WO2014083139A1 - Nouvelle forme amorphe de ticagrelor - Google Patents

Nouvelle forme amorphe de ticagrelor Download PDF

Info

Publication number
WO2014083139A1
WO2014083139A1 PCT/EP2013/075030 EP2013075030W WO2014083139A1 WO 2014083139 A1 WO2014083139 A1 WO 2014083139A1 EP 2013075030 W EP2013075030 W EP 2013075030W WO 2014083139 A1 WO2014083139 A1 WO 2014083139A1
Authority
WO
WIPO (PCT)
Prior art keywords
ticagrelor
amorphous form
solution
alcohol
solvent
Prior art date
Application number
PCT/EP2013/075030
Other languages
English (en)
Inventor
Anil Shahaji Khile
Vignesh Nair
Nikhil Trivedi
Nitin Sharadchandra Pradhan
Original Assignee
Actavis Group Ptc Ehf
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Actavis Group Ptc Ehf filed Critical Actavis Group Ptc Ehf
Publication of WO2014083139A1 publication Critical patent/WO2014083139A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • 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.
  • 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 ⁇ 2 ⁇ (P2Y ADP or P2T A c) 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.
  • ⁇ 2 ⁇ P2Y ADP or P2T A c
  • 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.
  • CV cardiovascular
  • 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.
  • 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- (3
  • U.S. Patent Application No. 2007/0293513 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).
  • P-XRD powder X-ray diffraction
  • DSC differential scanning calorimetry
  • the '513 application teaches an amorphous form of ticagrelor (Form a), and a process for preparing it.
  • 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.
  • 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.
  • Solvent medium, volume of the solvent medium and mode of isolation play very important role in obtaining one polymorphic form over another.
  • 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:
  • the invention also relates to a process for the preparation of the amoiphous form of ticagrelor according to the invention, comprising the steps of:
  • step-(a) optionally subjecting the solution obtained in step-(a) to a carbon treatment or a silica gel treatment;
  • step-(a) 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:
  • 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.
  • CV cardiovascular
  • ACS acute coronary syndrome
  • 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.
  • 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.
  • 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.
  • 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.
  • terapéuticaally effective amount 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.
  • delivering 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.
  • 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.
  • 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.
  • binder 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(TM) F68, PLURONIC(TM) 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.
  • filler 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.
  • 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.
  • 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.
  • 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(TM)), carsium (e.g., Amberlite(TM)), 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.
  • starches such as corn starch, potato starch, pregelatinized, sweeteners, clays, such as bentonite, microcrystalline cellulose (e.g., Avicel(TM)), carsium (e.g., Amberlite(TM)), alginates, sodium starch glycolate, gums
  • 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(TM)s), polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethy
  • micronization means a process or method by which the size of a population of particles is reduced.
  • micron or " ⁇ " both are same refers to “micrometer” which is lxl 0 "6 meter.
  • crystalline particles means any combination of single crystals, aggregates and agglomerates.
  • Particle Size Distribution 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., (D 50 )” correspondingly, means the median of said particle size distribution.
  • the important characteristics of the PSD are the (D 90 ), which is the size, in microns, below which 90% of the particles by volume are found, and the (D 50 ), which is the size, in microns, below which 50% of the particles by volume are found.
  • 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.
  • amorphous means a solid without long-range crystalline order.
  • 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.
  • 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.
  • reflux temperature / "boiling point” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
  • BET Brunauer, Emmett and Teller
  • the invention refers to an amorphous form of ticagrelor of Formula I:
  • the amorphous form of ticagrelor according to the invention is essentially free of crystalline forms of ticagrelor.
  • 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 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.
  • 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.
  • 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:
  • step-(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.
  • 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.
  • 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.
  • step-(a) 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.
  • the alcohol or mixture of alcohols may also comprise small amounts of non-alcohol solvents/other solvents, such as up to 10 % by volume.
  • 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.
  • step-(b) The carbon treatment or silica gel treatment in step-(b) is carried out by methods known in the art.
  • 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.
  • 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 m 2 /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.
  • 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 4xl0 2 Pa to 66.7xl0 3 Pa, preferably at a pressure of 4xl0 2 Pa to 3.3xl0 3 Pa.
  • the solvent in step-(c) is evaporated in a rotary evaporator at a pressure of between 4xl0 2 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.
  • the solvent is removed at a pressure of about 66.7x10 3 Pa (500 mm Hg) or less, more specifically at about 26.7x10 3 Pa (200 mm Hg) or less, still more specifically at about 10.7xl0 3 Pa (80 mm Hg) or less, and most specifically from about 7xl0 2 Pa (5 mm Hg) to about 3.3xl0 3 Pa (25 mm Hg), or 4xl0 2 Pa (5 mm Hg) to 3.3xl0 3 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.
  • 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.
  • ICH International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use
  • the drying can be carried out at atmospheric pressure or reduced pressures, such as below about 26.7x10 3 Pa (200 mm Hg), or below about 6.7x10 3 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:
  • 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.
  • a pharmaceutical composition preferably a solid dosage form or oral suspension
  • the amorphous form of ticagrelor of Formula I according to the invention and one or more pharmaceutically acceptable excipients.
  • 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.
  • 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.
  • 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.
  • compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors.
  • 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.
  • 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.
  • 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.
  • 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 pharmaceutical
  • 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.
  • CV cardiovascular
  • ACS acute coronary syndrome
  • 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.
  • 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.
  • compositions comprising amorphous ticagrelor according to the invention prepared according to the processes disclosed herein and one or more pharmaceutically acceptable excipients.
  • 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.
  • Ticagrelor 500 mg was dissolved in methanol (5 ml) at 20-25°C. The resulting clear solution was evaporated under vacuum (7xl0 2 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%).
  • 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.
  • 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).
  • 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 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).
  • 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.
  • 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).
  • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une nouvelle forme amorphe du ticagrelor, un procédé permettant sa préparation, des compositions pharmaceutiques comprenant cette nouvelle forme amorphe de ticagrelor, et l'utilisation de la nouvelle forme amorphe de ticagrelor en tant que médicament.
PCT/EP2013/075030 2012-11-29 2013-11-29 Nouvelle forme amorphe de ticagrelor WO2014083139A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN3660/DEL/2012 2012-11-29
EP12194810.3 2012-11-29
EP12194810 2012-11-29
IN3660DE2012 2012-11-29

