FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE: PROCESS FOR PREPARATION OF SUGAMMADEX
SOLARA ACTIVE PHARMA SCIENCES LIMITED
An Indian company having its registered office at
201, Devavrata, Sector 17, Vashi, Navi Mumbai- 400 703,
Maharashtra, India
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present application relates to a process for the preparation of Sugammadex. More particularly the present application relates to an industrially viable process for preparation of Sugammadex sodium.
BACKGROUND OF THE INVENTION
Sugammadex sodium, a modified gamma cyclodextrin, is the active ingredient in the USFDA approved drug product BRIDION® and is indicated for the reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adults undergoing surgery.
Sugammadex sodium i.e. 6-Per-deoxy-6-per-(2-carboxyethyl)thio-Y-cyclodextrin sodium, is an octa substituted y-cyclodextrin derivative with a lipophilic core and a hydrophilic periphery, and has the following structure.

Formula I
PCT publication WO 01/40316 disclose 6-mercapto-cyclodextrin derivatives including Sugammadex as useful compounds in the reversal of drug-induced neuromuscular block. This publication discloses a process for preparation of

Sugammadex sodium which involves iodination of y cyclodextrin in presence of triphenylphosphine (PPh3) and dimethylformamide to obtain 6-per-deoxy-6-per-iodo-y-cyclodextrin as a yellow solid, reacting the iodo-y-cyclodextrin compound with 3-mercaptopropionic acid in presence of sodium hydride and dimethylformamide to obtain 6-Per-deoxy-6-per-(2-carboxyethyl)thio-Y-cyclodextrin (Sugammadex), sodium salt as white solid.
Processes for the preparation of Sugammadex sodium have been described in various patent publications including WO 2012/025937, CN 104844732, WO 2017/084401, and CN 106749771. However, the synthetic methods described in the . prior art are not effective for large scale production because of tedious workup procedures, poor yield, lower purity, difficulties in handling the toxic reagents; thus, the processes are not suitable for commercial scale up.
There remains a need for a commercially advantageous and industrially viable process for preparing Sugammadex sodium in better yield and purity. It is therefore an object of this invention to provide a commercially advantageous and industrially viable process for preparing Sugammadex sodium.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an illustration of a powder X-ray diffractogram (PXRD) Sugammadex sodium prepared according to Example 7.
SUMMARY OF THE INVENTION
In an aspect, the present application provides a process for preparing Sugammadex or a pharmaceutically acceptable salt thereof, the process comprising:
reacting a compound of Formula II


Formula II
wherein: Y is a -leaving group, selected from the group consisting of halide such as CI, Br or I; and sulfuric or sulfonic ester, such as tosylate, mesylate, napthtalenesulfonate or triflate; with 3-mercaptopropionic acid or an amine salt thereof, in presence of a base in a suitable organic solvent, to form Sugammadex or a pharmaceutically acceptable salt thereof.
In an aspect, the present application provides a process for preparing an amine salt of 3-mercaptopropionic acid, the process comprising, reacting 3-mercaptopropionic acid with an amine, in a suitable organic solvent.
In an aspect, the present application provides Sugammadex sodium which is substantially free of process related impurities.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances.
As used herein, the term "salt" or "pharmaceutically acceptable salt" refers to those salts of the compounds formed by the process of the present invention which are safe and effective in human beings and that possess the desired biological activity.

Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et a/. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free acid or base with a suitable base or acid. Examples of pharmaceutically acceptable salts include, but are not limited to: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorsulfonate, citrate, formate, fumarate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, representative alkali or alkaline earth metal salts such as sodium, lithium, potassium, calcium, magnesium, nontoxic ammonium/quaternary ammonium, and the like.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms "comprising" and "comprises" mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. The terms "about," "substantially" and the like are to be construed as modifying a term or value such that it is not an absolute, but does not read on the prior art. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by one skilled in the art. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
The term "optionally" is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

