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International Journal of Medicine and Pharmacy, Vol. 1 No.

1, December 2013

33

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(K30), 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 Missions College of Pharmacy, Vinayaka Missions University,


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

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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.

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Assay:
In house HPLC based method of assay was developed or both APIs. 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 250C.
The results are shown in Figure. No: 10, 11, 12, 13 & 14.
Compatibility Studies 6:
DrugExcipients 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.
1
2
3
4
5
6
7
8
9
10
11
12
13
14

Ingredient
Atorvastatin Calcium
Atorvastatin Calcium : Calcium carbonate
Atorvastatin Calcium : Lactose DCL-11
Atorvastatin Calcium : MCC pH-102
Atorvastatin Calcium : Croscarmellose Sodium
Atorvastatin Calcium : Cross povidone
Atorvastatin Calcium : Purified Talc
Atorvastatin Calcium : Sodium Lauryl Sulphate
Atorvastatin Calcium : Calcium Stearate
Atorvastatin Calcium : Erythrocin Supra
Atorvastatin Calcium : HPMC E-15
Atorvastatin Calcium : HPC
Atorvastatin Calcium : Titanium dioxide
Atorvastatin Calcium : All excipients

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Ratio
1
1:1
1:1
1:1
1:1
1:1
1:3
1:3
1:3
1:0.5
1:0.5
1:0.5
1:0.5
1:1

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Protocol for drug-excipients compatibility for Ezetimibe


Table.No:2 Ratio of Ezetimibe to Excipients Taken For Compatibility Study
S.No.
1
2
3
4
5
6
7
8

Ingredient
Ezetimibe
Ezetimibe + Lactose Monohydrate
Ezetimibe + PVP K 30
Ezetimibe + HPMC k 15M
Ezetimibe + HPMC k 4M
Ezetimibe + Aerosil
Ezetimibe + Mg. Stearate
Ezetimibe + All excipients

Ratio
1
1:1
1:1
1:1
1:1
1:0.5
1:0.5
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).

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Table No: 3 Formulation of Atorvastatin Calcium IR Tablet


Batch. No
Ingredient
Atorvastatin
Calcium
Calcium
Carbonate
Lactose DCL 11
MCC pH-102
Croscarmellos
e Sodium
Cross
Povidone
Talc
Sodium Lauryl
Sulphate
Calcium
Stearate
Tablet weight

ATF1

ATF2

ATF3

ATF4

ATF5
mg/tablet
20.70
20.70

20.70

20.70

20.70

11

11

11

11

54

52

50

19.50
2

19.50
4

ATF6

ATF7

ATF8

ATF9

20.70

20.70

20.70

20.70

11

11

11

11

11

47.65

52

50

44

47.65

40

19.50
6

19.85
8

19.50
-

19.50
-

19.50
-

19.50
-

19.50
8

1
1

1
1

1
1

1
1

1
1

1
1

1
1

1
1

1
1

0.8

0.8

0.8

0.8

0.8

0.8

0.8

0.8

0.8

110mg

110mg

110mg

110mg

110mg

110mg

110mg

110mg

110mg

Table No: 4 Film Coating for Atorvastatin Calcium IR Tablets


S.NO
Ingredients
1
2
3
4

Ingredients

Quantity(mg)
For One tablet

Erythrocin Supra
Protectab HP
Polysorbate 80
Purified Water

0.05
1.8
0.8
Qs

Table No: 5 Optimized Parameters for Film Coating for Atorvastatin Calcium IR Tablets
Conditions
Inlet air temperature (C)
Product temperature (C)
Outlet air temperature (C)
Spray rate (ml/min)
Atomizing air pressure (psi)
Pan speed (rpm)

Pre-heating
55-60
55-60
35-60
35-37

Coating
60-65
50-55
55-60
1-2
20
35-37

Drying
50
55-60
50-55
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 50C.
Remove the trolley and do the reshuffling. Again dry the material for 20 minutes.

