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Printed by: Dang Van Vu Official Date: Official as of 01-May-2020 Document Type: USP @2023 USPC
Do Not Distribute DOI Ref: u4h4m DOI: https://doi.org/10.31003/USPNF_M3160_02_01
1

System suitability solution: 0.8 mg/mL of USP

Aminophylline Tablets Theophylline RS and 1 µg/mL of USP Theophylline Related
DEFINITION Compound F RS in water prepared as follows. Transfer
Aminophylline Tablets contain an amount of aminophylline 21 mg of USP Theophylline RS to a 25-mL volumetric flask
equivalent to NLT 93.0% and NMT 107.0% of the labeled and add 15 mL of water. Sonicate to dissolve, add 1 mL of
amount of anhydrous theophylline (C7H8N4O2). Impurity stock solution, and dilute with water to volume.
Standard solution: 0.17 mg/mL of USP Theophylline RS in
[NOTE—The ammoniacal odor present in the vapor space
water. Sonicate to dissolve as needed.
above the Tablets is often quite strong, especially when
Sample solution: Nominally 0.17 mg/mL of anhydrous
bottles having suitably tight closures are newly opened.
theophylline from NLT 20 finely powdered Tablets in water
This is due to ethylenediamine vapor pressure
prepared as follows. Transfer 34 mg of anhydrous
build-up, a natural condition in the case of
theophylline from a portion of the powder to a 200-mL
aminophylline.]
volumetric flask. Add 20 mL of water and mix for 1 min.
IDENTIFICATION Add an additional 140 mL of water and sonicate for 30 min.
Dilute with water to volume. Pass through a suitable filter
Change to read: of 0.22-µm pore size, discarding the first 2–3 mL.
Chromatographic system
• A. ▲SPECTROSCOPIC IDENTIFICATION TESTS á197ñ, Infrared (See Chromatography á621ñ, System Suitability.)
Spectroscopy: 197K▲ (CN 1-May-2020) Mode: LC
Analysis: Macerate a quantity of Tablets, equivalent to Detector: UV 270 nm
500 mg of aminophylline, with 25 mL of water, and filter. Column: 2.1-mm × 10-cm; 1.7-µm packing L1
The filtrate is alkaline to litmus. To the filtrate add 1 mL of Column temperature: 40°
3 N hydrochloric acid, stir, and if necessary, chill to

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Flow rate: 0.4 mL/min
precipitate the theophylline. Filter, and retain the filtrate, Injection volume: 1 µL
free from washings. Use the filtrate in Identification C. Wash System suitability
the theophylline crystals so obtained with small quantities Samples: System suitability solution and Standard solution
of ice-cold water, and dry at 105° for 1 h. Suitability requirements
Acceptance criteria: The IR spectrum of theophylline so ci Resolution: NLT 2.0 between theophylline and
obtained corresponds to that of USP Theophylline RS. theophylline related compound F, System suitability
• B. The retention time of the major peak of the Sample solution
solution corresponds to that of the Standard solution, as Relative standard deviation: NMT 1.0%, Standard
obtained in the Assay. solution
• C. Analysis
ffi
Sample: The filtrate obtained in Identification A Samples: Standard solution and Sample solution
Analysis: To the Sample add 0.5 mL of benzenesulfonyl Calculate the percentage of the labeled amount of
chloride and 5 mL of 1 N sodium hydroxide to render theophylline (C7H8N4O2) in the portion of Tablets taken:
alkaline, shake by mechanical means for 10 min, and add
5 mL of 3 N hydrochloric acid to acidify. Chill, collect the Result = (rU/rS) × (CS/CU) × 100
precipitated disulfonamide of ethylenediamine, and wash
O

