[go: up one dir, main page]

WO2014115169A2 - Crizotinib solid dispersion - Google Patents

Crizotinib solid dispersion Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
crizotinib
solvent
pharmaceutically acceptable
solid dispersion
mixture
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IN2014/000052
Other languages
French (fr)
Other versions
WO2014115169A3 (en
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Dasari Muralidhara Reddy
Thungathurthy Srinivasa Rao
Bandi Vamsi Krishna
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hetero Research Foundation
Original Assignee
Hetero Research Foundation
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 Hetero Research Foundation filed Critical Hetero Research Foundation
Publication of WO2014115169A2 publication Critical patent/WO2014115169A2/en
Anticipated expiration legal-status Critical
Publication of WO2014115169A3 publication Critical patent/WO2014115169A3/en
Ceased legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention provides a compound of 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.

Description

CRIZOTINIB SOLID DISPERSION
This application claims the benefit of Indian Provisional Patent Application No. 329/CHE/2013, filed on January 24, 2013, which is incorporated herein by reference.
Filed of the Invention
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.
Background of the Invention
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:
Figure imgf000002_0001
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. 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. .
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.
U.S. patent application publication no. 2008/293769 disclosed crystalline Form 1 of crizotinib. The patent application also described an amorphous Form of crizotinib.
We have found a novel compound of 3-[(R)-l -(2,6-dichIoro-3-fluoro-phenyl)- ethoxy]-5-(l -piperidin-4-yl- l H-pyrazoI-4-yl)-pyrazin-2-ylamine oxalate (crizotinib oxalate salt) is useful intermediate for the preparation of crizotinib.
We have also found a novel process for the preparation of crizotinib using novel intermediate.
We have also found a process for the purification of crizotinib.
It was observed that the crystalline Form and amorphous Form of crizotinib either not reproducible or not stable. We have also found 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.
Thus, 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.
Summary of the Invention
In one aspect, 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:
.Oxalate II
Figure imgf000004_0001
In another aspect, the present invention provides a process for the preparation of crizotinib oxalate salt of formula II, which comprises:
a) dissolving tert-butyl 4-(4-{6-amino-5-[(lR)-l-(2,6-dichloro-3- fluorophenyl)ethoxy]pyridin-3 -yl } - 1 H-pyrazol- 1 -yl)piperidine- 1 -carboxylate in a chlorinated solvent;
b) adding sulfuric acid or 1 ,4-dioxane hydrochloride to the solution obtained in step
(a);
c) adding water to the reaction mass;
d) pH of the reaction mass was adjusted to 9.5 to 10.5 with a base;
e) adding a solution of oxalic acid; and
f) isolating the crizotinib oxalate salt.
In another aspect, the present invention provides a pharmaceutical composition comprising crizotinib oxalate salt and a pharmaceutically acceptable excipient.
In another aspect, the present invention provides a novel process for the preparation of crizotinib using novel intermediate, which comprises:
a) dissolving crizotinib oxalate salt in a water, a chlorinated solvent or mixture thereof;
b) adjusting the pH of the reaction mass to 9.5 to 10.5 with sodium carbonate;
c) adding a nitrile solvent to the reaction mass; and
d) isolating crizotinib.
In another aspect, the present invention provides a process for the purification of crizotinib, which comprises:
a) suspending crizotinib in dimethylformamide, dimethylacetamide, dimethyl sulfoxide or mixture thereof;
b) heating the suspension above 60°C;
c) adding water to the solution obtained in step (b) above 60°C; and
d) isolating the highly pure crizotinib.
In another aspect, the present invention provides a process for the purification of crizotinib, which comprises:
a) dissolving crizotinib in an alcoholic solvent, a chlorinated solvent or mixture thereof; b) concentrating the solution to obtain a residual solid;
c) adding a nitrile solvent to the residual solid;
d) heating the contents at reflux; and
e) isolating the highly pure crizotinib.
In another aspect, the present invention provides amorphous solid dispersion of crizotinib 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 crizotinib in combination with a pharmaceutically acceptable carrier, which comprises:
a) preparing a solution comprising a mixture of crizotinib 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 crizotinib 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 crizotinib in combination with a pharmaceutically acceptable carrier, which comprises:
a) preparing a solution comprising crizotinib oxalate salt in a chlorinated solvent and water;
b) adjusting the pH of the solution to 9.5 to 10.5 with sodium carbonate;
c) separating out the organic layer;
d) adding water to the oragnic layer;
e) concentrating the organic layer to obtain a residual solid;
f) 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
