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WO2019038718A1 - Formes cristallines de lumacaftor - Google Patents

Formes cristallines de lumacaftor Download PDF

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Publication number
WO2019038718A1
WO2019038718A1 PCT/IB2018/056401 IB2018056401W WO2019038718A1 WO 2019038718 A1 WO2019038718 A1 WO 2019038718A1 IB 2018056401 W IB2018056401 W IB 2018056401W WO 2019038718 A1 WO2019038718 A1 WO 2019038718A1
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Prior art keywords
lumacaftor
crystalline form
another embodiment
designated
carried out
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WO2019038718A4 (fr
Inventor
Ramkinkar SANTRA
Chandra Has Khanduri
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Sun Pharmaceutical Industries Ltd
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Sun Pharmaceutical Industries Ltd
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Publication of WO2019038718A4 publication Critical patent/WO2019038718A4/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention provides solvates of lumacaftor, a crystalline form of lumacaftor, processes for their preparation, pharmaceutical compositions comprising them, and their use for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation in the CFTR gene.
  • CF cystic fibrosis
  • Lumacaftor of Formula I is chemically known as 3-[6-( ⁇ [l-(2,2-difluoro-l,3- benzodioxol-5-yl)cyclopropyl]carbonyl ⁇ amino)-3-methylpyridin-2-yl]benzoic acid.
  • Lumacaftor in combination with Ivacaftor is indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation in the CFTR gene.
  • CF cystic fibrosis
  • the present invention provides solvates of lumacaftor, a crystalline form of lumacaftor, processes for their preparation, pharmaceutical compositions comprising them, and their use for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation in the CFTR gene.
  • the solvates of lumacaftor and crystalline form of lumacaftor of the present invention have good solubility, storage and handling stability, and bioavailability.
  • a first aspect of the present invention provides lumacaftor w-heptane solvate designated as crystalline form S 1 of lumacaftor.
  • a second aspect of the present invention provides a process for preparing lumacaftor w-heptane solvate designated as crystalline form S 1 of lumacaftor comprising the steps of:
  • a third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising lumacaftor w-heptane solvate designated as crystalline form S I of lumacaftor, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • a fourth aspect of the present invention provides the use of lumacaftor w-heptane solvate designated as crystalline form S 1 of lumacaftor for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation in the CFTR gene.
  • CF cystic fibrosis
  • a fifth aspect of the present invention provides lumacaftor 1,2-dimethoxyethane solvate designated as crystalline form S2 of lumacaftor.
  • a sixth aspect of the present invention provides a process for preparing lumacaftor 1,2-dimethoxyethane solvate designated as crystalline form S2 of lumacaftor comprising dissolving lumacaftor in 1,2-dimethoxyethane or in a mixture of 1,2-dimethoxyethane and other solvents.
  • a seventh aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising lumacaftor 1,2-dimethoxyethane solvate designated as crystalline form S2 of lumacaftor, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • An eighth aspect of the present invention provides the use of lumacaftor 1,2- dimethoxyethane solvate designated as crystalline form S2 of lumacaftor for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation in the CFTR gene.
  • a ninth aspect of the present invention provides a crystalline form designated as crystalline form S3 of lumacaftor.
  • a tenth aspect of the present invention provides a process for preparing a crystalline form designated as crystalline form S3 of lumacaftor comprising the steps of: a) dissolving lumacaftor in a solvent; and
  • An eleventh aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form designated as crystalline form S3 of lumacaftor, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • a twelfth aspect of the present invention provides the use of a crystalline form designated as crystalline form S3 of lumacaftor for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation in the CFTR gene.
  • CF cystic fibrosis
  • Figure 1 depicts the X-ray Powder Diffractogram (herein after XRPD) pattern of lumacaftor w-heptane solvate designated as crystalline form S 1 of lumacaftor.
  • Figure 2 depicts the Infrared absorption spectrum (herein after IR spectrum) of lumacaftor w-heptane solvate designated as crystalline form S 1 of lumacaftor.
  • Figure 3 depicts the TGA thermogram of lumacaftor w-heptane solvate designated as crystalline form S 1 of lumacaftor.
  • Figure 4 depicts the XRPD pattern of lumacaftor 1,2-dimethoxyethane solvate designated as crystalline form S2 of lumacaftor.
  • Figure 5 depicts the IR spectrum of lumacaftor 1,2-dimethoxyethane solvate designated as crystalline form S2 of lumacaftor.
