WO2014115169A2 - Dispersion solide de crizotinib - Google Patents

Dispersion solide de crizotinib Download PDF

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Publication number
WO2014115169A2
WO2014115169A2 PCT/IN2014/000052 IN2014000052W WO2014115169A2 WO 2014115169 A2 WO2014115169 A2 WO 2014115169A2 IN 2014000052 W IN2014000052 W IN 2014000052W WO 2014115169 A2 WO2014115169 A2 WO 2014115169A2
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Prior art keywords
crizotinib
solvent
pharmaceutically acceptable
solid dispersion
mixture
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PCT/IN2014/000052
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English (en)
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WO2014115169A3 (fr
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Dasari Muralidhara Reddy
Thungathurthy Srinivasa Rao
Bandi Vamsi Krishna
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Hetero Research Foundation
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Publication of WO2014115169A2 publication Critical patent/WO2014115169A2/fr
Publication of WO2014115169A3 publication Critical patent/WO2014115169A3/fr

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention provides a compound of 3-[(R)-l-(2,6-dichloro-3-fluoro- phenyl)-ethoxy]-5-( l -piperidin-4-yl-l H-pyrazol-4-yl)-pyrazin-2-ylamine oxalate (crizotinib oxalate salt), process for its preparation and pharmaceutical compositions comprising it.
  • the present invention also provides a novel process for the preparation of crizotinib using novel intermediate.
  • the present invention further provides a process for the purification of crizotinib.
  • the present invention further provides a novel amorphous solid dispersion of crizotinib in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
  • Crizotinib is known by the chemical name 3-[(R)- l -(2,6-dichloro-3-fluoro- phenyl)-ethoxy]-5-( l -piperidin-4-yl- lH-pyrazol-4-yl)-pyrazin-2-ylamine and has the structural formula:
  • Crizotinib is antineoplastic protein kinase inhibitors.
  • the generic name crizotinib is marketed by PFIZER under the brand name XALK.ORI®. Crizotinib and its process were disclosed in U.S. patent no. 7,858,643.
  • 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.
  • 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. .
  • Crizotinib can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
  • crystalline Form and amorphous Form of crizotinib either not reproducible or not stable.
  • a novel amorphous solid dispersion of crizotinib in combination with a pharmaceutically acceptable carrier The amorphous solid dispersion of crizotinib is stable, reproducible and so, the amorphous solid dispersion of crizotinib is suitable for formulating crizotinib.
  • Normally amorphous Forms are hygroscopic.
  • Amorphous solid dispersion of crizotinib is found to be non-hygroscopic.
  • one object of the present invention is to provide a compound of 3-[(R)-l- (2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(l -piperidin-4-yl- lH-pyrazol-4-yI)-pyrazin-2- ylamine oxalate (crizotinib oxalate salt), process for its preparation and pharmaceutical compositions comprising it.
  • Another object of the present invention is to provide a process for the preparation of crizotinib using novel intermediate.
  • Another object of the present invention is to provide a process for the purification of crizotinib.
  • Another object of the present invention is to provide a novel amorphous solid dispersion of crizotinib in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
  • the present invention provides 3-[(R)-l -(2,6-dichloro-3-fluoro- phenyl)-ethoxy]-5-(l -piperidin-4-yl- l H-pyrazol-4-yl)-pyrazin-2-ylamine oxalate (crizotinib oxalate salt) of formula 11:
  • the present invention provides a process for the preparation of crizotinib oxalate salt of formula II, which comprises:
  • the present invention provides a pharmaceutical composition comprising crizotinib oxalate salt and a pharmaceutically acceptable excipient.
  • the present invention provides a novel process for the preparation of crizotinib using novel intermediate, which comprises:
  • the present invention provides a process for the purification of crizotinib, which comprises:
  • step (b) adding water to the solution obtained in step (b) above 60°C;
  • the present invention provides a process for the purification of crizotinib, which comprises:
  • the present invention provides amorphous solid dispersion of crizotinib in combination with a pharmaceutically acceptable carrier.
  • the present invention there is provided a process for the preparation of amorphous solid dispersion of crizotinib in combination with a pharmaceutically acceptable carrier, which comprises:
  • the present invention there is provided a process for the preparation of amorphous solid dispersion of crizotinib in combination with a pharmaceutically acceptable carrier, which comprises:
  • step (e) adding one or more pharmaceutically acceptable carriers selected from copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus and a solvent to the residual solid obtained in step (e); and
  • the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of amorphous solid dispersion of crizotinib along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
  • Figure 1 is a powder X-ray diffractogram patterns of crystalline 3-[( )- l-(2,6- dichloro-3-fluoro-phenyl)-ethoxy]-5-(l -piperidin-4-yl-l H-pyrazol-4-yl)-pyrazin-2- ylamine oxalate (crizotinib oxalate salt) of formula II.
  • Figure 2 is a powder X-ray diffractogram patterns of amorphous solid dispersion of crizotinib 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 m A.
  • room temperature refers to temperature at about 25 to 35°C.
  • step (b) adding sulfuric acid or 1 ,4-dioxane hydrochloride to the solution obtained in step (a);
  • the chlorinated solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methylene chloride, chloroform, carbontetrachl ride and ethylene dichloride, and more preferably the chlorinated solvent is methylene chloride.
