WO2007016209A2

WO2007016209A2 - Pure 1,2-benzisoxazole-3-methane-sulfonic acid sodium salt and purification process

Info

Publication number: WO2007016209A2
Application number: PCT/US2006/029121
Authority: WO
Inventors: Marioara Mendelovici; Natalia Shenkar
Original assignee: Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals Usa, Inc.
Priority date: 2005-07-28
Filing date: 2006-07-28
Publication date: 2007-02-08
Also published as: WO2007016209A3

Abstract

The present invention provides chemically pure sodium salt of 1,2-benzisoxazofe-3-methane-sulfonic acid, the sodium salt of 1,2-benzisoxazole-3-methane-sulfonic acid of high assay, or chemically pure sodium salt of 1,2-benzisoxazole-3-methane-sulfonic acid of high assay, and processes for preparing the same via purification. The present invention also provides monohydrate form of the chemically pure sodium salt of 1,2-benzisoxazole-3-methane-sulfonic acid, the sodium salt of 1,2-benzisoxazole-3-methane-sulfonic acid of high assay, or chemically pure sodium salt of 1,2-benzisoxazole-3-methane-sulfonic acid of high assay. Furthermore, the present invention provides anhydrous form of the chemically pure sodium salt of 1,2-benzisoxazole-3-methane-sulfonic acid, the sodium salt of 1,2-benzisoxazole-3-methane-sulfonic acid of high assay, or chemically pure sodium salt of 1,2-benzisoxazole-3-methane-sulfonic acid of high assay. One of the embodiments of the present invention is directed to a process for preparing zonisamide using the chemically pure sodium salt of 1,2-benzisoxazole-3-methane-sulfonic acid, the sodium salt of 1,2-benzisoxazole-3- methane-sulfonic acid of high assay, or chemically pure sodium salt of 1,2-benzisoxazole-3-methane-sulfonic acid of high assay.

Description

PURE 1,2-BENZISOXAZOLE-S-METHANE-SULFONIC ACID SODIUM SALT AND PURIFICATION PROCESS

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. Provisional Application No. 60/702,994 filed July 28, 2005, the disclosure of which is incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention concerns chemically pure sodium salt of l,2-benzisoxazole-3- methane sulfonic acid (BOS-Na), a process for purifiying the sodium salt and a process for preparing zonisamide using the BOS-Na.

BACKGROUND OF THE INVENTION l,2-Benzisoxazole-3-methane sulfonamide or 3-(sulfamoylmethyl)-l,2-benzisoxazole of formula (I):

(I)

which is also known as zonisamide, is currently available as an anti-epileptic agent which possesses anti-convulsant and anti-neurotoxic effects. l,2-Benzisoxazole-3-methane~sulfonic acid (BOS-H) is useful as an intermediate in the preparation of zonisamide. BOS-H can be prepared by a sulfonation reaction as described in WO 2004/020419. The reaction product may be isolated as the sodium salt, calcium salt or barium salt of BOS-H. WO 2004/020419 also discloses polymorphic forms of BOS-H and salts of BOS-H (BOS-salts). BOS-H free acid is known to be a highly hygroscopic compound. The alkaline and alkaline-earth salts (sodium salt, barium salt, calcium salt) of BOS-H are also hygroscopic. (Siggia, Quantitative Organic Analysis of Functional Groups, 4^th edition, p. 792; C. Sutter, The Organic Chemistry of Sulfur, the 1946 edition, John Wiley & Sons, N. Y.). Prior art processes for the preparation of the sodium salt, i.e. BOS-Na, of BOS-H are disclosed in JP 53-77053 and usually include adding aqueous NaOH to a reaction mixture containing BOS-H. BOS-Na, obtained for example, according to the process disclosed in JP 53-77053 is a white solid having a relative high content of inorganic salts, and generally has an assay of only 85-90% or at most, of about 92 to 95%. WO 03/072552 discloses the preparation of zonisamide starting with BOS-H or a

BOS-salt and chlorinating the BOS-H or BOS-salt to form l,2-benzisoxazole-3-methane- sulfonyl chloride (BOS-Cl) followed by amidation, wherein the BOS-Cl can be represented by formula (II).

(H)

There is a need for efficient processes for purifying BOS-Na.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides chemically pure BOS-Na.

In another embodiment, the present invention provides BOS-Na of high assay.

In yet another embodiment, the present invention provides chemically pure BOS-Na of high assay. In one of the embodiments, the present invention provides a process for purifying

BOS-Na comprising the steps of: combining BOS-Na, at least one Cj-C₄ alcohol and water to form a mixture; heating the mixture; and recovering the BOS-Na from the heated mixture.

In another embodiment, the present invention provides a process for preparing BOS-Cl from BOS-Na, comprising the steps of: combining BOS-Na with an inert organic solvent and a chlorinating agent to form a reaction mixture; heating the reaction mixture; and removing the inert organic solvent and any excess of the chlorinating agent from the heated reaction mixture to obtain BOS-Cl as a residue.

