WO2014083139A1

WO2014083139A1 - Novel amorphous form of ticagrelor

Info

Publication number: WO2014083139A1
Application number: PCT/EP2013/075030
Authority: WO
Inventors: Anil Shahaji Khile; Vignesh Nair; Nikhil Trivedi; Nitin Sharadchandra Pradhan
Original assignee: Actavis Group PTC ehf
Current assignee: Actavis Group PTC ehf
Priority date: 2012-11-29
Filing date: 2013-11-29
Publication date: 2014-06-05
Anticipated expiration: 2015-05-29

Abstract

The present invention refers to a novel amorphous form of ticagrelor, a process for the preparation thereof, pharmaceutical compositions comprising said novel amorphous form of ticagrelor, and to the use of the novel amorphous form of ticagrelor as medicament.

Description

NOVEL AMORPHOUS FORM OF TICAGRELOR

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

U.S. Patent Nos. 6,251,910 and 6,525,060 disclose a variety of triazolo[4,5-d] pyrimidine derivatives, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof. These compounds act as Ρ₂τ (P2Y_ADP or P2T_Ac) receptor antagonists and they are indicated for use in therapy as inhibitors of platelet activation, aggregation and degranulation, promoters of platelet disaggregation and anti-thrombotic agents. Among them, Ticagrelor, [l S-(la,2a,3 (lS*,2R*),5p)]-3-[7-[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, acts as Adenosine uptake inhibitor, Platelet aggregation inhibitor, P2Y12 purinoceptor antagonist and Coagulation inhibitor. It is indicated for the treatment of thrombosis, angina, Ischemic heart diseases and coronary artery diseases. Ticagrelor is represented by the following structural formula I:

Ticagrelor is

° the first reversibly binding oral adenosine diphosphate (ADP) receptor antagonist and is chemically distinct from thienopyridine compounds like clopidogrel. It selectively inhibits P2Y12, a key target receptor for ADP. ADP receptor blockade inhibits the action of platelets in the blood, reducing recurrent thrombotic events. The drug has shown a statistically significant primary efficacy against the widely prescribed clopidogrel (Plavix) in the prevention of cardiovascular (CV) events including myocardial infarction (heart attacks), stroke, and cardiovascular death in patients with ACS.

Various processes for the preparation of ticagrelor, its enantiomers and related compounds, and their pharmaceutically acceptable salts are disclosed in U.S. Patent Nos. 6,251,910; 6,525,060; 6,974,868; 7,067,663; and 7,250,419; U.S. Patent application Nos. 2007/0265282, 2007/0293513 and 2008/0214812; and European Patent Nos. EP0996621 and EP1135391; and PCT Publication Nos. WO2008/018823 and WO2010/030224.

According to U.S. Patent No. 5,747,496, the 4,6-dichloro-5-nitro-2- (propylthio)pyrimidine of formula II is prepared by adding propyl iodide to a suspension of 4,6- dihydroxy-2-mercaptopyrimidine in water containing sodium hydroxide; the reaction mixture is stirred for 2 weeks and then the reaction mass is concentrated to half volume; followed by the addition of hydrochloric acid and isolating the product by filtration to produce 2-propylthio- pyrimidine-4,6-diol. The 2-propylthio-pyrimidine-4,6-diol is then reacted with excess fuming nitric acid to produce 5-nitro-2-propylthiopyrimidine-4,6-diol. The 5-nitro-2- propylthiopyrimidine-4,6-diol is reacted with phosphoryl chloride in the presence of N,N- dimethylaniline at reflux to produce a reaction mass. The cooled reaction mass is poured onto ice followed by extracting with diethyl ether to afford a solution; then the combined extracts are dried and concentrated. The residue is chromatographed (Si02, light petrol) to produce 4,6- dichloro-5-nitro-2-(propylthio)pyrimidine.

