WO2021095015A1 - Solid forms of tezacaftor, processes for their preparation and pharmaceutical compositions thereof - Google Patents

Solid forms of tezacaftor, processes for their preparation and pharmaceutical compositions thereof Download PDF

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Publication number
WO2021095015A1
WO2021095015A1 PCT/IB2020/060732 IB2020060732W WO2021095015A1 WO 2021095015 A1 WO2021095015 A1 WO 2021095015A1 IB 2020060732 W IB2020060732 W IB 2020060732W WO 2021095015 A1 WO2021095015 A1 WO 2021095015A1
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Prior art keywords
tezacaftor
crystal
piperazine
acetate
accordance
Prior art date
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PCT/IB2020/060732
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French (fr)
Inventor
Ram Thaimattam
Rajesh EDUPUGANTI
Nageswara Rao REGANDLA
Uma Maheswara Rao VASIREDDI
Suresh Babu RADHAKRISHNAN
Pavan Kumar SEETHAMRAJU
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Laurus Labs Limited
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Publication of WO2021095015A1 publication Critical patent/WO2021095015A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C15/00—Cyclic hydrocarbons containing only six-membered aromatic rings as cyclic parts
    • C07C15/02—Monocyclic hydrocarbons
    • C07C15/067—C8H10 hydrocarbons
    • C07C15/08—Xylenes
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/12—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1, 3, and 7, e.g. caffeine

Definitions

  • the present invention generally relates to solid forms of Tezacaftor, processes for their preparation and pharmaceutical composition containing the same.
  • the present invention also relates to stable amorphous form of Tezacaftor, its preparation and pharmaceutical composition containing the same.
  • Cystic fibrosis is a rare, life-shortening genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which results in construction of a defective CFTR protein.
  • the tunnel-shaped CFTR protein is a chloride channel responsible for controlling the transport of anions and water into and out of epithelial cells.
  • the most frequent mutation found in about 70% of cystic fibrosis patients, results in deletion of phenylalanine at position 508 of the CFTR amino acid sequence, referred to as F508del-CFTR. This defective protein is unable to fold correctly, hindering its ability to exit the endoplasmic reticulum and migrate to the cell surface.
  • the defective protein In addition to reduced mobility, the defective protein also has impaired channel gating.
  • the reduced number of CFTR proteins at the cell membrane plus defective gating results in decreased anion secretion and an imbalance of ion and fluid flux.
  • a defective CFTR protein in epithelial cells results in the buildup of thick mucus that can cause lung infections and lung damage.
  • Vertex Pharmaceuticals As a treatment for cystic fibrosis, Vertex Pharmaceuticals has developed two types of drugs to modulate the function of the defective CFTR protein.
  • the drugs termed correctors facilitate transport of protein to the cell surface while those termed potentiators help facilitate chloride trafficking at the cell surface by increasing the time the gate of the protein is open.
  • the two types of drugs can work in tandem to improve overall chloride transport, resulting in healthier lung function.
  • Symdeko is a combination of tezacaftor and Ivacaftor.
  • Tezacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) corrector while Ivacaftor is a CFTR potentiator.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • Ivacaftor is a CFTR potentiator.
  • Tezacaftor moves the defective CFTR protein onto the cell surface, while ivacaftor helps to facilitate the opening of the chloride channel on the cell surface to increase chloride transport.
  • Symdeko is specifically indicated for the treatment of patients with cystic fibrosis (CF) aged 12 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • Tezacaftor is chemically designated as (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l- (2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- yl)cyclopropanecarboxamide.
  • the structural Formula of Tezacaftor is represented as follows:
  • Tezacaftor and its process for the preparation were first disclosed in U.S. Patent No. 7,645,789 ("the '789 patent”).
  • the ‘789 patent process involves isolation of tezacaftor as a creamy colored foamy solid after column chromatography using a mixture of 50-100% Ethyl acetate-hexanes.
  • the foamy solid resulted in the ‘789 patent is not well characterized and does not disclose any polymorphic information.
  • the present inventors have found that the resulting Tezacaftor was obtained in an amorphous form.
  • Discovering solid forms such as new polymorphic forms, solvates or co-crystals of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate forms that facilitate conversion to other solid-state forms.
  • New polymorphic forms, solvates or co-crystals of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product.
  • Tezacaftor such as new co-crystal forms, solvates, hydrates and/or polymorphs thereof. Further, it would be desirable to have reliable processes for producing these solid forms and use of such solid forms in the preparation of another form of Tezacaftor such as amorphous form.
  • amorphous form of tezacaftor was selected as the most appropriate physical form for development due to increased solubility as compared to a crystalline form.
  • the present invention provides a stable amorphous form of Tezacaftor, wherein the stable amorphous Tezacaftor does not convert to any other solid forms when stored at a temperature of up to about 40°C and at a relative humidity of about 25% to about 75% up to about three months.
  • the present invention provides solid forms of Tezacaftor, including its co crystals, solvates, hydrates and/or polymorphs, processes for their preparation, pharmaceutical compositions containing the same and use of such solid forms of Tezacaftor in the preparation of another form of Tezacaftor such as amorphous form of Tezacaftor.
  • the present invention also relates to stable amorphous form of Tezacaftor, its preparation and pharmaceutical composition containing the same.
  • the present invention provides solid forms of Tezacaftor.
  • the present invention provides the solid forms of Tezacaftor may exist in the form of co-crystals, solvates, hydrates, polymorphs, polymorphs of co-crystals or polymorphs of solvates or polymorphs of hydrates.
  • the present invention provides solvates of Tezacaftor.
  • the present invention provides Tezacaftor o- xylene solvate.
  • the present invention provides crystalline Tezacaftor o-xylene solvate.
  • the present invention provides crystalline Tezacaftor o-xylene solvate characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 01.
  • the present invention provides crystalline Tezacaftor o-xylene solvate characterized by a H NMR Spectrum substantially in accordance with Figure 02.
  • the present invention provides crystalline Tezacaftor o-xylene solvate characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 03.
  • DSC differential scanning calorimetry
  • the present invention provides crystalline Tezacaftor o-xylene solvate characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 04.
  • TGA thermogravimetric analysis
  • the present invention provides a process for the preparation of o-xylene solvate of Tezacaftor, comprising: a) dissolving or suspending Tezacaftor in o-xylene solvent; and b) isolating Tezacaftor o-xylene solvate.
  • the present invention provides co-crystals of Tezacaftor.
  • the present invention provides co-crystals of Tezacaftor, wherein the co-crystal former is selected from the group comprising caffeine, piperazine, piperidine, 4-amino pyridine, imidazole, morpholine 4-hydroxy pyridine, paraxanthine, theophylline, theobromine, DDQ, Hexamethylenetetramine, 2 -hydroxy- 1,4- napthoquinone, nicotinamide, isonicotinamide and the like.
  • the co-crystal former is selected from the group comprising caffeine, piperazine, piperidine, 4-amino pyridine, imidazole, morpholine 4-hydroxy pyridine, paraxanthine, theophylline, theobromine, DDQ, Hexamethylenetetramine, 2 -hydroxy- 1,4- napthoquinone, nicotinamide, isonicotinamide and the like.
  • the present invention provides a process for the preparation of co-crystal of Tezacaftor, comprising: a) providing a solution or suspension comprising Tezacaftor and a co-crystal former in one or more solvents; and b) isolating the co-crystals of Tezacaftor.
  • the present invention provides a process for the preparation of co-crystals of Tezacaftor, comprising: a) providing a solution or suspension comprising Tezacaftor and a co-crystal former in one or more solvents; and b) isolating the co-crystals of Tezacaftor; wherein the co-crystal former is selected from the group comprising caffeine, piperazine, piperidine, 4-amino pyridine, imidazole, morpholine 4-hydroxy pyridine, paraxanthine, theophylline, theobromine, DDQ, Hexamethylenetetramine, 2 -hydroxy- 1,4-napthoquinone, nicotinamide, isonicotinamide and the like.
  • the co-crystal former is selected from the group comprising caffeine, piperazine, piperidine, 4-amino pyridine, imidazole, morpholine 4-hydroxy pyridine, paraxanthine, theophy
  • the present invention provides Tezacaftor piperazine co-crystal.
  • the present invention provides a process for the preparation of Tezacaftor piperazine co-crystal, comprising: a) providing a solution or suspension comprising Tezacaftor and piperazine in one or more organic solvents; and b) isolating the Tezacaftor piperazine co-crystal.
  • the present invention provides crystalline Forms of Tezacaftor piperazine co-crystal designated as Form 1, Form 2 or Form 3.
  • the present invention provides Tezacaftor piperazine co-crystal Form 1.
  • the present invention provides Tezacaftor piperazine co-crystal Form 1 characterized by X-Ray powder diffraction (PXRD) pattern substantially in accordance with Figure 05.
  • the present invention provides Tezacaftor piperazine co-crystal Form 1 characterized by an X-Ray powder diffraction (XRD) pattern having one or more peaks at about 3.7, 7.2, 10.8, 13.6, 14.4, 17.2, 18.0 and 19.0 ⁇ 0.2° 2Q.
  • XRD X-Ray powder diffraction
  • the present invention provides Tezacaftor piperazine co-crystal Form 1 characterized by a 1H NMR Spectrum substantially in accordance with Figure 06.
  • the present invention provides Tezacaftor piperazine co-crystal Form 1 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 07.
  • DSC differential scanning calorimetry
  • the present invention provides Tezacaftor piperazine co-crystal Form 1 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 08.
  • TGA thermogravimetric analysis
  • the present invention provides Tezacaftor piperzine co-crystal Form 1 characterized by one or more of the following: a powder X- Ray diffraction (XRD) pattern substantially in accordance with Figure 05; a 1H NMR Spectrum substantially in accordance with Figure 06; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 07 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 08.
  • XRD powder X- Ray diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the present invention provides Tezacaftor piperazine co-crystal Form 2.
  • the present invention provides Tezacaftor piperazine co-crystal Form 2 characterized by X-Ray powder diffraction (PXRD) pattern substantially in accordance with Figure 09.
  • the present invention provides Tezacaftor piperazine co-crystal Form 2 characterized by an X-Ray powder diffraction (XRD) pattern having one or more peaks at about 3.8, 7.7, 12.4,14.2, 18.3 and 19.6 ⁇ 0.2° 2Q.
  • XRD X-Ray powder diffraction
  • the present invention provides Tezacaftor piperazine co-crystal Form 2 characterized by a 1H NMR Spectrum substantially in accordance with Figure 10.
  • the present invention provides Tezacaftor piperazine co-crystal Form 2 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 11.
  • DSC differential scanning calorimetry
  • the present invention provides Tezacaftor piperazine co-crystal Form 2 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 12.
  • TGA thermogravimetric analysis
  • the present invention provides Tezacaftor piperzine co-crystal Form 2 characterized by one or more of the following: a powder X- Ray diffraction (XRD) pattern substantially in accordance with Figure 09; a 1H NMR Spectrum substantially in accordance with Figure 10; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 11 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 12.
  • XRD powder X- Ray diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the present invention provides Tezacaftor piperazine co-crystal Form 3.
  • the present invention provides Tezacaftor piperazine co-crystal Form 3 characterized by X-Ray powder diffraction (PXRD) pattern substantially in accordance with Figure 13.
  • PXRD X-Ray powder diffraction
  • the present invention provides Tezacaftor piperazine co-crystal Form 3 characterized by an X-Ray powder diffraction (XRD) pattern having one or more peaks at about 4.8, 9.2, 13.7, 14.3, 17.9, 19.6, 20.1 and 20.6 ⁇ 0.2° 2Q.
  • XRD X-Ray powder diffraction
  • the present invention provides Tezacaftor piperazine co-crystal Form 3 characterized by a 1H NMR Spectrum substantially in accordance with Figure 14.
  • the present invention provides Tezacaftor piperazine co-crystal Form 3 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 15.
  • DSC differential scanning calorimetry
  • the present invention provides Tezacaftor piperazine co-crystal Form 3 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 16.
  • TGA thermogravimetric analysis
  • the present invention provides Tezacaftor piperzine co-crystal Form 3 characterized by one or more of the following: a powder X- Ray diffraction (XRD) pattern substantially in accordance with Figure 13; a 1H NMR Spectrum substantially in accordance with Figure 14; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 15 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 16.
  • XRD powder X- Ray diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the present invention provides Tezacaftor caffeine co-crystal.
  • the present invention provides a process for the preparation of Tezacaftor caffeine co-crystal, comprising: a) providing a solution or suspension comprising Tezacaftor and caffeine in one or more organic solvents; and b) isolating Tezacaftor caffeine co-crystal.
  • the present invention provides crystalline Form of Tezacaftor caffeine co-crystal.
  • the present invention provides Tezacaftor caffeine co-crystal characterized by X-Ray powder diffraction (PXRD) pattern substantially in accordance with Figure 17.
  • PXRD X-Ray powder diffraction
  • the present invention provides Tezacaftor caffeine co-crystal characterized by a 1H NMR Spectrum substantially in accordance with Figure 18.
  • the present invention provides Tezacaftor caffeine co-crystal characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 19.
  • DSC differential scanning calorimetry
  • the present invention provides Tezacaftor caffeine co-crystal characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 20.
  • TGA thermogravimetric analysis
  • the present invention provides Tezacaftor caffeine co-crystal characterized by one or more of the following: a powder X-Ray diffraction (XRD) pattern substantially in accordance with Figure 17; a 1H NMR Spectrum substantially in accordance with Figure 18; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 19 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 20.
  • XRD powder X-Ray diffraction
  • 1H NMR Spectrum substantially in accordance with Figure 18
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the solid forms of Tezacaftor of the present invention may be used as an intermediate in obtaining high purity Tezacaftor.
  • the solid forms of Tezacaftor of the present invention may be used as an intermediate in obtaining high purity amorphous Tezacaftor.
  • the present invention provides a process for the preparation of amorphous form of Tezacaftor, wherein the process involves Tezacaftor o- xylene solvate of the invention as intermediate.
  • the present invention provides a process for the preparation of amorphous Tezacaftor comprising: a) dissolving or suspending Tezacaftor in o-xylene solvent, b) isolating Tezacaftor o-xylene solvate, and c) drying the Tezacaftor o-xylene solvate at about 25°C to about 85°C to obtain amorphous form.
  • the co-crystal forms of Tezacaftor of the present invention may be used as an intermediate in obtaining high purity Tezacaftor.
  • the present invention provides a process for the preparation of Tezacaftor, comprising: a) preparing a co-crystal of Tezacaftor; and b) converting the co-crystal of Tezacaftor in to Tezacaftor.
  • the present invention provides a process for the preparation of Tezacaftor, comprising: a) preparing a co-crystal of Tezacaftor; and b) converting the co-crystal of Tezacaftor in to Tezacaftor; wherein the co-crystal is selected from the group comprising caffeine, piperazine, piperidine, 4-amino pyridine, imidazole, morpholine 4-hydroxy pyridine, paraxanthine, theophylline, theobromine, DDQ, Hexamethylenetetramine, 2 -hydroxy- 1,4-napthoquinone, nicotinamide, isonicotinamide and the like.
  • the present invention provides a process for the preparation of Tezacaftor, comprising: a) dissolving or suspending Tezacaftor co-crystal in a suitable solvent, b) optionally treating the step a) reaction mass with a suitable acid or base, and c) isolating the Tezacaftor.
  • the present invention provides a process for the preparation of amorphous form of Tezacaftor, wherein the process involves one or more of co-crystal forms of Tezacaftor of the invention as an intermediate.
  • the present invention provides a process for the preparation of amorphous Tezacaftor, comprising: a) dissolving or suspending Tezacaftor co-crystal in a suitable solvent, b) optionally treating the step a) reaction mass with a suitable acid or base, and c) isolating the amorphous Tezacaftor.
  • the present invention provides a process for the preparation of amorphous Tezacaftor, comprising: a) dissolving or suspending Tezacaftor co-crystal in a suitable solvent, b) optionally treating the step a) reaction mass with a suitable acid or base, c) concentrating the reaction mass, d) treating the step c) reaction mass with a suitable solvent, e) adding an anti-solvent to the step d) solution or vice-versa, and f) isolating the amorphous Tezacaftor.
  • the present invention provides processes for the preparation of amorphous form of Tezacaftor.
  • the present invention provides a process for preparation of amorphous form of Tezacaftor, comprising: a) providing a solution or suspension of Tezacaftor in a suitable solvent (SI), b) removing the solvent from the step a) reaction mass, c) optionally adding a suitable solvent (S2) to the step b), and d) isolating the amorphous form.
  • the present invention provides a process for preparation of amorphous form of Tezacaftor, comprising: a) providing a solution or suspension of Tezacaftor in a suitable solvent (SI), b) removing the solvent from the step a) reaction mass, c) optionally adding a suitable solvent (S2) to the step b), and d) isolating the amorphous form; wherein the suitable solvent (SI) is selected from the group consisting of ketones, alcohols, esters, nitriles, ethers or mixtures thereof; and the suitable solvent (S2) is selected from the group consisting of water, aliphatic hydrocarbons, alicyclic hydrocarbons and the like or mixtures thereof.
  • the present invention provides a process for preparation of amorphous form of Tezacaftor, comprising: a) providing a solution or suspension of Tezacaftor in one or more solvents; b) adding a suitable anti- solvent to the step a) solution or vice-versa; and c) isolating the amorphous form.
  • the present invention provides a process for preparation of amorphous form of Tezacaftor, comprising: a) providing a solution or suspension of Tezacaftor in one or more solvents; b) adding a suitable anti- solvent to the step a) solution or vice-versa; and c) isolating the amorphous form.
  • the one or more solvents are selected from the group consisting of alcohols, sulfoxides, amides, ketones, esters or mixtures thereof;
  • the suitable anti-solvent is selected from the group consisting of water, aliphatic hydrocarbons, alicyclic hydrocarbons, ethers and the like or mixtures thereof.
  • the present invention provides stable amorphous form of Tezacaftor.
  • the present invention provides stable amorphous form of Tezacaftor which remains stable when stored and does not convert to any other solid form when stored at a temperature of up to about 40°C and at a relative humidity of about 25% to about 75% up to about three months or more.
  • the stable amorphous form of Tezacaftor does not convert to any other solid forms when stored at a temperature of up to about 40°C and at a relative humidity of about 25% to about 75% up to about three months.
  • the present invention provides an amorphous form of Tezacaftor having a HPLC purity of about 99.5% or more as determined by high performance liquid chromatography (HPLC).
  • the present invention provides a pharmaceutical composition comprising amorphous form of Tezacaftor prepared by the processes of the present invention and at least one pharmaceutical acceptable excipient.
  • Figure 1 is the characteristic powder XRD pattern of Tezacaftor o-xylene solvate.
  • Figure 2 is the characteristic 1 H NMR Spectrum of Tezacaftor o-xylene solvate.
