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International Journal of Medicine and Pharmacy, Vol. 1 No. 1, December 2013 33

©American Research Institute for Policy Development www.aripd.org/ijmp

“Formulation, Evaluation and Development of Immediate Release Film

Coated Tablets of Atorvastatin and Sustained Release Film Coated Tablets

of Ezetimibe in Capsules Form Usp”

P.Palanisamy1

B.Jayakar1

R.Margret Chandira1

B.S.Venkateshwarlu1

A.Pasupathi1

Abstract

The present study deals with the formulation of film coated immediate release tablet of

Atorvastatin and sustained release tablet of ezetimibe. Atorvastatin is a selective

competitive inhibitor of HMG CoA reductase while Ezetimibe is a lipid lowering drug.

Atorvastatin reduces total cholesterol, low density lipoprotein (LDL). HMG CoA

reductase catalyzes the HMG CoA to mevolanate, which is the limiting step in cholesterol

biosynthesis. It also reduces the VLDL cholesterol and triglyceride. The drug powders

were subjected to preformulation studies. The drug and excipients compatability were

carried out by FT-IR studies and DSC studies. In the present study the tablets were

prepared by wet granulation method using binding agents like polyvinyl pyrolidone(K-

30), sodium sulphate, microcrystalline cellulose, Crospovidone, Croscarmellose sodium

and magnesium stearate. The prepared tablet formulations were evaluated for various parameters like weight variation, hardness, friability, disintegration time, and drug

content. Along with these drug excipients interaction, In-vitro dissolution studies and

stability studies also performed. Drug excipients studies, FT-IR spectroscopic studies and

DSC studies revealed that there are no drug – excipients interaction. In-vitro release

studies were carried out in USP-XXII tablet dissolution apparatus –II using 0.05M

phosphate buffer pH-6.4 and 0.5% SLS in acetate buffer as dissolution medium and

HPLC analyzed for Atorvastatin at 242nm and Ezetimibe at 232nm.

Keyword: Atorvastatin, Ezetimibe, Crospovidone and Croscarmellose sodium.

Introduction

Convenient oral drug delivery

The convenient oral drug delivery has been known for decades is the most widely utilized route

of administration among all the routes. It remains the preferred route of administration in the discovery

and development of new drug candidates.

1 Department of Pharmaceutics, Vinayaka Mission’s College of Pharmacy, Vinayaka Missions University,

Yercaud Main Road, Kondappanaickenpatty, Salem (D.T) 636 008, Tamilnadu, India



34 International Journal of Medicine and Pharmacy, Vol. 1 No. 1, December 2013

©American Research Institute for Policy Development www.aripd.org/ ijmp

The popularity of oral route is attributed to patient acceptance, ease of administration, accurate

dosing, cost effective manufacturing methods and generally improve the shelf life of the product1.

Immediate release tablets:

Immediate release tablets are designed to disintegrate and release the drug in absence of any

controlling features such as coating or other formulation techniques. Despite a rising interest incontrolled-release drug delivery systems, the most common tablets are those intended to be swallowed

whole, disintegrating and releasing their medicaments rapidly in the gastrointestinal tract. A

Disintegrant is a substance in a tablet formulation that enables the tablet to break up into smallerfragments upon contact with gastrointestinal fluids. Such a rapid rupture of the tablet matrix increases

the surface area of the tablet particles, Thereby increasing the rate of absorption of the active ingredientand producing the desired therapeutic action2.

Sustained release tablets:

Sustained release dosage forms are designed to achieve a prolonged therapeutic effect bycontinuously releasing drug over an extended period of time after administration of a single dose. The

advantages of sustained release dosage forms over conventional forms include the less fluctuation in

drug blood levels, frequency reduction in dosing, enhanced convenience and compliance, reduction inadverse side effects and reduction in overall health care costs. The rate of drug release from solid dosageform may be modified by the technologies, which in general are based on modifying drug dissolution

through the use of barrier coatings and controlling drug diffusion rates from dosage forms. Generally the

different techniques employed to fabricate the modified release dosage forms are coated beads, granulesand microspheres, multi tablet system, micro encapsulated drug, complex formation, ion exchange

resins, and embedding drug in slowly eroding or hydrophilic matrix system3.

Objective:

In pharmaceutical practice several approaches exist for administration of drug to the patient. Ifthe drug is given in conventional dosage form, it has to be administered several times to produce

designed therapeutic effect. Because of frequent dosing fluctuation in plasma drug level occur.

Fluctuation resulting from the conventional dosage form it minimize by sustained release dosage form.Drug concentration can be controlled within narrow therapeutic range by use sustained release system.Combination of two drugs gives synergistic action to reduce the VLDL and LDL. So that suchcombination tablet prepared.

Experimental work:

Atorvastatin calcium is a low humidity condition. Special care was taken for Atorvastatin

calcium processing in low humidity condition and geometric mixing is applied.

Materials and Methods

Atorvastatin calcium and Ezetimibe was procured by Wanbury limited (Mumbai, India),HPMC – K14, HPMC – K4, Calcium carbonate, Lactose DCL-11 and MCC pH-102 was gifted by FMC

Bio-polymer (India). Croscarmellose sodium and Cross povidone was gifted by Chetan & Chetan(India). Purified Talc, Sodium starch glycolate and calcium stearate was gifted by Cabot Sanmer (India).

Impurity profile:

Single and total impurities present in Active pharmaceutical ingredient (API) were measured byHPLC. The results are shown in Table. No: 13, 14. & Figure. No: 3,4.





Assay:

In house HPLC based method of assay was developed or both API’s. The sample of drug

solution was prepared and suitably diluted with mobile phase. Each sample was run andchromatograms were obtained. The concentration of drug was calculated as

Concentration of sample=Peak area of sample x Concentration of reference standard

Peak area of reference standard

The results are shown in figure. No: 3, 4.

Spectral Identification 4:

Excipients are integral components of almost all pharmaceutical dosage forms. The successfulformulation of a stable and effective solid dosage form depends on the careful selection of theexcipients, which are added to facilitate administration, to promote the consistent release and

bioavailability of the drug and protect it from degradation. Infra red spectroscopy is one of the most

powerful analytical techniques to identify functional groups of a drug.

In the present study, the potassium bromide disc (pellet) method was employed. Chemical

stability was confirmed by IR spectrometry.The results are shown in Figure. No: 5, 6, 7, 8 & 9.

Differential Scanning Calorimeter Studies 5:

The sample of plain drug was scanned in beginning. Than physical mixtures of drug with

excipients kept for one month, were scanned. Both the drug was scanned from50°C to 250

°C.