g) removing the solvent to obtain amorphous solid dispersion of crizotinib 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 crizotinib 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 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-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 m A.
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 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 II:
.Oxalate II
Figure imgf000007_0001
According to another aspect of the present invention, there is provided a process for the preparation of crizotinib oxalate salt of formula II, which comprises:
a) dissolving tert-butyl 4-(4-{6-amino-5-[( lR)- l-(2,6-dichloro-3- fluorophenyl)ethoxy]pyridin-3-yl}-lH-pyrazol- l -yl)piperidine-l -carboxylate in a chlorinated solvent;
b) adding sulfuric acid or 1 ,4-dioxane hydrochloride to the solution obtained in step (a);
c) adding water to the reaction mass;
d) pH of the reaction mass was adjusted to 9.5 to 10.5 with a base;
e) adding a solution of oxalic acid; and
f) isolating the crizotinib oxalate salt.
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.
According to another aspect of the present invention, there is provided 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.
According to another aspect of the present invention, there is provided a novel process for the preparation of crizotinib using novel intermediate, which comprises:
a) dissolving crizotinib oxalate salt in a water, a chlorinated solvent or mixture thereof;
b) adjusting the pH of the reaction mass to 9.5 to 10.5 with sodium carbonate;
c) adding a nitrile solvent to the reaction mass; and
d) isolating crizotinib. 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.
According to another aspect of the present invention, there is provided a process for the purification of crizotinib, which comprises:
a) suspending crizotinib in dimethylformamide, dimethylacetamide, dimethyl sulfoxide or mixture thereof;
b) heating the suspension above 60°C;
c) adding water to the solution obtained in step (b) above 60°C; and
d) isolating the highly pure crizotinib.
The term "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.
The reaction in 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.
According to another aspect of the present invention, there is provided a process for the purification of crizotinib, which comprises:
a) dissolving crizotinib in an alcoholic solvent, a chlorinated solvent or mixture thereof;
b) concentrating the solution to obtain a residual solid;
c) adding a nitrile solvent to the residual solid;
d) heating the contents at reflux; and
e) isolating the highly pure crizotinib. 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.
Preferably 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.
Preferably 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.
According to another aspect of the present invention, 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.
Amorphous solid dispersion of crizotinib 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 crizotinib.
The term "solid dispersion" herein 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. According to another aspect of 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:
a) preparing a solution comprising a mixture of crizotinib 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 crizotinib in combination with a pharmaceutically acceptable carrier.
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.
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 a process for the preparation of amorphous solid dispersion of crizotinib in combination with a pharmaceutically acceptable carrier, which comprises:
a) preparing a solution comprising crizotinib oxalate salt in a chlorinated solvent and water;
b) adjusting the pH of the solution to 9.5 to 10.5 with sodium carbonate;
c) separating out the oragnic layer; d) adding water to the organic layer;
e) concentrating the organic layer to obtain a residual solid;
f) 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
g) removing the solvent to obtain amorphous solid dispersion of crizotinib in combination with a pharmaceutically acceptable carrier.
Preferably 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.
Preferably 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.
Preferably 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.
According to another aspect of the present invention, there is provided pharmaceutical 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.
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-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 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; polyoxyethytene - 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 3-[(R)-l-(2,6-dichloro-3-fluoro-phenyI)-ethoxy]-5-(l-piperidin-4-yl- lH-pyrazoI-4-yl)-pyrazin-2-ylamine oxalate (crizotinib oxalate salt)
Tert-butyl 4-(4-{6-amino-5-[(l R)-l -(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin- 3-yl}- l H-pyrazol- l -yl)piperidine- l -carboxylate (25 gm) was dissolved in methylene chloride ( 150 ml) at room temperature and then cooled to 0 to 5°C. To the solution was added concentrated sulfuric acid ( 10 ml) slowly for 20 minutes at 0 to 5°C and temperature of the reaction mass was raised to room temperature. The reaction mass was maintained for 3 hours at room temperature and then added water ( 150 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 (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.