In the process for preparing BOS-Cl from BOS-Na, the stalling BOS-Na preferably is purified by the BOS-Na purification process of the present invention.

In yet another embodiment, the present invention provides a process for preparing zonisamide comprising obtaining BOS-Cl according to the BOS-Cl producing process of the present invention and converting the BOS-Cl to zonisamide.

In one of the embodiments, the present invention provides a pharmaceutical composition of zonisamide prepared according to the zonisamide producing process of the present invention, and at least one pharmaceutically acceptable excipient.

In another embodiment, the present invention provides a process for preparing a pharmaceutical formulation comprising combining zonisamide prepared according to the zonisamide producing process of the present invention with at least one pharmaceutically acceptable excipient.

In yet another embodiment, the present invention provides the use of zonisamide prepared according to the present invention, for the manufacture of a pharmaceutical composition.

DETAILED DESCRIPTION OF THE INVENTION

The term "chemical purity", in reference to BOS-Na, refers to a chemical purity by HPLC, wherein the area of the BOS-Na peak eluted from the HPLC is expressed as percent of the total area of all the HPLC peaks combined

As used herein, the term "chemically pure" referring to BOS-Na means BOS-Na having a chemical purity of about 98 area% to about 100 area% as determined by HPLC.

The term "assay" in reference to BOS-Na refers to the content, expressed as percent of the total sample weight, of BOS-Na in a BOS-Na sample. The BOS-Na sample may contain residual water, other residual solvents and other salts in addition to BOS-Na.

As used herein, the term "high assay" in reference to BOS-Na means BOS-Na having an assay of about 95% to about 100%. In preferred embodiments of the BOS-Na of the present invention, the BOS-Na has an assay of preferably about 98% to about 100%.

The term "crude" refers to a compound that has not undergone further purification by any known methods, such as, crystallization or suspension in appropriate solvents.

As used herein the term "aromatic solvent" refers to a C_6-1O aromatic hydrocarbon such as but not limited to benzene, xylene, or toluene. As used herein, the term "cooling gradually" to a target temperature means cooling a sample starting with the original sample temperature to reach the target temperature in a cooling duration ranging from about 20 minutes to about 210 minutes, preferably ranging from about 30 minutes to about 180 minutes, e.g., about 30 minutes, and more preferably ranging from about 60 minutes to about 180 minutes or ranging from about 120 minutes to about 180 minutes, e.g., about 60 minutes, about 120 minutes, or most preferably about 180 minutes.

As used herein, the term "anhydrous" refers to a water content of less than about 200 ppm. In a preferred embodiment, an "anhydrous" substance or "anhydrous conditions" used in the present invention can have a water content less than about 20 ppm. Inorganic salts may be removed from an organic compound by slurrying in water, but this procedure is not operable in the case of the salts of BOS-H due to their high water solubility.

The present invention provides chemically pure BOS-Na. Preferably, the BOS-Na has a chemical purity of about 99 to about 100 area %, more preferably, of about 99.5 to about 100 area %, and most preferably of about 100 area %, as determined by HPLC.

The present invention also provides BOS-Na of high assay. Preferably, the BOS-Na has an assay of about 98% to about 100%, more preferably, about 99% to about 100%, and most preferably about 100%, by HPLC.

The present invention further provides chemically pure BOS-Na of high assay. Also provided by the present invention is a process for purifying BOS-Na comprising the steps of: combining BOS-Na, at least one C₁-C₄ alcohol and water to form a mixture; heating the mixture; and recovering the BOS-Na from the heated mixture.

The BOS-Na to be purified in the above process may be obtained by any of the prior art processes, for example, the processes disclosed in WO 03/020708. Preferably, after combining BOS-Na, the at least one Ci-C₄ alcohol and water, a slurry is obtained. Preferably, the slurry contains a total Ci-C₄ alcohol:water volume ratio of about 10:90 to about 99:1, more preferably, about 50:50 to about 97:3, more preferably, about 70:30 to about 95:5, and , most preferably about 90:10, wherein the combined volumes of any Ci-C₄ alcohols present in the slurry is used in calculating the total Ci-C₄ alcohol:water volume ratio. Preferably, the Ci-C₄ alcohol is ethanol.

