Omeprazole

Monograph of Omeprazole (British Pharmacopoeia 2009)

Omeprazole

Chemical formula: C17H19N3O3SııMolecular weight: 345.4ıı

Action and use

Proton pump inhibitor; treatment of peptic ulcer disease.

Preparations

Gastro-resistant Omeprazole Capsules

Gastro-resistant Omeprazole Tablets

Definition

5-Methoxy-2-[(RS)-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulphinyl]-1H-

benzimidazole.

Content

99.0 per cent to 101.0 per cent (dried substance).

Characteristics

Appearance

White or almost white powder.

Solubility

Very slightly soluble in water, soluble in methylene chloride, sparingly soluble in ethanol (96

per cent) and in methanol. It dissolves in dilute solutions of alkali hydroxides.

It shows polymorphism.

Identification

ıA. Ultraviolet and visible absorption spectrophotometry.

Test solutionıDissolve 2.0 mg in 0.1 M sodium hydroxide and dilute to 100.0 ml with the

same solvent.

Spectral rangeı230-350 nm.

Absorption maximaıAt 276 nm and 305 nm.

Absorbance ratioıA305 / A276 = 1.6 to 1.8.

ıB. Infrared absorption spectrophotometry.

Comparisonıomeprazole CRS.

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Omeprazole

If the spectra obtained in the solid state show differences, dissolve the substance to be

examined and the reference substance separately in methanol R, evaporate to dryness and

record new spectra using the residues.

ıC. Examine the chromatograms obtained in the test for impurity C.

ResultsıThe principal spot in the chromatogram obtained with test solution (b) is similar in

position and size to the principal spot in the chromatogram obtained with reference solution

(a). Place the plate in a tank saturated with vapour from acetic acid R. The spots rapidly turn

brown.

Tests

Solution S

Dissolve 0.50 g in methylene chloride R and dilute to 25 ml with the same solvent.

Appearance of solution

Solution S is clear.

Impurities F and G

Maximum 0.035 per cent for the sum of the contents.

The absorbance of solution S measured at 440 nm is not greater than 0.10.

Impurity C

Thin-layer chromatography.

Solvent mixtureımethanol R, methylene chloride R (50:50 V/V).

Test solution (a)ıDissolve 0.10 g of the substance to be examined in 2.0 ml of the solvent

mixture.

Test solution (b)ıDilute 1.0 ml of test solution (a) to 10 ml with methanol R.

Reference solution (a)ıDissolve 10 mg of omeprazole CRS in 2.0 ml of methanol R.

Reference solution (b)ıDilute 1 ml of test solution (a) to 10 ml with the solvent mixture.

Dilute

1 ml of this solution to 100 ml with the solvent mixture.

Mobile phaseıMix 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.

Applicationı10 μl.

DevelopmentıOver a path of 15 cm.

DryingıIn air.

DetectionıExamine in ultraviolet light at 254 nm.

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Omeprazole

LimitsıTest solution:

(a) impurity C: any spot with a higher RF value than that of the spot due to omeprazole is not

more intense than the principal spot in the chromatogram obtained with reference solution

(b) (0.1 per cent).

Related substances

Liquid chromatography.

Test solutionıDissolve 3.0 mg of the substance to be examined in the mobile phase and

dilute to 25.0 ml with the mobile phase.

Reference solution (a)ıDissolve 1 mg of omeprazole CRS and 1 mg of omeprazole impurity

D CRS in the mobile phase and dilute to 10.0 ml with the mobile phase.

Reference solution (b)ıDilute 1.0 ml of the test solution to 100.0 ml with the mobile phase.

Dilute 1.0 ml of this solution to 10.0 ml with the mobile phase.

Column: ı

ı— size: l = 0.15 m, Ø = 4 mm;

ı— stationary phase: octylsilyl silica gel for chromatography R (5 μm).

Mobile phaseıMix 27 volumes of acetonitrile R and 73 volumes of a 1.4 g/l solution of

disodium hydrogen phosphate R previously adjusted to pH 7.6 with phosphoric acid R.

Flow rateı1 ml/min.

DetectionıSpectrophotometer at 280 nm.

