Sulbactam Sodium

(Ph Eur monograph 2209)

C₈H₁₀NNaO₅S    255.2    69388-84-7

Beta-lactam antibacterial.

Ph Eur

Sodium (2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide.

Semi-synthetic product derived from a fermentation product.

97.0 per cent to 102.0 per cent (anhydrous substance).

White or almost white, hygroscopic, crystalline powder.

Freely soluble in water, sparingly soluble in ethyl acetate, very slightly soluble in ethanol (96 per cent). It is freely soluble in dilute acids.

A.  Infrared absorption spectrophotometry (2.2.24).

Comparison  sulbactam sodium CRS.

B.  It gives reaction (a) of sodium (2.3.1).

The solution is clear (2.2.1).

Dissolve 2.0 g in water R and dilute to 20 ml with the same solvent.

Maximum 0.10 at 430 nm.

Dissolve 1.0 g in water R and dilute to 100.0 ml with the same solvent.

4.5 to 7.2; if the substance is sterile: 5.2 to 7.2.

Dissolve 1.0 g in carbon dioxide-free water R and dilute to 20 ml with the same solvent.

+ 219 to + 233 (anhydrous substance).

Dissolve 0.500 g in water R and dilute to 50.0 ml with the same solvent.

Liquid chromatography (2.2.29).

Solution A  2.72 g/l solution of potassium dihydrogen phosphate R adjusted to pH 4.0 with dilute phosphoric acid R.

Solution B  Dilute 2 ml of acetonitrile R1 to 100.0 ml with solution A.

Test solution  Suspend 77.0 mg of the substance to be examined in 2 ml of acetonitrile R1 and sonicate for about 5 min. Dilute to 100.0 ml with solution A.

Reference solution (a)  Suspend 70.0 mg of sulbactam CRS in 2 ml of acetonitrile R1 and sonicate for about 5 min. Dilute to 100.0 ml with solution A.

Reference solution (b)  Dilute 1.0 ml of reference solution (a) to 100.0 ml with solution B. Dilute 1.0 ml of this solution to 10.0 ml with solution B.

Reference solution (c)  Dissolve 15.0 mg of 6-aminopenicillanic acid R in solution A and dilute to 50.0 ml with solution A.

Reference solution (d)  Mix 1 ml of reference solution (a) and 1 ml of reference solution (c) and dilute to 25.0 ml with solution B.

Reference solution (e)  Dissolve 8 mg of sulbactam for peak identification CRS (containing impurities A, C, D, E and F) in 1 ml of acetonitrile R1, sonicate for about 5 min and dilute to 10 ml with solution B.

• — size: l  =  0.10 m, Ø  =  4.0 mm;

• — stationary phase: octadecylsilyl silica gel for chromatography R (3.0 µm);

• — temperature: 40 °C.

• — mobile phase A: 5.44 g/l solution of potassium dihydrogen phosphate R adjusted to pH 4.0 with dilute phosphoric acid R;

• — mobile phase B: acetonitrile R1;

Flow rate  1.0 ml/min.

Detection  Spectrophotometer at 215 nm.

Injection  20 µl of the test solution, solution B and reference solutions (b), (d) and (e).

Relative retention  With reference to sulbactam (retention  time  =  about  2.5  min): impurity  A  =  about  0.4; impurity  B  =  about  0.6; impurity  C  =  about  1.6; impurity  D  =  about  2.0; impurity  E  =  about  2.1; impurity  F  =  about  2.5.

Identification of impurities  Use the chromatogram supplied with sulbactam for peak identification CRS and the chromatogram obtained with reference solution (e) to identify the peaks due to impurities A, C, D, E and F.

System suitability  Reference solution (d):

• — resolution: minimum 7.0 between the peaks due to impurity B and sulbactam.

• — correction factors: for the calculation of content, multiply the peak areas of the following impurities by the corresponding correction factor: impurity  A  =  0.6; impurity  B  =  0.5; impurity  D  =  0.5; impurity  F  =  0.6;

• — impurity A: not more than 5 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.5 per cent);

• — impurities B, D, F: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (b) (0.1 per cent);

• — impurities C, E: for each impurity, not more than twice the area of the principal peak in the chromatogram obtained with reference solution (b) (0.2 per cent);

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

• — total: not more than 10 times the area of the principal peak in the chromatogram obtained with reference solution (b) (1.0 per cent);

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

Maximum 0.5 per cent m/m.

Maximum 20 ppm.

Dissolve 1.0 gin water R and dilute to 20 ml with the same solvent. 12 ml of the solution complies with test A. Prepare the reference solution using 10.0 ml of lead standard solution (2 ppm Pb) R.

Maximum 1.0 per cent, determined on 1.00 g.

Less than 0.17 IU/mg, if intended for use in the manufacture of parenteral preparations without a further appropriate procedure for the removal of bacterial endotoxins.

Liquid chromatography (2.2.29) as described in the test for related substances with the following modification.

Injection  Test solution and reference solution (a).

Calculate the percentage content of sulbactam sodium by multiplying the percentage content of sulbactam by 1.094 and using the declared content of sulbactam CRS.

In an airtight container. If the substance is sterile, store in a sterile, airtight, tamper-proof container.

Specified impurities  A, B, C, D, E, F.

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): G.

A.  (2S)-2-amino-3-methyl-3-sulphinobutanoic acid,

B.  R  =  NH₂, R′  =  H: (2S,5R,6R)-6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid (6-aminopenicillanic acid),

D.  R  =  Br, R′  =  H: (2S,5R,6R)-6-bromo-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid (6-bromopenicillanic acid),

F.  R  =  R′  =  Br: (2S,5R)-6,6-dibromo-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid (6,6-dibromopenicillanic acid),

C.  R  =  Br, R′  =  H: (2S,5R,6R)-6-bromo-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide (6-bromopenicillanic acid sulphone),

E.  R  =  R′  =  Br: (2S,5R)-6,6-dibromo-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide (6,6-dibromopenicillanic acid sulphone),

G.  (2E)-3-[[(1S)-1-carboxy-2-methyl-2-sulphinopropyl]amino]prop-2-enoic acid.

Ph Eur