Edition: BP 2025 (Ph. Eur. 11.6 update)
Action and use
Source of iron + Vitamin B component; used in treatment of iron-deficiency anaemia.
DEFINITION
Ferrous Fumarate and Folic Acid Tablets contain Ferrous Fumarate and Folic Acid Hydrate.
The tablets comply with the requirements stated under Tablets and with the following requirements.
Carry out the tests avoiding exposure to actinic light.
Content of ferrous fumarate, C4H2FeO4
90.0 to 105.0% of the stated amount.
Content of folic acid, C19H19N7O6
90.0 to 115.0% of the stated amount.
IDENTIFICATION
A. In the Assay for folic acid, 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).
B. Heat a quantity of the powdered tablets containing 0.77 g of Ferrous Fumarate with 25 mL of a mixture of equal volumes of hydrochloric acid and water on a water bath for 15 minutes, cool and filter. Retain the residue for test C. The filtrate yields reaction A characteristic of iron salts, Appendix VI.
C. Wash the residue reserved in test B with a mixture of 1 volume of 2M hydrochloric acid and 9 volumes of water and dry at 105°. Suspend 0.1 g of the residue in 2 mL of sodium carbonate solution and add potassium permanganate solution dropwise. The permanganate is decolourised and a brownish solution is produced.
TESTS
Dissolution
Comply with the requirements in the dissolution test for tablets and capsules, Appendix XII B1.
TEST CONDITIONS
(a) Use Apparatus 2, rotating the paddle at 75 revolutions per minute.
(b) Use 900 mL of 0.1M hydrochloric acid, at a temperature of 37°, as the medium.
For folic acid
PROCEDURE
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) After 60 minutes withdraw a sample of the medium and filter. Use the filtered medium, diluted with 0.1M hydrochloric acid if necessary, expected to contain 0.00004% w/v of folic acid.
(2) Disperse 10 mg of folic acid BPCRS in 75 mL of methanol and mix with the aid ultrasound for 15 minutes. Add 125 mL of 0.1M hydrochloric acid, mix with the aid of ultrasound for a further 15 minutes and dilute to 250 mL with 0.1M hydrochloric acid. Dilute 1 volume of the resulting solution to 100 volumes with 0.1M hydrochloric acid.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm x 4.6 mm) packed with base-deactivated octadecylsilyl silica gel for chromatography (5 μm) (Zorbax SB-C18 is suitable).
(b) Use gradient elution and the mobile phase described below.
(c) Use a flow rate of 0.7 mL per minute.
(d) Use a column temperature of 30°.
(e) Use a detection wavelength of 235 nm.
(f) Inject 300 μL of each solution.
MOBILE PHASE
Mobile phase A 1 volume of formic acid, 100 volumes of methanol and 900 volumes of water.
Mobile phase B 1 volume of formic acid, 100 volumes of water and 900 volumes of methanol.
| Time (Minutes) | Mobile phase A (% v/v) | Mobile phase B (% v/v) | Comment |
| 0-4 | 100 | 0 | isocratic |
| 4-9.5 | 100-10 | 0-90 | linear gradient |
| 9.5-9.6 | 10-100 | 90-0 | linear gradient |
| 9.6-20 | 100 | 0 | re-equilibration |
DETERMINATION OF CONTENT
Calculate the total content of C19H19N7O6 in the medium from the chromatograms obtained and using the declared content of C19H19N7O6 in folic acid BPCRS.
LIMITS
The amount of folic acid released is not less than 75% (Q) of the stated amount.
For ferrous fumarate
PROCEDURE
After 60 minutes withdraw a sample of the medium and filter. Titrate 100 mL of the filtrate with 0.01M ammonium cerium(IV) sulfate VS using ferroin solution as indicator.
DETERMINATION OF CONTENT
Calculate the total content of C4H2FeO4 in the medium taking each mL of 0.1M ammonium cerium(IV) sulfate VS to be equivalent to 16.99 mg of C4H2FeO4.
The amount of ferrous fumarate released is not less than 75% (Q) of the stated amount.
