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  • 22 Panthenol / Official Monographs

USP 32

Panthenol

mL of 0.01 N sulfuric acid is equivalent to 750 µg of

  • id=m60440=Panthenol=Pa-Pi- Acceptance criteria:

aminopropanol.

NMT 0.10%

C 9 H 19 NO 4

22 Panthenol / Official Monographs USP 32 mL of 0.01 N sulfuric acid is equivalent to(Comment on this Monograph) Monos.pdf) Acceptance criteria: aminopropanol. NMT 0.10% C H NO 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]. SPECIFIC TESTS • M ELTING R ANGE OR T EMPERATURE , Class I 〈 741 〉 : 64.5 ° –68.5 ° • O PTICAL R OTATION , Specific Rotation 〈 781S 〉 : +0.05 ° − 0.05 ° to Sample solution: 50 mg/mL, in water • L OSS ON D RYING 〈 731 〉 : Dry a sample in a vacuum over phosphorus pentoxide at 56 ° for 4 h: it loses NMT 0.5% of its weight. • P ACKAGING AND S TORAGE : Preserve in tight containers. • USP R EFERENCE S TANDARDS 〈 11 〉 USP Racemic Panthenol RS DEFINITION Panthenol is a racemic mixture of the dextrorotatory and levorotatory isomers of panthenol. It contains NLT 99.0% and NMT 102.0% of C H NO , calculated on the dried basis. IDENTIFICATION • A . I NFRARED A BSORPTION 〈 197M 〉 • B . P ROCEDURE 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. P ROCEDURE 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 • P ROCEDURE 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 300- mL flask fitted to a reflux condenser by means of a standard- taper 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 C H NO . Acceptance criteria: 99.0%–102.0% IMPURITIES Inorganic Impurities • R ESIDUE ON I GNITION 〈 281 〉 : Organic Impurities NMT 0.1% L IMIT OF A MINOPROPANOL 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) C H F N NaO S · 1.5H O 432.37 1 H -Benzimidazole, 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2- pyridyl)methyl]sulfinyl]-, sodium salt, hydrate (2:3); 5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2- pyridyl)methyl]sulfinyl]benzimidazole, sodium salt, sesquihydrate [164579-32-2]. DEFINITION Pantoprazole Sodium contains NLT 98.0% and NMT 102.0% of C H F N NaO S, calculated on the anhydrous basis. IDENTIFICATION I NFRARED A BSORPTION 〈 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 . I DENTIFICATION T ESTS —G ENERAL , Sodium 〈 191 〉 : Meets the requirements of the pyroantimonate precipitate test. ASSAY [ N OTE — Protect all solutions from light, and use amber autosampler vials and low-actinic glassware.] • P ROCEDURE 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. Acetonitrile–methanol 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 Acetonitrile–methanol mixture (85:15). Copyright  2008 The United States Pharmacopeial Convention. All Rights Reserved. For Discussion Purposes Only — Not for Dissemination " id="pdf-obj-0-33" src="pdf-obj-0-33.jpg">

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].

SPECIFIC TESTS

MELTING RANGE OR TEMPERATURE, Class I 741:

64.5°–68.5°

OPTICAL ROTATION, Specific Rotation 781S:

+0.05°

0.05° to

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

DEFINITION Panthenol is a racemic mixture of the dextrorotatory and levorotatory isomers of panthenol. It contains NLT 99.0% and NMT 102.0% of C 9 H 19 NO 4 , calculated on the dried basis.

IDENTIFICATION

A. INFRARED ABSORPTION 197MB. 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 300-

mL flask fitted to a reflux condenser by means of a standard- taper 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 C 9 H 19 NO 4 .

Acceptance criteria:

99.0%–102.0%

IMPURITIES Inorganic Impurities

RESIDUE ON IGNITION 281:

Organic Impurities

NMT 0.1%

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:
Add the following:

Pantoprazole Sodium

 
• Pantoprazole Sodium <a href=(Comment on this Monograph) id=m2631=Pantoprazole Sodium=Pa-Pi-Monos.pdf) C H F N NaO S · 1.5H O 432.37 1 H -Benzimidazole, 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2- pyridyl)methyl]sulfinyl]-, sodium salt, hydrate (2:3); 5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2- pyridyl)methyl]sulfinyl]benzimidazole, sodium salt, sesquihydrate [164579-32-2]. DEFINITION Pantoprazole Sodium contains NLT 98.0% and NMT 102.0% of C H F N NaO S, calculated on the anhydrous basis. IDENTIFICATION I NFRARED A BSORPTION 〈 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 . I DENTIFICATION T ESTS —G ENERAL , Sodium 〈 191 〉 : Meets the requirements of the pyroantimonate precipitate test. ASSAY [ N OTE — Protect all solutions from light, and use amber autosampler vials and low-actinic glassware.] • P ROCEDURE 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. Acetonitrile–methanol 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 Acetonitrile–methanol mixture (85:15). " id="pdf-obj-0-296" src="pdf-obj-0-296.jpg">

