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WO2017137900A1 - Lumacaftor amorphe et sa dispersion solide - Google Patents

Lumacaftor amorphe et sa dispersion solide Download PDF

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Publication number
WO2017137900A1
WO2017137900A1 PCT/IB2017/050679 IB2017050679W WO2017137900A1 WO 2017137900 A1 WO2017137900 A1 WO 2017137900A1 IB 2017050679 W IB2017050679 W IB 2017050679W WO 2017137900 A1 WO2017137900 A1 WO 2017137900A1
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Prior art keywords
lumacaftor
acid
amorphous
preparation
process according
Prior art date
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Ceased
Application number
PCT/IB2017/050679
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English (en)
Inventor
Lalitkumar Dilipsing RAJPUT
Malhari Deoram BHOR
Sonraj Bholenath JANGAM
Radhakrishna SHIVDAVKAR
Dhananjai Shrivastava
Girij Pal Singh
Arjun Nishikant Vinchurkar
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Lupin Ltd
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Lupin Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel amorphous form of lumacaftor and various methods for its preparation.
  • the present invention also relates to lumacaftor hydrobromide crystalline form A and process for its preparation.
  • the present invention also relates to the amorphous lumacaftor premixed with an excipient and process for the preparation of the premix.
  • the present invention is related to lumacaftor which is a drug for the treatment of cystic fibrosis.
  • the drug is designed to be effective in patients that have the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), the defective protein that causes the disease.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • Lumacaftor (I) chemically known as 3-[6-( ⁇ [l-(2,2-difluoro-l,3-benzodioxol-5-yl) cyclopropyl]carbonyl ⁇ amino)-3-methylpyridin-2-yl]benzoic acid is disclosed in the PCT application WO 2007/056341.
  • the patent US 8,507,534, US 8,461,342 and US 8,124,781 discloses polymorphic forms and processes for preparation of lumacaftor.
  • the present invention is directed to amorphous form of lumacaftor. It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to crystalline forms.
  • the thermodynamically stable forms are always preferred for the formulation because of their stability. For some therapeutic indications one bioavailability pattern may be favored over another. Therefore, there is a need to develop an amorphous form of lumacaftor which has improved characteristics.
  • the inventors of the present invention provide here efficient and simple processes to obtain amorphous lumacaftor.
  • the present invention is also directed to amorphous form of lumacaftor which is prepared via hydrobromide salt of lumacaftor.
  • the amorphous solid dispersions of an active pharmaceutical ingredient can provide further prospective opportunities to improve the performance profile of a pharmaceutical composition comprising the said API. Therefore, development of processes to prepare amorphous solid dispersion of an API is of importance.
  • the present invention provides a process for the preparation of amorphous lumacaftor and lumacaftor solid dispersion premixed with an excipient. Summary of the invention:
  • the present invention provides amorphous form of lumacaftor. It further provides various methods for its preparation, such as:
  • Method 1 dissolving the lumacaftor in suitable solvent followed by drying,
  • Method 2 dispersing lumacaftor in a solvent followed by base-acid treatment
  • Method 3 melting lumacaftor followed by cooling.
  • the present invention also relates to preparation of amorphous lumacaftor via lumacaftor hydrobromide salt.
  • the present invention also relates to the amorphous lumacaftor premixed with an excipient and process for the preparation of the premix.
  • the present invention further relates to a process for preparation of lumacaftor by crystallization from organic solvents.
  • Figure 1 X-ray powder diffractogram (XRPD) for amorphous lumacaftor obtained by the processes of the present invention.
  • Figure 2 X-ray powder diffractogram (XRPD) of novel crystalline form A of lumacaftor hydrobromide obtained by the processes of the present invention.
  • Figure 3 X-ray powder diffractogram (XRPD) for amorphous lumacaftor premixed with syloid 244FP.
  • An embodiment of the present patent application provides an amorphous form of lumacaftor.
  • suitable solvent in the method described above includes alcohols like methanol, ethanol, n-propanol, isopropanol, ketones like acetone, 2-butanone, methyl isobutyl ketone; esters like ethyl acetate and isopropyl acetate; ethers such as tetrahydrofuran, ethyl ether, methyl t-butyl ether, di-isopropyl ether; chlorinated hydrocarbons such as dichlorome thane, ethylene dichloride and chloroform, and mixtures thereof; the most preferred solvent is tetrahydrofuran.
  • the isolation techniques involve the use of spray drying, lyophilization etc. followed by vacuum drying of the material.
  • the present invention provides process for preparation of lumacaftor comprising:
  • the method described above includes dispersing lumacaftor in water followed by addition of a base to obtain clear solution followed by treatment with acid to obtain a solid that is filtered and dried.
  • the bases used in above method are selected from a group comprising of inorganic bases of hydroxides as sodium hydroxide, potassium hydroxide, lithium hydroxide, carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, organic bases such as triethyl amine, diisopropyl amine, DBU etc.