  • Figure 6 depicts the TGA thermogram of lumacaftor 1,2-dimethoxyethane solvate designated as crystalline form S2 of lumacaftor.
  • Figure 7 depicts the XRPD pattern of a crystalline form designated as crystalline form S3 of lumacaftor.
  • Figure 8 depicts the IR spectrum of a crystalline form designated as crystalline form S3 of lumacaftor.
  • Figure 9 depicts the TGA thermogram of a crystalline form designated as crystalline form S3 of lumacaftor.
  • ambient temperature refers to a temperature in the range of about 20°C to about 35°C.
  • solvate refers to a crystalline form of lumacaftor that incorporates a solvent in the crystal structure.
  • the solvent can be present in stoichiometric or non-stoichiometric amount.
  • solvent or “other solvents” refers to any solvent or solvent mixtures, including, for example, aromatic hydrocarbons, esters, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
  • aromatic hydrocarbons include toluene and xylene.
  • esters include ethyl acetate, w-propyl acetate, isopropyl acetate, and «-butyl acetate.
  • halogenated hydrocarbons include dichloromethane, chloroform, and 1,2- dichloroethane.
  • ketones include acetone and methyl ethyl ketone.
  • ethers include diethyl ether, methyl teri-butyl ether, and tetrahydrofuran.
  • polar aprotic solvents include N,N-dimethylformamide, N,N- dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone.
  • antisolvent refers to hydrocarbons such as hexane, heptane, cyclohexane, methylcyclohexane, «-pentane, and water.
  • dissolving includes stirring, slurrying, or a combination thereof.
  • micronization refers to any process or methods by which the size of the particles is reduced. Micronization can be carried out using any of the conventionally known mills, such as a ball mill, colloid mill, grinding mill, air jet mill, roller mil or impact mill.
  • Lumacaftor w-heptane solvate designated as crystalline form SI of lumacaftor is characterized by an XRPD pattern as depicted in Figure 1.
  • lumacaftor w-heptane solvate designated as crystalline form S 1 of lumacaftor is characterized by an XRPD pattern having interplanar spacing (d) values at about 12.90, 4.48, and 4.09 A.
  • Lumacaftor w-heptane solvate is further characterized by an XRPD pattern having interplanar spacing (d) values at about 8.41, 8.19, 6.99, 5.21, 4.87, 3.92, and 3.33 A.
  • lumacaftor w-heptane solvate designated as crystalline form S 1 of lumacaftor is characterized by an XRPD pattern having characteristic peak values (2 ⁇ ) at about 6.85, 19.84, 21.72 ⁇ 0.2.
  • Lumacaftor w-heptane solvate designated as crystalline form S 1 of lumacaftor is further characterized by an XRPD pattern having characteristic peak values (2 ⁇ ) at about 10.53, 10.80, 12.66, 17.01, 18.20, 22.69, and 26.75 ⁇ 0.2.
  • Table 1 provides the representative 2 ⁇ values, the corresponding d-spacing values (A), and the relative intensity of lumacaftor w-heptane solvate designated as crystalline form S 1 of lumacaftor.
  • lumacaftor w-heptane solvate designated as crystalline form SI of lumacaftor is characterized by IR spectrum as depicted in Figure 2.
  • lumacaftor w-heptane solvate designated as crystalline form SI of lumacaftor is characterized by a thermogravimetric analysis (TGA) thermogram, as depicted in Figure 3.
  • Lumacaftor w-heptane solvate designated as crystalline form SI of lumacaftor is prepared by a process comprising the steps of:
  • lumacaftor is dissolved in an aromatic hydrocarbon solvent. In another embodiment, lumacaftor is dissolved in an ester solvent. In another embodiment, lumacaftor is dissolved in a halogenated hydrocarbon solvent. In another embodiment, lumacaftor is dissolved in a ketone solvent. In another embodiment, lumacaftor is dissolved in a polar aprotic solvent. In another embodiment, lumacaftor is dissolved in an ether solvent. In another embodiment, lumacaftor is dissolved in diethyl ether. In another embodiment, lumacaftor is dissolved in tetrahydrofuran.
  • the dissolution of lumacaftor in a solvent is carried out at ambient temperature to the reflux temperature of the solvent. In one embodiment, the dissolution is carried out at ambient temperature. In another embodiment, dissolution is carried out at about 35°C to about 50°C. In another embodiment, dissolution is carried out at about 50°C to about 70°C. In another embodiment, dissolution is carried out at about 70°C to the reflux temperature of the solvent.