Publications (1)

Publication Number Publication Date
WO2014083139A1 true WO2014083139A1 (fr) 2014-06-05

Family

ID=50068956

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2013/075030 WO2014083139A1 (fr) 2012-11-29 2013-11-29 Nouvelle forme amorphe de ticagrelor

Country Status (1)

Country Link
WO (1) WO2014083139A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104193747A (zh) * 2014-08-12 2014-12-10 许彩霞 替卡格雷无定形的制备
WO2015162537A1 (fr) * 2014-04-23 2015-10-29 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Procédé de préparation de ticagrélor
CN105315282A (zh) * 2014-07-15 2016-02-10 博瑞生物医药（苏州）股份有限公司 一种制备替卡格雷无定型的方法
WO2016024225A1 (fr) * 2014-08-11 2016-02-18 Sun Pharmaceutical Industries Limited Ticagrelor amorphe stable et procédé pour sa préparation
USRE46276E1 (en) 1998-12-04 2017-01-17 Astrazeneca Uk Limited Triazolo(4,5-D)pyrimidine compounds
CN106645528A (zh) * 2016-11-25 2017-05-10 成都欣捷高新技术开发股份有限公司 一种替格瑞洛手性异构体含量的高效液相色谱检测方法
CN106841413A (zh) * 2015-12-04 2017-06-13 江苏恒瑞医药股份有限公司 一种替格瑞洛对映异构体、非对映异构体的分离检测方法
EP3266447A1 (fr) * 2016-02-12 2018-01-10 Ali Raif Ilac San. A.S. Procédé de production de formulations contenant du ticagrelor
CN111529491A (zh) * 2020-06-29 2020-08-14 合肥医工医药股份有限公司 一种速效安全的替格瑞洛口腔喷雾剂及其制备方法

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5747496A (en) 1995-07-11 1998-05-05 Astra Pharmaceuticals Limited Inhibitors of platelet aggregation
WO1999005143A1 (fr) 1997-07-22 1999-02-04 Astra Pharmaceuticals Ltd. Nouveaux composes
WO2000034283A1 (fr) 1998-12-04 2000-06-15 Astrazeneca Ab Nouveaux composes de triazolo(4,5-d)pyrimidine
US6251910B1 (en) 1997-07-22 2001-06-26 Astrazeneca Uk Limited 1,2,3-triazolo[4,5-d]pyrimidines as P2T receptor antagonists
WO2001092262A1 (fr) * 2000-06-02 2001-12-06 Astrazeneca Ab Nouvelle forme cristalline et amorphe d'un compose de triazolo(4,5-d)pyrimidine
US7067663B2 (en) 2000-06-02 2006-06-27 Astrazeneca Ab Triazolo pyrimidine compounds
WO2008018823A1 (fr) 2006-08-05 2008-02-14 Astrazeneca Ab Procédé de préparation de cyclopropylamines optiquement actives
WO2010030224A1 (fr) 2008-09-09 2010-03-18 Astrazeneca Ab Procédé pour préparer le [1s-[1-alpha,2-alpha,3-bêta(1s*,2r*)-5-bêta]]-3-[7-[2-(3,4-difluorophényl)-cyclopropylamino]-5-(propylthio)-3h-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyéthoxy)cyclopentane-1,2-diol et ses intermédiaires

