FIELD OF THE INVENTION The present invention relates to novel, consistently reproducible and industrially advantageous processes for the preparation of iron(III)-based phosphate adsorbent Sucroferric oxyhydroxide. Sucroferric oxyhydroxide comprises a polynuclear iron(III)-5 oxyhydroxide core that is stabilized with a carbohydrate shell composed of sucrose and starch. The carbohydrate shell stabilizes the iron(III)-oxyhydroxide core to preserve the phosphate adsorption capacity.
BACKGROUND OF THE INVENTION ' Phosphorus is critical for bone mineralization, cellular structure, genetic coding,
10 and energy metabolism. Phosphorus is present in nearly all foods, and GI absorption of dietary forms is very efficient. Phosphorus homeostasis is normally maintained through several mechanisms (renal excretion, cellular release, hormonal control, etc). When the phosphorus load (from GI absorption, exogenous administration, or cellular release) exceeds renal excretion and tissue uptake, hyperphosphatemia occurs.
15 Hyperphosphatemia is associated with significant increase in morbidity and
mortality, and may induce severe complications, such as hypocalcemia, decreasing of vitamin D production, metastatic calcification. Hyperphosphatemia is also contributing to the increased incidence of cardiovascular disease among dialysis-dependent patients, and can result in bone pathology.
20 At least 70% of patients with renal insufficiency or renal failure show
hyperphosphatemia. In many cases, restricting intake of dietary phosphorus is not sufficient to reduce serum phosphate levels into the normal range, and oral phosphate binders need to be taken.
Calcium and aluminum salts orally taken as treatment for hyperphosphatemia are
25 known. But there are concerns regarding their long-term safety. Magnesium-containing • phosphate binders have been used for treatment of hyperphosphatemia. However, such binders have been associated with hypermagnesemia, even with the use of a low magnesium dialysate.
U.S. Patent No. 6,174,442 (hereinafter referred to as the US'442 patent) discloses
30 an adsorbent for phosphate from aqueous medium, comprising polynuclear beta-iron hydroxide stabilized by at least one member selected from the group consisting of carbohydrates and humic acid, which is later named as Sucroferric oxyhydroxide.
According to the US'442 patent, the adsorbent is prepared by a process, comprising:
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mixing an aqueous solution of a base with an aqueous solution of an iron (III) salt containing chloride ions with formation of a suspension with a pH of 3 to 10; allowing the suspension to stand; washing a precipitate obtained with water; suspending the still moist precipitate in water with formation of a suspension with an iron content of up to 6% by weight; and adding at least one member selected from the group consisting of one or more carbohydrates and humic acid in an amount such that a solid obtained contains.a maximum of 40% by weight of iron.
However, the processes for preparation of the iron(III)-based phosphate adsorbent as described in the US'442 patent suffer from several disadvantages such as lack of reproducibility, lack of uniformity, poor product yield and poor product quality. The main drawback of the processes described in the US'442 patent is that the resulting iron(III)-based phosphate adsorbent material is not a uniform solid since lump formation is observed.
Sucroferric oxyhydroxide is approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the control of serum phosphorus levels in patients with chronic kidney disease (CKD) on dialysis. The finished product is sold under the trade name Velphoro® and it is orally administered as chewabte tablet (strength: 2500 mg) containing 500 mg iron as polynuclear iron(III)-oxyhydroxide, sucrose, and starches, also known as Sucroferric oxyhydroxide as active substance. The chemical name of the active substance (Sucroferric oxyhydroxide) is a mixture of polynuclear iron(III)-oxyhydroxide, sucrose, and starches, and its representative model structural formula is reported in the European Public Assessment Report No. EMA/567960/2014 dated June 26, 2014. Sucroferric oxyhydroxide comprises a polynuclear iron(III)-oxyhydroxide core that is stabilized with a carbohydrate shell composed of sucrose and starch. The carbohydrate shell stabilizes the iron(III)-oxyhydroxide core to preserve the phosphate adsorption capacity. Dietary phosphate binds strongly to sucroferric oxyhydroxide in the gastrointestinal (GI) tract. The bound phosphate is eliminated in the faeces and thereby prevented from absorption into the blood. As a consequence of the decreased dietary phosphate absorption, serum phosphorus concentrations are reduced.
U.S. Patent No. 4,970,079 (hereinafter referred to as the US'079 patent)
discloses a method of controlling serum phosphate levels in patients suffering from
hyperphosphatemia or patients predisposed to development of a hyperphosphatemic
Tcortdifion ByCcontac'firig {ingested, phosphate' with ahToxy-Sroh c6mpOutt 'selected from
3

