EP3829761A1 - Process for preparing an adsorbent for phosphate in aqueous medium - Google Patents

Process for preparing an adsorbent for phosphate in aqueous medium

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Publication number
EP3829761A1
EP3829761A1 EP19742785.9A EP19742785A EP3829761A1 EP 3829761 A1 EP3829761 A1 EP 3829761A1 EP 19742785 A EP19742785 A EP 19742785A EP 3829761 A1 EP3829761 A1 EP 3829761A1
Authority
EP
European Patent Office
Prior art keywords
suspension
iron
oxy
hydroxide
process according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19742785.9A
Other languages
German (de)
French (fr)
Inventor
Josep SALAET FERRÉ
Marta Pomares Marco
Francisco De Asís MARQUILLAS OLONDRIZ
Berta GIRBAU CAPELLA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Interquim SA
Original Assignee
Interquim SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Interquim SA filed Critical Interquim SA
Publication of EP3829761A1 publication Critical patent/EP3829761A1/en
Withdrawn legal-status Critical Current

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
    • B01J20/06—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising oxides or hydroxides of metals not provided for in group B01J20/04
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
    • B01D61/14—Ultrafiltration; Microfiltration
    • B01D61/145—Ultrafiltration
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
    • B01D61/14—Ultrafiltration; Microfiltration
    • B01D61/16—Feed pretreatment
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/3085—Chemical treatments not covered by groups B01J20/3007 - B01J20/3078
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2311/00—Details relating to membrane separation process operations and control
    • B01D2311/04—Specific process operations in the feed stream; Feed pretreatment
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2311/00—Details relating to membrane separation process operations and control
    • B01D2311/10—Temperature control
    • B01D2311/103—Heating
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2311/00—Details relating to membrane separation process operations and control
    • B01D2311/18—Details relating to membrane separation process operations and control pH control
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2311/00—Details relating to membrane separation process operations and control
    • B01D2311/24—Quality control
    • B01D2311/243—Electrical conductivity control
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2311/00—Details relating to membrane separation process operations and control
    • B01D2311/25—Recirculation, recycling or bypass, e.g. recirculation of concentrate into the feed
    • B01D2311/252—Recirculation of concentrate
    • B01D2311/2523—Recirculation of concentrate to feed side
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2315/00—Details relating to the membrane module operation
    • B01D2315/16—Diafiltration

Definitions

  • This invention relates to a process for preparing an adsorbent for phosphate comprising stabilized iron oxy-hydroxide in aqueous medium at industrial scale.
  • WO9201458A1 discloses a method of controlling serum phosphate levels in patients by use of phosphate adsorbers based on iron oxy-hydroxides which bind to ingested phosphate.
  • Sucroferric oxy-hydroxide (INN; trade name Velphoro, by Vifor Fresenius Medical Care Renal Pharma) is a non-calcium, iron-based phosphate binder used for the control of serum phosphorus levels in adult patients with chronic kidney disease on haemodialysis or peritoneal dialysis.
  • Sucroferric oxy-hydroxide is a complex which consist of polynuclear iron (III) oxy-hydroxide (pn-FeOOH), sucrose, and starch.
  • the pn-FeOOH moiety is chemically not stable and cannot be isolated and stored as an active pharmaceutical ingredient.
  • the sucrose and the starch are also necessary for the processability of the active substance during the manufacturing process of the finished product (cf. Chemical review for Velphoro of the FDA, page 8 or Assessment Report of the EMA, page 12).
  • Sucroferric oxy-hydroxide was first described in the patent family of US6174442B1 (EP0868125B1 ).
  • This patent describes polynuclear beta-iron hydroxide stabilized by carbohydrates and/or humic acid.
  • the product was prepared by reacting, in a first step, an aqueous solution of iron (III) chloride with an aqueous solution of a base which produced a suspension of polynuclear iron (III) oxy-hydroxide (pn-FeOOH).
  • the resulting suspension was washed with water to remove interfering anions, such as chloride ions.
  • the carbohydrate or humic acid was added to the suspension before the resulting beta-iron oxy-hydroxide ages.
  • W02009/062993A1 relates to pharmaceutical compositions comprising stabilized iron (III) oxy-hydroxide compounds.
  • Example 1 a premixture of the stabilized iron (III) oxy- hydroxide was obtained by mixing amounts/ratios of an iron oxy-hydroxide suspension prepared according to EP0868125B1 with several excipients. The suspension was subjected to spray drying at 135-200 °C to obtain a flowable powder.
  • W02008/071747A1 discloses a process for preparing iron (lll)-based phosphate adsorbent comprising iron (III) oxy-hydroxide, insoluble carbohydrate, such as starch; and soluble carbohydrate, such as sucrose.
  • the reaction between an aqueous solution of iron (III) salt and an aqueous base is performed in the presence of starch.
  • a precipitate containing iron (III) oxy-hydroxide and starch is isolated and washed three times with water using a decanter centrifuge
  • the resulting iron oxy-hydroxide may be stabilized by adding the soluble carbohydrate to the precipitate before the iron hydroxide ages.
  • the inventors have found a dynamic process based on the use of tangential-flow filtration to desalinate and concentrate the suspension of precipitated polynuclear iron (III) oxy- hydroxide, that allows reducing considerably the production times, avoids product loss, and maintain the stability and the phosphate binding capacity of the polynuclear iron (III)- oxy-hydroxide when the product is produced at industrial scale.
  • the most common uses of tangential-flow filtration are water treatments and purifications of biomolecules where the permeate is of most value.
  • tubular filtration membranes can be effectively used to desalinate the suspension of polynuclear iron (III) oxy-hydroxide by tangential-flow filtration is unexpected since one skilled in the art would have expected that the fine particles of the precipitated polynuclear iron (III) oxy-hydroxide had settled out in the membrane. He would have also expected that the use of a dynamic system that requires a huge amount of energy had produced the degradation of the polynuclear iron (III) oxy-hydroxide.
  • the process of the present invention is easy to set up and can be easily scaled-up, it is economical since the membranes can be reused, and allows achieving high concentrations in the suspension in less time than when centrifugal devices or static decantation systems are used, without degradation of the product.
  • an aspect of the present invention relates to a process for producing an adsorbent for phosphate from aqueous medium comprising polynuclear iron oxy- hydroxide stabilized by at least one constituent that inhibits ageing of the iron oxy- hydroxide, the process comprising the following steps:
  • step b) submitting the suspension of precipitated iron (III) oxy-hydroxide of step a) to a desalinization process through tangential-flow filtration which comprises the steps of: b1 ) pumping the suspension to a tubular filtration membrane which is connected to the feed reservoir to flow parallel to the membrane face, thereby interfering ions are removed from the suspension with the permeate;
  • step b) contacting the resulting aqueous suspension of step b) with at least one constituent that inhibits ageing of the iron oxy-hydroxide selected from the group consisting of one or more carbohydrates and/or humic acid; and
  • interfering ions refers to the chloride ions which are the anions of the trivalent iron compound used as starting material.
  • cross-flow filtration or “tangential-flow filtration” are used interchangeably herein to refer to a separation process that uses a tubular filtration membrane to separate the salts in a liquid on the basis of size and that it is characterized for operation in a recirculation mode where the retentate is returned to the system as feed. It is
  • the permeate is recovered from the system in a container and the retentate is recirculated to the feed tank. Recirculation of the retentate improves salt separation effectiveness.
  • feed or “feed flow” or “feed stream” refer to the suspension comprising polynuclear iron oxy-hydroxide that is delivered to the tubular filtration membrane.
  • permeate refers to the portion of the feed that has permeated through the membrane.
  • retentate refers to the suspension that has been retained by the membrane and is enriched in a retained species.
  • microfiltration membrane is used herein to refer to a membrane that has average diameter pore size in the range of about 0.1 pm to 0.65 pm.
