FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
"PROCESS FOR PREPARATION OF TICAGRELOR"
Glenmark Pharmaceuticals Limited;
Glenmark Generics Limited
an Indian Company, registered under the Indian company's Act 1957 and having its
registered office at
Glenmark House,
HDO- Corporate BIdg, Wing-A,
B. D. Sawant Marg, Chakala, Andheri (East), Mumbai- 400 099
The following specification particularly describes the invention and the manner in which it is to be performed.

BACKGROUND OF THE INVENTION
Technical Field
[0001] The present invention relates to a process for the preparation of amorphous
ticagrelor. The present invention relates to dimethyl formamide solvate of ticagrelor and
process for its preparation.
Description of the Related Art
[0002] Ticagrelor, also known as (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-
difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-
3-yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol, is represented by the structure of
formula I.

[0003] Ticagrelor is a P2Y12 platelet inhibitor indicated to reduce the rate of thrombotic
cardiovascular events in patients with acute coronary syndrome.
[0004] The object of the present invention is to provide a process for the preparation of
amorphous ticagrelor via solvates of ticagrelor.
SUMMARY OF THE INVENTION
[0005] The present invention provides a crystalline dimethyl formamide solvate of
ticagrelor characterized by an X-ray powder diffraction (XRPD) spectrum having peak
reflections at about 5.9,11.9,16.7,17.5 and 24.2 ±0.2 degrees 2 theta.
[0006] In another embodiment, the present invention provides a process for the
preparation of crystalline dimethyl formamide solvate of ticagrelor, the process
comprising:
(a) dissolving ticagrelor in dimethyl formamide, optionally in presence of additional
solvent, to form a solution;

(b) obtaining crystalline dimethyl formamide solvate of ticagrelor from the solution of step (a); and
(c) isolating the crystalline dimethyl formamide solvate of ticagrelor.
[0007] In another embodiment, the present invention provides a process for the preparation of ticagrelor in amorphous form, the process comprising:
(a) dissolving dimethyl formamide solvate of ticagrelor in a solvent to form a solution; and
(b) recovering ticagrelor in amorphous form from the solution of step (a).
[0008] In another embodiment, the present invention provides use Of dimethyl
formamide solvate of ticagrelor in the preparation of amorphous ticagrelor.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] Figure 1 is a characteristic XRPD of crystalline dimethyl formamide solvate of
ticagrelor as obtained in Example 1.
[0010] Figure 2 is a DSC thermogram of crystalline dimethyl formamide solvate of
ticagrelor as obtained in Example 1.
[0011] Figure 3 is an IR spectrum of crystalline dimethyl formamide solvate of ticagrelor
as obtained in Example 1.
[0012] Figure 4 is a TGA thermogram of crystalline dimethyl formamide solvate of
ticagrelor as obtained in Example 1.
[0013] Figure 5 is a characteristic XRPD of ticagrelor in amorphous form as obtained in
Example 9.
DETAILED DESCRIPTION OF THE INVENTION
[0014] The present invention provides a crystalline dimethyl formamide solvate of
ticagrelor.
[0015] In the present application, the term "room temperature" means a temperature of
about 25°C to about 30°C.
[0016] In one embodiment, the present invention provides a crystalline dimethyl
formamide solvate of ticagrelor characterized by an X-ray powder diffraction (XRPD)
spectrum having peak reflections at about 5.9, 11.9, 16.7, 17.5 and 24.2 ±0.2 degrees 2
theta.

[0017] In one embodiment, the present invention provides a crystalline dimethyl
formamide solvate of ticagrelor further characterized by an X-ray powder diffraction
(XRPD) spectrum having peak reflections at about 6.8, 14.2, 23.1 and 29.6 ±0.2 degrees
2 theta.
[0018] In one embodiment, the present invention provides a crystalline dimethyl
formamide solvate of ticagrelor characterized by an X-ray powder diffraction (XRPD)
spectrum having peak reflections at about 5.9, 6.8, 11.9, 14.2, 16.7, 17.5, 23.1, 24.2 and
29.6 ±0.2 degrees 2 theta.
[0019] In one embodiment, the present invention provides a crystalline dimethyl
formamide solvate of ticagrelor characterized by an X-ray powder diffraction (XRPD)
spectrum having peak reflections at about 5.9, 11.9, 16.7, 17.5 and 24.2 ±0.2 degrees 2
theta which is substantially in accordance with Figure 1.
[0020] In one embodiment, the present invention provides a crystalline dimethyl
formamide solvate of ticagrelor characterized by TGA thermogram, showing a weight
loss of about 9.00 weight% to 13.00 weight% determined over the temperature range of
0°C to 350°C and heating rate 10°C/min.
[0021] In one embodiment, the present invention provides a crystalline dimethyl
formamide solvate of ticagrelor characterized by TGA thermogram, showing a weight
loss of about 9.00 weight% to 13.00 weight% determined over the temperature range of
0°C to 350°C and heating rate 10°C/min which is in accordance with Figure 4.
[0022] In one embodiment, the present invention provides a crystalline dimethyl
formamide solvate of ticagrelor characterized by TGA thermogram, showing a weight
loss of about 9.4 weight% determined over the temperature range of 0°C to 100°C and
heating rate 10°C/min.
[0023] In one embodiment, the present invention provides a crystalline dimethyl
formamide solvate of ticagrelor characterized by gas chromatography analysis, showing
presence of about 9.50 weight% to 12.50 weight% of dimethyl formamide in residual
solvent analysis.
[0024] In one embodiment, the present invention provides a crystalline dimethyl
formamide solvate of ticagrelor characterized by high performance liquid

