FIELD OF THE INVENTION
The present invention provides an industrially viable, cost effective process, for manufacturing sugammadex and its sodium salt. More particularly, the present invention relates to the purification methods of sugammadex sodium and intermediates thereof.
BACKGROUND OF THE INVENTION
Sugammadex sodium is a modified y-cyclodextrin, with a lipophilic core and a hydrophilic periphery.
Sugammadex contains substituted y-cyclodextrin with eight recurring amylose units each
with five asymmetric carbon atoms, in total forty asymmetric carbon atoms for the whole
molecule. Suganimadex (designation a trade name "Bridion") is an agent for reversal _df„
neuromusciUar_bJj^ in general anaesthesia. This gamma
cyclodextrin has been modified from its natural state by placing eight carboxyl thio ether groups at the sixth carbon positions. These extensions extend the cavity size allowing greater encapsulation of the rocuronium molecule. These negatively charged extensions electrostatically bind to the positively charged ammonium group as well as contribute to the aqueous nature of the cyclodextrin.
Sugammadex as a substance is disclosed under US RE44733 which is a Reissue patent of US 6670340 Bl. US RE44733 discloses a process for preparation of Sugammadex (sodium salt) via intermediate 6-per-deoxy-6~per-iodo-y:cyclodextrin by using 3-Mercaptbpropionic acid, DMF & sodium- hydride.. This patent discloses a process tor preparation of sugammadex which involves iodination of dry y-cyclodextrin to obtain 6-per-deoxy-6-per-iodo-y-cyclodextrin as a yellow solid. The 6-per-deoxy-6-per-iodo-y-cyclodextrin was dissolved in dimethylformamide and added slowly to a mixture of 3-mercaptppropionic acid and sodium hydride in dry dimethylformamide. The process disclosed in US RE44733
suffers from the major drawback of low purity of sugammadex which is about 88.75 area
.'■ ■
% HPLC
PCT application 2012/025937 Al (hereinafter referred as WO'937) discloses the preparation of sugammadex by chlorination of y-cyclodextrin with phosphorous pentachloride in dimethylformamide. The chlorinated y-cyclodextrin was then dissolved in

dimethylformamide and added slowly to a mixture of 3-mercaptopropionic acid and sodium hydride in dimethylformamide followed by partial removal of dimethylformamide and dilution with ethanol to obtain a precipitate. The crude sugammadex was purified over silica gel and Sephadex G-25* column using water as eluent. The process disclosed in WO'937 suffers from major drawback of low purity of sugammadex which is about 94.35 area % HPLC.
Similarly,, another PCT application 2014/125501 Al (hereinafter referred as WO'501) discloses the preparation of sugammadex by chlorination of y-cyclodextrin with phosphorous pentachloride in dimethylformamide. The obtained mixture was hydrolyzed with aqueous sodium hydroxide solution to give 6-per-deoxy-6-per-chloro-7-cyclodextrin. The chlorinated y-cyclodextrin was added slowly to a mixture of 3-mercaptopropionic acid and sodium methoxide in methanol and dimethylformamide, then the crude sugammadex so obtained was purified by treating it with activated carbon in a mixture of water and methanol. The process disclosed in WO'501 suffers from the disadvantages of low purity of sugammadex which is 88.50 area % HPLC.
Based on aforesaid, there is an unmet requirement for the development of a process that yields sugammadex with high purity. The present invention is focussed to develop a process for preparing sugammadex wherein said process is simple, cost effective and commercially viable and results into the production of sugammadex with purity above 99.8% and preferably above 99.9%.
OBJECT OF THE INVENTION
The primary object of the present invention is to provide an improved process for the preparation of sugammadex. and its sodium salt, represented by Formula I

Another object'of the present invention is to provide an improved process for the purification of sugammadex and its pharmaceutically acceptable salts, wherein the salt preferably is sodium salt.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of sugammadex
and its sodium salt, comprising the steps of:
a) adding y-cyclodextrin compound of Formula II and a halogenating agent in dimethyl
formamide to give substantially pure crystalline halo-y-cyclodextrin compound of Formula
HI;

