Printed on: Sat Jun 26 2021, 05:52:36 AM Official Status: Currently Official on 26-Jun-2021 DocId: 1_GUID-62057678-318E-4547-9021-4120852719F0_4_en-US

(EST)
Printed by: Nguyen Nhan Official Date: Official as of 01-Aug-2017 Document Type: USP @2021 USPC
1

Sample solution: Dilute 5.0 mL of the Sample stock solution

Acetaminophen and Codeine with Mobile phase to 50 mL, and pass a portion through a
Phosphate Capsules filter of 1-µm pore size.
Chromatographic system
DEFINITION (See Chromatography á621ñ, System Suitability.)
Acetaminophen and Codeine Phosphate Capsules contain Mode: LC
NLT 90.0% and NMT 110.0% of the labeled amount of Detector: UV 214 nm
acetaminophen (C8H9NO2) and codeine phosphate Column: 4.6-mm × 25-cm; 5-µm packing L1
(C18H21NO3 · H3PO4 · ½H2O). Flow rate: 1.5 mL/min
Injection volume: 30 µL
IDENTIFICATION System suitability
• A. The retention times of the major peaks of the Sample Sample: Standard solution
solution correspond to those of the Standard solution, as Suitability requirements
obtained in the Assay. Resolution: NLT 2.0 between acetaminophen and
• B. THIN-LAYER CHROMATOGRAPHY codeine
Standard solution: 12 mg/mL each of USP Relative standard deviation: NMT 2.0% for
Acetaminophen RS and USP Codeine Phosphate RS in acetaminophen; NMT 3.0% for codeine
methanol Analysis
Sample solution: Transfer a portion of Capsule contents, Samples: Standard solution and Sample solution
equivalent to 12 mg of codeine phosphate, to a separator. Calculate the percentage of the labeled amount of
Add 5 mL of water, 1 mL of ammonium hydroxide, and acetaminophen (C8H9NO2) in the portion of Capsules
5 mL of methylene chloride. Shake for 1 min, and allow the taken:
layers to separate. Use the clear lower layer.

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Chromatographic system Result = (r U/r S) × (C S/C U) × 100
(See Chromatography á621ñ, General Procedures, Thin-Layer
Chromatography.) rU = peak response of acetaminophen from the
Adsorbent: 0.25-mm layer of chromatographic silica gel Sample solution
mixture rS = peak response of acetaminophen from the
Application volume: 10 µL
Developing solvent system: Methanol and ammonium
hydroxide (49:1)
ci CS
Standard solution
= concentration of USP Acetaminophen RS in the
Standard solution (mg/mL)
Analysis CU = nominal concentration of acetaminophen in the
Samples: Standard solution and Sample solution Sample solution (mg/mL)
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Allow the spots to dry after applying each sample to the
adsorbent. Develop the chromatogram in the Developing Calculate the percentage of the labeled amount of codeine
solvent system until the solvent front has moved phosphate (C18H21NO3 · H3PO4 · ½H2O) in the portion of
three-fourths of the length of the plate. Remove the plate Capsules taken:
from the developing chamber, mark the solvent front, and
allow the solvent to evaporate. Locate the spots on the Result = (r U/r S) × (C S/C U) × (M r1/M r2) × 100
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plate by examination under short-wavelength UV light.

