PROCESS FOR PREPARATION OF HIGHLY PURE SUGAMMADEX OR
ITS'S PHARMACEUTICALLY ACCEPTABLE SALTS AND
INTERMEDIATES THEREOF
FIELD OF INVENTION
The present invention relates to an improved and industrially scalable process for the preparation of highly pure Sugammadex or its pharmaceutical ly acceptable salts and intermediate thereof.
BACKGROUND OF THE INVENTION
Sugammadex sodium (I) (Org 25969) is indicated for reversal of neuromuscular blockade by the agent rocuronium and vecuronium in adults undergoing surgery It has been approved by US FDA and EMA under the brand name BRIDION®.
The US patent 6,670,340 discloses the process for the preparation of
Sugammadex sodium. The first stage in process involves the preparation of 6-per-
deoxy-6-per-iodo-gamma Cyclodextrin by reaction of gamma Cyclodextrin with
iodine in the presence of triphenylphosphine and DMF. The workup process involves
use of sodium methoxide as base to hydrolyse the formate esters formed during the
reaction. But the use of sodium methoxide leads to formation of elimination impurity
j.T- ft EC T r p. r Hf NlN. A.I 7 4 / 8 9 / .2JLLJ3 1_1- * QJa. .

(compound II) which will be carried over to next stage along with 6-perdeoxy-6-per-iodo gamma cyclodextrin. Next stage involves the reaction of 6-perdeoxy-6-per-iodo gamma cyclodextrin with 3-mercaptopropionic acid in the presence of alkali metal hydrides in an organic solvent to give the Sugammadex sodium salt. It was found difficult to handle alkali metal hydrides in industrial scale. Final product was purified by dialysis method for 36 hours. The dialysis method is expensive and is not feasible for industrial scale.
Adam et al, J.Med.Chem, 2002, 45, !806-1816 describes a process in which 6-perdeoxy-6-per-iodo gamma cyclodextrin was treated with methyl 3-mercapto propionate in presence of cesium carbonate to give methyl ester of Sugammadex which on hydrolysis with alkali gives Sugammadex sodium. This process leads to formation of significant quantity of thio hydroxyl Sugammadex (Compound (III)) which was found difficult to remove by any purification techniques.

The PCT publication WO 2012/025937 discloses a process for preparing the intermediate 6-perdeoxy-6-per-chloro gamma cyclodextrin, involves use of phosporous halides. Sugammadex sodium was prepared by using 6-perdeoxy-6-per-chloro gamma cyclodextrin, reaction of 6-perdeoxy-6-per-chloro gamma cyclodextrin with 3-mercapto propionic acid in the presence of alkali metal hydrides to give the Sugammadex sodium. Preparation of chloro gamma cyclodextrin intermediate using phosphoros pentachloride is associated with formation phosphorous impurities during the reaction, which are difficult to remove and also involves tedious workup procedure. Also, it was found difficult to handle alkali metal hydrides in industrial scale.
The PCT publications WO 2017/089966 and WO 2017/194001 disclose for preparing the intermediate 6-perdeoxy-6-per-chIoro gamma cyclodextrin, involves use of Oxalyl chloride and triphosgene. Sugammadex sodium was prepared by a reaction of 6-perdeoxy-6-per-chloro gamma cyclodextrin with 3-mercapto propionic acid in the presence of alkali metal hydrides to give the Sugammadex sodium.
Purification techniques in the above mentioned prior arts employ column chromatographic and/or membrane dialysis techniques which are costly and not convenient in large scale operations. Therefore, there exists a need for an improved