the group consisting of iron oxides, iron oxyhydroxides, and iron hydroxides. Two iron oxide minerals, goethite and ferrihydrite, were evaluated for potential phosphate binding properties.
U.S. Patent No. 5,846,426 (hereinafter referred to as the US'426 patent) discloses 5 the use of an adsorbent material modified with polynuclear metal oxyhydroxides for the selective elimination of inorganic phosphate from liquids, in particular from body fluids containing protein such as whole blood, plasma, liquid contents of the intestine as well as from dialysis fluid. However, the use of the water-soluble iron dextrans and dextrins described in this patent have the disadvantage that they are resorbable.
10 Complexes which release only a little iron can be produced by the use of cross-linked polysaccharide carriers. The disadvantages of these complexes, which are based on alpha-iron hydroxides, are firstly the high cost of the cross-linked polysaccharide carriers which have to be used, and secondly their phosphate adsorption capacity, which is in need of improvement.
15 U.S. Patent Application Publication No. 2009/0169645A1 (hereinafter the
US'645 application) describes a process for the preparation of a phosphate adsorbent analogous to the process described in the US'442 patent using iron (III) sulfate or iron (III) nitrate solution instead of iron (III) chloride as a starting material.
U.S. Patent No. 8,252,310 (hereinafter referred to as the US'310 patent)
20 discloses an iron(III)-based phosphate adsorbent for the adsorption of phosphate, which has higher phosphate binding capacity than the phosphate adsorbents known in the art, e.g., at least 20% higher than the adsorbent described in U.S. Patent No. 6,174,442. According to the US'310 patent describes a process for preparing an iron(III)-based phosphate adsorbent comprising iron(III) oxide-hydroxide, starch and sucrose, said
25 process comprising: (i) reacting an aqueous solution of iron(III) salt with an aqueous base at a pH from between 6 and 10 to form a mixture in which an iron oxide hydroxide precipitate begins to form; (ii) adding starch to the mixture of step i) prior to complete formation of the iron oxide hydroxide precipitate; (iii) allowing complete formation of the iron oxide hydroxide precipitate to occur; (iv) isolating the precipitate
30 formed according to step (iii); (v) suspending the isolated precipitate from step (iv) in an aqueous solution; (vi) adding sucrose and optionally at least one excipient selected from a preservative and a binder; and (vii) fluidized spray drying the solution from step to (vi) to yield an iron(III)-based phosphate adsorbent as a dry powder. n \ urri, u c: \„. n c v-i v-i **„:. £. A - u z> ' /. d i. / i. -H - "• "•
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However, the processes for preparation of the iron(III)-based phosphate adsorbent as described in the US'310 patent suffer from several disadvantages such as lack of reproducibility, lack of uniformity, poor product yield, poor product quality, and involves the use of tedious and cumbersome spray drying technique for isolation of the 5 product at higher temperature (e.g., an inlet temperature of 140°C). Moreover, the spray drying technique used for isolation of the product is not advisable for scale-up operations since it leads to yield loss and the solvent contained in reaction mass is completely vaporized while spray drying and entered into the environment. The main drawback of the processes for the production iron(III)-based phosphate adsorbent
10 described in the prior art is that the processes involve the use of a spray drying technique at higher temperature conditions (e.g., an inlet temperature of 140°C) for isolation of the product. However, the iron(III)-based phosphate adsorbents are not stable at such higher temperature conditions and hence, they lose their phosphate binding capacity.
15 A need still remains for novel, improved, industrially advantageous and
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commercially viable processes of preparing iron(III)-based phosphate adsorbents with high yield, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation.
SUMMARY OF THE INVENTION
The object of the present application is to provide novel, consistently reproducible and industrially advantageous processes for the preparation of iron(III)-based phosphate adsorbent 'Sucroferric oxyhydroxide' with high yield and purity.
In one aspect, provided herein is an iron(III)-based phosphate adsorbent Sucroferric oxyhydroxide.
In another aspect, provided herein are novel, consistently reproducible and industrially advantageous processes for the preparation of Sucroferric oxyhydroxide with high yield and purity.
The Sucroferric oxyhydroxide obtained by the processes described herein has
Phosphate binding capacity of at least 90%, preferably greater than about 95%, more
preferably greater than about 97%; and most preferably greater than about 99% (as
measured by ICP-MS at pH 3.0). For example, Phosphate binding capacity of the
Sucroferric oxyhydroxide obtained by the processes disclosed herein is about 90% to
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about 99.99%, and most preferably about 97% to about 99.99% (as measured by ICP-MSatpH3.0).
In another aspect, provided herein is a pharmaceutical composition comprising Sucroferric oxyhydroxide made by the processes described herein, and one or more 5 pharmaceutically acceptable excipients.
In another aspect, encompassed herein is a process for preparing a pharmaceutical formulation comprising combining Sucroferric oxyhydroxide made by the processes described herein with one or more pharmaceutically acceptable
excipients.
10 In another aspect, the Sucroferric oxyhydroxide made by the processes
described herein for use in the pharmaceutical compositions, has a D5o particle size of
less than or equal to about 20 microns, specifically about 1 micron to about 20 microns,
and most specifically about 3 microns to about 15 microns.
In another aspect, the Sucroferric oxyhydroxide made by the processes 15 described herein for use in the pharmaceutical compositions, has a D90 particle size of
less than or equal to about 40 microns, specifically about 5 microns to about 30
microns, and most specifically about 10 microns to about 25 microns.
The processes for the preparation of Sucroferric oxyhydroxide has the following
advantages over the processes described in the prior art: 20 i) consistently produces the Sucroferric oxyhydroxide with high purity and quality;
ii) avoids the use of expensive and tedious isolation techniques such as spray drying;
iii) involves the use of easy work-up methods and simple isolation techniques, and produce the product with higher yields.
25 DETAILED DESCRIPTION OF THE INVENTION
According to one aspect of the present invention, there is provided a process for the preparation of iron(III)-based phosphate adsorbent 'Sucroferric oxyhydroxide', comprising:
a) combining an aqueous solution of ferric chloride with an aqueous solution of an 30 inorganic base to form a first suspension;
b) washing the first suspension obtained in step-(a) with water to obtain a wet cake;
c) adding ethanol to the wet cake obtained in step-(b) while stirring to form a second
suspension;
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d) adding sucrose and starch to the second suspension obtained in step-(c) while stirring to produce a reaction mass; and
e) isolating the Sucroferric oxyhydroxide from the reaction mass obtained in the step-(d).
5 Exemplary inorganic bases used in step-(a) include, but are not limited to,
hydroxides, bicarbonates and carbonates of alkali or alkaline earth metals. Specific inorganic bases are sodium hydroxide and sodium carbonate. A most specific inorganic base used in step-(a) is sodium carbonate.
Combining of the aqueous solution of ferric chloride with the aqueous solution
10 of sodium carbonate in step-(a) is done in a suitable order, for example, the aqueous
solution of ferric chloride is added to the aqueous sodium carbonate solution, or
alternatively, the aqueous sodium carbonate solution is added to the aqueous solution of
ferric chloride. The addition is, for example, carried out slowly or drop-wise or in one
portion or in more than one portion. The addition is specifically carried out slowly or
15 drop-wise while stirring at a temperature of below about 25°C for about 20 minutes to 1
hour, and most specifically at a temperature of about 10°C to about 20°C for about 30
minutes to about 45 minutes. After completion of the addition process, the resulting
mass is stirred at a temperature of about 25°C to about 35°C for about 1 hour to about 5
hours, and most specifically for about 2 hours to about 3 hours, to form the first
20 suspension.
The washing in step-(b) is carried out by stirring the first suspension with water at a temperature of about 25°C to about 35°C for about 15 minutes to .about 1 hour and then filtered to obtain the wet cake.
In one embodiment, the water washings in step-(b) may be performed at least 25 once, preferably twice or thrice in order to ensure complete removal of any extraneous matter or undesired salts.
The addition of ethanol solvent to the wet cake in step-(c) is carried out slowly or drop-wise or in one portion or in more than one portion. The addition is specifically carried out in one portion while stirring at a temperature of about 25°C to about 35°C. 30 After completion of the addition process, the resulting mass is stirred at a temperature of about 25°C to about 35°C for about 5 minutes to about 30 minutes, and most specifically for about 10 minutes, to form the second suspension.
The addition of sucrose and starch to the second suspension in step-(d) is ■AT-E ^T eai¥ild£ut each, subsequeMy^irloneiporti'onirjr in fhoreLtHan dhe^portTon. Specifically,
7

