WO2014118808A2 - Ticagrelor solid dispersion - Google Patents

Ticagrelor solid dispersion Download PDF

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Publication number
WO2014118808A2
WO2014118808A2 PCT/IN2014/000079 IN2014000079W WO2014118808A2 WO 2014118808 A2 WO2014118808 A2 WO 2014118808A2 IN 2014000079 W IN2014000079 W IN 2014000079W WO 2014118808 A2 WO2014118808 A2 WO 2014118808A2
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Prior art keywords
ticagrelor
solid dispersion
pharmaceutically acceptable
solvent
amorphous
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PCT/IN2014/000079
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French (fr)
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WO2014118808A3 (en
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Dasari Muralidhara Reddy
Kesireddy Subash Chander Reddy
Katham SRINIVASA REDDY
Bandi Vamsi Krishna
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Hetero Research Foundation
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Publication of WO2014118808A3 publication Critical patent/WO2014118808A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • 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

Definitions

  • the present invention provides a novel amorphous sol id dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
  • Ticagrelor is known by the chemical name ⁇ lS-[la,2a,3p(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 and has the structural formula:
  • Ticagrelor is a platelet aggregation inhibitor.
  • the generic name ticagrelor is marketed by ASTRAZENECA under the brand name BRILINTA .
  • Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph.
  • Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
  • XRD X-ray diffraction
  • DSC Differential Scanning Calorimetry
  • IR Infrared spectrometry
  • Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.
  • Ticagrelor can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
  • IP.COM Journal no. IPCOM000207908D disclosed crystalline Form of ticagrelor. It was observed that the crystalline Forms and amorphous Form of ticagrelor either not reproducible or not stable.
  • an object of the present invention is to provide a novel amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
  • the present invention provides amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier.
  • the present invention there is provided a process for the preparation of amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier, which comprises:
  • compositions comprising a therapeutically effective amount of amorphous solid dispersion of ticagrelor along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
  • Figure 1 is. a powder X-ray diffractogram patterns of amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier.
  • Powder X-ray diffraction spectrum was measured on a bruker AXS D8 advance powder X-ray diffractometer having a copper- ⁇ radiation. Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two- theta, at 0.020 degrees two theta per step and a step time of 1 second. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 kV and current 35 mA.
  • room temperature refers to temperature at about 25 to 35 C.
  • amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier.
  • the powdered x-ray diffractogram (PXRD) of amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier is shown in figure 1.
  • the pharmaceutically acceptable carriers may be one or more of copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus.
  • the said pharmaceutically acceptable carriers are used to facilitate the presence of an amorphous ticagrelor.
  • solid dispersion refers to a composition prepared by dissolving or dispersing a substituted ticagrelor in an organic solvent or mixture of organic solvents with one or more pharmaceutically acceptable carriers and converting the solution or dispersion to a solid form.
  • a process for the preparation of amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier which comprises:
  • Ticagrelor used in step (a) may preferably be ticagrelor obtained by the known process.
  • the solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol, n-pentanol, methylene chloride, chloroform, carbontetrachloride and ethylene dichloride. More preferably the solvents are methylene chloride, dimethyl sulfoxide, dimethylacetamide, dimethylformamide and methanol.
  • the pharmaceutically acceptable carriers used in step (a) may be selected from copovidone, soluplus or hydroxypropyl methylcellulose.
  • the solvent may be removed from the solution in step (b) by known methods, for example, distillation or spray drying.
  • the distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure.
  • the distillation may preferably be carried out until the solvent is almost completely distilled off.
  • reduced pressure refers to a pressure of less than 100 mmHg.
  • spray drying refers to is a method of producing a dry powder from a liquid or slurry by rapidly drying with a hot gas.
  • compositions comprising a therapeutically effective amount of amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier and along with pharmaceutically acceptable excipients, and at least one pharmaceutically acceptable excipient.
  • amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
  • the present invention provides a pharmaceutical composition containing said solid dispersion along with the pharmaceutically acceptable excipients such as diluents, chelating agents, disintegrant, glidant, binders, surfactants, coloring agents and/or lubricants.
  • pharmaceutically acceptable excipients such as diluents, chelating agents, disintegrant, glidant, binders, surfactants, coloring agents and/or lubricants.
  • binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
