11/7/2020 USP-NF Mannitol

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© 2020 USPC

Mannitol
Portions of the monograph text that are national USP text, and are not part of the harmonized text, are marked with symbols (⧫⧫) to
specify this fact.

C6H14O6 182.17
D-Mannitol [69-65-8].

DEFINITION
Mannitol contains NLT 97.0% and NMT 102.0% of mannitol (C6H14O6), calculated on the dried basis.

IDENTIFICATION
Change to read:
• A. ▲SPECTROSCOPIC IDENTIFICATION TESTS 〈197〉, Infrared Spectroscopy: 197K▲ (CN 1-MAY-2020)
If the spectra shows differences, proceed as directed.
Standard solution: Dissolve 25 mg of USP Mannitol RS in a glass vial with 0.25 mL of distilled water without heating. The solution is
clear. Evaporate to dryness by one of the following methods. Heat in a microwave oven with a power range of 600–700 W for 20

L
min, or heat in an oven at 100° for 1 h, then gradually apply vacuum until a dry residue is obtained. Non-sticky, white, or slightly
yellowish powders are obtained.
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Sample solution: Dissolve 25 mg of Mannitol in a glass vial with 0.25 mL of distilled water without heating. The solution is clear.
Evaporate to dryness by one of the following methods. Heat in a microwave oven with a power range of 600–700 W for 20 min, or
heat in an oven at 100° for 1 h, then gradually apply vacuum until a dry residue is obtained. Non-sticky, white, or slightly yellowish
powders are obtained.
Analysis: Record new spectra using the residues from the Standard solution and the Sample solution.
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ASSAY
• PROCEDURE
Mobile phase: Degassed water
System suitability solution A: 25.0 mg/mL each of sorbitol and USP Mannitol RS
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System suitability solution B: 1.0 mg/mL each of maltitol and isomalt

Standard solution A: 50.0 mg/mL of USP Mannitol RS
Standard solution B: Dilute 2.0 mL of the Sample solution with water to 100.0 mL.
Standard solution C: Dilute 0.5 mL of Standard solution B with water to 20.0 mL.
Sample solution: 50.0 mg/mL of Mannitol
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Chromatographic system
(See Chromatography 〈621〉, System Suitability.)
Mode: LC
Detector: Refractive index
Column: 7.8-mm × 30-cm; packing L19
Temperatures
Detector: 40° (maintain at a constant temperature)
Column: 85 ± 2°
Flow rate: 0.5 mL/min
Injection volume: 20 µL
Run time: NLT 1.5 times the retention time of the mannitol peak. [NOTE—The retention time for mannitol is about 20 min.]
System suitability
Samples: System suitability solution A, System suitability solution B, Standard solution B, and Standard solution C
Suitability requirements
Resolution: NLT 2.0 between sorbitol and mannitol, System suitability solution A
Analysis
Samples: Standard solution A and Sample solution
Calculate the percentage of mannitol (C6H14O6) in the portion of Mannitol taken:

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11/7/2020 USP-NF Mannitol

Result = (rU/rS) × (CS/CU) × 100

rU = peak response from the Sample solution

rS = peak response from Standard solution A

CS = concentration of USP Mannitol RS in Standard solution A (mg/mL)

CU = concentration of the Sample solution (mg/mL)

Acceptance criteria: 97.0%–102.0% on the dried basis

IMPURITIES
• RELATED SUBSTANCES
Mobile phase, System suitability solution A, System suitability solution B, Standard solution B, Standard solution C, Sample
solution, Chromatographic system, and System suitability: Proceed as directed in the Assay.
Analysis
Samples: Standard solution B, Standard solution C, and Sample solution
Acceptance criteria: See Table 1 for the relative retention times.

Table 1

Name Relative Retention Time

Isomalt (1st peak) 0.60

Maltitol 0.69

Isomalt (2nd peak) 0.73

Mannitol L 1.0
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Sorbitol 1.2

[NOTE—Impurity A—Sorbitol; Impurity B—Maltitol; Impurity C—Isomalt.]