and industrially scalable process for the preparation of Sugammadex or its pharmaceutically acceptable salt.
OBJECT OF THE INVENTION
An object of the present invention is to provide an improved process for preparation of 6-perdeoxy-6-per-iodo gamma cyclodextrin which is the key intermediate in the preparation of Sugammadex or its pharmaceutically acceptable salts.
Another object of the present invention is to provide the purification process of 6-perdeoxy-6-per-iodo gamma cyclodextrin with good yield and high purity.
An objective of the present invention is to provide a process for preparation of highly pure Sugammadex or its pharmaceutically acceptable salts which is industrially scalable.
Another object of the present invention is to provide an improved process for purification of Sugammadex or its pharmaceutically acceptable salts with good yield and high purity.
SUMMARY OF THE INVENTION
One aspect of the present invention involves an improved process for the preparation of 6-per-deoxy-6-per-iodo- gamma cyclodextrin , comprising :
a) reacting y-cyclodextrin with a halogenating agent in the presence of triphenyl phosphine .
b) treating the reaction mass with metal hydroxide and
c) isolating 6-per-deoxy-6-per-iodo- gamma cyclodextrin.
Another aspect of the present invention involves a process for purification of 6-per-deoxy-6-per-iodo- gamma cyclodextrin comprising;
a) dissolving 6-per-deoxy-6-per-iodo- gamma cyclodextrin in a mixture of polar solvent and alcohol and

b) isolation of highly pure 6-per-deoxy-6-per-iodo- gamma cyclodextrin. Another aspect of the present invention involves an improved process for the preparation of Sugammadex or a pharmaceutical ly acceptable salt comprising
a) reacting the highly pure 6-per-deoxy-6-per-iodo- gamma cyclodextrin with 3-mercaptopropionic acid in the presence of metal hydroxide and.
b) isolation.
Another aspect of the present invention provides a process for purification of Sugammadex or its pharmaceutical ly acceptable salt comprising;
a) dissolving crude sugammadex or its pharmaceutical ly acceptable salt in water
b) adding the solution obtained in step (a) into alcoholic solvent
c) isolation of pure Sugammadex or its pharmaceutical ly acceptable salt.
Another object of the present invention provides a process for further purification
of Sugammadex or its pharmaceutical ly acceptable salt comprising;
a) dissolving pure sugammadex or its pharmaceutical ly acceptable salt in mixture of water and polar aprotic solvent
b) isolation of highly pure Sugammadex or its pharmaceutical^ acceptable salt.

Figure-I: PXRD of highly pure Sugammadex sodium.
DETAILED DESCRIPTION OF THE INVENTION
One embodiment of the present invention provides an improved process for preparation of 6-per-deoxy-6-per-iodo-gamma cyclodextrin comprising;
a) reacting y-cyclodextrin with a halogenating agent in the presence of triphenyl phosphine
b) treating the reaction mass with metal hydroxide and
c) isolating 6-per-deoxy-6-per-iodo- gamma cyclodextrin.

The halogenating agent used in step (a) is selected from chlorine, bromine and iodine; preferably iodine. The halogenations reaction is carried out in the presence of teriphenylphosphine or phosphorous halide; preferably triphenyl phosphine. The phosphorous halide is selected from phosphorous chloride, bromide or iodide.
The halogenations reaction is carried out in polar solvent such as formamide, N-methylformamide, N,N-dimethyl formamide, acetamide and the like; preferably N, N-dimethylformamide.
The ratio of halogenating agent is in the range of 15-40 moles; preferably 20-30 moles; more preferably 24 moles with respect to Gamma-cyclodextrin. The triphenylphosphine ratio is in the range of 15-40 moles; preferably 20-30 moles; more preferably 23 moles with respect to Gamma-cyclodextrin.
The halogenations reaction of step (a) is carried at in the temperature range between I0-I40°C; preferably 30-l20°C; more preferably 60-l20°C.
The reaction mass obtained in step (a) is treated with metal hydroxide. The metal hydroxide is selected from sodium hydroxide, potassium hydroxide, cesium hydroxide and the like; preferably sodium hydroxide. The pH of the reaction mass is adjusted using metal hydroxide to 8-13; preferably 9-12.
Isolation of crude 6-per-deoxy-6-per-iodo- gamma cyclodextrin is carried out by general isolation methods such as evaporation, precipitation and the like; preferably the reaction mass is added into water and the precipitate was filtered.
The present invention provides crude 6-per-deoxy-6-per-iodo-gamma-cyclodextrin having purity of 90-98% with mono -OH iodo compound controlled below 2%; preferably below 1%.
Another embodiment of the present invention involves a process for purification of 6-per-deoxy-6-per-iodo- gamma cyclodextrin comprising;
a) dissolution of crude 6-per-deoxy-6-per-iodo- gamma cyclodextrin in a mixture of polar solvent and alcohol and
b) isolation of highly pure 6-per-deoxy-6-per-iodo- gamma cyclodextrin.