  • pressure inlet is used here to refer to the feed pressure on inlet side of membrane.
  • Pressure outlet is the feed pressure on outlet side of membrane.
  • Permeate pressure is the permeate pressure on outlet side of membrane.
  • the process according to the invention allows producing an adsorbent for adsorbing phosphate from aqueous medium comprising polynuclear iron (III) oxy-hydroxide stabilized by at least one constituent that inhibits ageing of the iron oxy-hydroxide. It comprises several steps disclosed in detail below.
  • the polynuclear iron oxy-hydroxide is polynuclear beta-iron oxy-hydroxide.
  • the process comprises reacting in a feed reservoir a base, which is an alkali metal compound, with iron (III) chloride in water to yield a suspension of a pH of at least 3 of precipitated iron (III) oxy-hydroxide comprising from 50 to 120 L of water per Kg of Fe (FeC ).
  • the reaction product is an iron oxy-hydroxide in colloidal form together with a salt composed of the cation of the base and the anion of the trivalent iron compound.
  • this step is carried out at a temperature comprised from 10 to 25 °C.
  • the process of the present invention is that which comprises mixing an aqueous solution of a base, which is an alkali metal compound, with an aqueous solution of an iron (III) chloride, to form the suspension of precipitated iron (III) oxy-hydroxide.
  • the base is a carbonate or a bicarbonate of an alkali metal such as sodium or potassium.
  • the base is selected from sodium carbonate, and sodium bicarbonate.
  • the base is used in the form of aqueous solution.
  • the pH is comprised from 3 to 10.
  • the pH of the reaction mixture is at least about 6.
  • the pH is 6.5.
  • the amount of base added in step a) is the amount needed to get a pH of at least 3.
  • the suspension in step a) may either be allowed to stand or it can be submitted to intervals of stirring. In a particular embodiment, several cycles of stirring/stop/stirring the suspension of precipitated iron (III) oxy-hydroxide are performed, for instance, five cycles in another particular embodiment, the time of each stirring step and of each stop step is 10-15 minutes.
  • the suspension of precipitated iron oxy-hydroxide is submitted to a desalinization process through tangential-flow filtration to remove interfering ions such as chloride ions.
  • the suspension is maintained under stirring in a feed reservoir at a temperature comprised from 10 to 25 °C to avoid degradation of the product. Preferably, the temperature is from 15 to 25 °C.
  • the concentration of iron in the suspension before the desalinization process is 50-120 L of water per Kg of Fe, which corresponds to around 0.5-2% w/w (g Fe per g of suspension) determined by complexometric titration.
  • the suspension can be submitted directly to the tangential-flow filtration or it can be first diluted and then submitted to the tangential-flow filtration.
  • the concentration of iron in the suspension of step a) is 50 L of water per Kg of Fe (FeC ).
  • an amount from 1 to 70 L of water per Kg of Fe is added before the desalinization step.
  • an amount from 30 to 70 L of water per Kg of Fe is added before the desalinization step.
  • an amount from 50 to 70 L of water per Kg of Fe is added before the desalinization step.
  • the tangential-flow filtration in comparison to the dead-end filtration, allows the solids to be kept in suspension and minimizes the build-up of a filter cake to plug or foul the membrane.
  • filtration tubular membrane refers to a selectively permeable membrane for separating a feed, into a permeate stream and a retentate stream using a tangential flow filtration process.
  • tubular membranes are not self-supporting membranes. They are located on the inside of a tube, made of a special kind of material. This material is the supporting layer for the membrane.
  • the filtration tubular membrane may be a polymeric membrane or a ceramic membrane.
  • the membrane is a polymeric membrane.
  • polymeric membranes are polyvinylidine fluoride (PVDF) and polyether sulfone.
  • PVDF polyvinylidine fluoride
  • the PVDF is commercialized as DuraponeTM.
  • the membrane is a ceramic membrane.
  • the ceramic membrane may either have one canal or a plurality of canals. Ceramic membranes have been known for a considerable number of years.
  • a ceramic membrane comprises a layer of porous ceramic material with a pore diameter of the required size.
  • the average diameter pore is comprised from 0.1 to 0.65 pm. In a particular embodiment the average diameter pore sizes of the membrane is between 0.1 pm and 0.3 pm. In another particular embodiment the average diameter pore is 0.2 pm.
  • the membrane area is comprised from 0.07 m 2 to 1.75 m 2 .
  • the ceramic column has a diameter of 25 mm and a length 1 178 mm. In another particular embodiment, the ceramic column has 23 canals of 3.5 mm of equivalent diameter.
  • the membrane may be supported on a body of coarse pore ceramic material, in particular Zr0 2 -TiC> 2 , and the body and membrane may be sintered together.
  • the support body may be an elongate element, and may have a plurality of parallel longitudinal channels each lined with a thin membrane layer of the fine-pore ceramic material.
  • the desalinization process through tangential flow filtration comprises a first step b1 ) of pumping the suspension of precipitated iron (III) oxy-hydroxide through a tubular filtration membrane which is connected to the feed reservoir, to flow parallel to the membrane face, thereby interfering ions are removed from the suspension with the permeate which passes through the membrane walls.
  • the remainder suspension is flowed back to the feed reservoir (step b2).
  • the concentration of the iron (III) oxy-hydroxide in the suspension increases when eliminating the permeate through the membrane.
  • fresh deionized water is added to the feed reservoir to continue washing the iron oxy-hydroxide
  • the process of the present invention is that which comprises adding an amount of 230 to 460 L of water per Kg of Fe during the desalinization process.
  • the conductivity of the resulting suspension is equal to or less than 3.5 mS. In a particular embodiment, the conductivity of the resulting suspension is equal to or less than 2 mS.
  • step b4) is recirculated to reduce the volume of the suspension;
  • the process according to the invention further comprises reciculating the retentate obtained in step b4) until reaching a volume of 15 to 25 L per Kg of Fe in the feed reservoir.
  • the tangential-flow filtration process is carried out at a pressure inlet comprised from 100 to 300 KPa (1- 3 bars), preferably 200 KPa (2.0 bar) and a pressure outlet comprised from 50 to 200 KPa (0.5 to 2 bars), preferably, 150 KPa (1.5 bar).
  • the permeate pressure is comprised from 75 to 150 KPa (0.75 to 1.5 bars), preferably 20-30 KPa (0.2-0.3 bars), more preferably, 30 KPa (0.3 bars).
  • the tangential-flow filtration is carried out at a temperature comprised from 15 to 25 °C.
  • the filtration is carried out in discontinuous, the suspension is first diluted and then concentrated back to the starting volume. This process is then repeated until the required concentration of salts remaining in the reservoir is reached.
  • the filtration is a continuous process.
  • the continuous process is advantageous since it requires less filtrate volume to achieve the same degree of salt reduction as discontinuous tangential flow filtration. This represents a substantial saving in time.
  • both the discontinuous and the continuous process of desalinization of the present invention are carried out in a short time at industrial scale (150 Kg), generally it it takes about 24 hours.
  • the iron content of the suspension obtained is up to 6% w/w, preferably 2 to 6% w/w, most preferably, around 2-4% w/w (g Fe per g of suspension). In a particular embodiment, around 5.2% w/w of Fe.
  • the pH of the suspension is generally in the range of approximately 6.5 to 7.5 before further constituents are added.
  • the subsequent step comprises contacting the resulting aqueous suspension of step b) with at least one constituent that inhibits ageing of the iron oxy-hydroxide.
  • the at least one constituent that inhibits ageing of the iron oxy-hydroxide is selected from the group consisting of one or more carbohydrates and/or humic acid.
  • the constituent that inhibits ageing of the iron oxy- hydroxide is a carbohydrate selected from the group consisting of starch, sucrose, and mixtures thereof.
  • the constituent is preferably added in solid form.
  • the amount of carbohydrates or humic acid is preferably selected so that at least 0.5 g carbohydrate or humic acid are added per g of iron (calculated as Fe).
