WO2007016208A2

WO2007016208A2 - 1,2-benzisoxazole-3-methane-sulfonic acid ammonium salt

Info

Publication number: WO2007016208A2
Application number: PCT/US2006/029120
Authority: WO
Inventors: Marioara Mendelovici; Tamar Nidam
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: WO2007016208A3

Abstract

The present invention provides substantially isolated ammonium salt of 1,2- benzisoxazole-3-methane sulfonic acid (BOS-NH4), which can be crystalline. The present invention also provides substantially chemically pure BOS-NH4, which is non- hygroscopic or slightly hygroscopic. Another aspect of the present invention is directed to processes of preparing the BOS-NH4. The present invention also provides processes for preparing l,2-benzisoxazole-3-methane-sulfonyl chloride (BOS-Cl) using the BOS-NH4. The present invention also provides processes for preparing zonisamide using the BOS-NH4 or BOS-Cl.

Description

1,2-BENZISOXAZOLE-S-METHANE-SULFONIC ACID AMMONIUM SALT

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 60/702,993, filed July 28, 2005, the disclosure of which is incorporated by reference.

FIELD OF THE INVENTION

The invention concerns l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt (BOS-NFI₄) in an isolated form, which is a salt of l,2-benzisoxazole-3-methane~ sulfonic acid (BOS-H), useful as an intermediate for the preparation of zonisamide.

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 an intermediate in the preparation of zonisamide. It 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. BOS-H free acid is known to be highly hygroscopic. 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^l edition, p. 792; C. Sutler, The Organic Chemistry of Sulfur, the 1946 edition, John Wiley & Sons, N. Y.).

WO 03/072552 discloses the preparation of zonisamide starting with BOS-H or a salt of BOS-H (BOS-salt) by chlorinating the BOS-H or BOS-salt to form 1,2- benzisoxazole-3-methane-sulfonyl chloride (BOS-Cl) of formula (II), followed by amidation.

(H)

However, the chlorination step, leading to BOS-Cl, is sensitive to the content of water present in the BOS-H or BOS-salt because the BOS-Cl undergoes hydrolysis in the presence of water to give back BOS-H. Thus, it is very critical to prevent the water absorption of BOS-H or the previously known salts of BOS-H before the chlorination reaction. BOS-H or the previously known BOS-salts may be kept in anhydrous condition with a desiccant. But this requirement is not practical for industrial scale.

Therefore, there is a need for a new salt of BOS-H that is less hygroscopic than the known sodium, calcium or barium salts of BOS-H. Preferably, the new salt is non- hygroscopic, or only slightly hygroscopic.

SUMMARY OF THE INVENTION The present invention provides isolated BOS-NH₄ of formula (III):

(Ill) In one of the embodiments, the present invention provides crystalline form of BOS-NH₄.

In another embodiment, the present invention provides chemically pure BOS- NH₄. In yet another embodiment, the present invention provides a non-hydroscopic or slightly hygroscopic BOS-NH₄.

In one of the embodiments, the present invention provides a non-hydroscopic or slightly hygroscopic, chemically pure isolated crystalline form OfBOS-NH₄.

In another embodiment, the present invention provides a process for preparing BOS-NH₄ comprising reacting BOS-H with ammonia.

In yet another embodiment, the present invention provides a process for preparing BOS-NH₄ comprising: combining l,2-benzisoxazole-3-acetic acid (BOA), a polar or non-polar organic solvent, acetic anhydride and sulfuric acid; heating; adding ammonia; and recovering the BOS-NH₄. In one of the embodiments, the present invention provides a process for preparing zonisamide comprising obtaining BOS-NH₄ according to a BOS-NH₄ producing process of the present invention and converting it to zonisamide.

In another embodiment, the present invention provides a process for preparing BOS-Cl comprising reacting BOS-NH₄ with a chlorinating agent. In yet another embodiment, the present invention provides a process for preparing BOS-Cl, comprising: combining BOS-NH₄ with an inert organic solvent, and a chlorinating agent; heating; removing the inert organic solvent and any excess of the chlorinating agent to obtain BOS-Cl as a residue.

In one of the embodiments, the present invention provides a process for preparing zonisamide comprising obtaining BOS-Cl according to a BOS-Cl producing process of the present invention and converting it to zonisamide.

