ACECLOFENAC IP - API SPECIFICATION

ACTIVE PHAMACEUTICAL INGREDIENT SPECIFICATION

ACECLOFENAC

Synonyms : [[[2-[(2,6-Dichlorophenyl)amino]phenyl]acetyl]oxy]acetic acid.

SAMPLING AND HANDLING

STORAGE REQUIREMENT

Store protected from light.

SAMPLING

Carry out the sampling as per SOP

QUANTITY OF COMPOSITE SAMPLE FOR ANALYSIS

15 g

QUANTITY OF RESERVE SAMPLE

2 x 15 g

RETEST PERIOD

One year

HAZARDS AND PRECAUTIONS, IF ANY

Use hand gloves and nose mask while sampling.

DISPOSITION OF ANALYTICAL SAMPLE

Carry out disposition of analytical sample as per SOP

STANDARDS

Molecular Formula: C₁₆H₁₃Cl₂NO₄ Molecular weight : 354.20

DESCRIPTION: A White or almost white, crystalline powder.

SOLUBILITY: Freely soluble in acetone, Soluble in alcohol, chloroform; practically insoluble in water.

IDENTIFICATION:

Test A may be omitted if tests B and C are carried out. Tests B and C may be omitted if test A is carried out.

A] The infrared absorption spectrum of the residue is concordant with the reference spectrum of aceclofenac or with the spectrum obtained from aceclofenac RS.

B] When examined in the range of 220 nm to 370 nm, the 0.002% w/v solution in methanol shows an absorption maximum at 275 nm.

C] A blue colour develops and a precipitate is formed.

RELATED SUBSTANCES: In the chromatogram obtained with test solution, the area of any secondary peak it not more than 0.5 times the area of peak in the chromatogram obtained with reference solution (b) (0.5%) and the sum of areas of all secondary peaks is not more than the area of the peak in the chromatogram obtained with the reference solution (b) (2.0%).

HEAVY METALS: Not more than 10 ppm.

SULPHATED ASH: Not more than 0.1%

LOSS ON DRYING: Not more than 0.5% w/w

ASSAY: Aceclofenac contains: Not less than 99.0% and not more than 101.0%, calculated with reference to the dried substances.

Note: * Represents test to be carried out while retesting.

TESTS AND METHODS

DESCRIPTION: Examine the composite samples and note the observations.

SOLUBILITY:

Freely soluble in acetone (1 g in 10 ml)

Soluble in methanol (1 g in 30 ml)

Practically insoluble in water (0.01 gm in 100 ml and over)

IDENTIFICATION:

Test A may be omitted if tests B and C are carried out. Tests B and C may be omitted if test A is carried out.

A) The infrared absorption spectrum of the residue is concordant with the reference spectrum of aceclofenac or with the spectrum obtained from aceclofenac RS.

B) When examined in the range of 220 nm to 370 nm, the 0.002% w/v solution in methanol shows an absorption maximum at 275 nm.

C) Dissolve about 10 mg in 10 ml of alcohol R. To 1 ml of the solution, add 0.2 ml of a mixture, prepared immediately before use, of equal volumes of a 6 g/l solution of potassium ferricyanide R and a 9 g/l solution of ferric chloride R. Allow to stand protected from light for 5 min. Add 3 ml of a 10.0 g/l solution of hydrochloric acid R. Allow to stand protected from light for 15 min. A blue colour develops and a precipitate is formed.

RELATED SUBSTANCES: By Liquid chromatography

Prepare the solutions immediately before use.

Test solution Dissolve 50.0 mg of the substance to be examined in a mixture of 30 volumes of mobile phase A and 70 volumes of mobile phase B and dilute to 25.0 ml with the same mixture of solvents.

Reference solution (a) Dissolve 21.6 mg of diclofenac sodium CRS in a mixture of 30 volumes of mobile phase A and 70 volumes of mobile phase B and dilute to 50.0 ml with the same mixture of solvents.

RELATED SUBSTANCES CONTD.

