Buprenorphine

(Ph. Eur. monograph 1180)

C₂₉H₄₁NO₄    467.6    52485-79-7

Opioid receptor partial agonist; analgesic.

Ph Eur

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

98.5 per cent to 101.5 per cent (dried substance).

White or almost white, crystalline powder.

Very slightly soluble in water, freely soluble in acetone, soluble in methanol, slightly soluble in cyclohexane. It dissolves in dilute solutions of acids.

About 217 °C.

Infrared absorption spectrophotometry (2.2.24).

Comparison   buprenorphine CRS.

Dissolve 0.250 g in anhydrous ethanol R and dilute to 25.0 mL with the same solvent.

Solution S is clear (2.2.1) and colourless (2.2.2, Method II).

- 103 to - 107 (dried substance), determined on solution S.

Liquid chromatography (2.2.29).

Test solution  Dissolve 50.0 mg of the substance to be examined in methanol R and dilute to 10.0 mL with the same solvent.

Reference solution (a)  Dilute 1.0 mL of the test solution to 100.0 mL with methanol R. Dilute 1.0 mL of this solution to 10.0 mL with methanol R.

Reference solution (b)  Dissolve 5 mg of buprenorphine for system suitability CRS (containing impurities A, B, F, G, H and J) in 1.0 mL of methanol R.

• — size: l = 0.05 m, Ø = 4.6 mm;

• — stationary phase: end-capped octadecylsilyl silica gel for chromatography R (3.5 µm);

• — temperature: 30 °C.

• — mobile phase A: mix 10 volumes of acetonitrile R and 90 volumes of the following solution: dissolve 5.44 g of potassium dihydrogen phosphate R in 900 mL of water R, adjust to pH 4.5 with a 5 per cent V/V solution of phosphoric acid R and dilute to 1000 mL with water R;

• — mobile phase B: acetonitrile R;

Flow rate  1.3 mL/min.

Detection  Spectrophotometer at 240 nm.

Injection  5 µL.

Identification of impurities  Use the chromatogram supplied with buprenorphine for system suitability CRS and the chromatogram obtained with reference solution (b) to identify the peaks due to impurities A, B, F, G, H and J.

Relative retention  With reference to buprenorphine (retention time = about 8.5 min): impurity B = about 0.4; impurity J = about 1.1; impurity F = about 1.27; impurity H = about 1.33; impurity A = about 1.40; impurity G = about 1.8.

System suitability  Reference solution (b):

• — resolution: minimum 1.5 between the peaks due to buprenorphine and impurity J.

• — correction factor: for the calculation of content, multiply the peak area of impurity G by 0.3;

• — impurity H: not more than 2.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.25 per cent);

• — impurities A, B, F, J: for each impurity, not more than twice the area of the principal peak in the chromatogram obtained with reference solution (a) (0.2 per cent);

• — impurity G: not more than 1.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.15 per cent);

• — unspecified impurities: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.10 per cent);

• — total: not more than 7 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.7 per cent);

• — disregard limit: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.05 per cent).

Maximum 1.0 per cent, determined on 1.000 g by drying in an oven at 105 °C.

Dissolve 0.400 g in 40 mL of anhydrous acetic acid R. Titrate with 0.1 M perchloric acid, determining the end-point potentiometrically (2.2.20).

1 mL of 0.1 M perchloric acid is equivalent to 46.76 mg of C₂₉H₄₁NO₄.

Protected from light.

Specified impurities   A, B, F, G, H, J.

Other detectable impurities (the following substances would, if present at a sufficient level, be detected by one or other of the tests in the monograph. They are limited by the general acceptance criterion for other/unspecified impurities and/or by the general monograph Substances for pharmaceutical use (2034). It is therefore not necessary to identify these impurities for demonstration of compliance. See also 5.10. Control of impurities in substances for pharmaceutical use): C, D, E, I.

A. R = CH₂-CH₂-CH = CH₂: (2S)-2-[17-(but-3-enyl)-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol,

B. R = H: (2S)-2-(4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethano-14α-morphinan-7α-yl)-3,3-dimethylbutan-2-ol (norbuprenorphine),

H. R = CH₂-CH₂-CH₂-CH₃: (2S)-2-[17-butyl-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethano-14α-morphinan-7α-yl]3,3-dimethylbutan-2-ol,

C. 4,5α-epoxy-7α-[(1S)-1-hydroxy-1,2,2-trimethylpropyl]-3,6-dimethoxy-6α,14-ethano-14α-morphinan-17-carbonitrile,

D. R1 = R2 = CH₃: (2S)-2-[17-(cyclopropylmethyl)-4,5α-epoxy-3,6-dimethoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol (3-O-methylbuprenorphine),

E. R1 = R2 = H: (2S)-2-[17-(cyclopropylmethyl)-4,5α-epoxy-3,6-dihydroxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol (6-O-desmethylbuprenorphine),

F. 17-(cyclopropylmethyl)-4,5α-epoxy-6-methoxy-7α-[1-(1,1-dimethylethyl)ethenyl]-6α,14-ethano-14α-morphinan-3-ol,

G. R-R: 17,17′-di(cyclopropylmethyl)-4,5α;4′,5α′-diepoxy-7α,7α′-di[(1S)-1-hydroxy-1,2,2-trimethylpropyl]-6,6′-dimethoxy-2,2′-bi(6α,14-ethano-14α-morphinan)-3,3′-diol (2,2′-bibuprenorphine),

I. 17-(cyclopropylmethyl)-4′′,4′′,5′′,5′′-tetramethyl-4′′,5′′dihydro-(7βH)-6α,14-ethano-(5βH)-difurano[2′,3′,4′,5′:4,12,13,5;2′′,3′′:6,7]-14α-morphinan-3-ol,

J. (2S)-2-[17-(cyclopropylmethyl)-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-etheno-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol.

Ph Eur