According to U.S. Patent No. 6,525,060, ticagrelor is prepared by the condensation of 4,6- dichloro-5-nitro-2-(propylthio)pyrimidine with [3aR-(3aa,4a,6a,6aa)]-6-amino-tetrahydro-2,2- dimethyl-4H-cyclopenta-l,3-dioxol-4-ol, hydrochloride salt in the presence of N,N- diisopropylethylamine in tetrahydrofuran to produce [3aR-(3aa,4 ,6a,6a )]-6-[[6-chloro-5- nitro-2-(propylthio)-pyrimidin-4-yl]amino]-tetrahydro-2,2-dimethyl-4H-cyclopenta-l,3-dioxol-4- ol, followed by reduction in the presence of iron powder in acetic acid to produce [3aR- (3aa,4 ,6a,6aa)]-6-[[5-amino-6-chloro-2-( ropylthio)-pyrimidin-4-yl]amino]-tetrahydro-2,2- dimethyl-4H-cyclopenta-l,3-dioxol-4-ol, which is then reacted with isoamyl nitrite in acetonitrile to produce [3aR-(3a ,4a,6a,6aa)]-6-[7-chloro-5-(propylthio)-3H-l ,2,3-triazolo[4,5-d]- pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-l,3-dioxol-4-ol.

The resulting triazolo [4,5-d]-pyrimidin compound is reacted with ammonia in tetrahydrofuran to produce [3aR-(3aa,4a,6a,6aa)]-6-[7-amino-5-(propylthio)-3H-l,2,3- triazolo[4,5-d]-pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta- 1 ,3-dioxol-4-ol, which is then reacted with a solution of trifluoromethanesulfonyloxy-acetic acid methyl ester in tetrahydrofuran in the presence of butyllithium to produce [3aR-(3aa,4a,6a,6aa)]-6-[[7-amino- 5-(propylthio)-3H-l,2,3-triazolo[4,5-d]-pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta- l,3-dioxol-4-ol]oxy]acetic acid methyl ester, followed by bromination in the presence of isoamylnitrite in bromoform to produce [3aR-(3aa,4a,6a,6aa)]-6-[[7-bromo-5-(propylthio)-3H- 1 ,2,3 riazolo[4,5-d]^yrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta- 1 ,3-dioxol-4-ol]oxy] acetic acid methyl ester.

The resulting bromo compound is then reacted with (lR-trans)-2-(3,4- difluorophenyl)cyclopropanamine [R-(R*,R*)]-2,3-dihydroxybutanedioate (1: 1) salt in the presence of Ν,Ν-diisopropylethylamine in dichloromethane to produce [3aR- [3aa,4a,6a(lR*,2S*),6a ]]-[[6-[7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylthio)- 3H-l,2,3 riazolo[4,5-d]-pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-l,3-dioxol-4- ol]oxy]acetic acid methyl ester, followed by reaction with DIBAL-H in tetrahydrofuran to produce [3aR-[3aa,4a,6a(lR*,2S*),6aa]]-[[6-[7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-5- (propylthio)-3H-l,2,3 riazolo[4,5-d]-pyrimid^

dioxol-4-ol]oxy]-ethanol, which is then treated with trifluoroacetic acid in water to produce [1S- (l ,2a,3p(lS*,2R*),5 )]-3-[7-[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 (ticagrelor).

U.S. Patent Application No. 2007/0293513 (hereinafter referred to as the '513 application) discloses four crystalline forms (polymorphs I, II, III and IV) of the compound of formula I (ticagrelor), processes for their preparation, and characterizes the polymorphs by powder X-ray diffraction (P-XRD) pattern and melting points which were determined using differential scanning calorimetry (DSC).

The '513 application teaches an amorphous form of ticagrelor (Form a), and a process for preparing it. According to the teachings of the '513 application, the ticagrelor in substantially amorphous form is produced by a process which comprises freeze drying or spray drying a solution of ticagrelor using a suitable solvent system, for example ethanol/water. As per the process exemplified in the '513 application, the Form a of ticagrelor is prepared by dissolving ticagrelor in a 50% aqueous solution of ethanol, followed by the drop-wise addition of water and then freeze drying the resulting saturated solution using Virtis instrumentation under the following conditions (vacuum 2170 mT, run time 20.2 hours, condensed temperature -52°C, ambient temperature 20.3°C).

The '513 application also mentions that a substantially pure and essentially anhydrous Form a has an X-ray powder diffraction pattern containing no sharp peaks. The amorphous form (Form a) of ticagrelor obtained by the processes described in the '513 application is contaminated with one or more crystalline forms, for example with polymorph II as depicted in the powder X- ray diffraction pattern (Figure 1.5) reported in the '513 application. The '513 application further teaches that the Form a typically undergoes a glass transition followed by crystallization into one of the polymorph forms described therein, for example polymorph II, prior to melting.

