Omeprazole Delayed-Release Capsules, chemical structure, molecular formula, Reference Standards

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Omeprazole Delayed-Release Capsules

»Omeprazole Delayed-Release Capsules contain not less than 90.0percent and not more than 110.0percent of the labeled amount of omeprazole (C17H19N3O3S).

Labeling— When more than one Drug Releasetest is given,the labeling states the Drug Releasetest used only if Test 1is not used.

USP Reference standards á11ñ— USP Omeprazole RS.

Identification—

A:Thin-Layer Chromatographic Identification Test á201ñ—

Adsorbent: 0.25-mm chromatographic silica gel mixture,prewashed with methanol.

Diluent: a mixture of methylene chloride and methanol (1:1).

Test solution— Transfer the contents of not fewer than 5Capsules to a mortar,grind the Capsules,and mix.Transfer a weighed quantity of the powder,equivalent to about 10mg of omeprazole,to a suitable container.Add 2mLof Diluent,sonicate for 5minutes,and allow to settle for 20minutes before applying to the plate.

Standard solution— Dissolve an accurately weighed quantity of USP Omeprazole RSin Diluentto obtain a solution having a known concentration of about 5mg per mL.

Developing solvent system: a mixture of methylene chloride saturated with ammonia,methylene chloride,and isopropyl alcohol (2:2:1).

B: The retention time of the major peak in the chromatogram of the Assay preparationcorresponds to that in the chromatogram of the Standard preparation,as obtained in the Assay.

Drug release—

TEST1,METHOD Aá724ñ—

ACID RESISTANCE STAGE—

Medium: 0.1Nhydrochloric acid;500mL.

Apparatus 2: 100rpm.

Time: 2hours.

pH7.6Phosphate buffer,Mobile phase,andChromatographic system— Proceed as directed for Buffer stage.

Standard solution— Transfer about 50mg of USP Omeprazole RS,accurately weighed,to a 250-mLvolumetric flask,dissolve in 50mLof alcohol,dilute with 0.01Msodium borate solution to volume,and mix.Transfer 10.0mLof this solution into a 100-mLvolumetric flask,add 20mLof alcohol,dilute with 0.01Msodium borate solution to volume,and mix.

Test solution— After 2hours,filter the Dissolution Mediumcontaining the pellets through a sieve with an aperture of not more than 0.2mm.Collect the pellets on the sieve,and rinse them with water.Using approximately 60mLof 0.01Msodium borate solution,carefully transfer the pellets quantitatively to a 100-mLvolumetric flask.Sonicate for about 20minutes until the pellets are broken up.Add 20mLof alcohol to the flask,dilute with 0.01Msodium borate solution to volume,and mix.Dilute an appropriate amount of this solution with 0.01Msodium borate solution to obtain a solution having a concentration of about 0.02mg per mL.

Procedure— Separately inject equal volumes (about 20µL)of the Standard solutionand Test solutioninto the chromatograph,record the chromatograms,and measure the responses for the major peaks.Calculate the quantity,in mg,of omeprazole (C17H19N3O3S)dissolved in the Mediumby the formula:

T–CD(rU/rS),

in which Tis the labeled quantity,in mg,of omeprazole in the capsule;Cis the concentration,in mg per mL,of USP Omeprazole RSin the Standard solution;Dis the dilution factor used in preparing the Test solution;and rUand rSare the omeprazole peak responses obtained from the Test solutionand the Standard solution,respectively.

Tolerances— Level L1:no individual value exceeds 15%of omeprazole dissolved.Level L2:the average of 12units is not more than 20%of omeprazole dissolved,and no individual unit is greater than 35%of omeprazole dissolved.Level L3:the average of 24units is not more than 20%of omeprazole dissolved,not more than 2units are greater than 35%of omeprazole dissolved,and no individual unit is greater than 45%of omeprazole dissolved.

BUFFER STAGE—

Medium: pH6.8phosphate buffer,900mL.

Proceed as directed for Acid resistance stagewith a new set of capsules from the same batch.After 2hours,add 400mLof 0.235Mdibasic sodium phosphate to the 500mLof 0.1Nhydrochloric acid medium in the vessel.Adjust,if necessary,with 2Nhydrochloric acid or 2Nsodium hydroxide to a pHof 6.8±0.05.

Apparatus 2: 100rpm.

At the end of 30minutes,determine the amount of C17H19N3O3Sdissolved in pH6.8phosphate buffer by employing the following method.

pH10.4,0.235M Dibasic sodium phosphate— Dissolve 33.36g of anhydrous dibasic sodium phosphate in 1000mLof water,and adjust with 2Nsodium hydroxide to a pHof 10.4±0.1.

pH6.8Phosphate buffer— Add 400mLof 0.1Nhydrochloric acid to 320mLof pH10.4,0.235M Dibasic sodium phosphate,and adjust with 2Nhydrochloric acid or 2Nsodium hydroxide,if necessary,to a pHof 6.8±0.05.

pH7.6Phosphate buffer— Dissolve 0.718g of monobasic sodium phosphate and 4.49g of dibasic sodium phosphate in 1000mLof water.Adjust with 2Nhydrochloric acid or 2Nsodium hydroxide,if necessary,to a pHof 7.6±0.1.Dilute 250mLof this solution with water to 1000mL.