[NOTE—Isomalt elutes in two peaks.]
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[NOTE—Coelution of impurity B and the second peak of impurity C may be observed.]

Disregard limit: NMT 0.05%; any peak NMT the area of the principal peak obtained with Standard solution C
Sorbitol: NMT 2.0%; NMT the area of the principal peak obtained with Standard solution B
Sum of isomalt and maltitol: NMT 2.0%; NMT the area of the principal peak obtained with Standard solution B
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Unspeci ed impurities: NMT 0.10% for each impurity; NMT twice the area of the principal peak obtained with Standard solution C
Total impurities: NMT 2.0%; NMT the area of the principal peak obtained with Standard solution B
• REDUCING SUGARS
Ferric sulfate solution: Dissolve 50 g of ferric sulfate in an excess of water, add 200 mL of sulfuric acid, and dilute with water to 1000
mL.
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Copper sulfate solution: 69.2 mg/mL of copper sulfate (CuSO4 · 5H2O) in water

Sodium potassium tartrate solution: Dissolve 173 g of sodium potassium tartrate (C4H4KNaO6 · 4H2O) and 50 g of sodium hydroxide
in 400 mL of water. Heat to boiling, allow to cool, and dilute with carbon dioxide-free water to 500 mL.
Cupri-tartaric solution: Mix equal volumes of Copper sulfate solution and Sodium potassium tartrate solution immediately before use.
Sample: 7.0 g
Analysis: To the Sample add 13 mL of water. Boil gently with 40 mL of Cupri-tartaric solution for 3 min, and allow to stand for about 2
min. A precipitate is formed. Pass through a sintered-glass lter (10–16 µm) coated with diatomaceous earth or a sintered-glass
lter (5–10 µm). Wash the precipitate with hot water (at about 50°–60°) until the washing is no longer alkaline, and pass the
washings through the lter described above. Discard all the ltrate at this step. Immediately dissolve the precipitate in 20 mL of
Ferric sulfate solution, pass through the lter described above in a clean ask, and wash the lter with 15–20 mL of water. Combine
the washings and the ltrate, heat to 80°, and titrate with 0.02 M potassium permanganate VS.
Acceptance criteria: NMT 0.1%, expressed as glucose; NMT 3.2 mL of 0.02 M potassium permanganate VS is required to change the
color of the solution. The green color turns to pink, and the color persists at least 10 s.
• NICKEL
Sample solution: Suspend 10.0 g of Mannitol in 30 mL of dilute acetic acid [115–125 g/L of acetic acid (C2H4O2)], add water, and
shake to dissolve. Dilute with water to 100.0 mL. Add 2.0 mL of a saturated solution of ammonium pyrrolidinedithiocarbamate
(C5H12N2S2) (about 10 g/L) and 10.0 mL of water-saturated methyl isobutyl ketone (C6H12O, 4-methyl-2-pentanone), and then shake
for 30 s protected from bright light. Allow the layers to separate, and use the methyl isobutyl ketone layer.

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Blank solution: Treat water-saturated methyl isobutyl ketone as described for preparation of the Sample solution, omitting the
mannitol.
Standard solutions: Prepare three reference solutions in the same manner as the Sample solution but adding 0.5, 1.0, and 1.5 mL,
respectively, of nickel standard solution TS [10 ppm nickel (Ni)] in addition to the 10.0 g of the substance to be examined.
Instrumental conditions
(See Atomic Absorption Spectroscopy 〈852〉.)
Mode: Atomic absorption spectrophotometry
Analytical wavelength: 232.0 nm
Lamp: Nickel hollow-cathode
Flame: Air–acetylene
Analysis
Samples: Sample solution and Standard solutions
Set the zero of the instrument using the blank. Record the average of the steady readings for each of the Standard solutions and
the Sample solution. Between each measurement rinse with water, and ascertain that the reading returns to zero with the blank.
Plot the absorbances of the Standard solutions and the Sample solution versus the added quantity of nickel. Extrapolate the line
joining the points on the graph until it meets the concentration axis. The distance between this point and the intersection of the
axes represents the concentration of nickel in the Sample solution.
Acceptance criteria: NMT 1 µg/g

