12 Chapter 5,Omeprazole delayed release capsulesshodhganga.inflibnet.ac.in/bitstream/10603/13928/12/12_chapter 5.pdf · Chapter 5 OMEPRAZOLE DELAYED RELEASE CAPSULES ... Chapter 5

Chapter 5 OMEPRAZOLE DELAYED RELEASE CAPSULES

JJT University, Rajasthan

Page 98

5 OMEPRAZOLE GASTRO-RESITANCE CAPSULES

5.1 Aim

When there is puncture or a hole in the gut lining of duodenam, esophagus or stomach

is called peptic ulcer. It is also known as gastric ulcer when there is puncture in

stomach; when there is puncture in duodenam it is known as duodenal ulcer and when

in eosophagus it is known as esophagus ulcer. The main cause of ulcer is that when

the there is puncture in the lining of gastrointestinal tract due to production of acidic

gastric juice by stomach at gastric environment. This disease is common, which

effects number of people in the world yearly.

A group called Proton pump inhibitor is a class of drug whose main therapeutic effect

is reduction of production of gastric juice in the stomach. These active substance are

used in the treatment of many such disease such as Zollinger-Ellison syndrome,

Gastroesophageal reflux disease Laryngopharyngeal Reflux disease, Dispepsia, The

class called proton pump inhibitors acts by irreversible blockage of

Hydrogen/Potassium ATPase.these porton punp inhibitors bind to theese ATPase at

the final stage and hampers the gastric acid secretion.

DELAYED RELEASE SYSTEM 1

The design of the dosage form which are meant to be used for the treatment of gastric

ulcer is to be locally acting. The drug which have to be prepared delayed should have

been:

i) high degradation rate in stomach at acidic pH

ii) cause gastric irritation

iii) specific absorption site

iv) should have local effect

There are two types of the delayed release dosage form :

• Colonic release

• Intestinal release

Intestinal release dosage form: In a dosage form when the active content is released in

the basic pH of intestine and to protect the dosage form in the acidic environment of

the gastrointestinal dosage form. Intestinal release dosage form is against gastric



Page 99

irritation and protect the dosage form against the degradation of drug in acidic

environment of the intestinal tract.

Colonic release system : When the active content are meant to be delivered in the

Colon at specific site of action.

a) treatment for local ulcer

b) site specific absorption of protein and peptide drug

Therapeutically Actice content such as lansoprazole, Omeprazole, esomeprazole,

pantoprazole a typical proton pump inhibitor that have an irritant effect in the gastric

environment and unstable at the gastric pH. Due to these reason enteric coating is

required to such active content to provide its proper therapeutic effect and its

pharmacological action. Such proton pump inhibitors like omeprazole, lansoprazole,

rabeprazole etc are acid labile and unstable at acidic pH. These proton pump are

highly unstable at acidic pH of gastric environment and stable at basic pH, of the

intestine which is more than 5.5 so need to prepare enteric coated tablets of the

delayed release action.2

From all these molecule Omeprazole is promising molecule and it is used as an

antiulcer agent.

Before going to develop the formulation a detail product literature review was carried

out to know about the multi unit particulate system and type of dosage form available

in market. The present study was focused to formulate delayed release capsule by

multi unit particulate system Technique.

In primary trials various formulation combinations and parameters such as no. of

pellets, types of pellets. Degradation temperature of omeprazole, degradation

temperature of drug coating suspension, concentration of suspension, uniform sized

pellets undergo efficient coating. Sugar sphere has been found to be effective diluent

in the drug coating method.

Omeprazole turns black/brown when come in contact with moisture therefore pellets

were dried and undergo seal coating as early as possible. To avoid barrier diffusion

and moisture penetration seal coating was applied using Hypromellose.

To avoid degradation of Omeprazole in upper part of Gastro intestinal tract, above

developed pellets are further coated with enteric coating polymer. Coating was

performed in Fluid bed coater. Enteric coating polymer like



Page 100

hypromellose phthalate was used for the enteric coating for delay in the release of

active content from the dosage form. Above developed formulation were evaluated

for invitro release profile. Dissolution was performed in USP 32 apparatus paddle,

900 ml in acidic media i.e 0.1 N Hydrochloric acid for two hours enteric coated

pellets slowly release not more than 10% and after that in paddle 900 ml rapid

dissolution of pellets were observed.