chromatography (HPLC) analysis, showing presence of about 9.50 weight% to 12.50
weight% of dimethyl formamide in residual solvent analysis.
[0025] In one embodiment, the present invention provides a crystalline dimethyl
formamide solvate of ticagrelor characterized by TGA thermogram showing a weight
loss of about 10.07 weight% determined over the temperature range of 0°C to 100°C and
heating rate 10°C/min; and by HPLC analysis, showing presence of 11.86 weight% of
dimethyl formamide-in residual solvent analysis.
[0026] In one embodiment, the present invention provides a crystalline dimethyl
formamide solvate of ticagrelor characterized by TGA thermogram showing a weight
loss of about 10.47 weight% determined over the temperature range of 0°C to 100°C and
heating rate 10°C/min; and by HPLC analysis, showing presence of 10.92 weight% of
dimethyl formamide in residual solvent analysis.
[0027] In one embodiment, the present invention provides a crystalline dimethyl
formamide solvate of ticagrelor characterized by an X-ray powder diffraction (XRPD)
spectrum having peak reflections at about 5.9, 11.9, 16.7, 17.5 and 24.2 ±0.2 degrees 2
theta and TGA thermogram showing a weight loss of about 9.00 weight% to 13.00
weight% determined over the temperature range of 0°C to 350°C and heating rate
10°C/min.
[0028] In one embodiment, the present invention provides a crystalline dimethyl
formamide solvate of ticagrelor characterized by an X-ray powder diffraction (XRPD)
spectrum having peak reflections at about 5.9, 11.9, 16.7, 17.5 and 24.2 ±0.2 degrees 2
theta which is substantially in accordance with Figure 1 and TGA thermogram showing a
weight loss of about 9.00 weight% to 13.00 weight% determined over the temperature
range of 0°C to 350°C and heating rate 10°C/min which is in accordance with Figure 4.
[0029] In one embodiment, the present invention provides a crystalline dimethyl
formamide solvate of ticagrelor characterized by DSC thermogram having an
endothermic peak at about 83 ±2°C.
[0030] In one embodiment, the present invention provides a crystalline dimethyl
formamide solvate of ticagrelor characterized by DSC thermogram showing four
endothermic peaks, the main endotherm was at about with onset 82°C and other three

onset were observed at 113°C, 138°C and 145-149°C which is in accordance with Figure
2.
[0031] In one embodiment, the present invention provides a crystalline dimethyl
formamide solvate of ticagrelor characterized by an X-ray powder diffraction (XRPD)
spectrum having peak reflections at about 5.9, 11.9, 16.7, 17.5 and 24.2 ±0.2 degrees 2
theta and DSC thermogram having an endothermic peak at about 83 ±2°C.
[0032] The present invention provides a crystalline dimethyl formamide solvate of
ticagrelor characterized by an X-ray powder diffraction (XRPD) pattern as depicted in
Figure 1, a DSC thermogram as depicted in Figure 2; an IR spectrum as depicted in
Figure 3; a TGA thermogram as depicted in Figure 4.
[0033] The present invention provides dimethyl formamide monosolvate of ticagrelor.
[0034] The present invention provides a process for the preparation of crystalline
dimethyl formamide solvate of ticagrelor, the process comprising:
(a) dissolving ticagrelor in dimethyl formamide, optionally in presence of additional solvent, to form a solution;
(b) obtaining crystalline dimethyl formamide solvate of ticagrelor from the solution of step (a); and
(c) isolating the crystalline dimethyl formamide solvate of ticagrelor.
[0035] In (a) of the process for the preparation of crystalline dimethyl formamide solvate of ticagrelor, ticagrelor is dissolved in dimethyl formamide, optionally in presence of additional solvent, to form a solution.
[0036] The additional solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof. Preferably the solvent selected is isopropyl acetate, toluene, methyl tert-butyl ether, n-heptane.

[0037] Suitable temperature for dissolution of ticagrelor may range from about 20°C to about 120°C. Preferably, dissolution of ticagrelor is at about 25°C to about 80°C. Stirring may be continued for any desired time period to achieve a complete dissolution of ticagrelor. The stirring time may range from about 30 minutes to about 10 hours, or longer. The solution may be optionally treated with charcoal and filtered to get a particle-free solution.
[0038] In (b) of the process for the preparation of crystalline dimethyl formamide solvate of ticagrelor, dimethyl formamide solvate of ticagrelor is obtained from the solution of step (a), the process comprising: (i) cooling and stirring the solution obtained in (a); or (ii) removing the solvent from the solution obtained in (a); or
(iii) treating the solution of step (a) with an anti-solvent to form a mixture and optionally, cooling and stirring the obtained mixture.
[0039] In one embodiment, the dimethyl formamide solvate of ticagrelor is obtained by cooling and stirring the solution of step (a). The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about -20°C to about 30°C. Preferably, the solution is stirred for about 8 hours at about -10°C to about 0°C.
[0040] In one embodiment, the dimethyl formamide solvate of ticagrelor is obtained by removing the solvent from the solution obtained in (a). Removal of solvent may be accomplished by substantially complete evaporation of the solvent; or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg. [0041] In one embodiment, the dimethyl formamide solvate of ticagrelor is obtained by adding an anti-solvent to the solution obtained in (a) to form a mixture and optionally, cooling and stirring the obtained mixture. The stirring time may range from about 30 minutes to about 10 hours, or longer. The temperature may range from about -10°C to about 120°C. Preferably, the solution is stirred for about 8 hours at about -10°C to about 0°C.