  • the maximum content of carbohydrates and/or humic acid is not subject to any limits.
  • the content of carbohydrates is from 5 to 60% by weight (w/w).
  • Soluble carbohydrates can be used such as sugars, e.g. agarose, dextran, dextrin, dextran derivatives, cellulose and cellulose derivatives, saccharose, maltose, lactose, or mannitol.
  • the carbohydrate is starch, sucrose, dextrin, starch, or mixtures thereof.
  • starch as used herein includes any conventionally used starch products (such as potato starch, corn starch, rice starch, tapioca starch) in native, pregelatinized, degraded, modified and derivatized forms.
  • the process comprises a step d) which comprises drying the suspension thus obtained.
  • the drying can be carried out, for example, by concentration in vacuum or by spray drying.
  • the maximum iron content in the final product is around 40% w/w. In a particular embodiment the iron content is at least 20% w/w.
  • the iron content is given, it has been determined by complexometric titration following the method included in the Examples.
  • the polynuclear beta-iron oxy-hydroxide adsorbent obtained following the process of the present invention shows a good phosphate-binding capacity equal to the adsorbent obtained by the process using static washing instead of tangential-flow filtration at small scale, which evidence that following the process of the present invention, the product does not suffer more degradation when it is prepared at industrial scale.
  • the phosphate binding capacity is determined by spectrophotometric analysis as illustrated in the
  • the phosphate adsorbent of the present invention provides a phosphate binding capacity of at least 0.21 mgP/mgFe.
  • the phosphate binding capacity is equal to or higher than 0.23 mgP/mgFe.
  • the preparation process according to the invention allows obtaining a phosphate adsorbent for adsorbing phosphate from aqueous medium comprising polynuclear beta- iron oxy-hydroxide stabilized by at least one constituent that inhibits ageing of the iron oxy-hydroxide.
  • the adsorbents thus obtained are suitable for the adsorption of phosphates from aqueous solutions, for example, for the adsorption of inorganic phosphate and phosphate bonded to foodstuffs from body fluids, chyme and foodstuffs.
  • Diameter 25” - length 1178 mm.
  • Iron content (complexometric titration): The method is based on USP ⁇ 541 > and Ph. Eur. (2.2.20).
  • Test solution Transfer 1.5 g of the sample, accurately weighed, to a 100 ml. volumetric flask, dissolve with 10 mL of cone. HCI and 10 ml. of water at 45°C, allow the solution to cool at room temperature and dilute to volume with water. Prepare in duplicate.
  • Each mL of 0.1 N CuS0 4 is equivalent to 5.58 mg of Iron.
  • Phosphate adsorption method of analysis (by spectrophotometric analysis): The method is based on USP ⁇ 851 > / Ph. Eur. (2.2.25).
  • Phosphate stock solution Transfer 0.717 g of KhhPCU, accurately weighed, into a 500 mL volumetric flask, dissolve and dilute to volume with water. Transfer 5.0 mL of this solution to a 50 mL volumetric flask and dilute to volume with water.
  • Mix solution mix one part of Solution A and six parts of Solution B. Prepare the solution just before use and maintain the solution in an ice bath during the samples preparation.
  • 0.65 ppm Phosphorous solution Transfer 1.0 mL of the phosphate stock solution to a 50 mL volumetric flask and dilute to volume with water.
  • 1.30 ppm Phosphorous solution Transfer 2.0 ml. of the phosphate stock solution to a 50 ml. volumetric flask and dilute to volume with water.
  • 1.96 ppm Phosphorous solution Transfer 3.0 ml. of the phosphate stock solution to a 50 ml. volumetric flask and dilute to volume with water.
  • Phosphorous solution Transfer 5.0 ml. of the phosphate stock solution to a 50 ml. volumetric flask and dilute to volume with water.
  • 0.16 ppm Phosphorous solution Transfer 5.0 ml. of the 0.65 ppm Phosphorous solution to a 20 mL volumetric flask and dilute to volume with water.
  • 0.065 ppm Phosphorous solution Transfer 5.0 mL of the 0.65 ppm Phosphorous solution to a 50 mL volumetric flask and dilute to volume with water.
  • Phosphorous spiking solution Transfer 20.52 g of Na3P04-12H20, accurately weighed, to a 1 L volumetric flask, dissolve and dilute to volume with water.
  • Test solution Accurately weigh 250.0 mg of sample into a 50 mL centrifuge tube, Add 10.0 mL of the Phosphorous spiking solution. Adjust the pH to 3.0 with 6N acetic acid and allow the suspension to react for 2 hours at 37 °C. Thereafter, centrifuge the suspension at 4000 rpm during 10 min. Transfer the supernatant liquor to a 25 mL volumetric flask and dilute to volume with water. Transfer 1.0 mL of this solution to a 100 mL volumetric flask and dilute to volume with water. Prepare the sample in duplicate. Apply the molybdenum blue method to Phosphorous standards solutions and Test solutions.
  • the concentration of iron after the reaction and before the desalinization was 1 8%w/w (g Fe per g of suspension determined by complexometric titration).
  • Second decantation The reaction mixture was settled during 12 hours and 400 L of supernatant were being removed. 400 L of deionized water were added to the reactor and the reaction mixture was stirred for 15 minutes at 10-25°C (30 rpm). Then stirring was stopped.
  • Third decantation The reaction mixture was settled during 17 hours and 660 L of supernatant were being removed. 660 L of deionized water were added to the reactor and the reaction mixture was stirred for 15 minutes at 10-25°C (30 rpm). Then stirring was stopped.
  • the process of desalinisation ended after 6 days.
  • To the reaction mixture (632,75 kg, 4.3% of an iron content, determined by complexometric titration) were added 43,6 Kg of potato starch and 43,8 Kg of sucrose.
  • An aliquot of the reaction mixture was concentrated to 35°C in a rotary evaporator and dried at 35°C under high vacuum.23.2 g of powder with iron content 20.94% (determined by complexometric titration) was obtained.
  • Phosphate binding capacity was determined (by spectrophotometric analysis); 0.22 mgP/mgFe.
  • the rest of the batch was dried by spray-drying (146.34 Kg of Sucroferric oxy-hydroxide was obtained).
  • the suspension was concentrated to 35°C in a rotary evaporator and dried at 35°C under high vacuum. 19.48 g of powder with iron content 16.6% (determined by complexometric titration) was obtained. Phosphate binding capacity was determined (by spectrophotometric analysis); 0.19 mgP/mgFe.
  • comparative Example 1 shows that when the process disclosed in the prior art (cf. Example 1 of US6174442B1 ) is carried out at industrial scale (Batch: 150 Kg), a long time is required to carry out the decantations.
  • Comparative Example 2 shows that in conditions of prolonged stirring the product degrades. Therefore, it is unexpected that a dynamic process such as the tangential filtration used in the present invention where the mixture is continuously stirred could work since it would be expected that the product suffered degradation.

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  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
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Abstract

It relates to a process forproducing an adsorbent for adsorbing phosphate from aqueous medium comprising polynuclear iron (III) oxy-hydroxidestabilized by at least one constituent that inhibits ageing of the iron (III) oxy-hydroxidewhich is based on carrying out the desalinization step process by tangential-flow filtration using tubular filtration membranesto remove salts from the system in the permeate and where the retentate is recirculated to the feed tank. Recirculation of the retentate improves salt separation effectiveness.

Description

Process for preparing an adsorbent for phosphate in aqueous medium
This application claims the benefit of European Patent Application EP18382570 filed 30 July 2018
This invention relates to a process for preparing an adsorbent for phosphate comprising stabilized iron oxy-hydroxide in aqueous medium at industrial scale.
BACKGROUND ART
In a healthy person, normal serum phosphate levels are maintained by the regulation of dietary absorption, bone formation and resorption, equilibration with intracellular stores, and renal excretion. However, when kidney function is impaired, phosphate excretion declines and there is an abnormally elevated level of phosphate in the blood. This condition is known as hyperphosphataemia.
