Clopidogrel Bisulfate

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

DOWNLOAD PDF HERE

C₁₆H₁₆CINO2S · H₂SO₄            419.90

Thieno[3,2-c]pyridine-5(4H)-acetic acid, a-(2-chlorophenyl)-6,7-dihydro-, methyl ester, (S)-, sulfate (1:1);

Methyl (+)-(S)-a-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c)pyridine-5(4H)-acetate, sulfate (1:1) CAS RN^®: 120202-66-6; UNII: 08179HTP27.

1 DEFINITION

Clopidogrel Bisulfate contains NLT 97.0% and NMT 101.5% of clopidogrel bisulfate (C₁₆H₁₆CINO2S · H₂SO₄), calculated on the dried basis.

2 IDENTIFICATION

Change to read:

A. ^▲SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K_{▲(CN 1-MAY-2020)}

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, Sulfate(191): Meets the requirements

3 ASSAY

3.1 PROCEDURE

[NOTE-For all clopidogrel related compounds, the concentrations are expressed as bisulfate salts. Use bisulfate salt equivalents stated on USP Reference Standards labels to calculate the concentrations as appropriate.]

Buffer: 1.36 g/L of monobasic potassium phosphate in water

Mobile phase: Acetonitrile and Buffer (25:75)

System suitability stock solution: 100 µg/mL of USP Clopidogrel Bisulfate RS and 200 µg/mL of USP Clopidogrel Related Compound B RS in methanol

System suitability solution: 2.5 µg/mL of USP Clopidogrel Bisulfate RS and 5.0 µg/mL of USP Clopidogrel Related Compound B. RS in Mobile phase from System suitability stock solution

Standard stock solution: 1.0 mg/mL of USP Clopidogrel Bisulfate RS in methanol

Standard solution: 0.1 mg/mL in Mobile phase from the Standard stock solution

Sample stock solution: 1 mg/mL of Clopidogrel Bisulfate in methanol

Sample solution: 0.1 mg/mL in Mobile phase, from Sample stock solution

3.1.1 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 220 nm.

Column: 4.6-mm x 15-cm; packing L57

Flow rate: 1 mL/min

Injection volume: 10 µL

3.1.2 System suitability

Samples: System suitability solution and Standard solution

[NOTE-The relative retention times for the two enantiomers of clopidogrel related compound B and for clopidogrel are 0.8, 1.2, and 1.0, respectively.]

3.1.3 Suitability requirements

Resolution: Greater than 2.5 between clopidogrel and the first enantiomer of clopidogrel related compound B, System suitability solution

Relative standard deviation: NMT 1.0% from clopidogrel bisulfate, Standard solution

3.1.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of clopidogrel bisulfate (C₁₆H₁₆CINO₂S · H₂SO₄) in the portion of the sample taken:

                 Result = (r_U/r_S) x (C_S/C_U) × 100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution S

C_S = concentration of the Standard solution (mg/mL)

C_U = concentration of Sample solution (mg/mL)

Acceptance criteria: 97.0%-101.5% on the dried basis

4 IMPURITIES

RESIDUE ON IGNITION (281): NMT 0.1%

4.1 ORGANIC IMPURITIES

[NOTE-For all clopidogrel related compounds, the concentrations are expressed as bisulfate salts. Use bisulfate salt equivalents stated on USP Reference Standards labels to calculate the concentrations as appropriate.]

Buffer: 0.96 g/L sodium 1-pentanesulfonate. Adjust with phosphoric acid to a pH of 2.5.

Solution A: Acetonitrile

Solution B: Methanol

Mobile phase: See Table 1.

     Table 1
 

Diluent: Acetonitrile and Buffer (60:40)

System suitability solution: 6.5 mg/mL of USP Clopidogrel Bisulfate RS and 0.01 mg/mL each of USP Clopidogrel Related Compound A RS and USP Clopidogrel Related Compound B RS in Diluent

Standard solution: 6.5 µg/mL of USP Clopidogrel Bisulfate RS in Diluent

Sample solution: 6.5 mg/mL of Clopidogrel Bisulfate in Diluent

4.1.1 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: L.C

Detector: UV 220 nm

Column: 3.9-mm x 15-cm; 5-um packing L1

Column temperature: 30°

Flow rate: 1 mL/min

Injection volume: 10 µL

4.1.2 System suitability

Sample: System suitability solution

[NOTE-The relative retention times for clopidogrel related compound A, clopidogrel, and clopidogrel related compound B are given in Table 2.]

