Saccharin Sodium - Drug Future药物在线

Accessed from 128.83.63.20 by nEwp0rt1 on Mon Nov 28 04:32:40 EST 2011

USP 35 Official Monographs / Saccharin 4597

Diluent: 200 g/L solution of sodium acetate • USP REFERENCE STANDARDS 〈11〉
Hydrazine solution: 10.0 mg/mL of hydrazine sulfate. USP Saccharin Calcium RS
[NOTE—Allow to stand for 4–6 h.] USP o-Toluenesulfonamide RS
Methenamine solution: Transfer 2.5 g of methenamine to a C7H9NO2S 171.22
100-mL glass-stoppered flask, add 25.0 mL of water, insert USP p-Toluenesulfonamide RS
the glass stopper, and mix to dissolve. C7H9NO2S 171.22
Primary opalescent suspension: Transfer 25.0 mL of Hydra-
zine solution to the Methenamine solution in the 100-mL .
glass-stoppered flask. Mix, and allow to stand for 24 h.
[NOTE—This suspension is stable for 2 months, provided it is Saccharin Sodium
stored in a glass container free from surface defects. The
suspension must not adhere to the glass and must be well C7H4NNaO3S · 2H2O 241.20
mixed before use.]
Opalescence standard: Transfer 15.0 mL of the Primary C7H4NNaO3S 205.17
opalescent suspension and dilute to 1000 mL. [NOTE—This 1,2-Benzisothiazol-3(2H)-one, 1,1-dioxide, sodium salt,
suspension should not be used beyond 24 h after dihydrate;
preparation.] 1,2-Benzisothiazolin-3-one 1,1-dioxide sodium salt dihydrate
Reference suspension A: Opalescence standard and water (1 [6155-57-3].
in 20) Anhydrous [128-44-9].
Reference suspension B: Opalescence standard and water (1
in 10) DEFINITION
Sample solution: 200 mg/mL in Diluent Saccharin Sodium contains NLT 99.0% and NMT 101.0% of
Analysis
Samples: Diluent, Reference suspension A, Reference suspen- C7H4NNaO3S · 2H2O, calculated on the anhydrous basis.