The term "compound" as used herein, refers to the compounds of this application, which includes the key starting materials, intermediates and/or the final product. Specifically, it refers to the compounds of formulae I, II and/or III, or pharmaceutically acceptable salts thereof.
Unless specified otherwise, the term "solvent" or "organic solvent" also encompasses "inert organic solvent" and organic solvents that are "substantially anhydrous". The term "inert organic solvent" refers to an organic solvent which, under the reaction conditions of the process of this invention, does not enter into any appreciable reaction with either the reactants or the products, whereas the term "substantially anhydrous" means that the solvents are substantially free of trace amounts of water. Although anhydrous inert organic solvents are generally preferred in the reaction mixture, trace amounts of water, such as that often found in commercially available solvents, can be tolerated.
The term "anti-solvent" refers to a solvent in which a compound is insoluble or less soluble or sparingly soluble.
Inventors of the present application have developed a commercially viable process for preparing Sugammadex pharmaceutically acceptable salt thereof, in high yield and purity, which is devoid of the drawbacks of prior art.
In an aspect, the present application provides a process for preparing Sugammadex or a pharmaceutically acceptable salt thereof, the process comprising:
reacting a compound of Formula II


Formula II wherein: Y is a leaving group, selected from the group consisting of halide such as CI, Br or I; and sulfuric or sulfonic ester, such as tosylate, mesylate, napthtalenesulfonate or triflate; with 3-mercaptopropionic acid or an amine salt thereof, in presence of a base in a suitable organic solvent, to form Sugammadex or a pharmaceutically acceptable salt thereof.
In certain embodiments, the amine salt of 3-mercaptopropionic acid used in the reaction is selected from the group consisting of, triethanolamine, diethanolamine, propanolamine, monoethanolamine, methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, t-butylamine, pentylamine, isopentylamine, hexylamine, eyclohexylamine, dicyclohexylamine, cyclopentylamine, norbornylamine, octylamine, ethylhexylamine, nonylamine, decylamine, dimethylethanolamine, and the like.
In preferred embodiments, the amine salt of 3-mercaptopropionic acid used in the reaction is dicyclohexylamine salt.
In certain embodiments, base used in the reaction include inorganic or an organic base such as for example, diisopropylamine, dimethylamine, ethylenediamine, N,N-diisopropylmethylamine, 4-dimethylaminopyridine, N.N-diisopropylethylamine, triethylamine, aniline, pyridine, piperidine, potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acetate, potassium methoxide, sodium hydride, sodium carbonate;.sodium hydrogen carbonate, sodium hydroxide, sodium acetate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium carbonate, lithium hydrogen carbonate, lithium hydroxide, lithium acetate, lithium methoxide, barium hydroxide, calcium oxide; ammonia, ammonium chloride, and the like.
In preferred embodiments, base used in the reaction is selected from the group consisting of metal hydroxide and alkali metal alkoxide. In preferred embodiments, base used in the reaction is alkali metal alkoxide.
In more preferred embodiments, base used in the reaction is a sodium base, such as sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide or the like.

In some embodiments, compound of Formula II used in the reaction is a halo derivative of y-cyclodextrin (Y is a halide such as CI, Br, or I).
In certain embodiments, solvent used in the reaction is selected from the group consisting of: methanol, ethanol, 1-propanol, 2-propanol, tetrahydrofuran, dioxane, diethyl ether, methyl t-butyl ether, diisopropyl ether, butyl ether, diphenyl ether, methylphenyl ether, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, xylenes, hexane, heptane, acetonitrile, propionitrile, butyronitrile, benzonitrile, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, sulfolane, dichloromethane, dichloroethane, and mixtures thereof. Preferably, the solvent used for the reaction is selected from the group consisting of dimethyl sulfoxide, dimethylacetamide, dimethylformamide, and mixtures thereof.
In preferred embodiments, the reaction of compound of Formula II with 3-mercaptopropionic acid or an amine salt thereof, is carried out in presence of sodium methoxide in dimethyl sulfoxide solvent.
In certain embodiments, the compound of Formula II used in the reaction may include:
a. direct use of a reaction mixture containing Formula II compound that is obtained
in the course of its synthesis and that comprises a suitable solvent, or by
combining a solvent with the reaction mixture; or
b. dissolving Formula II compound in a solvent.
Suitable solvents useful in the reaction are similar to that described for aforementioned aspect of the application to result the compound of Formula I.
The compounds of Formula II used in the reaction, some of which are known from the literature, may be obtained by methods known from the literature, or using methods known to one skilled in the art. For example, compounds of Formula II wherein Y is a halide (CI, Br or I), can be prepared by reacting a y-cyclodextrin of Formula III