Formula II

Formula III

wherein X is halogen; and
b) converting crystalline halo-y-cyclodextrin compound of Formula III to sugammadex and
its sodium salt.
In other aspect, the present invention provides a process for the preparation of sugammadex sodium salt thereof, comprising the steps of:
a) adding y-cyclodextrin compound of Formula II and a halogenating agent in dimethyl formamide to give substantially pure crystalline halo-y-cyclodextrin compound of Formula
HI;
Formula II Formula III
wherein X is halogen;
b) reacting substantially pure crystalline halo-y-cyclodextrin compound of Formula III with 3-mercaptopropionic acid in presence of sodium hydride in dimethyl formamide to obtain sugammadex sodium salt of Formula I; and



NaO
NaQ o'
ONa
?
ONa
O S
NaO
O

OH
OH Kf S
•OH HO—< X0
OH H0° O 0
,OH HO.
OH
HO"
OH wn OH
O
O^ ONa
NaO
.OH H°\ A JO

^

Formula I
c) isolating and treating the sugammadex sodium salt of Formula I in water and dimethyl sulfoxide.
In another aspect, the present invention provides a method for the purification of sugammadex sodium salt of Formula I,

NaO
O ONa

NaO

Formula I
comprising of:
a) acidifying sugammadex sodium salt of Formula I to get sugammadex acid of Formula
IV;
DEL HI 1.2. - OS - 2" ©■ .19 1 ? : ®8'

Formula IV
b) optionally purifying the sugammadex acid of Formula IV;
c) adjusting pH of the sugammadex acid to 7.5 and above with sodium base;
d) adding Ci-Ce alcohol to get sugammadex sodium salt of Formula I;
e) dissolving the sugammadex sodium salt of Formula I in water; and
f) lyophilizing to get pure sugammadex sodium salt of Formula I.
In another aspect, the present invention provides a sugammadex sodium characterized by X-Ray Powder Diffraction (XRPD) peaks (29 values) at 5.57, 7.56, 10.41, 15.99±0.2°9.
In another aspect, the present invention provides Differential Scanning Colorimetry (DSC) of sugammadex sodium as represented in Fig. 4.
In another aspect, the present invention provides a crystalline chloro-y-cyclodextrin compound of Formula Ilia characterized by X-Ray Powder Diffraction (XRPD) peaks (20 values) at 5.76, 8.17, 11.49, 16.8O±O.2°0.
In another aspect, the present invention provides Differential Scanning Colorimetry (DSC) of crystalline chloro-y-cyclodextrin with characteristic peak at about 238.88°C with onset peak at about 231.29°C.

« 12

mr .«&-

In another aspect, the present invention provides a method for the preparation of substantially pure crystalline halo-y-cyclodextrin of Formula Ilia,

Formula III
comprising of:
a) adding y-cyclodextrin and halogenating agent in dimethyl formamide;
b) partially distilling dimethyl formamide and adding a mixture of water and acetone;
c) adjusting the pH to 7.5 and above by base to get a solid;
d) isolating the solid and adding dimethyl sulfoxide;
e) adding mixture of tert-butariol and water to get precipitates;
f) optionally repeating steps d) and e); and
g) isolating and drying to get crystalline halo-y-cyclodextrin of Formula III.
DETAILED DESCRIPTION OF THE INVENTION
Details of Drawings:
Fig. 1: X-Ray Powder Diffraction (XRPD) pattern of chloro-y-cyclodextrin of Formula Ilia,
Fig. 2: Differential scanning calorimetry (DSC) curve of chloro-y-cyclodextrin of Formula
Ilia,
Fig. 3: X-Ray Powder Diffraction (XRPD) pattern of sugammadex sodium of Formula I,
Fig. 4: Differential scanning calorimetry (DSC) curve of sugammadex sodium of Formula
I.
The present invention will now be explained in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit

',

f

/ ,
the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims.
The term "optional1' or "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 "substantially pure" as referred in the context of the present invention relates to substance that has purity preferably between about 95% and 100% by HPLC and total impurities between about 5%w/w to a non-detectable limit, more preferably between about 99% and 100% of purity by^HPLC and between about^%W\yand„nonrdetectablelimit-of the-tdtaMmpurities, and/most preferably, between about 99.9% and 100% of purity by HPLC and about l%w/w to a non-detectable limit of total impurities.