  • Figure 3 is the characteristic DSC thermogram of Tezacaftor o-xylene solvate.
  • Figure 4 is the characteristic TGA curve of Tezacaftor o-xylene solvate.
  • Figure 5 is the characteristic powder XRD pattern of Tezacaftor piperazine co-crystal Form
  • Figure 6 is the characteristic 1 H NMR Spectrum of Tezacaftor piperazine co-crystal Form
  • Figure 7 is the characteristic DSC thermogram of Tezacaftor piperazine co-crystal Form 1.
  • Figure 8 is the characteristic TGA curve of Tezacaftor piperazine co-crystal Form 1.
  • Figure 9 is the characteristic powder XRD pattern of Tezacaftor piperazine co-crystal Form
  • Figure 11 is the characteristic DSC thermogram of Tezacaftor piperazine co-crystal Form
  • Figure 12 is the characteristic TGA curve of Tezacaftor piperazine co-crystal Form 2.
  • Figure 13 is the characteristic powder XRD pattern of Tezacaftor piperazine co-crystal Form 3.
  • Figure 14 is the characteristic FI NMR Spectrum of Tezacaftor piperazine co-crystal Form
  • Figure 15 is the characteristic DSC thermogram of Tezacaftor piperazine co-crystal Form
  • Figure 16 is the characteristic TGA curve of Tezacaftor piperazine co-crystal Form 3.
  • Figure 17 is the characteristic powder XRD pattern of Tezacaftor caffeine co-crystal.
  • Figure 18 is the characteristic FI NMR Spectrum of Tezacaftor caffeine co-crystal.
  • Figure 19 is the characteristic DSC thermogram of Tezacaftor caffeine co-crystal.
  • Figure 20 is the characteristic TGA curve of Tezacaftor caffeine co-crystal.
  • Figure 21 is the characteristic powder X-ray diffraction (XRD) pattern of amorphous Tezacaftor prepared according to example 14 of the present invention.
  • Figure 22 is the characteristic powder X-ray diffraction (XRD) pattern of amorphous Tezacaftor prepared according to example 15 of the present invention.
  • Figure 23 is the characteristic powder X-ray diffraction (XRD) pattern of amorphous Tezacaftor prepared according to example 21 of the present invention.
  • Figure 24 is the characteristic powder X-ray diffraction (XRD) pattern of amorphous Tezacaftor prepared according to reference example 1.
  • Figure 25 is the characteristic powder X-ray diffraction (XRD) pattern of amorphous Tezacaftor, The X-ray powder diffraction data showed absence of crystalline tezacaftor in the amorphous Tezacaftor prepared according to the present invention at 25°C/60%RH.
  • Figure 26 is the characteristic powder X-ray diffraction (XRD) pattern of amorphous Tezacaftor, The X-ray powder diffraction data showed absence of crystalline tezacaftor in the amorphous Tezacaftor prepared according to the present invention at 40°C/60%RH.
  • XRD characteristic powder X-ray diffraction
  • the present invention provides solid forms of Tezacaftor, including its co-crystals, solvates, hydrates and/or polymorphs, processes for their preparation, pharmaceutical compositions containing the same and use of such solid forms of Tezacaftor in the preparation of another form of Tezacaftor such as amorphous form of Tezacaftor.
  • the present invention also relates to stable amorphous form of Tezacaftor, its preparation and pharmaceutical composition containing the same.
  • the solid forms and amorphous form of Tezacaftor obtained by process of the present invention are characterized by one or more analytical methods such as X-ray powder diffraction (XRPD) pattern, Differential scanning calorimetric (DSC), Thermo gravimetric analysis (TGA) and 1 H NMR Spectrum.
  • XRPD X-ray powder diffraction
  • DSC Differential scanning calorimetric
  • TGA Thermo gravimetric analysis
  • 1 H NMR Spectrum 1 H NMR
  • Tezacaftor which is used as a starting material is known in the art and can be prepared by the process known in art, for example Tezacaftor may be synthesized as disclosed in U.S. Patent No. 7,645,789.
  • the starting Tezacaftor may be in any form such as crude obtained directly from the reaction mass, crystalline, amorphous or other forms of Tezacaftor, including solid forms described herein the present invention.
  • the present invention provides solid forms of Tezacaftor.
  • the present invention provides the solid forms of Tezacaftor may exist in the form of co-crystals, solvates, hydrates, polymorphs, polymorphs of co-crystals or polymorphs of solvates or polymorphs of hydrates.
  • the present invention provides solvates of Tezacaftor.
  • the present invention provides Tezacaftor o-xylene solvate.
  • the present invention provides crystalline Tezacaftor o-xylene solvate.
  • the present invention provides crystalline Tezacaftor o-xylene solvate characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 01.
  • the present invention provides crystalline Tezacaftor o-xylene solvate characterized by a 11 NMR Spectrum substantially in accordance with Figure 02.
  • the present invention provides crystalline Tezacaftor o-xylene solvate characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 03.
  • DSC differential scanning calorimetry
  • the present invention provides crystalline Tezacaftor o-xylene solvate characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 04.
  • TGA thermogravimetric analysis
  • the present invention provides crystalline Tezacaftor o-xylene solvate characterized by one or more of the following: a powder X-Ray diffraction (XRD) pattern substantially in accordance with Figure 01; a 1H NMR Spectrum substantially in accordance with Figure 02; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 03 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 04.
  • XRD powder X-Ray diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the present invention provides a process for the preparation of Tezacaftor o-xylene solvate, comprising: a) dissolving or suspending Tezacaftor in o-xylene solvent; and b) isolating Tezacaftor o-xylene solvate.
  • Step a) of the forgoing process involves the dissolution of Tezacaftor in o-xylene solvent.
  • the reaction mixture may be heated to complete dissolution of the contents in o- xylene solvent.
  • the temperature during stirring can range from about 15°C to about 35°C; preferably, the contents were stirred for about 3 hrs to about 5 hrs at a temperature of about 20°C to about 30°C.
  • Tezacaftor o-xylene solvate may be carried out by any conventional techniques known in the art for example filtration.
  • the resultant Tezacaftor o-xylene solvate may optionally be further dried for about 2 hours to 25 hours at a temperature ranging from about 20°C to about 40°C. Drying can be suitably carried out in a vacuum tray dryer, vacuum oven, air oven, Rotocon Vacuum Dryer, Vacuum Paddle Dryer fluidized bed drier, spin flash dryer, flash dryer and the like.
  • the present invention provides co-crystals of Tezacaftor.
  • the present invention provides co-crystals of Tezacaftor; wherein the co-crystal is former selected from the group comprising caffeine, piperazine, piperidine, 4-amino pyridine, imidazole, morpholine 4-hydroxy pyridine, paraxanthine, theophylline, theobromine, DDQ, Hexamethylenetetramine, 2-hydroxy- 1,4-napthoquinone, nicotinamide or isonicotinamide.
  • the co-crystal is former selected from the group comprising caffeine, piperazine, piperidine, 4-amino pyridine, imidazole, morpholine 4-hydroxy pyridine, paraxanthine, theophylline, theobromine, DDQ, Hexamethylenetetramine, 2-hydroxy- 1,4-napthoquinone, nicotinamide or isonicotinamide.
  • the ratio of Tezacaftor to co-crystals former may be stoichiometric or non-stoichiometric according to the present invention.
  • the ratio of the compound to co-crystals former is about 1:1, 1.5:1, 1:1.5, 2:1 and 1:2 ratios is acceptable.
  • the present invention provides a process for the preparation of co crystals of Tezacaftor, comprising: a) providing a solution or suspension comprising Tezacaftor and a co-crystal former in one or more organic solvents; and b) isolating the co-crystals of Tezacaftor.
  • the step a) of aforementioned process involves, providing a solution or suspension includes any form of tezacaftor that may be mixed with one or more organic solvents and co-crystal former or includes any form of tezacaftor that may be combined with one or more organic solvents and then the co-crystal former may be mixed with the resulting solution or slurry.
  • the mixture may be formed by adding tezacaftor and co crystals former at the same time in to one or more organic solvents.
  • Examples of one or more organic solvents of step a) includes, but are not limited to esters such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, t- butyl acetate and the like; alcohols such as methanol, ethanol, isopropanol, n-propanol, n- butanol, isobutanol and the like; ethers such as tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like, hydrocarbon solvents such as hexane, n- heptane, cyclohexane and the like, halogenated hydrocarbon solvents such as
  • the temperature suitable for step a) reaction depends on the solvent used and the amount of tezacaftor and the amount of co-crystal former used in the reaction mass. Typically, the suitable temperature is from about 20°C to about reflux temperature of the solvent used; preferably the reaction temperature is about 20°C to about 80°C.
  • the co-crystal former of step a) includes, but is not limited to caffeine, piperazine, piperidine, 4-amino pyridine, imidazole, morpholine 4-hydroxy pyridine, paraxanthine, theophylline, theobromine, DDQ, Hexamethylenetetramine, 2-hydroxy- 1,4-napthoquinone, nicotinamide or isonicotinamide; preferably the co- crystal former is caffeine or piperazine.
  • the step b) of aforementioned process for the isolation of co-crystals of tezacaftor may be carried out by any conventional technique known in the art, for example, by filtration.
  • the isolation may be carried out by cooling the reaction mass to a suitable temperature, optionally seeding and filtering the precipitated product.
  • the suitable temperature for cooling is about 0°C to about 30° C; preferably the cooling temperature is room temperature.
  • the resultant co-crystals of Tezacaftor 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 drying can be carried out at a temperature ranging from about 20°C to about 70°C; preferably drying can be carried out at a temperature ranging from about 20°C-60°C for about 15 hrs to about 25 hrs.
  • the resultant co-crystals of Tezacaftor may optionally be further purified in a suitable organic solvent.
  • the present invention provides co-crystals of Tezacaftor having a chemical purity greater than or equal to about 97%, as measured by HPLC, preferably about 98% as measured by HPLC, and more preferably about 99.5%, as measured by HPLC.
  • the co-crystals of the present invention are obtained in substantially pure form.
  • co-crystals of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the co- crystals of the present invention forms solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • the present invention provides Tezacaftor piperazine co-crystal.
  • the present invention provides a process for the preparation of Tezacaftor piperazine co-crystal, comprising: a) providing a solution or suspension comprising Tezacaftor and piperazine in one or more organic solvents; and b) isolating the Tezacaftor piperazine co-crystal.
  • step a) of piperazine co -crystal formation and its procedure are same as to those described just as above for tezacaftor co-crystal.
  • the step b) of aforementioned process for the isolation of piperazine co-crystal tezacaftor may be carried out by any conventional technique known in the art, for example, by filtration or alternatively the isolation may be carried out by cooling the reaction mass to a suitable temperature preferably to room temperature, optionally seeding, filtering the precipitated product and the resultant piperazin co-crystals of Tezacaftor may optionally be further dried.
  • tezacaftor piperazine co-crystals recovered using the process as described just above is substantially in crystalline form.
  • isolation of piperazine co-crystal tezacaftor may be carried out by filtration to form crystalline Tezacaftor piperazine co-crystal Form 1.
  • the present invention provides Tezacaftor piperazine co-crystal Form 1.
  • the present invention provides Tezacaftor piperazine co-crystal Form 1 characterized by X-Ray powder diffraction (PXRD) pattern substantially in accordance with Figure 05.
  • PXRD X-Ray powder diffraction
  • the present invention provides Tezacaftor piperazine co-crystal Form 1 characterized by an X-Ray powder diffraction (XRD) pattern having one or more peaks at about 3.7, 7.2, 10.8, 13.6, 14.4, 17.2, 18.0 and 19.0 ⁇ 0.2° 2Q.
  • XRD X-Ray powder diffraction
  • the present invention provides Tezacaftor piperazine co-crystal Form 1 characterized by a 1H NMR Spectrum substantially in accordance with Figure 06.
  • the present invention provides Tezacaftor piperazine co-crystal Form 1 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 07.
  • DSC differential scanning calorimetry
  • the present invention provides Tezacaftor piperazine co-crystal Form 1 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 08.
  • TGA thermogravimetric analysis
  • the present invention provides Tezacaftor piperzine co-crystal Form 1 characterized by one or more of the following: a powder X-Ray diffraction (XRD) pattern substantially in accordance with Figure 05; a 1H NMR Spectrum substantially in accordance with Figure 06; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 07 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 08.
  • XRD powder X-Ray diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the isolation of piperazine co-crystal tezacaftor of step b) may alternatively be carried out by cooling the reaction mass to a suitable temperature preferably to room temperature, optionally seeding and is further treated with aliphatic hydrocarbon solvents selected from n-hexane, n-heptane, cyclohexane, cycloheptane and the like; preferably from n-heptane to form crystalline Tezacaftor piperazine co-crystal Form 2.
  • the present invention provides Tezacaftor piperazine co-crystal Form 2.
  • the present invention provides Tezacaftor piperazine co-crystal Form 2 characterized by X-Ray powder diffraction (PXRD) pattern substantially in accordance with Figure 09.
  • the present invention provides Tezacaftor piperazine co-crystal Form 2 characterized by an X-Ray powder diffraction (XRD) pattern having one or more peaks at about 3.8, 7.7, 12.4, 14.2, 18.3 and 19.6 ⁇ 0.2° 2Q.
  • XRD X-Ray powder diffraction
  • the present invention provides Tezacaftor piperazine co-crystal Form 2 characterized by a 1H NMR Spectrum substantially in accordance with Figure 10.
  • the present invention provides Tezacaftor piperazine co-crystal Form 2 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 11.
  • DSC differential scanning calorimetry
  • the present invention provides Tezacaftor piperazine co-crystal Form 2 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 12.
  • TGA thermogravimetric analysis
  • the present invention provides Tezacaftor piperzine co-crystal Form 2 characterized by one or more of the following: a powder X-Ray diffraction (XRD) pattern substantially in accordance with Figure 09; a 1H NMR Spectrum substantially in accordance with Figure 10; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 11 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 12.
  • XRD powder X-Ray diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Tezacaftor piperazine co-crystal Form 2 is dried at 45-55°C to obtain Tezacaftor piperazine co-crystal Form 3.
  • the present invention provides Tezacaftor piperazine co-crystal Form 3.
  • the present invention provides Tezacaftor piperazine co-crystal Form 3 characterized by X-Ray powder diffraction (PXRD) pattern substantially in accordance with Figure 13.
  • PXRD X-Ray powder diffraction
  • the present invention provides Tezacaftor piperazine co-crystal Form 3 characterized by an X-Ray powder diffraction (XRD) pattern having one or more peaks at about 4.8, 9.2, 13.7, 14.3, 17.9, 19.6, 20.1 and 20.6 ⁇ 0.2° 2Q.
  • XRD X-Ray powder diffraction
  • the present invention provides Tezacaftor piperazine co-crystal Form 3 characterized by a 1H NMR Spectrum substantially in accordance with Figure 14.
  • the present invention provides Tezacaftor piperazine co-crystal Form 3 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 15.
  • DSC differential scanning calorimetry
  • the present invention provides Tezacaftor piperazine co-crystal Form 3 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 16.
  • TGA thermogravimetric analysis
  • the present invention provides Tezacaftor piperzine co-crystal Form 3 characterized by one or more of the following: a powder X-Ray diffraction (XRD) pattern substantially in accordance with Figure 13; a 1H NMR Spectrum substantially in accordance with Figure 14; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 15 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 16.
  • XRD powder X-Ray diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the present invention provides Tezacaftor caffeine co-crystal.
  • the present invention provides a process for the preparation of Tezacaftor caffeine co-crystal, comprising: a) providing a solution or suspension comprising tezacaftor and caffeine in one or more organic solvents; and b) isolating tezacaftor caffeine co-crystal.
  • step a) of caffeine co-crystal formation and its procedure and step b) isolation procedure of tezacaftor caffeine co-crystal are same as to those described just as above for tezacaftor co-crystal.
  • the resultant tezacaftor caffeine co-crystal may optionally be further purified in a suitable organic solvent.
  • tezacaftor caffeine co-crystal recovered using the process as described just above is substantially a crystalline form.
  • the present invention provides tezacaftor caffeine co-crystal characterized by X-Ray powder diffraction (PXRD) pattern substantially in accordance with Figure 17.
  • PXRD X-Ray powder diffraction
  • the present invention provides tezacaftor caffeine co-crystal characterized by an X-Ray powder diffraction (XRD) pattern having one or more peaks at about 7.2, 8.6, 10.3, 12.0, 12.5, 14.5, 15.9 and 19.0 ⁇ 0.2° 20.
  • XRD X-Ray powder diffraction
  • the present invention provides tezacaftor caffeine co-crystal characterized by a 1H NMR Spectrum substantially in accordance with Figure 18.
  • the present invention provides tezacaftor caffeine co-crystal characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 19.
  • DSC differential scanning calorimetry
  • the present invention provides tezacaftor caffeine co-crystal characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 20.
  • TGA thermogravimetric analysis
  • the present invention provides tezacaftor caffeine co-crystal characterized by one or more of the following: a powder X-Ray diffraction (XRD) pattern substantially in accordance with Figure 17; a 1H NMR Spectrum substantially in accordance with Figure 18; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 19 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 20.
  • XRD powder X-Ray diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the solid forms of Tezacaftor of the present invention may be used as an intermediate in obtaining high purity Tezacaftor. In another embodiment, the solid forms of Tezacaftor of the present invention may be used as an intermediate in obtaining high purity amorphous Tezacaftor.
  • the present invention provides a process for the preparation of amorphous form of Tezacaftor, wherein the process involves Tezacaftor o-xylene solvate of the invention as intermediate.
  • the present invention provides a process for the preparation of amorphous Tezacaftor comprising: a) dissolving or suspending Tezacaftor in o-xylene solvent, b) isolating Tezacaftor o-xylene solvate, and c) drying the Tezacaftor o-xylene solvate at about 25°C to about 85°C to obtain amorphous form.
  • Step a) of the forgoing process involves the dissolution of Tezacaftor in o-xylene solvent.
  • the reaction mixture may be heated to complete dissolution of the contents in o- xylene solvent.
  • the temperature during stirring can range from about 15°C to about 35°C; preferably, the contents were stirred for about 3 hrs to about 5 hrs at a temperature of about 20°C to about 30°C.
  • Tezacaftor o-xylene solvate may be carried out by any conventional techniques known in the art for example filtration.
  • the resultant Tezacaftor o-xylene solvate may optionally be further dried for about 2 hours to 25 hours at a temperature ranging from about 25°C to about 40°C. Drying can be suitably carried out in a vacuum tray dryer, vacuum oven, air oven, Rotocon Vacuum Dryer, Vacuum Paddle Dryer fluidized bed drier, spin flash dryer, flash dryer and the like.
  • Tezacaftor o-xylene solvate obtained as above further drying at about 25°C to about 85°C under vacuum for a period of about 2 hrs to about 24 hrs to obtain amorphous form; typically drying of Tezacaftor o-xylene solvate was carried out at about 45 °C to about 60°C for about 14 hrs to about 18 hrs.
