Buprenorphine and Naloxone Sublingual 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

Buprenorphine and Naloxone Sublingual Tablets contain amounts of buprenorphine hydrochloride and naloxone hydrochloride equivalent to

NLT 90.0% and NMT 110.0% of the labeled amount of buprenorphine (C₂₉H₄₁NO₄) and naloxone (C₁₉H₂₁NO₄).

2 IDENTIFICATION

A. The retention times of the buprenorphine and naloxone peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay.

B. The UV absorption spectra of the buprenorphine and naloxone peaks of the Sample solution and those of the Standard solution exhibit maxima and minima at the same wavelengths, as obtained in the Assay.

3 ASSAY

Procedure

[Note—It is suggested to protect all solutions containing buprenorphine and naloxone from light.]

Buffer: 9 mM of dibasic ammonium phosphate in water. Adjust with a solution of phosphoric acid and water (1:1) to a pH of 6.2.

Solution A: Acetonitrile, methanol, and Buffer (7:3:90)

Solution B: Acetonitrile, methanol, and Buffer (56:24:20)

Mobile phase: See Table 1.

Solution C: Phosphoric acid and water (1:1000)

Diluent: Acetonitrile, methanol, and Solution C (7:3:90)

Standard solution: 0.57 mg/mL of USP Buprenorphine Hydrochloride RS and 0.13 mg/mL of USP Naloxone RS in Diluent

Sample solution: Nominally 0.52 mg/mL of buprenorphine and 0.13 mg/mL of naloxone prepared as follows. Transfer NLT 13 Tablets to a suitable volumetric flask, and add about 70% of the final volume of Diluent. Sonicate for 15 min with occasional swirling and shake for 15 min. Dilute with Diluent to volume. Pass a portion through a suitable filter of 0.45-µm pore size. Discard the first 5 mL of filtrate.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 280 nm. For Identification B, use a diode array detector in the range of 210–400 nm.

Column: 4.6-mm × 25-cm; 5-µm packing L11

Column temperature: 60°

Flow rate: 0.8 mL/min

Injection volume: 100 µL

System suitability

Sample: Standard solution

Tailing factor: NMT 2.0 for both buprenorphine and naloxone

Relative standard deviation: NMT 2.0% for both buprenorphine and naloxone

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of buprenorphine (C₂₉H₄₁NO₄) in the portion of Tablets taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × (M₁ / M₂) × 100

where:

rᵤ = peak response of buprenorphine from the Sample solution

rₛ = peak response of buprenorphine from the Standard solution

Cₛ = concentration of USP Buprenorphine Hydrochloride RS in the Standard solution (mg/mL)

Cᵤ = nominal concentration of buprenorphine in the Sample solution (mg/mL)

M₁ = molecular weight of buprenorphine, 467.65

M₂ = molecular weight of buprenorphine hydrochloride, 504.11

Calculate the percentage of the labeled amount of naloxone (C₁₉H₂₁NO₄) in the portion of Tablets taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

where:

rᵤ = peak response of naloxone from the Sample solution

rₛ = peak response of naloxone from the Standard solution

Cₛ = concentration of USP Naloxone RS in the Standard solution (mg/mL)

Cᵤ = nominal concentration of naloxone in the Sample solution (mg/mL)

Acceptance criteria: 90.0%–110.0% of the labeled amount of buprenorphine (C₂₉H₄₁NO₄) and naloxone (C₁₉H₂₁NO₄)

4 PERFORMANCE TESTS

Dissolution 〈711〉

Test 1 (RB 1-Nov-2024)

Medium: Water (deaerated for 5 min); 500 mL

Apparatus 1: 100 rpm

Time: 10 min

Buffer: 0.018 M monobasic potassium phosphate in water prepared as follows. Dissolve 2.4 g of monobasic potassium phosphate and 0.5 g of sodium hydroxide in each liter of water. Adjust with phosphoric acid to a pH of 6.8.

Solution A: Acetonitrile, methanol, and Buffer (40:20:40)

Solution B: Acetonitrile and Buffer (78:22)

Mobile phase: See Table 2.

Diluent: Methanol and water (50:50)

Standard solution: 0.01 mg/mL of USP Buprenorphine Hydrochloride RS and 0.0025 mg/mL of USP Naloxone RS in Diluent. Sonicate if necessary. Pass a portion through a suitable filter of 0.45-µm pore size. Discard the first 4 mL of filtrate.

