Action and use
Histamine H2 receptor antagonist; treatment of peptic ulceration.
DEFINITION
Famotidine Tablets contain Famotidine.
The tablets comply with the requirements stated under Tablets and with the following requirements.
Content of famotidine, C8H15N7O2S3
95.0 to 105.0% of the stated amount.
IDENTIFICATION
A. In the Assay, the chromatogram obtained with solution (1) shows a peak with the same retention time as the peak in the chromatogram obtained with solution (2).
B. Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions.
(1) Shake a quantity of the powdered tablets containing 40 mg of Famotidine with 4 mL of glacial acetic acid with the aid of ultrasound, dilute to 10 mL with the same solvent, centrifuge and use the clear supernatant liquid.
(2) 0.4% w/v of famotidine BPCRS in glacial acetic acid.
CHROMATOGRAPHIC CONDITIONS
(a) Use as the coating silica gel F254 (Fischer Silica Gel GF 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, allow it to dry in air and examine immediately under ultraviolet light (254 nm).
MOBILE PHASE
2 volumes of 13.5M ammonia, 20 volumes of toluene, 25 volumes of methanol and 40 volumes of ethyl acetate.
CONFIRMATION
The principal spot in the chromatogram obtained with solution (1) corresponds to that 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 phosphate buffer pH 4.5, at a temperature of 37°, as the medium prepared in the following manner. Dissolve 13.61 g of potassium dihydrogen orthophosphate in water, adjust the pH of the solution with orthophosphoric acid or 1M potassium hydroxide as necessary and add sufficient water to produce 1000 mL.
PROCEDURE
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Withdraw a sample of the medium, filter and centrifuge at 2000 revolutions per minute for 20 minutes. Dilute, if necessary, with the dissolution medium to produce a solution expected to contain 0.001% w/v of Famotidine.
(2) 0.001% w/v of famotidine BPCRS in the dissolution medium.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 4.6 mm) packed with end-capped octadecylsilyl silica gel for chromatography (5 μm) (Inertsil ODS-2 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1.4 mL per minute.
(d) Use a column temperature of 40°.
(e) Use a detection wavelength of 275 nm.
(f) Inject 50 μL of each solution.
MOBILE PHASE
7 volumes of acetonitrile and a mixture of 93 volumes of 0.1M sodium acetate containing 0.1% v/v of triethylamine the pH adjusted to 6.0 with glacial acetic acid.
DETERMINATION OF CONTENT
Calculate the total content of famotidine, C8H15N7O2S3, in the medium using the declared content of C8H15N7O2S3 in famotidine BPCRS.
Related substances
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
Solution A: 0.05M potassium dihydrogen orthophosphate adjusted to pH 6.0 with 1M potassium hydroxide.
(1) Add 200 mL of solution A to a quantity of whole tablets containing 0.2 g of Famotidine, mix with the aid of ultrasound for 5 minutes, add about 200 mL of methanol, shake for 60 minutes and add sufficient solution A to produce 500 mL.
(2) Dilute 1 volume of solution (1) to 100 volumes with solution A.
(3) Dilute 1 volume of solution (1) to 10 volumes with solution A and dilute 1 volume of the resulting solution to 50 volumes with solution A.
(4) Add 40 mL of acetonitrile to a mixture of 2 mg of each of famotidine impurity C BPCRS, famotidine degradation impurity 1 BPCRS (famotidine impurity F) and famotidine impurity D EPCRS (famotidine degradation impurity 2) mix with the aid of ultrasound for 2 minutes, cool, add 40 mL of methanol and sufficient solution A to produce 200 mL. Dilute 1 volume of the resulting solution to 5 volumes with solution A.
(5) Dissolve 8 mg of famotidine BPCRS in 15 mL of solution A with the aid of ultrasound, cool and add sufficient solution A to produce 20 mL (solution B); to 1 mL of this solution add 0.05 mL of hydrogen peroxide solution (10 vol) (generates famotidine degradation impurity 3).
(6) Dilute 1 volume of solution B with 100 volumes of solution A and further dilute a suitable volume with an equal volume of solution (4).
CHROMATOGRAPHIC CONDITIONS
The chromatographic conditions described under Dissolution may be used.
When the chromatograms are recorded under the prescribed conditions, the relative retention(s) with reference to famotidine (retention time about 5 minutes) are: famotidine degradation impurity 3, about 0.4; famotidine impurity F, about 0.6; famotidine impurity C, about 0.7; and famotidine impurity D, about 1.2.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (6):
the resolution between the peaks due to famotidine impurity C and famotidine is at least 1.4;
the resolution between the peaks due to famotidine and famotidine impurity D is at least 1.4.
If this resolution is not achieved adjust the content of acetonitrile or decrease the concentration of sodium acetate in the mobile phase.
LIMITS
In the chromatogram obtained with solution (1):
the areas of any peaks corresponding to impurities C, D, or F are not greater than the areas of the corresponding peaks in
the chromatogram obtained with solution (4) (0.5% of each);
the area of any peak corresponding to famotidine degradation impurity 3 is not greater than the area of the peak in the chromatogram obtained with solution (2) (1%);
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 secondary peaks is not greater than 2.5 times the principal peak in the chromatogram obtained with solution (2) (2.5%).
Disregard any peak with an area less than 0.25 times the area of the principal peak in the chromatogram obtained with solution (3) (0.05%).
ASSAY
Weigh and powder 20 tablets. Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
Solution A: 0.05M potassium dihydrogen orthophosphate adjusted to pH 6.0 with 1M potassium hydroxide.
(1) Add 200 mL of solution A to a quantity of whole tablets containing 0.2 g of Famotidine, mix with the aid of ultrasound for 5 minutes, add about 200 mL of methanol, shake for 60 minutes and add sufficient solution A to produce 500 mL. Dilute 1 volume of this solution to 5 volumes with solution A.
(2) Dissolve 8 mg of famotidine BPCRS in 4 mL of methanol, mix with the aid of ultrasound for 5 minutes and add sufficient solution A to produce 20 mL. Dilute 1 volume of this solution to 5 volumes with solution A.
CHROMATOGRAPHIC CONDITIONS
The chromatographic conditions described under Dissolution may be used.
DETERMINATION OF CONTENT
Calculate the content of C8H15N7O2S3 in the tablets using the declared content of C8H15N7O2S3 in famotidine BPCRS.
IMPURITIES
The impurities limited by the requirements of this monograph include impurities C, D, and F listed under Famotidine and the following:
3. 3-[2-(Diaminomethyleneamino)-1,3-thiazol-4-ylmethylsulfinyl]-N-sulfamoylpropanamidine.
