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International Journal of Universal Pharmacy and Bio Sciences 3(2): March-April 2014

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES IMPACT FACTOR 1.89***

ICV 5.13*** Pharmaceutical Sciences RESEARCH ARTICLE……!!!

FORMULATION AND IN-VITRO EVALUATION OF FAST DISSOLVING

TABLET OF OLMESARTAN MEDOXOMIL

Zinkal K Patel*, Rahul R. Patel, Dr K. R. Patel, Dr M. R. Patel.

Department of Pharmaceutics, Shri B. M. Shah College of Pharmaceutical Education and

Research Dhansura Road College campus Modasa, Dist:- Arvali. Pin code:- 383315 Gujarat,

(India).

KEYWORDS:

Olmesartan medoxomil;

solid-dispersion; FDT;

Solubility; dissolution;

superdisintegrants.

For Correspondence:

Zinkal K Patel*

Address:

Shri B. M. Shah College

of pharmaceutical

education and research

Modasa-383315, Dist:

Arvali. Gujarat, India

E-Mail id:-

[email protected]

om

ABSTRACT

The aim of this investigation was to formulation and in-vitro

evaluation of fast dissolving tablet of olmesartan medoxomil by

direct compression method. Oral bioavailability of olmesartan

medoxomil is very low (26%), due to its poor water solubility. For

this purpose, initially solubility of olmesartan medoxomil was

improved by using PEG 6000 and PVP K30 as a carriers by solid

dispersion techniques. The prepared solid dispersion powder were

evaluated for flow properties, solubility and in-vitro drug release,

FTIR analysis, DSC. Then optimized batch of solid dispersion(P4)

was used in formulation of fast dissolving tablet using different

superdisintegrants. Various batches of tablets were evaluated for

pre-compression and post-compression parameter of tablet.

Optimized batch contain 93.91CPR, 100.0% drug content,

17sec.disintegration time. optimized batch compared with

marketed formulation.



INTRODUCTION1, 2, 3, 4

Oral delivery is currently the gold standard in the pharmaceutical industry where it is regarded as the safest,

most convenient and most economical method of drug delivery. Oral route of drug administration become

popular route for systemic effects due to ease of ingestion, accurate dosage, self-medication, pain

avoidance. Also solid oral delivery systems do not require sterile conditions Fast dissolving drug delivery

system are Novel Drug Delivery techniques aim for designing dosage forms, convenient to be manufacture

and administer without water, free of side effects, offering immediate release and enhanced bioavailability,

so as to achieve better patient compliance.1 This segment of formulation is especially designed for

pediatric, geriatric, bedridden, psychotic patients who are unable to swallow or refuse to swallow

conventional oral formulation and also for active patients who are busy and traveling and may not have

access to water. United states Food And Drug Administration (FDA) defined fast dissolving tablet (FDT)

as “a solid dosage form containing medicinal substance or active ingredient which disintegrate or dissolve

rapidly within seconds when placed upon the tongue.” Fast dissolving tablets are also known as mouth-

dissolving tablets, rapid dissolving, melt-in mouth tablets, Orodispersible tablets, rapimelts, porous tablets,

quick dissolving, quick melt, quick disintegrating tablets.2

FDT prepared by various techniques like direct

compression, lyophilization, spray drying, sublimation, test masking etc. But commonly used method to

prepare FDT is direct compression. It is easiest way to manufacture tablets. Conventional equipments,

commonly available excipients and a limited number of processing steps are involved in direct

compression.

Hypertension is fast becoming a major public health problem in world. Olmesartan medoxomil (OLM) is

currently used as an alternative therapeutic antihypertensive agent for patient intolerant of angiotensin

converting enzyme inhibitor. It is known that diabetic patient are at increased risk of cardiovascular disease

and reduce vascular resistance and oxidative stress, addition to significant reducing BP in type -2 diabetic

patients.5, 6

OLM is a poorly aqueous soluble drug. Its solubility is reported to be 0.0077mg/ml. Rapid onset of action

is desirable to provide fast relief in treatment of heart failure. Therefore, it is necessary to enhance the

aqueous solubility and dissolution rate of OLM to obtain faster on set of action and improve its overall oral

bioavailability102

. Solubility of OLM is improve by solid dispersion because it cause reduction in particle

size, improve drug porosity, increase wettability and convert crystalline drug in to amorphous state. OLM

is a selective AT1 subtype angiotensin–II receptor antagonist that has been approved by US Food and Drug

Administration (FDA) for treatment of hypertension. OLM dose dependently reduces blood pressure



through arterial vasodilatation and reduce sodium retention. It is a prodrug that is rapidly de-esterified

during absorption from GIT to produce an active metabolite olmesartan.OLM is BCS class-II drug. i.e. low

solubility and high permeability. Oral bioavailability is very low (26%) due to its poor aqueous solubility.