[0042] The anti-solvent is selected such that dimethyl formamide solvate of ticagrelor is precipitated out from the solution.
[0043] The anti-solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof. Preferably the solvent selected is isopropyl acetate, toluene, methyl tert-butyl ether, n-heptane.
[0044] In (c) of the process for the preparation of crystalline dimethyl formamide solvate of ticagrelor, the crystalline dimethyl formamide solvate of ticagrelor is isolated by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like. [0045] The isolated crystalline dimethyl formamide solvate of ticagrelor may be further dried. Drying may be suitably carried out in an equipment known in the art, such as a tray drier, vacuum oven, air oven, fluidized bed drier, spin flash drier, flash drier and the like. The drying may be carried out at temperatures from about room temperature to about 100°C with or without vacuum. The drying may be carried out for any desired time until the required product quality is achieved. The drying time may vary from about 1 hour to about 25 hours, or longer.
[0046] In one embodiment, ticagrelor, a compound of formula I, is obtained by deprotecting the compound of formula III.


[0047] A suitable deprotecting reagent is selected from an acid or a base. [0048] A suitable acid includes, but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid. Preferably, the acid selected is hydrochloric acid.
[0049] A suitable base includes, but is not limited to alkali metal hydroxides such as
lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal
hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate,
caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as
sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride;
alkali metal alcoholates such as lithium methoxide, sodium methoxide, potassium
methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide,
potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert-butoxide,
potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide,
magnesium iso-propoxide; alkyl lithium such as n-butyl lithium; alkali metal acetates,
tertiary amines such as triethylamine, JV,iV-diisopropylethylamine; ammonia, pyridine,
piperidine, 4-dimethylaminopyridine, l,4-diazabicyclo[2.2.2]octane, 1,8-
diazabicyclo[5.4.0]undec-7-ene, potassium bis(trimethylsilyl)amide. Preferably the base selected is sodium hydroxide.
[0050] The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ethers such as tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-

propyl acetate, tert-butyl acetate and the like; water or mixtures thereof. Preferably the solvent selected is tetrahydrofuran, methanol, methanol-water mixture. [0051] The present invention provides a process for the preparation of ticagrelor in amorphous form, the process comprising:
(a) dissolving dimethyl formamide solvate of ticagrelor in a solvent to form a solution; and
(b) recovering ticagrelor in amorphous form from the solution of step (a).
[0052] In (a) of the process for the preparation of ticagrelor in amorphous form, dimethyl formamide solvate of ticagrelor is dissolved in a solvent to form a solution. [0053] The solvent used for dissolution of dimethyl formamide solvate of ticagrelor includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water; or mixtures thereof. Preferably the solvent selected is dichloromethane-methanol mixture. [0054] Suitable temperature for dissolution of dimethyl formamide solvate of ticagrelor in a solvent may range from about 25°C to about the reflux temperature of the solvent. Stirring may be continued for any desired time period to achieve a complete dissolution of the compound. The stirring time may range from about 30 minutes to about 1 hour, or longer. The solution may be optionally treated with charcoal and filtered to get a particle-free solution.
[0055] In (b) of the process for the preparation of ticagrelor in amorphous form, ticagrelor in amorphous form is recovered from the solution of step (a), the process comprising:
(i) removing the solvent from the solution obtained in (a); or (ii) treating the solution of step (a) with an anti-solvent.

[0056] In one embodiment, ticagrelor in amorphous form is recovered by removing the solvent from the solution of step (a). Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg, or evaporated by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying. Preferably solvent was removed by concentrating the solution under vacuum to give amorphous ticagrelor.
[0057] In one embodiment, ticagrelor in amorphous form is recovered by treating the solution of step (a) with an anti-solvent.
[0058] The anti-solvent is selected such that amorphous ticagrelor is precipitated out from the solution.
[0059] The anti-solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.
[0060] In one embodiment, the present invention provides a process for the preparation of ticagrelor in amorphous form, the process comprising:
(a) dissolving ticagrelor or solvate thereof in dichloromethane-methanol mixture to form a solution; and
(b) removing the solvent from the solution obtained in (a).
[0061] In one embodiment, the present invention provides a process for the preparation of ticagrelor in amorphous form, the process comprising:
(a) dissolving dimethyl formamide solvate. of ticagrelor in dichloromethane-methanol mixture to form a solution; and

