USP Pending Monograph

Draft 1For Public Comment

Rabeprazole / 1

BRIEFING
Rabeprazole Sodium. A new USP Pending Monograph
based on validated methods of analysis is being proposed.
The HPLC procedures in the Assay and the test for Organic
Impurities are based on analyses performed with the Inertsil
ODS 3V brand of L1 column. The typical retention time for
rabeprazole in the Assay and the test for Organic Impurities is
about 11 min.
Description and Solubility: White to slightly yellowish-white
solid. Very soluble in water and in methanol.
(SM3: E. Gonikberg.) Correspondence NumberC89188

Add the following:

Standard solution: 0.5 mg/mL of USP Rabeprazole Sodium RS in Diluent

Sample solution: 0.5 mg/mL of Rabeprazole Sodium in
Diluent
Chromatographic system
(See Chromatography 621, System Suitability.)
Mode: LC
Detector: UV 280 nm
Column: 4.6-mm 25-cm; 5-m packing L1
Flow rate: 1 mL/min
Injection volume: 10 L
System suitability
Sample: Standard solution
Suitability requirements:
Tailing factor: NMT 2.0
Relative standard deviation: NMT 0.73%
Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of rabeprazole sodium
(C18H20N3NaO3S) in the portion of Rabeprazole Sodium
taken:
Result = (rU/rS) (CS/CU) 100

Rabeprazole Sodium
Draft 1
c

rU
rS
CS

= peak response from the Sample solution

= peak response from the Standard solution
= concentration of USP Rabeprazole Sodium RS
in the Standard solution (mg/mL)
CU
= concentration of Rabeprazole Sodium in the
Sample solution (mg/mL)
Acceptance criteria: 98.0%102.0% on the dried basis

C18H20N3NaO3S
381.42
1H-Benzimidazole, 2-[[[4-(3-methoxypropoxy)-3-methyl2-pyridinyl]methyl]sulfinyl]-, sodium salt;
2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]benzimidazole sodium salt [117976-90-6].
DEFINITION
Rabeprazole Sodium contains NLT 98.0% and NMT 102.0%
of rabeprazole sodium (C18H20N3NaO3S), calculated on the
dried 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
ASSAY
PROCEDURE
[NOTERefrigerate solutions containing rabeprazole sodium until injected into the chromatograph. Without refrigeration, these solutions should be prepared fresh.]
Buffer: 1.75 g/L of monobasic potassium phosphate in
water, adjusted to a pH of 6.0 with dilute potassium hydroxide solution
Solution A: Acetonitrile and Buffer (35:65)
Solution B: Acetonitrile and water (90:10)
Mobile phase: See Table 1.
Table 1
Time
(min)
0
13.0
15.0
25.0

Solution A
(%)
100
100
60
60

Solution B
(%)
0
0
40
40

IMPURITIES
HEAVY METALS
Lead standard solution: Dilute 10 mL of the Standard
Lead Solution, prepared as directed in Heavy Metals 231,
with water to 100 mL.
Sodium sulfide solution: 5 g of sodium sulfide in 10 mL
of water and 30 mL of glycerin
Sample solution: Transfer 2.0 g of sample to a porcelain
crucible, cover loosely with a lid, and carbonize by gentle
ignition. Allow to cool, and add 2 mL of nitric acid and
5 drops of sulfuric acid. Heat cautiously until white fumes
are not evolved, and then incinerate by ignition at
500600 until carbonized substances are not observed.
Allow to cool, add 2 mL of hydrochloric acid, evaporate
to dryness on a hot plate, and moisten the residue with
3 drops of hydrochloric acid. Add 10 mL of hot water,
and warm for 2 min. Add 1 drop of phenolphthalein TS,
and add 6 N ammonium hydroxide dropwise until the
solution develops a pale red color. Add 2 mL of 1 N acetic acid, filter if necessary, and wash with 10 mL of water.
Transfer the filtrate and washing to a Nessler tube, and
add water to make 50 mL.
Control solution: Evaporate a mixture of 2 mL of nitric
acid, 5 drops of sulfuric acid, and 2 mL of hydrochloric
acid in a porcelain crucible on a hot plate, and moisten
the residue with 3 drops of hydrochloric acid. Proceed as
directed in the preparation of Sample solution beginning
with Add 10 mL of hot water, adding 2 mL of Lead
standard solution before adding water to make 50 mL.
Analysis: Add 1 drop of Sodium sulfide solution to the
Sample solution and Control solution, mix thoroughly, and
allow to stand for 5 min. Compare the colors of both
solutions by viewing the tubes downward or transversely
against a white background.
Acceptance criteria: NMT 10 ppm; the color of the Sample solution is not more intense than that of the Control
solution.
ORGANIC IMPURITIES
Buffer, Solution A, Solution B, and Diluent: Proceed as
directed in the Assay.
Mobile phase: See Table 2.

Return to original conditions and re-equilibrate the system.

