Extended use zirconium silicate compositions and methods of use thereof

Abstract

The present invention relates to zirconium silicate compositions having a lead content that is below 0.6 ppm and methods of manufacturing zirconium silicate at reactor volumes exceeding 200-L with a lead content below 1.1 ppm. The lead content of the zirconium silicate of this invention are within the levels that are considered acceptable for extended use given the dose requirements for zirconium silicate.

Claims

1. A method of treatment of hyperkalemia comprising administering over a period of more than 5 consecutive days to a patient in need thereof a cation exchange composition comprising a zirconium silicate of formula (I):
A.sub.pM.sub.xZr.sub.1-xSi.sub.nGe.sub.yO.sub.m  (I) where A is a potassium ion, sodium ion, rubidium ion, cesium ion, calcium ion, magnesium ion, hydronium ion or mixtures thereof, M is at least one framework metal, wherein the framework metal is hafnium (4+), tin (4+), niobium (5+), titanium (4+), cerium (4+), germanium (4+), praseodymium (4+), terbium (4+) or mixtures thereof, “p” has a value from about 1 to about 20, “x” has a value from 0 to less than 1, “n” has a value from about 0 to about 12, “y” has a value from 0 to about 12, “m” has a value from about 3 to about 36 and 1≤n+y≤12, wherein the composition exhibits a lead content below 0.6 ppm.

2. The method of claim 1, wherein the lead content ranges from 0.1 to 0.5 ppm.

3. The method of claim 1, wherein the lead content ranges from 0.3 to 0.5 ppm.

4. The method of claim 1, wherein the lead content ranges from 0.3 to 0.45 ppm.

5. The method of claim 1, wherein less than 7% of the particles in the composition have a diameter less than 3 microns.

6. The method of claim 1, wherein less than 0.5% of the particles in the composition have a diameter less than 1 microns.

7. The method of claim 1, wherein less than 7% of the particles in the composition have a diameter less than 3 microns, and the sodium content is below 12%.

8. The method of claim 1, wherein less than 7% of the particles in the composition have a diameter less than 3 microns, and the sodium content is 9% or less.

9. The method of claim 1, wherein the composition exhibits an XRD diffractogram having the two highest peaks occur at approximately 15.5 and 28.9, with the highest peak occurring at 28.9.

10. The method of claim 1, wherein the cation exchange composition has a pH that ranges from 7 to 9.

11. The method of claim 1, wherein the potassium loading capacity is between 2.7 and 3.7 mEq/g.

12. The method of claim 1, wherein the potassium loading capacity is approximately 3.5 mEq/g.

13. The method of claim 1, wherein the lead content is determined using inductively coupled plasma-mass spectrometry (ICP-MS).

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a polyhedral drawing showing the structure of zirconium silicate Na.sub.2.19ZrSi.sub.3.01O9.11*2.71H.sub.2O (MW 420.71)

(2) FIG. 2 shows a schematic drawing of a reaction vessel with baffles for production of zirconium silicate.

(3) FIG. 3 shows a diagram of the processing equipment used to produce zirconium silicate.

(4) FIG. 4 shows particle size distribution of a zirconium silicate prepared according to Example 3.

(5) FIG. 5 shows an XRD plot for zirconium silicate prepared according to Example 3.

DETAILED DESCRIPTION OF THE INVENTION

(6) The inventors have discovered novel zirconium silicate molecular sieve absorbers that address the need for extended use compositions having a low impurity profile. The zirconium silicate compositions meet the performance criteria for previously described zirconium silicate compositions, but also exhibit reduced impurities, particularly lead, which make the compositions suitable for extended use.

(7) The inventors have designed a reactor for larger-scale production of high purity, high-KEC ZS-9 crystals. See U.S. Pat. Nos. 8,802,152; 8,808,750; and 8,877,255. The reactor 200 has baffle structures 204 on its sidewalls, which in combination with the agitator 201 provide significant lift and suspension of the crystals during reaction and the creation of high purity, high KEC ZS-9 crystals. FIG. 2. The improved reactor can also include a cooling or heating jacket for controlling the reaction temperature during crystallization in addition to the baffle structures 204. Preferably the reactor has a volume of at least 20-L, more preferably 200-L, 500-L, 2000-L, or 5000-L, and within the range of 200-L to 30,000-L.

(8) The process flow for production of zirconium silicate is shown in FIG. 3. To a reactor are added a silicate source. The prior processes capable of manufacturing zirconium silicate having the desired characteristics for oral administration used sodium silicate as a source of silicate. The process also uses 50% NaOH solution, water and zirconium acetate which are charged to the reactor shown in FIG. 3. Also shown is a dryer in which the raw zirconium silicate product is fed. The zirconium silicate is cleaned, protonated and dried in the drier to produce the desired zirconium silicate along with aqueous waste material.