CD G)
co Q.
CD
CN
O CO

The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein^
Further characteristics and advantages of the process according to the invention will result from the description herein below of preferred exemplary embodiments, which are given as indicative and.non-limiting examples.
Accordingly, in one embodiment, the present invention provides a process for the
preparation of sugammadex and its sodium salt, comprising the steps of:
a) adding y-cyclodextrin compound of Formula II and a halogenating agent in dimethyl
formaniide to give substantially pure crystalline halo-y-cyclodextrin compound of Formula
III;

CO
©
CN
o
CO CO CN
3>
o
CN
CO

I; £»

I;.7;

CN

inw-f'"FT^Z.*Z^Ti if■ *■

^i^s^ss^^s^^s^s^^^^

Formula II

Formula III

wherein X is halogen; and
b) converting crystalline halo-y-cyclodextrin of Formula III to sugammadex and its sodium
salt.
In other embodiment, the halogenating agent used for halogenating compound of Formula II is selected from, but not limited to, a group comprising of oxalyl chloride, thionyl chloride, triphosgene, triphenyl phosphine, phosphorus pentachloride, phosphorus pentabromide, triphenyl bromide, N-bromo succinamide, N-iodosuccinimide, iodine, iodine chloride and the like.
In a preferred embodiment, y-cyclodextrin compound of Formula II may be added in a solution of halogenating agent in dimethyl formamide at a temperature in the range of 50-85°C and preferably at 65-75°C.
In further embodiment, the crystalline halo-y-cyclodextrin of Formula III as prepared by the process of the present invention may be converted to sugammadex and its sodium salt, by any conventional or prior known methods.
r
In another embodiment, the present t invention provides a process for the preparation of sugammadex sodium salt thereof, comprising steps of: a) adding y-cyclodextrin compound of Formula II and a halogenating agent in dimethyl formamide to give substantially pure crystalline halo-y-cyclodextrin compound of Formula
Hi;
17 - ©■$
10

Formula II

Formula III

wherein X is halogen;
b) reacting substantially pure crystalline halo-y-cyclodextrin compound of Formula III with 3 -mercap^jppion^ acidjn presence- of-sodium-hydride in dimethyl formamide to obtain sugammadex sodium salt of Formula I; and

NaO
CT ONa

NaO

Formula I
c) isolating and treating the sugammadex sodium salt in water and dimethyl sulfoxide.
In other embodiment, the halogenating agent used for halogenating compound of Formula II is selected from, but not limited to, a group comprising of oxalyl chloride, thionyl chloride, triphosgene, triphenyl phosphine, phosphorus pentachloride, phosphorus

S-'- - X7.

ii

pentabromide, triphenyl bromide, N-bromo succinamide, N-iodosuccinimide, iodine, iodine chloride and the like.
In a preferred embodiment, y-cyclodextrin compound of Formula II may be added in a solution of halogenating agent in dimethyl formamide at a temperature in the range of SO¬BS^ and preferably at65-75°C.
Moreover, in a preferred embodiment, the halo-y-cyclodextrin is chloro-y-cyclodextrin and is represented by Formula Ilia;

Cl
Formula Ilia
In another embodiment, the halo y-cyclodextrin compound of Formula III is reacted with 3-mercaptopropionic acid in the presence of alkali metal hydride such as sodium hydride in a suitable organic solvent selected from, but not limited to, the group comprising of dimethyl formamide (DMF), acetonitrile, dimethylsulfoxide (DMSO), ethyl acetate, n-pentyl acetate, butyl acetate, tert-butyl acetate, propionitrile, tetrahydrofuran, N-methyl-2-pyrrolidone and mixture thereof, and preferably the solvent used is dimethyl formamide.
In another embodiment, the present invention provides a method for the purification of sugammadex sodium salt of Formula I,
L.H I 1 2 - O 3, - 2 B1 9 17: p.??.-

NaO
O^ ONa

NaO

Formula I
comprising of:
a) acidifying sugammadex sodium salt of Formula I to get sugammadex acid of Formula
IV;

Formula IV
b) optionally purifying the sugammadex acid of Formula IV;
c) adjusting pH of the sugammadex acid to 7:5 and above with sddium base;
d) adding Ci-Ce alcohol to get sugammadex sodium salt of Formula I;,
e) dissolving the sugammadex sodium salt of Formula I in water; and
f) lyophilizing to get pure sugammadex sodium salt of Formula I.