Injectionı40 μl.

Run timeı3 times the retention time of omeprazole.

Relative retentionıWith reference to omeprazole (retention time = about 9 min): impurity A =

about 0.4; impurity E = about 0.6; impurity D = about 0.8; impurity B = about 0.9.

System suitabilityıReference solution:

(a) resolution: minimum 3.0 between the peaks due to impurity D and omeprazole; if

necessary, adjust the pH of the mobile phase or the concentration of acetonitrile R; an

increase in the pH will improve the resolution.

Limits: impurities A, B, D, E: for each impurity, not more than the area of the principal peak

in the chromatogram obtained with reference solution (b) (0.1 per cent);

ı— unspecified impurities: for each impurity, not more than the area of the principal peak in

the chromatogram obtained with reference solution (b) (0.10 per cent).

Chloroform and methylene chloride

Head-space gas chromatography: use the standard additions method.

Test solutionıPlace 0.50 g of the substance to be examined in a 10 ml vial. Add 4.0 ml of

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Omeprazole

dimethylacetamide R and stopper the vial.

Column: ı

ı— material: fused silica;

ı— size: l = 30 m, Ø = 0.32 mm;

ı— stationary phase: cross-linked poly[(cyanopropyl)(phenyl)][dimethyl]siloxane R (film

thickness 1.8 μm).

Carrier gasınitrogen for chromatography R.

Static head-space conditions that may be used:

ı— equilibration temperature: 80 °C;

ı— equilibration time: 1 h.

DetectionıFlame ionisation.

Limits:

ı— methylene chloride: maximum 100 ppm;

ı— chloroform: maximum 50 ppm.

Loss on drying

Maximum 0.2 per cent, determined on 1.000 g by drying under high vacuum at 60 °C for 4 h.

Sulphated ash (2.4.14)

Maximum 0.1 per cent, determined on 1.0 g.

Assay

Dissolve 1.100 g in a mixture of 10 ml of water R and 40 ml of ethanol (96 per cent) R.

Titrate with 0.5 M sodium hydroxide, determining the end-point potentiometrically.

1 ml of 0.5 M sodium hydroxide is equivalent to 0.1727 g of C17H19N3O3S.

Storage

In an airtight container, protected from light, at a temperature of 2 °C to 8 °C.

Impurities

Specified impuritiesıA, B, C, D, E, F, G.

Other detectable impuritiesı(The following substances would, if present at a sufficient level,

be detected by one or other of the tests in the monograph. They are limited by the general

acceptance criterion for other/unspecified impurities and/or by the general monograph

Substances for pharmaceutical use (2034). It is therefore not necessary to identify these

impurities for demonstration of compliance. See also 5.10. Control of impurities in

substances for pharmaceutical use): H, I.

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Omeprazole

ıA. 5-methoxy-1H-benzimidazole-2-thiol,

ıB. R = H, X = SO: 2-[(RS)-[(3,5-dimethylpyridin-2-yl)methyl]sulphinyl]-5-methoxy-

1Hbenzimidazole,

ıC. R = OCH3, X = S: 5-methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-

yl)methyl]sulphanyl]- 1H-benzimidazole (ufiprazole),

ıD. R = OCH3, X = SO2: 5-methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-

yl)methyl]sulphonyl]- 1H-benzimidazole (omeprazole sulphone),

ıH. R = Cl, X = SO: 2-[(RS)-[(4-chloro-3,5-dimethylpyridin-2-yl)methyl]sulfinyl]-5-

methoxy-1Hbenzimidazole,

ıE. X = SO: 4-methoxy-2-[[(RS)-(5-methoxy-1H-benzimidazol-2-yl)sulphinyl]methyl]-3,5-

dimethylpyridine 1-oxide,

ıI. X = SO2: 4-methoxy-2-[[(5-methoxy-1H-benzimidazol-2-yl)sulphonyl]methyl]-3,5-

dimethylpyridine 1-oxide,

ıF. R = OCH3, R¢ = H: 8-methoxy-1,3-dimethyl-12-thioxopyrido[1¢,2¢:3,4]imidazo[1,2-a]

benzimidazol-2(12H)-one,

ıG. R = H, R¢ = OCH3: 9-methoxy-1,3-dimethyl-12-thioxopyrido[1¢,2¢:3,4]imidazo[1,2-a]

benzimidazol-2(12H)-one.

