22

Panthenol / Official Monographs

USP 32
mL of 0.01 N sulfuric acid is equivalent to 750 g of aminopropanol. Acceptance criteria: NMT 0.10% SPECIFIC TESTS MELTING RANGE OR TEMPERATURE, Class I 741: 64.568.5 OPTICAL ROTATION, Specific Rotation 781S: 0.05 to +0.05 Sample solution: 50 mg/mL, in water LOSS ON DRYING 731: Dry a sample in a vacuum over phosphorus pentoxide at 56 for 4 h: it loses NMT 0.5% of its weight. ADDITIONAL REQUIREMENTS PACKAGING AND STORAGE: Preserve in tight containers. USP REFERENCE STANDARDS 11 USP Racemic Panthenol RS

Panthenol
(Comment on this Monograph)id=m60440=Panthenol=Pa-PiMonos.pdf)

C9H19NO4 205.25 Butanamide, 2,4-dihydroxy-N-(3-hydroxypropyl)-3,3-dimethyl-, ()-; ()-2,4-Dihydroxy-N-(3-hydroxypropyl)-3,3-dimethylbutyramide; ()-Pantothenyl alcohol [16485-10-2]. DEFINITION Panthenol is a racemic mixture of the dextrorotatory and levorotatory isomers of panthenol. It contains NLT 99.0% and NMT 102.0% of C9H19NO4, calculated on the dried basis. IDENTIFICATION A. INFRARED ABSORPTION 197M B. PROCEDURE Analysis: To 1 mL of a solution (1 in 10) add 5 mL of 1 N sodium hydroxide and 1 drop of cupric sulfate TS, and shake vigorously. Acceptance criteria: A deep blue color develops. C. PROCEDURE Analysis: To 1 mL of a solution (1 in 100) add 1 mL of 1 N hydrochloric acid, and heat on a steam bath for about 30 min. Cool, add 100 mg of hydroxylamine hydrochloride, mix, and add 5 mL of 1 N sodium hydroxide. Allow to stand for 5 min, then adjust with 1 N hydrochloric acid to a pH of between 2.5 and 3.0, and add 1 drop of ferric chloride TS. Acceptance criteria: A purplish-red color develops. ASSAY PROCEDURE Potassium biphthalate solution: Dissolve 20.42 g of potassium biphthalate in glacial acetic acid contained in a 1000-mL volumetric flask. If necessary, warm the mixture on a steam bath to dissolve, observing precautions against absorption of moisture. Cool to room temperature, and dilute with glacial acetic acid to volume. Sample solution: Transfer 400 mg of Panthenol to a 300mL flask fitted to a reflux condenser by means of a standardtaper glass joint. Add 50.0 mL of 0.1 N perchloric acid VS, and reflux for 5 h. Cool, observing precautions to prevent atmospheric moisture from entering the condenser, and rinse the condenser with glacial acetic acid, collecting the rinsings in the flask. Analysis: Titrate the Sample solution with Potassium biphthalate solution to a blue-green endpoint by using 5 drops of crystal violet TS as an indicator. Perform a blank determination, and note the difference in volumes required. Each mL of the difference in volumes of 0.1 N perchloric acid consumed is equivalent to 20.53 mg of C9H19NO4. Acceptance criteria: 99.0%102.0% IMPURITIES Inorganic Impurities RESIDUE ON IGNITION 281: NMT 0.1% Organic Impurities PROCEDURE: LIMIT OF AMINOPROPANOL Sample solution: 400 mg/mL Analysis: Titrate with 0.01 N sulfuric acid VS to a yellow endpoint, using bromothymol blue TS as an indicator. Each

Add the following:

Pantoprazole

Sodium

(Comment on this Monograph)id=m2631=Pantoprazole Sodium=Pa-Pi-Monos.pdf)

432.37 C16H14F2N3NaO4S 1.5H2O 1H-Benzimidazole, 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2pyridyl)methyl]sulfinyl]-, sodium salt, hydrate (2:3); 5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2pyridyl)methyl]sulfinyl]benzimidazole, sodium salt, sesquihydrate [164579-32-2]. DEFINITION Pantoprazole Sodium contains NLT 98.0% and NMT 102.0% of C16H14F2N3NaO4S, calculated on the anhydrous basis. IDENTIFICATION A. INFRARED ABSORPTION 197K B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. C. IDENTIFICATION TESTSGENERAL, Sodium 191: Meets the requirements of the pyroantimonate precipitate test. ASSAY [NOTEProtect all solutions from light, and use amber autosampler vials and low-actinic glassware.] PROCEDURE Ammonium phosphate buffer: Dissolve 1.32 g of dibasic ammonium phosphate in 1000 mL of water. Adjust with phosphoric acid to a pH of 7.5. Acetonitrilemethanol mixture: Prepare a mixture of acetonitrile and methanol (7:3). Diluent: Transfer 25 mL of ammonium hydroxide to a suitable container, and dilute with water to 500 mL. Solution A: Use a filtered and degassed mixture of Ammonium phosphate buffer and Acetonitrilemethanol mixture (85:15).

