Printed on: Thu Aug 17 2023, 10:32:06 PM(EST) Status: Currently Official on 18-Aug-2023 DocId: GUID-3C295111-A9C0-4784-97BD-C3D66B95E155_4_en-US

Printed by: Aigerim Bazilova Official Date: Official as of 01-May-2021 Document Type: NF @2023 USPC
Do Not Distribute DOI Ref: d3g8e DOI: https://doi.org/10.31003/USPNF_M77640_04_01
1

CU = concentration of Sorbitol in the Sample solution

Sorbitol (mg/g)
W = percentage obtained in the test for Water
Determination (%)

Acceptance criteria: 91.0%–100.5% on the anhydrous

C6H14O6 182.17 basis
D-Glucitol CAS RN®: 50-70-4. IMPURITIES
DEFINITION Change to read:
Sorbitol contains NLT 91.0% and NMT 100.5% of D-sorbitol
(C6H14O6), calculated on the anhydrous basis. The amounts • LIMIT OF NICKEL
of total sugars, other polyhydric alcohols, and any hexitol ▲
[NOTE—When water is specified as the diluent, use
anhydrides, if detected, are not included in the requirements, deionized ultra-filtered water. Use of glass volumetric
nor in the calculated amount as stated in General Notices, flasks is discouraged.]
5.60.10 Other Impurities in USP and NF Articles. Digest solution: Add 360 mL of hydrochloric acid,
ultratrace, and 240 mL of nitric acid, ultratrace, to 1200 mL
IDENTIFICATION of water.
• A. Blank solution: Add 40 mL of nitric acid, ultratrace, to a
Sample solution: 1 g of Sorbitol in 75 mL of water 2000-mL volumetric flask, dilute with water to volume, and
Analysis: Transfer 3 mL of Sample solution to a 15-cm test mix well.
tube and add 3 mL of a freshly prepared solution of catechol Internal standard solution: Transfer 2.0 mL of solution
(1 in 10), and mix. Add 6 mL of sulfuric acid, and then

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containing 1000 mg/L of yttrium1 to a 1000-mL volumetric
gently heat the tube in a flame for 30 s. flask, dilute with Blank solution to volume, and mix well. The
Acceptance criteria: A deep pink or wine-red color appears. Internal standard solution contains 2 µg/mL of yttrium.
• B. The retention time of the major peak of the Sample [NOTE—The concentration of the Internal standard solution
solution corresponds to that from the Standard solution, as can be adjusted if a high number of signal counts from the
obtained in the Assay. ci Internal standard solution causes an artifact.]
ASSAY Standard stock solution: [NOTE—Prepare this solution fresh
• PROCEDURE every 2 months.] Quantitatively dilute an accurately
Mobile phase: Use degassed water. measured volume of the solution containing 1000 mg/L
System suitability solution: Prepare a solution containing of nickel2 with Blank solution to obtain a solution containing
4.8 mg/g each of USP Sorbitol RS and mannitol. 10 µg/mL of nickel.
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Standard solution: 4.8 mg/g of USP Sorbitol RS Standard nickel solution A: [NOTE—Prepare this solution
Sample solution: Dissolve 0.10 g of Sorbitol in water and fresh weekly.] Pipet 1.0 mL of Standard stock solution into a
dilute with water to 20 g. Record the final solution weight, 200-mL volumetric flask. Dilute the content in the flask with
and mix thoroughly. Blank solution to volume, and mix well. This solution
Chromatographic system contains 50 ng/mL of nickel.
(See Chromatography á621ñ, System Suitability.) Standard nickel solution B: [NOTE—Prepare this solution
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Mode: LC fresh weekly.] Pipet 2.0 mL of Standard stock solution into a