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

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

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1: ¹H-NMR spectra of BOS-NH₄. Fig. 2: ¹H-NMR spectra OfBOS-NH₄. Fig. 3 : ¹³C NMR spectra OfBOS-NH₄. Fig. 4: ¹³C NMR spectra OfBOS-NH₄. Fig. 5: ¹³C NMR spectra OfBOS-NH₄. Fig. 6: Mass spectrum OfBOS-NH₄. Fig. 7: Powder X-ray diffractogram (PXRD) OfBOS-NH₄.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "hygroscopic" is defined as the ability to uptake water ranging from more than 2% to 15%, by weight, after being exposed to 80% relative humidity at room temperature for 24 hours. As used herein, the term "non-hydroscopic or slightly hydroscopic" is defined as the ability to uptake about 0% to 2%, by weight, of water after being exposed to 80% relative humidity at room temperature for 24 hours.

As used herein, the term "chemical purity" in reference to BOS-NH₄ refers to a chemical purity determined by HPLC, wherein the area of the BOS-NH₄ 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-NH₄ means BOS- NH₄ having a chemical purity of about 90 to about 100 area %, preferably about 95 to about 100 area %, more preferably about 98 to about 100 area %, further more preferably about 99 to about 100 area %, and even more preferably about 99.5 to about 100 area %, by HPLC.

As used herein, 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-J0 aromatic hydrocarbon such as but not limited to benzene, xylene, or toluene. As used herein, the term "room temperature" means about 2O⁰C to about 25⁰C.

As used herein, the term "anhydrous" refers to a water content of less than about 200 ppm water. In a preferred embodiment, an "anhydrous" substance or "anhydrous conditions" used in the present invention can have a water content of less than about 20 ppm.

The present invention provides isolated BOS-NH₄, having the chemical formula:

The present invention also provides crystalline form OfBOS-NH₄. The crystalline form OfBOS-NH₄, may be characterized by PXRD having peaks at about 17.6, 19.8, 24.0, 24.5, 24.8 and 25.0 ±0.2 degrees two-theta. The crystalline form OfBOS-NH₄ may further be characterized by X-ray powder diffraction peaks at about 5.1, 10.0, 22.5, 26.0, 27.0, 28.0, 29.6, 30.0, 31.1, and 32.8 ±0.2 degrees two theta. The crystalline form OfBOS-NH₄ may be characterized by an X-ray powder diffractogram substantially as depicted in Fig. 7. The BOS-NH₄ salt of the present invention can also be characterized by a ¹³C- NMR spectrum having carbon chemical shifts at about 153.92, 130.05, 124.66, 123.3, 109.33, 162.61, 121.76 and 48.1 ppm. The BOS-NH₄ salt of the present invention can also be characterized by a ¹³C- NMR spectrum substantially as depicted in Fig. 3-5. Moreover, BOS-NH₄ of the present invention may also be characterized by a ¹H-NMR spectrum having hydrogen chemical shifts at about 8.02, 7.59, 7.33, 7.66, 7.09 and 4.19 ppm. The BOS-NH₄ of the present invention may also be characterized by a ¹H-NMR spectrum substantially as depicted in Fig. 1 and 2. Also, BOS-NH₄ of the present invention can further be characterized by a mass spectrum (FAB(+), m/z) having a peak OfMH⁺ at about 231. The BOS-NH₄ of the present invention may also be characterized by the mass spectrum substantially as depicted in Fig. 6.

The present invention further provides chemically pure BOS-NH₄. Preferably, the BOS-NH₄ has a chemical purity of about 95 to about 100 area %, more preferably, about 98 to about 100 area %, further more preferably, about 99 to about 100 area %, and even more preferably, about 99.5 to about 100 area %, such as about 99.93, by HPLC. Also provided by the present invention is a non-hydroscopic or slightly hygroscopic BOS-NH₄. Preferably, the BOS-NH₄ of the present invention can absorb less than about 0.5%, by weight, of water, such as about 0.4% by weight of water, after being exposed to 80% relative humidity at room temperature for 24 hours. For instance, when the BOS-NH₄ of the present invention is spread into a thin layer (for example, when the BOS-NH₄ sample is spread out in an area of about 2 to 4 mm² per mg of the sample) and exposed to 80% relative humidity at room temperature for 24 hours, the water content of the BOS-NH₄ can increase by an amount of less than about 0.5%, such as about 0.4%, by weight. More preferably, the BOS-NH₄ of the present invention can absorb less than about 0.4%, by weight, of water, even more preferably less than about 0.2%, by weight, of water, and most preferably about 0%, by weight, of water after being exposed to 80% relative humidity at room temperature for 24 hours.

