Lisinopril Tablets

General Notices

Action and use

Angiotensin converting enzyme inhibitor.

Definition

Lisinopril Tablets contain Lisinopril Dihydrate.

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

Content of anhydrous lisinopril, C21H31N3O5

92.5 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 powdered tablets containing the equivalent of 10 mg of anhydrous lisinopril with 2 mL of water and add 8 mL of methanol.
(2) 0.11% w/v of lisinopril dihydrate BPCRS in a mixture of 20 volumes of water and 80 volumes of methanol.
chromatographic conditions
(a) Use as the coating silica gel GF254.
(b) Pre-wash the plate with methanol and allow to dry in air before use.
(c) Use the mobile phase as described below.
(d) Apply 20 µL of each solution.
(e) Develop the plate to 15 cm.
(f) After removal of the plate, dry in air, spray with a 0.2% w/v solution of ninhydrin in absolute ethanol, heat at 105° for 10 minutes and examine in daylight.
mobile phase

Equal volumes of glacial acetic acid, butan-1-ol, ethyl acetate and water.

confirmation

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

B. In the Assay, the principal peak in the chromatogram obtained with solution (1) has the same retention time as the peak due to lisinopril 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 900 mL of 0.1m hydrochloric acid, 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 30 minutes withdraw a 10 mL sample of the medium and filter. Use the filtered medium, diluted with 0.1m hydrochloric acid, if necessary.
(2) Dissolve a quantity of lisinopril dihydrate BPCRS in sufficient of the dissolution medium to produce a solution of the same concentration as that expected for solution (1).
chromatographic conditions

The chromatographic conditions described under Related substances may be used.

determination of content

Calculate the total content of lisinopril, C21H31N3O5, in the medium from the chromatograms obtained and using the declared content of C21H31N3O5, in lisinopril dihydrate BPCRS.

limits

The amount of anhydrous lisinopril released is not less than 85% of the stated amount.

Related substances

Carry out the method for liquid chromatography, Appendix III D, using the following solutions in a mixture of 1 volume of methanol and 4 volumes water (solvent A).

(1) Shake a quantity of the powdered tablets containing the equivalent of 20 mg of anhydrous lisinopril with solvent A with the aid of ultrasound for 5 minutes, dilute to 100 mL with solvent A, mix with the aid of ultrasound again for about 10 minutes ensuring that the temperature of the solution does not rise above room temperature, and filter through a 0.45-µm membrane filter.
(2) 0.0003% w/v of lisinopril diketopiperazine BPCRS.
(3) Dilute 1 volume of solution (1) to 100 volumes.
(4) Dilute 1 volume of solution (3) to 10 volumes.
(5) 0.022% w/v of lisinopril dihydrate BPCRS and 0.0002% w/v of lisinopril diketopiperazine BPCRS.
chromatographic conditions
(a) Use a stainless steel column (20 cm × 4.6 mm) packed with octylsilyl silica gel for chromatography (10 µm) (Lichrosorb RP-8 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 40°.
(e) Use a detection wavelength of 215 nm.
(f) Inject 20 µL of each solution.
mobile phase

200 volumes of acetonitrile R1 and 800 volumes of a 0.408% w/v solution of anhydrous potassium dihydrogen orthophosphate adjusted to pH 2.0 with orthophosphoric acid containing 0.125% w/v of sodium hexanesulfonate.

system suitability

The test is not valid unless:

in the chromatogram obtained with solution (5), the resolution factor between the peaks due to lisinopril and lisinopril diketopiperazine is at least 5.0;

in the chromatogram obtained with solution (4), the signal to noise ratio of the peak due to lisinopril is at least 10.

limits

In the chromatogram obtained with solution (1):

the area of any peak corresponding to lisinopril diketopiperazine is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (1.5%);

the area of any other secondary peak is not greater than 0.3 times the area of the principal peak in the chromatogram obtained with solution (3) (0.3%);

the sum of the areas of any other secondary peaks is not greater than 0.6 times the area of the principal peak in the chromatogram obtained with solution (3) (0.6%);

the sum of the content of lisinopril diketopiperazine and the nominal total content of any other impurities is not more than 2%.

Disregard any peak with an area less than the area of the principal peak in the chromatogram obtained with solution (4) (0.1%).

Assay

Carry out the method for liquid chromatography, Appendix III D. Using the following solutions in solvent A described under Related Substances.

(1) Shake 10 whole tablets with solvent A with the aid of ultrasound for 5 minutes, dilute to a suitable volume with solvent A, mix with the aid of ultrasound again for about 10 minutes ensuring that the temperature of the solution does not rise above room temperature, and filter through a 0.45-µm membrane filter. Dilute a volume of the filtrate with solvent A to produce a solution containing the equivalent of 0.02% w/v of anhydrous lisinopril.
(2) 0.022% w/v of lisinopril dihydrate BPCRS.
(3) 0.022% w/v of lisinopril dihydrate BPCRS and 0.0002% w/v of lisinopril diketopiperazine BPCRS.
chromatographic conditions

The chromatographic conditions described under Related substances may be used.

system suitability

The test is not valid unless, in the chromatogram obtained with solution (3), the resolution factor between the peaks due to lisinopril and lisinopril diketopiperazine is at least 5.0.

determination of content

Calculate the content of C21H31N3O5 in the tablets using the declared content of C21H31N3O5 in lisinopril dihydrate BPCRS.

Labelling

The quantity of active ingredient is stated in terms of the equivalent amount of anhydrous lisinopril.

IMPURITIES

The impurities limited by the requirements of this monograph include:

1. (2S)-2-[(3S,8aS)-3-(4-aminobutyl)-1,4-dioxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-phenylbutanoic acid (S,S,S-diketopiperazine) (Lisinopril Dihydrate impurity C),

2. (2S)-2-[(3S,8aR)-3-(4-aminobutyl)-1,4-dioxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-phenylbutanoic acid (R,S,S-diketopiperazine) (Lisinopril Dihydrate impurity D).