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Omeprazole

Drug Information

Company name

Technodrug Pharmaceutical Company

Drug Name

Generic name: Omeprazole

Brand name: Omsec

Drug Uses

Omeprazole is used for treating acid-induced inflammation and ulcers of the stomach and

duodenum, gastroesophageal reflux disease (GERD) and Zollinger-Ellison Syndrome. It also

is used in combination with antibiotics for eradicating H. pylori infection of the stomach.

How Taken

For ulcers, GERD and eradication of H. pylori the recommended dose for adults is 20-40 mg

daily. Ulcer healing usually occurs within 4-8 weeks. H. pylori infections are treated for 10-

28 days. Omeprazole OTC has been approved for more severe heartburn for up to two weeks.

For the management of Zollinger-Ellison Syndrome the starting dose for adults is 60 mg

daily, and the dose is adjusted based on either the response of symptoms or the actual

measurement of acid production. Doses greater than 80 mg should be divided. Doses up to

120 mg three times a day have been used in the treatment of Zollinger-Ellison Syndrome.

For maximal efficacy, Omeprazole tablets should be taken before meals, swallowed whole

and should not be crushed, chewed or opened.

Drug Class and Mechanism

Fig: Mechanism of action of Omeprazole

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Omeprazole

Omeprazole is in a class of drugs called proton pump inhibitors (PPI) which block the

production of acid by the stomach. Other drugs in the same class include lansoprazole,

rabeprazole, pantoprazole, and esomeprazole. Proton pump inhibitors are used for the

treatment of conditions such as ulcers, gastroesophageal reflux disease (GERD) and the

Zollinger-Ellison Syndrome which are all caused by stomach acid. Omeprazole, like other

proton-pump inhibitors, blocks the enzyme in the wall of the stomach that produces acid. By

blocking the enzyme, the production of acid is decreased, and this allows the stomach and

esophagus to heal. Omeprazole OTC has been approved for sale without a prescription.

Missed Dose

Take the missed dose as soon as possible. However, if it is almost time for the next dose, skip

the missed dose and take only the next regularly scheduled dose. Do not take a double dose of

this medication unless doctor directs otherwise.

Warnings/Precautions

There are no restrictions on food, beverages, or activities while taking Omeprazole, unless

otherwise directed by doctor. Omeprazole potentially can increase the concentrations in blood

of diazepam, warfarin, and phenytoin by decreasing the elimination of these drugs by the

liver. The absorption of certain drugs may be affected by stomach acidity, and, as a result,

Omeprazole and other PPIs that reduce stomach acid also reduce the absorption and

concentration in blood of ketoconazole and increase the absorption and concentration in

blood of digoxin. This may lead to reduced effectiveness of ketoconazole or increased

digoxin toxicity, respectively.

Possible Side Effects

Omeprazole like other PPIs is well-tolerated. The most common side effects are diarrhea,

nausea, vomiting, headaches, rash and dizziness. Nervousness, abnormal heartbeat, muscle

pain, weakness, leg cramps and water retention occur infrequently.

Each dose of Omeprazole powder for oral suspension contains 460 mg of sodium, and this

should be taken into consideration in patients who need sodium restricted diet.

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Omeprazole

More Information

If one experience an allergic reaction (difficulty breathing; closing of the throat; swelling of

the lips, tongue, or face; or hives), stop taking Omeprazole and seek emergency medical

attention.

Other, less serious side effects may be more likely to occur. Continue to take Omeprazole and

need to talk with doctor if patient experience

o drowsiness, dizziness, or headache;

o diarrhea, increased gas, or bloating; or

o itching.

Side effects other than those listed here may also occur. It is necessary to talk with

doctor about any side effect that seems unusual or that is especially bothersome.

Production of Omeprazole in Technodrug Pharmaceutical Company

Raw materials collection

Raw materials are the substances used in the primary production or manufacturing of goods.