Ferric iron
Dissolve a quantity of the powder prepared for the Assay for ferrous fumarate containing 1.5 g of Ferrous Fumarate in a mixture of 100 mL of water and 10 mL of hydrochloric acid by heating rapidly to the boiling point. Boil for 15 seconds, cool rapidly, add 3 g of potassium iodide, stopper, allow to stand in the dark for 15 minutes and titrate the liberated iodine with 0.1M sodium thiosulfate VS using starch mucilage as indicator. Repeat the operation without the substance being examined. The difference between the titrations is not more than 13.4 mL (5% ferric iron in Ferrous Fumarate).
Uniformity of Content
For folic acid
For tablets containing the equivalent of less than 2 mg and/or less than 2% w/w of folic acid.
Complies with the requirements stated under Tablets using the following method of analysis. Carry out the method for liquid chromatography, Appendix III D, using the following solutions in 135 volumes of methanol and 800 volumes of a 0.57% w/v solution of dipotassium hydrogen orthophosphate (solvent A).
(1) Place one tablet in 40 mL of solvent A, shake for a further 15 minutes, dilute to 50 mL with solvent A and filter (a 0.45- μm nylon filter is suitable).
(2) 0.0007% w/v of folic acid BPCRS in solvent A.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 μm) (Spherisorb ODS 1 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 277 nm.
(f) Inject 20 μL of each solution.
MOBILE PHASE
135 volumes of methanol and 800 volumes of a solution containing 0.938% w/v of sodium perchlorate and 0.075% w/v of potassium dihydrogen orthophosphate adjusted to pH 7.2 with 0.1M potassium hydroxide and diluted to 1000 volumes with water.
DETERMINATION OF CONTENT
Calculate the content of C19H19N7O6 in each tablet using the declared content of C19H19N7O6 in folic acid BPCRS.
ASSAY
Weigh and powder 20 tablets.
For ferrous fumarate
Disperse a quantity of the powder containing 0.3 g of Ferrous Fumarate in 7.5 mL of 1M sulfuric acid with gentle heating. Cool, add 25 mL of water and titrate immediately with 0.1M ammonium cerium(IV) sulfate VS using ferroin solution as indicator. Each mL of 0.1M ammonium cerium (IV) sulfate VS is equivalent to 16.99 mg of C4H2FeO4.
For folic acid
For tablets containing the equivalent of less than 2 mg and/or less than 2% w/w of folic acid
Use the average of the individual results obtained in the test for Uniformity of content.
For tablets containing the equivalent of 2 mg or more and 2% w/w or more of folic acid
Carry out the method for liquid chromatography, Appendix III D, using the following solutions in 135 volumes of methanol and 800 volumes of a 0.57% w/v solution of dipotassium hydrogen orthophosphate (solvent A).
(1) Mix a quantity of the powdered tablets containing the equivalent of 0.35 mg of folic acid in 40 mL of solvent A, mix for 5 minutes with the aid of ultrasound, shake for a further 15 minutes and dilute to 50 mL with solvent A and filter (a 0.45-μm nylon filter is suitable).
(2) 0.0007% w/v of folic acid BPCRS solvent A.
CHROMATOGRAPHIC CONDITIONS
Chromatographic conditions described under Uniformity of Content may be used.
MOBILE PHASE
135 volumes of methanol and 800 volumes of a solution containing 0.938% w/v of sodium perchlorate and 0.075% w/v of potassium dihydrogen orthophosphate adjusted to pH 7.2 with 0.1M potassium hydroxide and diluted to 1000 volumes with water.
When the chromatogram is recorded under the prescribed conditions, the retention time for folic acid is about 4.5 minutes.
DETERMINATION OF CONTENT
Calculate the content of C19H19N7O6 in the tablets using the declared content of C19H19N7O6 in folic acid BPCRS.
STORAGE
Ferrous Fumarate and Folic Acid Tablets should be protected from light.
LABELLING
For ferrous fumarate the quantity of the active ingredient is stated both as the amount of ferrous fumarate and in terms of the equivalent amount of ferrous iron.
