DESC:RELATED PATENT APPLICATION(S):

This application claims the priority to and benefit of Indian Patent Application No. 202041056388 filed on December 24, 2020; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION:

The present invention relates to a novel process for the preparation of Sodium zirconium cyclosilicate. More specifically, the invention relates to a novel process for preparation of ZS-9 form of sodium zirconium cyclosilicate having less metal impurities, particularly lead impurities.

BACKGROUND OF THE INVENTION:

Sodium zirconium cyclosilicate has the chemical formula Na~1.5H~0.5ZrSi3O9•2–3H2O. Sodium zirconium cyclosilicate exists in different forms. Among other forms, ZS-9 form of sodium zirconium cyclosilicate exhibits a high capacity to selectively entrap monovalent cations specifically excess potassium and ammonium ions in gastrointestinal tract. The high specificity of ZS-9 form is due to the chemical composition and diameter of the micro pores. ZS-9 form of sodium zirconium cyclosilicate microporous ion exchangers is approved for the treatment of hyperkalemia. Sodium zirconium cyclosilicate is non-absorbed, odorless, insoluble powder.

The Product is first disclosed in the Patent US 5338527 and discloses a process for the preparation of the same thereof. There are different forms of sodium zirconium cyclosilicate disclosed in the Patent US5891417. Among the forms, ZS-9 form is particularly used for absorption of potassium and ammonium ions from the gastrointestinal tract. During the preparation of ZS-9 of Sodium zirconium cyclosilicate other undesired crystalline forms are also formed. The undesired forms have to be controlled during the manufacturing process itself since reprocessing the product is difficult as it is insoluble in all solvents.

The Patent US 9662352 discloses the preparation of Sodium zirconium cyclosilicate by hydrothermal crystallizing of the reaction mixture prepared by combining zirconium acetate solution, source of silica, alkali metal hydroxide and water characterized by a specialized process and reactor configuration that lifts and more thoroughly suspends crystals throughout the reaction. This Patent also discloses the use and proper positioning of a baffle-like structure in relation to the agitator within the crystallization vessel and the cooling jacket comprising serpentine-type coils proximate to the outside wall of the reaction vessel in the reactor vessel to produces the desired ZS-9 form.

Besides the availability of process for the preparation of sodium zirconium cyclosilicate in state of the art, there is a need for a process for the preparation of pure sodium zirconium cyclosilicate ZS-9 form that is economically significant.

OBJECTS OF THE INVENTION:

The primary object of the present invention is to provide a process for the preparation of sodium zirconium cyclosilicate in a reactor.

Another object of the present invention is to provide an improved process for the preparation of sodium zirconium cyclosilicate with less metal impurities.

Another object of the invention is to provide a novel process for the preparation of ZS-9 crystal form of sodium zirconium cyclosilicate which is substantially free from the other forms such as ZS-7 and ZS-8.

Yet another object of the invention is to provide a pure sodium zirconium cyclosilicate crystal ZS-9 form having less metal impurities, particularly lead impurities less than about 0.5 ppm, preferably about 0.33 ppm.

SUMMARY OF THE INVENTION:

Accordingly, the present invention discloses and describes a novel process for the preparation of sodium zirconium cyclosilicate, more specifically ZS-9 form of sodium zirconium cyclosilicate which is substantially free from other forms such as ZS-7 and ZS-8 and having less metal impurities, particularly lead impurities less than about 0.5 ppm, preferably about 0.33 ppm.

A process for the preparation of sodium zirconium cyclosilicate form ZS-9 which is substantially free of other forms ZS-7 and ZS-8, wherein the process is performed in a reactor.

A pure sodium zirconium cyclosilicate ZS-9 form having less metal impurities are obtained by the process of the invention described, which is economically significant.

