PHARMACEUTICAL GRADE FERRIC CITRATE AND METHOD FOR ITS
PRODUCTION
Field of the invention
The present invention relates to a coordination complex of ferric citrate and ferric containing
compounds, a method for production and medical use thereof.
Background and the prior art
Coordination complexes of ferric citrate and ferric containing compounds are inorganic, ironbased
compounds that have the capacity to bind to phosphates and form non-absorbable
complexes with phosphates. Such ferric compounds are useful for the treatment of
hyperphosphatemia and metabolic acidosis.
Studies on the efficacy and tolerability of ferric compounds such as ferric citrate, ferric
ammonium citrate and ferric chloride as phosphate binders have been reported in various
publications.
Prior studies (US5753706, J Am Soc Neprol, Vol.10, Pagesl274-1280, 1999) indicate that
Ferric compounds are known to bind to dietary phosphate and dramatically alter phosphate
metabolism.
Method of preparation of pharmaceutical grade ferric citrate having BET active surface area
of at least 16 m /gm is mentioned in US7767851 & US8093423 for treating disorders related
to hypophosphatemia.
So there exists a scope to develop an improved process that yields pharmaceutical grade
ferric citrate having BET active surface area in the range of 1-15 m7 gm.
Object of the invention
Objective of the present invention is to provide a pharmaceutical grade ferric citrate.
A second objective of the present invention is to provide pharmaceutical grade ferric citrate
having BET active surface area in the range of 1- 15 m /gm.
A third objective of the present invention is to provide a pharmaceutical composition
comprising a therapeutically effective amount of pharmaceutical grade ferric citrate and a
pharmaceutically acceptable carrier, excipient or diluent.
Another objective of the present invention is to provide a pharmaceutical grade ferric citrate
for the treatment and/or prevention of hyperphosphatemia and metabolic acidosis.
Another objective of the present invention is to provide an improved process for preparation
of the said pharmaceutical grade ferric citrate.
Description of the invention
A process for the preparation of pharmaceutical grade ferric citrate of the present invention
comprises of combining ferric and citrate ions in water and precipitating the ferric citrate
from the aqueous solution by using an organic solvent. The organic solvent comprises
alcohols such as methanol, ethanol, isopropanol, etc.; ethers such as tetrahydrofuran etc.; and
ketones such as acetone etc.; or a mixture thereof.
The present invention does not involve formation of ferric hydroxide, thereby avoids the
cumbersome separation of the same. Said process also avoids formation of impurities due to
exposure of ferric hydroxide to air during unit operations.
According to the present invention, the source of ferric ion is ferric chloride, ferric nitrate or
ferric sulfate; preferably hydrated ferric chloride salt and source of citrate ion is salt of citric
acid; more preferably trisodiumcitrate dihydrate.
One of the methods for manufacturing pharmaceutical grade ferric citrate in accordance with
the present invention comprises of mixing the source of citrate ion and ferric chloride
hexahydrate in water to obtain a solution and precipitating the desired pharmaceutical grade
ferric citrate by adding alcohol to the solution.
According to the present invention, the pharmaceutical grade ferric citrate of the present
invention is synthesized by adding citric acid monohydrate to aqueous solution of sodium
hydroxide followed by addition of ferric chloride hexahydrate and precipitating the ferric
citrate by gradual addition of methanol.
Alternatively, the pharmaceutical grade ferric citrate of the present invention is synthesized
by mixing of aqueous solution of trisodiumcitrate dihydrate with ferric chloride hexahydrate
and precipitating the ferric citrate by gradual addition of methanol.
According to the present invention, the reaction is carried out at a temperature between about
50 and about 100 °C, preferably between about 55 and about 90 °C.
According to the present invention, the obtained precipitate of ferric citrate is isolated, for
example by decantation, filtration, centrifugation, preferably by filtration, and then washed
with alcohol. The alcohol comprises methanol, ethanol, isopropanol, etc.; preferably
methanol.
According to the present invention, the product is dried under vacuum at about 50 to 100 °C,
preferably at about 75 to 95 °C for 5-24 hours, preferably for 5-18 hours, or more preferably
for 10-12 hours.
The pharmaceutical grade ferric citrate is optionally purified by using alcohol to improve
colour and texture.
The pharmaceutical grade ferric citrate according to the invention is useful in the treatment
and/or prevention of hyperphosphatemia and metabolic acidosis in humans.
This invention further relates to a composition for treating hyperphosphatemia and metabolic
acidosis in the humans, comprising an effective amount of the pharmaceutical grade ferric
citrate.