When the BOS-NH₄ of the present invention is stored, immediately after preparation, in a capped plastic bottle placed in a room having about 40% to about 55% relative humidity and at about 20° to about 25° C, the water content by weight of the BOS-NH₄ determined with the Karl Fischer technique can be about 0.2% after such storage for one day and about 0.3% after such storage for 2 years. For comparison, when BOS-Na monohydrate prepared according to the process disclosed in WO 03/020708, is stored, immediately after preparation, under the same conditions in which the BOS-NH₄ of the present invention is stored (e.g., see Table II in Example 4 below), the BOS-Na monohydrate contains 1.5%, by weight, of water, as determined with the Karl Fischer technique, within 1-2 days of storage after preparation, and about 20%, by weight, of water after a 2-year storage.

Further provided by the present invention is a non-hydroscopic or slightly hygroscopic, chemically pure isolated crystalline form OfBOS-NH₄.

The present invention encompasses a process for preparing BOS-NH₄ comprising reacting BOS-H with ammonia. Typically, the addition of the ammonia results in the formation of a precipitate. The BOS-H may be prepared according to WO 2004/020419. Preferably, the BOS-H is formed by reaction of 1,2-benzisoxazole- 3-acetic acid (BOA) with acetic anhydride and sulfuric acid, preferably in the presence of at least one organic solvent, which can be selected from polar organic solvents, non- polar organic solvents and mixtures thereof.

The present invention encompasses a process for preparing BOS-NH₄ comprising: combining l,2-benzisoxazole-3-acetic acid (BOA), at least one organic solvent (which at least one organic solvent can be selected from polar organic solvents, non-polar organic solvents and mixtures thereof), acetic anhydride and sulfuric acid; heating; adding ammonia; and recovering the BOS-NH₄. Preferably, the heating is to a reflux temperature. Preferably, after heating a suspension is obtained, which suspension preferably contains BOS-H. Preferably, after adding the ammonia, a precipitate is obtained.

Preferably, the polar organic solvents are selected from the group consisting of: ethylacetate, ethylcellosolve, methylcellosolve, dichloroethane, dichloromethane, chloroform and mixtures thereof. The polar organic solvent is more preferably ethyl acetate. Preferably, the non-polar organic solvents are selected from the group consisting of: toluene, alkanes such as heptane and/or hexanes, and mixtures thereof. The ammonia is, preferably, aqueous ammonia, gaseous ammonia or gaseous ammonia dissolved in a solvent, and more preferably, aqueous ammonia.

Preferably, BOS-NH₄ is recovered from the suspension by any method known in the art, such as filtering and washing the precipitate with a polar or non-polar organic solvent.

Preferably, the BOS-NH₄ recovered from the processes mentioned above is chemically pure.

The present invention encompasses a process for preparing zonisamide comprising obtaining BOS-NH₄ according to the process of the present invention and converting it to zonisamide. The conversion may be done according to the disclosures of WO 03/072552 by converting a salt of BOS-H₅ i.e., BOS-NH₄ in this case, to BOS- Cl and then converting BOS-Cl to zonisamide. For instance, the l,2-benzisoxazole-3- methane sulfonic acid ammonium salt can be converted to the BOS-Cl with a process comprising reacting the l,2-benzisoxazole-3-methane sulfonic acid ammonium salt with a chlorinating agent to form the BOS-Cl; and 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. The present invention encompasses a process for preparing BOS-Cl comprising reacting BOS-NH₄ with a chlorinating agent. Preferably, the chlorinating agent is added dropwise for a duration, wherein the duration can be from about 15 minutes to about 60 minutes, preferably about 30 minutes. Also preferably, the reaction is conducted in the presence of a catalyst. The present invention also encompasses a process for preparing BOS-Cl, comprising: combining BOS-NH₄, an inert organic solvent and a chlorinating agent; heating; removing the inert organic solvent and any excess of the chlorinating agent to obtain BOS-Cl as a residue. Preferably, the chlorinating agent is added dropwise for a duration, wherein the duration can be from about 15 minutes to about 60 minutes, preferably about 30 minutes. Also preferably, the reaction involving the chlorinating agent is conducted in the presence of a catalyst. Preferably, prior to the heating, a slurry is obtained. The slurry is heated preferably to a temperature of about 4O⁰C to about 8O⁰C, more preferably, to a temperature of about 5O⁰C. Preferably, the heating is done while the slurry is vigorously stirred.

Preferably, the 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 inert organic solvent is an inert aromatic solvent. Preferably, the 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, when the chlorinating agent is thionyl chloride, a catalyst is added together with the thionyl chloride.

Preferably, the catalyst is a formamide, more preferably, a N,N-disubstituted formamide and most preferably, dimethyl formamide (DMF).