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

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 230 nm

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

Column temperature: 25°

Flow rate: 1.0 mL/min

Injection volume: 40 µL

System suitability

Sample: Standard solution

Tailing factor: NMT 2.0 for both buprenorphine and naloxone

Relative standard deviation: NMT 2.0% for both buprenorphine and naloxone

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of buprenorphine (C₂₉H₄₁NO₄) dissolved:

Result = (rᵤ / rₛ) × Cₛ × V × (M₁ / M₂) × (1/L₁) × 100

where:

rᵤ = peak response of buprenorphine from the Sample solution

rₛ = peak response of buprenorphine from the Standard solution

Cₛ = concentration of USP Buprenorphine Hydrochloride RS in the Standard solution (mg/mL)

V = volume of Medium, 500 mL

M₁ = molecular weight of buprenorphine, 467.65

M₂ = molecular weight of buprenorphine hydrochloride, 504.11

L₁ = label claim of buprenorphine (mg/Tablet)

Calculate the percentage of the labeled amount of naloxone (C₁₉H₂₁NO₄) dissolved:

Result = (rᵤ / rₛ) × Cₛ × V × (1/L₂) × 100

where:

rᵤ = peak response of naloxone from the Sample solution

rₛ = peak response of naloxone from the Standard solution

Cₛ = concentration of USP Naloxone RS in the Standard solution (mg/mL)

V = volume of Medium, 500 mL

L₂ = label claim of naloxone (mg/Tablet)

Tolerances: NLT 80% (Q) of the labeled amount of buprenorphine (C₂₉H₄₁NO₄) and naloxone (C₁₉H₂₁NO₄) is dissolved.

Test 2: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.

Medium: Water; 500 mL

Apparatus 1: 100 rpm

Time: 8 min

Solution A: 5 mL of phosphoric acid diluted with water to 10 mL

Solution B: Dissolve 1.0 g of sodium chloride and 0.2 g of octanesulfonic acid sodium salt in 1 L of water. Adjust with Solution A to a pH of 2.8.

Solution C: Methanol

Mobile phase: See Table 3.

Diluent: Methanol, water, and phosphoric acid (50:50:0.1)

Standard stock solution: 0.44 mg/mL of USP Buprenorphine Hydrochloride RS and 0.1 mg/mL of USP Naloxone RS in Diluent. Sonicate to dissolve, if necessary.

Standard solution: (L₁/500) mg/mL of buprenorphine from USP Buprenorphine Hydrochloride RS and (L₂/500) mg/mL of USP Naloxone RS from Standard stock solution in Medium, where L₁ and L₂ are the label claims of buprenorphine and naloxone in mg/Tablet, respectively

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size, discarding an appropriate volume of filtrate so that a consistent result can be obtained.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 230 nm

Column: 4.6-mm × 25-cm; 5-µm packing L1

Column temperature: 50°

Flow rate: 1.5 mL/min

Injection volume: 100 µL

System suitability

Sample: Standard solution

Tailing factor: NMT 2.0 for buprenorphine and naloxone

Relative standard deviation: NMT 2.0% for buprenorphine and naloxone

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of buprenorphine (C₂₉H₄₁NO₄) dissolved:

Result = (rᵤ / rₛ) × Cₛ × V × (M₁ / M₂) × (1/L₁) × 100

Calculate the percentage of the labeled amount of naloxone (C₁₉H₂₁NO₄) dissolved:

Result = (rᵤ / rₛ) × Cₛ × V × (1/L₂) × 100

Tolerances: NLT 80% (Q) of the labeled amount of buprenorphine (C₂₉H₄₁NO₄) and naloxone (C₁₉H₂₁NO₄) is dissolved.

Test 3: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3.

Medium: 0.01 N hydrochloric acid; 500 mL, deaerated, if necessary

Apparatus 1: 100 rpm

Time: 3 min

Solution A: Acetonitrile, water, and trifluoroacetic acid (10:90:0.1)

Solution B: Acetonitrile, water, and trifluoroacetic acid (90:10:0.1)

Mobile phase: See Table 4.

Standard stock solution A: 0.44 mg/mL of USP Buprenorphine Hydrochloride RS prepared as follows. Transfer a quantity of USP Buprenorphine Hydrochloride RS to an appropriate volumetric flask and dissolve in 10% of the flask volume of methanol. Sonicate for about 5 min with intermittent shaking to dissolve. Add 60% of the flask volume of Medium. Sonicate to dissolve, if necessary. Dilute with Medium to volume.

Standard stock solution B: 0.22 mg/mL of USP Naloxone RS in Medium. Sonicate to dissolve with intermittent shaking, if necessary.

