DESC:Field of the Invention:
The present invention relates to an improved, cost-effective, scalable and commercially viable process for the preparation of Sugammadex sodium.

Background of the Invention:
Sugammadex (Trade name: Bridion) is an agent for reversal of neuromuscular blockade by the agent rocuronium in general anaesthesia. It is the first selective relaxant binding agent (SRBA).
Sugammadex is first disclosed in US6670340 assigned to Akzo Nobel. Sugammadex sodium represented by compound of formula-I was approved in United States and Europe.

(I)
US 6670340 discloses process for preparation of Sugammadex sodium. The process as disclosed in this patent involves reaction of ?-cyclodextrin with iodine in presence of triphenylphosphine (PPh3) and DMF to give 6-per-deoxy-6-per-iodo-y-cyclodextrin (iodo intermediate). Then it is reacted with 3-mercapto propionic acid in presence of sodium hydride base in DMF under heating to give Sugammadex crude product.

Use of triphenylphosphine in this process results in the formation of triphenylphosphine oxide as a by-product, removal of which is very difficult as it requires repeated washing with the solvent and thereby leads to inconsistency in the yield of final product Sugammadex sodium.
Sodium hydride is highly pyrophoric and hazardous and need be avoided in manufacturing process. Additionally, the combination of DMF solvent and sodium hydride is not favorable from safety perspective and should be avoided.
The prior art procedures for the preparation of Sugammadex sodium is disclosed in WO 2012/025937A1, WO 2014/125501 A1, WO 2016/194001 A1, CN 104844732 A2, CN 105348412 A2, IN 290882, IN 667/CHE/2013 and IN 201741012475. Due to the formation of impurities, the yield and purity of the product becomes very low. In order to meet the ICH purity levels the content of the impurities must be reduced to meet the regulatory requirements.

Hence there is a need to develop a process which can be performed at an industrial scale. The present invention overcomes the problems associated with the prior art and provides a process for the preparation of Sugammadex sodium with better yield and purity.

Summary of Invention:

In one aspect, the present invention provides an improved process for the preparation of Sugammadex sodium of formula-I

(I)
which comprises:
a) reacting gamma-cyclodextrin of formula-II

(II)
with phosphorous pentachloride in dimethylformamide to give 6-perdeoxy-6-per-chloro gamma cyclodextrin of formula-III;

(III)
b) reacting compound of formula-III with 3-mercapto propionic acid of formula-IV

(IV)
in dimethylformamide in the presence of 30 % sodium methoxide in methanol to give crude Sugammadex sodium of Formula I;

c) converting the crude Sugammadex sodium into Sugammadex free acid of Formula V

(V)
by adding acetic acid in the presence of water to obtain Sugammadex free acid;
d) purification of Sugammadex free acid obtained in step c) by preparative HPLC to obtain pure Sugammadex free acid in solution form;
e) concentrate the solution obtained in step-d) up to 30 % by using reverse osmosis to obtain Sugammadex free acid;
f) purification of Sugammadex free acid obtained in step-e) by using membrane filtration technology;
g) converting pure Sugammadex free acid obtained in step f) in to Sugammadex sodium by reacting Sugammadex free acid with sodium hydroxide in water;
h) lyophilization of Sugammadex sodium obtained in step g) to give pure Sugammadex sodium.

In another aspect, the present invention provides an alternative process for the preparation of Sugammadex sodium of formula-I

(I)
which comprises:
a) reacting gamma-cyclodextrin of formula-II

(II)
with phosphorous pentachloride in dimethylformamide to give 6-perdeoxy-6-per-chloro gamma cyclodextrin of Formula-III;

(III)
b) reacting compound of Formula-III with 3-mercapto propionic acid of Formula IV

(IV)
in dimethylformamide in the presence of 30% sodium methoxide in methanol to give crude Sugammadex Sodium of Formula-I;
c) converting the crude Sugammadex sodium into Sugammadex free acid of Formula-V

(V)
by adding acetic acid in the presence of water to obtain Sugammadex free acid;
d) purification of Sugammadex free acid obtained in step c) by preparative HPLC to obtain pure Sugammadex free acid in solution form;
e) concentrate the compound obtained in step-d) up to 30 % by using reverse osmosis technique to obtain pure Sugammadex free acid solution;
f) converting the obtained pure Sugammadex free acid obtained in step e) in to Sugammadex sodium by reacting Sugammadex free acid with sodium hydroxide in water;
g) purification of Sugammadex sodium obtained in step-f) by using membrane filtration technology including continuous and batch diafiltration;
h) lyophilization of Sugammadex sodium obtained in step g) to give highly pure Sugammadex sodium.