Moreover, the process described in the '513 application involves tedious and cumbersome isolation techniques like freeze drying and spray drying, which are very expensive and time consuming methods, and often end up with low yields and low purity of product, thereby making the process industrially unfeasible.

Solvent medium, volume of the solvent medium and mode of isolation play very important role in obtaining one polymorphic form over another.

Hence, there is a strong technical and commercial desire to develop a modified process for the preparation of highly pure amorphous form of ticagrelor in order to overcome the problems associated with the prior art processes.

SUMMARY OF THE INVENTION

The present inventors have surprisingly and unexpectedly found an amorphous form of ticagrelor essentially free of crystalline forms that has high purity, adequate stability and good dissolution properties.

The amorphous form of ticagrelor essentially free of crystalline forms is consistently reproducible, do not have the tendency to convert to other forms, and is found to be more stable. The amorphous ticagrelor essentially free of crystalline forms disclosed herein exhibits properties making it suitable for formulating ticagrelor.

The present invention thus refers to an amorphous form of ticagrelor of Formula I:

characterized by having an X-ray powder diffraction pattern, when using a Cu-anode with a wavelength λ=1.54 Angstrom, which does not show crystalline forms of ticagrelor.

The invention also relates to a process for the preparation of the amoiphous form of ticagrelor according to the invention, comprising the steps of:

a) providing a solution of ticagrelor of Formula I in an alcohol or mixture of alcohols, wherein said alcohol or mixture of alcohols can comprise from 0 to 10% by volume of other solvents;

b) optionally subjecting the solution obtained in step-(a) to a carbon treatment or a silica gel treatment;

c) removing the solvent from the solution obtained in step-(a) or step-(b) under reduced pressure while maintaining the temperature of the solution in step-(c) in the range of from above the melting point of the solution up to the boiling point of the solution at the reduced pressure to provide the amorphous form of ticagrelor.

The invention also refers to an amorphous form of ticagrelor of Formula I:

obtainable or obtained by using a process according to the present invention. The invention also refers to a pharmaceutical composition, specifically a solid dosage form or oral suspension, comprising the amoiphous form of ticagrelor according to the invention and one or more pharmaceutically acceptable excipients.

The invention also refers to an amorphous form of ticagrelor according to the invention or the pharmaceutical composition according to the invention for use as medicament, preferably for use in the prevention of cardiovascular (CV) events including myocardial infarction (heart attacks), stroke, and cardiovascular death in patients with acute coronary syndrome (ACS) and the treatment of thrombosis, angina, ischemic heart diseases and coronary artery diseases.

The invention also refers to a process for preparing a pharmaceutical composition according to to the invention, wherein the process comprises combining the amorphous form of ticagrelor according to the invention with one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a characteristic powder X-ray diffraction (XRD) pattern of highly pure amorphous form of ticagrelor obtained according to example 1.

Figure 2 is a characteristic powder X-ray diffraction (XRD) pattern of crystalline form of ticagrelor obtained according to comparative example 1.

Figure 3 is a characteristic powder X-ray diffraction (XRD) pattern of crystalline form of ticagrelor obtained according to comparative example 2.

Figure 4 is a characteristic powder X-ray diffraction (XRD) pattern of crystalline form of ticagrelor obtained according to comparative example 3.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.

The term "pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable and includes that which is acceptable for veterinary use and/or human pharmaceutical use.

The term "pharmaceutical composition" is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.

The term "therapeutically effective amount" as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.

The term "delivering" as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host.

The term "buffering agent" as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dehydrate and other such material known to those of ordinary skill in the art.

The term "sweetening agent" as used herein is intended to mean a compound used to impart sweetness to a formulation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.

The term "binders" as used herein is intended to mean substances used to cause adhesion of powder particles in granulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, polyvinylpyrrolidone, compressible sugar (e.g., NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch, starch, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers (PLURONIC(™) F68, PLURONIC(™) F127), collagen, albumin, celluloses in non-aqueous solvents, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, microcrystalline cellulose, combinations thereof and other material known to those of ordinary skill in the art.

The term "diluent" or "filler" as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage formulations. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "glidant" as used herein is intended to mean agents used in solid dosage formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "lubricant" as used herein is intended to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "disintegrant" as used herein is intended to mean a compound used in solid dosage formulations to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pregelatinized, sweeteners, clays, such as bentonite, microcrystalline cellulose (e.g., Avicel(™)), carsium (e.g., Amberlite(™)), alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "wetting agent" as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, (e.g., TWEEN(™)s), polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxyl propylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP).

