Dihydrocodeine Bitartrate

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 

Dihydrocodeine Bitartrate contains NLT 98.0% and NMT 102.0% of dihydrocodeine bitartrate (C₁₈H₂₃NO_{3 .} C₄H₆O₆), calculated on the dried basis. 

2 IDENTIFICATION 

Change to read: 

2.1 A.

Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197A or 197K (CN 1-May-2020) 

Change to read: 

2.2 B. 

(USP 1-May-2019) The retention time of the dihydrocodeine peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay. 

Change to read: 

2.3 C. 

(USP 1-May-2019) Identification Tests—General 〈191〉, Chemical Identification Tests, Tartrate: Meets the requirements Delete the following: 

2.4 C. 

Analysis: To a solution of 20 mg in 5 mL of sulfuric acid in a test tube, add 1 drop of ferric chloride TS, and heat in a boiling water bath for 2 min. 

Acceptance criteria: Although the solution may darken, no blue color is produced (distinction from Codeine and morphine). (USP 1-May-2019) 

3 ASSAY 

Change to read: 

3.1 Procedure 

Buffer: Dissolve 2.0 g of monobasic potassium phosphate and 1.0 g of sodium 1-heptanesulfonate in 1000 mL of water. Adjust with 50% sodium hydroxide to a pH of 7.0. 

Solution A: Acetonitrile and Buffer (5:195) 

Solution B: Acetonitrile, Buffer, and water (140:35:10) 

Mobile phase: See Table 1. 

Table 1 

Standard solution: 2.25 mg/mL of USP Dihydrocodeine Bitartrate RS in Solution A. Sonicate to dissolve, if necessary.

Sample solution: 2.25 mg/mL of Dihydrocodeine Bitartrate in Solution A. Sonicate to dissolve, if necessary. 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 280 nm 

Column: 4.6-mm × 15-cm; 3.5-µm packing L1 

Column temperature: 45° 

Flow rate: 1.0 mL/min 

Injection volume: 20 µL 

System suitability 

Sample: Standard solution 

Suitability requirements 

Tailing factor: NMT 2.0 

Relative standard deviation: NMT 0.73% 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of dihydrocodeine bitartrate (C₁₈H₂₃NO_{3 .} C₄H₆O₆) in the portion of Dihydrocodeine Bitartrate taken:

Result = (r_u/r_s) × (C_s/C_u) × 100

r_u = peak response of dihydrocodeine from the Sample solution 

r_s = peak response of dihydrocodeine from the Standard solution 

C_s = concentration of USP Dihydrocodeine Bitartrate RS in the Standard solution (mg/mL) 

C_u = concentration of Dihydrocodeine Bitartrate in the Sample solution (mg/mL) (USP 1-May-2019) 

Acceptance criteria: 98.0%–102.0% on the dried basis 

4 IMPURITIES 

4.1 Residue on Ignition 〈281〉: NMT 0.1% 

Delete the following: 

4.2 Ordinary Impurities 〈466〉 

Standard solution and Sample solution: Water 

Eluant: A mixture of methylene chloride, methanol, and ammonium hydroxide (90:10:1) 

Visualization: 17, and view under short-wavelength UV light 

Acceptance criteria: Meet the requirements (USP 1-May-2019) 

Add the following: 

4.3 Organic Impurities 

Buffer, Solution A, Solution B, Mobile phase, Sample solution, and Chromatographic system: Proceed as directed in the Assay.

Sensitivity solution: 0.00113 mg/mL of USP Dihydrocodeine Bitartrate RS in Solution A. Sonicate to dissolve, if necessary.

System suitability stock solution A: 0.3 mg/mL each of USP Morphine Sulfate RS and USP Codeine Sulfate RS prepared as follows. Dissolve suitable amounts of USP Morphine Sulfate RS and USP Codeine Sulfate RS with 20% of the nal volume of methanol in a suitable volumetric ask. Dilute with Solution A to volume. Sonicate to dissolve, if necessary. 

System suitability stock solution B: Prepare as directed for the Standard solution in the Assay. 

System suitability solution: 0.015 mg/mL each of USP Morphine Sulfate RS and USP Codeine Sulfate RS, and 2.25 mg/mL of USP Dihydrocodeine Bitartrate RS prepared as follows. Dilute System suitability stock solution A with System suitability stock solution B.

Standard solution: 0.00225 mg/mL of USP Dihydrocodeine Bitartrate RS in Solution A. Sonicate to dissolve, if necessary.

System suitability 

Samples: Sensitivity solution, System suitability solution, and Standard solution 

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

Suitability requirements 

Resolution: NLT 2 between morphine and dihydrocodeine; NLT 2 between dihydrocodeine and codeine, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution 

Signal-to-noise ratio: NLT 10, Sensitivity solution 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of each impurity in the portion of Dihydrocodeine Bitartrate taken: 

Result = (r_u/r_s) × (C_s/C_u)  × (1/F) × 100 

r_u = peak response of each impurity from the Sample solution 

r_s = peak response of dihydrocodeine from the Standard solution 

C_s = concentration of USP Dihydrocodeine Bitartrate RS in the Standard solution (mg/mL) 

C_u = concentration of Dihydrocodeine Bitartrate in the Sample solution (mg/mL) 

F = relative response factor (see Table 2) 

Acceptance criteria: See Table 2. 

Table 2 

a Counter ion; not to be included in the total impurities. 

b 4,5α-Epoxy-17-methylmorphinan-3,6α-diol. 

c 4,5α-Epoxy-3,6-dimethoxy-17-methylmorphinan. 

5 SPECIFIC TESTS 

Delete the following: 

5.1 Ammonium Salts 

Analysis: To about 100 mg of Dihydrocodeine Bitartrate in a suitable test tube, add 5 mL of 1 N sodium hydroxide, and heat on a steam bath Acceptance criteria: The odor of ammonia is not detected (USP 1-May-2019) 

5.2 Loss on Drying 〈731〉 

Analysis: Dry Dihydrocodeine Bitartrate at 105° for 4 h. 

Acceptance criteria: NMT 0.5% 

Delete the following: 

5.3 Melting Range or Temperature 〈741〉, Class I:

186°–190°, but the range between beginning and end of melting does not exceed 2.5° (USP 1- May-2019) 

5.4 Optical Rotation 〈781S〉, Procedures, Specific Rotation 

Sample solution: 10 mg/mL of Dihydrocodeine Bitartrate in water 

Acceptance criteria: Between −72° and −75° 

5.5 pH 〈791〉 

Sample solution: 100 mg/mL of Dihydrocodeine Bitartrate in water 

Acceptance criteria: 3.2–4.2 

6 ADDITIONAL REQUIREMENTS 

Change to read: 

6.1 Packaging and Storage:

Preserve in tight containers. Protect from light. (USP 1-May-2019) 

Change to read: 

6.2 USP Reference Standards 〈11〉 

USP Codeine Sulfate RS (USP 1-May-2019) 

USP Dihydrocodeine Bitartrate RS 

USP Morphine Sulfate RS (USP 1-May-2019)