  • the solution can optionally be filtered to remove any extraneous matter.
  • the solution is cooled to ambient temperature to about 60°C. In one embodiment, the solution is cooled to ambient temperature. In another embodiment, the solution is cooled to about 35°C to about 45°C. In another embodiment, the solution is cooled to about 45°C to about 50°C. In another embodiment, the solution is cooled to about 50°C to about 60°C.
  • the solution of lumacaftor in a solvent is added to w-heptane. The addition is carried out at ambient temperature to a temperature of about 60°C. In one embodiment, the addition is carried out at ambient temperature. In another embodiment, the addition is carried out at about 35°C to about 45°C. In another embodiment, the addition is carried out at about 45 °C to about 60°C.
  • the reaction mixture is stirred for about 5 minutes to about 1 hour. In one embodiment, the reaction mixture is stirred for about 5 minutes to about 15 minutes. In another embodiment, the reaction mixture is stirred for about 15 minutes to about 30 minutes. In another embodiment, the reaction mixture is stirred for about 30 minutes to about 45 minutes. In another embodiment, the reaction mixture is stirred for about 45 minutes to about 1 hour.
  • Isolation of lumacaftor w-heptane solvate designated as crystalline form S I of lumacaftor can be carried out by concentration, precipitation, cooling, filtration, centrifugation, or combinations thereof, followed by drying. Drying can be carried out using any suitable method, such as, drying under reduced pressure, air drying, or vacuum tray drying. In one embodiment, drying is carried out under reduced pressure. In another embodiment, air drying is carried out. In another embodiment, vacuum tray drying is carried out. Drying can be carried out at a temperature of about 35°C to about 70°C. In one embodiment, drying is carried out at about 35°C to about 45°C. In another embodiment, drying is carried out at about 45 °C to about 55°C.
  • drying is carried out at about 55°C to about 70°C. Drying is carried out for a period of about 2 hours to about 24 hours. In one embodiment, drying is carried out for about 2 hours to about 5 hours. In another embodiment, drying is carried out for about 5 hours to about 10 hours. In another embodiment, drying is carried out for about 10 hours to about 15 hours. In another embodiment, drying is carried out for about 15 hours to about 20 hours. In another embodiment, drying is carried out for about 20 hours to about 24 hours.
  • the dried material can optionally be micronized. In one embodiment,
  • micronization is carried out using ball mill. In another embodiment, micronization is carried out using colloid mill. In another embodiment, micronization is carried out using grinding mill. In another embodiment, micronization is carried out using air jet mill. In another embodiment, micronization is carried out using roller mill. In another embodiment, micronization is carried out using impact mill.
  • Lumacaftor n-heptane solvate designated as crystalline form SI of lumacaftor can be administered as part of a pharmaceutical composition for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation in the CFTR gene.
  • a pharmaceutical composition comprising lumacaftor w-heptane solvate designated as crystalline form S 1 of lumacaftor and one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally other therapeutic ingredients.
  • Lumacaftor 1,2-dimethoxyethane solvate designated as crystalline form S2 of lumacaftor is characterized by an XRPD pattern as depicted in Figure 4.
  • lumacaftor 1,2-dimethoxyethane solvate designated as crystalline form S2 of lumacaftor is characterized by an XRPD pattern having interplanar spacing (d) values at about 6.18, 4.72, and 3.75 A.
  • Lumacaftor 1,2-dimethoxyethane solvate designated as crystalline form S2 of lumacaftor is further characterized by an XRPD pattern having interplanar spacing (d) values at about 11.35, 11.21, 6.08, 5.66, 4.69, 4.14, 3.78, and 3.19 A.
  • lumacaftor 1,2-dimethoxyethane solvate designated as crystalline form S2 of lumacaftor is characterized by an XRPD pattern having
  • Lumacaftor 1,2- dimethoxyethane solvate designated as crystalline form S2 of lumacaftor is further characterized by an XRPD pattern having characteristic peak values (2 ⁇ ) at about 7.79, 7.89, 14.58, 15.67, 18.93, 21.48, 23.55, and 28.00 ⁇ 0.2.
  • Table 2 provides the representative 2 ⁇ values, the corresponding d-spacing values (A), and the relative intensity of lumacaftor 1,2-dimethoxyethane solvate designated as crystalline form S2 of lumacaftor.
  • lumacaftor 1,2-dimethoxyethane solvate designated as crystalline form S2 of lumacaftor is characterized by IR spectrum as depicted in Figure 5.
