Mycophenolate Mofetil for Oral Suspension

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

Mycophenolate mofetil for Oral Suspension is a dry mixture of mycophenolate mofetil and one or more suitable buffers, colors, diluents, and flavors. It contains NLT 90.0% and NMT 110.0% of the labeled amount of mycophenolate mofetil (C₂₃H₃₁NO₇).

2 IDENTIFICATION

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A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Ultraviolet-Visible Spectroscopy: 1970- _{(CN 1-MAY-2020)} [NOTE-Alternatively, the UV spectra of the major peaks of the Sample solution and the Standard solution, as obtained in the Assay, may also be used to meet the Acceptance criteria.]

Standard stock solution: 0.5 mg/mL of USP Mycophenolate Mofetil RS prepared as follows. Transfer a suitable amount of USP Mycophenolate Mofetil RS to a volumetric flask, add water equivalent to 15% of the flask volume, shake, and mix. Add acetonitrile equivalent to 70% of the flask volume, and sonicate to dissolve. Dilute with acetonitrile to volume.

Standard solution: 0.01 mg/mL of USP Mycophenolate Mofetil RS in acetonitrile, from Standard stock solution

Sample stock solution: Nominally equivalent to 0.5 mg/mL of mycophenolate mofetil prepared as follows. Constitute the Mycophenolate Mofetil for Oral Suspension as directed in the labeling. Transfer a suitable amount of reconstituted oral suspension to a volumetric flask, add water equivalent to 15% of the flask volume, shake, and mix. Add acetonitrile equivalent to 70% of the flask volume and sonicate to dissolve. Dilute with acetonitrile to volume. Pass a portion of this solution through a suitable filter of 0.45-µm pore size.

Sample solution: Nominally equivalent to 0.01 mg/mL of mycophenolate mofetil in acetonitrile, from Sample stock solution

Acceptance criteria: The UV absorption spectrum of the Sample solution exhibits maxima and minima at the same wavelengths as those of the Standard solution _{(USP 1-May-2019)}

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A _{(USP 1-MAY-2019)} 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

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PROCEDURE

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Buffer 1: Pipet 10 mL of triethylamine into a 1000-mL volumetric flask containing about 950 mL of water, and mix. Adjust with phosphoric acid to a pH of 7.2, and dilute with water to volume.

Buffer 2: Pipet 10 mL of triethylamine into a 1000-mL volumetric flask containing about 950 mL of water, and mix. Adjust with phosphoric acid to a pH of 3.0, and dilute with water to volume.

Solution A: Buffer 1 and water (4:9)

Extraction solvent: Acetonitrile, Buffer 2, and water (13:4:9)

Diluent: Acetonitrile, Buffer 2, and water (7:4:9)

Mobile phase: Acetonitrile and Solution A (3:7)

Standard stock solution: 4 mg/mL of USP Mycophenolate Mofetil RS in Extraction solvent. Sonicate to aid the dissolution.

Standard solution: 0.4 mg/mL of USP Mycophenolate Mofetil RS in Diluent, from the Standard stock solution

Sample stock solution: Nominally equivalent to 4 mg/mL of mycophenolate mofetil prepared as follows. Constitute Mycophenolate Mofetil for Oral Suspension as directed on the label. Prepare a composite sample by mixing NLT 4 bottles of the constituted Mycophenolate Mofetil for Oral Suspension. Transfer a volume of the composite sample so obtained, equivalent to 800 mg of mycophenolate mofetil, to a 200-mL volumetric flask, and dilute with Extraction solvent to volume.

Sample solution: Nominally equivalent to 0.4 mg/mL of mycophenolate mofetil prepared as follows. Transfer 5.0 mL of the Sample stock solution to a 50-mL volumetric flask, and dilute with Diluent to volume. Pass through a filter of 0.45-um pore size.

Chromatographic system

(See Chromatography (621). System Suitability.)

Mode: LC

Detector: UV 249 nm. If this procedure is used for Identification A, use a diode array detector in the range of 200-400 nm _{(USP 1-May-2019)}

Column: 4.6-mm x 25-cm; 5-µm packing L11.