Example 2:
Preparation of crizotinib oxalate salt Tert-butyl 4-(4-{6-amino-5-[(lR)-l -(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin- 3-yl}- l H-pyrazol-l -yl)piperidine-l-carboxylate (10 gm) was dissolved in methylene chloride (60 ml) at room temperature and then cooled to 0 to 5°C. To the solution was added 1 ,4-dioxane hydrochloride (15%; 20 ml) slowly for 20 minutes at 0 to 5°C and temperature of the reaction mass was raised to room temperature. 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.
Example 3:
Preparation of crizotinib
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.
Example 4:
Preparation 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.
Example 5:
Purification 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.
Chromatographic purity: 99.8%.
Example 6:
Purification of 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.
Chromatographic purity: 99.8%.
Example 7 :
Preparation of amorphous crizotinib solid dispersion with copovidone
A mixture of crizotinib (50 gm) and copovidone (50 gm) was dissolved in methanol (1000 ml) at room temperature. The solvent was distilled off under reduced pressure at below 50°C to obtain 96 gm of amorphous crizotinib solid dispersion with copovidone.
Example 8:
Preparation of amorphous crizotinib solid dispersion with copovidone
A mixture of crizotinib (50 gm) and copovidone (25 gm) was dissolved in methanol (750 ml) at room temperature. The solvent was distilled off under reduced pressure at below 50°C to obtain 72 gm of amorphous crizotinib solid dispersion with copovidone. Example 9:
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 10:
Preparation of 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 1 1 :
Preparation of 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 12:
Preparation of 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.
Example 1 3:
Preparation of amorphous crizotinib solid dispersion with hydroxypropyl methylcellulose
A mixture of crizotinib (50 gm) and hydroxypropyl methylcellulose (25 gm) was dissolved in methanol (750 ml) at room temperature. 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 14:
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 :
Preparation of amorphous crizotinib solid dispersion with hydroxypropyl methylcellulose
Example 13 was repeated using dimethylacetamide solvent instead of methanol solvent to obtain amorphous crizotinib solid dispersion with hydroxypropyl methylcellulose.
Example 1 6:
Preparation of 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 17:
Preparation of 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 1 8:
Preparation of amorphous crizotinib solid dispersion with soluplus
A mixture of crizotinib ( 10 gm) and soluplus (10 gm) was dissolved in methanol (250 ml) at room temperature. The solvent was distilled off under reduced pressure at below 50°C to obtain 18 gm of amorphous crizotinib solid dispersion with soluplus. Example 1 9:
Preparation of amorphous crizotinib solid dispersion with soluplus Example 18 was repeated using dimethylformamide solvent instead of methanol solvent to obtain amorphous crizotinib solid dispersion with soluplus.
Example 20:
Preparation of amorphous crizotinib solid dispersion with soluplus
Example 18 was repeated using dimethylacetamide solvent instead of methanol solvent to obtain amorphous crizotinib solid dispersion with soluplus.
Example 21 :
Prepa ration of 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 22:
Preparation of 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.
Example 23:
Preparation of amorphous crizotinib solid dispersion with polyethylene glycol
A mixture of crizotinib ( 10 gm) and polyethylene glycol (5 gm) was dissolved in methanol (200 ml) at room temperature. The solvent was distilled off under reduced pressure at below 50°C to obtain 13 gm of amorphous crizotinib solid dispersion with polyethylene glycol.
Example 24:
Preparation of amorphous crizotinib solid dispersion with ethyl cellulose
A mixture of crizotinib (5 gm) and ethyl cellulose (5 gm) was dissolved in methanol ( 100 ml) at room temperature. The solvent was distilled off under reduced pressure at below 50°C to obtain 8 gm of amorphous crizotinib solid dispersion with ethyl cellulose. Example 25:
Preparation 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 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.
Example 26:
Preparation of amorphous crizotinib solid dispersion with hydroxypropyl methylcellulose
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.
Example 27:
Preparation of amorphous crizotinib solid dispersion with hydroxypropyl soluplus Crizotinib oxalate salt (6 gm) was dissolved in methylene chloride (60 ml) and water (60 m l) 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 soluplus (5 gm). The solvent was distilled off under reduced pressure at below 50°C to obtain 8 gm of amorphous crizotinib solid dispersion with soluplus. Example 28:
Preparation 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 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.
Example 29:
Preparation of amorphous crizotinib solid dispersion with hydroxypropyl methylcellulosc
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.
Example 30:
Preparation of amorphous crizotinib solid dispersion with soluplus
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.