Preferably, the mixture is heated to reflux temperature. Preferably, after heating, a solution is obtained. Optionally, any insoluble material may be removed from the solution by filtering. The filtrate obtained after removing the insoluble material may be reheated to reflux. The hot filtrate may be cooled prior to the recovery step, to obtain a precipitate of BOS-Na. The cooling of the hot filtrate is conducted, preferably gradually, to a temperature of about O⁰C to about -1O⁰C, more preferably to a temperature of about -5°C, to precipitate BOS- Na. The precipitated BOS-Na can then be recovered as a chemically pure BOS-Na, BOS-Na of the high assay, or chemically pure BOS-Na of the high assay. Gradual cooling of the BOS- Na solution increases the purity of the precipitated BOS-Na, while cooling to a low temperature increases the yield. When the solution is cooled gradually to a temperature of about -5⁰C, the BOS-Na yield is about 90% or higher, preferably the yield is about 92%. Direct cooling of the BOS-Na to about O⁰C achieves a crystallization yield ranging from about 80% to less than about 90%, preferably about 84%. Preferably, the BOS-Na obtained after the recovering procedure is chemically pure

BOS-Na, BOS-Na of a high assay, or chemically pure BOS-Na of a high assay.

Preferably, the recovery procedure is done by any methods known in the art, such as filtering the precipitate, washing and optionally, drying in a vacuum oven.

Preferably, the obtained BOS-Na is BOS-Na monohydrate, which is optionally dried to give anhydrous BOS-Na.

Also encompassed by the present invention is a process for preparing BOS-Cl from BOS-Na, comprising the steps of: combining BOS-Na with at least one inert organic solvent (wherein the at least one inert organic solvent can be selected from inert polar organic solvents, inert non-polar organic solvents and mixtures thereof) and a chlorinating agent to form a reaction mixture; heating the reaction mixture; and removing the at least one inert organic solvent and any excess of the chlorinating agent from the heated reaction mixture to obtain BOS-Cl as a residue.

Preferably, in the process for preparing BOS-Cl from BOS-Na, the starting BOS-Na is anhydrous. Optionally, prior to the process above BOS-Na monohydrate of the present invention is dried to obtain the anhydrous BOS-Na.

Preferably, the starting BOS-Na for the BOS-Cl producing process is chemically pure BOS-Na₅ BOS-Na of a high assay, or chemically pure BOS-Na of a high assay.

Preferably, the at least one inert organic solvent is selected from the group consisting of: ethyl acetate, chlorobenzene, ethers, THF, MTBE, chloroform, methylene chloride, dichloroethane, dichloromethane, toluene and mixtures thereof. Preferably, the at least one inert organic solvent is at least one inert aromatic solvent. Preferably, the at least one inert aromatic solvent is toluene. Preferably, the chlorinating agent is selected from the group consisting of: PCl₃, PCl₅, POCl₃ and thionyl chloride. More preferably, the chlorinating agent is thionyl chloride.

Preferably, the process further comprises adding a catalyst to the slurry. The catalyst is preferably a formamide, more preferably, a N,N-disubstituted formamide and most preferably, dimethyl formamide (DMF).

Preferably, prior to the heating a slurry is obtained. Preferably, the slurry is heated while being stirred vigorously.

The slurry is heated is to a temperature of, preferably about 4O⁰C to about 8O⁰C, and more preferably about 5O⁰C. Preferably, the excess of the chlorinating agent and the at least one inert organic solvent are removed by evaporation or distillation at reduced pressure.

The BOS-Cl residue obtained after the removal of the at least one inert organic solvent and chlorinating agent is recovered by any method known in the art, such as suspending in an inert organic solvent, preferably toluene, and filtering to remove any inorganic impurities, such as NaCl.

The present invention further encompasses a process for preparing zonisamide comprising obtaining BOS-Cl according to the BOS-Cl producing process of the present invention and converting the BOS-Cl to zonisamide. The conversion may be done according to the disclosures of WO 03/072552. For instance, the BOS-Cl can be converted to zonisamide with a process comprising reacting the BOS-Cl with ammonia. The conversion of BOS-Cl to zonisamide may also be performed according to the disclosures of JP 53-77057 or US 4,172,896..

Preferably, the BOS-Cl residue is combined with at least one inert organic solvent (wherein the at least one inert organic solvent can be selected from inert polar organic solvents, inert non-polar organic solvents and mixtures thereof) and ammonia to form a crude zonisamide precipitate. The ammonia is added to obtain a basic suspension with a pH, preferably, of about 9. The ammonia can be gaseous ammonia, and preferably anhydrous, gaseous ammonia. More preferably, the reaction of the BOS-Cl and ammonia in the at least one inert organic solvent is conducted under anhydrous conditions. More preferably, before the addition of the ammonia, the BOS-Cl is mixed with the at least one inert organic solvent at a temperature of about 2⁰C, or the BOS-Cl is mixed with the at least one inert organic solvent to form a mixture and the mixture is cooled to a temperature of about 2°C. Alternatively, the BOS-Cl is combined with the at least one inert organic solvent and the ammonia at a temperature of about 2⁰C. Preferably, the at least one inert organic solvent is an at least one inert aromatic solvent. More preferably, the at least one inert aromatic solvent is toluene.

The crude zonisamide may be recovered. Preferably, the recovery comprises adding a mineral acid, preferably HCl, filtering and washing with water.

