Stage 4 Harmonization Povidone 1

Official May 1, 2019

previously washed by passing steam through it. To the
Povidone absorption flask add 30 mL of a solution of boric acid
Portions of the monograph text that are national USP text, (1 in 25), 3 drops of bromocresol green-methyl red TS,
and are not part of the harmonized text, are marked with and sufficient water to immerse the lower end of the
symbols (◆◆) to specify this fact. condenser tube. Add 30 mL of a solution of sodium
hydroxide (2 in 5) through the funnel, rinse the funnel
cautiously with 10 mL of water, immediately close the
clamp attached to the rubber tube, and then start the
distillation with steam to obtain 80–100 mL of the
distillate. Remove the absorption flask from the lower
(C6H9NO)n end of the condenser tube, rinsing the end part with a
2-Pyrrolidinone, 1-ethenyl-, homopolymer; small quantity of water, and titrate the distillate with
1-Vinyl-2-pyrrolidinone polymer; 0.025 mol/L sulfuric acid VS until the color of the
Poly [(2-oxo-1-pyrrolidinyl)ethylene] [9003-39-8]. solution changes from green through pale grayish blue
to pale grayish red-purple. Perform a blank
DEFINITION determination in the same manner, and make any
Povidone is a chain polymer of 1-vinyl-2-pyrrolidone. It necessary correction.
contains NLT 11.5% and NMT 12.8% of nitrogen (N: Each milliliter of 0.025 mol/L sulfuric acid VS equals
14.01), calculated on the anhydrous basis. It has the 0.700 mg of nitrogen.▲ USP42
nominal K-value of NLT 10 and NMT 120. The nominal K- Acceptance criteria: 11.5%–12.8% on the anhydrous
value is shown on the label. basis
IDENTIFICATION IMPURITIES
• RESIDUE ON IGNITION á281ñ: NMT 0.1%
Change to read: • ◆ LEAD á251ñ
Test preparation: 1.0 g in 25 mL of water
• A. INFRARED ABSORPTION á197Kñ Acceptance criteria: NMT 10 ppm◆
Sample: Dry at 105° for 6 h.
▲
Acceptance criteria: Meets the requirements▲ USP42
Change to read:
• ◆B.
Sample solution: 20 mg/mL of Povidone • LIMIT OF ALDEHYDES
Analysis: To 10 mL of the Sample solution, add 20 mL of Solution A: Transfer 8.3 g of potassium pyrophosphate
1 N hydrochloric acid VS and 5 mL of potassium to a 500-mL volumetric flask and dissolve in 400 mL of
dichromate TS. water. Adjust, if necessary, with 1 N hydrochloric acid
Acceptance criteria: An orange-yellow precipitate is VS to a pH of 9.0, and dilute with water to volume.
formed.◆ Solution B: Transfer a quantity of lyophilized aldehyde
• ◆C. dehydrogenase, equivalent to 70 units, to a glass vial,
Solution A: Dissolve 75 mg of cobalt nitrate and 300 and dissolve in 10.0 mL of water. [NOTE—This solution
mg of ammonium thiocyanate in 2 mL of water. is stable for 8 h at 4°.]
Sample solution: 20 mg/mL of Povidone Solution C: Transfer 40 mg of nicotinamide adenine
Analysis: Combine Solution A and 5 mL of the Sample dinucleotide to a glass vial, and dissolve in 10.0 mL of
solution, and render the resulting solution acidic by the Solution A. [NOTE—This solution is stable for four weeks
addition of 3 N hydrochloric acid. at 4°.]
Acceptance criteria: A pale blue precipitate is formed.◆ Standard solution: Dissolve 0.140 g of acetaldehyde
• ◆D. ammonia trimer trihydrate in water to make 200.0 mL.
Sample solution: 5 mg/mL of Povidone Dilute 1.0 mL of the solution with Solution A to 100.0
Analysis: To 5 mL of the Sample solution, add a few mL.
drops of iodine TS. Sample solution: 10 mg/mL of Povidone in Solution A.
Acceptance criteria: A deep red color is produced.◆ Insert a stopper into the flask, heat at 60° for 1 h, and
• E. cool to room temperature.
Sample solution: 50 mg/mL of Povidone in water Instrumental conditions
Acceptance criteria: The substance dissolves. (See Ultraviolet-Visible Spectroscopy á857ñ.)
ASSAY Mode: UV
Analytical wavelength: 340 nm
Cell: 1 cm
Change to read:
Analysis
▲
• NITROGEN DETERMINATION▲ USP42 Samples: Standard solution, Sample solution, and
Sample: 0.1 g of Povidone water
Analysis: ▲Weigh the Sample accurately and place in a Pipet 0.5 mL each of the Standard solution, Sample
Kjeldahl flask. Add 5 g of a powdered mixture of 33 g solution, and water (used for blank test) into separate
of potassium sulfate, 1 g of cupric sulfate, and 1 g of cells. Add 2.5 mL of Solution A and 0.2 mL of Solution
titanium dioxide. Wash down any adhering sample C to each cell. Cover the cells to exclude oxygen. Mix
from the neck of the flask with a small amount of by inversion and allow to stand for 2–3 min at 22
water. Add 7 mL of sulfuric acid allowing it to flow ± 2°. Determine the absorbances of the solutions
down the inside wall of the flask. Heat the flask using the water as the reference. Add 0.05 mL of
gradually until the solution has a clear, yellow-green Solution B to each cell. Cover the cells to exclude
color and the inside wall of the flask is free from any oxygen. Mix by inversion and allow to stand for 5
carbonized material and then heat for an additional 45 min at 22 ± 2°. Determine the absorbances of the
min. After cooling, cautiously add 20 mL of water, and solutions, using the water as the reference.
connect the flask to the distillation apparatus