OLM given orally in single daily doses of 20mg-40mg. Having log p value 5.9 i.e. drug is lipophilic in

nature. Elimination half life of OLM is 13hrs and 99%plasma protein binding. Pka value is 4.37, 8, 9

MATERIALS AND METHOD

Olmesartan Medoxomil was obtained from Sun Pharma Ltd. Baroda. Kyron T-314 was obtained from

Corel Pharma Chem., Ahmadabad. Cross Carmellose Sodium, Crosspovidone, Avicel pH101, Aerosil was

obtained from Orbicular Pharma. Tech. Pvt Ltd. PEG 6000 was obtained from Modern chemical corp.,

Mumbai. PVP K30 was obtained from Oxford lab. Mumbai. Mannitol was obtained from Finar chemicals

ltd, Mumbai.Aspartame was obtained from Lesar Chemicals, Ahmedabad.

METHOD :

Preparation of the Solid Dispersions10, 11

Solid dispersion of olmesartan medoxomil (OLM) were prepared by solvent evaporation and fusion

method using PEG 6000 and PVP K30 as a carrier.

Solvent evaporation method

In this method, 1 : 1 ratio of PEG 6000 : drug (SE1) and PVP K30 : drug (SE2) were carefully transferred

into two beaker seperately and dissolved in methanol. The solution was transferred to a petridish and

solvent was allow to evaporate at room temperature for 1 hr and then dried at 600c for 6 hr in a hot air

oven. The mass obtained in each case was crushed, pulverized and sifted the 80#. All the solid dispersion

was preserved in well closed glass container till use.

By fusion method

In this method, 1 : 1 ratio of drug : PEG 6000 (FM1) and drug : PVP K30 : (FM2) was heated in two

different china dish to a temperature just above its melting point. The melt is solidified on an ice bath

under vigorous stirring. The mass obtained in each case was crushed, pulverized and sifted the 80#. All the

solid dispersion was preserved in well closed glass container till use. Solid dispersion prepared by PEG

6000 by fusion method give good solubility. So, it used in different ration like 1: 1(P1), 1: 2(P2), 1 : 3(P3),

1: 4(P4), 1: 5(P5), 1 : 6(P6).

Evaluation of solid dispersion12, 13

A. Saturation solubility studies

Saturation solubility was performed according to method reported by higuchi and cannors. Excess quantity

of solid dispersion, equivalent to 20 mg of drug was added to 100 ml conical flask containing 20ml 0.1N



Hcl and mixtures were shaken for 24 hour at 100rpm at room temperature in orbital shaker and filter

through whatman filter paper No.41. The filtrate was suitably diluted and analyzed spectrophotometrically

at 257nm against blank using UV visible spectrophotometer. The studies were carried out in triplicate and

average value (±SD) was noted

B. Dissolution study of solid dispersion

It was performed as described in Indian Pharmacopoeia 2010 using USP apparatus II (paddle). Quantity of

solid dispersion equivalent to 20 mg of drug was kept in a flask of the dissolution apparatus containing

900ml of 0.1N HCl as a dissolution media maintaining the temperature at 37±0.50C and at a speed of 50

rpm. Aliquot of dissolution medium (5ml) was withdrawn at a specific time intervals and the samples were

replaced with fresh dissolution medium. Sample was filter through whatman filter paper No.41. The filtrate

was suitably diluted and analyzed spectrophotometrically at 257nm against blank using UV visible

spectrophotometer.

C. Differential scanning calorimetry

Calorimetric measurements were performed with DSC instrument, over the temperature range from 30 to

300oC at heating and cooling rates of 50

oC/min. The temperature scale was calibrated with high purity

standards. The glass transition was reported as the point of inflection of specific heat increment. Samples of

OLM and solid dispersion powder were analysed in the aluminium pan and their DSC spectra were

recorded.