The results are shown in Figure. No: 10, 11, 12, 13 & 14.

Compatibility Studies 6:

Drug–Excipients compatibility was performed using HPLC method and by physicalobservation.

The results are shown in Table. No: 15, 16 & 17

Protocol for drug-excipients compatibility for Atorvastatin Calcium

Table.No:1 Ratio of Atorvastatin Calcium to Excipients Taken For Compatibility Study

S.No. Ingredient Ratio

1 Atorvastatin Calcium 1

2 Atorvastatin Calcium : Calcium carbonate 1:1

3 Atorvastatin Calcium : Lactose DCL-11 1:1

4 Atorvastatin Calcium : MCC pH-102 1:1

5 Atorvastatin Calcium : Croscarmellose Sodium 1:1

6 Atorvastatin Calcium : Cross povidone 1:17 Atorvastatin Calcium : Purified Talc 1:3

8 Atorvastatin Calcium : Sodium Lauryl Sulphate 1:3

9 Atorvastatin Calcium : Calcium Stearate 1:3

10 Atorvastatin Calcium : Erythrocin Supra 1:0.5

11 Atorvastatin Calcium : HPMC E-15 1:0.5

12 Atorvastatin Calcium : HPC 1:0.5

13 Atorvastatin Calcium : Titanium dioxide 1:0.5

14 Atorvastatin Calcium : All excipients 1:1





Protocol for drug-excipients compatibility for Ezetimibe

Table.No:2 Ratio of Ezetimibe to Excipients Taken For Compatibility Study

S.No. Ingredient Ratio

1 Ezetimibe 1

2 Ezetimibe + Lactose Monohydrate 1:1

3 Ezetimibe + PVP –K 30 1:1

4 Ezetimibe + HPMC k – 15M 1:1

5 Ezetimibe + HPMC k – 4M 1:1

6 Ezetimibe + Aerosil 1:0.5

7 Ezetimibe + Mg. Stearate 1:0.5

8 Ezetimibe + All excipients 1:1

Preformulation Studies of Pure Drug And Excipients 7-8 :

Preformulation study relates to pharmaceutical and analytical investigation carried out proceeding and supporting formulation development efforts of the dosage form of the drug substance.Preformulation yields basic knowledge necessary to develop suitable formulation for the toxicological

use. It gives information needed to define the nature of the drug substance and provide frame work forthe drug combination with pharmaceutical recipients in the dosage form. Hence, the following

Preformulation studies were performed on the obtained sample of drug.The results are shown in Table. No: 18, 19, 20 & 21.

Tablet Manufacturing

Manufacturing of Atorvastatin Calcium:

Manufacturing Procedure - Atorvastatin calcium tablets using direct compression:

(A) The corresponding amount of drug (Atorvastatin Calcium) was screened using screen #40,

and Lactose DCL-11 accurately weighted & screened using screen # 40. The screened powder was

transferred into the poly bag in 1:10 ratio and mixed for 3 minutes. Pass it every time through #40,further mix for 2 minutes. Geometric mixing with remaining Lactose DCL is done in same proportion.MCC pH-102 pass through # 40, mix well for 3 minutes with A & pass it through #40. CalciumCarbonate pass through screen #40, was transferred into the cage blender and mixed for 5 minutes.

Super-disintegrants and lubricants is accurately weighed & screen # 60 is then mixed in the poly bag or

cage blender for 3 minutes. The mixture was compressed into tablets using an instrumented tablet presswith 6mm punches for 100mg weight at 7-8kp hardness and tablets were collected during compressionfor in-process testing (weight, friability and hardness).





Table No: 3 Formulation of Atorvastatin Calcium IR Tablet

Batch. No ATF1 ATF2 ATF3 ATF4 ATF5 ATF6 ATF7 ATF8 ATF9

Ingredient mg/tablet

Atorvastatin

Calcium

20.70 20.70 20.70 20.70 20.70 20.70 20.70 20.70 20.70

CalciumCarbonate

11 11 11 11 11 11 11 11 11

Lactose DCL -11

54 52 50 47.65 52 50 44 47.65 40

MCC pH-102 19.50 19.50 19.50 19.85 19.50 19.50 19.50 19.50 19.50

Croscarmellose Sodium

2 4 6 8 - - - - 8

Cross

Povidone

- - - - 2 4 6 8 8

Talc 1 1 1 1 1 1 1 1 1

Sodium Lauryl

Sulphate

1 1 1 1 1 1 1 1 1

Calcium

Stearate

0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8

Tablet weight 110mg 110mg 110mg 110mg 110mg 110mg 110mg 110mg 110mg

Table No: 4 Film Coating for Atorvastatin Calcium IR Tablets

S.NO Ingredients Quantity(mg)

Ingredients For One tablet

1 Erythrocin Supra 0.05

2 Protectab – HP 1.8

3 Polysorbate – 80 0.8

4 Purified Water Qs

Table No: 5 Optimized Parameters for Film Coating for Atorvastatin Calcium IR TabletsConditions Pre-heating Coating Drying

Inlet air temperature (°C) 55-60 60-65 50

Product temperature (°C) 55-60 50-55 55-60

Outlet air temperature (°C) 35-60 55-60 50-55

Spray rate (ml/min) - 1-2 -

Atomizing air pressure (psi) - 20

Pan speed (rpm) 35-37 35-37 35-37

Tablet Manufacturing

Manufacturing of Ezetimibe:

Manufacturing Procedure – Ezetimibe tablets using wet granulation:

Pass Ezetimibe (Ingredient NO.1), Lactose (Ingredient No.2), PVP –K-30 (Ingredient NO.3)

and HPMC – K 15 (Ingredient NO.4) through # 60 sieve on a Mechanical Sifter. Mix Ezetimibe(Ingredient NO.1), Lactose (Ingredient NO.2) in geometrical manner. Transfer to the Planetary Mixer.Transfer the wet granular mass in Fluidized Bed Drier for drying and dry it for 15 minutes at 50˚C.

Remove the trolley and do the reshuffling. Again dry the material for 20 minutes.





Pass the dried mass through #30 sieve on Mechanical Sifter and the granules remain on the

sieve shall be passed through 2mm perforator on Multimill. Check and record the weight of the driedgranules. Repass the milled granules through #30S. S. sieve on a Mechanical Sifter to ensure correct

size of granules. Check the weight of the dried granules. Check L.O.D. (Range NMT 3% W/W).