(9) As discussed below in Example 2, the silicate source is colloidal silica (Ludox®) rather than sodium silicate. The inventors found that replacing the sodium silicate in known processes for manufacturing high quality zirconium silicates is ineffective. The present invention is based on the inventors' discovery that the reactor should not be initially charged with the colloidal silica but instead added to previously mixed sodium hydroxide and water. In addition, the agitation rate must be increased after addition of the colloidal silica for at least twenty minutes in order to break silica bonds and obtain a well mixed solution. Additional aspects of the inventive process can be understood by reference to Example 2 below.

(10) The zirconium silicate according to the invention exhibits a lead content below 1 ppm. More preferably, the lead content ranges from 0.1 and 0.8 ppm, more preferably from 0.3 to 0.6 ppm, and most preferably from 0.3 to 0.45 ppm. In one embodiment, the lead content is 0.38 ppm.

Comparative Example 1

(11) High capacity ZS-9 crystals were prepared in accordance with the following representative example.

(12) The reactants were prepared as follows. A 22-L Morton flask was equipped with an overhead stirrer, thermocouple, and an equilibrated addition funnel. The flask was charged with deionized water (8,600 g, 477.37 moles). Stirring was initiated at approximately 145-150 rpm and sodium hydroxide (661.0 g, 16.53 moles NaOH, 8.26 moles Na.sub.2O) was added to the flask. The flask contents exothermed from 24° C. to 40° C. over a period of 3 minutes as the sodium hydroxide dissolved. The solution was stirred for an hour to allow the initial exotherm to subside. Sodium silicate solution (5,017 g, 22.53 mole S02, 8.67 moles Na.sub.2O) was added. The sodium silicate was available from Sigma-Aldrich. To this solution, by means of the addition funnel, was added zirconium acetate solution (2,080 g, 3.76 moles ZrO.sub.2) over 30 min. The resulting suspension was stirred for an additional 30 min.

(13) The mixture was transferred to a 5-G Parr pressure vessel Model 4555 with the aid of deionized water (500 g, 27.75 moles). The reactor was fitted with a cooling coil having a serpentine configuration to provide a baffle-like structure within the reactor adjacent the agitator. The cooling coil was not charged with heat exchange fluid as it was being used in this reaction merely to provide a baffle-like structure adjacent the agitator.

(14) The vessel was sealed and the reaction mixture was stirred at approximately 230-235 rpm and heated from 21° C. to 140-145° C. over 7.5 hours and held at 140-145° C. for 10.5 hours, then heated to 210-215° C. over 6.5 hours where the maximum pressure of 295-300 psi was obtained, then held at 210-215° C. for 4 1.5 hours. Subsequently, the reactor was cooled to 45° C. over a period of 4.5 hours. The resulting white solid was filtered with the aid of deionized water (1.0 KG). The solids were washed with deionized water (40 L) until the pH of the eluting filtrate was less than 11 (10.54). A representative portion of the wet cake was dried in vacuo (25 inches Hg) overnight at 100° C. to give 1,376 g (87.1%) of ZS-9 as a white solid.

(15) As discussed in the '152 patent, the specific reactor configuration and process conditions of this Example demonstrated that higher capacity zirconium silicates could be achieved. For example, capacities ranging from 3.8-3.9 meq/g were achieved relative to prior processes that only achieved capacities in the range of 1.7-2.3 meq/g.

(16) The inventors have found, however, that material produced in accordance with this Example exhibits a lead content of 0.6 ppm. The lead content is determined using Inductively Coupled Plasma-Mass Spectrometry (ICP-MS). The samples were prepared with a 0.1 g weighed portion mixed with 0.5 mL hydrofluoric acid, 2 mL nitric acid, 1 mL hydrochloric acid, and 1 mL purified water. The sample is digested using a closed-vessel microwave system at a maximum of 200° C. until the material appeared dissolved. After cooling, internal standard solution was added and dilution with purified water to 50 g produced solutions for ICP-MS.

(17) The main contribution of lead to the zirconium silicate product comes from the reactants zirconium acetate and sodium silicate. This example illustrates that even when reagent grade materials (sodium silicate, zirconium acetate) are used as reactants, the level of lead can exceed that which is acceptable.

Example 2

(18) This example illustrates the production of zirconium silicate from the reaction of sodium silicate and zirconium acetate in a 500-L reactor. Sodium silicate (148.8 kg) and water (100.1 kg) were added to a 500-L reactor and stirred at a rate of 200 rpm. Sodium hydroxide (37.7 kg) was added and the remaining water (100.2 kg) was added. The agitation rate was lowered to 80 rpm and zirconium acetate (62.0 kg) was added along with water (49.4 kg) and the reactor was allowed to mix for 25-35 minutes. The reactor was heated to react the materials 210±5° C. for ≥48 hours at 140 rpm. The resultant material was protonated to a pH of 4.75 to 5.25 and dried to a moisture content of ≤5.0%.

(19) The composition has a volume weighted mean of 21.8 microns and a surface weighted mean of 13.56 microns. The material contains less than 0.05% of its volume under 1 micron, and less than 1.41% under 3 microns. The resultant material exhibits the characteristic XRD plot for ZS-9. There are undetectable levels of ZS-8 as shown by the absence of please within the range of 5-10 2-theta. As described in the inventors' prior patents, this material having a reduced amount of particulate fines and lacking soluble forms of zirconium silicate (ZS-8) is suitable for oral administration, for example in the treatment of hyperkalemia.