Formula III
with a halogenating agent optionally in presence of a base, in a suitable solvent.
Halogenating agent useful for this purpose include but not limited to: oxalyl halide, such as oxalyl chloride, oxalyl bromide, oxalyl iodide; phosphorus halides such as phosphorous pentachloride, phosphorous trichloride, phosphorous pentabromide, phosphorous tribromide, phosphorous pentaiodide, phosphorous triiodide; phosphoryl halides, such as phosphoryl chloride, phosphoryl bromide; sulfur halide such as thionyl chloride, thionyl bromide, sulfuryl chloride, methylsulfonyl chloride; quaternary ammonium halide such as tetraethylammonium chloride; halo succinimide such as N-Bromosuccinimide, N-chlorosuccinimide; halomethylenemorpholinium halide such as N-(chloromethylene)-morpholinium chloride; or the like.
Bases that are useful for the reaction include, but are not limited to: inorganic or an organic base such as for example, diisopropylamine, dimethylamine, ethylenediamine, N.N-diisopropylmethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylamine, aniline, pyridine, piperidine, potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acetate, potassium methoxide, sodium hydride, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium acetate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium carbonate, lithium hydrogen carbonate, lithium hydroxide, lithium acetate, lithium methoxide, barium hydroxide, calcium oxide; ammonia, ammonium chloride, and the like.

Solvents useful in the preparation of compound of Formula II include but not limited to: methanol, ethanol, 1-propanol, 2-propanol, tetrahydrofuran, dioxane, diethyl ether, methyl t-butyl ether, diisopropyl ether, butyl ether, diphenyl ether, methylphenyl ether, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, xylenes, hexane, heptane, acetonitrile, propionitrile, butyronitrile, benzonitrile, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, sulfolane, dichloromethane, dichloroethane, or mixtures thereof.
y-Cyclodextrin of Formula III is commercially available. y-Cyclodextrin can also be synthesized by methods known from the literature.
In an aspect, the present application provides a process for preparing an amine salt of 3-mercaptopropionic acid, the process comprising, reacting 3-mercaptopropionic acid with an amine, in a suitable organic solvent.
The amine used in the reaction is selected from the group consisting of, triethanolamine, diethanolamine, propanolamine, monoethanolamine, methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, t-butylamine, pentylamine, isopentylamine, hexylamine, cyclohexylamine, dicyclohexylamine, cyclopentylamine, norbornylamine, octylamine, ethylhexylamine, nonylamine, decylamine, dimethylethanolamine, and the like.
Suitable solvents useful in the reaction are similar to that described for aforementioned aspect of the application to result the compound of Formula I.
In preferred embodiments, the amine used in the reaction is dicyclohexylamine salt.
In an aspect, the present application provides a process for preparing Sugammadex or a pharmaceutically salt thereof, the process comprising:
i. reacting y-Cyclodextrin with a halogenating agent optionally in presence of a base, in a suitable solvent to provide 6-per-deoxy-6-per-halo-y-cyclodextrin;
ii. reacting 6-per-deoxy-6-per-halo-Y-cyclodextrin with 3-mercaptopropionic acid or a dicyclohexylamine salt thereof, in presence of a base in a suitable organic solvent, to form Sugammadex or a salt thereof; and