Table No: 6 Formulation of Ezetimibe Tablet

Batch.No EZF1 EZF2 EZF3 EZF4 EZF5 EZF6 EZF7 EZF8

Ingredients mg/tablet

Ezetimibe 10 10 10 10 10 10 10 10

Lactose Monohydrate 44.8 42.8 40.8 39.8 44.8 42.8 40.8 39.8

PVP – K 30 4 4 4 4 4 4 4 4

HPMC –k-15M 30 32 34 35 - - - -

HPMC –k-4M - - - - 30 32 34 35

IPA q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.

Aerosil 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2

Mg. Stearate 1 1 1 1 1 1 1 1

Tablet weight 90mg 90mg 90mg 90mg 90mg 90mg 90mg 90mg

Table No: 7 Film Coating for Ezetimibe SR Tablets

S.NO Ingredients Quantity(mg)

Ingredients For One tablet

1 Sunset Yellow Supra 0.05

2 Protectab – HP 1.8

3 Polysorbate – 80 0.8

4 Purified Water Qs

Table No: 8 Optimized Parameters for Film Coating for Ezetimibe SR Tablets

Conditions Pre-heating Coating Drying

Inlet air temperature (°C) 55-60 60-65 50

Product temperature (°C) 55-60 50-55 55-60

Outlet air temperature (°C) 35-60 55-60 50-55

Spray rate (ml/min) - 1-2 -

Atomizing air pressure (psi) - 20

Pan speed (rpm) 35-37 35-37 35-37

Post Compression Parameters 9-12

:

a) Weight Variation Test:

Twenty tablets were selected randomly from each batch and weighed individually to check for

weight variation. A little variation was allowed in the weight of a tablet according to U.S.Pharmacopoeia. The following percentage deviation in weight variation was allowed.

Average weight of a tablet Percentage deviation 130 mg or less ± 10

>130 mg and <324 mg ± 7.5

324mg or more ± 5





The results are shown in Table. No: 22, 23, 24 & 25.

b) Tablet Dimensions:

Thickness and diameter were measured using calibrated Vernier calipers. Five tablets of each

formulation were picked randomly and thickness and diameter was measured individually.

The results are shown in Table. No22, 23, 24 & 25.c) Thickness:

The thickness of the tablets was determined by Vernier calipers. Five tablets from each batchwere used and the average values were calculated. The results are shown in Table. No: 22, 23, 24 & 25.

d) Hardness:

Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. The

hardness of the tablets was determined using Monsanto hardness tester. It is expressed in kg/cm2. Five

tablets were randomly picked and hardness of the tablets was determined. The results are shown inTable. No: 22, 23, 24 & 25..

e) Friability test:

The friability of tablets was determined by using Roche friabilator. It is expressed in percentage(%). Twenty tablets were initially weighed (Wt) and transferred into friabilator. The friabilator was

operated at 25 rpm for 4 minutes or run up to 100revolutions. The tablets were weighed again (WF).

The % friability was then calculated by-

W (initial)-W (final)%F = ___________________×100

W (initial)

The results are shown in Table. No: 22 & 24.

f) Disintegration test:

The disintegration time for immediate release layer was determined using the disintegration

apparatus. One tablet was placed in each of six tubes placed in a beaker containing 1000 ml of purified

water maintained at 37 ± 20°C and the apparatus was operated. The time taken for the tablets todisintegrate and pass through the mesh was noted.The results are shown in Table. No: 22, 23, 24 & 25.

Method of Analysis 13-17

In Vitro Dissolution Study:

Dissolution study of Immediate release of different tablet formulations and sustained release

tablets were carried out separately and capsule form.

For Atorvastatin Calcium:

Dissolution Media : 900mL of 0.05M Phosphate buffer6.8 , 0.45 % SLM Acetate buffer PH 4.5

Bath volume : 900mL

RPM: 75

Apparatus: USP 2 Paddle





Sample Time: 5Minutes

For Ezetimibe:Dissolution Media : 900mL of 0.45% SLM Acetate buffer PH 4.5

RPM: 75Apparatus: USP 2 Paddle

Sample Time: 5Minutes

The results are shown in Table. No: 26 &32. & Figure. No: 15 to 19.

In-vitro Drug Release Kinetic Studies18

:

The dissolution data were subjected to release kinetic study. Drug dissolution from soliddosage form has been described by kinetic models in which the dissolved amount of drug (Q) iscompared to the Drug content (%) function of the test time (t). some analytical and kinetic models of

the Q versus t commonly used are Zero order, First order, Hixson – Crowell, Higuchi and Korsmeyer –

Peppas model to study the in-vitro kinetic release mechanism.

The results are shown in table.No: 33 & 34 Figure.No: 20 & 23

Stability Studies 19-20

:

Stability testing forms an integral part of formulation development. It is important to assess theeffect of temperature and humidity on stability of drug and in-vitro drug release rate. It helps togenerate information for predicting the shelf life of the product and recommended storage conditions.

Stability data is required to be submitted as part of the dossier submitted to the regulatory agencies.

Protocol For stability studies:

Formulation was selected on the basis of in-vitro drug release profile which was comparable to

that of the IR or SR formulation under reference i.e. optimized formula for both Atorvastatin &Ezetimibe batches. Optimized formula Batch.no: ATF9 for At orvastat in IR (10mg), in Alu BlisterPack. Optimized formula Batch.no: EZF8 for Ezetimibe in strip pack was tested for stability under two

conditions for a period of six months. The conditions for stability are as mentioned in Table. No: 35 &36

Table No: 9 Stability Condition For Atorvastatin (IR) & Ezetimibe (SR) Tablet

Study Storage condition Time Period Covered

Room Temperature(RT)

25°C ± 2°C/60%RH± 5%RH 6monthsTesting :If accelerated condition tablet is

passed

Accelerated 40°C ± 2°C/75%RH± 5%RH 6 months

Testing:1,2,3 & 6 month

These were evaluated for their physicochemical characteristics, drug content, assay and in-vitro release profile of Atorvastatin and Ezetimibe Tablet.

In–vitro release and content of active ingredients was estimated at one month interval

during to rage period.

Atorvastatin & Ezetimibe Tablet and Capsule Stability Study:(A Capsule with both)

After optimizations of three formulations i.e. Atorvastatin Calcium IR (20mg), & Ezetimibe

SR (10mg) Tablet individually, two formulations of Atorvastatin and Ezetimibe.





Tablet are put in a size one capsule and kept for six months stability as per ICH in Alu Alu Pack.

Each month sampling was done and all the parameters of tablet are analyzed.