Copyright 2008 The United States Pharmacopeial Convention. All Rights Reserved. For Discussion Purposes Only Not for Dissemination

USP 32
Solution B: Use the Acetonitrilemethanol mixture. Mobile phase: See the gradient table below.
Time (min) 0 10 35 36 46 Solution A (%) 86 86 42 86 86 Solution B (%) 14 14 58 14 14

Official Monographs / Pantoprazole 23

Acceptance criteria: NLT 98.0%102.0%

System suitability solution: Dissolve suitable amounts of USP Pantoprazole Sodium RS, USP Pantoprazole Related Compound A RS, and USP Pantoprazole Related Compound B RS in a mixture of acetonitrile and water (1:1) to obtain a solution having about 0.5 mg/mL of each component. Transfer 1 mL of this solution to a 100-mL volumetric flask, and dilute with Diluent to volume. Standard solution: Transfer about 20 mg of USP Pantoprazole Sodium RS weighed, to a 50-mL volumetric flask. Dissolve in 510 mL of a mixture of acetonitrile and water (1:1), and dilute with Diluent to volume. Further dilute with Diluent quantitatively, and stepwise if necessary, to obtain a solution having a known concentration of about 0.06 mg/mL. Sample solution: Transfer about 20 mg of Pantoprazole Sodium to a 50-mL volumetric flask. Dissolve in 510 mL of a mixture of acetonitrile and water (1:1), and dilute with Diluent to volume. Further dilute with Diluent quantitatively, and stepwise if necessary, to obtain a solution having a known concentration of about 0.06 mg/mL. Chromatographic system (See Chromatography 621, System Suitablility.) Mode: LC Detector: UV 285 nm Column: 3.9-mm 15-cm; 4-m packing L1 Temperature Column: 30 Autosampler: 4 Flow rate: 1 mL/min Injection size: 20 L System suitability Samples: System suitability solution and Standard solution [NOTEIdentify the components based on their relative retention times (see Impurity Table 1).] Suitability requirements Resolution: NLT 10.0 between pantoprazole related compound A and pantoprazole, System suitability solution Relative standard deviation: NMT 2.0%, Standard solution Analysis Samples: Standard solution and Sample solution Calculate the percentage of C16H14F2N3NaO4S in the portion of Pantoprazole Sodium taken: Result = (rU/rS) (CS/CU) 100 rU rS CS CU = peak response from the Sample solution = peak response from the Standard solution = concentration of USP Pantoprazole Sodium RS in the Standard solution (mg/mL) = concentration of Pantoprazole Sodium in the Sample solution (mg/mL)

IMPURITIES Inorganic Impurities HEAVY METALS, Method II 231: NMT 20 ppm Organic Impurities PROCEDURE [NOTEOn the basis of the synthetic route, perform either Test 1 or Test 2. Test 2 is recommended when impurities C, D, E, and F are potential related compounds.] Test 1 [NOTEProtect all solutions from light, and use amber autosampler vials and low-actinic glassware. ] Diluent, Mobile phase, System suitability solution, and Chromatographic system: Proceed as directed in the Assay. Standard solution: Transfer about 20 mg of USP Pantoprazole Sodium RS to a 50-mL volumetric flask. Dissolve in 510 mL of a mixture of acetonitrile and water (1:1), and dilute with Diluent to volume. Further dilute with Diluent quantitatively, and stepwise if necessary, to obtain a solution having a known concentration of about 0.0004 mg/mL. Sample solution: Transfer about 20 mg of Pantoprazole Sodium to a 50-mL volumetric flask. Dissolve in 5-10 mL of a mixture of acetonitrile and water (1:1), dilute with Diluent to volume, and mix. Chromatographic system: Prepare as directed in the Assay. System suitability Sample: System suitability solution Suitability requirements Resolution: NLT 10.0 between pantopazole related compound A and pantoprazole Analysis Samples: Standard solution and Sample solution Calculate the percentage of each impurity in the portion of Pantoprazole Sodium taken: Result = (rU/rS) (CS/CU) 100 = peak response of each impurity obtained from the Sample solution = peak response of pantoprazole obtained from rS the Standard solution = concentration of USP Pantoprazole Sodium RS CS in the Standard solution (mg/mL) = concentration of Pantoprazole Sodium in the CU Sample solution (mg/mL) Acceptance criteria: See Impurity Table 1 for individual impurities. The reporting level for impurities is 0.05%.
Impurity Table 1 Relative Retention Time 0.52 Acceptance Criteria NMT (%) 0.20

rU

Name Pantoprazole related compound Aa

a 5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfonyl]-1Hbenzimidazole. b 5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]thio]-1Hbenzimidazole.