In another aspect, the present invention provides purification process for crude Sugammadex sodium of formula-I

(I)
which comprises:

a) converting the crude Sugammadex sodium into Sugammadex free acid of Formula V

(V)
by adding acetic acid in the presence of water to obtain Sugammadex free acid;
b) purification of Sugammadex free acid obtained in step c) by preparative HPLC to obtain pure Sugammadex free acid in solution form;
c) concentrate the solution obtained in step-d) up to 30 % by using reverse osmosis to obtain Sugammadex free acid;
d) diafiltration of Sugammadex free Acid obtained in step-c) with suitable applied pressure, separate permeate and retentate;
e) adding water to retentate obtained in step-d);
f) recirculation of retentate obtained in step-e) and separate permeate;
g) adding water accordingly to retentate obtained in step-f) and recirculation of retentate for suitable times to obtain pure Sugammadex free acid.
h) converting pure Sugammadex free acid obtained in step g) in to Sugammadex sodium by reacting Sugammadex free acid with sodium hydroxide in water;
i) lyophilization of Sugammadex sodium obtained in step h) to give pure Sugammadex sodium.

In another aspect, the present invention provides an improved process for the preparation of Sugammadex sodium of formula-I,

(I)
which comprises:

a) converting the crude Sugammadex sodium into Sugammadex free acid of Formula V

(V)
by adding acetic acid in the presence of water to obtain Sugammadex free acid;
b) purification of Sugammadex free acid obtained in step c) by preparative HPLC to obtain pure Sugammadex free acid in solution form;
c) concentrate the solution obtained in step-d) up to 30 % by using reverse osmosis to obtain Sugammadex free acid;
d) converting pure Sugammadex free acid obtained in step g) in to Sugammadex sodium by reacting Sugammadex free acid with sodium hydroxide in water;
e) diafiltration of Sugammadex free Acid obtained in step-d) with suitable applied pressure, separate permeate and retentate;
f) dilution of retentate obtained in step-e) with water;
g) recirculation of retentate obtained in step-f) and separate permeate;
h) adding water accordingly to retentate obtained in step-g) and recirculation of retentate for suitable times to obtain pure Sugammadex free acid.
i) lyophilization of Sugammadex sodium obtained in step h) to give pure Sugammadex sodium.

In another aspect, the present invention provides an improved purification process for Sugammadex free acid of formula-V

(V)
which comprises,
a) concentrate the Sugammadex free acid solution obtained from preparative HPLC up to 30 % by using reverse osmosis technique to obtain pure Sugammadex free acid solution;
b) diafiltration of Sugammadex free Acid obtained in step-a) with suitable applied pressure, separate permeate and retentate;
c) dilution of retentate obtained in step-b) using water;
d) recirculation of retentate obtained in step-c) and separate permeate;
e) adding water accordingly to retentate obtained in step-d) and recirculation of retentate for 8 times to obtain pure Sugammadex free acid.

In an embodiment, the filter membrane comprises a material selected from the group consisting of polyether sulfone, polyether amine and combinations thereof.

In another aspect, the present invention provides an improved purification process for Sugammadex sodium of formula-I

(I)
which comprises,
a) concentrate the Sugammadex free acid solution up to 30 % obtained from preparative HPLC using reverse osmosis technique to obtain pure Sugammadex free acid solution;
b) converting the obtained pure Sugammadex free acid obtained in step a) in to Sugammadex sodium by reacting with sodium hydroxide in water;
c) diafiltration of Sugammadex sodium obtained in step-b) with suitable applied pressure and separate permeate and retentate;
d) dilution of retentate obtained in step-c) using water;
e) recirculation of retentate obtained in step-d) and separate permeate;
f) adding water accordingly to retentate obtained in step-e) and recirculation of retentate for 8 times to obtain pure Sugammadex sodium.

In another aspect, the present invention provides an improved process for the preparation of Sugammadex free acid of formula-V

(V)
which comprises:
a) converting crude Sugammadex sodium into Sugammadex free acid of Formula V by adding acetic acid in the presence of water;
b) purification of Sugammadex free acid obtained in step a) by preparative HPLC to obtain pure Sugammadex free acid in solution form;
c) concentrate the solution up to 30 % obtained in step-b) by using reverse osmosis to obtain Sugammadex free acid

In another aspect, the present invention provides an improved process for Sugammadex sodium of formula-I

(I)
which comprises,
a) reacting diafiltered Sugammadex free acid with aqueous sodium hydroxide solution to give Sugammadex sodium;
b) lyophilization of Sugammadex sodium obtained in step-a) to give pure Sugammadex sodium.

Brief description of the drawings:
Figure-1 represents membrane filtration technology of Sugammadex sodium

Detailed Description of the Invention:
Diafiltration is a fast and effective technique for desalting or buffer exchange of solutions. It can be performed in a continuous or discontinuous mode. Continuous diafiltration usually takes less volume to achieve the same degree of salt reduction as discontinuous diafiltration with sequential dilution and can be easier to perform.

