Claims:We Claim:
1. A process for the preparation of sugammadex sodium compound of Formula I, comprising the steps of:

a) adding ?-cyclodextrin compound of Formula II and trialkyl/ aryl phosphine in dimethyl formamide in presence of iodine solution to give iodo-?-cyclodextrin compound of Formula III,
;
b) adding methanolic solution of sodium methoxide and distilling solvents either partially or completely to get a crude compound of formula III;
c) adding acetone to the reaction mixture to afford iodo-?-cyclodextrin of Formula III;
d) optionally purifying the iodo-?-cyclodextrin of Formula III by recrystallization; and
e) reacting iodo-?-cyclodextrin of Formula III with sodium base in a suitable solvent to give sugammadex sodium compound of Formula I.

2. The process as claimed in claim 1, wherein said trialkyl/aryl phosphine is selected from trimethyl phosphine, tributyl phosphine, and triphenyl phosphine.

3. The process as claimed in claim 1, wherein said process of reacting pure iodo- ?-cyclodextrin of Formula III with sodium base comprises the steps of:
a) adding iodo-?-cyclodextrin compound of Formula III and 3-mercaptopropionic acid in dimethyl formamide;
,
b) adding alcoholic solution of sodium base to get sodium salt of sugammadex; and
c) isolating and lyophilizing to get sugammadex sodium.

4. The process as claimed in claim 3, wherein said sodium base is selected from sodium hydroxide, sodium hydride, sodium hexanoate, sodium C1-C6 alkoxide, and sodamide.

5. A process for purifying sugammadex sodium, comprising the steps of:
a) dissolving crude sugammadex sodium in water under stirring to get a clear solution;
b) adding suitable organic solvent to the clear solution to get a solid;
c) isolating the solid and optionally repeating steps a) to b); and
d) isolating and drying to get pure sugammadex sodium compound of Formula I.

6. The process as claimed in claim 5, wherein said organic solvent is selected from water, C1-C6 alcohols, dimethyl formamide (DMF), acetonitrile, dimethylsulfoxide (DMSO), acetone, and mixture thereof.

7. A method of purification of sugammadex sodium of Formula I comprising of:

a) dissolving sugammadex sodium of Formula I in water; and
b) lyophilizing to get pure sugammadex sodium of Formula I.

8. The process as claimed in claims 1 and 7, wherein said sugammadex sodium is isolated with purity of 99.0% and above.

9. The process as claimed in claim 1, wherein said sugammadex sodium is substantially free of impurities of Formula V, VI, and VII, wherein each impurity is less than about 0.3%w/w,

10. The process as claimed in claims 1 and 7, wherein said sugammadex sodium is characterized by particle size distribution with d90 between 0.1µm to 200µm.

Description-
FIELD OF THE INVENTION

Present invention relates to an industrially viable, cost effective process for manufacturing sugammadex sodium.

Present invention further provides purification methods of sugammadex sodium and intermediates thereof.

BACKGROUND OF THE INVENTION
Sugammadex sodium is a modified ?-cyclodextrin, with a lipophilic core and a hydrophilic periphery.

Sugammadex contains substituted ?-cyclodextrin with eight recurring amylose units each with five asymmetric carbon atoms, in total forty asymmetric carbon atoms for the whole molecule. Sugammadex (designation a trade name “Bridion”) is an agent for reversal of neuromuscular blockade by an agent rocuronium 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 6,670,340 B1. US RE44733 discloses a process for preparation of Sugammadex (sodium salt) via intermediate 6-per-deoxy-6-per-iodo-?-cyclodextrin by using 3-Mercaptopropionic acid, DMF & sodium hydride. This patent discloses a process for preparation of sugammadex which involves iodination of dry ?-cyclodextrin to get 6-per-deoxy-6-per-iodo-?-cyclodextrin as a yellow solid. The 6-per-deoxy-6-per-iodo-?-cyclodextrin was dissolved in dimethylformamide and added slowly to a mixture of 3-mercaptopropionic 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.
WO 2012/025937 A1 (hereinafter referred as WO'937) discloses the preparation of sugammadex by chlorination of ?-cyclodextrin with phosphorous pentachloride in dimethylformamide. The chlorinated ?-cyclodextrin was then dissolved in dimethyl formamide 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 get 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 using tedious purification process such as column chromatography.

