug fixed dose combination

formulations.

293

11.3. EXPERIMENTAL

11.3.1. Instrumentation

Peak HPLC containing LC 20AT pump and variable wavelength programmable

UV-Visible detector and Rheodyne injector was employed for investigation. The

chromatographic analysis was performed on a Chromosil C18 column (250 mm × 4.6

mm, 5µm). Degassing of the mobile phase was done using a Loba ultrasonic bath

sonicator. A Denwar Analytical balance was used for weighing the materials.

11.3.2. Chemicals and Solvents

The reference sample of Diacerien (API) was obtained from Cipla, Mumbai. The

Formulation DYCERIN (Diacerien) was procured from the local market. Methanol,

Water used was of HPLC grade and purchased from Merck Specialities Private Limited,

Mumbai, India.

11.3.3. The mobile phase

A mixture of Methanol: Water in the ratio of 80:20 v/v was prepared and used as

mobile phase.

11.3.4. Standard solution of the drug

For analysis 100 ppm standard solution was prepared, required concentrations

were obtained from 100 ppm solution by appropriate dilution.

11.3.5. Sample (Capsule) solution

The formulation tablets of Diacerien (DYCERIN - 50 mg) were crushed to give

finely powdered material. From the Powder prepared a 3 ppm solution with mobile phase

and then filtered through Ultipor N66 Nylon 6, 6 membrane sample filter paper.

294

11.4. METHOD DEVELOPMENT

For developing the method (as described in chapter 1 and 2), a systematic study of

the effect of various factors was undertaken by varying one parameter at a time and

keeping all other conditions constant. Method development consists of selecting the

appropriate wave length and choice of stationary and mobile phases. The following

studies were conducted for this purpose.

11.4.1. Detection wavelength

The spectrum of 10ppm solution of the Diacerien in methanol was recorded

separately on UV spectrophotometer. The peak of maximum absorbance wavelength was

observed. The spectra of Diacerien were showed maximum absorbance at 250nm.

11.4.2. Choice of stationary phase

Preliminary development trials have performed with octadecyl columns with

different types, configurations and from different manufacturers. Finally the expected

separation and peak shapes were obtained on Chromosil C18 (250 mm x 4.6 mm, 5μm)

column.

11.4.3. Selection of the mobile phase

In order to get sharp peak, low tailing factor and base line separation of the separation of

the components, a number of experiments were carried out by varying the composition of

various solvents and flow rate. To have an ideal separation of the drug under isocratic

conditions, mixtures of solvents like methanol, water and Acetonitrile with or without

different buffers indifferent combinations were tested as mobile phases on a Chromosil

C18 column. A mixture of Methanol : Water in the ratio of 80:20 v/v was proved to be

the most suitable of all the combinations since the chromatographic peak obtained was

better defined and resolved and almost free from tailing.

11.4.4. Flow rate

Flow rates of the mobile phase were changed from 0.5 – 1.5 mL/min for optimum

separation. A minimum flow rate as well as minimum run time gives the maximum

saving on the usage of solvents. It was found from the experiments that 0.5 mL/min flow

rate was ideal for the successful elution of the analyte.

295

11.4.5. Optimized chromatographic conditions

Chromatographic conditions as optimized above were shown in Table 11.2. These

optimized conditions were followed for the determination of Diacerien in bulk samples

and in its Formulations. The chromatogram of standard (3ppm) shown in Figure 11.B

Mobile phase Methanol :Water 80:20 v/v

Pump mode Isocratic

Mobile phase PH 7.5

Diluent Mobile phase

Column chromosil C18 column (250 mm x 4.6

mm, 5μ)

Column Temp Ambient

Wavelength

250 nm

Injection Volume 20 μl

Flow rate 0.5 mL/min

Run time 10 min

Retention Time 8.29 min

Table 11.2: Optimized chromatographic conditions for estimation Diacerien

296

Figure 11.B: Chromatogram of standard solution

297

11.5. VALIDATION OF THE PROPOSED METHOD

The proposed method was validated (as described in chapter 1 and 2) as per ICH

guidelines. The parameters studied for validation were specificity, linearity, precision,

accuracy, robustness, system suitability, limit of detection, limit of quantification, and

solution stability.

11.5.1. Specificity

The specificity of method was performed by comparing the chromatograms of

blank, standard and sample (Prepared from Formulation). It was found that there is no

interference due to excipients in the tablet formulation and also found good correlation

between the retention times of standard and sample. The specificity results are shown in

Table 11.3.

