WO2016088074A1 - Procédé pour la préparation d'ibrutinib amorphe - Google Patents

Procédé pour la préparation d'ibrutinib amorphe Download PDF

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Publication number
WO2016088074A1
WO2016088074A1 PCT/IB2015/059321 IB2015059321W WO2016088074A1 WO 2016088074 A1 WO2016088074 A1 WO 2016088074A1 IB 2015059321 W IB2015059321 W IB 2015059321W WO 2016088074 A1 WO2016088074 A1 WO 2016088074A1
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WO
WIPO (PCT)
Prior art keywords
ibrutinib
pharmaceutically acceptable
solid dispersion
alcohol
amorphous
Prior art date
Application number
PCT/IB2015/059321
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English (en)
Inventor
Vishweshwar Peddy
Dharma Jagannadha Rao Velaga
Srinivas RANGINENI
Original Assignee
Dr. Reddy’S Laboratories Limited
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 Dr. Reddy’S Laboratories Limited filed Critical Dr. Reddy’S Laboratories Limited
Publication of WO2016088074A1 publication Critical patent/WO2016088074A1/fr

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention provides process for the preparation of amorphous Ibrutinib and amorphous solid dispersion of Ibrutinib.
  • the drug compound having the adopted name "Ibrutinib” has a chemical name I- ((fl)-3-(4-amino-3-(4 ⁇ henoxyphenyl)-l/-/ ⁇ yrazo ⁇
  • Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK) and is approved in US for the treatment of patients with mantle cell lymphoma and chronic lymphocytic leukemia who have received at least one prior therapy.
  • BTK Bruton's tyrosine kinase
  • US patent 7,514,444 discloses process for the preparation of Ibrutinib.
  • US '444 discloses isolation of Ibrutinib by flash chromatography using dichloromethane and methanol as eluents.
  • WO 2013/184572A1 application discloses crystalline, solvates and amorphous form of Ibrutinib.
  • the application discloses polymorphic Forms A, B, C, D, E and F characterized by PXRD, IR, DSC and TGA.
  • WO '572 application discloses process for the preparation of amorphous form of Ibrutinib by dissolving Form A in dichloromethane. The solvent dichloromethane was removed under rotary evaporation to provide amorphous Ibrutinib.
  • CN103694241 A discloses crystal form A of Ibrutinib characterized by PXRD.
  • CN103923084A discloses crystal forms II, III, IV, V, VI, VII and VIII of Ibrutinib, characterized by PXRD pattern.
  • a single compound may give rise to a variety of solids having distinct physical properties.
  • the variation in the physical properties frequently results in differences in bioavailability, stability, etc.
  • polymorphic forms can vary in their physical properties, regulatory authorities require that efforts be made to identify all polymorphic forms, e.g., crystalline, amorphous, and pseudo polymorphic forms, e.g. solvates, etc., of new drug substances.
  • Some polymorphs of drug substances suffer from the drawbacks of conversion to other crystalline forms on storage resulting in concomitant change, not only in the physical form and shape of the drug crystals, but also the associated changes in distinct physical properties.
  • the molecules will revert to a more thermodynamically stable form, often a form with lower solubility.
  • Such a thermodynamically stable form may sometimes result in a reduced or suboptimal bioavailability, especially for oral administration.
  • thermodynamically stable forms of drug substances which would have the strengths of the crystalline forms, viz. thermodynamic stability, and those of the amorphous form, viz. enhanced solubility, rapid onset of action and an enhanced bioavailability.
  • the present invention provides a process for the preparation of amorphous form of Ibrutinib, comprising: a) providing a solution of ibrutinib in a solvent; and b) isolating amorphous form of Ibrutinib.
  • the present invention provides amorphous solid dispersion comprising Ibrutinib, together with one or more pharmaceutically acceptable carriers.
  • the present invention provides a process for preparing a solid dispersion of amorphous Ibrutinib together with one or more pharmaceutically acceptable carriers, comprising: a) providing a solution of Ibrutinib in combination with one or more pharmaceutically acceptable carriers, in a suitable solvent or mixture of solvents; and b) isolating amorphous solid dispersion comprising Ibrutinib and one or more pharmaceutically acceptable carriers.
  • Fig. 1 illustrates the PXRD pattern of amorphous Ibrutinib, obtained by the procedure of Example 1 .