  • diluents include calcium carbonate, calcium phosphate- dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like and mixtures thereof.
  • Surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical dosage forms.
  • polyethoxylated fatty acids and its derivatives for example, polyethylene glycol 400 distearate, polyethylene glycol-20 dioleate, polyethylene glycol 4 - 150 mono dilaurate, and polyethylene glycol - 20 glyceryl stearate; alcohol - oil transesterification products, for example, polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example, polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example, propylene glycol monocaprylate; mono and diglycerides, for example, glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example, polyethylene glycol - 20 sorbitan monooleate and sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example, polyethylene glycol - 20 cetyl ether and polyethylene glycol
  • disintegrants include low-substituted hydroxypropylcellulose (L-HPC), sodium starch glycollate, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium A-type (Ac-di-sol), starch, crystalline cellulose, hydroxypropyl starch, pregelatinized starch, and the like and mixtures thereof.
  • lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like and mixtures thereof.
  • Coloring agents include any FDA approved colors for oral use.
  • the reaction mass was stirred for 3 hours at room temperature and the solvent was distilled off under vacuum to obtain a residual mass.
  • the residual mass was adjusted to pH to 8 with sodium hydroxide (25%) and then extracted with ethyl acetate. The layers were separated and the organic layer was dried with sodium sulfate.
  • the solvent was distilled off under vacuum at below 40°C to obtain a solid.
  • To the solid was added acetonitrile (300 ml) at 55°C to obtain a clear solution. To the solution was then cooled to 10 to 15°C for 1 hour, filtered and then dried to obtain 23 gm of ticagrelor.
  • Example 2 Preparation of amorphous ticagrelor solid dispersion with copovidone Example 2 was repeated using dimethylformamide solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with copovidone.
  • Example 2 was repeated using dimethylacetamide solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with copovidone.
  • Example 6 was repeated using dimethylacetamide solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with copovidone.
  • Example 2 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with copovidone.
  • Example 7 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with copovidone.
  • Example 2 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with copovidone.
  • Example 8 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with copovidone.
  • Example 8 Preparation of amorphous ticagrelor solid dispersion with hydroxypropyl methylcellulose
  • Example 8 was repeated using dimethylformamide solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with hydroxypropyl methylcellulose.
  • Example 10
  • Example 8 was repeated using dimethylacetamide solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with hydroxypropyl methylcellulose.
  • Example 8 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with hydroxypropyl methylcellulose.
  • Example 8 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with hydroxypropyl methylcellulose.
  • Example 13
  • Example 13 was repeated using dimethylformamide solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with soluplus.
  • Example 13 was repeated using dimethylacetamide solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with soluplus.
  • Example 13 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with soluplus.
  • Example 13 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with soluplus.
  • the reaction mass was stirred for 3 hours at room temperature and the solvent was distilled off under vacuum to obtain a residual mass.
  • the residual mass was adjusted to pH to 8 with sodium hydroxide (25%) and then extracted with ethyl acetate. The layers were separated and the organic layer was dried with sodium sulfate.
  • the solvent was distilled off under vacuum at below 40°C and then added copovidone (26 gm) and methanol (260 ml) at room temperature.
  • the reaction mixture was stirred for 15 minutes and filtered through celite bed.
  • the solvent was distilled off under reduced pressure at below 50°C to obtain 50 gm of amorphous ticagrelor solid dispersion with copovidone.
  • the reaction mass was stirred for 3 hours at room temperature and the solvent was distilled off under vacuum to obtain a residual mass.
  • the residual mass was adjusted to pH to 8 with sodium hydroxide (25%) and then extracted with ethyl acetate. The layers were separated and the organic layer was dried with sodium sulfate.
  • the solvent was distilled off under vacuum at below 40 C and then added hydroxypropyl methylcellulose (26 gm) and methanol (260 ml) at room temperature.
  • the reaction mixture was stirred for 15 minutes and filtered through celite bed.
  • the solvent was distilled off under reduced pressure at below 50°C to obtain 49.5 gm of amorphous ticagrelor solid dispersion with hydroxypropyl methylcellulose.
  • the reaction mass was stirred for 3 hours at room temperature and the solvent was distilled off under vacuum to obtain a residual mass.
  • the residual mass was adjusted to pH to 8 with sodium hydroxide (25%) and then extracted with ethyl acetate. The layers were separated and the organic layer was dried with sodium sulfate.
  • the solvent was distilled off under vacuum at below 40°C and then added soluplus (26 gm) and methanol (260 ml) at room temperature.
  • the reaction mixture was stirred for 15 minutes and filtered through celite bed.
  • the solvent was distilled off under reduced pressure at below 50°C to obtain 48 gm of amorphous ticagrelor solid dispersion with soluplus.

