WO2018037350A1 - Formes solides de lumacaftor, leur procédé de préparation et leurs compositions pharmaceutiques - Google Patents

Formes solides de lumacaftor, leur procédé de préparation et leurs compositions pharmaceutiques Download PDF

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Publication number
WO2018037350A1
WO2018037350A1 PCT/IB2017/055074 IB2017055074W WO2018037350A1 WO 2018037350 A1 WO2018037350 A1 WO 2018037350A1 IB 2017055074 W IB2017055074 W IB 2017055074W WO 2018037350 A1 WO2018037350 A1 WO 2018037350A1
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Prior art keywords
lumacaftor
accordance
powder
ray diffraction
lumacaftor form
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PCT/IB2017/055074
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English (en)
Inventor
Ram Thaimattam
Suresh Babu RADHAKRISHNAN
Uma Maheswar Rao VASIREDDI
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Laurus Labs Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom

Definitions

  • the present invention relates to solid forms of lumacaftor, processes for their preparation and use of such solid forms in pharmaceutical compositions and to their use in therapy.
  • the present invention relates to solid forms of lumacaftor, including amorphous form, solvates and/or polymorphs of solvates, process for their preparation and a pharmaceutical composition comprising the same.
  • Cystic Fibrosis is a fatal autosomal recessive disease associated with defective hydration of lung airways due to the loss of function of the CF transmembrane conductance regulator (CFTR) channel at epithelial cell surfaces.
  • CFTR CF transmembrane conductance regulator
  • CFTR endogenously expressed in respiratory epithelia leads to reduced apical anion secretion causing an imbalance in ion and fluid transport.
  • anion transport contributes to enhanced mucus accumulation in the lung and the accompanying microbial infections that ultimately cause death in CF patients.
  • CF patients In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, results in death.
  • the majority of males with cystic fibrosis are infertile and fertility is decreased among females with cystic fibrosis.
  • Lumacaftor is available in a single pill with Ivacaftor combination, lumacaftor/ivacaftor having the brand name Orkambi, is used to treat people with cystic fibrosis who have the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR).
  • CFTR cystic fibrosis transmembrane conductance regulator
  • PCT publication No. WO2007/056341 discloses modulators of ATP-Binding Cassette (“ABC”) transporters including Cystic Fibrosis Transmembrane conductance Regulator (“CFTR”) such as lumacaftor.
  • ABSC ATP-Binding Cassette
  • CFTR Cystic Fibrosis Transmembrane conductance Regulator
  • PCT Publication No. WO2011/127290 (“the '290 publication”) disclosed crystalline Form A of lumacaftor hydrochloride salt and further disclosed various isostructural solvates of lumacaftor such as methanol solvate, ethanol solvate, acetone solvate, 2- propanol solvate, acetonitrile solvate, THF solvate, methyl acetate solvate, 2-butanone solvate, ethyl formate solvate and 2-methyl tetrahydro furan solvate and process for their preparation, wherein the process for preparing isostructural solvates involves the slurring of solvate reaction mixture for 48 hours.
  • various isostructural solvates of lumacaftor such as methanol solvate, ethanol solvate, acetone solvate, 2- propanol solvate, acetonitrile solvate, THF solvate, methyl acetate solvate
  • PCT Publication No. WO2017/056031 (“the '031 publication”) disclosed an amorphous form of lumacaftor.
  • PCT Publication No. WO 2017/056109 (“the ⁇ 09 publication”) disclosed an amorphous form of lumacaftor, crystalline lumacaftor acetic acid solvate and crystalline lumacaftor ethyl acetate solvate.
  • Suitable solid forms of a drug is a necessary stage for many orally available drugs.
  • Suitable solid forms possess the desired properties of a particular drug.
  • Such suitable forms often possess more favourable pharmaceutical and pharmacological properties or may be easier to process than known forms of the drug itself or may be used as a drug product intermediate during the preparation of the drug.
  • new drug formulations comprising crystalline forms of a given drug may have superior properties, such as solubility, dissolution, hygroscopicity and storage stability over existing formulations of the drug.
  • APIs active pharmaceutical ingredients
  • the present invention addresses the need in the art for pharmaceutically useful solid forms of lumacaftor that may have improved physicochemical properties, such as a higher solubility and dissolution rate, enhanced flow properties and enhanced stability.
  • New solid forms of lumacaftor such as amorphous lumacaftor, new solvates and/or polymorphs of solvates of lumacaftor have now been discovered.
  • the present invention provides solid forms of lumacaftor, including amorphous form, solvates and/or polymorphs of solvates, processes for their preparation, pharmaceutical compositions containing the same and to their use in therapy.
  • the present invention provides novel solid forms of lumacaftor.
  • the present invention provides the novel solid forms of lumacaftor exist in an amorphous form.
  • the present invention provides an amorphous Form of lumacaftor of Formula I; wherein the amorphous form has less than about 20% of crystalline form. In accordance with another embodiment, the present invention provides an amorphous Form of lumacaftor of Formula I; wherein the amorphous form has less than about 10% of crystalline form. In accordance with another embodiment, the present invention provides an amorphous Form of lumacaftor of Formula I; wherein the amorphous form has less than about 5% of crystalline form. In accordance with another embodiment, the present invention provides an amorphous Form of lumacaftor of Formula I; wherein the amorphous form has less than about 1% of crystalline form.
  • the present invention provides an amorphous form of lumacaftor characterized by a X-ray powder diffraction in accordance with Figure 01.
  • the present invention provides an amorphous form of lumacaftor characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 02.
  • DSC differential scanning calorimetry
  • the present invention provides an amorphous form of lumacaftor characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 03.
  • TGA thermogravimetric analysis
  • the present invention provides an amorphous form of lumacaftor, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 01, a differential scanning calorimetry (DSC) substantially in accordance with Figure 02 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 03.
  • PXRD powder X-Ray diffraction
  • DSC differential scanning calorimetry
  • TGA thermo gravimetric analysis
  • the present invention provides a process for preparation of amorphous form of lumacaftor, comprising:
  • step b) adding a suitable antisolvent to the step a) solution or vice-versa;
  • the present invention provides a process for preparation of amorphous form of lumacaftor, comprising:
  • step b) adding a suitable antisolvent to the step a) solution or vice-versa;
  • the one or more solvents are selected from the group consisting of organic acids, alcohols, ketones, esters, nitriles and the like and mixtures thereof; wherein the suitable antisolvent is selected from the group consisting of water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like; and mixtures thereof.
  • the present invention provides a process for preparation of amorphous form of lumacaftor, comprising:
  • step a) a) providing a solution of lumacaftor in formic acid; b) adding the solution of step a) into water or vice- versa;
  • the present invention provides a process for preparation of amorphous form of lumacaftor, comprising:
  • step b) adding the solution of step a) into water or vice- versa;
  • the present invention provides a process for preparation of amorphous form of lumacaftor, comprising:
  • the present invention provides a process for preparation of amorphous form of lumacaftor, comprising:
  • the present invention provides the novel solid forms of lumacaftor exist in the form of solvates or polymorphs of solvates.
