Hydrocodone Bitartrate and Homatropine Methylbromide 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 

Hydrocodone Bitartrate and Homatropine Methylbromide Tablets contain NLT 90.0% and NMT 110.0% of the labeled amounts of hydrocodone bitartrate disesquihydrate (C₁₈H₂₁NO₃.C₄H₆O₆. 2½H₂O) and homatropine methylbromide (C₁₇H₂₄BrNO₃). 

[Note—Use of silanized autosampler vials such as dimethyldichlorosilane vials¹ is required for Dissolution Test 1 and Test 2, the Limit tests, and the Assay to prevent drug degradation.] 

2 IDENTIFICATION 

The UV absorption spectra of the hydrocodone bitartrate and homatropine methylbromide peaks of the Sample solution and those of the Standard solution exhibit maxima and minima at the same wavelengths, as obtained in the Assay. 

The retention times of the hydrocodone bitartrate and homatropine methylbromide peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay. 

3 ASSAY 

Change to read: Procedure 

Buffer: 0.005 M dibasic potassium phosphate. Adjust with phosphoric acid to a pH of 6.4 ± 0.1  . Mobile phase: Acetonitrile and Buffer (30:170) 

Standard solution: 0.2 mg/mL of USP Hydrocodone Bitartrate RS and 0.06 mg/mL of USP Homatropine Methylbromide RS in Mobile phase Sample solution: Nominally 0.2 mg/mL of hydrocodone bitartrate and 0.06 mg/mL of homatropine methylbromide prepared as follows. Transfer a portion of fine powder from NLT 20 Tablets to a suitable volumetric flask. Add 60% of the nal volume of Mobile phase, sonicate for 15 min, and then shake with a wrist-action shaker for an additional 15 min. Dilute with Mobile phase to volume. Pass the solution through a suitable filter of 0.45-µm pore size. 

Chromatographic system 

Mode: LC 

Detectors 

Assay: UV 230 nm 

Identification test A: Diode array, UV 200–400 nm 

Column: 4.6-mm × 25-cm; 5-µm packing L7 

Flow rate: 1.5 mL/min 

Injection volume: 10 µL 

System suitability 

Sample: Standard solution 

[Note—The relative retention times for homatropine methylbromide and hydrocodone bitartrate are about 0.44 and 1.0, respectively.] Suitability requirements 

Resolution: NLT 2.5 between hydrocodone bitartrate and homatropine methylbromide 

Relative standard deviation: NMT 3.0% for each analyte 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of the labeled amount of homatropine methylbromide (C₁₇H₂₄BrNO₃) in the portion of Tablets taken:  

Result = (r_U/r_S) × (C_S/C_U) × 100 

r_U = peak response of homatropine methylbromide from the Sample solution 

r_S = peak response of homatropine methylbromide from the Standard solution 

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

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

Calculate the percentage of the labeled amount of hydrocodone bitartrate disesquihydrate (C₁₈H₂₁NO₃.C₄H₆O₆. 2½H₂O) in the portion of 18  

Tablets taken: 

Result = (r_U /r_S) × (C_S/C_U ) × (M_r1/M_r2) × 100  

r_U = peak response of hydrocodone bitartrate from the Sample solution 

r_S = peak response of hydrocodone bitartrate from the Standard solution 

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

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

M_r1 = molecular weight of hydrocodone bitartrate disesquihydrate, 494.49 

M_r2 = molecular weight of anhydrous hydrocodone bitartrate, 449.46 

Acceptance criteria: 90.0%–110.0% 

4 PERFORMANCE TESTS 

Dissolution 〈711〉 

Test 1 

Medium: Water; 900 mL, deaerated 

Apparatus 2: 50 rpm 

Time: 30 min 

Buffer and Mobile phase: Prepare as directed in the Assay. 

Standard solution: 0.0055 mg/mL of USP Hydrocodone Bitartrate RS and 0.00165 mg/mL of USP Homatropine Methylbromide RS in Medium 

Sample solution: Pass the solution under test through a suitable filter of 0.45-µm pore size. 

Chromatographic system: Proceed as directed in the Assay, with the following exception. 

Injection volume: 250 µL 

System suitability 

Sample: Standard solution 

Suitability requirements 

Resolution: NLT 13 between homatropine methylbromide and hydrocodone bitartrate 

Relative standard deviation: NMT 3.0% for each analyte 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of the labeled amounts of hydrocodone bitartrate disesquihydrate (C₁₈H₂₁NO₃.C₄H₆O₆. 2½H₂O) and 18  homatropine methylbromide (C₁₇H₂₄BrNO₃) dissolved: 

Result = (r_U/r_S ) × C_S × V × (1/L) × (M_r1/M_r2) × 100 

r_U = peak area of hydrocodone bitartrate or homatropine methylbromide from the Sample solution 

r_S = peak area of hydrocodone bitartrate or homatropine methylbromide from the Standard solution 

C_S = concentration of USP Hydrocodone Bitartrate RS or USP Homatropine Methylbromide RS in the Standard solution (mg/mL) 

V = volume of Medium, 900 mL 

L = label claim for each drug substance (mg/Tablet) 

M_r1 = molecular weight of hydrocodone bitartrate disesquihydrate, 494.49 

M_r2 = molecular weight of anhydrous hydrocodone bitartrate, 449.46  

Tolerances: NLT 80% (Q) of the labeled amounts of hydrocodone bitartrate disesquihydrate (C₁₈H₂₁NO₃.C₄H₆O₆. 2½H₂O) and homatropine 18 methylbromide (C₁₇H₂₄BrNO₃) is dissolved. 