5.2 OBJECTIVE :-

• Preparation and evaluation of gastric resistance capsules of omeprazole based on

enteric coating polymers that remains intact in gastric environment.

• To exercise various formulation variable and process variable that finally effect

the release of active content from the dosage form.

• Evaluation of different concentration of polymers that remains intact in gastric

environment at acidic pH and dissolves/disintegrate fast in intestine at basic pH.

• Study of different seal coating concentration which stabilize the active substance

from acidic environment.

• Polymer selection and its optimization that effects physical and chemical

properties of the dosage form.

5.3 Principles to achieve goal

• Pellets should have satisfactory physical properties.

• Enteric coated Pellets release not more than 10 % w/w of drug release for 45

minutes in pH 4.5 phosphate buffer.

• Enteric coated Pellets release immediate in 6.8 pH (previously exposed for 45

minutes in pH 4.5 phosphate buffer).

• Preparation of stable and bioequivalent formulation.



Page 101

5.4 Methodology

The aim of the product development was to formulate Omeprazole 20 mg Capsules,

which are robust, stable. The product development work was initiated with following

strategies for development of Omeprazole 20 mg Capsules.

Table 5.1: Comparative Composition of Omeprazole 20 mg capsules (Reference

Vs Test Product).

Name of material

Core material Omeprazole 20 mg

capsules

Losec 20 mg capsules

AstraZeneca UK Ltd., UK3

Sugar sphere � �

Mannitol � �

Hypromellose � �

Microcrystalline cellulose � �

Lactose anhydrous � �

Sodium lauryl sulphate � �

Disodium hydrogen

phosphate dihydrate � �

Hypromellose � �

Eudragit (Metha acrylic acid

copolymer) � �

Poly Ethylene glycol � �

Magnesium stearate � �

Hypromellose Phthalate � �

Disodium hydrogen

phosphate Dodecahydrate � �

Capsule shell

Gelatin � �

Colours E171 and E172 � �

� = present; � = absent



Page 102

5.5.1 Compatibility by Accelerated Thermal Analysis:

Selection of Excipients

Compatibility studies of Omeprazole blends with different excipients were

carried out by Accelerated Thermal Stress Study.

5.5.2 Excipient Compatibility Study:

The preformulation study was carried out with the following commonly used excipients. Table 5.2 :- Drug: Excipient Compatibility Study

Sr.

No. Excipient

Drug: Excipient

Ratio

1 Omeprazole API

2 Omeprazole + Sugar sphere (850 µ – 1000 µ ) 1:10

3 Omeprazole + Lactose anhydrous 1:0.5

4 Omeprazole + Hypromellose E5 1:0.5

5 Omeprazole + Sodium lauryl sulphate 1:0.5

6 Omeprazole + Disodium hydrogen phosphate

Dodecahtydrate

1:0.5

7 Omeprazole + Klucel EF 1:0.5

8 Omeprazole + Hypromellose Phthalate 1:2

9 Omeprazole + PEG 6000 1:0.5

10 Omeprazole + Diethyl phthalate 1:0.5

Preformulation study was performed by keeping the mixture of the API and different

excipients at following conditions:-

Table 5.3 : Preformulation Schedule

Sr.

No Condition Time points

1. Initial On 0th day

2. Accelarated condition as per ICH i.e 40 degree C and 75 % RH (closed vials)

2 Weeks

4 Weeks

3. Long term condition as per ICH i.e 25 degree C and 60 % RH (closed vials)

2 Weeks 4 Weeks



Page 103

• Samples shall be withdrawn at the mentioned time points from the respective

condition and shall be observed for any physical change (viz. change in color,

lump formation, caking, etc.). The samples, if required, shall also be analyzed by

HPLC to check for any new impurity/peak.

• The samples of 2 W for physical observation only.