Abstract

The present invention provides a novel amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.

Description

TICAGRELOR SOLID DISPERSION
This application claims the benefit of Indian Provisional Patent Application No. 468/CHE/2013, filed on February 04, 2013, which is incorporated herein by reference.
Filed of the Invention
The present invention provides a novel amorphous sol id dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
Background of the Invention
Ticagrelor is known by the chemical name { lS-[la,2a,3p(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 and has the structural formula:
Figure imgf000002_0001
Ticagrelor is a platelet aggregation inhibitor. The generic name ticagrelor is marketed by ASTRAZENECA under the brand name BRILINTA .
Ticagrelor and its process were disclosed in U.S. patent no. 6,525,060. Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.
Ticagrelor can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
U.S. patent no. 7,265,124 disclosed crystalline Form I, Form II, Form III, Form
IV and amorphous Form of ticagrelor.
Amorphous Form of ticagrelor was disclosed in IP.COM Journal no. IPCOM000207885D.
IP.COM Journal no. IPCOM000207908D disclosed crystalline Form of ticagrelor. It was observed that the crystalline Forms and amorphous Form of ticagrelor either not reproducible or not stable.
We have also found a novel amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier. The amorphous solid dispersion of ticagrelor is stable, reproducible and so, the amorphous solid dispersion of ticagrelor is suitable for formulating ticagrelor. Normally amorphous Forms are hygroscopic. Amorphous solid dispersion of ticagrelor is found to be non-hygroscopic. Thus, an object of the present invention is to provide a novel amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it. Summary of the Invention
In one aspect, the present invention provides amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier.
In another aspect, the present invention there is provided a process for the preparation of amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier, which comprises:
a) preparing a solution comprising a mixture of ticagrelor and one or more pharmaceutically acceptable carriers selected from copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus in a solvent; and b) removing the solvent to obtain amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier.
Yet in another aspect, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of amorphous solid dispersion of ticagrelor along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
Brief Description of the Drawing
Figure 1 is. a powder X-ray diffractogram patterns of amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier.
Powder X-ray diffraction spectrum was measured on a bruker AXS D8 advance powder X-ray diffractometer having a copper-Κα radiation. Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two- theta, at 0.020 degrees two theta per step and a step time of 1 second. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 kV and current 35 mA.
Detailed Description of the Invention The term "room temperature" refers to temperature at about 25 to 35 C.
According to one aspect of the present invention, there is provided amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier.
The powdered x-ray diffractogram (PXRD) of amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier is shown in figure 1.
Amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier having enhanced stability, dissolution properties that can be easily formulated into pharmaceutical compositions.
Preferably the pharmaceutically acceptable carriers may be one or more of copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus. The said pharmaceutically acceptable carriers are used to facilitate the presence of an amorphous ticagrelor.
The term "solid dispersion" herein refers to a composition prepared by dissolving or dispersing a substituted ticagrelor in an organic solvent or mixture of organic solvents with one or more pharmaceutically acceptable carriers and converting the solution or dispersion to a solid form.
According to another aspect of the present invention, there is provided a process for the preparation of amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier, which comprises:
a) preparing a solution comprising a mixture of ticagrelor and one or more pharmaceutically acceptable carriers selected from copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus in a solvent; and b) removing the solvent to obtain amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier.
Ticagrelor used in step (a) may preferably be ticagrelor obtained by the known process.
The solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol, n-pentanol, methylene chloride, chloroform, carbontetrachloride and ethylene dichloride. More preferably the solvents are methylene chloride, dimethyl sulfoxide, dimethylacetamide, dimethylformamide and methanol. Preferably the pharmaceutically acceptable carriers used in step (a) may be selected from copovidone, soluplus or hydroxypropyl methylcellulose.
The solvent may be removed from the solution in step (b) by known methods, for example, distillation or spray drying.
The distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is almost completely distilled off.
As used herein, "reduced pressure" refers to a pressure of less than 100 mmHg.
The term "spray drying" refers to is a method of producing a dry powder from a liquid or slurry by rapidly drying with a hot gas.
According to another aspect of the present invention, there is provided pharmaceutical compositions comprising a therapeutically effective amount of amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier and along with pharmaceutically acceptable excipients, and at least one pharmaceutically acceptable excipient. The amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
