DESC:RELATED PATENT APPLICATION(S)

This application claims the priority to and benefit of Indian Patent Application No. 202041027334 filed on June 27, 2020; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of iron (III)-based phosphate adsorbent. More particularly, the present invention relates to an improved process for the preparation of Sucroferric oxyhydroxide, suitable for large scale manufacturing.

BACKGROUND OF THE INVENTION

Sucroferric oxyhydroxide (VELPHORO®) is an iron-based phosphate binder for oral administration, indicated for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis. The chemical name of Sucroferric oxyhydroxide is mixture of polynuclear iron(III)-oxyhydroxide, sucrose, and starches. The active moiety of VELPHORO® - polynuclear iron(III)-oxyhydroxide (pn-FeOOH), is practically insoluble and therefore not absorbed and not metabolized. It was sufficiently demonstrated that the active moiety polynuclear iron(III)-oxyhydroxide cannot be isolated and stored without the sucrose, and starch. The hydrated pn-FeOOH core is wrapped by sucrose, as the presence of sucrose is essential for the maintenance of the hydrated structure of the polynuclear FeOOH and maintains the high phosphate adsorption capacity. Starches / carbohydrates, are used to improve process ability during the manufacturing process (EMA assessment report).

The mechanism of action as per the U.S. FDA drug label for VELPHORO® is that the phosphate binding takes place by ligand exchange between hydroxyl groups and/or water in Sucroferric oxyhydroxide and the phosphate in the diet, in the aqueous environment of the gastrointestinal tract. The bound phosphate is eliminated with faeces. Both serum phosphorus levels and calcium-phosphorus product levels are reduced as a consequence of the reduced dietary phosphate absorption.

Polynuclear beta-iron hydroxide stabilized by carbohydrates and/or humic acid, useful as an adsorbent for adsorbing phosphate and process for preparation thereof is described in WO 97/22266. Preparation of iron (III) based phosphate adsorbents are disclosed in various other publications.

However, the prior art methods are not suitable for large scale manufacturing. Accordingly, there remains a need for an efficient, industrially viable large-scale manufacturing process, capable of producing Sucroferric oxyhydroxide in high yield and having better properties, such as physicochemical characteristics, phosphate binding capacity etc.

OBJECTS OF THE INVENTION

The primary object of the invention is to provide an efficient and industry viable process for the preparation of Sucroferric oxyhydroxide.

Another object of the invention is to provide an improved process for large-scale manufacturing of Sucroferric oxyhydroxide in high yield.

Yet another object of the invention is to provide a pharmaceutical composition comprising an effective amount of Sucroferric oxyhydroxide prepared according to the process of the present invention.

SUMMARY OF THE INVENTION

One aspect of the present invention is to provide a process for preparing Sucroferric oxyhydroxide, comprising:
i. reacting an aqueous solution of iron (III) salt with an aqueous base at a temperature ranging about 0 to 10 °C to form a precipitate of iron oxy-hydroxide;
ii. optionally isolating the precipitate;
iii. holding the precipitate until the completion of the isolation of iron oxy-hydroxide, at a temperature ranging about 0 to 10 °C;
iv. suspending the precipitate in an aqueous solution;
v. adding sucrose and starch; and
vi. isolating Sucroferric oxyhydroxide.

In step i of the present invention, iron (III) salt is selected from the group comprising of iron (III) chloride, iron (III) nitrate, iron (III) acetate and iron (III) sulfate, or hydrates thereof.

In step i of the present invention, the said base is selected from the group comprising of hydroxide or carbonates of alkali or alkaline earth metals. The base is selected from the group comprising of sodium hydroxide, potassium hydroxide, sodium bicarbonate or sodium carbonate.

The pH of the reaction mixture in step i of the present invention, is maintained between about 3 and about 10.

In step iii of the present invention, the precipitate or slurry comprising the iron oxy-hydroxide is held at a temperature ranging about 2 to 8 °C.

In step iv of the present invention, the precipitate of iron oxy-hydroxide is suspended in water.

The starch in step v of the present invention is selected from the group comprising of corn starch, wheat starch, rice starch, maize starch, pea starch, potato starch, or mixture thereof. The said starch is native or pregelatinized starch, or mixtures thereof.