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24

Pantoprazole / Official Monographs

Impurity Table 1 (continued)

USP 32
= peak response of each impurity from the Sample solution rS = peak response of pantoprazole sodium from the Standard solution CS = concentration of USP Pantoprazole Sodium RS in the Standard solution (mg/mL) CU = concentration of Pantoprazole Sodium in the Sample solution (mg/mL) F = relative response factor given in Impurity Table 2 Acceptance criteria: See Impurity Table 2 for individual impurities. The reporting level for impurities is 0.05%.
Impurity Table 2 Relative Retention Time 0.9 Relative Response Factor (F) 1.0 Acceptance Criteria, NMT (%) 0.20

rU

Pantoprazole sodium Pantoprazole related compound Bb Any other individual impurity Total impurities
a

1.0 1.7

0.15 0.10 0.5

5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfonyl]-1Hbenzimidazole. b 5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]thio]-1Hbenzimidazole.

Test 2 Diluent: Prepare a mixture of acetonitrile and 0.001 N sodium hydroxide solution (1:1). Solution A: Prepare a solution of dibasic potassium phosphate (1.74 g/L) adjusted with a solution of phosphoric acid (330 g/L) to a pH of 7.00 0.05. Soution B: Use acetonitrile. Mobile phase: See the gradient table below.
Time (min) 0 40 45 4555 Solution A (%) 80 20 80 80 Solution B (%) 20 80 20 20

Name Pantoprazole related compound A Pantoprazole related compound B Pantoprazole related compound Ca Pantoprazole related compound Dc and Fe Pantoprazole related compound Ef Any other individual impurity Total impurities
a b

1.5

1.0

0.15

0.6

3.3

0.10b

1.2

1.0

0.20d

System suitability solution: Dissolve suitable amounts of USP Pantoprazole Sodium RS, USP Pantoprazole Related Compound A RS, USP Pantoprazole Related Compound B RS, USP Pantoprazole Related Compound C RS, USP Pantoprazole Related Compound D and F Mixture RS, and USP Pantoprazole Related Compound E RS in Diluent to obtain a solution containing about 0.46 mg/mL of pantoprazole sodium and about 1.3 g/mL of each of the related compounds A, B, C, and E, and about 1.3 g/mL of the D and F mixture. Standard solution: 0.03 mg/mL of USP Pantoprazole Sodium RS in Diluent Sample solution: 0.46 mg/mL of Pantoprazole Sodium in Diluent Chromatographic system (See Chromatography 621, System Suitability.) Mode: LC Detector: UV 290 and 305 nm Column: 4.6-mm 12.5-cm; 5-m packing L1 Column temperature: 40 Flow rate: 1 mL/min Injection size: 20 L System suitability Samples: System suitability solution and Standard solution at 290 nm Suitability requirements Resolution: NLT 1.5 between pantoprazole related compound E and pantoprazole related compound D and F, System Suitability solution Tailing factor: NMT 2.0, Standard solution Relative standard deviation: NMT 5.0%, Standard solution Analysis [NOTEPantoprazole related compound C is monitored at 305 nm, and all other compounds are monitored at 290 nm.] Samples: Standard solution and Sample solution Calculate the percentage of each impurity in the portion of Pantoprazole Sodium taken: Result = (rU/rS) (CS/CU) (1/F) 100

1.3

1.0

0.10

0.10 0.5

5-(Difluoromethoxy)-1H-benzimidazole-2-thiol. At 305 nm. c 5-(Difluoromethoxy)-2-[(RS)-[(3,4-dimethoxypyridin-2yl)methyl]sulfinyl]-1-methyl-1H-benzimidazole. dImpurities D and F are not fully resolved and should be integrated together. e 6-(Difluoromethoxy)-2-[(RS)-[(3,4-dimethoxypyridin-2yl)methyl]sulfinyl]-1-methyl-1H-benzimidazole. f Mixture of the stereoisomers of 6,6-bis(difluoromethoxy)-2,2bis[[(3,4dimethoxypyridin-2-yl)methyl]sulfinyl]-1H,1H-5,5-bibenzimidazolyl.