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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
Ingredients
Ezetimibe
Lactose Monohydrate
PVP K 30
HPMC k-15M
HPMC k-4M
IPA
Aerosil
Mg. Stearate
Tablet weight

EZF1

EZF2

EZF3

10
44.8
4
30
q.s.
0.2
1
90mg

10
42.8
4
32
q.s.
0.2
1
90mg

10
40.8
4
34
q.s.
0.2
1
90mg

EZF4
EZF5
mg/tablet
10
10
39.8
44.8
4
4
35
30
q.s.
q.s.
0.2
0.2
1
1
90mg
90mg

EZF6

EZF7

EZF8

10
42.8
4
32
q.s.
0.2
1
90mg

10
40.8
4
34
q.s.
0.2
1
90mg

10
39.8
4
35
q.s.
0.2
1
90mg

Table No: 7 Film Coating for Ezetimibe SR Tablets


S.NO
Ingredients
1
2
3
4

Ingredients

Quantity(mg)
For One tablet

Sunset Yellow Supra


Protectab HP
Polysorbate 80
Purified Water

0.05
1.8
0.8
Qs

Table No: 8 Optimized Parameters for Film Coating for Ezetimibe SR Tablets
Conditions
Inlet air temperature (C)
Product temperature (C)
Outlet air temperature (C)
Spray rate (ml/min)
Atomizing air pressure (psi)
Pan speed (rpm)

Pre-heating
55-60
55-60
35-60
35-37

Coating
60-65
50-55
55-60
1-2
20
35-37

Drying
50
55-60
50-55
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
130 mg or less
>130 mg and <324 mg
324mg or more
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Percentage deviation
10
7.5
5
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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 byW (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 20C 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 :
Bath volume :
RPM:
Apparatus:

900mL of 0.05M Phosphate buffer


6.8 , 0.45 % SLM Acetate buffer PH 4.5
900mL
75
USP 2 Paddle

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Sample Time:
For Ezetimibe:
Dissolution Media :
RPM:
Apparatus:
Sample Time:

5Minutes
900mL of 0.45% SLM Acetate buffer PH 4.5
75
USP 2 Paddle
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 or va s 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
Room Temperature
(RT)

Storage condition
25C 2C/60%RH 5%RH

Accelerated

40C 2C/75%RH 5%RH

Time Period Covered


6months
Testing :If accelerated condition tablet is
passed
6 months
Testing:1,2,3 & 6 month

These were evaluated for their physicochemical characteristics, drug content, assay and invitro release profile of Atorvastatin and Ezetimibe Tablet.
Invitro 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 thr ee formulations i.e. Atorvastatin Calcium IR (20mg), & Ezetimibe
SR (10mg) Tablet individually, two formulations of Atorvastatin and Ezetimibe.
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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
Room Temperature (RT)

Storage condition
25C 2C/60%RH 5%RH

Accelerated

40C 2C/75%RH 5%RH

Time Period Covered


6 months
Testing :If accelerated condition
tablet is passed
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
1
1
2
3
4
5
6
7

Concentration in ppm
0
10
20
50
100
120
160
200

Area
0
1827247.667
3618371.667
8959876.000
18118982.333
21555409.333
29532241.333
36224779.667

*MeanSD n=3
Fig. no: 1 Standard Calibration Curve of Atorvastatin Calcium

Table no: 12 Standard Calibration Curve of Ezetimibe


S.No
1
1
2
3
4
5

Concentration in ppm
0
10
20
30
40
50

Absorbance (nm)
0
0.153
0.314
0.448
0.593
0.741

*MeanSD n=3
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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
Impurity B
Impurity C
Impurity D
Any Other Impurity
Total Impurity
Assay
Conversional factor

0.04%
Not Detected
Not Detected
0.07%
Not Detected
0.35%
99.75%
1.0359

*MeanSD (n=6)
Figure No: 3 Atorvastatin calcium Assay Chromatogram

For Ezetimibe:
Table No: 14 Impurity Profile of Ezetimibe
Impurity A
Impurity B
Impurity C
Impurity D
Any Other Impurity
Total Impurity
Assay
Conversional factor

0.05%
Not Detected
Not Detected
0.06%
Not Detected
0.25%
99.85%
1

*MeanSD (n=6)

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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

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

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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 158.27C 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
137.21C 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 138.18C in DSC thermogram. This value matches with that given in the literature and
confirm the purity of API.
For Atorvastatin Calcium AND Ezetimibe Mixture:

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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 168.74C 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 @ 40C-75% RH
Ingredient

Ratio

Description
Related substance %w/w

1Month
25C/60%
RH
*
*

1 Month
40C/75
%RH
*
*

Atorvastatin Calcium
Atorvastatin Calcium : Calcium
carbonate
Atorvastatin Calcium : Lactose DCL-11

1
1:1

White to pale yellow, granular powder


White to pale yellow, granular powder

1:1

Atorvastatin Calcium : MCC pH-102


Atorvastatin Calcium : Croscarmellose
Sodium
Atorvastatin Calcium : Cross povidone