D. Fourier transform infrared (FTIR)

Drug - carrier interaction play a vital role in the release of drug from formulation. FTIR has been used to

study the physical and chemical interaction between drug and carriers. FTIR spectra of OLM and carrier

were recorded using KBR mixing method on FTIR instrument.

FORMULATION OF FAST DISSOLVING TABLET14

Fast Dissolving Tablet of OLM were prepared by direct compression method according to the formula

given in below table using optimized batch of solid dispersion(P4). Various superdisintigrants like CCS,

Crosspovidone, Kyrone T-314 are use in the range of 2%, 4%, 6% to select the optimum concentration of

superdisintigrants. All the required material were passed through sieve no.60# and mixed homogeneously

for 15 min. Finally magnesium stearate and aerosil were added and mixed for 1 min. This blend was

compressed using 8 mm size flat faced punch on rotary compression machine.

Mannitol act as diluent. Microcrystalline cellulose act as binder. Aspartame was used as a sweetener.

Aerosil was used as glidant and Magnesium stearate was used as lubricant.



(Table 1.1 - preliminary formulation of fast dissolving tablet)

INGREDIENTS

(mg)

PRELIMINARY FORMULATION BATCH CODE

F1 F2 F3 F4 F5 F6 F7 F8 F9

Solid dispersion

(1:4)

100 100 100 100 100 100 100 100 100

CCS 4 8 12 - - - - - -

Kyron T-314 - - - 4 8 12 - - -

Crosspovidone - - - - - - 4 8 12

Avicel pH-101 60 60 60 60 60 60 60 60 60

Mannitol 22 18 14 22 18 14 22 18 14

Aspartame 10 10 10 10 10 10 10 10 10

Mg.stearate 2 2 2 2 2 2 2 2 2

Aerosil 2 2 2 2 2 2 2 2 2

Total wt. 200 200 200 200 200 200 200 200 200

FORMULATION USING 32 FULL FACTORIAL DESIGN

15, 16

It is desirable to develop an acceptable pharmaceutical formulation in shortest possible time using

minimum number of man-hours and raw materials. The technique of factorial design is an effective method

of indicating the relative significance of a number of variables and their interactions. On the basis of

preliminary study to evaluate that whether in combination, superdisintegrants can give far better result or

not, A 32 randomized full factorial design was adopted to optimize the variables. It is suitable for

investigating the quadratic response surfaces and for constructing a second order polynomial model.

In this design two factors were evaluated, each at 3 levels, and experimental trials were performed at all 9

possible combinations.

Y= b0 + b1X1 + b2X2 + b12X1X2 + b11X11 + b22X22

To demonstrate graphically the influence of each factor on response, the response surface plots was

generated using statistical software 10.0 (stat soft. Inc, USA). Response Surface Methods are designs and

models for working with continuous treatment.

(Table 1.2 - Selection of independent and dependent variables)

Independent variables Dependent variables

X1 X2 Y1 Y2 Y3

Conc. of

crospovidone

Conc. of

kyrone T-314

Disintigration

time (Sec.)

Wetting time

(Sec.)

Drug release

at 5min.



(Table 1.3 - Actual and coded value for factorial design)

Batches Coded value Actual value(%)

X1 X2 X1 X2

E1 -1 -1 2 2

E2 -1 0 2 4

E3 -1 1 2 6

E4 0 -1 4 2

E5 0 0 4 4

E6 0 1 4 6

E7 1 -1 6 2

E8 1 0 6 4

E9 1 1 6 6

(Table 1.4 - Formulation of 32 Factorial Designs batches)

INGREDIENTS

(mg)

FORMULATION BATCH CODE

E1 E2 E3 E4 E5 E6 E7 E8 E9

Solid dispersion

(1:4)

100 100 100 100 100 100 100 100 100

Crosspovidone 4 4 4 8 8 8 12 12 12

Kyron T-314 4 8 12 4 8 12 4 8 12

Avicel pH-101 60 60 60 60 60 60 60 60 60

Mannitol 18 14 10 14 10 6 10 6 2

Aspartame 10 10 10 10 10 10 10 10 10

Mg.stearate 2 2 2 2 2 2 2 2 2

Aerosil 2 2 2 2 2 2 2 2 2

Total wt. 200 200 200 200 200 200 200 200 200

EVALUATION PARAMETERS OF TABLETS 18, 19, 20, 21

Weight variation was performed using 20Tablets and weighted individually to check for weight variation.

