Metronidazole Extended-Release 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

Metronidazole Extended-Release Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of metronidazole (C₆H₉N₃O₃).

2 IDENTIFICATION

Change to read:

A. ^▲SPECTROSCOPIC IDENTIFICATION TESTS (197), Ultraviolet-Visible Spectroscopy: 197U _{▲(CN 1-MAY-2020)}

Diluent: Methanol and sulfuric acid (350:1)

Standard stock solution: 15 mg/mL of USP Metronidazole RS in dilute hydrochloric acid (1 in 100). Sonicate to dissolve and pass through a suitable filter.

Standard solution: 18.8 µg/mL of USP Metronidazole RS in Diluent from Standard stock solution

Sample stock solution: Nominally 15 mg/mL of metronidazole prepared as follows. Finely powder NLT 5 Tablets and transfer an amount equivalent to 300 mg of metronidazole into a 20-mL volumetric flask. Add about 15 mL of dilute hydrochloric acid (1 in 100) and shake mechanically for 30 min. Dilute with dilute hydrochloric acid (1 in 100) to volume and shake well. Pass through a suitable filter.

Sample solution: Nominally equivalent to 18.8 µg/mL of metronidazole in Diluent from Sample stock solution

Wavelength range: 200-400 nm

Acceptance criteria: Meet the requirements

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

PROCEDURE

Buffer: 1.4 g/L of monobasic potassium phosphate in water

Mobile phase: Methanol and Buffer (30:70)

Standard solution: 0.1 mg/mL of USP Metronidazole RS in Mobile phase

Sample stock solution: Nominally 2.0 mg/mL of metronidazole from NLT 20 finely powdered Tablets in Mobile phase, prepared as follows. Transfer a suitable amount of the powder to a suitable volumetric flask. Add 60% of the flask volume with Mobile phase, and shake by mechanical means for 30 min. Dilute with Mobile phase to volume. Allow the solution to stand until the insoluble material settles.

Sample stock solution: Nominally 2.0 mg/mL of metronidazole from NLT 20 finely powdered Tablets in Mobile phase, prepared as follows.

Transfer a suitable amount of the powder to a suitable volumetric flask. Add 60% of the flask volume with Mobile phase, and shake by mechanical means for 30 min. Dilute with Mobile phase to volume. Allow the solution to stand until the insoluble material settles.

Sample solution: Nominally 0.1 mg/mL of metronidazole in Mobile phase from the Sample stock solution supernatant. Pass the solution through a suitable filter of 0.45-µm pore size.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 315 nm

Column: 4.6-mm x 25-cm; 5-µm packing 11

Temperatures

Column: 30°

Autosampler: 15°

Flow rate: 1 mL/min

Injection volume: 10 µL

Run time: 15 min

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of metronidazole (C₆H₉N₃O₃) in the portion of Tablets taken:

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

r_U = peak response of metronidazole from the Sample solution

r_S = peak response of metronidazole from the Standard solution S

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

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

Acceptance criteria: 90.0%-110.0%

4 PERFORMANCE TESTS

4.1 DISSOLUTION (711)

Medium: Water; 900 mL

Apparatus 2: 50 rpm

Times: 2, 6, 10, and 16 h

Standard solution: 16.65 µg/mL of USP Metronidazole RS in Medium

Sample solution: At the times specified, withdraw 10 mL of the solution under test and pass through a suitable filter of 0.45-µm pore size.

Replace the aliquots withdrawn for analysis with equal volumes of fresh portions of Medium maintained at 37°. Dilute with Medium to a concentration similar to that of the Standard solution.

Blank: Medium

Instrumental conditions

Mode: UV

Analytical wavelength: 320 nm

Cell: 1 cm

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C_i) of metronidazole (C₆H₉N₃O₃) in the sample withdrawn from the vessel at each time point (i).

                         Result = (A_U/A_S) × C_S × D

A_U = absorbance of the Sample solution

A_S = absorbance of the Standard solution

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

D = dilution factor, if needed

Calculate the percentage of the labeled amount (Q_i) of metronidazole (C₆H₉N₃O₃) dissolved at each time point (i).

                         Result₁ = C₁ x V x (1/L) x 100

                         Result₂ = {(C₂ x V)+ (C₁ x V_S)} x (1/L) x 100

                         Result₃ = {(C₃ x V) + [(C₂ + C₁) x V_S)} x (1/L) x 100

                         Result₄ = {(C₄ x V) + [(C₃ + C₂ + C₁) x V_S)} x (1/L) x 100

C_i = concentration of metronidazole in the portion of sample withdrawn at the specified time point (mg/mL)

V = volume of the Medium, 900 mL

L = label claim (mg/Tablet)

V_S = volume of the Sample solution withdrawn at each time point and replaced with Medium (mL)

Tolerances: See Table 1.

Table 1

The percentages (Q) of the labeled amount of metronidazole (C₆H₉N₃O₃) released at the times specified conform to Dissolution (711),

Acceptance Table 2.

4.2 UNIFORMITY OF DOSAGE UNITS (905)

Meet the requirements

5 IMPURITIES

ORGANIC IMPURITIES

Buffer: Dissolve 1.5 g of monobasic potassium phosphate in 900 mL of water, adjust with phosphoric acid to a pH of 3.2, and dilute with water to 1000 mL.

Diluent: Acetonitrile and Buffer (45:55)

Mobile phase: See Table 2.

Table 2

System suitability solution: 0.5 mg/mL of USP Metronidazole RS and 2.5 µg/mL of USP Tinidazole Related Compound A RS in Diluent. Sonicate, if necessary, to dissolve.

Standard solution: 0.75 µg/mL of USP Metronidazole RS in Diluent

Sample solution: Nominally 0.5 mg/mL of metronidazole from NLT 20 finely powdered Tablets in Diluent, prepared as follows. Transfer a suitable amount of the powder to a suitable volumetric flask. Add Diluent equivalent to 70% of the flask volume, sonicate for 15 min with intermittent shaking, and dilute with Diluent to volume. Allow the solution to stand until the insoluble material settles, and pass the supernatant through a suitable filter of 0.45-µm pore size.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 315 nm

Column: 4.6-mm × 25-cm; 5-µm packing L1

Autosampler temperature: 20°

Flow rate: 1 mL/min

Injection volume: 10 µL

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 2.0 between tinidazole related compound A and metronidazole, System suitability solution

Relative standard deviation: NMT 5.0% for metronidazole, 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 metronidazole from the Standard solution s

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

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

Acceptance criteria: See Table 3. Disregard any impurity peaks less than 0.05%.

Table 3

6 ADDITIONAL REQUIREMENTS

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

USP REFERENCE STANDARDS (11)

USP Metronidazole RS

USP Tinidazole Related Compound A RS

2-Methyl-5-nitroimidazole.

C₄H₅N₃O₂            127.10