• The preformulation sample of four week 40/75 closed condition and 25/60 closed

condition will be analysed for Related substance and assay.



Page 104

Observations:

Table 5.4 : Preformulation Observation (Initial)

Sample Ratio Description A B C D E F+G H I Single unlnown

Total Unknown impurities

Total impurities

Assay

Omeprazole 1 White powder 0.001 - 0.01 0.023 0.012 0.006 0.003 - 0.006 0.018 0.073 99.912 Omeprazole + Sugar sphere (850 µ – 1000 µ )

1:10 White powder 0.001 - 0.006 0.026 0.013 0.004 0.003 - 0.003 0.006 0.059 99.917

Omeprazole + Lactose anhydrous

1:0.5 White powder 0.001 - 0.007 0.143 0.013 0.005 0.002 - 0.005 0.013 0.186 99.781

Omeprazole + Hypromellose E5

1:0.5 White powder 0.001 - 0.006 0.041 0.013 0.003 0.003 - 0.005 0.011 0.081 99.900

Omeprazole + Sodium lauryl sulphate

1:0.5 White powder 0.001 - 0.007 0.025 0.013 0.004 0.005 - 0.004 0.008 0.064 99.923

Omeprazole + Disodium hydrogen phosphate Dodecahtydrate

1:0.5 White powder 0.001 - 0.008 0.021 0.014 0.006 0.003 - 0.004 0.012 0.063 99.912

Omeprazole + Klucel EF

1:0.5 White powder 0.002 - 0.009 0.027 0.013 0.004 0.003 - 0.005 0.007 0.068 99.920

Omeprazole + Hypromellose Phthalate

1:2 White powder 0.001 - 0.017 0.035 0.012 0.020 0.004 - 0.004 0.003 0.094 99.854

Omeprazole + PEG 6000

1:0.5 White powder 0.001 - 0.009 0.020 0.014 0.004 0.006 - 0.004 0.010 0.058 99.927

Omeprazole + Diethyl phthalate

1:0.5 White powder 0.002 - 0.008 0.021 0.013 0.004 0.004 - 0.006 0.010 0.063 99.921



Page 105

Table 5.5 : Preformulation Study Result - 250C / 60 % RH (4 Week)

Sample Ratio Descripti-on

A B C D E F+G H I Single unlnown


Total impurities

Assay

Omeprazole 1 White powder

0.002 0.000 0.009 0.020 0.017 0.007 0.005 0.000 0.005 0.025 0.085 99.868

Omeprazole + Sugar sphere (850 µ – 1000 µ )

1:10 White powder

0.001 0.000 0.008 0.021 0.012 0.007 0.004 0.000 0.005 0.026 0.079 99.882


1:0.5 White powder

0.002 0.000 0.010 0.149 0.017 0.008 0.004 0.000 0.008 0.028 0.123 99.845


1:0.5 White powder

0.002 0.000 0.011 0.033 0.015 0.005 0.004 0.000 0.006 0.031 0.101 99.886


1:0.5 White powder

0.002 0.000 0.011 0.021 0.016 0.006 0.004 0.000 0.005 0.026 0.086 99.899


1:0.5 White powder

0.002 0.000 0.016 0.021 0.046 0.033 0.004 0.000 0.008 0.046 0.168 99.772


1:0.5 White powder

0.002 0.000 0.010 0.024 0.018 0.006 0.004 0.000 0.006 0.023 0.087 99.891


1:2 White - brown powder

0.003 0.000 0.017 0.034 0.021 0.341 0.003 0.000 0.011 0.158 0.177 98.747


1:0.5 White powder

0.002 0.000 0.010 0.020 0.020 0.007 0.004 0.000 0.006 0.025 0.088 99.891


1:0.5 Black colour semi liquid

-- -- -- -- -- -- -- -- -- -- -- --



Page 106

Table 5.6 : Preformulation Study Result – 400C /75 % RH (4 Week)