Technodrug pharmaceutical company collects raw materials of omeprazole mainly from

China, India and America. Technodrug Company follows some rules and criteria for

purchasing raw materials. These include-

Elements and Performance Criteria

Elements Performance Criteria

1. Prepare to dispense raw materials 1.1. Materials are inspected to confirm

type, quality clearance, quantities and

identify any obvious contamination or non-

compliance

1.2. Measuring and weighing equipment is

selected appropriate to dispensing

requirements and checked to confirm

readiness for use

1.3. Containers/bags and labels are

available as required

1.4. Pre-start checks are carried out as

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Omeprazole

required by workplace requirements

2. Measure and/or weigh raw materials 2.1. Non-bulk ingredients and additives are

weighed/measured to meet production

requirements

2.2. Dispensed ingredients are labelled

according to workplace procedure

2.3. Accuracy of measuring/dispensing

equipment is monitored to identify

variation in operating conditions

2.4. Variation in equipment operation is

identified and maintenance requirements

are reported according to workplace

reporting requirements

2.5. The work area is maintained according

to housekeeping standards

2.6. Work is conducted in accordance with

workplace environmental guidelines

3. Shut down the dispensing process 3.1. Dispensing equipment is cleaned

according to workplace procedure

3.2. Unacceptable equipment/utensil

condition is identified and reported

3.3. Dispensed materials are recorded and

reconciled

3.4. Maintenance requirements are

identified and reported

Formulation of Omeprazole

In Technodrug Company the formulation of omeprazole is done by applying the following

procedure-

Omeprazole tablets (Enteric coated)

Omeprazole tablets (Enteric coated) with Na2HPO4

Omeprazole 20.0 mg 20.0 mgNa2HPO4 - 31.3 mgLudipress 228.75 mg 197.45 mg

Magnesium stearate 1.25 mg 1.25 mg

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Omeprazole

Total 250.0 mg 250.0 mg

Diameter 9 mm 9 mmBatch size 18.5 Kg 18.5 Kg

All ingredients are blended in the Diosna mixer V 50 for 3 min and compressed on a Kilian

RL 15 rotary press at 10 kN compression force.

During the manufacturing of omeprazole enteric coated tablet in Technodrug Company some

conditions are maintained throughout the process. These include-

Omeprazole tablets (Enteric coated)

Omeprazole tablets (Enteric coated) with Na2HPO4

Inlet air temperature 50 ºC 60 ºCOutlet air temperature 30 ºC 35 ºC

Air volume 360 m3/h 360 m3/hNozzle diameter 1.0 mm 1.0 mm

Atomizing air pressure 2.0 bar 2.0 barSpraying rate 20 g/min 10 g/minCoating level 3;6;10 mg polymer/cm2

Standard Operating Procedures (SOP) for Omeprazole Tablets Maintained by

Technodrug Pharmaceutical Company

Careful adherence to the preparative process is essential for preventing defects in the final

coated tablet of Omeprazole.

Core Substrate Formulation

When considering the preparation of a Omeprazole coated tablet, the core or substrate needs

to be formulated correctly so it can withstand the mechanical duress and the elevated heat and

humidity conditions of the coating process.

The design of a robust substrate has to be considered in terms of:

The excipient and active ingredients of the tablets must meet the desired the hardness

and friability level that will allow for appropriate drug release.

These tablets must exhibit hardness and friability properties that will allow them to

withstand the stress of the film coating process.

The adhesion of the coating to the surface of the core is maximized, especially when a

logo, or intagliation, is present.

The selected tablet shape is conducive to consistent mixing of the cores in the process

and uniform distribution of the coating.

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Omeprazole

The final coated dosage form will meet the ultimate stability objectives.

Success can only be ensured in the film coating process by reconciling the formulation, the

tablet design and the production parameters early in the development process.

Film Coating Selection

The selection of the right film coating for the application is critical in order to optimize the

adhesion values and tensile properties of the film with the processing conditions required to

achieve the best combination of product performance, appearance and process efficiency.

