FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
PATENTS RULES, 2003
COMPLETE SPECIFICATION
(see section 10 and rule 13)
1. TITLE OF THE INVENTION:
''A NOVEL PROCESS FOR THE PREPARATION OF FERRIC CITRATE WITH CONTROLLED SURFACE AREA"
2. APPLICANT(S):
A. NAME: Alkcm Laboratories Limited
IS. NATIONALITY: An Indian Company
C. ADDRESS; Alkem House, Devashish, Adjacent To
Matulya Centre, S.B.Marg, Lower
Parel, Mumbai - 400013, Maharashtra,
India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of
pharmaceutical grade ferric citrate with desired product attributes such as a controlled surface area and improved dissolution profile.
BACKGROUND OF THE INVENTION
ferric citrate is a slightly hygroscopic, amorphous, light brown to beige colored coordination complex , known chemically as 2-hydroxypropane-1,2,3-tricarboxylate; iron(3 l), contains about 20.17 % - 22.30%Iron and is represented by the chemical formula

ferric citrate is a phosphate binder indicated for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis.
Historically, preparations of ferric citrate have been carried out by the precipitation of ferric Hydroxide [Fe(OH)3] from aqueous solutions of soluble ferric salts by pH adjustment with inorganic base (typically NaOH) and then dissolution of the isolated ferric hydroxide with aqueous citric acid solution to give solutions of ferric citrate. The aqueous solutions of ferric citrate were then evaporated to dryness to provide solid ferric citrate. This preparative approach was widely published in texts and pharmaceutical references, for example: The National Standard Dispensatory (1909), A Treatise on Pharmacy for Students and Pharmacists (1916), Principles of Pharmacy (1 917),Remington's Pharmaceutical Sciences vol.6 (1917)

Polish patent application PL69800A5 discloses preparation offerric citrate
byhcaling Fe (OH)3 (reagent grade) with aqueous citric acid at 35°C followed by
precipitation of ferric citrate from the aqueous solution using methanol.
Colloids and Surfaces A: Physiochemical and Engineering Aspects, 79 (1993) 157-167 discloses the isolation of purified Fe (OH) 3 from ferric chloride solutions by precipitating with sodium hydroxide.
Dalton Transactions, 2009, 8618-8625 discloses properties of Iron (III) citrate speciation as a function of pH in aqueous solutions of ferric citrate prepared from Fe (OH)3 and aqueous citric acid.
U.S. Patent No. 5,753,706 teaches the use of ferric citrate to treat hypophosphatemia but docs not describe a process for the preparation of ferric citrate.
U.S. Patent No. 6,903,235 teaches the preparation of ferric citrate from a mixture of solid citric acid, solid ferric salt such as a ferric chloride/ferric sulfate / ferric nitrite salt and alcohol.
U.S. Patent No. 7,767,851 describes and claims a solid form of ferric citrate having a formula of C6H5O7Fe, having a BET surface area exceeding 16 m2/ gm , an intrinsic dissolution rate between 1.9 and 4.0 mg/cm2 /min, as determined by the USP intrinsic dissolution assay in water, wherein the solid form of ferric citrate is synthesized by a method comprising: (a) adding an alkaline metal hydroxide solution to a ferric chloride solution;(b) isolating a ferric hydroxide;c) forming a suspension of the ferric hydroxide precipitate in watcr;(d) adding citric acid to the suspension and forming a ferric-citric acid solution by heating said suspension with said citric acid; and(e) precipitating the solid form offerric citrate