The process of the present invention is advantageously suitable for a large-scale manufacturing.

Another aspect of the present invention is to provide a pharmaceutical composition comprising an effective amount of Sucroferric oxyhydroxide prepared according to the process of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

DEFINITIONS

Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances.

As used herein, iron oxy-hydroxide refers to FeO(OH), polynuclear FeOOH, Fe2O3×H2O, iron(III) oxide-hydroxide or ferric oxyhydroxide. Iron oxy-hydroxide as used herein includes, alpha, beta, gamma, and delta FeOOH or mixtures thereof. The iron oxy-hydroxide may comprise beta FeOOH optionally in admixture with other iron oxy-hydroxides.

The term “excipient” or “pharmaceutically acceptable excipient” means a component of a pharmaceutical product that is not an active ingredient, and includes but not limited to filler, diluent, disintegrants, glidants, stabilizers, surface active agents etc. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. One excipient can perform more than one function.

The term “stability” as used in the description includes both physical and chemical stability.

Unless otherwise specified, the term “phosphate adsorbent” or “phosphate binder” refers to Sucroferric oxyhydroxide or pharmaceutical composition thereof, that are capable to act as an adsorbent for phosphate from aqueous medium, and 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.

All temperatures are in degrees Celsius unless specified otherwise.

As used herein, the terms "comprising" and "comprise(s)" mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The term "including" is also to be construed as open ended. The terms "about," “substantially” and the like are to be construed as modifying a term or value such that it is not an absolute, but does not read on the prior art. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by one skilled in the art.

All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

The term "optionally" is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

As used herein, the term “anti-solvent” refers to a solvent that, when combined with a solution of the products obtained at various stages, reduces solubility of the said compounds, causing crystallization or precipitation in some instances spontaneously, and in other instances with additional steps.

Unless otherwise specified, the term “holding” may also be understood as maintaining, keeping, storing or allowing to stand at suitable conditions as desired in the present invention.

One of the major drawbacks of the prior art processes is, the said processes are not suitable for large scale commercial manufacturing, due to the time consumed in such lengthy procedures. The entire procedure for large scale batch lasts for several days which in turn impacts the efficiency and the properties of iron oxy-hydroxide, such as iron content/assay, dissolution, stability and phosphate binding capacity. Inventors of the present application have surprisingly discovered that, during large scale production, holding the precipitate comprising iron oxy-hydroxide until the completion of isolation (filtration) at a temperature ranging about 0 to 10 °C, avoids the problems associated with the reported methods and helps in achieving the efficiency and overall improving the properties of iron oxy-hydroxide and the final product Sucroferric oxyhydroxide. Thus, the present process solves the difficulties associated with the time consuming methods and is advantageously suitable for large scale manufacturing.

The first embodiment of the present invention is to provide a process for preparing Sucroferric oxyhydroxide, comprising:
i. reacting an aqueous solution of iron (III) salt with an aqueous base at a temperature ranging about 0 to 10 °C to form a precipitate of iron oxy-hydroxide;
ii. optionally isolating the precipitate;
iii. holding the precipitate until the completion of the isolation of iron oxy-hydroxide, at a temperature ranging about 0 to 10 °C;
iv. suspending the precipitate in an aqueous solution;
v. adding sucrose and starch; and
vi. isolating Sucroferric oxyhydroxide.
In step i of the present invention, the iron (III) salt useful for the reaction is selected from the group comprising iron (III) chloride, iron (III) nitrate, iron (III) acetate and iron (III) sulfate, or hydrates thereof. The aqueous solution of iron (III) salt for example is a solution of iron (III) salt in water. The solution of iron salt may comprise from about 3 to about 35 % (w/w). Preferably in step i of the present invention, the iron (III) salt useful for the reaction is iron (III) chloride, more preferably, iron (III) chloride hexahydrate.

In step i of the present invention, the base useful for the reaction may be hydroxide or carbonates of alkali or alkaline earth metals, such as for example, alkali carbonates, alkali bicarbonates and alkali metal hydroxides. Preferably, the base useful in step i, is selected from the group comprising of sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate and the like. The base is used in the form of aqueous solution, for example, aqueous sodium carbonate (sodium carbonate in water).

