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OMEPRAZOLE PELLETS

OPEN PART – TABLE OF CONTENTS

1. COMPANY PROFILE - 03

1.1. NAME AND ADDRESS OF THE MANUFACTURER - 05

2. FACILITIES DESCRIPTION - 06

3. ACTIVE INGREDIENTS - 07

3.1. ACTIVE INGREDIENTS: SPECIFICATIONS AND ROUTINE TESTS - 07

3.1.1. SPECIFICATIONS - 07

3.1.2 TEST METHODS - 09

3.2. ACTIVE INGREDIENTS -


15

3.2.1. NOMENCLATURE - 15

3.2.2. SCIENTIFIC DATA - 16

3.3. MANUFACTURE - 17

3.3.1. ROUTE OF SYNTHESIS - 17

3.3.2. FLOW CHART - 18

3.3.3 LIST OF CRITICAL PROCESS EQUIPMENTS - 20

3.4 QUALITY CONTROL DURING MANUFACTURE - 21

3.4.1. STARTING MATERIALS AND IN PROCESS MATERIALS - 21

3.4.2 INTERMEDIATES - 40

3.4.3 LIST OF QUALITY CONTROL INSTRUMENTS - 45

3.4.4 INPROCESS CONTROLS DURING SYNTHESIS - 46

Page No. 1
OMEPRAZOLE PELLETS

3.5. DEVELOPMENT CHEMISTRY - 47

3.5.1. STRUCTURE ELUCIDATION AND CONFIRMATION - 47

A) ELEMENTAL ANALYSIS - 47

B) ULTRAVIOLET SPECTRUM - 48

C) INFRARED SPECTRUM - 49

D) NMR SPECTRUM - 50

E) MASS SPECTRUM - 51

3.5.2. PHYSICO – CHEMICAL CHARACTERISTICS - 53

3.6. ANALYTICAL VALIDATION - 54

3.6.1 LIST OF POTENTIAL IMPURITIES - 54

3.6.2 METHODS USED TO STUDY IMPURITIES - 55

3.7. REFERENCE STANDARD AND WORKING STANDARD - 56

4. LIST OF PACKING MATERIALS - 58

4.1 SPECIFICATIONS - 59

5. BATCH ANALYSIS - 61

5.1 TEST RESULTS - 61

6. STABILITY STUDIES - 64

6.1 ACCLERATED STABILITY DATA REPORT - 65

6.2 LONG TERM STABILITY DATA REPORT - 68

7. MATERIAL SAFETY DATA SHEET - 71

8. VENDORS LIST - 76

Page No. 2
OMEPRAZOLE PELLETS

1. COMPANY PROFILE

The Company

Disto pharmaceuticals Pvt Ltd is an integrated formulations manufacturing


company based in Hyderabad, A.P., India. Our company is distinctive and known
for our high standards of quality.

Underlying our philosophy of consistent high quality is an effective blend of


technical expertise & experience, organizational strengths, infrastructure and
capability to work closely with our various clientele.

The People

Disto’s most valuable resource is its people. We have a team of dedicated


employees handling a wide range of operations that include Research &
Development, Production, Quality Assurance, Marketing, Purchasing and Finance.

As a whole, we represent a motivated and talented team working with a single-


minded commitment to consistently produce high-quality products to meet and
often surpass various quality standards.

Quality

Maintaining highest standards of quality is a continuous process at DISTO.


Our quality initiative covers all aspects, including product quality, Operational
quality and Environmental quality.

The involvement of every person through continual training programs marks


our Quality Assurance Programme, which includes strict process controls through
in-process checks, development of systems, procedures and relevant
documentation. We are in the process of obtaining WHO-GMP certifications.

Page No. 3
OMEPRAZOLE PELLETS

INFRASTRUCTURE & TECHNOLOGY

Disto pharmaceuticals Pvt Ltd is multi-locational company with plants at


various locations in Hyderabad, A.P. India., and a centralised Research &
Development unit with state-of-the-art equipment.

15 tons of Enteric Coated PFI’s (Pharmaceutical Formulation Ingredients /


Pellets) every month.

Our core team consists of highly qualified professionals with excellent


academic qualifications and exposure to business & technology development.

We are in the process of obtaining WHO-GMP certification.

Page No. 4
OMEPRAZOLE PELLETS

1.1. NAME AND ADDRESS OF THE MANUFACTURER

METROCHEM API PRIVATE LIMITED

Administrative Office:

Flat No. 302


Bhanu Enclave
Sunder Nagar
Erragadda
Hyderabad – 500 038
Ph + 91-40-23700421/23813969/23812317
Fax+ 91-40-23705088

Registered Office & Factory:

Plot No. 62/C/6


Pipeline Road
Phase-I
IDA, Jeedimetla
Hyderabad-500 055
Ph + 91-40-23193848
Fax + 91-40-23190806

www.metroapi.com

api@metroapi.com

Contact Person

Mr. N.Venkateswara Rao,


Managing Director.
Ph. + 91-40-23700421/23813969/23193848.
Fax +91-40-23705088/23190806

Page No. 5
OMEPRAZOLE PELLETS

2. FACILITIES DESCRIPTION

METROCHEM API PRIVATE LIMITED is an ISO 9001:2000 certified plant covering a


total area of 1006.50 sq mtrs. and with production facilities meeting GMP standards.

The production facilities are well designed for handling of materials & machines and
meeting required qualification.

Quality Control
The Q.C. department comprises of in process lab and instrumentation with well
instruments like HPLC, GC etc. It is maintained highly qualified and trained people is a core area
of our plant ensuring that the highest quality products are consistently manufactured.

Production floor
The Production floor consists of S.S. Reactors and Glass Lined Reactors. The area is
provided with proper concealed drainage facility and all process utilities are performed under
protective environment.

Utilities
The utilities include Boiler (Capacity 1000 Kg), Chilling plant (Capacity 2000 ltrs) and DM
Water plant (Capacity 1000 ltrs/hr) and the DM water is generating water, which meets all
required specifications.
Preventive Maintenance is being followed as per schedule for plant & utilities.

Ware house
The plant is having sufficient storage facility for rawmaterials. All solid Rawmaterials are
stored and identified properly. Liquid rawmaterials are stored in storage tanks appropriately.

A regular house keeping schedule with adequate preventive maintenance ensures that
the plant is consistently maintained as per GMP standards.

Page No. 6
OMEPRAZOLE PELLETS

3. ACTIVE INGREDIENTS

3.1. ACTIVE INGREDIENTS: SPECIFICATION AND ROUTINE TESTS

3.1.1. SPECIFICATIONS

Specification No.: MC/FP/O/S.02 Effective from: 01.03.2004

Specifications Supersedes : Nil Rev. No. : 00

Department : Quality Control Page : 1 of 1

Name of the Material/Code: OMEPRAZOLE POWDER BP / EP Category : Finished Product

01 Description A white or almost white powder


02 Solubility Soluble in methelene chloride. Sparingly soluble in Alcohol and
Methanol. Very slightly soluble in water and dissolves in diluted
solutions of Alkali Hydroxides.

03 Identification a) The 0.002% soln. In 0.1M NaOH shows two absorption maxima
at 276 nm and 305 nm and ratio is 1.6 to 1.8
b) The IR spectrum concordant with the spectrum of omeprazole
CRS.
c) The spot obtained by TLC the is similar in position and size to
the omeprazole CRS.

04 Appearance of solution 2 % solution in MDC is clear


05 Absorbance The absorbance of 2% soln in MDC at 440nm is not more than 0.1

06 Omeprazole impurity By TLC NMT 0.1 %


‘C’

07 Related substance by NMT 0.1 %


HPLC

08 Residual solvents Chloroform NMT 50 PPM


by Head-space gas Methylene chloride NMT 100 PPM
Chromatography Trichloro Ethylene NMT 100 PPM
09 Loss on Drying NMT 0.2% at 600 C under high vacuum for 4 hrs

10 Sulphated Ash NMT 0.1 %


11 Assay NLT 99.0 % and NMT 101.0 %
(Potentiometrically)

Page No. 7
OMEPRAZOLE PELLETS

Specification No.: MC/FP/O/S.03 Effective from: 01.03.2004

Specifications Supersedes : Nil Rev. No. : 00

Department : Quality Control Page : 1 of 1

Name of the Material/Code: OMEPRAZOLE POWDER USP Category : Finished Product

S.No. Test Specifications


01 Description A white or almost white powder
02 Solubility Very slightly soluble in water, soluble in Alcohol, in Methanol and
in Methelene Chloride, dissolves in diluted solutions of Alkali
Hydroxides
03 Identification
a) By TLC: The Rf value of principal spot of test should corresponds to the R f
value of USP Omeprazole R.S.
b) By Infrared The IR spectrum concordant with the spectrum of Omeprazole CSR.
Absorption

04 Completeness of solution Should meets the requirements, a solution in methelene chloride


containing 20 mg per ml. being used.

05 Color of Solution Determine the absorbance of the solution prepared for the
Completeness of solution test at 440 nm, in 1-cm cells, using
methylene chloride as the blank. The absorbance is not greater than
0.10.

06 Loss on drying at 600C Not more than 0.5 % W/W


for 4 hrs. under vacuum.

07 Residue on Ignition Not more than 0.1 % W/W


08 Heavy Metals Not more than 0.002%
09 Organic volatile impurities Should meet the requirements.
10 Chromatographic Purity
Method 1 (By TLC):
a) Individual impurity: Not more than 0.3%
b) Sum of Impurities: Not more than 1.0%
Method 2 (By HPLC):
a) Individual Impurity: Not more than 0.3%
b) Sum of Impurities: Not more than 1.0%

11 Assay Not less than 98.0% and


Not more than 102.0%

Page No. 8
OMEPRAZOLE PELLETS

3.1.2. TEST METHODS

Specification No. : MC/FP/O/S.02 Effective from: 01.03.2004

Method of Analysis Supersedes : Nil Rev. No. : 00

Department : Quality Control Page : 1 of 3

Name of the Material/Code: OMEPRAZOLE POWDER BP/EP Category : Finished Product

Page No. 9
OMEPRAZOLE PELLETS
S.No Test Method of Analysis

01. Description By visual observation

02. Solubility Soluble in methelene chloride. Sparingly soluble in Alcohol and


Methanol. Very slightly soluble in water and dissolves in diluted
solutions of Alkali Hydroxides.

03. Identification

a) BY U.V The 0.002% of solution in 0.1M NaOH shows two absorption maxima
at 276 nm and 305 nm and ratio is 1.6 to 1.8.

b) I.R.SPECTRUM The infrared absorption spectrum of a Potassium bromide dispersion of


sample exhibits maxima only at the same wavelengths as that of a
similar preparation of Omeprazole Reference standard.

c) BY T.L.C. Examine the chromatograms obtained in the test for Omeprazole


impurity C. The principal spot in the chromatogram obtained with test
solution (Dissolve 0.10 g. of the substance to be examined in 2.0 ml. of
methanol and take 1.0 ml. of this solution dilute to 10 ml. with
methanol.) is similar in position and size to the principal spot in the
chromatogram obtained with reference solution. Place the plate in a
tank saturated with vapour of acetic acid. The spots rapidly turn brown.