Hardness for FDT is usually kept in lower range to facilitate early disintegration in the mouth. It is

measured by hardness tester (Monsanto hardness tester). It measured in kg/cm2

or pound. Friability of each

batch was measure in “Electro lab friabilator”. Ten pre-weighed tablets were rotated at 25 rpm for 4 min or

total 100 times dropping a tablet at height of 6 inches in each revolutions, the tablets were then reweighed

and the percentage of weight loss was calculated by the following equation. Limit of friability is 0.1-.9%.



Disintegration time was carried out on 6 tablets using the apparatus specified in I.P. Distilled water at 37ºC

± 2ºC was used as a disintegration media and time requied for complete disintegration of tablet with no

palatable mass remaining in the apparatus was measured .

Dissolution test was performed in 0.1N HCl using USP apparatus-II (paddle). Tablet was kept in a flask of

the dissolution apparatus containing 900ml of 0.1N HCl maintaining at 37±0.50C and 50 rpm. Aliquot of

dissolution medium (5ml) was withdrawn at a specific time intervals and the samples were replaced with

fresh dissolution medium. Sample was filter through whatman filter paper No.41. The filtrate was suitably

diluted and analyzed spectrophotometrically at 257nm against blank using UV visible spectrophotometer.

In Drug content test ten tablets were weighed and powdered in a glass mortar. Quantity of powder

equivalent to 20mg was transferred in a 100 ml volumetric flask. Make final volume in volumetric flask up

to 100ml using 0.1N HCl and filter through whatman filter. The filtrate was suitably diluted and analyzed

spectrophotometrically at 257nm against blank using UV visible spectrophotometer.

Wetting time was closely related to the inner structure of the tablets and to the hydrophilicity of the

excipients. To measure wetting time, five circular tissue papers of 10cm diameter are placed in a petridish

with a 10cm diameter. 10ml of water containing eosin, a water soluble dye, is added to petridish. A tablet is

carefully placed on the surface of the tissue paper. The time required for water to reach upper surface of the

tablet is noted as a wetting time.

The stability studies were carried out on the most satisfactory formulations as per ICH guidelines Q1C. The

samples of optimized batch were kept at 40°C ± 5°C and 75% relative humidity for one month in vial

which is sealed with rubber cap. At the end of study the tablet were withdrawn and analyzed for physical

characterization such as Hardness, Drug content, Wetting time, Disintegrations, and Dissolution etc.

RESULT AND DISCUSSION

Phase Solubility Study of Preliminary Batches of Solid Dispersion

(Table 1.5 - phase solubility of preliminary batches of solid dispersion)

BATCH SOLUBILITY (mg/ml)

Pure drug 0.526 ±0.002

SE1 0.94 ±0.002

SE2 0.86 ±0.002

FM1 1.19 ±0.001

FM2 0.91 ±0.002

From above evaluation it was concluded that solid dispersion by fusion method with PEG 6000 give good

solubility. So, OLM : PEG 6000 in different ratio like 1:1, 1:2, 1:3, 1:4, 1:5, 1:6 were used in further study



to enhance solubility of drug. This all batches are evaluated for in-vitro dissolution, flow properties and

phase solubility study.

Phase solubility study of solid dispersion

(Table 1.6-phase solubility of solid dispersion batches)

BATCH SOLUBILITY (mg/ml)

P1 1.19 ±0.001

P2 1.26 ± 0.002

P3 1.73 ±0.002

P4 2.01 ± 0.001

P5 1.91±0.002

P6 1.77± 0.002

The improved solubilization of OLM is depend on hydrophilic nature of PEG 6000 and to reduction of

particle aggregation of the drug, increased wettability, dispersibility and alteration of surface properties of

drug particles.

Dissolution of Solid Dispersion

(Table 1.7 – % cumulative drug release of solid dispersion batches)

The rate of dissolution increases as concentration of PEG 6000 increases in solid dispersion upto 1:4 drug:

carrier ratio. Further improvement in concentration of PEG 6000 did not enhance the dissolution rate. This

might be due to viscous boundary layer formed by PEG 6000 in higher amount surround drug particles

which retard the drug release. So, 1:4 ratio of drug : carrier used in preparation of tablets

SR.NO. TIME

(min.)