C 16 H 14 F 2 N 3 NaO 4 S · 1.5H 2 O

432.37

1H-Benzimidazole, 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-

pyridyl)methyl]sulfinyl]-, sodium salt, hydrate (2:3);

5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-

pyridyl)methyl]sulfinyl]benzimidazole, sodium salt,

sesquihydrate [164579-32-2].

DEFINITION Pantoprazole Sodium contains NLT 98.0% and NMT 102.0% of C 16 H 14 F 2 N 3 NaO 4 S, 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 TESTS—GENERAL, 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.

Acetonitrile–methanol 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 Acetonitrile–methanol mixture (85:15).

Copyright 2008 The United States Pharmacopeial Convention.

All Rights Reserved.

For Discussion Purposes Only — Not for Dissemination

USP 32

Official Monographs / Pantoprazole

23

Solution B:

Use the Acetonitrile–methanol mixture.

Mobile phase:

   

NLT 98.0%–102.0%

See the gradient table below.

Acceptance criteria:

IMPURITIES

 

Time

Solution A

Solution B

(min)

(%)

(%)

Inorganic Impurities HEAVY METALS, Method II 231:

NMT 20 ppm

 
     

Organic Impurities

0

  • 86 14

PROCEDURE

10

 
  • 86 14

[NOTEOn the basis of the synthetic route, perform either

35

  • 42 58

 

Test 1 or Test 2. Test 2 is recommended when impurities C,

     

D, E, and F are potential related compounds.]

36

  • 86 14

Test 1

46

 
  • 86 14

[NOTEProtect all solutions from light, and use amber

System suitability solution:

Dissolve suitable amounts of

autosampler vials and low-actinic glassware. ] Diluent, Mobile phase, System suitability solution, and

USP Pantoprazole Sodium RS, USP Pantoprazole Related Compound A RS, and USP Pantoprazole Related Compound

Chromatographic system:

Assay.

Proceed as directed in the

 

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 to a 50-mL volumetric flask.

Dissolve in 5–10 mL of a mixture of acetonitrile and water (1:1), and dilute with Diluent to volume. Further dilute with

Standard solution:

Transfer about 20 mg of USP

Diluent quantitatively, and stepwise if necessary, to obtain a

Pantoprazole Sodium RS weighed, to a 50-mL volumetric

flask. Dissolve in 5–10 mL of a mixture of acetonitrile and

solution having a known concentration of about 0.0004 mg/mL.

water (1:1), and dilute with Diluent to volume. Further dilute

Sample solution:

Transfer about 20 mg of Pantoprazole

with Diluent quantitatively, and stepwise if necessary, to

Sodium to a 50-mL volumetric flask. Dissolve in 5-10 mL of

obtain a solution having a known concentration of about 0.06 mg/mL.

a mixture of acetonitrile and water (1:1), dilute with Diluent to volume, and mix.

Sample solution:

Transfer about 20 mg of Pantoprazole

Sodium to a 50-mL volumetric flask. Dissolve in 5–10 mL of

Chromatographic system:

Assay.

Prepare as directed in the

 

a mixture of acetonitrile and water (1:1), and dilute with

Chromatographic system

(See Chromatography 621, System Suitablility.)

System suitability

Diluent to volume. Further dilute with Diluent quantitatively,

Sample:

System suitability solution

 

and stepwise if necessary, to obtain a solution having a

Suitability requirements

known concentration of about 0.06 mg/mL.