  • Fig. 2 illustrates the PXRD pattern of amorphous solid dispersion of Ibrutinib with PVP- K30, obtained by the procedure of Example 2.
  • Fig. 3 illustrates the PXRD pattern of amorphous solid dispersion of Ibrutinib with HPC, obtained by the procedure of Example 3.
  • Fig. 4 illustrates the PXRD pattern of amorphous solid dispersion of Ibrutinib with HPMC, obtained by the procedure of Example 4.
  • Fig. 5 illustrates the PXRD pattern of amorphous Ibrutinib, obtained by the procedure of Example 5
  • Fig. 6 illustrates the PXRD pattern of amorphous Ibrutinib, obtained by the procedure of Example 6
  • the present invention provides a process for the preparation of amorphous form of Ibrutinib, comprising: a) providing a solution of Ibrutinib in a solvent; and b) isolating amorphous form of Ibrutinib.
  • Providing a solution of Ibrutinib in step a) includes: i) direct use of a reaction mixture containing Ibrutinib that is obtained in the course of its synthesis; or ii) dissolving Ibrutinib in a solvent.
  • the dissolution temperatures may range from about 0 °C to about the reflux temperature of the solvent, or less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of Ibrutinib is obtained without affecting its quality.
  • the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material.
  • the solution obtained above may be filtered to remove any insoluble particles.
  • the insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure.
  • the solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow.
  • the filtration apparatus may need to be preheated to avoid premature crystallization.
  • Ibrutinib can be dissolved in any suitable solvent. Suitable solvents include any solvents that have no adverse effect on the compound and can dissolve the starting material to a useful extent.
  • solvents include, but are not limited to: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, or diethyl ketone; esters, such as ethyl acetate, propyl acetate, isopropyl acetate, or butyl acetate; alcohols, such as methanol, ethanol, 1 -propanol, 2- propanol (isopropyl alcohol), 2-methoxyethanol, 1 -butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol, 1
  • the quantity of solvent used for dissolution depends on the solvent and the dissolution temperature adopted.
  • the concentration of ibrutinib in the solution may generally range from about 0.1 to about 10 g/ml in the solvent.
  • Step b) involves isolating amorphous form of ibrutinib from the solution obtained in step a).
  • Isolation of amorphous form of ibrutinib in step b) may involve methods including removal of solvent, cooling, crash cooling, concentrating the mass, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin- film drying, agitated thin film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, adding anti-solvent or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.
  • the amorphous form of ibrutinib as isolated may carry some amount of occluded mother liquor and may have higher than desired levels of impurities. If desired, this amorphous form may be washed with a solvent or a mixture of solvents to wash out the impurities.
  • Suitable temperatures for isolation may be less than about 120 °C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -40°C or any other suitable temperatures.
  • Isolation of amorphous ibrutinib may be effected by combining a suitable anti- solvent with the solution obtained in step a).
  • Anti-solvent refers to a liquid in which ibrutinib is less soluble or poorly soluble.
  • An inert anti-solvent has no adverse effect on the reaction and it can assist in the solidification or precipitation of the dissolved starting material.
  • Suitable anti-solvents that may be used include, but are not limited to: saturated or unsaturated, linear or branched, cyclic or acyclic, Ci to Ci 0 hydrocarbons, such as heptanes, cyclohexane, or methylcyclohexane; water; or any mixtures thereof.
  • the recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the Ibrutinib is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling; or bead milling.
  • the present invention provides amorphous solid dispersion comprising ibrutinib, together with one or more pharmaceutically acceptable carriers.
  • the present invention provides a process for preparing a solid dispersion of amorphous ibrutinib together with one or more pharmaceutically acceptable carriers, comprising: a) providing a solution of ibrutinib in combination with one or more pharmaceutically acceptable carrier, in a suitable solvent or mixture of solvents; b) isolating amorphous solid dispersion comprising Ibrutinib and one or more pharmaceutically acceptable carriers.