by mixing the ferric-citric acid solution with an organic solvent such as methanol, ethanol, isopropanol, THF,or acetone.
U.S. Patent No. 8,093,423 discloses a process for the preparation of ferric citrate similar to that of US 7,767,851 and claims a method of decreasing mortality rate in a dialysis patient, comprising administering to the patient an effective amount of ferric citrate having an intrinsic dissolution rate between 1.88 and 4.0 mg/cm2 /minto decrease mortality rate of the dialysis patient.
U.S. Patent No. 8,299,298 discloses a process for the preparation of ferric citrate similar to that of US 7,767,851 and claims a pharmaceutical composition comprising ferric citrate having a BET active surface area of at least 16 sq. m/g and a pharmaceutically suitable carrier, wherein the ferric citrate is present in an amount effective to reduce serum phosphate levels.
U.S. Patent No. 8,338,642 claims specifically ferric citrate having a surface area greater than 16 m2/gm.
U.S. Patent No. 8,754,257 discloses a process for the preparation of ferric citrate similar to that of US 7,767,851 and claims a pharmaceutical composition comprising a form of ferric citrate having an intrinsic dissolution rate of 1.88-4.0 mg/cm2 /min and a pharmaceutically suitable carrier, wherein the ferric citrate is present in an amount effective to reduce serum phosphate levels.
PUT publication WO2007062561 discloses a method for refining ferric citrate by a method comprising the steps of: (1) dissolving ferric citrate in water; (2) adding a solvent to obtain ppt.; and (3) drying. The solvent used in the method is one or more of alcohol, ketone, nitrile, alkane, ether, or ester. The ferric citrate so obtained is of loose and porous form and has a very large surface area. The present invention provides a pharmaceutical grade ferric citrate of surface area in

the range of 1-15 m2/gm and having improved product attributes and desired dissolution profile.
PCT publication WO2015110968 provides ferric citrate having a BET active surface area in the range of 1-15 m2 /gm prepared by mixing a source of citrate ion with source of ferric ion in aqueous solution; adding alcohol to the above solution; and filtering the mixture to obtain pharmaceutical grade ferric citrate.
PCT publication WO2016098131 discloses a process for preparing ferric citrate having (BET) surface area less than 14 sq./g and with intrinsic dissolution rate of about 0.1 - 1.5 mg/cm2 /min wherein the process comprises: a) adding alkali metal carbonate to an aqueous solution of ferric chloride at 25-30 °C; b) isolating solid ferric hydroxide at pH ranging from 6.8 to 8.5; c) adding of ferric hydroxide to an aqueous solution of citric acid monohydrate and heating at 80 to 120°C; d) reducing, the volume of water to 60% to 30% followed by precipitation of ferric citrate by adding it to water miscible organic solvent at 25-30°C or adding water miscible organic solvent to it. It also teaches a method for reducing the large BET surface area of ferric citrate (>16m2 /gm) to less than 14 m2 /gm by treating ferric citrate with a large surface area (>16 m2/gm) with a water miscible organic solvent having 10% water & blending it to achieve uniformity. The present invention involves heating ferric hydroxide supported on inert filter material such as cliatomaceous earth directly with aqueous citric acid to produce a product rich concentrate of ferric citrate-which is combined with a mixture of organic solvents such as acetone and methyl ethyl ketone in a 1:1 ratio to afford a pharmaceutical grade ferric citrateof BET surface area less than 15 m2 / gm and having advantageous dissolution profile.
PCT publication WO2016162888 discloses a process for the preparation of

pharmaceutical grade ferric citrate having a BET surface area less than 16m2 / gm and having a mean dissolution rate of 4 to 9 mg/cm2/ min by treating a solution of ferric salt with alkali metal carbonate, treating the resultant with a coagulating agent such as a hydrophobically modified copolymer like polydiallyammonium

halidc or acrylamide to form an intermediate ferric oxohydride mass which is then
heated with citric acid and then combined with an oreanic solvent selected from
methanol, ethanol. isopropylalcohol, butanol, acetone and tetrahydrofuran. The present invention employs a simple and cheap inert filter material such as diatomaceous earth to isolate ferric hydroxide as supported on the diatomaceous earth, and reacts the isolated ferric hydroxide supported on the diatomaceous earth with aqueous citric acid to afford an aqueous solution of ferric citrate., which is then combined with organic solvent mixture comprising acetone and methyl ethyl ketone to afford ferric citrate of BET surface area less than 15m2/gm and an intrinsic dissolution rate less than 1.80 mg/cm2/min.
PCT publication WO2017021921 discloses a one pot process for the preparation of ferric citrate by combining a ferric ion source, a citrate ion source and base in water & combining them with an organic solvent such as methanol, ether, and acetone.
Thus there is an unmet need to provide an economical, ecofriendly, and simple industrial process for the preparation of pharmaceutical grade ferric citrate with controlled surface area and overcome the difficulties encountered by prior art processes during the isolation and purification of ferric hydroxide due to its intrinsic colloidal properties.
The present invention provides a pharmaceutical grade ferric citrate having a BET surface area between 1-15 m2/ gm , an intrinsic dissolution rate less than 1.80mg/cm2/min, prepared by a process comprising heating directly the ferric hydroxide precipitated on an inert filter media such as diatomaceous earth with aqueous citric acid , filtering and concentrating the aqueous solution of the resultant ferric citrate and combining with a mixture of organic solvents comprising acetone and methyl ethyl ketone. The novel features of this invention that involves the use of ferric hydroxide precipitated on inert filter media as such for reacting with aqueous citric acid, the mixture of organic solvents comprising acetone and methyl ethyl ketone in a definite ratio, help control the BET surface