  • the co-crystals of tezacaftor of the present invention may be used as an intermediate in obtaining high purity tezacaftor.
  • the present invention provides a process for the preparation of tezacaftor, comprising: a) preparing a co-crystal of tezacaftor; and b) converting the co-crystal of Tezacaftor in to Tezacaftor.
  • reaction procedures for the preparation of tezacaftor co-crystals are same as to those described just as above. Further, conversion process of tezacaftor co-crystal into tezacaftor by breaking co-crystals followed by converting into tezacaftor either by solvent evaporation method or by solvent- antisolvent method which is same as to the procedures described just below.
  • the present invention provides a process for the preparation of amorphous form of Tezacaftor, wherein the process involves one or more of co-crystal forms of Tezacaftor of the invention as an intermediate.
  • the present invention provides a process for the preparation of amorphous tezacaftor, comprising: a) dissolving or suspending tezacaftor co-crystal in a suitable solvent, b) optionally treating the step a) reaction mass with a suitable acid or base, and c) isolating the amorphous tezacaftor.
  • the co-crystals of tezacaftor used in step a) includes but are not limited to caffeine, piperazine, piperidine, 4-amino pyridine, imidazole, morpholine 4-hydroxy pyridine, paraxanthine, theophylline, theobromine, DDQ, Hexamethylenetetramine, 2 -hydroxy- 1,4- napthoquinone, nicotinamide or isonicotinamide; preferably piperazine or caffeine co crystals of Tezacaftor are dissolved or suspended in a suitable solvent.
  • the temperature suitable for dissolving or suspending the tezacaftor co-crystal in the suitable organic solvents depends on the solvent and the amount of tezacaftor and the amount of co-crystal used in the reaction mass.
  • the suitable temperature is from about 20°C to about reflux temperature of the solvent used; preferably the reaction temperature is about 20°C to about 30°C.
  • the suitable solvent used herein for dissolution of tezacaftor co-crystal is selected from water or from a mixture of water and water immiscible organic solvent; wherein water immiscible organic solvent is selected from esters such as methyl acetate, ethyl acetate, isopropyl acetate n-propyl acetate, n-butyl acetate, t-butyl acetate, ethyl formate and the like; hydrocarbons such as hexane, heptane, cyclohexane and the like; ethers such as tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; chlorinated solvent such as dichloromethane, dichloroethane, chloroform and the like or mixtures thereof; preferably the suitable solvent is water, ethylformate or mixture
  • step b) of the foregoing process involves treating the step a) reaction mass with a suitable acid or a base.
  • the suitable acid used herein are selected from the group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, formic acid, sulphonic acid, benzene sulphonic or mixtures thereof.
  • the base used herein are selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium, carbonate, lithium carbonate, cesium carbonate or mixtures thereof.
  • the sequence of addition of the suitable acid or base is not particularly critical and the addition can be carried out in any known manner, for example, the suitable base or acid can be added into co-crystal of tezacaftor or co-crystal of tezacaftor may be added to the suitable base or acid.
  • Step c) of the aforementioned process involves the isolation of amorphous form of Tezacaftor is carried out by removal of solvent from the solution by, for example, substantially complete evaporation of the solvent, concentrating the solution, distillation or distillation under vacuum, cooling and filtering the solid under inert atmosphere.
  • Evaporation can be achieved at sub-zero temperatures by the lyophilisation or freeze drying technique, a rotational drying (such as with the Buchi Rotavapor), spray drying, fluid bed drying, flash drying, spin flash drying and thin-film drying; preferably, the solvent may be removed completely by distillation under vacuum at a temperature of about 25°C to about 60°C.
  • the amorphous form of Tezacaftor obtained by the above process may be dried for about 2 hours to 25 hours at a temperature of 40-70°C; preferably dried at a temperature of about 45°C to about 55°C for about 14-18 hrs. Drying can be suitably carried out in a vacuum tray dryer, vacuum oven, air oven, Rotocon Vacuum Dryer, Vacuum Paddle Dryer fluidized bed drier, spin flash dryer, flash dryer and the like.
  • Tezacaftor recovered using the processes of the present invention is in the form of substantially pure amorphous form.
  • the present invention provides a process for the preparation of amorphous tezacaftor, comprising: a) dissolving or suspending tezacaftor co-crystals in a suitable solvent, b) optionally treating the step a) reaction mass with a suitable acid or base, c) concentrating the reaction mass, d) treating the step c) reaction mass with a suitable solvent, e) adding an anti-solvent to the step d) solution or vice-versa, and f) isolating the amorphous Tezacaftor.
  • Step a) to b) of the aforementioned process is same as the process as described in the previous embodiment.
  • Step c) of the aforementioned process involves the concentration of product containing organic layer at a temperature of about 30-70°C; preferably at a temperature of about 40- 50°C.
  • Step d) of the aforementioned process involves dissolution of step c) reaction mass in a suitable solvent
  • suitable solvent includes but are not limited to alcohols such as methanol, ethanol, propanol, isopropanol, butanol and the like; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; nitriels such as acetonitrile, propionitrile and the like; sulfoxides such as dimethyl sulfoxide, diethyl sulfoxide and the
  • the dissolution temperatures may range from about 20°C to about reflux temperature of the solvent, depending on the solvent used for dissolution; preferably the dissolution temperatures may range from about 45 °C to about 55°C.
  • the resulting solution was further cooled to room temperature and may optionally be treated with carbon and the solution obtained above may optionally filtered to remove insoluble particles.
  • Step e) of the aforementioned process involves precipitation of tezacaftor by either addition of suitable antisolvent to the step d) solution or addition of step d) solution into a suitable antisolvent.
  • the suitable anti-solvent include, but are not limited to water, aliphatic hydrocarbons, alicyclic hydrocarbons, ethers and the like or mixtures thereof.
  • the aliphatic hydrocarbons include, but are not limited to propane, hexane, heptane and the like;
  • alicyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane and the like;
  • ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; water or mixtures thereof; preferably the suitable anti- solvent is water.
  • anti-solvent is carried out at a temperature of less than about 15°C; preferably at a temperature of about 0°C to about 10°C. Then the resultant mass is stirred for sufficient period of about 30 min to about 5 hours.
  • Step f) of the aforementioned process involves isolation of the amorphous for of Tezacaftor by any conventional technique known in the art, 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 drying can be carried out at a temperature ranging from about 25°C to about 65 °C for a time period ranging from about 5 hour to about 20 hours.
  • the present invention provides processes for the preparation of amorphous form of Tezacaftor.
  • the present invention provides a process for preparation of amorphous form of Tezacaftor, comprising: a) providing a solution or suspension of Tezacaftor in a suitable solvent (SI), b) removing the solvent from the step a) reaction mass, c) optionally adding a suitable solvent (S2) to the step b), and d) isolating the amorphous form.
  • the step a) of aforementioned process involves, providing a solution or suspension of Tezacaftor in a suitable solvent (SI).
  • the suitable solvent (SI) include, but are not limited to ketones, alcohols, esters, nitriles, ethers and the like or mixtures thereof.
  • the ketones include, but are not limited to acetone, methylethylketone, methylisobutylketone and the like; alcohols include, but are not limited to methanol, ethanol, propanol, isopropanol, butanol and the like; esters include, but are not limited to methyl acetate, ethyl acetate, ethyl formate, isopropyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like or mixtures thereof; preferably the suitable solvent (SI) is
  • the contents may be stirred for sufficient period of time at a suitable temperature of at about 25 °C to about reflux. Typically, the contents were stirred for about 10 min to about 2 hrs at a temperature of 45-65°C for complete dissolution.
  • Step b) of the aforementioned process involves removal of solvent to obtain amorphous Tezacaftor residue, wherein the removal of solvent includes evaporation, distillation or distillation under vacuum.
  • Evaporation can be achieved at sub-zero temperatures by the lyophilisation or freeze-drying technique, a rotational drying (such as with the Buchi Rotavapor), spray drying, fluid bed drying, flash drying, spin flash drying and thin-film drying; preferably, the solvent may be removed completely by distillation under vacuum at a temperature of about 40°C to about 70°C.
  • the amorphous tezacaftor residue so obtained may optionally recovered by using a suitable solvent (S2) at a temperature of about 10°C to about 40°C.
  • a suitable solvent (S2) at a temperature of about 10°C to about 40°C.
  • the addition of suitable solvent (S2) is carriedout at a temperature of 10-25°C.
  • the suitable solvent (S2) include, but are not limited to water, aliphatic hydrocarbons, alicyclic hydrocarbons and the like or mixtures thereof.
  • the 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; water and the like or mixture thereof; preferably the suitable solvent (S2) is cyclohexane.
  • S2 is cyclohexane.
  • the resultant amorphous form of Tezacaftor can be isolated by any conventional techniques known in the art for example filtration. Typically, if stirring is involved, the temperature during stirring can range from about 0°C to about 30°C.
  • the amorphous form of Tezacaftor obtained by the above process may be dried for about 2 hrs to 25 hrs; preferably dried at a temperature of 45-65°C for about 12 hrs to 18 hrs; Drying can be suitably carried out in a vacuum tray dryer, vacuum oven, air oven, Rotocon Vacuum Dryer, Vacuum Paddle Dryer fluidized bed drier, spin flash dryer, flash dryer and the like.
  • the present invention provides a process for preparation of amorphous form of Tezacaftor, comprising: a) providing a solution of Tezacaftor in one or more solvents; b) adding a suitable anti- solvent to the step a) solution or vice-versa; and c) isolating the amorphous form.
  • the step a) of the aforementioned process involves, dissolving tezacaftor in one or more solvents at a suitable temperature.
  • one or more organic solvents of step a) includes but are not limited to alcohols such as methanol, ethanol, propanol, isopropanol, butanol and the like; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; nitriels such as acetonitrile, propionitrile and the like; sulfoxides such as dimethyl sulfoxide, diethyl sulfoxide and the like; amides such as dimethyl formamide, dimethyl acetamide, N-methyl pyrroli
  • the suitable temperature for step a) reaction is about 20°C to about 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; preferably the step a) reaction is carried out at temperature of about 50°C to about 75°C.
  • Step b) of the aforementioned process involves precipitation of Tezacaftor by either addition of suitable antisolvent to the step a) solution or addition of step a) solution into a suitable antisolvent.
  • suitable anti-solvent is carried out at a temperature of less than about 15°C; preferably at a temperature of about 0°C to about 10°C. Then the resultant mass is stirred for sufficient period of about 30 min to about 5 hours.
  • the suitable anti-solvent include, but are not limited to water, aliphatic hydrocarbons, alicyclic hydrocarbons, ethers and the like or mixtures thereof.
  • the aliphatic hydrocarbons include, but are not limited to propane, hexane, heptane and the like;
  • alicyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane and the like;
  • ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; water or mixtures thereof; preferably the suitable antisolvent is water.
  • Tezacaftor isolation is carried out by any conventional technique known in the art, for example, filtration.
  • the resultant wet product may optionally be further dried for about 2 hours to 20 hours at a temperature of about 20°C to about 60°C. 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.
  • Tezacaftor recovered using the processes of the present invention are in the form of substantially pure amorphous form.
  • the amorphous form of tezacaftor obtained according to the present invention is stable during storage. This property is important and advantageous for the desired use of tezacaftor in pharmaceutical product formulations.
  • the present invention provides stable amorphous form of Tezacaftor.
  • the present invention provides stable amorphous form of Tezacaftor which remains stable when stored and does not convert to any other solid form when stored at a temperature of up to about 40°C and at a relative humidity of about 25% to about 75% up to about three months or more.
  • the amorphous form of Tezacaftor is stable when subjected to the real time and accelerated conditions, wherein the amorphous form of Tezacaftor is stored at 25 ⁇ 2°C/60 ⁇ 5% RH for a period three months and at 40 ⁇ 2°C/75 ⁇ 5% RH for a period of three months.
  • stable amorphous form of Tezacaftor refers to” amorphous form of Tezacaftor in which the PXRD pattern of the amorphous form do not change when stored at at a temperature of up to about 40°C and at a relative humidity of about 25% to about 75% up to about three months or more.
  • the present invention provides a method of packing amorphous form of Tezacaftor, comprising: placing amorphous form of Tezacaftor in LDPE bag under nitrogen atmosphere; placing the product containing Low-density polyethylene (LDPE) bag in a second LDPE bag under nitrogen atmosphere; keeping the silica gel packet between two LDPE bags and sealing; placing the second sealed bag in a triple laminated bag and sealing.
  • the amorphous form of Tezacaftor obtained by the processes of the invention is packed according to the above embodiment and stored for stability. A period of up to 3 months at real and accelerated conditions, the amorphous character was retained and does not convert to any other solid form when stored at a temperature of up to about 40°C and at a relative humidity of about 25% to about 75%.
  • the present invention further provides an amorphous form of tezacaftor, having a chemical purity of 98% or more as measure by HPLC, preferably 99% or more, more preferably 99.8% or more.
  • the amorphous form of tezacaftor may be obtained substantially free of any unknown impurity, e.g., a content of less than about 0.1% of impurities.
  • the present invention provide amorphous form of tezacaftor obtained by the above process, as analyzed using high performance liquid chromatography (“HPLC”) with the conditions are tabulated below:
  • the present invention also encompasses a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of amorphous form of tezacaftor prepared by the processes of the present invention with at least one pharmaceutically acceptable carrier or other excipients.
  • Amorphous Tezacaftor 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.
  • compositions of the invention may be combination products comprising one or more additional pharmaceutically active components in addition to Tezacaftor.
  • 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
  • Tezacaftor (3.02 gms) was dissolved in a mixture of 10% hexane in ethyl acetate (70 mL) at 60°C. The solvent was distilled completely under vacuum at 55-65°C and the obtained solids were dried at 50-60°C under vacuum for 13 hrs. Yield: 2.82 g.
  • Amorphous Form obtained according to the reference examples was analyzed by PXRD and is represented according to Fig. 24.
  • Tezacaftor (6.02 gms) was dissolved in a mixture of 100% in ethyl acetate (120 mL) at 60°C. The solvent was distilled completely under vacuum at 65-75°C and the obtained solids were dried at 50-60°C under vacuum for 13 hrs. Yield: 5.89 g.
  • Amorphous Tezacaftor (400.1 mg) and o-xylene (1.6 mL) were added in to a round bottom flask at 22-26°C and stirred for 5 mins at same temperature.
  • O-xylene (0.4 mL) was added to the resulting reaction mixture at 22-26°C.
  • the resulting reaction mixture was stirred for 4 hrs at 22-26 °C, filtered the solids, washed with o-xylene (0.4 mL) and suck dried for 15 mins. The resulting solid was dried under vacuum for 16 hrs at room temperature to obtain title compound. Yield: 120.2 mg.
  • EXAMPLE 3 Preparation of o-xylene solvate of Tezacaftor Amorphous Tezacaftor (400.3 mg) and o -xylene (1.6 mL) were added in to a round bottom flask at 22-26°C and stirred for 5 mins at same temperature. O-xylene (0.4 mL) was added to the resulting reaction mixture at 22-26°C. The resulting reaction mixture was stirred for 4 hrs at 22-26 °C, filtered the solids, washed with o-xylene (0.4 mL) and suck dried for 15 mins. The resulting solid was dried under vacuum for 16 hrs at room temperature to obtain title compound. Yield: 135.1 mg.
  • Tezacaftor 500 mg
  • piperazine 166 mg
  • Ethyl acetate (0.125 mL)
  • t-butyl acetate (1.375 mL) were added to the resulting reaction mixture at 22-26°C.
  • the temperature of the reaction mixture was raised to 68- 72°C and stirred for 10 mins at same temperature.
  • the resulting solution was cooled to 22- 26°C, seed crystals of Tezacaftor piperazine co-crystal was added and stirred for 2 hrs at 22-26°C.
  • the resulting solid was filtered, washed with t-butyl acetate (1 mL) and suck dried for 10 mins. The resulting solid was dried under vacuum for 16 hrs at room temperature to obtain title compound. Yield: 507 mg.
  • the PXRD is set forth in Figure 05
  • the 14 NMR is set forth in Figure 06
  • the DSC thermogram is set forth in Figure 07
  • the TGA is set forth in Figure 08.
  • Tezacaftor (200 mg) and piperazine (66 mg) were added in to a round bottom flask at 22- 26°C.
  • t-butyl acetate (3 mL) was added to the resulting reaction mixture at 22-26°C.
  • the resulting reaction mixture was stirred for 20 hrs at 22-26 °C, filtered the solids, washed with t-butyl acetate (0.5 mL) and suck dried for 10 mins.
  • the resulting solid was dried under vacuum for 20 hrs at room temperature to obtain title compound. Yield: 222 mg.
  • Tezacaftor (1.5 gm) and piperazine (496 mg) were added in to a round bottom flask at 22- 26°C.
  • Ethyl acetate (0.375 mL) and t-butyl acetate (4.125 mL) were added to the resulting reaction mixture at 22-26°C.
  • the temperature of the reaction mixture was raised to 68- 72°C and stirred for 10 mins at same temperature.
  • the resulting solution was cooled to 22- 26°C, seed crystals of Tezacaftor piperazine co-crystal was added and stirred for 2 hrs at 22-26°C.
  • Tezacaftor (2.02 gm) and piperazine (662.3 mg) were added in to a round bottom flask at 22-26°C.
  • Ethyl acetate (6 mL) was added to the resulting reaction mixture at 22-26°C.
  • the temperature of the reaction mixture was raised to 68-72°C, stirred for 10 mins at same temperature and then cooled to 22-26°C.
  • Seed crystals of Tezacaftor piperazine co-crystal was added to the resulting reaction mass and then n-heptane was added and stirred for 2 hrs at 22-26°C.
  • the resulting solid was filtered, washed with n-heptane (6 mL) and suck dried for 10 mins.
  • the resulting solid was dried under vacuum for 17 hrs at room temperature to obtain title compound. Yield: 2.60 gm.
  • the PXRD is set forth in Figure 09
  • the 1 H NMR is set forth in Figure 10
  • the DSC thermogram is set forth in Figure 11
  • the TGA is set forth in Figure 12.
  • Tezacaftor piperazine co-crystal (500.5 mg) obtained from ex-7 was further dried at a temperature of 45-55°C to obtain title compound. Yield: 445.3 gm.
  • the PXRD is set forth in Figure 13
  • the 1 H NMR is set forth in Figure 14
  • the DSC thermogram is set forth in Figure 15
  • the TGA is set forth in Figure 16.
  • Tezacaftor 500 mg
  • caffeine 280 mg
  • ethyl acetate 20 mL
  • the resulting solution was cooled to RT, stirred for 2 hrs at 22-26 °C, filtered the solids and suck dried for 10 mins.
  • the resulting solid was dried under vacuum for 16 hrs at room temperature to obtain title compound. Yield: 264 mg.