High phosphate levels can be avoided with phosphate binders and dietary restriction of phosphate. If the kidneys are operating normally, a saline diuresis can be induced to renally eliminate the excess of phosphate. In extreme cases, the blood can be filtered in a process called hemodialysis, removing the excess of phosphate.
The phosphate binding capacity of metal oxide oxy-hydroxides is known in the art. Its possible medical application is also known. For instance, WO9201458A1 discloses a method of controlling serum phosphate levels in patients by use of phosphate adsorbers based on iron oxy-hydroxides which bind to ingested phosphate.
Sucroferric oxy-hydroxide (INN; trade name Velphoro, by Vifor Fresenius Medical Care Renal Pharma) is a non-calcium, iron-based phosphate binder used for the control of serum phosphorus levels in adult patients with chronic kidney disease on haemodialysis or peritoneal dialysis. Sucroferric oxy-hydroxide is a complex which consist of polynuclear iron (III) oxy-hydroxide (pn-FeOOH), sucrose, and starch. The pn-FeOOH moiety is chemically not stable and cannot be isolated and stored as an active pharmaceutical ingredient. The sucrose and the starch are also necessary for the processability of the active substance during the manufacturing process of the finished product (cf. Chemical review for Velphoro of the FDA, page 8 or Assessment Report of the EMA, page 12).
Sucroferric oxy-hydroxide was first described in the patent family of US6174442B1 (EP0868125B1 ). This patent describes polynuclear beta-iron hydroxide stabilized by carbohydrates and/or humic acid. The product was prepared by reacting, in a first step, an aqueous solution of iron (III) chloride with an aqueous solution of a base which produced a suspension of polynuclear iron (III) oxy-hydroxide (pn-FeOOH). The resulting suspension was washed with water to remove interfering anions, such as chloride ions. Then, the carbohydrate or humic acid was added to the suspension before the resulting beta-iron oxy-hydroxide ages.
W02009/062993A1 relates to pharmaceutical compositions comprising stabilized iron (III) oxy-hydroxide compounds. In Example 1 a premixture of the stabilized iron (III) oxy- hydroxide was obtained by mixing amounts/ratios of an iron oxy-hydroxide suspension prepared according to EP0868125B1 with several excipients. The suspension was subjected to spray drying at 135-200 °C to obtain a flowable powder.
Finally, W02008/071747A1 discloses a process for preparing iron (lll)-based phosphate adsorbent comprising iron (III) oxy-hydroxide, insoluble carbohydrate, such as starch; and soluble carbohydrate, such as sucrose. The reaction between an aqueous solution of iron (III) salt and an aqueous base is performed in the presence of starch. A precipitate containing iron (III) oxy-hydroxide and starch is isolated and washed three times with water using a decanter centrifuge The resulting iron oxy-hydroxide may be stabilized by adding the soluble carbohydrate to the precipitate before the iron hydroxide ages.
Reproduction by the present inventors of the process of sucroferric oxy-hydroxide product patent (Example 1 of US6174442B1 ) at 150Kg scale, required six days to carry out the required decantations. Thus, there was an exponential increase in the time needed to carry out the washings, which is considered too long to be feasible when working at industrial scale.
From what is known in the art, there is still the need of finding new processes that allow preparing polynuclear iron (III) oxy-hydroxide at a large scale where the desalinization step requires shorter times and where the stability and the phosphate binding capacity of the final product is maintained.
SUMMARY OF THE INVENTION The inventors have found a dynamic process based on the use of tangential-flow filtration to desalinate and concentrate the suspension of precipitated polynuclear iron (III) oxy- hydroxide, that allows reducing considerably the production times, avoids product loss, and maintain the stability and the phosphate binding capacity of the polynuclear iron (III)- oxy-hydroxide when the product is produced at industrial scale. The most common uses of tangential-flow filtration are water treatments and purifications of biomolecules where the permeate is of most value. However, in the process under evaluation the remaining flow (retentate) that passes across the tubular filtration membrane (the suspension of polynuclear iron (III) oxy-hydroxide) is the product of interest. The fact that tubular filtration membranes can be effectively used to desalinate the suspension of polynuclear iron (III) oxy-hydroxide by tangential-flow filtration is unexpected since one skilled in the art would have expected that the fine particles of the precipitated polynuclear iron (III) oxy-hydroxide had settled out in the membrane. He would have also expected that the use of a dynamic system that requires a huge amount of energy had produced the degradation of the polynuclear iron (III) oxy-hydroxide.
Advantageously, the process of the present invention is easy to set up and can be easily scaled-up, it is economical since the membranes can be reused, and allows achieving high concentrations in the suspension in less time than when centrifugal devices or static decantation systems are used, without degradation of the product.
Accordingly, an aspect of the present invention relates to a process for producing an adsorbent for phosphate from aqueous medium comprising polynuclear iron oxy- hydroxide stabilized by at least one constituent that inhibits ageing of the iron oxy- hydroxide, the process comprising the following steps:
a) reacting in a feed reservoir a base, which is an alkali metal compound, with iron (III) chloride in water to yield a suspension of a pH of at least 3 of precipitated iron (III) oxy- hydroxide, wherein the suspension is either allowed to stand or it is submitted to intervals of stirring the suspension and stopping;
b) submitting the suspension of precipitated iron (III) oxy-hydroxide of step a) to a desalinization process through tangential-flow filtration which comprises the steps of: b1 ) pumping the suspension to a tubular filtration membrane which is connected to the feed reservoir to flow parallel to the membrane face, thereby interfering ions are removed from the suspension with the permeate;
b2) flowing back the remainder suspension to the feed reservoir;
b3) adding fresh deionized water to the feed reservoir;
b4) repeat the steps b1 )-b3) until the conductivity of the resulting suspension is equal to or less than 3.5 mS/cm;
c) contacting the resulting aqueous suspension of step b) with at least one constituent that inhibits ageing of the iron oxy-hydroxide selected from the group consisting of one or more carbohydrates and/or humic acid; and
d) drying the suspension obtained in step c). DETAILED DESCRIPTION OF THE INVENTION
All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader definition.
The term "interfering ions" refers to the chloride ions which are the anions of the trivalent iron compound used as starting material.
The terms "cross-flow filtration" or "tangential-flow filtration" are used interchangeably herein to refer to a separation process that uses a tubular filtration membrane to separate the salts in a liquid on the basis of size and that it is characterized for operation in a recirculation mode where the retentate is returned to the system as feed. It is
characterized because the majority of the feed flow travels tangentially across the surface of the membrane, rather than into the membrane. Thus, the permeate is recovered from the system in a container and the retentate is recirculated to the feed tank. Recirculation of the retentate improves salt separation effectiveness.
The terms "feed" or "feed flow" or "feed stream" refer to the suspension comprising polynuclear iron oxy-hydroxide that is delivered to the tubular filtration membrane.
The term "permeate" refers to the portion of the feed that has permeated through the membrane.
The term "retentate" refers to the suspension that has been retained by the membrane and is enriched in a retained species.
The term "microfiltration membrane" is used herein to refer to a membrane that has average diameter pore size in the range of about 0.1 pm to 0.65 pm.
The term“pressure inlet” is used here to refer to the feed pressure on inlet side of membrane.“Pressure outlet” is the feed pressure on outlet side of membrane.“Permeate pressure” is the permeate pressure on outlet side of membrane.
All % weights (%w/w) of iron throughout the description are expressed in relation to the total weight of the suspension, if not indicated otherwise. For the purposes of the present invention, any ranges given include both the lower and the upper end-points of the range. Ranges given, such as temperatures, times, percentages of components and the like, should be considered approximate, unless specifically stated.