Sample Ratio Descripti-on A B C D E F+G H I Single unlnown


Total impurities

Assay

Omeprazole 1 White powder

0.003 0.000 0.011 0.019 0.014 0.016 0.003 0.000 0.007 0.049 0.115 99.840

Omeprazole + Sugar sphere (850 µ – 1000 µ )

1:10 White powder

0.002 0.004 0.011 0.021 0.017 0.025 0.000 0.003 0.016 0.066 0.145 99.789


1:0.5 White powder

0.002 0.000 0.014 0.159 0.021 0.018 0.003 0.000 0.010 0.051 0.147 99.819


1:0.5 White powder

0.002 0.000 0.010 0.028 0.018 0.009 0.000 0.000 0.006 0.039 0.106 99.872


1:0.5 White powder

0.006 0.016 0.039 0.026 0.215 0.263 0.021 0.000 0.083 0.301 0.887 98.675


1:0.5 Light pink colour powder

0.002 0.000 0.012 0.021 0.020 0.015 0.003 0.000 0.006 0.041 0.114 99.859


1:0.5 White powder

0.002 0.000 0.011 0.024 0.018 0.013 0.000 0.000 0.006 0.030 0.098 99.875


1:2 Light pink colour powder

0.005 0.000 0.105 0.038 0.012 0.273 0.000 0.000 0.098 0.267 0.500 98.240


1:0.5 White powder

0.004 0.003 0.019 0.021 0.012 0.045 0.003 0.000 0.044 0.113 0.220 99.685


1:0.5 Black colour semi liquid

-- -- -- -- -- -- -- -- -- -- -- --


JJT University, Rajasthan Page 107

Conclusion: - The above mentioned data of compatibility study indicating that there is no

significant changes either in description nor in impurity level. Hypromellose phthalate

and Diethyl phthalate shows discoloration and significant degradation level. So decided

to go with seal coating in between drug coating and enteric coating.

5.6 Methodology

Studies performed on the active coating suspension

The mixture of Hydroxy Propyl cellulose (L-HPC) and Hypromellose (HPMC) was used

as a polymer solution. Lactose anhydrous was added as the filling material. Disodium

hydrogen Phosphate dodecahydrate was used as Stabilizing agent in the formulation.

Omeprazole was added but it very hardly became wet in the polymer solution in water.

Then it was decided to add a wetting material.

Anionic surfactant Sodium Lauryl sulphate was added into the formula as a wetting agent

and it was experienced that Omeprazole formed a suspension in a very short time.

The active coating suspension prepared according to the above formulation is sprayed on

the sugar spheres and the first coating layer is performed.

Studies performed on the Seal coating

Observing humidity and Temperature affect the Omeprazole, it was decided to perform

another coating (Protector coating) between the two coating processes (active and enteric

coating). By using HPMC solution in water, the protector coating was realized just before

the enteric coating process and thus, if the product is stored under ambient conditions, the

acidic residue of the enteric coating can degrade the Omeprazole active ingredient before

it is administered to a patient.the interaction of Omeprazole with the HPMC phthalate is

thus prevented by introduction of Barrier coating between drug coating layer and Enteric

Coating layer.

Studies performed on the enteric coating solution

To avoid from the contact of Omeprazole with the gastric juice, it was decided to perform

an enteric coating.

To improve the stability of the core that is containing Omeprazole the excipients should

give alkaline reaction. Hypromellose Phthalate is used as an enteric coating polymer. To

avoid from cracking of the coated substance, PEG 6000 was added into the coating

solution as plasticizer and purified talc as anti tacking agent.



Table-5.7 :- Process parameters of Fluid Bed Coater during drug coating on core

pellets

Parameters Value

Inlet air Temperature 50°C ± 5 °C

Bed Temperature 42 °C to 49 °C

Outlet Temperature 41 °C to 49 °C

Blower speed 1400-1600 RPM

CFM 320 - 425

Spray air Pressure 3 - 4kg/cm2

Seal Coating:

Dissolve Hypromellose E5 in purified water. And spray the solution on drug coated

pellets with below mentioned parameters.

Table-5.8 :- Process parameters of Fluid Bed Coater during seal coating on drug

coated pellets.

