Etodolac Capsules

General Notices

Action and use

Cyclo-oxygenase inhibitor; analgesic; anti-inflammatory.

Definition

Etodolac Capsules contain Etodolac.

The capsules comply with the requirements stated under Capsules and with the following requirements.

Content of etodolac C17H21NO3

95.0 to 105.0% of the stated amount.

Identification

A. To a quantity of the contents of the capsules containing about 0.1 g of Etodolac add 4 mL of 0.01m hydrochloric acid and mix with the aid of ultrasound for 5 minutes, shaking occasionally, centrifuge for 10 minutes, discard the supernatant liquid and wash the residue with 4 mL of water. Shake to disperse, centrifuge for 10 minutes and discard the supernatant liquid. Add 4 mL of 0.01m sodium hydroxide to the residue and mix with the aid of ultrasound for 5 minutes, shaking occasionally and centrifuge for 10 minutes. Transfer the supernatant liquid to a second centrifuge tube, add about 1 mL of 0.1m hydrochloric acid (the pH of the supernatant liquid should be 2 or less). Centrifuge for 10 minutes, discard the supernatant liquid and wash the residue with 4 mL of water, shake to disperse and centrifuge for 10 minutes. Discard the supernatant liquid and dry the residue at 105° for 1 hour. The infrared absorption spectrum of the residue, Appendix II A, is concordant with the reference spectrum of etodolac (RS 139).
B. In the Assay, the chromatogram obtained with solution (1) shows a peak with the same retention time as the peak due to etodolac in the chromatogram obtained with solution (2).

TESTS

Dissolution

Comply with the requirements for Monographs of the British Pharmacopoeia in the dissolution test for tablets and capsules, Appendix XII B1, using as the medium 900 mL of phosphate buffer pH 7.5 and rotating the basket at 100 revolutions per minute. Withdraw a 10 mL sample of the medium and measure the absorbance of the filtered sample, suitably diluted if necessary, at the maximum at 278 nm, Appendix II B. Measure the absorbance of a suitable solution of etodolac BPCRS prepared by dissolving 30 mg in 100 mL of the dissolution medium and diluting to a suitable volume with the dissolution medium and using dissolution medium in the reference cell. Calculate the total content of etodolac, C17H21NO3 in the medium from the absorbances obtained and from the declared content of C17H21NO3 in etodolac BPCRS.

Related substances

Carry out the method for thin-layer chromatography, Appendix III A, using a silica gel F254 precoated plate (Merck silica gel 60 F254 plates are suitable), previously activated by heating at 105° for 1 hour, and a mixture of 0.5 volumes of glacial acetic acid, 30 volumes of absolute ethanol and 70 volumes of toluene as the mobile phase. Place the plate in an unlined tank containing a solution prepared by dissolving 0.5 g of l-ascorbic acid in 20 mL of water and adding 80 mL of methanol. Allow the solution to ascend 1 cm above the line of application on the plate, remove the plate and allow it to dry for at least 30 minutes. Apply separately to the plate 10 µL of each of the following solutions in acetone. For solution (1) shake a quantity of the contents of the capsules containing 0.2 g of Etodolac with 20 mL of acetone, mix with the aid of ultrasound for 5 minutes and filter. For solution (2) dilute 1 volume of solution (1) to 200 volumes with acetone and for solution (3) dilute 1 volume of solution (2) to 2 volumes with acetone. After removal of the plate, allow it to dry in air and examine under ultraviolet light (254 nm). Any secondary spot in the chromatogram obtained with solution (1) is not more intense than the spot in the chromatogram obtained with solution (2) (0.5%) and not more than one such spot is more intense than the spot in the chromatogram obtained with solution (3) (0.25%).