NAME OF THE SOLUTION Retention Time in Minutes

Blank NO PEAKS

Diacerien (Standard) 8.29

Diacerien (Sample) 8.5

Table 11.3: Specificity study

11.5.2 Linearity

Linearity was performed by preparing mixed standard solutions of

Diacerien at different concentration levels including working concentration

mentioned in experimental condition i.e. 3ppm. Twenty micro liters of each

concentration was injected in duplicate into the HPLC system. The response was

read at 250 nm and the corresponding chromatograms were recorded. From these

chromatograms, the mean peak areas were calculated and linearity plots of

concentration over the mean peak areas were constructed individually. The

regressions of the plots were computed by least square regression method.

Linearity results were presented in Table 11.4.

298

Level Concentration of

Diacerien in ppm

Mean peak area

Level -1 1 54378.9

Level -2 2 104301.4

Level -3 3 158610.9

Level -4 4 209028.0

Level -5 5 261072.4

Range: 1-5ppm Slope

Intercept

Correlation coefficient

51811.36

2044.24

0.999

Table 11.4: Linearity Results

Figure 11.C: On X axis concentration of sample, On Y axis peak area response

0

50000

100000

150000

200000

250000

300000

0 1 2 3 4 5 6

Are

a

Concentration

Diacerein

299

11.5.3. Precision

Precision is the degree of repeatability of an analytical method under normal

Operational conditions. Precision of the method was performed as intraday precision,

Inter day precision.

11.5.3.1. Intraday precision

To study the intraday precision, six replicate standard solutions (5ppm) of

Diacerien were injected. The percent relative standard deviation (% RSD) was calculated

and it was found to be 0.916, which are well within the acceptable criteria of not more

than 2.0. Results of system precision studies are shown in Table 11.5.

SAMPLE

CONC(PPM) INJECTION No. PEAKS

AREA

R.S.D

(Acceptance

criteria ≤ 2.0%)

Diacerien

5

1 49266.99

0.916

2 47785.14

3 49185.61

4 48990.49

5 49161.94

6 48140.86

Table 11.5: System Precision (Intra Day)

11.5.3.2. Inter Day precision

To study the interday precision, six replicate standard solution of Diacerien was

injected on third day of sample preparation. The percent relative standard deviation (%

RSD) was calculated and it was found to be 0.399, which are well within the acceptable

criteria of not more than 2.0. Results of system precision studies are shown in Table 11.6.

300

SAMPLE

CONC (PPM) INJECTION No. PEAKS

AREA

R.S.D

(Acceptance

criteria ≤ 2.0%)

Diacerien

5

1 48327.10

0.399

2 48368.06

3 47640.57

4 48268.82

5 47869.36

6 48218.26

Table 11.6: System Precision (Inter Day)

11.5.4. Accuracy

The accuracy of the method was determined by standard addition method. A

known amount of standard drug was added to the fixed amount of pre-analyzed tablet

solution. Percent recovery was calculated by comparing the area before and after the

addition of the standard drug. The standard addition method was performed at 50%,

100% and 150% level of 2ppm. The solutions were analyzed in triplicate at each level as

per the proposed method. The percent recovery and % RSD was calculated and results

are presented in Table 11.7 Satisfactory recoveries ranging from 99.0 to 102.0 were

obtained by the proposed method. This indicates that the proposed method was accurate.

301

Level Amount of

Diacerien spiked

(ppm)

Amount of

Diacerien

recovered(ppm)

% Recovery

%RSD

50 %

3 3.01 100.3

0.678 3 2.97 99.00

3 2.98 99.33

100%

4 3.96 99.00

0.901 4 4.01 100.25

4 4.03 100.75

150%

5 4.96 99.2

0.759 5 4.97 99.4

5 5.03 100.6

Mean % of

recovery 99.75

Mean RSD =

0.779

Table11.7: Percentage Recovery and % RSD

11.5.5. Robustness

The robustness study was performed by slight modification in flow rate of Mobile

phase, pH of the buffer and composition of the mobile phase. Diacerien at 4 ppm

concentration was analyzed under these changed experimental conditions. It was

observed that there were no marked changes in chromatograms, which demonstrated that

the developed method was robust in nature. The results of robustness study are shown in

Table 11.8.

302

Condition Mean area % assay % difference

Unaltered 209028.0 100.0 0.0

Flow rate at 0.4 mL/min

Flow rate at 0.6mL/min

209441.6

208145.3

100.19

99.57

0.19

0.43

Mobile phase:

MEOH: Water

75% 25%

85% 15%

209047.2

208941.5

100.009

99.95

0.009

0.05

pH of mobile phase at 7.3 207922.5 99.47 0.53

pH of mobile phase at 7.7 208842.1 99.91 0.09

Table 11.8: Robustness

11.5.6. System suitability

System suitability was studied under each validation parameters by injecting six

replicates of the standard solution 2 ppm). The results obtained were within acceptable

limits (Tailing factor ≤2 and Theoretical plate’s ≥2000) and are represented in Table