with water. Recrystallize the washed precipitate from water, rU = peak response of theophylline from the Sample
and dry at 105° for 1 h. solution
Acceptance criteria: The dried precipitate melts at 164°– rS = peak response of theophylline from the Standard
171°. solution
ASSAY CS = concentration of USP Theophylline RS in the
• PROCEDURE Standard solution (mg/mL)
Solution A: 10 mM ammonium acetate prepared as follows. CU = nominal concentration of theophylline in the
Transfer 770.8 mg of ammonium acetate to a 1-L Sample solution (mg/mL)
volumetric flask, and dissolve in water to 80% of the flask
volume. Adjust with glacial acetic acid to a pH of 5.5 and Acceptance criteria: 93.0%–107.0%
dilute with water to volume. Pass through a suitable filter OTHER COMPONENTS
of 0.2-µm pore size. • CONTENT OF ETHYLENEDIAMINE
Solution B: Methanol Sample solution: Transfer a portion of the powdered
Mobile phase: See Table 1. Tablets, equivalent to 350 mg of aminophylline, prepared
in the Assay, into a 100-mL conical flask. Add 20 mL of
Table 1 water, and digest at 50°, with frequent shaking, for 30 min.
Time Solution A Solution B Cool, filter into a 250-mL conical flask, and wash with water
(min) (%) (%) until the last washing is neutral to litmus. Use the combined
0 98 2 filtrate and washings.
Titrimetric system
7 50 50 Mode: Direct titration
7.3 10 90 Titrant: 0.1 N hydrochloric acid VS
Endpoint detection: Visual
8.3 10 90
Analysis: Add methyl orange TS to the Sample solution, and
8.31 98 2 titrate. Each mL of 0.1 N hydrochloric acid is equivalent to
3.005 mg of ethylenediamine (C2H8N2).
12 98 2
Acceptance criteria: 140–190 mg of ethylenediamine
(C2H8N2) per gram of theophylline (C7H8N4O2) found in the
Impurity stock solution: 25 µg/mL of USP Theophylline Assay
Related Compound F RS in water

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Printed on: Thu Feb 09 2023, 12:04:36 AM(EST) Status: Currently Official on 09-Feb-2023 DocId: GUID-09E82524-1468-4B04-AC9B-EC9AF5F70EAB_2_en-US
Printed by: Dang Van Vu Official Date: Official as of 01-May-2020 Document Type: USP @2023 USPC
Do Not Distribute DOI Ref: u4h4m DOI: https://doi.org/10.31003/USPNF_M3160_02_01
2

PERFORMANCE TESTS Suitability requirements

• DISSOLUTION á711ñ Resolution: NLT 2.0 between theophylline and
For uncoated or plain coated tablets theophylline related compound F, System suitability
Medium: Water; 900 mL solution
Apparatus 2: 50 rpm Relative standard deviation: NMT 3.0% for each peak,
Time: 45 min Standard solution
Standard solution: USP Theophylline RS in Medium Analysis
Sample solution: Proceed as directed in the chapter for Samples: Standard solution and Sample solution
sample. Dilute with water to a concentration that is similar Calculate the percentage of theophylline related
to that of the Standard solution. compound D in the portion of Tablets taken:
Instrumental conditions
Mode: UV-Vis Result = (rU/rS) × (CS/CU) × 100
Analytical wavelength: UV about 269 nm
Analysis rU = peak response of theophylline related
Samples: Standard solution and Sample solution compound D from the Sample solution
Calculate the percentage of the labeled amount of rS = peak response of theophylline related
theophylline (C7H8N4O2) dissolved. compound D from the Standard solution
Tolerances: NLT 75% (Q) of the labeled amount of CS = concentration of USP Theophylline Related
theophylline (C7H8N4O2) is dissolved. Compound D RS in the Standard solution
• UNIFORMITY OF DOSAGE UNITS á905ñ (mg/mL)
Procedure for content uniformity CU = nominal concentration of aminophylline in the
Standard solution: 10 µg/mL of USP Theophylline RS Sample solution (mg/mL)

