Claims:WE CLAIM
1. An improved process for the preparation of ticagrelor, comprising the steps of:
a) cyclizing 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3] dioxol-4-yl)oxy)ethan-1-ol of Formula IV in presence of diazotizing reagent to give 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d] pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy) ethan-1-ol of Formula V, wherein said compound of Formula V is optionally not isolated;
;
b) condensing compound of Formula V with (1R,2S)-2-(3,4-difluorophenyl) cyclopropan-1-amine of Formula VI or salt thereof, in presence of suitable solvent to give 2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo [4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy) ethan-1-ol of Formula VII, wherein said compound of Formula VII is optionally not isolated;
; and
c) deprotecting compound of Formula VII in presence of suitable deprotecting agent in suitable solvent at suitable temperature to give ticagrelor of Formula I;
.
2. The process as claimed in claim 1, wherein said suitable solvent used in step c) is selected from dichloromethane, dichlorobenzene, chloroform, carbon tetrachloride, dichloroethane, water, methanol, ethanol, isopropanol, butanol, isobutanol, t-butanol and mixture thereof.

3. The process as claimed in claim 1, wherein said process is performed in situ without isolation of intermediates.

4. The process as claimed in claim 1, wherein said suitable temperature is in the range from 0oC to 25oC.

5. The process as claimed in claim 1, wherein said deprotection is step c) is carried out at a temperature in the range of 10oC -20oC.

6. A process for preparation of crystalline Form II of ticagrelor of Formula I, comprising the steps of:
a) providing a solution of ticagrelor in acetonitrile and isopropyl ether;
b) optionally distilling and adding ester solvent;
c) adding suitable solvent to either step a) or step b); and
d) isolating the crystalline Form II of ticagrelor of Formula I.

7. The process as claimed in claim 6, wherein said crystalline Form II of ticagrelor is having a purity of greater than about 99.0% as measured by HPLC.

8. The process as claimed in claim 6, wherein said suitable solvent is selected from cycloheptane, cyclohexane, n-heptane, hexane, isooctane, n-octane and mixture thereof,

9. The process as claimed in claim 1, wherein said ticagrelor is substantially free of compounds of Formulae VIII, IX, X, XI and XII, wherein each impurity is less than about 0.3% w/w;

10. A process for the preparation of amorphous solid dispersion of ticagrelor, wherein said process comprising the steps of:
a) providing a solution of ticagrelor in suitable solvent;
b) adding one or more pharmaceutically acceptable carrier; and
c) isolating the amorphous solid dispersion of ticagrelor.

Description:FIELD OF THE INVENTION

The present invention relates to an improved and cost effective process for preparation of Ticagrelor in good yield and purity. The invention further relates to process for preparation of Polymorphic Form-II of Ticagrelor.

Present invention further provides a process for the preparation of amorphous solid dispersion of ticagrelor with pharmaceutically acceptable carrier.

Moreover, present invention provides a process for the preparation of premix of ticagrelor with pharmaceutically acceptable carrier.

BACKGROUND OF THE INVENTION

Ticagrelor is a cyclopentyltriazolopyrimidine and P2Y12 ADP receptor antagonist that is used for the prevention of stroke, heart attack and events with acute coronary syndrome.

It is chemically known as (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5¬ (propylthio)-3H-[1,2,3]-triazolo[4,5-d] pyrimidin-3-yl]-5-(2¬ hydroxyethoxy)cyclopentane-1,2-diol and is represented by Formula I. Ticagrelor is a crystalline powder with an aqueous solubility of approximately 10 µg/mL at room temperature.

Ticagrelor and related compounds are disclosed in International patent publication nos. WO 00/34283 and WO 99/05143.

US patent number 7,067,663 B2 discloses process for the preparation of ticagrelor as represented in Scheme-1 below:

Scheme-1:

US’663 further discloses crystallization of Ticagrelor in ethyl acetate and isooctane or in isopropanol.

International patent publication nos. WO 01/92263 A1, WO 2010/030224 A1, WO2012/085665 A2, WO2012/138981 A2 and WO 2013/037942 A1 disclose processes for preparing ticagrelor.

US patent number US 9,233,966 B2 discloses process for preparing ticagrelor as mentioned in the scheme 2 below:

Scheme 2:

US’966 further discloses process for preparing solid dispersion of ticagrelor with PVP in presence of methanol.

