WO2015181800A2 - Methods for purifying chlorites and chlorates - Google Patents

Abstract

The present application relates to methods for purifying chlorites and chlorates. In particular, the present application relates to methods for preparing impurity-reduced sodium chlorite or sodium chlorate comprising a step of adding an antisolvent such as ethanol to aqueous solutions comprising the sodium chlorite or chlorate under conditions to obtain impurity-reduced sodium chlorite or chlorate solids and a sodium chlorite or chlorate-reduced solution. The impurity-reduced sodium chlorite or chlorate solids can optionally be recrystallized.

Description

TITLE: METHODS- FOf¾ jf¾!f YIU CHLQR1TES D CHLORATES

CROSS ^EEEREI^C TO RELATED APPLICATIONS

pCI01] The pmsmt application ciaims_: th benefit of priority from copending U.S. provisional patent application S..N. ©2/005,203 filed on Ma 30, 2015, the contents of which are Incorporated herein hf reference In their entirely.

FIELD

080i£J The present application relates to methods for purifying ehlorites and chlorates, in particular, the present application relates to methods for prepahng pharmaceutical-grade sodium chlorite or sodium chlorate, including adding an antlso!vent to apueous solutions comprising the sodium chlorite or chlorate.

B wmomm

¾0¾1 Processes for the purification of alkali metal ehtorites and: dhlorates such as sodium chlohfe and sodium chlorate are known,

108041 For example, US Patent; Nos. 8,067,03s and 8,231 ,856.disclose methods for the purification, of sodium chlorite wherein an aqueous solution comprising (im ure sodium chlorit is concentrated until one or more impurities precipitate. The impurities are separated from the chlorite and the resulting: solution is ;tbe subjected to conditions wherein the chlorite Is not: soluble but; the remaining impurities are soluble such as by inducing the chlorite to crystallize by cooling the apueous chlorite-contalning solution. The chlonte obtained from; the crystallization can be harvested by filtration arid: optionall reerysta!fized.

808S| PCI Application Publication No, 2012/027¾16 discloses that the sodium chlorite used in the experiments reported therein was 8Q% technical grad that was recn stalllzed twice from ef anoJ/w ter to give a filial purity of >96%, The purification of sodium chlonte comprising one or more recrysfalli ations from_, eihano!rwater has also been reported iri the academic literature,^"1

|0006J_. The purification or separation of sodium chlorit comprising partial evaporation of the solution and/or crystallization has also been disclosed,'*

|00δ?] IIS Patent No. 3,424, 562 discloses a method of s@ araii.Fi9 alkali metaifia!ates whose soiubilly In water on a weight basis is not as great as t he corresponding halide, from aqueous solutions con aining an alkali metal •halaie and the corresponding alkali metal halide. The method comprises adding a^■ sufficient amount of alcohol such as ethane! to■^■■selectively precipitate a major portion of the halate salt and, at most, only a small proportion of the halide salt and separating the- precipitate from the mixture,. The salt pairs which are taugh to be employable in the method do not include NaCI/NaCIOs,: fO00S] The purification or separation of sodium chlorate comprising partial evaporation of the solution and/or crystallization has also been disclosed,³

S M ARY

| 0¾i| Methods for preparing impurity-reduced sodiu chlorite or sodium chloral© comprising a ste of combining an anttsorvent such as ethane! and ah aqueous solution comprising the sodium chlorite- or chlorate under conditions to Obtain impurity-reduced sodium chlorite or chlorate solids have been developed in the studies of the present application,

|0010^'1 Accordingly, the pnesent application includes a method for preparing impurity-mduced sodium entente, comprising:

combining an antisolvent; and an aqueous sodium chlorite solution under conditions to obtain im UFiiy^edyc^d. sodium chlorite solids and sodium chiorife-reduced solution, wherein th aqueous sodium chlorite solution comprises one: or more impurities o is a: non~ pharmaceutical-grade chlorite solution; separating the Impurity-reduesd sodium chlorite solids from the SQcfiom chiorite-reduced solution- and optionally, maHi g" an aqueous solution of the impurit reduced sodium chlohte solids and repeating the adding and separating one or more times.

[001 1 |n an em odimen - t e eondiiiens to obtain the impuh y-rebueed sodium chlorite solids and the sodium Ghlon o-redueed solution comprise;

adding the anifsofvent: to the aqueous sodium chlorite solution to obtain an antisoivent-aqueous mixture; and

cooling the: antisolvent-aqueous mixture to obtain the impurity- reduced sodium chlohte solids and the sodium chlohte-reduced solution,

I 012J In a embodiment, the conditions t obtain the: impurity-reduced sodium -chlorite solids and the sodium chlonte-reduoed solution .comprise:

adding an aqueous sodiu chlorite solution to the antisolvent to obtain an antlsoivent-aqueous mixture:; and

cooling the

rniKture to obtain the Impurity- reduced sodium: chlorite solids and the sodium ohiorite-rediicecl solution,

[0013] an embodiment, the method further comprises recrysta!l ing the impurlty-redueed sodium ehlonfe solids. In another embodiment residual antisolvent s removed from the recr staliized impurity-reduced sodium chlorite solids by drying, for example, to compl wit regulatory requirements for obtaining pharmaeeuticaf-grade compounds,

|0014| In another embodiment the method: further comprise adding water to the impunfy-reduee sodium chlorite solid or the reerystalilzed Impurity-reduced sodium chlohte solid to obtain an aqueou solution comprising Impunty-reduced sodium chlohte. in a further embodiment, the method further comprises adding an ion selected from one or more of an hydroxide ion, a chloride ion, a chlorate: ion, and: a sulfate ion, each in: the ^"form of a -suitable salt, such as an alkali metal salt to the aqueous solution comprising: impurity-reduced sodium chlorite. 'OtSJ In an alternate embodiment of^" the present application, the aqueous sodium chibrife solution is obtained by; eomblning technical grad sodium chlorite w th a quantity of water insufficient to completely soiub&ze the technical qrade sodium chlorite to provide a mixture; stirring the mtuns to partially dissolve the technical grad sodium: chlorite to ^provide a slurry of undissolved solids and an aqueous sodium chlorite solution; and separating the undissolved solids from the aqueous sodium chlorite solution.

10018] In an embodiment the aqueous sodium chiodie solution is a concentrated aqueous sodium ehiorite solution.

|O017] In an embodiment the aqueous: sodium chlorite solution is treated with a base to adjust the pH so that ft Is greater than 7, in one embodiment the pH is adjusted: o: range between about pH 7 to 14, pH 8 to , pB 8 to 13 or pH 9 to 13, suitably the pH s adjusted io H § to 13.

01tl The present application also includes a method for preparing inipMUiy-redueed sodium chlorate, comprising;

combining an antiso!vent and an aqueous sodium chlorate solution unde conditions to obtain Impurity-reduced sodium chlorate solids and sodium chlorate-reduced: solution, wherein the sodium chlorate solution comprises one or more impurities or is a non- pharmaceutieai-grade chlorate solution; separating the Im urity-reduced sodium chlorate solids from the sodium: G lorate-reduoed solution; and optionall making an aqueous, solution, of the impurity reduced sodium chlorate solids and repeating the adding and separating on or more times.

fOQiSJ I an embodiment the condition to obtain the impurity-reduced sodium cHlorate solids: and the sodium chlorate-reduced solution compose:

combining the antisoivent and the aqueous sodium chlorate solution to obtai an: antisolvsni-aQueoys mixture; and cooling the antisolvenha ueoos: mixture to obtain the impurity- reduced sodium chlorate solids and the sodium chlorate- educed solution,

jlf 20} in an embodiment, the method further comprises reorystaiJzing the Impurity-reduced sodium chlorate solids.

|0O2t] Other features and advantages of the present application will become apparent from the fo lowing detailed description, it should fee understood, however, that the scope of the claims should not be limited by the preferred embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.

BRIEF DES IFT!0¾ OF THE ^ i SS

[0022] Th present application includes references to appended drawings In which;:

[0023J Figure 1 is a flow chart depicting a; sodium chlorite purification process In an exemplary embodiment of tbe resent ap lication,

i 0i:2 1 Figure 2 is a flow chart depicting a sodium chlorate unfleatlah iproeess In an exemplary embodiment of the -present application,

(002S Figure 3 is flo char depicting a variation (V -20-37) of a sodium chlorite purification process in an exemplary embodiment of the present apptlcatiom f¾G26J F gure 4 is a flow chart depicting a variation (V -20-39) of a sodium c lorite purification process in an exemplary embodiment o the present application.

002| Figure 5 is a flow c art depicting a

of a sodium chlorite purification process in an exemplary embodiment of Ihe present application.

[0028} Figure 6 is a flow chart depicting a variation (VfVI-20-51 } of a sodium chlorite purification process i an exemplar embodiment of the present application,

[0828] Figure 7 is_. a flow chart depleting a variatio (V ~2C §3} of a sodium chlorite purification process m an exemplary embodiment of the present application,

DETAILED DESCRIPTION 00301 Unless otherwise indicated, the definitions and embodiments described m this and other sections are intended to be applicable to all embodiments and aspects of the present: application herein described for which they are suitable as would be understood by a person skilled In the art.

|083iJ in understanding the scope of the present application, the term "comprising" and its derivatives, as used herein, are intended to h open ended term that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but do not exclude th presence of other unstated features, elements, components, groups, integers andVor steps. The foregoing also applies to words having similar meanings such as the terms, including", ^>:havlng" and tneir derivatives The term "consisting" and its derivatives, as used herein, are intended to be closed terms that specify the presence of the staled features, elements, components, groups. Integers, and/or steps, but exclude the presence of othe unstated features, elements, components, groups,, integers and/or steps. The term "consisting essentially of , as used herein, Is Intended to specify the presence of the stated features, elements, components, groups, integers, and/or steps as well as t ose that o not materially affect t e: basic and novel charactenstfeis) of features, elements, components, groups, Integers, and or steps.

00321 term "suitable" as used herein means that the selection of the particular conditions or reagent would depend on the specific manipulation or operation to e performed, but the selection would be well within the skill of a person trained in the art. All methods descri ed herein are to be conducted under conditions sufficient to. rovide the desired product.

[0^331 Terms of deg ee such as "substantial^, "about" and "approximately" as used herein mead a reasonable amount of deviation of the modified term such that the end resul is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies.

|¾34 As used in this application, the singular forms "a^K, ¾r an "the" include plural references unles the content clearly dictates otherwise. For example, an embodiment including^' "an anfisoiyenf should foe understood to present: certain aspects with one aiitisolvenf or two or more additional antlsoivents.

|O03§| In embodiments comprising an "additional" or "second" component, such as an additional or second antisoivent, the second component as used herein is chemically different from the other components or first component. A "third" oomponent is different from the other, first, and second components, and further enumerated or "additional" components are similarly different,

|0 3β The term "aniisoivenf as used herein refers to a solvent or a mixture o solvents having one or more pro e ies of being relatively inert to sodium ehlonte, sodium chlorate and wafer; having low ability to so!ubilize sodium ebiodt or sodium chlorate; being mise!h!e with water; and having tew toxicity. [06373 The term ΈΙϋΒ" as used herein refers to ethanoL

|003SJ The term '^••concentrated" with reference to aqueous sodium chlorite or sodium ehtorate solutions mean that t e aqueous solution contains an amount of sodium chlorite or sodium chlorate such that solid material is precipitated by, for example, a change in temperature or addition of an antlsolvent. An example of concentrated solutions include solutions containing approximately the maxi nurrs: amount of sodium chlorite or sodium chlorate, res eetlwly, Ihet can he dissolved ^"m the^■ aqueous solution under the conditions used. For example, the solubility of sodium chlorite: water is approximately 39 g/100 ml at 17 ^*C and approximately 100 g/1Q0 ml at 40 ^*€ ami the solubility of dium chlorate in wafer is approximately 79 g/lOO ML at 0 °C, approximately

101.0 ml ai2u -^*Q and a r ximately 230 g/100 mi at IPG ^SG;>

[00:391 T½ term " hafmaGOutioahgrade" as used herein refe s t sodium chlorite or sodium chlorate that is suitable for

example as a drug substance.

0040J The terms ''impure" and 'Impurities^" refer to substances that are not suitable for pharmaceutical use. for example as a: drug substance.

00 1 ^be term: 'Impurity-reduced" as used herein refers to_: a composition that has been processes' to ha fewer trr puhties comparec to a starting material {:e.:g, an aqueous solution of technical grade), or a composition processed to generat a pharmaceutical-grade substance, fo example, tc comply with regulatory agencies: in the U,S, or elsewhere. Typically, regulatory requirements require the removal of impurities fro materials to be used as drug substances. Processing: steps to reduce the risk of exposing; subjects to potentially harmful substances (due for example to unexpected contamination of drug substance a materials) er also optionall employed to assure t ie strength and purify ©f drug substances. Thus the term impurity reduced also encompasses a composition which was highl pure before performing the method, but in which the method can remove impurities in the event that they were present. fM42| The terms "fechnica grade" or "ana ytica! grade^" as used herein refer to sodium chlorite or sodium chlorate tha is not suitable for pharmaceutical use as drug substance, for example,, because if contains impurities or does not: otherwise meet regulatory requirements.