04. Appearance of 2% solution in MDC is clear.


Solution

05. Absorbance The absorbance of 2% soln in MDC at 440nm is not more than 0.1

06. Omeprazole Examine by thin-layer chromatography (2.2.27), using silica gel


Impurity 'C’ HF254 R as the coating substance.
Test solution (a). Dissolve 0.10 g. of the substance to be examined
in 2.0 ml. of methanol R.
Test solution (b). Dilute 1.0 ml. of test solution (a) to 10 ml with
methanol R.
Reference solution (a). Dissolve 9 mg of omeprazole CRS in 2.0 ml of
methanol R.
Reference solution (b). Dilute 1.0 ml of test solution (b) to 100 ml
with methanol R.

Specification No.: MC/FP/O/S.02 Effective from: 01.03.2004

Method of Analysis Supersedes : Nil Rev. No. : 00

Department : Quality Control Page : 2 of 3

Name of the Material/Code: OMEPRAZOLE POWDER BP/EP Category : Finished Product

Page No. 10
OMEPRAZOLE PELLETS
S.No Test Method of Analysis

Apply separately to the plate 10µl of each solution. Develop over a


path of 15 cm using a mixture of 20 volumes of 2-propanol R, 40
volumes of methylene chloride R previously shaken with
concentrated ammonia R (shake 100 ml of methylene chloride R
with 30 ml of concentrated ammonia R in a separating funnel, allow
the layers to separate and use the lower layer) and 40 volumes of
methylene chloride R. Allow the plate to dry in air. Examine in
ultraviolet light at 254 nm. Any spot in the chromatogram obtained
is not more intense than the spot in the chromatogram obtained with
reference solution (b) (0.1 percent).

07. Related Substances


by HPLC
07.1 Chromatographic 7.1.1 APPARATUS
Conditions The liquid chromatograph equipped with variable wave length
detector and integrator.

7.1.2 Column : Kromasil : C - 8 : 150 X 4 mm 5µm.

7.1.3 Wave Length: 280 nm.

7.1.4 Flow Rate :1.0 ml / min.

7.1.5 Load 20 µl

07.2. Mobile Phase A mixture of 27 volumes of acetonitrile and 73 volumes of 1.4 g/l.
solution of Disodium hydrogen phosphate previously adjusted pH to
7.6 with phosphoric acid.

07.3. Sample Preparation Weigh accurately about 0.01 gms of sample and dissolve it in 10 ml
of mobile phase.

07.4. Procedure Inject 20 µl of sample and record the Chromatograph.

07.5. Calculate Total of area of impurity peaks


--------------------------------------- X 100

Total of all areas of the peaks

Specification No.: MC/FP/O/S.02 Effective from: 01.03.2004

Method of Analysis Supersedes : Nil Rev. No. : 00

Department : Quality Control Page : 3 of 3

Name of the Material/Code: OMEPRAZOLE POWDER BP/EP Category : Finished Product

Page No. 11
OMEPRAZOLE PELLETS
S.No Test Method of Analysis

08. Residual Solvents Examine by head-space gas chromatography (2.2.28), using


by Head-Space the standard additions method. The content of chloroform is not more
Gas Chromatography than 50 ppm, the content of methylene
chloride is not more than 100 ppm and the content of
Trichloroethylene is not more than 100 ppm.
The chromatographic procedure:
i) a fused-silica column 30 m long and 0.32 mm in internal diameter
coated with a 1.8 µm film of cross linked poly [(cyanopropyl)
(methyl)] [(phenyl)(methyl)] siloxane,
ii) nitrogen for chromatography as the carrier gas.
iii) a flame – ionisation detector,
iv) a suitable headspace sampler.
Place 0.50 g of the substance to be examined in a 10 ml. vial. Add 4.0
ml of dimethylacetamide and stopper the vial. Equilibrate the vial at
800C for 1 hr.

09. Loss on drying Determined on 1.000 g by drying under high vacuum at 600C for 4 hr.

10. Sulphated Ash Heat a silica or platinum crucible to redness for 10 minutes in muffle
furnace, allow to cool in desiccator and weigh. Put 1 to 2 g. of the
substance, accurately weighed, into the crucible, ignite, gently at first,
until the substance is thoroughly charred. Cool, moisten the residue
with 1 ml. of Sulphuric acid, heat gently until white fumes are no
longer evolved and ignite at 8000 +/- 250 until all black particles have
disappeared. Conduct the ignition in a plate protected form air
currents. Allow the crucible to cool, add a few drops of Sulphuric acid
and heat. Ignite as before, allow to cool and weigh. Repeat the
operation until two successive weighings do not differ by more than
0.5 mg.

11. Assay Dissolve 1.100 g in a mixture of 10 ml of water and 40 ml.


(Potentiometrically) of alcohol. Titrate with 0.5 M sodium hydroxide, determining the end-
point potentiometrically.1 ml. of 0.5 M sodium hydroxide corresponds
to 0.1727 g. of C17H19N3O3S.

Specification No.: MC/FP/O/S.03 Effective from: 01.03.2004

Method of Analysis Supersedes : Nil Rev. No. : 00

Department : Quality Control Page : 1 of 3

Name of the Material/Code: OMEPRAZOLE POWDER USP Category : Finished Product

Page No. 12
OMEPRAZOLE PELLETS

S.No. Test Method of Analysis


01 Description By visual observation.
02 Solubility Very slightly soluble in water, soluble in Alcohol, in Methanol and
in Methelene Chloride, dissolves in diluted solutions of Alkali
Hydroxides

03 Identification
a) By TLC Determine TLC using Chromatographic Purity Method 1 as per
USP 26 Page 1350.
b) By Infrared Determine Infrared absorption using Method 197K as per USP 26
Absorption Page 2054.

04 Completeness of solution Determine Completeness of solution using Method 641 as per USP
26 Page 2139.

05 Color of Solution Determine the absorbance of the solution prepared for the
Completeness of solution test at 440 nm, in 1-cm cells, using
methylene chloride as the blank.

06 Loss on drying at 600C Determine Loss on drying using Method 731 as per USP 26 Page
for 4 hrs. under vacuum. 2172.

07 Residue on Ignition Determine Residue on Ignition using Method 281 as per USP 26
Page 2061.
08 Heavy Metals
Determine Heavy metals using Method II 231 as per USP 26 page
2057.

09 Organic volatile Determine Organic volatile impurities using Method IV 467 as per
impurities USP 26 Page 2077.

10 Chromatographic Purity Determine TLC using Chromatographic Purity Method 1 as per


a) Method 1 by TLC USP 26 Page 1350.

b) Method 2 by HPLC The liquid chromatograph is equipped with a 280 nm detector and
i) Chromatographic a 4.6 mm x 15 cm column that contains 5 m packing L7. The
system flow rate is about 0.8 ml per minute. Chromatograph the System
suitability solution, and record the peak responses as directed
under procedure: the capacity factor, k| , is not less than 6.0, the

Specification No.: MC/FP/O/S.03 Effective from: 01.03.2004

Method of Analysis Supersedes : Nil Rev. No. : 00

Department : Quality Control Page : 2 of 3

Name of the Material/Code: OMEPRAZOLE POWDER USP Category : Finished Product

Page No. 13
OMEPRAZOLE PELLETS

S.No. Test Method of Analysis

column efficiency is not less than 3000 theoretical plates, the


tailing factor is not more than 1.5, and the relative standard
deviation for replicate injections is not more than 1.0%

ii) Diluent Use Mobile Phase.

iii) Phosphate buffer Dissolve 0.725 gm. of Monobasic sodium phosphate and 4.472 gm
of anhydrous dibasic sodium phosphate in 300 ml of water, dilute
with water to 1000 ml, and mix. Dilute 250 ml. of this solution
with water to 1000 ml.

iv) Mobile Phase Prepare a filtered and degassed mixture of Phosphate buffer and
acetonitrile (3:1).

v) System suitability Dissolve an accurately weighed quantity of Omeprazole in Diluent


solution to obtain a solution containing about 0.16 mg per ml.

vi) Test solution Inject equal volumes of the Test solution and diluent into the
chromatograph, and allow the Test solution to elute for not less
than two times the retention time of omeprazole. Record the
chromatograms, and measure the peak responses.

vii) Calculate The percentage of each impurity in the portion of Omeprazole.


Formula: 100 (ri / rs )

Where
ri = The peak response for each impurity
rs = The sum of the responses of all of the peaks.

11 Assay The liquid chromatograph is equipped with a 280 nm detector and


i) Chromatographic a 4.6 mm x 15 cm column that contains 5 m packing L7. The
system flow rate is about 0.8 ml per minute. Chromatograph the System
suitability solution, and record the peak responses as directed
under procedure: the capacity factor, k| , is not less than 6.0, the
column efficiency is not less than 3000 theoretical plates, the
tailing factor is not more than 1.5, and the relative standard
deviation for replicate injections is not more than 1.0%

Specification No.: MC/FP/O/S.03 Effective from: 01.03.2004

Method of Analysis Supersedes : Nil Rev. No. : 00

Department : Quality Control Page : 3 of 3

Name of the Material/Code: OMEPRAZOLE POWDER USP Category : Finished Product

Page No. 14
OMEPRAZOLE PELLETS

S.No. Test Method of Analysis

ii) Diluent Prepare a mixture of 0.01 M sodium borate and acetonitrile (3:1)

iii) Phosphate buffer Dissolve 0.725 gm. of Monobasic sodium phosphate and 4.472 gm
of anhydrous dibasic sodium phosphate in 300 ml of water, dilute
with water to 1000 ml, and mix. Dilute 250 ml. of this solution
with water to 1000 ml.

iv) Mobile Phase Prepare a filtered and degassed mixture of Phosphate buffer and
acetonitrile (3:1).

v) Standard Preparation Dissolve an accurately weighed quantity of USP Omeprazole RS in


Diluent, and dilute quantitatively, and stepwise if necessary, with
Diluent to obtain a solution having a known concentration of about
0.2 mg per ml.

vi) Assay Preparation Transfer about 100 mg of Omeprazole, accurately weighed, to a 50


ml volumetric flask, dissolve in and dilute with Diluent to volume
and mix. Transfer5.0 ml of this solution to a 50 ml volumetric
flask, dilute with Diluent to volume, and mix.

vii) System suitability Dilute a volume of Standard preparation with Diluent to obtain an
solution solution containing about 0.1 mg of USP Omeprazole RS per ml.

viii) Procedure Separately inject equal volumes of the Standard preparation and
the Assay preparation into the chromatograph, record the
chromatograms, and measure the responses for the major peaks.

ix) Calculate The quantity, in mg of C17H19N3O3S in the portion of Omeprazole.