Alternatively, step i of the present invention, may be carried out optionally in a suitable organic solvent, selected from the group, alcohols, ketones, esters, ethers, aliphatic/aromatic hydrocarbons and halogenated hydrocarbons.

In step i of the present invention, the pH of the reaction mixture is maintained between about 3 and about 10, preferably between about 6 and about 8, more preferably about 6 and about 7.

Preferably the precipitate of iron oxy-hydroxide from step i is isolated using suitable techniques.

In step iii of the present invention, the precipitate of iron oxy-hydroxide or the slurry comprising iron oxy-hydroxide is held at a temperature ranging about 0 to 10 °C, until the isolation of iron oxy-hydroxide is complete. Preferably, the precipitate or slurry comprising the iron oxy-hydroxide is held at a temperature ranging about 2 to 8 °C. Holding the precipitate or slurry comprising at the above said temperature may be carried out in a suitable equipment useful for the purpose.

The isolation may last for a period of up to 3 days, for up to 5 days, or up to 7 days, depending on the batch size.

In step iv of the present invention, the precipitate of iron oxy-hydroxide is suspended in an aqueous solution. Preferably, the precipitate or slurry of iron oxy-hydroxide is washed with water or a suitable solvent prior to suspending in an aqueous solution.

In step iv of the present invention, the precipitate of iron oxy-hydroxide is suspended in water.

In step v of the present invention, sucrose and starch may be added to the suspension simultaneously or in any sequence as desired. Starch useful for the purpose, is selected from the group consisting of corn starch, wheat starch, rice starch, maize starch, pea starch, potato starch, or mixture thereof. The said starches useful for the purpose may be native or pregelatinized starch, or mixtures thereof.

Alternatively, a suitable solvent may be optionally added to the suspension prior to isolation of Sucroferric oxyhydroxide.

Suitable solvent as mentioned herein above is selected from the group, alcohols, ketones, esters, ethers, aliphatic/aromatic hydrocarbons and halogenated hydrocarbons, or mixtures thereof.

In step vi of the present invention, Sucroferric oxyhydroxide is isolated using a suitable technique.

The chemical transformations described throughout the application may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants.

In certain embodiments of the invention, unless otherwise specified, the reaction may be carried out at suitable temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures.

Suitable isolation technique, as mentioned herein above, include, but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, combining a solution with an anti-solvent, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, and the like. The isolation may be optionally carried out at atmospheric pressure or under a reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher than desired percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor. Evaporation as used herein refers to distilling a solvent completely, or almost completely, at atmospheric pressure or under a reduced pressure. Flash evaporation as used herein refers to distilling of solvent using techniques including, but not limited to, tray drying, spray drying, fluidized bed drying, or thin-film drying, under atmospheric or a reduced pressure.

In certain embodiments of the present application, the products obtained at different stages including Sucroferric oxyhydroxide may be optionally washed with suitable solvent and dried under suitable drying conditions. Drying may be suitably carried out using equipment such as air tray dryer, vacuum tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. The drying may be carried out at atmospheric pressure or under a reduced pressure at or less than about 80°C, or less than about 60°C, or less than about 50°C, or less than about 40°C, or any other suitable temperature until the satisfactory results are attained, without degrading in quality. The drying may be carried out for any desired time until the required purity is achieved. For example, it may vary from about 10 to about 50 hours, or longer.

The dried product may optionally be subjected to a particle size reduction technique to obtain desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation sifting; milling using mills, such as, for example, ball, roller, or hammer mills, or jet mills, including, for example, air jet mills; or any other conventional technique. The desired particle sizes may also be achieved directly from the reaction mixture by selecting equipment that is able to provide the compound with the desired particle sizes.

Accordingly, Sucroferric oxyhydroxide obtained according to the process of the invention, may have desired particle size of less than about 200 µm, less than about 150 µm, less than about 100 µm, less than about 90 µm, less than about 80 µm, less than about 60 µm, less than about 50 µm, less than about 40 µm, less than about 30 µm, less than about 20 µm, less than about 10 µm or less than about 5 µm. For example, Sucroferric oxyhydroxide may have a particle size, D10 in the range of about 2 to 5 µm, D50 in the range of about 17 to 20 µm, D90 in the range of about 50 to 60 µm.