Detector: Refractive index 200-mL volumetric flask. Dilute the content in the flask with
Column: 7.8-mm × 10-cm; packing L34 Blank solution to volume, and mix well. This solution
Temperatures contains 100 ng/mL of nickel.
Column: 50 ± 2° Standard nickel solution C: [NOTE—Prepare this solution
Detector: 35° fresh weekly.] Pipet 4.0 mL of Standard stock solution into a
Flow rate: 0.7 mL/min 200-mL volumetric flask. Dilute the content in the flask with
Injection volume: 10 µL Blank solution to volume, and mix well. This solution
System suitability contains 200 ng/mL of nickel.
Samples: System suitability solution and Standard solution Sample solution: Transfer 10.0 g of Sorbitol into a 125-mL
[NOTE—The relative retention times for mannitol and conical flask. Add 40 mL of Digest solution, and place on a
sorbitol are about 0.6 and 1.0, respectively.] hot plate. Heat the solution for about 20 min, being careful
Suitability requirements to prevent the solution from boiling over. Pull the sample
Resolution: NLT 2.0 between sorbitol and mannitol, off the hot plate just before it turns a dark caramel color.
System suitability solution [NOTE—Do not overburn the sample.] Transfer the flask’s
Relative standard deviation: NMT 2.0%, Standard contents into a clean, dry, 50-mL volumetric flask with
solution washings of Blank solution. Dilute with Blank solution to
Analysis volume. Filter the sample into a 15-mL centrifuge tube,
Samples: Standard solution and Sample solution using a 10-mL disposable syringe fitted with a syringe filter
Calculate the percentage of D-sorbitol (C6H14O6) in the of 0.45-µm pore size.
portion of Sorbitol taken: Instrumental conditions
(See Plasma Spectrochemistry á730ñ.)
Result = (rU/rS) × (CS/CU) × [100/(100 − W)] × 100 Mode: ICP–OES

rU = peak response of sorbitol from the Sample solution

rS = peak response of sorbitol from the Standard 1 Yttrium ICP standard solutions are commercially available. A suitable
solution yttrium ICP standard is available from LGC (www.lgcstandards.com) or
CS = concentration of USP Sorbitol RS in the Standard Millipore Sigma (www.sigmaaldrich.com).
2 Nickel ICP standard solutions are commercially available. A suitable nickel
solution (mg/g)
ICP standard is available from LGC (www.lgcstandards.com) or Millipore
Sigma (www.sigmaaldrich.com).

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Printed on: Thu Aug 17 2023, 10:32:06 PM(EST) Status: Currently Official on 18-Aug-2023 DocId: GUID-3C295111-A9C0-4784-97BD-C3D66B95E155_4_en-US
Printed by: Aigerim Bazilova Official Date: Official as of 01-May-2021 Document Type: NF @2023 USPC
Do Not Distribute DOI Ref: d3g8e DOI: https://doi.org/10.31003/USPNF_M77640_04_01
2

Emission wavelengths: 232.005 nm for nickel and Acceptance criteria: NMT 1 µg/g▲ (NF 1-May-2021)
371.029 nm for yttrium. Set the sample read time and • RESIDUE ON IGNITION á281ñ: NMT 0.1%, determined on a
other instrument parameters as appropriate or as 1.5-g portion
recommended by the instrument manufacturer. • REDUCING SUGARS
System suitability [NOTE—The amount determined in this test is not
Samples: Blank solution, Standard nickel solution included in the calculated amount as required in
A,Standard nickel solution B, and Standard nickel solution C General Notices, 5.60.10 Other Impurities in USP and
Suitability requirements NF Articles.]
[NOTE—Instrument performance must be verified to Sample solution: Dissolve 3.3 g of Sorbitol in 3 mL of water
conform to the manufacturer’s specifications for with the aid of gentle heat. Cool and add 20.0 mL of cupric
resolution and sensitivity. Before analyzing samples, citrate TS and a few glass beads. Heat so that boiling begins
the instrument must pass a suitable performance after 4 min, and maintain boiling for 3 min. Cool rapidly
check.] and add 40 mL of diluted acetic acid, 60 mL of water, and
Correlation coefficient: NLT 0.999, determined 20.0 mL of 0.05 N iodine VS. With continuous shaking, add
from the Calibration curve constructed in the Analysis 25 mL of a mixture of 6 mL of hydrochloric acid and 94 mL
Analysis of water.
Samples: Blank solution, Standard nickel solution Analysis: When the precipitate has dissolved, titrate the
A,Standard nickel solution B, Standard nickel solution C, and excess of iodine with 0.05 N sodium thiosulfate VS using
Sample solution 2 mL of starch TS, added toward the end of the titration, as
[NOTE—The following analysis is described for one type an indicator.
of ICP–OES instruments. If a different ICP–OES Acceptance criteria: NLT 12.8 mL of 0.05 N sodium
instrument is used, follow the instrument thiosulfate VS is required, corresponding to NMT 0.3% of
manufacturer’s recommendations for operation.]