Cumulative percentage drug release

P1 P2 P3 P4 P5 P6

1 0 0 0 0 0 0 0

2 5 29.57 34.57 38.71 41.85 37.15 33.05

3 10 40.21 48.21 51.33 56.42 49.28 42.79

4 15 51.64 57.64 63.29 68.35 61.87 54.25

5 20 60.15 69.15 72.45 79.29 73.46 63.96

6 25 69.44 77.44 83.61 88.78 80.11 72.35

7 30 78.83 83.93 89.25 95.61 87.65 82.43

Results are the mean of three observations. ± SD are less than 0.5



Differential scening calorimetry (DSC)

(Figure 1.1 - DSC spectra of OLM )

(Figure 1.2 - DSC spectra of solid dispersion)

The DSC thermograms (fig 5.8), shows endothermic peak of OLM at 182 0C, which corresponds to its

melting point, indicating its crystalline nature. Thermograms of solid dispersion observed the absence of a

peak, suggesting that OLM meight be in dissolved state in PEG 6000. The disappearance of endothermic or

exothermic peaks of drug is mostly an indication of formation of solid dispersion which is observed in

thermogram of solid dispersion(fig. 5.9) .

Fourier transform infrared (FTIR)

(Figure 1.3 - FTIR spectra of OLM)

IR spectra of olmesartan showed characteristic peaks at 2829 cm-1

(Aliphatic C–H strech), 2956 cm-1

(Aromatic C–H strech), 3290 cm-1

(Broad, intermolecular hydrogen bonded, O-H strech), 1832 cm-1

(C=O

of carboxylic group), 1600 cm-1

(ring C=C stretch), 1481 cm-1

(C–N strech), 1388 cm-1

(in plane O-H

bend), 1136 cm-1

(ring C-O-C stretch).



(Figure 1.4 - FTIR spectra of solid dispersion)

It was found that there were no considerable changes in the IR peaks of the solid dispersion when

compared to pure olmesartan. In the FTIR study, the breakdown of the intermolecular hydrogen bond

between the crystalline drug molecule and formation of hydrogen bond between the drug and the polymers

might be related to the slight shift of the absorption band

EVALUATION OF TABLET

Disintegration time of preliminary batches of tablets

BATCH F1 F2 F3 F4 F5 F6 F7 F8 F9

DT †

(sec.)

97 ±

1.7

91±

1.24

88 ±

1.63

79 ±

1.24

67 ±

2.05

65±

0.94

61 ±

1.69

56±

1.25

59±

1.69

From the above data, it was concluded that the disintegration time of three superdisintigrant in three

different concentrations are CCS> Kyrone T-314 > Crosspovidone. Different nine formulation are

obtained using 32 factorial design. These all formulation are evaluated for pre-compression and post-

compression parameter

Flow Properties of Factorial Design Batches of Tablet

(Table 1.8 - Flow Property of factorial design batches of tablet)

Batch Angle of

repose(Ө)

Bulk density

(g/ml)

Tapped density

(g/ml)

Carr’s

index (%)

Hausner

ratio

E1 31.29

0 0.494 0.564 12.41 1.14

E2 31.71 0 0.482 0.559 13.77 1.15

E3 33.37 0 0.482 0.560 14.28 1.16

E4 26.41 0 0.496 0.558 11.11 1.12

E5 25.15 0 0.495 0.557 11.13 1.12

E6 26.92 0 0.487 0.553 11.93 1.13

E7 31.76 0 0.479 0.550 12.90 1.14

E8 32.03 0 0.478 0.549 12.93 1.14

E9 32.74 0 0.485 0.564 14.00 1.16




(Table 1.9 - post compression parameter of factorial design batches)

Batch E1 E2 E3 E4 E5 E6 E7 E8 E9

Hardness*

(kg/cm2)

3.1 ±

0.23

3.0 ±

0.4

3.2 ±

0.23

2.8±

0.23

3.0±

0.40

3.0 ±

0.40

2.8 ±

0.23

3.3 ±

0.23

3.0±

0.40

Thickness*

(mm)

3.9

±

0.04

4.06

±

0.04

4.0

±

0.08

4.0

±

0.00

4.03

±

0.04

4.03

±

0.09

4.03

±

0.12

4.06

±

0.04

3.9

±

0.09

Friability*

(%)

0.66

±

0.04

0.60

±

0.05

0.65

±

0.05

0.47

±

0.02

0.41

±

0.02

0.47

±

0.04

0.76

±

0.03

0.82

±

0.04

0.88

±

0.04

Wt.

variation#

(%)

199

±3.6

200

±5.3

199

±5.3

200

±5.2

200

±3.7

199

±5.1

201

±4.4

201

±4.9

199

±5.7

Drug*

content(%)

97

±2.1

99

±1.2

96

±3.0

98

±1.6

100

±0.9

100

±4.0

99

±3.6

98

±2.0

96

±3.7

DT†

(sec.)