Preferably, the excess of the chlorinating agent and the inert organic solvent are removed by evaporation or distillation at reduced pressure to obtain a residue containing BOS-Cl.

The BOS-Cl in the residue obtained after the removal of the inert organic solvent and chlorinating agent is recovered by any method known in the art, such as suspending the residue in an inert organic solvent, e.g., an inert aromatic solvent such as toluene, to form a slurry with optional stirring, and filtering the slurry to remove inorganic impurities, such as NH₄Cl.

The present invention further encompasses a process for preparing zonisamide comprising obtaining BOS-Cl according to the process of the present invention and converting it to zonisamide. The conversion may be done according to the disclosures of JP 53-77057, US 4,172,896 and, preferably, WO 03/072552. Preferably, the recovered BOS-Cl obtained according to the process of the present invention is combined with an inert organic solvent and ammonia, to obtain crude zonisamide precipitate. More preferably, the BOS-Cl is combined with the inert organic solvent at a temperature of about 2⁰C. Preferably, the inert organic solvent is selected from the group consisting of: ethyl acetate, chlorobenzene, ethers, THF,

MTBE, chloroform, methylene chloride, dichloro ethane, dichloromethane, toluene and mixtures thereof. Preferably, the inert organic solvent is an inert aromatic solvent. Preferably, the inert aromatic solvent is toluene. Preferably, the reaction is conducted under anhydrous conditions. Preferably, the ammonia is gaseous ammonia, and more preferably, the gaseous ammonia is anhydrous. Ammonia is added to obtain a basic suspension. Preferably, the pH of the basic suspension is about 9. Preferably, the crude zonisamide precipitate is recovered. The zonisamide precipitate may be recovered by addition of a mineral acid, preferably HCl, filtering and washing with water, to obtain the crude zonisamide. The crude zonisamide recovered from the processes mentioned above may be purified by heating a solution of the crude zonisamide in a Cj-C₄ alcohol to reflux and recovering the purified zonisamide. Preferably the Ci-C₄ alcohol is ethanol. Crystals of pure zonisamide may be isolated from the hot solution by any method known in the art, such as, cooling and/or solvent removal by evaporation, preferably under reduced pressure such as vacuum, to obtain a precipitate and filtering.

In any of the processes of the present invention involving the recovering of a solid from a liquid, the recovering can be performed via decantation, centrifugation, or preferably filtration.

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, wherein more than one physical form of the zonisamide can be included in the composition.

The present invention further encompasses a process for preparing a pharmaceutical formulation 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.

Pharmaceutical compositions of the present invention optionally further comprise at least one other pharmaceutically active ingredients, hi addition, pharmaceutical compositions 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®), microfϊne 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 of the present invention 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 of the present invention 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 of the present invention 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.

The liquid pharmaceutical compositions of the present invention 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.

The 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, 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 tableted or other excipients can be added prior to tableting, such as a glidant and/or a lubricant. A tableting 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 tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting. A capsule filling of the present invention can comprise any of the aforementioned blends and granulates that were described with reference to tableting, only they are not subjected to a final tableting 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 not 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 may be 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.

Excipients not exemplified herein can be included in the pharmaceutical composition of the present invention. The excipients that can be used in the pharmaceutical composition of the present invention are not necessarily limited to those disclosed above. 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 all the prior art references, especially WO 03/020708, WO

03/072552 and WO 2004/020419, mentioned in the present patent application are incorporated by reference herein.

From the description of the present invention with reference to certain preferred embodiments, other embodiments would become apparent to one skilled in the art based on the disclosures of the specification. The invention is further illustrated by the following examples. It will be apparent to those skilled in the art that modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES

X-RAY

Powder x-ray diffractogram (PXRD) was obtained from the dried solid using a Scintag x-ray powder diffractometer model X¹TRA, with a Cu tube and solid state detector. A bound standard sample holder with bound zew background plate was used. Scanning parameters were 2-40 degrees.

HPLC

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: 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

DL 0.2 area%

MS

The mass spectrum was obtained using Fisons VG AutoSpecQ M 250 mass spectrometer. Ionization mode was fast atom bombardment (FAB).

¹H-NMR and ¹³C-NMR IH-NMR and 13C-NMR spectra were obtained in d6-DMSO with Bracker 400MHz.