  • the acid used in above method is selected from a group comprising of mineral acids such as hydrochloric acid, sulphuric acid, nitric acid, boric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, per chloric acid, hydro iodic acid etc.
  • mineral acids such as hydrochloric acid, sulphuric acid, nitric acid, boric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, per chloric acid, hydro iodic acid etc.
  • a process for preparation of lumacaftor comprising: a) heating lumacaftor up to 200-250°C,
  • the above method uses a melt crystallization technique for preparation of amorphous lumacaftor.
  • lumacaftor any physical form of lumacaftor such as crystalline, amorphous or their mixtures can be utilized as an input in these methods.
  • the amorphous form of lumacaftor obtained by the process of the present invention is characterized by XRPD (X-ray powder diffraction pattern) pattern as shown in figure 1.
  • the amorphous form of lumacaftor described herein is further identified by DSC with peak at 203.78°C.
  • the amorphous form of lumacaftor obtained by the process of the present invention is further characterized by IR peaks at 701.7, 907.6, 1031.9, 1155.5, 1238.4, 1373.7, 1413.9, 1463.9, 1508.1, 1497.2, 1691.2, 1723.7, 2929.4, 3071.7 and 3406.4 cm-1.
  • the effective amount of stable amorphous form of lumacaftor can be used to prepare pharmaceutical composition in association with one or more non-toxic pharmaceutically acceptable carriers and /or diluents thereof.
  • Another embodiment of the present invention is related to crystalline form A of lumacaftor hydrobromide.
  • the crystalline form A of lumacaftor hydrobromide obtained by the process of the present invention is characterized by XRPD pattern as shown in figure 2.
  • the crystalline form A of lumacaftor hydrobromide shows characteristic peaks in XRPD at 8.98 and 18.69 + 0.2 degree 2 ⁇ .
  • the crystalline form of lumacaftor hydrobromide is further characterized by peaks in XRPD at 10.08, 10.46, 14.25, 17.26, 17.40, 18.02, 18.53, 20.68, 25.76, 29.98 + 0.2 degree 2 ⁇ .
  • the crystalline form A of lumacaftor hydrobromide described herein is further identified by DSC with peak at 220.83°C.
  • Yet another embodiment of the present invention is to provide a process for the preparation of crystalline form A of lumacaftor hydrobromide which comprises hydrolysis of 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamido)- 3-methylpyridine-2-yl)-t-butylbenzoate (II).
  • acetonitrile used for preparation of lumacaftor hydrobromide is 5-30 times, preferably 10-15 times.
  • the quantity of hydrobromic acid used is 5-30 times, preferably 10-20 times.
  • the temperature at which the reaction is carried is 10-50°C.
  • the effective amount of crystalline lumacaftor hydrobromide can be used to prepare any physical form of lumacaftor such as crystalline, amorphous or their mixtures.
  • the lumacaftor can be obtained as per methods known in literature.
  • the organic solvent in step (a) is selected from benzene, toluene, xylene, hexane, heptane, cyclohexane, cycloheptane, methanol, ethanol, n-butanol, t-butanol, acetone, 2-butanone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, ethyl ether, methyl t-butyl ether, di-isopropyl ether; dichloromethane, ethylene dichloride, dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, isopropyl nitrile and chloroform, methanol, ethanol, propanol and mixtures thereof; the most preferred organic solvent is mixture of dichloromethane and methanol.
  • the excipients used in step (b) include, but not limited to mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol, inositol, trehalose, trehalose, maltose, raffinose, .alpha.-, .beta.- and .gamma.-cyclodextrins, gum arabic, sodium alginate, propylene glycol alginate, agar, gelatin, tragacanth, xanthan gum, starch, lectins, urea, chitosan, chitosan glutamate, hydroxypropyl beta.-cyclodextrin chitosan, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose (MC), cellulose acetate phthalate (CAP), hydroxyprop
  • dextrin, pullulan, corn starch and potato starch pregelatinized starches lactose, sucrose, glucose, reduced maltose, mannitol, sorbitol, xylitol, trehalose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, crystalline cellulose/carmellose sodium, hydroxypropyl cellulose, magnesium aluminometasilicate, silica excipients like silicon dioxide, syloid, light anhydrous silicic acid or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches or the like; disintegrants such as hydroxypropyl cellulose, low- substituted hydroxypropyl cellulose, croscarmellose sodium, a starch, methylcellulose, sodium alg
  • the excipient includes povidone like PVP K-30, copovidones like Kolidon VH-64, silica excipients like silicon dioxide, syloid FP silica, colloidal silica, preferably syloid FP silica.
  • the syloid FP silica excipients are micronized synthetic amorphous silica gels of high purity which are widely formulated into many pharmaceutical products. Syloid FP silica is available in various types such as 244FP, 63FP, 27FP.
  • the steps (a) to (c) can be carried out at 10-100°C, preferably 10-50°C; most preferably 25-40 °C.
