Indomethacin Extended-Release Capsules

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

Indomethacin Extended-Release Capsules contain NLT 90.0% and NMT 110.0% of the labeled amount of indomethacin (C₁₉H₁₆ClNO₄).

2 IDENTIFICATION

Change to read:

A.Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy:〈197K〉 (USP 1-May-2020)

Standard:

(USP 1-May-2020) Prepare a solution of 5 mg/mL of USP Indomethacin RS in acetone. Transfer 5 mL of this solution to a stoppered flask, add 20 mL of water, and shake for 2 min until a precipitate forms and crystallizes. filter and collect the crystals. Dry the crystals in air, then dry at a pressure below 5 mm of mercury at 100° for 2 h. (USP 1-May-2020)

Sample: (USP 1-May-2020) Shake a portion of Capsule contents, nominally equivalent to 50 mg of indomethacin, with 10 mL of acetone for about 2 min, and filter. Transfer 5 mL of the filtrate to a stoppered flask, add 20 mL of water, and shake for 2 min until a precipitate forms and crystallizes. Filter and collect the crystals. Dry the crystals in air, then dry at a pressure below 5 mm of mercury at 100° for 2 h. (USP 1- May-2020)

Acceptance criteria: The IR absorption spectrum of the Sample exhibits maxima only at the same wavelengths as that of the Standard.

(USP 1-May-2020)

Change to read:

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

1-May-2020)

Delete the following:

C.

Sample solution: Equivalent to 1 mg/mL of indomethacin in sodium hydroxide solution (0.4 mg/mL) from powdered Capsule contents

Analysis: Shake the Sample solution for 5 min, and filter. To 1 mL of the clear filtrate add 1 mL of 1 mg/mL sodium nitrite solution, mix, and allow to stand for 5 min. Add 0.5 mL of sulfuric acid.

Acceptance criteria: A golden yellow color develops. (USP 1-May-2020)

3 ASSAY

Change to read:

Procedure

Mobile phase: Methanol, water, and phosphoric acid (600:400:0.8)

Diluent: Phosphoric acid and water (1:99)

Standard solution: (USP 1-May-2020) 0.8 mg/mL of USP Indomethacin RS, prepared as follows. Transfer a suitable quantity of USP Indomethacin RS to a suitable volumetric flask, dissolve with 60% of the flask volume of acetonitrile, and dilute with Diluent to volume.(USP 1-May-2020)

Sample solution: Nominally 0.75 mg/mL of indomethacin prepared as follows. (USP 1-May-2020) Weigh and finely powder the contents of NLT 20 Capsules. Transfer a portion of the powder, nominally equivalent to 75 mg of indomethacin, to a 100-mL volumetric flask, add 40 mL of Diluent, and shake for 1 h. Sonicate for 15 min, add 40 mL of acetonitrile, sonicate for 15 min, and dilute with acetonitrile to volume.

Centrifuge a portion of this solution, and use the supernatant. (USP 1-May-2020)

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 240 nm

Column: 3.9-mm × 30-cm; 10-μm (USP 1-May-2020) packing L1

Flow rate: 2 mL/min

Injection volume: 20 μL

System suitability

Sample: Standard solution

(USP 1-May-2020)

Suitability requirements

(USP 1-May-2020)

Tailing factor: NMT 2.0

(USP 1-May-2020)

Relative standard deviation: NMT 2.0%

(USP 1-May-2020)

Analysis

Samples: Standard solution (USP 1-May-2020) and Sample solution

Calculate the percentage of the labeled amount of (USP 1-May-2020) indomethacin (C₁₉H₁₆ClNO₄) in the portion of Capsules taken:

Result = (r_U/r_S)x(C_S/C_U) × 100

r_U = peak response of indomethacin (USP 1-May-2020) from the Sample solution

r_S = peak response of indomethacin from the Standard solution (USP 1-May-2020)

C_S = concentration of USP Indomethacin RS in the Standard solution (USP 1-May-2020) (mg/mL)

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

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Change to read:

Dissolution 〈711〉

Test 1

(USP 1-May-2020)

Medium: pH 6.2 phosphate buffer (see Reagents and Reference Tables, Solutions, Buffer Solutions); 750 mL

Apparatus 1: 75 rpm

Times: 1, 2, 4, 6, 12, and 24 h

Standard solution: USP Indomethacin RS at a known concentration in Medium

Sample solution: Pass a portion of the solution under test through a suitable filter. Dilute with Medium, if necessary. (USP 1-May-2020)

Instrumental conditions

(See Ultraviolet-Visible Spectroscopy 〈857〉.)