The term "micronization" used herein means a process or method by which the size of a population of particles is reduced.

As used herein, the term "micron" or "μιη" both are same refers to "micrometer" which is lxl 0^"6 meter.

As used herein, "crystalline particles" means any combination of single crystals, aggregates and agglomerates.

As used herein, "Particle Size Distribution (PSD)" means the cumulative volume size distribution of equivalent spherical diameters as determined by laser diffraction in Malvern Master Sizer 2000 equipment or its equivalent. "Mean particle size distribution, i.e., (D₅₀)" correspondingly, means the median of said particle size distribution.

The important characteristics of the PSD are the (D₉₀), which is the size, in microns, below which 90% of the particles by volume are found, and the (D₅₀), which is the size, in microns, below which 50% of the particles by volume are found. Thus, a D90 or d(0.9) of less than 300 microns means that 90 volume-percent of the particles in a composition have a diameter less than 300 microns.

The term "amorphous" means a solid without long-range crystalline order.

The term "essentially free of crystalline forms" means that no crystalline polymorph forms of ticagrelor, preferably no crystalline compounds at all, can be detected within the limits of a powder X-ray diffractometer.

The term "highly pure" is meant having total purity, which includes both chemical and enantiomeric purity, greater than about 99%, specifically greater than about 99.5%, and more specifically greater than about 99.9% measured by HPLC.

As used herein, "reflux temperature"/ "boiling point" means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure. The abbreviation "BET" stands for the names Brunauer, Emmett and Teller.

The invention refers to the following embodiments:

The invention refers to an amorphous form of ticagrelor of Formula I:

characterized by having an X-ray powder diffraction pattern, when using a Cu-anode with a wavelength λ=1.54 Angstrom, which does not show crystalline forms of ticagrelor. In other words, the amorphous form of ticagrelor according to the invention is essentially free of crystalline forms of ticagrelor. Preferably, the X-ray powder diffraction pattern of the amorphous form of ticagrelor according to the present invention does not show any crystalline compounds at all (see Figure 1), meaning that the amorphous form of ticagrelor according to the invention is essentially free of any crystalline compounds. Figures 2-4 below show the presence of such crystalline compounds.

The amorphous form of ticagrelor according to the present invention, being essentially free of crystalline forms, is characterized by a powder XRD pattern substantially in accordance with Figure 1. The X-ray powder diffraction pattern shows no peaks, thus demonstrating the amorphous nature of the product.

The amorphous ticagrelor essentially free of crystalline forms obtained by the process disclosed herein is stable, consistently reproducible, has good dissolution properties, and is particularly suitable for bulk preparation and handling. The amorphous ticagrelor according to the present invention is suitable for formulating ticagrelor into pharmaceutical compositions or pharmaceutical dosage forms.

Preferably, the X-ray powder diffraction pattern of the amorphous form of ticagrelor does not show peaks which have a full width at half peak maximum of less than 3 degrees 2-theta, preferably of less than 2 degrees 2-theta. The full width at half peak maximum is the width of the peak at half height of the peak.

The total purity, including the chemical and chiral purity, of the amorphous ticagrelor essentially free of crystalline forms obtained by the process disclosed herein is preferably greater than about 99%, specifically greater than about 99.5%, more specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC. For example, the purity of the amorphous ticagrelor essentially free of crystalline forms can be about 99% to about 99.95%, or about 99.5% to about 99.99%. The highly pure ticagrelor of the present invention is stable and does not have the tendency to convert to other forms.

Ticagrelor as used herein as starting material can be obtained by processes described in the prior art, for example by the process described in the U.S. Patent Nos. 6,251,910 and 6,525,060.

The amorphous ticagrelor according to the invention can have a D90 particle size of less than or equal to about 400 microns, specifically about 1 micron to about 300 micron, and most specifically about 10 microns to about 150 microns, as determined by laser diffraction.

The particle sizes of the amorphous ticagrelor according to the invention can be produced by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.