Phosphate Binding capacity may be determined in assay done according to known methods.

Sucroferric oxyhydroxide prepared according to the process described herein contains about, 33% polynuclear iron(III)-oxyhydroxide, 30% sucrose, 28% starches, and up to 10% water on a weight basis.

The second embodiment of the present invention is to provide a pharmaceutical composition comprising an effective amount of Sucroferric oxyhydroxide prepared according to the process of the present invention.

Pharmaceutical compositions according to the present invention may be formulated in any conventional form, such as oral dosage forms or semi-solid formulations, for example, powders, granules, granulates, capsules, sachets, stick packs, bottles, tablets, dispersible tablets, film coated tablets, aqueous and non-aqueous gel, swallowable gel, fast-dispersing dosage, sachets and the like. Such pharmaceutical composition can be prepared by the methods known in the literature, or may be prepared by, an additional step, to step vi (isolation of the final product), For example, mixing, granulating, encapsulating and/or tabletting the phosphate adsorbent (Sucroferric oxyhydroxide) may be done, with pharmaceutically acceptable, excipients, carriers, diluents, fillers, binders, disintegrants, flow agents, lubricants, or mixture thereof, customary to one skilled in the art.

The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms “comprising” and “consisting of” may be replaced with either of the terms. In addition, the solvents, temperatures, reaction durations, etc. delineated herein are for purposes of illustration only and one of ordinary skill in the art will recognize that variation of the reaction conditions can produce the desired products accordingly.

Certain specific aspects and embodiments of the present invention will be better understood in connection with the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.

EXAMPLES

Example 1: Preparation of Sucroferric oxyhydroxide
Ferric chloride hexahydrate (60.9 g) was charged into a beaker of 1000 mL volume followed by distilled water (421 mL), then mixture was agitated to get a clear solution at 20-25°C. sodium carbonate (47.5 g) was charged in to a four-neck round bottom flask containing distilled water (301 mL) at 20-25°C. Above prepared solution of Ferric chloride was added dropwise under stirring to a four-neck round bottom flask containing sodium carbonate solution at 0-10°C. Ferric oxyhydroxide precipitation was observed and stirred for 2 hours at 20-25°C (pH of reaction mixture is in between 6.5 to 7.0). Water (605 mL) was added to a reaction mixture and stirred for 2 hours at 20-25°C (pH of supernatant layer is in between 6.5-7.0). Reaction mixture was settled for 4 hours and supernatant layer decantated. Obtained ferric oxyhydroxide slurry was kept at 0-10°C for up to four days. The resultant slurry was filtered, the wet cake was washed with water (360 mL X 3 times) and suck dried for 4-5 hours and unloaded. The resultant wet solid was charged in to a four-neck round bottom flask containing water (60 mL) at 20-25°C and stirred for 1 hour followed by the addition of sucrose (18.09 g) and potato starch (22.03 g) and stirred for 2 hours at 20-25°C. The resultant slurry was transferred to vacuum tray drier and flask was rinse with water (20 mL). Combined slurry was dried in oven under vacuum at 40-50°C for 45 hours to afford the title product.
Yield: 57.2 g.

Example 2: Preparation of Sucroferric oxyhydroxide
Ferric chloride hexahydrate (60.8 g) was charged into a beaker of 1000 mL volume followed by distilled water (420 mL), then mixture was agitated to get a clear solution at 20-25°C. Sodium carbonate (47.9 g) was charged in to a four-neck round bottom flask containing distilled water (300 mL) at 20-25°C. Above prepared solution of Ferric chloride was added dropwise under stirring to a four-neck round bottom flask containing sodium carbonate solution at 0-10°C. Ferric oxyhydroxide precipitation was observed and stirred for 2 hours at 20-25°C (pH of reaction mixture is in between 6.5 to 7.0). Water (600 mL) was added to a reaction mixture and stirred for 2 hours at 20-25°C (pH of supernatant layer is in between 6.5-7.0). Reaction mixture was settled for 4 hours and supernatant layer decantated. Obtained ferric oxyhydroxide slurry was kept at 0-10°C for up to four days. The resultant slurry was filtered, wet cake was washed with water (360 mL X 3 times) and suck dried for 4-5 hours and unloaded. The resultant wet solid was charged in to a four-neck round bottom flask containing water (60 mL) at 20-25°C and stirred for 1 hour followed by the addition of sucrose (18.05 g) and potato starch (22.04 g) and stirred for 2 hours at 20-25°C. The resultant slurry was transferred to vacuum tray drier and flask was rinse with water (20 mL). Combined slurry was dried in oven under vacuum at 40-50°C for 45 hours to afford the title product.
Yield: 56.2 g.

