Hypromellose Phthalate

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

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

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1 DEFINITION 

Hypromellose Phthalate is a monophthalic acid ester of hydroxypropyl methylcellulose. It contains methoxy (-OCH₃), hydroxypropoxy (-OCH₂CHOHCH₃), and phthalyl (o-carboxybenzoyl; C₈H₅O₃) groups. It contains NLT 21.0% and NMT 35.0% of phthalyl groups, calculated on the anhydrous basis. 

2 IDENTIFICATION 

Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K. Do not dry specimens. 

3  ASSAY 

Phthalyl Content Sample: 1 g 

Analysis: Transfer the Sample to a conical flask, dissolve in 50 mL of a mixture of alcohol, acetone, and water (2:2:1), add phenolphthalein TS, and titrate with 0.1 N sodium hydroxide VS. Perform a blank determination (see Titrimetry 〈541〉). 

Calculate the percentage of phthalyl groups in the portion of Hypromellose Phthalate taken: 

Result = [0.01 × M_r1 × (V/W)] − [2 × (M_r1/M_r2) × P] 

M_r1 = molecular weight of the phthalyl group, 149.1 

V = volume of 0.1 N sodium hydroxide consumed after correction for the blank (mL) 

W = weight of Hypromellose Phthalate taken, calculated on the anhydrous basis (g) 

M_r2 = molecular weight of phthalic acid, 166.1 

P = percentage of free phthalic acid found as directed in the test for Limit of Free Phthalic Acid 

Acceptance criteria: 21.0%–35.0% on the anhydrous basis 

4 IMPURITIES 

Residue on Ignition 〈281〉: NMT 0.20% 

Chloride and Sulfate 〈221〉, Chloride 

Sample solution: Dissolve 1.0 g in 40 mL of 0.2 N sodium hydroxide, add 1 drop of phenolphthalein TS, and add 2 N nitric acid dropwise, with stirring, until the red color is discharged. Add an additional 20 mL of 2 N nitric acid with stirring. Heat on a water bath, with stirring, until the gel-like precipitate formed becomes granular. Cool the mixture, and centrifuge. Separate the liquid phase, and wash the residue with three successive 20-mL portions of water, separating the washings by centrifuging. Dilute the combined liquids with water to 200 mL, mix, and filter. 

Standard solution: Treat 0.50 mL of 0.01 N hydrochloric acid with 10 mL of 0.2 N sodium hydroxide, add 7 mL of 2 N nitric acid, and dilute with water to 50 mL. 

Analysis: Add 1 mL of silver nitrate TS to the Standard solution. Add 1 mL of silver nitrate TS to a 50-mL portion of the Sample solution. After mixing, allow each solution to stand for 5 min protected from direct sunlight. Compare the turbidity of the solutions. Acceptance criteria: A 50-mL portion of the Sample solution shows no more chloride than the Standard solution (0.07%). 

Change to read: 

Limit of Free Phthalic Acid 

Mobile phase: 0.1% trifluoroacetic acid and acetonitrile (90:10) 

Standard solution: Weigh accurately and transfer 12.5 mg of phthalic acid to a 250-mL volumetric flask, and add 125 mL of acetonitrile. Add 25 mL of water, and dilute with acetonitrile to volume. 

Sample solution: Weigh accurately and transfer 200 mg of Hypromellose Phthalate to a 100-mL volumetric flask. Add 50 mL of acetonitrile, and sonicate to dissolve partially. Add 10 mL of water, and sonicate to dissolve. Cool to room temperature, and dilute with acetonitrile to volume. 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 235 nm 

Column: 4.6-mm × 25-cm; packing L1 with a high carbon load 

Flow rate: 2 mL/min 

Injection volume: 10 µL 

System suitability 

Sample: Standard solution 

Suitability requirements 

Relative standard deviation: NMT 1.0% for 5 (NF 1-May-2023) replicate injections 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of phthalic acid in the portion of Hypromellose Phthalate taken: 

Result = (r_U/r_S) × (C_S/C_U) × 100 

r_U = peak response of phthalic acid from the Sample solution 

r_S = peak response of phthalic acid from the Standard solution 

C_S = concentration of phthalic acid in the Standard solution (mg/mL) 

C_U = concentration of Hypromellose Phthalate in the Sample solution (mg/mL)  

Acceptance criteria: NMT 1.0% 

5 SPECIFIC TESTS 

Water Determination 〈921〉, Method I: NMT 5.0% 

Viscosity—Capillary Methods 〈911〉 

Sample solution: Dissolve 10 g, previously dried at 105° for 1 h, in 90 g of a mixture of methanol and methylene chloride (1:1 w/w) by mixing and shaking. 

Analysis: Determine the viscosity at 20 ± 0.1°. 

Acceptance criteria: 80%–120% of that indicated by the label 

6 ADDITIONAL REQUIREMENTS 

Packaging and Storage: Preserve in tight containers. 

 Labeling: Label it to indicate its viscosity and nominal phthalyl content. 

USP Reference Standards 〈11〉 

USP Hypromellose Phthalate RS