Parameters Value

Inlet air Temperature 50°C ± 5 °C

Bed Temperature 41 °C to 49 °C



CFM 360 - 425


Enteric Coating:

Mix Acetone and Ethanol in stainless steel container and then add Hypromellose

Phthalate under stirring till clear solution obtained. Then add PEG 6000 under stirring in

purified water till clear solution obtained and spray on the seal coated pellets with below

mentioned parameters.



Table-5.9 :- Process parameters of Fluid Bed Coater during enteric coating stage

Parameters Value

Inlet air tepmperature 45°C ± 5 °C

Bed temperature 39 °C to 45 °C



CFM 370 - 500


After enteric coating dry the pellets and then unload from FBP.Then the enteric coated

pellets bifurcated for filling of capsules in two different strength from the common pellets

Capsules were filled manually in size “2” EHG capsules

Method of analysis4 :-

Dissolution : Perform the dissolution test of the prepared capsules.

Mix 11 volumes of 0.25 Molar tri sodium orthophosphate and 22 volumes of 0.5 Molar

anhydrous disodium hydrogen orthophosphate dilute to 100 volumes with distilled water

and then adjust the pH if necessary, up to 11.0 with the alkalime material like

orthophosphoric acid or 10 Molar sodium hydroxide(solution A).

Mix 1 volume of ten Molar sodium hydroxide with 99 volumes of phosphate buffer pH

4.5 with 0.05 Molar – solution B.

Mix 5.2 volumes of 1 Molar anhydrous sodium dihydrogen orthophosphate and 63.2

volumes of 0.5 Molar anhydrous disodium hydrogen orthophosphate, dilute to 1000

volumes with distilled water and then adjust the pH of the solution up to 7.6 with alkaline

material like orthophosphoric acid or 10 Molar sodium hydroxide, as appropriate

(solution C).

Test Conditions

(a) Apparatus 2, paddle, 100 RPM

(b) Use as the media the solutions described sequentially as mentioned below.



Acid stage - pH 4.5

In the dissolution at acid stage 700 ml of 0.05 molar pH 4.5 phosphate buffer is used.

After 45 minutes, take out five ml of the medium and then transfer and filter the aliquot,

dilute to 25 ml with solution A and retain the samples for analysis as mentioned below.

Proceed immediately to the final stage.

Buffer stage – pH 6.8

Within five minutes, add 200 mL of solution B at 37°C to the vessel. Maintain the RPM

at 100 per minute and continue to operate the apparatus further for 45 min. take out 5 ml

of the medium, filter the aliquot, dilute to 25 ml with solution A and retain the samples

for analysis as described below.

Perform the analysis in chromatography as per

(a) Use the sample solutions taken above.

(b) Dissolve a sufficient quantity of omeprazole BPCRS in solution A and then dilute the

solution with distilled water

• Use a stainless steel column packed with octadecylsilyl silica of chromatography.

• Column temperature of 30 degree C

• Isocratic elution

• Detection wavelength of 302 nm.

• Suitable guard column

• Flow rate with 0.25 ml per minute

• Inject 10 micro ml

• Chromatography for eight times compare to omeprazole

Mobile phase : Take 35 volume of distilled water, then 25 volume of solution C and 40

volume of the acetonitrile. Adjust pH, if necessary, to 7.6 with 10 Molar NaOH.

System suitability

Not more than 2.0 symmetry factor of peak due to the omeprazole.



Content Determination

As per British Pharmacopoeia in the omeprazole monograph calculation ot total content

of C17H19N3O3S in the medium and compared with the declared content.

Limits

The amount of omeprazole released after the first stage is not more than 10 %w/w of the

specified amount. The amount of omeprazole released after the final stage should not be

less then 65% (Q) of the specified amount.

Assay:

The method of analysis for assay content was performed as

(1) Weigh the contents of 20 capsules and grind to a fine powder. Disperse a quantity

twenty four mg of omeprazole in of powder containing one fifty ml of mobile

phase.

(2) Add 0.0012 % of omeprazole reference standard in mobile phase

(3) Mix reference standard of omeprazole and impurity D in mobile phase and dilute

to hundred ml.