2-:.@si,9v 1.7 :a«

13

In other embodiment, the acidification in step a) is performed by treating the sugammadex sodium with acid selected from IN HC1, dilute sulphuric acid and the like. The said acidification may also occur during the treatment with prep HPLC using 0.2% formic acid in water: acetonitrile.
In other embodiment, sugammadex acid of Formula IV may optionally be purified to (, achieve desired purity and quality by techniques known in the art such as column chromatography, prep HPLC (0.2% formic acid in water: acetonitrile), fractional distillation, acid base treatment, lyophilisation, slurrying or recrystallization. Preferably, the techniques used for further treatment of sugammadex acid is by using prep HPLC (0.2% formic acid in water: acetonitrile) or by acid base treatment. For acid base treatment, the sugammadex acid is first converted to salt which is then further acidified to give pure sugammadex acid, wherein said salt is selected from alkali and alkaline earth metal such as sodium, potassium, calcium, cesium, magnesium, and the like.
In another embodiment, the sodium base used to react with sugammadex acid in step c) is selected from sodium hydroxide, sodium hydride, sodium hexanoate, sodium Ci-Ce alkoxide, sodamide and preferably the sodium base used is sodium methoxide or sodium 1 hexanoate.
,. In further embodiment, the present invention provides a method for the preparation of sugammadex sodium salt of formula I,
•i ■ ■ . • (
;
14 ...L.H3E. 1?--©S--Mtgt' l-7> 0-8'...

NaO
CT "ONa

NaO

^

Formula I
comprising of:
a) reacting halo-y-cyclodextrin compound of Formula III with 3-mercaptopropionic acid in
the presence of sodium hydride in dimethyl formamide to obtain sugammadex sodium salt;

Formula III
wherein X is halogen;
b) isolating and treating the sugammadex sodium salt in water and dimethyl sulfoxide;
c) acidifying the sugammadex sodium salt of step b) to get sugammadex acid of Formula IV;
-2Q19 .I-*-"- °*5 ■


cr OH
Formula IV . ^ =- —
d) adjusting^pFTof the sugammadex acid to 7.5 arid above with sodium base;
e) adding C1-C6 alcohol to get sugammadex sodium salt of Formula I;
f) dissolving the sugammadex sodium salt of Formula I in water; and
g) lyophilizing to get pure sugammadex sodium salt of Formula I.
In a preferred embodiment, the acidification of sugammadex sodium salt to hydrolyse it to acid in step c) is performed by treating with prep HPLC by using 0.2% formic acid in water: acetonitrile.
In another embodiment, the sodium base used_toxQact_with-sugammadex acid "in step d) is
seleCted""from sodium hydroxide, sodium hydride, sodium hexanoate, sodium Ci-Ce alkoxide, sodamide and preferably the sodium base used is sodium methoxide or sodium hexanoate.
In one another embodiment, the reaction of sugammadex acid with sodium base is carried out in presence of solvent such as water, methanol, ethanol, isopropanol and mixture thereof, and preferably it is carried out. in water.
In another embodiment, the alcohol used in step e) above is selected from methanol, ethanol, isopropanol and mixture thereof, and preferably it is carried out in rriethanol. •

In further embodiment, the present invention provides a method for the preparation of sugammadex sodium salt of formula I,