One aspect of the present invention is to provide a process for the preparation of sodium zirconium cyclosilicate form ZS-9, wherein the process is performed in a reactor, comprising the steps of:
(i) mixing a colloidal silica solution and sodium hydroxide solution in the reactor;
(ii) adding zirconium acetate solution to the mixture provided in step (i);
(iii) optionally, seeding crystalline form ZS-9 material obtained from previous batches in the mixture obtained in step (ii);
(iv) applying nitrogen pressure to the mixture provided in step (ii) or step (iii);
(v) stirring the reaction mixture obtained in step (iv) with the agitator at 150 to 350 RPM in the reactor at temperatures of 170° C to 250° C; and
(vi) obtaining sodium zirconium cyclosilicate from the reactor,
wherein the said reactor comprises:
? a reaction vessel having a volume of at least 2-L with an inside and outside wall;
? an agitator within the reaction vessel; and
? either a cooling jacket comprising serpentine-type coils proximate to the outside wall of the reaction vessel; or at least one baffle-like structure proximate the inside wall of the reaction vessel and placed in operative proximity to the agitator, to provide uniform suspension of solids within the reaction vessel,
wherein the obtained sodium zirconium cyclosilicate form ZS-9 is free of other forms ZS-7 and ZS-8 and have lead impurities less than about 0.5 ppm.

The stirring of the reaction mixture in step (i) or step (ii) of the said process, is carried out in the range of 100 to 500 RPM by using the agitator

In step (iv) of the aid process, 10 Kg/cm2 of nitrogen pressure of reaction mixture is applied.

The pH of the reaction mass in step (vi) is adjusted about 5 to 6 by dilute acid, wherein the dilute acid is dilute hydrochloric acid.

Preferably the obtained sodium zirconium cyclosilicate is washed with one or multiple washings with purified water.

The obtained sodium zirconium cyclosilicate is prepared within a small reactor having volume of 2-L to 10-L.

The obtained sodium zirconium cyclosilicate form ZS-9 have the lead impurities less than about 0.33 ppm.

The obtained sodium zirconium cyclosilicate is a white free flowing powder and less than 3 % of sodium zirconium cyclosilicate particles diameter is below than 3 µm.

The potassium exchange capacity of sodium zirconium cyclosilicate is about 2.7 to 3.5 mEq/g.

BRIEF DESCRIPTION OF FIGURES:

Fig-1: The XRPD pattern of sodium zirconium cyclosilicate resulted in Example-1
Fig-2: The XRPD pattern of sodium zirconium cyclosilicate resulted in Example-2
Fig-3: The Particle size distribution of sodium zirconium cyclosilicate resulted in Example-2 by Malvern Instruments Limited.
DETAILED DESCRIPTION OF THE INVENTION:

Accordingly, in one aspect the present invention discloses and describes an improved process for the preparation sodium zirconium cyclosilicate, more particularly ZS-9 form of sodium zirconium cyclosilicate which is substantially free from the other forms such as ZS-7 and ZS-8 and having less metal impurities less than about 0.5 ppm, preferably about 0.33 ppm.

A pure sodium zirconium cyclosilicate ZS-9 form having less metal impurities, particularly lead impurities less of about 0.33 ppm are obtained by the process of the invention as described herein.

A process for the preparation of sodium zirconium cyclosilicate in a reactor, comprising the steps of:
(i) mixing a colloidal silica solution and sodium hydroxide solution in the reactor;
(ii) adding zirconium acetate solution to the mixture provided in step (i);
(iii) optionally, seeding crystalline form ZS-9 material obtained from previous batches in the mixture obtained in step (ii);
(iv) applying nitrogen pressure to the mixture provided in step (ii) or step (iii);
(v) stirring the reaction mixture obtained in step (iv) with the agitator at 150 to 350 RPM in the reactor at temperatures of 170° C to 250° C; and
(vi) obtaining sodium zirconium cyclosilicate from the reactor,
wherein the said reactor comprises:
? a reaction vessel having a volume of at least 2-L with an inside and outside wall;
? an agitator within the reaction vessel; and
? either a cooling jacket comprising serpentine-type coils proximate to the outside wall of the reaction vessel; or at least one baffle-like structure proximate the inside wall of the reaction vessel and placed in operative proximity to the agitator, to provide uniform suspension of solids within the reaction vessel.

Step (i)
Step (i) of the present invention involves mixing a colloidal silica solution and sodium hydroxide solution in the reactor.

In one embodiment, providing a mixture of colloidal silica solution and sodium hydroxide solution in the reactor according to the step (i) of the present invention is preferably done by adding colloidal silica solution to a solution of sodium hydroxide in the reactor and stirring the mixture in the range of 100 to 500 RPM by using agitator for 20-60 minutes at temperatures at 25°C to 45°C.

