Working document QAS/10.

385 FINAL
December 2010

PARACETAMOL ORAL SOLUTION:

Final text for addition to THE INTERNATIONAL
PHARMACOPOEIA

(December 2010)
This monograph was adopted at the forty-fifth WHO Expert Committee on
Specifications for Pharmaceutical Preparations in October 2010 for addition to the
Fourth edition of The International Pharmacopoeia.

Other name. Acetaminophen oral solution.

Category. Non-opioid analgesic

Storage. Paracetamol oral solution should be kept in a well-closed container having a

child-resistant closure, protected from light.

Additional information
Strength in the current WHO Model list of essential medicines: 125 mg per 5 ml
(25 mg per ml). Strength in the current WHO Model list of essential medicines for
children: 125 mg per 5 ml (25 mg per ml).

Requirements

Complies with the monograph for "Liquid preparations for oral use".

Definition. Paracetamol oral solution is a solution of Paracetamol in a suitable

vehicle, which may be flavoured. It contains not less than 90.0% and not more than
110.0% of the amount of paracetamol (C8H9NO2) stated on the label.

For relevant solutions, such as solutions containing glycerol:

Manufacture. The method of manufacture is validated to demonstrate when relevant

that the oral solution, if tested, would comply with the following test.

Diethylene glycol and ethylene glycol

Carry out the test as described under 1.14.5 Gas chromatography using the
internal standard method.
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For the procedure use a capillary glass or quartz column (30m × 0.53 mm),
the inner surface of which is coated with a thick layer of macrogol 20M R
(1.0 μm). Maintain the temperature of the column at 100 °C for 5 minutes.
Increase the temperature at a rate of 10 °C per minute to 230 °C, and
maintain it at this point for 4 minutes. Maintain the temperature of the
injection port and the detector at 230 °C. Use helium R as the carrier gas
with a linear velocity of about 38 cm per second; use splitless injection
followed by a split ratio of 1:20 after 30 seconds; use a flame-ionization
detector.

Prepare the following solutions in a 1:1 mixture of acetonitrile R and water

R: for solution (A) weigh 0.350 g of the internal standard 1,4-butanediol R
and dilute to 100 ml; for solution (B) weigh 10.0 g of the oral solution, add
2.0 ml of solution (A) and dilute to 100 ml; for solution (C) weigh 0.500 g of
each ethylene glycol R, propylene glycol R and diethylene glycol R and
dilute to 100 ml; for solution (D) mix 2.0 ml of solution (C) with 2.0 ml of
solution (A) and dilute to 100 ml; for solution (F) weigh 10.0 g of
Paracetamol oral solution and dilute to 100 ml.

Inject separately 1.0 µl each of solutions (B), (D), and (F) and record the
chromatograms.

In the chromatogram obtained with solution (D), the analyte peaks are eluted
at the following relative retention with reference to 1,4-butanediol (retention
time about 14 minutes): propylene glycol about 0.73, ethylene glycol about
0.76, diethylene glycol about 1.04 and glycerol about 1.27. The test is not
valid unless the resolution between the peaks corresponding to ethylene
glycol and propylene glycol in the chromatogram obtained with solution (D)
is at least 4.0, and no peak having the same retention time as 1,4-butanediol
can be detected in the chromatogram obtained with solution (F).

Measure the areas of the peak responses in the chromatograms obtained with
solutions (B) and (D). In the chromatogram obtained with solution (B), the
ratio of the area of the peak for ethylene glycol to the area of the peak for the
internal standard is not greater than the ratio of the areas of the
corresponding peaks obtained with solution (D) (0.1%) and the ratio of the
area of the peak for diethylene glycol to the area of the peak for the internal
standard is not greater than the ratio of the areas of the corresponding peaks
obtained with solution (D) (0.1%).

Identity tests

A. Carry out test A.1 or, where UV detection is not available, test A.2.

A.1 Carry out the test as described under 1.14.1 Thin-layer chromatography,
using silica gel R6 as the coating substance and a mixture of 50 volumes of
acetone R, 50 volumes of toluene R and 1 volume of glacial acetic acid R as
the mobile phase.
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Apply separately to the plate 10 μl of each of the following two solutions.

For solution (A) shake a volume of the oral solution containing 125 mg of
Paracetamol with 25 ml of methanol R, dilute to 50 ml with the same
solvent, filter, and use the filtrate. For solution (B) use 2.5 mg of
paracetamol RS per ml of methanol R.

After removing the plate from the chromatographic chamber, allow it to dry
in a current of air.

