A MANUFACTURING PROCESS FOR AN IRON CONTAINING ADSORBENT
FIELD OF THE INVENTION
The present invention relates to an industrially viable process for the manufacturing of an
iron containing phosphate adsorbent, uses thereof and pharmaceutical compositions
containing it.
BACKGROUND OF THE INVENTION
Hyperphosphatemia is associated with significant increase in morbidity and mortality, and
may induce severe complications, such as hypocalcemia, decreasing of vitamin-D production
and metastatic calcification. Hyperphosphatemia is also contributing to the increased
incidence of cardiovascular disease among dialysis-dependent patients.
The phosphate binding capacity of iron oxide hydroxides is known in the art. The possible
medical application of iron hydroxides and iron oxide hydroxides as phosphate adsorbents is
also described.
US 4,970,079 patent discloses a method of controlling serum phosphate level in patients by
iron oxy-hydroxides which bind to ingested phosphate. US 5,514,281 patent also discloses a
process for the selective elimination of inorganic phosphate from body fluids by using a
polynuclear metal oxyhydroxide preferably iron (III) oxyhydroxide.
US 6,174,442 patent describes an adsorbent for phosphate and a process for the preparation
thereof, which contains polynuclear -iron hydroxide stabilized by carbohydrates and/or
humic acid.
In order to obtain an iron-based compound which can be used as a pharmaceutical, it is
necessary to have an iron-based compound which is stable. It is known that iron oxidehydroxide
is not a stable compound with time ageing occurs. Ageing usually not only
involves crystallization but also particle enlargement. Such ageing may alter the phosphate
binding of an iron oxide-hydroxide based phosphate adsorbent.
Accordingly, there exists a need for a process for manufacturing of an iron containing
phosphate adsorbent. The process needs to be scalable, robust and consistently producing an
iron containing phosphate adsorbent of the required pharmaceutical grade.
OBJECT OF THE INVENTION
It is an object of the present invention to provide a process for the manufacture of an iron
containing phosphate adsorbent, which is suitable for the preparation of a pharmaceutical
composition for the treatment of hyperphosphatemia.
It is another object of the present invention to provide an industrial viable process for the
manufacturing of an iron containing phosphate adsorbent.
It is yet another object of the present invention to provide an iron containing phosphate
adsorbent, wherein the said iron containing phosphate adsorbent comprises particles having
90% distribution in the range of 20 to 80 .
It is yet another object of the present invention to provide an iron containing phosphate
adsorbent, wherein the said iron containing phosphate adsorbent comprises particles having a
BET surface area of 0.1 to 50 m2/gm; preferably, 0.5 to 25 m2/gm; more preferably, 1 to 15
It is yet another object of the present invention to provide a pharmaceutical composition
comprising an effective amount of an iron containing phosphate adsorbent which is obtained
by following the process of the present invention.
BRIEF DESCRIPTION OF ACCOMPANYING FIGURE
FIG. 1: PXRD pattern of the iron containing phosphate adsorbent according to the present
invention.
FIG. 2: Schematic diagram outlining the method of manufacturing the iron containing
phosphate adsorbent according to the present invention.
DESCRIPTION OF THE INVENTION
The present invention relates to a process for the manufacture of an iron containing
phosphate adsorbent, pharmaceutical compositions containing it and uses thereof.
The present invention further relates to an industrially viable process for the manufacturing
of an iron containing phosphate adsorbent, pharmaceutical compositions containing it and
uses thereof.
An embodiment of the invention provides a manufacturing and quality control
process/analysis for making a pharmaceutical grade iron containing phosphate adsorbent.
The process of the present invention can be implemented at large scale to produce multikilogram
batches of pharmaceutical grade iron containing phosphate adsorbent.
The present invention further relates to an iron containing phosphate adsorbent, wherein the
said iron containing phosphate adsorbent comprises particles having a BET (Brunauer-
Emmett-Teller) surface area of 0.1 to 50 m2/gm; preferably, 0.5 to 25 m2/gm; more
preferably, 1 to 15 m /gm.