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Sample solution: Place 1 Tablet in a 250-mL volumetric
flask, add 200 mL of water, and shake by mechanical Calculate the percentage of any other individual
means until disintegration is complete. Add water to unspecified degradation product in the portion of Tablets
volume. Filter a portion of the mixture, discarding the first taken:
20 mL of the filtrate. Result = (rU/rS) × (CS/CU) × 100
Instrumental conditions
Mode: UV
Analytical wavelength: About 269 nm
Cell: 1 cm
ci rU

rS
= peak response of any other individual unspecified
degradation product from the Sample solution
= peak response of theophylline from the Standard
Blank: Water solution
Analysis
ffi
CS = concentration of USP Theophylline RS in the
Samples: Standard solution and Sample solution Standard solution (mg/mL)
Calculate the percentage of the labeled amount of CU = nominal concentration of aminophylline in the
anhydrous theophylline (C7H8N4O2) in the Tablet taken: Sample solution (mg/mL)
Result = (AU/AS) × (CS/CU) × 100 Acceptance criteria: See Table 2. Disregard peaks less than
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0.05%.
AU = absorbance of the Sample solution
AS = absorbance of the Standard solution Table 2
CS = concentration of USP Theophylline RS in the Relative Acceptance
Standard solution (µg/mL) Retention Criteria,
CU = nominal concentration of theophylline in the Name Time NMT (%)
Sample solution (µg/mL)
Theophylline related compound Ca, b 0.36 —
Acceptance criteria: Meet the requirements Theophylline related compound B a, c
0.63 —

IMPURITIES Theophylline related compound D 0.69 0.2

• ORGANIC IMPURITIES —
Dimethyl uric acida, d 0.76
Solution A, Solution B, Mobile phase, Impurity stock
solution, System suitability solution, and Theobrominea, e 0.82 —
Chromatographic system: Proceed as directed in the Theophylline 1.0 —
Assay.
Standard solution: 2.0 µg/mL each of USP Theophylline RS Theophylline related compound Fa 1.09 —
and USP Theophylline Related Compound D RS in water Caffeine a
1.20 —
Sample solution: Nominally 1.0 mg/mL of anhydrous
aminophylline from NLT 20 finely powdered Tablets in Any other individual unspecified degrada-
—
water prepared as follows. Transfer 10 mg of anhydrous tion product 0.2
aminophylline from a portion of the powder to a 10-mL Total degradation products — 0.5
volumetric flask. Add 5 mL of water and sonicate for 30 min.
Dilute with water to volume. Pass through a suitable filter a Process impurity included for identification only and not to be included in the
of 0.22-µm pore size, discarding the first 2–3 mL. calculation of total degradation products.
b N-(6-Amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)
System suitability
formamide.
Samples: System suitability solution and Standard solution c 3-Methyl-1H-purine-2,6-dione.
[NOTE—See Table 2 for relative retention times.] d 1,3-Dimethyl-7,9-dihydro-1H-purine-2,6,8(3H)-trione.
e 3,7-Dihydro-3,7-dimethylpurine-2,6(1H)-dione.

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Printed on: Thu Feb 09 2023, 12:04:36 AM(EST) Status: Currently Official on 09-Feb-2023 DocId: GUID-09E82524-1468-4B04-AC9B-EC9AF5F70EAB_2_en-US
Printed by: Dang Van Vu Official Date: Official as of 01-May-2020 Document Type: USP @2023 USPC
Do Not Distribute DOI Ref: u4h4m DOI: https://doi.org/10.31003/USPNF_M3160_02_01
3

ADDITIONAL REQUIREMENTS N-Methyl-5-(methylamino)-1H-imidazole-4-

• PACKAGING AND STORAGE: Preserve in tight containers. carboxamide hydrochloride monohydrate.
Store at controlled room temperature. C6H10N4O · HCl · H2O 208.65
• LABELING: Label the Tablets to state the content of USP Theophylline Related Compound F RS
anhydrous theophylline. 7-(2-Hydroxyethyl)-1,3-dimethyl-3,7-dihydro-1H-purine-
• USP REFERENCE STANDARDS á11ñ 2,6-dione.
USP Theophylline RS C9H12N4O3 224.22
USP Theophylline Related Compound D RS
Theophyllidine;

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ci
ffi
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