(b) removing the solvent from the solution obtained in (a).
[0062] In one embodiment, dimethyl formamide solvate of ticagrelor is dissolved in about 0.5:5 to about 0.5:25 mixture of methanol and dichloromethane to form a solution. [0063] In one preferred embodiment, the present invention provides a process for the preparation of ticagrelor in amorphous form, the process comprising:
(a) dissolving dimethyl formamide solvate of ticagrelor in dichloromethane-methanol mixture to form a solution; and
(b) removing the solvent from the solution obtained in (a) by concentrating the solution. [0064] The present invention provides use of dimethyl formamide solvate of ticagrelor in the preparation of amorphous ticagrelor.
[0065] Use of dimethyl formamide solvate of ticagrelor in the preparation of amorphous ticagrelor is advantageous as ticagrelor in amorphous form is obtained without formation of other crystalline forms (Form I, Form II, Form III, Form IV) of ticagrelor and the amorphous form of ticagrelor is substantially pure without contamination of other . crystalline forms of ticagrelor.
[0066] The present invention provides a process for the preparation of ticagrelor in amorphous form, the process comprising:
(a) dissolving a solvate of ticagrelor in a solvent to form a solution; and
(b) recovering ticagrelor in amorphous form from the solution of step (a).
[0067] In (a) of the process for the preparation of ticagrelor in amorphous form, a solvate of ticagrelor is dissolved in a solvent to form a solution.
[0068] The solvate of ticagrelor includes solvate with water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, ethyl acetate, n-butyl acetate, isobutyl acetate, acetonitrile, acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, chloroform, dichloromethane, hexane, n-heptane, toluene, N-methyl pyrrolidone, anisole, dimethyl formamide, dimethyl sulfoxide or mixtures thereof.
[0069] The solvent used for dissolution of the solvate of ticagrelor includes but is not limited to haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-

pentanol, 1-octanol and the like; ethers such as diethyl ether, diisopropyl ether, methyl
tert-butyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl
acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons
such as toluene, xylene, chlorobenzene, heptane, hexane, cyclohexane and the like;
dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; water; or mixtures thereof.
[0070] Stirring may be continued for any desired time period to achieve a complete
dissolution of the compound. The stirring time may range from about 30 minutes to about
3 hours, or longer. The solution may be optionally treated with charcoal and filtered to
get a particle-free solution.
[0071] In (b) of the process for the preparation of ticagrelor in amorphous form,
ticagrelor in amorphous form is recovered from the solution of step (a), the process
comprising:
(i) removing the solvent from the solution obtained in (a); or
(ii) treating the solution of step (a) with an anti-solvent.
[0072] The recovery of ticagrelor in amorphous form from the solution of step (a) is as
discussed supra.
[0073] In one embodiment, the present invention provides crystalline ticagrelor Form II
from a mixture of methyl isobutyl ketone and toluene.
[0074] In one embodiment, ticagrelor is dissolved in about 1:1 to about 1:5 mixture of
methyl isobutyl ketone and toluene to form a solution. Suitable temperature for
dissolution of ticagrelor in the mixture of methyl isobutyl ketone and toluene may range
from about 25°C to about the reflux temperature of the solvent. Stirring may be continued
for any desired time period to achieve complete dissolution of ticagrelor. Crystalline
ticagrelor Form II is obtained from the mixture of methyl isobutyl ketone and toluene by
cooling and stirring the solution. Crystalline ticagrelor Form II is isolated by any method
known in the art. The method, may involve any of techniques, known in the art, including
filtration by gravity or by suction, centrifugation, and the like.
[0075] In one embodiment, the present invention provides pharmaceutical compositions
comprising ticagrelor or salt thereof obtained by the processes herein described, having a
D50 and D90 particle size of less than about 150 microns, preferably less than about 100
microns, more preferably less than about 50 microns, still more preferably less than about

20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns. The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state ticagrelor into any of the foregoing desired particle size range. [0076] The present invention provides amorphous ticagrelor and crystalline solvates of ticagrelor, obtained by the above processes, as characterized and analyzed by following techniques:
A. X-ray powder diffraction profiles were obtained using an X-ray Diffractometer
(Philips X'Pert Pro, PANalytical). The measurements were carried out with a Pre FIX
module programmable divergence slit and anti-scatter Slit (Offset,0.00°) ; target, Cu;
filter, Ni; detector, X'Celerator; Scanning Mode; Active length (2Theta) = 2.122°;
generator 45KV ; tube current 40mAmp. The samples were scanned in the full 29 range
of 2-50" with a "time-per-step" optimized to 50 sec.
B. DSC (Mettler Toledo 822e): Temperature range is "30°C to 350°C" and heating
rate is 10°C/minute.
C. IR spectra were recorded using IR instrument- Perkin Elmer Spectrum One FTIR.
D. Thermo Gravimetric Analyzer: TGA Q500 V6.5. Thermogram was recorded at
30-350°C at the rate of 10°C/min.
E. Gas Chromatography Method:
Instrument: Gas chromatograph equipped with FID detector and Headspace.
Column: DB-624, 75m x 0.53mm, 3.0µm
Column Temp.: 40°C (hold for 5 minutes) to 220°C @ 25°C/minute (hold for 10
minutes)
Injector/detector: 200°C/270°C
Carrier gas: Nitrogen
Linear velocity: 30cm/sec
Split Ratio: (5: 1)
Diluent: Benzyl alcohol (Spectrochem, HPLC and GC grade)
Head Space Parameters:
Incubation Temperature: 80°C
Incubation Time: 10 minutes