[00431 The term "ohlorite-redueed" as used herein refers to a composition: that has reduced amount of chlorite in reference to a comparator composition,

[00 43 The term "chlorate-reduced" as used herein refers to a composition that has a reduced amount of chlorate in reference to a comparator composition,

If, Methods

|0δ §1 Methods for preparing impurity-reduced sodium chlorite or sodium chlorate comprising s step of combining art antisolvent and an aqueous -s lutio , such as a concentrated aqueous solution, comprising th sodium chlorite or chlorate tinder conditions to obtain impurity-reduced sodium chlorite or cnforate solids have been developed in the studies of the present application. The methods for purifying technical grade (about 80%) sodium chlorite have been observed to. give product having a purii above 9§,6% after two crystallizations. In. contrast to a Inown method, which was tasted in the present studies and observed to form a solid: block of material during the: initial er sCalkatlon step (see Example 1), the methods of the: present studies_, were observed to form suspensions hich were easily filterable. Simplified or modified methods of Example 1 (see Example 5_S Variation l-V) for purifying: technical grade {about 80%) sodium chlorite were also observed to give: roducts having: a purity above 90%, above 91 %, above 92%, above 93%, abov 94%-_?. above 96 :, above 98:%·, or above 97% or higher afte two- crystalli tions. Such methods are: useful for large scale procedures. The method for purifying sodium chlorate was observed to give higher yields .of product than a. method that did not use an aniisbivent (i) Sodium chfor&e purific&i&n -meth ds

0D46J he present application includes a method for preparing Impurity-reduced sodium chlorite, comprising:

adding .an anisolvent in an aqueous sodium chlorite solution under conditions to o in Impurity-reduced sodium chlorite solids and a sodium ehlerite-reduoed solution, wherein the aqueous sodium chlorite solution comprises on or more Impurities or Is a: non-pharmaoeutioal- grade Ghiarife solution;

separating: the impurity-reduced sodium chlorite solids from the sodium ohSorite-redueed salu!lon; and

optionally making an aqueous solution of the Impurity reduced sodium chlorite solids and repeating the adding and separating one or more times.

£00 71 The present application also includes a. method for preparing impurity-reduced sodium chlorite, comprising:

combining an antiso!yent and an aqueous sodium chlorite solution under conditions to obtain impurity-reduced sodium chlorite solids and a sodium ohior¾e~redu:ced solution,, wherein the aqueous sodium chlorite solution -comprises one or more impurities or is a non- pHarmaceuf icai-grade chlorite solution ;

separating the impurity-reduced sodium chlorite solids from the sodium chlorite-reduesd solution; and

optionally making an aqueou solution of the impurity reduced sodium chlorite solids and repeating the adding: and: separating one or more limes,

[G048J I an embodiment, the conditions to obtain the impurity-reduced sodium chlorite solids and the sodium chtorite-redueed solution comprise:

adding the antlsolvent fo_: an aqueous sodium chlorite solution to obtain an antiso vent-aqueoos mixture; and cooling the antisGiveni-aqueQus mixture to obtain the impurity- reduced sodium chlorite solids and the sodium ehtohfe reduced solution,

|Q04§] In an embodiment, the conditions to obtain the impurity-reduced sodium chlorite solids and the sodium chiqnte-reduced soMiofi comprise: adding an aqueous sodium chlorit solution- t the antisolvent to obtain an anllsoivent-aqueous mixture: and cooling the antisoivent-aqy o s mixture to obtain the impurity- reduced^' sodium chlorite solids and Hie sodium ohionte-reduced solution.

[QGSO] In an embodiment, the antisolvent is added to the aqueous sodium chlorite solution, or the aqueous sodium chlorite solution is added to the antisolvent a a first temperature, the antisoivent-aqueous mixture so obtained is then cooled te a second temperature and is substantially maintained at the second temperature to obtain the impurity-reduced sodium chlorite solids and the sodium chlqrlte-reduoed solution. In another embodiment, the antlsoiyent- queous mixture Is first cooled to an intermediate temperature before being further cooled to the second temperature, optionally being substantially maintained at the intermediate temperature for suitable period of time ; before being further cooled to the second temperature. The selection of suitable first, second and intermediate temperatures depends, for example, on the identity and/or ratio of the antiso!vent used and the selection can be made by a person skilled in the art. For example;, it will be appreciated by a person skilled in the art. that the first temperature is suitably below the boiling point of the ant soivent and the second and intermediate temperatures are suitably above the freezing point of the antisolvent-aqueous n^xture but low enough such that a desired amount of Impurity-reduced sodium chlorite solids Is obtained from the antisolvent- aqueous mixture.

051 i in an embodiment of the present application, the antisolvent is ethanoL the first temperature Is from about 2CTC to about 5^SC, about 0 C to about 3 C, 25 C to about 32 C or about 3CTC, the intermediate temperature from about -5*0 to about 5^eC^" w about 0 0 and the second temperature is from about -4CTC to about -1CTC, -25X to about -16 C or abou ~20^;>C.

[00 J It will foe appreciated by a person bil ed in the art that the method can f urther comprise agitation such as stirring during part or^■ail of the adding and cooling. Per example, the antisolvent is added to the aqueous- solution (or vice versa) white^■ stirring and/or the antlsotveot-agueous mixture is stirred during cooling from one tgm e a TO to another temperature such as from the first temperature to the second temperature or alternatively th intermediate temperature.

|00B3] I another embodiment, the antisolvent is added to the aqueous so ution (or vice versa) portion wise, fo example o r a time of from about 10 seconds to about 60 minutes, about 20 seconds to about 30 minutes, about 30 seconds to about 20 minutes, about 40 seconds to about 10_: minutes, about 50 seconds to about 5 minutes or about 1 minute to about 2 rninufes_s optionally; while stirring.

0054| In an embodiment, the aqueous chlorite solution s added to a container comprising the antisolvent to provide th antiso!venfcaqueous mixture. For example, the aqueous chlorite soiution is filtered: directly into a container, such as a flask, comprising the antisolvent. In an embodiment, th aniisoivenf in the container is kept at a first temperature between about room temperature and a tem e ature just below the boiling point of the antisolvent. In a further embodiment, the container comprising the antisolvent is kept at a first temperature of about 4S . In another embodiment, any Impurity-reduced sodium chlorite solids precipitated in the container at th first temperature upon add if an of the aqueous chlorite solution is collected, for example, by filtration:. In a fudber embodiment, the filtrate (a sodium c! lohte-reduced solution} from this latter filtration is- cooled to a second temperature (for example a temperature ot abou 4( ^SC to about ~WC, -25*0 to. about -15 -C or about - 2C C) and any further impurity-reduced: sodium ehlonfe solids precipitat is collected, for example by filtration. |O0§S| The time the antisolveni agueous mixture is substantially maintained at the first and second temperatures to obtain the impurity-reduced sodium entente solids and the: sodium chigrite-redueed solution may vary, for example, based on the identity and/or ratio of the: antisotven! used: andlor the desired yield of the impurity-reduced chlorite solids. The selection of .a suitable time can be made by a person skilled In the art and generally corres onds to the time it akes for suitable quantities of the impurity-reduced sodium chlorite solids to precipitate. In an embodiment the antisoivent-aqueous mixture is substantially maintained at the second temperature for a time of at least about one hour or a out on hou to about 48 :hour$, p0S6] It wilt he appreciated by a person skilled in the art that a useful antisofven for the methods for preparing impurity-reduced sodium chlorite of the present application will suitably be relatively inert, to sodium chlorite and water, have a low ability to soluhilize sodium chlorite and he substantially misc!bfe with water. In one embodiment, the antisolvenf Is soluble in water. In another embodiment the anflsoiveni has a high vapor pressure for example, a vapor pressure higher than that of water. For the reparation of impurity- reduced sodium chlorite useful for administration to subjects such as human subjects, the anfisolvent will also suitably have a low toxicit to such subjects. The selection of a suitable antisolveol for a particular method can be made by a person skilled in the art.

£00-57] In one embodiment, the antlsolvenf comprises a mixture of solvents that is either premixed before adding to the aqueou chlorite solution or are added as individual solvents o added as one or more mixtures of solvents.

[0058] in one embodiment the aniisolven comprises, consists essentially of or consists of a class 2 or class 3 approved solvent according to the U.S. Food and Drug Administration (Guidance for industry, Q3C - Tables and List_* U.S> Department of Health and Human Sen ices, Food and Drug Administration:, Center for Drug _. Evaluation and Research, Center for Biologies: Evaluation and Research, November 2003, Revision i ) or the European Medicines Agency *IGH Topie Q3C (H4) Impurities: Guidelin for Residual Solvents, European Medfeal Agency, Fepruam 2009), or a mixture thereof. In an embodiment the anfisoivent s selected from acetic acid acetone, anisole,. 1-bytanoi, 2~byfano!_f hutytaeetate, t-bufyimethy!ether, cu ene, dimethylsulfoxide, ethanol, ethyl: acetate, ethyl ether, ethyl formate, formic acid. oeptane, !sobuiyi acetate, isopropyl acetate, methyl acetate, 3~ et:hyl-1~ hutanol, meihy!ethyl ketone, meth ylisohutyl ketone, 2~mefhyl~1-propanoL pentane, l-pentaooj, 1-propanoi_s 2*pfopanql propyl acetate, aeetooitdle ohlorobenzene, chloroform, cyclohexaoe, 1 ,2-dichioreethane:, dfc !orornetliane, 1

,Ν·> dim fhylformamlde:, 1 ,4~dioxane, 2-ethQxyethanoi, efhy!eneg!yeol, formamide:, hexane, methanol, .2~meiho yet :anoi, methy!fcutyiketone, me hyScyclohexane, -meihylpyrrni one, nifomethane pyridine:, sulfoiane, tetrahydrofuiran, ietra ift, toluene, I -thchloroettiene, xylene and glycerol, and mixtures thereof.

[O Sil In another embodiment the aniisolveni is selected from acetic add, acetone_* anisoie, 1-hutaool 2¾utanoL hyfylaee!ata, f-butylmethytether, cumene,_: di et ylsyifoxtde, e rraoai ethyl acetate, ethyl: ether, ethyl formate, formic acid_* heptane, isobutyi acetate, isopropyl acetate, methyl acetate, 3- methyl-l -butanQl, metfiytethyl ketone, methyltsobutyi ketone, 2-metoyt~1- propahol, oon!ane, 1~pentanol_s 1-propanol, 2-propanol propyl acetate, acetonithte, i ,2-dimethoxyethane, , -dimethylacetamide, U,U~ dimelhylformamide, l^-dioxane, -efhoxyethanol, ethyleneejyeol, formamlde, hexane, methanol, 2-methoxyethanol ethylbutylketone, methy!cyclohexane:, -methylpyrroJidone, nllromethane, pyridine, sulfo!ane., tetrahydrofuran., tetral!n, to!dene, 1 ,1 ,2-trichloroethene, xylene and lycero and mixtures thereof,

C0060] In another embodiment, the solvent is a Glass 3 solvent or a mixture comprising Class 3: solvents or a mixture of Class 3 solvents, in an embodiment, the class 3 solvents are selected: from acetic acid, acetone:, anisole, 1-butaooi, 2-hutanoi, hutylacetafe t-buiytmethylet er:, cumene, d!metb lsulfoxide, emanei:, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobotyl acetate, isopropyl acetate, methyl acetate, 3~methyl1 - butanes, methyfethyl ketone, methyilsobutyl ketone, 2«methyH -propanol psntane, l-pentanoi, 1 -propanoi_c 2~propanol and propyl acetate, and mixtures thereof,

[t)9S1J In a further embodiment, the antisolvent comprises, consists essentially of o consists: ®f a C^alcohol, In another em odiment, th anfisolvent comprises, consists essentially of or consists of a

In another embodiment the■ antisolvent comprises, consists essentially of or consists of ethano!. In a further embodiment, t e antlsoivent Is ethanol.

in an embodiment, he ratio by volume of the ethanoi to the aqueous sodium: chlorite solution is from about 40' Q to about §0:40 or about mm.

[00831 The aqueous sodium chlorite solution is obtainable by various methods. The selection of a suitable method ean be made by a person skilled. the art. Alternately, aqueous sodium chlorite solutions containing: highl pure sodium chlorite are available from commercial source. Examples of highly pure sodium, chlorite solutions Include, but are not limited fo_!: 30X and^" Headline® (DuPont), AWWA and Ercopure 25 or 31 (ERCO C©rp A TA KLOR (QxyChem), and 25% Sodium chlorite 300W (Hanke & Sesdel), Sources of technical grade sodium chlorite powder include, but are not limited to, V R, Sigma Aidrieh and Fisher Scientific,

|Q0@4] In one embodiment the aqueous sodium chlorite solution is obtained by combining: water and technical grade sodium chlorite (80% sodium chlorite) at a ratio ( wt) of watersodium chlorite of about: 0.5:1 to about 2:1 , about 0.5:1 to about 1.7:1 about 0.7:1 to about 1.4:1 about 1 :1 to about 1.5:1, or about 165; 1 at about 20°C to about 90°C, or about 60°G to about 0°C or a out 70 ¾, or about 65^DC. o about 22°C. In another embodiment, the aqueous sodium chlorite solution Is obtained by combining water and technical grade sodium chlorite at a ratio fwtwi) of atersodiun chlorite of about 0.5:1 to about 1.6: 1 , or about 0.8:1 at about 6S°C to about !QC C, or at about: 100^SG. In another embodiment, the aqueous sodium chlorite: solution is obtained y combining water end technical grade sodium chlorite at a ratio (wtwt) of water:sodlum chlorite of about 1,35:1 at abou 20°C to about 30^BC, in another embodiment, the aqueous sodium chlorite solution is from- a commercial source, such as 25% sodium chlorite 300 (Hanke & Seidell containing about 25% highly pure sodium chlorite. Sodium: chlorite is precipitated from the highly pure solution by the addition of ethanoL

[00.65] in an embodiment, the aqueous sodium chlorite solution is obtained by concentrating an aqueous solution c mprisi g sodium chSorite under conditions to remove one or more impurities. The conditions to remove one or more impurities can van/ and the selectio of suitable: conditions for a particular method of the present application can be made by a person skilled in the art, 00601 in an embodiment the conditions to remove impurities from a aqueous solution comprising sodium chlorite comprise:

concentrating the aqueous solution comprising sodium chlorite under conditions to obtain solids comprising the impurities; and

collecting the solids comprising the impurities,

180673 In an embodiment the conditions to obtai solids comprising th Impurities comprise concentrating the aqueou solution comprising sodium chlorite at a temperature highe than ambient temperature and a pressure lower than ambient pressure for a time for the formation of the solids comprising the impurities to proceed to a sufficient extent. The time may Vary, for example based on the concentration: of the impurities and/or the volume of the apueoos solution.; The pressure ma vary, for example depending on the means used to reduce the pressure,. The selection of a suitable time, pressure and temperature fo a particular method of the application can he made b a person skilled in the art. in another embodiment, th aqueou sodium chlorite solution Is obtained by concentrating an aqueou solution comprising sodium chlorite at a temperature of i m about 5Q^*C to about 90 C or about 70^SC while applying vacuum, for example by using a rotary evaporator for a time until formation of a white solid is observed in substantially the entire volume of the formed suspension. In an embodiment, the solids comprising impurities are collected at a temperature higher then ambient temperature, In another embodiment, the collection Is at a temperature of from about 5^'CFC to about 90^*C or about ?Cf C, In a further embodiment of the present application, t e temperature is substantially the same as the temperature used: in the step of concentrating the aqueous; solution, -It will be appreciated by a person skilled In the art that prior to adding the antisolvent, or combining wit t e antisolvent the aqueous sodium chlorite solution so obtained is suitably cooled to a temperature that i at feast tower than the boiling point of the antisolvent,