Example 1: Preparation Of BOS-NH₄

Ethyl acetate (80 ml), l,2-benzisoxazole-3-acetic acid (BOA) (2Og) and acetic anhydride (23.17g) were charged into a three necked flask. The mixture was cooled to about O⁰C and then sulfuric acid 98% (22.2 g) was added while the temperature was maintained below 5⁰C. After the complete addition of sulfuric acid, the reaction mixture was heated to reflux and the reflux was maintained for two hours. Then the mixture was cooled to about 1O⁰C and neutralized with aqueous ammonia 25% (100 ml) (pH 11). During the addition of ammonia, a lot of heat was released and massive precipitation was obtained. To this suspension of precipitate obtained, water (50 ml) was added and stirring was applied for 1 hour at room temperature. The solid was filtered, washed with ethyl-acetate (2 x 20 ml) and dried in an oven at 5O⁰C for about 16 hours, to give 21.56 g of a dry solid. The dried solid obtained is BOS-NH₄ in purity of 99.93%, by HPLC. (0.2% water content based on Karl Fischer technique, K.F.).

Example 2: Preparation of Zonisamide from BOS-NH4

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 BOS-NH₄ (20 g), technical toluene (150 ml) and DMF (0.66 ml), to obtain a reaction slurry. The BOS-NH₄ was prepared with a procedure similar to the one described in Example 1. Thionyl chloride (24.6 ml) was added drop-wise to the reaction slurry over 30 minutes. The reaction mixture was then heated to 5O⁰C under nitrogen atmosphere, and stirred with a stirring rate of about 200-215 rpm. The reaction was completed after 5.5 hours (HPLC monitoring). The reaction solvent and excess thionylchloride were removed by evaporation on rotavapor or by vacuum distillation. The residue obtained after distillation was usually yellow. Toluene (150 ml) and 2 g tonsil were added to the residue to obtain a slurry, which was stirred at room temperature for 15 minutes. After 15 min, the inorganic materials were filtered and to the filtrate were added 2 g tonsil and 1 g active carbon SXl, followed by stirring for 15 minutes. Filtration, washing of the cake with 20 ml toluene and evaporation afforded the reaction product BOS-Cl (15.95g, 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 solurion. The obtained solution was then cooled to -2⁰C, and ammonia gas is bubbled through the solution until the pH was about 9, leading to a precipitate of zonisamide and ammonium chloride. The temperature was 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 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 is treated with active carbon SX₁ (0.4 g) for 30 minutes. The hot solution was then filtered under nitrogen atmosphere, cooled to -2⁰C 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 -5O⁰C, zonisamide crystals were obtained as a white powder (6.8g, yield 84.6%).

Example 3: Preparation of Zonisamide with Anhydrous Ammonia according to WO 03/072552

A 2 L reactor was charged with the solution of BOS-Cl in toluene. The mixture was cooled to 10-15°C 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)).

Example 4: Hygroscopicity Study

A 100 mg sample of l,2-benzisoxazole-3-methane-sulfonic acid sodium salt (BOS-Na) monohydrate obtained for example, according to the process disclosed in WO 03/ 020708, and a 100 mg sample of l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt (BOS-NH₄) prepared as described in Example 1 were spread as thin layers on open dishes, and put in controlled humidity cell at 80% relative humidity (RH) for 24 hours. The hygroscopicity of the samples was determined by weighing the samples before and after exposure to 80% relative humidity at room temperature for 24 hours. The extent of water uptake by the two samples in the 24-hour period is shown in Table II.

Table II

Example 5: Further Hygroscopicity Study The water content OfBOS-NH₄ prepared as described in Example 1 was determined with the K.F. technique after preparation and after storage in a plastic bottle under laboratory conditions for 2 years. The BOS-NH₄ had 0.2%, by weight, of water within a day after preparation, and 0.3%, by weight, of water after the 2-year storage. For comparison, a similar experiment was done with BOS-Na monohydrate. The BOS-Na monohydrate had 1.5%, by weight, of water within 1-2 days after preparation, and about 20%, by weight, of water after the 2-year storage. The data supports the data given in Example 3, showing the low hygroscopicity OfBOS-NH₄ compared with BOS-Na monohydrate.

Claims

WHAT IS CLAIMED IS:

1. A crystalline form of l,2~benzisoxazole-3-methane-sulfonic acid ammonium salt.

2. The crystalline form of l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 1 characterized by a powder X-ray diffractogram having peaks at about 17.6, 19.8, 24.0, 24.5, 24.8 and 25.0 ±0.2 degrees two-theta.

3. The crystalline form of l,2-benzisoxazole-3~methane-sulfonic acid ammonium salt according to claim 2, wherein the powder X-ray diffractogram have further peaks at about 5.1, 10.0, 22.5, 26.0, 27.0, 28.0, 29.6, 30.0, 31.1, and 32.8 ± 0.2 degrees two theta

4. The crystalline form of l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 1 characterized by an X-ray powder diffractogram substantially as depicted in Fig. 7.