The polar solvent in step (a) is selected from formamide, N-methylformamide, N,N-dimethyl formamide, acetamide and the like; preferably N, N-dimethylformamide. The alcohol solvent is selected from methanol, ethanol, propanol, isopropanol, n-butanol and the like; preferably methanol. The ratio of polar solvent and alcohol solvent is in the range of 1: 99 to 99: I; preferably 1: 1 to 1: 5.
The crude 6-per-deoxy-6-per-iodo- gamma-cyclodextrin is dissolved at the temperature range between 10-40°C; preferably 20-30°C.
Isolation of pure 6-per-deoxy-6-per-iodo- gamma-cyclodextrin is carried by precipitation, evaporation and the like; preferably precipitation by cooling the reaction mass.
The present invention provides 6-per-deoxy-6-per-iodo- gamma-cyclodextrin obtained having purity greater than 99% (by HPLC).
Another embodiment of the present invention involves an improved process for the preparation of Sugammadex or a pharmaceutically acceptable salt comprising
a) reacting the highly pure 6-per-deoxy-6-per-iodo- gamma cyclodextrin with 3-mercaptopropionic acid in the presence of metal hydroxide and .
b) isolation.
The pharmaceutically acceptable salt is selected from sodium, potassium, cesium and the like; preferably sodium salt.
The reaction of step (a) is carried out in mixture of polar solvent and alcoholic solvent. Polar solvent is selected from formamide, N-methylformamide, N,N-dimethyl formamide, acetamide and the like; preferably N, N-dimethylformamide. The alcohol solvent is selected from methanol, ethanol, propanol, isopropanol, n-butanol and the like; preferably methanol. The ratio of N,N-dimethyl formamide and alcohol is in the ratio of 1: 99 to 99: I; preferably 3: 2; more preferably 2: 1; most preferably 1.6: 1.
The mole ratio of 3-mercaptopropionic acid with respect to 6-per-deoxy-6-per-iodo- gamma cyclodextrin is in the range of 10-25 moles; preferably 13-17 moles.

The mole ratio of sodium hydroxide is in the range of 10-40 moles; preferably 15-30 moles.
The metal hydroxide is selected from sodium hydroxide, potassium hydroxide, cesium hydroxide and the like; preferably sodium hydroxide. The reaction is carried out in the temperature range between 10-90°C; preferably 40—55°C. Upon completion of the reaction, the reaction mass is cooled to 0-35°C; preferably 15-25°C.
Sugammadex or its pharmaceutical^ acceptable salt formed is isolated by evaporation, precipitation and the like; preferably isolation by precipitation.
The present invention process provides crude Sugammadex or is pharmaceutically acceptable salt having purity in the range of 92-98% (by HPLC).
Still another embodiment of the present invention provides a process for purification of Sugammadex or its pharmaceutically acceptable salt comprising;
a) dissolving crude sugammadex or its pharmaceutically acceptable salt in water
b) adding the solution obtained in step (a) into an alcoholic solvent
c) isolation of pure Sugammadex or a pharmaceutically acceptable salt.
The pharmaceutically acceptable salt is selected from sodium, potassium, cesium and the like; preferably sodium salt.
The crude Sugammadex or its pharmaceutically acceptable salt is dissolved in water in the temperature range between 10-50°C; preferably 20-30°C. The pH of the solution is adjusted to 6.5 to 7.5 preferably 6.0 to 7.0.
The solution obtained in step (a) is added into alcoholic solvent. The alcoholic solvent is selected from methanol, ethanol, propanol, isopropanol, n-butanol and the like; preferably methanol. The ratio of water and alcoholic solvent is in the range of 0.5: 1 to 1:8; preferably 1: 1 to 1:5.
The pure Sugammadex or its pharmaceutically acceptable salt is isolated by methods such as precipitation, evaporation and the like; preferably isolation by precipitation.