The analysis of active surface area is based on BET theory which describes the phenomenon
of mass and energy interaction and phase changes during gas adsorption onto solid surfaces
and in pore spaces. In BET active surface area measurement, the volume of a monolayer of
gas is determined which allows the surface area of the sample to be determined using the area
occupied by a single layer of adsorbed gas molecule.
The present invention further relates to an iron containing phosphate adsorbent, having
Particle Size Distribution (PSD) d(0.9) in the range of 20 to 80 .
As used herein, "Particle Size Distribution (PSD)" means the cumulative volume size
distribution of equivalent spherical diameters as determined by laser diffraction in Malvern
Master Sizer equipment or its equivalent.
The important characteristic of the PSD is d(0.9), which is the size, in microns, below which
90% of the particles by volume are found, Thus, for example, a d(0.9) of less than 80 microns
means that 90 volume-percent of the particles in a composition have a diameter less than 80
microns.
Preferably, the iron containing phosphate adsorbent is sucroferric oxyhydroxide which is a
mixture of polynuclear iron (III) oxyhydroxide or polynuclear iron (III) hydroxide stabilized
by sucrose and starches.
As is known to a person skilled in the art, "phosphate adsorbents" are compounds or
compositions that are capable to act as an adsorbent for phosphate from aqueous medium, for
example from aqueous solutions, in particular from physiological aqueous solutions. They
are particularly suitable as an adsorbent for inorganic phosphate and phosphate bonded to
foodstuffs, especially in a preparation for oral application for the prophylaxis and treatment
of hyperphosphatemia conditions, in particular in patients with chronic renal insufficiency,
which have a pathologically increased serum phosphate level.
The phosphate adsorbent, e.g. sucroferric oxyhydroxide, may be combined with one or more
pharmaceutically acceptable carriers and, optionally, one or more other conventional
pharmaceutical adjuvants and administered orally, in the form of tablets, chewable tablets,
mini-tablets (micro-tablets), granules, capsules, caplets, granules, powders etc. The
compositions may be prepared by conventional means or enabling technologies.
The present invention relates to a process for the manufacturing of an iron containing
phosphate adsorbent, which comprises the steps of:
(1) Mixing an aqueous solution of an iron (III) salt with an aqueous solution of a base
optionally in the presence of solvent- 1, to form a precipitate of ferric hydroxide;
(2) Isolating the precipitate and optionally washing with water;
(3) Slurrying the precipitate in water to obtain a suspension;
(4) Adding a carbohydrate and/or humic acid to the suspension;
(5) Adding solvent-2 to the suspension to obtain an iron containing phosphate adsorbent; and
(6) Isolating the iron containing phosphate adsorbent.
According to the present invention, the iron (III) salt comprises of iron (III) chloride, iron
(III) nitrate or iron (III) sulfate; preferably the iron salt comprises of iron (III) chloride, e.g.
solid iron (III) chloride hexahydrate.
As used herein, the term "iron (III) salt" also includes iron (II) salts. In a preferred aspect, the
presence of iron (II) salt in iron (III) salt is up to 10% w/w; more preferably, up to 5% w/w.
According to the present invention, the aqueous solution of iron (III) salt may be in particular
a solution of iron (III) salt, as herein above defined, in water.
According to the present invention, the base is a hydroxide ora carbonate of an alkali or
alkaline earth metal. Alkali carbonates, alkali bicarbonates and alkali metal hydroxides (e.g.
of sodium) are preferred as bases. In particular, the base is LiOH, KOH, NaOH, NaHC0 3
Na2C0 3, Ca(OH)2, Mg(OH)2, Li2C0 3, K2C0 3, CaC0 3 or MgC0 3; preferably Na2C0 3.
As used herein, the term "ferric hydroxide" includes a solid, a semi-solid or a suspension
comprising of ferric hydroxide, ferric oxyhydroxide, ferric oxide hydroxide, ferric oxide or
mixture thereof.
According to the present invention, the aqueous base may comprise of an aqueous solution
containing a base as hereinabove defined, in water.