Agitation Speed: 600 rpm
Syringe Temperature: 115°C
Injection Volume: 1.0 mL
F. HPLC Method:
Reagents, Solvents and Standards: Water (Milli Q or equivalent), Methanol (HPLC
Grade), o-phosphoric acid (AR Grade)
Chromatographic Conditions:
Apparatus: A High Performance Liquid Chromatograph equipped with quaternary
gradient pumps, variable wavelength UV detector attached with data recorder and
integrator software.
Column: GL Science, Inertsil ODS 3V, 250 x 4.6mm, 5µ
Column temperature: 25°C
Sample cooler temperature: 25°C
Mobile Phase:
Mobile Phase A = Buffer (100%)
Buffer: 1.0ml of o-phosphoric acid dissolve in 1000ml of water.
Mobile Phase B = Methanol (100%) .

Time (min.) % Mobile Phase
A % Mobile Phase B
0.01 97 03
12 91 03
14 10 90
20 10 90
22 97 03
30 97 03
Diluent: Methanol: Buffer (20:80, v/v)
Flow Rate:1.0mL/minute
Detection: UV 210nm
Injection Volume: 20µL
The retention time of dimethyl formamide is about 10.0 minutes under these conditions.
[0077] The examples that follow are provided to enable one skilled in the art to practice
the invention and are merely illustrative of the invention. The examples should not be
read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES
[0078] EXAMPLE 1 Preparation of dimethyl formamide solvate of ticagrelor
Ticagrelor (2g) was dissolved in dimethyl formamide (2mL) at about 55°C to about 60°C and isopropyl acetate (20mL) was added to it at about the same temperature. The mixture was stirred for about 30min at about 55°C to about 60°C. The mixture was then cooled to about 0°C to about 5°C and was stirred for about 2h. The temperature of the mixture was raised to about room temperature and the mixture was stirred for about 2h. The solid obtained was filtered, washed with chilled isopropyl acetate and dried at about 30°C to about 35°C for about 24h.
Dimethyl formamide content by Gas Chromatography: 10.04% TGA analysis of dimethyl formamide solvate of ticagrelor:

Solvent % loss up to 150°C
Dimethyl formamide 10.75%
XRPD peaks of dimethyl formamide solvate of ticagrelor:

Pos.
[°2Th.] d-spacing
(A) Rel. Int.
[%] Pos.
[°2Th.] d-spacing
(A) Rel. Int.
[%] Pos.
[°2Th.] d-spacing
[A) Rel. Int.
[%]
4.7 18.93 11.75 16.7 5.32 54.44 25.1 3.55 5.53
5.4 16.48 2.73 17.5 5.07 16.74 26.0 3.43 4.59
5.9 15.09 100.00 17.9 4.94 3.03 26.7 3.34 4.96
6.8 12.96 10.50 18.5 4.79 10.62 28.3 3.16 2.26
8.1 10.86 6.06 19.0 4.67 5.48 28.6 3.12 3.31
9.3 9.52 0.34 20.0 4.45 14.57 29.6 3.02 16.53
11.9 7.46 89.48 20.3 4.37 43.04 30.7 2.91 3.56
13.7 6.47 16.67 21.7 4.09 6.12 31.2 2.86 0.90
14.2 6.22 31.54 23.1 3.85 10.83 33.1 2.70 1.79
16.2 5.47 5.60 24.2 3.67 69.21 33.9 2.65 3.10
[0079] EXAMPLE 2 Preparation of dimethyl formamide solvate of ticagrelor
Ticagrelor (2g) was dissolved in a mixture of dimethyl formamide (2mL) and isopropyl acetate (20mL) at about 55°C to about 60°C and the mixture was stirred for about 30min at about the same temperature. The mixture was cooled to about 0°C to about 5°C and was stirred for about 2h. The temperature of the mixture was raised to about room temperature and the mixture was stirred for about 2h. The solid obtained was filtered,

washed with chilled isopropyl acetate and dried at about 30°C to about 35°C for about
24h.
TGA analysis of dimethyl formamide solvate of ticagrelor:

Solvent % loss up to 150°C
Dimethyl formamide 12.19%
[0080] EXAMPLE 3 Preparation of dimethyl formamide solvate of ticagrelor
Ticagrelor (2g) was dissolved in dimethyl formamide (2mL) at about 55°C to about 60°C and toluene (20mL) was added to it at about the same temperature. The mixture was stirred for about 30min at about 55°C to about 60°C. The mixture was then cooled to about 0°C to about 5°C and was stirred for about 10h. The solid obtained was filtered at about 0°C to about 5°C, washed with chilled toluene and dried at about 30°C to about 35°C for about 24h.
[0081] EXAMPLE 4 Preparation of dimethyl formamide solvate of ticagrelor
Ticagrelor (2g) was dissolved in dimethyl formamide (2mL) at about 45°C to about 50°C and methyl tert-butyl ether (30mL) was added to it at about the same temperature. The mixture was stirred for about 30min at about 45°C to about 50°C. The mixture was then cooled to about 0°C to about 5°C and was stirred for about 6h. The solid obtained was filtered at about 0°C to about 5°C, washed with chilled methyl tert-butyl ether and dried at about 30°C to about 35°C for about 24h.
[0082] EXAMPLE 5 Preparation of dimethyl formamide solvate of ticagrelor
Ticagrelor (2g) was dissolved in dimethyl formamide (2mL) at about 55°C to about 60°C and n-heptane (30mL) was added to it at about the same temperature. The mixture was stirred for about 30min at about 55°C to about 60°C. The mixture was then cooled to about room temperature and was stirred for about 6h. The solid obtained was filtered, washed with n-heptane and dried at about 30°C to about 35°C for about 24h.
[0083] EXAMPLE 6 Preparation of amorphous ticagrelor
A mixture of dimethyl formamide solvate of ticagrelor (5g) in dichloromethane and methanol was concentrated and degassed at about 40°C for about 2h to about 3h under vacuum to give amorphous ticagrelor.