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reducing sugars, as glucose.
Take 3 replicate scans with the integration set as • CHLORIDE AND SULFATE á221ñ, Chloride (if labeled for use in
recommended by the instrument manufacturer. Follow preparing parenteral dosage forms)
the instrument manufacturer’s recommendations for Sample: 1.5 g
delivering the sample. Add the Internal standard solution Acceptance criteria: The Sample shows no more chloride
in-line via a mixing block between the sample probe and than corresponds to 0.10 mL of 0.020 N hydrochloric acid
the spray chamber. Flush the samples through the
system before analysis. Program a read delay into the
sampling routine to allow for fluid flow equilibration
ci (NMT 0.0050%).
• CHLORIDE AND SULFATE á221ñ, Sulfate (if labeled for use in
preparing parenteral dosage forms)
after the high-speed flush, before the first analytical read Sample: 1.0 g
of the sample. Between samples, wash the pumping Acceptance criteria: The Sample shows no more sulfate
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system by flushing the Blank solution. than corresponds to 0.10 mL of 0.020 N sulfuric acid (NMT
Calibration curve: Generate the calibration curve using 0.01%).
the Blank solution, Standard nickel solution A, Standard
nickel solution B, and Standard nickel solution C as follows. SPECIFIC TESTS
Scan the Internal standard solution while running the • MICROBIAL ENUMERATION TESTS á61ñ and TESTS FOR
Blank solution to measure the intensity of the yttrium SPECIFIED MICROORGANISMS á62ñ: The total aerobic count
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emission. Hold this value constant throughout the using the Plate Method is NMT 103 cfu/g, and the total
remainder of the test. Separately scan the Blank solution, combined molds and yeasts count is NMT 102 cfu/g.
Standard nickel solution A,Standard nickel solution B, and • PH á791ñ: 3.5–7.0, in a 10% (w/w) solution in carbon
Standard nickel solution C for nickel and yttrium. dioxide-free water
[NOTE—Add the Internal standard solution via an in-line • WATER DETERMINATION á921ñ, Method I: NMT 1.5%
mixing chamber.] Normalize the yttrium intensity to the • CLARITY AND COLOR OF SOLUTION (if labeled for use in
value of the Internal standard solution. Apply this preparing parenteral dosage forms)
normalization factor to the nickel intensity, which is then Sample: 10.0 g
referred to as the corrected nickel intensity. Construct a Analysis: Dissolve the Sample in 100.0 mL of carbon
calibration curve by plotting the corrected nickel intensity dioxide-free water.
versus the known concentrations, in ng/mL, of the nickel. Acceptance criteria: The solution is clear and colorless.
Similarly, analyze the Sample solution. Plot the intensity of • BACTERIAL ENDOTOXINS TEST á85ñ (if labeled for use in
the emission of the Sample solution on the calibration preparing parenteral dosage forms): NMT 4 USP
curve. Determine the concentration of nickel (C), in ng/ Endotoxin Units/g for parenteral dosage forms having a
mL, in the Sample solution through the calibration curve. concentration of less than 100 g/L of sorbitol, and NMT
Calculate the content, in µg/g, of nickel in the portion of 2.5 USP Endotoxin Units/g for parenteral dosage forms
Sorbitol taken: having a concentration of 100 g/L or more of sorbitol
ADDITIONAL REQUIREMENTS
Result = (F × V × C)/W • PACKAGING AND STORAGE: Preserve in well-closed
containers. No storage requirements are specified.
F = conversion factor, 10–3 µg/ng (ng to µg)
• LABELING: Sorbitol intended for use in preparing parenteral
V = volume of the Sample solution, 50 mL
dosage forms is so labeled.
C = concentration of nickel in the Sample solution (ng/
• USP REFERENCE STANDARDS á11ñ
mL)
USP Sorbitol RS
W = weight of Sorbitol (g)

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