NaO
O" ONa

NaO

Formula I
comprising of:
a) reacting chloro-y-cyclodextrin compound of Formula Ilia with 3-mercaptopropionic acid
in the presence of sodium hydride in dimethyl formamide to obtain sugammadex sodium
salt; .
0H-_/V
H6 ^
,ci
Formula Ilia
b) isolating and treating the sugammadex sodium salt in water and dimethyl sulfoxide;
c) acidifying the sugammadex sodium salt of step b) to get sugammadex acid of Formula
IV;

ze

IT

Formula IV
d) adjusting pH of the sugammadex acid to 7.5 and above with sodium base;
e) adding C1-C6 alcohol to get sugammadex sodium salt of Formula I;
f) dissolving the sugammadex sodium salt of Formula I in water; and
g) lyophilizing to get pure sugammadex sodium salt of Formula I.
In a preferred embodiment, the present invention provides a method of purification of
sugammadex sodium comprising of:
a) acidifying the sugammadex sodium of Formula I to get sugammadex acid of Formula IV;

Formula IV.

■ss

X 12

17 ■

b) purifying the sugammadex acid of Formula IV by chromatography followed by
lyophilisation;
c) reacting the sugammadex acid of Formula IV with sodium base in a suitable solvent
followed by addition of alcohol to get sugammadex sodium salt of Formula I;

CD
G)
CO
0)
E o

Formula I
d) dissolving the sugammadex sodium salt of Formula I in water; and
e) lyophilizing to get pure sugammadex sodium salt of Formula I.
In another preferred embodiment, the chromatography techniques used for purifying the
sugammadex acid of Formula IV is selected from column chromatography or prep HPLC
(0.2% formic acid in water: acetonitrile). -
In another preferred embodiment, the sodium base used to react with sugammadex acid of Formula IV in step c) is selected from sodium hydroxide, sodium hydride, sodium hexanoate, sodium C1-C6 alkoxide, sodamide and preferably the sodium base used is sodium methoxide or sodium hexanoate.
; • '.
In another embodiment, the sugammadex sodium as prepared by the process of the present
invention is characterized by X-Ray Powder Diffraction (XRPD) peaks (20 values) at 5.57,
7.56, 10.41, 15,99±O.2°0. '

3>

TO

*U*I.-.. !-2v:-0:2£r2:

In yet another embodiment, the sugammadex sodium as prepared by the process of the present invention is further characterized by X-Ray Powder Diffraction (XRPD) peaks (29 values) at 12.62, 17.18±O.2°0.
In yet another embodiment, the sugammadex sodium as prepared by the process of the present invention is further characterized by X-Ray Powder Diffraction (XRPD) as represented in Fig. 3.
In yet another embodiment, the sugammadex sodium as prepared by the process of the present invention is further characterized by Differential Scanning Colorimetry (DSC) as represented in Fig. 4.
In another embodiment, the present invention provides substantially pure sugammadex
sodium free of impurities of Formula V, VI, and VII; wherein each impurity is less than
about 0.3%w/w o

ONa
NaO
Formula V
L.H.1 12--E

NaO
ONa
NaO
o
°\ V-OH - ,w \ fS CI
yS^/^c QH H0 OH yv

O^ ONa

NaO

Formula VI

, and

NaO
ONa
H6 OH Hcf lH y~s
H0-< \Q
O SH
NaO
O ONa NaO
Formula VII

o

ONa

In another embodiment, the present invention provides substantially pure sugammadex sodium free of impurities of Formula V, VI, and VII; wherein total impurities are less than about 1.0% w/w.
In another embodiment, the present invention provides pure sugammadex sodium with purity of 99.0% and above, and preferably 99.5% and above, and most preferably 99.9% and above.

I

21

In another embodiment, the present invention provides a method for the preparation of substantially pure crystalline halo-y-cyclodextrin of Formula III,

Formula III
comprising of:
a) adding y-cyclodextrin and a halogenating'agent in dimethyl formamide;
b) partially distilling dimethyl formamide and adding a mixture of water and acetone;
c) adjusting the pH to 7.5 and above by base to get a solid;
d) isolating the solid and adding dimethyl sulfoxide;
e) adding mixture of tert-butanol and water to get precipitates;
f) optionally repeating steps d) and e); and
g) isolating and drying to get halo-y-cyclodextrin of Formula III.
In another embodiment, the present invention provides a method for the preparation of substantially pure crystalline chloro-y-cyclodextrin of Formula Ilia,
-2019 "17 : 02i,