Step (ii)
Step (ii) of the present invention involves adding zirconium acetate solution to the mixture provided in step (i).

In one embodiment, the addition of zirconium acetate solution to the mixture according to the step (ii) of the present invention may be done directly into the reactor, preferably by slow addition of zirconium acetate in the reactor with stirring in the range of 100 to 500 RPM by agitator for 30-50 minutes.

Step (iii)
Step (iii) of the present invention involves optional seeding of crystalline form ZS-9 material obtained from previous batches in the mixture obtained in step (ii).

Preferably the process involves seeding of crystalline form ZS-9 material obtained from previous 10 batches in the reaction mixture obtained in step (ii).

Step (iv)
Step (iv) of the present invention involves applying nitrogen pressure to the mixture provided in step (ii) or step (iii).

In one embodiment, preferably 10 Kg/cm2 of nitrogen pressure is applied in step (ii) or step (iii) of the present invention and maintained during the step (iv).

Step (v)
Step (v) of the present invention involves stirring the reaction mixture obtained in step (iv) with the agitator at 150 to 350 RPM in the reactor at temperatures at 170°C to 250°C.

In one embodiment the step of stirring the reaction mixture obtained in step (iv) according to the step (v) is carried out in the range of 150 to 350 RPM by the agitator for 30 to 50 hours at temperatures above 170°C, preferably above 200°C, more preferably in the range of 170°C to 250°C.

Step (vi)
Step (vi) of the present invention involves obtaining sodium zirconium cyclosilicate from the reactor.

In one embodiment, preferably the pH of the reaction mass is adjusted to 4.5 to 5.5 by dilute acid solution after obtaining sodium zirconium cyclosilicate from the reactor as in step (vi) of the present invention, wherein dilute acid is dilute hydrochloric acid.

Preferably the obtained sodium zirconium cyclosilicate is washed with one or multiple washings with water.

Surprisingly the present inventors found that the process for achieving form ZS-9 of sodium zirconium cyclosilicate from the solution of silica and zirconium acetate, could be performed either in a cooling jacket comprising serpentine-type coils proximate to the outside wall of the reaction vessel; or at least one baffle-like structure proximate the inside wall of the reaction vessel and placed in operative proximity to the agitator within the reaction vessel. Whereas the previous process as described in the Patent US 9457050 ensures the presence of both the cooling jacket comprising serpentine-type coils proximate to the outside wall of the reaction vessel; and at least one baffle-like structure proximate the inside wall of the reaction vessel and placed in operative proximity to the agitator for achieving ZS-9 of sodium zirconium cyclosilicate either from colloidal silica and zirconium acetate.

The present inventors also found that the present process for achieving ZS-9 of sodium zirconium cyclosilicate free of other forms, from silica and zirconium acetate, results in sodium zirconium cyclosilicate containing less metal impurities, particularly lead impurities less than about 0.5 ppm, preferably 0.33 ppm.

Unexpectedly the process of the present invention is achieved in smaller reaction vessels of volume such as 2L (2-Litre) to 10L (10-Litre), whereas the prior art process as disclosed in the Patent US 9457050 is not suitable in smaller reaction vessels of volume lesser than 20 L (20-Litre).

The process of the present invention is consistently achieved in smaller reaction vessels of volume such as 2L (2-Litre) to 10L (10-Litre) could be achieved in large scale manufacturing of the product.

Sodium zirconium cyclosilicate resulted in the process of the present invention is the ZS-9 form of sodium zirconium cyclosilicate substantially free of the other forms such as ZS-7 and ZS-8.
A pure sodium zirconium cyclosilicate ZS-9 crystal form having the peaks pattern (2 Theta) are as shown in PXRD of Figure-1 and Figure-2. Further Sodium zirconium cyclosilicate ZS-9 crystal form particle size distribution is as shown in Figure-3.

The measured potassium exchange capacity of sodium zirconium cyclosilicate of the present invention is about 2.7 to 4 mEq/g, preferably 2.7 to 3.5 mEq/g.

Sodium zirconium cyclosilicate resulted in the process of the present invention is a white free flowing powder wherein less than 3% of sodium zirconium cyclosilicate particles has the diameter below 3 µm.

Preferably sodium zirconium cyclosilicate resulted in the process of the present invention is the ZS-9 form of sodium zirconium cyclosilicate containing lead impurities less than about 0.5 ppm, preferably about 0.33 ppm.