SPECIFIC TESTS
• MELTING RANGE OR TEMPERATURE 〈741〉, Class I
Melting point: 165°–170°
• APPEARANCE OF SOLUTION
Hydrazine sulfate solution: 10.0 mg/mL of hydrazine sulfate. Allow to stand for 4–6 h.
Methenamine solution: 2.5 g of methenamine in 25 mL of water, in a ground-glass-stoppered ask
Primary opalescent suspension: To the Methenamine solution, add 25.0 mL of the Hydrazine sulfate solution. Mix, and allow to stand
for 24 h. This suspension is stable for 2 months, provided it is stored in a glass container free from surface defects. The suspension
must not adhere to the glass and must be well mixed before use.
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Opalescence standard: Dilute 15.0 mL of the Primary opalescent suspension with water to 1000.0 mL. This suspension is freshly
prepared and may be stored for up to 24 h.
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Reference suspension: To 5.0 mL of Opalescence standard add 95.0 mL of water. Mix, and shake before use.
Standard solution: Pipet 3.0 mL of ferric chloride CS, 3.0 mL of cobaltous chloride CS, and 2.4 mL of cupric sulfate CS into a 1-L
volumetric ask. Dilute with 1% (w/v) hydrochloric acid to volume.
Sample solution: 100.0 mg/mL of Mannitol
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Analysis: Compare the color, clarity, and opalescence of equal volumes of the Reference suspension, Standard solution, and Sample
solution.
Acceptance criteria: The Sample solution is clear and colorless; its clarity is the same as that of water, or its opalescence is not more
pronounced than that of the Reference suspension, and it is not more intensely colored than the Standard solution.
• LOSS ON DRYING 〈731〉
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Sample: 1.000 g
Analysis: Dry the Sample at 105° for 4 h.
Acceptance criteria: NMT 0.5%
• CONDUCTIVITY
Sample: 20.0 g
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Analysis: Dissolve the Sample in carbon dioxide-free water prepared from distilled water by heating to 40°–50°, and dilute with the
same solvent to 100 mL. After cooling, measure the conductivity of the solution while gently stirring with a magnetic stirrer.
Acceptance criteria: NMT 20 µS/cm at 25°
• MICROBIAL ENUMERATION TESTS 〈61〉and TESTS FOR SPECIFIED MICROORGANISMS 〈62〉: The total aerobic microbial count (TAMC) is NMT 103 cfu/g,
and the total combined molds and yeasts count is NMT 102 cfu/g. It meets the requirements of the test for absence of Escherichia coli.
If intended for use in the manufacture of parenteral dosage forms, the TAMC is NMT 102 cfu/g.
• BACTERIAL ENDOTOXINS TEST 〈85〉: If intended for use in the manufacture of parenteral dosage forms without a further appropriate
procedure for the removal of bacterial endotoxins, less than 4 IU/g for parenteral dosage forms with a concentration of 100 g/L or less
of mannitol, and less than 2.5 IU/g for parenteral dosage forms with a concentration of more than 100 g/L of mannitol

ADDITIONAL REQUIREMENTS
• ⧫ PACKAGING AND STORAGE: Preserve in well-closed containers.⧫
• LABELING
The label states, where applicable, the maximum concentration of bacterial endotoxins.
The label states, where applicable, that the substance is suitable for use in the manufacture of parenteral dosage forms.
• USP REFERENCE STANDARDS 〈11〉
USP Mannitol RS

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11/7/2020 USP-NF Mannitol

Auxiliary Information- Please check for your question in the FAQs before contacting USP.

Topic/Question Contact Expert Committee

MANNITOL Tong Liu SE2020 Simple Excipients

Senior Scienti c Liaison

Chromatographic Database Information: Chromatographic Database

Most Recently Appeared In:

Pharmacopeial Forum: Volume No. 41(5)

Page Information:

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