Mode: UV

Analytical wavelength: 318 nm

Analysis

Samples: Standard solution and Sample solution

Tolerances: See Table 1.

Table 1

The percentages of the labeled amount of indomethacin (C₁₉H₁₆ClNO₄) dissolved at the times specified conform to Dissolution 〈711〉,

Acceptance Table 2.

Test 2: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.

Medium: pH 6.2 phosphate buffer (see Reagents and Reference Tables, Solutions, Buffer Solutions); 900 mL

Apparatus 1: 75 rpm (USP 1-May-2020)

Standard solution, Sample solution, and Analysis: Proceed as directed in Test 1.

Tolerances: See Table 2.

Table 2

The percentages of the labeled amount of indomethacin (C₁₉H₁₆ClNO₄) dissolved at the times specified conform to Dissolution 〈711〉,

Acceptance Table 2.

Test 3: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3.

Medium: pH 6.8 phosphate buffer (see Reagents and Reference Tables, Solutions, Buffer Solutions); 750 mL

Apparatus 1: 75 rpm (USP 1-May-2020)

Standard solution, Sample solution, and Analysis: Proceed as directed in Test 1.

Tolerances: See Table 3.

Table 3

The percentages of the labeled amount of indomethacin (C₁₉H₁₆ClNO₄ ) dissolved at the times specified conform to Dissolution 〈711〉,

Acceptance Table 2.

Test 4: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 4.

Medium: pH 6.2 phosphate buffer (see Reagents and Reference Tables, Solutions, Buffer Solutions); 900 mL

Apparatus 1: 75 rpm

Times: 1, 2, 4, 12, and 24 h

Mobile phase: Acetonitrile and 0.1% phosphoric acid (60:40)

Standard stock solution: 0.4 mg/mL of USP Indomethacin RS

(USP 1-May-2020) prepared as follows. Transfer a suitable amount of USP

Indomethacin RS into a suitable volumetric flask. Add 10% of the flask volume of acetonitrile, and sonicate to promote dissolution, if necessary. Dilute with Medium to volume.

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

Sample solution: Pass a portion of the solution under test through a suitable filter. Dilute with Medium, if necessary.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 235 nm

Column: 4.6-mm × 100-mm; 3.5-μm packing L1

Column temperature: 40°

Flow rate: 1.2 mL/min

Injection volume: 10 μL

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 3%

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C_i) of indomethacin (C₁₉H₁₆ClNO₄) in the sample withdrawn from the vessel at each time point (i):

Result = (r_U/r_S) × C_S

r_U/ = peak response of indomethacin from the Sample solution

r_S = peak response of indomethacin from the Standard solution

C_S = concentration of USP Indomethacin RS in the Standard solution (mg/mL) (USP 1-May-2020)

Calculate the percentages of the labeled amount (Q_ti) of indomethacin (C₁₉H₁₆ClNO₄ ) dissolved at each time point i:

Result₁ = C₁ × V × (1/L) × 100

Result₂ = {[C₂ × (V − V_S)] + [C₁× V_S]} × (1/L) × 100

Result₃ = {[C₃ × (V − {[i − 1] × V_S})] + [(C_[l-1] + C_[l-2] + ... + C₁) × V_S]} × (1/L) × 100

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

V = volume of the Medium, 900 mL

L = label claim of indomethacin (mg/Capsule)

V_S = volume of the Sample solution withdrawn from the Medium (mL)

Tolerances: See Table 4.