1:1
1:1

*
*

*
*

Atorvastatin Calcium : Purified Talc


Atorvastatin Calcium : Sodium Lauryl
Sulphate
Atorvastatin Calcium : Calcium Stearate
Atorvastatin Calcium : Erythrocin
Supra
Atorvastatin Calcium : HPMC E-15
Atorvastatin Calcium : HPC
Atorvastatin Calcium : Titanium dioxide
Atorvastatin Calcium : All excipients

1:3
1:3

White to pale yellow, granular FF


powder
White to pale yellow, granular powder
White to Greyish white , granular
powder
White to Grayish white , granular
powder
White to pale yellow, granular powder
White to pale yellow, granular powder

*
*

*
*

White to pale yellow, granular powder


White to pale yellow, granular FF
powder
White to pale yellow, granular powder
White to pale yellow, granular powder
White to pale yellow, granular powder
White to pale yellow, granular powder

*
*

*
*

*
*
*
*

*
*
*
*

1:1

1:3
1:0.5
1:0.5
1:0.5
1:0.5
1:1

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
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Table No: 16 Compatibility study of Ezetimibe with Excipients:The RS Data of Ezetimibe (By
HPLC) of 1 month excipients Compatability @ 40C-75% RH
Ingredient

Ratio

Ezetimibe
Ezetimibe : Lactose
Monohydrate
Ezetimibe : PVP K 30
Ezetimibe : HPMC k-15M
Ezetimibe : HPMC k-4M
Ezetimibe : IPA
Ezetimibe : Aerosil
Ezetimibe : Mg. Stearate
Ezetimibe : All Excipients

Description
Related substance %w/w

1Month
25C/60
%RH

1 Month
40C/75%
RH

1
1:1

White to pale yellow, granular powder


White to pale yellow, granular powder

*
*

*
*

1:1
1:1
1:1
1:0.5
1:3
1:3
1:1

White to pale yellow, granular FF powder


White to pale yellow, granular powder
White to Greyish white , granular powder
White to Grayish white , granular powder
White to pale yellow, granular powder
White to pale yellow, granular powder
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.
Result: * Indicated That No Change Was Observed
Table No: 17 Compatibility studies of Atorvastatin calcium & Ezetimibe: The RS Data of
Atorvastatin calcium & Ezetimibe (By HPLC) of 1 month excipients Compatability @ 40C-75% RH

Ingredient

Ratio
Related substance %w/w

Atorvastatin Calcium:
Ezetimibe

1:1

White to pale yellow,


granular powder

Description
1Month
25C/60%RH
*

1 Month
40C/75%RH
*

Discussion:
From this table it can be seen the Atorvastatin Calcium and Ezetimibe is compatible with all the
excipients used in the study.
Result: * Indicated That No Change Was Observed
For Atorvastatin calcium:
Table No: 18 Preformulation Study of Pure Drug (Atorvastatin Calcium).
S.NO.
1
2
3
4
5
6

Parameters
Bulk Density*
Tapped Density*
Angle of Repose*
Carrs Index*
Hausner Ratio*
Melting Point*

Solubility*

Result
Conclusion
0.675 gm/ml
-----0.75 gm/ml
----19.61
Excellent
10 %
Excellent Flow
1.11
Better Flow
159.2-160.7 C
---Freely soluble in methanol, slightly soluble in ethanol,
very slightly soluble in water

*MeanSD (n=6)
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Table No: 19 Preformulation Study of the blend (Atorvastatin Calcium)

Batch
Code
ATF1
ATF2
ATF3
ATF4
ATF5
ATF6
ATF7
ATF8
ATF9

Bulk
Density*
0.41
0.44
0.44
0.47
0.45
0.46
0.47
0.45
0.49

Tapped
Density*
0.47
0.52
0.51
0.54
0.50
0.53
0.52
0.52
0.55

Angle of
repose*
24.58
25.91
26.86
24.43
24.10
24.77
25.42
23.43
26.10

%
Compressibility*
12.76
15.38
13.72
12.96
12.00
13.20
9.61
12.60
9.05

Hausner
Ratio*
1.15
1.18
1.16
1.14
1.06
1.15
1.11
1.17
1.61

Loss on
Drying*
2.1
1.9
1.8
1.7
1.6
1.7
1.5
1.6
1.8

*MeanSD (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
1
2
3
4
5
6
7

Parameters
Bulk Density*
Tapped Density*
Angle of Repose*
Carrs Index*
Hausner Ratio*
Melting Point*
Solubility*

Result
Conclusion
0.665 gm/ml
-----0.65 gm/ml
----16.66
Excellent
11 %
Excellent Flow
1.103
Better Flow
135 140oC
---Freely soluble ij ethanol, methanol and acetone. Practically insoluble
in water.