The process according to the invention allows producing an adsorbent for adsorbing phosphate from aqueous medium comprising polynuclear iron (III) oxy-hydroxide stabilized by at least one constituent that inhibits ageing of the iron oxy-hydroxide. It comprises several steps disclosed in detail below. In a particular embodiment, in combination with any embodiment above or below, the polynuclear iron oxy-hydroxide is polynuclear beta-iron oxy-hydroxide.
First, the process comprises reacting in a feed reservoir a base, which is an alkali metal compound, with iron (III) chloride in water to yield a suspension of a pH of at least 3 of precipitated iron (III) oxy-hydroxide comprising from 50 to 120 L of water per Kg of Fe (FeC ). Thus, the reaction product is an iron oxy-hydroxide in colloidal form together with a salt composed of the cation of the base and the anion of the trivalent iron compound. Generally, this step is carried out at a temperature comprised from 10 to 25 °C.
In a particular embodiment, the process of the present invention is that which comprises mixing an aqueous solution of a base, which is an alkali metal compound, with an aqueous solution of an iron (III) chloride, to form the suspension of precipitated iron (III) oxy-hydroxide.
In a particular embodiment, the base is a carbonate or a bicarbonate of an alkali metal such as sodium or potassium. In another particular embodiment, the base is selected from sodium carbonate, and sodium bicarbonate. Generally, the base is used in the form of aqueous solution.
In a particular embodiment, the pH is comprised from 3 to 10. In a particular embodiment, the pH of the reaction mixture is at least about 6. In a particular embodiment the pH is 6.5. The amount of base added in step a) is the amount needed to get a pH of at least 3.
The suspension in step a) may either be allowed to stand or it can be submitted to intervals of stirring. In a particular embodiment, several cycles of stirring/stop/stirring the suspension of precipitated iron (III) oxy-hydroxide are performed, for instance, five cycles in another particular embodiment, the time of each stirring step and of each stop step is 10-15 minutes. In the step b) of the process of the present invention, the suspension of precipitated iron oxy-hydroxide is submitted to a desalinization process through tangential-flow filtration to remove interfering ions such as chloride ions. Generally, the suspension is maintained under stirring in a feed reservoir at a temperature comprised from 10 to 25 °C to avoid degradation of the product. Preferably, the temperature is from 15 to 25 °C.
In a particular embodiment, the concentration of iron in the suspension before the desalinization process is 50-120 L of water per Kg of Fe, which corresponds to around 0.5-2% w/w (g Fe per g of suspension) determined by complexometric titration.
Once the reaction is carried out, the suspension can be submitted directly to the tangential-flow filtration or it can be first diluted and then submitted to the tangential-flow filtration. In a particular embodiment of the process, the concentration of iron in the suspension of step a) is 50 L of water per Kg of Fe (FeC ). In another particular embodiment of this process, an amount from 1 to 70 L of water per Kg of Fe is added before the desalinization step. In another particular embodiment, an amount from 30 to 70 L of water per Kg of Fe is added before the desalinization step. In another particular embodiment, an amount from 50 to 70 L of water per Kg of Fe is added before the desalinization step.
Advantageously, the tangential-flow filtration in comparison to the dead-end filtration, allows the solids to be kept in suspension and minimizes the build-up of a filter cake to plug or foul the membrane.
The term "filtration tubular membrane" as used herein refers to a selectively permeable membrane for separating a feed, into a permeate stream and a retentate stream using a tangential flow filtration process. As it is known, tubular membranes are not self-supporting membranes. They are located on the inside of a tube, made of a special kind of material. This material is the supporting layer for the membrane. The filtration tubular membrane may be a polymeric membrane or a ceramic membrane.
In a particular embodiment, the membrane is a polymeric membrane. Examples of polymeric membranes are polyvinylidine fluoride (PVDF) and polyether sulfone. The PVDF is commercialized as Durapone™.
In another particular embodiment, optionally in combination with any embodiment of the invention described above or below, the membrane is a ceramic membrane. The ceramic membrane may either have one canal or a plurality of canals. Ceramic membranes have been known for a considerable number of years. A ceramic membrane comprises a layer of porous ceramic material with a pore diameter of the required size. For the purposes of carrying out the process of the invention the average diameter pore is comprised from 0.1 to 0.65 pm. In a particular embodiment the average diameter pore sizes of the membrane is between 0.1 pm and 0.3 pm. In another particular embodiment the average diameter pore is 0.2 pm.
Generally, the membrane area is comprised from 0.07 m2 to 1.75 m2.
In a particular embodiment the ceramic column has a diameter of 25 mm and a length 1 178 mm. In another particular embodiment, the ceramic column has 23 canals of 3.5 mm of equivalent diameter. The membrane may be supported on a body of coarse pore ceramic material, in particular Zr02-TiC>2, and the body and membrane may be sintered together. In a particular form of ceramic membrane, the support body may be an elongate element, and may have a plurality of parallel longitudinal channels each lined with a thin membrane layer of the fine-pore ceramic material.
The desalinization process through tangential flow filtration comprises a first step b1 ) of pumping the suspension of precipitated iron (III) oxy-hydroxide through a tubular filtration membrane which is connected to the feed reservoir, to flow parallel to the membrane face, thereby interfering ions are removed from the suspension with the permeate which passes through the membrane walls. The remainder suspension is flowed back to the feed reservoir (step b2). The concentration of the iron (III) oxy-hydroxide in the suspension increases when eliminating the permeate through the membrane. Then fresh deionized water is added to the feed reservoir to continue washing the iron oxy-hydroxide
suspension (step b3).
In a particular embodiment, the process of the present invention is that which comprises adding an amount of 230 to 460 L of water per Kg of Fe during the desalinization process.
The steps b1 )-b3) of the tangential-flow filtration are repeated until the required
concentration of salts remaining in the reservoir is reached. Generally, the salt for instance, sodium chloride formed by the reaction is practically eliminated at this stage in such a way that the final product would meet the salt content requirements of a
commercial product. This can be controlled by determining the conductivity of the resulting suspension which should be equal to or less than 3.5 mS. In a particular embodiment, the conductivity of the resulting suspension is equal to or less than 2 mS.
Once the conductivity of the suspension is equal to or less than 3.5 mS, no more water is added according to step b3). If desired the retentate obtained in step b4) is recirculated to reduce the volume of the suspension; In a particular embodiment, the process according to the invention further comprises reciculating the retentate obtained in step b4) until reaching a volume of 15 to 25 L per Kg of Fe in the feed reservoir.
In a particular embodiment, optionally in combination with any embodiments of the invention described above or below, the tangential-flow filtration process is carried out at a pressure inlet comprised from 100 to 300 KPa (1- 3 bars), preferably 200 KPa (2.0 bar) and a pressure outlet comprised from 50 to 200 KPa (0.5 to 2 bars), preferably, 150 KPa (1.5 bar). In another particular embodiment, the permeate pressure is comprised from 75 to 150 KPa (0.75 to 1.5 bars), preferably 20-30 KPa (0.2-0.3 bars), more preferably, 30 KPa (0.3 bars). In a particular embodiment, the tangential-flow filtration is carried out at a temperature comprised from 15 to 25 °C.
In a particular embodiment, the filtration is carried out in discontinuous, the suspension is first diluted and then concentrated back to the starting volume. This process is then repeated until the required concentration of salts remaining in the reservoir is reached.
In another particular embodiment, the filtration is a continuous process. This means that the water is added to the feed reservoir at the same rate as the permeate is generated. In this way the volume in the reservoir remains constant, but the salts that can freely permeate through the membrane are washed away. The continuous process is advantageous since it requires less filtrate volume to achieve the same degree of salt reduction as discontinuous tangential flow filtration. This represents a substantial saving in time. Advantageously, both the discontinuous and the continuous process of desalinization of the present invention are carried out in a short time at industrial scale (150 Kg), generally it it takes about 24 hours.
