USP Pending MonographDraft 1—For Public Comment Rabeprazole / 1

BRIEFING Standard solution: 0.5 mg/mL of USP Rabeprazole So-dium RS in Diluent

Sample solution: 0.5 mg/mL of Rabeprazole Sodium inDiluentRabeprazole Sodium. A new USP Pending Monograph

Chromatographic systembased on validated methods of analysis is being proposed.(See Chromatography ⟨621⟩, System Suitability.)The HPLC procedures in the Assay and the test for OrganicMode: LCImpurities are based on analyses performed with the InertsilDetector: UV 280 nmODS 3V brand of L1 column. The typical retention time forColumn: 4.6-mm × 25-cm; 5-µm packing L1rabeprazole in the Assay and the test for Organic Impurities isFlow rate: 1 mL/minabout 11 min.Injection volume: 10 µLDescription and Solubility: White to slightly yellowish-white

System suitabilitysolid. Very soluble in water and in methanol.Sample: Standard solutionSuitability requirements:Tailing factor: NMT 2.0

(SM3: E. Gonikberg.) Correspondence Number—C89188 Relative standard deviation: NMT 0.73%AnalysisSamples: Standard solution and Sample solutionCalculate the percentage of rabeprazole sodium(C18H20N3NaO3S) in the portion of Rabeprazole Sodiumtaken:Add the following:

Result = (rU/rS) × (CS/CU) × 100.

c.Rabeprazole Sodium rU = peak response from the Sample solution

Draft 1 rS = peak response from the Standard solutionCS = 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

IMPURITIES• HEAVY METALS

Lead standard solution: Dilute 10 mL of the StandardC18H20N3NaO3S 381.42Lead Solution, prepared as directed in Heavy Metals ⟨231⟩,1H-Benzimidazole, 2-[[[4-(3-methoxypropoxy)-3-methyl-with water to 100 mL.2-pyridinyl]methyl]sulfinyl]-, sodium salt;

Sodium sulfide solution: 5 g of sodium sulfide in 10 mL2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridyl]methyl-of water and 30 mL of glycerin]sulfinyl]benzimidazole sodium salt [117976-90-6].

Sample solution: Transfer 2.0 g of sample to a porcelainDEFINITION crucible, cover loosely with a lid, and carbonize by gentleRabeprazole Sodium contains NLT 98.0% and NMT 102.0% ignition. Allow to cool, and add 2 mL of nitric acid and

of rabeprazole sodium (C18H20N3NaO3S), calculated on the 5 drops of sulfuric acid. Heat cautiously until white fumesdried basis. are not evolved, and then incinerate by ignition at

500°–600° until carbonized substances are not observed.IDENTIFICATION Allow to cool, add 2 mL of hydrochloric acid, evaporate• A. INFRARED ABSORPTION ⟨197K⟩ to dryness on a hot plate, and moisten the residue with• B. The retention time of the major peak of the Sample 3 drops of hydrochloric acid. Add 10 mL of hot water,

solution corresponds to that of the Standard solution, as and warm for 2 min. Add 1 drop of phenolphthalein TS,obtained in the Assay. and add 6 N ammonium hydroxide dropwise until the

• C. IDENTIFICATION TESTS—GENERAL, Sodium ⟨191⟩ solution develops a pale red color. Add 2 mL of 1 N ace-tic acid, filter if necessary, and wash with 10 mL of water.ASSAY Transfer the filtrate and washing to a Nessler tube, and• PROCEDURE add water to make 50 mL.[NOTE—Refrigerate solutions containing rabeprazole so- Control solution: Evaporate a mixture of 2 mL of nitricdium until injected into the chromatograph. Without re- acid, 5 drops of sulfuric acid, and 2 mL of hydrochloricfrigeration, these solutions should be prepared fresh.] acid in a porcelain crucible on a hot plate, and moistenBuffer: 1.75 g/L of monobasic potassium phosphate in the residue with 3 drops of hydrochloric acid. Proceed aswater, adjusted to a pH of 6.0 with dilute potassium hy- directed in the preparation of Sample solution beginningdroxide solution with “Add 10 mL of hot water”, adding 2 mL of LeadSolution A: Acetonitrile and Buffer (35:65) standard solution before adding water to make 50 mL.Solution B: Acetonitrile and water (90:10) Analysis: Add 1 drop of Sodium sulfide solution to theMobile phase: See Table 1. Sample solution and Control solution, mix thoroughly, andallow to stand for 5 min. Compare the colors of bothsolutions by viewing the tubes downward or transversely

Table 1 against a white background.Time Solution A Solution B Acceptance criteria: NMT 10 ppm; the color of the Sam-(min) (%) (%) ple solution is not more intense than that of the Control

solution.0 100 0• ORGANIC IMPURITIES13.0 100 0

Buffer, Solution A, Solution B, and Diluent: Proceed as15.0 60 40 directed in the Assay.25.0 60 40 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 USP‘s Pending Monographs Guideline and is not a USP–NF monograph.http://www.usp.org