iii. optionally purifying Sugammadex or a pharmaceutically acceptable salt thereof.
Halogenating agent useful for this purpose include but not limited to oxalyl halide, such as oxalyl chloride, oxalyl bromide, oxalyl iodide; phosphorus halides such as phosphorous pentachloride, phosphorous trichloride, phosphorous pentabromide, phosphorous tribromide, phosphorous pentaiodide, phosphorous triiodide; phosphoryl halides, such as phosphoryl chloride, phosphoryl bromide; sulfur halide such as thionyl chloride, thionyl bromide, sulfuryl chloride, methylsulfonyl chloride; quaternary ammonium halide such as tetraethylammonium chloride; halo succinimide such as N-Bromosuccinimide, N-chlorosuccinimide; halomethylenemorpholinium halide such as N-(chloromethylene)-morpholinium chloride; or the like.
In some embodiments, base used in the reaction include inorganic or an organic base such as for example, diisopropylamine, dimethylamine, ethylenediamine, N,N-diisopropylmethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylamine, aniline, pyridine, piperidine, potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acetate, potassium methoxide, sodium hydride, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium acetate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium carbonate, lithium hydrogen carbonate, lithium hydroxide, lithium acetate, lithium methoxide, barium hydroxide, calcium oxide; ammonia, ammonium chloride, and the like.
Solvents useful for the reaction is selected from the group consisting of: methanol, ethanol, 1-propanol, 2-propanol, tetrahydrofuran, dioxane, diethyl ether, methyl t-butyl ether, diisopropyl ether, butyl ether, diphenyl ether, methylphenyl ether, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, xylenes, hexane, heptane, acetonitrile, propionitrile, butyronitrile, benzonitrile, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, sulfolane, dichloromethane, dichloroethane, and mixtures thereof.
Sugammadex or a pharmaceutically acceptable salt thereof can be purified by dissolving it in a suitable solvent such as water, mixing the resultant solution with an anti-solvent to isolate pure Sugammadex or a pharmaceutically acceptable salt thereof. It is also desirable to treat the mixture with activated carbon prior to addition

of an anti-solvent. The anti-solvent can be selected from alcoholic solvent such as methanol, ethanol, isopropyl alcohol, acetone, tetrahydrofuran, dimethylformamide and dimethyl sulfoxide or mixtures thereof. The choice of solvents, anti-solvents, methods of purification and isolation, is customary to one skilled in the art.
In various embodiments, the sodium content in Sugammadex sodium obtained according to the invention described herein is in a range of about 7% w/w to about 9% w/w, or about 7.5% w/w to about 8.5% w/w, or about 7.8% w/w to about 8.2% w/w.
The chemical transformations described throughout the application may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Reactants, reagents, bases, solvents used herein can suitably be employed in an amount in a range of about 0.9 equivalent (e.g., at least about 1 equivalent) to 60 equivalents per equivalent of the other compound (substrate).
In various embodiments, the reaction is carried out at suitable temperatures less than about 150°C, less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures.
Compounds employed at various stages of the process described herein (Formulae I, II or III) can be prepared as a pharmaceutically acceptable salt by reacting the free acid or base form of the compound with a pharmaceutically acceptable inorganic or organic acid or base. The free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt from, respectively. For example, a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). The completion of the reaction can be monitored by any suitable analytical technique.
The compounds at various stages of the processes including the final compound, of the present application may be isolated using conventional techniques known in the art. For example, useful techniques include, but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, combining a solution with an anti-solvent, adding seed crystals, evaporation,

flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, and the like. The isolation may be optionally carried out at atmospheric pressure or under a reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher than desired percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor. Evaporation as used herein refers to distilling a solvent completely, or almost completely, at atmospheric pressure or under a reduced pressure. Flash evaporation as used herein refers to distilling of solvent using techniques including, but not limited to, tray drying, spray drying, fluidized bed drying, or thin-film drying, under atmospheric or a reduced pressure.
The compounds obtained by the chemical transformations at various steps described herein can be used for their following steps without further purification, or can be effectively separated and purified by employing a conventional method known to one skilled in the art, such as recrystallization, column chromatography, by transforming them into a salt form, or by washing with an organic solvent or with an aqueous solution, eventually adjusting the pH. The compounds obtained at various stages of the processes may be purified by precipitation or slurrying in suitable solvents, or by commonly known recrystallisation techniques. The suitable recrystallisation techniques include, but are not limited to, steps of concentrating, cooling, stirring, or shaking a solution containing the compound, combination of a solution containing a compound with an anti-solvent, seeding, removal/partial removal of the solvent, or combinations thereof, evaporation, flash evaporation, or the like. An anti-solvent as used herein refers to a liquid in which a compound is poorly soluble. Compounds can be subjected to any of the purification techniques more than one time, or can be subjected to more than one of the purification techniques, until the desired purity is attained.
Compounds of the processes described herein may also be purified by slurrying in suitable solvents, for example, by providing a compound in a suitable solvent, if required heating the mixture to higher temperatures, subsequently cooling, and recovering a compound having a higher purity. Optionally, precipitation or crystallization at any of the steps described herein can be initiated by seeding of the reaction mixture with a small quantity of the desired product. Suitable solvents that can be employed for recrystallization or slurrying include, but are not limited to:

alcohols, such as methanol, ethanol, 1 -propanol, sopropyl alcohol; ethers, such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, and dioxane; esters, such as methyl acetate, ethyl formate, ethyl acetate, isopropyl acetate; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone; nitriles, such as acetonitrile and propionitrile; amides, such as formamide, N,N-dimethylformamide, and N,N-dimethylacetamide; sulfoxides, such as dimethyl sulfoxide; aliphatic and aromatic hydrocarbons, such as n-pentane, isopentane, hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, cyclohexane, cycloheptane, petroleum ethers, benzene, toluene, m-xylene, o-xylene, chlorobenzene and anisole; halogenated hydrocarbons such as dichloromethane, chloroform,-carbon tetrachloride; water; or mixtures of two or more thereof.
In certain aspects of the present application, the purified Sugammadex may be optionally washed with suitable solvent and dried under suitable drying conditions. Drying may be suitably carried out using equipment such as air tray dryer, vacuum tray dryer, vacuum oven, air.oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. The drying may be carried out at atmospheric pressure or under a reduced pressure at temperatures of less than about 150°C, or less than about 120°C, or less than about 100°C, or less than about 80°C, or less than about 65°C, or any other suitable temperature as long as Sugammadex or a salt thereof is not degraded in quality. The drying may be carried out for any desired time until the required purity is achieved. For example, it may vary from about 1 to about 10 hours, or about 1 to 24 hours, or longer.
The dried product may optionally be subjected to a particle size reduction technique to obtain desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation sifting; milling using mills, such as, for example, ball, roller, or hammer mills, or jet mills, including, for example, air jet mills; or any other conventional technique. The desired particle sizes may also be achieved directly from the reaction mixture by selecting equipment that is able to provide the compound with the desired particle sizes. Accordingly, Sugammadex sodium may have a desired particle size of less than about 200 pm, less than about 150 pm, less than about 100 μm, less than about 90

μm, less than about 80 pm, less than about 60 μm, less than about 50 pm, less than about 40 pm, less than about 30 pm, less than about 20 pm, less than about 10 pm or less than about 5 pm.
In another aspect, the present application provides Sugammadex sodium which is substantially free of process related impurities. In yet another aspect, Sugammadex sodium prepared according to the present invention has purity at least about 90%, at least about 95%, at least about 98% or at least about 99% by High-performance liquid chromatography (HPLC).
In certain aspects, Sugammadex or a salt thereof can be conveniently prepared, or formed during the process of the invention, as solvates (e.g., hydrates). Hydrates can be conveniently prepared by recrystallization from an aqueous/organic solvent
mixture.
In certain aspects, Sugammadex or a pharmaceutically acceptable salt thereof can conveniently be prepared in a desired solid-state form using techniques known in the art. The starting material, which can be used for the preparation of desired solid-state form, can be crude or pure Sugammadex obtained by any method known in the art. The starting material for preparing a desired polymorphic form include crystalline forms, amorphous, or mixtures of amorphous and crystalline forms of Sugammadex in any proportions, obtained by any method. For example, amorphous form of Sugammadex or a salt thereof can be obtained by, preparing a solution comprising Sugammadex or a salt thereof, and isolating an amorphous form of Sugammadex or a salt thereof. Isolation may be effected by removing the solvent, or by a precipitation technique. Suitable techniques which may be used for the removal of the solvent include using a rotational distillation device such as a Buchi Rotavapor®, spray drying, thin film drying, freeze drying (lyophilization), and the like, or any other suitable techniques. The solvent may be removed, optionally under reduced pressures, at temperatures less than about 100° C, less than about 75° C, less than about 60° C, less than about 50° C, or any other suitable temperatures. The choice of solvents, anti-solvents, methods of purification and isolation, is customary to one skilled in the art.
The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically

disclosed herein. Thus, for example, in each instance herein any of the terms "comprising" and "consisting of may be replaced with either of the terms. In addition, the solvents, temperatures, reaction durations, etc. delineated herein are for purposes of illustration only and one of ordinary skill in the art will recognize that variation of the reaction conditions can produce the desired products accordingly.
Certain specific aspects and embodiments of the present invention will be better understood in connection with the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.
EXAMPLES
Example 1: Preparation of dicyclohexylamine salt of 3-mercapto propionic acid.
3-Mercaptopropionic acid (50 g) was added to solution of acetone (400 mL) at 25-26 °C under argon atmosphere. To above solution dicyclohexylamine (102 g) was added dropwise at 0-10 °C under argon atmosphere. The reaction mixture was stirred at 25-26 °C for 1 hour. The solid thus obtained was collected by filtration, and suck dried for 30 minutes. The resultant wet solid was dried in oven under vacuum at 45-50 °C for 12-16 hours to afford the title compound. Yield: 120 g
Example 2: Preparation of 6-per-deoxy-6-per-chloro-Y-cycIodextrin.
Oxalyl chloride (66.56 mL) was added dropwise to dimethylformamide (400 mL) at -5 to 10 °C and the white solid thus precipitated was stirred for 1 hour at -5 to -10 °C. Gamma cyclodextrin (50 g) in dimethylformamide (400 mL) was added at -5 to 10 °C and the resulting mixture was stirred at 60 °C for 20 hours. The reaction mass was cooled to 0 °C, diluted with water (400 mL), followed by addition of 10 % sodium hydroxide to adjust the pH 7.5 to 8.5. The resultant mass was further diluted with water (400 mL) and stirred for 1 hour at 20-25 °C. The solid thus obtained was collected by filtration, washed with methanol/water (250 mL /250 mL) and dried under suction. The resultant wet solid was dried in oven under vacuum at 55 °C to afford the title compound as a white solid.

Yield: 53 g; Purity by HPLC: 97.76%
Example 3: Preparation of Sugammadex sodium.
3-Mercaptopropionic acid dicyclohexylamine salt (19.9 g) was added to dimethyl sulfoxide (50 mL) at 25-26 °C under argon atmosphere. Sodium methoxide (7.5 g) was added to reaction mixture at 25-26 °C under argon. Argon was purged in reaction mixture for 10-15 min. 6-per-deoxy-6-per-chloro-Y-cyclodextrin (5.0 g) was dissolved in 25 mL of dimethyl sulfoxide was added dropwise to the reaction mixture at 25-26 °C. The resulting reaction mass was heated to 70-73 °C and maintained for 20 hours. The reaction mass was cooled to 25-26 °C and methanol (100 mL) was added at 25-26 °C and stirred for 30 minutes at 25-26 °C. The solid thus obtained was collected by filtration under argon at 25-26 °C, washed with acetone (100 mL) and suck dried for 30 minutes. The wet solid obtained was transferred to the reactor under argon at 25-26 °C and water (80 mL) was added, followed by dropwise addition of methanol (320 mL) at 25-26 °C. and stirred for 30 min at 25-26 °C. The solid thus obtained was collected by filtration and suck dried for 30 minutes to afford the title compound.
Yield: 4.8 g; Purity by HPLC: 98.18%
Example 4: Preparation of Sugammadex sodium
3-Mercaptopropionic acid (90.5 mL) was added to a suspension comprising sodium methoxide (112.18 g) in dimethyl sulfoxide (1125 mL) at 20-25 °C under nitrogen atmosphere and stirred at 25 °C for 1 hour. 6-per-deoxy-6-per-chloro-Y-cyclodextrin (75 g) in dimethyl sulfoxide (375 mL) was added dropwise to the above reaction mixture at 20-25 °C and maintained for 20 hours at 70 °C. The reaction mixture was cooled to 50 °C, diluted with methanol (1125 mL) and stirred for 30 minutes. The solid thus obtained was collected by filtration, washed with methanol (500 mL) and dried under suction. The crude was dissolved in water (750 mL), treated with charcoal (10% w/w), stirred for 10-15 minutes at 20-25 °C and filtered. The resultant filtrate was diluted with methanol (1500 mL). The solid thus obtained was collected by filtration, washed with methanol (500 mL) and dried in oven under vacuum to obtain the title compound as white solid.
Yield: 97 g; Purity by HPLC: 98.11%