A pharmaceutical composition, for the treatment of hyperphosphatemia and metabolic
acidosis, comprising the ferric citrate of the present invention can be administered by orally.
The present invention also provides use of pharmaceutical grade ferric citrate of the present
invention in the manufacture of a medicament for treatment of hyperphosphatemia and
metabolic acidosis.
A pharmaceutical formulation can be adequately provided in unit dosage form and it can be
prepared by any method well-known in the field of pharmaceutical technology. Such method
comprises a step of mixing pharmaceutical grade ferric citrate of the present invention with at
least one auxiliary ingredient (e.g., a carrier).
Examples of forms of pharmaceutical formulations (dosage forms) include, but are not
limited to, oral formulations, such as tablets, pills, capsules, granules, powders, and
suspending agents.
Present invention is further illustrated with the following non-limiting examples.
Example-1: Preparation of Ferric Citrate
To a 1.0L four-neck round bottom flask, 150 gm trisodiumcitrate dihydrate and 172 ml
purified water were added. The reaction mass was stirred for 30 minutes to get clear solution.
138 gm ferric chloride hexahydrate was added to the solution and further stirred for 1 hour at
80-90°C. The reaction mass was cooled to 30°C and passed through filter paper. 1230 ml
methanol was slowly added into the filtrate and stirred for 1 hour. Precipitated product was
filtered and washed with 120 ml methanol. The product was dried under reduced pressure in
vacuum oven at 90°C.
Yield: 78% molar yield
Description: light yellow to brown colored powder
BET Active Specific Surface Area: 1.7 m /gm
Example-2: Preparation of Ferric Citrate
To a 2.0 L four-neck round bottom flask, 200 ml purified water and 44.4 gm sodium
hydroxide were added and stirred to make a solution. To the reaction mass, 77.7 gm citric
acid monohydrate was added and stirred for 30 minutes. Thereafter, 100 gm ferric chloride
hexahydrate was added to the reaction mass and further stirred fori hour at 50-55°C. The
reaction mass was cooled to 25°C and subsequently, 1200 ml of methanol was slowly added
to the reaction mass and stirred for 1 hour. Precipitated product was filtered and washed with
100 ml of methanol. The wet product was dried under reduced pressure.
Yield: 85% molar yield
Description: dark brown colored to red colored powder
BET Active Specific Surface Area: 11.7 m /gm
Example-3: Purification of Ferric Citrate:
To a 2.0 L four-neck round bottom flask, 150 ml of purified water and 100 gm ferric citrate
was added under stirring at room temperature and the reaction mixture was stirred for 1 hour
to get clear solution. Thereafter, 1000 ml of methanol was added to the reaction mass and
further stirred for 1 hour at room temperature. Precipitated product was filtered and
with 100 ml of methanol. The wet product was dried under reduced pressure.
Yield: 80% molar yield
Description: light yellow to brown colored powder
BET Active Specific Surface Area: 1.0 m /gm
CLAIMS
1. Ferric citrate having a BET active surface area in the range of 1-15 m7 gm.
2. A method for preparing pharmaceutical grade ferric citrate, comprising:
a. mixing source of citrate ion with source of ferric ion in aqueous solution;
b. adding alcohol to the above solution; and
c. filtering the mixture to obtain pharmaceutical grade ferric citrate.
3. A method for preparing the ferric citrate of claim 2, wherein the source citric ion is
selected from citric acid or trisodium citrate.
4. A method for preparing the ferric citrate of claim 2, wherein the source ferric ion is
selected from ferric chloride, ferric nitrate or ferric sulphate.
5. A method for preparing the ferric citrate of claim 4, wherein the source ferric ion is
ferric chloride hexahydrate.
6. A method for preparing the ferric citrate of claim 2, wherein the alcohol is selected
from methanol, ethanol or isopropyl alcohol.
7. A pharmaceutical composition comprising ferric citrate according to claim 1, having a
BET active surface area in the range of 1-15 m /gm and a suitable carrier.
8. The pharmaceutical composition of claim 7, wherein said composition is in an orally
administrable form.
9. The pharmaceutical composition of claim 8, wherein the orally administrable form is
selected from a tablet, a pill, a capsule, a granule, a powder or a suspension.
10. The pharmaceutical composition of claim 9, wherein the orally administrable form is a
tablet.
11. A method of treating hyperphosphatemia comprising administering ferric citrate
according to claim 1, having a BET active surface area in the range of 1-15 m /gm.
12. A method of treating metabolic acidosis comprising administering ferric
citrateaccording to claim 1, having a BET active surface area in the range of 1-15
m2/gm .