The word ‘Retentate’ defined as a compound of high molecular weight which is retained or separated by membrane. The word ‘permeate’ defined as a solutes of lower molecular weight which is pass through the membrane.

Discontinuous diafiltration by sequential dilution involves first diluting the sample with water or replacement buffer to a predetermined volume. The diluted sample is then concentrated back to its original volume by ultrafiltration. This process is repeated until the unwanted salts, solvents, or smaller molecules are removed. Each subsequent dilution removes more of the small molecules.

A typical continuous diafiltration system includes (a) pump (b) feed tank (c) heat exchanger (d) pressure control device (c) membrane filter module

In order to perform the diafiltration technology, the following conditions are considerable
a) Initial sample volume and concentration
b) Required final sample concentration
c) Stability of sample at various concentrations
d) Volume of buffer required for diafiltration
e) Total processing time
f) Size of feed tank

In yet another embodiment, the present invention provides a process for the purification of Sugammadex free acid by preparative HPLC using silica column of C18 bulk media with 10 or 16µm.

Conditions for chromatography:
The detailed chromatographic conditions were mentioned below:
Column : DAC Axial Compressor Column with 27 Cm length X 15 Cm internal ID with Kromosil Silica 16 Micron stationary phase
Wavelength (nm) : 210 nm
Buffer : 10 mM Ammonium formate (0.01% Acetic Acid) in water
Mobile phase-A : Buffer only
Mobile phase-B : Acetonitrile: Water (80:20 v/v)
Flow Rate : 600 mL/minute
Run time : 120 minutes
Mode : Gradient

Reagents:
i. Ammonium formate
ii. Acetonitrile
iii. Acetic Acid
iv. Milli-Q-Water.
Buffer: 10 mM Ammonium formate (0.01% Acetic Acid)
[For 50 L of water take 31.5 g of Ammonium formate & 5 ml of Acetic Acid]
Mobile Phase A: Buffer only
Mobile phase B: Acetonitrile: Water (80:20 v/v)
Mobile phase C: Washing solvent - Acetonitrile: Water (60:40 v/v)
Diluent: Water & Acetic acid
Sugammadex Free Acid Peak Retention Time: 40-45 minutes at 210 nm.
The above chromatographic conditions can be applied to 3 Kg by using silica of made of YMC Triart (or) Chromosil C18 bulk media with 10 (or) 16 uM.
Accordingly, the present invention provides an improved process for the preparation of highly pure Sugammadex free acid and its sodium salt.
Scheme-I illustrates an improved process for the preparation of Sugammadex sodium according to the present invention:

In step-a), reacting gamma-cyclodextrin of Formula II

(II)
with phosphorous pentachloride in dimethylformamide to give 6-perdeoxy-6-per-chloro gamma cyclodextrin of Formula III;

(III)
In step-b), reacting compound of Formula III with 3-mercapto propionic acid of Formula IV

(IV)
in dimethylformamide in the presence of 30% sodium methoxide in methanol to give crude Sugammadex Sodium of Formula I;
In step-c), converting the crude Sugammadex sodium into Sugammadex free acid of Formula V

(V)
by adding acetic acid in the presence of water to obtain Sugammadex free acid;
In step-d), purification of Sugammadex free acid obtained in step c) by preparative HPLC using silica column of C18 bulk media with 10 or 16 µm to obtain pure Sugammadex free acid in solution form;
In step-e), concentrate the solution obtained in step-d) up to 30 % by using reverse osmosis to obtain Sugammadex free acid solution;
In step-f), purification of Sugammadex free acid by using membrane filtration technology including continuous and batch diafiltration obtained in step-e) to obtain highly pure Sugammadex free acid;
In step-g), converting the obtained pure Sugammadex free acid obtained in step f) in to Sugammadex sodium by reacting Sugammadex free acid with sodium hydroxide in water;
In step-h), lyophilization of Sugammadex sodium obtained in step g) to give pure Sugammadex sodium.