  • the base used in step (d) may preferably be an organic base or an inorganic base selected from ammonium, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, and more preferably the base is sodium carbonate.
  • Isolation of crizotinib oxalate salt in step (f) may preferably be performed by conventional techniques such as centrifugation and filtration.
  • a pharmaceutical composition which comprises crizotinib oxalate salt and pharmaceutically acceptable carriers, diluents or excipients and optionally other therapeutic ingredients.
  • the salt may preferable be conveniently formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms.
  • the chlorinated solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methylene chloride, chloroform, carbontetrachioride and ethylene dichloride, and more preferably the chlorinated solvent is methylene chloride.
  • the nitrite solvent used in step (c) may preferably be a solvent or a mixture of solvents selected from acetonitrile, propionitrile, butyronitrile and benzonitrile, and more preferably the nitrile solvent is acetonitrile.
  • Crizotinib may be isolated in step (d) by the methods known such as filtration or centrifugation.
  • step (b) adding water to the solution obtained in step (b) above 60°C;
  • highly pure crizotinib refers to crizotinib having the purity greater than about 98% by weight, preferably greater than about 99% by weight, more preferably greater than about 99.5% by weight.
  • step (b) and step (c) may preferably be heated at about 65 to 75°C.
  • Isolation of highly pure crizotinib in step (d) may preferably be performed by conventional techniques such as centrifugation and filtration.
  • the alcoholic solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methanol, ethanol, isopropanol, n-butanol and n-pentanol, and more preferably the alcoholic solvent is methanol.
  • the chlorinated solvent used in step (a) may be a solvent or a mixture of solvents selected from methylene chloride, chloroform, carbontetrachloride and ethylene dichloride, and more preferably the chlorinated solvent is methylene chloride.
  • the solution is concentrated in step (b) by distilling off the solvent.
  • the distilling off 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.
  • the nitrile solvent used in step (c) may preferably be a solvent or a mixture of solvents selected from acetonitrile, propionitrile, butyronitrile and benzonitrile, and more preferably the nitrile solvent is acetonitrile.
  • Highly pure crizotinib may be isolated in step (e) by the methods known such as filtration or centrifugation.
  • amorphous solid dispersion of crizotinib in combination with a pharmaceutically acceptable carrier there is provided amorphous solid dispersion of crizotinib in combination with a pharmaceutically acceptable carrier.
  • the powdered x-ray diffractogram (PXRD) of amorphous solid dispersion of crizotinib in combination with a pharmaceutically acceptable carrier is shown in figure 2.
  • 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 crizotinib.
  • solid dispersion refers to a composition prepared by dissolving or dispersing a substituted crizotinib 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 crizotinib in combination with a pharmaceutically acceptable carrier which comprises:
  • Crizotinib used in step (a) may preferably be crizotinib 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 and n-pentanol. More preferably the solvents are 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.
  • amorphous solid dispersion of crizotinib in combination with a pharmaceutically acceptable carrier which comprises:
  • step (e) adding one or more pharmaceutically acceptable carriers selected from copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus and a solvent to the residual solid obtained in step (e); and
  • the chlorinated solvent used in step (a) may be a solvent or a mixture of solvents selected from methylene chloride, chloroform, carbontetrachloride and ethylene dichloride, and more preferably the chlorinated solvent is methylene chloride.
  • the solution is concentrated in step (e) by distilling off the solvent.
  • the distilling off 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.
  • the solvent used in step (f) may preferably be a solvent or a mixture of solvents selected from dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol and n-pentanol. More preferably the solvents are dimethyl sulfoxide, dimethylacetamide, dimethylformamide and methanol.
  • the pharmaceutically acceptable carriers used in step (f) may be selected from copovidone, soluplus or hydroxypropyl methylcellulose.
  • the solvent may be removed from the solution in step (g) 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.
  • compositions comprising a therapeutically effective amount of amorphous solid dispersion of crizotinib 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 crizotinib 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-tri basic, 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 monol
  • 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 layers were separated and the aqueous layer of the pH was adjusted to 10.0 with sodium carbonate.
  • the aqueous layer was extracted with methylene chloride and then dried with sodium sulfate.
  • To the aqueous layer was added a solution of oxalic acid (5.5 gm) in methanol ( 15 ml) and then maintained for 2 hours.
  • the separated solid was filtered and then dried to obtain 20 gm of crizotinib oxalate salt.
  • the reaction mass was maintained for 3 hours at room temperature and then added water (100 ml).
  • the layers were separated and the aqueous layer of the pH was adjusted to 10.0 with sodium carbonate.
  • the aqueous layer was extracted with methylene chloride and then dried with sodium sulfate.
  • To the aqueous layer was added a solution of oxalic acid (2.2 gm) in methanol (10 ml), maintained for 2 hours and then filtered.
  • the solid obtained was dried to obtain 7 gm of crizotinib oxalate salt.
  • Crizotinib oxalate salt (6 gm) was dissolved in methylene chloride (60 ml) and pH of the solution was adjusted to 10.0 with sodium carbonate. The solvent was distilled off under vacuum to obtain a residual solid. To the residual solid was added acetonitrile (30 ml) and maintained for 1 hour. The separated solid was filtered and then dried to obtain 3 gm of crizotinib.