PSD:D10:43.5µm,D50: 129.5um,D90:367.4µm
[0084] EXAMPLE 7 Preparation of amorphous ticagrelor
A mixture of dimethyl formamide solvate of ticagrelor (5g) in dichloromethane and methanol was concentrated and degassed at about 40°C for about 2h to about 3h under vacuum with slow stirring to give amorphous ticagrelor.
[0085] EXAMPLE 8 Preparation of amorphous ticagrelor
A mixture of dimethyl formamide solvate of ticagrelor (5g) in dichloromethane and methanol was concentrated and degassed at about 40°C for about 2h to about 3h under vacuum. Cyclohexane was added to the obtained residue and the mixture was stirred for about 15min to about 20min. The solid obtained was filtered under nitrogen and dried at about room temperature under vacuum to give amorphous ticagrelor.
[0086] EXAMPLE 9 Preparation of amorphous ticagrelor
A mixture of dimethyl formamide solvate of ticagrelor (5g) in dichloromethane and methanol was washed with water. The organic layer was dried over sodium sulphate and was concentrated and degassed at about 40°C for about 2h to about 3h under vacuum. Cyclohexane was added to the obtained residue and the mixture was stirred for about 15min to about 20min. The solid obtained was filtered under nitrogen and dried at about room temperature under vacuum to give amorphous ticagrelor.
[0087] EXAMPLE 10 Preparation of amorphous ticagrelor
A mixture of dimethyl formamide solvate of ticagrelor (5g) in dichloromethane and methanol was washed with water. The organic layer was dried over sodium sulphate and was concentrated and degassed at about 40°C for about 2h to about 3h under vacuum to give amorphous ticagrelor. PSD: D10: 37.2um, D50: 105.3µm,D90: 244.7µm
[0088] EXAMPLE 11 Preparation of dimethyl formamide solvate of ticagrelor
Ticagrelor (2g) was dissolved in dimethyl formamide (2mL) at about 55°C to about 60°C and n-propyl acetate (20mL) was added to it at about the same temperature. The mixture was stirred for about 30min at about 55°C to about 60°C. The mixture was then cooled to

about 0°C to about 5°C and was stirred for about 2h. The temperature of the mixture was raised to about room temperature and the mixture was stirred for about 2h. The solid obtained was filtered, washed with chilled n-propyl acetate and dried at about 30°C to about 35°C for about 24h.
[0089] EXAMPLE 12 Preparation of dimethyl formamide solvate of ticagrelor
A mixture of 2-{[(3aR,4S,6R,6aS)-6-(7-{[(1R2S)-2-(3,4-difluorophenyl)cyclopropyl] amino}-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-hexahydrocyclopenta[d][l,3]dioxol-4-yl]oxy}ethyl acetate, compound of formula III (10g), methanol and aqueous sodium hydroxide was stirred at about 20°C to about 25°C for about lh. Amberlite IR 120 H resin was added to the reaction mixture. The reaction mixture was concentrated under vacuum at about 30°C to about 35°C. Water and ethyl acetate was added to the reaction mixture. The organic layer was separated, washed with auueous sodium carbonate solution, concentrated and degassed. The residue obtained was dissolved in dimethyl formamide (10mL) at about 45°C to about 50°C and methyl tert-butyl ether (300mL) was added to it at about the same temperature. The mixture was stirred for about 30min. The mixture was then cooled to about 0°C to about 5°C and was stirred for about 6h. The solid obtained was filtered at about 0°C to about 5°C, washed with chilled methyl tert-butyl ether and dried at about 30°C to about 35°C for about 24h.
[0090] EXAMPLE 13 Preparation of dimethyl formamide solvate of ticagrelor
A mixture of 2-{[(3aR,4S,6R,6aS)-6-(7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino}-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyl-hexahydrocyclopenta[d][l,3]dioxol-4-yl]oxy}ethyl acetate, compound of formula III (10g), methanol and aqueous sodium hydroxide was stirred at about 20°C to about 25°C for about lh. Amberyst 36 (wet) ion exchange resin was added to the reaction mixture. The reaction mixture was concentrated under vacuum at about 30°C to about 35°C. Water and ethyl acetate was added to the reaction mixture. The organic layer was separated, washed with aqueous sodium carbonate solution, concentrated and degassed. The residue obtained was dissolved in dimethyl formamide (lOmL) at about 45°C to about 50°C and methyl tert-butyl ether (300mL) was added to it at about the same temperature. The mixture was stirred for about 30min. The mixture was then cooled to

