Loperamide Capsules

General Notices

Action and use

Opioid receptor agonist; antidiarrhoeal.

Definition

Loperamide Capsules contain Loperamide Hydrochloride.

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

Content of loperamide hydrochloride, C29H33ClN2O2,HCl

95.0 to 105.0% of the stated amount.

Identification

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 10 mg of Loperamide Hydrochloride with 10 mL of methanol for 5 minutes and filter.
(2) 0.1% w/v of loperamide hydrochloride BPCRS in methanol.
chromatographic conditions
(a) Use as the coating silica gel F254 (Merck silica gel 60 F254 plates are suitable).
(b) Use the mobile phase as described below.
(c) Apply 10 µL of each solution.
(d) Develop the plate to 15 cm.
(e) After removal of the plate, dry in air and examine under ultraviolet light (254 nm).
mobile phase

2.5 volumes of acetate buffer pH 4.7, 17.5 volumes of methanol, 27 volumes of ethyl acetate and 53 volumes of dichloromethane.

confirmation

The principal spot in the chromatogram obtained with solution (1) corresponds in position to that in the chromatogram obtained with solution (2).

B. In the Assay, the retention time of the principal peak in the chromatogram obtained with solution (1) is similar to that of the principal peak 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.

test conditions
(a) Use Apparatus 2, rotating the paddle at 50 revolutions per minute.
(b) Use 500 mL of a buffer solution prepared by mixing 20 volumes of 1m acetic acid with 60 volumes of water, adjusting the pH to 4.7 with 1m sodium hydroxide and diluting to 100 volumes with water, at a temperature of 37°, as the medium.
procedure

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

(1) After 45 minutes withdraw a 10-mL sample of the medium and filter. Dilute the filtrate, if necessary, with dissolution medium to produce a solution expected to contain 0.0004% w/v of Loperamide Hydrochloride.
(2) 0.0004% w/v of loperamide hydrochloride BPCRS in the dissolution medium.
chromatographic conditions
(a) Use a stainless steel column (15 cm × 4 mm) packed with end-capped octadecylsilyl silica gel for chromatography (4 µm) (Novapak C18 is suitable).
(b) Use isocratic elution and 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 226 nm.
(f) Inject 20 µL of each solution.
mobile phase

0.005m sodium octanesulfonate containing, per 1000 mL, 1 mL of 13.5m ammonia and 0.5 mL of triethylamine and adjusted to pH to 3.2 with orthophosphoric acid (solvent A).

45 volumes of solvent A and 55 volumes of acetonitrile.

determination of content

Calculate the total content of loperamide hydrochloride, C29H33ClN2O2,HCl, in the medium from the chromatograms obtained and using the declared content of C29H33ClN2O2,HCl in loperamide hydrochloride BPCRS.

Related substances

Carry out the method for liquid chromatography, Appendix III D, using the following freshly prepared solutions in solvent B.

35 volumes of 0.1m potassium dihydrogen orthophosphate, adjusted to pH 2.1 with orthophosphoric acid, and 65 volumes of methanol (solvent B).

(1) Shake a quantity of the contents of the capsules with a sufficient volume of solvent B to produce a solution containing 0.0035% w/v of Loperamide Hydrochloride. Filter and use the filtrate.
(2) Dilute 1 volume of solution (1) to 100 volumes.
(3) Dilute 1 volume of solution (2) to 5 volumes.
(4) 0.0035% w/v of loperamide hydrochloride BPCRS and 0.000035% w/v of loperamide N-oxide BPCRS (impurity F).
chromatographic conditions
(a) Use a stainless steel column (7.5 cm × 4.6 mm) packed with end-capped octadecylsilyl silica gel (5 µm) (Phenomenex Luna C18(2) is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1 mL per minute.
(d) Use a column temperature of 30°.
(e) Use a detection wavelength of 219 nm.
(f) Inject 20 µL of each solution.
(g) For solution (1), allow the chromatography to proceed for 3 times the retention time of loperamide.
mobile phase

5 volumes of tetrahydrofuran, 37 volumes of acetonitrile R1 and 58 volumes of a solution containing 0.46% w/v ammonium dihydrogen phosphate and 0.61% w/v sodium decanesulfonate, previously adjusted to pH 2.1 with orthophosphoric acid.

When the chromatograms are recorded under the prescribed conditions the retention relative to loperamide (retention time about 15 minutes) is: impurity F, about 1.2.

system suitability

The test is not valid unless, in the chromatogram obtained with solution (4), the resolution between the peaks due to loperamide and impurity F is at least 1.5.

limits

In the chromatogram obtained with solution (1):

the area of any peak corresponding to impurity F is not greater than twice the area of the principal peak in the chromatogram obtained with solution (2) (2.0%);

the area of any other secondary peak is not greater than the area of the principal peak in the chromatogram obtained with solution (3) (0.2%);

the sum of the areas of any other secondary peaks, excluding impurity F, is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (1.0%).

Disregard any peak with an area less than half the area of the principal peak in the chromatogram obtained with solution (3) (0.1%).

Uniformity of content

Capsules containing less than 2 mg and/or less than 2% w/w of Loperamide Hydrochloride comply with the requirements stated under Capsules using the following method of analysis. Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1) Add 150 mL of water to one whole capsule and mix with the aid of ultrasound for 30 minutes, shake mechanically for 30 minutes and dilute to 200 mL with acetonitrile, filter and use the filtrate.
(2) 0.001% w/v of loperamide hydrochloride BPCRS in a mixture of 45 volumes of water and 55 volumes of acetonitrile.
chromatographic conditions

The chromatographic conditions described under Dissolution may be used.

determination of content

Calculate the content of C29H33ClN2O2,HCl in each capsule using the declared content of C29H33ClN2O2,HCl in loperamide hydrochloride BPCRS.

Assay

For capsules containing the equivalent of less than 2 mg and/or less than 2% w/w of loperamide hydrochloride

Use the average of the individual results obtained in the test for Uniformity of content.

For capsules containing the equivalent of 2 mg or more and 2% w/w or more of loperamide hydrochloride

Weigh and powder the contents of 20 capsules. Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1) Mix a quantity of the mixed capsule contents containing 20 mg of Loperamide Hydrochloride with 90 mL of water with the aid of ultrasound for 10 minutes, shake for 30 minutes, dilute to 200 mL with acetonitrile and filter.
(2) 0.01% w/v of loperamide hydrochloride BPCRS in a mixture of 45 volumes of water and 55 volumes of acetonitrile.
chromatographic conditions

The chromatographic conditions described under Dissolution may be used.

determination of content

Calculate the content of C29H33ClN2O2,HCl in the capsules using the declared content of C29H33ClN2O2,HCl in loperamide hydrochloride BPCRS.

IMPURITIES

The impurities limited by the requirements of this monograph include impurity F listed under Loperamide Hydrochloride.