  • the present invention provides novel solid forms of lumacaftor, herein designated as lumacaftor Form-Ll, lumacaftor Form-L2, lumacaftor Form-L3, lumacaftor Form-L4, lumacaftor Form-L5, lumacaftor Form-L6, lumacaftor Form-L7, lumacaftor Form-L8, lumacaftor Form-L9, lumacaftor Form-LlO and lumacaftor Form-Ll 1.
  • the present invention provides lumacaftor Form-Ll.
  • the lumacaftor Form-Ll of the present invention is an acetic acid solvate.
  • the present invention provides crystalline lumacaftor Form-Ll characterized by a X-ray powder diffraction in accordance with Figure 04.
  • the present invention provides crystalline lumacaftor Form-Ll characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 05.
  • the present invention provides crystalline lumacaftor Form-Ll characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 06.
  • the present invention provides crystalline lumacaftor Form-Ll, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 04, a differential scanning calorimetry (DSC) substantially in accordance with Figure 05 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 06.
  • PXRD powder X-Ray diffraction
  • DSC differential scanning calorimetry
  • TGA thermo gravimetric analysis
  • the present invention provides lumacaftor Form-L2.
  • the lumacaftor Form-L2 of the present invention is a tert-butanol solvate.
  • the present invention provides crystalline lumacaftor Form-L2 characterized by a X-ray powder diffraction in accordance with Figure 07.
  • the present invention provides crystalline lumacaftor Form-L2 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 08.
  • DSC differential scanning calorimetry
  • the present invention provides crystalline lumacaftor Form-L2 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 09.
  • the present invention provides crystalline lumacaftor Form-L2, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 07, a differential scanning calorimetry (DSC) substantially in accordance with Figure 08 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 09.
  • PXRD powder X-Ray diffraction
  • DSC differential scanning calorimetry
  • TGA thermo gravimetric analysis
  • the present invention provides lumacaftor Form-L3.
  • the lumacaftor Form-L3 of the present invention is a dichloromethane solvate.
  • the present invention provides crystalline lumacaftor Form-L3 characterized by a X-ray powder diffraction in accordance with Figure 10.
  • the present invention provides crystalline lumacaftor Form-L3 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 11.
  • the present invention provides crystalline lumacaftor Form-L3 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 12.
  • TGA thermogravimetric analysis
  • the present invention provides crystalline lumacaftor Form-L3, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 10, a differential scanning calorimetry (DSC) substantially in accordance with Figure 11 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 12.
  • PXRD powder X-Ray diffraction
  • DSC differential scanning calorimetry
  • TGA thermo gravimetric analysis
  • the present invention provides lumacaftor Form-L4.
  • the lumacaftor Form-L4 of the present invention is an isopropyl acetate solvate.
  • the present invention provides crystalline lumacaftor Form-L4 characterized by a X-ray powder diffraction in accordance with Figure 13.
  • the present invention provides crystalline lumacaftor Form-L4 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 14.
  • DSC differential scanning calorimetry
  • the present invention provides crystalline lumacaftor Form-L4 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 15.
  • TGA thermogravimetric analysis
  • the present invention provides crystalline lumacaftor Form-L4, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 13, a differential scanning calorimetry (DSC) substantially in accordance with Figure 14 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 15.
  • PXRD powder X-Ray diffraction
  • DSC differential scanning calorimetry
  • TGA thermo gravimetric analysis
  • the present invention provides lumacaftor Form-L5.
  • the lumacaftor Form-L5 of the present invention is an ethyl acetate solvate.
  • the present invention provides crystalline lumacaftor Form-L5 characterized by a X-ray powder diffraction in accordance with Figure 16.
  • the present invention provides lumacaftor Form-L6.
  • the lumacaftor Form-L6 of the present invention is a cyclopentyl methyl ether solvate.
  • the present invention provides crystalline lumacaftor Form-L6 characterized by a X-ray powder diffraction in accordance with Figure 17. In accordance with another embodiment, the present invention provides lumacaftor Form-L7.
  • the lumacaftor Form-L7 of the present invention is an n-propanol solvate.
  • the present invention provides crystalline lumacaftor Form-L7 characterized by a X-ray powder diffraction in accordance with Figure 18. In accordance with another embodiment, the present invention provides lumacaftor Form-L8.
  • the lumacaftor Form-L8 of the present invention is an n-propyl acetate solvate.
  • the present invention provides crystalline lumacaftor Form-L8 characterized by a X-ray powder diffraction in accordance with Figure 19. In accordance with another embodiment, the present invention provides lumacaftor Form-L9.
  • the lumacaftor Form-L9 of the present invention is an isobutyl acetate solvate.
  • the present invention provides crystalline lumacaftor Form-L9 characterized by a X-ray powder diffraction in accordance with Figure 20.
  • the present invention provides lumacaftor Form-LlO.
  • the lumacaftor Form-LlO of the present invention is a dimethylformamide solvate.
  • the present invention provides crystalline lumacaftor Form-LlO characterized by a X-ray powder diffraction in accordance with Figure 21.
  • the present invention provides lumacaftor Form-Ll l.
  • the lumacaftor Form-Ll l of the present invention is a dimethylsulfoxide solvate.
  • the present invention provides crystalline lumacaftor Form-Ll l characterized by a X-ray powder diffraction in accordance with Figure 22.
  • the present invention provides a process for the preparation of novel solvates of lumacaftor.
  • the present invention provides a process for the preparation of crystalline lumacaftor Form LI to LI 1, comprising:
  • step b) optionally, heating the step a) reaction mixture
  • step c) optionally, cooling the mixture of step b);
  • the present invention provides a process for the preparation of crystalline lumacaftor Form LI to LI 1, comprising:
  • step b) optionally, heating the step a) reaction mixture
  • step c) optionally, cooling the mixture of step b);
  • the suitable organic solvent is selected from the group consisting of acetic acid, tert-butanol, dichloromethane, isopropyl acetate, ethyl acetate, cyclopentyl methyl ether, n-propanol, n-propyl acetate, isobutyl acetate, dimethyl formamide or dimethyl sulfoxide.
  • the present invention provides the use of novel solvate forms of lumacaftor as intermediates to prepare other solid forms of lumacaftor.
  • the present invention provides a process for the preparation of lumacaftor Form I, comprising:
  • step c) optionally, cooling the step b) solution
  • step d) adding a suitable anti-solvent to the step a) solution or vice versa; and e) isolating the lumacaftor Form I; wherein the crystalline lumacaftor Form LI to LI 1 are characterized by fig. 4 to 22 respectively.
  • the present invention provides a process for the preparation of amorphous form of lumacaftor, wherein the process involves the use of one or more novel solvate forms of lumacaftor of the invention as intermediates.