area and limit it to about 1-15 m2/ gmand also provide better product

The prior art process for obtaining a pharmaceutical grade ferric citrate is cumbersome and not industrially feasible as it does not provide an easy solution to isolate the key intermediate ferric hydroxide and does not disclose the advantageous use of inert filter material such as diatomaeeous earth for the isolation of the key intermediate ferric hydroxide whereas the present invention isolates ferric hydroxide supported on the diatomaeeous earth and utilizes it directly for the next step. The present invention also provides the amount of the organic solvent mixture comprising solvents such as acetone and methyl ethyl ketone that is critical in the formation of a pharmaceutical grade ferric citrate with desired product attributes such as low BET surface area, desired dissolution characteristics and intrinsic dissolution rates.
The following are the advantages of the improved process of the present invention over the prior art:
1. The process of the present invention which involves precipitation of ferric hydroxide onto diatomaeeous earth provides easily filtered solids that facilitates removal of soluble inorganic components and also provides facile control of residual soluble components such as residual chloride ion and thus results in ferric hydroxide of high purity whereas the prior art processes that utilized centrifugal sedimentation with specialized equipment to isolate ferric hydroxide followed by repeated cycles of re-suspension and centrifugation to remove soluble components were thus time consuming and cumbersome.
2. Precipitation of ferric citrate by addition of a concentrated aqueous ferric citrate solution into a blend of solvents such as a 1:1 weight ratio of acetone and methyl ethyl ketone provides easily filtered product solids with controlled surface area less than 1 5 m2/gmand desired dissolution profile.
3. The following are the additional process benefits conferred by the process of the present invention:

a.) Readily scalable for manufacturing.
b.) Facile control of residual chloride ion in both ferric hydroxide and ferric citrate c.) Readily filterable intermediate and product
d.) Controlled product attributes (low BET surface area, desired dissolution profile)
SUMMARY OF THE INVENTION
The present invention provides an economical, ecofriendly, and simple industrial process for the preparation of pharmaceutical grade ferric citrate with controlled surface area, composition, and purity, and overcomes the difficulties encountered by prior art processes during the isolation and purification of the intermediate ferric hydroxide (due to ferric hydroxide's intrinsic colloidal properties).
An aspect of the present invention is to provide a process for the preparation of ferric citrate comprising the steps of:
(a) adding an alkaline metal hydroxide solution to a solution of aqueous ferric chloride in the presence of diatomaceous earth; and isolating ferric hydroxide precipitated onto diatomaceous earth;
(b) heating a suspension of the isolated ferric hydroxide on diatomaceous earth as obtained from step (a) with aqueous citric acid solution to form ferric citrate solution;
(c) optionally filtering and/or concentrating the resultant suspension of step(b) to afford a product rich solution of ferric citrate.
(d) combining the resultant aqueous solution of ferric citrate with a solvent
mixture comprising acetone, methyl ethyl ketone or mixtures thereof; and
isolating ferric citrate.
A general aspect of the present invention is summarized by the following reaction scheme as in Figure-1 below:
Cont'd on next page