Generally, the iron content of the suspension obtained (calculated as Fe) is up to 6% w/w, preferably 2 to 6% w/w, most preferably, around 2-4% w/w (g Fe per g of suspension). In a particular embodiment, around 5.2% w/w of Fe.
The pH of the suspension is generally in the range of approximately 6.5 to 7.5 before further constituents are added. The subsequent step comprises contacting the resulting aqueous suspension of step b) with at least one constituent that inhibits ageing of the iron oxy-hydroxide. In a particular embodiment, the at least one constituent that inhibits ageing of the iron oxy-hydroxide is selected from the group consisting of one or more carbohydrates and/or humic acid. In a particular embodiment of the process, the constituent that inhibits ageing of the iron oxy- hydroxide is a carbohydrate selected from the group consisting of starch, sucrose, and mixtures thereof. Generally, the constituent is preferably added in solid form. Generally, the amount of carbohydrates or humic acid is preferably selected so that at least 0.5 g carbohydrate or humic acid are added per g of iron (calculated as Fe). The maximum content of carbohydrates and/or humic acid is not subject to any limits.
Generally, the content of carbohydrates is from 5 to 60% by weight (w/w). Soluble carbohydrates can be used such as sugars, e.g. agarose, dextran, dextrin, dextran derivatives, cellulose and cellulose derivatives, saccharose, maltose, lactose, or mannitol. In a particular embodiment, the carbohydrate is starch, sucrose, dextrin, starch, or mixtures thereof.
The term "starch" as used herein includes any conventionally used starch products (such as potato starch, corn starch, rice starch, tapioca starch) in native, pregelatinized, degraded, modified and derivatized forms.
Finally, the process comprises a step d) which comprises drying the suspension thus obtained. The drying can be carried out, for example, by concentration in vacuum or by spray drying. The maximum iron content in the final product is around 40% w/w. In a particular embodiment the iron content is at least 20% w/w. When in the present document the iron content is given, it has been determined by complexometric titration following the method included in the Examples. The polynuclear beta-iron oxy-hydroxide adsorbent obtained following the process of the present invention shows a good phosphate-binding capacity equal to the adsorbent obtained by the process using static washing instead of tangential-flow filtration at small scale, which evidence that following the process of the present invention, the product does not suffer more degradation when it is prepared at industrial scale. The phosphate binding capacity is determined by spectrophotometric analysis as illustrated in the
Examples of the present invention. Thus, the phosphate adsorbent of the present invention provides a phosphate binding capacity of at least 0.21 mgP/mgFe. In a particular embodiment, the phosphate binding capacity is equal to or higher than 0.23 mgP/mgFe. The preparation process according to the invention allows obtaining a phosphate adsorbent for adsorbing phosphate from aqueous medium comprising polynuclear beta- iron oxy-hydroxide stabilized by at least one constituent that inhibits ageing of the iron oxy-hydroxide.
With regard to the specific conditions for carrying out the process of the invention, the skilled person would know how to adjust the parameters of each of the steps indicated above in the light of the description and examples of the present invention.
The adsorbents thus obtained are suitable for the adsorption of phosphates from aqueous solutions, for example, for the adsorption of inorganic phosphate and phosphate bonded to foodstuffs from body fluids, chyme and foodstuffs.
Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps.
Furthermore, the word "comprise" encompasses the case of "consisting of". Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.
EXAMPLES
Equipment and methods of analysis
Conductimeter: Hand-held conductimeter TDS Meter (CON 6/TDS 6) Eutech Instruments Pte, Ltd. pHmeter: Metrohm 827 pH lab.
Ceramic column
Diameter: 25” - length 1178 mm.
Number of canals : 23
Canals equivalent diameter : 3.5 mm.
Nominal Porosity : 0,2 pm.
Iron content (complexometric titration): The method is based on USP <541 > and Ph. Eur. (2.2.20). Test solution: Transfer 1.5 g of the sample, accurately weighed, to a 100 ml. volumetric flask, dissolve with 10 mL of cone. HCI and 10 ml. of water at 45°C, allow the solution to cool at room temperature and dilute to volume with water. Prepare in duplicate.
Transfer 20.0 mL of the Test solution to a 250 mL glass vessel, add 0.85 g of ammonium peroxodisulphate, 100 mL of water and dissolve. Add 10 mL glacial acetic acid and adjust to pH=4.7 with 32% NaOH. Introduce the glass vessel in a water bath at 45°C a few minutes, add 20.0 mL of 0.1 N EDTA, stir the sample and introduce it in the water bath 5 minutes more. Titrate with 0.1 N CuS04, determining the endpoint potentiometrically, using a combine electrode of copper.
A blank test is carried out in the same conditions. The ammonium peroxodisulfate is not added.
Each mL of 0.1 N CuS04 is equivalent to 5.58 mg of Iron.
Phosphate adsorption method of analysis (by spectrophotometric analysis): The method is based on USP <851 > / Ph. Eur. (2.2.25).
Preparation of Solutions:
Phosphate stock solution: Transfer 0.717 g of KhhPCU, accurately weighed, into a 500 mL volumetric flask, dissolve and dilute to volume with water. Transfer 5.0 mL of this solution to a 50 mL volumetric flask and dilute to volume with water.
10% Ascorbic acid solution (Solution A): Transfer 0.50 g of ascorbic acid into a 500 mL volumetric flask, dissolve and dilute to volume with water. 0.42% Ammonium molybdate solution (Solution B): Transfer 4.2 g of ammonium molybdate tetrahydrate to a 1 L volumetric flask, add 28.6 mL of cone. hhSCU and dilute to volume with water.
Mix solution: mix one part of Solution A and six parts of Solution B. Prepare the solution just before use and maintain the solution in an ice bath during the samples preparation.
Phosphorous standard solutions:
0.65 ppm Phosphorous solution: Transfer 1.0 mL of the phosphate stock solution to a 50 mL volumetric flask and dilute to volume with water. 1.30 ppm Phosphorous solution: Transfer 2.0 ml. of the phosphate stock solution to a 50 ml. volumetric flask and dilute to volume with water. 1.96 ppm Phosphorous solution: Transfer 3.0 ml. of the phosphate stock solution to a 50 ml. volumetric flask and dilute to volume with water.
2.61 ppm Phosphorous solution: Transfer 4.0 ml. of the phosphate stock solution to a 50 ml. volumetric flask and dilute to volume with water.
3.26 ppm Phosphorous solution: Transfer 5.0 ml. of the phosphate stock solution to a 50 ml. volumetric flask and dilute to volume with water.
0.16 ppm Phosphorous solution: Transfer 5.0 ml. of the 0.65 ppm Phosphorous solution to a 20 mL volumetric flask and dilute to volume with water.
0.065 ppm Phosphorous solution: Transfer 5.0 mL of the 0.65 ppm Phosphorous solution to a 50 mL volumetric flask and dilute to volume with water. Phosphorous spiking solution: Transfer 20.52 g of Na3P04-12H20, accurately weighed, to a 1 L volumetric flask, dissolve and dilute to volume with water.
Test solution: Accurately weigh 250.0 mg of sample into a 50 mL centrifuge tube, Add 10.0 mL of the Phosphorous spiking solution. Adjust the pH to 3.0 with 6N acetic acid and allow the suspension to react for 2 hours at 37 °C. Thereafter, centrifuge the suspension at 4000 rpm during 10 min. Transfer the supernatant liquor to a 25 mL volumetric flask and dilute to volume with water. Transfer 1.0 mL of this solution to a 100 mL volumetric flask and dilute to volume with water. Prepare the sample in duplicate. Apply the molybdenum blue method to Phosphorous standards solutions and Test solutions. Transfer 5.0 mL of the each solution (Phosphorous standards solutions or Test solutions) to a 20 mL volumetric flask, add 7.0 mL of the Mix solution and dilute to volume with water. Incubate the solution 20 min at 45°C to complete color development. Measure the absorbance of the solutions at 820 nm using a spectrophotometer.