  • the present invention provides a process for the preparation of amorphous form of lumacaftor, comprising:
  • the crystalline lumacaftor is selected from the group consisting of Form LI, L2, L3, L4, L5, L6, L7, L8, L9, L10 and LI 1, which are characterized by fig. 4 to 22 respectively.
  • Figure 1 is the characteristic powder XRD pattern of amorphous form of Lumacaftor.
  • Figure 2 is the characteristic DSC thermogram of amorphous form of Lumacaftor.
  • Figure 3 is the characteristic TGA curve of amorphous form of Lumacaftor.
  • Figure 4 is the characteristic powder XRD pattern of lumacaftor Form-Ll.
  • Figure 5 is the characteristic DSC thermogram of lumacaftor Form-Ll.
  • Figure 6 is the characteristic TGA curve of lumacaftor Form-Ll.
  • Figure 7 is the characteristic powder XRD pattern of lumacaftor Form-L2.
  • Figure 8 is the characteristic DSC thermogram of lumacaftor Form-L2.
  • Figure 9 is the characteristic TGA curve of lumacaftor Form-L2.
  • Figure 10 is the characteristic powder XRD pattern of lumacaftor Form-L3.
  • Figure 11 is the characteristic DSC thermogram of lumacaftor Form-L3.
  • Figure 12 is the characteristic TGA curve of lumacaftor Form-L3.
  • Figure 13 is the characteristic powder XRD pattern of lumacaftor Form-L4.
  • Figure 14 is the characteristic DSC thermogram of lumacaftor Form-L4
  • Figure 15 is the characteristic TGA curve of lumacaftor Form-L4.
  • Figure 16 is the characteristic powder XRD pattern of lumacaftor Form- L5.
  • Figure 17 is the characteristic powder XRD pattern of lumacaftor Form- L6.
  • Figure 18 is the characteristic powder XRD pattern of lumacaftor Form- ⁇ L7.
  • Figure 19 is the characteristic powder XRD pattern of lumacaftor Form- L8.
  • Figure 20 is the characteristic powder XRD pattern of lumacaftor Form- L9.
  • Figure 21 is the characteristic powder XRD pattern of lumacaftor Form- ⁇ L10.
  • Figure 22 is the characteristic powder XRD pattern of lumacaftor Form- ⁇ Ll l.
  • solid forms herein used in this specification collectively represents an amorphous form, a crystalline form, solvates or their polymorphic forms.
  • solvate refers to a crystals form that incorporates a solvent in the crystal structure.
  • the solvent in a solvate may be present in either a stoichiometric or in a non- stoichiometric amount.
  • the present invention provides novel solid forms of lumacaftor, processes for their preparation and a pharmaceutical composition containing the same.
  • lumacaftor which is used as a starting material is known in the art and can be prepared by any known methods, for example lumacaftor may be synthesized as disclosed in international PCT publication WO 2007/056341.
  • the starting lumacaftor may be in any form such as crude obtained directly form the reaction mass, crystalline, amorphous or other forms of lumacaftor, including various solvates and hydrates known in the art as well as the novel solid forms described herein the present invention.
  • the present invention provides novel solid forms of lumacaftor, which are characterized by one or more of analytical techniques such as powder X-Ray diffraction (XRD), differential scanning calorimetry (DSC) and/or thermogravimetric analysis (TGA).
  • analytical techniques such as powder X-Ray diffraction (XRD), differential scanning calorimetry (DSC) and/or thermogravimetric analysis (TGA).
  • the present invention provides novel solid forms of lumacaftor. In another embodiment, the present invention provides novel solid forms of lumacaftor exist as an amorphous form.
  • the present invention provides an amorphous Form of lumacaftor of Formula I; wherein the amorphous form has less than about 20% of crystalline form.
  • the present invention provides an amorphous Form of lumacaftor of Formula I; wherein the amorphous form has less than about 10% of crystalline form.
  • the present invention provides an amorphous Form of lumacaftor of Formula I; wherein the amorphous form has less than about 5% of crystalline form. In another embodiment, the present invention provides an amorphous Form of lumacaftor of Formula I; wherein the amorphous form has less than about 1% of crystalline form.
  • the present invention provides an amorphous form of lumacaftor characterized by a X-ray powder diffraction in accordance with Figure 01.
  • the present invention provides an amorphous form of lumacaftor characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 02.
  • DSC differential scanning calorimetry
  • the present invention provides an amorphous form of lumacaftor characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 03.
  • TGA thermogravimetric analysis
  • the present invention provides an amorphous form of lumacaftor, characterized by a powder X-Ray diffraction (PXRD) pattern substantially in accordance with Figure 01, a differential scanning calorimetry (DSC) substantially in accordance with Figure 02 and/or a thermo gravimetric analysis (TGA) substantially in accordance with Figure 03.
  • PXRD powder X-Ray diffraction
  • DSC differential scanning calorimetry
  • TGA thermo gravimetric analysis
  • the present invention provides a process for preparation of amorphous form of lumacaftor, comprising:
  • step b) adding a suitable antisolvent to the step a) solution or vice-versa;
  • the starting material lumacaftor used in the present invention is known in the art and can be prepared by any known methods, for example lumacaftor may be synthesized as disclosed in international PCT publication WO 2007/056341.
  • the starting lumacaftor used herein in step a) may be any crystalline or other form of lumacaftor, including various solvates, hydrates, salts and cocrystals as long as amorphous lumacaftor is produced during the process of the invention or lumacaftor obtaining as existing solution from a previous processing step.
  • Step a) of providing a solution of lumacaftor may include dissolving any form of lumacaftor in one or more solvents at a temperature of about 20°C to about reflux temperature.
  • the one or more solvents include, but are not limited to organic acids selected from formic acid, acetic acid, propionic acid and the like; alcohols selected from methanol, ethanol, isopropanol and the like; ketones selected from acetone, methylisobutylketone, methylethylketone and the like; esters selected methyl acetate, ethyl acetate, isopropyl acetate and the like; nitriles selected from acetonitrile, propionitrile and the like; and mixture thereof, preferably the one or more solvents is formic acid or acetic acid.
  • the step a) reaction may optionally heat to dissolve all solids in one or more solvents.
  • the dissolution temperature for the lumacaftor may range from about 20° C to reflux temperature of the solvent used. Any other temperatures may also be acceptable, provided a clear solution of the concerned materials is obtained in the solvents chosen, and the starting materials are not degraded. It will be understood that the temperatures required will also be determined by the processing conditions for the recovery of the final product, such as the temperature of drying, the boiling point of the solvent, the homogeneity of the solution required after mixing solvents, the viscosity of the solution, the stability of the lumacaftor. Such variations are all included herein without any limitation.
  • Step b) of the aforementioned process involves precipitation of amorphous form of lumacaftor by either addition of suitable antisolvent to the lumacaftor solution of step a) or addition of step a) solution of lumacaftor into a suitable antisolvent.
  • suitable antisolvent include, but are not limited to water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like; and mixtures thereof.