© 2018 The United States Pharmacopeial Convention All Rights Reserved.

2 Povidone Stage 4 Harmonization
Official May 1, 2019
Calculate the percentage of aldehydes, expressed as Acceptance criteria: Salicylaldazine appears as a
acetaldehyde, in the portion of Povidone taken: fluorescent spot having an RF value of 0.3; and the
fluorescence of any salicylaldazine spot from the
Result = 100 × (CS/CU) × {[(AU2 − AU1) − (AB2 − AB1)]/[(AS2 Sample solution is not more intense than that produced
− AS1) − (AB2 − AB1)]} by the spot from the Standard solution (NMT 1 ppm of
hydrazine).
CS = concentration of acetaldehyde in the • VINYLPYRROLIDINONE
Standard solution, calculated from the Mobile phase: Water and acetonitrile (90:10)
weight of the acetaldehyde ammonia System suitability solution: Transfer 10 mg of
trimer trihydrate with the factor 0.72 vinylpyrrolidinone and 500 mg of vinyl acetate to a
(mg/mL). 100-mL volumetric flask, and dissolve in and dilute
[NOTE—The molar mass of acetaldehyde is with methanol to volume. Transfer 1.0 mL of this
44.05 g/mol, and the molar mass of solution to a 100-mL volumetric flask, and dilute with
acetaldehyde ammonia trimer Mobile phase to volume.
trihydrate is 183.26 g/mol. (44.05 × 3)/ Standard stock solution: 5 µg/mL of vinylpyrrolidinone
183.26 = 0.72] in Mobile phase
CU = concentration of the Sample solution Standard solution: 0.25 µg/mL of vinylpyrrolidinone
(mg/mL), ▲calculated on the anhydrous diluted from the Standard stock solution in Mobile phase
basis▲ USP42 Sample solution: 25 mg/mL of Povidone in Mobile
AU2 = absorbance of the solution from the phase
Sample solution, after addition of Solution B Chromatographic system
AU1 = absorbance of the solution from the (See Chromatography á621ñ, System Suitability.)
Sample solution, before addition of Solution Mode: LC
B Detector: UV 235 nm
AB2 = absorbance of the solution from the blank, Columns
after addition of Solution B Guard: 4.0-mm × 1.0-cm; packing L1
AB1 = absorbance of the solution from the blank, Analytical: 4.6-mm × 15-cm; 5-µm packing L1
before addition of Solution B Column temperature: 40°
AS2 = absorbance of the solution from the Flow rate: 1.0 mL/min
Standard solution, after addition of Solution Injection volume: 20 µL
B System suitability
AS1 = absorbance of the solution from the Samples: System suitability solution and Standard
Standard solution, before addition of solution
Solution B Suitability requirements
Resolution: NLT 2.0 between vinylpyrrolidinone and
Acceptance criteria: NMT 0.05% vinyl acetate, in this elution order, System suitability
solution
Change to read: Relative standard deviation: NMT 2.0% of
vinylpyrrolidinone for six injections, Standard
• LIMIT OF HYDRAZINE
solution
Standard solution: 9 µg/mL of salicylaldazine in
Analysis
toluene
Samples: Standard solution and Sample solution
Sample solution: Transfer 2.5 g to a 50-mL centrifuge
Record the chromatograms and measure the responses
tube, add 25 mL of water, and mix to dissolve. Add
for the vinylpyrrolidinone peak.
500 µL of a solution (1 in 20) of salicylaldehyde in
Calculate the percentage of vinylpyrrolidinone in the
methanol. Swirl and heat in a water bath at 60° for 15
sample taken:
min. Allow to cool and add 2.0 mL of toluene. Insert a
stopper in the tube, shake vigorously for 2 min, and Result = (rU/rS) × (CS/CU) × 100
centrifuge. Use the clear upper toluene layer in the
centrifuge tube as the Sample solution. rU = peak response of vinylpyrrolidinone from
Chromatographic system the Sample solution
(See Chromatography á621ñ, General Procedures, Thin- rS = peak response of vinylpyrrolidinone from
Layer Chromatography.) the Standard solution
Mode: TLC CS = concentration of vinylpyrrolidinone in the
Adsorbent: 0.25-mm layer of dimethylsilanized Standard solution (mg/mL)
chromatographic silica gel with fluorescent indicator CU = concentration of Povidone in the Sample
Application volume: 10 µL solution (mg/mL), calculated on the
Developing solvent system: Methanol and water anhydrous basis
(2:1)
Analytical wavelength: UV 365 nm Acceptance criteria: NMT 0.001%
Analysis • 2-PYRROLIDONE
Samples: Standard solution and Sample solution Mobile phase: Water and methanol (19:1)
Proceed as directed in the chapter. Allow the spots to Standard solution: 30 µg/mL of 2-pyrrolidinone in
dry, and develop the chromatogram with the Mobile phase
Developing solvent system until the solvent front has Sample solution: 5 mg/mL of Povidone in Mobile phase
moved three-fourths of the length of the plate. Chromatographic system
▲ USP42 Remove the plate from the chamber, mark
▲
(See Chromatography á621ñ, System Suitability.)
the solvent front, and allow the solvent to evaporate. Mode: LC
▲
Locate the spots on the plate by examination under Detector: UV 205 nm
UV light.▲ USP42