Test 2: If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 2. Medium: Water; 500 mL 

Apparatus 2: 50 rpm 

Time: 45 min 

Mobile phase: 1.4 g/L of octanesulfonic acid sodium salt and 0.1% phosphoric acid in a filtered and degassed mixture of acetonitrile and water (1:3) 

Standard solution A: 0.50 mg/mL of USP Hydrocodone Bitartrate RS in Mobile phase 

Standard solution B: 0.15 mg/mL of USP Homatropine Methylbromide RS in Mobile phase 

System suitability solution: 0.01 mg/mL of USP Hydrocodone Bitartrate RS and 0.003 mg/mL of USP Homatropine Methylbromide RS prepared as follows. Transfer adequate amounts of Standard solution A and Standard solution B to a suitable volumetric flask. Add 21% of the total volume of Mobile phase, and dilute with Medium to volume. 

Sample solution: Pass a 20-mL portion of the solution under test through a suitable filter of 0.45-µm pore size, discarding the first 2–3 mL. Mix thoroughly 15.0 mL of the filtrate with 5.0 mL of Mobile phase. 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 212 nm 

Column: 3.9-mm × 30-cm; packing L1 

Flow rate: 2.0 mL/min 

Injection volume: 200 µL System suitability 

Sample: System suitability solution 

Suitability requirements 

Resolution: NLT 2.2 between homatropine methylbromide and hydrocodone bitartrate 

Tailing factor: NMT 1.5 for each drug substance 

Relative standard deviation: NMT 3.0% for homatropine methylbromide; NMT 2.0% for hydrocodone bitartrate Analysis 

Samples: Standard solution A, Standard solution B, and Sample solution 

Calculate the percentage of the labeled amounts of hydrocodone bitartrate disesquihydrate (C₁₈H₂₁NO₃.C₄H₆O₆. 2½H₂O) and 18 homatropine methylbromide (C₁₇H₂₄BrNO₃) dissolved: 

Result = (r_U/r_S ) × C × D × V × (1/L) × (M_r1/M_r2) × 100 

r_U = peak area of hydrocodone bitartrate or homatropine methylbromide from the Sample solution 

r_S = peak area of hydrocodone bitartrate or homatropine methylbromide from the Standard solution 

C = concentration of USP Hydrocodone Bitartrate RS or USP Homatropine Methylbromide RS in the Standard solution (mg/mL) S 

D = dilution factor of the Sample solution 

V = volume of Medium, 500 mL 

L = label claim for each drug substance (mg/Tablet) 

M_r1 = molecular weight of hydrocodone bitartrate disesquihydrate, 494.49 

M_r2 = molecular weight of anhydrous hydrocodone bitartrate, 449.46 

Tolerances: NLT 75% (Q) of the labeled amounts of hydrocodone bitartrate disesquihydrate (C₁₈H₂₁NO₃.C₄H₆O₆. 2½H₂O) and homatropine 18  methylbromide (C₁₇H₂₄BrNO₃) is dissolved.  

Uniformity of Dosage Units 〈905〉: Meets the requirements 

5 IMPURITIES 

Limit of Dihydrocodeine Bitartrate, Hydrocodone Diol, and Related Substances 

Buffer: 0.005 M sodium 1-octanesulfonate. Adjust with glacial acetic acid to a pH of 2.5 ± 0.1. 

Mobile phase: Methanol and Buffer (40:60). Add 0.5 mL/L of triethylamine. 

System suitability stock solution: 0.02 mg/mL each of hydrocodone diol and USP Dihydrocodeine Bitartrate RS in Mobile phase System suitability solution: 0.1 µg/mL each of hydrocodone diol and USP Dihydrocodeine Bitartrate RS in Mobile phase from the System suitability stock solution 

Standard solution and Sample solution: Proceed as directed in the Assay. 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 280 nm 

Column: 4.6-mm × 25-cm; 5-µm packing L7 

Flow rate: 1.5 mL/min 

Injection volume: 200 µL 

Run time: NLT 1.7 times the retention time of hydrocodone bitartrate 

System suitability 

Sample: System suitability solution 

Suitability requirements 

Resolution: NLT 2.0 between hydrocodone diol and dihydrocodeine bitartrate 

Relative standard deviation: NMT 5.0% for both hydrocodone diol and dihydrocodeine bitartrate 