IN 4252/DEL/2015, discloses process of deprotecting protected ticagrelor at a lower temperature of 0oC and stirred for 3h. The ticagrelor once prepared is then purified in ethyl acetate. The above process suffers from a serious drawback of maintaining a peculiar temperature of 0oC for hours which is a cumbersome task if required to be performed at large scale.

The processes for the preparation of ticagrelor, described in the above mentioned prior art suffer from disadvantages as the processes involve tedious and cumbersome procedures such as lengthy and multiple synthesis steps, reactions under pressure and high temperature, longer reaction times, tedious work up procedures and/or multiple crystallizations or isolation steps.

Therefore, there remains a need to prepare ticagrelor and its intermediates of high purity and in good yield with reduced number of steps. Hence, the present invention is focussed towards the process for the preparation pure ticagrelor in high yields.

Accordingly, the present invention provides improved process for the preparation of ticagrelor which are suitable for industrial use.

OBJECT OF THE INVENTION

The main object of the present invention is to develop improved process for the preparation of ticagrelor which are suitable for industrial use.

Another object of the present invention is to develop the process for the pure ticagrelor in high yield.

Another object of the present invention is to provide amorphous solid dispersion and premix of ticagrelor with pharmaceutically acceptable carrier.

SUMMARY OF THE INVENTION

In main aspect, the present invention provides an improved process for the preparation of ticagrelor, comprising the steps of:
a) cyclizing 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3] dioxol-4-yl)oxy)ethan-1-ol of Formula IV in presence of diazotizing reagent to give 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d] pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy) ethan-1-ol of Formula V, wherein said compound of Formula V is optionally not isolated;
;
b) condensing compound of Formula V with (1R,2S)-2-(3,4-difluorophenyl) cyclopropan-1-amine of Formula VI or salt thereof, in presence of suitable solvent to give 2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo [4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy) ethan-1-ol of Formula VII, wherein said compound of Formula VII is optionally not isolated;
; and
c) deprotecting compound of Formula VII in presence of suitable deprotecting agent in suitable solvent at a suitable temperature to give ticagrelor of Formula I;
.

In another aspect, the present invention provides a process for the preparation of crystalline Form II of ticagrelor of Formula I, comprising the steps of:
a) providing a solution of ticagrelor in acetonitrile and isopropyl ether;
b) optionally distilling and adding ester solvent;
c) adding suitable solvent to either step a) or step b); and
d) isolating the crystalline form II of ticagrelor of Formula I.

In another aspect, the present invention provides a process for the preparation of amorphous solid dispersion of ticagrelor, wherein said process comprising the steps of:
a) providing a solution of ticagrelor in suitable solvent;
b) adding one or more pharmaceutically acceptable carrier; and
c) isolating the amorphous solid dispersion of ticagrelor.

In another aspect, the present invention provides a process for the preparation of premix of ticagrelor by mixing ticagrelor and pharmaceutically acceptable carrier, optionally in presence of a suitable solvent, followed by isolating to give the premix of ticagrelor.

DETAILED DESCRIPTION OF THE INVENTION

Definitions:
When a molecule or other material is identified herein as “pure”, it generally means, unless specified otherwise, that the material is 99% pure or more, as determined by methods conventional in art such as high performance liquid chromatography (HPLC) or optical methods. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities, and unreacted starting materials. In the case of stereoisomers, “pure” also means 99% of one enantiomer or diastereomer, as appropriate. “Substantially” pure means, the same as “pure except that the lower limit is about 98% pure or more and likewise, “essentially” pure means the same as “pure” except that the lower limit is about 95% pure.

All percentages and ratios used herein are by weight of the total composition, unless the context indicates otherwise. All temperatures are in degrees Celsius unless specified otherwise. All ranges recited herein include the endpoints, including those that recite a range “between” two values. As used herein, a “room” or “ambient” temperature includes temperatures from about 15°C to about 35°C, from about 20° C to about 30°C, or about 25°C.