Mobile phase— Transfer 340mLof acetonitrile to a 1000-mLvolumetric flask,dilute with pH7.6Phosphate bufferto volume,and pass through a membrane filter having a 0.5-µm or finer porosity.Make adjustments if necessary (see System Suitabilityunder Chromatography á621ñ).

Standard solution 1(for Capsules labeled 10mg)— Dissolve an accurately weighed quantity of USP Omeprazole RSin alcohol to obtain a solution having a known concentration of about 2mg per mL.Dilute with pH6.8Phosphate bufferquantitatively,and stepwise if necessary,to obtain a solution having a known concentration of about 0.01mg per mL.Immediately add 2mLof 0.25Msodium hydroxide to 10mLof this solution,and mix.[NOTE—Do not allow the solution to stand before adding the sodium hydroxide solution.]

Standard solution 2(for Capsules labeled 20mg and 40mg)— Proceed as directed for Standard solution 1,except to obtain a solution having a known concentration of about 0.02mg per mLbefore mixing with 2mLof 0.25Msodium hydroxide.

Test solution 1(for Capsules containing 10mg and 20mg)— Immediately transfer 5.0mLof the solution under test to a test tube containing 1.0mLof 0.25Msodium hydroxide.Mix well,and pass through a membrane filter having a 1.2-µm or finer porosity.Protect from light.

Test solution 2(for Capsules labeled 40mg)— Immediately transfer 5.0mLof the solution under test to a test tube containing 2.0mLof 0.25Msodium hydroxide and 5mLof pH6.8Phosphate buffer.Mix well,and pass through a membrane filter having a 1.2-µm or finer porosity.Protect from light.

Chromatographic system (see Chromatography á621ñ)— The liquid chromatograph is equipped with a 280-nm detector and a 4.0-mm ×12.5-cm analytical column that contains 5-µm packing L7.The flow rate is about 1.0mLper minute.Chromatograph the appropriate Standard solution,and record the peak responses as directed for Procedure:the column efficiency is not less than 2000theoretical plates,and the relative standard deviation for replicate injections is not more than 2.0%.

Procedure— Separately inject equal volumes (about 20µL)of the appropriate Standard solutionand the Test solutioninto the chromatograph,record the chromatograms,and measure the responses for the major peaks.Calculate the quantity,in mg,of omeprazole (C17H19N3O3S)dissolved by the formula:

VCD(rU/rS),

in which Vis the volume of Mediumin each vessel;Cis the concentration,in mg per mL,of USP Omeprazole RSin the appropriate Standard solution;Dis the dilution factor used in preparing the appropriateTest solution;and rUand rSare the omeprazole peak responses obtained from the appropriate Test solutionand the Standard solution,respectively.

Tolerances— For Capsules labeled 10and 20mg,not less than 75%(Q)of the labeled amount of C17H19N3O3Sis dissolved in 30minutes.For Capsules labeled 40mg,not less than 70%(Q)of the labeled amount of C17H19N3O3Sis dissolved in 30minutes.

TEST2á711ñ— If the product complies with this test,the labeling indicates that it meets USPDrug Release Test 2.

ACID RESISTANCE STAGE—

Medium: 0.1Nhydrochloric acid;900mL.

Apparatus 1: 100rpm.

Time: 2hours.

Procedure— After 2hours,remove each sample from the basket,and quantitatively transfer into separate volumetric flasks to obtain a solution having a final concentration of about 0.2mg per mL.Proceed as directed for the Assay preparation in the Assay,starting with “Add about 50mLof Diluent”.Calculate the quantity,in mg,of omeprazole (C17H19N3O3S)dissolved in the Mediumby the formula:

T–CD(rU/rS)

in which Tis the assayed quantity,in mg,of omeprazole in the capsule;Cis the concentration,in mg per mL,of USP Omeprazole RSin the Standard solution;Dis the dilution factor used in preparing the Test solution;and rUand rSare the omeprazole peak responses obtained from Test solutionand Standard solution,respectively.

Tolerances— It complies with the following Acceptance Table:

Acceptance Table

Level	Criterion
L1	the average of the 6units is not more than 10%of omeprazole dissolved
L2	the average of the 12units is not more than 10%of omeprazole dissolved
L3	the average of the 24units is not more than 10%of omeprazole dissolved

BUFFER STAGE—

Medium: 0.05MpH6.8phosphate buffer;900mL(see Reagents,Indicators,and Solutions).

Apparatus 1: 100rpm.

Time: 45minutes.