P06B| It is an embodiment that, phot to adding the antisolvent to the concentrated aqueous eh!odte solution (or vice versa) a suitable amount of water Is added to the concentrated aqueous chlorite solution to form a dilute aqueous chlorite solution. In an embodiment, the amount of water that is combined with the concentrated aqueous chlorite solution I about 1 % to about 50%, is about 2% to about 35%, Is about 5% to about 20 , or is about 6% to about 10% of the total volume of the concentrated aqueous sodium chlorite solution. In an embodiment, the amouot of water that is combined wit the. concentrated a ueous ohiodte solution is about ?% of the total volume of the concentrated aqueous sodium chlorite solution, i an embodiment the water fo dilution Is combined at a temperature between about room temperature and a temperature just below the boiling point of the antisolvent. In this e bo frnent, the antisolvent is added to the diluted aqueous ehlorite solution not to a concentrated chlorite solution, Οδδδ] In another embodiment, the concentrated aqueous chlorite solution Is added to a container comprising the antisolvent. For example, the aqueous chlorit solution is filtered to remove the solids comprising the impurities directly into a container, such as flask, comprising the antisolvent to provide the an isolvent-aqueous mixture. In an embodiment, the antisolvent in the container Is. kept at a temperature between about room temperature and a temperature .just below the boiling point of the antisoivent In a further embodiment, the aniisolvent i the container is ke at a temperature of about 45^SCX 11070] Ir an alternative embodiment of the present application, the aqueous sodium chlorite solution is obtained by:

adding water to Imputff sodium chlorite solids under conditions to obtain a stay made up of solids comprising impurities and aqueous solution comprising sodium chlorite .;

separating the aqueous solution comprising sodium chlorite from the solids comprising the impurities and, if required, concentrating the aqueous solution comprising sodium chlorite ,

10.071 J in another embodiment of the present application, the aqueous sodiurn chlorite is obtained by:

combining technical grade sodium chlorite with a quantity of water insufficient to completely soiubilize the technical grade sodium chlorite tOiprovide a mixture;

stirring the mixture to partially dissolve the technical grade sodium chlorite to provide slurry of undissolved solids and an aqueous sodium chlorite solution; and

separating the undissolved solids from th aqueous sodium chlorite solution..

fM?2] In one embodiment the amount of wafer added to the impu s chlorite solids or technical grade sodium chlorite is insufficient to dissolve all of the impure: sodium chlorite solids, in another embodiment., the amount of water Is selected: based on achieving: the: optimal purity of sodium chlorite over the optimal yield of sodium chlorite.

00733 in an embodiment, the conditions to obtain a slurry made u of solids comprising the impurities and the aqueous solution comprising sodium chlorite comprise combining water and the impure sodium chlorite solids or the technical grade sodium chlorite at a temperature of about 2(f:C to about iQCre, about 40^aC to about 85*0, about 85 C to about 5 0, or about tOC G.. or about 92°C for example white stirring. In an embodiment, the ratio (wt wf) or watensodium chlorite: Is about 0.5:1 to about 2:1 , or about 1.1 :1 , The selects of suitabl conditions: can be made by a person skilled I the art, S@?4| In another embodiment, the aqueous solution comprising sodium chlorite is separated from the solids comprising the impurities at a temperature of from abaiif: 25"C to about about 45X to about or about 6CTC to about S0*€;

[0G?§] in another embodiment, the aqueous solution comprising sodium chlorite :1s separated from the solids comprising the impurities using a hot filtration; For exampl the filtration Is performed using a hot Jacketed filter under positive pressure, in a further embodiment, the filtrate from the filtration Is kept a a temperatur that is above room temperature but below the boiling point of the anfisolvent, for example, for EtOR at a temperature of about 30*0 to about 45°C.

|007β in another embodiment, the aqueous chlorite solution is obtained by simply dissolving the sodium chlorite in a minimum: amount of water (for example a ratio (w i of wafer to chlorite of about 1 ,3:1 to about .&'L or about 1 .4:1 } at about room temperature. In an embodiment, no concentration or filtratio steps are performed,

077J In another embodiment, the aqueous solution comprising sodium chlorite Is separated fr m the solids comprising the impurities using a; mom temperature filtration. For example the sodium chlorite Is dissolved in water at a temperature of about 60°C to about 1GG*C, about 65^CC to about S FC, or about 7 C_r to forrn a hot aqueous solution which is cooled to room temperature resulting in precipitation of materials to form a suspsension. The suspensio i then filtered at room temperature: using positive pressure and the filtrate kept at about room temperature, fOoTSJ In an embodiment, the aqueous sodium chlorite solution is treated with a base to adjust the pH so that it is greater than 7. In one embodiment_: the pH is adjusted to range between about pH 7 to 14, pH 8 to 14, pH 8 to 13 or pH 9 to 13, suitably the is adjusted to pN 9 to 13. I another embodiment of the present application, the method further composes adding a ba . i the step of adding an antiso^'lvent- to the aqueous solution comprising- sodium chlorite, in an embodiment, the base comprises: an alkali metal hydroxide, in another embodiment, th alkali metal hydroxi e is sodium hydroxide. In a further embodiment about 0.1 wf to about 0.3 wt% or ^' about 0,2 wt% of base is added, based on the total weight of the antisoivent the aqueous solution comprising sodium chlorite and th base, fj#19 Once the aqueous solution is obtained, it may be subject to a: method for preparing Irnpurity-redueed sodium chlorite as described herein, fOOSO] The impurtty~reduc 3 sodium chlorite solids are separated from the sodium ehlorite-mduced solution by any suitable means, the selection of which can foe: made by a person skilled in the art. In an embodiment, the separation comprises filtration. In another embodiment the, filtration is carried out at a temperature that is substantially th same as the second temperature, used in the step of cooling the aqueous solution. In an embodiment, the filtration is carried out at a temperature of from about -40^s C to about -10^*0 or about ~2Q°C_S for example using pre-eooied filtration means. The impurity- reduced sodium chiorite solids are optionally washed with one or more portions of antisoivent 0001] In an embodiment, separation and/or collection steps comprise filtration. However,: an suitable method is used to separate and/or collect the various solids In the methods of the present application. The selection of a suitable method for separation/coliection can foe m d ; by a person skilled in the art:.

[0082] in an embodiment, the method for preparing impurity-reduced sodium chlorite according to the present application further comprises making an aqueous solution of the impurity reduced sodiu chlorite solids and repeating th adding and separating 1 , 2, 3, 4, 5, 6-, ^■?_< 8, 9 or 10 times.. In another embodiment, the method for preparing impurity-reduced sodium chlorite according to the present- application further comprises making an a ueous solution of the impurity reduced sodium chlorite solids and repeating: the adding and separating 1 _» 2, 3, 4, or 5 times. In an embodiment, the method for pre ar ng impurity-reduced sodium chlorite according to the present application further comprises making an aqueous solution of the mpurity reduced sodium chlorite solids and repealing the adding and separating until tH desired purity is obtained, for example, a pubt of about: 95%, 96%, ø? ,: 98%, %, 99,S%, 99.9% or more, in another embodimen the purity of the impurity reduced sodium chlorite solids is higher than 99%.

100831 It will be appreciated by a person skilled in the^: art: that the Impurity-reduced sodium chlorite solids can be suitabl further purified, for example,, by recrystaili ation to reduce the level of one or more impurities therein:. Accordingly, in an embodiment, the method furthe comprises recrystaHizing the impurity-reduced sodium chlorite solids.

0004] In an embodiment, the impurity-reduced sodium, chlorite solids are reerystallized i a solvent system comprising water and an antiso!vent. In another embodiment, the antisoivent is ethanol. In a further embodiment the solvent cornprlses wat and ethanol in a ration by volume of from about 20:80 to about 8Q:20. i still a further embodiment, the solvent: comprises water and ethanol In a ratio by volume of from about 4Θ 60 to about 60:40 or about 60:59,. The selection of suitable conditions for reerystallfcation can be mad by a person skilled in the art, fo example With reference to the conditions for obtaining impurity-reduced sodium chtonte solids and a sodium ehlorite- redueed solution and separating the impurity-reduced sodium chlorite solids from the sodium entente-reduced solutio discussed herein.

I an embodiment, the impurity-reduced sodium chlorite solids are dissolved in water, for example: at : temperature of from about SO to abou §0X or about 70X to obtain an aqueou solution. The aqueous solution so obtained can then be subjected to step which are similar to those embodiments discussed herei : for the aqueous solution comprising sod um chlorite to obtain reorystaized impurity-reduced sodium chlorite solids.

j[00i$J In an embodiment, the step of recr efall ation is repeated uM sodium chlorite of a desired purity is obtained. In an embodiment, the desired :purity:is about 95%, 96%, 9?%_:J 96%, 99%, 99.5%, 99.9% or more. |δ0Β7| In an embodiment, the method further comprises drying the impurity-reduced sodium chlorite solids and/or the recrystalfeed Impurif - redueed sodium chlorite solids. However, it will be appreciated by a person skilled in the art that drying sodium chlorite to the anhydrous state is not desirable due to the explosion hazard that the dry solid introduces. Alternatively, the impurity-reduced sodium chlorite solids and/or the re-crystallized Impurity-reduced sodium chlorite solids are not dried or are partially dried subsequent to separation (he. are "wet"} and can he used, for example to prepare an ac eoos solution comprising sodium chlorite.

(00881 In an embodiment, the method further comprises adding naler to the impurity-reduced sodium chlorite solids or the reerystailized impurity- reduced sodium chlorite solids to obtain an aqueous solution comprising, impurity-reduced sodium chlorite. In an embodiment the aqueou solution comprises about O.QS wt% to about 40 t% or about 2.5 wi:% sodium chionte, based on the total weight of the aqueous solution. In another embodiment, the Impurity-reduced sodium chlorite solids or the reerystaliized impurity- reduced sodium chlorite solids are wet. If will be appreciated by a person skilled in the ar that the- amount of water added to the wet impurity-reduced sodium chlorite solids or wet reerystaliized impurity-reduced sodium chlorite solids to obtain an aqueous solution -comprising impurity-reduoed sodium chiont having sodium chlorite of a particular concentration will depend, for example on the- amount of: water comprised in the. e impurity-reduced sodium chlorite solids or wet reerystaliized impurity-reduoed sodium chlorite solids. The amount of water comprised in the wet impurity-reduced sodium chlorite solids or wet: fecrysta!llzed impurity-reduced:^ sodium chlorite: solids can foe determined by a person skilled in the art and the amount of water added to obtain an aqueous solutio comprising impurity-reduoed sodium chlorite having sodium chlorite of a particular concentration can accordingly foe calculated by sued a e son:.

[0089J In another embodiment, an aqueous solution comprising impurity-reduoed sodium chlorite having a desired concentration of sodium chlorite, for example, about 10 wt% to about 4G t% or about 25 wt% sodium chlorite s prepared by adding water to wet, impurity-reduced sodium chlorite solids or wet, reorystailizert_>: impurity-reduced sodium chlorite solids, partially evaporating the resulting solution, etermining the concentration of the partially evaporated solution and adding a further portion of water to the partially evaporated: solution to obtain the aqueous solution having the desired concentration ef sodium chlorite. Advantageously, residual solvents that are more volatile than water are removed from th solution by this process. Accordingly, the inventors have developed a safer method of removing residual solvents than current methods of removing residual solvents: by drying of sodium chlorite. Crystals of sodium chlorite are highl unstable and poses a potential explosion hazard (ivtSDS). The levels of residual solvent can be measured by gas chromatography, in one embodiment, the level of residual solvent Is less than the level specified i the FDA's Guidance Document: ( 3C Impuhfes; Residual Solvents^

[0090] The concentration of the partially evaporated solution can be determined by standard means, such as titration, by a person skilled In the art and the amoun of water added to obtain the aetueous solution having the desired concentration of sodium chlorite; can accordingly he calculated by such a person. In one embodiment, the method is carried out by iodomefry.

[0091 J In another embodiment ot the present application, the method further comprises adding a base to the aqueous solution comprising impurity- reduced sodium chlorite. In a fuhber embodiment, the base comprises an alkali metal hydroxide, it is an embodiment that the alkali metal hydroxide is odium: hydroxide. In another embodiment, about 0.1 wt% to about 1 .0 t% or about 0.5 t of base is added to the a ueous solution comprising impurity- reduced sodium chlorite, based on the total weight of the aqueous solution.