Examine the chromatogram in ultraviolet light (254 nm).

The principal spot obtained with solution (A) corresponds in position,

appearance, and intensity to that obtained with solution (B).

A.2 Carry out the test as described under 1.14.1 Thin-layer chromatography,
using the conditions described above under test A.1 but using silica gel R5
as the coating substance. After removing the plate from the chromatographic
chamber, allow it to dry in a current of air. Expose the plate to iodine
vapours until spots appear and examine the chromatogram in daylight.

The principal spot obtained with solution (A) corresponds in position,

appearance, and intensity to that obtained with solution (B).

B. See the test described below under Assay. The retention time of the principal peak
in the chromatogram obtained with solution (1) corresponds to that obtained with
solution (2).

4-Aminophenol. Prepare fresh solutions, protect solutions from light and perform the
test without delay. Carry out the test as described under 1.14.4 High-performance
liquid chromatography, using the same chromatographic conditions as described
under Assay but using 272 nm as the detection wavelength.

Prepare the following solutions. For solution (1), shake a quantity of the oral solution
containing 125 mg of Paracetamol with about 15 ml of the solvent mixture. Dilute to
25 ml with the solvent mixture. Filter through a 0.45 μm filter, discarding the first
few ml of the filtrate. For solution (2), dissolve 12.5 mg of 4-aminophenol R and 12.5
mg of paracetamol RS in about 20 ml of solvent mixture, and dilute to 50 ml with the
solvent mixture. Dilute 5 ml of this solution to 50 ml with the solvent mixture.

Inject separately 20 μl each of solutions (1) and (2) and record the chromatograms.
[Depending on the formulation of the oral solution, there may be late-eluting
preservatives or other excipients (e.g. potassium sorbate, sodium benzoate, vanillin
and methyl hydroxybenzoate) present that can interfere with subsequent
chromatographic runs.]

In the chromatogram obtained with solution (2), the following peak is eluted at the
following relative retention, with reference to paracetamol (retention time about 8.5
minutes): 4-aminophenol about 0.54. The test is not valid unless the resolution
between the peaks corresponding to 4-aminophenol and paracetamol in the
chromatogram obtained with solution (3) is at least 4.0.
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In the chromatogram obtained with solution (1), the area of any peak corresponding to
4-aminophenol is not greater than the area of the corresponding peak in the
chromatogram obtained with solution (2) (0.5%).

Assay. Carry out the test as described under 1.14.4 High-performance liquid
chromatography, using a stainless steel column (25 cm x 4.6 mm), packed with
octasilyl silica gel for chromatography (5 μm).1 Prepare a solvent mixture consisting
of 0.4 volumes of formic acid (~1080 g/l) TS, 15 volumes of methanol R and 85
volumes of water R. As the mobile phase use a filtered and degassed solution of
0.01 M sodium butanesulfonate R in the above solvent mixture.

Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet
spectrophotometer set at a wavelength of 243 nm.

Prepare the following solutions. For solution (1), shake an accurately weighed
quantity of the oral solution containing about 25 mg of Paracetamol with about 60 ml
of the solvent mixture. Dilute to 100 ml with the solvent mixture. Dilute 10 ml of the
resulting solution to 50 ml with the solvent mixture. Filter a portion of this solution
through a 0.45 μm filter, discarding the first few ml of the filtrate. For solution (2),
accurately weigh about 12.5 mg of paracetamol RS and dissolve in about 30 ml of
solvent mixture. Dilute this solution to 50 ml with the solvent mixture. Dilute 10 ml
of the resulting solution to 50 ml with the solvent mixture. For solution (3), dissolve
12.5 mg of 4-aminophenol R and 12.5 mg of paracetamol RS in about 20 ml of
solvent mixture, and dilute to 50 ml with the solvent mixture. Dilute 5 ml of this
solution to 50 ml with the solvent mixture.

Inject separately 20 µl each of solutions (1), (2) and (3) and record the
chromatograms.

In the chromatogram obtained with solution (3), the following peak is eluted at the
following relative retention, with reference to paracetamol (retention time about
8.5 minutes): 4-aminophenol about 0.54. The test is not valid unless the resolution
between the peaks corresponding to 4-aminophenol and paracetamol in the
chromatogram obtained with solution (3) is at least 4.0.

Measure the areas of the peak responses in the chromatograms obtained with solutions
(1) and (2).

Determine the weight per ml (1.3.1) of the oral solution and calculate the content of
paracetamol (C8H9NO2), weight in volume, in the oral solution.

***

1
A Luna C8(2) column is suitable.