FIGURE-1-REACTION SCHEME:
a.) FeCl3+SOURCE OF HYDROXIDE ION SUCH AS Aq. NaOH
→

Fe(OH)3-supported 0n-DIATOMACEOUS
EARTH
+ INERT FIETER MATERIAL SUCH AS DIATOMACEOUS EARTH
b.) Fe (OH)3 -supported on- DIATOMACEOUS EARTH
+ SOURCE OF CITRATE ION SUCH AS AQ.CTTRIC ACID → FERRIC CITRATE (AQ.) +DIATOMACEOUS EARTH
FILTER/and/ CONCENTRATE
c.) FERRIC CITRATE (AQ.)+ DIATOMACEOUS EARTH → PRODUCT RICH AQUEOUS SOLUTION OF FERIC CTTRATE
d.) PRODUCT RICH AQUEOUS SOLUTION OK KERR1C CITRATE
+ ORGANIC SOLVEVENT SUCH AS ACETONE → FERRIC CTTRATE OF BETSURFACE AREA LESS
THAN 15m2/gm / METHYL ETHYL KETONE/ MIXTURES THEREOF
The key aspects of the present invention may be summarized as in the following steps:
A. A process for the preparation of ferric citrate comprising the steps of:
(a) adding an alkaline metal hydroxide solution to a solution of aqueous ferric chloride in the presence of diatomaceous earth; and isolating ferric hydroxide precipitated onto diatomaceous earth;
(b) heating a suspension of the isolated ferric hydroxide on diatomaceous earth as obtained from step (a) with aqueous citric acid solution to form ferric citrate solution:
(c) optionally filtering and/or concentrating the resultant suspension of step (b) to afford a product rich solution of ferric citrate.
(d) combining the resultant aqueous solution of ferric citrate with a solvent
mixture comprising acetone, methyl ethyl ketone or mixtures thereof; and
isolating ferric citrate.
B. A process for the preparation of ferric citratewith a BET surface area of 1-15
m2/gm comprising the steps of:


chloride in the presence of diatomaceous earth; and isolating ferric hydroxide precipitated onto diatomaceous earth;
(b) heating a suspension of the isolated ferric hydroxide on diatomaceous earth as obtained from step (a) with aqueous citric acid solution to form ferric citrate solution;
(c) optionally filtering and/or concentrating the resultant suspension of step (b) to afford a product rich solution of ferric citrate.
(d) combining the resultant aqueous solution of ferric citrate with a solvent
mixture comprising acetone, methyl ethyl ketone or mixtures thereof; and
isolating Ferric citrate.
C. The process according to A above, wherein the ferric citrate has a BET surface
area of about 1-1 5 m2 / gm.
D. The process according to C above, wherein the ferric citrate has a BRT surface
area of about 5-15 m2/ gm.
E the process according to A& B above, wherein the ferric citrate has an intrinsic dissolution rate less than 1.80 mg/cm 2/min
ABBREVIATIONS:
It should be noted that acronyms or symbols for reagents have the following definition:
1)E-diatomaceous earth
NaOH-sodium hydroxide
AgNO3-Silver nitrate
D/W-Distilled water
MEK-Methyl ethyl ketone
PSD-Particlc size distribution
POC EE-549-1 8-G is a representative batch of ferric citrate obtained by process of the present invention with BET surface area 11.55 m 2/gm.


present invention with BET surface area 10.62 m2/gm
KFERFP 1807 is a representative batch of ferric citrate obtained by process of the present invention with BET surface area of 10.68 m2 /gm
The prior art commercial sample of ferric citrate has a BET surface area of 8.8 m2 /gm
BRIEF DESCRIPTION OF TABLES AND DRAWING FIGURES
Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures wherein:
Table-1 summarises the effect of solvent on the BET surface area.
Table-2providcs a comparative table of composition of Ferric citrate of BET surface area less than 15 m2/gm prepared by process of the present invention for e.g. a representative batch -POC Sample- EE-549-18-G with BET surface area 11.55 m2 /gm vsprior art ferric citrate of surface area 8.8 m/gm.
Table-3provides analytical results of BET surface area calculated for different batches of ferric citrate prepared by process of the present invention.
Table-4 provides the intrinsic dissolution rate of Ferric citrate of batches: FB027709 having a BET surface area of 10.62 m2/gm & KFERFP1807 having a BET surface area of 10.68 m2/gm measured in solvents at varying pH such as pH =7 in Water, Phosphate Buffer at pH=8 , pH=1.0 HC1 , pH=1.5 HC1 at varying pressures & speed.
KIGURE-1 provides a reaction scheme summarizing a process for the preparation of Ferric citrate as per the present invention.
FIGURE-2—illustrates the XRD of a representative batch of Ferric citratc-POC EE-549-18-G having a BET surface area 11.55 m2/gm prepared by a process of the present invention.