Table No: 10 Stability Condition for Atorvastatin & Ezetimibe Capsule

Study Storage condition Time Period Covered

Room Temperature (RT) 25°C ± 2°C/60%RH± 5%RH 6 months

Testing :If accelerated conditiontablet is passed

Accelerated 40°C ± 2°C/75%RH± 5%RH 6 months

Testing:1,2,3 & 6 month

The results are shown in Table. No: 36 & 38.

Result and Discussion

Table no: 11 Standard Calibration Curve of Atorvastatin Calcium

S.No Concentration in ppm Area

1 0 0

1 10 1827247.6672 20 3618371.667

3 50 8959876.000

4 100 18118982.333

5 120 21555409.333

6 160 29532241.333

7 200 36224779.667

*Mean±SD n=3

Fig. no: 1 Standard Calibration Curve of Atorvastatin Calcium

Table no: 12 Standard Calibration Curve of Ezetimibe

S.No Concentration in ppm Absorbance (nm)

1 0 0

1 10 0.153

2 20 0.314

3 30 0.448

4 40 0.593

5 50 0.741

*Mean±SD n=3





Figure no: 2 Standard Calibration Curve of Ezetimibe

Impurity Profile and Assay:

For Atorvastatin calcium:

Table No: 13 Impurity Profile and Assay of Atorvastatin Calcium API

Impurity A 0.04%

Impurity B Not Detected

Impurity C Not Detected

Impurity D 0.07%

Any Other Impurity Not Detected

Total Impurity 0.35%

Assay 99.75%

Conversional factor 1.0359

*Mean±SD (n=6)

Figure No: 3 Atorvastatin calcium Assay Chromatogram

For Ezetimibe:

Table No: 14 Impurity Profile of Ezetimibe

Impurity A 0.05%

Impurity B Not Detected

Impurity C Not Detected

Impurity D 0.06%

Any Other Impurity Not Detected

Total Impurity 0.25%

Assay 99.85%

Conversional factor 1

*Mean±SD (n=6)





Figure No: 4 Ezetimibe Assay Chromatogram

FT-IR Spectroscopy:

The result of FT-IR study for Atorvastatin calcium and their excipients are shown in Figure. No

: 5 to 9.


Figure No: 5 FT-IR Spectrum of Atorvastatin Calcium Pure API

Figure No: 6 FT-IR Spectrum of Atorvastatin Clacium + All excipients

For Ezetimibe:

Figure No: 7 FT-IR Spectrum of Ezetimibe Pure API





Figure No: 8 FT-IR Spectrum of Ezetimibe + All excipients

For Atorvastatin Calcium and Ezetimibe:

Figure No: 9 FT-IR Graph of Atorvastatin Calcium and Ezetimibe

Discussion:

From this figure it was found that following API and their granules for compression match

with reference standard of the API.

DSC Studies:


Figure No: 10 DSC Graph of Atorvastatin Calcium Pure API

Discussion:

From this figure. No: 10 it can be seen that peak value of Atorvastatin Calcium was found to be

157.94°C in DSC thermogram. This value matches with that given in the literature and confirm the

purity of API.





Figure No: 11 DSC Graph of Atorvastatin Calcium + All Excipients

From this figure. No:11 it can be seen that peak value of Atorvastatin Calcium with allExcipients was found to be 158.27°C in DSC thermogram. This value matches with that given in the

literature and confirm the purity of API.

For Ezetimibe:

Figure No: 12 DSC Graph of Ezetimibe Pure API

From this figure. No:12 it can be seen that peak value of Ezetimibe pure drug was found to be

137.21°C in DSC thermogram. This value matches with that given in the literature and confirm the purity of API.

Figure No: 13 DSC Graph of Ezetimibe + All Excipients

From this figure. No:13 it can be seen that peak value of Ezetimibe with all Excipients wasfound to be 138.18°C in DSC thermogram. This value matches with that given in the literature and

confirm the purity of API.

For Atorvastatin Calcium AND Ezetimibe Mixture:





Figure No: 14 DSC Graphs of Atorvastatin Calcium and Ezetimibe

Discussion:

From this figure. No:14 it can be seen that peak value of Atorvastatin Calcium and Ezetimibe

was found to be 168.74°C in DSC thermogram. This value matches with that given in the literature andconfirm the purity of API.

Compatability studies:


Table No: 15 Compatibility study of Atorvastatin calcium with Excipients: The RS Data of

Atorvastatin calcium (By HPLC) of 1 month excipients Compatability @ 40°C-75% RH

Ingredient Ratio Description

Related substance %w/w 1Month 1 Month

25°C/60%

RH

40°C/75

%RH

Atorvastatin Calcium 1 White to pale yellow, granular powder * *

Atorvastatin Calcium : Calcium

carbonate

1:1 White to pale yellow, granular powder * *

Atorvastatin Calcium : Lactose DCL-11 1:1 White to pale yellow, granular FF

powder * *

Atorvastatin Calcium : MCC pH-102 1:1 White to pale yellow, granular powder * *

Atorvastatin Calcium : Croscarmellose

Sodium

1:1 White to Greyish white , granular

powder * *

Atorvastatin Calcium : Cross povidone 1:1 White to Grayish white , granular powder

* *

Atorvastatin Calcium : Purified Talc 1:3 White to pale yellow, granular powder * *

Atorvastatin Calcium : Sodium Lauryl

Sulphate


Atorvastatin Calcium : Calcium Stearate 1:3 White to pale yellow, granular powder * *

Atorvastatin Calcium : Erythrocin

Supra

1:0.5 White to pale yellow, granular FF

powder * *

Atorvastatin Calcium : HPMC E-15 1:0.5 White to pale yellow, granular powder * *

Atorvastatin Calcium : HPC 1:0.5 White to pale yellow, granular powder * *

Atorvastatin Calcium : Titanium dioxide 1:0.5 White to pale yellow, granular powder * *

Atorvastatin Calcium : All excipients 1:1 White to pale yellow, granular powder * *

Discussion:

From this table it can be seen the Atorvastatin calcium is compatible with all the excipients usedin the study.