  • the ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; aliphatic hydrocarbons include, but are not limited to hexane, heptane, propane and the like; alicyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like; and mixture thereof; preferably the suitable antisolvent is water.
  • the isolation of the resultant product is accomplished by conventional techniques such as removal of solvent from the solution by, for example, substantially complete evaporation of the solvent, concentrating the solution or by cooling to obtain amorphous form.
  • Evaporation can be achieved by a distillation, lyophilisation or freeze-drying technique, rotational drying (such as with the Buchi Rotavapor), spray drying, fluid bed drying, flash drying, spin flash drying, agitated thin-film drying and the like.
  • the reaction solution may be cooled to obtain amorphous lumacaftor and the resultant amorphous form can be recovered by conventional techniques, for example filtration.
  • the resultant product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like.
  • the present invention provides a process for preparation of amorphous form of lumacaftor, comprising:
  • step b) adding the solution of step a) into water or vice- versa;
  • the lumacaftor in the step a) may be any crystalline or other form of lumacaftor, including various solvates, hydrates, salts and cocrystals as long as amorphous lumacaftor is produced during the process of the invention or lumacaftor obtaining as existing solution from a previous processing step.
  • the step of providing a solution of lumacaftor may include dissolving any form of lumacaftor in formic acid or acetic acid at a temperature of about 20°C to about reflux temperature. Typically, stirring is involved for about 30 min at the same temperature.
  • Step b) of the aforementioned process involves addition of lumacaftor solution obtained from step a) into water or water may be added in to step a) solution of lumacaftor.
  • amorphous form of lumacaftor is carried out by any conventional techniques known in the art or methods described just as above, for example filtration.
  • the resultant wet product may optionally be further dried for about 2 hours to 20 hours. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like.
  • the present invention provides a process for preparation of amorphous form of lumacaftor, comprising:
  • Step a) of the forgoing process involves the dissolution of lumacaftor in a suitable solvent
  • the suitable solvent includes but are not limited to alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, t-butanol and the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, n- butyl acetate, t-butyl acetate and the like; ethers such as methyl tertiary butyl ether, tetrahydrofuran, dimethyl ether, diisopropyl ether, 1,4-dioxane and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionit
  • the dissolution temperatures may range from about 10°C to about reflux temperature of the solvent; preferably at a temperature of about 25 °C to about 35°C.
  • the step of removal of solvent may be carried out by one or more techniques known in the art, for example, distillation, distillation under vacuum, spray drying, agitated thin film drying ("ATFD"), and freeze drying (lyophilization).
  • the resultant wet product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like; preferably the solvent is removed by distillation under vacuum at about 50°C to about 60°C.
  • the lumacaftor recovered using the process of the present invention is in form of substantially pure amorphous lumacaftor.
  • the lumacaftor recovered using the process of the present invention is having less than about 20% of any crystalline form; preferably less than about 10%, more preferably less than 5%, most preferably less than about 1%.
  • the present invention provides the novel solid forms of lumacaftor, which may exist in the form of solvates or polymorphs of solvates.
  • the present invention provides novel solvates of lumacaftor, herein after designated as lumacaftor Form-Ll, lumacaftor Form-L2, lumacaftor Form- L3, lumacaftor Form-L4, lumacaftor Form-L5, lumacaftor Form-L6, lumacaftor Form- L7, lumacaftor Form-L8, lumacaftor Form-L9, lumacaftor Form-LlO and lumacaftor Form-Ll 1.
  • the present invention provides lumacaftor Form-Ll.
  • the lumacaftor Form-Ll of the present invention is an acetic acid solvate.
  • the present invention provides lumacaftor Form-Ll characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 04.
  • PXRD powder X-ray diffraction
  • the present invention provides lumacaftor Form-Ll characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.02, 7.71, 8.02, 8.78, 10.29, 10.71, 11.18, 12.10, 12.68, 13.79, 14.78, 15.19, 15.62, 16.44, 17.00, 17.76, 18.30, 18.75, 19.62, 20.36, 21.42, 22.01, 22.62, 23.36, 24.10, 24.41, 25.33, 26.24, 27.04, 27.89, 28.59, 29.04, 29.73, 30.61, 31.40, 32.22, 33.57, 34.78, 35.54, 36.13, 37.34, 38.42, 39.06, 39.97 and 41.70 ⁇ 0.2° 2 ⁇ .
  • the present invention provides lumacaftor Form-Ll characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 05.
  • DSC differential
  • the present invention provides lumacaftor Form-Ll characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 06.
  • TGA thermogravimetric analysis
  • the present invention provides lumacaftor Form-Ll characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 04, a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 05 and a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 06.
  • XRD X-Ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the present invention provides a process for the preparation of lumacaftor Form-Ll, comprising:
  • step b) optionally, heating the step a) reaction mixture
  • step c) optionally, cooling the mixture of step b);
  • the aforementioned process of lumacaftor Form-Ll includes dissolving lumacaftor in acetic acid at a suitable temperature, for example at about 20°C to about 40°C; preferably at about 20°C to about 30° and optionally the reaction mixture may be heated to about 50°C to about reflux temperature, preferably at about 55°C to about 65°C.
  • the reaction mixture is cooling the reaction mixture to room temperature for sufficient period of time, preferably for about 10 to 20 hours and isolating the lumacaftor Form LI by known methods in the art such as concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE), filtration under vacuum and the like; preferably filtration under vacuum.
  • the present invention provides lumacaftor Form-L2.
  • the lumacaftor Form-L2 of the present invention is a tert- butanol solvate.
  • the present invention provides lumacaftor Form-L2 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 07.
  • the present invention provides lumacaftor Form-L2 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 4.44, 6.07, 7.76, 8.23, 8.79, 9.65, 10.77, 11.24, 12.15, 12.73, 13.89, 14.40, 14.79, 15.20, 15.68, 16.48, 17.02, 17.80, 18.40, 18.79, 19.67, 20.34, 20.45, 21.41, 22.10, 22.66, 23.27, 24.39, 25.34, 26.28, 27.07, 27.73, 28.50, 29.04, 29.77, 30.64, 31.33, 32.33, 34.45 and 37.37 ⁇ 0.2° 2 ⁇ .
  • the present invention provides lumacaftor Form-L2 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 08.
  • DSC differential scanning calorimetry
  • the present invention provides lumacaftor Form-L2 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 09.
  • TGA thermogravimetric analysis
  • the present invention provides lumacaftor Form-L2 characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 07, a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 08 and a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 09.
  • XRD X-Ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the present invention provides a process for the preparation of lumacaftor Form-L2, comprising:
  • step b) optionally, heating the step a) reaction mixture
  • step c) optionally, cooling the mixture of step b);
  • the aforementioned process of lumacaftor Form-L2 includes dissolving lumacaftor in tert-butanol at a suitable temperature, for example at about 20°C to about 40°C; preferably at about 20°C to about 30° and optionally the reaction mixture may be heated to about 50°C to about reflux temperature, preferably at about 75°C to about 85°C.