Optionally, the crude zonisamide may be further purified, e.g., by chromatography or by crystallization from a solvent. Preferably, the purification comprises heating a solution of the crude zonisamide in at least one Ci-C₄ alcohol, preferably ethanol, to reflux. The crystals of pure zonisamide may be isolated from the hot solution by any method known in the art, such as, cooling to induce precipitation and filtering.

The present invention also provides a pharmaceutical composition comprising zonisamide prepared according to the process of the present invention, and at least one pharmaceutically acceptable excipient.

The present invention further encompasses a process for preparing a pharmaceutical composition comprising combining zonisamide prepared according to the process of the present invention, with at least one pharmaceutically acceptable excipient.

The present invention further encompasses the use of zonisamide prepared according to the process of the present invention, for the manufacture of a pharmaceutical composition.

Methods of administration of a pharmaceutical composition of the present invention can be administered in various preparations depending on the age, sex, and symptoms of the patient. The pharmaceutical compositions can be administered, for example, as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injection preparations (solutions and suspensions), and the like.

The pharmaceutical composition of the present invention can optionally include more than one form of zonisamide prepared according to the process of the present invention and/or at least one other pharmaceutically active ingredient. In addition, the pharmaceutical composition of the present invention can contain inactive ingredients such as diluents, carriers, fillers, bulking agents, binders, disintegrants, disintegration inhibitors, absorption accelerators, wetting agents, lubricants, glidants, surface active agents, flavoring agents, and the like.

Diluents increase the bulk of a solid pharmaceutical composition and can make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfine cellulose, lactose, starch, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, or talc.

Carriers for use in the pharmaceutical compositions may include, but are not limited to, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, or silicic acid.

Binders help bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include for example acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, or starch.

Disintegrants can increase dissolution. Disintegrants include, for example, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®) and starch.

Disintegration inhibitors may include, but are not limited to, white sugar, stearin, coconut butter, hydrogenated oils, and the like.

Absorption accelerators may include, but are not limited to, quaternary ammonium base, sodium laurylsulfate, and the like .

Wetting agents may include, but are not limited to, glycerin, starch, and the like. Adsorbing agents used include, but are not limited to, starch, lactose, kaolin, bentonite, colloidal silicic acid, and the like .

A lubricant can be added to the composition to reduce adhesion and ease release of the product from a punch or dye during tableting. Lubricants include for example magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.

Glidants can be added to improve the flowability of non-compacted solid composition and improve the accuracy of dosing. Excipients that can function as glidants include for example colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate. Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present invention include for example maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

Tablets can be further coated with commonly known coating materials such as sugar coated tablets, gelatin film coated tablets, tablets coated with enteric coatings, tablets coated with films, double layered tablets, and multi-layered tablets. Capsules can be coated with shell made, for example, from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.

Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.

In liquid pharmaceutical compositions of the present invention, zonisamide prepared according to the process of the present invention and any other solid ingredients are dissolved or suspended in a liquid carrier, such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.

Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.

Liquid pharmaceutical compositions of the present invention can also contain viscosity enhancing agents to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include for example acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar can be added to improve the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid can be added at safe levels to improve storage stability. A liquid composition according to the present invention can also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate.

Selection of excipients and the amounts to use can be readily determined by an experienced formulation scientist in view of standard procedures and reference works known in the art.

A composition for tableting or capsule filing can be prepared by wet granulation. In wet ^' granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, which causes the powders to clump up into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate can then be tabletted or other excipients can be added prior to tabletting, such as a glidant and/or a lubricant.

A tabletting composition can be prepared conventionally by dry blending. For instance, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can be compressed subsequently into a tablet.

As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well-suited to direct compression tabletting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tabletting is known to those in the art with experience and skill in particular formulation challenges of direct compression tabletting.

A capsule filling of the present invention can comprise any of the aforementioned blends and granulates that were described with reference to tabletting, only they are not subjected to a final tabletting step.

When shaping the pharmaceutical composition into pill form, any commonly known excipient used in the art can be used. For example, carriers include, but are not limited to, lactose, starch, coconut butter, hardened vegetable oils, kaolin, talc, and the like. Binders used include, but are not limited to, gum arabic powder, tragacanth gum powder, gelatin, ethanol, and the like. Disintegrating agents used include, but are not limited to, agar, laminalia, and the like .

For the purpose of shaping the pharmaceutical composition in the form of suppositories, any commonly known excipient used in the art can be used. For example, excipients include, but are riot limited to, polyethylene glycols, coconut butter, higher alcohols, esters of higher alcohols, gelatin, semisynthesized glycerides, and the like. When preparing injectable pharmaceutical compositions, solutions and suspensions are sterilized and are preferably made isotonic to blood. Injection preparations may use carriers commonly known in the art. For example, carriers for injectable preparations include, but are not limited to, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyoxyethylene sorbitan. One of ordinary skill in the art can easily determine with little or no experimentation the amount of sodium chloride, glucose, or glycerin necessary to make the injectable preparation isotonic. Additional ingredients, such as dissolving agents, buffer agents, and analgesic agents maybe added. If necessary, coloring agents, preservatives, perfumes, seasoning agents, sweetening agents, and other medicines may also be added to the desired preparations during the treatment of schizophrenia.