Preferably the present invention provides a pharmaceutical composition containing said solid dispersion along with the pharmaceutically acceptable excipients such as diluents, chelating agents, disintegrant, glidant, binders, surfactants, coloring agents and/or lubricants.
Specific examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
Specific examples of diluents include calcium carbonate, calcium phosphate- dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like and mixtures thereof. Surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical dosage forms. These include polyethoxylated fatty acids and its derivatives, for example, polyethylene glycol 400 distearate, polyethylene glycol-20 dioleate, polyethylene glycol 4 - 150 mono dilaurate, and polyethylene glycol - 20 glyceryl stearate; alcohol - oil transesterification products, for example, polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example, polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example, propylene glycol monocaprylate; mono and diglycerides, for example, glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example, polyethylene glycol - 20 sorbitan monooleate and sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example, polyethylene glycol - 20 cetyl ether and polyethylene glycol - 10 - 100 nonyl phenol; sugar esters, for example, sucrose monopalmitate; polyoxyethylene - polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for example, sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, and palmitoyl carnitine; and the like and mixtures thereof.
Specific examples of disintegrants include low-substituted hydroxypropylcellulose (L-HPC), sodium starch glycollate, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium A-type (Ac-di-sol), starch, crystalline cellulose, hydroxypropyl starch, pregelatinized starch, and the like and mixtures thereof.
Specific examples of lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like and mixtures thereof.
Coloring agents include any FDA approved colors for oral use.
The invention will now be further described by the following examples, which are illustrative rather than limiting.
Examples
Example 1 : Preparation of ticagrelor
(3aR-(3aa,4a,6a(lR*,2S*)6aa)-2-[6-({7-[2-(3,4-difluorophenyl)cyclopropyl] amino-5-^ropylthio)-3H-l,2,3-triazolo[4,5-d]pyrimidin-3yl)tetrahydro-2,2-dimethyl-4H- cyclopenta-l,3-dioxol-4yl)oxy]ethanol (30 gm) was dissolved in methanol (240 ml) and then added concentrated hydrochloric acid (90 ml) slowly for 15 minutes. The reaction mass was stirred for 3 hours at room temperature and the solvent was distilled off under vacuum to obtain a residual mass. The residual mass was adjusted to pH to 8 with sodium hydroxide (25%) and then extracted with ethyl acetate. The layers were separated and the organic layer was dried with sodium sulfate. The solvent was distilled off under vacuum at below 40°C to obtain a solid. To the solid was added acetonitrile (300 ml) at 55°C to obtain a clear solution. To the solution was then cooled to 10 to 15°C for 1 hour, filtered and then dried to obtain 23 gm of ticagrelor.
Example 2:
Preparation of amorphous ticagrelor solid dispersion with copovidone
A mixture of ticagrelor (10 gm) as obtained in example 1 and copovidone (10 gm) was dissolved in methanol (100 ml) at room temperature. The reaction mixture was stirred for 15 minutes and filtered through celite bed. The solvent was distilled off under reduced pressure at below 50°C to obtain 19 gm of amorphous ticagrelor solid dispersion with copovidone.
Example 3:
Preparation of amorphous ticagrelor solid dispersion with copovidone
A mixture of ticagrelor (10 gm) and copovidone (20 gm) was dissolved in methanol (150 ml) at room temperature. The reaction mixture was stirred for 15 minutes and filtered through ceiite bed. The solvent was distilled off under reduced pressure at below 50°C to obtain 28.5 gm of amorphous ticagrelor solid dispersion with copovidone.
Example 4:
Preparation of amorphous ticagrelor solid dispersion with copovidone Example 2 was repeated using dimethylformamide solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with copovidone.
Example 5:
Preparation of amorphous ticagrelor solid dispersion with copovidone
Example 2 was repeated using dimethylacetamide solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with copovidone. Example 6:
Preparation of amorphous ticagrelor solid dispersion with copovidone
Example 2 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with copovidone. Example 7:
Preparation of amorphous ticagrelor solid dispersion with copovidone
Example 2 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with copovidone. Example 8:
Preparation of amorphous ticagrelor solid dispersion with hydroxypropyl methylcellulose
A mixture of ticagrelor (10 gm) and hydroxypropyl methylcellulose (10 gm) was dissolved in methanol (100 ml) at room temperature. The reaction mixture was stirred for 15 minutes and filtered through celite bed. The solvent was distilled off under reduced pressure at below 50°C to obtain 18.5 gm of amorphous ticagrelor solid dispersion with hydroxypropyl methylcellulose.
Example 9:
Preparation of amorphous ticagrelor solid dispersion with hydroxypropyl methylcellulose Example 8 was repeated using dimethylformamide solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with hydroxypropyl methylcellulose. Example 10:
Preparation of amorphous ticagrelor solid dispersion with hydroxypropyl methylcellulose
Example 8 was repeated using dimethylacetamide solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with hydroxypropyl methylcellulose.
