Iron Sorbitol Injection

Definition

 

Iron Sorbitol Injection is a sterile colloidal solution of a complex of iron(III), Sorbitol and Citric Acid, stabilised with Dextrin and Sorbitol.

 

Production

 

Iron Sorbitol Injection is produced by a method of manufacture designed to provide an ironCsorbitol complex with appropriate iron absorption characteristics. This may be confirmed for routine control purposes by the use of an appropriate combination of physico-chemical tests, subject to the agreement of the competent authority.

 

The method of manufacture is validated to demonstrate that, if tested, the injection would comply with the following test.

 

Undue toxicity

 

Inject 20 µl mixed with 0.2 ml of sodium chloride injection into a tail vein of each of 10 mice; not more than three mice die within 5 days of injection. If more than three mice die within 5 days, repeat the test on another group of 20 mice. Not more than 10 of the 30 mice used in the combined tests die within 5 days of injection.

 

The injection complies with the requirements stated under Parenteral Preparations and with the following requirements.

 

Content of Fe

 

4.75 to 5.25% w/v.

 

Characteristics

 

A brown solution.

 

Identification

 

A.    Add 5M ammonia to 0.15 ml of the injection previously diluted to 5 ml with water . No precipitate is produced.

 

B.    To 1 ml add 4 ml of water  and 10 ml of hydrochloric acid, extract with three 15 ml quantities of di-isopropyl ether  and dilute the aqueous layer to 25 ml with water . To 0.5 ml add 10 ml of water , 2 ml of 1M sulphuric acid and 10 mg of sodium periodate, allow to stand for 10 minutes and add 10 ml of 0.05M sodium arsenite VS. When the solution is colourless add 10 ml of a 0.4% w/v solution of phenylhydrazine hydrochloride in 0.5M hydrochloric acid, allow to stand for 10 minutes, add 1 ml of dilute potassium hexacyanoferrate(III) solution, allow to stand for 15 minutes and add 3 ml of hydrochloric acid. A red colour is produced.

 

C.    Dilute 0.2 ml to 50 ml with water . To 5 ml add 1.5 ml of sulphuric acid and 1 ml of bromine water , heat on a water bath for 10 minutes and cool in ice. Add 4 ml of 0.025M bromine followed by 50 mg of potassium permanganate, shake well and allow to stand for 30 minutes. Decolorise the solution by the dropwise addition of a 10% w/v solution of hydrazine hydrate and shake with 15 ml of n-heptane for 10 minutes. Separate the heptane layer, wash with 10 ml of water  and shake with 10 ml of a solution containing 4% w/v of thiourea and 2% w/v of sodium tetraborate. A yellow colour is produced in the aqueous layer.

 

D.    Heat 0.15 ml of the injection with 2 ml of sulphuric acid until a charred residue is produced, extract the residue with 2M hydrochloric acid and filter. The filtrate yields reaction B characteristic of iron salts, Appendix VI, and a brown, flocculent precipitate with 5M ammonia.

 

Alkalinity

 

pH, 7.2 to 7.9, Appendix V L.

 

Viscosity

 

At 20, 7.0 to 11.0 mm2 sC1, Appendix V H, Method I, using a U-tube viscometer (size C).

 

Weight per ml

 

1.17 to 1.19 g, Appendix V G.

 

Arsenic

 

To 5.0 ml in a Kjeldahl flask add 10 ml of water  and 10 ml of nitric acid and heat until the vigorous evolution of brown fumes ceases. Cool, add 10 ml of sulphuric acid and heat again until fumes are evolved, adding nitric acid dropwise at intervals until oxidation is complete. Cool, add 30 ml of water , bring to the boil and continue boiling until the volume of liquid is reduced to about 20 ml; cool and dilute to 50 ml with water . Reserve a portion of the solution for the test for Lead. To 5 ml of the solution add 10 ml of water , 15 ml of stannated hydrochloric acid and 3 ml of tin(II) chloride solution AsT. Connect to a condenser and distil 15 ml into 10 ml of water . To the distillate add 0.2 ml of bromine water  and remove the excess of bromine with tin(II) chloride solution AsT. The solution complies with the limit test for arsenic, Appendix VII (2 µg per ml).