  • the present invention provides lumacaftor Form-L3.
  • the lumacaftor Form-L3 of the present invention is a dichloromethane solvate.
  • the present invention provides lumacaftor Form-L3 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 10.
  • PXRD powder X-ray diffraction
  • the present invention provides lumacaftor Form-L3 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.02, 7.72, 8.76, 10.78, 11.13, 120.9, 12.84, 13.87, 14.70, 15.72, 16.43, 17.02, 17.78, 18.22, 19.58, 20.34, 21.46, 21.99, 22.90, 23.52, 24.25, 25.40, 26.46, 27.12, 27.39, 27.57, 29.72, 30.67, 32.26, 24.75, 35.63, 37.34, 38.79 and 41.53 ⁇ 0.2° 2 ⁇ .
  • XRD X-Ray diffraction
  • the present invention provides lumacaftor Form-L3 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 11.
  • DSC differential scanning calorimetry
  • the present invention provides lumacaftor Form-L3 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 12.
  • TGA thermogravimetric analysis
  • the present invention provides lumacaftor Form-L3 characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 10, a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 11 and a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 12.
  • XRD X-Ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the present invention provides a process for the preparation of lumacaftor Form-L3, comprising:
  • step b) optionally, heating the step a) reaction mixture
  • the aforementioned process of lumacaftor Form-L3 includes dissolving lumacaftor in dichloromethane at a suitable temperature, for example at about 20°C to about 40°C; preferably at about 20°C to about 30° and optionally the reaction mixture may be heated to about 30°C to about reflux temperature, preferably at about 35°C to about 45°C.
  • the present invention provides lumacaftor Form-L4.
  • the lumacaftor Form-L4 of the present invention is an isopropyl acetate solvate.
  • the present invention provides lumacaftor Form-L4 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 13.
  • the present invention provides lumacaftor Form-L4 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.07, 7.73, 8.15, 8.78, 9.56, 10.67, 11.29, 12.11, 12.74, 14.33, 15.18, 15.71, 16.39, 17.55, 18.36, 19.62, 20.45, 21.39, 21.87, 22.06, 22.76, 24.40, 25.47, 26.41, 27.21, 27.91, 30.48 and 32.12 ⁇ 0.2° 2 ⁇ .
  • the present invention provides lumacaftor Form-L4 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 14.
  • DSC differential scanning calorimetry
  • the present invention provides lumacaftor Form-L4 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 15.
  • TGA thermogravimetric analysis
  • the present invention provides lumacaftor Form-L4 characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 13, a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 14 and a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 15.
  • XRD X-Ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the present invention provides a process for the preparation of lumacaftor Form-L4, comprising:
  • the aforementioned process of lumacaftor Form-L4 includes dissolving lumacaftor in isopropyl acetate at a suitable temperature, for example at about 20°C to about 50°C; preferably at about 20°C to about 30°C. Then removing the solvent from the resultant reaction solution by conventional techniques known in the art such as concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like; preferably evaporation under vacuum at about 50°C to about 60°C. The resulting solid can be dried under vacuum at a temperature of about 45°C to about 55°C for about 10 to 20 hours to obtain lumacaftor Form L4.
  • the present invention provides lumacaftor Form-L5.
  • the lumacaftor Form-L5 of the present invention is an ethyl acetate solvate.
  • the present invention provides lumacaftor Form-L5 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 16.
  • PXRD powder X-ray diffraction
  • the present invention provides lumacaftor Form-L5 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.04, 7.51, 7.73, 8.20, 8.74, 10.76, 11.18, 12.13, 12.66, 14.27, 14.83, 15.70, 16.32, 16.96, 17.81, 18.23, 18.82, 19.48, 19.70, 20.40, 21.27, 21.45, 22.05, 22.73, 23.66, 24.46, 25.44, 26.36, 27.45, 27.90, 28.44, 29.45, 30.57, 32.24, 34.49 and 35.81 ⁇ 0.2° 2 ⁇ .
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of lumacaftor Form-L5, comprising:
  • the aforementioned process of lumacaftor Form-L5 includes dissolving lumacaftor in ethyl acetate at a suitable temperature, for example at about 20°C to about 50°C; preferably at about 20°C to about 30°. Then removing the solvent from the resultant reaction solution by conventional techniques known in the art such as concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like; preferably evaporation under vacuum at about 50°C to about 60°C to obtain lumacaftor Form L5.
  • a suitable temperature for example at about 20°C to about 50°C; preferably at about 20°C to about 30°.
  • the present invention provides lumacaftor Form-L6.
  • the lumacaftor Form-L6 of the present invention is a cyclopentyl methyl ether solvate.
  • the present invention provides lumacaftor Form-L6 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 17.
  • PXRD powder X-ray diffraction
  • the present invention provides lumacaftor Form-L6 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.04, 7.64, 8.20, 8.84, 10.82, 11.24, 12.04, 12.88, 14.77, 15.70, 16.36, 17.67, 18.33, 19.59, 20.36, 21.37, 21.90, 21.91, 22.94, 24.13, 25.46, 26.23, 27.14, 30.63 and 32.03 ⁇ 0.2° 2 ⁇ .
  • the present invention provides a process for the preparation of lumacaftor Form-L6, comprising:
  • the aforementioned process of lumacaftor Form-L6 includes dissolving lumacaftor in cyclopentyl methyl ether at a suitable temperature, for example at about 20°C to about 50°C; preferably at about 20°C to about 30°. Then removing the solvent from the resultant reaction solution by conventional techniques known in the art such as concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like; preferably evaporation under vacuum at about 50°C to about 60°C to obtain lumacaftor Form L6.
  • the present invention provides lumacaftor Form-L7.
  • the lumacaftor Form-L7 of the present invention is an n- propanol solvate.
  • the present invention provides lumacaftor Form-L7 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 18.
  • PXRD powder X-ray diffraction
  • the present invention provides lumacaftor Form-L7 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.05, 7.59, 8.11, 8.78, 10.68, 11.10, 12.08, 12.68, 14.75, 15.22, 15.60, 16.71, 17.70, 18.25, 18.83, 19.53, 20.43, 21.22, 220.6, 22.76, 24.26, 25.52, 27.11, 27.86 and 29.69 ⁇ 0.2° 2 ⁇ .
  • the present invention provides a process for the preparation of lumacaftor Form-L7, comprising:
  • the aforementioned process of lumacaftor Form-L7 includes dissolving lumacaftor in n-propanol at a suitable temperature, for example at about 20°C to about 50°C; preferably at about 20°C to about 30°. Then removing the solvent from the resultant reaction solution by conventional techniques known in the art such as concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like; preferably evaporation under vacuum at about 50°C to about 60°C.
  • a suitable temperature for example at about 20°C to about 50°C; preferably at about 20°C to about 30°.
  • the resulting solid can be further dried under vacuum at a temperature of about 40°C to about 60°C to obtain lumacaftor Form L7.