  • lumacaftor 1,2-dimethoxyethane solvate designated as crystalline form S2 of lumacaftor is characterized by a thermogravimetric analysis (TGA) thermogram as depicted in Figure 6.
  • Lumacaftor 1,2-dimethoxyethane solvate designated as crystalline form S2 of lumacaftor is prepared by a process comprising dissolving lumacaftor in 1,2- dimethoxyethane or in a mixture of 1,2-dimethoxyethane and other solvents.
  • 1,2-dimethoxyethane is added to lumacaftor.
  • a mixture of 1,2-dimethoxyethane and an aromatic hydrocarbon is added.
  • a mixture of 1,2-dimethoxyethane and an ester is added.
  • a mixture of 1,2-dimethoxyethane and a halogenated hydrocarbon is added.
  • a mixture of 1,2-dimethoxyethane and a ketone is added.
  • a mixture of 1,2-dimethoxyethane and an ether is added.
  • a mixture of 1,2-dimethoxyethane and a polar aprotic solvent is added.
  • Lumacaftor 1,2-dimethoxyethane solvate designated as crystalline form S2 of lumacaftor is prepared by a process comprising dissolving lumacaftor in 1,2- dimethoxyethane or in a mixture of 1,2-dimethoxyethane and other solvents, followed by addition of an antisolvent.
  • a mixture of 1,2-dimethoxyethane and water is added.
  • a mixture of 1,2-dimethoxyethane and hexane is added.
  • a mixture of 1,2-dimethoxyethane and cyclohexane is added.
  • a mixture of 1,2-dimethoxyethane and methylcyclohexane is added.
  • a mixture of 1,2-dimethoxyethane and «-pentane is added.
  • the reaction is carried out at ambient temperature to reflux temperature. In one embodiment, the reaction is carried out at ambient temperature. In another embodiment, the reaction is carried out at about 35°C to about 50°C. In another embodiment, the reaction is carried out at about 50°C to about 65°C. In another embodiment, the reaction is carried out at about 65 °C to reflux temperature.
  • the reaction mixture can optionally be filtered to remove any extraneous matter.
  • the reaction mixture is kept at a temperature of about 15°C to ambient temperature for about 5 minutes to about 24 hours. In one embodiment, the reaction mixture is kept at about 15°C to about 20°C. In another embodiment, the reaction mixture is kept at about 20°C to about 25°C. In another embodiment, the reaction mixture is kept at about 25°C to about 30°C. In another embodiment, the reaction mixture is kept at about 30°C to about
  • the reaction mixture is kept for about 5 minutes to about 1 hour. In another embodiment, the reaction mixture is kept for about 1 hour to about 5 hours. In another embodiment, the reaction mixture is kept for about 5 hours to about 10 hours. In another embodiment, the reaction mixture is kept for about 10 hours to about 15 hours. . In another embodiment, the reaction mixture is kept for about 15 hours to about 20 hours. In another embodiment, the reaction mixture is kept for about 20 hours to about 24 hours.
  • the reaction mixture is stirred for about 5 minutes to about 24 hours. In one embodiment, the reaction mixture is stirred for about 5 minutes to about 1 hour. In another embodiment, the reaction mixture is stirred for about 1 hour to about 5 hours. In another embodiment, the reaction mixture is stirred for about 5 hours to about 10 hours. In another embodiment, the reaction mixture is stirred for about 10 hours to about 15 hours. . In another embodiment, the reaction mixture is stirred for about 15 hours to about 20 hours. In another embodiment, the reaction mixture is stirred for about 20 hours to about 24 hours.
  • Isolation of lumacaftor 1,2-dimethoxyethane solvate designated as crystalline form S2 of lumacaftor can be carried out by concentration, precipitation, cooling, filtration, centrifugation, or combinations thereof, followed by drying. Drying can be carried out using any suitable method, such as, drying under reduced pressure, air drying, or vacuum tray drying. In one embodiment, drying is carried out under reduced pressure. In another embodiment, air drying is carried out. In another embodiment, vacuum tray drying is carried out. Drying can be carried out at a temperature of about 35°C to about 70°C. In one embodiment, drying is carried out at about 35°C to about 45°C. In another embodiment, drying is carried out at about 45 °C to about 55°C.