Result: * Indicated That No Change Was Observed





Table No: 16 Compatibility study of Ezetimibe with Excipients:The RS Data of Ezetimibe (By

HPLC) of 1 month excipients Compatability @ 40°C-75% RH



25°C/60

%RH

40°C/75%

RHEzetimibe 1 White to pale yellow, granular powder * *

Ezetimibe : Lactose

Monohydrate


Ezetimibe : PVP – K 30 1:1 White to pale yellow, granular FF powder * *

Ezetimibe : HPMC –k-15M 1:1 White to pale yellow, granular powder * *

Ezetimibe : HPMC –k-4M 1:1 White to Greyish white , granular powder * *

Ezetimibe : IPA 1:0.5 White to Grayish white , granular powder * *

Ezetimibe : Aerosil 1:3 White to pale yellow, granular powder * *

Ezetimibe : Mg. Stearate 1:3 White to pale yellow, granular powder * *

Ezetimibe : All Excipients 1:1 White to pale yellow, granular powder * *

Discussion:

From this table it can be seen the Ezetimibe is compatible with all the excipients used in the

study.


Table No: 17 Compatibility studies of Atorvastatin calcium & Ezetimibe: The RS Data of

Atorvastatin calcium & Ezetimibe (By HPLC) of 1 month excipients Compatability @ 40°C-75% RH



25°C/60%RH 40°C/75%RH

Atorvastatin Calcium:

Ezetimibe

1:1 White to pale yellow,

granular powder

* *

Discussion:

From this table it can be seen the Atorvastatin Calcium and Ezetimibe is compatible with all the

excipients used in the study.



Table No: 18 Preformulation Study of Pure Drug (Atorvastatin Calcium).

S.NO. Parameters Result Conclusion

1 Bulk Density* 0.675 gm/ml ------

2 Tapped Density* 0.75 gm/ml -----

3 Angle of Repose* 19.61 Excellent

4 Carr’s Index* 10 % Excellent Flow

5 Hausner Ratio* 1.11 Better Flow

6 Melting Point* 159.2-160.7 °C ----

7 Solubility*Freely soluble in methanol, slightly soluble in ethanol,

very slightly soluble in water

*Mean±SD (n=6)





Table No: 19 Preformulation Study of the blend (Atorvastatin Calcium)

Batch

Code

Bulk

Density*

Tapped

Density*

Angle of

repose*

%

Compressibility*

Hausner

Ratio*

Loss onDrying*

ATF1 0.41 0.47 24.58 12.76 1.15 2.1

ATF2 0.44 0.52 25.91 15.38 1.18 1.9

ATF3 0.44 0.51 26.86 13.72 1.16 1.8ATF4 0.47 0.54 24.43 12.96 1.14 1.7

ATF5 0.45 0.50 24.10 12.00 1.06 1.6

ATF6 0.46 0.53 24.77 13.20 1.15 1.7

ATF7 0.47 0.52 25.42 9.61 1.11 1.5

ATF8 0.45 0.52 23.43 12.60 1.17 1.6

ATF9 0.49 0.55 26.10 9.05 1.61 1.8

*Mean±SD (n=6)

Discussion:

The physical parameters of drug as well as blends concluded that these were considerably good

to formulate the tablet using direct compression technique.

For Ezetimibe:

Table.No: 20 Preformulation Study of Pure Drug (Ezetimibe).

S.NO Parameters Result Conclusion

1 Bulk Density* 0.665 gm/ml ------

2 Tapped Density* 0.65 gm/ml -----

3 Angle of Repose* 16.66 Excellent

4 Carr’s Index* 11 % Excellent Flow

5 Hausner Ratio* 1.103 Better Flow

6 Melting Point* 135 – 140oC ----

7 Solubility*Freely soluble ij ethanol, methanol and acetone. Practically insoluble

in water.

*Mean±SD (n=6)

Table No: 21 Preformulation Study of the blend (Ezetimibe)

BatchCode

BulkDensity*

TappedDensity*

Angle ofrepose*

%Compressibility*

HausnerRatio*

Loss on

Drying*

EZF1 0.43 0.46 25.58 12.76 1.14 2.2

EZF2 0.42 0.51 24.91 13.38 1.15 1.3

EZF3 0.43 0.52 25.86 12.72 1.17 1.6

EZF4 0.45 0.53 25.48 13.96 1.15 1.4EZF5 0.46 0.52 26.10 13.00 1.09 1.5

EZF6 0.47 0.54 26.87 14.20 1.18 1.6

EZF7 0.44 0.52 26.42 10.61 1.14 1.7

EZF8 0.44 0.53 23.43 9.60 1.18 1.9

*Mean±SD (n=6)





Discussion:

The physical parameters of drug as well as blends concluded that these were considerably good

to formulate the tablet using wet granulation technique.

Table No: 22 Evaluation of Atorvastatin calcium Core IR-Tablets

BatchNo Weight variation(mm)** Diameter(mm)* Thickness(mm)* Hardness(kg/cm2)* Friability(%)* DisintegrationTime*

ATF1 111±6.5 5.39±0.02 3.32±0.03 3.45±0.21 0.25 53 seconds

ATF2 111±6.5 5.28±0.01 3.23±0.04 3.51±0.20 0.31 47 seconds

ATF3 112±5.6 5.39±0.03 3.34±0.04 3.45±0.14 0.28 49 seconds

ATF4 112±6.5 5.47±0.02 3.25±0.05 3.57±0.13 0.32 51 seconds

ATF5 111±5.8 5.38±0.03 3.36±0.04 3.67±0.12 0.34 48 seconds

ATF6 112±6.7 5.37±0.04 3.27±0.05 3.57±0.12 0.32 49 seconds

ATF7 110±5.8 5.48±0.03 3.26±0.06 3.89±0.14 0.34 46 seconds

ATF8 111±5.8 5.39±0.02 3.28±0.05 3.56±0.11 0.33 50 seconds

ATF9 111±6.8 5.49±0.01 3.25±0.06 3.87±0.15 0.35 51 seconds

*Mean±SD (n=6) **Mean±SD (n=20)

Table No: 23 Evaluation of Atorvastatin calcium Film Coated IR-Tablets

BatchNo

Weight variation(mm)**

Diameter(mm)*

Thickness(mm)*

Hardness(kg/cm

2)*

DisintegrationTime*

ATF1 114±6.5 5.69±0.01 3.42±0.03 4.15±0.21 1 mts 23 sec

ATF2 115±7.5 5.68±0.02 343±0.04 4.17±0.20 1 mts 33 sec

ATF3 116±6.6 5.69±0.02 3.44±0.04 3.75±0.14 1 mts 33 sec

ATF4 115±7.5 5.57±0.01 3.45±0.05 3.87±0.13 1 mts 35 sec

ATF5 114±7.8 5.68±0.02 3.46±0.04 3.87±0.12 1 mts 32 sec

ATF6 115±6.7 5.67±0.02 3.47±0.03 3.86±0.21 1 mts 26 sec

ATF7 114±6.8 5.65±0.03 3.55±0.04 3.88±0.13 1 mts 23 sec

ATF8 114±6.7 5.65±0.07 3.43±0.05 3.86±0.11 1 mts 33 sec

ATF9 114±7.8 5.69±0.03 3.45±0.06 3.87±0.15 1 mts 12 sec


Discussion:

The tablets were compressed at the average weight of 110mg. The weight variation of all

batches in the ranges of 114±6.5 to 116±6.6 mm. The tablets diameters are 5.57±0.01 to 5.69±0.03 mm.

