Co-proxamol Tablets

General Notices

Dextropropoxyphene Hydrochloride and Paracetamol Tablets
note: Co-proxamol Tablets are not currently licensed in the United Kingdom.

Action and use

Opioid analgesic + analgesic; antipyretic.

Definition

Co-proxamol Tablets contain Dextropropoxyphene Hydrochloride and Paracetamol in the proportions, by weight, 1 part to 10 parts.

The tablets comply with the requirements stated under Tablets, the requirements stated under Unlicensed Medicines and with the following requirements.

Content of dextropropoxyphene hydrochloride, C22H29NO2,HCl

95.0 to 105.0% of the stated amount.

Content of paracetamol, C8H9NO2

95.0 to 105.0% of the stated amount.

Identification

A. Shake a quantity of the powdered tablets containing 0.1 g of Dextropropoxyphene Hydrochloride with 20 mL of 0.1m hydrochloric acid for 5 minutes and filter. To the filtrate add 5 mL of 2m sodium hydroxide, extract with two 25-mL quantities of dichloromethane, wash the combined extracts with 10 mL of water, shake with anhydrous sodium sulfate, filter and evaporate the filtrate to dryness. Dissolve the residue in 2 mL of dichloromethane and add 50 µL, drop wise, onto the surface of a disc prepared from about 0.3 g of potassium bromide, allowing the solvent to evaporate between applications; dry the disc at 50° for 2 minutes. The infrared absorption spectrum of the resulting thin film, Appendix II A, is concordant with the reference spectrum of dextropropoxyphene (RS 091).
B. Shake a quantity of the powdered tablets containing 0.325 g of Paracetamol with 10 mL of acetone for 5 minutes, filter and evaporate the filtrate to dryness. The infrared absorption spectrum of the residue, Appendix II A, is concordant with the reference spectrum of paracetamol (RS 258).

TESTS

Dissolution

Comply with the requirements for Monographs of the British Pharmacopoeia in the dissolution test for tablets and capsules, Appendix XII B1.

test conditions
(a) Use Apparatus 2, rotating the paddle at 50 revolutions per minute.
(b) Use 900 mL of phosphate buffer pH 5.8, at a temperature of 37°, as the medium.
procedure

After 45 minutes withdraw a 20 mL sample of the medium and filter. Dilute the filtrate with 0.1m sodium hydroxide, if necessary, to give a solution expected to contain about 0.00075% w/v of Paracetamol. Measure the absorbance of this solution, Appendix II B, at the maximum at 257 nm using 0.1m sodium hydroxide in the reference cell.

determination of content

Calculate the total content of paracetamol, C8H9NO2, in the medium taking 715 as the value of A(1%, 1 cm) at the maximum at 257 nm.

4-Aminophenol

Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1) Shake a quantity of the powdered tablets containing 0.5 g of Paracetamol with 50 mL of the mobile phase for 10 minutes and filter.
(2) 0.001% w/v of 4-aminophenol in the mobile phase.
chromatographic conditions
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (10 µm) (Nucleosil C18 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 2 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 272 nm.
(f) Inject 20 µL of each solution.
mobile phase

0.01m sodium butanesulfonate in a mixture of 0.4 volumes of formic acid, 15 volumes of methanol and 85 volumes of water.

limits

In the chromatogram obtained with solution (1):

the area of any peak corresponding to 4-aminophenol is not greater than the area of the peak in the chromatogram obtained with solution (2) (0.1%).

Peaks with a long retention time may occur due to excipients.

Related substances

A. Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Shake a quantity of the powdered tablets containing 25 mg of Dextropropoxyphene Hydrochloride with 5 mL of acetonitrile for 2 minutes, add 5 mL of water, shake for a further 5 minutes, dilute to 25 mL with water, mix and filter (Whatman GF/F filter paper is suitable).
(2) 0.0005% w/v of 4-dimethylamino-3-methyl-1,2-diphenylbutan-2-ol hydrochloride BPCRS and 0.0005% w/v of (1S,2R)-1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl acetate BPCRS in a mixture of 1 volume of acetonitrile and 4 volumes of water.
chromatographic conditions
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 µm) (Nucleosil C18 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 2 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 215 nm.
(f) Inject 20 µL of each solution.
mobile phase

40 volumes of acetonitrile and 60 volumes of 0.2m sodium perchlorate, previously adjusted to pH 2.0 using 7m hydrochloric acid.

