Carbidopa and Levodopa 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

Carbidopa and Levodopa Extended-Release Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount 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.

B. The UV spectra 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 preparations from light.

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

Solution B: 11.6 g/L of monobasic sodium phosphate in water

Mobile phase: Solution A, Solution B, and water (0.13:95:4.87), prepared as follows. Add 0.13% of the final volume of Solution A to 95% of the final volume of Solution B. Adjust with phosphoric acid to a pH of 2.8. Dilute with water to final volume.

Standard solution: 0.1 mg/mL of USP Carbidopa RS and 0.4 mg/mL of USP Levodopa RS in solution, prepared as follows. Transfer accurately weighed portions of the Reference Standards into a suitable volumetric flask, and dissolve in 0.1 N phosphoric acid using 8% of the final volume. Sonication may be used to promote dissolution. Dilute with water to final volume.

Sample solution: Nominally 0.1 mg/mL of carbidopa and 0.4 mg/mL of levodopa from NLT 20 finely powdered Tablets, prepared as follows. Transfer an accurately weighed portion of the powder, equivalent to 1 Tablet weight, into a suitable volumetric flask, and dissolve in 0.1 N phosphoric acid, using 10% of the final volume. Sonicate for 10 min and then stir for 30 min. Dilute with water to volume and stir for another 20 min. Pass the solution through a suitable filter of 0.45-um pore size.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 280 nm. For Identification B, use a diode array detector in the range of 200-350 nm.

Column: 4.6-mm x 10-cm; 5-µm packing 11

Flow rate: 2 mL/min

Injection volume: 20 µL

Run time: NLT 4 times the retention time of levodopa

System suitability

Sample: Standard solution

[NOTE-The relative retention times for levodopa and carbidopa are 1.0 and 2.8, respectively.]

Suitability requirements

Tailing factor: NMT 1.5 for carbidopa; NMT 1.5 for levodopa

Resolution: NLT 6 between levodopa and carbidopa

Relative standard deviation: NMT 1.0% for carbidopa; NMT 1.0% for levodopa

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of carbidopa (C, H, N₂O) or levodopa (C,H, NO) 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

DISSOLUTION (711)

Test 1

Medium: 0.1 N hydrochloric acid: 900 ml. degassed with helium

Apparatus 2: 50 rpm

Times

For Tablets that contain 25 mg of carbidopa and 100 mg of levodopa: 0.5, 1, and 4 h

For Tablets that contain 50 mg of carbidopa and 200 mg of levodopa: 0.5, 1, 2.5, and 4 h

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

Solution B: 12.7 g/L of monobasic sodium phosphate in water

Mobile phase: Solution A, Solution B, and water (0.13:95:4.87), prepared as follows. Add 0.13% of the final volume of Solution A to 95% of the final volume of Solution B. Adjust with phosphoric acid to a pH of 2.8. Dilute with water to final volume.

Standard solution: 0.03 mg/ml. of USP Carbidopa RS and 0.1 mg/mL of USP Levodopa RS in Medium. Sonication may be used to aid in dissolution.

Sample solution

For Tablets that contain 25 mg of carbidopa and 100 mg of levodopa: Pass a portion of the solution under test through a suitable filter of 0.45-um pore size and discard the first 1-3 mL..

For Tablets that contain 50 mg of carbidopa and 200 mg of levodopa: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size, discard the first 1-3 mL, and dilute with Medium (50:50).

Chromatographic system

(See Chromatography (621). System Suitability.)

Mode: LC

Detector: UV 280 nm

Column: 3.9-mm x 30-cm; 10-µm packing 11

Flow rate: 2 mL/min

Injection volume: 20 µL

Run time: NLT 3 times the retention time of levodopa

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 2.0 between levodopa and carbidopa

Relative standard deviation: NMT 2.0% for carbidopa and NMT 2.0% for levodopa for six replicate injections

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C) of carbidopa (C₁₀H₁₄N₂O₄) and levodopa (C₉H₁₁NO₄) in the sample withdrawn from the vessel at each time point (/):

Result = (r_U/r_S) x C_S xD

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)

D = dilution factor for the Sample solution, if needed

Calculate the percentage of the labeled amount of carbidopa (C₁₀H₁₄N₂O₄) and levodopa (C₉H₁₁NO₄) dissolved at each time point (1):

Result₁ = C₁ x V x (1/L) x 100

Result₂ = {[C₂ x (V-V)]+(C₁ x V_S) x (1/L) x 100

Result₃ = ({C₃ x [V- (2xV)]+[(C₂ +C₁) x V_S]) x (1/L) x 100

Result₄ = ({C₄x [V-(3xV_S)]+[(C₃+C₂+C₁) x V_S]) x (1/L) x 100

Ci = concentration of carbidopa or levodopa in the portion of sample withdrawn at time point i (mg/mL)

V volume of the Medium, 900 mL

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

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

Tolerances

For Tablets that contain 25 mg of carbidopa and 100 mg of levodopa: See Table 1.