  • the present invention provides lumacaftor Form-L8.
  • the lumacaftor Form-L8 of the present invention is an n-propyl acetate solvate.
  • the present invention provides lumacaftor Form-L8 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 19.
  • PXRD powder X-ray diffraction
  • the present invention provides lumacaftor Form-L8 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.07, 7.60, 8.22, 8.74, 10.65, 11.16, 12.05, 12.71, 14.62, 15.03, 16.51, 17.76, 18.27, 19.63, 20.36, 21.33, 22.04, 22.59, 24.22, 25.26, 26.39, 27.01, 27.94, 30.57, 31.29, 32.12 and 33.51 ⁇ 0.2° 2 ⁇ .
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of lumacaftor Form-L8, comprising:
  • the aforementioned process of lumacaftor Form-L8 includes dissolving lumacaftor in n-propyl acetate at a suitable temperature, for example at about 20°C to about 50°C; preferably at about 20°C to about 30°. Then removing the solvent from the resultant reaction solution by conventional techniques known in the art such as concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like; preferably evaporation under vacuum at about 60°C to about 75°C to obtain lumacaftor Form L8.
  • a suitable temperature for example at about 20°C to about 50°C; preferably at about 20°C to about 30°.
  • the present invention provides lumacaftor Form-L9.
  • the lumacaftor Form-L9 of the present invention is an isobutyl acetate solvate.
  • the present invention provides lumacaftor Form-L9 characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 20.
  • PXRD powder X-ray diffraction
  • the present invention provides lumacaftor Form-L9 characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.06, 7.72, 8.20, 8.78, 10.78, 11.23, 12.21, 12.71, 14.41, 14.84, 15.65, 16.34, 17.83, 18.36, 19.72, 20.42, 21.41, 22.09, 22.74, 24.46, 25.42, 26.25, 27.16, 27.88, 28.71, 30.46, 32.07 and 34.59 ⁇ 0.2° 2 ⁇ .
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of lumacaftor Form-L9, comprising:
  • the aforementioned process of lumacaftor Form-L9 includes dissolving lumacaftor in isobutyl acetate at a suitable temperature, for example at about 20°C to about 50°C; preferably at about 20°C to about 30°. Then removing the solvent from the resultant reaction solution by conventional techniques known in the art such as concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like; preferably evaporation under vacuum at about 60°C to about 75°C obtain lumacaftor Form L9.
  • a suitable temperature for example at about 20°C to about 50°C; preferably at about 20°C to about 30°.
  • the present invention provides lumacaftor Form-LlO.
  • the lumacaftor Form-LlO of the present invention is a dimethyl formamide solvate.
  • the present invention provides lumacaftor Form-LlO characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 21.
  • PXRD powder X-ray diffraction
  • the present invention provides lumacaftor Form-LlO characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.06, 7.72, 8.12, 8.71, 10.82, 11.06, 12.14, 12.83, 13.65, 14.63, 15.02, 15.33, 15.78, 16.29, 16.95, 17.90, 18.20, 18.65, 19.51, 20.27, 21.29, 21.47, 21.97, 22.85, 24.34, 25.42, 26.63, 26.96, 27.45, 28.18, 29.60, 29.83, 31.70, 31.26, 32.04, 34.59, 35.64, 38.44 and 41.17 ⁇ 0.2° 2 ⁇ .
  • the present invention provides a process for the preparation of lumacaftor Form-LlO, comprising:
  • the aforementioned process of lumacaftor Form-LlO includes dissolving lumacaftor in dimethyl formamide at a suitable temperature, for example at about 20°C to about 40°C; preferably at about 20°C to about 30° and optionally the reaction mixture may be heated to about 50°C to about reflux temperature, preferably at about 50°C to about 70°C.
  • the present invention provides lumacaftor Form-Ll 1.
  • the lumacaftor Form-Ll 1 of the present invention is a dimethyl sulfoxide solvate.
  • the present invention provides lumacaftor Form-Ll l characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 22.
  • PXRD powder X-ray diffraction
  • the present invention provides lumacaftor Form-Ll l characterized by X-Ray diffraction (XRD) pattern having one or more peaks at about 6.05, 7.73, 8.19, 8.77, 10.74, 11.18, 12.12, 12.79, 12.98, 13.86, 14.35, 14.72, 15.14, 15.47, 15.65, 16.43, 16.98, 17.77, 18.31, 19.62, 20.37, 21.43, 22.02, 22.70, 22.97, 24.06, 24.39, 25.36, 26.27, 27.06, 27.94, 28.51, 28.98, 29.66, 30.59, 31.43, 32.14, 33.67, 34.78, 36.07, 37.35, 39.89 and 41.61 ⁇ 0.2° 2 ⁇ .
  • XRD X-Ray diffraction
  • the present invention provides a process for the preparation of lumacaftor Form-Ll 1, comprising:
  • the aforementioned process of lumacaftor Form-Ll l includes dissolving lumacaftor in dimethyl sulfoxide at a suitable temperature, for example at about 20°C to about 40°C; preferably at about 20°C to about 30° and optionally the reaction mixture may be heated to about 50°C to about reflux temperature, preferably at about 50°C to about 70°C. Then cooling the reaction mixture to room temperature and then removing the solvent from the resultant reaction solution by conventional techniques known in the art such as concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like; preferably evaporation under vacuum at less than about 90°C.
  • the resulting solid can be dried under vacuum at a temperature of less than about 80°C to obtain lumacaftor Form LI 1.
  • the present invention provides the use of novel solvate forms of lumacaftor as intermediates to prepare other solid forms of lumacaftor.
  • the present invention provides a process for the preparation of lumacaftor Form I, comprising:
  • step b) optionally, heating the step a) reaction mixture
  • step c) optionally, cooling the step b) solution
  • step d) adding a suitable anti-solvent to the step a) solution or vice versa;
  • LI 1 are characterized by fig. 4 to - 22 respectively.
  • the Lumacaftor Form I is a known compound and is disclosed in the literature, for example, disclosed in the US Patent No. 8,507,534.
  • the starting material of Lumacaftor solvates, used herein is known in the art or can be obtained by any of the methods known in the art or can be prepared according to the process of present invention described herein above.
  • the one or more solvents include, but are not limited to organic acids selected from formic acid, acetic acid, propionic acid and the like; alcohols selected from methanol, ethanol, isopropanol and the like; ketones selected from acetone, methylisobutylketone, methylethylketone and the like; esters selected methyl acetate, ethyl acetate, isopropyl acetate and the like; nitriles selected from acetonitrile, propionitrile and the like; and mixtures thereof, preferably the one or more solvent is acetic acid or formic acid.
  • organic acids selected from formic acid, acetic acid, propionic acid and the like
  • alcohols selected from methanol, ethanol, isopropanol and the like
  • ketones selected from acetone, methylisobutylketone, methylethylketone and the like
  • esters selected methyl acetate, ethyl acetate,
  • the step a) of providing a solution or suspension of lumacaftor solvates in one or more solvents may include heating the reaction mass to a temperature of about 50°C to about reflux temperature, preferably to a temperature of 65 °C to about 75°C.
