- British Pharmacopoeia Volume III
- Formulated Preparations: Specific Monographs
Paracetamol, Codeine Phosphate and Caffeine Capsules |
Analgesic; antipyretic; opioid receptor agonist.
Paracetamol, Codeine Phosphate and Caffeine Capsules contain Paracetamol, Codeine Phosphate and Caffeine.
The capsules comply with the requirements stated under Capsules and with the following requirements.
95.0 to 105.0% of the stated amount.
95.0 to 105.0% of the stated amount.
95.0 to 105.0% of the stated amount.
A. Shake a quantity of the contents of the capsules containing 0.5 g of Paracetamol with 20 mL of acetone, 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).
B. Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions.
(1) Shake a quantity of the contents of the capsules containing 24 mg of Codeine Phosphate with 30 mL of water for 1 minute and centrifuge. Decant, add 10 mL of 1m sodium hydroxide and 30 mL of dichloromethane to the supernatant liquid, shake for 1 minute and filter the dichloromethane layer through glass-fibre paper (Whatman GF/C is suitable).
(2) 0.08% w/v of codeine phosphate BPCRS in methanol (50%).
(3) 0.08% w/v each of codeine phosphate BPCRS and dihydrocodeine tartrate BPCRS in methanol (50%).
(a) Use as the coating silica gel F254.
(b) Use the mobile phase as described below.
(c) Apply 10 µL of each solution.
(d) Develop to 15 cm.
(e) After removal of the plate, dry in air, spray with ethanolic iron(iii) chloride solution and heat at 105° for 10 minutes and examine in daylight.
1 volume of 13.5m ammonia, 10 volumes of methanol and 90 volumes of dichloromethane.
The test is not valid unless the chromatogram obtained with solution (3) shows two clearly separated spots of different colours.
The principal spot in the chromatogram obtained with solution (1) corresponds in position and colour to that in the chromatogram obtained with solution (2).
C. In the Assay for codeine phosphate, the chromatogram obtained with solution (1) shows a peak with the same retention time as the principal peak in the chromatogram obtained with solution (2).
D. Shake a quantity of the contents of the capsules containing 0.03 g of Caffeine with 10 mL of water for 5 minutes, filter and add 10 mL of 1M sodium hydroxide. Extract with three 30-mL quantities of dichloromethane, washing each extract with the same 10 mL of water. Filter the combined extracts through absorbent cotton and evaporate the filtrate to dryness. Dissolve 10 mg of the residue in 1 mL of hydrochloric acid, add 0.1 g of potassium chlorate and evaporate to dryness in a porcelain dish. A reddish colour is observed which changes to purple when exposed to ammonia vapour.
E. In the Assay for caffeine, the chromatogram obtained with solution (1) shows a principal peak with the same retention time as the principal peak in the chromatogram obtained with solution (2).
Comply with the requirements for Monographs of the British Pharmacopoeia in the dissolution test for tablets and capsules, Appendix XII B1, using the following conditions.
(a) Use Apparatus 2 and rotate the paddle at 50 revolutions per minute.
(b) Use 900 mL phosphate buffer pH 5.8 as the dissolution medium at a temperature of 37°. After 45 minutes withdraw a sample of 20 mL of the medium and filter.
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Use the filtered dissolution medium, diluted with phosphate buffer pH 5.8, if necessary, to contain 0.005%w/v of Paracetamol.
(2) 0.005% w/v solution of paracetamol BPCRS in phosphate buffer pH 5.8.
The chromatographic conditions described under Uniformity of content may be used but with a detection wavelength of 243 nm.
Calculate the content of C8H9NO2 in the medium using the declared content of C8H9NO2 in paracetamol BPCRS.
(1) Use the filtered dissolution medium, diluted with phosphate buffer pH 5.8 if necessary, to contain 0.001% w/v of Codeine Phosphate.
(2) 0.001% w/v solution of codeine phosphate BPCRS in phosphate buffer pH 5.8.
The chromatographic conditions described under Uniformity of content may be used.
Calculate the content of C18H21NO3,H3PO4,½H2O in the medium using the declared content of C18H21NO3,H3PO4,½H2O in codeine phosphate BPCRS.
(1) Use the filtered dissolution medium, diluted with phosphate buffer pH 5.8, if necessary, to contain 0.001% w/v of Caffeine.
(2) 0.001% w/v solution of caffeine BPCRS in phosphate buffer pH 5.8.
The chromatographic conditions described under Uniformity of content may be used.
Calculate the content of C8H10N4O2 in the medium using the declared content of C8H10N4O2 in caffeine BPCRS.
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Shake a quantity of the contents of the capsules 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.
(a) Use a stainless steel column (25 cm x 4.6 mm) packed with octadecylsilyl silica gel for chromatography (10µm) (Nucleosil C18 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 2.0 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 272 nm.
(f) Inject 20 µL of each solution.
0.01m sodium butanesulfonate in a mixture of 0.4 volumes of formic acid, 15 volumes of methanol and 85 volumes of water.
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 long retention times may occur due to excipients.
A. Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions.