Etodolac acid dimer

Carry out the method for thin-layer chromatography, Appendix III A, using a silica gel F254 precoated plate (Merck silica gel 60 F254 plates are suitable), previously activated by heating at 105° for 1 hour, and a mixture of 3 volumes of glacial acetic acid, 17 volumes of 1,4-dioxan and 60 volumes of toluene as the mobile phase. Place the plate in an unlined tank containing a solution prepared by dissolving 0.5 g of l-ascorbic acid in 20 mL of water and adding 80 mL of methanol. Allow the solution to ascend 1 cm above the line of application on the plate, remove the plate and allow it to dry for at least 30 minutes. Apply separately to the plate 20 µL of each of the following solutions. For solution (1) shake a quantity of the contents of the capsules containing 0.6 g of Etodolac with 20 mL of acetone, mix with the aid of ultrasound for 5 minutes and filter. Solution (2) contains 0.003% w/v of etodolac acid dimer BPCRS in acetone. After removal of the plate, allow it to dry in air and examine under ultraviolet light (254 nm). Any secondary spot in the chromatogram obtained with solution (1) corresponding to the acid dimer is not more intense than the spot in the chromatogram obtained with solution (2) (0.1%).

Total methyl analogue impurities

Carry out the method for liquid chromatography, Appendix III D, using the following solutions. For solution (1) shake a quantity of the contents of the capsules containing 0.1 g of Etodolac with 40 mL of methanol, mix with the aid of ultrasound for 5 minutes, filter and dilute 10 mL of the filtrate to 25 mL with water. For solution (2) dilute 1 volume of a solution containing 0.025% w/v each of etodolac 1-methyl analogue BPCRS and etodolac 8-methyl analogue BPCRS in methanol to 50 volumes with water.

The chromatographic procedure may be carried out using (a) a stainless steel column (20 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 µm) (Spherisorb ODS 1 is suitable), (b) a mixture of 13 volumes of acetonitrile, 19 volumes of methanol and 68 volumes of a 1.74% w/v solution of dipotassium hydrogen orthophosphate as the mobile phase with a flow rate of 1.0 mL per minute and (c) a detection wavelength of 225 nm. Adjust the mobile phase, if necessary, to give a retention time of 14 to 20 minutes for etodolac. The order of elution of peaks in the chromatogram obtained with solution (2) is etodolac 8-methyl analogue and etodolac 1-methyl analogue. For solution (1) allow the chromatography to proceed for twice the retention time of the principal peak.

The test is not valid unless, in the chromatogram obtained with solution (2), the resolution factor between the two methyl analogue impurities is at least 0.75.

Calculate the percentage content of etodolac 1-methyl analogue and etodolac 8-methyl analogue in etodolac by reference to the corresponding peaks in the chromatogram obtained with solution (2). The total content is not greater than 1.0%.

Assay

Carry out the method for liquid chromatography, Appendix III D, using the following solutions. For solution (1) shake a quantity of the mixed contents of 20 capsules containing 50 mg of Etodolac with about 70 mL of 0.1m sodium hydroxide for 30 minutes, dilute to 100 mL with 0.1m sodium hydroxide, mix and filter through a glass-fibre filter (Whatman GF/C is suitable) and dilute 2 mL of the filtrate to 100 mL with the mobile phase. For solution (2) dilute 2 mL of a 0.05% w/v solution of etodolac BPCRS in 0.1m sodium hydroxide to 100 mL with the mobile phase. For solution (3) add 2 mL of a 0.05% w/v solution of etodolac 1-methyl analogue BPCRS in 0.1m sodium hydroxide to 2 mL of a 0.05% w/v solution of etodolac BPCRS in 0.1m sodium hydroxide and dilute to 100 mL with the mobile phase.

The chromatographic procedure may be carried out using (a) a stainless steel column (12.5 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 µm) (Spherisorb ODS 1 is suitable), (b) a mixture of 45 volumes of acetonitrile and 55 volumes of phosphate buffer pH 4.75 as the mobile phase with a flow rate of 1 mL per minute and (c) a detection wavelength of 225 nm.

The test is not valid unless the resolution factor between etodolac and etodolac 1-methyl analogue in the chromatogram obtained with solution (3) is at least 1.5.

Calculate the content of C17H21NO3 using the declared content of C17H21NO3 in etodolac BPCRS.