12 Chapter 5,Omeprazole delayed release...
Transcript of 12 Chapter 5,Omeprazole delayed release...
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
Chapter 5 OMEPRAZOLE DELAYED RELEASE CAPSULES
JJT University, Rajasthan
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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
Chapter 5 OMEPRAZOLE DELAYED RELEASE CAPSULES
JJT University, Rajasthan
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.
Chapter 5 OMEPRAZOLE DELAYED RELEASE CAPSULES
JJT University, Rajasthan
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
Chapter 5 OMEPRAZOLE DELAYED RELEASE CAPSULES
JJT University, Rajasthan
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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
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JJT University, Rajasthan
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• 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.
Chapter 5 OMEPRAZOLE DELAYED RELEASE CAPSULES
JJT University, Rajasthan
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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
Chapter 5 OMEPRAZOLE DELAYED RELEASE CAPSULES
JJT University, Rajasthan
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 Unknown impurities
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
Omeprazole + Lactose anhydrous
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
Omeprazole + Hypromellose E5
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
Omeprazole + Sodium lauryl sulphate
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
Omeprazole + Disodium hydrogen phosphate Dodecahtydrate
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
Omeprazole + Klucel EF
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
Omeprazole + Hypromellose Phthalate
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
Omeprazole + PEG 6000
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
Omeprazole + Diethyl phthalate
1:0.5 Black colour semi liquid
-- -- -- -- -- -- -- -- -- -- -- --
Chapter 5 OMEPRAZOLE DELAYED RELEASE CAPSULES
JJT University, Rajasthan
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 Unknown impurities
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
Omeprazole + Lactose anhydrous
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
Omeprazole + Hypromellose E5
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
Omeprazole + Sodium lauryl sulphate
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
Omeprazole + Disodium hydrogen phosphate Dodecahtydrate
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
Omeprazole + Klucel EF
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
Omeprazole + Hypromellose Phthalate
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
Omeprazole + PEG 6000
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
Omeprazole + Diethyl phthalate
1:0.5 Black colour semi liquid
-- -- -- -- -- -- -- -- -- -- -- --
Chapter 5 OMEPRAZOLE DELAYED RELEASE CAPSULES
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.
Chapter 5 OMEPRAZOLE DELAYED RELEASE CAPSULES
JJT University, Rajasthan Page 108
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
Outlet Temperature 40 °C to 49 °C
Blower speed 1400-1600 RPM
CFM 360 - 425
Spray air Pressure 3 - 4kg/cm2
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.
Chapter 5 OMEPRAZOLE DELAYED RELEASE CAPSULES
JJT University, Rajasthan Page 109
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
Outlet Temperature 38 °C to 41 °C
Blower speed 1400-1750 RPM
CFM 370 - 500
Spray air Pressure 3 - 4kg/cm2
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.
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JJT University, Rajasthan Page 110
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.
Chapter 5 OMEPRAZOLE DELAYED RELEASE CAPSULES
JJT University, Rajasthan Page 111
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.
Chapter 5 OMEPRAZOLE DELAYED RELEASE CAPSULES
JJT University, Rajasthan Page 112
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)
Chapter 5 OMEPRAZOLE DELAYED RELEASE CAPSULES
JJT University, Rajasthan Page 113
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
Chapter 5 OMEPRAZOLE DELAYED RELEASE CAPSULES
JJT University, Rajasthan Page 114
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 %
Chapter 5 OMEPRAZOLE DELAYED RELEASE CAPSULES
JJT University, Rajasthan Page 115
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 )
Size’2’ EHG capsule with pink colour body and reddish brown cap
containing white to yellowish pellets.
(pellets) White to yellowish pellets
4 C (Finished product )
Size’2’ EHG capsule with pink colour body and reddish brown cap
containing white to yellowish pellets.
(pellets) White to yellowish pellets
5 D (Finished product )
Size’2’ EHG capsule with pink colour body and reddish brown cap
containing white to yellowish pellets.
(pellets) White to yellowish pellets
6 E (Finished product )
Size’2’ EHG capsule with pink colour body and reddish brown cap
containing white to yellowish pellets.
(pellets) White to yellowish pellets
7 F (Finished product )
Size’2’ EHG capsule with pink colour body and reddish brown cap
containing white to yellowish pellets.
(pellets) White to yellowish pellets
8 G (Finished product )
Size’2’ EHG capsule with pink colour body and reddish brown cap
containing white to yellowish pellets.
(pellets) White to yellowish pellets
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.
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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
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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.
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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.
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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.
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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.
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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.