the sucrose and starch are added subsequently in one portion while stirring at a
temperature of about 25°C to about 35°C. After completion of the addition process, the
resulting mass is stirred at a temperature of about 25°C to about 35°C for about 1 hour
to about 3 hours.
5 In one embodiment, the sucrose in step-(d) is employed directly in the form of a
powder or alternatively in the form of an aqueous saturated solution. In a most
preferred embodiment, the sucrose in step-(d) is employed in the form of an aqueous
saturated solution.
The isolation of Sucroferric oxyhydroxide in step-(e) is carried out by the 10 methods such as filtration, filtration under vacuum, decantation, centrifugation or a
combination thereof.
According to another aspect of the present invention, there is provided a process
for the preparation of ,iron(III)-based phosphate adsorbent 'Sucroferric oxyhydroxide',
comprising: 15 a) combining an aqueous solution of ferric chloride with an aqueous solution of an
i
inorganic base to form a first suspension;
b) washing the first suspension obtained in step-(a) with water to obtain a wet cake;
c) adding aqueous saturated solution of sucrose to the wet cake obtained in step-(b) while stirring to form a second suspension;
20 d) adding ethanol to the second suspension obtained in step-(c) while stirring to form a third suspension;
e) adding starch to the third suspension obtained in step-(d) while stirring to produce
a reaction mass; and
f) isolating the Sucroferric oxyhydroxide from the reaction mass obtained in the step-
25 (e).
The process steps-(a) and (b) can be carried out by using the suitable reagents, methods, parameters and conditions as described hereinabove.
The addition of aqueous sucrose solution to the wet cake in step-(c) is carried
out in one portion or in more than one portion. Specifically, the sucrose solution is
30 added in one portion while stirring at a temperature of about 25°C to about 35°C. After
completion of the addition, the resulting mass is stirred at a temperature of about 25°C
to about 35°C for about 15 minutes to about 1 hour.
The addition of ethanol solvent to the second suspension in step-(d) is carried E M ^outVslo"wly^of d^op-wiSeSrin'oneT-porflon ur mSioW-thVn one portion.£l'rTe addition of
8