area 8.8.m2 / gm.
FIGURE-4-illustratcs the BHTsurface areaof ferric citrate of a representative batch FB027709 prepared by a process of the present invention.
FIGURE-5-iIlustrates the Dissolution profile of ferric citrate from a representative batch POC EE-549-18-G having a BET surface area 11.55 m2/gm prepared as per the present invention vs. Prior art ferric citrate with BET surface area 8.8 m2 /gm
DETAILED DESCRIPTION OF THE INVENTION
Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended steps.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or berth of the limits, ranges excluding either both of those included limits are also included in the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of


publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications arc cited.
It must be noted that as used herein and in the appended steps, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.
The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
A main aspect of the present invention is to provide a process for the preparation of ferric citrate comprising the steps of:
(a) adding an alkaline metal hydroxide solution to a solution of aqueous ferric
chloride in the presence of diatomaceous earth; and isolating ferric hydroxide
precipitated onto diatomaceous earth;
(b) heating a suspension of the isolated ferric hydroxide on diatomaceous earth as
obtained from step (a) with aqueous citric acid solution to form ferric citrate
solution;
(c) optionally filtering and/or concentrating the resultant suspension of step (b) to
afford a product rich solution of ferric citrate.

(d) combining he resultant aqueous solution of ferric citrate with a solvent
mixture comprising acetonc, methyl ethyl ketone or mixtures thereof; and isolating ferric citrate.
A still important aspect of the present invention is to provide a process for the preparation of ferric citrate with a BET surface area of 1-15 m2/gm comprising the steps of:
(a) adding an alkaline metal hydroxide solution to a solution of aqueous ferric chloride in the presence of diatomaceous earth; and isolating ferric hydroxide precipitated onto diatomaceous earth;
(h) heating a suspension of the isolated ferric hydroxide on diatomaceous earth as obtained from step (a) with aqueous citric acid solution to form ferric citrate solution;
(c) optionally filtering and/or concentrating the resultant suspension of step (b) to
afford a product rich solution of ferric citrate.
(d) combining the resultant aqueous solution of ferric citrate with a solvent
mixture comprising acetone, methyl ethyl ketone or mixtures thereof; and
isolating ferric citrate.
In a preferred embodiment, a solution of Ferric Chloride • 6H2O was prepared by dissolving it in water taken in a quantity ranging to about 3-4 times weight of ferric chloride.6H2O. A slurry of diatomaceous earth such as Celpure P 1000 (DE) {weighing about 1.8 times wrt weight of ferric chloride.6H2O} in water {weighing about 10 timeswrt weight of ferric chloride.6H2O} was prepared in a 4 necked RBF fitted with a condenser and stirrer. The reaction mixture was then cooled to a temperature of about -5° to 5°C. An aqueous cold solution of sodium hydroxide (3 equivalents wrtmoles of ferric chloride.6H2O) in water (4-5 equivalents wrt weight of ferric chloride.6H2O) was added to the aqueous mixture of ferric chloride and Celpure P1 000 (DE) at 0°C -5°C in about 30-120 minutes time.The mixture was then stirred at 0° to 5°C for 30-60 minutes and then warmed to 20° + 5°C.