  • Step a) involves providing a solution of ibrutinib in combination with at least one pharmaceutically acceptable carrier, in a suitable solvent or mixture of solvents;
  • Step a) may involve forming a solution of ibrutinib together with one or more pharmaceutically acceptable carriers.
  • a carrier enhances stability of the amorphous solid upon removal of solvent.
  • Providing the solution in step a) includes: i) direct use of a reaction mixture containing ibrutinib that is obtained in the course of its manufacture, if desired, after addition of one or more pharmaceutically acceptable carriers; or ii) dissolution of ibrutinib in a suitable solvent, either alone or in combination with one or more pharmaceutically acceptable carriers.
  • the quantity of solvent used for dissolution depends on the solvent and the dissolution temperature adopted.
  • the concentration of ibrutinib in the solution may generally range from about 0.1 to about 10 g/ml in the solvent.
  • ibrutinib Any physical form of ibrutinib, such as crystalline, amorphous or their mixtures may be utilized for providing a solution in step a).
  • Pharmaceutically acceptable carriers that may be used in step a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones (PVP), hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers
  • Ibrutinib and the pharmaceutically acceptable carrier may be dissolved either in the same solvent or they may be dissolved in different solvents and then combined to form a mixture.
  • the solid dispersion described herein includes ibrutinib and the carrier present in weight ratios ranging from about 5:95 to about 95:5. An example of a ratio is about 50:50.
  • the dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of ibrutinib is obtained without affecting its quality.
  • the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material.
  • the solution obtained above may be filtered to remove any insoluble particles.
  • the insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure.
  • the solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow.
  • the filtration apparatus may need to be preheated to avoid premature crystallization.
  • Suitable solvents that may be used in step a) include but are not limited to: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, or diethyl ketone; esters, such as ethyl acetate, propyl acetate, isopropyl acetate, or butyl acetate; alcohols, such as methanol, ethanol, 2-nitroethanol, 2- fluoroethanol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2- methoxyethanol, 1 -butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, neo-pentyl alcohol, t-pentyl alcohol,
  • Step b) involves isolating a solid dispersion of amorphous ibrutinib together with one or more pharmaceutically acceptable carriers.
  • Isolation of solid dispersion of amorphous form of ibrutinib in step b) may involve methods including removal of solvent, cooling, crash cooling, concentrating the mass, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, agitated thin film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.
  • the amorphous form of ibrutinib as isolated may carry some amount of occluded mother liquor and may have higher than desired levels of impurities. If desired, this amorphous form may be washed with a solvent or a mixture of solvents to wash out the impurities.
  • Suitable temperatures for isolation may be less than about 120°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -40°C or any other suitable temperatures.
  • the recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the ibrutinib is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling; or bead milling.
  • the present invention provides pharmaceutical composition comprising amorphous form of ibrutinib or amorphous solid dispersion of ibrutinib and at least one pharmaceutically acceptable excipient.
  • compositions include, but are not limited to, suitable surface modifiers.
  • suitable surface modifiers include various polymers, low molecular weight oligomers, natural products, and surfactants.
  • ibrutinib and 2 mL of dimethyl sulfoxide were charged into a round bottom flask at 25-30 °C.
  • 30 mL of demineralized water was taken and cooled to 5- 10 °C.
  • the above prepared ibrutinib solution was added and maintained for 10-15 minutes.
  • the contents were filtered and washed with 10 mL of demineralized water.
  • the obtained material was sucked dried for 10-15 minutes and dried in vacuum tray drier at 45-55 °C to obtain the title compound.