In general, the term “solid dispersion” refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components. The term “amorphous solid dispersion” as used herein, refers to stable solid dispersions comprising amorphous drug substance and a carrier matrix. By “amorphous drug substance,” it is meant that the amorphous solid dispersion contains drug substance in a substantially amorphous solid state form i.e. at least 80% of the drug substance in the dispersion is in an amorphous form. More preferably at least 90% and most preferably at least 95% of the drug substance in the dispersion is in amorphous form.

While the invention is susceptible to various modifications and 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 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 an improved process for the preparation of ticagrelor, comprising the steps of:
a) cyclizing 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3] dioxol-4-yl)oxy)ethan-1-ol of Formula IV in presence of diazotizing reagent to give 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d] pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy) ethan-1-ol of Formula V, wherein said compound of Formula V is optionally not isolated;
;
b) condensing compound of Formula V with (1R,2S)-2-(3,4-difluorophenyl) cyclopropan-1-amine of Formula VI or salt thereof, in presence of suitable solvent to give 2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo [4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy) ethan-1-ol of Formula VII, wherein said compound of Formula VII is optionally not isolated;
; and
c) deprotecting compound of Formula VII in presence of suitable deprotecting agent in suitable solvent at a suitable temperature to give ticagrelor of Formula I;
.

In another embodiment, the diazotizing reagent used for preparing compound of Formula V is selected from the group comprising of sodium nitrite, potassium nitrite, lithium nitrite, butyl nitrite and isoamyl nitrite. The suitable acid used for diazotization is acetic acid, propionic acid, hydrochloric acid, hydrobromide, pivalic acid and sulphuric acid.

In another embodiment, the present invention provides process of preparing ticagrelor by condensing compound of Formula V with (1R,2S)-2-(3,4-difluorophenyl) cyclopropan-1-amine of Formula VI or salt thereof, wherein said salts are selected from, but not limited to, hydrochloride salt, hydrobromide salt, S-(+)mandelate salt, R-(-) mandelate salt, L-(+)tartarate salt, D-(-)tartarate salt, (-)-dibenzoyl-L-tartarate salt, (+)-dibenzoyl-D-tartarate salt, (-)-di-para-toluoyl-D-tartarate salt, (+)-di-para-toluoyl-D-tartarate salt, (1R)-(-)-10-camphorsulfonate salt, and (1S)-(+)-10-camphorsulfonate salt.

In another embodiment, the present invention provides a process for the preparation of ticagrelor, comprising the steps of:
a) cyclizing 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3] dioxol-4-yl)oxy)ethan-1-ol of Formula IV in presence of diazotizing reagent to give 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d] pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy) ethan-1-ol of Formula V, wherein said compound of Formula V is optionally not isolated;
;
b) condensing compound of Formula V with (1R,2S)-2-(3,4-difluorophenyl) cyclopropan-1-amine of Formula VI or salt thereof, in presence of suitable solvent to give 2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo [4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy) ethan-1-ol of Formula VII, wherein said compound of Formula VII is optionally not isolated, and wherein said suitable solvent is selected from dichloromethane, dichlorobenzene, chloroform, carbon tetrachloride and dichloroethane;
; and
c) deprotecting compound of Formula VII in presence of deprotecting agent selected from hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, acetic acid, trifluoroacetic acid, in a presence of suitable solvent selected from dichloromethane, dichlorobenzene, chloroform, carbon tetrachloride, dichloroethane, water, methanol, ethanol, isopropanol, butanol, isobutanol, t-butanol and mixture thereof, at a suitable temperature of 0oC to room temperature to give ticagrelor of Formula I;
.

In another embodiment, present invention provides the process of preparing ticagrelor wherein deprotection is performed in presence of suitable solvent comprising mixture of halogenated solvent and protic solvent and is selected from dichloromethane, dichlorobenzene, chloroform, carbon tetrachloride, dichloroethane, water, methanol, ethanol, isopropanol, butanol, isobutanol, t-butanol and mixture thereof.

In another embodiment, the deprotection of compound of Formula VII is performed at a temperature in the range from 0oC to room temperature, preferably, at 10-30oC, most preferably, at 10-20oC.

In a preferred embodiment, the process of preparation of ticagrelor is performed in situ without isolation of intermediates.

In an optional embodiment, the present invention provides a process for the preparation of ticagrelor wherein the intermediates may be isolated after workup and/ or purified before proceeding to next step.