Example 11 :
Preparation of amorphous ticagrelor solid dispersion with hydroxypropyl methylcellulose
Example 8 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with hydroxypropyl methylcellulose.
Example 12:
Preparation of amorphous ticagrelor solid dispersion with hydroxypropyl methylcellulose
Example 8 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with hydroxypropyl methylcellulose. Example 13:
Preparation of amorphous ticagrelor solid dispersion with soluplus
A mixture of ticagrelor (10 gm) and soluplus (10 gm) was dissolved in methanol (100 ml) at room temperature. The reaction mixture was stirred for 15 minutes and filtered through celite bed. The solvent was distilled off under reduced pressure at below 50°C to obtain 18 gm of amorphous ticagrelor solid dispersion with soluplus. Example 14:
Preparation of amorphous ticagrelor solid dispersion with soluplus
Example 13 was repeated using dimethylformamide solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with soluplus.
Example 15:
Preparation of amorphous ticagrelor solid dispersion with soluplus
Example 13 was repeated using dimethylacetamide solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with soluplus.
Example 16:
Preparation of amorphous ticagrelor solid dispersion with soluplus
Example 13 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with soluplus.
Example 17:
Preparation of amorphous ticagrelor solid dispersion with soluplus
Example 13 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous ticagrelor solid dispersion with soluplus.
Example 18:
Preparation of amorphous ticagrelor solid dispersion with polyethylene glycol
A mixture of ticagrelor (10 gm) and polyethylene glycol (10 gm) was dissolved in methanol (100 ml) at room temperature. The reaction mixture was stirred for 15 minutes and filtered through celite bed. The solvent was distilled off under reduced pressure at below 50°C to obtain 18 gm of amorphous ticagrelor solid dispersion with polyethylene glycol.
Example 19:
Preparation of amorphous ticagrelor solid dispersion with ethyl cellulose A mixture of ticagrelor (10 gm) and ethyl cellulose (10 gm) was dissolved in methanol (100 ml) at room temperature. The reaction mixture was stirred for 15 minutes and filtered through celite bed. The solvent was distilled off under reduced pressure at below 50°C to obtain 18 gm of amorphous ticagrelor solid dispersion with ethyl cellulose.
Example 20:
Preparation of amorphous ticagrelor solid dispersion with copovidone
(3aR-(3aa,4a,6a(lR*,2S*)6aa)-2-[6-({7-[2-(3,4-difluorophenyl)cyclopropyl] amino-5-(propylthio)-3H-l ,2,3-triazolo[4,5-d]pyrimidin-3yl)tetrahydro-2,2-dimethyl-4H- cyclopenta-l,3-dioxol-4yl)oxy]ethanol (30 gm) was dissolved in methanol (240 ml) and then added concentrated hydrochloric acid (90 ml) slowly for 15 minutes. The reaction mass was stirred for 3 hours at room temperature and the solvent was distilled off under vacuum to obtain a residual mass. The residual mass was adjusted to pH to 8 with sodium hydroxide (25%) and then extracted with ethyl acetate. The layers were separated and the organic layer was dried with sodium sulfate. The solvent was distilled off under vacuum at below 40°C and then added copovidone (26 gm) and methanol (260 ml) at room temperature. The reaction mixture was stirred for 15 minutes and filtered through celite bed. The solvent was distilled off under reduced pressure at below 50°C to obtain 50 gm of amorphous ticagrelor solid dispersion with copovidone.
Example 21 :
Preparation of amorphous ticagrelor solid dispersion with hydroxypropyl methylcellulose
(3aR-(3aa,4a,6a(lR*,2S*)6aa)-2-[6-({7-[2-(3,4-difluorophenyl)cyclopropyl] amino-5-(propylthio)-3H-l,2,3-triazolo[4,5-d]pyrimidin-3yl)tetrahydro-2,2-dimethyl-4H- cyclopenta-l,3-dioxol-4yl)oxy]ethanol (30 gm) was dissolved in methanol (240 ml) and then added concentrated hydrochloric acid (90 ml) slowly for 15 minutes. The reaction mass was stirred for 3 hours at room temperature and the solvent was distilled off under vacuum to obtain a residual mass. The residual mass was adjusted to pH to 8 with sodium hydroxide (25%) and then extracted with ethyl acetate. The layers were separated and the organic layer was dried with sodium sulfate. The solvent was distilled off under vacuum at below 40 C and then added hydroxypropyl methylcellulose (26 gm) and methanol (260 ml) at room temperature. The reaction mixture was stirred for 15 minutes and filtered through celite bed. The solvent was distilled off under reduced pressure at below 50°C to obtain 49.5 gm of amorphous ticagrelor solid dispersion with hydroxypropyl methylcellulose.
Example 22:
Preparation of amorphous ticagrelor solid dispersion with soluplus
(3aR-(3aa,4a,6a(lR*,2S*)6aa)-2-[6-({7-[2-(3,4-difluorophenyl)cyclopropyl] amino-5-(propylthio)-3H-l,2,3-triazolo[4,5-d]pyrimidin-3yl)tetrahydro-2,2-dimethyl-4H- cyclopenta-l,3-dioxol-4yl)oxy]ethanol (30 gm) was dissolved in methanol (240 ml) and then added concentrated hydrochloric acid (90 ml) slowly for 15 minutes. The reaction mass was stirred for 3 hours at room temperature and the solvent was distilled off under vacuum to obtain a residual mass. The residual mass was adjusted to pH to 8 with sodium hydroxide (25%) and then extracted with ethyl acetate. The layers were separated and the organic layer was dried with sodium sulfate. The solvent was distilled off under vacuum at below 40°C and then added soluplus (26 gm) and methanol (260 ml) at room temperature. The reaction mixture was stirred for 15 minutes and filtered through celite bed. The solvent was distilled off under reduced pressure at below 50°C to obtain 48 gm of amorphous ticagrelor solid dispersion with soluplus.