Calculate the P content in the supernatant liquor of the samples by interpolation in the linear curve obtained with the Phosphorous standards solutions. The P adsorbed in sample will be the difference between the P spiked in sample and the P in the supernatant liquor. Express the results of the phosphate in-vitro adsorption as mg P/mg Fe. The in-vitro phosphate adsorption at pH=3.0 must be > 0.21 mg P/mg Fe.
Example 1 : Preparation of iron (III) oxy-hydroxide (Batch: 500 q, scale: 10 L)
In a 10 L reactor, it was added 252 g of sodium carbonate and 1.49 L of deionized water under mechanical stirring at 20°C. A solution was formed. To this solution, it was slowly added a solution of iron trichloride in deionized water (500 g of a solution of FeC (12.6% of iron) and 1.38L of deionized water). Temperature of the reaction mixture was controlled to 20°C during the addition. The precipitation of FeOOH took place. The reaction mixture was stirred for another 10-15 minutes at 10-25°C. Then, stirring was stopped for another 10-15 minutes. Another five cycles of stirring/stop/stirring were performed. pH of the reaction mixture was measured (pH:6.5).
4L of deionized water was added to the reaction mixture and it was kept under stirring during desalinization process through tangential flow filtration. The concentration of iron after the reaction and before the desalinization was 0.9%w/w (g iron per g of suspension, determined by complexometric titration). Conductivity of the reaction mixture was 43 mS/cm. The reaction mixture, agitated at 100 rpm, was pumped through a ceramic column at 15-25°C and re-circulated (Pressure inlet= 2.0 bar, Pressure outlet = 1.5 bar, Pressure permeate= 0.2-0.3 bar). A total of 28.5 L of deionized water were continuously added to the reactor during desalinization. The process of desalinization ended after 1 hour 30 minutes. After 34 L of permeate were discharged, the conductivity of the reaction mixture was 1.7 mS/cm and the final volume of the reaction mixture was concentrated to 1.4 L. the process of desalinization ended after 1 hour 30 min. To an aliquot of 53.87g of the reaction mixture (3.23% of iron content, determined by complexometric titration) were added 8.18 g of potato starch and 8.12 g of sucrose. The suspension was concentrated to 35°C in a rotary evaporator and dried at 35°C under high vacuum. 23.2 g of powder with iron content 20.94% (determined by complexometric titration) was obtained. Phosphate binding capacity was determined (by spectrophotometric analysis); 0.23 mgP/mgFe.
Example 2: Preparation of iron (III) oxy-hydroxide (Batch: 3 kg)
In a 20L reactor, it was added 1.44 Kg of sodium carbonate and 8,5 L of deionized water under mechanical stirring at 20°C. A solution was formed. To this solution, it was slowly added a solution iron trichloride in deionized water (3 Kg of a solution of FeC (12.0% of iron) and 7,9 L of deionized water). Temperature of the reaction mixture was controlled to 15-20°C during the addition. The precipitation of FeOOH took place. The reaction mixture was stirred for another 10-15 minutes at 10-25°C. Then, stirring was stopped for another 10-15 minutes. Five other cycles of stirring/stop/stirring were performed. pH of the reaction mixture was measured (pH: 6.2). Conductivity of the reaction mixture was 74 mS/cm. The concentration of iron after the reaction and before the desalinization was 1 8%w/w (g Fe per g of suspension determined by complexometric titration). The reaction mixture, agitated at 30-60 rpm, was pumped through a ceramic column at 15-25°C and recirculated (Pressure inlet= 2.0 bar, Pressure outlet= 1.5 bar, Pressure permeate= 0.2- 0.3 bar). 85 L of deionized water were continuously added to the reactor during
desalinisation. After 96 L of permeate were discharged, the conductivity of the reaction mixture is 3.2 mS/cm and the final volume of the reaction mixture was concentrated to 5.5L. The process of desalinization ended after 6 hours. To an aliquot of 67.5 g of the reaction mixture (5.19% of iron content, determined by complexometric titration) were added 5.71 g of potato starch and 5.71 g of sucrose. The suspension was concentrated to 35°C in a rotary evaporator and dried at 35°C under high vacuum. 18.7 g of powder with iron content 19.3% (determined by complexometric titration) was obtained. Phosphate binding capacity was being determined (by spectrophotometric analysis); 0.26 mgP/mgFe.
Comparative Example 1 : Preparation of iron (III) oxy-hydroxide following the process disclosed in Example 1 of US6174442B1 (Batch: 150 Kg)
In a 2000 L reactor, it was added 132 Kg of sodium carbonate and 619 L of deionized water under mechanical stirring at 20°C. A solution was formed. It was transferred to another 2000 L reactor of through 0.45 micron filter. To this solution, it was slowly added a solution iron trichloride in deionized water (275 Kg of a solution of FeC (12.0% of iron) and 542 L of deionized water). Temperature of the reaction mixture was controlled to 15°C during the addition. The precipitation of FeOOH took place. The reaction mixture was stirred for another 10-15 minutes at 10-25°C (30 rpm). Then, stirring was stopped for another 10-15 minutes. Five other cycles of stirring/stop/stirring were performed. pH of the reaction mixture was measured (pH: 6.7). 600L of deionized water was added to the reaction mixture and it was kept under stirring for 10 minutes.
First decantation: The reaction mixture was settled during 12 hours and 514 L of supernatant were being removed. 514 L of deionized water were added to the reactor and the reaction mixture was stirred for 15 minutes at 10-25°C (30 rpm). Then stirring was stopped.
Second decantation: The reaction mixture was settled during 12 hours and 400 L of supernatant were being removed. 400 L of deionized water were added to the reactor and the reaction mixture was stirred for 15 minutes at 10-25°C (30 rpm). Then stirring was stopped. Third decantation: The reaction mixture was settled during 17 hours and 660 L of supernatant were being removed. 660 L of deionized water were added to the reactor and the reaction mixture was stirred for 15 minutes at 10-25°C (30 rpm). Then stirring was stopped.
Fourth decantation: The reaction mixture was settled during 17 hours and 853 L of supernatant were being removed. 853 L of deionized water were added to the reactor and the reaction mixture was stirred for 15 minutes at 10-25°C (30 rpm). Then stirring was stopped.
Fifth decantation: The reaction mixture was settled during 22 hours and 1250 L of supernatant were being removed. Conductivity of the reaction mixture was 23,5 mS/cm.1250 L of deionized water were added to the reactor and the reaction mixture was stirred for 15 minutes at 10-25°C (30 rpm). Then stirring was stopped.
Sixth decantation: The reaction mixture was settled during 24 hours and 1250 L of supernatant were removed. Conductivity of the reaction mixture was 11 ,3 mS/cm.
1250 L of deionized water were being added to the reactor and the reaction mixture was stirred for 15 minutes at 10-25°C (30 rpm). Then stirring was stopped.
Seventh decantation: The reaction mixture was settled during 22 hours and 1300 L of supernatant were removed. Conductivity of the reaction mixture was 4,74 mS/cm. 1300 L of deionized water were being added to the reactor and the reaction mixture was stirred for 15 minutes at 10-25°C (30 rpm). Then stirring was stopped.
Eighth decantation: The reaction mixture was settled during 24 hours and 1300 L of supernatant were removed. Conductivity of the reaction mixture was 2,12 mS/cm.
The process of desalinisation ended after 6 days. To the reaction mixture (632,75 kg, 4.3% of an iron content, determined by complexometric titration) were added 43,6 Kg of potato starch and 43,8 Kg of sucrose. An aliquot of the reaction mixture was concentrated to 35°C in a rotary evaporator and dried at 35°C under high vacuum.23.2 g of powder with iron content 20.94% (determined by complexometric titration) was obtained. Phosphate binding capacity was determined (by spectrophotometric analysis); 0.22 mgP/mgFe. The rest of the batch was dried by spray-drying (146.34 Kg of Sucroferric oxy-hydroxide was obtained).