Formula Ilia
comprising of:
a) adding y-cyclodextrin and a chlorinating agent in dimethyl formamide;
b) partially distilling dimethyl formamide and adding a mixture of water and acetone;
c) adjusting the pH to 7.5 and above by base to get a solid;
d) isolating the solid and adding dimethyl sulfoxide;
e) adding mixture of tert-butanol and water to get precipitates;
f) optionally repeating steps d) and e); and
g) isolating and drying to get chloro-y-cyclodextrin of Formula Ilia.
In a preferred embodiment, y-cyclodextrin compound of Formula II is added to a chloronating agent in dimethyl foijmamide at a temperature in the range of 50-85°C and preferably at 65-75°C.
In other embodiment, the chlorinating agent used for preparing compound of Formula Ilia is selected from, but not limited to, a group comprising of oxalyl chloride, thionyl chloride, triphosgene, triphenyl phosphirie, phosphorus pentachloride, and the like.
Iri another aspect, the present invention provides crystalline chloro-y-cyclodextrin of Formula Ilia characterized by X-Ray Powder Diffraction (XRPD) peaks (20 values) at 5.76, 8.17,11.49, 16.8O±O.2°0,

/ Formula Ilia
In yet another embodiment, the crystalline chloro-y-cyclodextrin as prepared by the process of the present invention is further characterized by X-Ray Powder Diffraction (XRPD) peaks (20 values)at +4:68; 22:O3±O.2°0.
In yet another embodiment, the crystalline chloro-y-cyclodextrin as prepared by the process of the present invention is further characterized by X-Ray Powder Diffraction (XRPD) as represented in Fig. 1.
In another embodiment, the present invention provides Differential Scanning Colorimetry (DSC) of crystalline chloro-y-cyclodextrin with characteristic peak at about 238.88°C with onset peak at about 231.29°C.
In yet another embodiment, the crystalline chloro-y-cyclodextrin as prepared by the process of the present invention is further characterized by Differential Scanning Colorimetry (DSC) as represented in Fig. 2.
In yet another embodiment, the present invention provides crystalline chloro-y-cyclodextrin
having purity of 99.0% and above, and preferably 99.5% and above and most preferably
99.9% and above. ,
In one another embodiment, the present invention provides use of sugammadex and sodium salt thereof, for the reversal of neuromuscular blockade induced by the steroidal

neuromuscular blocking agents (NMBA) such as rocuronium, vecuronium and pipecuronium, wherein said sugammadex or its sodium salt is prepared as per the process of the present invention.
In another embodiment, the present invention further provides isolation of pure sugammadex and its sodium salt, wherein said sugammadex and its sodium salt is amorphous in nature.
In preferred embodiment, the present invention provides amorphous form of sugammadex sodium free of crystalline form.
In further embodiment, the present invention further relates to a composition comprising substantially pure sugammadex sodium of Formula-I along with at least one pharmaceutically acceptable excipients, wherein said sugammadex sodium is prepared as per the process of the present invention.
In another embodiment, the present invention provides the sugammadex and its sodium salt that is characterized by particle size distribution wherein, dw is 0.1 ^m to 200|im.
In another embodiment, the present invention provides the sugammadex and its sodium salt that is characterized by particle size distribution wherein, dw is 2.0 |am to 150^m.
The present invention is explained below by way of examples. However, the examples are provided as one of the possible way to practice the invention and should not be considered as limitation of the scope of the invention.
EXAMPLES
EXAMPLE 1: Preparation of chloro gamma-cyclodextrin of Formula Ilia
Charged DMF (250ml) into RBF and cooled to 10-25°C followed by slow addition of thionyl chloride (25 eq.). Charged dried gammacyclodexin solution (50gm in 250 ml of DMF) and raised the temperature up to 65-75°C and stirred for 16-20 hrs. After reaction completion, distilled off the 2V of dimethyl formamide (DMF) and cooled the reaction mass followed by addition of 250 ml of water and 200ml of acetone. Added 20% of aq. sodium