Resolution:

NLT 10.0 between pantopazole related

compound A and pantoprazole

Analysis

 

Mode: LC

Samples:

Standard solution and Sample solution

Detector:

UV 285 nm

 

Calculate the percentage of each impurity in the portion

Column:

3.9-mm × 15-cm; 4-µm packing L1

of Pantoprazole Sodium taken:

Temperature

Column: 30°

 

Result = (r U /r S ) × (C S /C U ) × 100

 

Autosampler: 4°

 

Flow rate:

1 mL/min

 

r U

= peak response of each impurity obtained from

r S

C S

C U

Acceptance criteria:

See Impurity Table 1 for individual

Injection size:

20 µL

the Sample solution

System suitability

= peak response of pantoprazole obtained from

Samples:

System suitability solution and Standard solution

the Standard solution

[NOTEIdentify the components based on their relative

= concentration of USP Pantoprazole Sodium RS

retention times (see Impurity Table 1).] Suitability requirements

Resolution:

NLT 10.0 between pantoprazole related

compound A and pantoprazole, System suitability solution

in the Standard solution (mg/mL) = concentration of Pantoprazole Sodium in the Sample solution (mg/mL)

Relative standard deviation:

NMT 2.0%, Standard

impurities. The reporting level for impurities is 0.05%.

 

solution

 

Analysis

 

Impurity Table 1

Samples:

Standard solution and Sample solution

 

Relative

 

Calculate the percentage of C 16 H 14 F 2 N 3 NaO 4 S in the

portion of Pantoprazole Sodium taken:

Name

Retention

Time

Acceptance

Criteria

NMT (%)

 

Result = (r U /r S ) × (C S /C U ) × 100

Pantoprazole related compound A a

0.52

0.20

r U

r S

C S

C U

= peak response from the Sample solution

 

= peak response from the Standard solution

a 5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfonyl]-1H-

= concentration of USP Pantoprazole Sodium RS in

benzimidazole.

the Standard solution (mg/mL) = concentration of Pantoprazole Sodium in the Sample solution (mg/mL)

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

Copyright 2008 The United States Pharmacopeial Convention.

All Rights Reserved.

For Discussion Purposes Only — Not for Dissemination

  • 24 Pantoprazole / Official Monographs

USP 32

Impurity Table 1 (continued)

r U

= peak response of each impurity from the Sample solution

r S

= peak response of pantoprazole sodium from the

C S

Standard solution = concentration of USP Pantoprazole Sodium RS

C U

in the Standard solution (mg/mL) = 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

Relative

Acceptance

Retention

Response

Criteria,

Name

Time

Factor (F)

NMT (%)

 
  • 0.9 1.0

 

0.20

   
  • 1.5 1.0

0.15

 
  • 0.6 3.3

 

0.10

b

   
  • 1.2 1.0

0.20

d

   
  • 1.3 1.0

0.10

 

0.10

Total

0.5

a 5-(Difluoromethoxy)-1H-benzimidazole-2-thiol. b At 305 nm. c 5-(Difluoromethoxy)-2-[(RS)-[(3,4-dimethoxypyridin-2-

 

yl)methyl]sulfinyl]-1-methyl-1H-benzimidazole.

d Impurities D and F are not fully resolved and should be integrated together. e 6-(Difluoromethoxy)-2-[(RS)-[(3,4-dimethoxypyridin-2-

 

yl)methyl]sulfinyl]-1-methyl-1H-benzimidazole.

 

f Mixture of the stereoisomers of 6,6-bis(difluoromethoxy)-2,2bis[[(3,4-

dimethoxypyridin-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, light-

 

resistant 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

Pantoprazole sodium

1.0

 

Pantoprazole related compound B b

1.7

0.15

Any other individual impurity

0.10

Total impurities

0.5

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

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

Pantoprazole

phosphoric acid (330 g/L) to a pH of 7.00 ± 0.05.

related

Soution B:

Use acetonitrile.

 

compound A

Pantoprazole

Mobile phase:

See the gradient table below.

 

related

Time

Solution A

Solution B

compound B

(min)

(%)

(%)

Pantoprazole

     

0

 
  • 80 related

20

 

40

 
  • 20 compound C a

80

45

 

20

  • 80 Pantoprazole

  • 80 compound D c

45–55

 

20

related

System suitability solution:

Dissolve suitable amounts of

and F e

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

Pantoprazole related compound E f

Any other

USP Pantoprazole Related Compound E RS in Diluent to

individual

obtain a solution containing about 0.46 mg/mL of

impurity

pantoprazole sodium and about 1.3 µg/mL of each of the related compounds A, B, C, and E, and about 1.3 µg/mL of the D and F mixture.

impurities

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-µm packing L1

Column temperature:

40°

 

Flow rate:

1 mL/min

Injection size:

20 µL

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 = (r U /r S ) × (C S /C U ) × (1/F) × 100

Copyright 2008 The United States Pharmacopeial Convention.

All Rights Reserved.