Example 3: Preparation of Sucroferric oxyhydroxide
Ferric chloride hexahydrate (30.3 g) was charged into a beaker of 500 mL volume followed by distilled water (210 mL), then mixture was agitated to get a clear solution at 20-25°C. sodium carbonate (23.8 g) was charged in to a four-neck round bottom flask containing distilled water (150 mL) at 20-25°C. Above prepared solution of Ferric chloride was added dropwise under stirring to a four-neck round bottom flask containing sodium carbonate solution at 0-10°C. Ferric oxyhydroxide precipitation was observed and stirred for 2 hours at 20-25°C (pH of reaction mixture is in between 6.5 to 7.0). Water (300 mL) was added to a reaction mixture and stirred for 2 hours at 20-25°C (pH of supernatant layer is in between 6.5-7.0). Reaction mixture was settled for 4 hours and supernatant layer decantated. Obtained ferric oxyhydroxide slurry was kept at 0-10°C for up to four days. The resultant slurry was filtered, wet cake was washed with water (180 mL X 3 times) and suck dried for 4-5 hours and unloaded. The resultant wet solid was charged in to a four-neck round bottom flask containing water (30 mL) at 20-25°C and stirred for 1 hour followed by the addition of sucrose (9.07 g) and potato starch (11.05 g) and stirred for 2 hours at 20-25°C. The resultant slurry was transferred to vacuum tray drier and flask was rinse with water (10 mL). Combined slurry was dried in oven under vacuum at 40-50°C for 40 hours to afford the title product.
Yield: 28.2 g.
,CLAIMS:1) A process for preparing Sucroferric oxyhydroxide, comprising:
i. reacting an aqueous solution of iron (III) salt with an aqueous base at a temperature ranging about 0 to 10 °C to form a precipitate of iron oxy-hydroxide;
ii. optionally isolating the precipitate;
iii. holding the precipitate until the completion of the isolation of iron oxy-hydroxide, at a temperature ranging about 0 to 10 °C;
iv. suspending the precipitate in an aqueous solution;
v. adding sucrose and starch; and
vi. isolating Sucroferric oxyhydroxide.

2) The process as claimed in claim 1, wherein the said iron (III) salt in step i, is selected from the group comprising of iron (III) chloride, iron (III) nitrate, iron (III) acetate and iron (III) sulfate, or hydrates thereof.

3) The process as claimed in claim 1, wherein the said base in step i, is selected from the group comprising of hydroxide or carbonates of alkali or alkaline earth metals.

4) The process as claimed in claim 1, wherein the said base in step i, is selected from the group comprising of sodium hydroxide, potassium hydroxide, sodium bicarbonate or sodium carbonate.

5) The process as claimed in claim 1, wherein the pH of the reaction mixture in step i, is maintained between about 3 and about 10.

6) The process as claimed in claim 1, wherein the precipitate or slurry comprising the iron oxy-hydroxide in step iii, is held at a temperature ranging about 2 to 8 °C.

7) The process as claimed in claim 1, wherein the precipitate of iron oxy-hydroxide in step iv, is suspended in water.

8) The process as claimed in claim 1, wherein the starch in step v, is selected from the group comprising of corn starch, wheat starch, rice starch, maize starch, pea starch, potato starch, or mixture thereof.

9) The process as claimed in claim 1, wherein the said starch in step v, is native or pregelatinized starch, or mixtures thereof.

10) A pharmaceutical composition comprising an effective amount of Sucroferric oxyhydroxide prepared according to the process as claimed in any of the preceding claims.