5. The crystalline form of l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 1 characterized by a ¹³C-NMR spectrum having carbon chemical shifts at about 153.92, 130.05, 124.66, 123.3, 109.33, 162.61, 121.76 and 48.1 ppm.

6. The crystalline form of l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 1 characterized by a ¹H-NMR spectrum having hydrogen chemical shifts at about 8.02, 7.59, 7.33, 7.66, 7.09 and 4.19 ppm.

7. The crystalline form of l,2-benzisoxazole-3-methane-sulfonic acid ammonium according to claim 1 characterized by a mass spectrum (FAB(+), m/z) substantially as depicted in Fig. 6.

8. The crystalline form of l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 1, wherein the crystalline form is isolated.

9. The crystalline form of l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 1 having a chemical purity of about 90% to about 100% based on area percent by HPLC.

10. The crystalline form of l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 9 having a chemical purity of about 98% to about 100%.

11. The crystalline form of l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 10 having a chemical purity of about 99% to about 100%.

12. The crystalline form of l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 11 having a chemical purity of about 99.5 to about 100%.

13. The crystalline form of l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 12 having a chemical purity of about 99.93%.

14. The crystalline form of l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 1 capable of absorbing about 0% to about 2%, by weight, of water after being exposed to 80% relative humidity at room temperature for 24 hours.

15. The crystalline form of l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 14 capable of absorbing less than about 0.5% by weight of water after being exposed to 80% relative humidity at room temperature for 24 hours.

16. The crystalline form of l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 15 capable of absorbing about 0.4% by weight of water after being exposed to 80% relative humidity at room temperature for 24 hours.

17. The crystalline form of l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 1 capable of absorbing about 0.3% by weight of water after being stored in a capped plastic bottle placed in a room having about 40% to about 55% relative humidity and at about 20° to about 25° C for 2 years.

18. The crystalline form of l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 9, wherein the crystalline form can absorb about 0% to about 2%, by weight, of water after being exposed to 80% relative humidity at room temperature for 24 hours.

19. The crystalline form of l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 18, wherein the crystalline form can absorb less than about 0.5% by weight of water after being exposed to 80% relative humidity at room temperature for 24 hours.

20. The crystalline form of l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 19, wherein the crystalline form can absorb about 0.4% by weight of water after being exposed to 80% relative humidity at room temperature for 24 hours!

21. The crystalline form of l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 9 capable of absorbing about 0.3% by weight of water after being stored in a capped plastic bottle placed in a room having about 40% to about 55% relative humidity and at about 20° to about 25° C for 2 years.

22. Isolated l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt.

23. The isolated l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 22 characterized by a C-NMR spectrum having carbon chemical shifts at about 153.92, 130.05, 124.66, 123.3, 109.33, 162.61, 121.76 and 48.1 ppm.

24. The isolated l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 22 characterized by a ¹H-NMR spectrum having hydrogen chemical shifts at about 8.02, 7.59, 7.33, 7.66, 7.09 and 4.19 ppm.

25. The isolated l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 22 characterized by a mass spectrum (FAB(+), m/z) substantially as depicted in Fig. 6.

26. l,2-Benzisoxazole-3-methane-sulfonic acid ammonium salt having a chemical purity of about 90% to about 100% based on area percent by HPLC.

27. The l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 26 having a chemical purity of about 98% to about 100%.

28. The l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 27 having a chemical purity of about 99% to about 100%.

29. The l,2~benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 28 having a chemical purity of about 99.5 to about 100%.

30. The l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 29 having a chemical purity of about 99.93%.

31. The l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 27, wherein the l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt is crystalline and characterized by a powder X-ray diffractogram having peaks at about 17.6, 19.8, 24.0, 24.5, 24.8 and 25.0 ±0.2 degrees two-theta.

32. The l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 31, wherein the powder X-ray diffractogram have further peaks at about 5.1, 10.0, 22.5, 26.0, 27.0, 28.0, 29.6, 30.0, 31.1, and 32.8 ± 0.2 degrees two theta

33. The l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 27, wherein the l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt is crystalline and characterized by an X-ray powder diffractogram substantially as depicted in Fig. 7.

34. The l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 27 characterized by a ¹³C-NMR spectrum having carbon chemical shifts at about 153.92, 130.05, 124.66, 123.3, 109.33, 162.61, 121.76 and 48.1 ppm.

35. The l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 27 characterized by a ¹H-NMR spectrum having hydrogen chemical shifts at about 8.02, 7.59, 7.33, 7.66, 7.09 and 4.19 ppm.

