Mycophenolic Acid Delayed-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

Mycophenolic Acid Delayed-Release Tablets contain an amount of mycophenolate sodium equivalent to NLT 95.0% and NMT 105.0% of the labeled amount of mycophenolic acid (C₁₇H₂₀O₆).

2 IDENTIFICATION

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

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

3 ASSAY

PROCEDURE

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Solution A: Dissolve 21 g of citric acid in a suitable volume of water, add 200 mL of 1 M sodium hydroxide solution, and dilute with water to 1 L.

Buffer: Solution A and 0.1 M hydrochloric acid (399:601)

Solution B: Acetonitrile, Buffer, and water (40:15:45)

Solution C: Acetonitrile and Buffer (85:15)

Mobile phase: See Table 1. Return to original conditions, and re-equilibrate the system.

Table 1

Diluent: Solution B

Standard solution: 0.385 mg/mL of USP Mycophenolate Sodium RS in Diluent. Stir magnetically for at least 60 min to aid dissolution.

Sample stock solution: Nominally equivalent to 9 mg/mL of mycophenolic acid in Diluent prepared as follows. Transfer NLT 25 Tablets to a volumetric flask and add Diluent to volume. Add a stirring bar and stir vigorously for at least 60 min. Centrifuge a portion of the suspension and use the clear supernatant.

Sample solution: Nominally equivalent to 0.36 mg/mL of mycophenolic acid in Diluent from Sample stock solution

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 251 nm or diode array. [NOTE-Use a diode array detector to perform Identification B.]

Column: 4.6-mm x 25-cm, 5-µm packing 17

Column temperature: 40°

Flow rate: 1 mL/min

Injection volume: 10 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of mycophenolic acid (C₁₇H₂₀O₆) in the portion of Tablets taken:

Result = (r_u /r_s ) × (C_s /C_u ) × (M_r1 /M_r2 ) × 100

r_u = peak response of mycophenolate from the Sample solution

r_s = peak response of mycophenolate from the Standard solution

C_s = concentration of USP Mycophenolate Sodium RS in the Standard solution (mg/mL)

C_u = nominal concentration of mycophenolic acid in the Sample solution (mg/mL)

M_r1 = molecular weight of mycophenolic acid, 320.34

M_r2 = molecular weight of mycophenolate sodium, 342.32

Acceptance criteria: 95.0%–105.0%

4 PERFORMANCE TESTS

DISSOLUTION (711)

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4.1 Acid stage

Acid stage medium: 0.1 N hydrochloric acid: 750 mL

Apparatus 2: 50 rpm

Time: 2 h

Determine the percentage of the labeled amount of mycophenolic acid (C₁₇H₂₀O₆) dissolved by using one of the following procedures.

Spectrophotometric procedure

(See Ultraviolet-Visible Spectroscopy (857).)

Standard solution: Transfer USP Mycophenolate Sodium RS to a suitable volumetric flask, dissolve in methanol equivalent to 5% of the final volume, and dilute with Acid stage medium to volume to obtain the solution having the following concentrations:

For Tablets labeled to contain 180 mg of mycophenolic acid: 0.0128 mg/mL of USP Mycophenolate Sodium RS

For Tablets labeled to contain 360 mg of mycophenolic acid: 0.0256 mg/mL of USP Mycophenolate Sodium RS

Sample solution: Centrifuge portions of the solution under test or pass through a suitable glass fiber filter of 1-µm pore size.

Instrumental conditions

Mode: UV

Analytical wavelength: 250 nm

Cell path length

For Tablets containing 180 mg of mycophenolic acid per Tablet: 0.2 cm

For Tablets containing 360 mg of mycophenolic acid per Tablet: 0.1 cm

Blank: Acid stage medium

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of mycophenolic acid (C₁₇H₂₀O₆) dissolved:

Result = (A_u /A_s ) × (C_s /L) × V × (M_r1 /M_r2 ) × 100

A_u = absorbance of the Sample solution

A_s = absorbance of the Standard solution

C_s = concentration of USP Mycophenolate Sodium RS in the Standard solution (mg/mL)

L = label claim (mg/Tablet)

V = volume of Acid stage medium, 750 mL

M_r1 = molecular weight of mycophenolic acid, 320.34

M_r2 = molecular weight of mycophenolate sodium, 342.32

Chromatographic procedure

Solution A: Solution of 4 mL of triethylamine in 1300 mL of water. Adjust with phosphoric acid to a pH of 5.3.

Mobile phase: Acetonitrile and Solution A (35:65)

Diluent: Mixture of 0.1 N hydrochloric acid and 0.2 M sodium phosphate (75:25), adjusted with either 2 M sodium hydroxide or hydrochloric acid to a pH of 6.8

Standard solution: Solution of USP Mycophenolate Sodium RS in Diluent, equivalent to (L/1000) mg/mL of mycophenolic acid, where L is the label claim in mg/Tablet

Sample solution: Mix 10 mL of the solution under test and 10 mL of 0.2 M sodium phosphate.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 250 nm

Column: 4.6-mm x 25-cm; 5-µm packing 111

Temperatures

Autosampler: 4^o

Column: 45^o

Flow rate: 1.5 mL/min

Injection volume: 5 µL

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 mycophenolic acid (C₁₇H₂₀O₆) dissolved:

(r_u /r_s ) × (C_s /L) × V × D × (M_r1 /M_r2 ) × 100

r_u = peak response from the Sample solution

r_s = peak response from the Standard solution

C_s = concentration of USP Mycophenolate Sodium RS in the Standard solution (mg/mL)

L = label claim (mg/Tablet)

V = volume of Acid stage medium, 750 mL

D = dilution factor for the Sample solution

M_r1 = molecular weight of mycophenolic acid, 320.34

M_r2 = molecular weight of mycophenolate sodium, 342.32

Tolerances: NMT 5% of the labeled amount of mycophenolic acid (C₁₇H₂₀O₆) is dissolved.