The invention also refers to a process for the preparation of the amorphous form of ticagrelor according to the invention, comprising the steps of:

a) providing a solution of ticagrelor of Formula I in an alcohol or mixture of alcohols wherein said alcohol or mixture of alcohols can comprise from 0 to 10% by volume of other solvents; the alcohol or mixture of alcohols can also comprises from 0 to 5% by volume of other solvents or from 0 to 5% by volume of other solvents while no water is present; preferably, no other solvents are present; b) optionally subjecting the solution obtained in step-(a) to a carbon treatment or a silica gel treatment; Applying a carbon treatment or a silica gel treatment may help removing impurities from the solution. Without wishing to be bound to any theory, it is believed that a carbon treatment or a silica treatment further reduces the tendency of ticagrelor to form the undesired crystal forms due to the presence of nucleation sites.

c) removing the solvent from the solution obtained in step-(a) or step-(b) under reduced pressure while maintaining the temperature of the solution in step-(c) in the range of from above the melting point of the solution, such as 5°C, 10°C, 20° or 50°C above the melting point, up to the boiling point of the solution at the reduced pressure to provide the amorphous form of ticagrelor. The temperature of the solution in step-(c) can also be in the range of from 5°C, 10°C, 20° or 30°C up to the boiling point of the solution at the reduced pressure. The temperature of the solution in step-(c) can also be in the range of from 20°C, 10° or 5°C below the boiling point of the solution at the reduced pressure up to the boiling point of the solution at the reduced pressure to ensure a fast evaporation of the solvent. Preferably, the removal of the solvent in step-(c) is not a freeze drying or spray-drying process.

Step-(a) of providing a solution of ticagrelor includes dissolving ticagrelor in the alcohol solvent, or obtaining an existing solution from a previous processing step.

The ticagrelor can be dissolved in the solvent at a temperature of below about reflux temperature of the solvent used, specifically at about 15°C to about 60°C, and still more specifically at about 20°C to about 40°C. Thus, the solution of ticagrelor in said alcohol solvent in step (a) can be obtained by dissolving ticagrelor of Formula I in said alcohol solvent at a temperature in the range of from 15°C up to the boiling point of the alcohol or mixture of alcohols, preferably said temperature range is from 15°C to 40°C. The suspension can be heated until a visually clear solution is formed. The solution obtained in step-(a) is optionally stirred at a temperature of about 15°C to the reflux temperature of the solvent used for at least 20 minutes, and specifically at a temperature of about 20°C to the reflux temperature of the solvent used from about 30 minutes to about 2 hours.

The alcohol or mixture of alcohols used in step-(a) can be selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, and mixtures thereof; preferably the alcohol is methanol, specifically dry methanol. As described above, the alcohol or mixture of alcohols may also comprise small amounts of non-alcohol solvents/other solvents, such as up to 10 % by volume. Likewise, if the alcohol or mixture of alcohols includes the preferred alcohol solvents defined above, small amounts of other solvents, preferably other alcohols, such as from 0 to 10 % or from 0 to 5% by volume may also be present. The alcohol or mixture of alcohols can also comprise the above preferred alcohols and from 0 to 10% or from 0 to 5% by volume of other solvents while no water is present; preferably, no other solvents are present; specifically, the alcohol or mixture of alcohols does not include any water. The preferred alcohol or mixture of alcohols used in step-(a) can also be selected from the group consisting of methanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, and mixtures thereof, while the above definitions regarding the presence of other solvents equally apply.

The carbon treatment or silica gel treatment in step-(b) is carried out by methods known in the art. For example, step-(b) can be carried out by stirring the solution of step-(a) with powdered or finely powdered carbon or silica gel at a temperature in the range of from 0°C to below 70°C, specifically at a temperature of about 20°C to about 40°C; specifically the temperature is below the boiling point of the solution, such as at least 5°C, 10°C or 20°C below the boiling point. Stirring can be performed for least 15 minutes or for at least 30 minutes for e.g. up to 2 hours or 1 hour. Then, the solution/mixture is filtered through a filter that is suitable for removing said charcoal or silica gel, such as hyflo® to obtain a filtrate. The carbon treatment or silica gel treatment in step-(b) can be carried out by using carbon/silica having a specific BET surface area of 500-2000 m²/g as measured by ISO 9277:2010(E) standard with carbon dioxide at 25°C and using static volumetric or multipoint methods. The activated carbon can be powdered activated carbon which passes a sieve with 1 mm or 2 mm size.