sion B, Sample solution, and water IDENTIFICATION
Transfer a sufficient portion of Sample solution to a test tube • A. INFRARED ABSORPTION 〈197K〉
of colorless, transparent, neutral glass with a flat base and
an internal diameter of 15–25 mm to obtain a depth of Sample: Dry at 105° to constant weight.
40 mm. Similarly transfer portions of Reference suspension • B. PROCEDURE
A, Reference suspension B, water, and Diluent to separate
matching test tubes. Compare solutions in diffused Sample solution: 100 mg/mL
daylight, viewing vertically against a black background Potassium pyroantimonate solution: Dissolve 2 g of potas-
(see Spectrophotometry and Light-Scattering 〈851〉, Visual sium pyroantimonate in 95 mL of hot water. Cool quickly,
Comparison). [NOTE—The diffusion of light must be such and add 50 mL of a potassium hydroxide solution (50
that Reference suspension A can readily be distinguished mg/mL) and 1 mL of sodium hydroxide solution (8.5 in
from water, and that Reference suspension B can readily be 100). Allow to stand for 24 h, filter, and dilute with water to
distinguished from Reference suspension A.] 150 mL.
Acceptance criteria: The Sample solution shows the same Analysis: To the Sample solution add 2 mL of 15% potas-
clarity as that of water, or Diluent, or its opalescence is NMT sium carbonate, and heat to boiling. No precipitate is
that of Reference suspension A. formed. Add 4 mL of Potassium pyroantimonate solution, and
• COLOR OF SOLUTION heat to boiling. Allow to cool in ice water and, if necessary,
Diluent A: 200 g/L solution of sodium acetate rub the inside of the test tube with a glass rod.
Diluent B: 10 g/L solution of hydrochloric acid Acceptance criteria: A dense precipitate is formed.
Standard stock solution: Ferric chloride CS, cobaltous chlo- • C. Sodium salts impart an intense yellow color to a nonlumi-
ride CS, cupric sulfate CS, and Diluent B (3.0:3.0:2.4:1.6) nous flame.
Standard solution: Standard stock solution and Diluent B
(1:99). [NOTE—Prepare the Standard solution immediately ASSAY
before use.] • PROCEDURE
Sample solution: Use the Sample solution from Clarity of
Solution. Sample solution: Dissolve 150 mg of Saccharin Sodium in
Analysis 50 mL of glacial acetic acid. [NOTE—Slight heating may be
Samples: Diluent A, Standard solution, Sample solution, and needed to dissolve the sample.]
water Analysis: Titrate the Sample solution with 0.1 N perchloric
Transfer a sufficient portion of the Sample solution to a test acid, determining the endpoint potentiometrically. Perform
tube of colorless, transparent, neutral glass with a flat base a blank determination, and make any necessary correction
and an internal diameter of 15–25 mm to obtain a depth (see Titrimetry 〈541〉). Each mL of 0.1 N perchloric acid is
of 40 mm. Similarly transfer portions of the Standard solu- equivalent to 20.52 mg of C7H4NNaO3S.
tion, Diluent A, and water to separate matching test tubes. Acceptance criteria: 99.0%–101.0% on the anhydrous basis
Compare solutions in diffused daylight, viewing vertically
against a white background (see Spectrophotometry and IMPURITIES
Light-Scattering 〈851〉, Visual Comparison). Inorganic Impurities
Acceptance criteria: The Sample solution has the appear- • HEAVY METALS, Method I 〈231〉
ance of water or Diluent A, or is not more intensely colored
than the Standard solution. Sample: 4 g in 46 mL of water
ADDITIONAL REQUIREMENTS Analysis: Add 4 mL of dilute hydrochloric acid (1 in 12),
• PACKAGING AND STORAGE: Preserve in well-closed containers. mix, and rub the inner wall of the vessel with a glass rod
Store at room temperature. until crystallization begins. Allow the solution to stand for 1
• LABELING: Where the quantity of saccharin calcium is indi- h, then pass through a dry filter, discarding the first 10 mL
cated in the labeling of any preparation containing Saccharin of the filtrate. Use 25 mL of the subsequent filtrate for the
Calcium, this shall be expressed in terms of saccharin Test Preparation.
(C7H5NO3S).

Official from May 1, 2012
Copyright (c) 2011 The United States Pharmacopeial Convention. All rights reserved.

Accessed from 128.83.63.20 by nEwp0rt1 on Mon Nov 28 04:32:40 EST 2011 USP 35
4598 Saccharin / Official Monographs