*MeanSD (n=6)
Table No: 21 Preformulation Study of the blend (Ezetimibe)
Batch
Code
EZF1
EZF2
EZF3
EZF4
EZF5
EZF6
EZF7
EZF8

Bulk
Density*
0.43
0.42
0.43
0.45
0.46
0.47
0.44
0.44

Tapped
Density*
0.46
0.51
0.52
0.53
0.52
0.54
0.52
0.53

Angle of
repose*
25.58
24.91
25.86
25.48
26.10
26.87
26.42
23.43

%
Compressibility*
12.76
13.38
12.72
13.96
13.00
14.20
10.61
9.60

Hausner
Ratio*
1.14
1.15
1.17
1.15
1.09
1.18
1.14
1.18

Loss on
Drying*
2.2
1.3
1.6
1.4
1.5
1.6
1.7
1.9

*MeanSD (n=6)

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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
ATF1
ATF2
ATF3
ATF4
ATF5
ATF6
ATF7
ATF8
ATF9

Weight variation
(mm)**
1116.5
1116.5
1125.6
1126.5
1115.8
1126.7
1105.8
1115.8
1116.8

Diameter
(mm)*
5.390.02
5.280.01
5.390.03
5.470.02
5.380.03
5.370.04
5.480.03
5.390.02
5.490.01

Thickness
(mm)*
3.320.03
3.230.04
3.340.04
3.250.05
3.360.04
3.270.05
3.260.06
3.280.05
3.250.06

Hardness
(kg/cm2)*
3.450.21
3.510.20
3.450.14
3.570.13
3.670.12
3.570.12
3.890.14
3.560.11
3.870.15

Friability
(%)*
0.25
0.31
0.28
0.32
0.34
0.32
0.34
0.33
0.35

Disintegration
Time*
53 seconds
47 seconds
49 seconds
51 seconds
48 seconds
49 seconds
46 seconds
50 seconds
51 seconds

*MeanSD (n=6) **MeanSD (n=20)


Table No: 23 Evaluation of Atorvastatin calcium Film Coated IR-Tablets
Batch
No
ATF1
ATF2
ATF3
ATF4
ATF5
ATF6
ATF7
ATF8
ATF9

Weight variation
(mm)**
1146.5
1157.5
1166.6
1157.5
1147.8
1156.7
1146.8
1146.7
1147.8

Diameter
(mm)*
5.690.01
5.680.02
5.690.02
5.570.01
5.680.02
5.670.02
5.650.03
5.650.07
5.690.03

Thickness
(mm)*
3.420.03
3430.04
3.440.04
3.450.05
3.460.04
3.470.03
3.550.04
3.430.05
3.450.06

Hardness
(kg/cm2)*
4.150.21
4.170.20
3.750.14
3.870.13
3.870.12
3.860.21
3.880.13
3.860.11
3.870.15

Disintegration
Time*
1 mts 23 sec
1 mts 33 sec
1 mts 33 sec
1 mts 35 sec
1 mts 32 sec
1 mts 26 sec
1 mts 23 sec
1 mts 33 sec
1 mts 12 sec

*MeanSD (n=6) **MeanSD (n=20)


Discussion:
The tablets were compressed at the average weight of 110mg. The weight variation of all
batches in the ranges of 1146.5 to 1166.6 mm. The tablets diameters are 5.570.01 to 5.690.03 mm.
The tablets thickness is 3.420.03 to 3.550.04 mm. The tablets hardness are 3.860.11 to 4.170.20
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
EZF1
EZF2
EZF3
EZF4
EZF5
EZF6
EZF7
EZF8

Weight variation
(mm)**
907.5
917.1
916.6
916.8
915.8
926.7
925.8
925.8

Diameter
(mm)*
5.290.02
5.280.01
5.270.03
5.270.02
5.380.03
5.250.04
5.280.03
5.290.02

Thickness
(mm)*
3.210.03
3200.04
3.240.04
3.210.05
3.230.04
3.210.05
3.220.06
3.230.05

Hardness
(kg/cm2)*
3.410.21
3.410.20
3.470.11
3.470.12
3.570.13
3.670.14
3.690.13
3.640.12

