Pharmacopeial Forum
Vol. 31(4) [July–Aug. 2005] HARMONIZATION 1225
MONOGRAPHS (USP) the preparation of potassium pyroantimonate TS has changed,
the preparation of the potassium pyroantimonate solution for
this test is added to comply with the harmonization draft.
(8) Water—No change.
(9) Readily carbonizable substances—No change.
(10) Selenium—This test is deleted because it is unnecessary for
this compound.
(11) Limit of toluenesulfonamides—The test method and limits are
changed to those of the European Pharmacopoeia, which in-
clude a more modern test method. The Test solution is correct-
ed to that of the EP. Editorial changes are made.
BRIEFING (12) Heavy metals—No change.
(13) Limit of benzoate and salicylate—No change.
(14) Organic volatile impurities—No change.
(15) Assay—No change.
Saccharin Sodium, USP 28 page 1745 and page 612 of PF
31(2) [Mar.–Apr. 2005]. The United States Pharmacopeia is the co-
ordinating pharmacopeia for the international harmonization of the (EMC: J. Lane) RTS—42529-1
compendial standards for the Saccharin Sodium monograph, as
part of the process of international harmonization of monographs
and general analytical methods of the European, Japanese, and
United States pharmacopeias. The following monograph, which
represents the ADOPTION STAGE 6 document, is based in part
on comments from the Japanese Pharmacopoeia and the European
Pharmacopoeia in response to the Provisional Harmonized Text Change to read:
Stage 5A and 5B drafts prepared by the United States Pharmaco-
peia. Saccharin Sodium
Pharmacopeial Discussion Group Sign-Off Document
Attributes EP JP USP
Definition + + +
Identification B + + +
Identification C – + +
Acidity or alkalinity + + +
C7H4NNaO3S 2H2O 241.20
Water + + + 1,2-Benzisothiazol-3(2H)-one, 1,1-dioxide, sodium salt, dihy-
Readily carbonizable drate.
substances + + + 1,2-Benzisothiazolin-3-one 1,1-dioxide sodium salt dihydrate
Limit of benzoate [6155-57-3].
and salicylate – + + Anhydrous 205.17 [128-44-9].
Assay + + +
» Saccharin Sodium contains not less than 98.0 per-
Legend: + will adopt and implement; – will not stipulate. cent and not more than 101.0 percent of C7H4NNaO3S,
Nonharmonized attributes: Packaging and storage, Heavy calculated on the anhydrous basis.
metals, Labeling, Clarity of solution, Color of solution, Limit of
toluenesulfonamides, Identification A (IR). Packaging and storage—Preserve in well-closed containers.
Specific local attributes: USP: Organic volatile impurities; JP: Labeling—Where the quantity of saccharin sodium is indicated in
Description. the labeling of any preparation containing Saccharin Sodium, this
Reagents and reference materials: Each pharmacopeia will shall be expressed in terms of saccharin (C7H5NO3S).
adapt the text to take account of local reference materials and re-
agent specifications. USP Reference standards h11i—USP o-Toluenesulfonamide RS.
Differences between the ADOPTION STAGE 6 document and USP p-Toluenesulfonamide RS.
the current NF monograph include the following: Identification—
(1) In the opening paragraph (the Definition)—The lower limit is A: The residue obtained by igniting it responds to the tests for
changed from not less than 98.0 percent to not less than 99.0 Sodium h191i.
percent. B: To 10 mL of a solution (1 in 10) add 1 mL of hydrochloric
(2) Packaging and storage—Storage conditions at room temper- acid: a crystalline precipitate of saccharin is formed. Wash the pre-
ature are added. cipitate with cold water until the last washing is free from chloride,
(3) Labeling—No change. and dry at 1058 for 2 hours: it melts between 2268 and 2308, the
(4) USP Reference standards—A reference for Saccharin Sodium procedure for Class I being used (see Melting Range or Tempera-
is added for use in the Identification test A. ture h741i).