[0092] In a further embodiment of the present application, the method further comprises adding an alkali metal chlorid ion to the aqueous solution comprising impurity-reduced: sodium chlorite, in another embodiment, the alkali metal chloride ion is from sodium chloride. In a further embodiment, at least 2 wt% of 2 wt% to about 5 wt% of alkali metal chloride ion is added. based on the total weight of the aqueous solution comprising sodium chlorite,, in an embodiment the alkali metal chloride on: is added as a final ste of the me hod on_. alternatively, is added prior t use of the impurity-reduced sodium chlorite. If included in the method, the alkali metal chloride ion-containing solution may be diluted prior to use of the: impurity-reduced sodium chlorite, for example, to render the solution containing sodium chloride Isotonic for administration to a subject.

f 9@¾ In an embodiment of the present: application, the method comprises further adding: sulfate Ions, via a suitable satiate sail, to the aqueous solution comprising impuoiy-redueed sodium chlorite, lo another embodiment, the sulfate ions stabilize the sodium chlorite solution. In a further embodiment, at least about 0,8 t% or about 0.8 wl to about 3 wt% of sulfate ion is added:, based on the total weight of the aqueous: solution comprising sodium chlorite:,

O ] In an embodiment of the present application, the method furthe comprises adding chlorate ions, vi : a suitable alkali chlorate, to the aqueous solution comprising: fmpori!y-redueed sodium chlorite. In another embodiment, the chlorate Ions act io preserve the sodium ehior!te solution. In a further embodiment, at: least bout^' 1.6. wt% or about 1 j i% to about 3 wf% of sodium chbrate ion is added, based on th total weight of the aqueous solution comprising sodium entente,

(ii) Sodium ch!o^eM w/ r eafton m hods

§ siiJ The present application also includes a method for preparing impurit -reduoed: sodium chlorate, comprising:

combining a antisolvent and a aqueous sodium chlorate solution, o adding an anlisolwent to a aqueous sodium, chlorate solution, or vice versa, under conditions to o tan impuhty-reduced: sodium chlorate solids and a sodium chlorate-reduced solution, wherein the sodium chlorate solution comprises one or more impuritie or is a nen-phar aceuttcal~grade chlorate: solution; separating the im u -rec uc^d sodium chlorate solids from the sodium chlorate-reduced solution; and

optionally making an aqueous solution of the impurity reduce sodium chlorate solids and repeating the adding and separating one or more t mes,

§S§SJ In_. an embodiment, the conditions _: to obtai the Impurity-reduce sodium chlorate solids and the sodiu : chlorate-reduced solution: comprise;

adding the antisolvent to the aqueous sodium chlorate solution to obtain an anfeolveofc-aqueous mixture; and

cooling the antisoivent-aciueeus mixture to obtain the iropurity- redueed sodium chlorate solids and the sodium chlorate-reduced solution.

JO0S7J In an embodiment, in conditions to obtain the im urity-reduced sodium chlorate solids and the sodium ehlorate-nadueed solution comprise;

adding the aqueous sodium chlorate solution to the anfisoivent to obtain an antisoivenf-aqueous mixlure; and

cooling the antisolvent-aqueous mixture fa obtain the Impurity- reduced sodium: chlorate solids and the sodium chio.n3te-»reduced solution.

[00981 In an embodiment, the antisolvent Is added id the aqueous sodiunr chlorate solution, or vice versa, at a first temperature, the antisolvenb aqueous mixture so obtained is then cooled to second temperature and Is substantially maintained at the second temperature to obtain the impurity- reduced sodium chlorate solids and the sodium chlorate-reduced solution. In another embodiment the antlsoiyeot-aqueous: mixture is first cooled to an intermediate, temperature fcefore being furthe cooled to the second temperature, optionally being substantially maintained at the intermediate temperature for a suitable period of time before being furthe cooled to the second temperature. The selection of suitable first, second and intermediate temperatures depends, for example, on the identit and/o ratio of the antisolvenf used and the selection can be made by a person skilled in. the art. For example, it will be appreciated by a person skilled in the art that the first temperature is suitably below the boiling point of the antlso!vent and the second and Intermediate temperatures are suitably abov th freezing: point of the .water-anfisolvenf mixture but lo enough such that a desired amount: of Impurity-reduced sodium chlorate solids is obtained from the antisolvent-water mixture.

| 9S1 ln_: an embodiment of the present application, the antlsoiyent is efbanoL the first temperature is from about S^s to about W C, 25^ίί€ to about 32^*C or about 1CTC^', me intermediate temperature Is from about -5^*0 to about abou ψθ and the second temperature is from about to about

C, to abou 1^'6*C or about -2CTC,

|8 1OO| It w ll be appreciated by a person: skilled in the art that the method can further comprise agitation such as stiffing during part: or all of the addin and cooling. For example, th antisofvent Is added to the aqueous solution while stirring and/or the antiselvent aqueoys mixture is stirred during cooling from one temperature to another temperature such as from the first temperature to the:: second temperature or alternatively the intermediate temperature:;

00101} In another emboctiment the antiselvent is added to the aqueous solution, o vice versa, portion wis , for example ever a time, of from about 30 seconds to about 1 hour, about 1 minute to about 50 minutes, abou 5 minutes to about 40 minutes, or about 25 minutes: to about 35 minutes, optionally while stirring,

|00102] The time the antiselvent-aqueous mixture i substantiall maintained at the second temperature to obtain: the impunty-mdueed sodium chlorate solids and the sodium chlprate-reduoed solution may vary, for example, based on the Identify arsdmr ratio of the antisolvoot used and/or the desired yiel of the impMrity-redu€€d chlorate solds. The selection of a suitable time ca be rnada by person skilled in the art end generally corresponds to the time it take for suitable quantities of the impurity-reduced sodium chlorate solids to precipitate, in an embodiment, the antisolvent-aqueous mixture is substantially .maintained at the second temperature for a time of at least about on hour or about one hour to about 48 hrs.

00103| It will, be appreciated y a person skilled: in the art tha a useful anfisoivenf far the method tor preparing impurity-reduced sodium chlorate of the present application will suitably fee relatively inert to -. sodium^' chlorate nd wafer, have lew abilit to soiubize sodium chlorate and be substantially mlseihie with water. In one embodiment, the antisolvent Is: soluble in water, in another embodiment,: the antisolvent has a high vapor pressure for example, a vapor pressure higher than that of water. Fo the preparation of impurity- reduoed sodium chlorat useful for the administration to subjects such a human subjects:, the antisolvent will also suitably have a tow toxicity to such subjects. The selection of a suitable antisolvent for a particular method can he made by a person skilled in the art OW } In one embodiment, the antisolvent comprises a mixture of solvents that is either remtxed before adding to the: aqueous ehionfe solution or are added as individual solvents or added as one or more mixtures of solvents, SIISS] In one embodiment th antisolvent comprises, consists essentially of or consists of a class 2 or clas 3 approved solvent according to the US. Food and Drug Administration {Guidance far industry, Q3C - Tables and List, U.S. Department of Healift and Human Services, Foo and Drug Administration, Center for Drug Evaluation and Research, Center for Biologies Evaluation and Research, November 2003, Revision 1) or the European yedielne Agency CH Topic Q3C ( 4) impuntles:; Guideline for Residual Solvents,: European edical Agency, February, 2GQS1 or a mixture thereof, in an embodiment, the antisolvent is selected from acetic acid, acetone, anlsoie, l-Duiano!, 2- utanol, butyiaceiate, t- utylmethylether, cumene, dimethyisulfoxide, efhanel, ethyl acetate:, ethyl ether, ethyl formate, formic acid, heptane, Isobutyl acetate, sopropyl acetate, methyl acetate, 3- ethyi~1- utano!, methylefhy! ketone, mefhyflsohutyt ketone, 2--methvt-'Ppropanoi_J pentane, 1-pentano , l-propancl, 2--propanol propyl acetate, aeetonithie, chlofo enzene, chloroform, eydohexane, l,2 tfehloroethane, dfchldmm^thane, 1 ,2-dSmethoxyeihane, _; -a¾ethyiacetamicie_s H,N- dl ethyifprma lde, 1,4~dfoxaoe,_: 2-etboxyeihanol, etnyienegiyeOl,- formamide, hexane, methanol, 2~niethoxyethanol_! me hyibutylkeione:, n hyicyclohexane, N-methylpyrroiid.one. ni romethane, pyridine, -sulfolane, rshydrofuran, tetralin, toluene, 1.,1_.,2~†dehioroetrene_., xylene and glycerol and mixtures thereof,

[0O1:06J In another embodiment, the antisolvent s selected from acetic acid, acetone, anlsole, -hutanol, 2-butanoi, bufyfacefate, t~hutyimethylether_< curnene, eflmethyisulfoxide, ethanol, ethyl acetate, ethyl ether, e!byl formate, formic acid, heptane, isobutyl acetate, isopropyi acetate, methyl acetate, 3- methyM-butanol, methylethy! kefone. methylisobuiyl ketone, 2-methyM- propanol penfane, 1-pentanol, 1-propanol 2-propanoi propyl acetate, acetonitrte, 1_s2 jlmeihoxyethane, Ν,Ν-dimethylacetamide:, N..N- :dlni¾th lfom^amlde, 1 ,4-dloxane, 2-ethoxyethanol, ethytenegiycol, formamide, Hexane, methanol, 2-methoxyethanoi, ethyibutylketone, methylcyclohexarse, -methylpyrrolidone, nitromethane, pyri ne,: sutfpta e, tetrahydrofuran, tetrafin, toluene, 1 ,1 ,2-trichiQroe hene:, xylene and glycerol, and mixtures thereof.

[00107] In another embodiment trie solvent is selected. a Glass 3 solvent or a mixture comprising Class 3 solvents or a mixture of Glass 3 solvents. In an embodiment the class 3 solvent are selected from acetic acid, acetone, anisoie, j-butanoL 2-feutanol, butylaoetate, t^»byiylmefhy ether, .cumene,- iniethyisuifoxlde, ethanol,, ethyl acetate, ethyl ether, ethyl formate, formic add, heptane, Isobutyl acetate, Isopropyi acetate, methyl acetate, 3-methyl-1- bulanol, roethylethyl ketone, mefhyilso utyi kefone, 2-methyi~-1 -propanol, pentane, 1-pentanoi, 1-propanoi, 2-propanol and propyl acetate, and mixtures thereof,

001083 in. an embodiment, the antisolvent comprises, consists essentially of o consists of a C alc shoi. In another embodiment, the antlsoivent em rises* consists essentially of or con i ts of a ¾..₃ateohoL in another embodiment, the antfso vent comprises, consists essentia ly o or consists of ethanot In a further embod ment, the ahfisolvent Is eihanoi. f 00100] in an embodiment, the ratio by volume of the ethanot ID the aqueous sodium chlorate solutio Is from about 1:2 to about 4:1 , & ϊ 1:1 to about 3:1 or about 2. L

Ι0Θ1101 The aqueous sodium: chlorate solution is obtainable by various methods, The selection of a suitabte method can be made by a person skilled in the am In an embodime.nl ike aqueous sodium chlorate solution Is .o tained by adding wafer to impure sodium chlorate solids under conditions to obtain the aqueous sodium .chlorate solution. The: selection of suitable condition can .be made by person skilled in the art in an embodiment, the conditions comprise adding the water to sufficient uantities of the impure sodium: chlorate solids and then sti ing for a time and at a temperature until the dissolution of the sodium chlorate: in the. water Is substantially complete. n an embodiment, the temperature is from about $GX to ahout 9QX or about ^' _.70^*0.

[0811 ] in another embodiment, the impur sodium chlo ate: solids comprise one or more impurities and the method further comprises separating the impurities from: the aqueous sodium chlorate solution. The separation can be earned euPhy any suitable means:, the selection of which can be made b a person skilled in the art., Irv an embodiment,: the separation comprises filtration- at a temperature that is substantially the same as the temperature used in the step of obtaining the aqueous sodium chlorate solution, fo example about 50X to houtW or about 76X.

[00112] The impurity-reduced: sodiu chlorate solids can be separated tom toe sodium chlorate-reduced aqueous solution by any suitable means, the selection of which can be made by a person skilled in the art, in m embodiment, th separation comprises filtration. In another embodiment, the filtration: is carried ou at a temperature that is substantially th same as, the second temperature used in the step of cooling the agueous solution. In an embodiment, the filtration is carried out at a temperature of from about -4QX to about -40*0 or about -28 C, for example using pre-eooled filtration means. The Impurity-reduced sodium chlorate solids are optionally washed with one or more portions of antisoivent

(00113 J in an embodiment th method for preparing Inipunty-reduced sodium chlorate according to the present application further comprises making an aqueous solution of the impurit reduced sodium chlorate solids and repeating the adding and separating 1 , 2., 3, 4, S_s 6, ·?. 8, 9 or 10 times. In another embodiment, the method for preparing impurity-reduced sodium chlorate according to the present application further comprises, making an aqueous solution of the Impurity- reduce sodium chlorate solids and repeating fhe_: dding and separating 1 , 2, 3, 4, or $ times. In an embodiment the method for preparing impurity-reduced sodium chlorate according to the present application further comprises makin an aqueous solution of th impurity reduced sodium chlorate solids and repeating the adding and separating until the desired purity is obtained, for -example, a purify of about 95%, 96%, 97%, 98%, 99%, 99.5%, 99 J% or more. In another embodiment, the purity of the impurity reduced sodium chlorate solids is higher than 98%,

[001141 it will fee appreciated by a person skilled n the art that the impurity-reduced -sodium chlorate solids can be suitably further purified, for example, oy reerystalllz tion to reduce the level of one or more impurities fhere!m Accordingly, in an embodiment, th rnefhod further comprises recrystalfcing the impurity-reduced sodium chlorate solids, in an embodiment, the impurity-reduced sodium chlorate solids are recrys ailteed in a solvent system comprising water and an antisoivent. The selection of suitable conditions tor recrystallteatlon can be made by a person skilled in the art, for example with reference: to the conditions for obtaining impurity-reduced sodium chlorate solids and a sodium chlor te-reduced solution and separating the impurity-reduced sodium chlorate solids from the sodium chlorate-reduced solution discussed herein.

|O0115] In an embodiment, the step of recrystalifeafion is repeated until sodium chlorate of a desired purit is obtained. In an embodiment, the desired arty- is about §5%, m%, §J%_> 98%. 99 ;, 98.5%, 99.9% or more.. In another embodiment, the purity of the impure- sodium chlorate solids is higher than 99%. it will foe appreciated by a person skilled In the art that the methods for preparing Impurity-reduced sodium chlorate of the present application will be useful to crystallise sodium chlorate having such a purity, for example under good manufacturing practice (&MP) conditions without the introduction of new impurities and/or lowering of the initial chemical purity,

[0011β| In an embodiment, the method urther comprises drying the impurity-reduced sodium chlorate solids and/o the recrystallized impurity- reduced sodium chlorate solids. In another em odiment, the method further comprises adding water to the impurity- reduced sodium chlorate solids or the reorystaize-d impurity-reduced sodium chlorate solids to obtain an aqueous solution comprising impurity-reduced sodium chlorate:.