© 2018 The United States Pharmacopeial Convention All Rights Reserved.

Stage 4 Harmonization Povidone 3
Official May 1, 2019
Columns water drops at a rate of about 1 mL/min. When the
Guard: 4.0-mm × 1.0-cm; packing L1 level of the water is near the top of the strongly acidic
Analytical: 4.6-mm × 15-cm; 5-µm packing L1 ion-exchange resin layer, introduce 100 mL of the
Column temperature: 40° Sample stock solution into the column. Disregard the
Flow rate: 0.8 mL/min [NOTE—The retention time of first 2 mL of the eluate, then collect 1.5 mL of the
2-pyrrolidinone is about 7 min.] solution, and use this as the Sample solution.
[NOTE—The retention time of 2-pyrrolidinone is Chromatographic system
about 7 min.] (See Chromatography á621ñ, System Suitability.)
Injection volume: 50 µL Mode: LC
System suitability Detector: UV 210 nm
Sample: Standard solution Column: ▲7.9▲ USP42-mm × 30-cm; ▲10▲ USP42-µm
Suitability requirements packing L17
Column efficiency: NLT 5000 theoretical plates for Column temperature: 35°
the 2-pyrrolidinone peak Flow rate: 1.0 mL/min [NOTE—The retention time of
Symmetry factor: NMT 1.5 for the 2-pyrrolidinone formic acid is about 8 min.]
peak [NOTE—The retention time of formic acid is about 8
Relative standard deviation: NMT 2.0% of 2- min.]
pyrrolidinone for six injections Injection volume: 50 µL
Analysis System suitability
Samples: Standard solution and Sample solution Sample: Standard solution
Record the chromatograms and measure the responses Suitability requirements
for the 2-pyrrolidinone peak. Column efficiency: NLT 1000 theoretical plates for
Calculate the percentage of 2-pyrrolidinone in the the formic acid peak
sample taken: Symmetry factor: 0.5–1.5 for the formic acid peak
Relative standard deviation: NMT 2.0% of formic
Result = (rU/rS) × (CS/CU) × 100 acid for six injections
Analysis
rU = peak response of 2-pyrrolidinone from the Samples: Standard solution and Sample solution
Sample solution Record the chromatograms and measure the responses
rS = peak response of 2-pyrrolidinone from the for the formic acid peak.
Standard solution Calculate the percentage of formic acid in the sample
CS = concentration of 2-pyrrolidinone in the taken:
Standard solution (mg/mL)
CU = concentration of Povidone in the Sample Result = (rU/rS) × (CS/CU) × 100
solution (mg/mL), calculated on the
anhydrous basis rU = peak response of formic acid from the
Sample solution
Acceptance criteria: NMT 3.0% rS = peak response of formic acid from the
• PEROXIDES Standard solution
Sample solution: 40 mg/mL of Povidone in water, CS = concentration of formic acid in the
calculated on the anhydrous basis Standard solution (mg/mL)
Blank: To 25 mL of the Sample solution, add 2 mL of CU = concentration of Povidone in the Sample
13% sulfuric acid. solution (mg/mL), calculated on the