The excipients mentioned above are merely examples of excipients that can be included in the pharmaceutical compositions of the present invention, and are not meant to be all inclusive. Excipients not specifically mentioned herein can be included in the pharmaceutical compositions of the present invention.

The amount of zonisamide prepared according to the process of the present invention contained in a pharmaceutical composition according to the present invention is not specifically restricted; however, the dose should be sufficient to treat, ameliorate, or reduce the condition.

The disclosures of prior art references mentioned in the present patent application are hereby incorporated by reference.

With the description of the preferred embodiments of the present invention in the present patent application, other embodiments will become apparent to one skilled in the art based on the disclosures of the specification. The invention is further defined by reference to the following examples describing in detail the process and compositions of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES HPLC Analysis of the Assay of BOS-Na:

Column & Packing: Zorbax RX C-18 150*4.6mm, 5 micron, P.N. 883967- 902

MP: 65% 0.005M *TBAHS ; 35% MeOH

Flow Rate : 1.0 ml/min Detector: , 237 nm

Column Temperature: Room temperature

Sample Volume: 20 microliters

Diluent: Methanol:H₂O (3:7)

Sample Concentration: 1 mg/ml

Analysis of the Purity of BOS-Na:

Column & Packing: Zorbax RX C-18 150*4.6mm, 5 micron, P.N. 883967-

902

Mobile phase: 65% 0.005M*TBAHS; 35% MeOH

Flow rate: l.O ml/min.

Detector: 237 nm

Column Temperature: Room temperature

Sample Volume: 20 1

Sample Concentration: 1 mg/ml

Diluent: MeOH:H₂O (3:7)

DL 0.15 area %

Example 1 Purification of BOS-Na A batch of BOS-Na (30 g) (batch number 2002003, assay by HPLC 92.3% pure) was suspended in 600 ml ethanol containing 10% v/v water and heated to reflux. Almost all the solid was dissolved; the insoluble material was filtered from the hot slurry. The filtrate was then reheated to reflux and gradually cooled to a temperature of -5⁰C. The solid was filtered, washed with ethanol and dried at 8O⁰C under vacuum until the water content (via the Karl Fischer technique) is less than 1.5%. The crystallized material weighed 25.44 g having an improved assay and purity (assay and purity by HPLC 100%, K.F. 1.56%) (yield 91.9%). The crystallization yield depended on the cooling temperature. When the refluxed filtrate was gradually cooled to the temperature of -5⁰C, the yield of the crystallized material was about 90-92%. When the cooling was to O⁰C, the yield was 84%. The crystallized wet solid was BOS-Na monohydrate.

Drying the crystallized wet solid, which is BOS-Na monohydrate, at 5O⁰C under reduced pressure gave dried BOS-Na (-7.3% water). But drying the crystallized wet solid at 8O⁰C under reduced pressure gave anhydrous BOS-Na having a water content of 1.56% by the Karl Fischer technique. Example 2: Preparation of zonisamide from BOS-Na

A) Preparation of BOS-Cl

A 0.25 1 three necked flask equipped with condenser, thermometer and mechanical stirrer was charged at a temperature in the range 25-27⁰C, with purified BOS-Na (20 g), technical toluene (150 m and DMF (0.66 ml), to obtain a reaction slurry. The BOS-Na was purified by the procedure similar to one described in Example 1. To the reaction slurry, thionyl chloride (24.6 ml) was added drop-wise o 30 minutes. The reaction mixture was then heated to 5O⁰C under nitrogen atmosphere, and stirred with stirring rate of about 200-215 rpm. The reaction was completed after 5.5 hours (HPLC monitoring) followed by removing the solvent and excess thionyl chloride by evaporation on rotavapor or by vacui distillation. The residue obtained after distillation was usually yellow. Toluene (150 ml) and 2 g tonsi were added to the residue to obtain a slurry, which was stirred at room temperature for 15 minutes. AJ 15 min, the inorganic materials were filtered and to the filtrate were added 2 g tonsil and 1 g active car SXl, followed by stirring for 15 minutes. Filtration, washing of the cake with 20 ml toluene and evaporation afforded the reaction product BOS-Cl (15.94 g, yield 80.9%).

B) Preparation of crude Zonisamide

A 0.25 ml three necked flask was charged with BOS-Cl (13 g) and toluene (130 ml) to obtain a solution. The obtained solution was then cooled to ~2°C, and ammonia gas was bubbled through the solution until the pH was of about 9, leading to a precipitate of zonisamide and ammonium chloride. The temperature naturally increased to room temperature followed by adding 43 ml water and 3.4 ml HCl 32%, and stirring for 30 minutes. Filtration and washing with water (13 ml) and ethanol tech. (13 ml) afforded the wet product. Drying at 5O⁰C gave the crude zonisamide (10.6 g, yield 91.6%).