According to the present invention, the amount of the base is used in order to obtain the
desired pH to produce the colloidal suspension or precipitate of ferric hydroxide, e.g. to
adjust the pH of the solution resulting from the mixing the aqueous solution of the base to a
pH between about 3 and about 10, preferably between about 6 and about 8, more preferably
about 7.
According to the present invention, a water miscible solvent- 1 may be optionally added in the
step-1, such as straight or branched chain alcohols, ketones or ethers. Preferably, such an
alcohol is methanol, ethanol, isopropanol, n-propanol or a combination thereof. In most
preferred aspect, such alcohol is ethanol. Preferably, such a ketone is acetone. Preferably,
such an ether is tetrahydrofuran, 1,4-dioxane or a combination thereof.
According to the present invention, the reaction, in particular the step (1), is preferably done
at a temperature between about 1°C and about 45°C, preferably between about 2°C and about
25°C, more preferably between 5 to 15°C.
According to the present invention, in the step (2) the obtained ferric hydroxide precipitate is
isolated by techniques known in the art, e.g. by siphoning, decantation, filtration,
centrifugation, and then washed with water. The precipitate is washed once or several times,
preferably three times with water.
According to the present invention, the product is then suspended in water. A minimum
amount of water is needed so that the suspension is processed. For example the ratio amount
of water/phosphate adsorbent is from about 0.4 to about 5, preferably 0.5 to 3, more
preferably 0.5 to 2.
According to the present invention, the carbohydrate is a soluble and/or an insoluble
carbohydrate.
According to the present invention, the soluble carbohydrate is a glucose derivative. Glucose
derivatives are agarose, dextran, dextrin, dextran derivatives, cellulose, cellulose derivatives,
sucrose, maltose, lactose, mannitol or mixture thereof. Preferred glucose derivatives are
sucrose, maltodextrin or a mixture thereof. Most preferred glucose derivative is sucrose.
According to the present invention, the amount of soluble carbohydrate, e.g. glucose
derivative, added in step (4) is about 5 to about 40 weight%, preferably about 10 to about 35
weight%, based on the weight of the phosphate adsorbent. Preferably about 10 to about 35
weight% sucrose or about 15 to about 30 weights% sucrose is used.
According to the present invention, the insoluble carbohydrate is starch. Starch is corn starch,
wheat starch, rice starch, maize starch, pea starch, potato starch, pregelatinized maize starch
or mixture thereof. Preferably starch is a mixture of potato starch and pregelatinized maize
starch.
In the step (5), solvent-2 is added. In a preferred aspect of the present invention, the solvent
is straight or branched chain alcohols, ketones, ethers or a mixture thereof. In another
preferred aspect, such alcohol is methanol, ethanol, isopropanol, n-propanol or a mixture
thereof. In another preferred aspect, such ketone is acetone. In another preferred aspect, such
ether is tetrahydrofuran, 1,4-dioxane ora mixture thereof.
According to the present invention, the step (6) comprises of isolating the phosphate
adsorbent. Such isolation is carried out using techniques known in the art. In a preferred
aspect of the present invention, the isolation is carried out with filtration, centrifugation or
spray drying technique.
Optionally, the product is dried under vacuum at about 20 to 50°C, preferably at about 25 to
35°C for 5-24 hours, preferably for 5-18 hours, or more preferably for 10-12 hours.
According to the present invention, there is provided an industrially viable process for
manufacturing an iron containing phosphate adsorbent having high phosphate binding
capacity in form of a dry powder.
The iron containing phosphate adsorbent obtained by the process of the present invention has
a BET surface area of 0.1 to 50 m27gm; preferably, 0.5 to 25 m2 gm; more preferably, 1 to 15
m /gm.
The iron containing phosphate adsorbent obtained by the process of the present invention has
a Particle Size Distribution (PSD) d(0.9) in the range of 20 to 80 .
The iron containing phosphate adsorbent obtained by the process of the present invention has
x-ray amorphous.
Furthermore a formulation step can be performed following step (6). For example mixing,
granulating, encapsulating and/or tableting the phosphate adsorbent may be done, with
adequate excipients if necessary.