Acceptance criteria: NMT 10 ppm Acceptance criteria: No precipitate or violet color appears.
Organic Impurities SPECIFIC TESTS
• PROCEDURE 1: LIMIT OF TOLUENESULFONAMIDES • WATER DETERMINATION, Method I 〈921〉: NMT 15.0%
• READILY CARBONIZABLE SUBSTANCES 〈271〉
Internal standard solution: 0.25 mg/mL of caffeine in
methylene chloride Sample solution: 40 mg/mL in sulfuric acid (94.5%–95.5%
Standard stock solution: 20.0 µg/mL of USP o-Toluenesul- (w/w) of H2SO4), maintained at 48°–50° for 10 min
fonamide RS and 20.0 µg/mL of USP p-Toluenesulfonamide Acceptance criteria: The Sample solution has no more color
RS in methylene chloride than Matching Fluid A, when viewed against a white
Standard solution: Evaporate 5.0 mL of Standard stock so- background.
lution to dryness in a stream of nitrogen. Dissolve the resi- • ACIDITY OR ALKALINITY
due in 1.0 mL of the Internal standard solution. Sample solution: 100 mg/mL in carbon dioxide-free water
Sample stock solution: 200 mg/mL in water. If necessary, Analysis: To 10 mL of the Sample solution add 1 drop of
adjust the pH to 7–8 with 1 N sodium hydroxide or 1 N phenolphthalein TS.
hydrochloric acid before final dilution. Acceptance criteria: No pink color is produced. Then add 1
Sample solution: Shake 50 mL of the Sample stock solution drop of 0.1 N sodium hydroxide: a pink color is produced.
with four quantities each of 50 mL of methylene chloride. • CLARITY OF SOLUTION
Combine the lower layers, dry over anhydrous sodium sul- [NOTE—The Sample solution is to be compared to Reference
fate, and filter. Wash the filter and the sodium sulfate with suspension A and to water in diffused daylight 5 min after
10 mL of methylene chloride. Combine the solution and preparation of Reference suspension A.]
the washings, and evaporate almost to dryness in a water Diluent: 200-g/L solution of sodium acetate
bath at a temperature not exceeding 40°. Using a small Hydrazine solution: 10.0 mg/mL of hydrazine sulfate.
quantity of methylene chloride, quantitatively transfer the [NOTE—Allow to stand for 4–6 h.]
residue into a suitable 10-mL tube, evaporate to dryness in Methenamine solution: Transfer 2.5 g of methenamine to a
a stream of nitrogen, and dissolve the residue in 1.0 mL of 100-mL glass-stoppered flask, add 25.0 mL of water, insert
the Internal standard solution. the glass stopper, and mix to dissolve.
Blank solution: Evaporate 200 mL of methylene chloride to Primary opalescent suspension: Transfer 25.0 mL of Hydra-
dryness in a water bath at a temperature not exceeding zine solution to the Methenamine solution in the 100-mL
40°. Dissolve the residue in 1 mL of methylene chloride. glass-stoppered flask. Mix, and allow to stand for 24 h.
Chromatographic system [NOTE—This suspension is stable for 2 months, provided it is
(See Chromatography 〈621〉, System Suitability.) stored in a glass container free from surface defects. The
suspension must not adhere to the glass and must be well
Mode: GC mixed before use. Allow the suspension to stand for 24 h.]
Detector: Flame ionization Opalescence standard: Transfer 15.0 mL of the Primary
Column: 0.53-mm × 10-m fused silica column, coated opalescent suspension and dilute to 1000 mL. [NOTE—This
with G3 phase (film thickness, 2 µm) suspension should not be used beyond 24 h after
Temperature preparation.]
Reference suspension A: Opalescence standard and water (1
Injector: 250° in 20)
Detector: 250° Reference suspension B: Opalescence standard and water (1
Column: 180° in 10)
Carrier gas: Nitrogen Sample solution: 200 mg/mL in Diluent
Flow rate: 10 mL/min Analysis
Injection size: 1 µL Samples: Diluent, Reference suspension A, Reference suspen-
Split ratio: 2:1 sion B, Sample solution, and water
System suitability
Samples: Standard solution and Blank solution Transfer a sufficient portion of the Sample solution to a test
[NOTE—The substances are eluted in the following order: tube of colorless, transparent, neutral glass with a flat base
o-toluenesulfonamide, p-toluenesulfonamide, and and an internal diameter of 15–25 mm to obtain a depth
caffeine.] of 40 mm. Similarly transfer portions of Reference suspen-
Suitability requirements: No peaks at the retention sion A, Reference suspension B, water, and the Diluent to
times for the internal standard, o-toluenesulfonamide, or separate matching test tubes. Compare solutions in dif-
p-toluenesulfonamide, Blank solution fused daylight, viewing vertically against a black back-
Resolution: NLT 1.5 between o-toluenesulfonamide and ground (see Spectrophotometry and Light-Scattering 〈851〉,
p-toluenesulfonamide, Standard solution Visual Comparison).
Analysis [NOTE—The diffusion of light must be such that Reference
Samples: Standard solution and Sample solution suspension A can readily be distinguished from water, and
Acceptance criteria: If any peaks due to o-toluenesulfona- that Reference suspension B can readily be distinguished
mide and p-toluenesulfonamide appear in the chromato- from Reference suspension A.]
gram obtained with the Sample solution, the ratio of their Acceptance criteria: The Sample solution shows the same
areas to that of the Internal standard solution is NMT the clarity as that of water, or Diluent, or its opalescence is NMT
corresponding ratio in the chromatogram obtained with that of Reference suspension A.
the Standard solution. • COLOR OF SOLUTION
Individual impurities: See Impurity Table 1. Diluent A: 200-g/L solution of sodium acetate
Diluent B: 10-g/L solution of hydrochloric acid
Name Impurity Table 1 Standard stock solution: Ferric chloride CS, cobaltous chlo-
o-Toluenesulfonamide ride CS, cupric sulfate CS, and Diluent B (3.0:3.0:2.4:1.6)
p-Toluenesulfonamide Acceptance Criteria, Standard solution: Standard stock solution and Diluent B (1
NMT (ppm) in 100). [NOTE—Prepare the Standard solution immediately
10 before use.]
10 Sample solution: Use the Sample solution from the test for
Clarity of Solution.
• PROCEDURE 2: LIMIT OF BENZOATE AND SALICYLATE Analysis
Sample solution: 50 mg/mL Samples: Diluent A, Standard solution, Sample solution, and
Analysis: To 10 mL of the Sample solution add 5 drops of water
6 N acetic acid, and then add 3 drops of ferric chloride TS.