The cake of Fc (OH)3 supported on diatomaccous earth was filtered on ordinary whatman filter paper/filter cloth, and washed with D/W (about 24 equivalentswrt
weight of ferric chloride.6H2O) until the filtrate is free of chloride (negative to
AgNO3ppt test) and suck dried until no further drip is observed and a wet, clay-like filter cake of ferric hydroxide supported on diatomaceous earth is obtained.
The wet cake of Fe (OH) 3 supported on diatomaceous earth was then added to a solution of citric acid monohydratc (about 1.25 equivalcntswrtmoles of ferric chloride.6H2O) in D/W (about 12 equivalents wrt weight of Ferricchloride.6H2O)and the resultant reaction mixture healed so as to facilitate the formation of ferric citrate.The temperature of the reaction is preferably about 100°C, more preferably about 78-82°C.
The reaction mixture is maintained at preferably about 100°C, more preferably about 78-82°C temperature until complete conversion of the reactants to ferric citrate.In a specific embodiment, the resultant reaction mixture was heated to about 78-82°C and maintained for about 2 hours.
The resultant reaction mixture was then cooled to 20-30°C and filtered, the cake washed and rinsed further with D/W (taken in a quantity weighing about 12 cquivalcntswrtweight of ferric chloride.6H2O).
Optionally, the volume of the filtrate can be reduced by evaporation, preferably in an evaporator under reduced pressure. In an embodiment, the product rich filtrate of ferric citrate is vacuum distilled at about 60°C, at about 100 mm Hg to afford a concentrated product rich solution containing ferric citrate. The product rich aqueous concentrate was then added to a stirred mixture of organic solvent mixtures such as acetone and MEK. In a preferred embodiment, the product rich aqueous concentrate was added to a stirred 1:1 mixture of organic solvent mixture such as acetone and MEK in about 30 minutes or more at about 20-30°C.Thc mixture then stirred at 30 minutes or more at about 20-30°C.

The fine precipitated solids were filtered and then rinsed with fresh acetone. The cake was de-liquored , transferred to a drying dish and vacuum dried at
temperature 40-60°C,and pressure < 80 mmHg, de-lumped to afford dried ferric citrale powder in about 91% yield.
The organic solvents for precipitation of ferric citrate may be selected from protic and aprotic solvents or mixtures thereof such as alcohols like methanol, clhanol, isopropyl alcohol; ketones such as acetone, Ethyl methyl ketone; ethers such as leterahydrofuran, 1,4-dioxane; nitrilcs such as acetonitrile ; amides such as dimelhylacetamide, dimethylformamide ; or other aprotic polar solvents such asdimethylsulfoxide.
The table below summarises the effect of the relative amounts of the combining organic solvents forming the mixture on the BET surface area of ferric citrate. The type of organic solvent or mixtures thereof employed for precipitating ferric citrate from its aqueous solution and the ratio in which they are combined is critical in controlling the BET surface area of the final ferric citrate. The BET surface area of commercially available ferric citrate is about 8.8 m 2/gm whereas the ferric citrate obtained by the process of the present invention is less than 15 m2/gm, preferably about 1-15 m2/gm, more preferably about 5-15m2/gm. A 100% weight of pure acetone when combined with an aqueous solution of ferric citrate afforded ferric citrate with a BET surface area of 40.99 m2/gm, whereas a 90% Acetone & 10% MEK mixture by weight afforded ferric citrate with BET surface area 33.08 m2/gm, while a 75% acetone & 25% MEK mixture by weight afforded ferric citrate of 28 m2/gm.A 50% acetone & 50% MEK mixture when combined with an aqueous solution of ferric citrateafforded ferric citrate of BET surface area 11.55 m2/gm.Thc present inventors observed that removal of water from ferric citrate solution became difficult at lower weight percentage of acetone and also posed difficulties in isolation of the product.

TABLE-1 SOLVENT EFFECTS ON BET SURFACE AREA

POC EE-
S49-18-G Acetone Wt% MEK Wt% BET Surface
Area m2/g

100% 0% 40.99

90% 10% 33.08

75% 25% 28.00

50% 50% 11.55

25% 75% 1.51

0% 100% 0.50
In some embodiments, the BET surface area was calculated for different batches of ferric citrate prepared by process of the present invention. In certain embodiments, such as ferric citrate obtained from batch FB0F277009 had a D90 PSDof 42.1 µm andBET of 10.62 m2/gm. In still some other embodiments such as ferric citrate obtained from batch FER/FP/002/013 had a D90 PSDof 55,0 pm and BET of 9.06 m27gm. In yet another embodiment, e.g.ferric citrate obtained from batch FER/FP/002/019had a D90 PSDof 47.9µm andBET of 10.15 m2/gm.
The dissolution profile of ferric citrate from a representative batch POC EE-549-18-G having a BET surface area 11.55 m2/gm prepared as per the present invention vs. Prior art ferric citrate with BET surface area 8.8 m2/gm is illustrated in Figurc-5.