carbonate solution and adjusted the pH to 8.0 - 9.0. Added water and stirred the reaction mass. Filtered the material at 25-30°C. Wet cake so obtained was washed with water and dried.
Purified the solid cake in DMF (3 V), acetone (3 V) and water (3V). Filtered and washed with DM water and acetone to get chloro gamma-cyclodextrin of formula III. Alternatively,.purified the solid cake by adding in 6V of dimethyl sulfoxide (DMSO) and stirred to dissolve the material. Filtered the unwanted residue and added tert-butanol (7V) and water (7V) and stirred the reaction mass. Filtered the material arid washed the solid so obtained with 100ml of water and tert-butanol mixture. Again charged wet material with in 3V of DMSO and stirred to dissolve the material followed by addition of tert-butanol: water mixture (3V:3V). Stirred the reaction mass and filtered and washed the solid cake so obtained with tert-butanol and water mixture. Dried the material to get 37.5g of chloro-y-cyclodextrin of Formula Ilia. .
EXAMPLE 2: Preparation of sugammadex sodium of Formula I
Charged DMF (30V) into RBF and cooled it to 5-10°C. Added sodium hydride (36 eq) lot wise at 20-30°C under nitrogen atmosphere. Added chloro gamma-cyclodextrin (50g in 5V DMF) to the reaction mass at 20-35°C. Slowly added 3-mercaptopropionic acid (18 eq) at 20-30°C. Raised the temperature to 6Q-70°C and maintained for 15-20 h under nitrogen. After completion of reaction charged methanol (8.0 V) and water (10 V) at 15-30pC. Filtered the solid material and washed with methanol. Dissolved the material so obtained in water (3 V) and added dimethyl sulfoxide (6Y) at 25-30°C and stirred for 30-45 min. Filtered the crude so obtained and dissolved it in water (3 V). Adjusted the pH 2 to 5 with IN HC1 solution. Filtered the solid material and washed with water (IV) to get sugammadex acid. Purified the sugammdex acid using prep HPLC (0.2% formic acid in water: acetonitrile) and then distilled the acetonitrile at 40-50°C under reduced pressure. The process is then followed by lyophilization to get pure sugammadex acid.
Charged purified sugammedex acid in DM water (3 V) and adjusted the pH to 8.0 by addition of sodium hydroxide solution or sodium methoxide or sodium hexanoate followed by addition of methanol (15 V). Filtered the solids so obtained and washed with methanol. Dissolved the solid in water and lyophilized to get pure sugammadex sodium.

EXAMPLE 3: Preparation of sugammadex sodium of Formula I
Charged DMF (30V) into RBF and cooled it to 5-10°C. Added sodium hydride (36 eq) lot wise at 20-30°C under nitrogen atmosphere. Added chloro gamma-cyclodextrin (50g in 5V DMF) to the reaction mass at 20-35°C. Slowly added 3-mercaptopropionic acid (18 eq) at 20-30°C. Raised the temperature to 60-70°C and maintained for 15-20 h under nitrogen. After completion of reaction charged water (10 V) at 15-30°C. Filtered the solid material and washed with 1 Vol of DMSO. Dissolved the material so obtained in water (6 V) and added dimethyl sulfoxide (6V) at 25-30°C and stirred for 30-45 min. Filtered the crude so obtained and dissolved it in water (3 V) followed by addition of 6V of methanol. Filtered the solid material and washed with methanol (IV) and then dried to get 58g of sugammadex sodium.
The crude material so obtained is acidified and purified by using prep HPLC (0.2% formic acid in 80 water: 20 acetonitrile) and then partial concentrated the fraction of prep HPLC material through nano filtration to get the liquid material, adjusted the pH to 9.5-10.0 with sodium methoxide solution. Crystallized the addition of methanol (50 V). Filtered the solids so obtained and dissolved the solid in water followed by lyophilization to get 18g of pure sugammadex sodium. Purity: NLT 99.0%
EXAMPLE 4: Preparation of amorphous form of Sugammadex sodium:
To 10,Og of sugammadex sodium was added 10V of water and stirred at ambient temperature for 5-6h follpwed by lyophilization to get 9.0 g of pure amorphous sugammadex sodium.