11.9. Thus, the system meets suitable criteria.

Parameter Tailing factor Theoretical plates

Specificity study 1.54 41802

Linearity study 1.34 69829

Precision study 1.46 47785

Table 11.9: System Suitability

11.5.7. Limit of detection and Limit of quantification

Limit of detection (LOD) is defined as the lowest concentration of analyte that

gives a detectable response. Limit of quantification (LOQ) is defined as the lowest

Concentration that can be quantified reliably with a specified level of accuracy and

303

Precision. For this sample was dissolved by using Mobile Phase and injected until peak

was disappeared. After 15ng/ml dilution, Peak was not clearly observed. So it confirms

that 0.06ppm is limit of Detection and 0.18ppm dilution is Limit of Quantification. For

this study six replicates of the analyte at lowest concentration were Measured and

quantified. The LOD and LOQ of Diacerien are given in Table 11.10.

parameter Measured volume

Limit of Quantification 0.18ppm

Limit of Detection 0.06ppm

Table 11.10: LOQ and LOD

Formulation:

For assay 20 Diacerein (DICERIN - 50mg) tablets were weighing and calculate

the average weight. Accurately weigh and transfer the sample equivalent to 10mg of

Diacerein in to a 10ml volumetric flask. Add diluent and sonicate to dissolve it

completely and make volume up to the mark with diluents. Mix well and filter through

0.45um filter. Further pipette 1ml of the above stock solution into a 10ml volumetric

flask and dilute up to mark with diluents and finally 3 ppm were prepared. Mix well and

filter through 0.45um filter. An aliquot of this solution was injected into HPLC system.

Peak area of Diacerein was measured for the determination.

304

11.6. RESULTS AND DISCUSSION

Proper selection of the stationary phase depends up on the nature of the

sample, molecular weight and solubility. The drug Diacerein in non-polar. Non-polar

compounds preferably analyzed by reverse phase columns. Among C8 and C18, C18

column was selected. Non-polar compound is very attractive with reverse phase columns.

So the elution of the compound from the column was influenced by polar mobile phase.

Mixture of water and methanol was selected as mobile phase and the effect of

composition of mobile phase on the retention time of Diacerein was thoroughly

investigated. The concentration of the water and methanol were optimized to give

symmetric peak with short run time (Figure 11.B). A system suitability test was applied

to representative chromatograms for various parameters. The results obtained were within

acceptable limits and are represented in Table 11.9. Thus, the system meets suitable

criteria.

Five points graphs was constructed covering a concentration range 1ppm –

5ppm (Three independent determinations were performed at each concentration). Linear

relationships between the peak area signals of Diacerein the corresponding drug

concentration was observed. The linearity range of Diacerien with coefficient of

correlation, (r= 0.9999), Intercept (2044.24), Slope (51811.36) were found. ). The data of

regressing analysis of the calibration curves are shown in Table 11.4. Precision was

evaluated by carrying out six independent sample preparation of a single lot of

formulation. The sample solution was prepared in the same manner as described in

sample preparation. Percentage relative standard deviation (%RSD) was found for

Intraday-0.916, Interday-0.399) to be less than 2% for within a day and day to day

variations, which proves that method is precise. Results are shown in Table 11.5, 11.6.

To check the degree of accuracy of the method, recovery studies were

performed in triplicate by standard addition method at 50%, 100% and 150%. Known

amounts of standard were added to pre-analyzed samples and were subjected to the

proposed HPLC method. Results of recovery studies are shown range 99.00-101.45%.

The mean recovery data obtained for each level as well as for all levels combined (Table

305

11.7) were within 2.0% of the label claim for the active substance with an R.S.D. < 2.0%,

which satisfied the acceptance criteria set for the study.

The proposed method has been applied to the assay of commercial tablets

(DYCERIN - 50 mg) containing Diacerien. Sample was analyzed for five times after

extracting the drug as mentioned in assay sample preparation of the experimental section.

After analysis test result assay of Diacerien in Tablet is 15.7% and is very close to the

labeled amount.

Statistical analysis of the results has been carried out revealing high accuracy

and good precision. The RSD for all parameters was found to be less than two, which

indicates the validity of method and assay results obtained by this method are in fair

agreement. The developed method can be used for routine quantitative simultaneous

estimation of Diacerein in multi component pharmaceutical preparation. The proposed

method is simple, sensitive and reproducible and hence can be used in routine for

simultaneous determination of Diacerein in bulk as well as in pharmaceutical

preparations.

306

11.7. BIBILOGRAPHY

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10. “Development and validation of UV- Spectrophotometric method for the

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14. Eurasian J. Anal. Chem; “A Simple HPLC Method for Quantitation of Diacerein

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Formulation”; Journal of Pharmacy Research; 2010; 3(2): 361-63.

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plasma”; Journal of Chromatography B; 2009; 877(11-12, 15): 1145-1148.