Iron sucrose complexes and method of manufacture thereof
A process is provided for preparing an iron sucrose complex, substantially free of excipients, for providing an iron sucrose complex co-precipitated with sucrose, and for providing iron sucrose complexes in aqueous solution.
1. A process of preparing a co-precipitate comprising iron sucrose complex and sucrose, comprising the steps of:
(a) reacting ferric hydroxide and sucrose in an aqueous reaction mixture comprising sodium ions, at a selected molar ratio of sucrose to ferric hydroxide, for a selected time interval, at a selected temperature, and at a pH in the range from about 6.5 to about 13;
(b) isolating iron sucrose complex from the reaction mixture;
(c) dissolving the isolated iron sucrose complex in an aqueous solvent to form a solution;
(d) forming a mixture by adding to the solution formed in step (c) at least one water-miscible organic solvent in an amount sufficient to precipitate iron sucrose complex from the solution;
(e) collecting the purified iron sucrose complex from the mixture formed in step (d);
(f) dissolving the purified iron sucrose complex product formed in step (e) in an aqueous sucrose solution;
(g) forming a mixture by adding to the iron sucrose complex solution formed in step (f) at least one water-miscible organic solvent in an amount sufficient to co-precipitate iron sucrose complex and sucrose; and
(h) collecting the co-precipitate formed in step (g).
2. A process according to claim 1 , further comprising the step of drying the co-precipitate.
3. A process according to claim 1 , wherein the ratio of purified iron sucrose complex to aqueous sucrose solution is in the range from about 1:0.5 to about 1:10 by weight.
4. A process according to claim 1 , wherein the aqueous sucrose solution has a concentration in the range from about 10% to about 50% weight/volume.
5. A process according to claim 1 , wherein the water-miscible organic solvent is selected from the group consisting of methanol, ethanol, acetone, tetrahydrofuran, dioxane, acetonitrile and mixtures thereof.
6. A process of preparing an aqueous solution of sucrose and iron sucrose complex, comprising the steps of:
(a) reacting ferric hydroxide and sucrose in an aqueous reaction mixture comprising sodium ions, at a selected molar ratio of sucrose to ferric hydroxide, for a selected time interval, at a selected temperature, and at a pH in the range from about 6.5 to about 13;
(b) isolating iron sucrose complex from the reaction mixture;
(c) dissolving the isolated iron sucrose complex in an aqueous solvent to form a solution;
(d) forming a mixture by adding to the solution formed in step (c) at least one water-miscible organic solvent in an amount sufficient to precipitate iron sucrose complex, from the solution;
(e) collecting the purified iron sucrose complex from the mixture formed in step (d);
(f) dissolving the purified iron sucrose complex product formed in step (e) in an aqueous sucrose solution;
(g) forming a mixture by adding to the iron sucrose complex solution formed in step (f) at least one water-miscible organic solvent in an amount sufficient to co-precipitate iron sucrose complex and sucrose;
(h) collecting the co-precipitate formed in step (g); and
(i) dissolving the collected co-precipitate in water.
7. A process of preparing a co-precipitate comprising iron sucrose complex and sucrose, the process comprising the steps of:
(a) providing a reaction mixture comprising a ferric salt dissolved in an aqueous medium;
(b) adding to the reaction mixture a first base in an amount in the range from about 1 to about 2 equivalents based on the amount of ferric salt;
(c) allowing the reaction mixture to equilibrate for a time interval in the range from about 10 to about 60 minutes;
(d) forming a mixture by adding sucrose to the equilibrated reaction mixture of step (c) in a selected molar ratio based on the ferric salt;
(e) heating the mixture formed in step (d) to a first temperature;
(f) forming a mixture by adding to the heated mixture formed in step (e) a second base in an amount sufficient to adjust the pH of the reaction mixture to a selected pH;
(g) heating the mixture formed in step (f) at a second temperature for a selected time interval;
(h) after the selected time interval, cooling the reaction mixture to a temperature in the range of from about 20° to about 30° C.; and
(i) isolating the co-precipitate from the cooled reaction mixture.
8. A process according to claim 7 , wherein selected molar ratio of sucrose to the ferric salt is in the range from about 2:1 to about 50:1.
9. A process according to claim 7 , wherein the step of isolating the co-precipitate comprises the steps of:
(a) forming a mixture by adding to the cooled reaction mixture at least one water-miscible organic solvent in an amount sufficient to co-precipitate iron sucrose complex and sucrose;
(b) collecting the co-precipitate formed in step (a); and optionally
(c) drying the collected co-precipitate.
10. A process according to claim 9 , wherein the cooled reaction mixture is optionally concentrated prior to the addition of the water-miscible organic solvent.
11. A process according to claim 7 , wherein the first temperature is a temperature in the range of from about 60° C. to about 90° C.
12. A process according to claim 7 , wherein the second temperature is a temperature in the range of from about 75° C. to about 120° C.
13. A process according to claim 7 , wherein the first and second bases are selected from the group consisting of alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, water soluble amines, and combinations thereof.