  • the PXRD is set forth in Figure 17
  • the 1 H NMR is set forth in Figure 18
  • the DSC thermogram is set forth in Figure 19
  • the TGA is set forth in Figure 20.
  • Tezacaftor 100 mg
  • caffeine 75 mg
  • t-butyl acetate 1.5 mL
  • the resulting reaction mixture was stirred for 16 hrs at 22-26 °C, filtered the solids, washed with t-butyl acetate (0.5 mL) and suck dried for 10 mins.
  • the resulting solid was dried under vacuum for 2 hrs at room temperature and then at 51-55 °C for 16 hrs to obtain title compound. Yield: 128 mg.
  • Tezacaftor 500 mg
  • caffeine 187 mg
  • ethyl acetate 20 mL
  • Tezacaftor 500 mg
  • caffeine 187 mg
  • ethyl acetate 20 mL
  • the resulting solution was cooled to RT, seeded with Tezacaftor caffeine co-crystal.
  • the resulting reaction mixture was stirred for 24 hrs at 22-26 °C, filtered the solids and suck dried for 10 mins.
  • the resulting solid was dried under vacuum for 20 hrs at room temperature to obtain title compound. Yield: 148 mg.
  • EXAMPLE 12 Preparation of caffeine co-crystal of tezacaftor Tezacaftor (500 mg), caffeine (373 mg) and ethyl acetate (20 mL) were added in to a round bottom flask at 70°C. The resulting solution was cooled to RT, stirred for 2 hrs at 22-26 °C, filtered the solids and suck dried for 10 mins. The resulting solid was dried under vacuum for 16 hrs at room temperature to obtain title compound. Yield: 423 mg.
  • Amorphous Tezacaftor (400.3 mg) and o-xylene (1.6 mL) were added in to a round bottom flask at 22-26°C and stirred for 5 mins at same temperature.
  • O-xylene (0.4 mL) was added to the resulting reaction mixture at 22-26°C.
  • the resulting reaction mixture was stirred for 4 hrs at 22-26 °C, filtered the solids, washed with o-xylene (0.4 mL) and suck dried for 15 mins.
  • the resulting solid was dried under vacuum for 4 hrs at room temperature and further dried at 50-55°C for 16 hrs to obtain title compound. Yield: 122.4 mg.
  • Tezacaftor (2 gm) and isopropyl acetate (20 mL) were added in to a round bottom flask at 22-26°C.
  • Caffeine (1.50 gm) was added to the resulting reaction mixture at 22-26°C and stirred for 30 mins.
  • Isopropyl acetate (20 ml) was added to the resulting reaction mixture at 22-26°C and stirred for 17 hrs, filtered, washed with Isopropyl acetate (10 mL) and suck dried for 30 mins.
  • Ethyl formate (30 mL) and water (30 mL) were added to the resulting solid at 22-26°C and stirred for 10 mins.
  • the organic layer was separated.0.49N of hydrochloric acid (1.33 mL of Con HC1 in 30 mL of water) was added to the resulting organic layer at 22-26°C and stirred for 10 mins. The organic layer was separated and the combined organic layer was washed with 5 % sodium bicarbonate (30 mL). The separated organic layer was washed with water (30 mL) and 5% sodium chloride solution (20 mL) was added to the resulting organic layer. The layers were separated and the resulting organic layer was dried with sodium sulphate (2 gm). The organic layer was distilled at 40- 45°C and co-distilled with methanol (60 mL) at 43-47°C.
  • Tezacaftor (10 gm) and piperazine (3.31 gm) were added in to a round bottom flask at 22- 26°C.
  • Ethyl acetate (2.5 mL) and t-butyl acetate (27.5 mL) were added to the resulting reaction mixture at 22-26°C.
  • the temperature of the reaction mixture was raised to 68- 72°C and stirred for 20 mins at same temperature.
  • the resulting solution was cooled to 22- 26°C, seed crystals of Tezacaftor piperazine co-crystal was added and stirred for 15 mins at 22-26°C.
  • t-butyl acetate was added to the resulting reaction mixture at 22-26°C and stirred for 60 mins.
  • Tezacaftor (2.01 gm) and piperazine (661.8 mg) were added in to a round bottom flask at 22-26°C.
  • Ethyl acetate (6 mL) was added to the resulting reaction mixture at 22-26°C.
  • the temperature of the reaction mixture was raised to 68-72°C and stirred for 10 mins at same temperature.
  • the resulting solution was cooled to 22-26°C, seed crystals of Tezacaftor piperazine co-crystal was added at same temeparature and and stirred for 5 mins.
  • N- heptane was added to the resulting reaction mixture at 22-26°C and stirred for 2 hrs.
  • the organic layer was dried with sodium sulphate (1 gm), distilled until 4 volumes remains in the at 43-47°C and co-distilled with methanol (2* 20 mL) at 48-52°C until 4 volumes remains in the flask.
  • the reaction mixture was cooled to 22-26°C and then added to pre-cooled water at 0-5°C, stirred for 30 mins, filtered the solids, washed with water (5 mL) and suck dried for 15 mins.
  • the resulting solid was dried under vacuum initial at room temperature for 2 hrs and then further dried at 48-52°C for 14 hrs to obtain title compound. Yield: 1.29 gm.
  • Tezacaftor (2 gm) and isopropyl acetate (20 mL) were added in to a round bottom flask at 22-26°C.
  • Caffeine (1.50 gm) was added to the resulting reaction mixture at 22-26°C and stirred for 30 mins.
  • Isopropyl acetate (20 ml) was added to the resulting reaction mixture at 22-26°C and stirred for 17 hrs, filtered, washed with Isopropyl acetate (10 mL) and suck dried for 30 mins.
  • Ethyl formate (30 mL) and water (30 mL) were added to the resulting solid at 22-26°C and stirred for 10 mins.
  • Tezacaftor piperazine co-crystal (5 gms), Ethyl formate (50 mL) and water (50 mL) were added in to a round bottom flask at 22-26°C and stirred for 10 mins. Con hydrochloric acid (293 pi) was added and the reaction mixture was stirred for 20 mins at 22-26°C. The organic layer was separated and the combined organic layer was washed with water (50 ml). The organic layer was distilled at 40-45°C and co-distilled with methanol (100 mL) at 51-55°C until 20 mL remains in the flask.
  • Tezacaftor (1.01 gm) and piperazine (334.1 mg) were added in to a round bottom flask at 22-26°C.
  • t-butyl acetate (5 mL) was added to the resulting reaction mixture and stirred for 5 hrs at 22-26°C.
  • the temperature of the reaction mixture was raised to 63-67°C and stirred for 10 mins at same temperature.
  • the resulting solution was cooled to 22-26°C, seed crystals of Tezacaftor piperazine co-crystal was added and stirred for 5 mins at 22- 26°C.
  • t-butyl acetate (5 mL) was added to the resulting reaction mixture at 22-26°C and stirred for 13 hrs.
  • Tezacaftor (2.04 gm), Caffeine (1.49 gm) and isopropyl acetate (20 mL) were added in to a round bottom flask at 22-26°C.
  • the resulting reaction mixture at 22-26°C and stirred for 1 hr, filtered.
  • Isopropyl acetate (10 mL) was to added to the resulting reaction mixture at 22- 26°C, stirred for 16 hrs, filtered, washed with isopropyl acetate (2 mL) and suck dried for 15 mins.
  • Ethyl formate (60 mL) and water (60 mL) were added to the resulting solid at 22- 26°C and stirred for 10 mins.
  • Tezacaftor 501.9 mg
  • acetone 10 mL
  • the solvent was distilled completely under vacuum at 45-55°C.
  • Cyclohexane 5 mL was added to the resulting foamy solid at 10-15°C and stirred for 30 min.
  • the solid obtained was filtered, washed with cyclohexane (2 ml) and suck dried for 10 mins.
  • the resulting solid was dried under vacuum for 13 hrs at 55-65°C to obtain title compound. Yield: 268.2 mg.
  • the PXRD is set forth in Figure-23.
  • Tezacaftor 501.2 mg
  • Methanol 10 mL
  • the solvent was distilled completely under vacuum at 55-65°C and the obtained solids were dried at 55-65°C under vacuum for 14 hrs to obtain title compound. Yield: 355.3 mg.
  • Tezacaftor 500.8 mg
  • acetone 10 mL
  • the solvent was distilled completely under vacuum at 45-55°C and the obtained solids were dried at 55-65°C under vacuum for 14 hrs to obtain title compound.. Yield:312.2 mg.
  • Tezacaftor 501.5 mg
  • ethyl formate 10 mL
  • the solvent was distilled completely under vacuum at 45-55°C and the obtained solids were dried at 55-65°C under vacuum for 14 hrs to obtain title compound.. Yield:321.4 mg.
  • EXAMPLE 25 Preparation of amorphous form of Tezacaftor (methanol-water) Tezacaftor (100.1 mg) and methanol (0.4 mL) were added in to a round bottom flask at 60°C. The resulting solution was cooled to 20-25°C and added to pre-cooled water (2 mL) at 0-5°C. The reaction mixture was stirred for 60 mins at 0-5 °C, filtered the solids, washed with water (0.4 mL) and suck dried for 15 mins. The resulting solid was dried under vacuum for 16 hrs at room temperature to obtain title compound. Yield:47.2 mg.
  • EXAMPLE 26 Preparation of amorphous form of Tezacaftor (dimethyl sulfoxide-water) Tezacaftor (101.3 mg) and dimethyl sulfoxide (0.2 mL) were added in to a round bottom flask at 60°C. The resulting solution was cooled to 20-25°C and added to pre-cooled water (2 mL) at 0-5°C. The reaction mixture was stirred for 60 mins at 0-5 °C, filtered the solids, washed with water (0.4 mL) and suck dried for 15 mins. The resulting solid was dried under vacuum for 16 hrs at room temperature to obtain title compound. Yield: 40.5 mg.
  • Tezacaftor (301.1 mg) and methanol (1.2 mL) were added in to a round bottom flask at 55- 65°C.
  • the resulting solution was cooled to 20-25°C and added to pre-cooled water (6 mL) at 0-5°C.
  • the reaction mixture was stirred for 30 mins at 0-5 °C, filtered the solids, washed with water (0.6 mL) and suck dried for 15 mins.
  • the resulting solid was dried under vacuum for 4 hrs at room temperature and further dried under vacuum for 12 hrs at 50°C to obtain title compound. Yield: 217.5 mg.
  • Tezacaftor (302.1 mg) and dimethyl sulfoxide (0.6 mL) were added in to a round bottom flask at 55-65°C.
  • the resulting solution was cooled to 20-25°C and added to pre-cooled water (6 mL) at 0-5°C.
  • the reaction mixture was stirred for 30 mins at 0-5 °C, filtered the solids, washed with water (0.6 mL) and suck dried for 15 mins.
  • the resulting solid was dried under vacuum for 4 hrs at room temperature and further dried under vacuum for 12 hrs at 50°C to obtain title compound. Yield:219.4 mg.
  • EXAMPLE 29 Stability study for amorphous form of Tezacaftor of the invention:
  • Tezacaftor The amorphous form of Tezacaftor is packed in LDPE bag under nitrogen atmosphere and placed in another LDPE bag, filled with nitrogen and kept silica gel packet between the bags, tied with strip seal. Kept the bag in triple laminated sunlight barrier bag and sealed with heat sealer. The stability of the samples was tested at 25 ⁇ 2°C/60 ⁇ 5% and 40 ⁇ 2°C/75 ⁇ 5%RH respectively. The results are shown in below table 1:
  • Figures 25 & 26 are the characteristic powder X-ray diffraction (XRD) pattern of amorphous Tezacaftor,
  • XRD X-ray diffraction

Abstract

The present invention relates to solid forms of Tezacaftor, including its co-crystals, solvates, hydrates and/or polymorphs, processes for their preparation, pharmaceutical compositions containing the same and use of such solid forms of Tezacaftor in the preparation of another form of Tezacaftor such as amorphous form of Tezacaftor. The present invention also provides stable amorphous form of Tezacaftor, its preparation and pharmaceutical composition containing the same.

Description

“SOLID FORMS OF TEZACAFTOR, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THEREOF”
FIELD OF THE INVENTION
The present invention generally relates to solid forms of Tezacaftor, processes for their preparation and pharmaceutical composition containing the same. The present invention also relates to stable amorphous form of Tezacaftor, its preparation and pharmaceutical composition containing the same.
BACKGROUND OF THE INVENTION
Cystic fibrosis is a rare, life-shortening genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which results in construction of a defective CFTR protein. The tunnel-shaped CFTR protein is a chloride channel responsible for controlling the transport of anions and water into and out of epithelial cells. The most frequent mutation, found in about 70% of cystic fibrosis patients, results in deletion of phenylalanine at position 508 of the CFTR amino acid sequence, referred to as F508del-CFTR. This defective protein is unable to fold correctly, hindering its ability to exit the endoplasmic reticulum and migrate to the cell surface. In addition to reduced mobility, the defective protein also has impaired channel gating. The reduced number of CFTR proteins at the cell membrane plus defective gating results in decreased anion secretion and an imbalance of ion and fluid flux. In the lungs, a defective CFTR protein in epithelial cells results in the buildup of thick mucus that can cause lung infections and lung damage.
As a treatment for cystic fibrosis, Vertex Pharmaceuticals has developed two types of drugs to modulate the function of the defective CFTR protein. The drugs termed correctors facilitate transport of protein to the cell surface while those termed potentiators help facilitate chloride trafficking at the cell surface by increasing the time the gate of the protein is open. The two types of drugs can work in tandem to improve overall chloride transport, resulting in healthier lung function.
Symdeko is a combination of tezacaftor and Ivacaftor. Tezacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) corrector while Ivacaftor is a CFTR potentiator. Tezacaftor moves the defective CFTR protein onto the cell surface, while ivacaftor helps to facilitate the opening of the chloride channel on the cell surface to increase chloride transport.
Symdeko is specifically indicated for the treatment of patients with cystic fibrosis (CF) aged 12 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence.
Tezacaftor is chemically designated as (R)-l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(l- (2,3-dihydroxypropyl)-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lH-indol-5- yl)cyclopropanecarboxamide. The structural Formula of Tezacaftor is represented as follows:
Figure imgf000003_0001
Tezacaftor and its process for the preparation were first disclosed in U.S. Patent No. 7,645,789 ("the '789 patent"). The ‘789 patent process involves isolation of tezacaftor as a creamy colored foamy solid after column chromatography using a mixture of 50-100% Ethyl acetate-hexanes. The foamy solid resulted in the ‘789 patent is not well characterized and does not disclose any polymorphic information. On repetition of the ‘789 patent process, the present inventors have found that the resulting Tezacaftor was obtained in an amorphous form.
U.S. Patent No. 8,802,868 (“the 868 patent”) disclosed crystalline Form A of Tezacaftor.
Discovering solid forms such as new polymorphic forms, solvates or co-crystals of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate forms that facilitate conversion to other solid-state forms. New polymorphic forms, solvates or co-crystals of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product.
In view of the foregoing, it would be desirable to provide new solid forms of Tezacaftor such as new co-crystal forms, solvates, hydrates and/or polymorphs thereof. Further, it would be desirable to have reliable processes for producing these solid forms and use of such solid forms in the preparation of another form of Tezacaftor such as amorphous form.
Further, it has been disclosed in the art that amorphous form of tezacaftor was selected as the most appropriate physical form for development due to increased solubility as compared to a crystalline form.
Hence, it is desirable to have amorphous form of tezacaftor with high purity to meet the needs of regulatory agencies, which is commercially feasible and process for its preparation which is highly reproducible in large scale production with greater yield, higher purity. Further, the present invention provides a stable amorphous form of Tezacaftor, wherein the stable amorphous Tezacaftor does not convert to any other solid forms when stored at a temperature of up to about 40°C and at a relative humidity of about 25% to about 75% up to about three months.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides solid forms of Tezacaftor, including its co crystals, solvates, hydrates and/or polymorphs, processes for their preparation, pharmaceutical compositions containing the same and use of such solid forms of Tezacaftor in the preparation of another form of Tezacaftor such as amorphous form of Tezacaftor. The present invention also relates to stable amorphous form of Tezacaftor, its preparation and pharmaceutical composition containing the same.
In accordance with one embodiment, the present invention provides solid forms of Tezacaftor.
In accordance with another embodiment, the present invention provides the solid forms of Tezacaftor may exist in the form of co-crystals, solvates, hydrates, polymorphs, polymorphs of co-crystals or polymorphs of solvates or polymorphs of hydrates.
In accordance with another embodiment, the present invention provides solvates of Tezacaftor.
In accordance with another embodiment, the present invention provides Tezacaftor o- xylene solvate.
In accordance with another embodiment, the present invention provides crystalline Tezacaftor o-xylene solvate.
In accordance with another embodiment, the present invention provides crystalline Tezacaftor o-xylene solvate characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 01.
In accordance with another embodiment, the present invention provides crystalline Tezacaftor o-xylene solvate characterized by a H NMR Spectrum substantially in accordance with Figure 02.
In accordance with another embodiment, the present invention provides crystalline Tezacaftor o-xylene solvate characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 03.
In accordance with another embodiment, the present invention provides crystalline Tezacaftor o-xylene solvate characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 04. In accordance with another embodiment, the present invention provides a process for the preparation of o-xylene solvate of Tezacaftor, comprising: a) dissolving or suspending Tezacaftor in o-xylene solvent; and b) isolating Tezacaftor o-xylene solvate.
In accordance with another embodiment, the present invention provides co-crystals of Tezacaftor.
In accordance with another embodiment, the present invention provides co-crystals of Tezacaftor, wherein the co-crystal former is selected from the group comprising caffeine, piperazine, piperidine, 4-amino pyridine, imidazole, morpholine 4-hydroxy pyridine, paraxanthine, theophylline, theobromine, DDQ, Hexamethylenetetramine, 2 -hydroxy- 1,4- napthoquinone, nicotinamide, isonicotinamide and the like.
In accordance with another embodiment, the present invention provides a process for the preparation of co-crystal of Tezacaftor, comprising: a) providing a solution or suspension comprising Tezacaftor and a co-crystal former in one or more solvents; and b) isolating the co-crystals of Tezacaftor.
In accordance with another embodiment, the present invention provides a process for the preparation of co-crystals of Tezacaftor, comprising: a) providing a solution or suspension comprising Tezacaftor and a co-crystal former in one or more solvents; and b) isolating the co-crystals of Tezacaftor; wherein the co-crystal former is selected from the group comprising caffeine, piperazine, piperidine, 4-amino pyridine, imidazole, morpholine 4-hydroxy pyridine, paraxanthine, theophylline, theobromine, DDQ, Hexamethylenetetramine, 2 -hydroxy- 1,4-napthoquinone, nicotinamide, isonicotinamide and the like.
In accordance with another embodiment, the present invention provides Tezacaftor piperazine co-crystal.
