Printed on: Mon Oct 24 2022, 08:31:47 PM(EST) Status: Currently Official on 25-Oct-2022 DocId: GUID-6A0B0F3C-FA70-433C-AD55-2020BBC64718_4_en-US

Printed by: Maria Christina Official Date: Official as of 01-May-2019 Document Type: USP & NF @2022 USPC
DOI Ref: 1ctq4 DOI: https://doi.org/10.31003/USPNF_M39215_04_01
1

Analysis: Add the Sample solution to exactly 50 mL of water

Hypromellose in a beaker. Insert a thermometer into the solution. Stir the
Portions of this monograph that are national USP text, and are solution on a magnetic stirrer/hot plate, and begin heating
not part of the harmonized text, are marked with symbols at a rate of 2°–5°/min. Determine the temperature at
(◆ ◆) to specify this fact. which a turbidity increase begins to occur, and designate
this temperature as the flocculation temperature.
Cellulose, 2-hydroxypropyl methyl ether; Acceptance criteria: The flocculation temperature is higher
Cellulose hydroxypropyl methyl ether CAS RN®: 9004-65-3. than 50°.
DEFINITION ASSAY
Hypromellose is a methyl and hydroxypropyl mixed ether of
cellulose. It contains, calculated on the dried basis, methoxy Change to read:
(–OCH3: 31.03) and hydroxypropoxy (–OC3H6OH: 75.09)
• PROCEDURE
groups conforming to the limits for the types of [CAUTION—Hydriodic acid and its reaction byproducts
Hypromellose (hydroxypropyl methylcellulose) set forth in are highly toxic. Perform all steps in the preparation
the following table. of the Standard solution and the Sample solution in a
properly functioning hood. Specific safety practices to
Methoxy Hydroxypropoxy be followed are to be identified to the analyst
(%) (%) performing this test.]
Substitution Type Min. Max. Min. Max. Apparatus: For the reaction vial, use a 5-mL pressure-tight
serum vial, 50 mm in height, 20 mm in outside diameter,
1828 16.5 20.0 23.0 32.0 and 13 mm in inside diameter at the mouth. The vial is

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2208 19.0 24.0 4.0 12.0 equipped with a pressure-tight septum with a
polytetrafluoroethylene-faced butyl rubber and an airtight
2906 27.0 30.0 4.0 7.5
seal using an aluminum crimp or any sealing system that
2910 28.0 30.0 7.0 12.0 provides sufficient airtightness. Use a heater having a
heating module that has a square-shaped aluminum block
with holes 20 mm in diameter and 32 mm in depth, into
IDENTIFICATION
• A.
Sample: 1 g
Analysis: Gently add the Sample to the top of 100 mL of
ci which the reaction vial fits. The heating module is also
equipped with a magnetic stirrer capable of mixing the
contents of the vial, or use a reciprocal shaker that
water in a beaker, and allow to disperse over the surface, performs a reciprocating motion of about 100 times/min.
tapping the top of the container to ensure an even Hydriodic acid: Use a reagent with a typical concentration
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dispersion of the substance. Allow the beaker to stand for of hydrogen iodide (HI) of about 57%.
1–2 min. Internal standard solution: 30 mg/mL of n-octane in
Acceptance criteria: The powdered material aggregates on o-xylene
the surface. Standard solution: Into a suitable serum vial, weigh
• B. between 60 and 100 mg of adipic acid, and add 2.0 mL of
Sample: 1 g Hydriodic acid and 2.0 mL of Internal standard solution.
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Analysis: Add the Sample to 100 mL of boiling water, and Close the vial securely with a suitable septum stopper.
stir the mixture using a magnetic stirrer with a bar Weigh the vial and contents, add between 15 and 22 µL of
25-mm long. isopropyl iodide through the septum with a syringe, weigh
Acceptance criteria: A slurry is formed, but the powdered again, and calculate the weight of isopropyl iodide added,
material does not dissolve. Cool the slurry to 10°, and stir by difference. Add 45 µL of methyl iodide similarly, weigh
using a magnetic stirrer. The resulting liquid is a clear or again, and calculate the weight of methyl iodide added, by
slightly turbid solution with thickness dependent on the difference. Shake the reaction vial well, and allow the layers
viscosity grade. to separate. Use the upper layer as the Standard solution.
• C. Sample solution: Transfer 0.065 g of Hypromellose to a
Solution A: Sulfuric acid and water (9 in 10). 5-mL thick-walled reaction vial equipped with a
[NOTE—Carefully add sulfuric acid to water.] pressure-tight septum-type closure, add between 60 and
Sample solution: 0.1 mL of the solution prepared for 100 mg of adipic acid, and pipet 2.0 mL of Internal standard
Identification B solution into the vial. Cautiously pipet 2.0 mL of
Analysis: To the Sample solution add 9 mL of Solution A, and Hydriodic acid into the mixture, immediately cap the vial
shake. Heat in a water bath for exactly 3 min, immediately tightly, and weigh. Using the magnetic stirrer equipped in
cool in an ice bath, and add carefully 0.6 mL of the heating module, or using a reciprocal shaker, mix the
ninhydrin TS. Shake, and allow to stand at 25°. contents of the vial continuously, heating and maintaining
Acceptance criteria: A red color develops at first that the temperature of the contents at 130 ± 2° for 60 min. If a
changes to purple within 100 min. reciprocal shaker or magnetic stirrer cannot be used, shake
• D. the vial well by hand at 5-min intervals during the initial
Sample solution: 2–3 mL of the solution prepared for 30 min of the heating time. Allow the vial to cool, and
Identification B weigh. If the weight loss is ▲≥26 mg▲ (USP 1-May-2019) or there
Analysis: Pour the Sample solution onto a glass slide as a thin is evidence of a leak, discard the mixture, and prepare
film, and allow the water to evaporate. another Sample solution.
Acceptance criteria: A coherent, clear film forms on the Chromatographic system
glass slide. (See Chromatography á621ñ, System Suitability.)
• E. Mode: GC
Sample solution: 50 mL of the solution prepared in Detector: Thermal conductivity or hydrogen
Identification B flame-ionization