(5) Clarity of solution—This test is added to comply with EP
standards. Alkalinity—A solution (1 in 10) is neutral or alkaline to litmus,
(6) Color of solution—This test is added to comply with EP stan- but no red color is produced with phenolphthalein TS.
Harmonization
dards.
(7) Identification—Identification tests A, B, and D are replaced
with a more definitive IR absorption test. Identification test
C is retained, but separated into two tests (B and C). Because
# 2005 The United States Pharmacopeial Convention, Inc. All Rights Reserved.
Pharmacopeial Forum
1226 HARMONIZATION Vol. 31(4) [July–Aug. 2005]
Toluenesulfonamides— » Saccharin Sodium contains not less than 99.0
Internal standard solution,Standard stock solution, and Stan-
dard preparations—Prepare as directed for Internal standard solu- percent and not more than 101.0 percent of
tion, Standard stock solution, and Standard preparations in the test
for Toluenesulfonamides under Saccharin (see NF monograph).
Test preparation—Prepare as directed under Column Partition C 7 H 4 NNaO 3 S 2H 2 O, calculated on the anhy-
Chromatography (see Chromatography h621i), employing a chro-
matographic tube fitted with a porous glass disk in its base, a plas- drous basis.
tic stopcock on the delivery tube, and a reservoir on the top. Add a
mixture consisting of 10 g of Solid Support and a solution of 2.0 g,
accurately weighed, of Saccharin Sodium in 8.0 mL of sodium car- Packaging and storage—Preserve in well-closed con-
bonate solution (1 in 20), and proceed as directed under Test prep-
aration in the test for Toluenesulfonamides under Saccharin (see tainers. Store at room temperature. Store at room tempera-
NF monograph), beginning with ‘‘Pack the contents.’’
Chromatographic system and Procedure—Proceed as directed ture.
for Chromatographic system and Procedure in the test for Toluene-
sulfonamide under Saccharin (see NF monograph). Labeling—Where the quantity of saccharin sodium is indi-
Heavy metals, Method I h231i—Dissolve 4 g in 46 mL of water,
add 4 mL of 1 N hydrochloric acid, mix, and rub the inner wall of cated in the labeling of any preparation containing Saccha-
the vessel with a glass rod until crystallization begins. Allow the
solution to stand for 1 hour, and then filter through a dry filter, dis- rin Sodium, this shall be expressed in terms of saccharin
carding the first 10 mL of the filtrate: the limit, determined on 25
mL of the subsequent filtrate, is 0.001%. (C7H5NO3S).
Organic volatile impurities, Method IV h467i: meets the re-
quirements. USP Reference standards h11i—USP Saccharin Sodium
Other requirements—It responds to Identification tests A and B,
and meets the requirements of the tests for Water, Benzoate and RS. USP o-Toluenesulfonamide RS. USP p-Toluenesulfona-
salicylate, Selenium, and Readily carbonizable substances under
Saccharin Calcium. mide RS.
Assay—Proceed with Saccharin Sodium as directed in the Assay
under Saccharin Calcium. Each mL of 0.1 N sodium hydroxide is Clarity of solution—[NOTE—The Test solution is to be
equivalent to 20.52 mg of C7H4NNaO3S.
compared to Reference suspension A and to water in dif-
fused daylight 5 minutes after preparation of Reference sus-
&Saccharin Sodium pension A.]
Hydrazine solution—Transfer 1.0 g of hydrazine sulfate
to a 100-mL volumetric flask, dissolve in and dilute with
water to volume, and mix. Allow to stand for 4 to 6 hours.
Methenamine solution—Transfer 2.5 g of methenamine to
C7H4NNaO3S 2H2O 241.20 a 100-mL glass-stoppered flask, add 25.0 mL of water, in-
sert the glass stopper, and mix to dissolve.
1,2-Benzisothiazol-3(2H)-one, 1,1-dioxide, sodium salt, Primary opalescent suspension—[NOTE—This suspension
dihydrate. is stable for 2 months, provided it is stored in a glass con-
1,2-Benzisothiazolin-3-one 1,1-dioxide sodium salt dihy- tainer free from surface defects. The suspension must not
drate [6155-57-3]. adhere to the glass and must be well mixed before use.]