The present invention is explained in detail with reference to the following examples described below, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.

EXAMPLES:

Example-1:

Sodium hydroxide solution (178 gm of sodium hydroxide in 1250 ml of water) was added to 5L-autoclave reactor having an agitator within the reaction vessel and fitted with a cooling jacket having a serpentine configuration to provide a baffle-like structure within the reactor. Silica solution (435 gm) was added slowly into the reactor at 500 RPM by the agitator for 40 ± 10 minutes at 35°C and then stirred for 500 RPM for 40 ± 10 minutes. Zirconium acetate solution (250 gm) was slowly into the reaction mixture at 170-230 RPM by the agitator for 40 ± 10 minutes and then stirred for 40 ± 10 minutes with 170-230 RPM. After the stirring of the rection mixture, the reactor was sealed; 10 Kg of nitrogen pressure was applied; heated to 220°C; and the reaction mixture was stirred at 170-230 RPM by the agitator at 34-38 kg pressure for 40 to 48 hours. The progress of the reaction was monitored by PXRD. After the completion reaction, the reaction mass was cooled to 40 ± 5°C. The solid was filtered under vacuum, slurried in water (1000 ml) and stirred at 35 ± 5°C for 40 ± 10 minutes. The solid was then filtered and slurried in water (1000 ml). The pH of the contents was adjusted to 5.0 to 5.5 by 25% dilute hydrochloric acid; stirred at 35 ± 5°C for 40 ± 10 minutes and filtered. The filtered solid was again slurried in water (750 ml) and stirred at 35 ± 5°C for 40 ± 10 minutes. The solid was filtered and dried at 85 ± 5°C under vacuum for 5 hours ± 30 minutes. Yield: 136 gm; The zirconium content was about 21%; the silicon content was about 20%; and the sodium content was about 9%; Elemental impurities by ICP-MS: Lead: 0.24 ppm; Cadmium: 0.14 ppm; Copper: 0.54 ppm; Nickel: 5.62 ppm; Cobalt: 0.19 ppm; Manganese: 1.59 ppm; Zinc: 0.39 ppm.

Example-2:

Sodium hydroxide solution (178 gm of sodium hydroxide in 1250 ml of water) was added to 5L-autoclave reactor having an agitator within the reaction vessel and fitted with a cooling jacket having a serpentine configuration to provide a baffle-like structure within the reactor. Silica solution (435 gm) was added slowly into the reactor at 500 RPM by the agitator for 40 ± 10 minutes at 35± 5°C and then stirred for 500 RPM for 40 ± 10 minutes. Zirconium acetate solution (250 gm) was slowly into the reaction mixture at 220-230 RPM by the agitator for 40 ± 10 minutes and then stirred for 40 ± 10 minutes with 170-230 RPM. After the stirring of the reaction mixture, Zirconium cyclosilicate form ZS-9 (1.25 gm) was added (for seeding) into the reactor; the reactor was sealed; 10 Kg of nitrogen pressure was applied; heated to 220°C; and the reaction mixture was stirred at 170-230 RPM by the agitator at 34-38 kg pressure for 40 to 48 hours. The progress of the reaction was monitored by PXRD. After the completion of the reaction, the reaction mass was cooled to 40°C ± 5°C. The solid was filtered under vacuum, slurried in water (1000 ml) and stirred at 35 ± 5°C for 40 ± 10 minutes. The solid was then filtered under vacuum and slurried in water (1000 ml). The pH of the contents was adjusted to 5.0 to 5.5 by 25% dilute hydrochloric acid; stirred at 35°C for 40 ± 10 minutes and filtered. The filtered solid was again slurried in water (750 ml) and stirred at 35 ± 5°C for 40 ± 10 minutes. The solid was filtered and dried at 80± 5°C under vacuum for 5 hours ± 30 minutes. Yield: 140 gm.