Scheme-II illustrates an alternative process for preparation of Sugammadex sodium according to the present invention:

In step-a), reacting gamma-cyclodextrin of Formula II

(II)
with phosphorous pentachloride in dimethylformamide to give 6-perdeoxy-6-per-chloro gamma cyclodextrin of Formula III;

(III)
In step-b), reacting compound of Formula III with 3-mercapto propionic acid of Formula IV

(IV)
in dimethylformamide in the presence of 30% sodium methoxide in methanol to give crude Sugammadex Sodium of Formula I;
In step-c), converting the crude Sugammadex sodium into Sugammadex free acid of Formula V

(V)
by adding acetic acid in the presence of water to obtain Sugammadex free acid;
In step-d), purification of Sugammadex free acid obtained in step c) by preparative HPLC using silica column of C18 bulk media with 10 or 16µm to obtain pure Sugammadex free acid in solution form;
In step-e), concentrate the compound obtained in step-d) up to 30 % by using reverse osmosis technique to obtain pure Sugammadex free acid solution;
In step-f), converting the obtained pure Sugammadex free acid obtained in step e) in to Sugammadex sodium by reacting Sugammadex free acid with sodium hydroxide in water;
In step-g), purification of Sugammadex sodium obtained in step-f) by using membrane filtration technology including continuous and batch diafiltration to obtain highly pure Sugammadex sodium;
In step-h), lyophilization of Sugammadex sodium obtained in step g) to give highly pure Sugammadex sodium.

6-perdeoxy-6-per-chloro gamma cyclodextrin of Formula III may be also be prepared by any of processes reported in literature, for example, according to the methods disclosed in Indian patent application no. IN 2459/CHE/2010 or IN 667/CHE/2013 which is incorporated herein by reference.

In another embodiment, the present invention provides purification process for crude Sugammadex sodium of formula-I

(I)
which comprises:

a) converting the crude Sugammadex sodium into Sugammadex free acid of Formula-V

(V)
by adding acetic acid in the presence of water to obtain Sugammadex free acid;
b) purification of Sugammadex free acid obtained in step c) by preparative HPLC to obtain pure Sugammadex free acid in solution form;
c) concentrate the solution obtained in step-d) up to 30 % by using reverse osmosis to obtain Sugammadex free acid;
d) diafiltration of Sugammadex free Acid obtained in step-c) with suitable applied pressure, separate permeate and retentate;
e) dilution of retentate obtained in step-d) using water;
f) recirculation of retentate obtained in step-e) and separate permeate;
g) adding water accordingly to retentate obtained in step-f) and recirculation of retentate for suitable times to obtain pure Sugammadex free acid.
h) converting pure Sugammadex free acid obtained in step g) in to Sugammadex sodium by reacting Sugammadex free acid with sodium hydroxide in water;
i) lyophilization of Sugammadex sodium obtained in step h) to give pure Sugammadex sodium.

In another embodiment, the present invention provides an improved process for the preparation of Sugammadex sodium of formula-I,

(I)
which comprises:

a) converting the crude Sugammadex sodium into Sugammadex free acid of Formula V

(V)
by adding acetic acid in the presence of water to obtain Sugammadex free acid;
b) purification of Sugammadex free acid obtained in step c) by preparative HPLC to obtain pure Sugammadex free acid in solution form;
c) concentrate the solution obtained in step-d) up to 30 % by using reverse osmosis to obtain Sugammadex free acid;
d) converting pure Sugammadex free acid obtained in step g) in to Sugammadex sodium by reacting Sugammadex free acid with sodium hydroxide in water;
e) diafiltration of Sugammadex free Acid obtained in step-d) with suitable applied pressure, separate permeate and retentate;
f) dilution of retentate obtained in step-e) using water;
g) recirculation of retentate obtained in step-f) and separate permeate;
h) adding water accordingly to retentate obtained in step-g) and recirculation of retentate for suitable times to obtain pure Sugammadex free acid;
i) lyophilization of Sugammadex sodium obtained in step h) to give pure Sugammadex sodium.

In another embodiment, the present invention provides a process for purification of Sugammadex free acid of Formula V

(V)
which comprises:
a) concentrate the Sugammadex free acid solution up to 30 % obtained from preparative HPLC using silica column of C18 bulk media with 10 or 16µm using reverse osmosis technique to obtain pure Sugammadex free acid solution;
b) diafiltration of Sugammadex free Acid obtained in step-a) with suitable applied pressure, separate permeate and retentate;
c) dilution of retentate obtained in step-b) using water;
d) recirculation of retentate obtained in step-c) and separate permeate;
e) adding water accordingly to retentate obtained in step-d) and recirculation of retentate for 8 times to obtain pure Sugammadex free acid.

In step-b) the suitable applied pressure may be ranged from 0.2 kg/cm2 to 28.55 kg/cm2. Preferably 0.8 kg/cm2 to 1.2 kg/cm2

Pore size of membrane filter used in the diafiltration is ranged from 0.5 microns to 1000 Daltons.

In an embodiment, the filter membrane comprises a material selected from the group consisting of polyether sulfone, polyether amine and combinations thereof.

The solution retained by the membrane is known as the concentrate or retentate. The solution that passes through the membrane is known as the filtrate or permeate.