Analysis 

Sample: Sample solution 

Calculate the percentages of hydrocodone diol and dihydrocodeine bitartrate in the portion of Tablets taken: 

Result = (r_U/r_T) × 100 

r_U = peak response of either hydrocodone diol or dihydrocodeine bitartrate from the Sample solution 

r_T = peak response of hydrocodone bitartrate from the Sample solution  

Calculate the percentage of each individual related substance in the portion of Tablets taken: 

Result = (r_U/r_T) × 100 

r_U = peak response of any individual related substance from the Sample solution with a relative retention time of NLT 0.42 in relation to the retention time of hydrocodone bitartrate 

r_T = sum of all peak responses from the Sample solution 

Acceptance criteria: See Table 1. 

Table 1 

^a 4,5-Dihydroxy-3-methoxy-17-methylmorphinan-6-one. 

Change to read: 

Limit of Homatropine Hydrobromide and Related Substances 

Buffer: 0.005 M dibasic potassium phosphate. Adjust with phosphoric acid to a pH of 6.4 ± 0.1  . Mobile phase: Acetonitrile and Buffer (30:170). Filter and degas. 

Standard solution: 0.6 µg/mL of homatropine hydrobromide in Mobile phase 

Sample solution: Proceed as directed in the Assay. 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 210 nm 

Column: 4.6-mm × 25-cm; 5-µm packing L7 

Flow rate: 1.5 mL/min 

Injection volume: 10 µL 

Run time: NLT 1.6 times the retention time of hydrocodone bitartrate 

System suitability 

Sample: Standard solution 

Suitability requirements 

Relative standard deviation: NMT 5.0% 

Analysis 

Sample: Sample solution 

Calculate the percentage of homatropine hydrobromide in the portion of Tablets taken: 

Result = (r_U/r_T) × 100 

r_U = peak response of homatropine hydrobromide from the Sample solution 

r_T = peak response of homatropine methylbromide from the Sample solution 

Calculate the percentage of each individual related substance in the portion of Tablets taken: 

Result = (r_U/r_T) × 100 

r_U = peak response of any individual related substance from the Sample solution with a relative retention time less than 0.44 in  relation to the retention time of hydrocodone bitartrate 

r_T = sum of all peak responses from the Sample solution  

Acceptance criteria: See Table 2. 

Table 2 

^a 4,5-Dihydroxy-3-methoxy-17-methylmorphinan-6-one. 

bImpurities are quantified in the test for Limit of Dihydrocodeine Bitartrate, Hydrocodone Diol, and Related Substances are not included in Total impurities. 

Limit of Tropine 

Standard stock solution: 150 µg/mL of tropine in diethyl ether 

Standard solution 1: 75 µg/mL of tropine from the Standard stock solution in diethyl ether 

Standard solution 2: 37.5 µg/mL of tropine from the Standard solution 1 in diethyl ether 

Standard solution 3: 18.75 µg/mL of tropine from the Standard solution 2 in diethyl ether 

Standard solution 4: 9.38 µg/mL of tropine from the Standard solution 3 in diethyl ether 

Sample solution: Finely powder 25 Tablets, and add to a centrifuge tube. Pipet 5.0 mL of diethyl ether into the centrifuge tube, mix on a vortex mixer for 5 min, centrifuge, and use the supernatant. 

Chromatographic system 

(See Chromatography 〈621〉, Thin-Layer Chromatography.) 

Application volume: 500 µL 

Developing solvent system: Alcohol and ammonium hydroxide (400:100) 

Spray reagent: Dissolve 300 mg of platinic acid in 3 mL of diluted hydrochloric acid. Add 97 mL of water and 100 mL of 6% potassium iodide in water, and mix. 

Analysis 

Samples: Standard stock solution, Standard solution 1, Standard solution 2, Standard solution 3, Standard solution 4, and Sample solution Apply the Standard stock solution, Standard solution 1, Standard solution 2, Standard solution 3, Standard solution 4, and Sample solution to a TLC plate and proceed as directed in the chapter. After the plate has dried, position it in a chamber saturated with iodine vapor for about 30 min, then place it in a hood to allow the iodine to sublime from the plate, and spray the plate with Spray reagent until spots appear. 

Acceptance criteria: Any spot from the Sample solution occurring at an R value corresponding to tropine is not greater in size or intensity F than the corresponding spot from Standard solution 2 (0.5%); NMT 0.5% of tropine. 

6 ADDITIONAL REQUIREMENTS 

Packaging and Storage: Preserve in tight, light-resistant containers. 

Labeling: When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 is not used. USP Reference Standards 〈11〉 

USP Dihydrocodeine Bitartrate RS 

USP Homatropine Methylbromide RS 

USP Hydrocodone Bitartrate RS 

₁ A suitable grade is available from Analytical Research and Testing, Somerville, NJ; Fax: 908-725-8848.