The tablets thickness is 3.42±0.03 to 3.55±0.04 mm. The tablets hardness are 3.86±0.11 to 4.17±0.20kg/cm

2. The disintegration time is important parameter of tablets. The disintegration time ranges of 1

minutes 12 seconds to 1 minutes 35 seconds.

Table No: 24 Evaluation of Ezetimibe Core SR-Tablets

Batch

No

Weight variation

(mm)**

Diameter

(mm)*

Thickness

(mm)*

Hardness

(kg/cm2)*

Friability

(%)*

Disintegratio

n Time*

EZF1 90±7.5 5.29±0.02 3.21±0.03 3.41±0.21 0.35 54 seconds

EZF2 91±7.1 5.28±0.01 320±0.04 3.41±0.20 0.31 49 seconds

EZF3 91±6.6 5.27±0.03 3.24±0.04 3.47±0.11 0.38 47 seconds

EZF4 91±6.8 5.27±0.02 3.21±0.05 3.47±0.12 0.34 50 seconds

EZF5 91±5.8 5.38±0.03 3.23±0.04 3.57±0.13 0.35 45 seconds

EZF6 92±6.7 5.25±0.04 3.21±0.05 3.67±0.14 0.33 47 seconds

EZF7 92±5.8 5.28±0.03 3.22±0.06 3.69±0.13 0.36 45 seconds

EZF8 92±5.8 5.29±0.02 3.23±0.05 3.64±0.12 0.37 52 seconds






Table No: 25 Evaluation of Ezetimibe Film Coated SR-Tablets

Batch

No

Weight variation (mm)** Diameter

(mm)*

Thickness

(mm)*

Hardness

(kg/cm2)*

Disintegration

Time*

EZF1 95±7.3 5.30±0.01 3.22±0.03 3.46±0.21 1 mts 28 sec

EZF2 94±7.2 5.29±0.02 3.21±0.04 3.51±0.20 1 mts 37 sec

EZF3 95±6.8 5.29±0.04 3.25±0.04 3.52±0.11 1 mts 39 sec

EZF4 96±6.7 5.31±0.03 3.23±0.05 3.57±0.12 1 mts 39 sec

EZF5 95±6.8 5.33±0.05 3.24±0.04 3.67±0.13 1 mts 37 sec

EZF6 95±6.7 5.35±0.02 3.23±0.05 3.69±0.14 1 mts 35 sec

EZF7 96±5.8 5.35±0.04 3.24±0.06 3.70±0.13 1 mts 33 sec

EZF8 96±6.8 5.35±0.01 3.25±0.05 3.65±0.12 1 mts 36 sec


Discussion:

The tablets were compressed at the average weight of 90mg. The weight variation of all batches in the ranges of 94±7.2 to 96±6.7 mm. The tablets diameters are 5.29±0.02 to 5.35±0.04 mm.

The tablets thickness is 3.21±0.04 to 3.25±0.05 mm. The tablets hardness are 3.46±0.21 to 3.46±0.21

kg/cm2

. The disintegration time is important parameter of tablets. The disintegration time ranges of 1minutes 28 seconds to 1 minutes 39 seconds.

In-Vitro Dissolution Studies:

Table No: 26 Dissolution Profile of the Atorvastatin calcium IR Tablets ATF1-ATF9

% Cumulative Amount of Drug Release

Time

(Minutes)

ATF1 ATF2 ATF3 ATF4 ATF5 ATF6 ATF7 ATF8 ATF9

0 0 0 0 0 0 0 0 0 0

5 52.34 56.13 58.54 60.61 53.78 56.67 58.89 60.45 65.19

10 72.35 74.87 76.78 77.89 71.26 73.98 76.54 78.76 84.12

15 79.87 80.98 82.45 84.27 77.89 78.98 80.78 82.54 97.01

20 82.47 84.89 86.79 88.97 81.89 83.27 84.98 86.87 100.1730 90.12 92.35 94.18 96.78 89.19 93.89 94.89 96.87 103.12

*Mean±SD (n=6)

Figure No: 15 Dissolution Profile of the Atorvastatin calcium IR Tablets ATF1-ATF9

Discussion:

For Atorvastatin calcium FC tablets direct granulation method was selected. Optimization wasfound that based on the in-vitro drug release profile. Here two super disintegrants i.e. croscarmellose

sodium and croscarmellose sodium different concentrations. From this result it can be indicated that the,

optimized formulated tablet (ATF9) were within the Pharmacopeial specifications.





Table No: 27 Dissolution Profile of the Atorvastatin calcium IR Tablet Optimized Formulation

ATF9 with Innovator Tablet


Time in (Minutes) ATF9 INNOVATOR

5 65.19 68.4

10 84.12 85.715 97.01 98.8

20 100.17 99.8

30 103.12 101.30

*Mean±SD (n=6)

Figure No: 16 Dissolution Profile of the Atorvastatin calcium IR Tablet Optimized Formulation

ATF9 with Innovator Tablet

Table No: 28 Assay of the Atorvastatin Calcium IR Tablets

Assay

Atorvastatin Calcium Optimized (ATF9) (Alu Blister Pack)

Mean SD RSD

101.56 1.7 1.7

*Mean±SD (n=6)

Discussion:

From this result it can be indicated that the, optimized formulated tablet (ATF9) assay were

within the Pharmacopeial specifications.

Table No: 29 Dissolution Profile of the Ezetimibe SR Tablets EZF1-EZF8


Time (Hours) EZF1 EZF2 EZF3 EZF4 EZF5 EZF6 EZF7 EZF8

0 0 0 0 0 0 0 0 0

1 30.98 25.34 24.98 21.78 31.23 28.98 23.56 16.353 45.76 44.65 41.76 38.89 46.89 43.67 39.56 28.25

6 58.71 56.89 54.78 53.54 59.78 58.53 56.67 54.78

8 87.76 83.78 81.79 78.98 88.98 86.65 80.97 70.29

12 98.87 97.89 96.78 94.32 98.34 96.98 91.73 89.76

*Mean±SD (n=6)





Figure No: 17 Dissolution Profile of the Ezetimibe SR Tablets EZF1-EZF8

Discussion:

For Ezetimibe FC tablets wet granulation method was selected. Optimization was found that

based on the in-vitro drug release profile. Here two binders used i.e. HPMC k – 15 and HPMC k - 4

different concentrations. From this result it can be indicated that the, optimized formulated tablet(EZF8) were within the Pharmacopeial specifications.