For Discussion Purposes Only — Not for Dissemination

USP 32

 

Official Monographs / Pantoprazole

 

25

   

Analysis

 
 

Samples:

Standard solution and Sample solution

Calculate the percentage of C 16 H 15 F 2 N 3 O 4 S in the portion of

Pantoprazole Sodium Delayed-Release Tablets

 

Tablets taken:

Result = (r U /r S ) × (C S /C U ) × (M r1 /M r2 ) × 100

r U

r S

C S

C U

M r1

M r2

= peak response from the Sample solution

= peak response from the Standard solution

DEFINITION

= concentration of USP Pantoprazole Sodium RS in

Pantoprazole Sodium Delayed-Release Tablets contain an amount of Pantoprazole Sodium equivalent to NLT 90.0% and

the Standard solution (mg/mL) = concentration of pantoprazole in the Sample

NMT 110.0% of the labeled amount of pantoprazole (C 16 H 15 F 2 N 3 O 4 S).

solution (mg/mL) = molecular weight of pantoprazole, 383.37

= molecular weight of pantoprazole sodium,

IDENTIFICATION The retention time of the major peak of the Sample solution

ASSAY

PROCEDURE

405.35

corresponds to that of the Standard solution, as obtained in the Assay.

Acceptance criteria:

IMPURITIES Organic Impurities

PROCEDURE

90.0%–110.0%

 

Solution A:

Dissolve 3.85 g of ammonium acetate and 1.1

Mobile phase, System suitability solution,

Prepare as directed in the Assay.

 

g of tetrabutylammonium hydrogen sulfate in 1 L of water, and adjust with ammonium hydroxide solution diluted 1:1

Diluent:

Mixture of acetonitrile and 0.02 N sodium

hydroxide (1:1)

Mobile phase:

Prepare a mixture of acetonitrile and

Solution A (35:65).

Chromatographic system, and Sample solution:

with water to a pH of 7.9.

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

Standard solution:

Transfer a weighed quantity of USP

Suitability requirements

 

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,

[NOTEIdentify the components on the basis of their relative retention times in Impurity Table 1.]

and dilute with 0.02 N sodium hydroxide to volume to

  • 0.2 mg/mL of pantoprazole sodium.

System suitability solution:

Prepare a solution in 0.02 N

 

obtain a solution having a known concentration of about

Name

Relative

Retention

Limit

(%)

 

sodium hydroxide, using sonication if necessary, containing about 0.2 mg/mL of pantoprazole sodium and about 0.0004

1.0

mg/mL each of pantoprazole related compound A and

1.2

0.5

c

pantoprazole related compound B.

Pantoprazole related compound

1.3

0.5

Sample solution:

Transfer 5 Tablets into a suitable

A d

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%

Pantoprazole related compound B e

2.7

0.3

of the final volume, shake mechanically for about 60 min,

0.2

and dilute with Diluent to volume. Pass through a suitable

1.0

filter, and dilute the filtrate with 0.02 N sodium hydroxide to obtain a solution having a known concentration of about

a 5-(Difluoromethoxy)-2-[(RS)-[(3,4-dimethoxypyridin-2-

 
  • 0.2 mg/mL of pantoprazole, based on the label claim.

Chromatographic system (See Chromatography 621, System Suitability.) Mode: LC

yl)methyl]sulfinyl]-1-methyl-1H-benzimidazole.

b 6-(Difluoromethoxy)-2-[(RS)-[(3,4-dimethoxypyridin-2-

yl)methyl]sulfinyl]-1-methyl-1H-benzimidazole.

  • c Impurities D and F are not fully resolved and should be integrated

 

Detector:

UV 290 nm

together.

Column:

4.6-mm × 25-cm; 5-µm packing L1

  • d 5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfonyl]-1H-

 

Flow rate:

1 mL/min

benzimidazole.

 

Injection size:

20 µL

e 5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]thio]-1H-

System suitability

benzimidazole.

Samples:

Standard solution and System suitability solution

Resolution:

NLT 3 between the pantoprazole and the

 

Suitability requirements

Resolution:

NLT 3 between the pantoprazole and

pantoprazole related compound A peak, System suitability solution

pantoprazole related compound A, System suitability

solution

Tailing factor:

NMT 2.0 for the pantoprazole peak,

System suitability solution

 

Tailing factor:

NMT 2.0, System suitability solution

Relative standard deviation:

NMT 10.0%, Standard

Relative standard deviation:

NMT 2.0% for replicate

solution

injections, Standard solution

Copyright 2008 The United States Pharmacopeial Convention.

All Rights Reserved.