According to the present invention, pharmaceutical composition of the invention refers to
pharmaceutical composition containing the iron containing phosphate adsorbent.
The iron containing phosphate adsorbent according to the invention is, therefore, useful in the
treatment and/or prevention of hyperphosphatemia, hypercalcemia, hyperparathyroidism
reduction, in cardiovascular morbidity and mortality, renal osteodystrophy, calciphylaxis and
soft tissue calcifications. In particular the iron containing phosphate adsorbent according to
the present invention is suitable for the treatment and/or prevention of hyperphosphatemia in
humans.
The phosphate adsorbent of the present invention and pharmaceutical composition containing
it are more particularly useful in patients with hyperphosphatemia, e.g. for dialysis-dependent
patients, e.g. hemodialysis, or patients suffering from advanced chronic kidney diseases
(CKD), chronic renal failure, chronic renal insufficiency, end-stage renal disease.
In another embodiment of the invention, the phosphate adsorbent of the invention and
pharmaceutical compositions containing it, are also useful for selectively removing inorganic
phosphate or eliminating inorganic phosphate from dialysis fluids, whole blood or plasma;
e.g. in patients on dialysis, e.g. on chronic hemodialysis, by administering to said subject an
effective amount of the iron containing phosphate adsorbent according to the present
invention.
Pharmaceutical compositions according to the present invention may be formulated in any
conventional form, preferably or dosage forms, preferred formulations are powder, granulate,
tablet, for example dispersible tablet. Such pharmaceutical composition can be prepared by
the methods known in the literature.
Examples
In examples which are intended to illustrate embodiments of the invention but which are not
intended to limit the scope of the invention:
) Method of Making an Iron Containing Phosphate Adsorbent
To a solution of 1.96 kg sodium carbonate dissolved in 12.5 liter water, solution of 2.5 kg
iron (III) chloride hexahydrate dissolved in 17.5 liter water was added at a temperature of 5 -
10°C. The resulting mixture was stirred for 90 to 120 minutes at 5 - 10°C. (25.0x3) liter water
was added to the reaction mass and raised the temperature at 15 - 20°C with stirring. Stopped
the stirring, settled precipitate and the supernatant water was removed. The precipitate was
filtered and washed with 1.25 liter water. A suspension of the precipitate was prepared in
water. To this, 875.0 gm sucrose and 695.0 gm potato starch were added and stirred for 120
minutes at 25 - 35°C. Cooled the reaction mass at 10 - 15°C and stirred for 90 to 120 minutes.
25.0 liters cold acetone was added to the reaction mass at 10 - 15°C and stirred for 90 to 120
minutes. The final product was filtered and washed with 1.25 liter cold acetone and further
dried under vacuum at 30-35°C.
Yield: 2.08 kg
) Large-scale Method of Making an Iron Containing Phosphate Adsorbent
An aqueous solution of sodium carbonate and an aqueous solution of iron (III) chloride
hexahydrate were mixed at a temperature of 5 - 10°C, optionally in the presence of solvent- 1.
A volume of aqueous solution of sodium carbonate necessary to maintain the pH at about 7.0
to form a colloidal suspension of ferric hydroxide. The resulting mixture was stirred for 90 to
120 minutes at 5 - 10°C. Water was added to the reaction mass with stirring. Stopped the
stirring, settled precipitated product and the water was decanted or siphoned. The precipitated
product was further filtered and washed with using water. Suspension of the precipitated
product was prepared in the water. Subsequently, sucrose and starch were added in to the
suspension and stirred for 120 minutes at 25 - 35°C. Cooled the reaction mixture at 10 - 15°C
and stirred for 90 to 120 minutes. Solvent-2 was added to the reaction mixture at 10 - 15°C
and stirred for 90 to 120 minutes. The product was filtered and washed with the solvent-2 and
further dried under vacuum at 30-35°C.
Few illustrative examples provided in Table- 1, wherein the iron containing phosphate
adsorbents were prepared according to the process of example-2 using the respective
combination of Solvent- 1 and Solvent-2 as given in the table:
Table-1
3) Physical Properties of an Iron Containing Phosphate Adsorbents prepared as per above
example-2.