WO 2014/125501 Al (hereinafter referred as WO'501) discloses the preparation of sugammadex by chlorination of ?-cyclodextrin with phosphorous pentachloride in dimethylformamide. The geted mixture was hydrolyzed with aqueous sodium hydroxide solution to give 6-per-deoxy-6-per-chloro-7-cyclodextrin. The chlorinated ?-cyclodextrin was added slowly to a mixture of 3-mercaptopropionic acid and sodium methoxide in methanol and dimethylformamide, and then the crude sugammadex so geted 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.

WO 2017/084401 A1 (hereinafter referred as WO'401) discloses the preparation of sugammadex sodium by reacting ?-cyclodextrin with iodine in the presence of triphenylphosphine in dimethylformamide to afford an intermediate, 6-per-deoxy-6-iodo-?-cyclodextrin. Adding methanol solution of sodium methoxide into the reaction system followed by the addition of acetone without removal of the solvents under reduced pressure to get the crude product of 6-per-deoxy-6-iodo-?-cyclodextrin as a solid after filtration. Reacting thus geted 6-per-deoxy-6-iodo-?-cyclodextrin with 3-mercaptopropionic acid in the presence of sodium hydride, to get a crude product of 6-per-deoxy-6-per-(2-carboxyethyl)thio-?-cyclodextrin sodium salt (sugammadex sodium), further purifying the crude sugammadex sodium by passing through adsorbents followed by recrystallization. WO’401 suffers from the disadvantages wherein the process requires the use of adsorbent and huge amount of solvents.

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 sodium 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 sodium, represented by Formula I
.

Another object of the present invention is to provide a process for the purification of sugammadex sodium.

Another object of the present invention is to provide a process for the preparation of iodo-?-cyclodextrin compound of Formula III.
Another object of the present invention is to provide a process for the purification of iodo-?-cyclodextrin compound of Formula III.

SUMMARY OF THE INVENTION
In main aspect, the present invention provides a process for the preparation of sugammadex sodium compound of Formula I, comprising the steps of:

a) adding ?-cyclodextrin compound of Formula II and trialkyl/ aryl phosphine in dimethyl formamide in presence of iodine solution to give iodo-?-cyclodextrin compound of Formula III,
;
b) adding methanolic solution of sodium methoxide and distilling solvents either partially or completely to get a reaction mixture;
c) adding acetone to the reaction mixture to afford iodo-?-cyclodextrin of Formula III;
d) purifying the iodo-?-cyclodextrin of Formula III by recrystallization; and
e) reacting pure iodo-?-cyclodextrin of Formula III with sodium base in a suitable solvent to give sugammadex sodium compound of Formula I.

In another aspect, the present invention provides a process for the preparation of sugammadex sodium compound of Formula I, comprising the steps of:

a) adding iodo-?-cyclodextrin compound of Formula III and 3-mercaptopropionic acid in dimethyl formamide;
,
b) adding alcoholic solution of sodium base to get sodium salt of sugammadex; and
c) lyophilizing to get sugammadex sodium.

In another aspect, the present invention provides a process for the preparation of sugammadex sodium, comprising the steps of:
a) reacting ?-cyclodextrin compound of Formula II with triphenylphosphine and iodine in the presence of dimethyl formamide;
b) adding methanolic solution of sodium methoxide to get reaction mixture;
c) distilling the solvents either partially or completely from the reaction mixture under vacuum at 70-75oC followed by cooling the reaction mass up to 5-25oC to get a reaction mass;
d) adding acetone to the reaction mass and isolating crude 6-per-deoxy-6-iodo-?-cyclodextrin of Formula III by filtration;
e) purifying the crude 6-per-deoxy-6-iodo-?-cyclodextrin of Formula III in suitable solvent;
f) reacting the pure compound of Formula III with 3-mercaptopropionic acid and methanolic solution of sodium methoxide in dimethyl formamide to get crude sugammadex sodium compound of Formula I; and
g) lyophilizing to get pure sugammadex sodium of Formula I.