4.1.3 Suitability requirements

Peak-to-valley ratio (H_p/H_v): NLT 10 where H_p, is the height above the baseline of the peak due to clopidogrel related compound B and H_v is the height above the baseline of the lowest point of the curve separating clopidogrel related compound B and clopidogrel, System suitability solution.

4.1.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of clopidogrel related compound A, clopidogrel related compound B, and any other individual impurity in the portion of the sample taken:

                 Result = (r_U/r_S) x (C_S/C_U) × 100

r_U = peak response of clopidogrel related compound A, clopidogrel related compound B, or any other impurity from the Sample solution

r_S = peak response of clopidogrel from the Standard solution

C_S = concentration of the Standard solution (mg/mL)

C_U = concentration of the Sample solution (mg/mL)

Acceptance criteria: See Table 2.

   Table 2

^a (+)-(S)-(o-Chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid.

^b Methyl (+/-)-(o-chlorophenyl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-acetate.

^c Disregard any peak less than 0.05%.

4.2 LIMIT OF CLOPIDOGREL RELATED COMPOUND C

Mobile phase: Heptane and dehydrated alcohol (85:15)

Standard solution: 0.02 mg/mL each of USP Clopidogrel Bisulfate RS, USP Clopidogrel Related Compound B RS, and USP Clopidogrel Related Compound C RS prepared as follows. Dissolve a quantity of USP Clopidogrel Bisulfate RS, USP Clopidogrel Related Compound B RS, and USP Clopidogrel Related Compound C RS in dehydrated alcohol (about 50% of the volume of the flask), and dilute with heptane to volume.

Sample solution: 2 mg/mL of Clopidogrel Bisulfate prepared as follows. Transfer 100 mg of Clopidogrel Bisulfate to a 50-mL volumetric flask, dissolve in 25 mL of dehydrated alcohol, and dilute with heptane to volume.

4.2.1 Chromatographic system

(See Chromatography (621). System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm x 25-cm; 10-um packing 180

Flow rate: 0.8 mL/min

Injection volume: 10 µL

Run time: 1.25 times the retention time of clopidogrel

4.2.2 System suitability

Sample: Standard solution

[NOTE-The relative retention times for clopidogrel related compound B, clopidogrel, and clopidogrel related compound C are 0.7, 1.0, and 0.6, respectively.]

4.2.3 Suitability requirements

Resolution: NLT 2.0 between clopidogrel related compound C and clopidogrel related compound B

Signal-to-noise ratio: NLT 20 for clopidogrel related compound C peak

4.2.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of clopidogrel related compound C in the portion of the sample taken:

                 Result = (r_U/r_S) x (C_S/C_U) × 100

r_U = peak response of clopidogrel related compound C from Sample solution

r_S = peak response of clopidogrel related compound C from Standard solution

C_S = concentration of the clopidogrel related compound C in Standard solution (mg/mL)

C_U = concentration of Clopidogrel Bisulfate in the Sample solution (mg/ml.)

Acceptance criteria: NMT 0.5%

5 SPECIFIC TESTS

LOSS ON DRYING (731)

Analysis: Dry a sample at 105 for 2 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in well-closed containers and store at controlled room temperature.

USP REFERENCE STANDARDS (11)

USP Clopidogrel Bisulfate RS

USP Clopidogrel Related Compound A RS

(+)-(S)-(o-Chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid, hydrochloride.

C₁₅H₁₄CINO₂S · HCI       344.26

USP Clopidogrel Related Compound B RS

Methyl (+/-)-(o-chlorophenyl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-acetate, hydrochloride.

C₁₆H₁₇CI₂NO₂S       358.28

USP Clopidogrel Related Compound CRS

Methyl (-)-(R)-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate, hydrogen sulfate.

C₁₆H₁₆CINO₂S · H₂SO₄       419.90