  • drying is carried out at about 55°C to about 70°C. Drying is carried out for a period of about 2 hours to about 24 hours. In one embodiment, drying is carried out for about 2 hours to about 5 hours. In another embodiment, drying is carried out for about 5 hours to about 10 hours. In another embodiment, drying is carried out for about 10 hours to about 15 hours. In another embodiment, drying is carried out for about 15 hours to about 20 hours. In another embodiment, drying is carried out for about 20 hours to about 24 hours.
  • the dried material can optionally be micronized.
  • micronization is carried out using ball mill.
  • micronization is carried out using colloid mill.
  • micronization is carried out using grinding mill.
  • micronization is carried out using air jet mill.
  • micronization is carried out using roller mill.
  • micronization is carried out using impact mill.
  • Lumacaftor 1,2-dimethoxyethane solvate designated as crystalline form S2 of lumacaftor can be administered as part of a pharmaceutical composition for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation in the CFTR gene. Accordingly, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising lumacaftor 1,2- dimethoxyethane solvate designated as crystalline form S2 of lumacaftor and one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally other therapeutic ingredients. Crystalline form designated as crystalline form S3 of lumacaftor is characterized by an XRPD pattern as depicted in Figure 7.
  • crystalline form designated as crystalline form S3 of lumacaftor is characterized by an XRPD pattern having interplanar spacing (d) values at about 5.05, 4.09, 4.01 and 3.97 A.
  • Crystalline form designated as crystalline form S3 of lumacaftor is further characterized by an XRPD pattern having interplanar spacing (d) values at about 6.53, 5.30, 4.69, 4.28, 3.56, and 2.93 A.
  • crystalline form designated as crystalline form S3 of lumacaftor is characterized by an XRPD pattern having characteristic peak values (2 ⁇ ) at about 17.56, 21.71, 22.18, and 22.38 ⁇ 0.2.
  • Crystalline form designated as crystalline form S3 of lumacaftor is further characterized by an XRPD pattern having characteristic peak values (2 ⁇ ) at about 13.57, 16.72, 18.92, 20.75, 25.03, and 30.47 ⁇ 0.2.
  • Table 3 provides the representative 2 ⁇ values, the corresponding d-spacing values (A), and the relative intensity of the crystalline form designated as crystalline form S3 of lumacaftor.
  • crystalline form designated as crystalline form S3 of lumacaftor is characterized by IR spectrum as depicted in Figure 8.
  • crystalline form designated as crystalline form S3 of lumacaftor is characterized by a thermogravimetric analysis (TGA) thermogram as depicted in Figure 9.
  • TGA thermogravimetric analysis
  • Crystalline form designated as crystalline form S3 of lumacaftor is prepared by a process comprising the steps of:
  • crystalline form designated as crystalline form S3 of lumacaftor is prepared by dissolving lumacaftor in a solvent.
  • an aromatic hydrocarbon solvent is used.
  • an ester solvent is used.
  • a halogenated hydrocarbon solvent is used.
  • a ketone solvent is used.
  • a polar aprotic solvent is used.
  • an ether solvent is used.
  • diethyl ether is used.
  • tetrahydrofuran is used.
  • Dissolution of lumacaftor in a solvent is carried out at ambient temperature to the reflux temperature of the solvent. In one embodiment, dissolution is carried out at ambient temperature. In another embodiment, dissolution is carried out at a temperature of about 35°C to 50°C. In another embodiment, dissolution is carried out at a temperature of about 50°C to about 70°C. In another embodiment, dissolution is carried out at the reflux temperature of the solvent.
  • the solution of lumacaftor in a solvent can optionally be filtered to remove any extraneous matter.
  • the solution of lumacaftor in a solvent can optionally be concentrated under reduced pressure.
  • the solution of lumacaftor in a solvent is added to an antisolvent.
  • the antisolvent is hexane.
  • the antisolvent is cyclohexane.
  • the antisolvent is methylcyclohexane.
  • the addition of antisolvent is carried out at a temperature of about 15°C to about 60°C. In one embodiment, the addition is carried out at about 15°C to ambient temperature. In another embodiment, the addition is carried out at about 35°C to about 45°C. In another embodiment, the addition is carried out at about 45°C to about 60°C.
  • the reaction mixture is stirred for about 5 minutes to about 1 hour. In one embodiment, the reaction mixture is stirred for about 5 minutes to about 20 minutes. In another embodiment, the reaction mixture is stirred for about 20 minutes to about 40 minutes. In another embodiment, the reaction mixture is stirred for about 40 minutes to about 1 hour.