Friability
(%)*
0.35
0.31
0.38
0.34
0.35
0.33
0.36
0.37

Disintegratio
n Time*
54 seconds
49 seconds
47 seconds
50 seconds
45 seconds
47 seconds
45 seconds
52 seconds

*MeanSD (n=6) **MeanSD (n=20)


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Table No: 25 Evaluation of Ezetimibe Film Coated SR-Tablets
Batch
No
EZF1
EZF2
EZF3
EZF4
EZF5
EZF6
EZF7
EZF8

Weight variation (mm)**


957.3
947.2
956.8
966.7
956.8
956.7
965.8
966.8

Diameter
(mm)*
5.300.01
5.290.02
5.290.04
5.310.03
5.330.05
5.350.02
5.350.04
5.350.01

Thickness
(mm)*
3.220.03
3.210.04
3.250.04
3.230.05
3.240.04
3.230.05
3.240.06
3.250.05

Hardness
(kg/cm2)*
3.460.21
3.510.20
3.520.11
3.570.12
3.670.13
3.690.14
3.700.13
3.650.12

Disintegration
Time*
1 mts 28 sec
1 mts 37 sec
1 mts 39 sec
1 mts 39 sec
1 mts 37 sec
1 mts 35 sec
1 mts 33 sec
1 mts 36 sec

*MeanSD (n=6) **MeanSD (n=20)


Discussion:
The tablets were compressed at the average weight of 90mg. The weight variation of all
batches in the ranges of 947.2 to 966.7 mm. The tablets diameters are 5.290.02 to 5.350.04 mm.
The tablets thickness is 3.210.04 to 3.250.05 mm. The tablets hardness are 3.460.21 to 3.460.21
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
Time
(Minutes)
0
5
10
15
20
30

ATF1

ATF2

0
52.34
72.35
79.87
82.47
90.12

0
56.13
74.87
80.98
84.89
92.35

% Cumulative Amount of Drug Release


ATF3
ATF4
ATF5
ATF6
0
58.54
76.78
82.45
86.79
94.18

0
60.61
77.89
84.27
88.97
96.78

0
53.78
71.26
77.89
81.89
89.19

0
56.67
73.98
78.98
83.27
93.89

ATF7

ATF8

ATF9

0
58.89
76.54
80.78
84.98
94.89

0
60.45
78.76
82.54
86.87
96.87

0
65.19
84.12
97.01
100.17
103.12

*MeanSD (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.
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Table No: 27 Dissolution Profile of the Atorvastatin calcium IR Tablet Optimized Formulation
ATF9 with Innovator Tablet
Time in (Minutes)
5
10
15
20
30

% Cumulative Amount of Drug Release


ATF9
INNOVATOR
65.19
68.4
84.12
85.7
97.01
98.8
100.17
99.8
103.12
101.30

*MeanSD (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


Atorvastatin Calcium Optimized (ATF9) (Alu Blister Pack)
Mean
SD
RSD
101.56
1.7
1.7

Assay
*MeanSD (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)
0
1
3
6
8
12

EZF1
0
30.98
45.76
58.71
87.76
98.87

% Cumulative Amount of Drug Release


EZF2
EZF3
EZF4
EZF5
0
0
0
0
25.34
24.98
21.78
31.23
44.65
41.76
38.89
46.89
56.89
54.78
53.54
59.78
83.78
81.79
78.98
88.98
97.89
96.78
94.32
98.34

EZF6
0
28.98
43.67
58.53
86.65
96.98

EZF7
0
23.56
39.56
56.67
80.97
91.73

EZF8
0
16.35
28.25
54.78
70.29
89.76

*MeanSD (n=6)

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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
1
3
5
8
12

% Cumulative Amount of Drug Release


EZF8
INNOVATOR
16.35
18.78
28.25
30.76
54.78
57.65
70.29
74.67
89.76
92.43

*MeanSD (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
102.46
1.6

RSD
1.6

*MeanSD (n=6)

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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
0
0.00
5
65.19
10
84.12
15
97.01
20
100.17
30
103.12
1 Hour
NA
3 Hour
NA
6 Hour
NA
8 Hour
NA
12 Hour
NA

EZF8
NA
NA
NA
NA
NA
NA
16.35
28.25
54.78
70.29
89.76

*MeanSD (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

0
1
3
6
8
12

0
1.0000
1.7321
2.4495
2.8284
3.4641

0
0.0000
0.4771
0.7782
0.9031
1.0792

% of Drug
Release
(Zero Order)
0
16.35
28.25
54.98
70.20
89.21

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% of Drug
Unreleased

Log % of
Drug Release

Log % of Drug
Unreleased

0
83.65
71.8
45.02
29.8
10.79

0
1.2135
1.4510
1.7402
1.8463
1.9504

0
1.9224
1.8561
1.6534
1.4742
1.0330

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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