  • Crizotinib oxalate salt (6 gm) was dissolved in water (60 ml) and pH of the solution was adjusted to 10.0 with sodium carbonate. The reaction mass was maintained for 1 hour and filtered. The solid obtained was dried to obtain 3 gm of crizotinib.
  • Crizotinib ( 1 0 gm; Chromatographic purity: 98%) was dissolved in dimethylformamide (80 ml) and then heated to 65 to 70°C to obtain a clear solution. The solution was filtered the particles and then added water (160 ml) slowly for 30 minutes at 65 to 70 C. The solution was stirred for 30 minutes at 65 to 70 C and then cooled to room temperature. The contents were stirred for 1 hour at room temperature and filtered. The solid obtained was dried to obtain 8 gm of highly pure crizotinib.
  • Crizotinib 10 gm; Chromatographic purity: 98%) was dissolved in methanol (100 ml) and dimethylformamide ( 100 ml) and stirred for 10 minutes at room temperature. The solvent was distilled off under vacuum at 45 to 50°C and then added acetonitrile (50 ml). The contents were heated to reflux and stirred for 1 hour at reflux. The solution was then cooled to room temperature and stirred for 1 hour. The separated solid was filtered and then dried to obtain 8.5 gm of highly pure crizotinib.
  • Example 7 Preparation of amorphous crizotinib solid dispersion with copovidone Example 7 was repeated using dimethylformamide solvent instead of methanol solvent to obtain amorphous crizotinib solid dispersion with copovidone.
  • Example 7 was repeated using dimethylacetamide solvent instead of methanol solvent to obtain amorphous crizotinib solid dispersion with copovidone.
  • Example 7 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to obtain amorphous crizotinib solid dispersion with copovidone.
  • Example 7 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous crizotinib solid dispersion with copovidone.
  • crizotinib 50 gm
  • hydroxypropyl methylcellulose 25 gm
  • the solvent was distilled off under reduced pressure at below 50°C to obtain 71 gm of amorphous crizotinib solid dispersion with hydroxypropyl methylcellulose.
  • Example 1 3 Preparation of amorphous crizotinib solid dispersion with hydroxypropyl methylcellulose
  • Example 1 3 was repeated using dimethylformamide solvent instead of methanol solvent to obtain amorphous crizotinib solid dispersion with hydroxypropyl methylcellulose.
  • Example 1 5 Example 1 5 :
  • Example 13 was repeated using dimethylacetamide solvent instead of methanol solvent to obtain amorphous crizotinib solid dispersion with hydroxypropyl methylcellulose.
  • Example 13 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to obtain amorphous crizotinib solid dispersion with hydroxypropyl methylcellulose.
  • Example 13 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous crizotinib solid dispersion with hydroxypropyl methylcellulose.
  • Example 18 was repeated using dimethylacetamide solvent instead of methanol solvent to obtain amorphous crizotinib solid dispersion with soluplus.
  • Example 18 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to obtain amorphous crizotinib solid dispersion with soluplus.
  • Example 18 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous crizotinib solid dispersion with soluplus.
  • crizotinib 10 gm
  • polyethylene glycol 5 gm
  • the solvent was distilled off under reduced pressure at below 50°C to obtain 13 gm of amorphous crizotinib solid dispersion with polyethylene glycol.
  • Crizotinib oxalate salt (6 gm) was dissolved in methylene chloride (60 ml) and water (60 ml) at room temperature. The pH of the solution was adjusted to 10.0 with sodium carbonate and then the layers were separated. The organic layer was added water (60 ml) and then dried with sodium sulfate. The layer was treated with carbon and then concentrated to obtain a residual solid. To the residual solid was added methanol (100 ml) and copovidone (5 gm). The solvent was distilled off under reduced pressure at below 50°C to obtain 8.5 gm of amorphous crizotinib solid dispersion with copovidone.
  • Crizotinib oxalate salt (6 gm) was dissolved in methylene chloride (60 ml) and water (60 ml) at room temperature. The pH of the solution was adjusted to 10.0 with sodium carbonate and then the layers were separated. The organic layer was added water (60 ml) and then dried with sodium sulfate. The layer was treated with carbon and then concentrated to obtain a residual solid. To the residual solid was added methanol (100 ml) and hydroxypropyl methylcellulose (5 gm). The solvent was distilled off under reduced pressure at below 50°C to obtain 8.5 gm of amorphous crizotinib solid dispersion with hydroxypropyl methylcellulose.
  • Crizotinib oxalate salt (6 gm) was dissolved in water (60 ml) and pH of the solution was adjusted to 10.0 with sodium carbonate. The reaction mass was maintained for I hour and then added copovidone (3 gm) was dissolved in methanol (60 ml) at room temperature. The solvent was distilled off under reduced pressure at below 50°C to obtain 5.5 gm of amorphous crizotinib solid dispersion with copovidone.
  • Crizotinib oxalate salt (6 gm) was dissolved in water (60 ml) and pH of the solution was adjusted to 1 0.0 with sodium carbonate. The reaction mass was maintained for 1 hour and then added hydroxypropyl methylcellulose (3 gm) was dissolved in methanol (60 ml) at room temperature. The solvent was distilled off under reduced pressure at below 50°C to obtain 5 gm of amorphous crizotinib solid dispersion with hydroxypropyl methylcel lulose.
  • Crizotin ib oxalate salt (6 gm) was dissolved in water (60 ml) and pH of the solution was adjusted to 1 0.0 with sodium carbonate. The reaction mass was maintained for 1 hour and then added soluplus (3 gm) was dissolved in methanol (60 ml) at room temperature. The solvent was distilled off under reduced pressure at below 50°C to obtain 5 gm of amorphous crizotinib solid dispersion with soluplus.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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Abstract