The table below is a comparative table of composition of Ferric citrate of BIT surface area less than 15 m7gm prepared by process of the present invention for e.g.-a representative batch -POC Sample- EE-549-18-G with BET surface area 11.55 m /gm vs. Prior art ferric citrate of surface area 8.8 m2/gm.

TABLE-2- comparative table of composition of Ferric citrate of BIT surface area less than 15
2
m /gm prepared by process of the present invention for e.g.-a representative batch -POC Sample-
EE-549-18-G with BET surface area 11.55 m2/gm vsprior art ferric citrate of surface area 8.8

m2 /gm
Fe ELEMENTAL
SAMPLE
NAME ASSA Y
W/W % BY
UV- LOSS
ON DRYI
NG
(%) XRPD ANALYSIS BET
SURFAC E AREA
m2/g CURAT
E
w/w%
BY HPLC

CARBO HYDROGE


VIS N N
Commercially
available Ferric
citralc of
Surface area 8.8
m2/gm 88.9 n/a Fig-3 24.25 2.44 8.8 64.66
EE-549-18-G-
Representative
batch of Ferric
citrate prepared
by a process of
the present
invention 91.6 2.4 Fig-2 24.27 2.71 11.55 63.11


The inventors of the present invention found that it is possible to make ferric citraic tablets with similar dissolution profde as Auryxia© tablets despite having a BHT surface area of less than 15m /gm. Preferably BHT surface area of ferric citrate is about 1-15 m /gm. More preferably the BET surface area of ferric citrate is about 5-15 m2/gm.
The tablets made according to the invention comprise one or more excipients selected from the group comprising of hinders, distntegranls, glidants, flow control agents, lubricants, and surfactants and coating agents. In one embodiment of the invention, the tablets comprise
(i) ferric citrate with a BET surface area < 15 m 2/gm and intrinsic dissolution rate less than 1.80 mg/cm2/min
(ii) One or more excipients selected from disintegrants and binders.
(iii) flow aids like lubricants and glidants and
(iv)Suitable coating.
EXAMPLE^!
Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the stepped invention. It should be emphasized that the above-described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are preferred by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof,

The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.
KXAMPLK-1 Batch POC HK-549-18-G
A solution of Ferric Chloride • 6H2O (50.00 g, 0.1850moles) in water(200g) was added to a slurry of Celpure P1000 (DE)(90.56 gm) in water taken in a 4 necked RBF with a condenser and stirrer. The reaction mixture then cooled to -5° to 5°C. An aqueous cold solution of sodium hydroxide (22.20 g, 0.555molcs) in water (199.8 gm) was added to the aqueous mixture of ferric chloride and Celpure P1000 (DP) at 0°C -5°C in 30-120 minutes time. The mixture was then stirred at 0° to 5°C for 30-60 minutes and then warmed to 20°± 5°C.The cake of Fe(OH)3 supported on diatomaccous earth was filtered on ordinary whatman filter paper , and washed with D/W (1.2P) until the filtrate is free of chloride (negative to AgNO3ppt test) and suck dried until no further drip is observed and a wet, clay-like filter cake is obtained. The wet cake of Fe(OH)3 supported on diatomaceous earth was then added to a solution of citric acid monohydrate(48.59 g, 0.2132 moles) in D/W (556 g) and the resultant reaction mixture was heated to about 78-82°C and maintained at 78-82°C for two hours. The resultant reaction mixture was then cooled to 20-30°C and filtered, the cake washed and rinsed further with D/W (600g). The product rich filtrate of ferric citrate is then vacuum distilled at < 60°C, < 100 mm 11g to afford about 183 g to 194g of the concentrated product rich solution containing Ferric citrate. The product rich aqueous concentrate was then added to a 1:1 stirred mixture of acetone(400gm) / MPK(400gm) in about 30 minutes or more at 20-30°C.The mixture then stirred at 30 minutes or more at 20-30°C. The fine precipitated solids were filtered, rinsed with fresh acetone. The cake was dc-liquored, transferred to a drying dish and vacuum dried at temperature 40-60°C, andpressure < 80 mmHg, de-lumped to afford dried ferric citrate powder (45.31 g, 90.62% yield.) {45.31 g Ferric citrate from 50.0 g Ferric Chloride • 6H2O (0.9062 kg/kg)}BET surface area of Batch POC EH-549-18-G 11.55m2/gm IDR ??