Claims

We claim:
1. A 3-[(R)- l -(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(l-piperidin-4-yl-lH-pyrazol-4- yl)-pyrazin-2-ylamine oxalate (crizotinib oxalate salt) of formula II:
.Oxalate
Figure imgf000022_0001
A process for the preparation of crizotinib oxalate salt of formula II, which comprises:
a) dissolving tert-butyl 4-(4-{6-amino-5-[(l R)- l-(2,6-dichloro-3- fluoiOphenyl)ethoxy]pyridin-3-yl}- l H-pyrazol- l -yl)piperidine- l -carboxylate in a chlorinated solvent;
b) adding sulfuric acid or 1 ,4-dioxane hydrochloride to the solution obtained in step (a);
c) adding water to the reaction mass;
d) pH of the reaction mass was adjusted to 9.5 to 10.5 with a base;
e) add ing a solution of oxalic acid; and
f) isolating the crizotinib oxalate salt.
The process as claimed in claim 2, wherein the chlorinated solvent used in step (a) is a solvent or a mixture of solvents selected from methylene chloride, chloroform, carbontetrach loride and ethylene dichloride.
The process as claimed in claim 2, wherein the base used in step (d) is an organic base or an inorganic base selected from ammonium, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
Pharmaceutical compositions comprising a therapeutically effective amount of crizotinib oxalate salt and at least one pharmaceutically acceptable excipient.
The pharmaceutical composition as claimed in claim 5 wherein the crizotinib oxalate salt is formulated into tablets, capsules, suspensions, dispersions or injectables.
7. A process for the preparation of crizotinib using novel intermediate, which comprises: a) d issolving crizotinib oxalate salt in a water, a chlorinated solvent or mixture thereof;
b) adjusting the pH of the reaction mass to 9.5 to 10.5 with sodium carbonate; c) add ing a nitrile solvent to the reaction mass; and
d) isolating crizotinib.
8. The process as claimed in claim 7, wherein the chlorinated solvent used in step (a) is a solvent or a mixture of solvents selected from methylene chloride, chloroform, carbontetrachloride and ethylene dichloride.
9. The process as claimed in claim 7, wherein the nitrile solvent used in step (c) is a solvent or a mixture of solvents selected from acetonitrile, propionitrile, butyronitrile and ben zo nitrile.
10. A process for the purification of crizotinib, which comprises:
a) suspending crizotinib in dimethylformamide, dimethylacetamide, dimethyl su l fox ide or mixture thereof;
b) heating the suspension above 60°C;
c) adding water to the solution obtained in step (b) above 60°C; and
d) isolating the highly pure crizotinib.
1 1 . The process as claimed in claim 10, wherein the reaction in step (b) and step (c) is heated at about 65 to 75°C.
12. A process for the purification of crizotinib, which comprises:
a) dissolving crizotinib in an alcoholic solvent, a chlorinated solvent or mixture thereof;
b) concentrating the solution to obtain a residual solid;
c) adding a nitrile solvent to the residual solid;
d) heating the contents at reflux; and
e) isolating the highly pure crizotinib.
13. The process as claimed in claim 12, wherein the alcoholic solvent used in step (a) is a solvent or a mixture of solvents selected from methanol, ethanol, isopropanol, n- butanol and n-pentanol.
14. The process as claimed in claim 12, wherein the chlorinated solvent used in step (a) is a solvent or a mixture of solvents selected from methylene chloride, chloroform, carbontetrachloride and ethylene dichloride.