For Discussion Purposes Only — Not for Dissemination

  • 26 Pantoprazole / Official Monographs

USP 32

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 = (r U /r S ) × (C S /C U ) × (M r1 /M r2 ) × 100

r U

r S

C S

C U

M r1

M r2

= peak response for each impurity 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 solution (mg/mL) = molecular weight of pantoprazole, 383.37 = molecular weight of pantoprazole sodium,

405.35

Acceptance criteria:

The limits are given in Impurity Table

1. The reporting level for impurities is 0.1%.

PERFORMANCE TESTS

UNIFORMITY OF DOSAGE UNITS 905:

DISSOLUTION 711

Meet the requirements

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

120 min

Time:

After 120 min, withdraw an aliquot, pass through a suitable 0.45-µm 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.

Prepare a mixture of pH 6.8 phosphate buffer

Diluent:

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.

Solution under test

Sample solution:

Chromatographic system

 

(See Chromatography 621, System Suitability.) Mode: LC

Detector:

UV 290 nm

Column:

4.6-mm × 7.5-cm; 3-µm packing L1

Column temperature:

30°

 

Flow rate:

1 mL/min

Injection size:

10 µL

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 = (r U /r S ) × C S × (M r1 /M r2 ) × V × (100/L)

r U

r S

C S

M r1

M r2

= 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 = molecular weight of pantoprazole sodium,

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-µm 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.

 

NLT 75% (Q) of the labeled amount of

Tolerances:

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

0.1 N hydrochloric acid; 1000 mL

Acid stage medium:

 

Apparatus 2:

100 rpm

Time:

2 h

Transfer a quantity of USP

Standard stock solution:

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.

Pass a portion of the solution under

Sample solution:

test through a suitable 10-µm 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 = (A U /A S ) × C S × V × (100/L)

A U

= absorbance from the Sample solution

A S

= absorbance from the Standard solution

C S

= concentration of pantoprazole from the Acid stage working standard solution (mg/mL)

V

= volume, 1 L

L

= Tablet label claim of pantoprazole (mg)

NMT 10% of the labeled amount of amount

Tolerances:

of pantoprazole is dissolved.

pH 6.8 phosphate buffer; 1000

Buffer stage Buffer stage medium:

mL

Copyright 2008 The United States Pharmacopeial Convention.

All Rights Reserved.

For Discussion Purposes Only — Not for Dissemination

USP 32

Official Monographs / Pantoprazole

27

 

Apparatus 2:

100 rpm

 

Mode:

LC

Time:

45 min

Detector:

UV 290 nm

Buffer stage working standard solution:

Dilute an

Column:

4.6-mm × 25-cm; 5-µm packing L1.

appropriate volume of the Standard stock solution as

Temperature

described under Acid stage to 250 mL with Buffer stage

Column: Ambient

 

medium in such a way to obtain a final concentration of

Autosampler: 4°

about 100% of the Tablet label claim/L.

Flow rate:

1.5 mL/min

Sample solution:

Pass a portion of the solution under

Injection size:

10 µL

test through a suitable 10-µm filter.

 

System suitability

 

Analysis:

Determine the amount of pantoprazole

Sample:

Standard solution

dissolved by using UV absorption at the wavelength of

Suitability requirements

 

maximum absorbance at about 288 nm on portions of

Column efficiency:

NLT 7500 theoretical plates

the Sample solution in comparison to Buffer stage working

 

Tailing factor:

NMT 2.0

standard solution using a 0.5-cm path length cell and

Relative standard deviation:

NMT 2.0%

 

Buffer stage medium as blank.

Analysis

Calculate the amount of pantoprazole dissolved:

Samples:

Standard solution and Sample solution

 

Result = (A U /A S ) × C S × V × (100/L)

Calculate the amount of pantozalole released, as a percentage, in the Acid stage:

 

A U

= absorbance from the Sample solution

Result = A [(r U /r S ) × C S × D U × (M r1 /M r2 ) × V × (100/L)

A S

= absorbance from the Buffer stage working

standard solution

A

= percentage of pantoprazole as determined in

C S

= concentration of pantoprazole from the Buffer

the Assay

stage working standard solution (mg/mL)

r U

= peak response from the Sample solution

  • V = volume of the Buffer stage medium, 1 L

r S

= peak response from the Standard solution

  • L = Tablet label claim of pantoprazole (mg)

C S

= concentration of pantoprazole sodium in the

 

Tolerances:

NLT 75% (Q) of the labeled amount of

Standard solution (mg/mL)

pantoprazole is dissolved.