about 0°C to about 5°C and was stirred for about 6h. The solid obtained was filtered at about 0°C to about 5°C, washed with chilled methyl tert-butyl ether and dried at about 30°C to about 35°C for about 24h.
EXAMPLE 14 Preparation of ticagrelor Form II
Ticagrelor (5g) was dissolved in isopropyl acetate at about 50°C and n-heptane was added to it at about the same temperature. The mixture was then cooled to about room temperature and was stirred for about 60min. The solid obtained was filtered, washed with n-heptane and dried at about 45 °C to give ticagrelor Form II.
Example 15 Preparation of ticagrelor Form II
Ticagrelor (5g) was dissolved in isopropyl acetate at about 50°C and toluene was added to it at about the same temperature. The mixture was then cooled to about room temperature and was stirred for about 60min. The solid obtained was filtered, washed with toluene and dried at about 47°C to give ticagrelor Form II.
Example 16 Preparation of ticagrelor Form II
Ticagrelor (10g) was dissolved in isopropyl acetate at about 60°C and hexane was added to it at about the same temperature. The mixture was then cooled to about room temperature and was stirred for about 60min. The solid obtained was filtered, washed with hexane and dried at about 45°C to give ticagrelor Form II.
Example 17 Preparation of ticagrelor Form II
Ticagrelor (5g) was dissolved in methyl isobutyl ketone at about 70°C and n-heptane was added to it at about the same temperature. The mixture was then cooled to about room temperature and was stirred for about 60min. The solid obtained was filtered, washed with n-heptane and dried at about 45°C to give ticagrelor Form II.
Example 18 Preparation of ticagrelor Form II
Ticagrelor (5g) was dissolved in isopropyl acetate at about 60°C and petroleum ether was added to it at about the same temperature. The mixture was then cooled to about room temperature and was stirred for about 60min. The solid obtained was filtered, washed with petroleum ether and dried at about 45°C to give ticagrelor Form II.

Example 19 Preparation of ticagrelor Form II
Ticagrelor (5g) was dissolved in methyl isobutyl ketone at about 60°C and isopropyl ether was added to it at about the same temperature. The mixture was then cooled to about room temperature and was stirred for about 60min. The solid obtained was filtered, washed with isopropyl ether and dried at about 45°C to give ticagrelor Form II.
Example 20 Preparation of ticagrelor Form II
Ticagrelor (5g) was dissolved in ethyl acetate at about 60°C and heptane was added to it at about the same temperature. The mixture was then cooled to about room temperature and was stirred for about 60min. The solid obtained was filtered, washed with heptane and dried at about 45°C to give ticagrelor Form II.
Example 21 Preparation of ticagrelor Form II
Ticagrelor (10g) was dissolved in methyl isobutyl ketone at about 60°C and petroleum ether was added to it at about the same temperature. The mixture was then cooled to about room temperature and was stirred for about 60min. The solid obtained was filtered, washed with petroleum ether and dried at about 45 °C to give ticagrelor Form II.
Example 22 Preparation of ticagrelor Form II
Ticagrelor (5g) was dissolved in methyl isobutyl ketone (25mL) at about 70°C and toluene (75mL) was added to it at about the same temperature. The mixture was then cooled to about room temperature and was stirred for about 60min. The solid obtained was filtered, washed with toluene and dried at about 45°C to give ticagrelor Form II. PSD: Before milling- D10: 3µm, D50: 9µm, D90: 27µm
After milling- D10: 1.87µm, D50: 4.6um, D90: 11.4µm
Example 23 Preparation of ticagrelor Form II
Ticagrelor (lg) was dissolved in acetone (4mL) at about 35°C. The solution was then cooled to about room temperature and was stirred for about 5 Oh. The solid obtained was filtered, washed with petroleum ether and dried at about 45°C to give ticagrelor Form II.

Example 24 Preparation of ticagrelor Form II
Ticagrelor (lg) was dissolved in tetrahydrofuran (3mL) at about 25 °C and toluene (30mL) was added to it at about the same temperature. The solution was stirred for about 3h. The solid obtained was filtered, washed with toluene and dried at about 50°C to give ticagrelor Form II.
Example 25 Preparation of ticagrelor Form II
Ticagrelor (lg) was dissolved in methyl isobutyl ketone (5mL) at about 70°C and methyl tert-butyl ether (15mL) was added to it at about 50°C. The solution was then cooled to about room temperature and was stirred for about 4h. The solid obtained was filtered, washed with methyl tert-butyl ether and dried at about 50°C to give ticagrelor Form II.
Example 26 Preparation of ticagrelor Form II
Ticagrelor (lg) was dissolved in toluene (15mL) at about 95°C. The solution was then cooled to about room temperature and was stirred for about 2h. The solid obtained was filtered, washed with toluene and dried at about 45°C to give ticagrelor Form II.
Example 27 Preparation of ticagrelor Form II
Ticagrelor (lg) was dissolved in a mixture of methyl isobutyl ketone (5mL) and toluene (10mL) at about 80°C. The solution was stirred for about 15min and n-heptane (10mL) was slowly added to it at about 80°C. The solution was then cooled to about room temperature. The solid obtained was filtered, washed with n-heptane and dried at about 50°C in vacuum to give ticagrelor Form II.
Example 28 Preparation of ticagrelor Form II
Ticagrelor (1g) was stirred in diisopropyl ether (20mL) at about 65°C for about 12h. The solution was then cooled to about room temperature and was stirred for about 2h. The solid obtained was filtered, washed with diisopropyl ether and dried at about 45 °C to give ticagrelor Form II.
Example 29 Preparation of ticagrelor Form II
Ticagrelor (lg) was dissolved in a mixture of ethylene glycol (5mL) and toluene (lOmL) at about 70°C. The solution was then cooled to about room temperature and was stirred