Chromatographic condition

The method for determination of assay is similar to related substance but 305 nm

detection wavelength.

Determination of content

As per British Pharmacopoeia in the omeprazole monograph calculation ot total content

of C17H19N3O3S in the medium and compared with the declared content.



Table 5.10: Formulation of Omeprazole delayed release capsules

Sr.No. Batch No. A B C D E F G

Drug Coating

1. Sugar Sphere (850 –

1000 micron) 170.40 146.30 158.35 156.35 149.35 154.35 157.40

2. Hypromellose E5 4.00 4.000 4.00 4.00 4.00 4.00 4.00

3. Hydroxy Propyl

cellulose (Klucel EF) 6.00 6.000 6.00 6.00 6.00 6.00 6.00

4. Lactose Anhydrous 8.00 8.000 8.00 8.00 8.00 8.00 8.00

5. Sodium lauryl sulphate

(SLS) 0.50 0.50 0.50 0.50 0.50 0.50 0.50

6. Omeprazole 20.00 20.000 20.00 20.00 20.00 20.00 20.00

7.

Disodium Hydrogen

phosphate

Dodecahydrate

2.00 2.000 2.00 2.00 2.00 2.00 2.00

8. Pu. Water Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. Q.S.

Avg. wt. of drug coated

pellets 210.90 186.80 198.85 196.85 189.85 194.85 197.90

Seal Coating

9. Hypromellose E5 1.000 9.00 5.00 7.00 14.00 9.00 14.00

10. Pu. water Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. Q.S.

Avg. wt. of seal coated

pellets

(% weight gain on drug

coated pellets )

211.90

(0.50)

195.80

(4.82)

203.85

(2.51)

203.85

(3.55)

203.85

(7.37)

203.85

(4.61)

211.90

(7.07)

Enteric Coating

11. Hypromellose Phthalate 18.00 34.00 26.00 26.00 26.00 26.00 18.00

12. PEG 6000 0.10 0.20 0.15 0.15 0.15 0.15 0.10

13. Pu. warer Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. Q.S.

14. Acetone Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. Q.S.

15. Ethanol Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. Q.S.

Avg. wt. of seal coated

pellets

(% weight gain on seal

coated pellets)

230.00

(8.54)

230.00

(17.47)

230.00

(12.83)

230.00

(12.83)

230.00

(12.83)

230.00

(12.83)

230.00

(8.54)



Q.S. – Quantity sufficient

Dissolution profile comparision in 700 ml pH 4.5 phosphate buffer followed by 900 ml of

pH 6.8 phosphate buffer

Apparatus :- paddle

RPM :- 100

Table 5.11 : Dissolution profile

Sr.

No. Batch No.

Reference

samples A B C D F G H

1.

phosphate

buffer pH

4.5 (45

minutes)

3.8 8.9 0.1 5.1 3.4 2.7 3.0 9.2

2.

phosphate

buffer pH

6.8

(5 minutes)

(10 minutes)

(15 minutes)

(20 minutes)

(30 minutes)

(45 minutes)

78

96

98

98

99

98

90

92

92

92

91

90

24

71

90

96

98

98

69

90

96

98

99

98

81

94

98

98

99

99

65

90

96

100

99

98

69

89

96

99

100

98

70

92

96

97

98

96



Dissolution profile comparion

0

20

40

60

80

100

120

0 10 20 30 40 50

times in minutes

% c

um

ula

tive

dru

g d

isso

lve

B.No. TT0040

B.No. A

B.No. B

B.No. C

B.No. D

B.No. E

B.No. F

B.No. G

Figure 17 :- Dissolution profile comparision in pH 6.8 phosphate buffer

Table 5.12 Assay

Sr.

No. Batch No.

Reference

samples A B C D E F G

1 Assay 99.3 % 95.7 % 100.1 % 99.1 % 99.9 % 98.3 % 98.1 % 99.3 %



Table 5.13 Description

Sr. No. Batch No. Description

1

Reference samples

IM6750

(Finished product )

Size ‘2’ Empty hard gelatin capsule with opaque red brown cap marked

A/OM and opaque pink body marked 20.

