Theophylline in Dextrose Injection

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

Theophylline in Dextrose Injection is a sterile solution of Theophylline and Dextrose in Water for Injection. It contains NLT 93.0% and NMT 107.0% of the labeled amount of anhydrous theophylline (C₇H₈N₄O₂) and NLT 95.0% and NMT 105.0% of the labeled amount of dextrose (C₆H₁₂O₆ · H₂O).

2 IDENTIFICATION

A. The UV spectrum of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

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

C.

Sample solution: Theophylline in Dextrose Injection

Analysis: Add a few drops of the Sample solution to 5 mL of hot alkaline cupric tartrate TS.

Acceptance criteria: A red-to-orange precipitate of cuprous oxide is formed.

3 ASSAY

3.1 Theophylline

Solution A: 10 mM ammonium acetate prepared as follows. Transfer 771 mg of ammonium acetate to a 1-L volumetric flask, and dissolve in 80% of the flask volume of water. Adjust with glacial acetic acid to a pH of 4.8 and dilute with water to volume. Pass through a suitable filter of 0.2-μm pore size.

Solution B: Methanol

Mobile phase: See Table 1.

Table 1

Standard solution: 0.1 mg/mL of USP Theophylline RS

Sample solution: Nominally 0.1 mg/mL of theophylline prepared as follows. Transfer 5 mg of theophylline from a volume of Injection to a 50- mL volumetric flask. Dissolve and dilute with water to volume.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 270 nm. For Identification A, use a photodiode array detector in the range of 210–400 nm.

Column: 2.1-mm × 10-cm; 1.7-μm packing L7

Column temperature: 40°

Flow rate: 0.4 mL/min

Injection volume: 1 μL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of theophylline (C₇H₈N₄O₂) in the portion of Injection taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U  = peak response of theophylline from the Sample solution

r_S = peak response of theophylline from the Standard solution

C_S = concentration of USP Theophylline RS in the Standard solution (mg/mL)

C_U = nominal concentration of theophylline in the Sample solution (mg/mL)

Acceptance criteria: 93.0%–107.0%

3.2 Dextrose

Sample solution: Nominally 2–5 g of dextrose per 100 mL, prepared as follows. Transfer a volume of Injection containing 2–5 g of dextrose to a 100-mL volumetric flask. Add 0.2 mL of 6 N ammonium hydroxide, and dilute with water to volume.

Analysis

Sample: Sample solution

Determine the angular rotation in a suitable polarimeter tube (see Optical Rotation 〈781〉).

Calculate the percentage of the labeled amount of dextrose (C₆H₁₂O₆ · H₂O) in the portion of Injection taken:

Result = [(100 × a)/(l × α)] × (1/C_U) × (M_r1 /M_r2 ) × 100

a = observed angular rotation of the Sample solution (°)

l = length of the polarimeter tube (dm)

α = midpoint of the specific rotation range for anhydrous dextrose, 52.9°

C_U = nominal concentration of dextrose in the Sample solution (g/100 mL)

M_r1 = molecular weight of dextrose monohydrate, 198.17

M_r2 = molecular weight of anhydrous dextrose, 180.16

Acceptance criteria: 95.0%–105.0%

4 IMPURITIES

4.1 Organic Impurities

Solution A, Solution B, and Mobile phase: Prepare as directed in the Assay.

System suitability solution: 0.4 μg/mL each of USP Theophylline Related Compound D RS and 5-hydroxymethylfurfural

Standard solution: 0.4 μg/mL each of USP Theophylline RS and USP Theophylline Related Compound D RS

Sample solution: Nominally 400 μg/mL of theophylline in water prepared as follows. Transfer 4 mg of theophylline from a volume of Injection to a 10-mL volumetric flask. Dissolve and dilute with water to volume.

4.2 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 270 nm

Column: 2.1-mm × 10-cm; 1.7-μm packing L7

Column temperature: 40°

Flow rate: 0.4 mL/min

Injection volume: 2.5 μL

4.3 System suitability

Samples: System suitability solution and Standard solution

[Note—See Table 2 for relative retention times.]

4.4 Suitability requirements

Resolution: NLT 1.1 between theophylline related compound D and 5-hydroxymethylfurfural, System suitability solution

Relative standard deviation: NMT 5.0% for theophylline and theophylline related compound D, Standard solution

4.5 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of theophylline related compound D in the portion of Injection taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of theophylline related compound D from the Sample solution

r_S = peak response of theophylline related compound D from the Standard solution

C_S = concentration of USP Theophylline Related Compound D RS in the Standard solution (μg/mL)

C_U = nominal concentration of theophylline in the Sample solution (μg/mL)

Calculate the percentage of any other individual unspecified degradation product in the portion of Injection taken:

Result = (r_U/r_S ) × (C_S/C_U) × 100

r_U = peak response of any other individual unspecified degradation product from the Sample solution

r_S = peak response of theophylline from the Standard solution

C_S = concentration of USP Theophylline RS in the Standard solution (μg/mL)

C_U = nominal concentration of theophylline in the Sample solution (μg/mL)

Acceptance criteria: See Table 2. Disregard peaks less than 0.1%.

Table 2

^a 5-Hydroxymethylfurfural; the content of this impurity is controlled in the Limit of 5-Hydroxymethylfurfural and Related Substances test.

Limit of 5-Hydroxymethylfurfural and Related Substances

Cation-exchange column: Proceed as directed in Chromatography 〈621〉 using a chromatographic tube capable of providing a 0.8- × 4-cm bed volume (or 2 mL) of 100- to 200-mesh, strongly acidic styrene-divinylbenzene cation-exchange resin. Condition the column by washing with 30 mL of water, discarding the eluate.

Sample solution: Pass a volume of Injection containing 100 mg of hydrous dextrose through the resin bed in the Cation-exchange column, allowing the sample to flow down the wall of the column so as not to disturb the resin bed, and collect the eluate in a 50-mL volumetric flask. Wash the column with 25 mL of water, and collect the eluate in the same 50-mL volumetric flask. Dilute the eluate with water to volume.

Blank solution: Pass 27 mL of water through a freshly conditioned Cation-exchange column, collecting the eluate in a 50-mL volumetric flask.

Fill with water to volume.

Instrumental conditions

Mode: UV

Analytical wavelength: 284 nm

Cell: 1 cm

Blank: Blank solution

Analysis

Samples: Sample solution and Blank solution

Determine the absorbance of the Sample solution and Blank solution with a suitable spectrophotometer.

Acceptance criteria: The absorbance is NMT 0.25.

5 SPECIFIC TESTS

Bacterial Endotoxins Test 〈85〉: NMT 1.0 USP Endotoxin Unit/mg of anhydrous theophylline

pH 〈791〉

Sample solution: NMT 5% of dextrose from a portion of Injection in water, diluted with water if necessary

Acceptance criteria: 3.5–6.5

Other Requirements: It meets the requirements in Injections and Implanted Drug Products 〈1〉.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in single-dose containers, preferably of Type I or Type II glass, or of a suitable plastic material. Store at

controlled room temperature.

USP Reference Standards 〈11〉

USP Theophylline RS

USP Theophylline Related Compound D RS

Theophyllidine;

N-Methyl-5-(methylamino)-1H-imidazole-4-carboxamide hydrochloride monohydrate.

C₆H₁₀N₄O · HCl · H₂O 208.65