Carbidopa and Levodopa Orally Disintegrating 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

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Carbidopa and Levodopa Orally Disintegrating Tablets contain NLT 90.0% and NMT 110.0% of the labeled amounts of carbidopa (C₁₀H₁₄N₂O₄) and levodopa (C₉H₁₁NO₄).

2 IDENTIFICATION

A. The retention times of the major peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay.

3 ASSAY

PROCEDURE

Protect the volumetric solutions from light.

Buffer: 6.6 g/L of monobasic sodium phosphate in water, adjusted with phosphoric acid to a pH of 2.2

Mobile phase: Alcohol and Buffer (5:95)

Standard solution: 0.025 mg/mL of USP Carbidopa RS and 0.25 mg/mL of USP Levodopa RS in Mobile phase

Sample stock solution: Transfer NLT 10 Tablets to a 1-L volumetric flask. Add 750 mL of Mobile phase, sonicate for 20 min, and then stir for 20 min. Dilute with Mobile phase to volume.

Sample solution: Dilute the Sample stock solution with Mobile phase to obtain a nominal concentration of carbidopa of between 0.025 and 0.07 mg/mL and a nominal concentration of levodopa of 0.25 mg/mL.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 280 nm

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

Autosampler temperature: 6°

Flow rate: 1 mL/min

Injection volume: 20 µL

System suitability

Sample: Standard solution

[NOTE-The relative retention times for levodopa and carbidopa are 0.42 and 1.0, respectively.]

Suitability requirements

Tailing factor: NMT 2.4 for both the levodopa and carbidopa peaks

Relative standard deviation: NMT 2.0% for both carbidopa and levodopa

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amounts of carbidopa (C₁₀H₁₄N₂O₄) and levodopa (C₉H₁₁NO₄) in the portion of Tablets taken:

Result = (r_U/r_S) x (C_S/C_U) × 100

r_U = peak response of carbidopa or levodopa from the Sample solution

r_S = peak response of carbidopa or levodopa from the Standard solution

C_S = concentration of USP Carbidopa RS or USP Levodopa RS in the Standard solution (mg/mL)

C_U = nominal concentration of carbidopa or levodopa in the Sample solution (mg/mL)

Acceptance criteria: 90.0%-110.0% each of the labeled amounts of carbidopa and levodopa

4 PERFORMANCE TESTS

DISINTEGRATION (701): NMT 60 s

DISSOLUTION (711)

Test 1

Medium: 0.1 N hydrochloric acid: 750 mL

Apparatus 2: 50 rpm

Time: 10 min

Solution A: 0.24 g/L of sodium 1-decanesulfonate in water

Mobile phase: Dissolve 11.0 g of monobasic sodium phosphate monohydrate in 1 L of water. Add 1.3 mL of Solution A, and adjust with phosphoric acid to a pH of 2.8.

Standard solution: (L/800) mg/mL each of USP Carbidopa RS and USP Levodopa RS in Medium, where L is the label claim in mg/Tablet of carbidopa or levodopa

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size, and discard the first 3 mL.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 280 nm

Column: 4.6-mm x 15.0-cm, 5-µm packing 11

Autosampler temperature: 4"

Flow rate: 2 mL/min

Injection volume: 20 µL

System suitability

Sample: Standard solution

[NOTE-The relative retention times for levodopa and carbidopa are 0.4 and 1.0, respectively.]

Suitability requirements

Tailing factor: NMT 2.0 for both levodopa and carbidopa

Relative standard deviation: NMT 2.0% for both levodopa and carbidopa

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amounts of carbidopa (C₁₀H₁₄N₂O₄) and levodopa (C₉H₁₁NO₄) dissolved:

Result = (r_U/r_S) x C_S x Vx (1/L) x 100

r_U = peak response of carbidopa or levodopa from the Sample solution

r_S = peak response of carbidopa or levodopa from the Standard solution

C_S = concentration of USP Carbidopa RS or USP Levodopa RS in the Standard solution (mg/mL)

V = volume of the Medium, 750 mL

L = label claim of carbidopa or levodopa (mg/Tablet)

Tolerances: NLT 75% (0) of the labeled amount of carbidopa (C₁₀H₁₄N₂O₄)  is dissolved, and NLT 75% (0) of the labeled amount of levodopa (C₉H₁₁NO₄) is dissolved.

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

Medium: 0.1 N hydrochloric acid; 750 ml, degassed

Apparatus 2: 75 rpm

Time: 15 min

Solution A: 0.24 g/L of sodium 1 decanesulfonate in water

Mobile phase: 12.5 g/L of monobasic sodium phosphate dihydrate prepared as follows. Transfer an appropriate amount of monobasic

sodium phosphate dihydrate to a suitable volumetric flask. Dissolve in 95% of the flask volume of water. Add 0.13% of the flask volume of

Solution A, and adjust with phosphoric acid to a pH of 2.8±0.05. Dilute with water to volume. Standard stock solution 1: 0.19 mg/ml. of USP Carbidopa RS in Medium, Transfer an appropriate amount of USP Carbidopa RS to a suitable volumetric flask. Add about 60% of the flask volume of Medium and sonicate to promote dissolution. Allow the solution to cool to room temperature and dilute with Medium to volume.

Standard stock solution 2: 1.1 mg/mL of USP Levodopa RS in Medium. Transfer an appropriate amount of USP Levodopa RS to a suitable volumetric flask. Add about 60% of the flask volume of Medium and sonicate to promote dissolution. Allow the solution to cool to room temperature and dilute with Medium to volume.