SPECIFIC TESTS WATER DETERMINATION, Method I 921:

5.0%8.0%

ADDITIONAL REQUIREMENTS PACKAGING AND STORAGE: Preserve in well-closed, lightresistant containers. Store at room temperature. LABELING: If a test for Procedure, under Organic Impurities other than Test 1 is used, then the labeling states the test with which the article complies. USP REFERENCE STANDARDS 11 USP Pantoprazole Related Compound A RS USP Pantoprazole Related Compound B RS USP Pantoprazole Related Compound C RS USP Pantoprazole Related Compound D and F Mixture RS USP Pantoprazole Related Compound E RS USP Pantoprazole Sodium RS 3

Copyright 2008 The United States Pharmacopeial Convention. All Rights Reserved. For Discussion Purposes Only Not for Dissemination

USP 32
Add the following:
Pantoprazole

Official Monographs / Pantoprazole 25

Analysis Samples: Standard solution and Sample solution Calculate the percentage of C16H15F2N3O4S in the portion of Tablets taken: Result = (rU/rS) (CS/CU) (Mr1/Mr2) 100 = peak response from the Sample solution = peak response from the Standard solution = concentration of USP Pantoprazole Sodium RS in the Standard solution (mg/mL) = concentration of pantoprazole in the Sample CU solution (mg/mL) Mr1 = molecular weight of pantoprazole, 383.37 = molecular weight of pantoprazole sodium, Mr2 405.35 Acceptance criteria: 90.0%110.0% rU rS CS IMPURITIES Organic Impurities PROCEDURE Mobile phase, System suitability solution, Chromatographic system, and Sample solution: Prepare as directed in the Assay. Standard solution: 0.0004 mg/mL. Dilute the Standard solution, prepared as directed in the Assay, with 0.02 N sodium hydroxide. System suitability Samples: Standard solution and System suitability solution Suitability requirements [NOTEIdentify the components on the basis of their relative retention times in Impurity Table 1.]
Impurity Table 1 Name Pantoprazole Related compounds Da and Fb Pantoprazole related compound Ad Pantoprazole related compound Be Any other individual impurity Total impurities
a

Tablets

Sodium Delayed-Release

(Comment on this Monograph)id=m2632=Pantoprazole Sodium Delayed-Release Tablets=Pa-Pi-Monos.pdf) DEFINITION Pantoprazole Sodium Delayed-Release Tablets contain an amount of Pantoprazole Sodium equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of pantoprazole (C16H15F2N3O4S). IDENTIFICATION The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. ASSAY PROCEDURE Solution A: Dissolve 3.85 g of ammonium acetate and 1.1 g of tetrabutylammonium hydrogen sulfate in 1 L of water, and adjust with ammonium hydroxide solution diluted 1:1 with water to a pH of 7.9. Diluent: Mixture of acetonitrile and 0.02 N sodium hydroxide (1:1) Mobile phase: Prepare a mixture of acetonitrile and Solution A (35:65). Standard solution: Transfer a weighed quantity of USP Pantoprazole Sodium RS to a suitable volumetric flask, add 0.02 N sodium hydroxide to about 60% of the final volume, sonicate for 5 min to dissolve, add about 2% of acetonitrile, and dilute with 0.02 N sodium hydroxide to volume to obtain a solution having a known concentration of about 0.2 mg/mL of pantoprazole sodium. System suitability solution: Prepare a solution in 0.02 N sodium hydroxide, using sonication if necessary, containing about 0.2 mg/mL of pantoprazole sodium and about 0.0004 mg/mL each of pantoprazole related compound A and pantoprazole related compound B. Sample solution: Transfer 5 Tablets into a suitable volumetric flask. [NOTEUse 50-mL or 100-mL volumetric flasks for Tablets containing 20 or 40 mg of pantoprazole/Tablet, respectively.] Add Diluent to about 60% of the final volume, shake mechanically for about 60 min, and dilute with Diluent to volume. Pass through a suitable filter, and dilute the filtrate with 0.02 N sodium hydroxide to obtain a solution having a known concentration of about 0.2 mg/mL of pantoprazole, based on the label claim. Chromatographic system (See Chromatography 621, System Suitability.) Mode: LC Detector: UV 290 nm Column: 4.6-mm 25-cm; 5-m packing L1 Flow rate: 1 mL/min Injection size: 20 L System suitability Samples: Standard solution and System suitability solution Suitability requirements Resolution: NLT 3 between the pantoprazole and pantoprazole related compound A, System suitability solution Tailing factor: NMT 2.0, System suitability solution Relative standard deviation: NMT 2.0% for replicate injections, Standard solution