III. Product-By-Process

[0011?! ft. will he appreciated b a person skilled in the art that ne products are obtained b conducting the methods of the application. Accordingly, in one aspect, the application provides tor a product obtained by a method of the application.

£001183 I one embodiment, the present application includes a product produced by a method for preparing impurity-reduced sodium -chlorite, comprising::

combining an antisolvenf and an aqueous sodium chlorite solution, or adding an antisoivent to an aqyeous sodium chlorite solution or vice versa, under conditions- to obtain impurity-reduced sodium chlorite solids and a sodium chlorite-reduced solution, wherein the aqueous sodium chlorite solution comprises one or more impurities or Is a non-pharmaceutical-grade chlorite solotion; separating the impurity-reduced sodium chlorite solids from the sodium chlorite-reduced solution; and optionally making an aqueous solution of the Impurity reduce sodium chlorite solids and repeating: the adding ¾nd separating one or more times.

[00119] In another embodiment the present application includes a product produced by a method for preparing Impurity-reduced sodium chlorate, comprising: combining; an antisolvent and an aqueous sodium chlorate solution, or adding an antisolvent to an aqueous sodium chlorate solution, or vice versa, under conditions to ofetain impurity-reduced sodium chlorate solid and sodium chlorate-reduced solution, wherein the sodium chlorate solution: -comprises one or more impurities or is a non-phafmaceutioa -grade chlorate solution; separating the impurity-reduced sodium chlorate solids from the sodium chlorate-reduced solution; and optionally making an aqueous solution of the impurity reduced sodiu chlorate solids; and repeating the adding and separating, one or more ti mes,

100120] The following non-limiting examples are illustrative of the present application;

EXAMPLES

E m le 1 ; Fiirifieaffoin of Solium Chlorite

A, Crystallization of Sodio Chlorite from Aqueous Solutions 001211 The sodium chlorite technical grade used in the present ex eriments- as starting material was from Sigma Aldnch, item no. 244155. Table 1 shows the content of various Ions ;by ion chromatograph analysis of the starting material.

[00122J i the procedure disclosed in US Patent Mos. 8,087,035 and 8,231 ,858 the method Included the hot filtration of saturated sodium chlorite solution, followed by freezing: of the filtrate at -2S°€ while standing for 24 h, ooid filtra io or eeotrifogailon of the solid, and then its repeated crystallization from water. In these patents, the ratio of solute/water was not mentioned.

pQ123f in the present experiments the ratio of aCl¾/wa er of 1 :1 was used as it corresponds to the chlorite solubility in water at approximately 4CFC' This ratio was oaleulated based on the approximate content of aCIGs;: for the starting materia! with an about Q% pohiy the ratio of solid : ¾vater wa 1TX8...

f00124| The present studies: attempted to replicate the procedure disclosed in US ; Patent Nos. 8,067^' _f035 and 8,231 ,8δδ, A ose separat on of impurities via the hot filtration step was observed (Table 1 , Entries 2 and 6). Ho ever, difficulties were encountered relating to the filtration of the thick suspensions formed during the crystallizations, which hardened in the freezer (-2CTC) into stone-like blocks. This observation indicates that the process would be quite difficult to scale up, and would fee both physically and mechanically demanding,

tS SSf While not wishing to be limited: by theory, a rnafor problem of the known process, namel filtration of the cold hardened suspensions, has its roots in the physical propertie of sodium chlorite. Sodium chlorite possesses a high solubility in water (about 38%: at 2®"€) and the ability to crystallize in t!ie form of a trihydrafe at a temperature belo 38^;'G^¾,° thereby consuming a substantial part of water in: which It is dissolved. This leads to the fofmation of a very thick suspension due to the high ratio of solid material to wafer (1:0,8). The situation is aggravated by the precipitation of trihydrate as more water {0.3? mass aq.) is removed from solution, leaving only 0.43 mass eg, of water in the media for dissolution; of the impurities. Such a low quantity of water is: insufficient to perform a proper filtration as a big part o the mother liquor remains adsorbed on the filtered solid. A wash with water would be useful, but would lead to substantial loss of material.

B, De¥elQpmeni of Alternative ^eorystal!kation fethesls

c lil A trial to improve the fllterahllify of the suspensio formed during cooling of the concentrated sodium chlorite solutions was undertaken starting from 1 GO g of the technical grade NaClC¾ (Table 1 , Entries. 1 and 640), Tr e sodium chlorite was dissolved in water using the 1 :0.8 ratio used previously and the possi ilities presented by addition of stirring and antisoivents to: the above method were explored. The fixate, after hot filtration , was divided into three parts,

1001271 The first portion wa cooled to room temperature while constantly stirring, followed by cooling to -20^*0 In a freezer while standing. The solid was formed not as a block, but as a solid easily broken u Into smaller particles:. After transferring to a filter, it was filtered with a sintered glass filter and dried to give 30,0 g of solid product (Table 1 , Entry 8). The product had a purity of 97.6% by ion chromatography (IC). However, the procedure: is still quite labor intensive and may, for example be inconvenient: for scale up due to the formation of a thick suspension,

|G0128 The second portion was cooled to room temperaiym while stining, and the precipitated solid was removed by filtration, The filtrate was then cooled ip ~20"C in a freezer where It also formed a mixture of solid large sized particles. After being; filtered and combined with the product from filtration at room: temperature, 33.7 g of the product (Table 1 Entry ? was obtained. However, its purit was lower (94 7%) than thai observed for Table 1 , Entry 8 and the procedure may still not be convenient for large: scale production-,

[00129] I wa decided to introduce a second solvent which is an antlsolvent to sodium chlorite in the process of crystallization of sodium chlorite, allowing an increase in the amount of supernatant and giving the possibility to wash the filtered solid, in the present studies, second solvent possessing tr¾ following four main properties was sought; (1 ) relatively inert to sodium chlorite and water; (2) low ability¹ to soiubilize sodium chlorite; (¾ miscihie: with water; and (4) low toxicity to ihumans, Ethandl was chosen for its ability to satisfy these criteria, initially, it was thought that a possible oxidation of the alcohol by sodium chlorite would be problematic. However, a literature search revealed that such a reaction does not proceed at a significant rale under ambient co ditions and in the afosenee of a eatalysf (TEMPO) and secondary oxidant { aO ?)^? .

00130] It was experimentally determined that the solubility of sodium chlorite- in §ø% aqueous et anoi at room temperature is about 19,5 g/100 nil. To test the use of an anttsplvent in the crystallization of sodium chlorite, a trial was performed m\ng the ird par! of -the filtrate from the hot: .filtration discussed above.

(001311 ¾e third portion; was diluted with water and 100% EtOH to achieve an approximate ratio of 1 : 1 : 1 NaGiOg (dr mass) ; H¾Q (mass) ; EtOH (volume) (considering that 75% of the starting materia! remains dissolved) and cooled to ~2Q^e-C, Th mixture was quite movable and easily filterable. After filtration and drying, 31.7 g of the product (comprises sodium chlorite trihydrate} was obtained (Table 1 , Entry 9), 20 g of it was reciystailized again from 50% EtOH to: give 14.2 g of crystalline material (Table 1, Entry 10). This method was observed to he the most convenient and scalable

[001321 During analysis of the product obtained from the rperystalli atlori using the EtOH antlsolvenf , an unexpected chlorate presence in the product of the second crystallization was detected (Table 1 , Entry 10). The analysi was repeated and the result: was similar. This observation will be discussed below,

C. Use of Different Ratios of Ethan©!: Water In the Cry a Mzaikms

[00133] Studies aimed at optimizing the eihanol concentration were carried out. Three parallel crystallization trials were performed from 40, S0_: and 60% (% by volume) aqueous ethanol The analytical data for these trials are shown In Table 2.

|00134] The conclusions derived from these experiments are; The method is convenient and robust, giving very pure product after two crystallizations (with purity above 99,5%) at ail investigated concentrations: (Table 2, Entries 4, 8 and 8), The concentration of 60% gives a slightly higher yield and it is the middle of the investigated^' area of concentrations ^'{Table 2. ; Entry 4}.

0.. Origin of Chlorate Observed m Table 1_s Entry 10

|0 1 11 Investigations of the stability of the sodium chlorite solution were also conducted triggered b the unexpecte observation of the presence of chlorate in the product of the second crystallizations (Table 1 , Entry 1 ø). While net wishing: to: be limited by theory, one hypothesis was proposed: that it could be caused by decomposition of WCK¾> which ma be present in trace concentrations in aqueous sodium chlorite solutions due to the equilibrium which: exists between chlorite and chlorous acid c!unng crystallization. D0130J The addition of small amounts (about 0.2% w/w) of NaOH to raise phi and decrease acid formatio was investigated.

I0O137J While no other experiments supported this hypothesis, it was also decided to check the longer-term (relative to the process time) stability of aqueous solutions of NaCl¾. A. fresh solution of 25% sodium chlorite was prepared from Table 2, Entry 4, lis initial pH was recorded as 10,6, The sample was stored for about 2: weeks at room temperature. After 10 days of storage, the pH of the solution: was observed to have dropped to 10,34. Ion Chromatography analysis of the solution after 2 weeks storage showed accumulation: of only Q.74% chlorate and 0.76%: chloride (Table 2, Entr 9} whereas the expected ratio of formation of these anions from chlorite should be 2:1 , and not 1:1,

foi 38] While chlorate formation from a chlorite solution Is a theoretical possibility through the formation of chlorous acid (HC^'i0₂) b hydrolysis and subsequent disproportienafien of this compound the results presented here demonstrated that almost no detectable amount of Chlorate should be formed during the crystallization process, which is much shorter than 2 weeks. Accordingly, while not wishing: to be limited by theory,, the chlorate finding in the sample of Table: l , Entry 10 could be explained_^ for example b cross- contaminat!on or by long storage of its analytical solution. 0139] Although the formation of chlorate during the crystallization process was unl kely, as an additional precaution, two separate larger scale batches were manufactured under different conditions: one in the; absence of NaOH. and the second one in the presence of 0.2% ( wj of NaOH b the crystallization.

E, Larger Scat Batches of Sodium Chlorite

[06 1 1 he larger scal batches were manufactured^ starting from ?SQ ø of the sam technical grade NaClQ? from Sigma. Aldrieh (Table 3, Entry ·!■:, After hot filtration, the filtrate was divided into two parts: one part (Table 3_S Entry 2: Table 4, Entries 1 and 3) was crystallized wit the addition of sodium hydroxide fQ..2% of the: mass of dry sodium chlorite), while the second: part was ^'crystallized without; introduction of any addiflona! material (Tabl 3, Entr 3; Tabl 4, Entries 2 and 4). The details of the procedure are given below. The analytical results of both batches are shown in Tables 3 and 4,

[00141] The comparison of the results from the two batches shows that addition of NaOH during the crystallizatio process decreased the yield (68% vs, §9%) and slightly decreased the product purity after the second recipystalNza ion (©8.6% vs. 99,3%:_: mostly due to less^' effective removal of the chloride salt).

[0 _.42] The variation in residual EfOH and assayed amounts of sodium chlorite In Table 3 can be explained by difference in the extent of drying. It was found that if is difficult to perform reproducible drying, as the initially formed trihydrate of NaCIC¾. easily loses wafer during vacuum drying. The exhaustive drying of the solid salt to the anhydrous state is not desirable due to the explosion hazard that the dr solid Introduces,

F. Formation of 25% tftvt Solutions of S©d?ym Chlorite

00143] Sodium chlorite {236.22 g_t Table 3, Entry 2, containing 33.2% of water), sodium hydroxide (3,0 g, lot # 83714, Caledon) and USP grade water (360-78 g) were mixed to obtain 800 g of an about 25% solution of sodium chlorite containing 0.5% of sodium hydroxide. The solution obtained was analyzed to show a 25,1 % content of dissolved sodium chlorite,

100144] Sodium chlorite (197,36 §, Table 3, Entry 3, containing 19,5% of water), sodium hydroxide (3,0 g, lot # S3?14_s Celedon) and USP grade wate (399,84 g) were mixed to obtain 600 g of an about 25% solution of sodium chlorite containing 0,5% of sodium hydroxide. The solution obtained was analyzed to show a 24,4% content of dissolved sodium chlorite,

G. .Alternative, Hfetfeci for esidual Solvent emov l

| 014Sj In view of th Issues associated with drying sodium, chlorite It was proposed that if ma be useful to use a method wherein instead of a thorough drying of the solid, the solid would only be dried slightly (or even not at all after filtration), dissolved In an excess of wafer and the resulting solution subjected to partial evaporation to Ma n a volume slightly below the calculated desired volume. Ethanol as the lower boiling solvent, should be removed preferentially during this procedure. Finally, the concentratio of the formed solution would he determined by titration, followed by dilution to the desired concentration, f 001:46] To test this proposed route, an additional trial, was conducted where pure Na.Ci0₂ (Table 1 , Entry S) was re-erptallized from: 50%: EtOH, Afte filtration, die wet product was divided Μύ two equal parts: 20 g of the. firs one was dissolved in 80 mL water (4 volumes total weight 100 gj; 20 § of the second one was dried at room temperature under vacuum for 1 h₅ and then also was dissolved in SO mL water. Both solutions were then evaporated to about 40 ml. volume. The mass of the first solution was 44, i g (Table 6, Entr 1 }:, and the second one was 48,7 g (Table S, Entry 2). Anelytieal results Of both experiments are given in Table. 5, These studies showed that such a method could be used for preparation of 25% aqueous solutions Of NaCIO? without drying of the wet product of the second crystallization of sodium chlorite. Ι Proc.ed.pre for Purification of Sodium C lorite {?§ø^■ø genie)

[00147] A scheme descr bing th flow of an embodiment 10 of the method- developed n the present studies is presented In Figure 1 ,

I. Materials

[00148] Technical grade sodium chlorite (750 g); 100% Ethanol (1800 ml) and United States Pharmacopeia (USP) grade water (2260 ml).