Example-3:

Sodium hydroxide solution (376.46 gm of sodium hydroxide in 2080 ml of water) was added to 10L- autoclave reactor having an agitator within the reaction vessel and fitted with baffles within the reactor. Colloidal silica solution (923.46 gm) was added slowly into the reactor at 420 ± 20 RPM by the agitator for 30 ± 10 minutes at 35 ± 10°C and then stirred for 420 ± 20 RPM for 40 ± 10 minutes. Zirconium acetate solution (520 gm) was slowly into the reaction mixture at 300 ± 10 RPM by the agitator for 40 ± 10 minutes and then stirred for 40 ± 10 minutes with 300 ± 10 RPM. After the stirring of the reaction mixture, Sodium Zirconium cyclosilicate form ZS-9 (2.6 gm) was added (for seeding) into the reactor; the reactor was sealed; 10 Kg/cm2 of nitrogen pressure was applied; heated to 220°C; and the reaction mixture was stirred at 215 ± 10°C with 300 ± 10 RPM by the agitator at 34-38 kg pressure for 40 to 48 hours. The progress of the reaction was monitored by PXRD. After the completion of the reaction, the reaction mass was cooled to 30 ± 10°C. The solid was filtered under vacuum, slurried in water (2080 ml) and stirred at 35 ± 5°C for 40 ± 10 minutes. The solid was then filtered under vacuum and slurried in water (2080 ml). The pH of the contents was adjusted to 5.0 to 5.5 by 25% dilute hydrochloric acid; stirred at 35 ± 5°C for 40 ± 10 minutes and filtered. The filtered solid was again slurried in water (1560 ml) and stirred at 35 ± 5°C for 40 ± 10 minutes. The solid was filtered and dried at 80 ± 5°C under vacuum for 5 hours ± 30 minutes. Yield: 333 gm.

The pH of the final dried API: 8.9 & zirconium content: 19.73%; the silicon content: 20.25%; the sodium content:7.68%; Elemental impurities by ICP-MS: Lead: 0.278 ppm; Cadmium: 0.024 ppm; Copper: 1.378 ppm; Nickel: 10 ppm.
,CLAIMS:1) A process for preparation of sodium zirconium cyclosilicate form ZS-9, wherein the process is performed in a reactor, comprising the steps of:
(i) mixing a colloidal silica solution and sodium hydroxide solution in the reactor;
(ii) adding zirconium acetate solution to the mixture provided in step (i);
(iii) optionally, seeding crystalline form ZS-9 material obtained from previous batches in the mixture obtained in step (ii);
(iv) applying nitrogen pressure to the mixture provided in step (ii) or step (iii);
(v) stirring the reaction mixture obtained in step (iv) with the agitator at 150 to 350 RPM in the reactor at temperatures of 170° C to 250° C; and
(vi) obtaining sodium zirconium cyclosilicate from the reactor,
wherein the said reactor comprises:
? a reaction vessel having a volume of at least 2-L with an inside and outside wall;
? an agitator within the reaction vessel; and
? either a cooling jacket comprising serpentine-type coils proximate to the outside wall of the reaction vessel; or at least one baffle-like structure proximate the inside wall of the reaction vessel and placed in operative proximity to the agitator, to provide uniform suspension of solids within the reaction vessel,
wherein the obtained sodium zirconium cyclosilicate form ZS-9 is free of other forms ZS-7 and ZS-8 and have lead impurities less than about 0.5 ppm.

2) The process as claimed in claim 1, wherein the stirring of the reaction mixture in step (i) or step (ii), is carried out in the range of 100 to 500 RPM by using the agitator.

3) The process as claimed in claim 1, wherein in step (iv) 10 Kg/cm2 of nitrogen pressure of reaction mixture is applied.

4) The process as claimed in claim 1, wherein the pH of the reaction mass in step (vi) is adjusted about 5 to 6 by dilute acid.

5) The process as claimed in claim 4, wherein dilute acid is dilute hydrochloric acid.

6) The process as claimed in claim 1, wherein the reaction mass of sodium zirconium cyclosilicate is washed with purified water.

7) The process as claimed in claim 1, wherein the obtained sodium zirconium cyclosilicate is prepared within a small reactor having volume of 2-L to 10-L.

8) The process as claimed in claim 1, wherein the lead impurities are less than about 0.33 ppm.

9) The process as claimed in claim 1, wherein the obtained sodium zirconium cyclosilicate is a white free flowing powder and less than 3 % of sodium zirconium cyclosilicate particles diameter is below than 3 µm.

10) The process as claimed in claim 1, wherein potassium exchange capacity of sodium zirconium cyclosilicate is about 2.7 to 3.5 mEq/g.