Acceptance criteria: The R F values of the two principal rU = peak response of codeine from the Sample
spots of the Sample solution correspond to those of the solution
Standard solution. rS = peak response of codeine from the Standard
solution
ASSAY CS = concentration of USP Codeine Phosphate RS in
• PROCEDURE the Standard solution (mg/mL)
Solution A: Dissolve 2.04 g of monobasic potassium CU = nominal concentration of codeine phosphate in
phosphate in 950 mL of water. Add 2 mL of triethylamine, the Sample solution (mg/mL)
adjust with phosphoric acid to a pH of 2.35, and dilute with M r1 = molecular weight of codeine phosphate, 406.37
water to 1000 mL.
M r2 = molecular weight of anhydrous codeine
Mobile phase: Methanol and Solution A (8:92)
phosphate, 397.37
Codeine phosphate standard stock solution: 0.3 mg/mL
of USP Codeine Phosphate RS in Mobile phase Acceptance criteria
Standard solution: 0.3 mg/mL of USP Acetaminophen RS Acetaminophen: 90.0%–110.0%
and 0.3J mg/mL of codeine phosphate in Mobile phase, Codeine phosphate: 90.0%–110.0%
prepared as follows. Transfer an appropriate amount of USP
Acetaminophen RS and a suitable volume (multiplied by J) PERFORMANCE TESTS
of Codeine phosphate standard stock solution (J being the • DISSOLUTION á711ñ
ratio of the labeled amount, in mg, of codeine phosphate Medium: 0.01 N hydrochloric acid; 900 mL
to that of acetaminophen) to a suitable volumetric flask. Apparatus 2: 50 rpm
Dilute with Mobile phase to volume. Time: 30 min
Sample stock solution: Nominally 3.0 mg/mL of Analysis: Determine the percentage of the labeled amount
acetaminophen and 3.0J mg/mL of codeine phosphate of acetaminophen (C8H9NO2) and codeine phosphate
(equivalent to 2.93J mg/mL of anhydrous codeine (C18H21NO3 · H3PO4 · ½H2O) dissolved by using the method
phosphate) in Mobile phase, prepared as follows. Transfer a set forth in the Assay, except use 0.01 N hydrochloric acid
portion of the combined contents, equivalent to 300 mg of to prepare the Codeine phosphate standard stock solution,
acetaminophen, from NLT 20 Capsules, to a 100-mL and make any other necessary volumetric adjustments.
volumetric flask. Add 75 mL of Mobile phase, and sonicate
for 10 min. Dilute with Mobile phase to volume.

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Printed by: Nguyen Nhan Official Date: Official as of 01-Aug-2017 Document Type: USP @2021 USPC
2

Tolerances: NLT 75% (Q) of the labeled amount of F = dilution volume, 1000 mL
acetaminophen (C8H9NO2) and codeine phosphate
(C18H21NO3 · H3PO4 · ½H2O) is dissolved. Calculate the quantity, in mg, of codeine phosphate
• UNIFORMITY OF DOSAGE UNITS á905ñ (C18H21NO3 · H3PO4 · ½H2O) in the Capsule taken:
Procedure for content uniformity
Solution A, Mobile phase, Codeine phosphate standard Result = (r U/r S) × C S × (M r1/M r2) × F
stock solution, Standard solution, Chromatographic
system, and System suitability: Proceed as directed in rU = peak response of codeine from the Sample
the Assay. solution
Sample stock solution: Transfer the contents of 1 Capsule rS = peak response of codeine from the Standard
to a 100-mL volumetric flask. Add 75 mL of Mobile phase, solution
and sonicate for 10 min. Dilute with Mobile phase to CS = concentration of USP Codeine Phosphate RS in
volume. the Standard solution (mg/mL)
Sample solution: Dilute 5.0 mL of the Sample stock M r1 = molecular weight of codeine phosphate, 406.37
solution with Mobile phase to 50 mL, and pass a portion M r2 = molecular weight of anhydrous codeine
through a suitable filter of 1-µm pore size. phosphate, 397.37
Analysis F = dilution volume, 1000 mL
Samples: Standard solution and Sample solution
Calculate the quantity, in mg, of acetaminophen Acceptance criteria: Meet the requirements
(C8H9NO2) in the Capsule taken: IMPURITIES
• 4-AMINOPHENOL IN ACETAMINOPHEN-CONTAINING DRUG
Result = (r U/r S) × C S × F PRODUCTS á227ñ: Meet the requirements

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rU = peak response of acetaminophen from the ADDITIONAL REQUIREMENTS
Sample solution • PACKAGING AND STORAGE: Preserve in tight, light-resistant
rS = peak response of acetaminophen from the containers, and store at controlled room temperature.
Standard solution • USP REFERENCE STANDARDS á11ñ
CS = concentration of USP Acetaminophen RS in the USP Acetaminophen RS
Standard solution (mg/mL)
ci USP Codeine Phosphate RS
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