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5747496A (en) 1995-07-11 1998-05-05 Astra Pharmaceuticals Limited Inhibitors of platelet aggregation
US6251910B1 (en) 1997-07-22 2001-06-26 Astrazeneca Uk Limited 1,2,3-triazolo[4,5-d]pyrimidines as P2T receptor antagonists
WO1999005143A1 (fr) 1997-07-22 1999-02-04 Astra Pharmaceuticals Ltd. Nouveaux composes
EP0996621A1 (fr) 1997-07-22 2000-05-03 Astra Pharmaceuticals Limited Nouveaux composes
US6974868B2 (en) 1998-12-04 2005-12-13 Astrazeneca Ab Compounds
EP1135391A1 (fr) 1998-12-04 2001-09-26 AstraZeneca AB Nouveaux composes de triazolo(4,5-d)pyrimidine
US6525060B1 (en) 1998-12-04 2003-02-25 Astrazeneca Uk Limited Triazolo(4,5-d)pyrimidine compounds
WO2000034283A1 (fr) 1998-12-04 2000-06-15 Astrazeneca Ab Nouveaux composes de triazolo(4,5-d)pyrimidine
US7250419B2 (en) 1998-12-04 2007-07-31 Astrazeneca Ab Trisubstituted triazolopyrimidines for use in platelet aggregation inhibition
US20070265282A1 (en) 1998-12-04 2007-11-15 Astrazeneca Ab Novel compounds
US20080214812A1 (en) 1998-12-04 2008-09-04 Astrazeneca Ab Trisubstituted triazolopyrimidines for use in platelet aggregation inhibition
WO2001092262A1 (fr) * 2000-06-02 2001-12-06 Astrazeneca Ab Nouvelle forme cristalline et amorphe d'un compose de triazolo(4,5-d)pyrimidine
US7067663B2 (en) 2000-06-02 2006-06-27 Astrazeneca Ab Triazolo pyrimidine compounds
US20070293513A1 (en) 2000-06-02 2007-12-20 Astrazeneca Ab Cristalline and amorphous form of a triazolo (4,5-d) pyridimine compound
WO2008018823A1 (fr) 2006-08-05 2008-02-14 Astrazeneca Ab Procédé de préparation de cyclopropylamines optiquement actives
WO2010030224A1 (fr) 2008-09-09 2010-03-18 Astrazeneca Ab Procédé pour préparer le [1s-[1-alpha,2-alpha,3-bêta(1s*,2r*)-5-bêta]]-3-[7-[2-(3,4-difluorophényl)-cyclopropylamino]-5-(propylthio)-3h-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyéthoxy)cyclopentane-1,2-diol et ses intermédiaires