 

D U

= dilution factor of the Sample solution

Test 3:

[NOTEIf the product complies with this test, the

M r1

= molecular weight of pantoprazole, 383.37

labeling indicates that the product meets USP Dissolution

M r2

= molecular weight of pantoprazole sodium,

Test 3. Proceed as directed for Procedure for Method B under

405.35

Apparatus 1 and Apparatus 2, Delayed-Release Dosage Forms.]

V

= volume of Acid stage medium, 1000 mL

Acid stage

L

= Tablet label claim (mg)

Acid stage medium:

0.1 N hydrochloric acid; 1000 mL

Tolerances:

NMT 10% of the labeled amount of amount

 

Apparatus 2:

100 rpm

of pantoprazole is dissolved.

 

Time:

2 h

Buffer stage

Dilute ammonia solution:

Transfer 40 mL of strong

Buffer stage medium:

pH 6.8 phosphate buffer; 1000

 

ammonia solution to a 100-mL volumetric flask, and dilute

mL

with water to volume.

 

Apparatus 2:

100 rpm

Buffer solution:

Transfer 1.5 g of ammonium acetate to a

Time:

45 min

1000-mL volumetric flask. Dissolve in and dilute with

Standard solution:

Further dilute an appropriate volume

water to volume. Adjust the pH to 7.0 ± 0.1 with Dilute ammonia solution.

of the Standard solution prepared in the Acid stage with Buffer stage medium to obtain a solution having a known

 

Mobile phase:

Methanol and Buffer solution (2:3)

concentration of about 0.04 mg/mL.

Standard solution:

0.4 mg/mL. Transfer a quantity of

 

Sample solution:

Transfer a separate Tablet to the vessel

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.

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

Sample solution:

After 2 h in the Acid stage medium,

the specified conditions. After 45 min, withdraw 10 mL of

decant the medium from the vessel, remove the Tablet

from the vessel, and dry it with tissue paper. Transfer the

the solution under test and pass through a suitable 0.45- µm filter

Tablet to a suitable volumetric flask, add 20% of the final

Analysis:

Determine the amount of pantoprazole released

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.

to the Buffer stage medium using the same chromatographic procedure as directed for the Acid stage with the exception of injecting about 50 µL of the Standard solution and Sample solution.

Chromatographic system (See Chromatography 621, System Suitability.)

 

Copyright 2008 The United States Pharmacopeial Convention.

All Rights Reserved.

For Discussion Purposes Only — Not for Dissemination

  • 28 Pantoprazole / Official Monographs

USP 32

   

Trichloroacetic acid solution:

300 mg/mL reagent grade

trichloroacetic acid. [NOTEThis solution may be stored at room temperature.]

Standard solution:

40 µg/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 µg/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 S 1 , 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 S 2 , 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 S 3 , to which 2.0 mL of Standard solution is added, and for 2 tubes, labeled U 2 , 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

Papain

tubes in the 40° water bath for 30–40 min to allow the

Result = A × C × (F/3)

 

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

Papain [9001-73-4].

280 nm, of the filtrates of all solutions against their

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

 

respective blanks. Plot the absorbance readings for S 1 , S 2 , and S 3 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:

equivalent of 1 µg of tyrosine from a specified casein substrate under the conditions of the Assay, using the enzyme

A

= activity of the USP Reference Standard in Units/mg

concentration that liberates 40 µg of tyrosine/mL of Sample solution.

C

= concentration obtained from the standard curve (mg/mL)

 

F

= factor derived from 100 × (50/2) × (10/1.5),

ASSAY

50,000

CASEIN DIGESTIVE POWER

Acceptance criteria:

NLT 6000 Units/mg of Papain

Dibasic sodium phosphate, 0.05 M:

7.1 mg/mL

anhydrous

 

dibasic sodium phosphate. Add 1 drop of toluene as a preservative.

 

SPECIFIC TESTS

PH 791:

4.8–6.2, in a solution (1 in 50)

Citric acid, 0.05 M:

10.5 mg/mL citric acid monohydrate.

Add 1 drop of toluene as a preservative.

LOSS ON DRYING 731:

Dry a sample in a vacuum oven at

60° for 4 h: it loses NMT 7.0% of its weight.

Casein substrate:

20 mg/mL Hammersten-type casein in

ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE:

Preserve in tight, light-resistant

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

± 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.]

containers, in a cool place.

  • 6.0 USP REFERENCE STANDARDS 11

USP Papain RS

Buffer solution (phosphate–cysteine 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

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