For film coating processes, the latest technology allows for the application of aesthetic and

functional films at elevated solids levels when compared to conventional, more mature

formulations. The advantages of high solids include but are not limited to the following:

Improving productivity and reducing energy and labor costs

Speeding the application of the protective coatings to the tablet which ultimately

lessens the chance for defects such as edge chipping and erosion

The reduction of the amount of water utilized in the procedure, keeping moisture

away from tablets containing sensitive actives

With the appropriate early stage consideration a high solids film coating process can produce

omeprazole tablets that are visually identical and are uniformly functional.

Quality Control

All their products are manufactured as per the regulations and guidelines of the World Health

Organization's Good Manufacturing Practice (WHO GMP). Significant portion of the

investments made in manufacturing have been in terms of putting up high-end technologies

and automated facilities that ensure the highest levels of process compliance and product

quality. Their quality policy not only extends through in house operations but also extends to

vendors who are our suppliers for active product ingredients and execipients. All the

processes are backed by a sophisticated Quality Assurance System ensuring Quality product

at each and every step from acquiring of raw materials through manufacturing to the finished

formulations.

Quality Control, which forms a key unit of a Quality Assurance System, is well equipped

with most sophisticated, ultra-modern and state-of-the-art instruments like: Gas

Chromatography, High Performance Lipid Chromatography, UV Spectrophotometer,

Automated Dissolution Apparatus, Karl Fischer Titrator, Polarimeter, all of which conform to

GMP guidelines, are employed for testing.

Quality Assurance

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Omeprazole

The Quality Assurance Department, managed by qualified personnel, constantly examines

quality aspects at every stage of manufacture. A comphresnsive system ensures that there is

total traceability of data right from inflow of material to testing to release, to manufacturing

& to dispatch. The documentation system also covers qualification of area, machines & also

covers records related to calibration & validation. They assure quality of our products by

regularly inspecting the facilities, systems and procedures to meet the current GMP norms.

The employees are trained periodically on GMP requirements. they have well defined

validation master plan, which ensures smooth functioning of machines and hence the process.

They also have a well-defined stability protocol and programme that ensures the velocity of

the claimed shelf life.

Quality Assurance (QA) procedures ensure that the quality of the products is maintained by

strict compliance with British Pharmacopoeias specifications on raw materials, packaging

materials and finished products. The quality Assurance department assures quality through a

well designed quality management programme. The programme begins with the following:

Documentation related to product development.

Development of prototype

Assessment of prototype

Evaluation of prototype in terms of quality as well as cost effectiveness

Systematic scale and transfer of technology in production

Through well defined testing procedures for incoming raw material and packaging

materials

Through evaluation of production stages wide in-process quality control test

Through testing of final product

Our company has its own GMP System:

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Omeprazole

Quality Team

Quality Assurance and Control teams consist of highly qualified and well-trained

professionals in the fields of Analytical and Organic Chemistry. They continuously monitor

the quality of our product at all stages of manufacturing using validated analytical methods.

No quality policy can be complete if it is not packed up by the trained manpower. They have

cogently devised training programme which is not only aimed at imparting awareness and

training right from worker level to management level too. They take actions not only to build

quality product but also to develop quality people and the systems that go a long way to

assure a top quality product.

Packaging

Blister packs are commonly used for omeprazole. It can provide barrier protection for shelf

life requirements, and a degree of tamper resistance. A pictorial figure of packaging of

omeprazole 20 mg is given below.

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Omeprazole

Storage

1. Omeprazole should be kept on a place where children cannot reach it.

2. A locked cupboard at least one-and-a-half metres above the ground is a good place to

store medicines.

3. Tablets should be kept in the blister pack until it is time to take them.

4. Tablets should be kept in a cool dry place where the temperature stays below 25°C.

5. Heat and dampness can destroy omeprazole.

Conclusion

Omeprazole is one of the most selling drugs in our country. Currently many multinational as

well as local pharmaceutical companies are manufacturing the drug in variety of formulation

in large scale. Our objective was to learn its manufacturing process and details information

regarding its characteristics, mechanism, raw material, project plan, packaging, storage

conditions and areas of distribution etc. We have taken information from Mahmudul Hasan

(ID: 2006-3-70-022). He helped us a lot and without his contribution this assignment was not

possible. We pay gratitude to his help.

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