Anhydrous 205.17 [128-44-9]. Transfer 25.0 mL of Hydrazine solution to the Methenamine
solution in the 100-mL glass-stoppered flask. Mix, and al-
low to stand for 24 hours.
Harmonization
# 2005 The United States Pharmacopeial Convention, Inc. All Rights Reserved.
Pharmacopeial Forum
Vol. 31(4) [July–Aug. 2005] HARMONIZATION 1227
Opalescence standard—[NOTE—This suspension should Color of solution—
not be used beyond 24 hours after preparation.] Transfer Standard stock solution—Combine 3.0 mL of ferric chlo-
15.0 mL of the Primary opalescent suspension to a 1000- ride CS, 3.0 mL of cobaltous chloride CS, 2.4 mL of cupric
mL volumetric flask, dilute with water to volume, and mix. sulfate CS, and 1.6 mL of dilute hydrochloric acid (10 g per
Reference suspensions—Transfer 5.0 mL of the Opales- L).
cence standard to a 100-mL volumetric flask, dilute with Standard solution—[NOTE—Prepare the Standard solution
water to volume, and mix to obtain Reference suspension immediately before use.] Transfer 1.0 mL of Standard stock
A. Transfer 10.0 mL of the Opalescence standard to a sec- solution to a 100-mL volumetric flask, dilute with dilute hy-
ond 100-mL volumetric flask, dilute with water to volume, drochloric acid (10 g per L) to volume, and mix.
and mix to obtain Reference suspension B. Test solution—Use the Test solution from the test for Clar-
Test solution—Dissolve 5.0 g of test material in about 20 ity of solution.
mL of a 200 g per L solution of sodium acetate, dilute with Procedure—Transfer a sufficient portion of the Test solu-
water the same solution to 25 mL, and mix. tion to a test tube of colorless, transparent, neutral glass with
Procedure—Transfer a sufficient portion of the Test solu- a flat base and an internal diameter of 15 mm to 25 mm to
tion to a test tube of colorless, transparent, neutral glass with obtain a depth of 40 mm. Similarly transfer portions of Stan-
a flat base and an internal diameter of 15 mm to 25 mm to dard solution, a 200 g per L solution of sodium acetate, and
obtain a depth of 40 mm. Similarly transfer portions of Ref- water to separate matching test tubes. Compare the Test so-
erence suspension A, Reference suspension B, water, and a lution, the Standard solution, a 200 g per L solution of so-
200 g per L solution of sodium acetate to separate matching dium acetate, and water in diffused daylight, viewing
test tubes. Compare the Test solution, Reference suspension vertically against a white background (see Visual Compari-
A, Reference suspension B, water, and a 200 g per L solution son under Spectrophotometry and Light-Scattering h851i).
of sodium acetate in diffused daylight, viewing vertically The Test solution has the appearance of water or of the
against a black background (see Visual Comparison under 200 g per L solution of sodium acetate, or is not more in-
Spectrophotometry and Light-Scattering h851i). [NOTE— tensely colored than the Standard solution.
The diffusion of light must be such that Reference suspen- Identification—
sion A can readily be distinguished from water, and that Ref- A: Infrared Absorption h197Ki—Dry the specimen at
erence suspension B can readily be distinguished from 1058 for 2 hours before use.
Reference suspension A.] The Test solution shows the same B: To a solution (1 in 10) add 2 mL of 15% potassium
clarity as that of water, or of the 200 g per L solution of so- carbonate, and heat to boiling. No precipitate is formed.
dium acetate, or its opalescence is not more pronounced Add 4 mL of potassium pyroantimonate TS Potassium
than that of Reference suspension A. pyroantimonate solution, and heat to boiling. Allow to cool
in ice water and, if necessary, rub the inside of the test tube
with a glass rod. A dense precipitate is formed.