Standard solution: (L₁/500) mg/mL of buprenorphine from USP Buprenorphine Hydrochloride RS and (L₂/500) mg/mL of USP Naloxone RS from Standard stock solution A and Standard stock solution B in Medium, where L₁ and L₂ are the label claims of buprenorphine and naloxone in mg/Tablet, respectively

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.45-µm pore size, discarding an appropriate volume of filtrate so that a consistent result can be obtained.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 240 nm

Column: 4.6-mm × 25-cm; 5-µm packing L11

Column temperature: 45°

Flow rate: 1.5 mL/min

Injection volume: 100 µL

System suitability

Sample: Standard solution

Tailing factor: NMT 2.0 for buprenorphine and naloxone

Relative standard deviation: NMT 2.0% for buprenorphine and naloxone

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of buprenorphine (C₂₉H₄₁NO₄) dissolved:

Result = (rᵤ / rₛ) × Cₛ × V × (M₁ / M₂) × (1/L₁) × 100

Calculate the percentage of the labeled amount of naloxone (C₁₉H₂₁NO₄) dissolved:

Result = (rᵤ / rₛ) × Cₛ × V × (1/L₂) × 100

Tolerances: NLT 80% (Q) of the labeled amount of buprenorphine (C₂₉H₄₁NO₄) and NLT 75% (Q) of the labeled amount of naloxone (C₁₉H₂₁NO₄) is dissolved.

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

Organic Impurities

[Note—It is suggested to protect all solutions containing buprenorphine and naloxone from light.]

Buffer, Solution A, Solution B, Mobile phase, Solution C, Diluent, Sample solution, and Chromatographic system:

Proceed as directed in the Assay.

Standard solution: 0.0015 mg/mL of USP Buprenorphine Hydrochloride RS and 0.0004 mg/mL of USP Naloxone RS in Diluent

System suitability

Sample: Standard solution

Relative standard deviation: NMT 5% for buprenorphine and naloxone

Analysis

Samples: Sample solution and Standard solution

Identify the buprenorphine degradation products using the relative retention times given in Table 5.

Calculate the percentage of each buprenorphine related degradation product in the portion of Tablets taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × (M₁ / M₂) × 100

where:

rᵤ = peak response of each individual buprenorphine related degradation product from the Sample solution

rₛ = peak response of buprenorphine from the Standard solution

Cₛ = concentration of USP Buprenorphine Hydrochloride RS in the Standard solution (mg/mL)

Cᵤ = nominal concentration of buprenorphine in the Sample solution (mg/mL)

M₁ = molecular weight of buprenorphine, 467.65

M₂ = molecular weight of buprenorphine hydrochloride, 504.11

Identify the naloxone degradation products using the relative retention times given in Table 5.

Calculate the percentage of each naloxone related degradation product and any other degradation product in the portion of Tablets taken:

Result = (rᵤ / rₛ) × (Cₛ / Cᵤ) × 100

where:

rᵤ = peak response of each naloxone related degradation product or any other degradation product from the Sample solution

rₛ = peak response of naloxone from the Standard solution

Cₛ = concentration of USP Naloxone RS in the Standard solution (mg/mL)

Cᵤ = nominal concentration of naloxone in the Sample solution (mg/mL)

Acceptance criteria: See Table 5. Disregard any peaks below 0.05%.

a. Quantified relative to naloxone.

b. (S)-2-(4,5α-Epoxy-3-hydroxy-6-methoxy-6α,14-ethanomorphinan-7α-yl)-3,3-dimethylbutan-2-ol.

c. These are process impurities and are excluded from the total degradation products.

d. 4,5α-Epoxy-7α-[(S)-2-hydroxy-3,3-dimethylbutan-2-yl]-3,6-dimethoxy-6α,14-ethanomorphinan-17-carbonitrile.

e. (S)-2-[17-(Cyclopropylmethyl)-4,5α-epoxy-3,6-dihydroxy-6α,14-ethanomorphinan-7α-yl]-3,3-dimethylbutan-2-ol.

f. Quantified relative to buprenorphine.

g. (S)-2-[17-(Cyclopropylmethyl)-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethanomorphinan-7β-yl]-3,3-dimethylbutan-2-ol.

h. (S)-2-[17-(But-3-en-1-yl)-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethanomorphinan-7α-yl]-3,3-dimethylbutan-2-ol.

i. (S)-2-[17-(Cyclopropylmethyl)-4,5α-epoxy-3,6-dimethoxy-6α,14-ethanomorphinan-7α-yl]-3,3-dimethylbutan-2-ol.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers, and store at controlled room temperature.

Add the following:

Labeling: The labeling states the Dissolution test used only if Test 1 is not used.▲ (RB 1-Nov-2024)

USP Reference Standards 〈11〉

USP Buprenorphine Hydrochloride RS

USP Naloxone RS