  • the lumacaftor solvates used herein as a starting material is selected from the group consisting of lumacaftor acetic acid solvate (Form-Ll), lumacaftor tert-butanol solvate (Form-L2), lumacaftor dichloromethane solvate (Form- L3), lumacaftor isopropylacetate solvate (Form-L4), lumacaftor ethylacetate solvate (Form-L5), lumacaftor cyclopentyl methyl ether solvate (Form-L6), lumacaftor n- propanol solvate (Form-L7), lumacaftor n-propyl acetate solvate (Form-L8), lumacaftor isobutyl acetate solvate (Form-L9), lumacaftor di
  • Step d) of the aforementioned process involves the isolation of lumacaftor Form I by either addition of suitable antisolvent to the lumacaftor solution of step c) or addition of step c) solution of lumacaftor into a suitable antisolvent.
  • the suitable antisolvent include, but are not limited to water, ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like; and mixtures thereof.
  • the ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like;
  • aliphatic hydrocarbons include, but are not limited to hexane, heptane, propane and the like;
  • alicyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like; and mixture thereof; preferably the suitable antisolvent is water.
  • the isolation of lumacaftor Form I is carried out by any conventional techniques known in the art or methods described just as above, for example filtration.
  • the resultant wet product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like.
  • the present invention provides a process for the preparation of amorphous form of lumacaftor, wherein the process involves the use of one or more novel solvate forms of lumacaftor of the invention as intermediates.
  • the present invention provides a process for the preparation of amorphous form of lumacaftor, comprising:
  • step b) adding a suitable anti-solvent to the step a) solution or vice versa;
  • crystalline lumacaftor is selected from the group consisting of Form LI, L2, L3, L4, L5, L6, L7, L8, L9, L10 and LI 1, which are characterized by fig. 4 to 22 respectively.
  • the lumacaftor solvates used herein as a starting material is selected from the group consisting of lumacaftor acetic acid solvate (Form-Ll), lumacaftor tert-butanol solvate (Form-L2), lumacaftor dichloromethane solvate (Form- L3), lumacaftor isopropylacetate solvate (Form-L4), lumacaftor ethylacetate solvate (Form-L5), lumacaftor cyclopentyl methyl ether solvate (Form-L6), lumacaftor n- propanol solvate (Form-L7), lumacaftor n-propyl acetate solvate (Form-L8), lumacaftor isobutyl acetate solvate (Form-L9), lumacaftor di
  • the one or more solvents include, but are not limited to organic acids selected from formic acid, acetic acid, propionic acid and the like; alcohols selected from methanol, ethanol, isopropanol and the like; ketones selected from acetone, methylisobutylketone, methylethylketone and the like; esters selected methyl acetate, ethyl acetate, isopropyl acetate and the like; nitriles selected from acetonitrile, propionitrile and the like; and mixture thereof, preferably the one or more solvent is acetic acid or formic acid.
  • organic acids selected from formic acid, acetic acid, propionic acid and the like
  • alcohols selected from methanol, ethanol, isopropanol and the like
  • ketones selected from acetone, methylisobutylketone, methylethylketone and the like
  • esters selected methyl acetate, ethyl acetate, is
  • the step a) of providing a solution or suspension of lumacaftor solvates in one or more solvents may include heating the reaction mass to a temperature of about 50°C to about reflux temperature, preferably to a temperature of 65 °C to about 75°C.
  • Step c) of the aforementioned process involves the isolation of lumacaftor Form I by either addition of suitable antisolvent to the lumacaftor solution of step a) or addition of step a) solution of lumacaftor into a suitable antisolvent.
  • step a) reaction solution may cooled initially to a temperature of about 30°C or less and later to a temperature of about 0°C to about 10°C.
  • the suitable antisolvent used herein is same as described just above; preferably the suitable antisolvent is water.
  • the isolation of amorphous lumacaftor is carried out by any conventional techniques known in the art or methods described just as above, for example filtration.
  • the resultant wet product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like.
  • the present invention provides lumacaftor prepared by the processes described above, having a chemical purity of 98% or more as measured by HPLC, preferably 99% or more, more preferably 99.5% or more.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of the novel solid forms of lumacaftor described above and at least one or more pharmaceutically acceptable excipients.
  • the amorphous form of lumacaftor is stable during storage. This property is important and advantageous for the desired use of lumacaftor in pharmaceutical product formulations.
  • the amorphous form of lumacaftor of the present invention has commercially acceptable pharmacokinetic characteristics, solubility, flow properties, stability, and the like.
  • the products may optionally be milled to get the desired particle size distributions. Milling or micronization may be performed prior to drying, or after the completion of drying of the products. The milling operation reduces the size of particles and increases surface area of particles by colliding particles with each other at high velocities.
  • the present invention also encompasses a pharmaceutical composition comprising a therapeutically effective amount of an amorphous form of lumacaftor with at least one pharmaceutically acceptable carrier or other excipients.
  • the present invention further provides, when a pharmaceutical composition comprising amorphous from of lumacaftor prepared according to the present invention is formulated for oral administration or parenteral administration.
  • Dso and D90 particle size of the unformulated amorphous lumacaftor of the present invention used as starting material in preparing a pharmaceutical composition generally is less than 500 microns preferably less than about 300 microns, more preferably less than 150 microns, still more preferably less than about 50 microns and still more preferably less than about 10 microns.
  • any milling, grinding, micronizing or other particle size reduction method known in the art can be used to bring the solid state amorphous lumacaftor of the present invention into any desired particle size range as set forth above.
  • Amorphous lumacaftor described in the present invention may be formulated into solid pharmaceutical products for oral administration in the form of capsules, tablets, pills, powders or granules.
  • the active ingredient is combined with one or more pharmaceutically acceptable excipients.
  • the drug substance also may be formulated into liquid compositions for oral administration including for example solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffins.
  • compositions for parenteral administration may be suspensions, emulsions or aqueous or non-aqueous, sterile solutions.
  • a solvent or vehicle propylene glycol, polyethylene glycol, vegetable oils, olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed.
  • Suitable pharmaceutical compositions are solid dosage forms, such as tablets with immediate release or sustained release of the active principle, effervescent tablets or dispersion tablets and capsules.
  • the pharmaceutical compositions of the invention may be combination products comprising one or more additional pharmaceutically active components in addition to lumacaftor.