(pellets) White enteric coated granules

2 A (Finished product )

Size’2’ EHG capsule with pink colour body and reddish brown cap

containing brown to black pellets.

(pellets) Brown to black pellets

3 B (Finished product )


containing white to yellowish pellets.

(pellets) White to yellowish pellets

4 C (Finished product )




5 D (Finished product )




6 E (Finished product )




7 F (Finished product )




8 G (Finished product )




5.7 Photostability study

Formulation was exposed to Visible for 300 Hrs with 4.0 K LUX and for Ultraviolet light

it was exposed for 200 Hrs with one Watts Hours/Sq meter as per ICH guideline.

The main aim and objective of the photostability study of Omeprazole gastro resistance/

delayed release capsules.



Procedure5

For the purpose of the study, Omeprazole gastro resistance capsules.shall be exposed to

light in a Photostability chamber. The product will be exposed as such (unpacked), in the

immediate pack and in marketing pack. Control samples (+ve and -ve controls) will also

be maintained as samples not exposed and samples exposed after wrapping with

aluminium foil.

Omeprazole gastro resistance capsules 20 mg

Table 5.14

Sample No. Sample Quantity required (Capsules)

S1 Not irradiated product (+ve control)

30

S2 Product as such (unpacked) 30

S3 Product in immediate pack (Alu – Alu Blister)

30

S4 Product in market pack 30’s Count (40 CC HDPE Bottle with Desiccant)

30

S5 Product in market pack 30’s Count (40 CC HDPE Bottle)

30

S6 Product in marketing pack (in carton) (Alu – Alu Blister)

30

S7 Product in Alu pouch (-ve control) 30

Total (Capsules) 210

Table 5.15 Characteristics of chamber

Model NEC 103 RSPS Temperature 25 ± 2 °C Irradiate Area 430 x 410 mm

Photostability chamber should be set so as to produce NLT 1.2 million Lux hours for the

visible light and NLT 200 Watthours/ square meter for UV light in irradiate area.

Procedure

Exposure of Visible light and UV light should be measured using calibrated LUX meter

and UV meter.

All the samples should be placed in the chamber, maintaining the temperature at 25 ± 2°C

and should be exposed to visible and UV light using a fluorescent lamp for visible light



and UV lamp for UV light. Measured value of Lux for visible light and Watts / sq meter

for UV light should be fed in the controller of the chamber.

The following samples will be tested as required after the end of total exposure of UV

and visible light.

Monitoring

Table 5.16 Following controls should be monitored during the study.

1 Temperature

2 Lux Exposed

3 UV Exposed

Analysis of Irradiated product

Irradiated samples should be withdrawn from the chamber after the completion of

exposure time and should be analysed as mention bellow as per shelf life specification.

Not irradiated (+ve control) sample should be analysed in the same way if required.

Table 5.17 Test to be performed

Sr. No. Test to be performed

1. Description

2. Assay

3. Chromatographic purity

Analysis

Irradiated samples should be withdrawn from the chamber after the completion of

exposure time and should be analysed for Description, Assay and Related Substances as

per shelf life specification. Not irradiated (+ve control) sample should be analysed in the

same way if required.



Table 5.18 : Photostability study of Omeprazole 20 mg capsules

Batch No: D Strength 20 mg

Condition Limit

Initial open petri

dish Alu/Alu blister

HDPE container

Alu/Alu blister in carton

Description * * ** * * *

Assay 95-105% 102.20% 101.40% 102.00% 101.10% 99.80% RS

ImpA NMT0.2% 0.027% 0.123% 0.072% 0.077% 0.076% ImpB NMT0.2% 0.000% 0.000% 0.000% 0.000% 0.000% ImpC NMT0.2% 0.008% 0.027% 0.016% 0.018% 0.017% ImpD NMT0.2% 0.025% 0.032% 0.033% 0.032% 0.032% ImpE NMT0.2% 0.021% 0.051% 0.025% 0.028% 0.026%

Imp F+G NMT0.5% 0.036% 0.452% 0.298% 0.297% 0.285% Imp H NMT0.2% 0.003% 0.000% 0.000% 0.000% 0.000% Imp I NMT0.2

% 0.004% 0.007% 0.004% 0.004% 0.000% Unknown impurity

NMT0.2%

0.010% 0.128% 0.081% 0.088% 0.079% Total

impurity NMT2.0%

0.199% 1.292% 0.856% 0.847% 0.815%

*Size’2’ EHG capsule with pink colour body and reddish brown cap containing

white to yellowish pellets.