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Printed on: Mon Oct 24 2022, 08:31:47 PM(EST) Status: Currently Official on 25-Oct-2022 DocId: GUID-6A0B0F3C-FA70-433C-AD55-2020BBC64718_4_en-US
Printed by: Maria Christina Official Date: Official as of 01-May-2019 Document Type: USP & NF @2022 USPC
DOI Ref: 1ctq4 DOI: https://doi.org/10.31003/USPNF_M39215_04_01
2

Column: ▲0.53-mm × 30-m fused silica capillary, coated IMPURITIES

with a 3-μm layer of phase G1. Use a guard column if • RESIDUE ON IGNITION á281ñ
necessary. Sample: 1.0 g
Temperatures Acceptance criteria: NMT 1.5%
Injection port: 250°
Detector: 280° SPECIFIC TESTS
Column: See the temperature program shown in Table 1. • PH á791ñ
Sample: Use the solution prepared in the tests for Viscosity
Table 1 —Capillary Methods and Viscosity—Rotational Methods.
Analysis: Read the indicated pH value after the probe has
Hold Time been immersed for 5 ± 0.5 min.
Initial Temperature Final at Final
Temperature Ramp Temperature Temperature Acceptance criteria: 5.0–8.0
(°) (°/min) (°) (min) • LOSS ON DRYING á731ñ
Sample: 1.0 g
50 0 50 3
Analysis: Dry the Sample at 105° for 1 h.
50 10 100 — Acceptance criteria: NMT 5.0%
8▲ (USP 1-May-2019)
• VISCOSITY—CAPILLARY METHODS á911ñ and VISCOSITY—
100 34.9 250
ROTATIONAL METHODS á912ñ
Method 1: This method is applied to Hypromellose samples
Carrier gas: ▲Helium▲ (USP 1-May-2019) with a viscosity type of less than 600 mPa · s.
Flow rate: With the Standard solution, adjust the flow rate Sample solution: Transfer a quantity of Hypromellose
so that the retention time of the internal standard is about equivalent to 4 g of solids, calculated on the dried basis,
10 min ▲(about 4.3 mL/min).▲ (USP 1-May-2019) to a tared, wide-mouth centrifuge bottle. Add hot water