Official from May 1, 2012
Copyright (c) 2011 The United States Pharmacopeial Convention. All rights reserved.

Accessed from 128.83.63.20 by nEwp0rt1 on Mon Nov 28 04:32:40 EST 2011

USP 35 Official Monographs / Saccharin 4599

Transfer a sufficient portion of the Sample solution to a test Procedure—Separately inject equal volumes (about 10 µL) of
tube of colorless, transparent, neutral glass with a flat base the Standard preparation and the Assay preparation into the
and an internal diameter of 15–25 mm to obtain a depth chromatograph using a suitable microsyringe or sampling valve,
of 40 mm. Similarly transfer portions of the Standard solu- record the chromatograms, and measure the responses for the
tion, Diluent A, and water to separate, matching test major peaks. Calculate the quantity, in mg, of saccharin
tubes. Compare the solutions in diffused daylight, viewing (C7H5NO3S) in each mL of the Oral Solution taken by the
vertically against a white background (see Spectrophotome- formula:
try and Light-Scattering 〈851〉, Visual Comparison).
Acceptance criteria: The Sample solution has the appear- (100C / V)(rU / rS)
ance of water or Diluent A, or is not more intensely colored
than the Standard solution. in which C is the concentration, in mg per mL, of USP
Saccharin RS in the Standard preparation, V is the volume, in
ADDITIONAL REQUIREMENTS mL, of Oral Solution taken, and rU and rS are the peak responses
• PACKAGING AND STORAGE: Preserve in well-closed containers. obtained from the Assay preparation and the Standard prepara-
tion, respectively.
Store at room temperature.
• LABELING: Where the quantity of saccharin sodium is indi- S. accharin Sodium Tablets

cated in the labeling of any preparation containing Saccharin » Saccharin Sodium Tablets contain the equiva-
Sodium, this shall be expressed in terms of saccharin lent of not less than 95.0 percent and not more
(C7H5NO3S). than 110.0 percent of the labeled amount of
• USP REFERENCE STANDARDS 〈11〉 saccharin (C7H5NO3S).
USP Saccharin Sodium RS
USP o-Toluenesulfonamide RS Packaging and storage—Preserve in well-closed containers.