Reference solution (b) Dilute 2.0 ml of the test solution to 10.0 ml with a mixture of 30 volumes of mobile phase A and 70 volumes of mobile phase B.

Reference solution (c) Mix 1.0 ml of reference solution (a) and 1.0 ml of reference solution (b) and dilute to 100.0 ml with a mixture of 30 volumes of mobile phase A and 70 volumes of mobile phase B.

Reference solution (d) Dissolve 4.0 mg of aceclofenac impurity F CRS, 2.0 mg of aceclofenac impurity H CRS and 2.0 mg of diclofenac impurity A CRS (aceclofenac impurity I) in a mixture of 30 volumes of mobile phase A and 70 volumes of mobile phase B and dilute to 10.0 ml with the same mixture of solvents.

Reference solution (e) Mix 1.0 ml of reference solution (b) and 1.0 ml of reference solution (d) and dilute to 100.0 ml with a mixture of 30 volumes of mobile phase A and 70 volumes of mobile phase B.

Column:

—size: l = 0.25 m, Ø = 4.6 mm,

—stationary phase: spherical end-capped octadecylsilyl silica gel for chromatography R (5 µm) with a pore size of 10 nm and a carbon loading of 19 per cent,

—temperature: 40 °C.

Mobile phase:

—Mobile phase A: 1.12 g/l solution of phosphoric acid R adjusted to pH 7.0 using a 42 g/l solution of sodium hydroxide R,

—Mobile phase B: water R, acetonitrile R (1:9 V/V),

Flow rate 1.0 ml/min.

Detection Spectrophotometer at 275 nm.

Injection 10 µl; inject the test solution and reference solutions (c) and (e).

Relative retention with reference to aceclofenac (retention time = about 14 min): impurity A = about 0.8; impurity G = about 1.3; impurity H = about 1.5; impurity I = about 2.3; impurity D = about 2.6; impurity B = about 2.7; impurity E = about 2.8; impurity C = about 3.0; impurity F = about 3.2.

System suitability Reference solution (c):

—Resolution: minimum 5.0 between the peaks due to aceclofenac and to impurity A.

Limits:

—impurity A: not more than the area of the corresponding peak in the chromatogram obtained with reference solution (c) (0.2 per cent),

—impurities B, C, D, E, G: for each impurity, not more than the area of the peak due to aceclofenac in the chromatogram obtained with reference solution (e) (0.2 per cent),

—impurity F: not more than the area of the corresponding peak in the chromatogram obtained with reference solution (e) (0.2 per cent),

—impurity H: not more than the area of the corresponding peak in the chromatogram obtained with reference solution (e) (0.1 per cent),

—impurity I: not more than the area of the corresponding peak in the chromatogram obtained with reference solution (e) (0.1 per cent),

—any other impurity: not more than half the area of the peak due to aceclofenac in the chromatogram obtained with reference solution (e) (0.1 per cent),

—total: not more than 0.7 per cent,

—disregard limit: 0.1 times the area of the peak due to aceclofenac in the chromatogram obtained with reference solution (e) (0.02 per cent).

HEAVY METALS: (Refer GTP/23):

To 2.0 g in a silica crucible, add 2 ml of sulphuric acid R to wet the substance. Heat progressively to ignition and continue heating until an almost white or at most a greyish residue is obtained. Carry out the ignition at a temperature not exceeding 800 °C. Allow to cool. Add 3 ml of hydrochloric acid R and 1 ml of nitric acid R. Heat and evaporate slowly to dryness. Cool and add 1 ml of a 100 g/l solution of hydrochloric acid Rand 10.0 ml of distilled water R. Neutralise with a 1.0 g/l solution of ammonia R using 0.1 ml of phenolphthalein solution R as indicator. Add 2.0 ml of a 60 g/l solution of anhydrous acetic acid R and dilute to 20 ml with distilled water R. 12 ml of the solution complies with limit test A. Prepare the standard using lead standard solution (1 ppm Pb) R.