36. The l,2-benzisoxazole-3-methane-sulfonic acid ammonium according to claim 27 characterized by a mass spectrum (FAB(+), m/z) substantially as depicted in Fig. 6.

37. The l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 27 capable of absorbing about 0% to about 2%, by weight, of water after being exposed to 80% relative humidity at room temperature for 24 hours.

38. The l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 37 capable of absorbing less than about 0.5 % by weight of water after being exposed to 80% relative humidity at room temperature for 24 hours.

39. The l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 38 capable of absorbing about 0.4% by weight of water after being exposed to 80% relative humidity at room temperature for 24 hours.

40. The l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 27 capable of absorbing about 0.3% by weight of water after being stored in a capped plastic bottle placed in a room having about 40% to about 55% relative humidity and at about 20° to about 25° C for 2 years.

41. l,2-Benzisoxazole-3-methane-sulfonic acid ammonium salt capable of absorbing about 0% to about 2%, by weight, of water after being exposed to 80% relative humidity at room temperature for 24 hours.

42. The l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 41 capable of absorbing less than about 0.5% by weight of water after being exposed to 80% relative humidity at room temperature for 24 hours.

43. The l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt according to claim 42 capable of absorbing about 0.4% by weight of water after being exposed to 80% relative humidity at room temperature for 24 hours.

44. l,2-Benzisoxazole-3-methane-sulfonic acid ammonium salt capable of absorbing about 0.3% by weight of water after being stored in a capped plastic bottle placed in a room having about 40% to about 55% relative humidity and at about 20° to about 25° C for 2 years.

45. A process for preparing l,2-benzisoxazole-3-methane sulfonic acid ammonium salt, comprising:

(1) reacting l,2-benzisoxazole-3-methane sulfonic acid with ammonia to form BOS-NH₄; and

(2) recovering the l,2-benzisoxazole-3-methane sulfonic acid ammonium salt.

46. The process of claim 45, further comprising mixing l,2-benzisoxazole-3-acetic acid, acetic anhydride and sulfuric acid to form the l,2-benzisoxazole-3-methane sulfonic acid before step (1).

47. The process of claim 46, wherein the l,2-benzisoxazole-3-acetic acid, acetic anhydride and sulfuric acid are mixed in at least one organic solvent.

48. The process of claim 47, wherein after the l,2-benzisoxazole-3 -acetic acid, acetic anhydride and sulfuric acid are mixed in the at least one organic solvent to form a mixture, the mixture is heated before adding the ammonia.

49. The process of claim 48, wherein the heating is to reflux.

50. The process of claim 48, wherein after the heating a suspension containing the 1,2- benzisoxazole-3-methane sulfonic acid is obtained.

51. The process of claim 45, wherein a precipitate is formed after the addition of the ammonia.

52. The process of claim 48, wherein the at least one organic solvent is at least one polar organic solvent.

53. The process of claim 52, wherein the at least one polar organic solvent is selected from the group consisting of ethyl acetate, ethylcellosolve, methylcellosolve, dichloroethane, dichloromethane, chloroform and mixtures thereof.

54. The process of claim 53, wherein the at least one organic solvent is ethyl acetate.

55. The process of claim 48, wherein the at least one organic solvent is at least one non-polar organic solvent.

56. The process of claim 55, wherein the at least one non-polar organic solvent is selected from the group consisting of toluene, alkanes and mixtures thereof.

57. The process of claim 56, wherein the alkanes are hexanes and heptane.

58. The process of claim 45, wherein the ammonia is aqueous ammonia, gaseous ammonia or gaseous ammonia dissolved in a solvent.

59. The process of claim 58, wherein the ammonia is aqueous ammonia.

60. The process of claim 45, wherein the recovered l,2-benzisoxazole-3-methane sulfonic acid ammonium salt has a chemical purity of about 90% to about 100% based on area percent by HPLC.

61. A process for preparing l,2-benzisoxazole-3-methane-sulfonyl chloride (BOS-Cl), comprising reacting l,2-benzisoxazole-3-methane sulfonic acid ammonium salt with a chlorinating agent.

62. The process of claim 61, wherein the reacting step is conducted with a catalyst.

63. The process of claim 61, wherein the reacting step is conducted by mixing the 1,2- benzisoxazole-3 -methane sulfonic acid ammonium salt and chlorinating agent in at least one inert organic solvent to form a mixture, and wherein the process further comprises heating the mixture; and removing the inert organic solvent and any excess of the chlorinating agent to obtain the BOS-Cl as a residue.

