Noncrystallizing Sorbitol Solution

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

DOWNLOAD PDF HERE

1 DEFINITION 

Noncrystallizing Sorbitol Solution is an aqueous solution containing NLT 45.0% (w/w) of d-sorbitol (C₆H₁₄O₆). The amounts of total sugars, other polyhydric alcohols, and any hexitol anhydrides, if detected, are not included in the requirements nor in the calculated amount as stated in General Notices, 5.60.10 Other Impurities in USP and NF Articles. 

2 IDENTIFICATION 

A.

Sample solution: Dissolve 1.4 g of Noncrystallizing Sorbitol Solution in 75 mL of water. 

Analysis: Transfer 3 mL of Sample solution to a 15-cm test tube. Add 3 mL of a freshly prepared solution of catechol (1 in 10), and mix. Add 6 mL of sulfuric acid, mix again, and gently heat the tube in a ame for 30 s. 

Acceptance criteria: A deep pink or wine-red color appears. 

B. The retention time of the major peak from the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. 

C. Limit of Diethylene Glycol and Ethylene Glycol 

Diluent: Acetone and water (96:4) 

Standard solution: 0.08 mg/mL each of USP Diethylene Glycol RS and USP Ethylene Glycol RS in Diluent 

Sample solution: Transfer 2.0 g of Noncrystallizing Sorbitol Solution to a 25-mL volumetric flask. Add 1.0 mL of Diluent to the flask, and mix on a vortex mixer for 3 min. Add the remaining Diluent to the flask to volume in 3 equal portions. Mix on a vortex mixer for about 3 min after each addition of Diluent. Pass a portion of the supernatant layer obtained through a 0.45-µm nylon filter. Discard the first 2 mL of the filtrate, and collect the rest of the filtrate for analysis. [Note—Acetone is used to precipitate sorbitol.] 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: GC 

Detector: Flame ionization 

Column: 0.32-mm × 15-m fused-silica capillary column; 0.25-µm layer of phase G46 

Temperatures 

Detector: 300° 

Injection port: 240° 

Column: See Table 1. 

Table 1 

Carrier gas: Helium 

Flow rate: 3.0 mL/min 

Injection volume: 1.0 µL 

Injection type: Split, split ratio 10:1. [Note—A split liner, deactivated with glass wool, is used.] 

System suitability 

Sample: Standard solution 

[Note—Diethylene glycol elutes after ethylene glycol.] 

Suitability requirements 

Resolution: NLT 30 between ethylene glycol and diethylene glycol 

Analysis 

Samples: Standard solution and Sample solution 

Based on the Standard solution, identify the peaks of ethylene glycol and diethylene glycol. Compare the peak areas of ethylene glycol and diethylene glycol in the Standard solution and the Sample solution. 

Acceptance criteria 

Diethylene glycol: The peak area of diethylene glycol in the Sample solution is NMT the peak area of diethylene glycol in the Standard solution, corresponding to NMT 0.10% of diethylene glycol in Noncrystallizing Sorbitol Solution. 

Ethylene glycol: The peak area of ethylene glycol in the Sample solution is NMT the peak area of ethylene glycol in the Standard solution, corresponding to NMT 0.10% of ethylene glycol in Noncrystallizing Sorbitol Solution. 

3 ASSAY 

Procedure 

Mobile phase: Use degassed water. 

System suitability solution: 4.8 mg/g each of mannitol and USP Sorbitol RS 

Standard solution: 4.8 mg/g of USP Sorbitol RS 

Sample solution: Weigh 0.20 g of Noncrystallizing Sorbitol Solution, and dissolve in and dilute with water to 20 g. Record the nal solution weight. 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: Refractive index 

Column: 7.8-mm × 10-cm; packing L34 

Temperatures 

Detector: 35° 

Column: 50 ± 2° 

Flow rate: 0.7 mL/min 

Injection volume: 10 µL 

System suitability 

Samples: System suitability solution and Standard solution 

[Note—The relative retention times for mannitol and sorbitol are about 0.6 and 1.0, respectively, System suitability solution.] Suitability requirements 