2013 The United States Pharmacopeia. All Rights Reserved.

USP Pending Monograph2 / Rabeprazole Draft 1—For Public Comment

Table 2 Table 3 (Continued)

Time Solution A Solution B Relative Relative Acceptance(min) (%) (%) Retention Response Criteria,

Name Time Factor NMT (%)0 100 0Rabeprazole 1.00 — —40.0 100 0Rabeprazole chloro50.0 50 50analog (rabeprazole60.0 50 50related compound F) 1.1 1.0 0.10

Return to original conditions and re-equilibrate the system. Rabeprazole sulfoneSensitivity solution: 0.25 µg/mL of USP Rabeprazole So- analog (rabeprazoledium RS in Diluent related compound

System suitability solution: 2.5 µg/mL each of USP D) 1.4 1.0 0.8Rabeprazole Sodium RS, USP Rabeprazole Related Com- Rabeprazole sulfidepound B RS, USP Rabeprazole Related Compound D RS, analog (rabeprazoleUSP Rabeprazole Related Compound E RS, and USP related compound E) 3.4 1.0 0.15Rabeprazole Related Compound F RS in Diluent Any unspecified impu-

—Standard solution: 0.5 µg/mL of USP Rabeprazole So- rity 1.0 0.10dium RS in Diluent

Total impurities — — 1.0Sample solution: 0.5 mg/mL of Rabeprazole Sodium ina

.2-[[(4-Methoxy-3-methyl-2-pyridyl)methyl]sulfinyl]benzimidazole. Diluent. [NOTE—This solution is stable for 6 h when storedin a refrigerator. Without refrigeration, this solution SPECIFIC TESTSshould be prepared fresh.] • LOSS ON DRYING ⟨731⟩

Chromatographic system Analysis: Dry a sample under vacuum at 120° for 3 h.(See Chromatography ⟨621⟩, System Suitability.) [NOTE—During the analysis, the color of the sample mayMode: LC change from white to off-white.]Detector: UV 280 nm Acceptance criteria: NMT 7.0%Column: 4.6-mm × 25-cm; 5-µm packing L1Flow rate: 1 mL/min ADDITIONAL REQUIREMENTSInjection volume: 20 µL • PACKAGING AND STORAGE: Preserve in tight containers, pro-

System suitability tected from light. Store in a refrigerator.Samples: Sensitivity solution and System suitability • USP REFERENCE STANDARDS ⟨11⟩solution USP Rabeprazole Sodium RS

Suitability requirements: USP Rabeprazole Related Compound B RSResolution: NLT 1.5 between rabeprazole and Rabeprazole N-oxiderabeprazole related compound F, System suitability 2-[[(1H-Benzo[d]imidazol-2-yl)sulfinyl]methyl]-solution 4-(3-methoxypropoxy)-3-methylpyridine 1-oxide.

Signal-to-noise ratio: NLT 10, Sensitivity solution C18H21N3O4S 375.44Analysis USP Rabeprazole Related Compound D RSSamples: Standard solution and Sample solution Rabeprazole sulfone analogCalculate the percentage of each impurity in the portion 2-[[[4-(3-Methoxypropoxy)-3-methyl-of Rabeprazole Sodium taken: 2-pyridyl]methyl]sulfonyl]benzimidazole.

C18H21N3O4S 375.44Result = (rU/rS) × (CS/CU) × (1/F) × 100 USP Rabeprazole Related Compound E RS

Rabeprazole sulfide analogrU = peak response of each impurity from the 2-[[4-(3-Methoxypropoxy)-3-methyl-

Sample solution 2-pyridyl]methylthio]benzimidazole.rS = peak response of rabeprazole from the C18H21N3O2S 343.44

Standard solution USP Rabeprazole Related Compound FCS = concentration of USP Rabeprazole Sodium RS Rabeprazole chloro analog

in the Standard solution (mg/mL) 2-[[(4-Chloro-3-methyl-CU = concentration of Rabeprazole Sodium in the 2-pyridyl)methyl]sulfinyl]benzimidazole.

Sample solution (mg/mL) C14H12ClN3OS 305.78b (1-Sep-2013)F = relative response factor (see Table 3)

Acceptance criteria: See Table 3. Disregard any peak be-low 0.05%.

Table 3

Relative Relative Acceptance Retention Response Criteria,

Name Time Factor NMT (%)Rabeprazole N-oxide(rabeprazole relatedcompound B) 0.46 1.7 0.15

Rabeprazole methoxyanaloga

. 0.73 1.3 0.15a

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

This monograph has been developed under USP‘s Pending Monographs Guideline and is not a USP–NF monograph.http://www.usp.org

2013 The United States Pharmacopeia. All Rights Reserved.