In another aspect, the present invention provides a process for the purification of sugammadex sodium, comprising the steps of:
a) dissolving crude sugammadex sodium in water under stirring to get a clear solution;
b) adding suitable organic solvent to the clear solution to get a solid;
c) isolating the solid and optionally repeating steps a) to b); and
d) isolating and drying to get pure sugammadex sodium compound of Formula I.

In another aspect, the present invention is to provide a process for the purification of sugammadex sodium, comprising the steps of:
a) dissolving crude sugammadex sodium in water under stirring to get a clear solution;
b) adding dimethyl sulfoxide or methanol to the clear solution to get a solid mass;
c) filtering the solid and optionally repeating steps a) to b); and
d) isolating and drying to get pure sugammadex sodium compound of Formula I.

In another aspect, the present invention provides a method of purification of sugammadex sodium of Formula I comprising of:

a) dissolving sugammadex sodium of Formula I in water; and
b) lyophilizing to get pure sugammadex sodium of Formula I.

In another aspect, 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. 1.

In another aspect, the sugammadex sodium as prepared by the process of the present invention is further characterized by Differential Scanning Colorimetry (DSC) as represented in Fig. 2.

DETAILED DESCRIPTION OF THE INVENTION
Drawings:
Fig. 1: X-Ray Powder Diffraction (XRPD) pattern of pure sugammadex sodium of Formula I,
Fig. 2: Differential scanning calorimetry (DSC) curve of pure 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 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 "optional" 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 “pure” as referred in the context of the present invention relates to substance that has purity preferably between about 99% and 100% by HPLC and total impurities between about 1%w/w to non-detectable limit, more preferably between about 99.1% and 99.99% of purity by HPLC.

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.

In one embodiment, the present invention provides a process for the preparation of sugammadex sodium compound of Formula I, comprising the steps of:

a) adding ?-cyclodextrin compound of Formula II and trialkyl/ aryl phosphine in dimethyl formamide in presence of iodine solution to give iodo-?-cyclodextrin compound of Formula III,
;
b) adding methanolic solution of sodium methoxide and distilling solvents either partially or completely to get a reaction mixture;
c) adding acetone to the reaction mixture to afford iodo-?-cyclodextrin of Formula III;
d) purifying the iodo-?-cyclodextrin of Formula III by recrystallization; and
e) reacting pure iodo-?-cyclodextrin of Formula III with sodium base in a suitable solvent to give sugammadex sodium compound of Formula I.

In an another embodiment, the ?-cyclodextrin of Formula II is first reacted with trialkyl/ aryl phosphine in dimethyl formamide solvent wherein said trialkyl/ aryl phosphine is selected from tertiary organic phosphines such as trimethyl phosphine, tributyl phosphine, and triphenyl phosphine.

In a preferred embodiment, the ?-cyclodextrin of Formula II and a solution of iodine in dimethyl formamide is heated at a temperature in the range of 50-85oC and preferably at 65-75oC.

In another embodiment, the present invention provides a process for the preparation of sugammadex sodium compound of Formula I, comprising the steps of:

a) adding iodo-?-cyclodextrin compound of Formula III and 3-mercaptopropionic acid in dimethyl formamide;
,
b) adding alcoholic solution of sodium base to get sodium salt of sugammadex; and
c) lyophilizing to get sugammadex sodium.