Claims

We claim:
1. Amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier.
2. The amorphous solid dispersion of claim 1, wherein the pharmaceutically acceptable carriers may be one or more of copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus.
3. The amorphous solid dispersion of claim 1, having powdered X-ray diffractogram as shown in figure 1.
4. A process for the preparation of amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier, which comprises:
a) preparing a solution comprising a mixture of ticagrelor and one or more pharmaceutically acceptable carriers selected from copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus in a solvent; and b) removing the solvent to obtain amorphous solid dispersion of ticagrelor in combination with a pharmaceutically acceptable carrier.
5. The process as claimed in claim 4, wherein the solvent used in step (a) is a solvent or a mixture of solvents selected from dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol, n-pentanol, methylene chloride, chloroform, carbontetrachloride and ethylene dichloride.
6. The process as claimed in claim 5, wherein the solvents are methylene chloride, dimethyl sulfoxide, dimethylacetamide, dimethylformamide and methanol.
7. The process as claimed in claim 4, wherein the pharmaceutically acceptable carriers used in step (a) is selected from copovidone, soluplus or hydroxypropyl methylcellulose.
8. Pharmaceutical compositions comprising a therapeutically effective amount of amorphous solid dispersion of ticagrelor along with pharmaceutically acceptable excipients, and at least one pharmaceutically acceptable excipient.
9. The pharmaceutical composition as claimed in claim 8, wherein the amorphous solid dispersion of ticagrelor is formulated into tablets, capsules, suspensions, dispersions or injectables.
PCT/IN2014/000079 2013-02-04 2014-01-31 Ticagrelor solid dispersion WO2014118808A2 (en)