Comparative Example 2: Evaluation of the stability of a suspension of FeOOH
(stirrinq/non-stirrinq) In a 500 ml. reactor, it is added 28.8 g of sodium carbonate and 171 mL of deionized water under mechanical stirring at 20°C (250 rpm). To this solution, it was slowly added a solution iron trichloride in deionized water (60 g of a solution of FeCI3 (12.0% of iron) and 158 mL of deionized water). Temperature of the reaction mixture was controlled to 15°C during the addition. The precipitation of FeOOH took place. The reaction mixture was stirred for another 10-15 minutes at 10-25°C. Then, stirring was stopped for another 10-15 minutes. Five other cycles of stirring/stop/stirring were performed. pH of the reaction mixture was measured (pH: 7.22). The amount of suspension (suspension A) was divided in two parts:
Blank stability data:
180 mL of deionized water was added to 195 mL of the above suspension (suspension A) and treated with stirring (250 rpm) for 15 min, at 20-25°C, allowed to stand for 1 hour. The supernatant liquid was removed by decantation. 180 mL of deionized water was added to the reaction mixture. This procedure was repeated five times. Conductivity of the suspension was measured after desalinisation; 3 mS/cm. 6.95 g of potato starch and 6.89 g of sucrose were added to the reaction mixture. The suspension was concentrated to 35°C in a rotary evaporator and dried at 35°C under high vacuum.20.69 g of powder with iron content 18.3% (determined by complexometric titration) was obtained. Phosphate binding capacity was determined (by spectrophotometric analysis); 0.28 mgP/mgFe.
Stability 5 days under stirring:
180 mL of deionized water was added to 195 mL of (suspension A) and it was kept under mechanical stirring (250 rpm) for 96 hours (4 days) at 20-25°C. Afterwards, it was allowed to stand for 1 hour. The supernatant liquid was removed by decantation. 180 mL of deionized water was added to the reaction mixture, treated with stirring (250 rpm) for 15 min, at 20-25°C, allowed to stand for 1 hour. This procedure was repeated five times. Conductivity of the suspension was measured after desalinisation; 1 ,5 mS/cm. 7.42 g of potato starch and 7.36 g of sucrose is added to the reaction mixture. The suspension was concentrated to 35°C in a rotary evaporator and dried at 35°C under high vacuum. 19.48 g of powder with iron content 16.6% (determined by complexometric titration) was obtained. Phosphate binding capacity was determined (by spectrophotometric analysis); 0.19 mgP/mgFe.
This Example illustrates the fact that by maintaining under stirring the suspension of FeOOH the time needed to make the decantations in comparative Example 1
(reproduction of the Example 1 of US6174442B1 ), the suspension of FeOOH degrades.
In short, comparative Example 1 shows that when the process disclosed in the prior art (cf. Example 1 of US6174442B1 ) is carried out at industrial scale (Batch: 150 Kg), a long time is required to carry out the decantations. Comparative Example 2 shows that in conditions of prolonged stirring the product degrades. Therefore, it is unexpected that a dynamic process such as the tangential filtration used in the present invention where the mixture is continuously stirred could work since it would be expected that the product suffered degradation.
REFERENCES CITED IN THE APPLICATION - WO9201458A1
- US6174442B1
- EP0868125B1
- W02009/062993A1
- W02008/071747A1
- Chemical review for Velphoro of the FDA, page 8 or Assessment Report of the EMA, page 12
- USP <541 > and Ph. Eur. (2.2.20).
- USP <851 > / Ph. Eur. (2.2.25).

Claims

1. A process for producing an adsorbent for phosphate from aqueous medium comprising polynuclear iron (III) oxy-hydroxide stabilized by at least one constituent that inhibits ageing of the iron oxy-hydroxide, the process comprising the following steps: a) reacting in a feed reservoir a base, which is an alkali metal compound, with iron (III) chloride in water to yield a suspension of a pH of at least 3 of precipitated iron (III) oxy- hydroxide, wherein the suspension is either allowed to stand or it is submitted to intervals of stirring the suspension and stopping; b) submitting the suspension of precipitated iron (III) oxy-hydroxide of step a) to a desalinization process through tangential flow filtration which comprises the steps of: b1 ) pumping the suspension to a tubular filtration membrane which is connected to the feed reservoir to flow parallel to the membrane face, thereby interfering ions are removed from the suspension with the permeate; b2) flowing back the remainder suspension to the feed reservoir; b3) adding fresh deionized water to the feed reservoir; and b4) repeat the steps b1 )-b3) until the conductivity of the resulting suspension is equal to or less than 3.5 mS/cm; c) contacting the resulting aqueous suspension of step b) with at least one constituent that inhibits ageing of the iron oxy-hydroxide selected from the group consisting of one or more carbohydrates and/or humic acid; and d) drying the suspension obtained in step c).
2. The process according to claim 1 , which comprises mixing an aqueous solution of a base, which is an alkali metal compound, with an aqueous solution of an iron (III) chloride, to form the suspension of precipitated iron (III) oxy-hydroxide.
3. The process according to any of the claims 1-2, wherein the base is either a carbonate or a bicarbonate of an alkali metal.
4. The process according to any of the claims 1-3, wherein the pH of the suspension of step a) is comprised from 3 to 10.
5. The process according to any of the claims 1-4, wherein step a) comprises intervals of stirring the suspension and stopping.
6. The process according to any of the claims 1-5, wherein the concentration of iron in the suspension before the desalinization process is 50-120 L of water per Kg of Fe.
7. The process according to any of the claims 1-6, wherein the tubular filtration membrane is a ceramic membrane comprising either one canal or a plurality of canals.
8. The process according to claim 7, wherein the pore size of the membrane is between 0.1 pm and 0.65 pm.
9. The process according to any of the claims 1-8, wherein in the tangential-flow filtration the pressure inlet is from 100 to 300 KPa, the pressure outlet is from 50 to 200 KPa; the permeate pressure is 75-150 KPa.
10. The process according to any of the claims 1-9, wherein the desalinization process is carried out at a temperature from 15 to 25 °C.
1 1. The process according to any of the claims 1-10, wherein the tangential-flow filtration is a continuous process.
12. The process according to any of the claims 1-1 1 , wherein the process comprises adding an amount of 230 to 460 L of water per Kg of Fe during the desalinization process.
13. The process according to any of the claims 1-2 wherein the conductivity of the suspension resulting from step b4) is equal to or less than 3.5 mS.
14. The process according to any of the claims 1-13, comprising a step comprising the recirculation of the retentate obtained in step b4), and wherein the recirculation is carried out until reaching a volume of 15 to 25 L per Kg of Fe in the feed reservoir.
15. The process according to any of the claims 1-14, wherein the polynuclear iron (III) oxy-hydroxide is beta-iron (III) oxy-hydroxide.
EP19742785.9A 2018-07-30 2019-07-29 Process for preparing an adsorbent for phosphate in aqueous medium Withdrawn EP3829761A1 (en)

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EP3932535A1 (en) * 2020-07-01 2022-01-05 Vifor Fresenius Medical Care Renal Pharma, Ltd. Manufacturing method for polynuclear iron compounds stabilized by carbohydrates and/or humic acid

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US4970079A (en) 1989-06-05 1990-11-13 Purdue Research Foundation Method and composition of oxy-iron compounds for treatment of hyperphosphatemia
DE19547356A1 (en) 1995-12-19 1997-06-26 Vifor Int Ag Adsorbent for phosphate from aqueous medium, its preparation and use
PT2319804E (en) * 2006-12-14 2014-11-24 Novartis Ag Iron(iii)-carbohydrate based phosphate adsorbent
TWI468167B (en) 2007-11-16 2015-01-11 威佛（國際）股份有限公司 Pharmaceutical compositions

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