Relative Retention Time 1.0 1.2 1.3 2.7

Limit (%) 0.5c 0.5 0.3 0.2 1.0

5-(Difluoromethoxy)-2-[(RS)-[(3,4-dimethoxypyridin-2yl)methyl]sulfinyl]-1-methyl-1H-benzimidazole. b 6-(Difluoromethoxy)-2-[(RS)-[(3,4-dimethoxypyridin-2yl)methyl]sulfinyl]-1-methyl-1H-benzimidazole. c Impurities D and F are not fully resolved and should be integrated together. d 5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfonyl]-1Hbenzimidazole. e 5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]thio]-1Hbenzimidazole.

Resolution: NLT 3 between the pantoprazole and the pantoprazole related compound A peak, System suitability solution Tailing factor: NMT 2.0 for the pantoprazole peak, System suitability solution Relative standard deviation: NMT 10.0%, Standard solution

Copyright 2008 The United States Pharmacopeial Convention. All Rights Reserved. For Discussion Purposes Only Not for Dissemination

26

Pantoprazole / Official Monographs

Analysis Samples: Standard solution and Sample solution Record the chromatograms for at least three times the retention time of the pantoprazole peak. Calculate the percentage of each impurity in the portion of Pantoprazole Sodium taken: Result = (rU/rS) (CS/CU) (Mr1/Mr2) 100 = peak response for each impurity from the Sample solution = peak response from the Standard solution rS = concentration of USP Pantoprazole Sodium RS CS in the Standard solution (mg/mL) = concentration of pantoprazole in the Sample CU solution (mg/mL) = molecular weight of pantoprazole, 383.37 Mr1 = molecular weight of pantoprazole sodium, Mr2 405.35 Acceptance criteria: The limits are given in Impurity Table 1. The reporting level for impurities is 0.1%. rU rU rS CS

USP 32
= peak response from the Sample solution = peak response in the Working standard solution = concentration of pantoprazole sodium in the Working standard solution (mg/mL) = molecular weight of pantoprazole, 383.37 Mr1 = molecular weight of pantoprazole sodium, Mr2 405.35 V = volume of Medium (mL) L = Tablet label claim (mg) Tolerances: NMT 10% of the labled amount of amount of pantoprazole is dissolved Buffer stage Buffer stage medium: pH 6.8 phosphate buffer; 1000 mL Apparatus 2: 75 rpm Time: 30 min Analysis: After 30 min, withdraw an aliquot, pass through a suitable 0.45-m filter, and immediately dilute a portion of the filtrate by a factor of 2 with 0.5 N sodium hydroxide. Determine the amount of pantoprazole dissolved in the Buffer stage using the same procedure as for the Acid stage. Tolerances: NLT 75% (Q) of the labeled amount of amount of pantoprazole is dissolved. Test 2: [NOTEIf the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 2. Proceed as directed for Procedure for Method B under Apparatus 1 and Apparatus 2, Delayed-Release Dosage Forms.] Acid stage Acid stage medium: 0.1 N hydrochloric acid; 1000 mL Apparatus 2: 100 rpm Time: 2 h Standard stock solution: Transfer a quantity of USP Pantoprazole Sodium RS to a suitable volumetric flask. Dissolve first in 0.1 N sodium hydroxide, using 10% of the final volume, then dilute with pH 6.8 phosphate buffer to volume, to obtain a solution having a known concentration of about 0.46 mg of pantoprazole sodium/mL. Mix well until a clear solution is obtained. Calculate the concentration in mg of pantoprazole/mL, the molecular weights of pantoprazole and pantoprazole sodium being 383.37 and 405.35, respectively. Acid stage working standard solution: Dilute an appropriate volume of the Standard stock solution to 1 L with Acid stage medium in such a way to obtain a final concentration of about 10% of the Tablet label claim/L. Sample solution: Pass a portion of the solution under test through a suitable 10-m filter. Analysis: Determine the amount of pantoprazole dissolved by using UV absorption at the wavelength of maximum absorbance at about 305 nm on portions of the Sample solution in comparison to the Acid stage working standard solution using a 4-cm path length cell and Acid stage medium as blank. Drain the Acid stage medium from each vessel and replace with Buffer stage medium. Calculate the amount of pantoprazole dissolved by the formula: Restult = (AU/AS) CS V (100/L) = absorbance from the Sample solution = absorbance from the Standard solution = concentration of pantoprazole from the Acid stage working standard solution (mg/mL) V = volume, 1 L L = Tablet label claim of pantoprazole (mg) Tolerances: NMT 10% of the labeled amount of amount of pantoprazole is dissolved. Buffer stage Buffer stage medium: pH 6.8 phosphate buffer; 1000 mL AU AS CS