15. The process as claimed in claim 12, wherein the nitrile solvent used in step (c) is a solvent or a mixture of solvents selected from acetonitrile, propionitrile, butyronitrile and benzonitrile.
16. Amorphous solid dispersion of crizotinib in combination with a pharmaceutically acceptable carrier.
17. The amorphous solid dispersion of claim 16, wherein the pharmaceutically acceptable carriers may be one or more of copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus.
18. The amorphous solid dispersion of claim 16, having a powder X-ray diffractogram as shown in figure 2.
19. A process for the preparation of amorphous solid dispersion of crizotinib in combination with a pharmaceutically acceptable carrier, which comprises:
a) preparing a solution comprising a mixture of crizotinib 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 crizotinib in combination with a pharmaceutically acceptable carrier.
20. The process as claimed in claim 19, wherein the solvent used in step (a) is a solvent or a m ixture of solvents selected from dimethyl sulfoxide, dimethylacetamide, d imethylforinamide, methanol, ethanol, isopropanol, n-butanol and n-pentanol.
21. The process as claimed in claim 20, wherein the solvents are dimethyl sulfoxide, d imethylacetamide, dimethylformamide and methanol.
22. The process as claimed in claim 19, wherein the pharmaceutically acceptable carriers used in step (a) is selected from copovidone, soluplus or hydroxypropyl methylcellulose.
23. A process for the preparation of amorphous solid dispersion of crizotinib in combination with a pharmaceutically acceptable carrier, which comprises: a) preparing a solution comprising crizotinib oxalate salt in a chlorinated solvent and water;
b) adjusting the pH of the solution to 9.5 to 10.5 with sodium carbonate;
c) separating out the oragnic layer;
d) adding water to the organic layer;
e) concentrating the organic layer to obtain a residual solid;
f) 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 g) removing the solvent to obtain amorphous solid dispersion of crizotinib in combination with a pharmaceutically acceptable carrier.
24. The process as claimed in claim 23, wherein the chlorinated solvent used in step (a) is a solvent or a mixture of solvents selected from methylene chloride, chloroform, carbontetrachloride and ethylene dichloride.
25. The process as claimed in claim 23, 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 and n-pentanol.
26. The process as claimed in claim 25, wherein the solvents are dimethyl sulfoxide, dimethylacetamide, dimethylformamide and methanol.
27. The process as claimed in claim 23, wherein the pharmaceutically acceptable carriers used in step (a) is selected from copovidone, soluplus or hydroxypropyl methylcellulose.
28. Pharmaceutical compositions comprising a therapeutically effective amount of amorphous sol id dispersion of crizotinib along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
29. The pharmaceutical composition as claimed in claim 28, wherein the amorphous solid dispersion of crizotinib is formulated into tablets, capsules, suspensions, dispersions or injectables.
PCT/IN2014/000052 2013-01-24 2014-01-23 Crizotinib solid dispersion Ceased WO2014115169A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN329/CHE/2013 2013-01-24
IN329CH2013 2013-01-24

Publications (2)

Publication Number Publication Date
WO2014115169A2 true WO2014115169A2 (en) 2014-07-31
WO2014115169A3 WO2014115169A3 (en) 2016-02-25