Specifically, the finely powdered carbon is an active carbon. A specific mesh size of silica gel is 0.4 mm- 0.5 mm (40-500 mesh), and more specifically 0.25 mm- 0.125 mm (60-120 mesh).

The solvent in step-(c) is removed at reduced pressure e.g. by evaporation under vacuum such as by using a rotary evaporator. The solution may also be completely evaporated in, for example, a pilot plant Rota vapor, a Vacuum Paddle Dryer or an agitated thin film dryer ("ATFD") to obtain a dry amorphous powder. The solvent in step-(c) can be evaporated at a pressure of between 4xl0² Pa to 66.7xl0³ Pa, preferably at a pressure of 4xl0² Pa to 3.3xl0³ Pa. Preferably, the solvent in step-(c) is evaporated in a rotary evaporator at a pressure of between 4xl0² Pa to 66.7x103 Pa, preferably at a pressure of 4x102 Pa to 3.3x103 Pa while preferably maintaining the temperature of the rotary evaporator bath in a range of from 25°C to 60°C, preferably in a range of from 40°C to 50°C. The temperature of the solution in step-(c) during evaporation at the above described reduced pressures can also be in the range of from 5°C, 10°C, 20° or 30°C up to the boiling point of the solution at the reduced pressure. The temperature of the solution in step-(c) can also be in the range of from 20°C, 10° or 5°C below the boiling point of the solution at the reduced pressure up to the boiling point of the solution at the reduced pressure to ensure a fast evaporation of the solvent.

Specifically, the solvent is removed at a pressure of about 66.7x10³ Pa (500 mm Hg) or less, more specifically at about 26.7x10³ Pa (200 mm Hg) or less, still more specifically at about 10.7xl0³ Pa (80 mm Hg) or less, and most specifically from about 7xl0² Pa (5 mm Hg) to about 3.3xl0³ Pa (25 mm Hg), or 4xl0² Pa (5 mm Hg) to 3.3xl0³ Pa (25 mm Hg).

The removal of solvent in step-(c) can be carried out at a temperature of below about 60°C, specifically at about 25°C to about 55°C, and still more specifically at about 40°C to about 50°C.

Another suitable method for removing the solvent is vertical agitated thin-film drying (or evaporation). Agitated thin film evaporation technology involves separating the volatile component using indirect heat transfer coupled with mechanical agitation of the flowing film under controlled conditions. In vertical agitated thin-film drying (or evaporation) (ATFD-V), the starting solution is fed from the top into a cylindrical space between a centered rotary agitator and an outside heating jacket. The rotor rotation agitates the downside-flowing solution while the heating jacket heats it.

The amorphous ticagrelor according to the invention may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines.

The drying can be carried out at atmospheric pressure or reduced pressures, such as below about 26.7x10³ Pa (200 mm Hg), or below about 6.7x10³ Pa (50 mm Hg), at temperatures such as about 25°C to about 70°C. The drying can be carried out for any desired time period that achieves the desired result, such as times about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing conditions should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, and the like. Drying equipment selection is well within the ordinary skill in the art.

The invention also refers to an amorphous form of ticagrelor of Formula I:

obtainable or obtained by using a process according to the invention.

The invention also refers to a pharmaceutical composition, preferably a solid dosage form or oral suspension, comprising the amorphous form of ticagrelor of Formula I according to the invention and one or more pharmaceutically acceptable excipients. Thus, encompassed herein is the use of the highly pure amorphous ticagrelor essentially free of crystalline forms for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.

A specific pharmaceutical composition of highly pure amorphous ticagrelor essentially free of crystalline forms is preferably selected from a solid dosage form and an oral suspension.

Pharmaceutical compositions can comprise at least a therapeutically effective amount of amorphous ticagrelor according to the invention. Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, elixir, aerosol, syrup, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes or any other acceptable route of administration. Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, troches, sachets, suspensions, powders, lozenges, elixirs and the like. The highly pure amorphous ticagrelor essentially free of crystalline forms may also be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes.

The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinabove.

Capsule dosage forms contain highly pure amorphous ticagrelor essentially free of crystalline forms within a capsule which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. Suitable enteric coating agents include phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxy methyl ethyl cellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, the coating agents may be employed with suitable plasticizers and/or extending agents. A coated capsule or tablet may have a coating on the surface thereof or may be a capsule or tablet comprising a powder or granules with an enteric-coating.

Tableting compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors. For example, the compositions described herein may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols such as mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.

Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.

The invention also refers to a process for preparing a pharmaceutical composition according to the invention, wherein the process comprises combining the amorphous form of ticagrelor according to the invention with one or more pharmaceutically acceptable excipients.

According to another aspect, the amorphous ticagrelor according to the invention is used in a method of treating a patient suffering from thrombosis, angina, ischemic heart diseases and coronary artery diseases, comprising administering a therapeutically effective amount of the amorphous ticagrelor according to the invention, or a pharmaceutical composition that comprises a therapeutically effective amount of amorphous ticagrelor according to the invention along with pharmaceutically acceptable excipients.

According to another aspect, there is provided pharmaceutical compositions comprising amorphous ticagrelor according to the invention prepared according to the processes disclosed herein and one or more pharmaceutically acceptable excipients.

INSTRUMENTAL DETAILS:

X-Ray Powder Diffraction (P-XRD):

The X-Ray powder diffraction was measured by an X-ray powder Diffractometer equipped with a Cu-anode (λ=1.54 Angstrom), X-ray source operated at 40kV, 40 mA and a Ni filter is used to strip K-alpha radiation. Two-theta calibration is performed using an NIST SRM 1976, Corundum standard. The sample was analyzed using the following instrument parameters: measuring range= 3-45° 2Θ; step width = 0.01579°; and measuring time per step = 0.11 second. The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrate the process of this invention. However, it is not intended in any way to limit the scope of the present invention.

EXAMPLES

Example

Preparation of Amorphous Form of Ticagrelor

Ticagrelor (500 mg) was dissolved in methanol (5 ml) at 20-25°C. The resulting clear solution was evaporated under vacuum (7xl0² Pa/5 mm Hg) on rotary evaporator while maintaining the temperature at 45-50°C. The resulting powder was further dried under vacuum at 45-50°C to give 450 mg of ticagrelor as off white powder (Yield: 90% w/w; Purity by HPLC: 99.68%).

Analytical Result:

The ticagrelor powder obtained by the above process is characterized by an X-ray powder diffraction pattern as depicted in Figure 1, which shows no peaks, thus demonstrating the amorphous nature of the product, which is essentially free from crystalline forms.

The following experiments (comparative examples) have been conducted by the present inventors to produce amorphous form of ticagrelor using the same process as exemplified above with different solvents under substantially same conditions (such as dichloromethane, methyl ethyl ketone and ethyl acetate), but it has been found that these experiments end up with crystalline forms and could not produce amorphous form of ticagrelor.

COMPARATIVE EXAMPLES

Comparative Example 1

Ticagrelor (500 mg) was dissolved in dichloromethane (15 ml) at 40-45°C and the resulting solution was evaporated under vacuum on rotary evaporator at 40-45°C. The resulting powder was further dried under vacuum at 50-55°C to give 400 mg of ticagrelor as off white powder (Yield: 80% w/w).

Analytical Result:

The ticagrelor powder obtained by the above process is characterized by an X-ray powder diffraction pattern as depicted in Figure 2, which shows peaks expressed as 2-theta angle positions at about 5.44, 6.73, 10.59, 13.45, 14.82, 18.25, 19.19, 19.72, 22.63 and 24.23 ± 0.2 degrees, thus demonstrating the crystalline nature of the product. Comparative Example 2

Ticagrelor (500 mg) was dissolved in methyl ethyl ketone (5 ml) at 65-70°C and the resulting solution was evaporated under vacuum on rotary evaporator at 50-55°C. The resulting powder was further dried under vacuum at 50-55°C to give 480 mg of ticagrelor as off white powder (Yield: 96% w/w).

Analytical Result:

The ticagrelor powder obtained by the above process is characterized by an X-ray powder diffraction pattern as depicted in Figure 3, which shows peaks expressed as 2-theta angle positions at about 5.48, 5.85, 6.74, 12.56, 13.45, 13.97, 17.48, 18.27, 19.15, 19.51, 21.35, 22.12, 22.67 and 24.22 ± 0.2 degrees, thus demonstrating the crystalline nature of the product.

Comparative Example 3

Ticagrelor (500 mg) was dissolved in ethyl acetate (10 ml) at 60-70°C and the resulting solution was evaporated under vacuum on rotary evaporator at 50-55°C. The resulting powder was further dried under vacuum at 50-55°C to give 480 mg of ticagrelor as off white powder (Yield: 96% w/w).