In another embodiment, the present invention provides a process for the preparation of ticagrelor wherein said process comprises the steps of reacting 4,6-dichloro-2-(propylthio)pyrimidin-5-amine of Formula II with 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol tartarate salt of Formula III in presence of base to give 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3] dioxol-4-yl)oxy)ethan-1-ol of Formula IV, and converting compound of Formula IV to ticagrelor;
.

In another embodiment, the present invention provides a process for preparation of crystalline Form II of ticagrelor of Formula I, comprising the steps of:
a) providing a solution of ticagrelor in acetonitrile and isopropyl ether;
b) optionally distilling and adding ester solvent;
c) adding suitable solvent to either step a) or step b); and
d) isolating the crystalline Form II of ticagrelor of Formula I.

In a preferred embodiment, the suitable solvent used for re-precipitation/precipitation and washing of ticagrelor is selected from the group comprising of cycloheptane, cyclohexane, n-heptane, hexane, isooctane, n-octane and mixture thereof.

In another embodiment, the present invention provides crystalline Form II characterized by purity of 99.0% and above, preferably 99.5% and above as measured by HPLC.

The compounds at various stages of the process may be recovered using conventional techniques known in the art. For example, useful techniques include, but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, and the like. The isolation may be optionally carried out at atmospheric pressure or under a reduced pressure. Evaporation as used herein refers to distilling a solvent completely, or almost completely, at atmospheric pressure or under a reduced pressure. Flash evaporation as used herein refers to distilling of solvent using techniques including, but not limited to, tray drying, spray drying, fluidized bed drying, or thin-film drying, under atmospheric or a reduced pressure.

In other embodiment, the isolation of ticagrelor is performed by methods known in the art or any procedure disclosed in the present invention, wherein said method is selected from, but not limited to, filtration, distillation, solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD), filtration, lyophilization and the like. The resulting solid may be optionally further dried. Drying may be suitably carried out using equipment such as a tray dryer (VTD or ATD), vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 150°C, less than about 100°C, less than about 60°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, from about 1 hour to about 15 hours, or longer.

In another embodiment, the present invention provides pure ticagrelor substantially free of compounds of Formulae VIII, IX, X, XI and XII, wherein each impurity is less than about 0.3% w/w; preferably less than about 0.1% w/w;
, , , , and .

In another embodiment, the present invention provides a process for the preparation of amorphous solid dispersion of ticagrelor, wherein said process comprising the steps of:
a) providing a solution of ticagrelor in suitable solvent;
b) adding one or more pharmaceutically acceptable carrier; and
c) isolating the amorphous solid dispersion of ticagrelor.

In another embodiment, ticagrelor as used for preparing amorphous solid dispersion, can be either crystalline, amorphous or mixture in nature.

In preferred embodiment, the solid dispersion is a substance obtained by dispersing ticagrelor into a carrier in a mono-molecular state. In this dispersion, the ticagrelor remains in a completely amorphous state. Generally, the amorphous form is in a higher energetic state compared to the crystalline form and is therefore expected to have a higher absorptivity.

In another embodiment, the present invention provides a process for the preparation of premix of ticagrelor by mixing ticagrelor and pharmaceutically acceptable carrier, optionally in presence of a suitable solvent, followed by isolating to give the premix of ticagrelor.

In another embodiment, pharmaceutically acceptable carrier used for preparing solid dispersion or premix may include, but not limited to, an inorganic oxide such as SiO2, TiO2, ZnO2, ZnO, Al2O3 and zeolite; a water insoluble polymer is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene glycol, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolat, and cross-linked styrene divinyl benzene or any other excipient at any aspect of present application. In an embodiment, atleast one pharmaceutically acceptable excipient may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30 (plasdone K-29/32), povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxy methyl ethyl cellulose and the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other excipient at any aspect of present application. The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Solid dispersions of the present application also include the solid dispersions obtained by combining ticagrelor with a suitable non-polymeric excipient by employing techniques known in the art or procedures described or exemplified in any aspect of the instant application.

In further embodiment, the present invention provides ticagrelor prepared as per the process of the present invention is characterized by particle size distribution wherein, d90 is between 0.1µm to 200µm, preferably, d90 is between 2.0 µm to 150µm, most preferably, d90 is between 5.0µm and 50µm.