Formula: 500 C (ru / rs)

Where

C = Concentration in mg per ml., of USP Omeprazole


RS in the Standard preparation,

ru & rs = The peak responses obtained from the Assay


preparation and the Standard preparation.

3.2 ACTIVE INGREDIENTS

Page No. 15
OMEPRAZOLE PELLETS

3.2.1 NOMENCLATURE

 Recommended International Non-proprietary Name (INN)


Omeprazole.

 Compendial Name
Omeprazole.

 Chemical Name
5-Methoxy-2-[[(4-methoxy-3,5-dimethylpyridine-2-yl)methyl]Sulfinyl]-1H-
benzimidazole

 Company or Laboratory Code


Ome Pharma

 Other Non-proprietary Name (s)


H-168/68, Antra, Gasterlac,Losel, Mepral, Mopral, Omepral, Omeprazen,
Parizac,Pepticum, Prilosec

 United States Adopted Name (USAN)


Omeprazole.

 Japanese Accepted Name (JAN)


Omeprazole.

 British Approved Name (BAN)


Omeprazole.

 Chemical Abstract Service (CAS) Registry Number


73590-58-6

3.2.2 SCIENTIFIC DATA

Page No. 16
OMEPRAZOLE PELLETS

Structural Formula :

OCH3
CH3 CH3 OCH3
N
O

N CH2 S N
H

Chemical Name : 5-Methoxy-2-[[(4-methoxy-3,5-dimethylpyridine-2-yl) methyl]


Sulfinyl] -1H-benzimidazole

Structural Formula : C17H19N3O3S

Molecular weight : 345.42

CAS Registry Number : 73590-58-6


(CAS No.)

3.3. MANUFACTURE

Page No. 17
OMEPRAZOLE PELLETS

3.3.1 ROUTE OF SYNTHESIS

The synthesis consists of eight stages.

Stage –I : 3,5-Dimethyl-4-nitropyridine-N-oxide is condensed with SMO to give 4-methoxy 3,5


dimethyl pyridine N-oxide.

Stage – II: 4-methoxy 3,5 dimethyl pyridine N-oxide protonised with DMS to give salt of 4-
methoxy 3,5 dimethyl pyridine N-methoxy methosulphate.

Stage – III: Protanated Sulphide salt of 4-methoxy 3,5 dimethyl pyridine N-oxide is rearranged
with Ammonium per Sulphate to give 2-Hydroxy methyl-3,5-Dimethyl-4-methoxy pyridine hydro
sulphate.

Stage – IV: 2-Hydroxy methyl-3,5-Dimethyl-4-methoxy pyridine hydro sulphate is basified with


Na2CO3 lye solution to give 2-Hydroxy methyl-3,5-Dimethyl-4-methoxy pyridine.

Stage – V: 2-Hydroxy methyl-3,5-dimethyl-4-methoxy-pyridine is reacted with Thionyl chloride


to give 2-chloromethyl 3,5-dimethyl-4-methoxy-pyridine hydrochloride.

Stage – VI: 2-chloromethyl 3,5-dimethyl-4-methoxy-pyridine hydrochloride condensed with 5-


Methoxy-2-mercaptobenzimidazole to give 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-
2-methyl] thio]-1 H-benzimidazole.

Stage – VII: 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-2-methyl] thio]-1 H-


benzimidazole is oxidized in the presence of methanol with hydrogen peroxide to give Omeprazole
Technical.

Stage – VIII (Purification): Omeprazole technical purified with IPA, MDC, Acetone and
Methanol to give Omeprazole.

Omeprazole Technical Omeprazole Purified.

After purification, the material dried, tested, pulverised, sifted and packed as per customer
requirements.

3.3.2 FLOW CHART

Page No. 18
OMEPRAZOLE PELLETS

3,5-Dimethyl-4-
nitropyridine-N-oxide
SMO Stage - I

4-methoxy 3,5 dimethyl pyridine N-oxide

Stage – II
DMS

4-methoxy 3,5 dimethyl pyridine


N-methoxy methosulphate

Ammonium per sulphate Stage – III

2-Hydroxy methyl-3,5-Dimethyl-4-
methoxy pyridine hydro sulphate

Na2CO3 lye solution Stage – IV

2-Hydroxy methyl-3,5-Dimethyl
-4-methoxy pyridine

Thionyl chloride Stage – V

2-chloromethyl 3,5-dimethyl-4-methoxy-
pyridine hydrochloride

5-methoxy 2-mercapto Stage – VI


benzimidazole
5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)
-2-methyl] thio]-1 H-benzimidazole

Stage – VI

Page No. 19
OMEPRAZOLE PELLETS

Methanol
Hydrogen peroxide Stage – VII

5-Methoxy-2-[[(4-methoxy-3,5-dimethylpyridine-2-yl)
methyl]Sulfinyl]-1H-benzimidazole Technical

Iso propyl alcohol


Methylene chloride Stage – VIII
Acetone
Methanol

Omeprazole Purified

Packing

3.3.3. LIST OF CRITICAL PROCESS EQUIPMENTS

Page No. 20
OMEPRAZOLE PELLETS
S.
NAME OF THE EQUIPMENT / MOC CAPACITY LOCATION
NO
01 S.S.Reactor 1600 Ltrs. Production Block
02 S.S Reactor 1600 Ltrs. Production Block
03 Glass lined Reactor 1600 Ltrs. Production Block
04 S.S. Reactor 1200 Ltrs. Production Block
05 Glass lined Reactor 1600 Ltrs. Production Block
06 S.S. Reactor 1000 Ltrs. Production Block
07 S.S. Reactor 800 Ltrs. Production Block
08 S.S. Reactor 1000 Ltrs. Production Block
09 S.S. Reactor 2000 Ltrs. Production Block
10 S.S. Reactor 1000 Ltrs. Production Block
11 S.S. Reactor 2500 Ltrs. Production Block
12 S.S. Reactor (Open Jacket) 300 Ltrs. Production Block
13 S.S. Reactor (Open Jacket) 100 Ltrs. Production Block
14 S.S. Reactor (Open Jacket) 500 Ltrs. Production Block
15 S.S. Reactor (Open Jacket) 500 Ltrs. Production Block
16 Centrifuge 36” Production Block
17 Centrifuge 36” Production Block
18 Ice Brine Pump 2 HP Production Block
19 Centrifuge 36” Production Block
20 Leaf Filter 30 Ltrs. Production Block
21 Leaf Filter 50 Ltrs. Production Block
22 Leaf Filter 100 Ltrs. Production Block
23 Leaf Filter 50 Ltrs. Production Block
24 Leaf Filter 30 Ltrs. Production Block
25 Leaf Filter 50 Ltrs. Production Block
26 Leaf Filter 50 Ltrs. Production Block
27 Water-Demineralization plant 1000 Ltrs/hr Plant
28 Vacuum Pump 5 HP Maintenance
29 Vacuum Pump 5 HP Maintenance
30 Vacuum Pump 5 HP Maintenance
31 Vacuum Pump 5 HP Maintenance
32 Vacuum Pump 5 HP Maintenance

3.4. QUALITY CONTROL DURING MANUFACTURE

3.4.2. STARTING MATERIALS AND IN PROCESS MATERIALS

Page No. 21
OMEPRAZOLE PELLETS

Starting materials used in the manufacture are well controlled. Records indicate the
origin date of receipt, date of analysis and date of release by the Quality Assurance Department. All
materials received are checked, sampled, Quarantined tested and release as per the written
specification and standard test procedure.

Identification of each material used in the process:

No material is transferred from the quarantined area or taken into use to any
production process until and unless it is released by quality Assurance. Appropriate status labeling
system is being followed to ensure that only approved material is allowed to production area.

List of starting materials

S.No Name of the Materials


01 Nitro compound of omeprazole
02 Methanol
03 Caustic soda flakes
04 Dimethyl sulphate (sealed drums)
05 Chloroform
06 Toluene
07 Ammonium per sulphate
08 Activated carbon
09 Thionyl chloride
10 2-Mercapato 5-methoxy benzimidazole
11. Ethyl acetate
12. Hydrose
13. EDTA
14. Triethylamine
15. Ammonium molybdate
16. Acetone
17. Iso propyl alcohol
18. Methylene chloride

Specifications of starting materials are provided in the subsequent pages.

Specifications of starting materials

Specification No.: MC/IM/O/S.01 Effective from: 01.03.2004

Page No. 22
OMEPRAZOLE PELLETS

Specifications Supersedes : New Rev. No : 00

Department : Quality Control Page : 1 of 1

Name of the Material/Code: Nitro compound of Omeprazole/ O-II Category : Rawmaterial


Mol formula : C7H8N2O3
Chemical Name: 3,5-Dimethyl-4-nitro pyridine N-oxide Mol wt. : 168