Procedure— Proceed as directed for Acid resistance stagewith a new set of capsules from the same batch.After 2hours,replace the acid medium with the buffer medium and continue the test for 45more minutes.Determine the amount of C17H19N3O3Sdissolved from UVabsorbances at the wavelength of maximum absorbance at about 305nm on portions of the solutions under test passed through a 0.2µm nylon filter,in comparison with a Standard solution having a known concentration of USP Omeprazole RSin the same Medium.

Tolerances— It complies with the Acceptance Tableunder Dissolution á711ñ.Not less than 75%(Q)of the labeled amount of C17H19N3O3Sis dissolved in 45minutes.

Uniformity of dosage units á905ñ: meet the requirements.

Chromatographic purity—

Diluent,Solution A,Solution B,Mobile phase,and Chromatographic system— Proceed as directed in the Assay.

Standard solution— Prepare as directed for the Standard preparation in the Assay.

Test solution— Use the Assay preparation.

Procedure— Separately inject equal volumes (about 10µL)of the Standard solutionand the Test solutioninto the chromatograph,record the chromatograms,and measure all of the peak responses.Calculate the percentage of each impurity in the portion of Capsules taken by the formula:

(10C/FA)(ri/rS),

in which Cis the concentration,in µg per mL,of USP Omeprazole RSin the Standard solution;Fis the relative response factor (see Notebelow for values);Ais the quantity,in mg,of omeprazole in the portion of Capsules taken,as determined in the Assay;riis the peak response for each impurity obtained from the Test solution;and rSis the peak response for omeprazole obtained from the Standard solution:not more than 0.5%of any individual impurity is found,and not more than 2.0%of total impurities is found.[NOTE—The relative response factor,F,equals 1.6and 3.1for peaks with a relative retention time of about 0.33and 0.64,respectively;and equals 1.0for peaks obtained from all other impurities.]

Assay—

Diluent— Dissolve 7.6g of sodium borate decahydrate in about 800mLof water.Add 1.0g of edetate disodium,and adjust with 50%sodium hydroxide solution to a pHof 11.0±0.1.Transfer the solution to a 2000-mLvolumetric flask,add 400mLof dehydrated alcohol,and dilute with water to volume.

Solution A— Prepare a filtered and degassed solution of 6.0g of glycine in 1500mLof water.Adjust with 50%sodium hydroxide solution to a pHof 9.0,and dilute with water to 2000mL.

Solution B— Use a filtered and degassed mixture of acetonitrile and methanol (85:15).

Mobile phase— Use variable mixtures of Solution Aand Solution Bas directed for Chromatographic system.Make adjustments if necessary (see System Suitabilityunder Chromatography á621ñ).

Standard preparation— Dissolve,by sonicating,an accurately weighed quantity of USP Omeprazole RSin Diluent,and dilute quantitatively,and stepwise if necessary,with Diluentto obtain a solution having a known concentration of about 0.2mg per mL.

Assay preparation— Weigh and mix the contents of not fewer than 20Capsules.Transfer an accurately weighed portion of the mixture,equivalent to about 20mg of omeprazole,to a 100-mLvolumetric flask,add about 50mLof Diluent,and sonicate for 15minutes.Cool,dilute with Diluentto volume,mix,and pass through a membrane filter having 0.45-µm or finer porosity.[NOTE—Bubbles may form just before bringing the solution to volume.Add a few drops of dehydrated alcohol to dissipate the bubbles if they persist for more than a few minutes.]

Chromatographic system (see Chromatography á621ñ)— The liquid chromatograph is equipped with a 305-nm detector and a 4.6-mm ×15-cm column that contains 5-µm base-deactivated packing L7.The flow rate is about 1.2mLper minute.The chromatograph is programmed as follows.

Time (minutes)	Solution A %	Solution B %	Elution
0–20	88®40	12®60	linear gradient
20–21	40®88	60®12	linear gradient
21–25	88	12	isocratic

Chromatograph the Standard preparation,and record the peak responses as directed for Procedure:the column efficiency is not less than 20,000theoretical plates;the tailing factor is not less than 0.8and not more than 2;and the relative standard deviation for replicate injections is not more than 2.0%.

Procedure— Separately inject equal volumes (about 10µL)of the Standard preparationand the Assay preparationinto the chromatograph,record the chromatograms,and measure the peak responses.Calculate the quantity,in mg,of omeprazole (C17H19N3O3S)in the portion of Capsules taken by the formula:

DC(rU/rS),

in which Dis the dilution factor of the Assay preparation;Cis the concentration,in mg per mL,of USP Omeprazole RSin the Standard preparation;and rUand rSare the peak responses obtained from the Assay preparationand the Standard preparation,respectively.

USP28

Auxiliary Information— Staff Liaison:Elena Gonikberg,Ph.D.,Scientist

Expert Committee:(PA4)Pharmaceutical Analysis 4

USP28–NF23Page 1417

Pharmacopeial Forum:Volume No.30(1)Page 143

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