 

Copper

 

To 5.0 ml add 5 ml of nitric acid and heat until the vigorous evolution of brown fumes ceases. Cool, add 2 ml of sulphuric acid and heat again until fumes are evolved, adding nitric acid dropwise at intervals until oxidation is complete. Cool, add 25 ml of hydrochloric acid, warm to dissolve, cool and extract with four 25 ml quantities of isobutyl acetate, discarding the extracts. Evaporate the acid solution to dryness, adding nitric acid dropwise if charring occurs. Dissolve the residue in 10 ml of 1M hydrochloric acid, reserving a portion of the solution for the test for Zinc. To 1 ml add 25 ml of water  and 1 g of citric acid, make alkaline to litmus paper  with 5M ammonia, dilute to 50 ml with water , add 1 ml of sodium diethyldithiocarbamate solution and allow to stand for 5 minutes. Any colour obtained is not more intense than that produced by treating in the same manner a mixture of 3 ml of copper standard solution (10 ppm Cu) and 1 ml of 1M hydrochloric acid beginning at the words 'add 25 ml of water ¼' (60 µg per ml).

 

Lead

 

To 16.0 ml of the solution prepared in the test for Arsenic add 50 ml of hydrochloric acid and extract with four 20 ml quantities of isobutyl acetate, discarding the extracts. Evaporate the acid solution to dryness and dissolve the residue in 20 ml of water . 12 ml of the solution complies with limit test A for heavy metals, Appendix VII. Use lead standard solution (2 ppm Pb) to prepare the standard (25 µg per ml).

 

Zinc

 

To 5.0 ml of the solution reserved in the test for Copper add 15 ml of 1M sodium hydroxide, boil, filter, wash the residue with water  and dilute the combined filtrate and washings to 25 ml with water . To 5 ml add 5 ml of 1M hydrochloric acid and 2 g of ammonium chloride, dilute to 50 ml with water , add 1 ml of freshly prepared dilute potassium hexacyanoferrate(II) solution and allow to stand for 20 minutes. Any opalescence produced is not greater than that obtained when 1 ml of freshly prepared dilute potassium hexacyanoferrate(II) solution is added to a solution prepared from 3 ml of zinc standard solution (25 ppm Zn), 3 ml of 1M sodium hydroxide, 6 ml of 1M hydrochloric acid and 2 g of ammonium chloride diluted to 50 ml with water  and allowed to stand for 20 minutes (150 µg per ml).

 

Iron absorption

 

Complies with the test described under Iron Dextran Injection.

 

Bacterial endotoxins

 

The endotoxin limit concentration is 0.50 IU per mg of iron, Appendix XIV C.

 

Assay

 

To 2 g add 10 ml of water  and 5 ml of sulphuric acid and stir for several minutes. Allow to stand for 5 minutes, cool and dilute to 50 ml with water . Prepare a suitable zinc amalgam by covering 300 g of zinc shot with a 2% w/v solution of mercury(II) chloride and stirring for 10 minutes. Decant the solution, wash the residue three times with water  and transfer it to a column (30 cm 18 mm) fitted with a sintered-glass disc (BS porosity No. 0). Activate the zinc amalgam by passing through the column 200 ml of 0.5M sulphuric acid. Pass the prepared solution slowly through the column and wash successively with 50 ml of water , four 25 ml quantities of 0.5M sulphuric acid and 50 ml of water . Titrate the combined washings with 0.1M ammonium cerium(IV) sulphate VS using ferroin solution as indicator. Each ml of 0.1M ammonium cerium(IV) sulphate VS is equivalent to 5.585 mg of Fe. Using the weight per ml of the injection calculate the percentage w/v of Fe.

 

Storage

 

Iron Sorbitol Injection should not be stored at a low temperature and should not be allowed to freeze.

 

Labelling

 

The strength is stated as the equivalent amount of iron, Fe, in a suitable dose-volume.

 

Action and use

 

Used in the treatment of anaemia.