(20) The inventors have found, however, that material produced in accordance with this example exhibits levels of lead above the suitable level given the required dosing of the drug. See Table 2 below. In particular, the resulting product was found to have a level of lead of 1.0 ppm. The main contribution of lead to the zirconium silicate product comes from the reactants zirconium acetate (0.28 ppm) and sodium silicate (0.38 ppm). Forms of zirconium acetate having lower levels of lead are unavailable on a commercial scale. Although other forms of silicate, colloidal silica, were found having undetectable levels of lead, colloidal silica is unsuitable in the above process for reaction with zirconium acetate to form zirconium silicate. The inventors have found that the level of lead in the final product tends to be higher when the level of lead in the reagents is uncontrolled, which can be the case with bulk suppliers of these reagents. Similar levels of lead on the order of 1-1.1 ppm were observed when the reaction was conducted at a scale of 200-L and 500-L in reactor volume.

Example 3

(21) This example illustrates the production of zirconium silicate from the reaction of colloidal silica and zirconium acetate in a 500-L reactor. The inventors found that in order to react colloidal silica with zirconium acetate, the process must include additional steps and different agitation rates. For example, the colloidal silica process requires a step of increased agitation (200 rpm) for ≥20 minutes to break silica bonds and obtain a well mixed solution. The inventors found that through this process the level of lead could be lowered below 1 ppm, and as shown below can be lowered to 0.38 ppm in a 500-L reactor.

(22) Sodium hydroxide (97.2 kg) is mixed with 84.5 kg of water and agitated at 150 rpm while 108.8 kg colloidal silica (Ludox®) is added. Agitation continues at the same rate while 10.5 kg water is used to clear the colloidal silica from the charge line into the reactor. Once the colloidal silica is charged to the reactor, the agitation is increased to 200 rpm for at least 20 minutes to break the silica bonds and obtain a well mixed solution. The agitation is reduced to 100 rpm while additional 52.9 kg water is added, and then increased to 200 rpm for at least five more minutes.

(23) The agitation is then decreased to 150 rpm while 81.0 kg of zirconium acetate is added over a period of approximately 30 minutes. Water (62.8 kg) is added and stirring continued for about 30 minutes prior to heating.

(24) The reactor is heated to 210° C. as quickly as possible while mixing at 150 rpm. The reactor is maintained at 210±5° C. for at least 36 hours. Upon completion, the material is protonated twice to a pH within the range of 4.75 to 5.25. The material is dried to a moisture content of less than 5% by heating at 160° C. for 30 minutes.

(25) The particle size distribution of the resulting zirconium silicate prepared in accordance with this example is shown in FIG. 4. The composition exhibited a particle size distribution of about 2% below 3 microns. The XRD plot showed the characteristics for ZS-9, including that the tow highest peaks occur at approximately 15.5 and 28.9, with the highest peak occurring at approximately 28.9. There are undetectable levels of ZS-8 as shown by the absence of please within the range of 5-10 2-theta. See FIG. 5. The resultant zirconium silicate was a white free flowing powder essentially free of debris and particulars. The FTIR spectra exhibited bands at approximately 799 and 917 cm.sup.−1 which were consistent with previously acceptable lots. The suitable FTIR spectra is shown in the inventors' prior patents. The pH of the resulting material was 9. The measured potassium loading capacity was 3.5 mEq/g. The zirconium content was about 21.7%, the silicon content was approximately 17%, and the sodium content was approximately 7.3%. The moisture content of the final product was 5%.

(26) The level of lead in the final product produced by the above process using colloidal silica was 0.38 ppm, which is a suitable level for the long term administration of this composition.

(27) Other embodiments and uses of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. All references cited herein, including all U.S. and foreign patents and patent applications, are specifically and entirely hereby incorporated herein by reference. It is intended that the specification and examples be considered exemplary only, with the true scope and spirit of the invention indicated by the following claims.

(28) TABLE-US-00001 ANALYSIS TABLE 2 500-L Process w/ NaAc - Example 2 Example 3 Acceptance Zirconium Sodium Zirconium Zirconium Colloidal Zirconium criteria (ppm) Acetate Silicate Silicate Acetate Silica Silicate Arsenic 1.5 ND ND ND ND 0.06 ND Cadmium 0.5 0.05 ND ND 0.05 ND ND Copper 300 ND 0.09 0.57 0.05 0.08 0.19 Iridium 10 ND ND ND ND ND ND Lead 0.5 0.28 0.38 1.00 0.13 ND 0.38 Mercury 3 ND ND ND ND ND ND Molybdenum 300 0.45 0.37 0.46 0.42 ND 1.2 Nickel 20 ND ND 2.79 ND ND 2.56 Palladium 10 ND ND ND ND ND ND Platinum 10 ND ND ND ND ND ND Rhodium 10 ND ND ND ND ND ND Ruthenium 10 ND ND ND ND ND ND Vanadium 10 ND ND ND ND 0.33 ND