Standard solution

For Tablets labeled to contain 10 mg of carbidopa and 100 mg of levodopa: 0.015 mg/mL of USP Carbidopa RS from Standard stock

solution 1 and 0.13 mg/mL of USP Levodopa RS from Standard stock solution 2 in Medium

For Tablets labeled to contain 25 mg of carbidopa and 100 or 250 mg of levodopa: 0.038 mg/mL of USP Carbidona RS from Standard stock solution 1 and 0.22 mg/ml. of USP Levodopa RS from Standard stock solution 2 in Medium

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-um pore size, and discard the first 2 mL.

Chromatographic system

(See Chromatography (621). System Suitability.)

Mode: LC

Detector: UV 280 nm

Column: 3.9-mm x 30.0-cm, 10-um packing 11

Flow rate: 2 mL/min

Injection volume: 20 µL

Run time: NLT 1.3 times the retention time of carbidopa

System suitability

Sample: Standard solution

[NOTE-The relative retention times for levodopa and carbidopa are 0.4 and 1.0, respectively.)

Suitability requirements

Resolution: NLT 6 between levodopa and carbidopa

Tailing factor: NMT 2.0 for both levodopa and carbidopa

Relative standard deviation: NMT 2.0% for both levodopa and carbidopa

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amounts of carbidopa (C₁₀H₁₄N₂O₄) and levodopa (C₉H₁₁NO₄) dissolved:

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

r_U = peak response of carbidopa or levodopa from the Sample solution

r_S = peak response of carbidopa or levodopa from the Standard solution

C_S = concentration of USP Carbidona RS or USP Levodopa RS in the Standard solution (mg/mL)

V = volume of the Medium, 750 mL

L = label claim of carbidopa or levodopa (mg/Tablet)

Tolerances: NLT 75% (Q) of the labeled amount of carbidopa (C₁₀H₁₄N₂O₄) is dissolved, and NLT 75% (Q) of the labeled amount of levodopa (C₉H₁₁NO₄) is dissolved.

UNIFORMITY OF DOSAGE UNITS (905): Meet the requirements

5 IMPURITIES

Change to read:

ORGANIC IMPURITIES

Protect all analytical solutions from light, and maintain them at 2"-8" until they are injected.

Diluent: Methanol and 0.1 N bydrochloric acid (30:70)

Mobile phase: 13.8 g/L of monobasic sodium phosphate monohydrate in water, adjusted with phosphoric acid to a pH of 2.7

System suitability solution: 0.025 mg/ml. each of USP Carbidopa RS, USP Levodopa RS, USP Levodopa Related Compound A RS, USP Levodopa Related Compound B RS, and USP Methyldopa RS in Diluent

Standard solution: 0.025 mg/mL of USP Levodopa RS in Diluent

Sample solution: Transfer a weighed quantity of powder equivalent to 250 mg of levodopa from NLT 20 finely powdered Tablets to a 100-mL volumetric flask. Add 80 ml. of Diluent, sonicate for 10 min, and then stir for 30 min. Dilute with Diluent to volume. Centrifuge, and inject the supernatant within 2 h.

Chromatographic system

(See Chromatography (621). System Suitability.)

Mode: LC

Detector: UV 280 nm.

Column: 4.6-mm x 25-cm; 5-um packing LZ

Autosampler temperature: 4"

Flow rate: 1.5 mL/min

Injection volume: 20 µL

Run time: 6 times the retention time of carbidopa

System suitability

Samples: System suitability solution and Standard solution

[NOTE-For the relative retention times, see Table 1. If peak fronting for levodopa related compound A is observed, lowering the column

temperature to 15" is recommended to eliminate this problem.]

Resolution: NLT 1.5 between levodopa related compound A and levodopa, NLT 2.0 between carbidopa and levodopa related compound B, and NLT 1.5 between methyldopa and carbidopa; System suitability solution

Suitability requirements

Relative standard deviation: NMT 5.0% for levodopa, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of all impurities and any unspecified degradation product other than methyldopa and 3,4-dihydroxyphenylacetone, based on the label claim of levodopa in the portion of Tablets taken:

Result = (r_U/r_S) x (C_S/C_U) × (1/F) × 100

r_U = peak response of levodopa related compound A or any unspecified degradation product from the Sample solution

r_S = peak response of levodopa from the Standard solution

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

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

F = relative response factor (see Table 1)

Calculate the percentage of methyldopa and 3,4-dihydroxyphenylacetone based on the label claim of carbidopa in the portion of Tablets taken:

Result = (r_U/r_S) x (C_S/C_U) × (1/F) × 100

r_U = peak response of methyldopa or 3,4-dihydroxyphenylacetone from the Sample solution

r_S = peak response of levodopa from the Standard solution

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

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

F = relative response factor (see Table 1)

Acceptance criteria: See Table 1.

^a Individual impurity based on the label claim of levodopa.

^b Individual impurity based on the label claim of carbidopa.

^c Process-related impurities, included for identification only; not to be included in total impurities.

^d (S)-2-Hydrazinyl-3-(4-hydroxy-3-methoxyphenyl)-2-methylpropanoic acid.

^e Excluding all process impurities and 3,4-dihydroxyphenylacetone.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed, light-resistant containers, and store at controlled room temperature.

Labeling: The labeling states the Dissolution test used only if Test 1 is not used.

Change to read:

USP Reference Standards 〈11〉

USP Carbidopa RS

USP Levodopa RS

USP Levodopa Related Compound A RS

3-(2,4,5-Trihydroxyphenyl)-L-alanine (RB 1-May-2022)

C₉H₁₁NO₅ 213.19

USP Levodopa Related Compound B RS

3-Methoxytyrosine.

C₁₃H₁₄NO₄ 211.22 (RB 1-May-2022)

USP Methyldopa RS