Table 1

For Tablets that contain 25 mg of carbidopa and 200 mg of levodopa: See Table 2.

Table 2

The percentages of the labeled amounts of carbidopa (C₁₀H₁₄N₂O₄) and levodopa (C₉H₁₁NO₄) 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: Simulated gastric fluid TS (prepared without enzymes); 900 mL

Apparatus 2: 50 rpm

Times: 0.5, 1, 2, and 3 h

Buffer: 6.8 g/L of monobasic potassium phosphate and 1.0 g/L of 1-hexanesulfonic acid in water. Adjust with phosphoric acid to a pH of 3.3.

Mobile phase: Filtered and degassed mixture of methanol and Buffer (20:80)

Standard solution: (L/900) mg/mL each of USP Carbidopa RS and USP Levodopa RS in Medium, where L is the label claim, in mg/Tablet

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-μm pore size.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 280 nm

Column: 4.6-mm × 15-cm; 5-μm packing L7

Flow rate: 1 mL/min

Injection volume: 20 μL

Run time: NLT 2.5 times the retention time of levodopa

System suitability

Sample: Standard solution

[Note—The relative retention times for levodopa and carbidopa are 1.0 and 1.4, respectively.]

Suitability requirements

Resolution: NLT 2.0 between levodopa and carbidopa

Column ifieciency: NLT 4000 theoretical plates for both carbidopa and levodopa

Tailing factor: NMT 2.0 for both carbidopa and levodopa

Relative standard deviation: NMT 1.0% for both carbidopa and levodopa

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C) of carbidopa (C₁₀H₁₄N₂O₄) and levodopa (C₉H₁₁NO₄) in the sample withdrawn from the vessel at each time point (i):

Result = (r_U/r_S) x C_S

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)

Calculate the percentage of the labeled amount of carbidopa (C₁₀H₁₄N₂O₄) and levodopa (C₉H₁₁NO₄) dissolved at each time point (1):

Result₁ = C₁ x V x (1/L) x 100

Result₂ = {[C₂ x (V-V)]+(C₁ x V_S) x (1/L) x 100

Result₃ = ({C₃ x [V- (2xV)]+[(C₂ +C₁) x V_S]) x (1/L) x 100

Result₄ = ({C₄x [V-(3xV_S)]+[(C₃+C₂+C₁) x V_S]) x (1/L) x 100

Ci = concentration of carbidopa or levodopa in the portion of sample withdrawn at time point i (mg/mL)

V volume of the Medium, 900 mL

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

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

Tolerances: See Table 3.

Table 3

The percentages of the labeled amounts of carbidopa (C₁₀H₁₄N₂O₄) and levodopa (C₉H₁₁NO₄) 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, Apparatus 2, Solution A, Solution B, Mobile phase, Standard solution, Chromatographic system, and System suitability: Proceed as directed in Test 1.

Times: 0.5, 1, 2.5, and 4 h

Sample solution: Pass a portion of the solution under test through a suitable filter.

Analysis: Proceed as directed in Test 1.

Tolerances: See Table 4.

Table 4

The percentages of the labeled amounts of carbidopa (C₁₀H₁₄N₂O₄) and levodopa (C₉H₁₁NO₄) 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: 0.1 N hydrochloric acid; 900 mL

Apparatus 2: 50 rpm

Times: 1, 3, and 6 h

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

Solution B: 11.6 g/L of monobasic sodium phosphate in water

Mobile phase: Solution A, Solution B, and water (0.13:95:4.87), prepared as follows. Add 0.13% of the final volume of Solution A to 95% of the final volume of Solution B. Adjust with phosphoric acid to a pH of 2.8. Dilute with water to final volume.

Standard solution: (L/900) mg/mL each of USP Carbidopa RS and USP Levodopa RS in Medium, where L is the label claim, in mg/Tablet

Sample solution: Withdraw a 10.0-mL aliquot at each time point and pass a portion of the solution under test through a suitable filter.