We Claim:
1. A process for the preparation of sugammadex and its sodium salt, comprising the steps
of:
a) adding y-cyclodextrin compound of Formula II and a halogenating agent in dimethyl
formamide to give substantially pure crystalline halo-y-cyclodextrin compound of Formula
HI;
Formula II Formula III
wherein X is halogen; and
b) converting crystalline halo-y-cyclodextrin compound of Formula III to sugammadex and
its sodium salt.
2. A process for the preparation of sugammadex sodium salt comprising the steps of:
a) adding y-cyclodextrin compound of Formula II and a halogenating agent in dimethyl
formamide to give substantially pure crystalline halo-y-cyclodextrin compound of Formula
III;

Formula II Formula HI
wherein X is halogen;
b) reacting substantially pure crystalline halo-y-cyclodextrin compound of Formula III with 3-mercaptopropionie-acid-in-presence ofsodium hydride in dimethyl formamide to obtain sugammadex sodium salt of Formula I; and
Formula I
c) isolating and treating the sugammadex sodium salt in water and dimethyl sulfoxide.
3. The process as claimed in claim 1, wherein said halogenating agent used in step a) is selected from the group comprising of oxalyl chloride, thionyl chloride, triphosgene, triphenyl phosphine, phosphorus pentachloride, phosphorus pentabromide, triphenyl bromide, N-bromo succinamide, N-iodosuccinimide, iodine, and iodine chloride.

4. The process as claimed in claim 1, wherein said process of preparing substantially pure
crystalline form of halo-y-cyclodextrin of Formula III in step a) comprises of:
a) adding y-cyclodextrin and a halogenating agent in dimethyl formamide;
b) partially distilling dimethyl formamide and adding a mixture of water and acetone;
c) adjusting the pH to 7.5 and above by base to get a solid;
d) isolating the solid and adding dimethyl sulfoxide;
e) adding mixture of tert-butanol and water to get precipitates;
f) optionally repeating steps d) and e); and
g) isolating and drying to get halo-y-cyclodextrin of Formula III.
5. The process as claimed in claim 4, wherein said crystalline halo-y-cyclodextrin is chloro-
y-cyclodextrin and is represented by Formula Ilia,
Formula Ilia
6. A substantially pure crystalline form of chloro-y-cyclodextrin characterized by at least one of:
a) X-Ray Powder Diffraction (XRPD) peaks (29 values) at 5.76, 8.17, 11.49, 16.8O±O.2°0; and is having substantially same representation as in Fig. 1; and
b) Differential Scanning Colorimetry (DSC) with characteristic peak at about 238.88°C with onset peak at about 231.29°C.

7. The process as claimed in claim 2, comprises of purifying sugammadex sodium salt of
Formula I as obtained in step c), wherein said process comprises of;
a) acidifying sugammadex sodium salt of Formula I to get sugammadex acid of Formula
IV;
b) optionally purifying the sugammadex acid of Formula IV;
/C) adjusting pH of the sugammadex acid to 7.5 and above with sodium base;
d) adding Ci-Ce alcohol to get sugammadex sodium salt of Formula I;
e) dissolving the sugammadex sodium salt of Formula I in water; and
f) lyophilizing to get pure sugammadex sodium salt of Formula I.

8. The process as claimed in claim 7, wherein said sodium base is selected from sodium metfroxide, sodium hexanoate, sodium ethoxide, and sodium hydroxide.
9. The process as claimed in claims 1, 2 and 7, wherein said sugammadex sodium of Formula I is characterized by atleast one of,

a) X-Ray Powder Diffraction (XRPD) peaks (29 values) at 5.57, 7.56, 10.41, 15.99±O.2°0, and is having substantially same representation as in Fig. 3; and
b) Differential Scanning Colorimetry (DSC) as represented in Fig. 4.

10. Substantially pure sugammadex sodium free of impurities of Formula V, VI, and VII; wherein each impurity is less than about 0.3%w/w,
Formula V .

Formula VI