Harmonization
# 2005 The United States Pharmacopeial Convention, Inc. All Rights Reserved.
Pharmacopeial Forum
1228 HARMONIZATION Vol. 31(4) [July–Aug. 2005]
Potassium pyroantimonate solution—Dissolve 2 g of po- chloride to 50.0 mL. Evaporate 5.0 mL of the final solution
tassium pyroantimonate in 95 mL of hot water. Cool quick- to dryness in a stream of nitrogen. Dissolve the residue in
ly, and add a solution containing 2.5 g of potassium 1.0 mL of the Internal standard solution.
hydroxide in 50 mL of water and 1 mL of sodium hydroxide Test solution—Suspend 10.0 g of the substance to be ex-
solution (8.5 in 100). Allow to stand for 24 hours, filter, and amined in 20 mL of water, and dissolve using 5 mL to 6 mL
dilute with water to 150 mL. of 1 10 N sodium hydroxide. Dissolve 10.0 g of the sub-
C: Sodium salts impart an intense yellow color to a non- stance to be examined in about 45 mL of water. If necessary,
luminous flame. adjust the solution with 1 N sodium hydroxide or 1 N hydro-
Acidity or alkalinity—To a solution of 1.0 g in 10 mL of chloric acid to a pH of 7 to 8, and dilute with water to 50
carbon dioxide-free water add 1 drop of phenolphthalein mL. Shake the solution with four quantities each of 50
TS: no pink color is produced. Then add 1 drop of 0.1 N mL of methylene chloride. Combine the lower layers, dry
sodium hydroxide: a pink color is produced. over anhydrous sodium sulfate, and filter. Wash the filter
Water, Method I h921i: not more than 15.0%. and the sodium sulfate with 10 mL of methylene chloride.
Combine the solution and the washings, and evaporate al-
Readily carbonizable substances h271i—Dissolve 200
most to dryness in a water bath at a temperature not exceed-
mg in 5 mL of sulfuric acid (between 94.5% and 95.5%
ing 408. Using a small quantity of methylene chloride,
[w/w] of H2SO4), and keep at a temperature of 488 to 508
quantitatively transfer the residue into a suitable 10-mL
for 10 minutes: the solution has no more color than Match-
tube, evaporate to dryness in a stream of nitrogen, and dis-
ing Fluid A, when viewed against a white background.
solve the residue in 1.0 mL of the Internal standard solu-
Heavy metals, Method I h231i—Dissolve 4 g in 46 mL of
tion.
water, add 4 mL of dilute hydrochloric acid (1 in 12), mix,
Blank solution—Evaporate 200 mL of methylene chlo-
and rub the inner wall of the vessel with a glass rod until
ride to dryness in a water bath at a temperature not exceed-
crystallization begins. Allow the solution to stand for 1
ing 408. Dissolve the residue in 1 mL of methylene chloride.
hour, then pass through a dry filter, discarding the first 10
Chromatographic system (see Chromatography h621i)—
mL of the filtrate, and use 25 mL of the subsequent filtrate
The instrument gas chromatograph is equipped with a
for the Test Preparation: the limit is 0.001%.
flame-ionization detector and contains a 0.53-mm 6 10-m
Limit of toluenesulfonamides—
fused silica column, coated with G3 phase (film thickness 2
Internal standard solution—Dissolve 25 mg of caffeine in
mm). The injector port, column, and detector temperatures
methylene chloride, and dilute with the same solvent to 100
are maintained at about 2508, 1808, and 2508, respectively;
mL.
and nitrogen is used as the carrier gas at a flow rate of about
Reference solution—Dissolve 20.0 mg of USP o-Toluene-
10 mL per minute. The injector employs a split ratio of 1 : 2.
sulfonamide RS and 20.0 mg of USP p-Toluenesulfonamide
Procedure—Inject about 1 mL of the Reference solution.