La présente invention concerne un composé de sel d'oxalate de crizotinib, son procédé de préparation et des compositions pharmaceutiques le comprenant. La présente invention concerne également un nouveau procédé pour la préparation de crizotinib à l'aide d'un nouvel intermédiaire. La présente invention concerne en outre un procédé pour la purification de crizotinib. La présente invention concerne en outre une nouvelle dispersion solide amorphe de crizotinib en combinaison avec un support pharmaceutiquement acceptable, son procédé de préparation et des compositions pharmaceutiques la comprenant.
PCT/IN2014/000052 2013-01-24 2014-01-23 Dispersion solide de crizotinib WO2014115169A2 (fr)

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IN329CH2013 2013-01-24
IN329/CHE/2013 2013-01-24

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WO2014115169A2 true WO2014115169A2 (fr) 2014-07-31
WO2014115169A3 WO2014115169A3 (fr) 2016-02-25

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115887406A (zh) * 2022-12-24 2023-04-04 山东理工职业学院 一种克唑替尼胶囊的制备方法
CN115919866A (zh) * 2022-12-07 2023-04-07 深圳海王医药科技研究院有限公司 特泊替尼固体分散体及其制备方法
CN116688139A (zh) * 2023-06-25 2023-09-05 深圳市新阳唯康科技有限公司 一种克唑替尼药物组合物及其制备方法和应用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100859891B1 (ko) * 2004-08-26 2008-09-23 화이자 인코포레이티드 단백질 키나제 억제제로서 거울상이성질체적으로 순수한아미노헤테로아릴 화합물
CA2632283C (fr) * 2005-12-05 2011-06-21 Pfizer Products Inc. Polymorphes d'un inhibiteur de c-met/hgfr
PT1959955E (pt) * 2005-12-05 2011-01-04 Pfizer Prod Inc Método para tratar o crescimento celular anómalo

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115919866A (zh) * 2022-12-07 2023-04-07 深圳海王医药科技研究院有限公司 特泊替尼固体分散体及其制备方法
CN115887406A (zh) * 2022-12-24 2023-04-04 山东理工职业学院 一种克唑替尼胶囊的制备方法
CN115887406B (zh) * 2022-12-24 2024-02-13 山东理工职业学院 一种克唑替尼胶囊的制备方法
CN116688139A (zh) * 2023-06-25 2023-09-05 深圳市新阳唯康科技有限公司 一种克唑替尼药物组合物及其制备方法和应用
CN116688139B (zh) * 2023-06-25 2024-03-29 深圳市新阳唯康科技有限公司 一种克唑替尼药物组合物及其制备方法和应用

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