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CN104193747A (en) * 2014-08-12 2014-12-10 许彩霞 Preparation of amorphous ticagrelor
WO2015001489A1 (en) * 2013-07-01 2015-01-08 Ranbaxy Laboratories Limited Pharmaceutical compositions of ticagrelor
WO2015039513A1 (en) * 2013-09-22 2015-03-26 成都盛迪医药有限公司 Ticagrelor solid dispersion and preparation method thereof
USRE46276E1 (en) 1998-12-04 2017-01-17 Astrazeneca Uk Limited Triazolo(4,5-D)pyrimidine compounds
WO2017182455A1 (en) 2016-04-18 2017-10-26 Amneal Pharmaceuticals Company Gmbh Stable pharmaceutical composition of amorphous ticagrelor
EP3266447A1 (en) * 2016-02-12 2018-01-10 Ali Raif Ilac San. A.S. Production process for formulations containing ticagrelor
WO2020021110A1 (en) 2018-07-27 2020-01-30 Krka, D.D., Novo Mesto Pharmaceutical composition of ticagrelor
WO2022261735A1 (en) * 2021-06-14 2022-12-22 Libbs Farmacêutica Ltda Pharmaceutical composition and use of the pharmaceutical composition
WO2024021802A1 (en) * 2022-07-27 2024-02-01 江苏慧聚药业股份有限公司 Solid ticagrelor dispersion, method for preparing same, and use thereof

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GB0013407D0 (en) * 2000-06-02 2000-07-26 Astrazeneca Ab Forms of a chemical compound
TR200909798T1 (en) * 2007-07-12 2010-05-21 Dr. Reddy's Laboratories Ltd. O-desmethylvenlafaxine.
US20100272815A1 (en) * 2009-04-28 2010-10-28 Actavis Group Ptc Ehf Amorphous form of tapentadol hydrochloride
EP2633857B1 (en) * 2009-12-23 2015-08-12 ratiopharm GmbH Solid pharmaceutical dosage form of ticagrelor and acetylsalicylic acid
US9233966B2 (en) * 2012-04-05 2016-01-12 Dr. Reddy's Laboratories Limited Preparation of ticagrelor

Cited By (9)

* Cited by examiner, † Cited by third party
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USRE46276E1 (en) 1998-12-04 2017-01-17 Astrazeneca Uk Limited Triazolo(4,5-D)pyrimidine compounds
WO2015001489A1 (en) * 2013-07-01 2015-01-08 Ranbaxy Laboratories Limited Pharmaceutical compositions of ticagrelor
WO2015039513A1 (en) * 2013-09-22 2015-03-26 成都盛迪医药有限公司 Ticagrelor solid dispersion and preparation method thereof
CN104193747A (en) * 2014-08-12 2014-12-10 许彩霞 Preparation of amorphous ticagrelor
EP3266447A1 (en) * 2016-02-12 2018-01-10 Ali Raif Ilac San. A.S. Production process for formulations containing ticagrelor
WO2017182455A1 (en) 2016-04-18 2017-10-26 Amneal Pharmaceuticals Company Gmbh Stable pharmaceutical composition of amorphous ticagrelor
WO2020021110A1 (en) 2018-07-27 2020-01-30 Krka, D.D., Novo Mesto Pharmaceutical composition of ticagrelor
WO2022261735A1 (en) * 2021-06-14 2022-12-22 Libbs Farmacêutica Ltda Pharmaceutical composition and use of the pharmaceutical composition
WO2024021802A1 (en) * 2022-07-27 2024-02-01 江苏慧聚药业股份有限公司 Solid ticagrelor dispersion, method for preparing same, and use thereof

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