In accordance with another embodiment, the present invention provides a process for the preparation of Tezacaftor piperazine co-crystal, comprising: a) providing a solution or suspension comprising Tezacaftor and piperazine in one or more organic solvents; and b) isolating the Tezacaftor piperazine co-crystal.
In accordance with another embodiment, the present invention provides crystalline Forms of Tezacaftor piperazine co-crystal designated as Form 1, Form 2 or Form 3.
In accordance with another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 1. In accordance with another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 1 characterized by X-Ray powder diffraction (PXRD) pattern substantially in accordance with Figure 05.
In accordance with another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 1 characterized by an X-Ray powder diffraction (XRD) pattern having one or more peaks at about 3.7, 7.2, 10.8, 13.6, 14.4, 17.2, 18.0 and 19.0 ±0.2° 2Q.
In accordance with another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 1 characterized by a 1H NMR Spectrum substantially in accordance with Figure 06.
In accordance with another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 1 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 07.
In accordance with another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 1 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 08.
In accordance with another embodiment, the present invention provides Tezacaftor piperzine co-crystal Form 1 characterized by one or more of the following: a powder X- Ray diffraction (XRD) pattern substantially in accordance with Figure 05; a 1H NMR Spectrum substantially in accordance with Figure 06; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 07 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 08.
In accordance with another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 2.
In accordance with another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 2 characterized by X-Ray powder diffraction (PXRD) pattern substantially in accordance with Figure 09.
In accordance with another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 2 characterized by an X-Ray powder diffraction (XRD) pattern having one or more peaks at about 3.8, 7.7, 12.4,14.2, 18.3 and 19.6 ±0.2° 2Q.
In accordance with another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 2 characterized by a 1H NMR Spectrum substantially in accordance with Figure 10. In accordance with another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 2 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 11.
In accordance with another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 2 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 12.
In accordance with another embodiment, the present invention provides Tezacaftor piperzine co-crystal Form 2 characterized by one or more of the following: a powder X- Ray diffraction (XRD) pattern substantially in accordance with Figure 09; a 1H NMR Spectrum substantially in accordance with Figure 10; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 11 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 12.
In accordance with another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 3.
In accordance with another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 3 characterized by X-Ray powder diffraction (PXRD) pattern substantially in accordance with Figure 13.
In accordance with another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 3 characterized by an X-Ray powder diffraction (XRD) pattern having one or more peaks at about 4.8, 9.2, 13.7, 14.3, 17.9, 19.6, 20.1 and 20.6 ±0.2° 2Q.
In accordance with another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 3 characterized by a 1H NMR Spectrum substantially in accordance with Figure 14.
In accordance with another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 3 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 15.
In accordance with another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 3 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 16.
In accordance with another embodiment, the present invention provides Tezacaftor piperzine co-crystal Form 3 characterized by one or more of the following: a powder X- Ray diffraction (XRD) pattern substantially in accordance with Figure 13; a 1H NMR Spectrum substantially in accordance with Figure 14; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 15 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 16. In accordance with another embodiment, the present invention provides Tezacaftor caffeine co-crystal.
In accordance with another embodiment, the present invention provides a process for the preparation of Tezacaftor caffeine co-crystal, comprising: a) providing a solution or suspension comprising Tezacaftor and caffeine in one or more organic solvents; and b) isolating Tezacaftor caffeine co-crystal.
In accordance with another embodiment, the present invention provides crystalline Form of Tezacaftor caffeine co-crystal.
In accordance with another embodiment, the present invention provides Tezacaftor caffeine co-crystal characterized by X-Ray powder diffraction (PXRD) pattern substantially in accordance with Figure 17.
In accordance with another embodiment, the present invention provides Tezacaftor caffeine co-crystal characterized by a 1H NMR Spectrum substantially in accordance with Figure 18.
In accordance with another embodiment, the present invention provides Tezacaftor caffeine co-crystal characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 19.
In accordance with another embodiment, the present invention provides Tezacaftor caffeine co-crystal characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 20.
In accordance with another embodiment, the present invention provides Tezacaftor caffeine co-crystal characterized by one or more of the following: a powder X-Ray diffraction (XRD) pattern substantially in accordance with Figure 17; a 1H NMR Spectrum substantially in accordance with Figure 18; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 19 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 20.
In accordance with another embodiment, the solid forms of Tezacaftor of the present invention may be used as an intermediate in obtaining high purity Tezacaftor.
In accordance with another embodiment, the solid forms of Tezacaftor of the present invention may be used as an intermediate in obtaining high purity amorphous Tezacaftor.
In accordance with another embodiment, the present invention provides a process for the preparation of amorphous form of Tezacaftor, wherein the process involves Tezacaftor o- xylene solvate of the invention as intermediate. In accordance with another embodiment, the present invention provides a process for the preparation of amorphous Tezacaftor comprising: a) dissolving or suspending Tezacaftor in o-xylene solvent, b) isolating Tezacaftor o-xylene solvate, and c) drying the Tezacaftor o-xylene solvate at about 25°C to about 85°C to obtain amorphous form.
In accordance with another embodiment, the co-crystal forms of Tezacaftor of the present invention may be used as an intermediate in obtaining high purity Tezacaftor.
In accordance with another embodiment, the present invention provides a process for the preparation of Tezacaftor, comprising: a) preparing a co-crystal of Tezacaftor; and b) converting the co-crystal of Tezacaftor in to Tezacaftor.
In accordance with another embodiment, the present invention provides a process for the preparation of Tezacaftor, comprising: a) preparing a co-crystal of Tezacaftor; and b) converting the co-crystal of Tezacaftor in to Tezacaftor; wherein the co-crystal is selected from the group comprising caffeine, piperazine, piperidine, 4-amino pyridine, imidazole, morpholine 4-hydroxy pyridine, paraxanthine, theophylline, theobromine, DDQ, Hexamethylenetetramine, 2 -hydroxy- 1,4-napthoquinone, nicotinamide, isonicotinamide and the like.
In accordance with another embodiment, the present invention provides a process for the preparation of Tezacaftor, comprising: a) dissolving or suspending Tezacaftor co-crystal in a suitable solvent, b) optionally treating the step a) reaction mass with a suitable acid or base, and c) isolating the Tezacaftor.
In accordance with another embodiment, the present invention provides a process for the preparation of amorphous form of Tezacaftor, wherein the process involves one or more of co-crystal forms of Tezacaftor of the invention as an intermediate.
In accordance with another embodiment, the present invention provides a process for the preparation of amorphous Tezacaftor, comprising: a) dissolving or suspending Tezacaftor co-crystal in a suitable solvent, b) optionally treating the step a) reaction mass with a suitable acid or base, and c) isolating the amorphous Tezacaftor.
In accordance with another embodiment, the present invention provides a process for the preparation of amorphous Tezacaftor, comprising: a) dissolving or suspending Tezacaftor co-crystal in a suitable solvent, b) optionally treating the step a) reaction mass with a suitable acid or base, c) concentrating the reaction mass, d) treating the step c) reaction mass with a suitable solvent, e) adding an anti-solvent to the step d) solution or vice-versa, and f) isolating the amorphous Tezacaftor.
In accordance with another embodiment, the present invention provides processes for the preparation of amorphous form of Tezacaftor.
In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of Tezacaftor, comprising: a) providing a solution or suspension of Tezacaftor in a suitable solvent (SI), b) removing the solvent from the step a) reaction mass, c) optionally adding a suitable solvent (S2) to the step b), and d) isolating the amorphous form.
In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of Tezacaftor, comprising: a) providing a solution or suspension of Tezacaftor in a suitable solvent (SI), b) removing the solvent from the step a) reaction mass, c) optionally adding a suitable solvent (S2) to the step b), and d) isolating the amorphous form; wherein the suitable solvent (SI) is selected from the group consisting of ketones, alcohols, esters, nitriles, ethers or mixtures thereof; and the suitable solvent (S2) is selected from the group consisting of water, aliphatic hydrocarbons, alicyclic hydrocarbons and the like or mixtures thereof.
In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of Tezacaftor, comprising: a) providing a solution or suspension of Tezacaftor in one or more solvents; b) adding a suitable anti- solvent to the step a) solution or vice-versa; and c) isolating the amorphous form.
In accordance with another embodiment, the present invention provides a process for preparation of amorphous form of Tezacaftor, comprising: a) providing a solution or suspension of Tezacaftor in one or more solvents; b) adding a suitable anti- solvent to the step a) solution or vice-versa; and c) isolating the amorphous form. wherein the one or more solvents are selected from the group consisting of alcohols, sulfoxides, amides, ketones, esters or mixtures thereof; wherein the suitable anti-solvent is selected from the group consisting of water, aliphatic hydrocarbons, alicyclic hydrocarbons, ethers and the like or mixtures thereof.
In accordance with another embodiment, the present invention provides stable amorphous form of Tezacaftor. In accordance with another embodiment, the present invention provides stable amorphous form of Tezacaftor which remains stable when stored and does not convert to any other solid form when stored at a temperature of up to about 40°C and at a relative humidity of about 25% to about 75% up to about three months or more.
In accordance with another embodiment, the stable amorphous form of Tezacaftor does not convert to any other solid forms when stored at a temperature of up to about 40°C and at a relative humidity of about 25% to about 75% up to about three months.
In accordance with another embodiment, the present invention provides an amorphous form of Tezacaftor having a HPLC purity of about 99.5% or more as determined by high performance liquid chromatography (HPLC).
In accordance with another embodiment, the present invention provides a pharmaceutical composition comprising amorphous form of Tezacaftor prepared by the processes of the present invention and at least one pharmaceutical acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.
Figure 1 is the characteristic powder XRD pattern of Tezacaftor o-xylene solvate.
Figure 2 is the characteristic 1 H NMR Spectrum of Tezacaftor o-xylene solvate.
Figure 3 is the characteristic DSC thermogram of Tezacaftor o-xylene solvate.
Figure 4 is the characteristic TGA curve of Tezacaftor o-xylene solvate.
Figure 5 is the characteristic powder XRD pattern of Tezacaftor piperazine co-crystal Form
1.
Figure 6 is the characteristic 1 H NMR Spectrum of Tezacaftor piperazine co-crystal Form
1.
Figure 7 is the characteristic DSC thermogram of Tezacaftor piperazine co-crystal Form 1. Figure 8 is the characteristic TGA curve of Tezacaftor piperazine co-crystal Form 1.
Figure 9 is the characteristic powder XRD pattern of Tezacaftor piperazine co-crystal Form
2. Figure 10 is the characteristic FI NMR Spectrum of Tezacaftor piperazine co-crystal Form
2.
Figure 11 is the characteristic DSC thermogram of Tezacaftor piperazine co-crystal Form
2.
Figure 12 is the characteristic TGA curve of Tezacaftor piperazine co-crystal Form 2.
Figure 13 is the characteristic powder XRD pattern of Tezacaftor piperazine co-crystal Form 3.
Figure 14 is the characteristic FI NMR Spectrum of Tezacaftor piperazine co-crystal Form
3.
Figure 15 is the characteristic DSC thermogram of Tezacaftor piperazine co-crystal Form
3.
Figure 16 is the characteristic TGA curve of Tezacaftor piperazine co-crystal Form 3.
Figure 17 is the characteristic powder XRD pattern of Tezacaftor caffeine co-crystal.
Figure 18 is the characteristic FI NMR Spectrum of Tezacaftor caffeine co-crystal.
Figure 19 is the characteristic DSC thermogram of Tezacaftor caffeine co-crystal.
Figure 20 is the characteristic TGA curve of Tezacaftor caffeine co-crystal.
Figure 21 is the characteristic powder X-ray diffraction (XRD) pattern of amorphous Tezacaftor prepared according to example 14 of the present invention.
Figure 22 is the characteristic powder X-ray diffraction (XRD) pattern of amorphous Tezacaftor prepared according to example 15 of the present invention.
Figure 23 is the characteristic powder X-ray diffraction (XRD) pattern of amorphous Tezacaftor prepared according to example 21 of the present invention..
Figure 24 is the characteristic powder X-ray diffraction (XRD) pattern of amorphous Tezacaftor prepared according to reference example 1.
Figure 25 is the characteristic powder X-ray diffraction (XRD) pattern of amorphous Tezacaftor, The X-ray powder diffraction data showed absence of crystalline tezacaftor in the amorphous Tezacaftor prepared according to the present invention at 25°C/60%RH. Figure 26 is the characteristic powder X-ray diffraction (XRD) pattern of amorphous Tezacaftor, The X-ray powder diffraction data showed absence of crystalline tezacaftor in the amorphous Tezacaftor prepared according to the present invention at 40°C/60%RH.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides solid forms of Tezacaftor, including its co-crystals, solvates, hydrates and/or polymorphs, processes for their preparation, pharmaceutical compositions containing the same and use of such solid forms of Tezacaftor in the preparation of another form of Tezacaftor such as amorphous form of Tezacaftor. The present invention also relates to stable amorphous form of Tezacaftor, its preparation and pharmaceutical composition containing the same.
The solid forms and amorphous form of Tezacaftor obtained by process of the present invention are characterized by one or more analytical methods such as X-ray powder diffraction (XRPD) pattern, Differential scanning calorimetric (DSC), Thermo gravimetric analysis (TGA) and 1 H NMR Spectrum.
The X-Ray powder diffraction data reported herein is analyzed using Rigaku Miniflex bench top X-ray powder Diffractometer equipped with a Cu-anode ([l] =1.54 Angstrom), X-ray source operated at 40kV, 15 mA. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using aluminium sample holders with the following instrument parameters: measuring range=3-40°29; step size=0.02°; and Time per step=10 deg/min. The X-ray powder diffraction recorded using this method may present an additional non-relevant peak at about 38°2Q which is due to the use of Aluminum sample holder hence the same peak can be disregarded; or by using PANalytical X’per pro X-ray powder Diffractometer equipped with a Cu-anode ([l] =1.54 Angstrom), X-ray source operated at 45kV, 40 mA. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=3-45°20; step size=0.01°; and Time per step=50 sec.
All DSC data reported herein were analyzed in hermitically sealed aluminium pan (with pin hole), with a blank hermitically sealed aluminium pan as the reference and were obtained using DSC (DSC Q200, TA instrumentation, Waters) at a scan rate of 10°C per minute, Temperature range 50 to 280 °C with an Indium standard.
All TGA data reported herein were analyzed using TGA Q500 V 20.13 build 39 in platinum pan with a temperature rise of about 10°C/min in the range of Room temperature to 250°C.
1 H-NMR spectra recorded on a Bruker Avance-II 300 MHz spectrometer at a 1 H Larmor frequency of 300.131 MHz. As used herein in this specification, unless otherwise specified, Tezacaftor, which is used as a starting material is known in the art and can be prepared by the process known in art, for example Tezacaftor may be synthesized as disclosed in U.S. Patent No. 7,645,789. The starting Tezacaftor may be in any form such as crude obtained directly from the reaction mass, crystalline, amorphous or other forms of Tezacaftor, including solid forms described herein the present invention.
In accordance with one embodiment, the present invention provides solid forms of Tezacaftor.
In another embodiment, the present invention provides the solid forms of Tezacaftor may exist in the form of co-crystals, solvates, hydrates, polymorphs, polymorphs of co-crystals or polymorphs of solvates or polymorphs of hydrates.
In another embodiment, the present invention provides solvates of Tezacaftor.
In another embodiment, the present invention provides Tezacaftor o-xylene solvate.
In another embodiment, the present invention provides crystalline Tezacaftor o-xylene solvate.
In another embodiment, the present invention provides crystalline Tezacaftor o-xylene solvate characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 01.
In another embodiment, the present invention provides crystalline Tezacaftor o-xylene solvate characterized by a 11 NMR Spectrum substantially in accordance with Figure 02.
In another embodiment, the present invention provides crystalline Tezacaftor o-xylene solvate characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 03.
In another embodiment, the present invention provides crystalline Tezacaftor o-xylene solvate characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 04.
In another embodiment, the present invention provides crystalline Tezacaftor o-xylene solvate characterized by one or more of the following: a powder X-Ray diffraction (XRD) pattern substantially in accordance with Figure 01; a 1H NMR Spectrum substantially in accordance with Figure 02; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 03 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 04.
In another embodiment, the present invention provides a process for the preparation of Tezacaftor o-xylene solvate, comprising: a) dissolving or suspending Tezacaftor in o-xylene solvent; and b) isolating Tezacaftor o-xylene solvate.
Step a) of the forgoing process involves the dissolution of Tezacaftor in o-xylene solvent. Optionally the reaction mixture may be heated to complete dissolution of the contents in o- xylene solvent. Typically, if stirring is involved, the temperature during stirring can range from about 15°C to about 35°C; preferably, the contents were stirred for about 3 hrs to about 5 hrs at a temperature of about 20°C to about 30°C.
The isolation of Tezacaftor o-xylene solvate may be carried out by any conventional techniques known in the art for example filtration. The resultant Tezacaftor o-xylene solvate may optionally be further dried for about 2 hours to 25 hours at a temperature ranging from about 20°C to about 40°C. Drying can be suitably carried out in a vacuum tray dryer, vacuum oven, air oven, Rotocon Vacuum Dryer, Vacuum Paddle Dryer fluidized bed drier, spin flash dryer, flash dryer and the like.
In another embodiment, the present invention provides co-crystals of Tezacaftor.
In another embodiment, the present invention provides co-crystals of Tezacaftor; wherein the co-crystal is former selected from the group comprising caffeine, piperazine, piperidine, 4-amino pyridine, imidazole, morpholine 4-hydroxy pyridine, paraxanthine, theophylline, theobromine, DDQ, Hexamethylenetetramine, 2-hydroxy- 1,4-napthoquinone, nicotinamide or isonicotinamide.
The ratio of Tezacaftor to co-crystals former may be stoichiometric or non-stoichiometric according to the present invention. For example, the ratio of the compound to co-crystals former is about 1:1, 1.5:1, 1:1.5, 2:1 and 1:2 ratios is acceptable.
In another embodiment, the present invention provides a process for the preparation of co crystals of Tezacaftor, comprising: a) providing a solution or suspension comprising Tezacaftor and a co-crystal former in one or more organic solvents; and b) isolating the co-crystals of Tezacaftor.
The step a) of aforementioned process involves, providing a solution or suspension includes any form of tezacaftor that may be mixed with one or more organic solvents and co-crystal former or includes any form of tezacaftor that may be combined with one or more organic solvents and then the co-crystal former may be mixed with the resulting solution or slurry. Alternatively, the mixture may be formed by adding tezacaftor and co crystals former at the same time in to one or more organic solvents.
Examples of one or more organic solvents of step a) includes, but are not limited to esters such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, t- butyl acetate and the like; alcohols such as methanol, ethanol, isopropanol, n-propanol, n- butanol, isobutanol and the like; ethers such as tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like, hydrocarbon solvents such as hexane, n- heptane, cyclohexane and the like, halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, chloroform and the like, nitriles such as acetonitrile, propionitrile and the like; water or mixtures thereof; preferably the one or more organic solvent is ethyl acetate, isopropyl acetate, t-butyl acetate or mixtures thereof.