In another embodiment, the present invention provides an improved purification process for Sugammadex sodium of formula-I
which comprises,
a) concentrate the Sugammadex free acid solution up to 30 % obtained from preparative HPLC using silica column of C18 bulk media with 10 or 16 µm by using reverse osmosis technique to obtain pure Sugammadex free acid;
b) converting the obtained pure Sugammadex free acid obtained in step a) in to Sugammadex sodium by reacting Sugammadex free acid with sodium hydroxide in water;
c) diafiltration of Sugammadex sodium obtained in step-b) with suitable applied pressure and separate permeate and retentate;
d) dilution of retentate obtained in step-c) using water;
e) recirculation of retentate obtained in step-d) and separate permeate;
f) adding water accordingly to retentate obtained in step-e) and recirculation of retentate for 8 times to obtain pure Sugammadex sodium.

In step-c) the suitable applied pressure may be ranged from 0.2 kg/cm2 to 28.55 kg/cm2. Preferably 0.8 kg/cm2 to 1.2 kg/cm2
Pore size of membrane filter used in the diafiltration is ranged from 0.5 microns to 1000 Daltons.

In another embodiment, the present invention provides an improved process for the preparation of Sugammadex free acid of formula-V

(V)
which comprises:
a) converting crude Sugammadex sodium into Sugammadex free acid of Formula V by adding acetic acid in the presence of water;
b) purification of Sugammadex free acid obtained in step a) by preparative HPLC using silica column of C18 bulk media with 10 or 16 µm to obtain pure Sugammadex free acid in solution form;
c) concentrate the solution obtained in step-d) up to 30 % using reverse osmosis to obtain Sugammadex free acid

In another embodiment, the present invention provides an improved process for Sugammadex sodium of formula-I

(I)
which comprises,
c) reacting diafiltered Sugammadex free acid with aqueous sodium hydroxide solution to give Sugammadex sodium;
d) lyophilization of Sugammadex sodium obtained in step-a) to give pure Sugammadex sodium.

In yet another embodiment, the process of the present invention does not have any effect on the content of the sodium in Sugammadex sodium final API.

Sugammadex sodium may be also be prepared by any of processes reported in literature, for example, according to the methods disclosed in Indian patent application no. IN 2459/CHE/2010 or IN 667/CHE/2013 which is incorporated herein by reference.
Experimental portion
The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.
Example 1: Preparation of 6-perdeoxy-6-per-chloro Gamma Cyclodextrin
Phosphorous pentachloride (565 grams) was added slowly to dimethylformamide (DMF) (2200 mL) under nitrogen atmosphere at 25-40 °C. Stirred the reaction mixture at 25-40 °C for 1 hour. Gamma-cyclodextrin (220 grams) was added lot wise into above reaction mixture at 25-50°C. The temperature of the reaction mass was raised to 65-70 °C and stirred the reaction at this temperature for 28 hours. The reaction mixture was cooled to 0-10 °C and quenched with pre-cooled water (3520 mL). Adjusted the pH of the reaction mass to 10.0-12.0 with 30% sodium methoxide in methanol at 25-40 °C and maintained the reaction mass at this temperature for 2 hours. The reaction mass was filtered under vacuum and washed with water (440 mL) and suck dried for 30 minutes to yield titled compound as wet material (1700 grams).
Example 2: Purification of 6-perdeoxy-6-per-chloro Gamma Cyclodextrin
Purified water (6600 mL) was added to the wet compound (1700 gram) obtained in Example-1. Heated the reaction mass to 60-65 º C and maintained the reaction at this temperature for 2 hours. Filtered the reaction mass, washed with water (440 mL) and dried the compound to yield 211 grams of the title compound.