ethanol is specifically carried out in one portion while stirring at a temperature of about
25°C to about 35°C. After completion of the addition, the resulting mass is stirred at a
temperature of about 25°C to about 35°C for about 5 minutes to about 30 minutes, and
most specifically for about 10 minutes, to form the third suspension.
5 The addition of starch to the third suspension in step-(e) is carried out in one
portion or in more than one portion. Specifically, the starch is added in one portion while stirring at a temperature of about 25°C to about 35°C. After completion of the addition, the resulting mass is stirred at a temperature of about 25°C to about 35°C for about 1 hour to about 3 hours.
10 The isolation of Sucroferric oxyhydroxide in step-(f) is carried out by the
methods such as filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
According to another aspect of the present invention, there is provided a process for the preparation of iron(III)-based phosphate adsorbent 'Sucroferric oxyhydroxide',
15 comprising:
a) combining an aqueous solution of ferric chloride with an aqueous solution of an inorganic base to form a first suspension;
b) washing the first suspension obtained in step-(a) with water to obtain a wet cake;
c) adding aqueous saturated solution of sucrose to the wet cake obtained in step-(b)
20 while stirring to form a second suspension;
d) adding starch to the second suspension obtained in step-(c) while stirring to form a third suspension;
e) adding ethanol to the third suspension obtained in slep-(d) while stirring to form a reaction mass; and
25 f) isolating the Sucroferric oxyhydroxide from the reaction mass obtained in the step-
(e).
The process steps-(a) and (b) can be carried out by using the suitable reagents,
methods, parameters and conditions as described hereinabove.
The addition of aqueous sucrose solution to the wet cake in step-(c) is carried
30 out in one portion or in more than one portion. Specifically, the sucrose solution is
added in one portion while stirring at a temperature of about 25°C to about 35°C. After
completion of the addition, the resulting mass is stirred at a temperature of about 25°C
to about 35°C for about 5 minutes to about 1 hour, preferably for about 10 minutes to
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The addition of starch to the second suspension in step-(d) is carried out in one
portion or in more than one portion. Specifically, the starch is added in one portion
while stirring at a temperature of about 25°C to about 35°C. After completion of the
addition, the resulting mass is stirred at a temperature of about 25°C to about 35°C for
5 about 5 minutes to about 1 hour, preferably for about 10 minutes to about 15 minutes.
The addition of ethanol solvent to the third suspension in step-(e) is carried out slowly or drop-wise or in one portion or in more than one portion. The addition of ethanol is specifically carried out in one portion while stirring at a temperature of about 25°C to about 35°C. After completion of the addition, the resulting mass is stirred at a 10 temperature of about 25°C to about 35°C for about 30 minutes to about 5 hours, and most specifically for about 1 hour to about 3 hours.
The isolation of Sucroferric oxyhydroxide in step-(f) is carried out by the
methods such as filtration, filtration under vacuum, decantation, centrifugation or a
combination thereof
15 The iron(III)-based phosphate adsorbent 'Sucroferric oxyhydroxide' obtained
by the above processes may optionally be washed with ethanol, and further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is 20 within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines. Drying equipment selection is well within the ordinary skill in the art.
Preferably, the drying is carried out at under vacuum at a temperature of about 25°C to about 35°C for about 1 hour to about 10 hours, preferably for about 4 hours to 25 about 6 hours.
The Sucroferric oxyhydroxide obtained by the processes described herein has Phosphate binding capacity of at least 90%, preferably greater than about 95%, more preferably greater than about 97%; and most preferably greater than about 99% (as measured by ICP-MS at pH 3.0). For example, Phosphate binding capacity of the 30 Sucroferric oxyhydroxide obtained by the processes disclosed herein is about 90% to about 99.99%, and most preferably about 97% to about 99.99% (as measured by ICP-MS at pH 3.0).
In one embodiment, the Sucroferric oxyhydroxide made by the processes A-T E-M Tdescri^ed" fieftirtfof'usewuie pharmaceutical;cbrriposftions; has a$DS(£particle size of
10