Diluent: Methanol, water, and diethylamine (800:200:1),
adjusted to a pH of 10.0 with dilute phosphoric acid

This monograph has been developed under USPs Pending Monographs Guideline and is not a USPNF monograph.
http://www.usp.org
2013 The United States Pharmacopeia. All Rights Reserved.

USP Pending Monograph

Draft 1For Public Comment

2 / Rabeprazole
Table 2
Time
(min)
0
40.0
50.0
60.0

Table 3 (Continued)

Solution A
(%)
100
100
50
50

Solution B
(%)
0
0
50
50

Return to original conditions and re-equilibrate the system.

Sensitivity solution: 0.25 g/mL of USP Rabeprazole Sodium RS in Diluent
System suitability solution: 2.5 g/mL each of USP
Rabeprazole Sodium RS, USP Rabeprazole Related Compound B RS, USP Rabeprazole Related Compound D RS,
USP Rabeprazole Related Compound E RS, and USP
Rabeprazole Related Compound F RS in Diluent
Standard solution: 0.5 g/mL of USP Rabeprazole Sodium RS in Diluent
Sample solution: 0.5 mg/mL of Rabeprazole Sodium in
Diluent. [NOTEThis solution is stable for 6 h when stored
in a refrigerator. Without refrigeration, this solution
should be prepared fresh.]
Chromatographic system
(See Chromatography 621, System Suitability.)
Mode: LC
Detector: UV 280 nm
Column: 4.6-mm 25-cm; 5-m packing L1
Flow rate: 1 mL/min
Injection volume: 20 L
System suitability
Samples: Sensitivity solution and System suitability
solution
Suitability requirements:
Resolution: NLT 1.5 between rabeprazole and
rabeprazole related compound F, System suitability
solution
Signal-to-noise ratio: NLT 10, Sensitivity solution
Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of each impurity in the portion
of Rabeprazole Sodium taken:
Result = (rU/rS) (CS/CU) (1/F) 100
rU

= peak response of each impurity from the

Sample solution
rS
= peak response of rabeprazole from the
Standard solution
CS
= concentration of USP Rabeprazole Sodium RS
in the Standard solution (mg/mL)
CU
= concentration of Rabeprazole Sodium in the
Sample solution (mg/mL)
F
= relative response factor (see Table 3)
Acceptance criteria: See Table 3. Disregard any peak below 0.05%.

Name
Rabeprazole
Rabeprazole chloro
analog (rabeprazole
related compound F)
Rabeprazole sulfone
analog (rabeprazole
related compound
D)
Rabeprazole sulfide
analog (rabeprazole
related compound E)
Any unspecified impurity
Total impurities

Relative
Retention
Time
1.00

Relative
Response
Factor

Acceptance
Criteria,
NMT (%)

1.1

1.0

0.10

1.4

1.0

0.8

3.4

1.0

0.15

1.0

0.10
1.0

a 2-[[(4-Methoxy-3-methyl-2-pyridyl)methyl]sulfinyl]benzimidazole.
.

SPECIFIC TESTS
LOSS ON DRYING 731
Analysis: Dry a sample under vacuum at 120 for 3 h.
[NOTEDuring the analysis, the color of the sample may
change from white to off-white.]
Acceptance criteria: NMT 7.0%
ADDITIONAL REQUIREMENTS
PACKAGING AND STORAGE: Preserve in tight containers, protected from light. Store in a refrigerator.
USP REFERENCE STANDARDS 11
USP Rabeprazole Sodium RS
USP Rabeprazole Related Compound B RS
Rabeprazole N-oxide
2-[[(1H-Benzo[d]imidazol-2-yl)sulfinyl]methyl]4-(3-methoxypropoxy)-3-methylpyridine 1-oxide.
C18H21N3O4S 375.44
USP Rabeprazole Related Compound D RS
Rabeprazole sulfone analog
2-[[[4-(3-Methoxypropoxy)-3-methyl2-pyridyl]methyl]sulfonyl]benzimidazole.
C18H21N3O4S 375.44
USP Rabeprazole Related Compound E RS
Rabeprazole sulfide analog
2-[[4-(3-Methoxypropoxy)-3-methyl2-pyridyl]methylthio]benzimidazole.
C18H21N3O2S 343.44
USP Rabeprazole Related Compound F
Rabeprazole chloro analog
2-[[(4-Chloro-3-methyl2-pyridyl)methyl]sulfinyl]benzimidazole.
C14H12ClN3OS 305.78b (1-Sep-2013)

Table 3

Name
Rabeprazole N-oxide
(rabeprazole related
compound B)
Rabeprazole methoxy
analoga
.

Relative
Retention
Time

Relative
Response
Factor

Acceptance
Criteria,
NMT (%)

0.46

1.7

0.15

0.73

1.3

0.15

a 2-[[(4-Methoxy-3-methyl-2-pyridyl)methyl]sulfinyl]benzimidazole.
.

This monograph has been developed under USPs Pending Monographs Guideline and is not a USPNF monograph.
http://www.usp.org
2013 The United States Pharmacopeia. All Rights Reserved.