Temperatures

Autosampler: 5°

Column: 45°

Flow rate: 1.5 mL/min

Injection volume: 20 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 mycophenolate mofetil (C₂₃H₃₁NO₇) in the portion of Mycophenolate Mofetil for Oral Suspension taken:

Result = (r_u /r_s ) × (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 USP Mycophenolate Mofetil RS _{(USP 1-May-2019)} in the Standard solution (mg/mL)

C_u = nominal concentration of mycophenolate mofetil in the Sample solution (mg/mL)

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

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DISSOLUTION (711)

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Medium: 0.1 N hydrochloric acid: 900 mL, deaerated

Apparatus 2: 40 rpm

Time: 20 min

Standard solution: 0.278 mg/mL of USP Mycophenolate Mofetil RS in Medium

Sample solution: Reconstitute Mycophenolate Mofetil for Oral Suspension according to the labeling instructions. Shake well. Use a separate 3-mL syringe for each vessel. Withdraw 2 mL of suspension. Remove air bubbles from the syringe. Adjust the volume to 1.2 mL and accurately weigh the filled syringe. Operate the apparatus, holding the syringe above the surface of the medium, at a location that is halfway between the paddle shaft and the vessel wall. Carefully introduce the sample to the vessel over a 5-10 s period. Weigh the empty syringe and determine the weight of the sample (g). At the time specified, withdraw an aliquot and immediately pass through a suitable filter of 10-um pore size, discarding the first few milliliters.

Instrumental conditions

(See Ultraviolet-Visible Spectroscopy (857).)

Mode: UV

Analytical wavelength: 304 nm

Cell: 0.2 cm

Blank: Medium

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of mycophenolate mofetil dissolved:

Result = (A_u /A_s ) × (C_s /L) × (V₁ /V₂ ) × 100

A_u = absorbance of the Sample solution

A_s = absorbance of the Standard solution

C_s = concentration of USP Mycophenolate Mofetil RS (USP 1-May-2019) in the Standard solution (mg/mL)

L = suspension label claim of mycophenolate mofetil (mg/mL)

V₁ = volume of Medium, 900 (mL)

V₂ = volume of sample (mL), weight (g) of the sample divided by the density of the suspension (g/mL)

Tolerances: NLT 80% (Q) of the labeled amount of mycophenolate mofetil is dissolved.

UNIFORMITY OF DOSAGE UNITS (905): Meets the requirements

DELIVERABLE VOLUME (698): Meets the requirements

5 IMPURITIES

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ORGANIC IMPURITIES

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

System suitability solution: 0.01 mg/mL of USP Mycophenolate Mofetil Related Compound A RS and 0.01 mg/mL of USP Mycophenolate

Mofetil Related Compound B RS in Diluent. [NOTE-The relative retention times for mycophenolate mofetil related compound A and mycophenolate mofetil related compound B are 0.40 and 0.46, respectively, measured with respect to mycophenolate mofetil.]

Sensitivity solution: 0.2 µg/mL in Diluent from the Standard solution

System suitability

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

Suitability requirements

Resolution: NLT 2.0 between mycophenolate mofetil related compound A and mycophenolate mofetil related compound B, 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

[NOTE-The run time for the Sample solution is NLT 1.5 times the retention time of the mycophenolate mofetil peak.]

Calculate the percentage of each impurity in the portion of Mycophenolate Mofetil for Oral Suspension taken:

Result = (r_u /r_s ) × (C_s /C_u ) × (1/F) × 100

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

r_s = peak response of mycophenolate mofetil from the Standard solution

C_s = concentration of USP Mycophenolate Mofetil RS (USP 1-May-2019) in the Standard solution (mg/mL)

C_u = nominal concentration of mycophenolate mofetil in the Sample solution (mg/mL)

F = relative response factor (see Table 1)

Acceptance criteria: See Table 1. The reporting threshold is 0.05%. (USP 1-May-2019)

Table 1

^a (E)-6-(1,3-Dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid.

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

Acceptance criteria: 6.0–7.0

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers, and store at controlled room temperature.

USP Reference Standards 〈11〉

USP Mycophenolate Mofetil RS

USP Mycophenolate Mofetil Related Compound A RS

2-Morpholinoethyl (E)-6-(1,3-dihydro-4,6-dihydroxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate.

C₂₂H₂₉NO₇              419.47

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.

C₁₉H₂₀O₆                 320.34