Table 4

The percentages of the labeled amount of indomethacin (C₁₉H₁₆ClNO₄) dissolved at the times specified conform to Dissolution 〈711〉,

Acceptance Table 2.

Test 5: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 5.

Medium: pH 6.2 phosphate buffer (see Reagents and Reference Tables, Solutions, Buffer Solutions); 750 mL

Apparatus 1: 75 rpm

Times: 1, 2, 4, 6, 12, and 24 h

Standard stock solution: 0.5 mg/mL of USP Indomethacin RS in methanol. Sonicate, if needed, to dissolve.

Standard solution: 0.025 mg/mL of USP Indomethacin RS from the Standard stock solution diluted in Medium. Pass through a suitable filter of 0.45-μm pore size.

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-μm pore size. Dilute with Medium, if necessary.

Instrumental conditions

(See Ultraviolet-Visible Spectroscopy 〈857〉.)

Mode: UV

Analytical wavelength: 318 nm

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 1.0%

Analysis: Replace the volume of medium withdrawn for analysis with an equal volume of fresh Medium after each sampling.

Samples: Standard solution and Sample solution

Calculate the concentration, C_i, of indomethacin (C₁₉H₁₆ClNO₄ ) in the sample withdrawn from the vessel at each time point (i):

C_i = (A_U/A_S) × C_S× D

A_U = absorbance of the Sample solution at time point (i)

A_S = absorbance of the Standard solution

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

D = dilution factor for the Sample solution

Calculate the percentage of the labeled amount of indomethacin (C₁₉H₁₆ClNO₄) dissolved at each time point (i):

Result₁ = (C₁× V) × (1/L) × 100

Result₂ = [(C₂ × V) + (C₁× V_S)] × (1/L) × 100

Result₃ = {(C_i × V) + [(C_[l-1] + C_[l-2] + ... + C₁) × V_S]} × (1/L) × 100

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

V = volume of Medium, 750 mL

L = label claim (mg/Capsule)

V_S = volume of the Sample solution withdrawn at each time point (mL)

Tolerances: See Table 5.

Table 5

The percentages of the labeled amount of indomethacin (C₁₉H₁₆ClNO₄ ) dissolved at the times specified conform to Dissolution 〈711〉,

Acceptance Table 2.

Change to read:

Uniformity of Dosage Units 〈905〉: Meets the requirements (USP 1-May-2020)

Procedure for content uniformity

Solution A: Dissolve 17.42 g of dibasic potassium phosphate in 800 mL of water, adjusting with phosphoric acid to a pH of 7.5, and diluting with water to 1000 mL (pH 7.5 phosphate buffer).

Diluent: Methanol and Solution A (1:1)

Standard solution: 25 μg/mL of USP Indomethacin RS in Diluent

Sample solution: Nominally 25 μg/mL of indomethacin in Diluent, prepared as follows. Transfer the contents of 1 Capsule to a 200-mL volumetric flask, and add 100 mL of Diluent. Sonicate until the contents are dispersed, dilute with Diluent to volume, and centrifuge. Dilute a portion of the clear solution with Diluent to obtain the above concentration.

Instrumental conditions

(See Ultraviolet-Visible Spectroscopy 〈857〉.)

Mode: UV

Analytical wavelength: 318 nm

Cell: 1 cm

Blank: Methanol and Solution A (1:1)

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount (USP 1-May-2020) of indomethacin (C₁₉H₁₆ClNO₄) in the Capsule taken:

Result = (A_U/A_S) × (C_S/C_U) × 100

A_U= absorbance of the Sample solution

A_S = absorbance of the Standard solution

C_S = concentration of USP Indomethacin RS in the Standard solution (μg/mL)

C_U = nominal concentration of indomethacin in the Sample solution (μg/mL)

(USP 1-May-2020)

5 IMPURITIES

Delete the following:

Limit of 4-Chlorobenzoic Acid

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

Analysis

Samples: Standard solution B and Sample solution

Using the peak responses measured and recorded in the Assay, calculate the percentage of 4-chlorobenzoic acid (C₁₉H₁₆ClNO₄) in the portion of Capsules 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

C_S = concentration of 4-chlorobenzoic acid in Standard solution B (mg/mL)

C_U = measured concentration of indomethacin in the Sample solution as determined from the Assay (mg/mL)

Acceptance criteria: NMT 0.44% (USP 1-May-2020)

Add the following:

Organic Impurities

Solution A: Dilute 1 mL of phosphoric acid with water to 1000 mL.