S.No. Test Specifications

01 Description An yellowish to pale yellow colored crystalline powder

02 Solubility Soluble in Methanol, Chloroform & Methylene chloride. Slightly


soluble in water. Insoluble in n-Hexane

03 Identification

a) by TLC Should be positive

04 Melting Range Between 174 to 178oC

05 Loss on drying Not more than 0.5%

06 Related substances
by HPLC

a) Total impurity Not more than 1.0%


b) Individual Impurity Not more than 0.5%

07 Purity by HPLC NLT 99%

Specifications Specification No. : MC/RM/S-21 Date of preparation : 21.04.03

Supersedes : Nil Effective from : 01.05.03

Page No. 23
OMEPRAZOLE PELLETS

Department : Quality Control Page : 1 of 1

Name of the material/Code : Methanol/ML Molecular Formula : CH3OH

Chemical Name : Methyl Alcohol Molecular Weight : 32

S.No. Test Specifications

01 Description A clear colorless liquid

02 Solubility Miscible with water, benzene, ether and most of the organic
solvents.

03 Identification
a) Boiling Range Between 64 – 65.5 0C

04 Specific Gravity 0.77 – 0.79 gm/ml.

05 Moisture content by KFR Not more than 0.1% w/v.

06 Purity by GC Not less than 99.80%.

Specification No. : MC/RM/S-07 Date of preparation : 21.04.03


Specifications
Supersedes : Nil Effective from : 01.05.03

Page No. 24
OMEPRAZOLE PELLETS

Department : Quality Control Page : 1 of 1

Name of the material/Code : Caustic Soda flakes/CSF Molecular Formula : NaOH

Chemical Name : Sodium hydroxide flakes Molecular Weight : 40.01

S.No. Test Specifications

01 Description White sticks, pellets, fused mass or scales strongly alkaline and
corrosive and Hygroscopic material.

02 Solubility Freely soluble in water and methanol.

03 Identification
a) Test for Sodium A solution (1g in 20 ml) gives the reaction of sodium.

04 Assay by Chemical
a) Total Alkali Not less than 95.0%.

b) Sodium Carbonate Not more than 3.0%


Content

Specification No. : MC/RM/S-12 Date of preparation : 21.04.03


Specifications
Supersedes : Nil Effective from : 01.05.03

Page No. 25
OMEPRAZOLE PELLETS

Department : Quality Control Page : 1 of 1

Name of the material/Code : Dimethyl Sulphate/DMS Molecular Formula : C2H6O4S

Chemical Name : Sulfuric acid dimethyl ester Molecular Weight : 126.13

S.No. Test Specifications

01 Description A clear colorless liquid

02 Solubility Soluble in ether, dioxane, acetone and aromatic hydrocarbons.

03 Identification

a) Specific Gravity 1.30 – 1.33 gm/ml

04 Free acidity Not more than 0.5%

05 Assay by Chemical Not less than 98.0 % w/w

Specifications Specification No. : MC/RM/S-08 Date of preparation : 21.04.03

Supersedes : Nil Effective from : 01.05.03

Page No. 26
OMEPRAZOLE PELLETS

Department : Quality Control Page : 1 of 1

Name of the material/Code : Chloroform/CFM Molecular Formula : CHCl3

Chemical Name : Tri Chloro methane Molecular Weight : 119.38

S.No. Test Specifications

01 Description A clear colorless liquid with characteristic odor.

02 Solubility Miscible with alcohol, benzene, ether etc.

03 Identification
a) Boiling Range between 59 – 620 C.

04 Specific Gravity 1.46 – 1.49 gm/ml.

05 Moisture Content Not more than 0.1%

06 Purity by GC Not less than 99.8%

Specification No. : MC/RM/S-27 Date of preparation : 21.04.03


Specifications
Supersedes : Nil Effective from : 01.05.03

Page No. 27
OMEPRAZOLE PELLETS

Department : Quality Control Page : 1 of 1

Name of the material/Code : Toluene/TOL Molecular Formula : C7H8

Chemical Name : Methyl benzene Molecular Weight : 92.13

S.No. Test Specifications

01 Description A clear colorless liquid.

02 Solubility Miscible with ethyl alcohol, chloroform, ether, acetone, glacial


acetic acid, carbon disulphide.

03 Identification
a) Boiling Range Between 109 – 112 0C

04 Specific Gravity 0.86 – 0.88 gm/ml.

05 Moisture Content by KFR Not more than 0.10%

06 Assay by Chemical Not less than 99.80%.

Specification No. : MC/RM/S-04 Date of preparation : 21.04.03


Specifications
Supersedes : Nil Effective from : 01.05.03

Page No. 28
OMEPRAZOLE PELLETS

Department : Quality Control Page : 1 of 1

Name of the material/Code: Ammonium per sulphate/APS Molecular Formula : H8N2O8S2

Chemical Name : Ammonium peroxydisulphate Molecular Weight : 228.20

S.No. Test Specifications

01 Description A white granular crystals or crystalline powder.

02 Solubility Soluble in water.

03 Water content Not more than 0.5% w/w

Identification by
04 Assay by Chemical Not less than 98.0%.

05 PH (5% sol) between 2.50 to 4.50

06 Iron Test Not more than 20 ppm

Specification No. : MC/RM/S-03 Date of preparation : 21.04.03


Specifications
Supersedes : Nil Effective from : 01.05.03

Page No. 29
OMEPRAZOLE PELLETS

Department : Quality Control Page : 1 of 1

Name of the material/Code : Activated carbon/AC Molecular Formula : C

Chemical Name : Activated carbon Molecular Weight : 12

S.No. Test Specifications

01 Description A black, odorless granular powder.

02 pH (5% solution) between 5.5 to 7.5

03 Identification by
MB value 304 - 336

Specifications Specification No. : MC/RM/S-26 Date of preparation : 21.04.03

Supersedes : Nil Effective from : 01.05.03

Page No. 30
OMEPRAZOLE PELLETS

Department : Quality Control Page : 1 of 1

Name of the material/Code : Thionyl Chloride/TC Molecular Formula : SOCl2

Chemical Name : Sulfurous Oxychloride Molecular Weight : 118.98

S.No. Test Specifications

01 Description Colorless to pale yellow or reddish, fuming, refractive liquid.

02 Solubility Miscible with benzene, chloroform, carbon tetra chloride.

03 Identification
a) Boiling Range Between 74 – 76 0C

04 Specific Gravity 1.62 – 1.64 gm/ml.

05 Assay by Chemical Not less than 98.0%.

Specification No. : MC/RM/S-20 Date of preparation : 21.04.03


Specifications
Supersedes : Nil Effective from : 01.05.03

Page No. 31
OMEPRAZOLE PELLETS

Department : Quality Control Page : 1 of 1


Name of the material/Code/Ref:
2-Mercapto-5-Methoxy Benzimidazole/BI Molecular Formula : C8H8N2SO

Chemical Name : 2-Mercapto-5-Methoxy Benzimidazole Molecular Weight : 180.00

S.No. Test Specifications

01 Description Off White to pale yellow crystalline powder.

02 Solubility Soluble in Dimethyl formamide and sparingly soluble in methanol.

03 Identification
a) Melting Range between 2520 C– 2600C

04 Moisture Content Not more than 0.5% w/v

05 TLC Single spot.

06 Purity by HPLC Not less than 99.0%.

Specifications Specification No. : MC/RM/S-13 Date of preparation : 21.04.03

Supersedes : Nil Effective from : 01.05.03

Page No. 32
OMEPRAZOLE PELLETS

Department : Quality Control Page : 1 of 1

Name of the material/Code : Ethyl Acetate/EA Molecular Formula : C4H8O2

Chemical Name : Acetic acid ethyl ester Molecular Weight : 88.10

S.No. Test Specifications

01 Description A clear colorless volatile liquid with fruit odor.

02 Miscibility Miscible with alcohol, chloroform ether, and acetone etc.

03 Identification
a) Boiling Range between 760 – 790C

04 Specific Gravity 0.89 – 0.91 gm/ml.

04 Moisture Content Not more than 0.2%.

06 Purity by GC Not less than 99.80%.

Specification No. : MC/RM/S-16 Date of preparation : 21.04.03


Specifications
Supersedes : Nil Effective from : 01.05.03

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OMEPRAZOLE PELLETS

Department : Quality Control Page : 1 of 1

Name of the material/Code/ : Sodium Hydrosulfite/Hydrose Molecular Formula : Na2S2O4

Chemical Name : Sodium Dithionite Molecular Weight : 174.10

S.No. Test Specifications

01 Description A white or grayish – white crystalline powder.

02 Solubility Freely soluble in water and slightly in alcohol.

Identification by
03 Assay by Chemical Not less than 80.0%.

04 PH (5% sol) between 6.50 and 7.50

Specification No. : MC/RM/S-28 Date of preparation : 21.04.03


Specifications
Supersedes : Nil Effective from : 01.05.03

Page No. 34
OMEPRAZOLE PELLETS

Department : Quality Control Page : 1 of 1


Molecular Formula:
Name of the material/Code: Ethylene Diamine Tetra Acetate/ EDTA C10H14N2Na2O8.2H2O

Chemical Name : Ethylene Diamine Tetra Acetate Molecular Weight : 372.04

S.No. Test Specifications

01 Description A white crystalline powder, odorless and bitter taste.

02 Solubility Soluble in water, slightly soluble in Alcohol.

Identification by
03 pH between 4.0 – 6.0

04 Iron Not more than 5 ppm.

05 Cyanide Not more than 10 ppm.

06 Assay Not less than 98.0%

Specification No. : MC/RM/S-35 Date of preparation : 21.04.03


Specifications
Supersedes : Nil Effective from : 01.05.03

Page No. 35
OMEPRAZOLE PELLETS

Department : Quality Control Page : 1 of 1

Name of the material/Code : Triethyl Amine /TEA Molecular Formula: (C2H5)3N

Chemical Name : Triethyl Amine Molecular Weight : 101.19

S.No. Test Specifications

01 Description A clear colourless liquid, flammable liquid and corrosive.

02 Specific Gravity 0.71 – 0.74 gm/ml

Identification by
03 Boiling Range 860 – 900C

04 Moisture content NMT 0.50%

05 Assay by Chemical NLT 99.0%

Analytical Method No:MC/RM/S-05 Date of preparation : 21.04.03


Specifications
Supersedes : Nil Effective from : 01.05.03

Page No. 36
OMEPRAZOLE PELLETS

Department : Quality Control Page : 1 of 1

Name of the material/Code : Ammonium Molybdate/Cox Molecular Formula : H24Mo7N6O24

Chemical Name : Ammonium para molybdate Molecular Weight : 1163.89

S.No. Test Specifications

01 Description A colorless or slightly greenish or yellowish crystals.

02 Solubility Soluble in 2.3 parts water. Practically in soluble in alcohol.

Identification by
03 pH (5% solution) between 4.0 – 6.0

04 Assay by Chemical Not less than 99.0%

Specification No. : MC/RM/S-02 Date of preparation : 21.04.03

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OMEPRAZOLE PELLETS
Specifications Supersedes : Nil Effective from : 01.05.03

Department : Quality Control Page : 1 of 1

Name of the material/Code : Acetone/AO Molecular Formula : C3H6O 4

Chemical Name : 2 – Propanone Molecular Weight : 58.08

S.No. Test Specifications

01 Description A clear colorless liquid with characteristic odor., chloroform and ether

02 Identification
a) Boiling Range between 54 – 570C

03 Specific Gravity 0.78 – 0.79 gm/ml.

04 Moisture Content Not more than 0.2% w/v.

05 Purity by GC Not less than 99.80%

Specifications
Specification No. : MC/RM/S-17 Date of preparation : 21.04.03

Page No. 38
OMEPRAZOLE PELLETS

Supersedes : Nil Effective from : 01.05.03

Department : Quality Control Page : 1 of 1

Name of the material/Code : Isopropyl Alcohol/IPA Molecular Formula : C3H8O

Chemical Name : 2 - Propanol Molecular Weight : 60.09

S.No. Test Specifications

01 Description A clear colorless liquid.

02 Solubility Miscible with water, chloroform and ether etc.

03 Specific Gravity 0.78 – 0.80 gm/ml.

04 Moisture Content Not more than 0.2%.w/v

Identification by
05 Boiling Range 81.00 – 83.50C

06 Purity by GC Not less than 99.80%.

07 Non volatile matter NMT 0.001% w/v

Specifications
Specification No. : MC/RM/S-21 Date of preparation : 21.04.03

Page No. 39
OMEPRAZOLE PELLETS

Supersedes : Nil Effective from : 01.05.03

Department : Quality Control Page : 1 of 1

Name of the material/Code : Methylene chloride/MDC Molecular Formula : CH2Cl2

Chemical Name : Dichloromethane Molecular Weight : 84.94

S.No. Test Specifications

01 Description A clear colorless liquid

02 Solubility Miscible with alcohol and solvent etc.

03 Specific Gravity 1.31 – 1.33 gm/ml.

04 Moisture content by KFR Not more than 0.1% w/v.

05 Identification by
Boiling Range 38 – 41 0C

06 Purity by GC Not less than 99.80%.

07 Non volatile matter Not more than 0.05% Wt/v

3.4.2. INTERMEDIATES

Page No. 40
OMEPRAZOLE PELLETS

List of Intermediates

Sl No Name of the Intermediates


01. 2-Hydroxy methyl-4-methoxy-3,5-dimethyl pyridine hydrochloride
02 2-Chloro Methyl 4-Methoxy-3, 5-Dimethyl Pyridine Hydrochloride
5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-2-methyl] thio]-1 H-
03 benzimidazole
04. Omeprazole Technical

Specifications of Intermediates are provided in the subsequent pages.