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

Abstract

L'invention concerne un procédé pour la préparation d'ibrutinib amorphe et de dispersions solides d'ibrutinib.
PCT/IB2015/059321 2014-12-03 2015-12-03 Procédé pour la préparation d'ibrutinib amorphe WO2016088074A1 (fr)

Applications Claiming Priority (2)

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IN6061/CHE/2014 2014-12-03
IN6061CH2014 2014-12-03

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017137446A1 (fr) * 2016-02-09 2017-08-17 Azad Pharmaceutical Ingredients Ag Procédé de synthèse d'ibrutinib amorphe stable
WO2019070698A1 (fr) 2017-10-02 2019-04-11 Johnson Matthey Public Limited Company Nouvelles formes d'ibrutinib
WO2019195827A1 (fr) 2018-04-06 2019-10-10 Johnson Matthey Public Limited Company Nouvelle forme d'ibrutinib
WO2019213184A1 (fr) 2018-05-03 2019-11-07 Juno Therapeutics, Inc. Polythérapie d'une thérapie par lymphocytes t à récepteur antigénique chimérique (car) et d'un inhibiteur de btk
WO2020239065A1 (fr) * 2019-05-31 2020-12-03 江苏恒瑞医药股份有限公司 Dispersion solide et procédé de préparation correspondant
CN113135917A (zh) * 2020-01-16 2021-07-20 北京赛思源生物医药技术有限公司 一种依鲁替尼的无定型物及其药用组合物
US11576917B2 (en) 2018-01-20 2023-02-14 Natco Pharma Limited Pharmaceutical compositions comprising Ibrutinib
WO2023220655A1 (fr) 2022-05-11 2023-11-16 Celgene Corporation Méthodes pour surmonter la résistance aux médicaments par ré-sensibilisation de cellules cancéreuses à un traitement avec une thérapie antérieure par l'intermédiaire d'un traitement avec une thérapie par lymphocytes t
RU2816913C2 (ru) * 2019-05-31 2024-04-08 Цзянсу Хэнжуй Медсин Ко., Лтд. Твердая дисперсия и способ ее получения

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008039218A2 (fr) * 2006-09-22 2008-04-03 Pharmacyclics, Inc. Inhibiteurs de la tyrosine kinase de bruton
US20140275126A1 (en) * 2013-03-15 2014-09-18 Janssen Pharmaceutica Nv Processes and intermediates for preparing a medicament

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008039218A2 (fr) * 2006-09-22 2008-04-03 Pharmacyclics, Inc. Inhibiteurs de la tyrosine kinase de bruton
US20140275126A1 (en) * 2013-03-15 2014-09-18 Janssen Pharmaceutica Nv Processes and intermediates for preparing a medicament

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017137446A1 (fr) * 2016-02-09 2017-08-17 Azad Pharmaceutical Ingredients Ag Procédé de synthèse d'ibrutinib amorphe stable
GB2558514A (en) * 2016-02-09 2018-07-18 Azad Pharmaceutical Ingredients Ag Process for the synthesis of stable amorphous ibrutinib
WO2019070698A1 (fr) 2017-10-02 2019-04-11 Johnson Matthey Public Limited Company Nouvelles formes d'ibrutinib
US11576917B2 (en) 2018-01-20 2023-02-14 Natco Pharma Limited Pharmaceutical compositions comprising Ibrutinib
WO2019195827A1 (fr) 2018-04-06 2019-10-10 Johnson Matthey Public Limited Company Nouvelle forme d'ibrutinib
WO2019213184A1 (fr) 2018-05-03 2019-11-07 Juno Therapeutics, Inc. Polythérapie d'une thérapie par lymphocytes t à récepteur antigénique chimérique (car) et d'un inhibiteur de btk
WO2020239065A1 (fr) * 2019-05-31 2020-12-03 江苏恒瑞医药股份有限公司 Dispersion solide et procédé de préparation correspondant
RU2816913C2 (ru) * 2019-05-31 2024-04-08 Цзянсу Хэнжуй Медсин Ко., Лтд. Твердая дисперсия и способ ее получения
CN113135917A (zh) * 2020-01-16 2021-07-20 北京赛思源生物医药技术有限公司 一种依鲁替尼的无定型物及其药用组合物
WO2023220655A1 (fr) 2022-05-11 2023-11-16 Celgene Corporation Méthodes pour surmonter la résistance aux médicaments par ré-sensibilisation de cellules cancéreuses à un traitement avec une thérapie antérieure par l'intermédiaire d'un traitement avec une thérapie par lymphocytes t

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