Omeprazole Monograph of Omeprazole (British Pharmacopoeia 2009) Omeprazole

Chemical formula: C17H19N3O3SMolecular weight: 345.4 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]-1Hbenzimidazole. 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 A. Ultraviolet and visible absorption spectrophotometry. Test solutionDissolve 2.0 mg in 0.1 M sodium hydroxide and dilute to 100.0 ml with the same solvent. Spectral range230-350 nm. Absorption maximaAt 276 nm and 305 nm. Absorbance ratioA305 / A276 = 1.6 to 1.8. B. Infrared absorption spectrophotometry. Comparisonomeprazole CRS.

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. C. Examine the chromatograms obtained in the test for impurity C. ResultsThe 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 mixturemethanol R, methylene chloride R (50:50 V/V). Test solution (a)Dissolve 0.10 g of the substance to be examined in 2.0 ml of the solvent mixture. Test solution (b)Dilute 1.0 ml of test solution (a) to 10 ml with methanol R. Reference solution (a)Dissolve 10 mg of omeprazole CRS in 2.0 ml of methanol R.

Reference solution (b)Dilute 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 phaseMix 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. Application10 l. DevelopmentOver a path of 15 cm. DryingIn air. DetectionExamine in ultraviolet light at 254 nm.

Omeprazole LimitsTest 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 solutionDissolve 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)Dissolve 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)Dilute 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: size: l = 0.15 m, = 4 mm; stationary phase: octylsilyl silica gel for chromatography R (5 m). Mobile phaseMix 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 rate1 ml/min. DetectionSpectrophotometer at 280 nm. Injection40 l. Run time3 times the retention time of omeprazole. Relative retentionWith 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 suitabilityReference 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); 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.

Omeprazole Test solutionPlace 0.50 g of the substance to be examined in a 10 ml vial. Add 4.0 ml of dimethylacetamide R and stopper the vial. Column: material: fused silica; size: l = 30 m, = 0.32 mm; stationary phase: cross-linked poly[(cyanopropyl)(phenyl)][dimethyl]siloxane R (film thickness 1.8 m). Carrier gasnitrogen for chromatography R. Static head-space conditions that may be used: equilibration temperature: 80 C; equilibration time: 1 h. DetectionFlame ionisation. Limits: methylene chloride: maximum 100 ppm; 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 impuritiesA, B, C, D, E, F, G. Other detectable impurities(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.

Omeprazole

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

B. R = H, X = SO: 2-[(RS)-[(3,5-dimethylpyridin-2-yl)methyl]sulphinyl]-5-methoxy1Hbenzimidazole, C. R = OCH3, X = S: 5-methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulphanyl]1H-benzimidazole (ufiprazole), D. R = OCH3, X = SO2: 5-methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2yl)methyl]sulphonyl]- 1H-benzimidazole (omeprazole sulphone), H. R = Cl, X = SO: 2-[(RS)-[(4-chloro-3,5-dimethylpyridin-2-yl)methyl]sulfinyl]-5-methoxy1Hbenzimidazole,

E. X = SO: 4-methoxy-2-[[(RS)-(5-methoxy-1H-benzimidazol-2-yl)sulphinyl]methyl]-3,5dimethylpyridine 1-oxide, I. X = SO2: 4-methoxy-2-[[(5-methoxy-1H-benzimidazol-2-yl)sulphonyl]methyl]-3,5dimethylpyridine 1-oxide,

F. R = OCH3, R = H: 8-methoxy-1,3-dimethyl-12-thioxopyrido[1,2:3,4]imidazo[1,2-a] benzimidazol-2(12H)-one, G. R = H, R = OCH3: 9-methoxy-1,3-dimethyl-12-thioxopyrido[1,2:3,4]imidazo[1,2-a] benzimidazol-2(12H)-one.

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

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.

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
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drowsiness, dizziness, or headache; diarrhea, increased gas, or bloating; or 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 includeElements and Performance Criteria Elements 1. Prepare to dispense raw materials Performance Criteria 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 2. Measure and/or weigh raw materials required by workplace requirements 2.1. Non-bulk ingredients and additives are weighed/measured to meet production

Omeprazole 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 3. Shut down the dispensing process workplace environmental guidelines 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 procedureOmeprazole tablets (Enteric coated) 20.0 mg 228.75 mg 1.25 mg 250.0 mg 9 mm 18.5 Kg

Omeprazole Na2HPO4 Ludipress Magnesium stearate Total Diameter Batch size

Omeprazole tablets (Enteric coated) with Na2HPO4 20.0 mg 31.3 mg 197.45 mg 1.25 mg 250.0 mg 9 mm 18.5 Kg

Omeprazole 10 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 includeOmeprazole tablets (Enteric Omeprazole tablets (Enteric coated) coated) with Na2HPO4 50 C 60 C 30 C 35 C 3 360 m /h 360 m3/h 1.0 mm 1.0 mm 2.0 bar 2.0 bar 20 g/min 10 g/min 3;6;10 mg polymer/cm2

Inlet air temperature Outlet air temperature Air volume Nozzle diameter Atomizing air pressure Spraying rate Coating level

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. 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.

Omeprazole 11 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 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

Omeprazole 12 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:

Omeprazole 13

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.

Omeprazole 14

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 25C. 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.