Resolution: NLT 2.0 between sorbitol and mannitol, System suitability solution 

Relative standard deviation: NMT 2.0%, Standard solution 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of d-sorbitol (C₆H₁₄O₆) in the portion of Noncrystallizing Sorbitol Solution taken: 

Result = (r_U/r_S) × (C_S/C_U) × 100 

r_U = peak response of sorbitol from the Sample solution 

r_S = peak response of sorbitol from the Standard solution 

C_S = concentration of USP Sorbitol RS in the Standard solution (mg/g) 

C_U = concentration of Noncrystallizing Sorbitol Solution in the Sample solution (mg/g) 

Acceptance criteria: NLT 45.0% 

4 IMPURITIES 

Residue on Ignition 〈281〉: NMT 0.1%, calculated on the anhydrous basis, determined on a 2-g portion 

Change to read: 

Limit of Nickel 

[Note—When water is specified as the diluent, use deionized ultra-filtered water. Use of glass volumetric flasks is discouraged.]

Digest solution: Add 360 mL of hydrochloric acid, ultratrace, and 240 mL of nitric acid, ultratrace, to 1200 mL of water.

Blank solution: Add 40 mL of nitric acid, ultratrace, to a 2000-mL volumetric flask, dilute with water to volume, and mix well.

Internal standard solution: Transfer 2.0 mL of solution containing 1000 mg/L of yttrium¹ to a 1000-mL volumetric flask, dilute with Blank solution to volume, and mix well. The Internal standard solution contains 2 µg/mL of yttrium. [Note—The concentration of the Internal standard solution can be adjusted if a high number of signal counts from the Internal standard solution causes an artifact.]

Standard stock solution: [Note—Prepare this solution fresh every 2 months.] Quantitatively dilute an accurately measured volume of the solution containing 1000 mg/L of nickel² with Blank solution to obtain a solution containing 10 µg/mL of nickel. 

Standard nickel solution A: [Note—Prepare this solution fresh weekly.] Pipet 1.0 mL of Standard stock solution into a 200-mL volumetric flask. Dilute the content in each flask with Blank solution to volume, and mix well. This solution contains 50 ng/mL of nickel.

Standard nickel solution B: [Note—Prepare this solution fresh weekly.] Pipet 2.0 mL of Standard stock solution into a 200-mL volumetric flask. Dilute the content in each flask with Blank solution to volume, and mix well. This solution contains 100 ng/mL of nickel.

Standard nickel solution C: [Note—Prepare this solution fresh weekly.] Pipet 4.0 mL of Standard stock solution into a 200-mL volumetric flask. Dilute the content in each flask with Blank solution to volume, and mix well. This solution contains 200 ng/mL of nickel.

Sample solution: Transfer a quantity of Noncrystallizing Sorbitol Solution, equivalent to 10.0 g on the anhydrous basis, into a 125-mL conical flask. Add 40 mL of Digest solution, and place on a hot plate. Heat the solution for about 20 min, being careful to prevent the solution from boiling over. Pull the sample off of the hot plate just before it turns a dark caramel color. [Note—Do not overburn the sample.] Transfer the flask's contents into a clean, dry, 50-mL volumetric flask with washings of Blank solution. Dilute with Blank solution to volume. Filter the sample into a 15-mL centrifuge tube, using a 10-mL disposable syringe fitted with a syringe filter of 0.45-µm pore size. Instrumental conditions (See Plasma Spectrochemistry 〈730〉.) 

Mode: ICP–OES 

Emission wavelengths: 232.005 nm for nickel and 371.029 nm for yttrium. Set the sample read time and other instrument parameters as appropriate or as recommended by the instrument manufacturer. 

System suitability 

Samples: Blank solution, Standard nickel solution A, Standard nickel solution B, and Standard nickel solution C Suitability requirements 

[Note—Instrument performance must be verified to conform to the manufacturer's specifications for resolution and sensitivity. Before analyzing samples, the instrument must pass a suitable performance check.] 

Correlation coefficient: NLT 0.999, determined from the Calibration curve constructed in the Analysis 

Analysis 

Samples: Blank solution, Standard nickel solution A, Standard nickel solution B, Standard nickel solution C, and Sample solution [Note—The following analysis is described for one type of ICP–OES instruments. If a different ICP–OES instrument is used, follow the instrument manufacturer's recommendations for operation.] 