II. Equipment

|0&1 S| One neck 3 L round bottom flask (RBF)₅ one neck 1 L RBF, .rotary evaporator, thermomete (-20 to 70*C), 1 L sintered glass funfre! (2 pes), 5 L ice-salt bath, stir plate, 2" stir bar, 2 L Sunsen flask^", 1 I Edenmeyer flask, 1 L measuring cylinder, 1 L bea¾ec plastic powder funnel (2 pes) and stainless steel spatula.

IH, Procedure

[00150] The rotary evaporator water path was pre~heated to the target temperature of ?0^SQ. 750 ± 0.5 g of technical grade (80%) sodium chlorite was weighed into a i L beaker. The weighed -sodium chlorite was then transferred to a pre-weighed 3 L -neck- RBP. 1500 ± 10 ml of USP grad water was then added to the contents of the flask. The flask win the obtained suspension was fixed on the rotary- evaporator and the flask rotated in the hot bath until a solution aS: obtained; a- slight turbidity was allowed (Figure 1 , step 12}, Vacuum was then applied, arid the water partially evaporated until crystallization of a white solid was observed i the entire volume of the formed suspension (Figure 1 , step 14). 00 513 ϋί# vacuum pump was then turned off and the vacuum released. The flask with the suspension was weighed and the weight of suspension adjusted to 1240^' ± 1 g by addition of USP water or continuing evaporation of excess water (Figure 1 , step 1& The flask wa then fixed on the rotary evaporator and the flask ith the suspension rotated in the hot (70 C) water bath for 30 m^'ln (Figure 1, step 18). The homogenized hot suspension was filtered using a 1 L sintered glass funnel and a 2 L Bur sen flask under -moder te vacuum at: the- beginning, then under full vacuum (Figure 1 step 20). The solid collected lay filtration (about. 137 g, dry weigh!) was disposed of (Figure 1, step 22),

I00152J The filtrate from the Bunsen .flask .was weighed and transferee* to a 2 L Erfenrneyer flask equipped with a stir plate nd; a 2" stir bar. The Bunsen flask was rinsed witb the -required amount of water to adjust the total weight of the solution to 1125 g and the washings, combined with the filtrate (Figure 1, ste 24), About 560 ml of 100% efhanol was added portion wise at about 30 *C to the Erienmeyer flask while stirring over a 1-2 mln period (Figure 1 , step 28). In the meantime, about 3 kg of a cooling ice-salt mixture (about 0,5 kg of NaCI per about 2.5 kg of Ice) was prepared. The Erlennieyer flask was placed into an empty cooling bath, The cooling ice-salt mixture was added to the cooling oath and the contents of the flask cooled to a temperature below 0°C, The stir bar was removed, the Erlennieyer flask covered with aluminum foil and the flask stored i a *20°C freezer for at least 1 (Figure 1, step 28} along with filtration kit of a 1 L sintered glass funnel and 2 L Bunsen flask. The contents of the Erlennieyer flask were then quickly filtered using the pre- coded filtration kit (Figure 30 , step 3D). The cold filtrate was used to facilitate transfer of any remaining solid materia! in the Erlenmeyer flask. The filtrate was then discarded (Figure 1 , step 321. The solid was^' pressed and washed on the filter with 1 0% ethane! (2 x 150 ml). The solid was then transferred into a pra-we!ghed 3 L rotary: evaporator RBF and dried under vacuum at 30±3¾ (hath) until the difference: between two consecutive weighings, 10 minutes apart was less tha 2 g (Figure 1. step 34),

[00153] An analytical sample (1 ± 0,1 g of the dried first crystallization product was transferred Into a 4 ^:ml amber vial {Figure 1 ste 36). The solid in the 3 L RBF was then weighed after sampling, 0.26 volume of water based on the weigh of the solid was then added and the solid dissolved in the water with heating. (Figure 1 step 33), The rotary evaporator's bath temperature was: set to 70^*0. The warm solution was transferred into a 1 L Erlenmeyer flask equipped with a stir bar and placed on a stir plate. The solution wa allowed to cool down b low 30ⁿC. Th same volume of 100 ethanol, as the total volume of water (0.83 volumes based on the weight of the solid) was added portion wise to the contents of the E enmeyer flask white stirring (Figure 1 , ste 40). About 3 kg of a cooling lee-salit mixtur (about Q $ kg of aCI per a out 2:25 kg of ice) was prepared. The Erlenmeyer flask was placed into the empty cooling hath. The -fee-salt mixture was then added to the cooling bath and the contents of the flask cooled to a temperature below OX wth stirring. The stir bar was removed, the Erlenmeyer flask covered with aluminum foil and the. flask stored in a -20X f eezer for at least 1 h (Figure 1, ste 42) along with a filtration kit of a 1 L sintered glass funnel and a 2 L Synsen flask. The contents of the Edenmeyer flask were quickly filtered using the pre-cooied filtration kit (Figure- 1 _: step 44). The cold filtrate was used to facilitate the transfer of any remaining solid material in the Erlenmeyer flask. The filtrate was then discarded (Figure 1 _s step 4§). The solid was pressed and washed on the filter with 100 eihaool (2 x 126 ml),

[801S4] The wet solid was weighed (Figure 1₁ step 48), An analytical sample (1 ± 0.1 g) of the wet second crystallization product was then transferre into a 4 ml amber vial (Figure 1._s step 50). Four parts of water were added to the wet solid and the weight of the mixture recorded (Figure , step 52). The mixture was concentrated in vacuo until th mass reduced to 0.45-040 pads of its initial weight (Figure 1 step :54). An analytical sample ( ml) of the concentrated sodium chlorite solution was transferred into a 4 mL amber vial and submitted for iodomeiry analysis (Figure 1 _< step 56), The -concentrated solution was stored in a fridge (2-B-C) while: the analysis was being executed. The analytical results were received and the amoun of sodium hydroxide and -water necessary to obtain a mixture of sodium hydroxide: (0.5%), sodium chlorite (25%.):, and ater (74,5%) calculated. The solution was then prepared according to calculations (Figure: 1\ step Si). An analytical sample (3 rnL) of the- obtained sodium chlorite solution was transferred and submitted for final QC release testing (Figure 1 , step 80.)- The final solution was then packed in containers of an appropriate size and stored in the fridge at a temperature of 2-S*€ (Figure 1 , step 62). Exam le 2 Crystallization o? Sodium Chlorate

A. Crystallization of Sodium Chlorate from Water and kqm Ethan®! 0 15S] As the purity of commercially available sodium chlorate from Sigma-Aidihch (Item no. 40301 §.;: Table β, Entry 1^") is higher than 90%, an intent of the study was to develop a scalable procedure for the crystallization of such sodium chlorate: under goo manufacturing practice (©MP) conditions without if : introductio of new impurities or lowering of th Initial chemica purity, 00156] The first attempt to- reor taiilzei 100 g of sodium chlorate from a minimal amoun of water (78 mL) even with deep cooling at -20^¾C yielded only 41 g of dry: product (Table 6, Entry 2). A partial removal of water (about 35 ml) gave more material (30 g. Table 8, Entry 3). This fact led to the observation that: the solubilit of sodium chlorate is less temperature dependent than that Of sodium chlorite. Thus, It was decided to apply the earlier developed purification protocol of sodium ehiohte from 50% etnanoi for reerystal izallon of sodium chlorate.

J¾0157l The trial procedure Included dissolving the starting material in a minimal amount of water at ?0°C, partial crystallization of sodium chlorate by cooling down to about 2*C followed by forced precipitation of more material at dilution with an egual volume of 100% efhanol. Filtration a this stage afforded a 88% yield of the material (Table 6, Entry 4). A higher dilution of the filtrate with more efhanol (2.S volume equiv.) and deeper cooling {~20°C^:.} allowed more material to be recovered raising the total yield to 80% (Table 8, Entr 5), The purity of the starting and recrystallized material is presented in Tabie 6.

B< Fr eetl re for Fyr flcatior? of Sodium Chlorate (S§8 § scale)

[001 SS| A larger scale procedure starting from SCO g of sodium chlorate from Sigma-Aldrich was prepared and successfully implemented, where a highe yield of product was: obtained (Table ?); A scheme describing the flow of an embodiment 100 of the method, developed In the resent studies s presented in Figure 2.

L Materials

[001.SS] Sodium chlorate (§00 g); 100% Ethanoi (1800 ml); and United States Pharmacopeia (USP) grade water (400 rnL),

|0 160| One neck 3 L RBF, stir late, 3^:: stir bar, heating mantle, thermometer (-20 to +?0^i>C)_; 0.5 L sintered glass funnel, cooling (10 L) ice- water hath, overhead stirrer, stir rod, i L 8unsen flask, 4 L Erienmeyer flask, 2 I graduated cylinder, 1 L header, 2 L addition funnel, plastic powder tunnel (2 pes) and stainless steel spatula, ill. Procedure 00161] 500 g of sodium chlorate was weighed in a 1 L beaker. The weighed sodium chlorate was transferred to a 4 L Er!enrneyer flask equipped with a; heating mantle, stir plate, 3" stir bar and a 2 L addition funnel. 400 ± 5 jjsL of IfSF grade water was added to the contents of the flask.. The suspension was heated to about 7CFC and stirred until dissolution of sodium chlorate was complete (Figure 2, step 102). The obtained solution was hot- filtered through a sintered glass funnel into a l l Bunsen flask (Figure 2, step 104). The filtrate was then transferred to a 4 L Erienmeyer flask equipped with an overhead stirrer and stir rod. The mixture was stirre until th formed suspension sooted down to 5^*€ then the: flask immersed into an ice-water bath with continued stirring until the tempeMiyre decreased below 0 (Figure 2, step 106).

100102] 1400 ml of 100% ethanoi was measured and added to the content of the flask over a 30 ± 5 min period using a 2 L addition funnel (Figure 2, step 108), The stirring was continued while cooling in an ice-water hath for 1 h (Figure 2, step 1 10} then the flask with the suspension stored in a -20¾ freezer for at least 1 h (Figure 2, ste 1 12) along with a L Sunsen flask and a 2 L sintered glass funnel. Th separated material in the Erlenmeyer flask was filtered under vacuum using the preeooiedi filtration kit (Figure; ¾ step 114). The cold filtrate was used to facilitate transfer of the remaining solid material from; the Edenme e flask. The filtrate wa then discarded (Figure 2, step 116).

|0i183J The solid was pressed, washed on the filter with 10S% efhanol (2 100 rnL). The solid was transferred into a pre^we!ghed 3 L rotary evaporator round bottom flask and dried under vacuum at 40 ± ψθ- (hath) until the difference between two consecutive weighings 10 minutes apart was less than 0.5 g (Figure 2, step 118), An analyticai sample (1 ± 0.1 g) of the dried product was the transferred into a 4 rnL amber vial (Figure 2, step 120}» The obtained purified sodium chlorate was then packaged In appropriate steed amber glass containers and stored in a fridge (Figure 2, ste 122},

Exam le 3: Purification of Sodium Chlo it without. Ha ting OQocentr tmg 01§ ] Water Is added to powdered technical grade sodium chlorite at ambient temperature i an amount Insufficienl; to fully dissolve the powder thereby forming a slurry. The slurry Is then filtered to remove the impurities that remain in the soild_: phase. As certain ini;purities_: In the technical grade sodium chlorite are less soluble than the sodium chlorite, adding insufficient, wafer to dissolve the powder will result in a substantial amount of these impurities remaining in the solid phase. After filtration, ethane! is added to the filtrate and the sodium chlorite crystallized and optionally reerystalilzed as detailed In: Example 1.

Examples 4i Pyrificat p of Sodium Chterlte from oncentrated Solution

|δδ1ΒΒ Ethanol Is added to highly pyre solution of sodium chlorite available from a commercial source e.<g, 25 Sodium chlorite 300W (Hanke & Seidel}} to precipitate out the sodium chlorite. Due to th high purity of sodium chlorite in solution, when ethanoi i added, impurities remain in solution while sodium chlorite precipitates: out. Th sodium chlorite Is optionall crystallized and optionall recrysta!iized as detailed in: Example . Example S: Var ation in the ^sthod of Purification ©f Sodium Chlorite using the Procedure of Example 1H

[00186] Technical grade sodium chlorite solid underwent crystallization using five modified processes of the procedure reporting n Example 1 H, Two rounds of each crystallization, process were applied sequentiall to Improve material purity. Each method commenced using 100 g of Sodium Chlorite solid.

Vari ation J

100167)_. In the first variation (V -2G-37, shown schematically in Figure 3). ho trituration of the technical grade sodium chlorite solid (i OOg) with wate (80 ml) at 70 ^' wa conducted instead of its complete dissolution In a large volume of wafer and partial evaporation of the solution. The goal was to simplify the process and allow for an efficient, cost effective process. The remaining steps of this variation were similar to those of Example 1H. Therefore the resulting suspension was hot filtered , with washing with about 6 mi of wafer, to obtain a solid (sample 10,3 g) and a filtrate. The filtrate was cooled to 38-46 ¾ and EIDH ant [solvent (85 ml) was added io form a precipitate. The filtrat was then cooled to -20 ⁹C, The resulting precipitate was collected (102,5 g. sample VM-20-37-1 }. The- filtrate from this-^' filtration was labelled a sample VSy1~20~3?~iF (6.4 gj. The solid was recrystalJized again from water and athanol to provide solid sample VM-20-3?- 2 (94.3 g) and filtrate sample: V -2G~37~2F (13,3 g).