  • Isolation of crystalline form designated as crystalline form S3 of lumacaftor can be carried out by concentration, precipitation, cooling, filtration, centrifugation, or combinations thereof, followed by drying. Drying can be carried out using any suitable method, such as, drying under reduced pressure, air drying, or vacuum tray drying. In one embodiment, drying is carried out under reduced pressure. In another embodiment, air drying is carried out. In another embodiment, vacuum tray drying is carried out. Drying can be carried out at a temperature of about 35°C to about 70°C. In one embodiment, drying is carried out at about 35°C to about 45 °C. In another embodiment, drying is carried out at about 45°C to about 55°C. In another embodiment, drying is carried out at about 55°C to about 70°C.
  • Drying is carried out for a period of about 2 hours to about 24 hours. In one embodiment, drying is carried out for about 2 hours to about 5 hours. In another embodiment, drying is carried out for about 5 hours to about 10 hours. In another embodiment, drying is carried out for about 10 hours to about 15 hours. In another embodiment, drying is carried out for about 15 hours to about 20 hours. In another embodiment, drying is carried out for about 20 hours to about 24 hours.
  • the dried material can optionally be micronized.
  • micronization is carried out using ball mill.
  • micronization is carried out using colloid mill.
  • micronization is carried out using grinding mill.
  • micronization is carried out using air jet mill.
  • micronization is carried out using roller mill.
  • micronization is carried out using impact mill.
  • Crystalline form designated as crystalline form S3 of lumacaftor can be administered as part of a pharmaceutical composition for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation in the CFTR gene. Accordingly, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising crystalline form designated as crystalline form S3 of lumacaftor and one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally other therapeutic ingredients.
  • the X-ray powder diffraction pattern was recorded using a PANalytical ® instrument; Model X'pert PRO; Detector: X'celerator ® . Step size: 0.02; Range: 3-40 degree 2 theta; CuKa radiation at 45kV and 40 mA.
  • the TGA was recorded using a TA Instruments ® Q500 between 30°C and 300°C at 10°C/min scan rate.
  • the IR spectrum was recorded using a Perkin Elmer ® Spectrum One FT-IR spectrometer.
  • Example 1 Preparation of lumacaftor ra-heptane solvate designated as crystalline form S 1 of lumacaftor
  • Lumacaftor (0.4 g) was dissolved in tetrahydrofuran (2 mL) at 65°C. The solution was filtered and cooled to 45°C to 50°C. The solution was then added to w-heptane (62.5 mL) at ambient temperature. The reaction mixture was stirred for 10 minutes. The reaction mixture was filtered. The solid was dried under reduced pressure at 50°C for 14 hours to obtain lumacaftor w-heptane solvate.
  • Lumacaftor (0.25 g) was dissolved in a mixture of 1,2-dimethoxy ethane (1.35 mL) and water (0.5 mL) at 65°C. The solution was kept for slow evaporation at ambient temperature. The solid material precipitated after 30 minutes. Water (5 mL) was added to the reaction mixture. The reaction mixture was stirred for 30 minutes. The reaction mixture was filtered. The solid was dried under reduced pressure at 50°C for 14 hours to obtain lumacaftor 1,2-dimethoxy ethane solvate.
  • Example 3 Preparation of crystalline form designated as crystalline form S3 of lumacaftor
  • Lumacaftor (0.4 g) was dissolved in tetrahydrofuran (2 mL) at 70°C. The solution was cooled to ambient temperature. The solution was added to cyclohexane (80 mL) at ambient temperature. The reaction mixture was stirred for 20 minutes. The reaction mixture was filtered. The solid was dried under reduced pressure at 60°C for 14 hours to obtain crystalline form designated as form S3 of lumacaftor.

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des solvates de lumacaftor, une forme cristalline de lumacaftor, des procédés pour leur préparation, des compositions pharmaceutiques les comprenant, et leur utilisation pour le traitement de la fibrose kystique (FK) chez des patients âgés de 6 ans et plus, qui sont homozygotes pour la mutation F508del dans le gène CFTR.
PCT/IB2018/056401 2017-08-23 2018-08-23 Formes cristallines de lumacaftor Ceased WO2019038718A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
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CA2995133A1 (fr) * 2015-08-11 2017-02-16 Crystal Pharmatech Co., Ltd. Forme cristalline d'acide 3-(6-(1-(2,2-difluorobenzo [d] [1,3] dioxole-5-yl) cyclopropanecarboxamido)-3-methylpyridine-2-yl) benzoique et son procede de preparation
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