PERFORMANCE TESTS UNIFORMITY OF DOSAGE UNITS 905: Meet the requirements DISSOLUTION 711 Test 1: [NOTEProceed as directed for Procedure for Method B under Apparatus 1 and Apparatus 2, Delayed-Release Dosage Forms.] Acid stage Acid stage medium: 0.1 N hydrochloric acid; 1000 mL Apparatus 2: 75 rpm Time: 120 min After 120 min, withdraw an aliquot, pass through a suitable 0.45-m filter, and immediately dilute a portion of the filtrate by a factor of 2 with 0.5 N sodium hydroxide. Transfer the Tablets to the vessels containing the Buffer stage medium. Determine the amount of pantoprazole dissolved in the Acid stage using the following procedure. Diluent: Prepare a mixture of pH 6.8 phosphate buffer and 0.5 N sodium hydroxide (1:1). Mobile phase: Prepare a filtered and degassed mixture of acetonitrile, triethylamine, and water (40:1:60). Adjust with phosphoric acid to a pH of 7.0 0.05. Standard stock solution: Transfer about 20 mg of USP Pantoprazole Sodium RS to a 50-mL volumetric flask. Add about 30 mL of 0.02 N sodium hydroxide, and sonicate until dissolved. Add 2 mL of acetonitrile, and dilute with 0.02 N sodium hydroxide to volume. Working standard solution: Transfer 1.0 mL of the Standard stock solution to a 20-mL volumetric flask, and dilute with Diluent to volume. Sample solution: Solution under test Chromatographic system (See Chromatography 621, System Suitability.) Mode: LC Detector: UV 290 nm Column: 4.6-mm 7.5-cm; 3-m packing L1 Column temperature: 30 Flow rate: 1 mL/min Injection size: 10 L System suitability Sample: Working standard solution Suitability requirements Tailing factor: NMT 2.5 Relative standard deviation: NMT 2.0% Analysis Samples: Working standard solution and Sample solution Calculate the amount of pantoprazole released, as a percentage, in the Acid stage: Result = (rU/rS) CS (Mr1/Mr2) V (100/L)

Copyright 2008 The United States Pharmacopeial Convention. All Rights Reserved. For Discussion Purposes Only Not for Dissemination

USP 32
Apparatus 2: 100 rpm Time: 45 min Buffer stage working standard solution: Dilute an appropriate volume of the Standard stock solution as described under Acid stage to 250 mL with Buffer stage medium in such a way to obtain a final concentration of about 100% of the Tablet label claim/L. Sample solution: Pass a portion of the solution under test through a suitable 10-m filter. Analysis: Determine the amount of pantoprazole dissolved by using UV absorption at the wavelength of maximum absorbance at about 288 nm on portions of the Sample solution in comparison to Buffer stage working standard solution using a 0.5-cm path length cell and Buffer stage medium as blank. Calculate the amount of pantoprazole dissolved: Result = (AU/AS) CS V (100/L) = absorbance from the Sample solution = absorbance from the Buffer stage working standard solution = concentration of pantoprazole from the Buffer CS stage working standard solution (mg/mL) V = volume of the Buffer stage medium, 1 L L = Tablet label claim of pantoprazole (mg) Tolerances: NLT 75% (Q) of the labeled amount of pantoprazole is dissolved. Test 3: [NOTEIf the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 3. Proceed as directed for Procedure for Method B under Apparatus 1 and Apparatus 2, Delayed-Release Dosage Forms.] Acid stage Acid stage medium: 0.1 N hydrochloric acid; 1000 mL Apparatus 2: 100 rpm Time: 2 h Dilute ammonia solution: Transfer 40 mL of strong ammonia solution to a 100-mL volumetric flask, and dilute with water to volume. Buffer solution: Transfer 1.5 g of ammonium acetate to a 1000-mL volumetric flask. Dissolve in and dilute with water to volume. Adjust the pH to 7.0 0.1 with Dilute ammonia solution. Mobile phase: Methanol and Buffer solution (2:3) Standard solution: 0.4 mg/mL. Transfer a quantity of USP Pantoprazole Sodium RS to a suitable volumetric flask, add 10% of the final volume of methanol, sonicate, and dilute with Mobile phase to volume. Sample solution: After 2 h in the Acid stage medium, decant the medium from the vessel, remove the Tablet from the vessel, and dry it with tissue paper. Transfer the Tablet to a suitable volumetric flask, add 20% of the final volume of methanol, and sonicate for about 20 min. Dilute with Mobile phase to volume to obtain a final concentration of about 0.4 mg/mL of pantoprazole. Mix well, centrifuge, and use the supernatant. Chromatographic system (See Chromatography 621, System Suitability.) AU AS