Specification No.: MC/IM/O/S.03 Effective from: 01.03.2004

Page No. 41
OMEPRAZOLE PELLETS

Specifications Supersedes : New Rev. No : 00

Department : Quality Control Page : 1 of 1


Name of the Material/Code:
2-Hydroxy methyl-4-methoxy-3,5-dimethyl pyridine Category : Intermediate
hydrochloride / O-VI HHCl

S.No. Test Specifications

01 Description An off white to yellowish powder. Hygroscopic.

02 Solubility Soluble in water and methanol. Insoluble in ether.

03 Identification by TLC Should be positive.

04 Water by KFR Not more than 0.5%

05 Related substances
by HPLC

a) Total impurity Not more than 2.0%


b) Individual Impurity Not more than 1.0%

06 Purity by HPLC NLT 98%

Specification No.: MC/IM/O/S.04 Effective from: 01.03.2004

Page No. 42
OMEPRAZOLE PELLETS

Specifications Supersedes : New Rev. No : 00

Department : Quality Control Page : 1 of 1


Name of the Material/Code:
2-Chloro Methyl 4-Methoxy-3, 5-Dimethyl Pyridine Category : Intermediate
Hydrochloride/O-VII

S.No. Test Specifications

01 Description Off white crystalline powder

02 Solubility Freely soluble in methelene chloride, chloroform, methanol and


water. Slightly soluble in Acetone and Ethyl Acetate.

03 Identification by I.R. The IR Spectrum is concordant to the spectrum of Standard.

04 Melting Range Melts Between1300 - 135oC

05 Related substances
by HPLC

a) Total impurity Not more than 1.0%


b) Individual Impurity Not more than 0.5%

06 Loss on drying Not more than 0.5%

07 Purity by HPLC NLT 99.0%

Specification No.: MC/IM/O/S.05 Effective from: 01.03.2004

Page No. 43
OMEPRAZOLE PELLETS

Specifications Supersedes : New Rev. No : 00

Department : Quality Control Page : 1 of 1


Name of the Material/Code:
5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-2-methyl] Category : Intermediate
thio]-1 H-benzimidazole / O-VIII

S.No. Test Specifications

01 Description Off white to pale yellow colored crystalline powder.

02 Solubility Soluble in Methanol, Methylene chloride and chloroform.


Insoluble in water.

03 Identification
a) by IR or The IR Spectrum is concordant to the spectrum of Standard.
b) by TLC Should be positive
04 Melting Range Between 1180- 120oC

05 Loss on drying Not more than 0.5%

06 Related substances
by HPLC

a) Total impurity Not more than 1.0%


b) Individual Impurity Not more than 0.5%

07 Assay by Chemical Not less than 99% and not more than 101% w/w
(on dry basis)

Specification No.: MC/TE/O/S.06 Effective from: 01.03.2004

Page No. 44
OMEPRAZOLE PELLETS

Specifications Supersedes : New Rev. No : 00

Department : Quality Control Page : 1 of 1

Name of the Material/Code : OMEPRAZOLE TECHNICAL Category : Intermediate

S.No. Test Specifications

01 Description A white to off white powder.

02 Solubility Soluble in Methanol, Methylene chloride and chloroform.


Insoluble in water.

03 Identification
a) by TLC The spot obtained by TLC is similar in position and size to the
standard.
04 Related substances
by HPLC
a) Total impurity Not more than 2.0%
b) Individual Impurity Not more than 1.0%

05 Purity by HPLC Not less than 98.0%

3.4.3. LIST OF QUALITY CONTROL INSTRUMENTS

Page No. 45
OMEPRAZOLE PELLETS

S.NO NAME MAKE LOCATION

01 Electronic Balance ATCO Q.C.

02 Electronic Balance Dhona Q.C.


03 KFR Apparatus Datla Inst. Q.C.
04 Melting Apparatus Polyman’s Q.C.
05 U.V. Chamber Datla Inst. Q.C.
06 Digital Potentiometer Datla Inst. Q.C.
07 Digital pH meter Datla Inst. Q.C.
08 Vacuum Oven Cintex Q.C.
09 Temperature oven Pathak Q.C
10 Muffle furnace Pathak Q.C.
11 HPLC SHIMADZU Instrumentation
12 GC ASHCO Instrumentation
13 Polarimeter ADVANCE Instrumentation
14 ULTRA SONICATOR SUPERSONICS Instrumentation
15 Digital pH meter Datla Inst. Instrumentation
16 Analytical Balance AND GR 202 Instrumentation
17 Dissolution Test Apparatus LAB INDIA Instrumentation

Page No. 46
OMEPRAZOLE PELLETS

3.4.4 INPROCESS CONTROLS DURING SYNTHESIS

Limit
S.No Stage Sample Name Test
(Specifications)
01 Stage –V 2-Hydroxy methyl-4- Related Individual
methoxy-3,5-dimethyl substance by Impurity not
pyridine hydrochloride HPLC more than 2.0%
02 Stage – VI 2-Chloro Methyl 4-Methoxy- Related Individual
3, 5-Dimethyl Pyridine substance by Impurity not
Hydrochloride HPLC more than 1.0%
03 Stage – VII 5-Methoxy-2-[[(4-methoxy- Related Individual
3,5-dimethyl-2-pyridinyl)-2- substance by Impurity not
methyl] thio]-1 H- HPLC more than 1.0%
benzimidazole
04 Stage – VIII 5-Methoxy-2-[[(4-methoxy- Related Individual
3,5-dimethylpyridine-2- substance by Impurity not
yl)methyl]Sulfinyl]-1H- HPLC more than 2.0%
benzimidazole Technical

Page No. 47
OMEPRAZOLE PELLETS
3.5. DEVELOPMENT CHEMISTRY

3.5.1 STRUCTURE ELUCIDATION AND CONFIRMATION

The molecular structure is confirmed of Omeprazole was investigated by the


following techniques. Its structure is confirmed by the elemental analysis, Ultra – Violet
spectrophotometry, Infrared absorption spectrophotometry, proton nuclear magnetic
resonance spectrometry, and mass spectrophotometry. Details of the test methods used, and
result obtained are given below.

Structural data

A. ELEMENTAL ANALYSIS:

S.No. Element % Calculated % Found

01 C 59.13 59.41

02 H 5.50 5.75

03 N 12.17 12.05

04 O 13.91 14.15

05 S 9.27 8.62

Page No. 48
OMEPRAZOLE PELLETS
B. ULTRA ---- VIOLET SPECTRUM:

When a 0.002 % w/v solution of Omeprazole in 0.1N NaOH solution was scanned from
200nm to 350nm, two maxima at 306.4 nm and 225.5 nm are obtained as shown in Fig .1. The
peaks absorbances are listed below.

Wave length (cm –1 ) Data

306.4 0.487 ABS

225.5 0.567 ABS

1) 306.4 nm = Benzimidazole moiety

2) 225.5 nm = The E 2 band from the two aromatic rings.

Page No. 49
OMEPRAZOLE PELLETS

C. INFRA RED SPECTRUM

The Infrared spectrum for Omeprazole in a K Br powder as obtained on a VECTOR22


FTIR is illustrated Fig.1. The major absorption bands for the Infrared frequencies and the
corresponding assignments are listed below.

OCH3
CH3 CH3 OCH3
N
O

N CH2 S N
H

Frequency cm -1 Assignments

3066.00 N – H stretches
2989.0
2908.0
2808.0 C – H stretches
1629.0
1587.0
1513.0
1467.0 C = C, C = N aromatic rings

1204.0
1157.0 Sp2 – C – O of ethers O- CH3

1079.0
1016.0 Sp3 – C – O of ethers O- CH3
964.0
884.0
824.0 = C – H of the aromatic and pyridine rings

Page No. 50
OMEPRAZOLE PELLETS
D. NMR SPECTRUM

OCH3
CH3 CH3 OCH3
N
O

N CH2 S N
H

ASSIGNMENT MULTIPLICITY CHEMICAL SHIFT

5’ CH3 s 2.12 δ

3’ CH3 s 2.21 δ

5 OCH3 s 3.60 δ

4’ – OCH3 s 3.83 δ

S – CH2 s 4.74 δ

4 – CH 6-CH m 6.95 to 6.91 δ

7 CH d 7.51 – 7.26 δ

6’ CH s 8.20 δ

E) MASS SPECTRUM

Page No. 51
OMEPRAZOLE PELLETS
OCH3
CH3 CH3 OCH3
N
O

N CH2 S N
H

Molecular formula: C17H19N3O3S, Mol. Wt.: 345.42

M/Z ASSIGNMENT STRUCTURE


+
CH3O
O CH3 CH3
CH3O N
+ S
345 (15%) C17H19N3O3S
N N

H
+
CH3O
CH3
CH3O N CH3
+ S
329 (20%) C17H19N3O2S
N N

H
O CH3
+
H3C CH2
CH3O N
+
296 (96%) C17H18N3O2 N
N
H
O
CH3O N
.
+ S+
195 (15%) C8H7N2O2S
N
H

+
O 3HC N
.
C8H8N2OS+ SH
180 (95%)
N
H

Page No. 52
OMEPRAZOLE PELLETS

+O N
.
+ SH
165 (92%) C7H5N2OS
N
H

CH3O
H3C CH3
+
150 (85%) C9H12NO +
H2C N

+
CH3O
.
CH3
+ +
137 (67%) C8H11NO H2C N

OH

3HC CH3

136 (60%) C8H10NO+ N


+H2C

3HC CH3

120 (72%) C8H10N+


H3C N

Conclusion: Based on Elemental Analysis, UV spectrum and IR spectrum, NMR spectrum and Mass
spectrum, it is concluded and conforms the structure of Omeprazole.

3.5.2. PHYSICO – CHEMICAL CHARACTERISTICS

01. Description : A white or almost white powder.

Page No. 53
OMEPRAZOLE PELLETS
02. Solubility : Soluble in methelene chloride. Sparingly soluble in Alcohol
and Methanol. Very slightly soluble in water and dissolves
in diluted solutions of Alkali Hydroxides.