Varjat|oo.,il

[0018§] I the second variation (V -20-39, shown schematicall in Figure: 4j^:, a ho (65 ¾;} aqueous solution containing the technical grade sodium chlorite solid and 118 ml of water was concentrated by vacuum evaporation. The formed suspension wa filtered and the solid (sample VM- 20-39*W_s.9:8 g) collected while keeping the temperature of th : filtrate around 4S *C (no preoipflateT An appropriate amount of water (-5 mil) was added to the suspension to dilute the concentration, followed by addition of the anti- solvent (EtOH, 80 mi.)). The the formed mixture was allowed to cooi to -20 ^eC. The oredpifaied materia! (sample V * -38* jf> 72 a then isolated by filtration and the reorystallization steps using wate nd eihanol were repeated to provide solid sample νΜ-20-39~2 (85 g) and a filtrat (sample Vfyi-2G~39~2F_;. 11 ,4 g H69J In_. the third variation (VM-20~83, shown schematically In Figure

5) , a hot ueous solution of technical grade sodium chlorite solid I 118 ml water was concentrateit by vacuum evaporation. The formed suspension was filtered: through, a hot jacketed filter unde positive pressure into a receiver flask (to -avoid solvent evaporation and formation of crystalline product In the filtrate to provide a solid (sample V ~20-83- _t 10,4 g) and a filtrate,. The receiver flask contained the anti-solvent (EtOH, 75 ml.) re-heated to 45 ^¾C, Contact with EtOH induced preeipitaio The precipitated material was isolated :by filtration without further oooling_: ( r^' crop, sample ¥^20-83-1 , 25.4 § . The filtrate was cooled to -20 Filtration of the resulting precipitated material provided a 2^!¾ crop (sample ·^■ 78.6 g) and a further filtrate (sample ¥ ~20~83"2F:, 6.1 g)..

[001701 In tre fourth method (VM^Q-St shown schematically in Figure^;

6 _:? technical grade sodium chlorite solid was dissolved in a minimal amount of alor (136 L) at room temperature. To the solution the anti-solvent (EtOR SO ml) was added at room t¾r >pef fyre^: in a amount to precipitate a significant amount of solid. The solid was filtered to provide solid sample VM~ 20-51-1 (7.1 g); and_: the filtrate was: diluted with additional amount of EtOH (60 ml.) and the precipitate solid collected to pravide further solid sampl Vlv½0- 51-2 (7.4 ). To the filtrate was added an additional amount Of EtOH (38 ml) followed by: cooling to induce crystallisation of the remaining salt from the solution, which was collected to provide solid sample Vivt-2{ Si-3 (§6.6 g) and filtrate sample V -5i^«3Fi1?<8: g). pW7i} in the fifth method shown schematically n Figure 7), technical grad sodium chlorite solid was dissolved in water (110 ml) at §2 ^SC to form a hot aqueous solution. The solution was cooled to room temperature: allowing precipitatio of materials to form a suspension. The termed suspension was filtered under positive pressure (to avoid solvent evaporation and formation of crystalline :product in the filtrate): and the solid (sample Vlvl- 20-53-Vy, 16,5 §i was collected into a receiver fl sk keeping the temperature of the filtrat at roam temperature. Ethanol anti-solvent (10 ml), was added: to the filtrate to induce precipitation at room temperature and the precipitated material was collected at room temperature without cooling. The precipitate was collected by filtration as the≠ crop (sample Vf$-20.-53-1_f. 43.7 g). The filtrate was cooled to -20 and the precipitat was collected by filtration as the 2 crop (sampl W½0-^3-2, 55,8 gf, The filtrate from the 2^RfS crop was labelled a sample Vf Q~ 3~2F (9.8 g).

.Reparation of 2S¾. ( ..SQd?yffi- Chlorite solutkft

OI0172J The recrystalfeed sodium chlorite resulting from methods 1-5 (after 2 rounds o recrysfatlization} underwent, dissolution to prepare a 25 (w w) Sodium Chlorit solution by dissolving in an excess of carbon dioxide free water for injection with 0.5% aOH. Target concentration of sodium chlorite was achieved by partial evaporation to remove residual solvent.

Alternative: Using Sodium Chlorite Solution as Starting Materia!

[60173] The method of Example 1H, along with variations l~V ^'described^' above are modified: by the use of 31% |w w : fechnical grade: sodium chlorite solution as the starting_, material. This starting materia! is about 300 g of supplied solution (ie. containing about 100 g sodium chlorite}.

Exam le Additional Purification of Sodium Chjor fe With or Without Spiking with Dschromate

[00174] The: purification procedure for sodium:: chlorate described in Example 28 was repeated using >9$% raw sodium chlorate supplied from Canexus/Quandra (sample no. RIV15039) either as is or spiked with 30 ppm of dichromate. The purified sample obt ined from the unspiked procedure wa VM-2O-m and from the spiked sample wa V -¾0-6 . The objective of spiking the sodium, chlorate starting material was to demonstrate the abilit of process of the application to remove dichromate that could be present in the raw niateria! (sodium dlerrmrnate s used as a ca lysl in production- of HaCiO-,}.

E ample 7: HPLC An l sis f0¾1 5f The samples from obtained rom variations hV described in Example § above and for chlorate method described In Example 8 were tested for impurities using the HPLC method outlined in this report.

[00176} The HPLC method used is as describe in the following documents (Novo Manufacturing 8mbB_; anziehen); SOP: A-HPL01 ; ADS: OXOFE ; F10; TCOO,

|G0i??j The system was calibrated as outlined in the documents listed above using the following: concentrations:

Chloride: 380 ppm

Chlorite 880 ppm

Nitrate (internal Standard;} 385 ppm

Chlorate 29? ppm

Sulfate 186 ppm

Sodiuw^:€:hiorai&

|¾017SJ The sodium chlorit samples (primary samples) were provided In volumes of approximately ml.. i order to work as economically as possible and to save sample volume for potential future analysis,: the following procedure was applied:

[80179] Smnpi® ^Uist 2~oll polypropylen reaoflo vessel with screw cap was placed on: an. analytical balance and adjusted to zero, 10 pL of primar sample was pipetted and the weight protocoled.. 2000 pi water wa added and: the weight protocoled. The vessel was closed and Its oentent homogenized y repeated inversion w ich caused the entrapped alrfeubbt to move. f OI O] $®fflfit&$c>tu0 far ^: PLC: To a 5-mL volumetric flask, 2§Q p! of t&tema)^' standard solution and 200 μΙ o sample dilution m. pipetted fine procedure according to the SOP uses a IQ-ml volumetric flask and each 400 pi of intefnahstandafd or sample dilution, respectively}. The volume as completed with aluenl After hcmogenfeafbn, an aliquoi was placed n an autosatnpier v al and 20 pi were injected lo the MPLC system,

[00181j Each sample was run twice, an initial screening of the results revealed a hig similarity of the replicates, and therefore only every first run has been evaluated.

Sodium cfiiofBte

0018 3 Sample lluti : Using water as diluent, the following solutions were prepared:

VIV1-20-S9: 28,3 m;g/25 ml.

VM-20-61 : 57.1 mg/50 ml

R 5039: 28.3 mg/25 ml

The sample solutions for HP!X were prepare as described afeover for sodium chlorite.

100183] Rm ii®

J 0114J The samples were tested fo the presence of chloride, chlorite, nitrites., chlorate and sulfate. Table ^"8 shows the percentage of chlorite o chlorate and impurities from the samples tested, A subset of the chlorite samples (onl desired: precipitated products;, not filtrates or waste solutions) wer reanalyzed after approximately 9 weeks o storage n a refHgeraiDf (2-8· *€) The chlorite sample codes are as follows:

Sodium: Chlorite Samples

RF5161 ~~ technical grade solid chlorite starting material

05 31 * technical grade ohlonte solution starting material Vanation I

Vf¾r20~3?~ ~ waste

V ~2P"37-1 - 1^sicrysfa1!izafion, 1^stcfo

V -20-37-2 - ^ά crystallization: soifci

V -2Q-37-1F™ 1^st crystallization, Filtrate

yy~2:0-3?~2F ~ 2 crystallization, Filtrate

Variation II

VM-20-39-W - waste

V -20-39-2 - 2^nd crystallization, solid

V ~20-39~1F - 1^st crystallization, Filtrate

V^2^'0~3½F ~ 2^nd crystallization, Filimte

Variation III

V*2G~83- - waste

V -20-83-1 - ^'crystallization, 1^Bl crop

yy~2D~83~2 ~≠ crystallization, 2^!¾i crop

VM-2t)--83-2F.- 1^st crystallization, Filtrate

Variation IV

¥ ~20-5 -1 - waste 1

V -20-51-2--was!»2

^:V¾l-2?Q-51-3—1^st crystallization, 1 orop

v -2G-5i~3F^■■- 1^st crystallization, Filtrate

Variation V

V ~20~53- ~ waste

VM-20-53-1 ~t^si crystallisation, 1^¾tcrop

yy~2G~53~2 - 1^si crystallization, erop

V -20-53-2F - 2^oa crystallization, Filtrate

RM8039 raw material >99%, supplied by Cane asQu df V -.28-S9, after the reorysta izatlon process o dlehrornafe spiking

Vi¾f^»10"#1 after the reerysiaJlization process diciiromaie spiking

Ex mple 8: Heav letals Stody

Technical grade chlorite or chlorate may contain heav metals that require removal during cGMP manufacturing processes, t e sodium chlorate samples obtained in Example 6 were analyzed using IGP~MS tor the presence of heav metals including arsenic, eadmfurrh mercury, lead and cbmmium. The results are shown in Table S,

OO106| it was observed that both the spiked and non-spiked samples meet the IVT 20 ppn requirement for chromium, .meaning that the feerystallization process successfully removed the dichfoniafe,

|001 7] White the present application has been: described with reference to what are_: presently considered to be the preferred examples, it is to be understood that the application is not limited to the disclosed examples. To the contrary, the present :application is intended to cover various modifications and equivalent arrangements Included within the sprit and scope of the appended claims,

3301 18] All publications, patents and patent applications are herein incorporated by reference in their entiret to the same extent as: if each individual publication, patent or patent application was specifically and individually indicated to be incorporated b reference in its entirety, Where a term m the present application is found to be defined differently in a document Incorporated herein by reference, the definition provided herein is to serve as the definition for the term.

FULL CITATIONS. FOR DOCUMENTS REFE RED TO IN THE SPECIFICATION

¹ Simoyi, RH Pattern formation and symmetry-breaking bifurcations fueled by dissipation of chemical energy A possible model for morphogenesis? P& . Appk Chem, 1999, im, 1007-1017: Umife, TP and Groves, JT Catalytic generation of chlorine dioxide from chlorite using a water-soluble manganese porphyrin. Angew. Ch&m, int. .2011 , 50. 695-698: Pointier, G et al Kinetics and mechanism of the: reaction betwee chlorite ion and hypeohJoreus: acid:. J. foys_* C &m, 1990, 94, 2S64~29S8; Ghsgwads etal, S~ Oxygenation of fMocarhamides I!: Oxidation of trimeihyithiourea by chlorite and chlorine dioxide. J, Phys. Ghent A 2005, 109:6, 1094-1104; Chinake et at Oxidation of formaldehyde by chlorite in basic and slightly acidic media:. J, PHy$.. Ch&m. A 1998, 10.2:3, 606-811; Chinake et at Qx ha!ogen-so!fur chemistry; Kinetics and mechanism o the oxidation of a Bunle salt: 2- aminoethanethiolsyifu !c acid by chlorite. Phys, Chem Ch m. Phy$> 2001 , 3, 4957-4964: Horviih et ai. Diffusion-driven front instabiiiiies in the chlorite- fetrafnionate reaction. . Chem, Phys. 1998, 108, 1447-1461 ; aftrncigh et al Convective instabiiiiie induced by an exothermic autocatatyiio chemJoai reaction. Phys, Rev, E 1996, 52, 1606- 613; fvlar incigh et al. Formation of thermal plumes in an autocatalytie exothermic chemical reaction. Phys. Rev. E 1996, 52, 6146-6153; Simoyi et ai. Travelling wave in: the ohiohfe-thiourea reaction. Mema i- mrmaM emtcai neites 1991, 23:5, 419-429.

² Hoist, Production of sodium chlorite: Survey of prevalent manufacturing methods, industrial and Engineering Chemistry 1950, 42:1 2359-2371; US Patent No. 2,169,068 Preparation of sodium chlorate and sodium chlorite and the separation thereof; Belgian Patent No. 449,413 Precede de fabrication de ehiorites aleeta US Patent No, 2.498,289 Process for the separation and recovery of inorganic salts; USSR: Patent No. 327,132 A way of Isolating impurities from sodium chlorite solution; US Patent Application Publication No, 2:0:08/02133 1 Substance for the treatment of infections. UK Patent $o< mpr vements in the man«facture_: of chlorates of the alkalies; US Patent No. 2,189,086: Preparation of: sodium chlorate and sodium chlorite an the separation thereof; Belgian Patent Ho, 449,413 Precede da fabrfeMon.de ehlorites alcaii s; US Patent o. 2,511 ,616 Process for making sodium chlorate: US Patent No. 3_!043J§? Electrolytic; : fGduetlon of sod sum chlorate; Canadian Patent No. §76,68? Biee!mlyiio production of sodium chlorate; Canadian Patent No. Crystallka ioo of alkali metal chlorate from an alkali metal chlorate-alkali metal chloride solution; US Patent No. 3,611 ,619 Crystallization of alkali metal chlorate fem an alkali metal ch rate- alkali metal chloride solution; US Patent No. 3,690,845 Gr stallfeat!on of a metal chlorate from a ehiorate-chioride containing solution;: US Patent No. 3,883,40©; Process for recovering electrol flcaHy produced alkali metal chlorates; US Patent No, 4 Q2.3Q5 Productson of sodium: chlorate; Canadian: Patent No. 1,287,5 6 Production of sodium chlorate; US Patent No. 5,108,722 Sulfate removal from chlorate liquor; Canadian Patent No, 2,082,473 Sulphate removal process; US Patent No, 5,681 ,446 Impurity removal for sodium chlorate.

⁴ Olimann's Encyclopedia of Industrial Chemistry, p, 853. ^" d Eng. Chem, 1940, 32, 89§.

⁶ J Am, £h&m. Soe, 185S, 77, 79S.

⁷ J, Org- Ci n 1999, ©4, 2564. Org, Synt , WQQ _; 81_* 6.

Table 2: ^'Cfystatlizaflo» from Aqueous hanol

Content In % by peak area in 1C

Sample ^'No.

mo cr Bf CIG₃ HO:; SO Overall Yield f%)

1 Solid from hoi filtration. 74.11 D^{i ! i} Traces D 19,04

2 (50% EtOH) After first crystallization. 96.22 3,42 ND 0.19 ' ND 0.1

3 Filtrate of first crystallization. 39.08 58.26 0.38 1.90 0.20 0,18 :

4 After second crystallization,_. 99.68 0.13 ND ND ND 0.19 57

5 (40% EiOH) After first crystallization. 97.42. 2.34 ND ND ND 0.24 ....