TABLE-3 below provides ANALYTICAL RESULTS OF BET SURFACE AREA CALCULATED FOR DIFFERENT BATCHES OF FERRIC CITRATE

TABLE-3ANALYTICAL RESULTS OF BET SURFACE AREA CALCULATED FOR DIFFERENT BATCHES OF FERRIC CURATE PREPARED BY PROCESS OF THE PRESENT INVENTION
S.No Batch No Particle size-D(90) µm Specific surface area(BET) m2/gm
1 FB0F277009 42.1 10.62
2 FLR/FP/002/013 55.0 9.06
3 FER/FP/002/019 47.9 10.15
4 KFERFP1807 47.4 10.68
Table-4 provides the intrinsic dissolution rate of Ferric citrate of batches FB027709 having a BET surface area of 10.62 m2/gm & KFERFP1807 having a BET surface area of 10.68 m2/gm measured in solvents at varying pH such as pH=7 in Water, Phosphate Buffer at pH=8 , pH=1.0 HC1 , pH = 1.5 HC1 at varying Pressures & speed.

TABLE-4- Intrinsic Dissolution Rate of Ferric citrate prepared by process of the present invention
API Batch no. Dissolution medium Speed inRPM Pressure in tons Ferric
citrate in mg/min/cm2
FB0F277009 Water 50 2.5 1.51

FB0F277009 Water 100 0.25 0.49
FB0F277009 Water 200 2.5 1.40
F277009 pH 1.0HC1 100 0.25 0.82
FB0F277009 pH1.5HCl 100 0.25 0.50 5
FB0F277009 Water pH 8.00 50 0.25 1.29
FB0F277009 pH 8.00
phosphate
buffer 100 0.25 1.30 10
KFKRFP1807 Water 100 0.5 1.56
KFERFP1807 Water 100 1.0 1.57
KFERFP1807 pH8.0 phosphate buffer 100 1.0 1.66
The percentage dissolution of ferric citrate obtained from a representative batch POCEE-549-18-G of the present invention was compared with that of prior art ferric citrate having a BLT surface area of 8.8 m2/gm at varying time intervals is illustrated in figure-5.

WE CLAIM:

use of diatomaccous earth wherein the process comprises:
(a) combining an alkaline metal hydroxide solution and an aqueous ferric
chloride solution in the presence of diatomaccous earth to obtain ferric
hydroxide on diatomaccous earth;
(b) heating a suspension of ferric hydroxide on diatomaccous earth with an
aqueous citric acid solution to form ferric citrate solution;
(c) optionally filtering and/or concentrating the suspension of step (b) to
afford a product rich solution of ferric citrate;
(d) combining the resultant aqueous solution of ferric citrate witha solvent
mixture comprising acetone, methyl ethyl ketone to obtain ferric citrate.
2. A process for the preparation of ferric citrate with a BKT surface area of 1 15
m /gm.wherein the process comprises use of diatomaccous earth.
3. A process according to claim-3,wherein the process comprises:
(a) combining an alkaline metal hydroxide solution and an aqueous ferric
chloride solution in the presence of diatomaccous earth to obtain ferric
hydroxide on diatomaccous earth;
(b) heating a suspension of ferric hydroxide on diatomaccous earth with an
aqueous citric acid solution to form ferric citrate solution;
(c) optionally filtering and/or concentrating the suspension of step (b) to
afford a product rich solution of ferric citrate:
(d) combining the resultant aqueous solution of ferric citrate with a solvent
mixture comprising acetone, methyl ethyl ketone to obtain ferric citratewith a
BKT surface area of 1-15 m2/gm.

4. The process according to claim-3, wherein preferably the BET surface area of
ferric citrate is about 5-15 m2/ gm,
5. The process according to any of the preceding claims, wherein the ferric citrate
has an intrinsic dissolution rate less than 1.80 mg/cm2 /min.