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


R2
0.984
0.966
0.984
0.950

Release kinetics
Zero order equation
First order equation
Higuchi (diffusion) co-efficient
Korsmeyer Peppas coefficient
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)
Parameter
s
Weight
variation
(mm)**
Diameter
(mm)*

1st Month
RT
40C
104 7.8 103.57
.6

Initial
1047.8

2nd Month
RT
40C
103.5 103.57
7.8
.2

3rd Month
RT
40C
103.5 103.2
7.8
7.1

6th Month
RT
40C
103.37 103.16
.6
.99

5.690.03

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)*

3.450.06

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)*

3.870.15

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

*MeanSD (n=6) **MeanSD(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
*Assay
*% of
Cumulativ
e Release
*% of
Cumulativ
e Release
(Capsule)

101.26
0.435

1st Month
RT
40C
101.26 101.200
0.435
.421

103.12

102.67

102.76

102.67

102.01

102.67

101.65

102.63

101.25

103.08

102.58

102.67

102.43

102.47

102.35

101.98

102.32

101.78

Initial

2nd Month
RT
40C
101.260 101.120
.435
.435

3rd Month
RT
40C
101.26 101.010
0.435
.435

6th Month
RT
40C
101.25 101.01
0.432
0.422

*MeanSD (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.
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For Ezetimibe:
Table No: 37 Stability Studies Data of the Ezetimibe SR Optimized Formulations
(EZF8) (Blister Pack)
Paramete
rs
Weight
variation
(mm)**
Diameter
(mm)*
Thickness
(mm)*
Hardness
(kg/cm2)*
Disintegr
ation
Time*

Initial
966.8

5.350.0
1
3.250.0
5
3.650.1
2
1 mts 36
sec

1st Month
RT
40C
966.5
966.4

2nd Month
RT
40C
966.4
966.2

3rd Month
RT
40C
966.4 966.1

5.320.
02
3.240.
05
3.640.
11
1 mts
35 sec

5.320.
01
3.240.
04
3.640.
09
1 mts
34 sec

5.320.
01
3.240.
03
3.640.
08
1 mts
34 sec

5.320.
01
3.230.
04
3.630.
10
1 mts 34
sec

5.310.
01
3.210.
04
3.620.
10
1 mts 32
sec

6th Month
RT
40C
957.4
956.
6

5.270.
01
3.180.
04
3.560.
10
1 mts
28 sec

5.300.
01
3.210.
03
3.610.
06
1 mts 32
sec

5.25
0.02
3.16
0.03
3.54
0.12
1 mts
21 sec

*MeanSD (n=6) **MeanSD(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
*Assay

*% of
Cumulativ
e Release
*% of
Cumulativ
e Release
(Capsule)

Initial

1st Month
RT
40C

2nd Month
RT
40C

3rd Month
RT
40C

6th Month
RT
40C
102.2 102.2
70.4 10.4
47
44

102.28
0.455

102.28
0.453

102.250
.448

102.270.
452

102.24
0.447

102.27
0.449

102.230
.446

89.76

89.75

89.74

89.73

89.73

89.73

89.71

89.72

89.70

89.77

89.76

89.74

89.76

89.74

89.75

89.72

89.74

89.68

*MeanSD (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 w a s seen that A t o r v a s t a t i n c a lc i u m I R T a b l et s Batch. No: ATF9,
Ezetimibe SR tablet Batch. No: EZF8 and Capsule was showing good stability for six months
accelerated condition @ 40C &75%RH. It was found that post compr ess ion par a met er s ,
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.
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International Journal of Medicine and Pharmacy, Vol. 1 No. 1, December 2013

57

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 At or va s 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 A t o r v a s t a t i n c a l c i u m I R T a b l et s Batch. No: ATF9,
Ezetimibe SR tablet Batch. No: EZF8 and Capsule was showing good stability for six months
accelerated condition @ 40C &75%RH. It was found that dissolution and assay value are not
affected for the batch, and total impurity is also less than 1%.
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International Journal of Medicine and Pharmacy, Vol. 1 No. 1, December 2013

Acknowledgements
Authors are thankful to Prof (Dr.).B.Jaykar, Principal Vinayaka Missions College of Pharmacy,
Salem, Tamil nadu and providing all the facilities for this research project.

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