Table No: 30 Dissolution Profile of the Ezetimibe SR Tablet Optimized Formulation EZF8 with

Innovator Tablet


Time in Hours EZF8 INNOVATOR

1 16.35 18.78

3 28.25 30.76

5 54.78 57.65

8 70.29 74.67

12 89.76 92.43

*Mean±SD (n=6)

Figure No: 18 Dissolution Profile of the Ezetimibe SR Tablet Optimized Formulation EZF8 with

Innovator Tablet

Table No: 31 Assay of the Ezetimibe

Assay

Ezetimibe Optimized EZF4 (Alu Blister Pack)

Mean SD RSD

102.46 1.6 1.6

*Mean±SD (n=6)





Discussion:

From this result it can be indicated that the, optimized formulated tablet (EZF8) assay were

within the Pharmacopeial specifications.

Table No: 32 Dissolution Profile of the Capsule Optimized Formulations (ATF9 & EZF8)

% Cumulative Amount of Drug ReleaseTime in Minutes / Hours ATF9 EZF8

0 0.00 NA

5 65.19 NA

10 84.12 NA

15 97.01 NA

20 100.17 NA

30 103.12 NA

1 Hour NA 16.35

3 Hour NA 28.25

6 Hour NA 54.78

8 Hour NA 70.29

12 Hour NA 89.76

*Mean±SD (n=6)

Figure No: 19 Dissolution Profile of the Capsule Optimized formulations (ATF9 & EZF8)

Table No: 33 Kinetic Release Studies or Optimized Formulation

Time inHour

√ Timein Hour

Logtime

% of DrugRelease

(Zero Order)

% of DrugUnreleased

Log % ofDrug Release

Log % of DrugUnreleased

0 0 0 0 0 0 0

1 1.0000 0.0000 16.35 83.65 1.2135 1.9224

3 1.7321 0.4771 28.25 71.8 1.4510 1.85616 2.4495 0.7782 54.98 45.02 1.7402 1.6534

8 2.8284 0.9031 70.20 29.8 1.8463 1.4742

12 3.4641 1.0792 89.21 10.79 1.9504 1.0330





Figure No: 20 Zero Order Release Kinetics of SR tablet of Ezetimibe

Figure No: 21 first Order Release Kinetics of SR tablet of Ezetimibe

Figure No: 22 Higuchi kinetics of SR tablet of Ezetimibe

Figure No: 23 Korsmeyer – Peppas kinetics of SR tablet of Ezetimibe





Table. No: 34 Regression Coefficient (R2) of the optimized formulation

Release kinetics R2

Zero order equation 0.984

First order equation 0.966

Higuchi (diffusion) co-efficient 0.984

Korsmeyer Peppas coefficient 0.950

Discussion:

The release of drug from Ezetimibe SR tablet followed Zero Order kinetics.

Stability Studies:


Table No: 35 Stability Studies Data of the Atorvastatin Calcium IR Optimized Formulations(ATF9) (ALU BLISTER PACK)

Parameter

s

Initial 1st Month 2

n Month 3

r Month 6

t Month

RT 40°C RT 40°C RT 40°C RT 40°CWeight

variation

(mm)**

104±7.8 104± 7.8 103.5±7

.6

103.5±

7.8

103.5±7

.2

103.5±

7.8

103.2±

7.1

103.3±7

.6

103.1±6

.99

Diameter(mm)*

5.69±0.03 5.68±0.03

5.67±0.03

5.68±0.03

5.67±0.02

5.67±0.03

5.66±0.01

5.65±0.02

5.63±0.02

Thickness

(mm)*

3.45±0.06 3.44±

0.06

3.45±

0.06

3.45±

0.06

3.44±

0.05

3.45±

0.06

3.43±

0.04

3.44±

0.05

3.41±

0.02

Hardness

(kg/cm2)*

3.87±0.15 3.86±

0.15

3.86±

0.14

3.86±

0.15

3.86±

0.12

3.86±

0.15

3.85±

0.10

3.84±

0.14

3.83±

0.08

Disintegrat

ion Time*

1 mts 12

sec

1 mts 12

sec

1 mts 11

sec

1 mts

11 sec

1 mts 11

sec

1 mts

11 sec

1 mts

10 sec

1 mts 08

sec

1 mts 06

sec

*Mean±SD (n=6) **Mean±SD(n=20)

Table No: 36 Stability Studies Data of the Assay & Dissolution Study of Atorvastatin Calcium IR

Optimized Formulations (ATF9), Capsules (ALU BLISTER PACK) & Alu Alu Pack

Parameter

s

Initial 1st Month 2

n Month 3

r Month 6

t Month

RT 40°C RT 40°C RT 40°C RT 40°C

*Assay 101.26

±0.435

101.26±

0.435

101.20±0

.421

101.26±0

.435

101.12±0

.435

101.26±

0.435

101.01±0

.435

101.25±

0.432

101.01

±0.422

*% of

Cumulativ

e Release

103.12 102.67 102.76 102.67 102.01 102.67 101.65 102.63 101.25

*% of

Cumulativ

e Release

(Capsule)

103.08 102.58 102.67 102.43 102.47 102.35 101.98 102.32 101.78

*Mean±SD (n=6)

Discussion: Assay*Mean=Not less than 75% ; Dissolution**Mean = Not less than 80%.The results indicated that the, optimized formulated tablets were within the Pharmacopeial

specifications.





For Ezetimibe:

Table No: 37 Stability Studies Data of the Ezetimibe SR Optimized Formulations(EZF8) (Blister Pack)

Paramete

rs

Initial 1st Month 2

nd Month 3

rd Month 6

th Month

RT 40°C RT 40°C RT 40°C RT 40°C

Weight

variation

(mm)**

96±6.8 96±6.5 96±6.4 96±6.4 96±6.2 96±6.4 96±6.1 95±7.4 95±6.

6

Diameter

(mm)*

5.35±0.0

1

5.32±0.

02

5.32±0.

01

5.32±0.

01

5.31±0.

01

5.32±0.