Instrumental conditions anhydrous basis
(See Ultraviolet-Visible Spectroscopy á857ñ.)
Mode: UV-Vis Acceptance criteria: NMT 0.5%
Analytical wavelength: 405 nm
Cell: 1 cm SPECIFIC TESTS
Analysis • PH á791ñ
Sample: Sample solution Sample solution: 50 mg/mL in water
To 25 mL of the Sample solution, add 2 mL of titanium Acceptance criteria: 3.0–5.0 for Povidone having a
trichloride–sulfuric acid TS, and allow to stand for 30 nominal K-value of 30 or less; 4.0–7.0 for Povidone
min. Measure the absorbance of a portion of this having a nominal K-value greater than 30
solution against the Blank. • WATER DETERMINATION á921ñ, Method I: NMT 5.0%
Acceptance criteria: NMT 0.35, corresponding to NMT • K-VALUE
400 ppm, expressed as H2O2 Sample solution: Weigh a quantity of undried
Povidone, equivalent on the anhydrous basis, to the
amount specified in Table 1.
Change to read:
• FORMIC ACID Table 1
Mobile phase: Diluted perchloric acid (1 in 700) Quantity
Standard solution: 10 µg/mL of formic acid in water Nominal K-value (g)
Sample stock solution: 20 mg/mL of Povidone in water ≤18 5.00
Sample solution: Transfer a suspension of strongly
acidic ion-exchange resin (use the hydrogen form of >18 to ≤95 1.00
ion-exchange resin) in water to a column of about 8 >95 0.10
mm in inside diameter to give a packing depth of
about 20 mm in length. Keep the strongly acidic ion-
exchange resin layer constantly immersed in water. Dissolve it in 50 mL of water in a 100-mL volumetric
Pour 5 mL of water and adjust the flow rate so that flask, and dilute to volume. Allow to stand for 1 h.

© 2018 The United States Pharmacopeial Convention All Rights Reserved.

4 Povidone Stage 4 Harmonization
Official May 1, 2019
Analysis Acceptance criteria
Samples: Sample solution and water K-value of Povidone having a stated (nominal) K-
Determine the viscosity of the Sample solution and the value of NMT 15: 85.0%–115.0% of the stated
water, using a capillary-tube viscometer (see Viscosity values
—Capillary Methods á911ñ), at 25 ± 0.2°. K-value of Povidone having a stated K-value or a
Calculate the K-value of Povidone: stated K-value range with an average of more
than 15: 90.0%–108.0% of the stated value or of the
Result = 300� log � + � + 1.5� log � ) 2 + 1.5� log � average of the stated range

− � ] / 0.15� + 0.003�2 ) ADDITIONAL REQUIREMENTS

• ◆PACKAGING AND STORAGE: Preserve in tight containers.◆
• LABELING: Label it to state, as part of the official title, the
c = weight, on the anhydrous basis, of the K-value or K-value range of Povidone.
specimen tested in each 100.0 mL of • ◆USP REFERENCE STANDARDS á11ñ
solution (g) USP Povidone RS ◆
z = viscosity of the Sample solution relative to
that of water

© 2018 The United States Pharmacopeial Convention All Rights Reserved.