The above said purification process provides Sugammadex or its pharmaceutically acceptable salt having purity 98-99% (by HPLC)
Another object of the present invention provides a process for further purification of Sugammadex or its pharmaceutically acceptable salt comprising;
a) dissolving pure sugammadex or a pharmaceutically acceptable salt in mixture
of water and polar aprotic solvent and
b) isolation of highly pure Sugammadex or its pharmaceutically acceptable salt.
Pure Sugammadex or its pharmaceutically acceptable salt is dissolved in mixture
of water and the solvent selected from dimethylsulfoxide, N,N-dimethylformamide and the like. The ratio of water and the amide solvent is 1:99 to 99: I; preferably 1:1 to 1:5.
The Sugammadex or its pharmaceutically acceptable salt is isolated by methods such as precipitation, evaporation and the like; preferably isolation by precipitation.
„The above .said . purification process provides Sugammadex or its pharmaceutically acceptable salt having purity greater than 99% (by HPLC)
The present invention also provides a pharmaceutical composition comprising Sugammadex or its pharmaceutically acceptable salts which is obtained according to the present invention. The composition optionally comprises bulking agent, antioxidant, pH agjusting agent, tonicity adjusting agent, surfactant, solubilizer, chelating agent and buffer. The pharmaceutical compostion is. suitable for oral and parenteral administration. For parenteral administration the composition is in the form of lyophilized powder for injection, ready to use solution and concentrate solution for injection. The ready to use solution comprises aqueous solution, non¬aqueous solution or mixture thereof.
Some aspects and embodiments of the invention are illustrated with few examples below. The examples are not intended to limit the scope of the invention in any manner.

EXPERIMENTAL DETAILS
Examples 1:
Preparation of 6-per-deoxy-6-per-iodo-y-cyclodextrin
Triphenylphosphine (46g, 177.3 mmols) was dissolved in 160ml of dimethylformamide at 25-30°C and iodine (47g, 185 mmoles) was slowly added to the solution in 10-15 minutes at 2-8°C. To this mixture was added dry gamma Cyclodextrin (lOg, 7.7 mmoles) and the solution was heated to 80 to 85°C and kept stirring at this temperature for 24 hours. pH of the solution adjusted to 9-12 with dilute sodium hydroxide solution and stirred. Reaction mixture poured into water (500 ml) and stirred for 30 min., and precipitated material filtered washed with acetone and dried to obtain crude, 6-per-deoxy-6-per-iodo-gamma-cyclodextrin (15 g), as a yellow powder. Yield: 15 g,
Purity by HPLC: Main peak purity 96.4%. Monohydroxy iodo compound: 0.4%. Examples 2: Purification of crude 6-per-deoxy-6-per-iodo- gamma-cyclodextrin The solid obtained from example 1 was dissolved in dimethylformamide (10 ml) per gram of crude 6-per-deoxy-6-per-iodo- gamma-cyclodextrin at 25-30°C with stirring. Methanol (10 ml) was added and heated to 60-70°C. Cooled to room temperature and separated material filtered and dried to obtain pure 6-per-deoxy-6-per-iodo- gamma-cyclodextrin. Yield: 9.0 g
Purity by HPLC: Main peak purity 99.1%. Monohydroxy iodo compound: 0.2% Examples 3: Preparation of Sugammadex sodium
sodium hydroxide (5.5g, 138 mmols) was dissolved in methanol (44 ml) at 25-30°C under complete argon atmosphere. 3-mercapto propionic acid (7.3g, 69 mmols) was added slowly to the sodium hydroxide in methanol at 25-30°C and stirred. Example 2 (lOg, 4.6 mmols) in dimethylformamide (100 ml) was added to the above reaction mixture and stirred for 12 hours at 45-50°C. After completion of the reaction, the reaction mass was cooled to 25-30°C and methanol (100 ml) was added to precipitate the material which was filtered, and dried to obtain crude Sugammadex sodium,