Analytical Result:

The ticagrelor powder obtained by the above process is characterized by an X-ray powder diffraction pattern as depicted in Figure 4, which shows peaks expressed as 2-theta angle positions at about 5.54, 6.82, 10.68, 13.52, 18.33, 19.24, 22.72 and 24.30 ± 0.2 degrees, thus demonstrating the crystalline nature of the product.

CITED DOCUMENTS

1 EP0996621 Al (published as WO 9905143 Al);

2 EP1 135391 Al (published as WO 00/34283 Al);

3 US 5,747,496;

4 US 6,251,910 Bl ; US 6,525,060 Bl; US 6,974,868 B2; US 7,067,663 B2; US 7,250,419 B2; US 2007/0265282 Al; US 2007/0293513 Al; US 2008/0214812 Al; WO2008/018823; and WO2010/030224 Al.

Claims

1. Amorphous form of ticagrelor of Formula I:

The amorphous form of ticagrelor of claim 1, wherein said X-ray powder diffraction pattern does not show peaks which have a full width at half peak maximum of less than 3 degrees 2-theta, preferably of less than 2 degrees 2-theta.

The amorphous form of ticagrelor of claim 1 or 2, having a chemical and/or chiral purity that is greater than 99%, preferably greater than 99.5%, as measured by HPLC.

The amorphous form of ticagrelor of any of the preceding claims, having a D₉₀ particle size of less than or equal to 400 microns, preferably 1 micron to 300 microns, as determined by laser diffraction.

Process for the preparation of the amorphous form of ticagrelor according to any of claims 1-4, comprising the steps of:

b) optionally subjecting the solution obtained in step-(a) to a carbon treatment or a silica gel treatment; c) removing the solvent from the solution obtained in step-(a) or step-(b) under reduced pressure while maintaining the temperature of the solution in step-(c) in the range of from above the melting point of the solution up to the boiling point of the solution at the reduced pressure to provide the amorphous form of ticagrelor.

6. The process of claim 5, wherein the alcohol or mixture of alcohols used in step-(a) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, and mixtures thereof; preferably the alcohol is methanol; and/or wherein the solution of ticagrelor in said alcohol solvent in step (a) is obtained by dissolving ticagrelor of Formula I in said alcohol solvent at a temperature in the range of from 15°C up to the boiling point of the alcohol or mixture of alcohols, preferably said temperature range is from 15°C to 40°C.

7. The process of claim 5 or 6, wherein step-(b) is carried out by stirring the solution of step- (a) with powdered carbon or silica gel at a temperature in the range of from 0°C to below 70°C for at least 15 minutes and filtering the resulting solution to remove said carbon or silica and provide a solution.

8. The process of any of claims 5-7, wherein the solvent in step-(c) is evaporated at a pressure of between 4xl0² Pa to 66.7xl0³ Pa, preferably at a pressure of 4xl0² Pa to 3.3xl0³ Pa.

9. The process of any of claims 5-8, wherein the carbon treatment or silica gel treatment is carried out by using carbon/silica having a specific BET surface area of 500-2000 m²/g as measured by ISO 9277:2010(E) standard with carbon dioxide at 25°C and using static volumetric or multipoint methods.

10. The process of any of claims 5-9, wherein the alcohol or mixture of alcohols used in step- (a) does not comprise water.

11. Amorphous form of ticagrelor of Formula I:

obtainable or obtained by using a process as defined in any of claims 5-10.

12. Pharmaceutical composition, preferably a solid dosage form or oral suspension, comprising the amorphous form of ticagrelor of Formula I according to any of claims 1-4 and 11 and one or more pharmaceutically acceptable excipients.

13. Process for preparing a pharmaceutical composition according to claim 12, wherein the process comprises combining the amorphous form of ticagrelor according to any of claims 1-4 and 11 with one or more pharmaceutically acceptable excipients.

14. Amorphous form of ticagrelor according to any of claims 1-4 and 11 for use as medicament.

15. Amorphous form of ticagrelor according to any of claims 1-4 and 11 or the pharmaceutical composition of claim 12 for use in the prevention of cardiovascular (CV) events including myocardial infarction (heart attacks), stroke, and cardiovascular death in patients with acute coronary syndrome (ACS) and the treatment of thrombosis, angina, ischemic heart diseases and coronary artery diseases.