C7H9NO2S 171.22 USP Reference standards 〈11〉—
USP p-Toluenesulfonamide RS USP Saccharin RS
Completeness of solution—Place 5 Tablets in a 250-mL
C7H9NO2S 171.22 beaker containing 150 mL of water at 25°. Stir for 5 minutes:
all of the Tablets dissolve to give a clear or practically clear
. solution.
Identification—
Saccharin Sodium Oral Solution
A: Dissolve a quantity of Tablets, equivalent to about 1 g of
» Saccharin Sodium Oral Solution contains the saccharin, in 10 mL of water, filter if necessary, and to the
equivalent of not less than 95.0 percent and not solution add 5 mL of 3 N hydrochloric acid: a white precipitate
more than 105.0 percent of the labeled amount of saccharin is formed. Collect the precipitate on a filter, wash
of saccharin (C7H5NO3S). with small portions of cold water until the last washing is prac-
tically free from chloride, and dry it at 105° for 2 hours: the
Packaging and storage—Preserve in tight containers. saccharin so obtained melts between 226° and 230°, the proce-
dure for Class I being used (see Melting Range or Temperature
USP Reference standards 〈11〉— 〈741〉).
USP Saccharin RS
Identification— [NOTE—Use the saccharin obtained in Identification test A for
Identification tests B and C.]
A: Transfer a volume of Oral Solution, equivalent to about
100 mg of saccharin, to a small dish, evaporate to dryness, and B: Dissolve about 100 mg in 5 mL of sodium hydroxide
gently fuse the residue over a small flame until it no longer solution (1 in 20), evaporate to dryness, and gently fuse the
evolves ammonia. Allow the residue to cool, dissolve in 20 mL residue over a small flame until it no longer evolves ammonia.
of water, neutralize the solution with 3 N hydrochloric acid, and Allow the residue to cool, dissolve in 20 mL of water, neutralize
filter: the addition of 1 drop of ferric chloride TS to the filtrate with 3 N hydrochloric acid, and filter: the addition of a drop of
produces a violet color. ferric chloride TS to the filtrate produces a violet color.

B: It responds to the tests for Sodium 〈191〉. C: Mix 20 mg with 40 mg of resorcinol, add 10 drops of
pH 〈791〉: between 3.0 and 5.0. sulfuric acid, and heat the mixture in a suitable liquid bath of
Assay— 200° for 3 minutes. Allow it to cool, and add 10 mL of water
and an excess of 1 N sodium hydroxide: a fluorescent green
Mobile phase—Mix 5 mL of 10 percent tetramethylammo- liquid results.
nium hydroxide solution and 400 mL of water in a 500-mL Limit of ammonium salts—Dissolve a quantity of powdered
volumetric flask, adjust with phosphoric acid to a pH of 4.0, Tablets, equivalent to about 300 mg of saccharin, in 5 mL of
and mix. Add 50 mL of methanol to the solution, dilute with water, and warm with 3 mL of 1 N sodium hydroxide: the odor
water to volume, mix, and degas the solution. of ammonia is not perceptible.
Assay—Weigh and finely powder not fewer than 20 Tablets.
Standard preparation—Add to an accurately weighed quan- Transfer an accurately weighed portion of the powder, equiva-
tity of USP Saccharin RS an amount of 0.1 N sodium hydroxide lent to about 100 mg of saccharin, to a 100-mL volumetric
sufficient to dissolve the solid, and dilute quantitatively with flask, add about 50 mL of water, agitate until the Tablet mate-
water to obtain a solution having a known concentration of rial is dissolved or evenly dispersed, dilute with water to vol-
about 1.2 mg of saccharin per mL. ume, and mix. Transfer 10.0 mL to a separator, add 2 mL of
3 N hydrochloric acid, and extract with five 20-mL portions of a
Assay preparation—Transfer an accurately measured volume solvent composed of chloroform and alcohol (9:1). Collect the
of Oral Solution, equivalent to about 120 mg of saccharin, to a combined extracts in a beaker, and evaporate on a steam bath
100-mL volumetric flask, dilute with water to volume, and mix. to dryness with the aid of a current of air. Dissolve the residue
in 10 mL of sodium hydroxide solution (1 in 250), transfer the
Chromatographic system (see Chromatography 〈621〉)—The solution with the aid of water to a 200-mL volumetric flask,
liquid chromatograph is equipped with a 257-nm detector and
a 4.6-mm × 25-cm column that contains packing L1. The flow
rate is about 2 mL per minute. Chromatograph three replicate
injections of the Standard preparation, and record the peak re-
sponses as directed for Procedure: the relative standard deviation
is not more than 2.0%.

Official from May 1, 2012
Copyright (c) 2011 The United States Pharmacopeial Convention. All rights reserved.