**Size’2’ EHG capsule with pink colour body and reddish brown cap containing

brown to black pellets.

Conclusion:

From photostability data it can be concluded that formulation is light sensitive as there is

change in description of unpacked capsules and change in impurity level (increase in

trend )so decided to pack as soon as possible and intermediate product should be stored in

light resistant container.



5.8 Figure 18: Process Flow Diagram: Omeprazole Capsules 20 mg

Ingredients / Inputs

Step / Process / Equipment

Sugar sphere(850-1000 µm)

1 Drug Coating

(Fluid bed equipment)

Hypromellose

Hydroxy propyl cellulose

Lactose anhydrous

Sodium lauril sulphate

Omeprazole

Disodium hydrogen phosphate

Purified water*

Hypromellose

Purified water*

2

Seal Coating (Fluid bed equipment)

Hypromellose phthalate

PEG 6000

Acetone*

Absolute alcohol *

Purified water *

3 Enteric Coating

(Fluid bed equipment)

4 Filling of Capsules

Empty hard gelatin capsules

5 Packing

* Shall not present in the final product except traces and lost during processing.



5.9 Result and Discussion:

In the modern studies the role of pellets preparation its design, development and

commercialization in remarkablelly increasing. Product development of active content in

pellets form like coated pellets in the empty hard gelatin capsules provide flexibility for

site specific target release active content release rate. Proton pump inhibitor such as

omeprazole which causes irritation in the gastric environment and absorbed through out

the gastrointestinal tract. Due to its unstable nature of active content at acidic

environment the delayed release coating is required. Drug content of Batch No. A, B, C,

D, E, F and G found satisfactory shows that the process is sufficiently optimized and no

loss found during pelletisation. The above mentioned data reveals that 0.5 % w/w weight

gain seal coated pellets shows discoloration of pellets. This shows that increase in seal

coating required to protect the drug form enteric coated layer. 17.5 % w/w weight gain

Enteric coated pellets shows slower initial release as compare to reference samples.

Weight gain of seal coating on drug coated pellets from two and half percent to around

seven and half percent weight by weight and weight gain of enteric coating on seal coated

pellets from eight and half percent to seventeen and half percent weight by weight reveals

good dissolution characteristics and pass as per British Pharmacopoeia 2012.

5.10 Conclusion:

From the above executed trials it had been concluded the for seal coating stage in B.No.

A it is 0.5 % w/w weight gain it shows discoloration of pellets. B.No. B,C,D,E,F,G

passes dissolution as per British Pharmacopoeia 2012 but B.No. D with 3.5 w/w seal

coating and 12.8 % w/w enteric coating shows closer dissolution profile compare to other

batches with reference sample.



5.11 Resferances:

1) Ghebre SI., “Pharmaceutical Pelletization Technology”, Marcel Dekker, Inc., New

York, 1989.

2) Bardou M., Janet M., “Pantoprazole: from drug metabolism to clinical relevance”,

Expert Opinion on Drug Metabolism and Toxicology, April 2008; Volume 4(4), 471-

483.

3) “Package Insert, AstraZeneca group of companies, LOSEC (Omeprazole) capsules”,

April 2007.

4) “British Pharmacopoeia 2012”, Formulated preparation: specific monographs Gastro-

resistant Omeprazole capsules. Volume 1 and 2.

5) “International council of Harmonization Topic Q1B Photostability Testing of New

Active Substances and Medicinal Products”, January, 1998; CPMP / ICH / 279 / 95,

1-9.

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