Example 5: Preparation of Sugammadex sodium
3-Mercaptopropionic acid (24 mL) was added to a suspension of sodium hydroxide (22.16 g) in dimethyl sulfoxide (200 mL) at 20-25 °C under argon atmosphere and stirred at 20-25 °C for 30 minutes. 6-per-deoxy-6-per-chloro-y-cyclodextrin (20 g) in dimethyl sulfoxide (200 mL) was added dropwise at 20-25 °C. The reaction mixture was heated to 70 °C and stirred for 20-24 hours. The reaction mixture was later cooled to 20-25 °C, diluted with methanol (200 mL) and stirred for 15-30 minutes. The solid thus obtained was collected by filtration, washed with methanol (5 x 200 mL) and dried under vacuum to obtain crude Sugammadex sodium. Crude Sugammadex sodium (2.0 g) was recrystallized from DMF/water (60 mL / 24 mL) at 80 °C, followed by washing with acetone (2x10 mL) to obtain title compound as white solid.
Yield: 1.2 g; Purity by HPLC: 97.83%
Example 6: Purification of Sugammadex Sodium
Sugammadex sodium (105 g) was added to dimethylformamide (3150 mL) at 20-25 °C under nitrogen atmosphere and the mixture was heated to 75-78 °C. To the reaction mixture water (1365 mL) was added dropwise at 75-78 °C and stirred for 30 minutes at 75-78 °C. The reaction mixture was cooled to 25 °C and the solid precipitated was collected by filtration, washed with methanol (400 mL) and dried under suction. The resultant solid was dissolved in water (240 mL) and to this, methanol (1200 mL) was added dropwise and the reaction mixture was stirred for 30 minutes at 20-25 °C. The solid thus obtained was collected by filtration, washed with methanol (400 mL) and dried under suction. The resultant solid was dried in oven under vacuum at 55 °C for 48 hours to obtain the title compound as white solid.
Yield: 66 g; Purity by HPLC: 99.4%
Example 7: Purification of Sugammadex sodium.
Crude Sugammadex sodium (120 g) was suspended in dimethylformamide (3600 mL) and heated to 76-80 °C under Argon purging. Deoxygenated water (1440

ml_) was added at 76-80 °C. The reaction mixture was stirred at 76-80 °C for 30 minutes until clear solution was observed. The reaction mixture was gradually cooled to 40-45 °C for 2-4 hours. The reaction mixture was further cooled to 35-40°C and stirred for 1 hour. The solid precipitated was collected by filtration, washed with DMF/water mixture (90 mL/30 mL) and dried under suction, followed by drying under vacuum at 45-50 °C for 12 hours to obtain a white solid (72.8 g).
The above crude material (71 g) was dissolved in water (99.4 mL) / methanol (99.4 mL) and passed through celite bed and washed with mixture of water (7.1 mL) / methanol (7.1 mL). The solution was heated to 55-60 °C and methanol (319.5 mL) was added. The reaction mixture was stirred for 30 minutes and allowed to cool to 35-40 °C for 3 hours. The reaction mixture was further cooled to 35-40°C and stirred for 1 hour. The solid precipitated was collected by filtration, washed with methanol/water (56.08 mL/7.01 mL) mixture and dried under suction, followed by dried under vacuum not less than 650 mm at 60-65 °C for 10 hours to afford Sugammadex sodium as off white solid (42 g).
The above material (40 g) was taken in denatured ethanol (400 mL) and stirred for 2 hours at 20-30 °C. The solid was collected by filtration, washed with denatured ethanol (40 mL) and dried under suction, followed by under vacuum not less than 650 mm at 65-70 °C for 20 hours to obtain pure Sugammadex sodium as off white solid. Powder X-ray diffraction pattern of the obtained solid is as given in Figure 1.
Yield: 37.9 g; Purity by HPLC: 98.97%