Replace the 10.0-mL aliquot withdrawn for analysis with a 10.0-mL aliquot of Medium.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 280 nm

Column: 3.9-mm × 30-cm; 10-μm packing L1

Flow rate: 2 mL/min

Injection volume: 50 μL

Run time: NLT 3 times the retention time of levodopa

System suitability

Sample: Standard solution

[Note—The relative retention times for levodopa and carbidopa are 1.0 and 2.5, respectively.]

Suitability requirements

Resolution: NLT 2.0 between levodopa and carbidopa

Tailing factor: NMT 2.0 for both carbidopa and levodopa

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

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C ) of carbidopa (C₁₀H₁₄N₂O₄) and levodopa (C₉H₁₁NO₄) in the sample withdrawn from the vessel at each time point (i):

Result = (r_U/r_S) × C_S

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)

Calculate the percentage of the labeled amount of carbidopa (C₁₀H₁₄N₂O₄) and levodopa (C₉H₁₁NO₄) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

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

Result₃ = [(C₃ × V) + (C₂ + C₁ ) × V_S ] × (1/L) × 100

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

V = volume of the Medium, 900 mL

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

V_S = volume of the Sample solution withdrawn from the vessel and replaced with Medium, 10 mL

Tolerances: See Table 5.

Table 5

The percentages of the labeled amounts of carbidopa (C₁₀H₁₄N₂O₄) and levodopa (C₉H₁₁NO₄) 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: 0.1 N hydrochloric acid; 900 mL

Apparatus 2: 50 rpm

Times: 0.5, 1, 2.5, and 4 h

Mobile phase: 13.6 g/L of monobasic potassium phosphate adjusted with phosphoric acid to a pH of 3.0

Standard solution: (L/900) mg/mL each of USP Carbidopa RS and USP Levodopa RS in Medium, where L is the label claim, in mg/Tablet.

[Note—This solution is stable for 1 day if stored at 23°–27°.]

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-μm pore size, and discard the first 4–5 mL.

[Note—This solution is stable for 1 day if stored at 23°–27°.]

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 282 nm

Column: 4.6-mm × 15-cm; 5-μm packing L7

Flow rate: 1.5 mL/min

Injection volume: 20 μL

Run time: NLT 3 times the retention time of levodopa

System suitability

Sample: Standard solution

[Note—The relative retention times for levodopa and carbidopa are 1.0 and 1.6, respectively.]

Suitability requirements

Resolution: NLT 2.0 between levodopa and carbidopa

Tailing factor: NMT 2.0 for both carbidopa and levodopa

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

Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C ) of carbidopa (C₁₀H₁₄N₂O₄) and levodopa (C₉H₁₁NO₄) in the sample withdrawn from the vessel at each time point (i):

Result = (r_U/r_S) x C_S

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)

Calculate the percentage of the labeled amount of carbidopa (C₁₀H₁₄N₂O₄) and levodopa (C₉H₁₁NO₄) dissolved at each time point (i):

Result₁ = C₁× V × (1/L) × 100

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

Result₃ = ({C₃ × [V − (2 × V )]} + [(C₂ + C₁ ) × V ]) × (1/L) × 100

Result₄ = ({C₄ × [V − (3 × VS )]} + [(C₃ + C₂ + C₁ ) × V_S ]) × (1/L) × 100

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

V = volume of the Medium, 900 mL

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

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

Tolerances: See Table 6.

The percentages of the labeled amounts of carbidopa (C₁₀H₁₄N₂O₄) and levodopa (C₉H₁₁NO₄) dissolved at the times specified conform to

Dissolution 〈711〉, Acceptance Table 2.

Test 6: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 6.

Medium: 0.1 N hydrochloric acid; 900 mL degassed under vacuum

Apparatus 1: 75 rpm

Times: 0.5, 1, 2.5, and 3.5 h

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

Mobile phase: To each liter of 12.5 g/L of monobasic sodium phosphate dihydrate, add 1.3 mL of Solution A and adjust with phosphoric acid to a pH of 2.8.

Standard solution: 0.03 mg/mL of USP Carbidopa RS and 0.11 mg/mL of USP Levodopa RS in Medium

Sample solution

For Tablets that contain 25 mg of carbidopa and 100 mg of levodopa: Pass a portion of the solution under test through a suitable filter of 0.45-μm pore size, discard the first 2 mL, and use the remaining filtrate. Use within 24 h.

