“formulation, evaluation and development of...

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


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 in controlled-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 smaller fragments 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 ingredient and producing the desired therapeutic action2. Sustained release tablets:

Sustained release dosage forms are designed to achieve a prolonged therapeutic effect by

continuously 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 in adverse side effects and reduction in overall health care costs. The rate of drug release from solid dosage form 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, granules and 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. 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 reduce the VLDL and LDL. So that such combination 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 by

HPLC. 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 and chromatograms 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 successful

formulation of a stable and effective solid dosage form depends on the careful selection of the excipients, 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 physical

observation. 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 1:1 7 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 for the 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. Calcium Carbonate 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 press with 6mm punches for 100mg weight at 7-8kp hardness and tablets were collected during compression for 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

Calcium Carbonate

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 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

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 dried granules. 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 batch

were 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 in Table. 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 to disintegrate 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 buffer 6.8 , 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: 75 Apparatus: 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 Studies 18:

The dissolution data were subjected to release kinetic study. Drug dissolution from solid

dosage form has been described by kinetic models in which the dissolved amount of drug (Q) is compared 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 the

effect of temperature and humidity on stability of drug and in-vitro drug release rate. It helps to generate 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 orvas tat in IR (10mg), in Alu 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. 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 6months Testing :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 condition tablet 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 1827247.667 2 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. For Atorvastatin calcium:

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: For Atorvastatin Calcium:

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 all

Excipients 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 was

found 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 and confirm the purity of API. Compatability studies: For Atorvastatin calcium:

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 used in 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

Ingredient Ratio Description

Related substance %w/w 1Month 1 Month 25°C/60%RH

40°C/75%RH

Ezetimibe 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

Ingredient Ratio Description Related substance %w/w 1Month 1 Month

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.


For Atorvastatin calcium:

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 on Drying*

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 1.8 ATF4 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)

Batch Code

Bulk Density*

Tapped Density*

Angle of repose*

% Compressibility*

Hausner Ratio*

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 1.4 EZF5 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

Batch No

Weight variation (mm)**

Diameter (mm)*

Thickness (mm)*

Hardness (kg/cm2)*

Friability (%)*

Disintegration Time*

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

Batch No


Diameter (mm)*

Thickness (mm)*

Hardness (kg/cm2)*


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±0.20 kg/cm2. 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


Diameter (mm)*

Thickness (mm)*

Hardness (kg/cm2)*

Friability (%)*


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)*


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 1 minutes 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 86.87 100.17 30 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 was found 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

% Cumulative Amount of Drug Release Time in (Minutes) ATF9 INNOVATOR

5 65.19 68.4 10 84.12 85.7 15 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

% Cumulative Amount of Drug Release 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 16.35 3 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

% Cumulative Amount of Drug Release 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 Release Time 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 in Hour

√ Time in Hour

Log time

% of Drug Release

(Zero Order)

% of Drug Unreleased

Log % of Drug Release

Log % of Drug Unreleased

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 1.8561 6 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:

For Atorvastatin Calcium:

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

Parameters

Initial 1st Month 2nd Month 3rd Month 6th Month RT 40°C RT 40°C RT 40°C RT 40°C


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


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

Parameters

Initial 1st Month 2nd Month 3rd Month 6th 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 Cumulative Release

103.12 102.67 102.76 102.67 102.01 102.67 101.65 102.63 101.25

*% of Cumulative 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 2nd Month 3rd Month 6th 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±0.01

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±0.12

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


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 2nd Month 3rd Month 6th Month

RT 40°C RT 40°C RT 40°C RT 40°C *Assay 102.28

±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

102.27±0.4

47

102.21±0.4

44 *% of Cumulative Release

89.76 89.75 89.74 89.73 89.73 89.73 89.71 89.72 89.70

*% of Cumulative 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 wa s seen that At or vas ta t in ca lc iu m IR T ab let s Batch. No: ATF9, Ezetimibe SR tablet Batch. No: EZF8 and Capsule was showing good stability for six months accelerated condition @ 40°C &75%RH. It was found that post compress ion 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 selective competitive 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. It also 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 excipients compatability 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-drug interaction such as low humidity condition and geometric mixing is applied to avoid content uniformity 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 no incompatibility 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 compression technique (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 and magnesium stearate.

For Atorvastatin calcium FC tablets direct granulation method was selected. Optimization was

found 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. 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 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 Atorvas ta t in IR (10mg), in Alu 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 t in ca lc iu m IR T a b let s Batch. No: ATF9, Ezetimibe SR tablet Batch. No: EZF8 and Capsule was showing good stability for six months accelerated condition @ 40°C &75%RH. It was found that dissolution and assay value are not affected 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,

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