Official Monographs / Pantoprazole 27

Mode: LC Detector: UV 290 nm Column: 4.6-mm 25-cm; 5-m packing L1. Temperature Column: Ambient Autosampler: 4 Flow rate: 1.5 mL/min Injection size: 10 L System suitability Sample: Standard solution Suitability requirements Column efficiency: NLT 7500 theoretical plates Tailing factor: NMT 2.0 Relative standard deviation: NMT 2.0% Analysis Samples: Standard solution and Sample solution Calculate the amount of pantozalole released, as a percentage, in the Acid stage: Result = A [(rU/rS) CS DU (Mr1/Mr2) V (100/L) = percentage of pantoprazole as determined in the Assay = peak response from the Sample solution rU = peak response from the Standard solution rS = concentration of pantoprazole sodium in the CS Standard solution (mg/mL) = dilution factor of the Sample solution DU Mr1 = molecular weight of pantoprazole, 383.37 = molecular weight of pantoprazole sodium, Mr2 405.35 V = volume of Acid stage medium, 1000 mL L = Tablet label claim (mg) Tolerances: NMT 10% of the labeled amount of amount of pantoprazole is dissolved. Buffer stage Buffer stage medium: pH 6.8 phosphate buffer; 1000 mL Apparatus 2: 100 rpm Time: 45 min Standard solution: Further dilute an appropriate volume of the Standard solution prepared in the Acid stage with Buffer stage medium to obtain a solution having a known concentration of about 0.04 mg/mL. Sample solution: Transfer a separate Tablet to the vessel containing Acid stage medium, and proceed as directed for the Acid stage. After 2 h, decant the Acid stage medium, add the Buffer stage medium, and operate the apparatus at the specified conditions. After 45 min, withdraw 10 mL of the solution under test and pass through a suitable 0.45m filter Analysis: Determine the amount of pantoprazole released to the Buffer stage medium using the same chromatographic procedure as directed for the Acid stage with the exception of injecting about 50 L of the Standard solution and Sample solution. A

Copyright 2008 The United States Pharmacopeial Convention. All Rights Reserved. For Discussion Purposes Only Not for Dissemination

28

Pantoprazole / Official Monographs

Calculate the amount of pantoprazole dissolved: Result = (rU/rS) CS (Mr1/Mr2) V (100/L) = peak response from the Sample solution = peak response from the Standard solution = concentration of sodium pantoprazole from the Standard solution (mg/mL) = molecular weight of pantoprazole, 383.37 Mr1 = molecular weight of pantoprazole sodium, Mr2 405.35 V = volume of Medium, 1000 mL L = Tablet label claim of pantoprazole (mg) Tolerances: NLT 75% (Q) of the labeled amount of amount of pantoprazole is dissolved. rU rS CS