01

5.27±0.

01

5.30±0.

01

5.25±

0.02

Thickness(mm)*

3.25±0.05

3.24±0.05

3.23±0.04

3.24±0.04

3.21±0.04

3.24±0.03

3.18±0.04

3.21±0.03

3.16±0.03

Hardness

(kg/cm2)*

3.65±0.1

2

3.64±0.

11

3.63±0.

10

3.64±0.

09

3.62±0.

10

3.64±0.

08

3.56±0.

10

3.61±0.

06

3.54±

0.12

Disintegr

ation

Time*

1 mts 36

sec

1 mts

35 sec

1 mts 34

sec

1 mts

34 sec

1 mts 32

sec

1 mts

34 sec

1 mts

28 sec

1 mts 32

sec

1 mts

21 sec

*Mean±SD (n=6) **Mean±SD(n=20)

Table No: 38 Stability Studies Data of the Assay & Dissolution Study of Ezetimibe SR Optimized

Formulations (EZF8), Capsules (Alu blister Pack & Alu Alu Pack)

Parameters Initial 1st Month 2

nd Month 3

rd Month 6

th Month

RT 40°C RT 40°C RT 40°C RT 40°C

*Assay102.28

±0.455

102.28

±0.453

102.25±0

.448

102.27±0.

452

102.24±

0.447

102.27±

0.449

102.23±0

.446

102.2

7±0.4

47

102.2

1±0.4

44

*% of

Cumulativ

e Release

89.76 89.75 89.74 89.73 89.73 89.73 89.71 89.72 89.70

*% ofCumulativ

e Release

(Capsule)

89.77 89.76 89.74 89.76 89.74 89.75 89.72 89.74 89.68

*Mean±SD (n=6)

Discussion: Assay*Mean=Not less than 75% ; Dissolution**Mean = Not less than 80%.The results indicated that the, optimized formulated tablets were within the Pharmacopeial

specifications.

Discussion:

From Table, it was seen that Atorvastatin calcium IR Tablets Batch. No: ATF9,

Ezetimibe SR tablet Batch. No: EZF8 and Capsule was showing good stability for six monthsaccelerated condition @ 40°C &75%RH. It was found that post compression parameters,dissolution and assay value are not affected for the batch, and total impurity is also less than 1%.

Summary and Conclusion

The present study deals with the formulation of film coated tablets of Atorvastatin calcium

and Ezetimibe tablets in capsule form as a model drug which is used for the treatment of selectivecompetitive inhibitor of HMG Co-A reductase while Ezetimibe is a lipid lowering drugs.





Atorvastatin reduces total cholesterol, low density lipoprotein (LDL). HMG Co – A reductase

catalyzes the HMG Co – A to mevolanate, which is the rate limiting step in cholesterol biosynthesis. Italso reduces the VLDL cholesterol and triglyceride.

In pharmaceutical practice several approaches exist for administration of drug to the patient.

If the drug is given in conventional dosage form, it has to be administered several times to produce

designed therapeutic effect. Because of frequent dosing fluctuation in plasma drug level occur.Fluctuation resulting from the conventional dosage form it minimize by sustained release dosage form.Drug concentration can be controlled within narrow therapeutic range by use sustained release system.

Combination of two drugs gives synergistic action to VLDL and LDL. So that such combination tablet prepared.

The drug powders were subjected to preformulation studies. The drug and excipientscompatability were carried out by FT-IR studies. In the present study compressed tablet of

Azithromycin dihydrate by using HPMC k -15, HPMC k – 4, starch, lactose DCL-15, Dibasic calcium

phosphate, MCCP and Croscarmellose sodium. “Film coating of Protectab HP-1 Sunset yellow Lake

IPA coating 3 %w/w was done on Atorvastatin and Ezetimibe tablets as to avoid in the drug-druginteraction such as low humidity condition and geometric mixing is applied to avoid contentuniformity and segregation”.

The FT-IR studies it was found that following API and their granules for compression match

with reference standard of the API. From this result it can be concluded that API is pure noincompatibility was found, which no changes its properties. The drug and excipients compatability

studies it can be seen the Atorvastatin and Ezetimibe is compatible with all the excipients used. No physical changes in colour and appearance. From this result it can be concluded that the, impurities and

degradation of drug was also within limits. The physical parameters of drug as well as blends

concluded that these were considerably good to formulate the tablet using direct compressiontechnique (Atorvastatin). In the Ezetimibe study the tablets were prepared by wet granulation

method using binding agents like PVP – k – 30, HPMC – k - 15M, HPMC – k – 4M andmagnesium stearate.

For Atorvastatin calcium FC tablets direct granulation method was selected. Optimization wasfound that based on the in-vitro drug release profile. Here two super disintegrants i.e. croscarmellosesodium and croscarmellose sodium different concentrations. From this result it can be indicated that the,optimized formulated tablet (ATF9) were within the Pharmacopeial specifications. From this result it

can be indicated that the, optimized formulated tablet (ATF9) assay were within the Pharmacopeial

specifications. For Ezetimibe FC tablets wet granulation method was selected. Optimization was found

that based on the in-vitro drug release profile. Here two binders used i.e. HPMC k – 15 and HPMC k -4 different concentrations. From this result it can be indicated that the, optimized formulated tablet(EZF8) were within the Pharmacopeial specifications. The result it can be indicated that the, optimized

formulated tablet (EZF9) assay were within the Pharmacopeial specifications. From the pharmacokinetic parameters release of drug from Ezetimibe SR tablet followed Zero Order kinetics.

Optimized formulation was selected on the basis of in-vitro drug release profile which wascomparable to that of the IR or SR formulation under reference i.e. optimized formula for bothAtorvastatin & Ezetimibe batches. Optimized formula Batch.no: ATF9 for Ator vas ta t in IR (10mg), inAlu Blister Pack. Optimized formula Batch.no: EZF8 for Ezetimibe in strip pack was tested for stability

under two conditions for a period of six months. Accelerated stability studies of promising formulations

indicated that there are no changes of At or va s ta ti n ca lc iu m IR Ta b let s Batch. No: ATF9,

Ezetimibe SR tablet Batch. No: EZF8 and Capsule was showing good stability for six monthsaccelerated condition @ 40°C &75%RH. It was found that dissolution and assay value are notaffected for the batch, and total impurity is also less than 1%.




Acknowledgements

Authors are thankful to Prof (Dr.).B.Jaykar, Principal Vinayaka Mission’s College of Pharmacy,

Salem, Tamil nadu and providing all the facilities for this research project.

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