The peaks, in order of emergence, are due to 4-dimethylamino-3-methyl-1,2-diphenylbutan-2-ol hydrochloride and (1S,2R)-1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl acetate.

system suitability

The test is not valid unless, in the chromatogram obtained with solution (2), the resolution factor between the two peaks is at least 1.5.

limits

In the chromatogram obtained with solution (1):

the areas of any peaks corresponding to 4-dimethylamino-3-methyl-1,2-diphenylbutan-2-ol hydrochloride and (1S,2R)-1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl acetate are not greater than the areas of the respective peaks in the chromatogram obtained with solution (2) (0.5%).

B. Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions.
(1) Transfer a quantity of the finely-powdered tablets containing 1.0 g of Paracetamol to a ground-glass-stoppered 15 mL centrifuge tube, add 5 mL of peroxide-free ether, shake for 30 minutes, centrifuge at 1000 revolutions per minute for 15 minutes or until a clear supernatant liquid is obtained and use the supernatant liquid.
(2) Dilute 1 mL of solution (1) to 10 mL with ethanol (96%).
(3) 0.0050% w/v of 4′-chloroacetanilide in ethanol (96%).
(4) Dissolve 0.25 g of 4′-chloroacetanilide and 0.10 g of paracetamol in sufficient ethanol (96%) to produce 100 mL.
chromatographic conditions
(a) Use as the coating silica gel F254.
(b) Use the mobile phase described below.
(c) Apply 200 µL of solution (1) and 40 µL of each of solutions (2), (3) and (4).
(d) Develop the plate to 14 cm.
(e) After removal of the plate, dry in air and examine under ultraviolet light (254 nm).
mobile phase

10 volumes of toluene, 25 volumes of acetone and 65 volumes of chloroform.

system suitability

The test is not valid unless the chromatogram obtained with solution (4) shows two clearly separated principal spots, the spot corresponding to 4′-chloroacetanilide having the higher Rf value.

limits

In the chromatogram obtained with solution (1):

any spot corresponding to 4′-chloroacetanilide is not more intense than the spot in the chromatogram obtained with solution (3) (0.005%).

In the chromatogram obtained with solution (2):

any secondary spot with an Rf value lower than that of 4′-chloroacetanilide is not more intense than the spot in the chromatogram obtained with solution (3) (0.25%).

Assay

Weigh and powder 20 tablets.

For dextropropoxyphene hydrochloride

Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1) Disperse a quantity of the powdered tablets containing 32.5 mg of Dextropropoxyphene Hydrochloride in 100 mL of 0.02m hydrochloric acid, mix with the aid of ultrasound for 15 minutes, allow to cool, dilute to 500 mL with a mixture of equal volumes of acetonitrile and 0.02m hydrochloric acid and filter (Whatman GF/C filter paper is suitable).
(2) 0.0065% w/v of dextropropoxyphene hydrochloride BPCRS in a mixture of 40 volumes of acetonitrile and 60 volumes of 0.02m hydrochloric acid.
(3) 0.0005% w/v of 4-dimethylamino-3-methyl-1,2-diphenylbutan-2-ol hydrochloride BPCRS and 0.0005% w/v of (1S,2R)-1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl acetate BPCRS in a mixture of 1 volume of acetonitrile and 4 volumes of water.
chromatographic conditions
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 µm) (Nucleosil C18 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 2 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 215 nm.
(f) Inject 20 µL of each solution.
mobile phase

40 volumes of acetonitrile and 60 volumes of 0.2m sodium perchlorate, previously adjusted to pH 2.0 using 7m hydrochloric acid.

system suitability

The test is not valid unless, in the chromatogram obtained with solution (3), the resolution factor between the two peaks is at least 1.5.

determination of content

Calculate the content of C22H29NO2,HCl in the tablets using the declared content of C22H29NO2,HCl in dextropropoxyphene hydrochloride BPCRS.

For paracetamol

Disperse a quantity of the powdered tablets containing 0.325 g of Paracetamol in 5 mL of water, add 100 mL of methanol and shake. Add 300 mL of water, shake for 5 minutes, allow to cool, dilute to 500 mL with water, mix and filter. Dilute 5 mL of the filtrate to 250 mL with 0.01m sodium hydroxide and measure the absorbance of the resulting solution at the maximum at 257 nm, Appendix II B. Calculate the content of C8H9NO2 in the tablets taking 715 as the value of A(1%, 1 cm) at the maximum at 257 nm.

Storage

Co-proxamol Tablets should be protected from light.