Example 3: Preparation of Sugammadex Sodium
Mixture of 3-mercapto propionic acid (220 grams) and DMF (400 mL) was added to 30% solution of sodium methoxide in methanol (746 grams) at 25-35° C and stirred the reaction mass for about 1.5 hours at the same temperature. The compound from example-1 (200 grams) in DMF (1500 mL) was added to the reaction mixture at 25-35 °C, heated the reaction mass to 75-80 °C and maintained at the same temperature for about 75-80 °C for 24 hours. After completion of the reaction, the reaction mass was cooled to 25-35 °C, methanol (2000 mL) was added to the reaction mass and stirred for 1 hour at the same temperature. The resultant solid was filtered, washed with methanol (800 mL) and dried at 55-60 °C for 12 hours to yield 460 grams of the title compound.
Example 4: Purification of Sugammadex Sodium
Step-(i):
Mixture of purified water (690 mL) and methanol (690 ml) was added to the crude compound (460 grams) obtained in Example-3 at 25-35 ºC and stirred the reaction mass at the same temperature until the formation of clear solution. Activated carbon (115 grams) and added to the above reaction mass at 25-35 ºC and stirred for 30 minutes. Filtered the reaction mass on hyflow bed, washed the cake with purified water (230 mL) and methanol (230 mL) and suck dried for 30 minutes. Methanol (5980 ml) was added to the above filtrate at 25-35 º C and stirred the reaction mass at the same temperature for 2 hours. Filtered the obtained solid, washed with methanol (1840 mL) and dried under hot air oven at 55-60 °C for 14 hours to obtain 240 grams of the title compound.
Step-(ii):
DMF (6 L) was added to the dry compound obtained in Example-4 at 25-35ºC and stirred for dissolution. Heated the reaction mass to 85-90 ºC, purified water (2400 mL) was added and stirred the reaction mass for 30 minutes at the same temperature. Slowly cooled the reaction mass to 25-35 ºC and stirred at the same temperature for 12 hours. Filtered the obtained solid, washed with methanol (960 mL) and dried under hot air oven at 55-60 °C for 8 hours to obtain 176 grams of the title compound.
Step-(iii):
To the compound (176 grams) obtained in Example-5 purified water (528 mL) was added and stirred the reaction mass for dissolution. pH of the reaction mass adjusted to 7.0-7.5 with hydrochloric acid (7 mL in purified water 45 mL) at 25-35 ºC and stirred the reaction mass for 15 minutes at the same temperature. Filtered the contents, washed with water (88 mL) and suck dried for 15 minutes. To the filtrate (820 mL) thus obtained was added methanol (6160 mL) at 25-35 ºC and stirred the reaction for 1 hour at the same temperature. Filtered the solid obtained, washed with methanol (704 mL), dried under hot air oven at 55-60 °C for 10 hours to obtain 154 grams of the title compound.
Step-(iv):
Methanol (1.5 L) was added to the crude compound (150 grams) obtained in Example-6 at 25-35 ºC and stirred the reaction mass at the same temperature for 10 minutes. Heated the reaction mass to 60-65 º C and purified water (450 mL) was added at the same temperature. Methanol (2250 mL) was added slowly to the reaction mass at 60-65 ºC and stirred the reaction mass for 1 hour ate the same temperature. Cooled the reaction mass to 25-35 º C and stirred at the same temperature for 2 hours. Filtered the solid obtained, washed with methanol (600 mL), dried under hot air oven at 55-60 °C for 10 hours to obtain 121 grams of the title compound.
Example 5: Preparation of Sugammadex Free acid
Sugammadex sodium obtained in Example-7 was dissolved in water (11.25 volumes) and 6.5 equivalents of acetic acid was added. Stirred the mixture and sonicated the sample for 5 minutes, injected the sample in silica column of C18 bulk media with 10 or 16µm and collected the Sugammadex free acid fraction in solution form. The collected Sugammadex free acid fraction was distilled below 60°C to obtain pure Sugammadex free acid.
Example 6: Preparation of Sugammadex sodium
Water (200 mL) was added to the Sugammadex acid obtained in Example-7 at 25-35 ºC and stirred for dissolution. pH of the reaction mass was adjusted to 9.0-9.5 with sodium hydroxide solution (NaOH flakes 14.7 grams in purified water 60 mL) at 25-35 ºC and stirred the reaction mass for 15 minutes. pH of the reaction mass was adjusted to 7.0 to 7.5 with hydrochloric acid solution (15 mL HCl dissolved in purified water 60 mL) at 25-35 ºC and stirred the reaction for 10 minutes. Activated carbon (5.0 grams) was added to the reaction mass at 25-35 ºC and stirred the reaction at the same temperature for 15 minutes. Filtered the carbon, washed the bed with purified water (50 mL). The filtrate thus obtained was subjected to lyophilization to get 84 grams of pure Sugammadex sodium.
Example 7: Preparation of Sugammadex sodium
Sugammadex free acid obtained from the above Example-8 was is dissolved in water and neutralized by using aqueous sodium hydroxide solution. Methanol (30 volume) was added to the resulting reaction mixture at 25-30 °C and stirred for 1 hour at the same temperature. The resulting reaction mixture was filtered and washed with methanol. The obtained wet compound was dissolved in a mixture of methanol (9.5 volume) and water (0.5 volume). The resulting reaction mixture was stirred for 1 hour at 25-30 °C. Filtered the precipitated solid and washed with methanol. The obtained compound was dissolved in water at 25-30 °C and lyophilized to get the title compound.
Example 8: Preparation of Sugammadex sodium
Sugammadex free acid obtained from the above Example-8 was dissolved in water and neutralized by using aqueous sodium hydroxide solution. Methanol (30 volumes) was added to the resulting reaction mixture at 25-30 °C and stirred for 1 hour at the same temperature. The resulting reaction mixture was filtered and washed with methanol. The obtained wet compound was dissolved in a mixture of DMF (25 volumes) and water (10 volumes). The resulting reaction mixture was stirred for 1 hour at 25-30 °C. Filtered the precipitated solid and washed with methanol. The obtained compound was dissolved in water at 25-30 °C and lyophilized to get the title compound.