For Tablets that contain 50 mg of carbidopa and 200 mg of levodopa: Pass a portion of the solution under test through a suitable filter of 0.45-μm pore size, discard the first 2 mL, and dilute with Medium (50:50). Use within 24 h.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 280 nm

Column: 3.9-mm × 30-cm; 10-μm packing L1

Flow rate: 2 mL/min

Injection volume: 20 μL

Run time: NLT 3 times the retention time of levodopa

System suitability

Sample: Standard solution

[Note—The relative retention times for levodopa and carbidopa are 1.0 and 2.8, respectively.]

Suitability requirements

Resolution: NLT 2.0 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 concentration (C ) of carbidopa (C₁₀H₁₄N₂O₄) and levodopa (C₉H₁₁NO₄) in the sample withdrawn from the vessel at each time point (i):

Result = (r_U/r_S) × C_S × D

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)

D = dilution factor for the Sample solution, if needed

Calculate the percentage of the labeled amount of carbidopa (C₁₀H₁₄N₂O₄) and levodopa (C₉H₁₁NO₄) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

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

Result₃ = ({C₃ × [V − (2 × V )]} + [(C₂ + C₁ ) × V ]) × (1/L) × 100

Result₄ = ({C₄ × [V − (3 × V )]} + [(C₃+ C₂ + C₁ ) × V ]) × (1/L) × 100

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

V = volume of the Medium, 900 mL

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

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

Tolerances: See Table 7.

The percentages of the labeled amounts of carbidopa (C₁₀H₁₄N₂O₄) and levodopa (C₉H₁₁NO₄) dissolved at the times specified conform to

Dissolution 〈711〉, Acceptance Table 2.

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

ORGANIC IMPURITIES

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

Buffer: 6 g/L of anhydrous monobasic sodium phosphate in water. Adjust with phosphoric acid to a pH of 2.2.

Mobile phase: Alcohol and Buffer (5:95)

System suitability solution: 1 µg/mL of USP Levodopa Related Compound B. RS and 125 µg/mL of USP Carbidopa RS in Mobile phase

Standard solution: 1.25 µg/mL of USP Carbidopa RS and 5 µg/mL of USP Levodopa RS in Mobile phase

Sensitivity solution: 0.125 µg/mL of USP Carbidopa RS and 0.5 µg/mL of USP Levodopa RS in Mobile phase from the Standard solution

Sample solution: Nominally 0.125 mg/mL of carbidopa and nominally 0.5 mg/mL of levodopa in Mobile phase from NLT 10 finely powdered Tablets, prepared as follows. Transfer an accurately weighed portion of the powder into a suitable volumetric flask, dissolve in Mobile phase, and pass through a suitable filter.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 280 nm

Column: 4.6-mm x 15-cm; 5-µm packing 11

Autosampler temperature: 6°

Flow rate: 1 mL/min

Injection volume: 20 µL

Run time: NLT 6 times the retention time of carbidopa

System suitability

Samples: System suitability solution, Standard solution, and Sensitivity solution

[NOTE-For the relative retention times, see Table 8.1

Suitability requirements

Resolution: NLT 1.5 between carbidopa and levodopa related compound B, System suitability solution

Relative standard deviation: NMT 3.0% for both carbidopa and levodopa for five replicate injections, Standard solution

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

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of dihydroxybenzaldehyde, dihydroxyphenylacetone, and any unspecified carbidopa degradant 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) x 100

r_U = peak response of dihydroxybenzaldehyde, dihydroxyphenylacetone, or any unspecified carbidopa degradant from the Sample solution

r_S = peak response of carbidopa from the Standard solution

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

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

Frelative response factor (see Table 8)

Calculate the percentage of levodopa related compound A and any unspecified levodopa degradant 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 levodopa degradant 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)

Frelative response factor (see Table 8)

Acceptance criteria: See Table 8. The reporting threshold is 0.05%, relative to the drug substance.

Table 8

^a Individual impurity based on label claim of levodopa.

^b 3-(3,4,6-Trihydroxyphenyl)alanine.

^c Individual impurity based on label claim of carbidopa.

^d This impurity is listed for information only. It is monitored in the drug substance. This impurity is not to be reported and is not to be included in the total degradants.

^e 3,4-Dihydroxybenzaldehyde.

^f 3,4-Dihydroxyphenylacetone.

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

6 ADDITIONAL REQUIREMENTS

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

Labeling: When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 is not used.

USP Reference Standards 〈11〉

USP Carbidopa RS

USP Levodopa RS

USP Levodopa Related Compound B RS

3-Methoxytyrosine.

C₁₃H₁₄NO₄ 211.21