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Injection volume: 1–2 µL (90°–99°) to obtain a total weight of the sample and water
▲
Injection type: Split ratio, 40:1 of 200.0 g. Capping the bottle, stir by mechanical means
Run time: 20.3 min at 400 ± 50 rpm for 10–20 min until the particles are
System suitability thoroughly dispersed and wetted out. Scrape down the
Sample: Standard solution ci walls of the bottle with a spatula, if necessary, to ensure
Suitability requirements that there is no undissolved material on the sides of the
Resolution: Methyl iodide, isopropyl iodide, and the bottle, and continue the stirring in a cooling water bath
internal standard are eluted in this order, with resolution equilibrated at a temperature below 10° for another 20–
NLT 5 between these peaks. 40 min. Adjust the solution weight, if necessary, to
Relative standard deviation: NMT 2.0% for 6 injections 200.0 g, using cold water. Centrifuge the solution, if
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of the Standard solution, using the ratio of the peak area necessary, to expel any entrapped air. If any foam is
of methyl iodide, isopropyl iodide to that of the internal present, remove with a spatula.
standard.▲ (USP 1-May-2019) Analysis: Determine the viscosity at 20 ± 0.1° in a suitable
Analysis viscometer of the Ubbelohde type as directed in Viscosity
Samples: Upper layer of the Standard solution and the —Capillary Methods á911ñ.
Sample solution Acceptance criteria: 80%–120% of the viscosity stated
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Calculate the percentage of methoxy (–OCH3) in the on the label

portion of Hypromellose taken: Method 2: This method is applied to Hypromellose samples
with a viscosity type of 600 mPa · s or higher.
Result = 21.864 × (RUa/RSa) × (WSa/WU) Sample solution: Transfer a quantity of Hypromellose
equivalent to 10 g of solids, calculated on the dried basis,
RUa = peak area ratio of methyl iodide to n-octane from to a tared, wide-mouth centrifuge bottle, and add hot
the Sample solution water (90°–99°) to obtain a total weight of the sample and
RSa = peak area ratio of methyl iodide to n-octane from water of 500.0 g. Capping the bottle, stir by mechanical
the Standard solution means at 400 ± 50 rpm for 10–20 min until the particles
WSa = weight of methyl iodide in the Standard solution are thoroughly dispersed and wetted out. Scrape down
(mg) the walls of the bottle with a spatula, if necessary, to
WU = weight of Hypromellose, calculated on the dried ensure that there is no undissolved material on the sides
basis, taken for the Sample solution (mg) of the bottle, and continue the stirring in a cooling water
bath equilibrated at a temperature below 10° for another
Calculate the percentage of hydroxypropoxy (–OC3H6OH) 20–40 min. Adjust the solution weight, if necessary, to
in the portion of Hypromellose taken: 500.0 g, using cold water. Centrifuge the solution, if
necessary, to expel any entrapped air. If any foam is
Result = 44.17 × (RUb/RSb) × (WSb/WU) present, remove with a spatula.
Analysis: Equip a suitable single-cylinder type rotational
RUb = peak area ratio of isopropyl iodide to n-octane viscometer (Brookfield type LV model, or equivalent), and
from the Sample solution determine the viscosity of this solution at 20 ± 0.1° under
RSb = peak area ratio of isopropyl iodide to n-octane the operating conditions specified in Table 2.
from the Standard solution
WSb = weight of isopropyl iodide in the Standard Table 2
solution (mg) Labeled Viscositya Rotor Revolution Calculation
WU = weight of Hypromellose, calculated on the dried (mPa · s) No. (rpm) Multiplier
basis, taken for the Sample solution (mg)
600 or more and less
than 1400 3 60 20
Acceptance criteria: See the limits, calculated on the dried
basis, in the table in the Definition. 1400 or more and less
than 3500 3 12 100

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Printed on: Mon Oct 24 2022, 08:31:47 PM(EST) Status: Currently Official on 25-Oct-2022 DocId: GUID-6A0B0F3C-FA70-433C-AD55-2020BBC64718_4_en-US
Printed by: Maria Christina Official Date: Official as of 01-May-2019 Document Type: USP & NF @2022 USPC
DOI Ref: 1ctq4 DOI: https://doi.org/10.31003/USPNF_M39215_04_01
3

Table 2 (continued) between subsequent measurements. Repeat the

Labeled Viscositya Rotor Revolution Calculation operation twice to rotate the spindle as specified above,
(mPa · s) No. (rpm) Multiplier and average the three readings.
Acceptance criteria: 75%–140% of the viscosity stated
3500 or more and less
than 9500 4 60 100 on the label
9500 or more and less ADDITIONAL REQUIREMENTS
than 99,500 4 6 1000 • ◆PACKAGING AND STORAGE: Preserve in well-closed
99,500 or more 4 3 2000
containers. No storage requirements are specified.◆
• LABELING: Label it to indicate its substitution type and its
a The labeled viscosity is based on the manufacturer’s specifications. nominal viscosity value in millipascals per second (mPa · s).

Allow the spindle to rotate for 2 min before taking the

measurement. Allow a rest period of at least 2 min

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