In further embodiment the present invention provides ticagrelor prepared as per the process of the present invention is characterized by particle size distribution wherein d10 is between 0.01µm and 5.0µm; d50 is between 1.0µm and 20.0µm; and d90 is between 5.0µm and 50µm.

Further, the present invention has the advantage of providing ticagrelor characterized by purity of 99.0% and above.

In another embodiment, the present invention is directed towards a pharmaceutical composition comprising a pharmaceutically effective amount of the ticagrelor in combination with pharmaceutically acceptable excipients, wherein said ticagrelor is prepared as per the process of the present invention.

In a preferred embodiment, the present invention provides a process for the preparation of amorphous solid dispersion of ticagrelor, wherein said process comprising the steps of:
a) providing a solution of ticagrelor in alcohol;
b) adding mixture of plasdone K-29/32;
c) adding aprotic solvent selected from methyl tert-butyl ether, isopropyl ether, n-heptane, cyclohexane, n-hexane, and mixture thereof; and
d) isolating the amorphous solid dispersion of ticagrelor.

Certain specific aspects and embodiments of the present application will be explained in details with reference of the following examples, which are provided only for purposes of illustration and should not able constructed as limited the scope of the application in any manner.

EXAMPLES
EXAMPLE 1: Preparation of 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d] [1,3] dioxol-4-yl)oxy)ethan-1-ol of Formula IV
To a solution of 2-((3aR,4S,6R,6aS)-6-amino 2,2 dimethyl tetrahydro-3aH cyclopenta[d] [1,3]dioxol-4-yloxy)ethanol L-tartaric acid in ethanol (500ml) was added 4,6-dichloro-2-propylthiopyrimidine-5-amine and triethylamine in a autoclave at 20-25ºC. Closed the autoclave and filled 2-6 Kg/cm2 nitrogen pressure and heated at 105-110ºC. Stirred the reaction mixture at 105-110ºC for 20-24 hours. After completion of reaction, cooled the reaction mixture to room temperature, and distilled the solvents under vacuum. Charged ethyl acetate and brine solution and stirred at room temperature. Separated the layers and distilled under reduced pressure. Crystallized the solid so obtained with Cyclohexane and dried at 45-50ºC to give desired compound.

EXAMPLE 2: Preparation of Ticagrelor
Charged acetic acid, DM water and compound of Formula IV from example 1, in the round bottom flask at 20-25º. Cooled the reaction mixture at 0-5ºC. Charged sodium nitrile and DM water and stirred for 1 hour. After completion of reaction, quenched the reaction mass in dichloromethane and 30% potassium carbonate solution in water. Stirred and separated the layers to get 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d] pyrimidin-3-yl)-2,2-dimethyl tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy) ethan-1-ol of Formula V in organic layer. Proceeded the organic layer i.e. dichloromethane layer as such in next step. Added (1R,2S)-2-(3,4-difluorophenyl) cyclopropan-1-amine of Formula VI hydrochloride salt to dichloromethane layer followed by slow addition of diisopropyl ethylamine. Stirred at 3-5 hours and added water to the reaction mixture so obtained. Separated the layers to get 2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo [4,5-d] pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy) ethan-1-ol in the organic layer. Partially distilled the organic layer and added methanol to the organic layer. Cooled the reaction mixture to 10oC and added conc. HCl diluted with methanol to the reaction mixture. Stirred for 20-24 hours. Adjusted the pH to 5-9 with the help of NaOH solution. Distilled out the methanol completely. Charged Ethyl acetate and 10% sodium chloride solution followed by stirring and separating the layers. Distilled out the organic layer completely to get crude ticagrelor.