In another embodiment, the ?-cyclodextrin mercapto propionic ester (prepared by reacting ?-cyclodextrin of Formula III with mercapto propionic acid) is reacted with sodium base wherein said sodium base 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 present invention provides a process for the preparation of sugammadex sodium, comprising the steps of:
a) reacting ?-cyclodextrin compound of Formula II with triphenylphosphine and iodine in the presence of dimethyl formamide;
b) adding methanolic solution of sodium methoxide to get reaction mixture;
c) distilling the solvents either partially or completely from the reaction mixture under vacuum at 70-75oC followed by cooling the reaction mass up to 5-25oC to get a reaction mass;
d) adding acetone to the reaction mass and isolating crude 6-per-deoxy-6-iodo-?-cyclodextrin of Formula III by filtration;
e) purifying the crude 6-per-deoxy-6-iodo-?-cyclodextrin of Formula III in suitable solvent;
f) reacting the pure compound of Formula III with 3-mercaptopropionic acid and methanolic solution of sodium methoxide in dimethyl formamide to get crude sugammadex sodium compound of Formula I; and
g) lyophilizing to get pure sugammadex sodium of Formula I.

In another embodiment, the solvent comprising mixture of dimethyl formamide and methanol is distilled in step (c) to get a reaction mass, wherein said solvent is distilled partially up to 70% of the total volume of solvent.

In another embodiment, the solvent comprising mixture of dimethyl formamide and methanol is distilled in step (c) to get a reaction mass, wherein said solvent is distilled completely till dryness to get a crude solid mass.

In another embodiment, the present invention provides a process for the purification of sugammadex sodium, comprising the steps of:
a) dissolving crude sugammadex sodium in water under stirring to get a clear solution;
b) adding suitable organic solvent to the clear solution to get a solid;
c) isolating the solid and optionally repeating steps a) to b); and
d) isolating and drying to get pure sugammadex sodium compound of Formula I.

In another embodiment, suitable solvents used for the purification of 6-per-deoxy-6-iodo-?-cyclodextrin of Formula III and sugammadex sodium of Formula I, is selected from, but not limited to, the group comprising of water, C1-C6 alcohols, dimethyl formamide (DMF), acetonitrile, dimethylsulfoxide (DMSO), acetone, and mixture thereof, and preferably the solvent used is dimethyl formamide, water, actone, tert.-butanol & dimethyl sulfoxide.

In another embodiment, the present invention is to provide a process for the purification of sugammadex sodium, comprising the steps of:
a) dissolving crude sugammadex sodium in water under stirring to get a clear solution;
b) adding dimethyl sulfoxide or methanol to the clear solution to get a solid mass;
c) filtering the solid and optionally repeating steps a) to b); and
d) isolating and drying to get pure sugammadex sodium compound of Formula I.

In another embodiment, the present invention is to provide a process for the purification of sugammadex sodium, comprising the steps of:
a) dissolving crude sugammadex sodium in water under stirring to get a clear solution;
b) adding dimethyl sulfoxide or methanol to the clear solution to get a solid mass;
c) filtering the solid and added water to get a clear solution;
d) adding methanol to the clear solution of step c) to get a solid; and
d) isolating and drying to get pure sugammadex sodium compound of Formula I.

In a preferred embodiment, the present invention provides a method of purification of sugammadex sodium of Formula I comprising of:

a) dissolving the sugammadex sodium of Formula I in water; and
b) lyophilizing to get pure sugammadex sodium of Formula I.

In 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. 1.

In 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. 2.

In another embodiment, the present invention provides pure sugammadex sodium substantially free of impurities of Formula V, VI, and VII; wherein each impurity is less than about 0.3%w/w
, , and
.

In another embodiment, the present invention provides pure sugammadex sodium substantially 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.

In further embodiment, the present invention provides a composition comprising 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 sodium prepared as per the process of the present invention wherein said sugammadex sodium is characterized by particle size distribution wherein, d90 is 0.1µm to 200µm.

In another embodiment, the present invention provides the sugammadex sodium prepared as per the process of the present invention wherein said sugammadex sodium is characterized by particle size distribution wherein, d90 is 2.0 µm to 150µm.