(1) Shake a quantity of the contents of the capsules containing 50 mg of Codeine Phosphate with 50 mL of 0.1m hydrochloric acid for 10 minutes and filter. Make the filtrate alkaline with 5m sodium hydroxide and extract with two 40 mL quantities of dichloromethane. Wash the combined extracts with 10 mL of water, filter through a layer of anhydrous sodium sulfate on an absorbent cotton plug moistened with dichloromethane, evaporate the filtrate to dryness at a temperature not exceeding 45° using a rotary evaporator and dissolve the residue in 2 mL of dichloromethane.
(2) Dilute 1.5 volumes of solution (1) to 100 volumes with dichloromethane.
(3) Dilute 1 volume of solution (1) to 100 volumes with dichloromethane.
(a) Use as the coating silica gel G.
(b) Use the mobile phase described below.
(c) Apply 20 µL of each solution.
(d) Develop the plate to 15 cm.
(e) After removal of the plate, allow to dry in air and spray with potassium iodobismuthate solution.
6 volumes of 13.5m ammonia, 30 volumes of cyclohexane and 72 volumes of absolute ethanol.
In the chromatogram obtained with solution (1):
any secondary spot is not more intense than the spot in the chromatogram obtained with solution (2) (1.5%);
not more than one spot with an Rf value higher than that of the principal spot is more intense than the spot in the chromatogram obtained with solution (3) (1%).
B. Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions.
(1) Transfer a quantity of the contents of the capsules containing 1.0 g of Paracetamol to a ground-glass-stoppered 15 mL centrifuge tube, add 5 mL of peroxide-free ether, shake mechanically 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 BPCRS in sufficient ethanol (96%) to produce 100 mL.
(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) Pour the mobile phase into an unlined tank, immediately place the prepared plate in the tank, close the tank and allow the solvent front to ascend 14 cm above the line of application.
(e) After removal of the plate, dry in a current of warm air and examine under ultraviolet light (254 nm).
10 volumes of toluene, 25 volumes of acetone and 65 volumes of dichloromethane.
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.
Any spot corresponding to 4′-chloroacetanilide in the chromatogram obtained with solution (1) is not more intense than the spot in the chromatogram obtained with solution (3) (0.005%).
Any secondary spot in the chromatogram obtained with solution (2) 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%).
Capsules containing less than 2 mg and/or less than 2% w/w of Codeine Phosphate comply with the requirements stated under Capsules, with respect to the content of Codeine Phosphate, using the following method of analysis.
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Add 100 mL of the mobile phase to the contents of one capsule and mix with the aid of ultrasound until completely dispersed. Shake for 10 minutes, dilute to 200 mL with the mobile phase, filter through a glass-fibre filter (Whatman GF/C is suitable) and use the filtrate.
(2) 0.004% w/v of codeine phosphate BPCRS in the mobile phase.
(a) Use a stainless steel column (10 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 µm) (Nucleosil C18 is suitable).
(b) Use isocratic elution using the mobile phase described below.
(c) Use a flow rate of 1.5 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 220 nm.
(f) Inject 20 µL of each solution.
0.01m sodium pentanesulfonate in a mixture of 22 volumes of methanol and 78 volumes of water, the pH of the solution being adjusted to 2.8 using 2m hydrochloric acid.
Calculate the content of C18H21NO3,H3PO4,½H2O in each capsule using the declared content of C18H21NO3,H3PO4,½H2O in codeine phosphate BPCRS.
Mix the contents of 20 capsules. Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Shake a quantity of the contents of the capsules containing 500 mg of Paracetamol with 100 mL of the mobile phase for 10 minutes, dilute to 200 mL with the same solvent, filter through a glass-fibre filter (Whatman GF/C is suitable) and dilute 5 mL of the filtrate to 250 mL with the mobile phase.
(2) 0.005% w/v of paracetamol BPCRS in the mobile phase.
The chromatographic conditions described under Uniformity of content may be used but with a detection wavelength of 243 nm.
Calculate the content of C8H9NO2 using the declared content of C8H9NO2 in paracetamol BPCRS.
Mix the contents of 20 capsules. Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Shake a quantity of the contents of the capsules containing 8 mg of Codeine Phosphate with 100 mL of the mobile phase for 10 minutes, dilute to 200 mL with the same solvent, filter through a glass-fibre filter (Whatman GF/C is suitable) and use the filtrate.
(2) 0.004% w/v of codeine phosphate BPCRS in the mobile phase.
The chromatographic conditions described under Uniformity of content may be used.
Calculate the content of C18H21NO3,H3PO4,½H2O using the declared content of C18H21NO3,H3PO4,½H2O in codeine phosphate BPCRS.
Mix the contents of 20 capsules. Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Shake a quantity of the contents of the capsules containing 30 mg of Caffeine with 100 mL of the mobile phase for 10 minutes and filter through a glass-fibre filter (Whatman GF/C is suitable) and dilute 5 mL of the filtrate to 50 mL with the mobile phase.
(2) 0.003%w/v of caffeine BPCRS in the mobile phase.
The chromatographic conditions described under Uniformity of content may be used.
Calculate the content of C8H10N4O2 in each capsule using the declared content of C8H10N4O2 in caffeine BPCRS.