The temperature suitable for step a) reaction depends on the solvent used and the amount of tezacaftor and the amount of co-crystal former used in the reaction mass. Typically, the suitable temperature is from about 20°C to about reflux temperature of the solvent used; preferably the reaction temperature is about 20°C to about 80°C.
The co-crystal former of step a) includes, but is not limited to caffeine, piperazine, piperidine, 4-amino pyridine, imidazole, morpholine 4-hydroxy pyridine, paraxanthine, theophylline, theobromine, DDQ, Hexamethylenetetramine, 2-hydroxy- 1,4-napthoquinone, nicotinamide or isonicotinamide; preferably the co- crystal former is caffeine or piperazine.
The step b) of aforementioned process for the isolation of co-crystals of tezacaftor may be carried out by any conventional technique known in the art, for example, by filtration. Alternatively the isolation may be carried out by cooling the reaction mass to a suitable temperature, optionally seeding and filtering the precipitated product. The suitable temperature for cooling is about 0°C to about 30° C; preferably the cooling temperature is room temperature.
The resultant co-crystals of Tezacaftor 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 drying can be carried out at a temperature ranging from about 20°C to about 70°C; preferably drying can be carried out at a temperature ranging from about 20°C-60°C for about 15 hrs to about 25 hrs.
The resultant co-crystals of Tezacaftor may optionally be further purified in a suitable organic solvent.
In another embodiment, the present invention provides co-crystals of Tezacaftor having a chemical purity greater than or equal to about 97%, as measured by HPLC, preferably about 98% as measured by HPLC, and more preferably about 99.5%, as measured by HPLC.
In another embodiment, the co-crystals of the present invention are obtained in substantially pure form.
Furthermore, some of the co-crystals of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the co- crystals of the present invention forms solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
In another embodiment, the present invention provides Tezacaftor piperazine co-crystal.
In another embodiment, the present invention provides a process for the preparation of Tezacaftor piperazine co-crystal, comprising: a) providing a solution or suspension comprising Tezacaftor and piperazine in one or more organic solvents; and b) isolating the Tezacaftor piperazine co-crystal.
Examples of one or more organic solvents of step a) of piperazine co -crystal formation and its procedure are same as to those described just as above for tezacaftor co-crystal.
The step b) of aforementioned process for the isolation of piperazine co-crystal tezacaftor may be carried out by any conventional technique known in the art, for example, by filtration or alternatively the isolation may be carried out by cooling the reaction mass to a suitable temperature preferably to room temperature, optionally seeding, filtering the precipitated product and the resultant piperazin co-crystals of Tezacaftor may optionally be further dried.
In another embodiment, tezacaftor piperazine co-crystals recovered using the process as described just above is substantially in crystalline form.
In another embodiment, isolation of piperazine co-crystal tezacaftor may be carried out by filtration to form crystalline Tezacaftor piperazine co-crystal Form 1.
In another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 1.
In another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 1 characterized by X-Ray powder diffraction (PXRD) pattern substantially in accordance with Figure 05.
In another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 1 characterized by an X-Ray powder diffraction (XRD) pattern having one or more peaks at about 3.7, 7.2, 10.8, 13.6, 14.4, 17.2, 18.0 and 19.0 ±0.2° 2Q.
In another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 1 characterized by a 1H NMR Spectrum substantially in accordance with Figure 06. In another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 1 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 07.
In another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 1 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 08.
In another embodiment, the present invention provides Tezacaftor piperzine co-crystal Form 1 characterized by one or more of the following: a powder X-Ray diffraction (XRD) pattern substantially in accordance with Figure 05; a 1H NMR Spectrum substantially in accordance with Figure 06; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 07 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 08.
In another embodiment, the isolation of piperazine co-crystal tezacaftor of step b) may alternatively be carried out by cooling the reaction mass to a suitable temperature preferably to room temperature, optionally seeding and is further treated with aliphatic hydrocarbon solvents selected from n-hexane, n-heptane, cyclohexane, cycloheptane and the like; preferably from n-heptane to form crystalline Tezacaftor piperazine co-crystal Form 2.
In another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 2.
In another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 2 characterized by X-Ray powder diffraction (PXRD) pattern substantially in accordance with Figure 09.
In another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 2 characterized by an X-Ray powder diffraction (XRD) pattern having one or more peaks at about 3.8, 7.7, 12.4, 14.2, 18.3 and 19.6 ±0.2° 2Q.
In another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 2 characterized by a 1H NMR Spectrum substantially in accordance with Figure 10.
In another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 2 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 11.
In another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 2 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 12. In another embodiment, the present invention provides Tezacaftor piperzine co-crystal Form 2 characterized by one or more of the following: a powder X-Ray diffraction (XRD) pattern substantially in accordance with Figure 09; a 1H NMR Spectrum substantially in accordance with Figure 10; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 11 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 12.
In another embodiment, Tezacaftor piperazine co-crystal Form 2 is dried at 45-55°C to obtain Tezacaftor piperazine co-crystal Form 3.
In another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 3.
In another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 3 characterized by X-Ray powder diffraction (PXRD) pattern substantially in accordance with Figure 13.
In another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 3 characterized by an X-Ray powder diffraction (XRD) pattern having one or more peaks at about 4.8, 9.2, 13.7, 14.3, 17.9, 19.6, 20.1 and 20.6 ±0.2° 2Q.
In another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 3 characterized by a 1H NMR Spectrum substantially in accordance with Figure 14.
In another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 3 characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 15.
In another embodiment, the present invention provides Tezacaftor piperazine co-crystal Form 3 characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 16.
In another embodiment, the present invention provides Tezacaftor piperzine co-crystal Form 3 characterized by one or more of the following: a powder X-Ray diffraction (XRD) pattern substantially in accordance with Figure 13; a 1H NMR Spectrum substantially in accordance with Figure 14; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 15 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 16.
In another embodiment, the present invention provides Tezacaftor caffeine co-crystal.
In another embodiment, the present invention provides a process for the preparation of Tezacaftor caffeine co-crystal, comprising: a) providing a solution or suspension comprising tezacaftor and caffeine in one or more organic solvents; and b) isolating tezacaftor caffeine co-crystal.
Examples of one or more organic solvents of step a) of caffeine co-crystal formation and its procedure and step b) isolation procedure of tezacaftor caffeine co-crystal are same as to those described just as above for tezacaftor co-crystal.
The resultant tezacaftor caffeine co-crystal may optionally be further purified in a suitable organic solvent.
In another embodiment, tezacaftor caffeine co-crystal recovered using the process as described just above is substantially a crystalline form.
In another embodiment, the present invention provides tezacaftor caffeine co-crystal characterized by X-Ray powder diffraction (PXRD) pattern substantially in accordance with Figure 17.
In another embodiment, the present invention provides tezacaftor caffeine co-crystal characterized by an X-Ray powder diffraction (XRD) pattern having one or more peaks at about 7.2, 8.6, 10.3, 12.0, 12.5, 14.5, 15.9 and 19.0 ±0.2° 20.
In another embodiment, the present invention provides tezacaftor caffeine co-crystal characterized by a 1H NMR Spectrum substantially in accordance with Figure 18.
In another embodiment, the present invention provides tezacaftor caffeine co-crystal characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 19.
In another embodiment, the present invention provides tezacaftor caffeine co-crystal characterized by a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 20.
In another embodiment, the present invention provides tezacaftor caffeine co-crystal characterized by one or more of the following: a powder X-Ray diffraction (XRD) pattern substantially in accordance with Figure 17; a 1H NMR Spectrum substantially in accordance with Figure 18; a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 19 and/or a thermogravimetric analysis (TGA) curve substantially in accordance with Figure 20.
In another embodiment, the solid forms of Tezacaftor of the present invention may be used as an intermediate in obtaining high purity Tezacaftor. In another embodiment, the solid forms of Tezacaftor of the present invention may be used as an intermediate in obtaining high purity amorphous Tezacaftor.
In another embodiment, the present invention provides a process for the preparation of amorphous form of Tezacaftor, wherein the process involves Tezacaftor o-xylene solvate of the invention as intermediate.
In another embodiment, the present invention provides a process for the preparation of amorphous Tezacaftor comprising: a) dissolving or suspending Tezacaftor in o-xylene solvent, b) isolating Tezacaftor o-xylene solvate, and c) drying the Tezacaftor o-xylene solvate at about 25°C to about 85°C to obtain amorphous form.
Step a) of the forgoing process involves the dissolution of Tezacaftor in o-xylene solvent. Optionally the reaction mixture may be heated to complete dissolution of the contents in o- xylene solvent. Typically, if stirring is involved, the temperature during stirring can range from about 15°C to about 35°C; preferably, the contents were stirred for about 3 hrs to about 5 hrs at a temperature of about 20°C to about 30°C.
The isolation of Tezacaftor o-xylene solvate may be carried out by any conventional techniques known in the art for example filtration. The resultant Tezacaftor o-xylene solvate may optionally be further dried for about 2 hours to 25 hours at a temperature ranging from about 25°C to about 40°C. Drying can be suitably carried out in a vacuum tray dryer, vacuum oven, air oven, Rotocon Vacuum Dryer, Vacuum Paddle Dryer fluidized bed drier, spin flash dryer, flash dryer and the like.
Tezacaftor o-xylene solvate obtained as above further drying at about 25°C to about 85°C under vacuum for a period of about 2 hrs to about 24 hrs to obtain amorphous form; typically drying of Tezacaftor o-xylene solvate was carried out at about 45 °C to about 60°C for about 14 hrs to about 18 hrs.
In another embodiment, the co-crystals of tezacaftor of the present invention may be used as an intermediate in obtaining high purity tezacaftor.
In another embodiment, the present invention provides a process for the preparation of tezacaftor, comprising: a) preparing a co-crystal of tezacaftor; and b) converting the co-crystal of Tezacaftor in to Tezacaftor.
The reaction procedures for the preparation of tezacaftor co-crystals are same as to those described just as above. Further, conversion process of tezacaftor co-crystal into tezacaftor by breaking co-crystals followed by converting into tezacaftor either by solvent evaporation method or by solvent- antisolvent method which is same as to the procedures described just below.
In another embodiment, the present invention provides a process for the preparation of amorphous form of Tezacaftor, wherein the process involves one or more of co-crystal forms of Tezacaftor of the invention as an intermediate.
In another embodiment, the present invention provides a process for the preparation of amorphous tezacaftor, comprising: a) dissolving or suspending tezacaftor co-crystal in a suitable solvent, b) optionally treating the step a) reaction mass with a suitable acid or base, and c) isolating the amorphous tezacaftor.
The co-crystals of tezacaftor used in step a) includes but are not limited to caffeine, piperazine, piperidine, 4-amino pyridine, imidazole, morpholine 4-hydroxy pyridine, paraxanthine, theophylline, theobromine, DDQ, Hexamethylenetetramine, 2 -hydroxy- 1,4- napthoquinone, nicotinamide or isonicotinamide; preferably piperazine or caffeine co crystals of Tezacaftor are dissolved or suspended in a suitable solvent. The temperature suitable for dissolving or suspending the tezacaftor co-crystal in the suitable organic solvents depends on the solvent and the amount of tezacaftor and the amount of co-crystal used in the reaction mass. Typically, the suitable temperature is from about 20°C to about reflux temperature of the solvent used; preferably the reaction temperature is about 20°C to about 30°C.
The suitable solvent used herein for dissolution of tezacaftor co-crystal is selected from water or from a mixture of water and water immiscible organic solvent; wherein water immiscible organic solvent is selected from esters such as methyl acetate, ethyl acetate, isopropyl acetate n-propyl acetate, n-butyl acetate, t-butyl acetate, ethyl formate and the like; hydrocarbons such as hexane, heptane, cyclohexane and the like; ethers such as tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; chlorinated solvent such as dichloromethane, dichloroethane, chloroform and the like or mixtures thereof; preferably the suitable solvent is water, ethylformate or mixtures thereof.
Optionally the step b) of the foregoing process involves treating the step a) reaction mass with a suitable acid or a base.
The suitable acid used herein are selected from the group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, formic acid, sulphonic acid, benzene sulphonic or mixtures thereof. The base used herein are selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium, carbonate, lithium carbonate, cesium carbonate or mixtures thereof.
The sequence of addition of the suitable acid or base is not particularly critical and the addition can be carried out in any known manner, for example, the suitable base or acid can be added into co-crystal of tezacaftor or co-crystal of tezacaftor may be added to the suitable base or acid.
Step c) of the aforementioned process involves the isolation of amorphous form of Tezacaftor is carried out by removal of solvent from the solution by, for example, substantially complete evaporation of the solvent, concentrating the solution, distillation or distillation under vacuum, cooling and filtering the solid under inert atmosphere. Evaporation can be achieved at sub-zero temperatures by the lyophilisation or freeze drying technique, a rotational drying (such as with the Buchi Rotavapor), spray drying, fluid bed drying, flash drying, spin flash drying and thin-film drying; preferably, the solvent may be removed completely by distillation under vacuum at a temperature of about 25°C to about 60°C.
The amorphous form of Tezacaftor obtained by the above process may be dried for about 2 hours to 25 hours at a temperature of 40-70°C; preferably dried at a temperature of about 45°C to about 55°C for about 14-18 hrs. Drying can be suitably carried out in a vacuum tray dryer, vacuum oven, air oven, Rotocon Vacuum Dryer, Vacuum Paddle Dryer fluidized bed drier, spin flash dryer, flash dryer and the like.
Tezacaftor recovered using the processes of the present invention is in the form of substantially pure amorphous form.
In another embodiment, the present invention provides a process for the preparation of amorphous tezacaftor, comprising: a) dissolving or suspending tezacaftor co-crystals in a suitable solvent, b) optionally treating the step a) reaction mass with a suitable acid or base, c) concentrating the reaction mass, d) treating the step c) reaction mass with a suitable solvent, e) adding an anti-solvent to the step d) solution or vice-versa, and f) isolating the amorphous Tezacaftor.
Step a) to b) of the aforementioned process is same as the process as described in the previous embodiment.
Step c) of the aforementioned process involves the concentration of product containing organic layer at a temperature of about 30-70°C; preferably at a temperature of about 40- 50°C. Step d) of the aforementioned process involves dissolution of step c) reaction mass in a suitable solvent, Examples of suitable solvent includes but are not limited to alcohols such as methanol, ethanol, propanol, isopropanol, butanol and the like; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; nitriels such as acetonitrile, propionitrile and the like; sulfoxides such as dimethyl sulfoxide, diethyl sulfoxide and the like; amides such as dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like or mixtures thereof; preferably the suitable solvent is methanol, dimethyl sulfoxide or mixtures thereof.
The dissolution temperatures may range from about 20°C to about reflux temperature of the solvent, depending on the solvent used for dissolution; preferably the dissolution temperatures may range from about 45 °C to about 55°C. The resulting solution was further cooled to room temperature and may optionally be treated with carbon and the solution obtained above may optionally filtered to remove insoluble particles.
Step e) of the aforementioned process involves precipitation of tezacaftor by either addition of suitable antisolvent to the step d) solution or addition of step d) solution into a suitable antisolvent.
The suitable anti-solvent include, but are not limited to water, aliphatic hydrocarbons, alicyclic hydrocarbons, ethers and the like or mixtures thereof. The aliphatic hydrocarbons include, but are not limited to propane, hexane, heptane and the like; alicyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; water or mixtures thereof; preferably the suitable anti- solvent is water.
The addition of anti-solvent is carried out at a temperature of less than about 15°C; preferably at a temperature of about 0°C to about 10°C. Then the resultant mass is stirred for sufficient period of about 30 min to about 5 hours.
Step f) of the aforementioned process involves isolation of the amorphous for of Tezacaftor by any conventional technique known in the art, 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 drying can be carried out at a temperature ranging from about 25°C to about 65 °C for a time period ranging from about 5 hour to about 20 hours.
In another embodiment, the present invention provides processes for the preparation of amorphous form of Tezacaftor. In another embodiment, the present invention provides a process for preparation of amorphous form of Tezacaftor, comprising: a) providing a solution or suspension of Tezacaftor in a suitable solvent (SI), b) removing the solvent from the step a) reaction mass, c) optionally adding a suitable solvent (S2) to the step b), and d) isolating the amorphous form.
The step a) of aforementioned process involves, providing a solution or suspension of Tezacaftor in a suitable solvent (SI). The suitable solvent (SI) include, but are not limited to ketones, alcohols, esters, nitriles, ethers and the like or mixtures thereof.
The ketones include, but are not limited to acetone, methylethylketone, methylisobutylketone and the like; alcohols include, but are not limited to methanol, ethanol, propanol, isopropanol, butanol and the like; esters include, but are not limited to methyl acetate, ethyl acetate, ethyl formate, isopropyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like or mixtures thereof; preferably the suitable solvent (SI) is ethylacetate, methanol, acetone, ethyl formate or mixtures thereof.
In order to form a solution of step a), the contents may be stirred for sufficient period of time at a suitable temperature of at about 25 °C to about reflux. Typically, the contents were stirred for about 10 min to about 2 hrs at a temperature of 45-65°C for complete dissolution.
Step b) of the aforementioned process involves removal of solvent to obtain amorphous Tezacaftor residue, wherein the removal of solvent includes evaporation, distillation or distillation under vacuum. Evaporation can be achieved at sub-zero temperatures by the lyophilisation or freeze-drying technique, a rotational drying (such as with the Buchi Rotavapor), spray drying, fluid bed drying, flash drying, spin flash drying and thin-film drying; preferably, the solvent may be removed completely by distillation under vacuum at a temperature of about 40°C to about 70°C.
The amorphous tezacaftor residue so obtained may optionally recovered by using a suitable solvent (S2) at a temperature of about 10°C to about 40°C. Preferably, the addition of suitable solvent (S2) is carriedout at a temperature of 10-25°C. The suitable solvent (S2) include, but are not limited to water, aliphatic hydrocarbons, alicyclic hydrocarbons and the like or mixtures thereof. The 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; water and the like or mixture thereof; preferably the suitable solvent (S2) is cyclohexane. The resultant amorphous form of Tezacaftor can be isolated by any conventional techniques known in the art for example filtration. Typically, if stirring is involved, the temperature during stirring can range from about 0°C to about 30°C.
The amorphous form of Tezacaftor obtained by the above process may be dried for about 2 hrs to 25 hrs; preferably dried at a temperature of 45-65°C for about 12 hrs to 18 hrs; Drying can be suitably carried out in a vacuum tray dryer, vacuum oven, air oven, Rotocon Vacuum Dryer, Vacuum Paddle Dryer fluidized bed drier, spin flash dryer, flash dryer and the like.