4.2 Buffer stage

Buffer stage medium: After 2 h, continue with a pH 6.8 phosphate buffer as follows. Add 250 mL of 0.2 M sodium phosphate and adjust, if necessary, with 2 M sodium hydroxide or hydrochloric acid to a pH of 6.8; 1000 mL. [NOTE-If the volume of the sample withdrawn is greater than 2 mL, replace it with Acid stage medium. Alternatively, increase the volume of 0.2 M sodium phosphate being added to obtain the final volume of 1000 mL and adjust, if necessary, with 2 M sodium hydroxide or hydrochloric acid to a pH of 6.8.]

Apparatus 2: 50 rpm

Time: 1 h. [NOTE-The total time for this analysis is 3 h, where 2 h is from the Acid stage and 1 h is from the Buffer stage.] Determine the percentage of the labeled amount of mycophenolic acid (C₁₂H₂O) dissolved by using one of the following procedures.

Spectrophotometric procedure

(See Ultraviolet-Visible Spectroscopy (857).)

Standard solution: Solution of USP Mycophenolate Sodium RS, equivalent to (L/1000) mg/mL of mycophenolic acid, where L is the label claim, in mg/Tablet. Prepare the solution as follows. Transfer USP Mycophenolate Sodium RS to a suitable volumetric flask, dissolve in methanol equivalent to 5% of the final volume, and dilute with Buffer stage medium to volume.

Sample solution: Centrifuge portions of the solution under test or pass through a suitable glass fiber filter of 1-µum pore size.

Instrumental conditions

Mode: UV

Analytical wavelength: 250 nm

Cell path length

For Tablets containing 180 mg of mycophenolic acid per Tablet: 0.2 cm

For Tablets containing 360 mg of mycophenolic acid per Tablet: 0.1 cm

Blank: Buffer stage medium

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of mycophenolic acid (C₁₇H₂₀O₆) dissolved:

Result = (A_u /A_s ) × (C_s /L) × V × (M_r1 /M_r2 ) × 100

A_u = absorbance of the Sample solution

A_s = absorbance of the Standard solution

C_s = concentration of USP Mycophenolate Sodium RS in the Standard solution (mg/mL)

L = label claim (mg/Tablet)

V = volume of Buffer stage medium, 1000 mL

M_r1 = molecular weight of mycophenolic acid, 320.34

M_r2 = molecular weight of mycophenolate sodium, 342.32

Chromatographic procedure

Solution A, Mobile phase, Standard solution, and Chromatographic system: Proceed as directed under Chromatographic procedure in

4.3 Acid stage

Sample solution: Pass the solution under test through a suitable polyethersulfone membrane filter of 0.45-µm pore size and discard a few milliliters of the filtrate.

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of mycophenolic acid (C₁₇H₂₀O₆) dissolved:

(r_u /r_s ) × (C_s /L) × V × (M_r1 /M_r2 ) × 100

r_u = peak response from the Sample solution

r_s = peak response from the Standard solution

C_s = concentration of USP Mycophenolate Sodium RS in the Standard solution (mg/mL)

L = label claim (mg/Tablet)

V = volume of Buffer stage medium, 1000 mL

M_r1 = molecular weight of mycophenolic acid, 320.34

M_r2 = molecular weight of mycophenolate sodium, 342.32

Tolerances: NLT 80% (Q) of the labeled amount of mycophenolic acid (C₁₇H₂₀O₆) is dissolved.

Uniformity of Dosage Units 〈905〉, Weight Variation: Meet the requirements

5 IMPURITIES

ORGANIC IMPURITIES

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

System suitability solution: 0.36 µg/mL of USP Mycophenolate Mofetil Related Compound B RS and 0.385 mg/mL of USP Mycophenolate

Sodium RS in Diluent. Stir magnetically for at least 60 min to aid dissolution.

Sensitivity solution: 0.18 µg/mL of USP Mycophenolate Sodium RS in Diluent from Standard solution

System suitability

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

Suitability requirements

Resolution: NLT 1.5 between the mycophenolate mofetil related compound B and mycophenolate peaks, System suitability solution

Tailing factor: NMT 2.0, Standard solution

Relative standard deviation: NMT 2.0%, Standard solution

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

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Tablets taken:

Result = (r_u /r_s ) × (C_s /C_u ) × (M_r1 /M_r2 ) × 100

r_u = peak response of each individual impurity from the Sample solution

r_s = peak response of mycophenolate from the Standard solution

C_s = concentration of USP Mycophenolate Sodium RS in the Standard solution (mg/mL)

C_u = nominal concentration of mycophenolic acid in the Sample solution (mg/mL)

M_r1 = molecular weight of mycophenolic acid, 320.34

M_r2 = molecular weight of mycophenolate sodium, 342.32

Acceptance criteria: See Table 2. The reporting threshold is 0.05%.

^a It is a process impurity and is listed for identication only. It is controlled in the drug substance. It is not reported for the drug product and should not be included in the total impurities.

^b 2-(Ethoxycarbonyl)benzoic acid.

^c Ethyl (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoate.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers, and protect from moisture. Store at controlled room temperature.

USP Reference Standards 〈11〉

USP Mycophenolate Mofetil Related Compound B RS

(RS)-7-Hydroxy-5-methoxy-4-methyl-6-[2-(5-methyl-2-oxo-tetrahydrofuran-5-yl)ethyl]-3H-isobenzofuran-1-one.

C₁₇H₂₀O₆            320.34

USP Mycophenolate Sodium RS