03. Pka : Not applicable.

04 Particle size : The powder mesh size for commercial requirement is 100
mesh

3.6. ANALYTICAL VALIDATION

3.6.1 LIST OF POTENTIAL IMPURITIES

1) 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl-2-methyl]thio]-1 H-benzimidazole
( Omeprazole Sulphide)

Page No. 54
OMEPRAZOLE PELLETS
OCH3
CH3 CH3 OCH3
N

N CH2 S N
H

2)5-Methoxy-2-[((4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-sulphinyl]-1 H-benzimidazole-1-
oxide. (Omeprazole N-Oxide )

OCH3
CH3 CH3 OCH3
N
O

N CH2 S N
H
O

3) 5-Methoxy-2-[[(methoxy-3,5-dimethylpyridin-2-yl)methyl]sulphonyl]-1 H-
benzimidazole ( Omeprazole Sulphone )

OCH3
CH3 CH3 OCH3
N
O

N CH2 S N

O H

3.6.2. METHODS USED TO STUDY IMPURITES

By HPLC

Page No. 55
OMEPRAZOLE PELLETS

Apparatus
The liquid chromatograph equipped with variable wavelength detector and integrator.

Column : Kromasil : C - 18 : 250 X 4.6mm 5µm.


Wave Length: 280 nm.
Flow Rate :1.0 ml / min.
Load 20 µl

Mobile Phase: Weigh about1.400 gms of Disodium hydrogen phosphate and dissolve in 1000 ml of HPLC
grade water and add 608 ml of Acetonitrile and adjust the pH to 7.2 with 1N ortho phosphoric acid.

Sample preparation: Weigh accurately about 0.01 gms of sample in a 10 ml volumetric flask dissolve and
dilute to volume with mobile phase.

3.7. REFERNCE STANDARD AND WORKING STANDARD

PRODUCT : OMEPRAZOLE POWDER (Working Standard)

BATCH NO : O/WS/01

01. Description : A White or almost white powder

Page No. 56
OMEPRAZOLE PELLETS
02. Assay : 99.91%
03. Identification by I.R. : To be concordant with the reference standard.

Storage conditions:

a. Do not dry before using


b. Keep container tightly closed.
c. Protect from moisture.
d. Store in a cold place.

Preparation of Working Standard:

Procedure: Omeprazole working standard is obtained as Omeprazole pure compound prepared it


derivative omeprazole sodium and it is purified in methanol to Omeprazole working standard.

Qualification of Working standard

Omeprazole Working standard B.No. O/WS/01 is standardized with respect to USP Reference
standard Lot No. H1B211

Working Reference
Sl.No Test Specifications
Standard Result Standard Result
Assay by HPLC NLT 98.0% and NMT
01 (on dry basis) 99.91% 100.02% 102.0%
Sum of
02 Impurities 0.09% 0.02% NMT 1.0%
To be concordant with
03 I.R. Complies Complies the reference standard.

Remarks: The prepared working standard complies with respect to values obtained as per
Reference standard.

Certificate of analysis of Omeprazole Working standard

PRODUCT NAME : OMEPRAZOLE POWEDER USP

Page No. 57
OMEPRAZOLE PELLETS
BATCH NO : O/WS/01 MFG. DATE : JUNE, 2004
MFG. LICENCE NO : 22/RR/AP/99/B/R/C EXP DATE : MAY 2007
TEST PROTOCOL : USP
S.No Test Specifications Result
01 Description A white or almost white powder A White powder
02 Solubility Very slightly soluble in water, soluble in Alcohol, in Complies
Methanol and in Methelene Chloride, dissolves in
diluted solutions of Alkali Hydroxides
03 Identification
a) By TLC: The Rf value of principal spot of test should Complies
correspond to the Rf value of USP Omeprazole R.S.
b) By Infrared The IR spectrum concordant with the spectrum of Complies
Absorption Omeprazole CSR.
04 Completeness of Should meet the requirements, a solution in Complies
solution methelene chloride containing 20 mg per ml. being
used.
05 Color of Solution Determine the absorbance of the solution prepared for Complies
the Completeness of solution test at 440 nm, in 1-cm
cells, using methylene chloride as the blank. The
absorbance is not greater than 0.10.
06 Loss on drying at 600C NMT 0.5 % W/W 0.115%
for 4 hrs under vacuum
07 Residue on Ignition NMT 0.1 % W/W 0.052%
08 Heavy Metals NMT 0.002% Complies.
09 Organic volatile Should meet the requirements. Complies.
impurities
10 Chromatographic
Purity:
Method 1 (By TLC):
a) Individual impurity NMT 0.3% 0.05%
b) Sum of Impurities NMT 1.0% 0.20%
Method 2 (By HPLC):
a) Individual Impurity NMT 0.3% 0.04%
b) Sum of Impurities NMT 1.0% 0.09%
11 Assay by HPLC NLT 98.0% and NMT 102.0% 99.91%
(On dry Basis)
Remarks: The above product complies the USP Specifications with respect to the above tests.
Packaging and Storage: Preserve in tight containers and store in a cold place, protected from moisture.

4. LIST OF PACKING MATERIALS

Page No. 58
OMEPRAZOLE PELLETS
Packing and labeling material are stored in a separate place and packing materials
like polythene bags and Fiber/HDPE drums and labels are conveniently stored in locked
cabinets. Records are kept for packaging and labeling material and distribution for use.

POLYTHENE BAGS:

These bags are used for packing the finished product. Quality is suitable for food
grade and a certificate is obtained from the supplier for each consignment.

FIBER/ HDPEDRUMS:

Fiber Drums, HDPE Drums which are used for the packing the product, are of
standard quality with regard to weight, strength and durability . The following tests are
conducted before accepting consignment.

a. Physical appearance , sealing, dimensions etc.


b. Suitability with respect to storage conditions and safety of materials.

4.1 SPECIFICATIONS

Page No. 59
OMEPRAZOLE PELLETS

ANALYTICAL TEST REPORT OF POLYTHENE BAGS

S.No Tests Acceptance Specifications Method of Analysis


01 Description Polythene bags with three By visual observation
ends sealed and one end
open
02 Thickness of the Not less than 0.2 mm See the thickness with the help
bag of a Micrometer screw gauge.
03 Dimensions Length – 36’ + 0.5’ See the thickness with the help
Width – 24” + 0.5’ of a Micrometer screw gauge.
04 Quality Should be food grade Report of the quality should be
obtained from the supplier.

ANALYTICAL TEST REPORT OF FIBER BOARD DRUMS

Page No. 60
OMEPRAZOLE PELLETS

S.No Tests Acceptance Specifications Method of Analysis


01 Description Cylindrical drums made By visual observation
from Fiber polycoated
material sealed with hard
board one end and the top
lid is removable, provide
with galvanized ring.
02 Weight to the Not less than See the weight on a standard
drums a. 3.2 Kgs + 0.1 kg–16”x18” balance
b.4.2 Kgs + 0.1kg - 16”x30”
03 Plywood thickness Not less than 7 mm See the thickness with the help
of a micrometer screw gauge
04 Fiber board Not less than 3 mm See the thickness with the help
thickness of a micrometer gauge.

HDPE DRUMS

S.No Tests Acceptance Specifications Method of Analysis


01 Description Cylindrical drums made By visual observation
from polyethylene sealed
with polyethylene one end
and the top lid is removable,
provide with galvanized
ring.
02 Size of the drums Height 525 + 2 mm Seethe size with standard
Diameter 330 + 2 mm measurements
Mouth size 250 + 2 mm

5. BATCH ANALYSIS

5.1 TEST RESULTS

Page No. 61
OMEPRAZOLE PELLETS

BATCH NO : O/200405053 MFG. DATE : MAY, 2004


DATE OF ANALYSIS : MAY, 2004 EXP. DATE : APRIL, 2007

S.No Test Specifications Result

01 Description A white or almost white powder White powder


02 Solubility Very slightly soluble in water, soluble in Alcohol, Complies
in Methanol and in Methylene Chloride, dissolves
in diluted solutions of Alkali Hydroxides

03 Identification a) The 2% solution in 0.1 NaOH shows two 1.62


absorption maxima at 276 nm and 305 nm and
ratio is 1.6 to 1.8.
b) The IR spectrum concordant with the spectrum Complies
of omeprazole CRS.
c) The spot obtained by TLC the is similar in Complies
position and size to the omeprazole CRS.

04 Appearance of solution 2 % solution in MDC is clear Complies


05 Absorbance The absorbance of 2% soln in MDC at 440nm is 0.040
not more than 0.1
06 Omeprazole impurity ‘C’ By TLC NMT 0.1 % Complies
07 Related substance NMT 0.1 % 0.027%
by HPLC
08 Residual solvents Chloroform NMT 50 PPM NIL
by Head-space gas Methylene chloride NMT 100 PPM NIL
Chromatography Trichloro Ethylene NMT 100 PPM NIL
09 Loss on Drying NMT 0.2% at 600 C under high vacuum for 4 hrs 0.109 %

10 Sulphated Ash NMT 0.1 % 0.053%


11 Assay (Potentiometrically) NLT 99.0 % and NMT 101.0 % 99.82%
Remarks: The above product complies the B.P. with respect to the above tests.
Storage Conditions: Store in an airtight container, protected from light, at a temperature between 20 to 80C

Page No. 62
OMEPRAZOLE PELLETS

BATCH NO : O/200405054 MFG. DATE : MAY, 2004


DATE OF ANALYSIS : MAY, 2004 EXP. DATE : APRIL, 2007
S.No Test Specifications Result

01 Description A white or almost white powder White powder


02 Solubility Very slightly soluble in water, soluble in Alcohol, Complies
in Methanol and in Methylene Chloride, dissolves
in diluted solutions of Alkali Hydroxides

03 Identification a) The 2% solution in 0.1 NaOH shows two 1.64


absorption maxima at 276 nm and 305 nm and
ratio is 1.6 to 1.8.
b) The IR spectrum concordant with the spectrum Complies
of omeprazole CRS.
c) The spot obtained by TLC the is similar in Complies
position and size to the omeprazole CRS.

04 Appearance of solution 2 % solution in MDC is clear Complies


05 Absorbance The absorbance of 2% soln in MDC at 440nm is 0.044
not more than 0.1
06 Omeprazole impurity ‘C’ By TLC NMT 0.1 % Complies
07 Related substance NMT 0.1 % 0.025%
by HPLC
08 Residual solvents Chloroform NMT 50 PPM NIL
by Head-space gas Methylene chloride NMT 100 PPM NIL
Chromatography Trichloro Ethylene NMT 100 PPM NIL
09 Loss on Drying NMT 0.2% at 600 C under high vacuum for 4 hrs 0.112 %

10 Sulphated Ash NMT 0.1 % 0.055%


11 Assay (Potentiometrically) NLT 99.0 % and NMT 101.0 % 99.84%
Remarks: The above product complies the B.P. with respect to the above tests.
Storage Conditions: Store in an airtight container, protected from light, at a temperature between 20 to 80C

Page No. 63
OMEPRAZOLE PELLETS
BATCH NO : O/200405055 MFG. DATE : MAY, 2004
DATE OF ANALYSIS : MAY 2004 EXP. DATE : APRIL, 2007
S.No Test Specifications Result

01 Description A white or almost white powder White powder


02 Solubility Very slightly soluble in water, soluble in Alcohol, Complies
in Methanol and in Methylene Chloride, dissolves
in diluted solutions of Alkali Hydroxides

03 Identification a) The 2% solution in 0.1 NaOH shows two 1.63


absorption maxima at 276 nm and 305 nm and
ratio is 1.6 to 1.8.
b) The IR spectrum concordant with the spectrum Complies
of omeprazole CRS.
c) The spot obtained by TLC the is similar in Complies
position and size to the omeprazole CRS.