In another embodiment, the present invention provides a process for preparation of amorphous form of Tezacaftor, comprising: a) providing a solution of Tezacaftor in one or more solvents; b) adding a suitable anti- solvent to the step a) solution or vice-versa; and c) isolating the amorphous form.
The step a) of the aforementioned process involves, dissolving tezacaftor in one or more solvents at a suitable temperature. Examples of one or more organic solvents of step a) includes but are not limited to alcohols such as methanol, ethanol, propanol, isopropanol, butanol and the like; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; nitriels such as acetonitrile, propionitrile and the like; sulfoxides such as dimethyl sulfoxide, diethyl sulfoxide and the like; amides such as dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like or mixtures thereof; preferably the one or more solvent is methanol, dimethyl sulfoxide or mixtures thereof.
The suitable temperature for step a) reaction is about 20°C to about 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; preferably the step a) reaction is carried out at temperature of about 50°C to about 75°C.
Step b) of the aforementioned process involves precipitation of Tezacaftor by either addition of suitable antisolvent to the step a) solution or addition of step a) solution into a suitable antisolvent.
The addition of suitable anti-solvent is carried out at a temperature of less than about 15°C; preferably at a temperature of about 0°C to about 10°C. Then the resultant mass is stirred for sufficient period of about 30 min to about 5 hours.
The suitable anti-solvent include, but are not limited to water, aliphatic hydrocarbons, alicyclic hydrocarbons, ethers and the like or mixtures thereof. The aliphatic hydrocarbons include, but are not limited to propane, hexane, heptane and the like; alicyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; water or mixtures thereof; preferably the suitable antisolvent is water.
The isolation of amorphous form of Tezacaftor is carried out by any conventional technique known in the art, for example, filtration.
The resultant wet product may optionally be further dried for about 2 hours to 20 hours at a temperature of about 20°C to about 60°C. 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 Tezacaftor recovered using the processes of the present invention are in the form of substantially pure amorphous form.
The amorphous form of tezacaftor obtained according to the present invention is stable during storage. This property is important and advantageous for the desired use of tezacaftor in pharmaceutical product formulations.
In another embodiment, the present invention provides stable amorphous form of Tezacaftor.
In another embodiment, the present invention provides stable amorphous form of Tezacaftor which remains stable when stored and does not convert to any other solid form when stored at a temperature of up to about 40°C and at a relative humidity of about 25% to about 75% up to about three months or more.
The amorphous form of Tezacaftor is stable when subjected to the real time and accelerated conditions, wherein the amorphous form of Tezacaftor is stored at 25±2°C/60±5% RH for a period three months and at 40±2°C/75±5% RH for a period of three months.
The term “stable amorphous form of Tezacaftor refers to” amorphous form of Tezacaftor in which the PXRD pattern of the amorphous form do not change when stored at at a temperature of up to about 40°C and at a relative humidity of about 25% to about 75% up to about three months or more.
In another embodiment, the present invention provides a method of packing amorphous form of Tezacaftor, comprising: placing amorphous form of Tezacaftor in LDPE bag under nitrogen atmosphere; placing the product containing Low-density polyethylene (LDPE) bag in a second LDPE bag under nitrogen atmosphere; keeping the silica gel packet between two LDPE bags and sealing; placing the second sealed bag in a triple laminated bag and sealing. The amorphous form of Tezacaftor obtained by the processes of the invention is packed according to the above embodiment and stored for stability. A period of up to 3 months at real and accelerated conditions, the amorphous character was retained and does not convert to any other solid form when stored at a temperature of up to about 40°C and at a relative humidity of about 25% to about 75%.
The present invention further provides an amorphous form of tezacaftor, having a chemical purity of 98% or more as measure by HPLC, preferably 99% or more, more preferably 99.8% or more. Moreover, the amorphous form of tezacaftor may be obtained substantially free of any unknown impurity, e.g., a content of less than about 0.1% of impurities.
In another embodiment, the present invention provide amorphous form of tezacaftor obtained by the above process, as analyzed using high performance liquid chromatography (“HPLC”) with the conditions are tabulated below:
Figure imgf000028_0001
Gradient Program:
Figure imgf000028_0002
The present invention also encompasses a pharmaceutical composition comprising a therapeutically effective amount of amorphous form of tezacaftor prepared by the processes of the present invention with at least one pharmaceutically acceptable carrier or other excipients.
Amorphous Tezacaftor 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. In these compositions, 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. As 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.
Optionally, the pharmaceutical compositions of the invention may be combination products comprising one or more additional pharmaceutically active components in addition to Tezacaftor.
Pharmaceutically acceptable excipients 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 cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethyl celluloses, methyl celluloses, various grades of methyl methacrylates, and waxes. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, film coating agents, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, and antioxidants.
EXAMPLES
The following non-limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.
REFERENCE EXAMPLE 1:
Preparation of amorphous form of Tezacaftor The following example was carried out following the teaching of example in col 468 of US 7,645,789 (10% hexane in ethyl acetate)
Tezacaftor (3.02 gms) was dissolved in a mixture of 10% hexane in ethyl acetate (70 mL) at 60°C. The solvent was distilled completely under vacuum at 55-65°C and the obtained solids were dried at 50-60°C under vacuum for 13 hrs. Yield: 2.82 g.
Amorphous Form obtained according to the reference examples was analyzed by PXRD and is represented according to Fig. 24.
REFERENCE EXAMPLE 2:
Preparation of amorphous form of Tezacaftor
The following example was carried out following the teaching of example in col 468 of US 7,645, 789 (100% ethyl acetate).
Tezacaftor (6.02 gms) was dissolved in a mixture of 100% in ethyl acetate (120 mL) at 60°C. The solvent was distilled completely under vacuum at 65-75°C and the obtained solids were dried at 50-60°C under vacuum for 13 hrs. Yield: 5.89 g.
EXAMPLE 1: Preparation of o-xylene solvate of Tezacaftor
Amorphous Tezacaftor (3.5 g) and o-xylene (10.5 mL) were added in to a round bottom flask at 22-26°C and stirred for 5 mins at same temperature. O-xylene (9 mL) was added to the resulting reaction mixture at 22-26°C. The resulting reaction mixture was stirred for 4 hrs at 22-26 °C, filtered the solids, washed with o-xylene (9 mL) and suck dried for 15 mins. The resulting solid was dried under vacuum for 13 hrs at room temperature to obtain title compound. Yield:535.3 mg. The PXRD is set forth in Figure 01, The 1 H NMR is set forth in Figure 02, The DSC thermogram is set forth in Figure 03, The TGA is set forth in Figure 04.
EXAMPLE 2: Preparation of o-xylene solvate of Tezacaftor
Amorphous Tezacaftor (400.1 mg) and o-xylene (1.6 mL) were added in to a round bottom flask at 22-26°C and stirred for 5 mins at same temperature. O-xylene (0.4 mL) was added to the resulting reaction mixture at 22-26°C. The resulting reaction mixture was stirred for 4 hrs at 22-26 °C, filtered the solids, washed with o-xylene (0.4 mL) and suck dried for 15 mins. The resulting solid was dried under vacuum for 16 hrs at room temperature to obtain title compound. Yield: 120.2 mg.
EXAMPLE 3: Preparation of o-xylene solvate of Tezacaftor Amorphous Tezacaftor (400.3 mg) and o -xylene (1.6 mL) were added in to a round bottom flask at 22-26°C and stirred for 5 mins at same temperature. O-xylene (0.4 mL) was added to the resulting reaction mixture at 22-26°C. The resulting reaction mixture was stirred for 4 hrs at 22-26 °C, filtered the solids, washed with o-xylene (0.4 mL) and suck dried for 15 mins. The resulting solid was dried under vacuum for 16 hrs at room temperature to obtain title compound. Yield: 135.1 mg.
EXAMPLE 4: Preparation of piperazine co-crystal of tezacaftor
Tezacaftor (500 mg) and piperazine (166 mg) were added in to a round bottom flask at 22- 26°C. Ethyl acetate (0.125 mL) & t-butyl acetate (1.375 mL) were added to the resulting reaction mixture at 22-26°C. The temperature of the reaction mixture was raised to 68- 72°C and stirred for 10 mins at same temperature. The resulting solution was cooled to 22- 26°C, seed crystals of Tezacaftor piperazine co-crystal was added and stirred for 2 hrs at 22-26°C. The resulting solid was filtered, washed with t-butyl acetate (1 mL) and suck dried for 10 mins. The resulting solid was dried under vacuum for 16 hrs at room temperature to obtain title compound. Yield: 507 mg. The PXRD is set forth in Figure 05, The 14 NMR is set forth in Figure 06, The DSC thermogram is set forth in Figure 07, The TGA is set forth in Figure 08.
EXAMPLE 5: Preparation of piperazine co-crystal of tezacaftor
Tezacaftor (200 mg) and piperazine (66 mg) were added in to a round bottom flask at 22- 26°C. t-butyl acetate (3 mL) was added to the resulting reaction mixture at 22-26°C. The resulting reaction mixture was stirred for 20 hrs at 22-26 °C, filtered the solids, washed with t-butyl acetate (0.5 mL) and suck dried for 10 mins. The resulting solid was dried under vacuum for 20 hrs at room temperature to obtain title compound. Yield: 222 mg.
EXAMPLE 6: Preparation of piperazine co-crystal of tezacaftor
Tezacaftor (1.5 gm) and piperazine (496 mg) were added in to a round bottom flask at 22- 26°C. Ethyl acetate (0.375 mL) and t-butyl acetate (4.125 mL) were added to the resulting reaction mixture at 22-26°C. The temperature of the reaction mixture was raised to 68- 72°C and stirred for 10 mins at same temperature. The resulting solution was cooled to 22- 26°C, seed crystals of Tezacaftor piperazine co-crystal was added and stirred for 2 hrs at 22-26°C. The resulting solid was filtered, washed with t-butyl acetate (3 mL) and suck dried for 10 mins. The resulting solid was dried under vacuum for 16 hrs at room temperature to obtain title compound. Yield: 1.76 gm.
EXAMPLE 7: Preparation of piperazine co-crystal of tezacaftor
Tezacaftor (2.02 gm) and piperazine (662.3 mg) were added in to a round bottom flask at 22-26°C. Ethyl acetate (6 mL) was added to the resulting reaction mixture at 22-26°C. The temperature of the reaction mixture was raised to 68-72°C, stirred for 10 mins at same temperature and then cooled to 22-26°C. Seed crystals of Tezacaftor piperazine co-crystal was added to the resulting reaction mass and then n-heptane was added and stirred for 2 hrs at 22-26°C. The resulting solid was filtered, washed with n-heptane (6 mL) and suck dried for 10 mins. The resulting solid was dried under vacuum for 17 hrs at room temperature to obtain title compound. Yield: 2.60 gm. The PXRD is set forth in Figure 09, The 1 H NMR is set forth in Figure 10, The DSC thermogram is set forth in Figure 11, The TGA is set forth in Figure 12.
EXAMPLE 8: Preparation of piperazine co-crystal of tezacaftor
Tezacaftor piperazine co-crystal (500.5 mg) obtained from ex-7 was further dried at a temperature of 45-55°C to obtain title compound. Yield: 445.3 gm. The PXRD is set forth in Figure 13, The 1 H NMR is set forth in Figure 14, The DSC thermogram is set forth in Figure 15, The TGA is set forth in Figure 16.
EXAMPLE 9: Preparation of caffeine co-crystal of tezacaftor
Tezacaftor (500 mg), caffeine (280 mg) and ethyl acetate (20 mL) were added in to a round bottom flask at 70°C. The resulting solution was cooled to RT, stirred for 2 hrs at 22-26 °C, filtered the solids and suck dried for 10 mins. The resulting solid was dried under vacuum for 16 hrs at room temperature to obtain title compound. Yield: 264 mg. The PXRD is set forth in Figure 17, The 1 H NMR is set forth in Figure 18, The DSC thermogram is set forth in Figure 19, The TGA is set forth in Figure 20.
EXAMPLE 10: Preparation of caffeine co-crystal of tezacaftor
Tezacaftor (100 mg) and caffeine (75 mg) were added in to a round bottom flask at 22- 26°C. t-butyl acetate (1.5 mL) were added to the resulting reaction mixture at 22-26°C. The resulting reaction mixture was stirred for 16 hrs at 22-26 °C, filtered the solids, washed with t-butyl acetate (0.5 mL) and suck dried for 10 mins. The resulting solid was dried under vacuum for 2 hrs at room temperature and then at 51-55 °C for 16 hrs to obtain title compound. Yield: 128 mg.
EXAMPLE 11: Preparation of caffeine co-crystal of tezacaftor
Tezacaftor (500 mg), caffeine (187 mg) and ethyl acetate (20 mL) were added in to a round bottom flask at 70°C. The resulting solution was cooled to RT, seeded with Tezacaftor caffeine co-crystal. The resulting reaction mixture was stirred for 24 hrs at 22-26 °C, filtered the solids and suck dried for 10 mins. The resulting solid was dried under vacuum for 20 hrs at room temperature to obtain title compound. Yield: 148 mg.
EXAMPLE 12: Preparation of caffeine co-crystal of tezacaftor Tezacaftor (500 mg), caffeine (373 mg) and ethyl acetate (20 mL) were added in to a round bottom flask at 70°C. The resulting solution was cooled to RT, stirred for 2 hrs at 22-26 °C, filtered the solids and suck dried for 10 mins. The resulting solid was dried under vacuum for 16 hrs at room temperature to obtain title compound. Yield: 423 mg.
EXAMPLE 13: Preparation of amorphous form of Tezacaftor
Amorphous Tezacaftor (400.3 mg) and o-xylene (1.6 mL) were added in to a round bottom flask at 22-26°C and stirred for 5 mins at same temperature. O-xylene (0.4 mL) was added to the resulting reaction mixture at 22-26°C. The resulting reaction mixture was stirred for 4 hrs at 22-26 °C, filtered the solids, washed with o-xylene (0.4 mL) and suck dried for 15 mins. The resulting solid was dried under vacuum for 4 hrs at room temperature and further dried at 50-55°C for 16 hrs to obtain title compound. Yield: 122.4 mg.
EXAMPLE 14: Preparation of amorphous form of Tezacaftor
Tezacaftor (2 gm) and isopropyl acetate (20 mL) were added in to a round bottom flask at 22-26°C. Caffeine (1.50 gm) was added to the resulting reaction mixture at 22-26°C and stirred for 30 mins. Isopropyl acetate (20 ml) was added to the resulting reaction mixture at 22-26°C and stirred for 17 hrs, filtered, washed with Isopropyl acetate (10 mL) and suck dried for 30 mins. Ethyl formate (30 mL) and water (30 mL) were added to the resulting solid at 22-26°C and stirred for 10 mins. The organic layer was separated.0.49N of hydrochloric acid (1.33 mL of Con HC1 in 30 mL of water) was added to the resulting organic layer at 22-26°C and stirred for 10 mins. The organic layer was separated and the combined organic layer was washed with 5 % sodium bicarbonate (30 mL). The separated organic layer was washed with water (30 mL) and 5% sodium chloride solution (20 mL) was added to the resulting organic layer. The layers were separated and the resulting organic layer was dried with sodium sulphate (2 gm). The organic layer was distilled at 40- 45°C and co-distilled with methanol (60 mL) at 43-47°C. The resulting residue was dissolved in DMSO (0.2 mL) and methanol (6 ml) at 48-52°C, cooled to 22-26°C and added to pre-cooled water (60 mL) at 0-5°C. The reaction mixture was stirred for 30 mins at 0-5 °C, filtered the solids, washed with water (10 mL) and suck dried for 10 mins. The resulting solid was dried under vacuum initial at room temperature for 2 hrs and then further dried at 48-52°C for 14 hrs to obtain title compound. Yield: 1.28 gm. The PXRD is set forth in Figure-21.
EXAMPLE 15: Preparation of amorphous form of Tezacaftor
Tezacaftor (10 gm) and piperazine (3.31 gm) were added in to a round bottom flask at 22- 26°C. Ethyl acetate (2.5 mL) and t-butyl acetate (27.5 mL) were added to the resulting reaction mixture at 22-26°C. The temperature of the reaction mixture was raised to 68- 72°C and stirred for 20 mins at same temperature. The resulting solution was cooled to 22- 26°C, seed crystals of Tezacaftor piperazine co-crystal was added and stirred for 15 mins at 22-26°C. t-butyl acetate was added to the resulting reaction mixture at 22-26°C and stirred for 60 mins. The resulting solid was filtered, washed with t-butyl acetate (20 mL) and suck dried for 15 mins. Ethyl formate (150 mL) and water (150 mL) were added to the resulting solid at 22-26°C and stirred for 10 mins. Con hydrochloric acid (820 mΐ) was added and the reaction mixture was stirred for 20 mins at 22-26°C. The organic layer was separated and the combined organic layer was washed with water (100 ml). The organic layer was distilled at 40-45°C and co-distilled with methanol (200 mL) at 51-55°C until 40 mL remains in the flask. DMSO (1 mL) was added to the resulting solution at 24-26°C and was added to pre-cooled water (300 mL) at 0-5°C. The reaction mixture was stirred for 30 mins at 0-5 °C, filtered the solids, washed with water (50 mL) and suck dried for 20 mins. The resulting solid was dried under vacuum initial at room temperature for 2 hrs and then further dried at 48-52°C for 13 hrs to obtain title compound. Yield: 8.45 gm. The PXRD is set forth in Ligure-22.
EXAMPLE 16: Preparation of amorphous form of Tezacaftor
Tezacaftor (2.01 gm) and piperazine (661.8 mg) were added in to a round bottom flask at 22-26°C. Ethyl acetate (6 mL) was added to the resulting reaction mixture at 22-26°C. The temperature of the reaction mixture was raised to 68-72°C and stirred for 10 mins at same temperature. The resulting solution was cooled to 22-26°C, seed crystals of Tezacaftor piperazine co-crystal was added at same temeparature and and stirred for 5 mins. N- heptane was added to the resulting reaction mixture at 22-26°C and stirred for 2 hrs. The resulting solid was filtered, washed with n-heptane (6 mL) and suck dried for 15 mins. Ethyl formate (20 mL) was added to the resulting solid at 22-26°C. 0.2N Con hydrochloric acid (20 mL) was added and the reaction mixture was stirred for 10 mins at 22-26°C. The organic layer was separated and the combined organic layer was washed with sodium bicarbonate (20 mL) and the resulting organic layer washed with water and layers were separated. The organic layer was dried with sodium sulphate (1 gm), distilled until 4 volumes remains in the at 43-47°C and co-distilled with methanol (2* 20 mL) at 48-52°C until 4 volumes remains in the flask. The reaction mixture was cooled to 22-26°C and then added to pre-cooled water at 0-5°C, stirred for 30 mins, filtered the solids, washed with water (5 mL) and suck dried for 15 mins. The resulting solid was dried under vacuum initial at room temperature for 2 hrs and then further dried at 48-52°C for 14 hrs to obtain title compound. Yield: 1.29 gm.