27 ±

1.7

29 ±

1.24

31 ±

1.63

28 ±

1.24

22 ±

2.05

26 ±

0.94

33 ±

1.69

36 ±

1.25

36 ±

1.69

Wett. Time

(sec.)*

22±

1.24

24±

3.74

25±

0.74

21 ±

1.7

17±

1.69

20 ±

0.47

28 ±

1.24

30 ±

0.81

31±

1.25

WAR

(%)*

71.6

± 2.5

63.7

± 1.7

54.6

± 2.9

75.3

± 1.3

83.6

± 2.4

79.7

± 1.6

44.3

± 2.0

39.4

± 1.2

35.6

± 1.2

* All values are mean ± SD, (n =3), † All values are mean ± SD, (n =6), # All

values are mean ± SD, (n =20).

In-Vitro Dissolution of Factorial Design Batches of Tablet

(Table 1.10 - % cumulative drug release of factorial design batches)

TIME

(Min.)

Cumulative Percentage Drug Release

E1 E2 E3 E4 E5 E6 E7 E8 E9

0 0 0 0 0 0 0 0 0 0

5 41.08 37.51 40.25 48.98 52.51 49.35 43.33 36.75 38.57

10 52.61 46.86 53.44 60.03 64.77 57.19 52.13 47.48 46.85

15 60.23 55.92 62.73 68.47 71.34 68.53 59.24 54.23 53.46

20 68.53 65.44 70.69 76.11 79.82 76.27 66.97 61.94 60.87

25 74.35 73.17 77.24 82.25 86.14 85.29 73.86 69.17 67.42

30 81.03 85.25 84.18 89.09 93.91 91.05 80.74 76.02 73.93




( Figure 1.5 - % cumulative drug release of factorial design batches)

RESPONSE SURFACE PLOT:

it was observed that crosspovidone with

combination of kyrone T-314 is very

effective to decease the disintegration

timeThe high values of X12 Coefficient

also suggest that the interaction between

X1 and X2 has significant effect on

disintegration time.



effective to decease the wetting time

which is desirable. The high values of X12

Coefficient also suggest that the

interaction between X1 and X2 has

significant effect on wetting time.

0102030405060708090

100

0 5 10 15 20 25 30

E1 E2 E3 E4 E5 E6 E7 E8 E9

Time (Min.)

% C

PR





effective to increase drug release at 5 min

which is desirable. The high values of X12

Coefficient also suggest that the

interaction between X1 and X2 has

significant effect on drug release at 5 min.

CONCLUSION

From the above work it was concluded that the release of drug from the E5 formulation was quick when

compared to other formulation. It shows that the combined effect of crosspovidone and kyrone T-314

gives synergistic effect. Undoubtedly the availability of various technologies and the manifold advantages

of FDT will surely enhance the patient compliance, low dosing, rapid onset of action, increased

bioavailability, low side effect, good stability and its popularity in near future

ACKNOWLEDGEMENT

We are thankful to Sun Pharma Ltd. Baroda, Corel Pharma Chem., Ahmadabad, Orbicular Pharma. Tech.

Pvt Ltd. , Modern chemical corp., Mumbai. , Oxford lab. Mumbai. , Lesar Chemicals, Ahmedabad., Finar

chemicals ltd, Mumbai for the gift samples of the drug and excipients, Department of Pharmaceutics,

Nootan Pharmacy College, Visnagar for providing facilities to carry out DSC study. We are also thankful

to Shri B. M. Shah College of Pharmaceutical Education and Research, modasa. for providing the

opportunity to carry out our research work successfully. I heartly thanks to Patel, Dr k. r. patel, Dr m. r.

patel for providing us Kind support all the time throughout the work.

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