Family

ID=51228161

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2014/000052 Ceased WO2014115169A2 (en) 2013-01-24 2014-01-23 Crizotinib solid dispersion

Country Status (1)

Country Link
WO (1) WO2014115169A2 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115887406A (en) * 2022-12-24 2023-04-04 山东理工职业学院 A kind of preparation method of crizotinib capsule
CN115919866A (en) * 2022-12-07 2023-04-07 深圳海王医药科技研究院有限公司 Tepontinib solid dispersion and preparation method thereof
CN116688139A (en) * 2023-06-25 2023-09-05 深圳市新阳唯康科技有限公司 Crizotinib pharmaceutical composition, and preparation method and application thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2007002312A (en) * 2004-08-26 2007-04-16 Pfizer Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors.
PT1963302E (en) * 2005-12-05 2013-04-09 Pfizer Prod Inc Polymorphs of a c-met/hgfr inhibitor
PL1959955T3 (en) * 2005-12-05 2011-04-29 Pfizer Prod Inc Method of treating abnormal cell growth

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115919866A (en) * 2022-12-07 2023-04-07 深圳海王医药科技研究院有限公司 Tepontinib solid dispersion and preparation method thereof
CN115887406A (en) * 2022-12-24 2023-04-04 山东理工职业学院 A kind of preparation method of crizotinib capsule
CN115887406B (en) * 2022-12-24 2024-02-13 山东理工职业学院 A kind of preparation method of crizotinib capsule
CN116688139A (en) * 2023-06-25 2023-09-05 深圳市新阳唯康科技有限公司 Crizotinib pharmaceutical composition, and preparation method and application thereof
CN116688139B (en) * 2023-06-25 2024-03-29 深圳市新阳唯康科技有限公司 Crizotinib pharmaceutical composition, and preparation method and application thereof

Also Published As

Publication number Publication date
WO2014115169A3 (en) 2016-02-25

Similar Documents

Publication Publication Date Title
JP6770035B2 (en) Amorphous letermovir and its solid pharmaceutical formulation for oral administration
WO2014118808A2 (en) Ticagrelor solid dispersion
WO2014076712A2 (en) Lurasidone hydrochloride solid dispersion
US9624172B2 (en) Polymorphs of lomitapide and its salts
US8703788B2 (en) Polymorph of nilotinib hydrochloride
JP2005533755A (en) Lansoprazole polymorph and process for its preparation
CN108137605A (en) Crystal form of ACP-196 and its preparation method and pharmaceutical composition
US7947699B2 (en) Anhydrous amorphous imatinib mesylate
CA2912902A1 (en) Polymorphic forms of nilotinib hydrochloride
WO2013160916A1 (en) Sunitinib malate solid dispersion
WO2014115169A2 (en) Crizotinib solid dispersion
WO2013150544A2 (en) Ivabradine hydrochloride solid dispersion
WO2014174529A2 (en) Polymorphs of avanafil
CN102070605B (en) Imatinib mesylate polymorph and pharmaceutical composition
JP5260959B2 (en) Pharmaceutical composition comprising a salt of mirtazapine
WO2013171766A2 (en) Saxagliptin solid dispersion
WO2014108921A2 (en) Carvedilol phosphate solid dispersion
US20150141457A1 (en) Elvitegravir solid dispersion
CN105228986B (en) A kind of lorcaserin eutectic and preparation method thereof, pharmaceutical composition and purposes
WO2014013505A2 (en) Amorphous vildagliptin
WO2014102832A2 (en) Saxagliptin hydrochloride solid dispersion
WO2013164857A1 (en) Desvenlafaxine succinate solid dispersion
WO2017145089A1 (en) Crystalline form x of bosutinib
EP3408264A1 (en) Nilotinib dinitrate (v) and crystalline forms thereof
CA2829186A1 (en) Amorphous form of lopinavir and ritonavir mixture

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: 14743833

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct app. not ent. europ. phase

Ref document number: 14743833

Country of ref document: EP

Kind code of ref document: A2