β After second crystallization. 99.86 0.14 ND ND ND ND 56

7 (60% ^'EtOH): After fir t crystallization. 90.94 8.64 ND 0/1-0 ND 0.32 _

8 After second crystallization. 99.84 0.16 ND ND ND ND : 54

9 23% solution after 2 weeks 98.5 0,76 ND 0,74 ND NO —

^[11 ND ~ not detected.

T ble 4: 10 Data of t e Larger Scale Batches

Sample No. Con! enl m % by e k area in tc

Chlorite Bromate Chloride Nitrite Bromide Chioraie Nitrate Sulfate

1 (without NaOH; 94.71 D^{iT| ""} 4,92 NO ND ND ND 0.37 1^¾ recrysialiizatioii)

2 (with 2% NaOH; 95_>:4 ND 4.1 D ND ND ND 0,41 1^st recr staHization)

3 (without NaOH: 98.59 ND 1.11 ND ND ND ND 0.30 2 ^d recrystaillzatlon}

4 (with 0.2% NaOH: 99.34 NO 0.08 ND ND ND ND 0.58 2^nc1 reorystatation)

ND .= not detected.

Table 5: Anal tical Results of Trials for EtOH Removal

was .dis ol ed in water, evaporated to -1/2 volume.

GC ~ gas chromatography,

HO - not detected.

Table 8: IC Data of Sodum Cll ratfe (IB ak area %

ND ·- not detected.

Table 7: Ars lrica Results of f ¾ Larger Scale Sodium Chlorate Batch

l^¾ GC ~ gas chromatography,

KF ~ Karl Fischer titration.

i¾ I CP ~ .inductively coupled plasma spectrometry,

By area under the curve (AUG). Other anions: Cf_f SO/' Br^', BrC¼f, HO¾, ClOa, Nt¾^' no detected.

Ta le : Pi $& M$ Em !%rcerrtage of the f½sp¾ctiy« Sodium Sait

Claims

Claims:

1 . A malted for preparing impurity-reduced sodium ohiGhte, comprising; combining an antisotvent and an aqueous sodium chlorite solution under conditions to obtain Impurity-reduced sodium chlorite solids and a sodium chlorite-reduced solution, wherein the aqueous sodium chlorite solution comprises one or mom impurities or is a non~ pharmaceutical grade sodium chlorite so ution - separating the impurity-reduced sodium chlorite solids fro tf e sodium c lorite-reduced solution; and optionally making an aqueous solution of the impurity re uced sodium chlorite solids and repealing the: adding and separating one or more times.

2. The method of claim 1 , wherein the conditions to obtain the impurity- reduced sodiu chlorite solids, and the sodium chiorite-reduced solution comprise- adding the antisoivent to the aqueous sodium chlorite solution to obtain an antisclvent-aqueous mixture; and cooling: the antisoivent-aqueous mixture to obtain ihe impurity- reduced sodium chlorite, solids and the sodiura chloh!e-mduoed: solution,

3. The method of claim 1 , wrserein the conditions to obtain th Impurity- reduced sodium chlorite solids and the sodium ohlonte- reduced solution comprise;

adding the aqueous sodium chlorite solution to the antisolvent to- obtain an aniisoiveni-a u ous mixture; and cooling the antisolvent-aqueous mixture to obtain the impurity- reduce sodium chlorite solids and the sodium: chiorite-redoeed sol uf ion. 4, The method of any one of claims 1 to 3, wherein the aqueous sodium chlorite solution is a concentrated aqueous sodium chlorite solutio and is obtained by concentrating an aqueous solution comprising sodium chlorit under conditions to remove impurities,

§. The method of c a m 4, wherein the conditions to remove impurities comprise; concentrating the aqueous solution comprising sodium chlorit under conditions to obtain solids comprising the impurities; and collecting the solids comprising the impurities,

6. The method of claim 5_: wherein., rior to addition of the antisDlvent the concentrated aqueous sodium chlorite solution an amount of water is combined wit the concentrated aqueous sodium chlorite solution to obtain a diluted aqueous sodium chlorite solution and the anfisolvent is added to the diluted aqueous sodium chlorit solution.

?, The method of claim 6, wherein the amoun of water combined with the concentrated aqueous sodium chlorite solution is about 1% to about 59% of the total volume of the concentrated aqueous sodium chiorfte solution.

8. The method of any one of claims 1 to 3, wherein the aqueous sodium chlorite solution is obtained by combining water and technical grade sodium chlorite at a ratio wt:wt) Of watecsodium chlorite of aboul 0.5:1 to about 2:1 ,. about: CtS:1 to about 17:1 , about 8.7:1 to about 14:1 , abou 1.1 :15:1 , or about 16:5 1 , at about to abo t f0¾, about 60^S!C to about 8O C, about ?ø¾, about i§¾ or abou 22^δΟ, The method of: any one of claims 1 to 3, wherein the aqueous sodium chlorite solution is obtained b combining water and technical grade sodium chlorite at a ratio (wt:wt) of watensodiym chlorite of about 0,6:1 to about 15:1 or about 0,8:1 at about 85°0 te about: 100^aC, or at about 1QQ°C.

10. The method of any one of claims 1 to 3,. wherein the -aqueous sodium chlorite solution is from a commercial source,

11. The method of any one of claims 1 to 3, wherein the aqueous sodium chlorite solution s obtained by:

^■combining ater and impure, sodium chlorite solids under conditions to obtain a slurry made up of solids comprising impurities and an aqueous solution comprising sodium chlorite;

separating the aqueous solution comprising sodium chlorite from the solids comprising impurities: and

if required, concentrating the aqueous solution comprising sodium chlorite.

12. The method of -any one of claims 1 to 3, wherein the aqueous sodium; chlorite is op ned by: combining technical grade sodium chlorite with a quantity of water insufficient to completely sofuhiliz the technical grade sodium chlorite to provide a mixture; stirring the mixture to partially dissolve the technical grade sodium chlorite to provide a slurry of undissolved solids and an aqueous sodium chlorite solution; and: separating the undissolved solids from the aqueous sodium ohlo ite solution

1.3. The method of claim 11 or 12, wherein the conditions, to obtain slurr made up of solids comprising the impurities and the aqueous solution comprising sodium chlorite comprise combining water and the impure sodium chlorite solids or the technical grade sodium chlorite at a temperature of about 20 to about: 100^*0, about 40 C to about 85-C, about 6S to about ?rc, about 100^aC or about 92°C,

14. The. method of cl im- 1 , wherein the ratio (w M): or watensodiuim chlorite is- about 0\S:1 to about 2:1 , or about i ;t.

15. The method of claim 12, wherein the aqueous solution comprising sodium chlorite is separated fr m: the solids comprising the impurities at a temperature of from about 2§*C to about S8*C_$. about 45^*0 to about S^C o about. SiTC to aboot lO^C,

18. The method of claim 15, wherein the. aqueous solution comprising sodium chlorite is separated from the solids comprising the impurities using a hot filtration.

17, The method of claim 12, wherein the a ueous solution comprising sodium chlorite is separated from the soiids comprising the impurities using a room temperature filtration using: positive pressure,

18, The method of any one of claims 1 to 3., wherein the aqueous chlorite solution is obtained by dissolving the sodium: chlorite in minimum amount of water (for example a ratio (w wt) of water to chlorite of about 1 ,3:1 to about 1.5: , or about: A :1 at about room temperature,

18. The method of claim 5, wherein_: the solids are: collected by filtration of the aqueous sodium chlorite solution directly Into a container comprising the antssolvent to provide the antlsolvent-aqueous mixture.

20, The method of claim 19, wheroih the antisolvent in the container Is kept at a temperature between about room temperature and a temperature below the boiling point of the antisoivent, for example at about 4$°C.

21. The method: of ny one of claims 1 to, -2.0, wherein the antisolvent is selected from: acetic acid,: acetone, ahisole, 1-butanc.l, 2-butar?ot_; butylacetate, t-butvimethyiether, cumehe, dimethyisuifdKide, ethanoi, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane. Isohutyt acetate, isopropyl acetate, methyl acetate^ S-mefh hi-hutanol, mefhytethyi ketone, meth lisobutyl ketone, 2~meth;yh1~propanol._:. entao , l-pentanoL 1-propano!_t 2-propa.not, propyl acetate acetonitrile, cWbmbeiisen , chloroform cyeio exana, 1,2- dichlorQeihane, diehiofomefhane, 1 -dlmefho yethane,: N,N- dime hyfaceta?Tiide_f ^ -dsmeth tformamide, 1 ^cfexane, S-eihoxyethanot, ethyleneglycot, fermamsda, tiexane, metl ariol, 2~m©i qxy¾¾anot met!iyibutylketona, methylcyclohexane,

pyridine, sulfetene, teirahydroluran, i¾

xylene and glycerol and mixtures thereof.

22. The method of claim 21 , wherein the antisoiveni is selected from acetic acid, acetone, anisoie, l-byfanot 2-butanoi, feutylaeetate, f~ ytylmefhy!ether, eurnene, dlmefhylsuJfo¾de_:( ethanoi ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isofeutyf acetate,, isopropyi acetate, methyl acetate, 3- methyl- 1-5utanol. rnethyietby! ketone, methylisobufyl ketone, 2- ethyH- propanol, .;pent .ft ₅ l^pentano l^m anoL 2-propanol and propyl acetate, and mixtures thereof.

23. The method of any one of claims 1 to 23, wherein the antisolvent comprises ef! anot

24. The method of an one of claims 1 to 2D, wherein the antsolvent is ethanol,

25. The method of claim 23 or 24, wherein the ratio by volume of the ethanol to the aqueous sodium chlorite solution Is about 40:60 to about 60-40,

26:, The method of any one of claims 1 to- 2S, wherein the method furthe comprises recfystaliizing the impynty-recluGed sodium chlorite solids,

27. The method of any one of claims 1 to 26, wherein the: method further comprises adding water to tlie impurlty-redyced sodium chlorite solids or the recrystal!ized tmpehty-rec!nced sodium chlorite solids to obtain an aqueous solution comprising impuniy-redueed sodlym chlonie.

28, The method of claim 27, wherein the method furthe comprises adding a base lo the aqueous solution comprising Impunty-reduoed sodium chlorite.

29. The met od of claim 27 or 2S_* wherein the niethed further comprises adding an hydroxide Ion, a chloride inm a sulfate ion, and/or a c lorate ion to the aqueous solution com nslng impunty^redyced sodium ch!offe

30. A product produced by the method according to any one of claims 1~

31. A method for preparing impurity-reduced sodium chlorate, comprising:

combining an rtiso sni and an aqueous sodium chlorate solution under conditions t obtain impurity-reduced sodium chlorate solids and: a: sodium chlorate-reduced solution, wherein the sodium chlorate solution comprises one or more: Impurities or is a non- pharoiaeeufeai grade sodium ehlorate solution;

se arating the impufiy--redyced: sodium chlorate solids rom th sodium chlorate-reduced solution; and

optionally making an aqueou solution of the Impurit reduced sodium chlorate solids and repeating the adding and separating on or more times, 2. The method of claim 3t_.,_: wherein the condition to obtain the Impurity- reduce sodium chlorate solids, and the sodium chlorate-reduced solu ion comprise: combining the antisolvent and the aqueou sodium chlorate solution to obtain an anflsolvent-aquecus mixture; and

cooling the antlsoivent-aqyeous mixture to obtain the impunfy- reduced sodium ehlorate solids and the sodium chlorate-reduced solution^".

33. Th method o claim 31 or 32, wherein the aqueous sodium chlorate solution is prepared by adding water to sodium chlorate solids under conditions to obtain the concentrated aqueous sodiurfichlorale solution, 34, The method of any one of claims 31 to 33, wherein the antisolve t is selected from acetic acid, acetone, aniso!e, 1~hutanoi, 2-butanoi, butyiaeetate, Pbutylmethyfether, cumerte, diniethylsuifoxlde, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, bepta:ne,_: Isobutyf acetate, isopropyi acetate, methyl acetate, 3- et yl-1-butanol, met!iylefhyl ketone, msthyiisGbutyi ketone, 2-roeihyl~1-propanof, pentane, 1-pentanol, 1~propanoL 2~propanol, propyl acetate, acetonMe,

ehior fbmi,_; eycjohexane, 1 ,2- dichioroethane:, diehlorornefhane, l^-dsmethoxyeihane, N,N- diinethylaeetarnide, Ν,Ν-dimethylformamide, 1 ,4-dioxane, 2-efhoxyetbanol, efhyienegiycoi, formamide, hexane, methanol, 2~methoxyethanol inetbyfbutyiketone, me hyteyelo exane, -met yIpyrr¾lldone, niiromethane_s pyridine, sulfolane_: tetrahydrofuran, tetraNn, toluene, 1 ,1 ,2~tnchtor iethene_f xylene and glycerol, and mix iims thereof,

35, The method of claim.34, wherein the anfisofvent is selected tern acetic acid, acetone, anisoie, -butanoL 2-butanoi, butyiaeetate, l-hutyi ethySether, eufftenfe, dimethylsulfoxide, ethanol, ethy acetate, ethyl ether, ethyl formate, formic add, heptane, isabutyl acetate, isopropyf -. eta , methyl acetate, 3~ methyl- 1 --buianoi, ethy!etftyl ketone, methylisobufyi ketone, 2-methyh1- prepanol, pentan^, 1-pentanoL 1-propanol, 2-propano! and propyl acetate, and mixtures thereof.

36, The method of claim 35, wherein the antisoiverrt comprises ethanol. 3?. The method of claim 38, wherein the antisolvenf is ethanol.

38, The method of claim 38 o 37, wherein the ratio by volume of th ethanol to the concentrated aqueous sodium chlorate solution is about 2.5:1.

39, The method of any one of claims 31 to 33, wherein the method further comprises recrysig!feing the impurity-reduced sodium chlorate solids,

40, A product produced by the method according t any one of claims 31 to 39