WE CLAIM:
1. A process for preparing Sugammadex or a pharmaceutically acceptable salt
thereof, the process comprising:
reacting a compound of Formula II

Formula II
wherein: Y is a leaving group, selected from the group consisting of halide such as CI, Br or I; and sulfuric or sulfonic ester, such as tosylate, mesylate, napthtalenesulfonate or triflate; with 3-mercaptopropionic acid or an amine salt thereof, in presence of a base in a suitable organic solvent, to form Sugammadex or a pharmaceutically acceptable salt thereof.
2. The process as claimed in claim 1, wherein the amine salt is selected from the group consisting of isopentyiamine, hexylamine, cyclohexylamine, dicyclohexylamine, cyclopentylamine and mixtures thereof.
3. The process as claimed in claim 1 wherein the base is selected from the group consisting of sodium ethoxide, sodium tert-butoxide, sodium hydride, sodium methoxide, sodium hydroxide and mixtures thereof.
4. The process as claimed in claim 1, wherein the suitable organic solvent is selected from the group consisting of methanol, ethanol, 1-propanol, dimethylformamide,

dimethylacetamide, acetonitrile, acetone, methyl isobutyl ketone, dimethyl sulfoxide, dichloromethane and mixtures thereof.
5. A process for preparing Sugammadex or a pharmaceutically salt thereof, the
process comprising:
a. reacting y-Cyclodextrin with a halogenating agent optionally in presence of a
base, in a suitable solvent to provide 6-per-deoxy-6-per-halo-Y-cyclodextrin;
b. reacting 6-per-deoxy-6-per-halo-Y-cyclodextrin with dicyclohexylamine salt of
3-mercaptopropionic acid, in presence of a base in a suitable organic solvent,
to form Sugammadex or a salt thereof; and
c. optionally purifying Sugammadex or a pharmaceutical^ acceptable salt thereof.
6. The process as claimed in claim 5, wherein the halogenating agent in step a) is selected from the group consisting of N-chlorosuccinimide, oxalyl chloride, oxalyl bromide, thionyl chloride tetraethylammonium chloride and mixtures thereof.
7. The process as claimed in claim 5, wherein the base in step a) is selected from the group consisting of sodium ethoxide, sodium hydroxide, sodium tert-butoxide, sodium hydride, sodium methoxide and mixtures thereof.
8. The process as claimed in claim 5, wherein the suitable solvent in step a) is selected from the group consisting of water, methanol, ethanol, 1-propanol, dimethylformamide, dimethylacetamide, acetonitrile, acetone, methyl isobutyl ketone, dimethyl sulfoxide, dichloromethane and mixtures thereof.
9. The process as claimed in claim 5, wherein the base in step b) is selected from the group consisting of sodium ethoxide, sodium tert-butoxide, sodium hydride, sodium methoxide, sodium hydroxide and mixtures thereof and the suitable organic solvent is selected from the group consisting of methanol, ethanol, 1-propanol, dimethylformamide, dimethylacetamide, acetonitrile, acetone, methyl isobutyl ketone, dimethyl sulfoxide, dichloromethane and mixtures thereof.

10. The process as claimed in any of the preceding claims, wherein Sugammadex sodium obtained is characterized by powder X-ray diffraction pattern as shown in Figure 1.