Solution B: Acetonitrile

Mobile phase: See Table 6.

Table 6

Diluent: Acetonitrile and water (60:40)

Sensitivity solution: 0.4 μg/mL of USP Indomethacin RS in Diluent. Sonicate to dissolve if needed.

Standard solution: 0.8 μg/mL of USP Indomethacin RS, 1.1 μg/mL of USP Indomethacin Related Compound A RS, and 3.3 μg/mL of USP

Indomethacin Related Compound B RS in Diluent. Sonicate to dissolve if needed.

Sample solution: Nominally 750 μg/mL of indomethacin in Diluent, prepared as follows. Transfer a suitable quantity of the contents of

Capsules (NLT 20), equivalent to about 75 mg of indomethacin, to a 100-mL volumetric flask. Add about 60 mL of Diluent, shake gently for 5 min, then sonicate for about 10 min with intermittent shaking. Dilute with Diluent to volume. Pass through a suitable filter of 0.45-μm pore size.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

[Note—Rinsing with 2 mL of methanol and water (80:20) may be used before and after injection.]

Mode: LC

Detector: UV 230 nm

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

Temperatures

Autosampler: 6°

Column: 40°

Flow rate: 1 mL/min

Injection volume: 10 μL

System suitability

Samples: Sensitivity solution and Standard solution

Suitability requirements

Relative standard deviation: NMT 5.0% for indomethacin, indomethacin related compound A, and indomethacin related compound B,

Standard solution

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

Analysis

Samples: Standard solution and Sample solution

Calculate the percentages of indomethacin related compound A and indomethacin related compound B in the portion of Capsules taken:

Result = (r_U/r_S)x(C_S/C_U ) × 100

r_U = peak response of indomethacin related compound A or indomethacin related compound B from the Sample solution

r_S = peak response of indomethacin related compound A or indomethacin related compound B from the Standard solution

C_S = concentration of the corresponding USP Reference Standard in the Standard solution (μg/mL)

C_U = nominal concentration of indomethacin in the Sample solution (μg/mL)

Calculate the percentage of any unspecified degradation product in the portion of Capsules taken:

Result = (r_U/r_S)x(C_S/C_U) × 100

r_U = peak response of any unspecified degradation product from the Sample solution

r_S = peak response of indomethacin from the Standard solution

C_S = concentration of USP Indomethacin RS in the Standard solution (μg/mL)

C_U = nominal concentration of indomethacin in the Sample solution (μg/mL)

Acceptance criteria: See Table 7.

Table 7

^a Process impurity listed for peak identification only, and not to be reported or to be included in the total degradation products.

^b 4-Chloro-N-(4-methoxyphenyl)benzamide.

^c 1-(4-Chlorobenzoyl)-1-(4-methoxyphenyl)-2-(4-chlorobenzoyl)hydrazide.

^d 4-Chloro-N′-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetyl)-N-(4-methoxyphenyl)benzohydrazide.

6 ADDITIONAL REQUIREMENTS

Change to read:

Packaging and Storage: Preserve in well-closed containers. Store at controlled room temperature. (USP 1-May-2020)

Change to read:

Labeling: When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 is not used. (USP 1-May- 2020)

Change to read:

USP Reference Standards 〈11〉

USP Indomethacin RS

USP Indomethacin Related Compound A RS

2-(5-Methoxy-2-methyl-1H-indol-3-yl)acetic acid.

C₁₂H₁₃NO₃ 219.24

USP Indomethacin Related Compound B RS

4-Chlorobenzoic acid.

C₇H₅ClO₂ 156.57 (USP 1-May-2020)