Riociguat Tablets

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

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

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1 DEFINITION

Riociguat Tablets contain NLT 95.0% and NMT 105.0% of the labeled amount of riociguat (C₂₀H₁₉FN₈O₂).

2 IDENTIFICATION

A. The UV spectrum of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

3 ASSAY

3.1 Procedure

[Note—Protect all solutions containing riociguat from light.]

Buffer: Phosphoric acid in water (5.5:1000). Adjust with phosphoric acid to a pH of 1.6.

Mobile phase: Acetonitrile and Buffer (23:77)

Diluent: Acetonitrile and Buffer (20:80)

Standard solution: 0.1 mg/mL of USP Riociguat RS in Diluent. Sonicate to dissolve as necessary.

System suitability solution: 0.1 mg/mL of USP Riociguat System Suitability Mixture II RS in Diluent. Sonicate to dissolve as necessary.

Sample solution: Nominally 0.1 mg/mL of riociguat in Diluent prepared as follows. Transfer NLT 5 Tablets to a suitable volumetric flask and add 70% of the flask volume of the Diluent. Shake for 15 min on a shaker to completely disintegrate the Tablets. Dilute with Diluent to volume. (Alternatively, the flask can be sonicated for 30 min to disintegrate the Tablets, and then dilute with Diluent to volume.) Centrifuge a portion of the resulting solution and use the clear supernatant.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 210 nm. For Identification A, use a diode array detector in the range of 210–400 nm.

Column: 4.6-mm × 10-cm; 3.5-µm packing L1

Column temperature: 40°

Flow rate: 2.0 mL/min

Injection volume: 5 µL

Run time: NLT 4 times the retention time of riociguat

System suitability

Samples: Standard solution and System suitability solution

[Note—See Table 1 for the relative retention times. The relative retention times for riociguat related compound A, riociguat, and riociguat related compound C are 0.65, 1.0, and 2.4, respectively.]

Suitability requirements

Resolution: NLT 5.0 between riociguat related compound A and riociguat, System suitability solution

Tailing factor: 1.0–1.5, Standard solution

Relative standard deviation: NMT 1.0% from 6 replicate injections, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of riociguat (C₂₀H₁₉FN₈O₂) in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of riociguat from the Sample solution

r_S = peak response of riociguat from the Standard solution

C_S = concentration of USP Riociguat RS in the Standard solution (mg/mL)

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

Acceptance criteria: 95.0%–105.0%

4 PERFORMANCE TESTS

4.1 Dissolution 〈711〉

Medium: pH 6.8 phosphate buffer containing 0.1% sodium lauryl sulfate, prepared as follows. Dissolve 2.75 g of sodium phosphate, dibasic, dihydrate, 0.48 g of citric acid, and 1.0 g of sodium lauryl sulfate in 1 L of water and adjust with 0.1 N sodium hydroxide solution or phosphoric acid to a pH of 6.8; 900 mL.

Apparatus 2: 75 rpm

Time: 15 min

Buffer: Dissolve 1.54 g/L of ammonium acetate in water and adjust with glacial acetic acid to a pH of 4.0.

Mobile phase: Acetonitrile and Buffer (45:55)

Standard stock solution: 0.028 mg/mL of USP Riociguat RS in methanol

Standard solution: (L/900) mg/mL of USP Riociguat RS in Medium from Standard stock solution, where L is the label claim of riociguat in mg/Tablet

Sample solution: A filtered portion of the solution under test

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 326 nm

Column: 4.6-mm × 6-cm; 5-µm packing L1

Column temperature: 40°

Flow rate: 2.3 mL/min

Injection volume: 100 µL

Run time: NLT 1.9 times the retention time of riociguat

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 1.5% from 6 replicate injections

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of riociguat (C₂₀H₁₉FN₈O₂) dissolved:

Result = (r_U/r_S) × C_S × V × (1/L) × 100

r_U = peak response of riociguat from the Sample solution

r_S = peak response of riociguat from the Standard solution

C_S= concentration of USP Riociguat RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

Tolerances: NLT 80% (Q) of the labeled amount of riociguat is dissolved.

4.2 Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

5.1 Organic Impurities

[Note—Protect all solutions containing riociguat from light.]

Buffer, Mobile phase, Diluent, System suitability solution, Sample solution, and Chromatographic system: Proceed as directed in the Assay.

Standard solution: 0.0001 mg/mL of USP Riociguat RS in Diluent. Sonicate to dissolve as needed.

System suitability

Samples: System suitability solution and Standard solution

[Note—See Table 1 for the relative retention times. The relative retention times for riociguat related compound A, riociguat, and riociguat related compound C are 0.65, 1.0, and 2.4, respectively.]

Suitability requirements

Resolution: NLT 5.0 between riociguat related compound A and riociguat, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution

Signal-to-noise ratio: NLT 10, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each individual degradation product in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of each individual degradation product from the Sample solution

r_S = peak response of riociguat from the Standard solution

C_S = concentration of USP Riociguat RS in the Standard solution (mg/mL)

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

Acceptance criteria: See Table 1. The reporting threshold is 0.1%.

Table 1

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers. Store at controlled room temperature.

USP Reference Standards 〈11〉

USP Riociguat RS

USP Riociguat System Suitability Mixture II RS

This is a mixture containing (approximately 0.2% of riociguat related compound A and 0.5% of riociguat related compound C):

Riociguat

Riociguat related compound A: Methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate; also known as Nelociguat.

C₁₉H₁₇FN₈O₂ 408.40

Riociguat related compound C: Methyl {4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-(methylamino)pyrimidin-5-yl}methylcarbamate.

C₂₁H₂₁FN₈O₂ 436.45 (USP 1-Aug-2022)