USP 32
Trichloroacetic acid solution: 300 mg/mL reagent grade trichloroacetic acid. [NOTEThis solution may be stored at room temperature.] Standard solution: 40 g/mL USP Papain RS in Buffer solution made from 1 mg/mL USP Papain RS in Buffer solution. [NOTEUse within 30 min after preparation.] Sample solution: 40 g/mL Papain in Buffer solution made from 1 mg/mL Papain in Buffer solution. [NOTEUse within 30 min after preparation.] Analysis: Into each of 12 test tubes (18- 150-mm) pipet 5.0 mL of Casein substrate. Place in a water bath at 40, and allow 10 min to reach bath temperature. Into each of two of the tubes (the tests are run in duplicate except for the blanks) labeled S1, pipet 1.0 mL of the Standard solution and 1.0 mL of the Buffer solution, mix by swirling, note zero time, insert the stopper, and replace in the bath. Into each of 2 tubes, labeled S2, pipet 1.5 mL of Standard solution and 0.5 mL of Buffer solution, and proceed as before. Repeat this procedure for 2 more tubes, labeled S3, to which 2.0 mL of Standard solution is added, and for 2 tubes, labeled U2, to which 1.5 mL of Sample solution and 0.5 mL of Buffer solution are added. After 60 min, accurately timed, add to all 12 tubes 3.0 mL of Trichloroacetic acid solution, and shake vigorously. With the 4 tubes to which no Standard solution or Sample solution was added, prepare blanks by pipeting, respectively, 1.0 mL of Standard solution and 1.0 mL of Buffer solution; 1.5 mL of Standard solution and 0.5 mL of Buffer solution; 2.0 mL of Standard solution; and 1.5 mL of Sample solution and 0.5 mL of Buffer solution. Replace all tubes in the 40 water bath for 3040 min to allow the precipitated protein to coagulate fully. Filter through medium-porosity filter paper, discarding the first 3 mL of the filtrate (filtrates used are clear). Read the absorbances, at 280 nm, of the filtrates of all solutions against their respective blanks. Plot the absorbance readings for S1, S2, and S3 against the enzyme concentration of each corresponding level. By interpolation from this curve, taking into consideration dilution factors, calculate the potency in Units in the weight of Papain taken: Result = A C (F/3) = activity of the USP Reference Standard in Units/mg C = concentration obtained from the standard curve (mg/mL) F = factor derived from 100 (50/2) (10/1.5), 50,000 Acceptance criteria: NLT 6000 Units/mg of Papain SPECIFIC TESTS PH 791: 4.86.2, in a solution (1 in 50) LOSS ON DRYING 731: Dry a sample in a vacuum oven at 60 for 4 h: it loses NMT 7.0% of its weight. ADDITIONAL REQUIREMENTS PACKAGING AND STORAGE: Preserve in tight, light-resistant containers, in a cool place. USP REFERENCE STANDARDS 11 USP Papain RS A

ADDITIONAL REQUIREMENTS PACKAGING AND STORAGE: Preserve in well-closed containers. Store at controlled room temperature. LABELING: Label Tablets to indicate that they must not be split, chewed, or crushed before administration. When more than one Dissolution test is given, the labeling states the test used only if Test 1 is not used. USP REFERENCE STANDARDS 11 USP Pantoprazole Related Compound A RS USP Pantoprazole Related Compound B RS USP Pantoprazole Sodium RS3

Papain
(Comment on this Monograph)id=m60570=Papain=Pa-PiMonos.pdf) Papain [9001-73-4]. DEFINITION Papain is a purified proteolytic substance derived from Carica papaya Linn e (Fam. Caricaceae). Papain, when assayed as directed herein, contains NLT 6000 Units/mg. Papain of a higher digestive power may be reduced to the official standard by admixture with papain of lower activity, lactose, or other suitable diluents. One USP Unit of Papain activity is the activity that releases the equivalent of 1 g of tyrosine from a specified casein substrate under the conditions of the Assay, using the enzyme concentration that liberates 40 g of tyrosine/mL of Sample solution. ASSAY CASEIN DIGESTIVE POWER Dibasic sodium phosphate, 0.05 M: 7.1 mg/mL anhydrous dibasic sodium phosphate. Add 1 drop of toluene as a preservative. Citric acid, 0.05 M: 10.5 mg/mL citric acid monohydrate. Add 1 drop of toluene as a preservative. Casein substrate: 20 mg/mL Hammersten-type casein in Dibasic sodium phosphate, 0.05 M. Place in a boiling water bath for 30 min with occasional stirring. Cool to room temperature, and add Citric acid, 0.05 M to adjust to pH 6.0 0.1. Stir the solution rapidly and continuously during the addition of the Citric acid, 0.05 M to prevent precipitation of the casein. Dilute with water to 100 mL. [NOTEPrepare fresh daily.] Buffer solution (phosphatecysteine disodium ethylenediaminetetraacetate buffer): Dissolve 3.55 g of anhydrous dibasic sodium phosphate in 400 mL water in a 500-mL volumetric flask. Add 7.0 g of disodium edetate and 3.05 g of cysteine hydrochloride monohydrate. Adjust with 1 N hydrochloric acid or 1 N sodium hydroxide to pH 6.0 0.1, dilute with water to volume, and mix. [NOTEPrepare fresh daily.]

Papain Tablets for Topical Solution

(Comment on this Monograph)id=m60600=Papain Tablets for Topical Solution=Pa-Pi-Monos.pdf) DEFINITION Papain Tablets for Topical Solution contain NLT 100.0% of the labeled potency.

Copyright 2008 The United States Pharmacopeial Convention. All Rights Reserved. For Discussion Purposes Only Not for Dissemination