less than or equal to about 20 microns, specifically about 1 micron to about 20 microns, and most specifically about 3 microns to about 15 microns.
In another embodiment, the Sucroferric oxyhydroxide made by the processes described herein for use in the pharmaceutical compositions, has a D90 particle size of 5 less than or equal to about 40 microns, specifically about 5 microns to about 30 . microns, and most specifically about 10 microns to about 25 microns.
According to another aspect, there is provided Sucroferric oxyhydroxide having
a D50 particle size of less than or equal to about 20 microns, specifically about 1 micron
to about 20 microns, and most specifically about 3 microns to about 15 microns.
10 The Sucroferric oxyhydroxide obtained by the processes disclosed herein is a
uniform powder, which has very good flow properties and is consistently reproducible,
and is found to be more stable. The Sucroferric oxyhydroxide obtained by the processes
disclosed herein exhibits properties making it suitable for formulating Sucroferric
oxyhydroxide.
15 Further encompassed herein is the use of the Sucroferric oxyhydroxide, made
by the processes disclosed herein, for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.
A specific pharmaceutical composition of Sucroferric oxyhydroxide is selected
from a solid dosage form and an oral suspension.
20 As used herein, the term "micron" or "urn" both are equivalent and refer to
"micrometer" which is lxlO-6 meter.
As used herein, "Particle Size Distribution (P.S.D)" means the cumulative
volume size distribution of equivalent spherical diameters as determined by laser
diffraction in Malvern Master Sizer 2000 equipment or its equivalent.
25 The important characteristics of the PSD is the D90 or D(0.90), which is the size,
in microns, below which 90% of the particles by volume are found, and the D50, which
is the size, in microns, below which 50% of the particles by volume are found. Thus, a
D50 or D(0.50) of less than 20 microns means that 50 volume-percent of the particles in
a composition have a diameter of less than 20 microns.
30 According to another aspect, there are provided pharmaceutical compositions
comprising Sucroferric oxyhydroxide prepared according to the processes disclosed herein and one or more pharmaceutical^ acceptable excipients.
According to another aspect, there is provided a process for preparing a
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11

according to processes disclosed herein, with one or more pharmaceutically acceptable
excipients.
Yet in another embodiment, pharmaceutical compositions comprise at least a therapeutically effective amount of Sucroferric oxyhydroxide made by the process
5 disclosed herein. Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, elixir, syrups, etc.
Pharmaceutical compositions according to the invention may be formulated in any conventional form, preferably oral dosage forms, e.g. powders, granules, granulates, capsules, sachets, bottles, tablets, dispersible tablets, film coated tablets,
10 uniquely coated tablets, syrups, suspensions, aqueous and non aqueous gel, swallowable gel, fast-dispersing dosage, chewable dosage forms, and the like.
Preferred formulations are powder, granulate, tablet, for example dispersible tablet. In a preferred embodiment of the invention, the pharmaceutical composition is prepared in the form of a powder or a granulated product, which is optionally filled into
15 powder containers such as bottle, capsule, sachet or stick pack.
The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents,
20 sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described herein below.
Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate,
25 crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide. INSTRUMENTAL DETAILS: Phosphate binding capacity test at pH 3.0 by ICP-MS (%):
30 Instrument Operational conditions:
ICP-MS system: Agilent 7900 Inductively Coupled Plasma Mass Spectrometry (ICP-MS) with Auto Sampler(G3286A) or equivalent; Name of the element: Phosphorus(P); Forward power : 1200-1600 W; Reflected power: < 20 W; Sample uptake time: 30 sec;
^ M T StaMiz^ kimei 40~ ^&?^ Spfc&M: 2 G3? $robe Crihse(sarhpl'c): 51® sec; Probe
12