  • compositions include, but are not limited to, diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol and sugar; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropylmethyl celluloses and pregelatinized starch; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidones, croscarmellose sodium and colloidal silicon dioxide; lubricants such as stearic acid, talc, magnesium stearate and zinc stearate; glidants such as colloidal silicon dioxide; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, complex forming agents such as various grades of cyclodextr, bind
  • Formic acid (2.5 mL) and lumacaftor (1.4 gms) were added in to a round bottom flask at 24°C to 28°C, stirred the solution at same temperature for about 5-10 minutes and the resulting solution was added to pre cooled water at 0°C to 5°C (500 mL). Stirred for about 30 minutes at this temperature and the precipitated solid was filtered and dried the solid in an oven under vacuum at 40°C for about 16 hrs. Yield: 1.22 gms.
  • the PXRD is set forth in Figure 1
  • the DSC thermogram is set forth in Figure 2
  • the TGA is set forth in Figure 3.
  • Formic acid (0.833 mL) and lumacaftor (500 mg) were added in to a round bottom flask at 24°C to 28°C, stirred the solution at same temperature for about 5-10 minutes.
  • Pre cooled water at 0°C to 5°C (50 ml) was added to the resulting solution and stirred for about 30 minutes at same temperature.
  • the precipitated solid was filtered and dried the solid under vacuum at 50 C for about 16 hrs. Yield: 362 mg.
  • Acetic acid (1.5 mL) and lumacaftor (300 mg) were added in to a round bottom flask at 24°C to 28°C.
  • the resulting solution was heated to 58°C to 62°C and stirred for about 10 minutes and allowed to cool to room temperature.
  • Pre cooled water at 0°C to 5°C (30 mL) was added to the reaction solution and the precipitated solid was filtered and dried the solid in an oven under vacuum at about 45°C for about 6 hrs.
  • Acetic acid (1.5 mL) and Lumacaftor (300 mg) were added in to a round bottom flask at 24°C to 28°C.
  • the resulting solution was heated to 58°C to 62°C and allowed to cool to room temperature.
  • the resultant solution was added to pre cooled water at 0°C to 5°C (30 mL) and stirred for about 30 minutes and the precipitated solid was filtered and dried the solid under vacuum at 45°C for 6 hrs. Yield: 280 mg.
  • EXAMPLE 7 Preparation of amorphous form of lumacaftor (n-propanol) n-propanol (20 mL) and Lumacaftor (235 mg) were added in to a round bottom flask at 24°C to 28°C. The resulting solution was stirred at room temperature and the solvent was evaporated under vacuum at 55°C to get the title compound. Yield: 245 mg.
  • EXAMPLE 8 Preparation of amorphous form of lumacaftor (tert-butanol)
  • Acetic acid (1.5ml) and Lumacaftor (300 mg) were added in to a round bottom flask at 24°C to 28°C.
  • the resulting solution was heated to about 55-65°C, stirred and then cooled to room temperature for 16 hours.
  • the obtained solid was filtered and suck dried.
  • the wet solid was further dried at 40-50°C under vacuum for 16 hours to obtain lumacaftor Form-Ll. Yield: 210 mg.
  • the PXRD is set forth in Figure 04
  • the DSC thermogram is set forth in Figure 05
  • the TGA is set forth in Figure 06.
  • the PXRD is set forth in Figure 07
  • the DSC thermogram is set forth in Figure 08
  • the TGA is set forth in Figure 09.
  • EXAMPLE 14 Preparation of Lumacaftor Form-L6 Cyclopentyl methyl ether (20 ml) and Lumacaftor (200 mg) were added in to a round bottom flask at 24°C to 28°C. The resulting solution was stirred at room temperature and the solvent was evaporated under vacuum at 50-60°C to get lumacaftor Form L6. Yield: 220 mg. The PXRD is set forth in Figure 17.
  • EXAMPLE 15 Preparation of Lumacaftor Form-L7
  • Lumacaftor (468 mg) and n-propanol (40 mL) were added in to a round bottom flask at 24°C to 28°C. The resulting solution was stirred at room temperature and the solvent was evaporated under vacuum at 50-60°C. The solid obtained was further dried under vacuum at about 45-55 °C for 16 hours to yield lumacaftor Form L7. Yield: 439 mg.
  • the PXRD is set forth in Figure 18.
  • EXAMPLE 16 Preparation of Lumacaftor Form-L8 Lumacaftor (300 mg) and n-propyl acetate (30 mL) were added in to a round bottom flask at 24°C to 28°C. The resulting solution was stirred at room temperature and the solvent was evaporated under vacuum at 60-70°C to yield lumacaftor Form L8. Yield: 300 mg. The PXRD is set forth in Figure 19.
  • EXAMPLE 17 Preparation of Lumacaftor Form-L9
  • EXAMPLE 20 Preparation of Lumacaftor form-I from Lumacaftor DCM solvate:
  • Lumacaftor DCM solvate (5g) and formic acid (20mL) were added into a round bottom flask at 25-35°C. The temperature of the reaction mass was raised to 65-75°C
  • Lumacaftor DCM solvate (5g) and formic acid (15 mL) were added into a round bottom flask at 25-35°C. The temperature of the reaction mass was raised to 65-75°C and maintained for 10-20 min. The solution was gradually cooled to 2-8°C and then added to pre-cooled water (500 ml). The precipitated material was slurred for 5-10 min, filtered and dried at 60°C to obtain amorphous Lumacaftor. Yield: 3.9g; HPLC purity 99.67%.

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Abstract

La présente invention concerne de manière générale de nouvelles formes solides de lumacaftor, comprenant une forme amorphe, des solvates et/ou des polymorphes, des procédés pour leur préparation, des compositions pharmaceutiques les contenant et leur utilisation en thérapie.
PCT/IB2017/055074 2016-08-23 2017-08-23 Formes solides de lumacaftor, leur procédé de préparation et leurs compositions pharmaceutiques WO2018037350A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2022232634A1 (fr) 2021-04-29 2022-11-03 Novartis Ag Chimères ciblant la désubiquitinase et procédés associés

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011133953A1 (fr) * 2010-04-22 2011-10-27 Vertex Pharmaceuticals Incorporated Compositions pharmaceutiques et leurs administrations
US20130085158A1 (en) * 2010-04-07 2013-04-04 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US20140023706A1 (en) * 2010-04-07 2014-01-23 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid and administration thereof
WO2015073231A1 (fr) * 2013-11-12 2015-05-21 Vertex Pharmaceuticals Incorporated Procédé de préparation de compositions pharmaceutiques pour le traitement de maladies à médiation assurée par le cftr

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130085158A1 (en) * 2010-04-07 2013-04-04 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
US20140023706A1 (en) * 2010-04-07 2014-01-23 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid and administration thereof
WO2011133953A1 (fr) * 2010-04-22 2011-10-27 Vertex Pharmaceuticals Incorporated Compositions pharmaceutiques et leurs administrations
WO2015073231A1 (fr) * 2013-11-12 2015-05-21 Vertex Pharmaceuticals Incorporated Procédé de préparation de compositions pharmaceutiques pour le traitement de maladies à médiation assurée par le cftr

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022232634A1 (fr) 2021-04-29 2022-11-03 Novartis Ag Chimères ciblant la désubiquitinase et procédés associés

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