Example 9: Purification of Sugammadex free acid using Dia filtration
Sugammadex free acid obtained from the above Example-8 was concentrated up to 30 % of its total volume by reverse osmosis. Water was added to the obtained solution and subjected to the feed tank by suitable applied pressure. The sample solution was pressurized through the membrane to the filtrate side. Both the permeate and retentate were separated and water was added to the obtained retentate. Re circulated the retentate with applied pressure through the membrane and water was added to corresponding retentate followed by recirculated up to 8 times to get the pure Sugammadex free acid.

Example 10: Preparation of Sugammadex sodium
Sugammadex free acid obtained from the above Example-12 was dissolved in water and neutralized by using aqueous sodium hydroxide solution. Methanol (30 volumes) was added to the resulting reaction mixture at 25-30 °C and stirred for 1 hour at the same temperature. The resulting reaction mixture was filtered and washed with methanol. The obtained wet compound was dissolved in a mixture of DMF (25 volumes) and water (10 volumes). The resulting reaction mixture was stirred for 1 hour at 25-30 °C. Filtered the precipitated solid and washed with methanol. The obtained compound was dissolved in water at 25-30 °C and lyophilized to get the title compound.
Example-11: Purification of Sugammadex sodium using Diafiltration
Sugammadex free acid obtained from the above Example-8 was concentrated up to 30 % of its total volume by reverse osmosis. The obtained free acid was converted to its sodium salt using aqueous sodium hydroxide solution. Water was added to the obtained solution and subjected to the feed tank by suitable applied pressure. The sample solution was pressurized through the membrane to the filtrate side. Both the permeate and retentate were separated and water was added to the obtained retentate. Re circulated the retentate with applied pressure through the membrane and water was added to the corresponding retentate followed by recirculated up to 8 times to get the pure Sugammadex sodium.
,CLAIMS:

1. An improved process for preparation of Sugammadex sodium of Formula I

(I)
which comprises:
a) reacting gamma-cyclodextrin of Formula II

(II)
with phosphorous pentachloride in dimethylformamide to give 6-perdeoxy-6-per-chloro gamma cyclodextrin of Formula III;

(III)
b) reacting compound of Formula III with 3-mercapto propionic acid of Formula IV

(IV)
in dimethylformamide in the presence of 30% sodium methoxide in methanol to give crude Sugammadex Sodium of Formula I;
c) converting the obtained crude Sugammadex sodium into Sugammadex free acid of Formula V

(V)
by adding acetic acid in the presence of water to obtain Sugammadex free acid;
d) purification of Sugammadex free acid obtained in step c) by preparative HPLC to obtain pure Sugammadex free acid in solution form;
e) concentrate the solution obtained in step d) up to 30 % by using reverse osmosis to obtain solid pure Sugammadex free acid;
f) converting the obtained pure Sugammadex free acid obtained in step e) in to Sugammadex sodium by reacting Sugammadex free acid with sodium hydroxide in water;
g) purification of Sugammadex sodium obtained in step-f) with diafiltration
h) lyophilization of Sugammadex sodium obtained in step g) to give pure Sugammadex sodium.

2. An improved process for preparation of Sugammadex sodium of Formula-I

(I)
which comprises:
a) reacting gamma-cyclodextrin of Formula-II

(II)
with phosphorous pentachloride in dimethylformamide to give 6-perdeoxy-6-per-chloro gamma cyclodextrin of Formula-III;

(III)
b) reacting compound of Formula-III with 3-mercapto propionic acid of Formula-IV

(IV)
in dimethylformamide in the presence of 30% sodium methoxide in methanol to give crude Sugammadex Sodium of Formula-I;
c) converting the obtained crude Sugammadex sodium into Sugammadex free acid of Formula-V

(V)
by adding acetic acid in the presence of water to obtain Sugammadex free acid;
d) purification of Sugammadex free acid obtained in step c) by preparative HPLC to obtain pure Sugammadex free acid in solution form;
e) concentrate the solution up to 30 % obtained in step d) by using reverse osmosis to obtain solid pure Sugammadex free acid;
f) purification of Sugammadex free acid obtained in step-e) using diafiltration;
g) converting the obtained pure Sugammadex free acid obtained in step f) in to Sugammadex sodium by reacting Sugammadex free acid with sodium hydroxide in water
h) lyophilization of Sugammadex sodium obtained in step g) to give pure Sugammadex sodium.