04 Appearance of solution 2 % solution in MDC is clear Complies


05 Absorbance The absorbance of 2% soln in MDC at 440nm is 0.041
not more than 0.1
06 Omeprazole impurity ‘C’ By TLC NMT 0.1 % Complies
07 Related substance NMT 0.1 % 0.028%
by HPLC
08 Residual solvents Chloroform NMT 50 PPM NIL
by Head-space gas Methylene chloride NMT 100 PPM NIL
Chromatography Trichloro Ethylene NMT 100 PPM NIL
09 Loss on Drying NMT 0.2% at 600 C under high vacuum for 4 hrs 0.108 %

10 Sulphated Ash NMT 0.1 % 0.052%


11 Assay (Potentiometrically) NLT 99.0 % and NMT 101.0 % 99.81%
Remarks: The above product complies the B.P. with respect to the above tests.
Storage Conditions: Store in an airtight container, protected from light, at a temperature between 20 to 80C

6. STABILITY STUDIES

Conditions:

Accelerated: Temperature: 250C+20C, Relative Humidity: 65%+5%

Page No. 64
OMEPRAZOLE PELLETS

Long term: Temperature: 60C+20C, Relative Humidity: 60%+5%

Time frame & Schedules:

Accelerated : Total time for the study : 6months

Schedules : Sample tested are initial and at every month for 6 months.

Long term : Total time for the study : 12months

Schedules : Sample tested are initial and at 3,6,9 and 12 months upto submission and continued
till completion as per schedule.

Number of batches :

Accelerated : First three commercial batches will be kept for stability studies. Whenever a change
implemented, one to three batches will be kept for stability depending on level of change.

Long term : First three commercial batches will be kept for stability studies.

Samples packing :

Sample are stored as per market simulated conditions.

Testing Parameters:

01). Description
02). Identification
3) Related Impurities by HPLC
4) Assay

6.1 ACCLERATED STABILITY DATA REPORT

ACCELERATED STABILITY DATA

Page No. 65
OMEPRAZOLE PELLETS

Name of product : Omeprazole Batch Qty : 50.0 Kgs

Batch Number : O/200210005 Manufacturing date: October 2002

TIME
TESTS
Initial
1Month 2Months 3Months 4 Months 5Months 6Months
A white or A white or A white or A white or A white or A white or A white or
almost almost almost almost almost almost almost
Description
white white white white white white white
powder powder powder powder powder powder powder
Identification
Complies Complies Complies Complies Complies Complies Complies
Related
Impurities by 0.11% 0.11% 0.11% 0.13% 0.13% 0.13% 0.14%
HPLC
Assay by
99.75% 99.74% 99.73% 99.72% 99.71% 99.67% 99.65%
HPLC

Date of
analysis 26.10.2002 26.11.2002 26.12.2002 26.01.2003 26.02.2003 26.03.2003 26.04.2003

Analysed on
25.10.2002 25.11.2002 25.12.2002 26.01.2003 26.02.2003 26.03.2003 26.04.2003

Storage condition : Store in well – closed containers


Temperature : 250 C + 20 C
Relative Humidity : 65 % + 5%

ACCELERATED STABILITY DATA

Page No. 66
OMEPRAZOLE PELLETS

Name of product : Omeprazole Batch Qty : 50.0 Kgs

Batch Number : O/200211006 Manufacturing date: November 2002.


TESTS TIME

Initial 1Month 2Months 3Months 4 Months 5Months 6Months

Description A white or A white or A white or A white or A white or A white or A white or


almost almost almost almost almost almost almost
white white white white white white white
powder powder powder powder powder powder powder
Identification
Complies Complies Complies Complies Complies Complies Complies
Related
Impurities by 0.14% 0.14% 0.14% 0.15% 0.16% 0.16% 0.16%
HPLC
Assay by
99.72% 99.69% 99.69% 99.67% 99.65% 99.64% 99.62%
HPLC

Date of
analysis 26.11.2002 26.12.2002 26.01.2003 26.02.2003 26.03.2003 26.04.2003 26.05.2003

Analysed on
25.11.2002 25.12.2002 25.01.2003 25.02.2003 25.03.2003 25.04.2003 25.05.2003

Storage condition : Store in well – closed containers


Temperature : 250 C + 20 C
Relative Humidity : 65 % + 5%

ACCELERATED STABILITY DATA

Page No. 67
OMEPRAZOLE PELLETS

Name of product : Omeprazole Batch Qty : 50.0 Kgs

Batch Number : O/200212007 Manufacturing date: December 2002.


TIME

TESTS
Initial 1Month 2Months 3Months 4 Months 5Months 6Months

A white or A white or A white or A white or A white or A white or A white or


Description almost almost almost almost almost almost almost
white white white white white white white
powder powder powder powder powder powder powder
Identification Complies Complies Complies Complies Complies Complies Complies

Related
Impurities by 0.07% 0.09% 0.09% 0.09% 0.11% 0.12% 0.13%
HPLC
Assay by
99.81% 99.79% 99.78% 99.76% 99.76% 99.75% 99.73%
HPLC

Date of
analysis 26.12.2002 26.01.2003 26.02.2003 26.03.2003 26.04.2003 26.05.2003 26.06.2003

Analysed on
25.12.2002 25.01.2003 25.02.2003 25.03.2003 25.04.2003 25.05.2003 25.06.2003

Storage condition : Store in well – closed containers


Temperature : 250 C + 20 C
Relative Humidity : 65 % + 5%

6.2 LONG TERM STABILITY DATA REPORT

LONGTERM STABILITY DATA

Page No. 68
OMEPRAZOLE PELLETS

Name of product : Omeprazole Batch Qty : 50.0 Kgs

Batch Number : O/200210005 Manufacturing date: October, 2002


TESTS TIME

Initial
3Months 6Months 9 Months 12 Months 15Months 18 Months
Description A white or A white or A white or A white or A white or A white or A white or
almost almost almost almost almost almost almost
white white white white white white white
powder powder powder powder powder powder powder
Identification Complies Complies Complies Complies
Complies Complies Complies
Related
Impurities by 0.11% 0.12% 0.13% 0.13% 0.15% 0.15% 0.16%
HPLC
Assay by
99.75% 99.71% 99.70% 99.66% 99.65% 99.59% 99.51%
HPLC

Date of
analysis 26.10.2002 26.01.2003 26.04.2003 26.07.2003 26.10.2003 26.01.2004 26.04.2004

Analysed on 26.07.2003 26.10.2003 26.01.2004 26.04.2004


25.10.2002 26.01.2003 25.04.2003

Storage condition : Store in well – closed containers


Temperature : 60 C + 20 C
Relative Humidity : 60% + 5%

LONGTERM STABILITY DATA

Page No. 69
OMEPRAZOLE PELLETS

Name of product : Omeprazole Batch Qty : 50.0 Kgs

Batch Number : O/200211006 Manufacturing date: November, 2002


TESTS TIME

Initial 3 Months 6 Months 9 Months 12 Months 15Months 18 Months

Description A white or A white or A white or A white or A white or A white or A white or


almost almost almost almost almost almost almost
white white white white white white white
powder powder powder powder powder powder powder
Identification Complies Complies Complies Complies Complies Complies Complies

Related
Impurities by 0.14% 0.15% 0.15% 0.16% 0.18% 0.18% 0.19%
HPLC
Assay by
99.72% 99.71% 99.69% 99.65% 99.64% 99.63% 99.62%
HPLC

Date of
analysis 24.11.2002 24.02.2003 24.05.2003 24.08.2003 24.11.2003 24.02.2004 24.05.2004

Analysed on 24.08.2003 24.11.2003 24.02.2004 24.05.2004


24.11.2002 24.02.2003 24.05.2003

Storage condition : Store in well – closed containers


Temperature : 60 C + 20 C
Relative Humidity : 60% + 5%

LONGTERM STABILITY DATA

Page No. 70
OMEPRAZOLE PELLETS

Name of product : Omeprazole Batch Qty : 50.0 Kgs

Batch Number : O/200212007 Manufacturing date: December 2002


TESTS TIME

Initial 3 Months 6 Months 9 Months 12 Months 15Months 18 Months

Description A white or A white or A white or A white or A white or A white or A white or


almost almost almost almost almost almost almost
white white white white white white white
powder powder powder powder powder powder powder
Identification Complies Complies Complies Complies Complies Complies Complies

Related
Impurities by 0.07% 0.07% 0.09% 0.11% 0.13% 0.14% 0.14%
HPLC
Assay by
99.81% 99.80% 99.78% 99.77% 99.65% 99.64% 99.62%
HPLC

Date of
analysis 26.12.2002 26.03.2003 26.06.2003 26.09.2003 26.12.2003 26.03.2004 26.06.2004

Analysed on 26.09.2003 26.12.2003 26.13.2004 26.06.2004


25.12.2002 26.03.2003 25.06.2003

Storage condition : Store in well – closed containers


Temperature : 60 C + 20 C
Relative Humidity : 60% + 5%

Conclusion: Based on above study and observation the product is stable under specified conditions of
storage. There is no significant change in accelerated studies.

MATERIAL MSDS No .: MC/FP/O/MSDS.03 Effective from : 01.03.2004


SAFETY
DATA Supersedes : Nil Rev. No. : 00
SHEET
Department : Quality Control Page : 1 of 5

Page No. 71
OMEPRAZOLE PELLETS
Name of the Material/Code: OMEPRAZOLE POWDER Category : Finished Product

Address: Flat No. 302,Bhanu Enclave, Sunder Nagar, Erragadda, Hyderabad-500 038, INDIA.
Phone: +91-40-23700421/23813969/23812317. Fax: +91-40-23705088.
Web: www.metroapi.com E-mail: api@metroapi.com.

WARNING STATEMENT:
WARNING : NOT FOR DIRECT HUMAN CONSUMPTION. AVOID INGESTION, INHALATION & SKIN CONTACT.
FOR PROCESSING USE ONLY.
SECTION 1 – IDENTITY

COMMON NAME : OMEPRAZOLE POWDER

SYNONYMS : ---------

CAS NUMBER : 73590-58-6

RTECS NUMBER : ---------

CHEMICAL NAME : (RS)-5-Methoxy-2-[[(4-methoxy-3,5-dimethylpyridine-2-yl)methyl]


Sulphinyl]-1H-benzimidazole.