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 Iodo gamma-cyclodextrin of Formula III:
Charged DMF (1000ml) in RBF and cooled the solution to 10-25oC under nitrogen atmosphere. Added 404.42 g of tripheny phosphine (TPP) to the reaction mixture and stirred to get cleared solution. To the reaction mixture was added iodine solution (410 g of Iodine in 500 ml of DMF) at 20-25°C followed by stirring for 2 hrs. Charged 100.0 g of dried Gammacyclodextrin to the reaction mass at 20-25°C and raised the temperature to 65-70°C and stirred for 20-24 hrs. After the completion of reaction, distilled off the dimethyl formamide at 70-75°C under vacuum, followed by cooling the reaction mass at 10-15°C. Charged sodium methoxide solution and stirred for 2.0 hrs and followed by addition of 7000 ml of acetone to the reaction mixture. Adjusted the pH of the reaction mass to 8-9 by using 20% sodium carbonate solution at 10-20°C and then, charged 6000 ml DM water to the resultant reaction mass and stirred for 6-8 hrs at 25-30°C. Filtered the reaction mass and washed with methanol to get crude compound of Formula III. Added 500 ml of methanol to the obtained crude of compound of Formula III and stirred for 30 mins. Filtered and washed the wet cake of the product with 100 ml of methanol. Added 500 ml of dimethyl formamide to the obtained wet cake and stirred at 50°C followed by addition of 1000 ml of acetone under stirring for 1.0 hr. Filtered the reaction mass and washed with 200 ml of acetone to get wet cake. Wet cake was further charged with 250 ml DMSO and 500 ml 50% tert-butanol solution in water to the reaction mixture and stirred for 1.0 hr at 20-30°C. Filtered and washed the product with 100 ml 50% tert. butanol solution in water, dried the material in hot air oven at 65-70°C for 10-15hrs to get pure titled compound. (Moisture NMT 2.5%); Yield: 100g (90-110g).

EXAMPLE 2: Preparation of Sugammadex Sodium of Formula I:
Charged 2000 ml of DMF in RBF and added 121.78 g of 3-Mercaptopropionic acid (3-MPA) under stirring condition at room temperature for 15-20 min to get clear solution followed by slow addition of 413.6 g of sodium methoxide (30%) at 0-10°C to the reaction mass. Stirred the reaction mass at 20-30°C for 30 min and then charged the solution of compound of Formula III (100.0 g compound of Formula III in 1000 ml of DMF) at 0-10°C. Stirred the reaction mass for 2-4 hr at 65-70°C. After completion of the reaction, cooled the reaction mass up to 20-30°C and slowly quenched the reaction mass in 1000 ml of DM water and stirred for 1-2 hr at 25-30°C. Filtered the reaction mass and washed the solid with mixture of 100 ml of dimethyl formamide and 200 ml of methanol to get the crude sugammadex sodium. Added 300 ml of DM water to the obtained crude sugammadex sodium and stirred at room temperature to get cleared solution followed by drop wise addition of 500 ml of DMSO at 25-30°C. Stirred the reaction mass for 1-2 hrs at 25-30°C. Filtered the reaction mass and washed the solid with 100 ml of dimethylsufloxide to get a wet cake. Added 200 ml of DM water and stirred at 25-30°C to get clear solution followed by slow addition of 2000 ml of methanol at 25-30°C. Stirred the reaction mass at 25-30°C for 1-2 hrs. Filtered the reaction mass and washed with 200 ml of methanol, dried under reduced pressure at 40-45°C to get pure sugammadex sodium.
HPLC Purity: 99.0%
EXAMPLE 3: Preparation of pure Sugammadex sodium:
To 10.0g of sugammadex sodium was added 10V of water and stirred at ambient temperature for 5-6h followed by lyophilization to get 9.0 g of pure sugammadex sodium.
HPLC Purity: 99.5%