rinse(standard): 10 sec; Rinse-1 time : 30 sec; Probe Rinse-1 time: 30 sec; Rinse-2 time: 30 sec; Probe Rinse-2 time: 30 sec; Plasma mode: Low matrix; Tune mode: HEHe; Full Quant analysis: Yes; Units: ppm; Levels: 6 (except level-1); Peak pattern: 1 points; Replicates: 3; Diluent : 4.0 % Nitric acid. 5 Iron Assay by AAS (%w/w): Method Details:
AAS system: VARIAN AA240 Atomic Absorption spectroscopy; Name of the element: Iron (Fe); Lamp:.Iron hallow cathode lamp; Wavelength: 248.3 nm; Standard uptake time: 30 sec; Sample uptake time: 50 sec; Standard replicates: 3; Sample
10 replicates: 5; Instrument mode: Absorbance; Background correction: Off; Slit width: 0.2 nm; Air flow: 3.50 L/min; Acetylene flow: 1.50 L/min; Calibration Algorithm: Linear.
Particle Size Method of Analysis (PSD): Particle Size Distribution (PSD) is determined by laser diffraction in a Malvern
15 Mastersizer 2000 (Ver. 5.22) equipment or its equivalent under the following conditions: Accessory Name = Hydro 2000S; Dispersant = Ethanol; Dispersant Refractive Index = 1.36; Absorption = 1.0; Obscuration limit = 10% to 20%; Measurement time = 10 seconds; Measurement snaps = 10000; Background time = 10 seconds; Background snaps = 10000; Pump/Stir speed = 2000 RPM.
20 The following examples are given for the purpose of illustrating the present
invention and should not be considered as limitation on the scope or spirit of the invention.
EXAMPLES Example 1
25 Preparation of Sucroferric oxyhydroxide
A solution of sodium carbonate (44 kg) in water (240 L) was taken into a reactor and then cooled to 10-20°C. Aqueous Ferric chloride solution (25 kg in 320 L of water) was added slowly to the sodium carbonate solution at 10-20°C for 30-45 minutes. After completion of the addition, the temperature of the resulting mass was raised to 25-35°C
30 and then stirred for 2-3 hours at the same temperature. Water (500 L) was added to the reaction mass at 25-35°C and then stirred for 30 minutes at the same temperature. The reaction mass was filtered and the wet cake was taken into a reaction flask, followed by the addition of water (500 L) at 25-35°C and then stirring for 30 minutes at the same
E ™ TternpJ?afe>THe relic~tioV'maV&-wai; Eliered^and'th^efesultinglwdt^cdkeTiwas washed
13

with water (25 L). The wet cake was taken into a reaction flask, followed by the addition of ethanol (400 L) at 25-35°C and then stirring the mass at the same temperature for 5 to 10 minutes. To the resulting mass, sucrose (12.0 kg) and starch (11.0 kg) were added at 25-35°C and then stirred for 1-3 hours at the same temperature. The reaction mass was filtered and then washed with ethanol (25 L) to give 41 kg of wet material. The wet material was dried under vacuum at 25-30°C for 4-6 hours to produce 34 kg of Sucroferric oxyhydroxide [Iron content by AAS: 22.1% w/w; Particle size distribution: D(0.90) = 17.7 urn and D(0.50) = 6.15 um; Phosphate binding Capacity by ICP-MS at pH 3.0: 98.6%].
Example 2 Preparation of Sucroferric oxyhydroxide
A solution of sodium carbonate (44 g) in water (240ml) was taken into a reaction flask and then cooled to 10-20°C. Aqueous Ferric chloride solution (25 g in 320 ml water) was added drop-wise to the sodium carbonate solution at 10-20°C for 30-45 minutes. After completion of the addition, the temperature of the resulting mass was raised to 25-35°C and then stirred for 2-3 hours at the same temperature. Water (500 ml) was added to the reaction mass at 25-35°C and then stirred for 30 minutes at the same temperature. The reaction mass was filtered and the wet cake was taken into a reaction flask, followed by the addition of water (500 ml) at 25-35°C and then stirring for 30 minutes at the same temperature. The reaction mass was filtered and the resulting wet cake was washed with water (25 ml). The resulting wet cake was taken into a reaction flask, followed by the addition of aqueous saturated solution of sucrose (12 g of sucrose in 12 ml of water) at 25-35°C and then stirring the reaction mass for 15 minutes to 1 hour at the same temperature. Ethanol (400 ml) was added to the resulting suspension at 25-35°C and then stirred for 5 to 10 minutes at the same temperature. Starch (11.0 gj was added to the resulting suspension at 25-35°C and then stirred for 1-3 hours at the same temperature. The reaction mass was filtered and washed with ethanol (25 ml) to give 44 g of wet material. The wet product was dried under vacuum at 25-30°C for 4-6 hours to give 32.5 g of pure Sucroferric oxyhydroxide [Iron content by AAS: 22.6% w/w; Particle size distribution: D(0.90) = 22.6 um and D(0.50) = 6.97 urn; Phosphate binding Capacity by ICP-MS at pH 3.0: 98.2%].
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Example 3 Preparation of Sucroferric oxyhydroxide
A solution of sodium carbonate (44 g) in water (240ml) was taken into a reaction flask and then cooled to 10-20°C. Aqueous Ferric chloride solution (25 g in 320 ml water) 5 was added drop-wise to the sodium carbonate solution at 10-20°C for 30-45 minutes. After completion of the addition, the temperature of the resulting mass was raised to 25-35°C and then stirred for 2-3 hours at the same temperature. Water (500 ml) was added to the reaction mass at 25-35°C and then stirred for 30 minutes at the same temperature. The reaction mass was filtered and the wet cake was taken into a reaction
10 flask, followed by the addition of water (500 ml) at 25-35°C and then stirring for 30 minutes at the same temperature. The reaction mass was filtered and the resulting wet cake was washed with water (25 ml). The wet cake was taken into a reaction flask, followed by the addition of aqueous saturated solution of sucrose (12 g of sucrose in 12 ml of water) at 25-35°C and then stirring for 10-15 minutes at the same temperature.
15 Starch (11.0 g) was added to the resulting suspension at 25-35°C and then stirred for
10-15 minutes at the same temperature. Ethanol (400 ml) was added to the resulting
suspension at 25-35°C and then stirred for 1-3 hours at the same temperature. The
Oi reaction mass was filtered and washed with ethanol (25 ml) to give 40.5 g of wet
(0
Q- product. The wet product was dried under vacuum at 25-30°C for 4-6 hours to give
^ 20 31.5 g of pure Sucroferric oxyhydroxide [Iron content by AAS: 23% w/w; Particle size
t* distribution: D(0.90) = 24.5 urn and D(0.50) = 7.6 um; Phosphate binding Capacity by
£ ICP-MS at pH 3.0: 97.4%].
i_
O
LL¬
CS Example 4
£2 25 Preparation of Sucroferric oxyhydroxide
© The process exemplified in example 1 was repeated by using an aqueous saturated
^" solution of sucrose (12 kg of sucrose in 12 L of water) instead of sucrose powder. The
o
CN
K 30 binding Capacity by ICP-MS at pH 3.0: 99%]
CO
yield of Sucroferric oxyhydroxide obtained was 32 kg [Iron content by AAS: 20.2% w/w; Particle size distribution: D(0.90) = 15.8 um and D(0.50) = 6.0 urn; Phosphate
5 Unless otherwise indicated, the following definitions are set forth to illustrate
J and define the meaning and scope of the various terms used to describe the invention
cap A.T£MTheg£F ICE CHE-M^JU U/Q5/2Q17 14^ 55
CN 15