Yield: I4g
Purity by HPLC: i) Main peak purity 97.5%, Monohydroxy Sugammadex sodium: 1.0%
Examples 4: Purification of Sugammadex sodium
The crude Sugammadex Sodium (14g) from example 3 dissolved in water (190 ml), pH adjusted to 7-8 using dil. Hydrochloric acid. The solution was added to ethanol (950 ml) under argon atmosphere. The solid was filtered and dried to obtain pure Sugammadex sodium. Yield: 12g
Purity by HPLC: Main peak purity 98.5%, Monohydroxy Sugammadex sodium: 0.5 %
Examples 5: Purification to obtain highly pure Sugammadex sodium The Sugammadex sodium (12.0g) obtained from example 4 dissolved in water (200 ml) and dimethylformamide (200 ml) at 25-30°C followed by diluted with . dimethylformamide. The solid was filtered and dried to get highly pure Sugammadex sodium.Yield: 9g
Purity by.HPLC: i) Main peak purity: 99.1%, Mono hydroxy sugammadex sodium: 0.2%, Impurity at RRT 0.80: 0.05%& at RRT 0.86: 0.07% (due to Sulphoxides), Impurity at RRT: 1.06: 0.16% , Impurity at RRT: 1.20 : Not detected (sulphone impurity) and Impurity at RRT: 1.30: 0.02% (monothiohydroxy Sugammadex sodium).

We claim:
1. A process for the preparation of 6-per-deoxy-6-per-iodo-gamma cyclodextrin ,
comprising :
a) reacting y-cyclodextrin with a halogenating agent in the presence of triphenyl phosphine .
b) treating the reaction mass with metal hydroxide and
c) isolating 6-per-deoxy-6-per-iodo- gamma cyclodextrin

2. The process according to claim 1, wherein the mole ratio of halogenating agent and triphenylphosphine is in the range of 15-40 moles each with respect to Gamma-cyclodextrin.
3. The process according to claim 2, wherein mole ratio of halogenating agent and triphenylphosphine is in the range of 20-30 moles each with respect to Gamma-cyclodextrin.
4. The process according to claim 1, wherein the metal hydroxide is selected from sodium hydroxide, potassium hydroxide and cesium hydroxide.
5. A process for the purification of 6-per-deoxy-6-per-iodo- gamma cyclodextrin
comprising;
a) dissolution of crude 6-per-deoxy-6-per-iodo- gamma cyclodextrin in a mixture of polar solvent and alcohol and
b) Isolation of highly pure 6-per-deoxy-6-per-iodo- gamma cyclodextrin.

6. The process according to claim 5, wherein the polar solvent is selected from formamide, N-methylformamide, N.N-dimethyl formamide and acetamide and the alcoholic solvent is selected from methanol, ethanol, propanol, isopropanol and n-butanol.
7. The process according to claim 5, wherein highly pure 6-per-deoxy-6-per-iodo-gamma cyclodextrin having purity greater than 99% (by HPLC)

8. A process for preparation of Sugammadex or its pharmaceutically acceptable salts
comprising
a) reacting the highly pure 6-per-deoxy-6-per-iodo- gamma cyclodextrin with 3-mercaptopropionic acid in the presence of metal hydroxide and
b) isolation.
9. A process for purification of Sugammadex or its pharmaceutically acceptable salt
comprising;
a) dissolving crude sugammadex or its pharmaceutically acceptable salt in water
b) adding the solution obtained in step (a) into an alcoholic solvent and
c) isolation of pure Sugammadex or a pharmaceutically acceptable salt.
10. A process for purification of Sugammadex or its pharmaceutically acceptable salt
comprising;
a) dissolving pure sugammadex or a pharmaceutically acceptable salt in mixture of water and polar aprotic solvent and
b) isolation of highly pure Sugammadex or its pharmaceutically acceptable salt.