C) Preparation of zonisamide crystals

A 0.25 1 three necked flask was charged with crude zonisamide (8 g) and ethanol tech. (80 ml), to obtain a solution. The obtained solution was heated to reflux and treated with active carbon SX₁ (0.4 g) for 30 minutes. The hot solution was then filtered under nitrogen atmosphere, cooled to ~2°C and stirred at 2⁰C for 1 hour. A solid was collected by filtration and washed with ethanol tech. (8 ml). After drying the washed solid in oven at ~50°C, zonisamide crystals were obtained as a white powder (6.8 g; yield 84.6%). Example 3: Preparation of Zonisamide with Anhydrous Ammonia according to WO 03/072552

A 2 L reactor was charged with a solution of BOS-Cl in toluene. The mixture was cooled to 10-15⁰C and anhydrous ammonia gas was bubbled through the mixture. The temperature of the mixture was maintained at 10-15°C. The amidation reaction was monitored by HPLC. After the reaction was completed the inorganic salts were filtered out. The solid was reslurried (triturated)in water at room temperature, filtered and washed with 95% ethanol to provide crude product zonisamide (wet crude:166 grams; yield: 91.25 %; content of BOS- NH₄:2.5%(wt/wt)).

Claims

WHAT IS CLAIMED IS:

1. A process for purifying l,2-benzisoxazole-3-methane-sulfonic acid sodium salt, comprising: (a) mixing l,2-benzisoxazole-3-methane-sulfonic acid sodium salt with at least one

Ci-C₄ alcohol and water to form a mixture;

(b) heating the mixture; and

(c) recovering the l,2-benzisoxazole-3-methane-sulfonic acid sodium salt from the product of step (b).

2. The process of claim 1, wherein the at least one Ci-C₄ alcohol comprises ethanol.

3. The process of claim 2, wherein the at least one Ci-C₄ alcohol is ethanol.

4. The process of claim 1, wherein the mixture has a total Ci-C₄ alcohol:water volume ratio of about 10:90 to about 99:1, wherein the total Ci-C₄ alcohol:water volume ratio is based on the combined volumes of any Ci-C₄ alcohol present in the mixture.

5. The process of claim 4, wherein the total Ci-C₄ alcohol:water volume ratio is about 50:50 to about 97:3.

6. The process of claim 5, wherein the total Ci-C₄ alcohol:water volume ratio is about 70:30 to about 95:5.

7. The process of claim 6, wherein the total Ci-C₄ alcohol:water volume ratio is about 90:10.

8. The process of claim 1, wherein the mixture in step (a) is a slurry.

9. The process of claim 1, wherein the mixture is heated in step (b) to a reflux temperature.

10. The process of claim 1, wherein the mixture is heated in step (b) to dissolve the 1,2- benzisoxazole-3-methane-sulfonic acid sodium salt.

11. The process of claim 10, further comprising removing any insoluble material from the heated mixture to form a liquid, and then recovering the l,2-benzisoxazole-3-methane- sulfonic acid sodium salt from the liquid in step (c).

12. The process of claim 11, further comprising cooling the liquid, prior to the recovering step of step (c), to obtain a precipitate of the l,2-benzisoxazole-3-methane-sulfonic acid sodium salt.

13. The process of claim 12, wherein the liquid is cooled gradually to a temperature of about O⁰C to about -1O⁰C.

14. The process of claim 13, wherein the temperature is about -5⁰C.

15. The process of claim 13, wherein the liquid is cooled to the temperature of about O⁰C to about -10⁰C in a cooling duration of about 20 minutes to about 210 minutes.

16. The process of claim 15, wherein the cooling duration is about 30 minutes.

17. The process of claim 15, wherein the cooling duration is about 60 minutes.

18. The process of claim 15, wherein the cooling duration is about 180 minutes.

19. The process of claim 13, wherein the liquid is cooled to about O⁰C and wherein the yield ranges from about 80% to less than about 90%.

20. The process of claim 19, wherein the yield is about 84%.

21. The process of claim 14, wherein the yield is about 90% or higher.

22. The process of claim 21, wherein the yield is about 92%.

23. The process of claim 1, wherein the purified l,2-benzisoxazole-3-methane-sulfonic acid sodium salt obtained has a chemical purity of about 98 area% to about 100 area% as determined by HPLC.

24. The process of claim 1, wherein the purified l,2-benzisoxazole-3-melhane-sulfonic acid sodium salt obtained has an assay of about 95% to about 100%.

25. The process of claim 23, wherein the purified l,2-benzisoxazole-3-methane-sulfonic acid sodium salt obtained has an assay of about 95% to about 100%.