The term "pharmaceutically acceptable" means that which is useful in preparing
a pharmaceutical composition that is generally non-toxic and is not biologically
undesirable, and includes that which is acceptable for veterinary use and/or human
pharmaceutical use.
5 The term "pharmaceutical composition" is intended to encompass a drug
product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by 10 admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.
The term "therapeutically effective amount" as used herein means the amount
of a compound that, when administered to a mammal for treating a state, disorder or
condition, is sufficient to effect such treatment. The "therapeutically effective amount"
15 will vary depending on the compound, the disease and its severity and the age, weight,
physical condition and responsiveness of the mammal to be treated.
The term "delivering" as used herein means providing a therapeutically
effective amount of an active ingredient to a particular location within a host causing a
therapeutically effective blood concentration of the active ingredient at the particular
20 location. This can be accomplished, e.g., by topical, local or by systemic administration
of the active ingredient to the host, e.g., human, animal, etc.
The term "buffering agent" as used herein is intended to mean a compound used
to resist a change in pH upon dilution or addition of acid of alkali. Such compounds
include, by way of example and without limitation, potassium metaphosphate,
25 potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and
dihydrate and other such materials known to those of ordinary skill in the art.
The term "sweetening agent" as used herein is intended to mean a compound
used to impart sweetness to a formulation. Such compounds include, by way of
example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin
30 sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary
skill in the art.
The term "binders" as used herein is intended to mean substances used to cause
adhesion of powder particles in granulations. Such compounds include, by way of
£ w ^xamfle" *■ and~: ~wimW^ limitation^ '' S tragacanth,
16

carboxymethylcellulose sodium, polyvinylpyrrolidone, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch, starch, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers, collagen, albumin, celluloses in non-aqueous solvents, polypropylene
5 glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, microcrystalline cellulose, combinations thereof and other material known to those of ordinary skill in the art.
The term "diluents" or "filler" as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression
10 characteristics in the preparation of solid dosage formulations. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.
15 The term "glidant" as used herein is intended to mean agents used in solid
dosage formulations to improve flow-properties during tablet' compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other .such materials known to
20 those of ordinary skill in the art.
The term "lubricant" as used herein is intended to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and
25 other such materials known to those of ordinary skill in the art.
The term "disintegrant" as used herein is intended to mean a compound used in solid dosage formulations to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato
30 starch, pregelatinized, sweeteners, clays, such as bentonite, microcrystalline cellulose, carsium, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to
those of ordinary skill in the art.
c M i urr \. \_ t v_ n c t-i nKi, £ /. > u r.- ? z U) i. ? i, ^ "■ J ^
17