EXAMPLE 17: Preparation of amorphous form of Tezacaftor
Tezacaftor (2 gm) and isopropyl acetate (20 mL) were added in to a round bottom flask at 22-26°C. Caffeine (1.50 gm) was added to the resulting reaction mixture at 22-26°C and stirred for 30 mins. Isopropyl acetate (20 ml) was added to the resulting reaction mixture at 22-26°C and stirred for 17 hrs, filtered, washed with Isopropyl acetate (10 mL) and suck dried for 30 mins. Ethyl formate (30 mL) and water (30 mL) were added to the resulting solid at 22-26°C and stirred for 10 mins. The organic layer was separated.0.49N of hydrochloric acid (1.33 mL of Con HC1 in 30 mL of water) was added to the resulting organic layer at 22-26°C and stirred for 10 mins. The organic layer was separated and the combined organic layer was washed with 5 % sodium bicarbonate (30 mL) and water (30 ml). The organic layer was distilled at 40-45°C and co-distilled with methanol (60 mL) at 43-47°C. The resulting residue was dissolved in methanol (15 mL) at 60°C. The solvent was distilled completely under vaccum at 55-65°C and the obtained solids were dried at 55-65°C under vacuum for 12-16 hrs to obtain title compound. Yield: 1.06 gm.
EXAMPLE 18: Preparation of amorphous form of Tezacaftor
Tezacaftor piperazine co-crystal (5 gms), Ethyl formate (50 mL) and water (50 mL) were added in to a round bottom flask at 22-26°C and stirred for 10 mins. Con hydrochloric acid (293 pi) was added and the reaction mixture was stirred for 20 mins at 22-26°C. The organic layer was separated and the combined organic layer was washed with water (50 ml). The organic layer was distilled at 40-45°C and co-distilled with methanol (100 mL) at 51-55°C until 20 mL remains in the flask. DMSO (0.5 mL) was added to the resulting solution at 24-26°C and was added to pre-cooled water (100 mL) at 0-5°C. The reaction mixture was stirred for 30 mins at 0-5 °C, filtered the solids, washed with water (20 mL) and suck dried for 20 mins. The resulting solid was dried under vacuum initial at room temperature for 2 hrs and then further dried at 48-52°C for 13 hrs to obtain title compound. Yield: 4.7 gm.
EXAMPLE 19: Preparation of amorphous form of Tezacaftor
Tezacaftor (1.01 gm) and piperazine (334.1 mg) were added in to a round bottom flask at 22-26°C. t-butyl acetate (5 mL) was added to the resulting reaction mixture and stirred for 5 hrs at 22-26°C. The temperature of the reaction mixture was raised to 63-67°C and stirred for 10 mins at same temperature. The resulting solution was cooled to 22-26°C, seed crystals of Tezacaftor piperazine co-crystal was added and stirred for 5 mins at 22- 26°C. t-butyl acetate (5 mL) was added to the resulting reaction mixture at 22-26°C and stirred for 13 hrs. The resulting reaction mixture was cooled to 0-5°C, stirred for 1 hrs, filtered, washed with t-butyl acetate (3 mL) and suck dried for 15 mins. Ethyl formate (60 mL) and water (60 mL) were added to the resulting solid at 22-26°C and stirred for 10 mins. Con hydrochloric acid (0.167 mL) was added and the reaction mixture was stirred for 10 mins at 22-26°C. The organic layer was separated and the combined organic layer was washed with sodium bicarbonate (10 mL) and the resulting organic layer washed with water and layers were separated. The organic layer was dried with sodium sulphate (1 gm), distilled the organic layer at 58-62°C to obtain title compound. Yield: 0.82 gm.
EXAMPLE 20: Preparation of amorphous form of Tezacaftor
Tezacaftor (2.04 gm), Caffeine (1.49 gm) and isopropyl acetate (20 mL) were added in to a round bottom flask at 22-26°C.The resulting reaction mixture at 22-26°C and stirred for 1 hr, filtered. Isopropyl acetate (10 mL) was to added to the resulting reaction mixture at 22- 26°C, stirred for 16 hrs, filtered, washed with isopropyl acetate (2 mL) and suck dried for 15 mins. Ethyl formate (60 mL) and water (60 mL) were added to the resulting solid at 22- 26°C and stirred for 10 mins. Con hydrochloric acid (331 pL) was added and the reaction mixture was stirred for 20 mins at 22-26°C. The organic layer was separated and the combined organic layer was washed with with water and layers were separated. The combined organic layer was dried with sodium sulphate (2 gm), distilled the organic layer at 53-57°C to obtain title compound. Yield: 1.66 gm.
EXAMPLE 21: Preparation of amorphous form of Tezacaftor (acetone-cyclohexane)
Tezacaftor (501.9 mg) and acetone (10 mL) were added in to a round bottom flask at 50°C. The solvent was distilled completely under vacuum at 45-55°C. Cyclohexane (5 mL) was added to the resulting foamy solid at 10-15°C and stirred for 30 min. The solid obtained was filtered, washed with cyclohexane (2 ml) and suck dried for 10 mins. The resulting solid was dried under vacuum for 13 hrs at 55-65°C to obtain title compound. Yield: 268.2 mg. The PXRD is set forth in Figure-23.
EXAMPLE 22: Preparation of amorphous form of Tezacaftor (Methanol)
Tezacaftor (501.2 mg) and Methanol (10 mL) were added in to a round bottom flask at 60°C. The solvent was distilled completely under vacuum at 55-65°C and the obtained solids were dried at 55-65°C under vacuum for 14 hrs to obtain title compound. Yield: 355.3 mg.
EXAMPLE 23: Preparation of amorphous form of Tezacaftor (Acetone)
Tezacaftor (500.8 mg) and acetone (10 mL) were added in to a round bottom flask at 50°C. The solvent was distilled completely under vacuum at 45-55°C and the obtained solids were dried at 55-65°C under vacuum for 14 hrs to obtain title compound.. Yield:312.2 mg.
EXAMPLE 24: Preparation of amorphous form of Tezacaftor (Ethyl formate)
Tezacaftor (501.5 mg) and ethyl formate (10 mL) were added in to a round bottom flask at 50°C. The solvent was distilled completely under vacuum at 45-55°C and the obtained solids were dried at 55-65°C under vacuum for 14 hrs to obtain title compound.. Yield:321.4 mg.
EXAMPLE 25: Preparation of amorphous form of Tezacaftor (methanol-water) Tezacaftor (100.1 mg) and methanol (0.4 mL) were added in to a round bottom flask at 60°C. The resulting solution was cooled to 20-25°C and added to pre-cooled water (2 mL) at 0-5°C. The reaction mixture was stirred for 60 mins at 0-5 °C, filtered the solids, washed with water (0.4 mL) and suck dried for 15 mins. The resulting solid was dried under vacuum for 16 hrs at room temperature to obtain title compound. Yield:47.2 mg.
EXAMPLE 26: Preparation of amorphous form of Tezacaftor (dimethyl sulfoxide-water) Tezacaftor (101.3 mg) and dimethyl sulfoxide (0.2 mL) were added in to a round bottom flask at 60°C. The resulting solution was cooled to 20-25°C and added to pre-cooled water (2 mL) at 0-5°C. The reaction mixture was stirred for 60 mins at 0-5 °C, filtered the solids, washed with water (0.4 mL) and suck dried for 15 mins. The resulting solid was dried under vacuum for 16 hrs at room temperature to obtain title compound. Yield: 40.5 mg.
EXAMPLE 27: Preparation of amorphous form of Tezacaftor (methanol-water)
Tezacaftor (301.1 mg) and methanol (1.2 mL) were added in to a round bottom flask at 55- 65°C. The resulting solution was cooled to 20-25°C and added to pre-cooled water (6 mL) at 0-5°C. The reaction mixture was stirred for 30 mins at 0-5 °C, filtered the solids, washed with water (0.6 mL) and suck dried for 15 mins. The resulting solid was dried under vacuum for 4 hrs at room temperature and further dried under vacuum for 12 hrs at 50°C to obtain title compound. Yield: 217.5 mg.
EXAMPLE 28: Preparation of amorphous form of Tezacaftor (dimethyl sulfoxide-water)
Tezacaftor (302.1 mg) and dimethyl sulfoxide (0.6 mL) were added in to a round bottom flask at 55-65°C. The resulting solution was cooled to 20-25°C and added to pre-cooled water (6 mL) at 0-5°C. The reaction mixture was stirred for 30 mins at 0-5 °C, filtered the solids, washed with water (0.6 mL) and suck dried for 15 mins. The resulting solid was dried under vacuum for 4 hrs at room temperature and further dried under vacuum for 12 hrs at 50°C to obtain title compound. Yield:219.4 mg.
EXAMPLE 29: Stability study for amorphous form of Tezacaftor of the invention:
The amorphous form of Tezacaftor is packed in LDPE bag under nitrogen atmosphere and placed in another LDPE bag, filled with nitrogen and kept silica gel packet between the bags, tied with strip seal. Kept the bag in triple laminated sunlight barrier bag and sealed with heat sealer. The stability of the samples was tested at 25±2°C/60±5% and 40±2°C/75±5%RH respectively. The results are shown in below table 1:
Table 1:
Figure imgf000037_0001
Figures 25 & 26 are the characteristic powder X-ray diffraction (XRD) pattern of amorphous Tezacaftor, The X-ray powder diffraction data showed absence of crystalline tezacaftor in the amorphous Tezacaftor prepared according to the present invention at 25°C/60%RH and at 40°C/60%RH storage conditions respectively.
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be constructed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.

Claims

WE CLAIM:
Claim 1: A stable amorphous form of Tezacaftor, wherein the amorphous form of Tezacaftor does not convert to any other solid form when stored at a temperature of up to about 40°C and at a relative humidity of about 25% to about 75% for about three months or more.
Claim 2: A process for the preparation of stable amorphous form of Tezacaftor comprising: a) dissolving or suspending Tezacaftor in o-xylene solvent, b) isolating Tezacaftor o-xylene solvate, and c) drying the Tezacaftor o-xylene solvate at about 25°C to about 85°C to obtain stable amorphous form.
Claim 3: The process as claimed in claim 2, wherein the drying is carried out at about 45°C to about 60°C.
Claim 4: A process for the preparation of stable amorphous form of tezacaftor, comprising: a) dissolving or suspending tezacaftor co-crystal in a suitable solvent, b) optionally treating the step a) reaction mass with a suitable acid or base, and c) isolating the amorphous tezacaftor.
Claim 5: The process as claimed in claim 4, wherein the tezacaftor co-crystal is selected from the group comprising caffeine, piperazine, piperidine, 4-amino pyridine, imidazole, morpholine 4-hydroxy pyridine, paraxanthine, theophylline, theobromine, DDQ, Hexamethylenetetramine, 2 -hydroxy- 1,4- napthoquinone, nicotinamide or isonicotinamide.
Claim 6: The process as claimed in claim 4, wherein the suitable solvent is selected from water or a mixture of water and water immiscible organic solvent; wherein the water immiscible organic solvent is selected from methyl acetate, ethyl acetate, isopropyl acetate n-propyl acetate, n-butyl acetate, t-butyl acetate, ethyl formate, hexane, heptane, cyclohexane, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, dichloromethane, dichloroethane, chloroform or mixtures thereof.
Claim 7: The process as claimed in claim 4, wherein the step a) reaction is carried out at a temperature from about 20°C to about 30°C.
Claim 8: The process as claimed in claim 4, wherein the acid is selected from the group comprising of hydrochloric acid, hydrobromic acid , sulfuric acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, formic acid, sulphonic acid, benzene sulphonic or mixtures; and the base is selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium, carbonate, lithium carbonate, cesium carbonate or mixtures thereof.
Claim 9: The process as claimed in claim 4, wherein the step c) comprises isolation of amorphous Tezacaftor by removal of solvent from the solution.
Claim 10: The process as claimed in claim 9, wherein the solvent is removed by distillation under vacuum at a temperature of about 25 °C to about 60°C.
Claim 11: The process as claimed in claim 4, wherein the step c) further comprises the steps of: a) concentrating the reaction mass, b) treating the step a) reaction mass with a suitable solvent, c) adding an anti-solvent to the step b) solution or vice-versa, and d) isolating the amorphous Tezacaftor.
Claim 12: The process as claimed in claim 11, wherein the concentration is carried out at a temperature from about 40 to about 50°C.
Claim 13: The process as claimed in claim 11, wherein the suitable solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, acetone, methyl isobutyl ketone, methyl ethyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, acetonitrile, propionitrile, dimethyl sulfoxide, diethyl sulfoxide, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone or mixtures thereof. Claim 14: The process as claimed in claim 11, wherein the step b) reaction is carried out at a temperature from about 45 °C to about 55°C.
Claim 15: The process as claimed in claim 11, wherein the anti-solvent is selected from the group consisting of water, propane, hexane, heptane, cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane or mixtures thereof.
Claim 16: The process as claimed in claim 11, wherein the isolation of the amorphous form of Tezacaftor is carried out by filtration.
Claim 17: The process as claimed in claim 4, wherein the tazacaftor co-crystals are tazacaftor caffeine co-crystal or tazacaftor piperazine co-crystal.
Claim 18: Tezacaftor o-xylene solvate.
Claim 19: The compound as claimed in claim 18, wherein the Tezacaftor o-xylene is characterized by X-Ray powder diffraction (XRD) pattern substantially in accordance with Figure 01.
Claim 20: A process for the preparation of Tezacaftor o-xylene solvate, comprising: c) dissolving or suspending Tezacaftor in o-xylene solvent; and d) isolating Tezacaftor o-xylene solvate.
Claim 21: The process as claimed in claim 20, wherein the dissolution of Tezacaftor in o- xylene solvent is carried out at temperature of about 20°C to about 30°C.
Claim 22: The process as claimed in claim 20, wherein the isolation of Tezacaftor o-xylene solvate is carried out by filtration.
Claim 23: Co-crystals of Tezacaftor, wherein the co-crystal former is selected from the group comprising caffeine , piperazine, piperidine, 4-amino pyridine, imidazole, morpholine 4-hydroxy pyridine, paraxanthine, theophylline, theobromine, DDQ, Hexamethylenetetramine, 2-hydroxy- 1,4- napthoquinone, nicotinamide or isonicotinamide.
Claim 24: A process for the preparation of co-crystal of Tezacaftor, comprising: a) providing a solution or suspension comprising Tezacaftor and a co-crystal former in one or more solvents; and b) isolating the co-crystals of Tezacaftor.
Claim 25: The process as claimed in claim 24, wherein the co-crystal former is selected from the group comprising caffeine, piperazine, piperidine, 4-amino pyridine, imidazole, morpholine 4-hydroxy pyridine, paraxanthine, theophylline, theobromine, DDQ, Hexamethylenetetramine, 2 -hydroxy- 1,4- napthoquinone, nicotinamide or isonicotinamide.
Claim 26: The process as claimed in claim 24, wherein the one or more organic solvents are selected from the group consisting of methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, acetone, methyl ethyl ketone, methyl isobutyl ketone, hexane, heptane, cyclohexane, dichloromethane, dichloroethane, chloroform, acetonitrile, propionitrile, water or mixtures thereof.
Claim 27: The process as claimed in claim 24, wherein the step a) reaction is carried out at suitable temperature from about 20°C to about reflux temperature.
Claim 28: The process as claimed in claim 24, wherein the isolation of co-crystals of tezacaftor further comprises cooling the reaction mass to a suitable temperature, optionally seeding and filtering the precipitated product.
Claim 29: Tezacaftor piperazine co-crystal.
Claim 30: A process for the preparation of Tezacaftor piperazine co-crystal, comprising: a) providing a solution or suspension comprising Tezacaftor and piperazine in one or more organic solvents; and b) isolating the Tezacaftor piperazine co-crystal. Claim 31: The process as claimed in claim 30, wherein the organic solvent is selected from esters selected from methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; alcohols selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol; ketones selected from acetone, methyl ethyl ketone, methyl isobutyl ketone; halogenated hydrocarbon solvents selected from dichloromethane, dichloroethane, chloroform; nitriles selected from acetonitrile, propionitrile; water and mixtures thereof.
Claim 32: The process as claimed in claim 30, wherein the organic solvent is ethyl acetate, isopropyl acetate, t-butyl acetate or mixtures thereof.
Claim 33: The process as claimed in claim 30, wherein the isolation of tezacaftor piperazine co-crystal is carried out by filtration or by cooling the reaction mass to a suitable temperature, optionally seeding, further treating with aliphatic hydrocarbon solvents and optionally drying.
Claim 34: The process as claimed in claim 33, wherein the aliphatic hydrocarbon solvents are selected from n-hexane, n-heptane, cyclohexane or cycloheptane.
Claim 35: Tezacaftor piperazine co-crystal Form 1 characterized by powder X-ray diffraction pattern substantially in accordance with Figure 5.
Claim 36: Tezacaftor piperazine co-crystal Form 1 characterized by powder X-ray diffraction pattern peaks at about 3.7, 7.2, 10.8, 13.6, 14.4, 17.2, 18.0 and 19.0 ±0.2° 2Q.
Claim 37: Tezacaftor piperazine co-crystal Form 2 characterized by powder X-ray diffraction pattern substantially in accordance with Figure 9.
Claim 38: Tezacaftor piperazine co-crystal Form 2 characterized by powder X-ray diffraction pattern peaks at about 3.8, 7.7, 12.4, 14.2, 18.3 and 19.6 ±0.2° 2Q.
Claim 39: Tezacaftor piperazine co-crystal Form 3 characterized by powder X-ray diffraction pattern substantially in accordance with Figure 13. Claim 40: Tezacaftor piperazine co-crystal Form 3 characterized by powder X-ray diffraction pattern peaks at about 4.8, 9.2, 13.7, 14.3, 17.9, 19.6, 20.1 and 20.6 ±0.2° 2Q.
Claim 41: Tezacaftor caffeine co-crystal.
Claim 42: Tezacaftor caffeine co-crystal characterized by X-Ray powder diffraction (PXRD) pattern substantially in accordance with Figure 17.
Claim 43: A process for the preparation of Tezacaftor caffeine co-crystal, comprising: a) providing a solution or suspension comprising tezacaftor and caffeine in one or more organic solvents; and b) isolating tezacaftor caffeine co-crystal.
Claim 44: The process as claimed in claim 43, wherein the organic solvent is selected from esters selected from methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate; alcohols selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol; ketones selected from acetone, methyl ethyl ketone, methyl isobutyl ketone; halogenated hydrocarbon solvents selected from dichloromethane, dichloroethane, chloroform; nitriles selected from acetonitrile, propionitrile; water and mixtures thereof.
Claim 45: A pharmaceutical composition comprising amorphous form of Tezacaftor prepared according to claims 1-17 and at least one pharmaceutically acceptable excipient.
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