64. The process of claim 63, wherein the mixture is a slurry prior to heating and the slurry is heated to a temperature of about 4O⁰C to about 8O⁰C.

65. The process of claim 64, wherein the temperature is about 5O⁰C.

66. The process of claim 64, wherein the slurry is stirred vigorously during heating.

67. The process of claim 63, 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.

68. The process of claim 67, wherein the at least one inert organic solvent is aromatic.

69. The process of claim 68, wherein the at least one inert organic solvent comprises toluene.

70. The process of claim 61, wherein the chlorinating agent is selected from the group consisting of PCl₃, PCl₅, POCl₃ and thionyl chloride.

71. The process of claim 70, wherein the chlorinating agent is thionyl chloride.

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

73. The process of claim 72, wherein the catalyst is a N,N-disubstituted formamide.

74. The process of claim 73, wherein the catalyst is dimethyl formamide.

75. The process of claim 63, further comprising suspending the residue in an inert organic solvent to obtain a slurry; stirring the slurry; and filtering the slurry to remove inorganic impurities resulting in a filtrate containing the BOS-Cl.

76. The process of claim 75, wherein the inert organic solvent is aromatic.

77. The process of claim 76, wherein the insert organic solvent is toluene.

78. A process for preparing zonisamide, comprising

(a) preparing l,2-benzisoxazole-3-methane sulfonic acid ammonium salt according to the process of claim 45; and

(b) converting the l,2-benzisoxazole-3-methane sulfonic acid ammonium salt to zonisamide.

79. The process of claim 78, wherein step (b) is performed by converting the 1,2- benzisoxazole-3-methane sulfonic acid ammonium salt to l,2-benzisoxazole-3- methane-sulfonyl chloride (BOS-Cl); and then converting the BOS-Cl to zonisamide.

80. The process of claim 79, wherein the l,2-benzisoxazole-3-methane sulfonic acid ammonium salt is converted to the BOS-Cl with a process comprising reacting the 1,2- benzisoxazole-3-methane sulfonic acid ammonium 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.

81. A process for preparing zonisamide, comprising

(a) preparing l,2-benzisoxazole-3-methane-sulfonyl chloride (BOS-Cl) according to the process of claim 61; and (b) converting the BOS-Cl to zonisamide.

82. The process of claim 81, wherein step (b) is conducted by a process comprising reacting the BOS-Cl with ammonia to form zonisamide.

83. The process of claim 82, further comprising purifying the zonisamide by a procedure comprising crystallization from a Ci-C₄ alcohol.

84. The process of claim 82, wherein the ammonia is anhydrous.

85. The process of claim 84, wherein the ammonia is gaseous.

86. The process of claim 82, wherein the BOS-Cl is reacted with the ammonia under anhydrous conditions to form the zonisamide.

87. The process of claim 82, wherein the BOS-Cl is reacted with the ammonia in the presence of at least one inert organic solvent to form the zonisamide as a precipitate.

88. The process of claim 87, wherein the BOS-Cl is reacted with the ammonia in the presence of the atleast one inert organic solvent at a temperature of about 2⁰C to form the zonisamide as a precipitate.

89. The process of claim 87, 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.

90. The process of claim 87, wherein the at least one inert organic solvent is aromatic.

91. The process of claim 90, wherein the at least one inert aromatic solvent is toluene.

92. The process of claim 87, wherein the mixture comprising the BOS-Cl, ammonia and the at least one inert organic solvent is a basic suspension.

93. The process of claim 92, wherein the basic suspension has a pH of about 9.

94. The process of claim 87, further comprising adding a mineral acid to the zonisamide precipitate; filtering the zonisamide precipitate; and washing the filtered zonisamide precipitate with water before subjecting the zonisamide to the optional purifying step.

95. The process of claim 83, wherein the Ci-C₄ alcohol is ethanol.

96. 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 78; and (ii) mixing the zonisamide with the at least one pharmaceutically acceptable excipient to obtain the pharmaceutical composition.

97. The l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt prepared by the process of claim 45.

98. The l,2-benzisoxazole-3~methane-sulfonic acid ammonium salt of claim 97, wherein the l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt has a chemical purity of about 90% to about 100% based on area percent by HPLC.

99. The l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt of claim 97, wherein the l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt is crystalline.

100. The l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt of claim 97, wherein the l,2-benzisoxazole-3-methane-sulfonic acid ammonium salt can uptake about 0% to about 2%, by weight, of water after being exposed to 80% relative humidity at a temperature of about 2O⁰C to about 25⁰C for about 24 hours.