RS in methylene chloride, and dilute with the same solvent
Adjust the sensitivity of the detector so that the height of the
to 100.0 mL. Dilute 5.0 mL of the solution with methylene
peak due to caffeine is not less than 50% of the full scale of
Harmonization
# 2005 The United States Pharmacopeial Convention, Inc. All Rights Reserved.
Pharmacopeial Forum
Vol. 31(4) [July–Aug. 2005] HARMONIZATION 1229
the recorder. The substances are eluted in the following or-
MONOGRAPHS (NF)
der: o-toluenesulfonamide, p-toluenesulfonamide, and caf-
feine. The test is not valid unless the resolution between
the peaks due to o-toluenesulfonamide and p-toluenesulfon-
amide is at least 1.5. Inject about 1 mL of the Blank solution.
In the chromatogram obtained, verify that there are no peaks
BRIEFING
with the same retention times as the internal standard, o-tol-
uenesulfonamide, and p-toluenesulfonamide. Inject about 1
Silicon Dioxide, NF 23 page 3073 and page 7187 of PF 24(6)
mL of the Test solution and 1 mL of the Reference solution. If [Nov.–Dec. 1998]. The Japanese Pharmacopoeia is the coordinat-
ing pharmacopoeia for the international harmonization of the com-
any peaks due to o-toluenesulfonamide and p-toluenesul- pendial standards for the Silicon Dioxide monograph, as part of the
process of international harmonization of monographs and general
fonamide appear in the chromatogram obtained with the analytical methods of the European, Japanese, and United States
pharmacopeias. The following monograph, which represents the
Test solution, the ratio of their areas to that of the internal Revised OFFICIAL INQUIRY STAGE 4 document, is based
in part on comments from the Japanese Pharmacopoeia and the Eu-
standard is not greater than the corresponding ratio in the ropean Pharmacopoeia in response to the Provisional Harmonized
Text Stage 4 draft prepared by the Japanese Pharmacopoeia.
chromatogram obtained with the Reference solution (10 Differences between the Revised OFFICIAL INQUIRY
STAGE 4 document and the current NF monograph include the
ppm of o-toluenesulfonamide and 10 ppm of p-toluenesul- following:
(1) In the opening paragraph (the Definition)—The Definition is
fonamide). modified to include the term, "separating," to allow for the
two processes of manufacturing, gel and precipitate. An upper
limit for Assay is added. The current EP lower limit of 98.0%
Limit of benzoate and salicylate—To 10 mL of a solution is adopted.
(2) Packaging and storage—No change. The USP text is retained
(1 in 20), previously acidified with 5 drops of 6 N acetic ac- as a nonharmonized attribute.
(3) Labeling—The requirement to label the different types of sil-
id, add 3 drops of ferric chloride TS: no precipitate or violet ica are omitted, because the Definition is changed. A require-
ment to label with the bulk density is added.
color appears. (4) Identification—Two additional identification procedures are
added to strengthen the monograph.
Organic volatile impurities, Method I h467i: meets the (5) pH—The limit is unchanged, but the slurry concentration is
slightly less.
requirements. (6) Loss on drying—The drying time and temperature are
changed to 2 hours and 1058, respectively, and the limit is in-
Assay—Dissolve, with the aid of slight heating if necessary, creased to 7.0%, as related to the time and temperature
change.
about 150 mg of Saccharin Sodium, accurately weighed, in (7) Loss on ignition—The ignition time is increased from 1 hour
to 2 hours.
50 mL of glacial acetic acid. Titrate with 0.1 N perchloric (8) Heavy metals—The USP test is retained as a nonharmonized
attribute.
acid, determining the endpoint potentiometrically. Perform (9) Chloride—The test is omitted, because it is not necessary.
(10) Hydrochloric acid soluble substances—This test is added to
a blank titration, if necessary, and make the appropriate cor- indirectly control levels of aluminum and calcium.
(11) Sulfate—The JP test is adopted and the limit is increased to
rection. Each mL of 0.1 N perchloric acid is equivalent to 1.0%.
(12) Organic volatile impurities—This test is retained as a specific
20.52 mg of C7H4NNaO3S.&2S (USP29) local attribute for USP.
(13) Arsenic—This test is retained as a nonharmonized attribute.
(14) Iron—This test is added to limit iron impurities.
Harmonization
# 2005 The United States Pharmacopeial Convention, Inc. All Rights Reserved.