3. A purification process for crude Sugammadex sodium of formula-I

(I)
which comprises:
a) converting the obtained crude Sugammadex sodium into Sugammadex free acid of Formula-V

(V)
by adding acetic acid in the presence of water to obtain Sugammadex free acid;
b) purification of Sugammadex free acid obtained in step c) by preparative HPLC to obtain pure Sugammadex free acid in solution form;
c) concentrate the solution obtained in step-d) up to 30 % by using reverse osmosis to obtain Sugammadex free acid;
d) diafiltration of Sugammadex free Acid obtained in step-c) with suitable applied pressure, separate permeate and retentate;
e) dilution of retentate obtained in step-d) using water;
f) recirculation of retentate obtained in step-e) and separate permeate;
g) adding water accordingly to retentate obtained in step-f) and recirculation of retentate for suitable times to obtain pure Sugammadex free acid;
h) converting pure Sugammadex free acid obtained in step g) in to Sugammadex sodium by reacting Sugammadex free acid with sodium hydroxide in water;
i) lyophilization of Sugammadex sodium obtained in step h) to give pure Sugammadex sodium.

4. An improved process for the preparation of Sugammadex sodium of formula-I

(I)
which comprises:

a) converting the crude Sugammadex sodium into Sugammadex free acid of Formula-V

(V)
by adding acetic acid in the presence of water to obtain Sugammadex free acid;
b) purification of Sugammadex free acid obtained in step c) by preparative HPLC to obtain pure Sugammadex free acid in solution form;
c) concentrate the solution obtained in step-d) up to 30 % by using reverse osmosis to obtain Sugammadex free acid;
d) converting pure Sugammadex free acid obtained in step g) in to Sugammadex sodium by reacting Sugammadex free acid with sodium hydroxide in water;
e) diafiltration of Sugammadex free Acid obtained in step-d) with suitable applied pressure, separate permeate and retentate;
f) dilution of retentate obtained in step-e) using water;
g) recirculation of retentate obtained in step-f) and separate permeate;
h) adding water accordingly to retentate obtained in step-g) and recirculation of retentate for suitable times to obtain pure Sugammadex free acid.
i) lyophilization of Sugammadex sodium obtained in step h) to give pure Sugammadex sodium.

5. An improved process for the purification of Sugammadex sodium of formula-1

(I)
which comprises;
a) concentrate the Sugammadex free acid solution up to 30 % obtained by preparative HPLC using silica column of C18 bulk media with 10 or 16µm by using reverse osmosis to obtain solid pure Sugammadex free acid;
b) converting the obtained pure Sugammadex free acid obtained in step a) in to Sugammadex sodium by reacting Sugammadex free acid with sodium hydroxide in water;
c) diafiltration of Sugammadex sodium obtained in step-b) with suitable applied pressure and separate permeate and retentate;
d) dilution of retentate obtained in step-c) using water;
e) recirculation of retentate obtained in step-d) and separate permeate;
f) adding water accordingly to retentate obtained in step-e) and recirculation of retentate for 8 times to obtain pure Sugammadex sodium.

6. An improved process for the purification of Sugammadex free acid of Formula-V

(V)
which comprises;
a) concentrate the Sugammadex free acid solution up to 30 % obtained by preparative HPLC using reverse osmosis to obtain pure Sugammadex free acid;
b) purification of Sugammadex free acid obtained in step-a) by using diafiltration under suitable pressure;
c) separate permeate and water added to the obtained retentate;
d) re-circulate the obtained retentate in step-c), separate permeate and diluted the obtained retentate using water;
e) repetition of recirculation of the obtained retentate in step-d) and separate permeate;
f) converting the obtained pure Sugammadex free acid obtained in step e) in to Sugammadex sodium by reacting Sugammadex free acid with sodium hydroxide in water;
g) lyophilization of Sugammadex sodium obtained in step f) to give pure Sugammadex sodium.

7. An improved purification process for Sugammadex sodium of Formula-I

(I)
which comprises,
e) reacting diafiltered Sugammadex free acid with aqueous sodium hydroxide solution to give Sugammadex sodium;
f) lyophilization of Sugammadex sodium obtained in step-a) to give pure Sugammadex sodium.

8. An improved process for the preparation of Sugammadex free acid of formula-V

(V)
which comprises:
a) converting crude Sugammadex sodium into Sugammadex free acid of Formula V by adding acetic acid in the presence of water to obtain Sugammadex free acid;
b) purification of Sugammadex free acid obtained in step c) by preparative HPLC to obtain pure Sugammadex free acid in solution form;
c) concentrate the solution up to 30 % obtained in step-d) using reverse osmosis to obtain Sugammadex free acid.

9. The process according to claims 1-8, preparative HPLC using silica of made of YMC Triart or Chromosil C18 bulk media with 10 or 16 µm

10. The process according to claims 1-8, pressure is ranged from 0.05 to 28.55 kg/cm2