26. The process of claim 1, wherein the purified l,2-benzisoxazole-3-methane-sulfonic acid sodium salt obtained is a monohydrate of l,2-benzisoxazole-3-methane-sulfonic acid sodium salt, and wherein the monohydrate has a chemical purity of about 98 area% to about 100 area% as determined by HPLC.

27. The process of claim 1, wherein the purified l,2~benzisoxazole-3-methane-sulfonic acid sodium salt obtained is a monohydrate of l,2-benzisoxazole-3-methane-sulfonic acid sodium salt, and wherein the monohydrate has an assay of about 95% to about 100%.

28. The process of claim 26, wherein the monohydrate has an assay of about 95% to about 100%.

29. A monohydrate of l,2-benzisoxazole-3-methane-sulfonic acid sodium salt having a chemical purity of about 98 area% to about 100 area% as determined by HPLC.

30. A monohydrate of l,2-benzisoxazole-3-methane-sulfonic acid sodium salt having an assay of about 95% to about 100%.

31. The monohydrate of claim 29, wherein the monohydrate has an assay of about 95% to about 100%.

32. A monohydrate of l,2-benzisoxazole-3-methane-sulfonic acid sodium salt prepared by the process of claim 1, wherein the monohydrate has a chemical purity of about 98 area% to about 100 area% as determined by HPLC.

33. A monohydrate of l,2-benzisoxazole-3-methane-sulfonic acid sodium salt prepared by the process of claim 1, wherein the monohydrate has an assay of about 95% to about 100%.

34. The monohydrate of claim 32 having an assay of about 95% to about 100%.

35. A process for preparing l,2-benzisoxazole-3-methane-sulfonyl chloride (BOS-Cl), comprising:

(A) combining l,2-benzisoxazole-3-methane-sulfonic acid sodium salt, at least one inert organic solvent and a chlorinating agent to form a reaction mixture;

(B) heating the reaction mixture; and

(C) removing the at least one inert organic solvent and any excess chlorinating agent from the heated reaction mixture to obtain the BOS-Cl as a residue.

36. The process of claim 35, further comprising obtaining the l,2-benzisoxazole-3-methane- sulfonic acid sodium salt used in step (A) by a process comprising:

(a) mixing l,2-benzisoxazole-3-methane-sulfonic acid sodium salt with at least one C₁-C₄ alcohol and water to form a mixture;

(b) heating the mixture; and

37. The process of claim 36, wherein the at least one C₁-C₄ alcohol comprises ethanol.

38. The process of claim 36, wherein the mixture has a total C₁-C₄ alcohol:water volume ratio of about 10:90 to about 99:1, wherein the total C₁-C₄ alcohohwater volume ratio is based on the combined volumes of any Ci-C₄ alcohol present in the mixture.

39. The process of claim 38, wherein the total C₁-C₄ alcohol:water volume ratio is about 50:50 to about 97:3.

40. The process of claim 39, wherein the total C₁-C₄ alcohol:water volume ratio is about 70:30 to about 95:5.

41. The process of claim 40, wherein the total Cj-C₄ alcohol:water volume ratio is about 90:10.

42. The process of claim 36, wherein the mixture in step (a) is a slurry.

43. The process of claim 36, wherein the mixture is heated in step (b) to a reflux temperature.

44. The process of claim 36, wherein the mixture is heated in step (b) to dissolve the 1,2- benzisoxazole-3-methane-sulfonic acid sodium salt.

45. The process of claim 44, further comprising removing any insoluble material from the heated mixture to form a liquid, and then recovering the l,2-benzisoxazole-3~methane~

, sulfonic acid sodium salt from the liquid in step (c).

46. The process of claim 45, further comprising cooling the liquid, prior to the recovering step of step (c), to obtain a precipitate of the l,2-benzisoxazole-3-methane-sulfonic acid sodium salt.

47. The process of claim 46, wherein the liquid is cooled gradually to a temperature of about O⁰C to about -1O⁰C.

48. The process of claim 47, wherein the temperature is about -5⁰C.

49. The process of claim 47, wherein the liquid is cooled to the temperature of about O⁰C to about -1O⁰C in a cooling duration of about 20 minutes to about 210 minutes.

50. The process of claim 49, wherein the cooling duration is about 30 minutes.

51. The process of claim 49, wherein the cooling duration is about 60 minutes.

52. The process of claim 49, wherein the cooling duration is about 180 minutes.

53. The process of claim 35, wherein the l,2-benzisoxazole-3-methane-sulfonic acid sodium salt used in step (A) is anhydrous.

54. The process of claim 36, wherein l,2-benzisoxazole-3-methane-sulfonic acid sodium salt recovered in step (c) is dried before being used in step (A).

55. The process of claim 35, wherein the l,2-benzisoxazole-3-methane-sulfonic acid sodium salt used in step (A) has a chemical purity of about 98 area% to about 100 area% as determined by HPLC and/or an assay of about 95% to about 100%.