> BET active Surface Area:
• Instrument : Surface area analyzer
• Condition : Surface area (m /gm) at N2.P/P0 = 10%
Table-2
> Phosphate Binding Capacity at pH 3.0:
• Method : Ion Chromatography
Instrument : Metrohm IC equipped with pump, Injector,
conductivity detector and recorder.
Column Dionex Ion Pac AS-1 1 (4.0 x 250mm), 13
Guard column Dionex Ion Pac AG-1 1 (4.0 x 50mm), 13
Buffer preparation Weigh accurately about 2.1 18g of Sodium carbonate
and 180mg of Sodium hydroxide in 1700mL water.
Mobile phase preparation : Buffer and acetonitrile (1700:300).
Results: Phosphate binding of an iron containing phosphate adsorbents obtained by
following the process of the present invention found in the range of 30 mg/gm to 60 mg/gm.
Particle Size Distribution:
Instrument Model : Malvern Mastersizer 2000 Particle size analyzer
Sampling Unit : Hydro 2000S
Analysis Model : General Purpose
Dispersant : 0.1% Span 85 in n-Hexane
Dispersant RI : 1.380
Stirrer Speed : 2200 RPM
Absorption : 1
Particle RI : 1.5
Obscuration : 10% to 20%
Sample Measurement time : 12 seconds
Background Measurement time : 12 seconds
Table-3
Particle size distribution
Example no.
d(0.9) ()
3d 43.67
3e 65.37
3f 37.75
CLAIMS
1. A process for the preparation of an iron containing phosphate adsorbent, which process
comprises the steps of:
(1) Mixing an aqueous solution of an iron (III) salt with an aqueous solution of a base
optionally in the presence of solvent- 1 to form a precipitate;
(2) Isolating the precipitate and optionally washing with water;
(3) Slurrying the precipitate in water to obtain a suspension;
(4) Adding a carbohydrate and/or humic acid to the suspension;
(5) Adding solvent-2 to the suspension to obtain an iron containing phosphate adsorbent;
and
(6) Isolating the iron containing phosphate adsorbent.
2. The process for the preparation of an iron containing phosphate adsorbent of claim- 1,
wherein the iron (III) salt is iron (III) chloride, iron (III) nitrate or iron (III) sulfate.
3. The process for the preparation of an iron containing phosphate adsorbent of claim-2,
wherein the iron (III) salt is an iron (III) chloride.
4. The process for the preparation of an iron containing phosphate adsorbent of claim- 1,
wherein the base is a hydroxide or a carbonate of alkali or alkaline earth metals.
5. The process for the preparation of an iron containing phosphate adsorbent of claim-4,
wherein the base is selected from LiOH, KOH, NaOH, NaHC0 3 Na2C0 3, Ca(OH)2,
Mg(OH)2, Li2C0 3, K2C0 3, CaC0 3, MgC0 3 and a mixture thereof.
6. The process for the preparation of an iron containing phosphate adsorbent of claim- 1,
wherein the solvent- 1 is selected from methanol, ethanol, isopropanol, n-propanol,
butanol and a combination thereof.
7. The process for the preparation of an iron containing phosphate adsorbent of claim- 1,
wherein the carbohydrate is a soluble carbohydrate or an insoluble carbohydrate.
8. The process for the preparation of an iron containing phosphate adsorbent of claim- 1,
wherein the solvent-2 is selected from an alcohol, ketone, ether, ester and a mixture
thereof.
9. An iron containing phosphate adsorbent having 90% of the particle by volume in the
range of 20to 80.
10. An iron containing phosphate adsorbent having a BET active surface area less than 15
11. A pharmaceutical composition comprising an iron containing phosphate adsorbent
according to claim-9, wherein 90% of the particle by volume are present in the range of
20 to 80 and a suitable carrier.
12. A pharmaceutical composition comprising an iron containing phosphate adsorbents
according to claim-10, having a BET active surface area less than 15 m /gm and a
suitable carrier.