EXAMPLE 3: Preparation of Ticagrelor
Charged acetic acid, DM water and compound of Formula IV from example 1, in the round bottom flask at 20-25º. Cooled the reaction mixture at 0-5ºC. Charged sodium nitrile and DM water and stirred for 1 hour. After completion of reaction, quenched the reaction mass in dichloromethane and 30% potassium carbonate solution in water. Stirred and separated the layers to get 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d] pyrimidin-3-yl)-2,2-dimethyl tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy) ethan-1-ol of Formula V in organic layer. Proceeded the organic layer i.e. dichloromethane layer as such in next step. Added (1R,2S)-2-(3,4-difluorophenyl) cyclopropan-1-amine of Formula VI hydrochloride salt to dichloromethane layer followed by slow addition of diisopropyl ethylamine. Stirred at 3-5 hours and added water to the reaction mixture so obtained. Separated the layers to get 2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3]triazolo [4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy) ethan-1-ol in the organic layer. Partially distilled the organic layer and added methanol to the organic layer. Cooled the reaction mixture to 15oC and added conc. HCl diluted with methanol to the reaction mixture. Stirred for 20-24 hours. Adjusted the pH to 5-9 with the help of NaOH solution. Distilled out the methanol completely. Charged Ethyl acetate and 10% sodium chloride solution followed by stirring and separating the layers. Distilled out the organic layer completely to get crude ticagrelor.

EXAMPLE 4: Preparation of Ticagrelor
Charged acetic acid, DM water and compound of Formula IV from example 1, in the round bottom flask at 20-25º. Cooled the reaction mixture at 0-5ºC. Charged sodium nitrile and DM water and stirred for 1 hour. After completion of reaction, quenched the reaction mass in dichloromethane and 30% potassium carbonate solution in water. Stirred and separated the layers to get 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d] pyrimidin-3-yl)-2,2-dimethyl tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy) ethan-1-ol of Formula V in organic layer. Proceeded the organic layer i.e. dichloromethane layer as such in next step. Added (1R,2S)-2-(3,4-difluorophenyl) cyclopropan-1-amine of Formula VI hydrochloride salt to dichloromethane layer followed by slow addition of diisopropyl ethylamine. Stirred at 3-5 hours and added water to the reaction mixture so obtained. Separated the layers to get 2-(((3aR,4S,6R,6aS)-6-(7-(((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[1,2,3] triazolo [4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3] dioxol-4-yl)oxy) ethan-1-ol in the organic layer. Distilled the organic layer and added methanol to the crude solid so obtained. Cooled the reaction mixture to 0-5oC and added conc. HCl diluted with methanol to the reaction mixture. Stirred for 20-24 hours. Adjusted the pH to 5-9 with the help of NaOH solution. Distilled out the methanol completely. Charged Ethyl acetate and 10% sodium chloride solution followed by stirring and separating the layers. Distilled out the organic layer completely to get crude ticagrelor.

EXAMPLE 5: Purification of Ticagrelor
Charged acetonitrile and Isopropyl ether to the crude ticagrelor. Heated at 55-60ºC and then cooled to 0-5ºC. Filtered and added ethyl acetate to the solid so obtained. Heated and charged aluminium oxide, stirred and filtered through hyflo, followed by addition of n-Heptane to the filtrate for precipitation. Filtered the precipitates and dried under vacuum at 45-50ºC to get pure ticagrelor with purity 99.9% by HPLC.

EXAMPLE 6: Purification of Ticagrelor
Charged acetonitrile and Isopropyl ether to the crude ticagrelor. Heated at 55-60ºC and then cooled to 0-5ºC. Filtered and added acetonitrile and Isopropyl ether (1:1) to the solid so obtained and added aluminium oxide, stirred and filtered through hyflo, followed by addition of n-Heptane to the filtrate for precipitation. Filtered the precipitates and dried under vacuum at 45-50ºC to get pure ticagrelor with purity 99.9% by HPLC.

EXAMPLE 7: Purification of Ticagrelor
Charged acetonitrile and Isopropyl ether to the crude ticagrelor. Heated at 55-60ºC and then cooled to 0-5ºC. Filtered and added acetonitrile and Isopropyl ether (1:1) to the solid so obtained and added aluminium oxide, stirred and filtered through hyflo, followed by addition of iso-octane to the filtrate for precipitation. Filtered the precipitates and dried under vacuum at 45-50ºC to get pure ticagrelor with purity 99.95% by HPLC.

EXAMPLE 8: Solid Dispersion of Ticagrelor
Added 100ml of methanol to ticagrelor (10.0g) followed by addition of plasdone K-29/32 (10g). Heated at 40-65oC followed by removal of methanol under vacuum. Charged methyl tert-butyl ether (80ml), followed by stirring at room temperature. Filtered the solids so obtained and dried under vacuum to get solid dispersion of ticagrelor with plasdone K-29/32.