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Amorphous Forms of (1S,2S,3R,5S)-3-[7-[[1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol", IP.COM JOURNAL - IPCOM000207885D, vol. 11, no. 6B, 6, 15 June 2011 (2011-06-15), XP002690055, ISSN: 1533-0001 *
VOGEL, A. I.; FURNISS, B.S.; HANNAFORD, A.J.; SMITH, P.W.G.; TATCHELL, A.R.: "Vogel's Textbook of Practical Organic Chemistry", 1996, ADDISON WESLEY LONGMAN LIMITED, ISBN: 0-582-46236-3, article "Use of Decoulourising Carbon", pages: 140 - 140, XP002690072 *
VOGEL, A.I.; FURNISS, B.S.; HANNAFORD, A.J.; SMITH, P.W.G.; TATCHELL, A.R.: "Vogel's Textbook of Practical Organic Chemistry", 1996, ADDISON WESLEY LONGMAN LIMITED, ISBN: 0-582-46236-3, article "2.27 Distillation under Diminished Pressure ('Vacuum' Distillation)", pages: 181 - 186, XP002690073 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE46276E1 (en) 1998-12-04 2017-01-17 Astrazeneca Uk Limited Triazolo(4,5-D)pyrimidine compounds
WO2015162537A1 (fr) * 2014-04-23 2015-10-29 Glenmark Pharmaceuticals Limited; Glenmark Generics Limited Procédé de préparation de ticagrélor
CN105315282A (zh) * 2014-07-15 2016-02-10 博瑞生物医药（苏州）股份有限公司 一种制备替卡格雷无定型的方法
CN105315282B (zh) * 2014-07-15 2018-09-21 博瑞生物医药（苏州）股份有限公司 一种制备替卡格雷无定型的方法
WO2016024225A1 (fr) * 2014-08-11 2016-02-18 Sun Pharmaceutical Industries Limited Ticagrelor amorphe stable et procédé pour sa préparation
US10017515B2 (en) 2014-08-11 2018-07-10 Sun Pharmaceutical Industries Limited Stable amorphous ticagrelor and a process for its preparation
CN104193747A (zh) * 2014-08-12 2014-12-10 许彩霞 替卡格雷无定形的制备
CN106841413A (zh) * 2015-12-04 2017-06-13 江苏恒瑞医药股份有限公司 一种替格瑞洛对映异构体、非对映异构体的分离检测方法
CN106841413B (zh) * 2015-12-04 2020-07-28 江苏恒瑞医药股份有限公司 一种替格瑞洛对映异构体、非对映异构体的分离检测方法
EP3266447A1 (fr) * 2016-02-12 2018-01-10 Ali Raif Ilac San. A.S. Procédé de production de formulations contenant du ticagrelor
CN106645528A (zh) * 2016-11-25 2017-05-10 成都欣捷高新技术开发股份有限公司 一种替格瑞洛手性异构体含量的高效液相色谱检测方法
CN111529491A (zh) * 2020-06-29 2020-08-14 合肥医工医药股份有限公司 一种速效安全的替格瑞洛口腔喷雾剂及其制备方法
CN111529491B (zh) * 2020-06-29 2022-04-22 合肥医工医药股份有限公司 一种速效安全的替格瑞洛口腔喷雾剂及其制备方法

Similar Documents

Publication Publication Date Title
WO2014083139A1 (fr) Nouvelle forme amorphe de ticagrelor
US20150329546A1 (en) Novel crystalline form of ticagrelor and process for the preparation thereof
US20110014291A1 (en) Novel Polymorphs of Bosentan
US20100272815A1 (en) Amorphous form of tapentadol hydrochloride
WO2012004677A1 (fr) Formes à l'état solide de sels d'étoricoxib
JP2021523918A (ja) Ｔｌｒ７／ｔｌｒ８阻害剤の結晶形態
US20110021547A1 (en) Substantially Pure and a Stable Crystalline Form of Bosentan
US7947699B2 (en) Anhydrous amorphous imatinib mesylate
JP2008543976A (ja) ペメトレキセド二酸の医薬上許容される凍結乾燥塩の調製方法
KR20030069796A (ko) 졸피뎀 헤미타르트레이트
US20100297241A1 (en) Amorphous Fesoterodine Fumarate
JP2008543975A (ja) 高度に純粋なペメトレキセド二酸およびその調製方法
WO2009053840A2 (fr) Formes solides de sels de (±)-o-déméthylvenlafaxine
CN111699190A (zh) 比卡格韦钠的晶形
US20090061005A1 (en) Paliperidone Polymorphs
WO2009106997A9 (fr) L-(+)-tartrate d’arformotérol amorphe
US9593117B2 (en) Crystalline form of N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide for the treatment of myeloproliferative disorders
CN105418614A (zh) 替格瑞洛的新结晶形式及其制备方法和用途
US20100260851A1 (en) Novel Polymorph of Atorvastatin Calcium and Use Thereof for the Preparation of Amorphous Atorvastatin Calcium
CA2801842A1 (fr) Co-precipites amorphes de tartrate de varenicline
US9598413B2 (en) Crystalline form of N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-D]pyrrolo[2,3-B]pyridine-7-carboxamide for the treatment of myeloproliferative disorders
US9464086B2 (en) Crystalline forms of N,N-dicyclopropyl-4-(1,5-dimethyl-1 H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-D]pyrrolo[2,3-B]pyridine-7-carboxamide for the treatment of myeloproliferative disorders
US20160090385A1 (en) Crystalline forms of n,n-dicyclopropyl-4-(1,5-dimethyl-1h-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboximide for the treatment of myeloproliferative disorders
EP3704124A1 (fr) Sel cristallin d'un inhibiteur de poly(adp-ribose) polymérase tricyclique
US20100204296A1 (en) Novel Polymorphs of Darifenacin Free Base and its Hydrobromide Salt

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13827004

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13827004

Country of ref document: EP

Kind code of ref document: A1