The term "wetting agent" as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium 5 chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, 10 carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP).
All ranges disclosed herein are inclusive and combinable. While the invention
15 has been described with reference to a preferred embodiment, it will be understood by
those skilled in the art that various changes may be made and equivalents may be
substituted for elements thereof without departing from the scope of the invention. In
O) addition, many modifications may be made to adapt a particular situation or material to
Q. the teachings of the invention without departing from essential scope thereof.
^ 20 Therefore, it is intended that the invention not be limited to the particular embodiment
disclosed as the best mode contemplated for carrying out this invention, but that the
c invention will include all embodiments falling within the scope of the appended claims.
o
25
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■
18

We claim:
1. A process for the preparation of iron(III)-based phosphate adsorbent 'Sucroferric
oxyhydroxide', comprising:
a) combining an aqueous solution of ferric chloride with an aqueous solution of an inorganic base to form a first suspension;
b) washing the first suspension obtained in step-(a) with water to obtain a wet cake;
c) adding ethanol to the wet cake obtained in step-(b) while stirring to form a second suspension;
d) adding sucrose and starch to the second suspension obtained in step-(c) while stirring to produce a reaction mass; and
e) isolating the Sucroferric oxyhydroxide from the reaction mass obtained in the step-(d).

2. The process of claim 1, wherein the inorganic base used in step-(a) is selected from the group consisting of hydroxides, bicarbonates and carbonates of alkali or alkaline earth metals; wherein the sucrose in step-(d) is employed directly in the form of a powder or in the form of an aqueous saturated solution; and wherein the isolation of Sucroferric oxyhydroxide in step-(e) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
3. The process of claim 1, wherein the inorganic base used in step-(a) is sodium carbonate; wherein the sucrose in step-(d) is employed in the form of an aqueous saturated solution; and wherein the isolation of Sucroferric oxyhydroxide in step-(e) is carried out by filtration or filtration under vacuum.
4. A process for the preparation of iron(III)-based phosphate adsorbent 'Sucroferric oxyhydroxide', comprising:

a) combining an aqueous solution of ferric chloride with an aqueous solution of an inorganic base to form a first suspension;
b) washing the first suspension obtained in step-(a) with water to obtain a wet cake;
c) adding aqueous saturated solution of sucrose to the wet cake obtained in step-
I- 0 F ^bj-white stimng^totfbrm a second suspension; 6 1 7 1. A = 5-5
19

d) adding ethanol to the second suspension obtained in step-(c) while stirring to form a third suspension;
e) adding starch to the third suspension obtained in step-(d) while stirring to produce a reaction mass; and
f) isolating the Sucroferric oxyhydroxide from the reaction mass obtained in the step-(e).
5. The process of claim 4, wherein the inorganic base used in step-(a) is selected from the group consisting of hydroxides, bicarbonates and carbonates of alkali or alkaline earth metals; and wherein the isolation of Sucroferric oxyhydroxide in step-(f) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
The process of claim 5, wherein the inorganic base used in step-(a) is sodium carbonate; and wherein the isolation of Sucroferric oxyhydroxide in step-(f) is carried out by filtration or filtration under vacuum.
7. A process for the preparation of iron(III)-based phosphate adsorbent 'Sucroferric
oxyhydroxide', comprising:
20 a) combining an aqueous solution of ferric chloride with an aqueous solution of an
inorganic base to form a first suspension;
b) washing the first suspension obtained in step-(a) with water to obtain a wet
cake;
c) adding aqueous saturated solution of sucrose to the wet cake obtained in step-
25 (b) while stirring to form a second suspension;
d) adding starch to the second suspension obtained in step-(c) while stirring to form a third suspension;
e) adding ethanol to the third suspension obtained in step-(d) while stirring to form
a reaction mass; and
30 f) isolating the Sucroferric oxyhydroxide from the reaction mass obtained in the
step-(e).
c, oi \ urr ,1. U c. \~ try c vu r-i ,«■- i. .4 A * u > > l u \- ? > ^ "J "•
20

8. The process of claim 7, wherein the inorganic base used in step-(a) is sodium carbonate; and wherein the isolation of Sucroferric oxyhydroxide in step-(f) is carried out by filtration or filtration under vacuum.
9. Sucroferric oxyhydroxide having a D50 particle size of less than or equal to about 20 microns.
10. The compound of claim 9, wherein the Sucroferric oxyhydroxide has a D50 particle size of specifically about 1 micron to about 20 microns.
21