56. The process of claim 35, wherein the chlorinating agent is selected from the group consisting OfPCl₃, PCl₅, POCl₃ and thionyl chloride.

57. The process of claim 56, wherein the chlorinating agent is thionyl chloride.

58. The process of claim 35, wherein the at least one inert organic solvent is selected from the group consisting of ethyl acetate, chlorobenzene, ethers, tetrahydrofuran, MTBE, chloroform, methylene chloride, dichloroethane, dichloromethane, toluene and mixtures thereof.

59. The process of claim 58, wherein the at least one inert organic solvent is aromatic.

60. The process of claim 59, wherein the at least one inert organic solvent comprises toluene.

61. The process of claim 35, wherein the reaction mixture further comprises a chlorination catalyst.

62. The process of claim 61, wherein the chlorination catalyst is a formamide.

63. The process of claim 62, wherein the chlorination catalyst is a N,N-disubstituted formamide.

64. The process of claim 63, wherein the chlorination catalyst is dimethyl formamide.

65. The process of claim 35, wherein the reaction mixture is a slurry step (A), and the slurry is heated to a temperature of about 4O⁰C to about 8O⁰C in step (B).

66. The process of claim 65, wherein the temperature is about 5O⁰C.

67. The process of claim 65, wherein the slurry is stirred vigorously during heating.

68. A process for preparing zonisamide, comprising: (a) mixing l,2-benzisoxazole-3-methane-sulfonic acid sodium salt with at least one

Cj-C₄ alcohol and water to form a mixture;

(b) heating the mixture;

(c) recovering the l,2-benzisoxazole-3-methane-sulfonic acid sodium salt from the product of step (b); and (d) converting the l,2-benzisoxazole-3-methane-sulfonic acid sodium salt to zonisamide.

69. The process of claim 68, wherein step (d) is performed by converting the 1,2- benzisoxazole-3-methane sulfonic acid sodium salt to l,2-benzisoxazole-3-methane-sulfonyl chloride (BOS-Cl), and then converting the BOS-Cl to zonisamide.

70. The process of claim 69, wherein the l,2-benzisoxazole-3 -methane sulfonic acid sodium salt is converted to the BOS-Cl with a process comprising reacting the l,2-benzisoxazole-3- methane sulfonic acid sodium salt with a chlorinating agent to form the BOS-Cl; and the BOS- Cl is converted to zonisamide with a process comprising reacting the BOS-Cl with ammonia.

71. The process of claim 70, wherein the BOS-Cl is reacted with the ammonia under anhydrous conditions. I

72. The process of claim 71, wherein the ammonia is gaseous.

73. The process of claim 68, wherein the at least one Ci-C₄ alcohol comprises ethanol.

74. The process of claim 68, wherein the mixture has a total C₁-C₄ alcoholrwater volume ratio of about 10:90 to about 99: 1 , and wherein the total C₁-C₄ alcohohwater volume ratio is based on the combined volumes of any C₁-C₄ alcohol present in the mixture.

75. The process of claim 74, wherein the total C₁-C₄ alcohol:water volume ratio is about 50:50 to about 97:3.

76. The process of claim 75, wherein the total C₁-C₄ alcohol:water volume ratio is about 70:30 to about 95:5.

77. The process of claim 76, wherein the total Cj-C₄ alcohol:water volume ratio is about 90:10.

78. The process of claim 68, wherein the mixture in step (a) is a slurry.

79. The process of claim 68, wherein the mixture is heated in step (b) to a reflux temperature.

80. The process of claim 68, wherein the mixture is heated in step (b) to dissolve the 1,2- benzisoxazole-3-methane-sulfonic acid sodium salt.

81. The process of claim 80, further comprising removing any insoluble material from the heated mixture to form a liquid, and then recovering the l,2-benzisoxazole~3-methane- sulfonic acid sodium salt from the liquid in step (c).

82. The process of claim 81, further comprising cooling the liquid, prior to the recovering step of step (c), to obtain a precipitate of the l,2-benzisoxazole-3-methane-sulfonic acid sodium salt.

83. The process of claim 82, wherein the liquid is cooled gradually to a temperature of about 0⁰C to about -10⁰C.

84. The process of claim 83, wherein the temperature is about -5⁰C.

85. The process of claim 83, wherein the liquid is cooled to the temperature of about O⁰C to about -1O⁰C in a cooling duration of about 20 minutes to about 210 minutes.

86. The process of claim 85, wherein the cooling duration is about 30 minutes.

87. The process of claim 85, wherein the cooling duration is about 60 minutes.

88. The process of claim 85, wherein the cooling duration is about 180 minutes.

89. A process for preparing a pharmaceutical composition comprising zonisamide and at least one pharmaceutically acceptable excipient, the process comprising:

(i) providing zonisamide prepared by the process of claim 68; and (ii) mixing the zonisamide with the at least one pharmaceutically acceptable excipient to obtain the pharmaceutical composition.