Methadone Hydrochloride Tablets

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 

Methadone Hydrochloride Tablets contain NLT 93.0% and NMT 107.0% of the labeled amount of methadone hydrochloride (C₂₁H₂₇NO.HCl).

2 IDENTIFICATION 

Change to read: 

A. Thin-Layer Chromatographic Identification Test 〈201〉 

Sample: Equivalent to 5 mg of methadone hydrochloride from a quantity of finely powered Tablets 

Developing solvent system: Alcohol, glacial acetic acid, and water (5:3:2) 

Analysis: Shake the Sample with 5 mL of sodium carbonate TS, and extract with 5 mL of chloroform. Proceed as directed using iodoplatinate TS to visualize the spots. 

Acceptance criteria: Meet the requirements 

Add the following: 

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

3 ASSAY 

Change to read: 

Procedure 

Mobile phase: Acetonitrile and 0.03 M monobasic potassium phosphate (40:60). Adjust with phosphoric acid to a pH of 3.2. Standard solution: 0.4 mg/mL of USP Methadone Hydrochloride RS in Mobile phase 

Sample solution: Nominally 0.4 mg/mL of methadone hydrochloride in Mobile phase prepared as follows. Transfer an amount of finely powdered Tablets (NLT 20) equivalent to 10 mg of methadone hydrochloride to a 25-mL volumetric flask. Add 10 mL of Mobile phase, and sonicate briefly. Shake by mechanical means for about 15 min, dilute with Mobile phase to volume. Pass through a suitable filter of 0.45-µm pore size.  

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 254 nm 

Column: 3.9-mm × 30-cm; 10-μm  packing L11 

Flow rate: 1.5 mL/min 

Injection volume: 10 µL 

Run time: NLT 1.5 times the retention time of methadone  

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 methadone hydrochloride (C₂₁H₂₇NO.HCl)

Result = (r_U/r_S) × (C_S/C_U) × 100 

r_U = peak response of methadone from the Sample solution 

r_S = peak response of methadone from the Standard solution 

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

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

Acceptance criteria: 93.0%–107.0% 

4 PERFORMANCE TESTS 

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Dissolution 〈711〉 

Medium: Water; 500 mL 

Apparatus 1: 100 rpm 

Time: 45 min 

Determine the percentage of the labeled amounts of methadone hydrochloride (C₂₁H₂₇NO.HCl) dissolved by using one of the following procedures. 

Spectroscopic procedure  

Standard solution: USP Methadone Hydrochloride RS in Medium 

Sample solution: Pass a portion of the solution under test through a suitable filter. Transfer a volume of the filtrate equivalent to about 400 µg of methadone hydrochloride into a suitable separator. Add 1 mL of glacial acetic acid and 20 mL of a solution of bromocresol purple prepared by dissolving 200 mg of bromocresol purple in 1000 mL of dilute glacial acetic acid (1 in 50). Mix, and extract with 20.0 mL of chloroform.  

Instrumental conditions 

Mode: Vis 

Analytical wavelength: 405 nm 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of the labeled amount of methadone hydrochloride (C₂₁H₂₇NO.HCl) dissolved in comparison with the chloroform extract similarly prepared from the Standard solution: 

Result = (A_U/A_S) × (C_S/C_U) × V × (1/L) × 100 

A_U = absorbance of the Sample solution  

A_S = absorbance of the Standard solution 

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

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

V = volume of Medium, 500 mL 

L = label claim (mg/Tablet) 

Chromatographic procedure 

Buffer: Dissolve 9.8 g of phosphoric acid in 1000 mL of water. Adjust with triethylamine to a pH of 3.6. 

Mobile phase: Acetonitrile and Buffer (30:70) 

Standard stock solution: 0.25 mg/mL of USP Methadone Hydrochloride RS prepared as follows. Transfer a suitable amount of USP Methadone Hydrochloride RS to a volumetric flask and add acetonitrile to 20% of the flask volume. Add water to 60% of the flask volume and sonicate for about 5 min to dissolve. Dilute with water to volume. 

Standard solution: 20 µg/mL of USP Methadone Hydrochloride RS in Medium from the Standard stock solution Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size. Discard the first few milliliters of the filtrate. 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 292 nm 

Column: 4.6-mm × 10-cm; 3.5-µm packing L7 

Column temperature: 30° 

Flow rate: 1 mL/min 

Injection volume: 50 µL 

Run time: NLT 1.3 times the retention time of methadone 

System suitability 

Sample: Standard solution 

Suitability requirements 

Tailing factor: NMT 2.0 

Relative standard deviation: NMT 2.0% 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of the labeled amount of methadone hydrochloride (C₂₁H₂₇NO.HCl) dissolved: 

Result = (r_U/r_S) × (C_S/L) × V × 100 

r_U = peak response of methadone from the Sample solution

r_S = peak response of methadone from the Standard solution 

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

L = label claim (mg/Tablet) 

V = volume of Medium, 500 mL  

Tolerances: NLT 75% (Q) of the labeled amount of methadone hydrochloride (C₂₁H₂₇NO.HCl) is dissolved 

Uniformity of Dosage Units 〈905〉: Meet the requirements 

Add the following: 

5 IMPURITIES 

Organic Impurities 

Buffer: Dissolve 9.8 g of phosphoric acid in 1000 mL of water. Adjust with triethylamine to a pH of 3.6. 

Mobile phase: Acetonitrile and Buffer (30:70) 

Diluent: Acetonitrile and Buffer (40:60) 

Standard stock solution A: 0.25 mg/mL of USP Methadone Hydrochloride RS prepared as follows. Transfer a suitable amount of USP Methadone Hydrochloride RS to a volumetric flask and add acetonitrile to 20% of the flask volume. Add water to 60% of the flask volume and sonicate for about 5 min to dissolve. Dilute with water to volume. 

Standard stock solution B: 0.1 mg/mL of USP Methadone Hydrochloride RS in Mobile phase from Standard stock solution A Standard solution: 0.5 µg/mL of USP Methadone Hydrochloride RS in Diluent from Standard stock solution B 

Sensitivity solution: 0.25 µg/mL of USP Methadone Hydrochloride RS in Diluent from the Standard solution 

Sample solution: Nominally 0.5 mg/mL of methadone hydrochloride prepared as follows. Transfer Tablets (NLT 5) equivalent to 50 mg of methadone hydrochloride to a 100-mL volumetric flask. Add 80 mL of Diluent and shake for about 60 min. Dilute with Diluent to volume. Pass through a suitable filter of 0.45-µm pore size. Discard the first few milliliters of the filtrate. 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 210 nm 

Column: 4.6-mm × 25-cm; 3.5-µm packing L7 

Column temperature: 30° 

Flow rate: 1 mL/min 

Injection volume: 50 µL 

Run time: NLT 3.5 times the retention time of methadone 

System suitability 

Samples: Standard solution and Sensitivity solution 

Suitability requirements 

Tailing factor: NMT 2.0, Standard 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 any individual degradation product in the portion of Tablets taken: 

Result = (r_U/r_S) × (C_S/C_U) × 100 

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

r_S = peak response of methadone from the Standard solution 

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

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

Acceptance criteria: The reporting threshold is 0.05%. 

Any individual degradation product: NMT 0.2% 

Total degradation products: NMT 1.2%  

6 ADDITIONAL REQUIREMENTS 

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Packaging and Storage: Preserve in well-closed containers. Store at controlled room temperature and protect from light.  USP Reference Standards 〈11〉 

USP Methadone Hydrochloride RS