Take 3 replicate scans with the integration set as recommended by the instrument manufacturer. Follow the instrument manufacturer's recommendations for delivering the sample. Add the Internal standard solution in-line via a mixing block between the sample probe and 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 after the high-speed flush, before the first analytical read of the sample. Between samples, wash the pumping system by flushing the Blank solution. 

Calibration curve: Generate the calibration curve using the Blank solution, Standard nickel solution A, Standard nickel solution B, and Standard nickel solution C as follows. Scan the Internal standard solution while running the Blank solution to measure the intensity of the yttrium emission. Hold this value constant throughout the remainder of the test. Separately scan the Blank solution, Standard nickel solution A, Standard nickel solution B, and Standard nickel solution C for nickel and yttrium. [Note—Add the Internal standard solution via an in-line mixing chamber.] Normalize the yttrium intensity to the value of the Internal standard solution. Apply this normalization factor to the nickel intensity, which is then referred to as the corrected nickel intensity. Construct a calibration curve by plotting the corrected nickel intensity versus the known concentrations, in ng/mL, of nickel. 

Similarly, analyze the Sample solution. Plot the intensity of the emission of the Sample solution on the calibration curve. Determine the concentration of nickel (C), in ng/mL, in the Sample solution through the calibration curve. 

Calculate the content, in µg/g, of nickel in the solid portion of Noncrystallizing Sorbitol Solution taken: 

Result = (F × V × C)/W 

F = conversion factor, 10–3 µg/ng (ng to µg) 

V = volume of the Sample solution, 50 mL 

C = concentration of nickel in the Sample solution (ng/mL) 

W = weight of Noncrystallizing Sorbitol Solution calculated on the anhydrous basis (g) 

Acceptance criteria: NMT 1 µg/g

Reducing Sugars 

[Note—The amount determined in this test is not included in the calculated amount as requested in General Notices, 5.60.10 Other Impurities in USP and NF Articles.] 

Sample: An amount of Noncrystallizing Sorbitol Solution, equivalent to 3.3 g on the anhydrous basis 

Analysis: To the Sample, add 3 mL of water, 20.0 mL of cupric citrate TS, and a few glass beads. Heat so that boiling begins after 4 min, and maintain boiling for 3 min. Cool rapidly and add 40 mL of diluted acetic acid, 60 mL of water, and 20.0 mL of 0.05 N iodine VS. With continuous shaking, add 25 mL of a mixture of 6 mL of hydrochloric acid and 94 mL of water. When the precipitate has dissolved, titrate the excess of iodine with 0.05 N sodium thiosulfate VS using 2 mL of starch TS, added toward the end of the titration, as an indicator. 

Acceptance criteria: NLT 12.8 mL of 0.05 N sodium thiosulfate VS is required corresponding to NMT 0.3% of reducing sugars, on the anhydrous basis, as Glucose. 

5 SPECIFIC TESTS 

Microbial Enumeration Tests 〈61〉 and Tests for Specified Microorganisms 〈62〉: The total aerobic microbial count using the Plate Method is NMT 103 cfu/mL, and the total combined molds and yeasts count is NMT 102 cfu/mL. 

pH 〈791〉: 5.0–7.5, in a 14% (w/w) solution of Noncrystallizing Sorbitol Solution in carbon dioxide-free water 

Water Determination 〈921〉, Method I: 28.5%–31.5% 

6 ADDITIONAL REQUIREMENTS 

Packaging and Storage: Preserve in well-closed containers. No storage requirements are specified. 

USP Reference Standards 〈11〉 

USP Diethylene Glycol RS 

USP Ethylene Glycol RS 

USP Sorbitol RS 

¹ Yttrium ICP standard solutions are commercially available. A suitable yttrium ICP standard is available from LGC (www.lgcstandards.com) or Millipore Sigma (www.sigmaaldrich.com). 

² Nickel ICP standard solutions are commercially available. A suitable nickel ICP standard is available from LGC (www.lgcstandards.com) or Millipore Sigma (www.sigmaaldrich.com).