for about 18h. The solid obtained was filtered, washed with toluene and dried at about 50°C to give ticagrelor Form II.
EXAMPLE 30 Preparation of dimethyl formamide solvate of Ticagrelor
A mixture of 2-{[(3aR,4S,6R,6aS)-6-[7-chloro-5-(propylsulfanyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl-hexahydrocyclopenta[d][l,3]dioxol-4-yl]oxy}ethyl acetate (15g), (lR,2S)-2-(3,4-difluorophenyl)cyclopropanamine hydrochloride (7.2g) and diisopropyl ethyl amine (14.4g) in dichloromethane was stirred at about 20°C to about 25°C. Water was then added to the reaction mixture. The organic layer was separated, washed with aqueous sodium carbonate solution, concentrated and degassed. Methanol was then added to the above residue. The reaction mixture was cooled and concentrated hydrochloric acid was added to it under stirring. The reaction was stirred for about 20h to about 24h at about 0°C to about 10°C. Water and dichloromethane was added to the reaction mixture. The organic layer was separated, washed with aqueous sodium bicarbonate solution, concentrated and degassed. The residue obtained was dissolved in dimethyl formamide (9mL) at about 40°C to about 50°C and toluene (142mL) was added to it at about the same temperature. The mixture was stirred for about 30min. The mixture was then cooled to about 0°C to about -10°C and was stirred for about 6h to about 8h. The solid obtained was filtered at about 0°C to about -10°C, washed with toluene and dried at about 30°C to about 35°C for about 24h. TGA analysis of dimethyl formamide solvate of ticagrelor:

Solvent % loss up to 100°C
Dimethyl formamide 10.06%
EXAMPLE 31 Preparation of amorphous ticagrelor
A mixture of dimethyl formamide solvate of ticagrelor (9g) in toluene was stirred at
about 65°C for about 20min. The solvent was completely distilled under vacuum. To the
above residue, dichloromethane and methanol was added. The clear solution was
concentrated and degassed at about 40°C for about 5h to about 6h under vacuum. The
solid obtained was dried at about room temperature under vacuum to give amorphous
ticagrelor.
PSD: D10: 24.6µm, D50: 87.1 µm, D90: 185.2µm

CLAIMS:
1. A crystalline dimethyl formamide solvate of ticagrelor characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 5.9, 11.9, 16.7, 17.5 and 24.2 ±0.2 degrees 2 theta.
2. The solvate of claim 1, characterized by TGA thermogram, showing a weight loss of about 9.00 weight% to 13.00 weight% determined over the temperature range of 0°C to 350°C and heating rate 10°C/min.
3. The solvate of claim 1, characterized by DSC thermogram having an endothermic peak at about 83 ±2°C.
4. The solvate of claim 1, characterized by data selected from the group consisting of: an X-ray powder diffraction (XRPD) pattern as depicted in Figure 1, a DSC thermogram as depicted in Figure 2; an IR spectrum as depicted in Figure 3; a TGA thermogram as depicted in Figure 4; and any combination thereof.
5. A process for the preparation of crystalline dimethyl formamide solvate of ticagrelor, the process comprising:

(a) dissolving ticagrelor in dimethyl formamide, optionally in presence of additional solvent, to form a solution;
(b) obtaining crystalline dimethyl formamide solvate of ticagrelor from the solution of step (a); and
(c) isolating the crystalline dimethyl formamide solvate of ticagrelor.
6. The process of claim 5, wherein the step (b) of obtaining dimethyl formamide
solvate of ticagrelor comprises:
(i) cooling and stirring the solution obtained in (a); or
(ii) removing the solvent from the solution obtained in (a); or
(iii) treating the solution of step (a) with an anti-solvent to form a mixture and optionally,
cooling and stirring the obtained mixture.

7. A process for the preparation of ticagrelor in amorphous form, the process
comprising:
(a) dissolving dimethyl formamide solvate of ticagrelor in a solvent to form a solution; and
(b) recovering ticagrelor in amorphous form from the solution of step (a).
8. The process of claim 7, wherein the step (b) of recovering ticagrelor in amorphous
form comprises:
(i) removing the solvent from the solution obtained in (a); or (ii) treating the solution of step (a) with an anti-solvent.
9. The process of claim 8, wherein the solvent is removed from the solution by concentrating the solution, or completely evaporating the solvent, or removing the solvent by lyophilisation, freeze-drying, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.
10. The use of dimethyl formamide solvate of ticagrelor in the preparation of amorphous ticagrelor.