CHEMICAL FAMILY : BENZIMIDAZOLE

THERAPEUTIC CATEGORY : ANTIULCERATIVE

Formula : C17H19N3O3S
SECTION 2 - HAZARDOUS INGREDIENTS
PRINCIPAL HAZARDOUS COMPONENTS ( S ) / [ CHEMICAL & COMMON NAME ( S ) ]
NAME PERCENTS THRESHOLD LIMIT
VALUE ( LIMITS )
(RS)-5-Methoxy-2-[[(4-methoxy-3,5 PURE MATERIAL NOT ESTABLISHED
-dimethylpyridine-2-yl)methyl]
Sulphinyl]-1H-benzimidazole

Compiled by Checked by Approved by


Date: Date: Date:

MATERIAL MSDS No .: MC/FP/O/MSDS.03 Effective from : 01.03.2004


SAFETY
DATA Supersedes : Nil Rev. No. : 00
SHEET
Department : Quality Control Page : 2 of 5

Page No. 72
OMEPRAZOLE PELLETS
Name of the Material/Code: OMEPRAZOLE POWDER Category : Finished Product
SECTION 3 – PHYSICAL AND CHEMICAL CHARACTERISTICS
(Fire & Explosion Data )

BOILING : N /A

SPECIFIC GRAVITY ( H2O =1 ) : N /A

VAPOUR PRESSURE (mm Hg ) : N /A

PERCENT VOLATILE BY VOLUME ( % ) : N /A

VAPOUR DENSITY ( AIR =1 ) : N /A

SOLUBILITY IN WATER : Insoluble


REACTIVITY IN WATER : N /A

APPEARANCE AND ODOUR : A white to off-white crystalline powder.


FLASH POINT : N /A

FLAMMABLE LIMITS IN AIR ( % ) : Lower – N / A Upper – N / A


BY VOLUME
EXTINGUISHER MEDIA : Water spray, dry chemical, carbon dioxide or foam as
appropriate for surrounding fire and material.

AUTO- IGNITION TEMPERATURE : N /A

SPECIAL FIRE FIGHTING PROCEDURE : AS with all fires, evacuate personnel to safe area. Fire fighter
should use self-contained breathing equipment and
protective clothing.

UNUSUAL FIRE AND EXPLOSION : This material is assumed to be combustible. As with all dry
HAZARDOUS powders it is advisable to ground mechanical equipment in
contact with dry material to dissipate the potent build up of
static electricity. When heated to decomposition, material
emits toxic fumes. Emits toxic fumes under the conditions.

Compiled by Checked by Approved by


Date: Date: Date:

MATERIAL MSDS No .: MC/FP/O/MSDS.03 Effective from : 01.03.2004


SAFETY
DATA Supersedes : Nil Rev. No. : 00
SHEET
Department : Quality Control Page : 3 of 5

Page No. 73
OMEPRAZOLE PELLETS
Name of the Material/Code: OMEPRAZOLE POWDER Category : Finished Product

SECTION 4 – PHYSICAL HAZARDS

STABILITY : (X) Unstable ( ) Stable


CONDITIONS TO AVOID : TEMPERATURE ABOVE 8OC AND RELATIVE HUMIDITY 50%.
INCOMPATIBILITY : N /A
(MATERIALS TO AVOID)
HAZARDOUS POLYMERISATION : When heated to decomposition material emits toxic
fumes. Emits toxic fumes under fire conditions.
HAZARDOUS POLYMERISATION : ( ) May occur
( X ) Will not occur
SECTION 5 – HEALTH HAZARDS
THRESHOLD LIMIT VALUE : None established.
PRECAUTIONS TO CONSIDER : Persons developing hypersensitivity (anaphylactic)
reactions must receive immediate medical attention,
material may be irritating to mucous membranes and
respiratory tract. When handling avoids all contact and
inhalation of dust, fumes, mists, and / or vapors associated
with the materials. Keep container tightly closed and use
with adequate ventilation, wash thoroughly after handling.
Individuals working with chemicals should consider all
chemicals to be potentially hazardous, even if their
individual may be and characterized are unknown.
CARCINOGEN OR POTENTIAL CARCINOGEN : I.A.R.C
Monographs ( ) Yes ( X ) No
OSHA ( ) Yes ( X ) No
OTHAR N /A
ACGIH OTHER EXPOSURE
TLV : N / A LIMIT (S) USED : N / A
OSHA PERMISSIBLE EXPOSURE LIMIT : Not established
OTHER EXPOSURE LIMIT USED : Not established

Compiled by Checked by Approved by


Date: Date: Date:

MATERIAL MSDS No .: MC/FP/O/MSDS.03 Effective from : 01.03.2004


SAFETY
DATA Supersedes : Nil Rev. No. : 00
SHEET
Department : Quality Control Page : 4 of 5

Page No. 74
OMEPRAZOLE PELLETS
Name of the Material/Code: OMEPRAZOLE POWDER Category : Finished Product

EMERGENCY AND FIRST AID PROCEDURE : Remove from exposure. Remove contaminated clothing.
Person developing serious hypersensitivity reactions must
receive immediate medical attention. Upon eye or skin
contact, flush affected area with copious quantities of
water. Obtain medical attention.

1. INHALATION : May cause irritation of respiratory of respiratory tract.


Avoid inhalation. Remove to fresh air.

2. EYES : May cause irritation. Flush with copious quantities of


water.

3. SKIN : May cause irritation. Flush with copious quantities of


water.

4. INGESTION : May cause irritation. Flush out mouth with water.

SECTION 6 – SPECIAL PROTECTION INFORMATION

RESPIRATORY PROTECTION : NOISH approved respirator


( SPECIFY TYPE)
VENTILATION : Adequate
LOCAL EXHAUST : Recommended
MECHANICAL (GENERAL) : Recommended
OTHER : N /A

PROTECTIVE GLOVES : Rubber

EYE PROTECTION : Safety goggles

OTHER PROTECTIVE CLOTHING : Appropriate laboratory apparel, protect


OR EQUIPMENT exposed skin.

Compiled by Checked by Approved by


Date: Date: Date:

MATERIAL MSDS No .: MC/FP/O/MSDS.03 Effective from : 01.03.2004


SAFETY
DATA Supersedes : Nil Rev. No. : 00
SHEET
Department : Quality Control Page : 5 of 5

Page No. 75
OMEPRAZOLE PELLETS
Name of the Material/Code: OMEPRAZOLE POWDER Category : Finished Product

SECTION 7 – SPECIAL PROTECTIONS AND SPILL / LEAK PROCEDURES

PRECAUTIONS TO BE TAKEN IN HANDLING : Store in tight container as defined in the United States
AND STORAGE Pharmacopoeia. This material should be handled and
stored per label and other instructions to ensure product
integrity.

OTHER PRECAUTIONS : Avoid contact with eyes, skin or clothing. Avoid breathing
dust or mist. Use with adequate dust control. Wash
thoroughly after handling. Wear fresh clothing daily. Wash
contaminated clothing before reuse. Do not permit eating,
drinking or smoking near material.

STEPS TO BE TAKEN IN CASE MATERIAL IS : Wear approved respiratory and chemically compatible
SPILLED OR RELEASED gloves. Vacuum or sweep of spillage in appropriate
container for waste disposal. Wash contaminated clothing
before reuse. Ventilate area and wash spill site.

WASTE DISPOSAL METHODS : Dispose of waste in accordance with all applicable laws.

Compiled by Checked by Approved by


Date: Date: Date:

8. VENDORS LIST
The company is procuring rawmaterials from approved vendors.

S.No. Name of the Material Name of the Vendor


01 Nitro compound of Omeprazole 1. Sigachi Laboratories ltd., Hyderabad

Page No. 76
OMEPRAZOLE PELLETS
02 Methanol 1. Aerochem, Hyderabad.
2. Jay Ambe Enterprises, Hyderabad
3. Best chem, Hyderabad
4. Jay Enterprises, Mumbai
5. Vijayasri chem Agencies, Hyderabad
6. Omega Enterprises, Mumbai
7. Fine chem, Hyderabad
03 Caustic Soda flakes 1. Rasayan Marketing, Hyderabad
2. Laxmi Nursing Chemicals, Hyderabad
3. The Andhra Sugars Ltd. Hyderabad
4. Parichem Pharma, Hyderabad
5. Srivasta Enterprises, Hyderabad
04 Dimethyl Sulphate 1. Industrial solvents, Hyderabad.
2. Herms chemicals company (p) Ltd.
05 Chloroform 1. Swastik Chemicals, Hyderabad
2. Jay Ambe Enterprises, Hyderabad
3. Sayar Chemicals, Hyderabad
4. S.N.Sales, Hyderabad
06 Toluene 1. Swastik Chemicals, Hyderabad
2. Sandeep Enterprises, Hyderabad
3. Vardhman Chemical Industries,
Hyderabad
4. Unichem Corporation, Hyderabad.
07 Ammonium per sulphate 1. Gujarat persalts private limited. Gujarat
08 Activated carbon 1. Swastik Chemicals, Hyderabad
09 Thionyl chloride 1. Parichem Pharma, Hyderabad
2. Sarthank Enterprises, Hyderabad
10 2-Mercapto 5-methoxy benzimidazole 1. Everest organics Ltd., Hyderabad
2. Sharon Bio medicine, Mumbai
3. Nirayu Ltd., Baroda
11 Ethyl acetate 1. Vardhman chemical industries,
Hyderabad
2. Sandeep Enterprises, Hyderabad
3. Sri Vasavi chemicals corporation, Hyd.
12 Hydrose 1. Srivasta Enterprises, Hyderabad
2. Sandeep Enterprises, Hyderabad.
13 EDTA 1. Sandeep Enterprises, Hyderabad
2. Classic chemicals, Hyderabad.
3. Piyush chemicals, Hyderabad.
14 Triethyl amine 1. Balaji Amines Ltd., Hyderabad
2. Parichem Pharma, Hyderabad.
15 Ammonium molybdate 1. Yogi dye Chemicals, Mumbai
2. Rajesh Enterprises, Mumbai
16 Acetone 1. Vardhaman Chemical Industries,
Hyderabad
2. Unichem Corporation, Hyderabad
3. Swastik Chemicals, Hyderabad
17 Iso propyl alcohol 1. Navodaya Chemicals, Hyderabad
2. Jay Ambe Enterprises, Hyderabad
3. Ponpure Chem (P) Ltd. Hyderabad
4. Swastik Chemicals, Hyderabad.
18 Methylene chloride 1. Swastik Chemicals, Hyderabad

Page No. 77
OMEPRAZOLE PELLETS
2. Jay Enterprises, Mumbai
3. Vardhman chemical Industries,
Hyderabad
4. APL chemi labs, Hyderabad
5. Aerochem, Hyderabad.

Page No. 78