  • Isolation of lumacaftor premixed with excipient can be achieved by various methods such as concentration, removal of solvent by evaporation, distillation, crash cooling, flash evaporation, rotational drying, spray drying, thin film drying, freeze drying, and lyophilization.
  • the amorphous lumacaftor premixed with excipient obtained by the process of the present invention is characterized by XRPD (X-ray powder diffraction pattern) as shown in figure 3.
  • the amorphous lumacaftor premixed with excipient of the present invention may be formulated as solid oral dosage forms such as powders, granules, pellets, tablets and capsules, suppositories, sachets, troches or lozenges, liquid oral dosage forms such as syrups, suspensions, dispersions, emulsions, injectables.
  • Another embodiment of the present invention is related to process for the preparation of lumacaftor by crystallization using a suitable organic solvent.
  • the organic solvent is selected from esters such as ethyl acetate, methyl acetate, tertiary butyl acetate, isopropyl acetate etc.
  • the most preferred solvent is ethyl acetate.
  • the quantity of ethyl acetate used for crystallization of lumacaftor is 5-30 times, preferably 10-20 times.
  • the temperature at which the reaction is carried is 40-100°C.
  • the effective amount of lumacaftor can be used to prepare any physical form of lumacaftor such as crystalline, amorphous or their mixtures.
  • the lumacaftor used as input can be obtained as per methods known in literature.
  • the powder X-ray diffraction spectrum is measured using Philips (PAN analytical X'pert pro) diffractogram (copper anti cathode) and expressed in terms of inter planar distance d, Bragg' s angle 2 theta, intensity (expressed as a percentage of the most intense peak).
  • the scanning parameters include: measurement range 3-40 degrees two theta; measurement temperature 25 °C; continuous scan.
  • Example 1 Preparation of amorphous lumacaftor
  • Lumacaftor (4gm) was dissolved in tetrahydrofuran (40 ml). The reaction mixture was heated to 62°C and filtered. The reaction mixture was concentrated under reduced pressure. The resulting amorphous lumacaftor was dried in oven under reduced pressure. Yield: 3.7 gm
  • Lumacaftor (2 gm) was added to water (100 ml). To the mixture was added 0.1 N sodium hydroxide (100 ml) till the reaction mixture became clear. The solution was filtered. To the filtered solution was added 0.1 N hydrochloric acid (80 ml) till the solid precipitated. The obtained solid was filtered and dried in oven under reduced pressure.
  • Lumacaftor (3 gm) was taken into a sublimation apparatus. The tube of the apparatus was heated at 210°C for 4 hours till the solid melted. The obtained molten liquid was cooled to 30°C in two hours. The solid was removed by scratching.
  • Example 5 Preparation of Lumacaftor from lumacaftor Hydrobromide salt.
  • Lumacaftor (20 gm) was added to methanol (800 ml) at 25°C.
  • dichloromethane 40ml was added.
  • the reaction mixture was heated at 60°C till a clear solution was obtained.
  • the reaction mixture was filtered and the solution was spray dried. Yield: 10.2 gm
  • Example 7 Preparation of lumacaftor premix with povidone K-30
  • Lumacaftor (15 gm) was added to methanol (30 ml). To the reaction mixture dichloromethane (120 ml) was added. The reaction mixture was heated to 37°C till clear solution was obtained. The reaction mixture was cooled to 25 °C and povidone K-30 (3.75 gm) was added. The reaction mixture was stirred to obtain a clear solution. The solution was filtered and washed with dichloromethane (7.5 ml). The filtrate was spray dried.
  • Example 8 Preparation of lumacaftor premix with Kolidon VH-64
  • Lumacaftor (15 gm) was added to methanol (30 ml). To the reaction mixture dichloromethane (120 ml) was added. The reaction mixture was heated to 37°C till clear solution was obtained. The reaction mixture was cooled to 25 °C and Kolidon VH-64 (3.75 gm) was added. The reaction mixture was stirred to obtain a clear solution. The solution was filtered and washed with dichloromethane (7.5 ml). The filtrate was spray dried.
  • Lumacaftor (15 gm) was added to dichloromethane (120 ml). To the reaction mixture methanol (30 ml) was added. The reaction mixture was heated to 37°C till clear solution was obtained. The reaction mixture was cooled to 25 °C and syloid 244FP (3.75 gm) was added. The reaction mixture was stirred to obtain a clear solution. The filtrate was spray dried. Yield : 16.8 gm
  • Lumacaftor (10 gm) was charged to ethyl acetate (120 ml). The reaction mixture was heated to 80 °C till a clear solution was obtained. The reaction mass was cooled to 30°C and the solid was stirred. The solid was further cooled to 0-5 °C and filtered and dried. The solid was washed with chilled ethyl acetate. The resulting solid was dried under reduced pressure.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une nouvelle forme de lumacaftor amorphe et sa préparation par divers procédés. La présente invention concerne également une nouvelle forme A cristalline de bromhydrate lumacaftor et son procédé de préparation. La présente invention concerne du lumacaftor amorphe prémélangé avec un excipient et un procédé de préparation de ce prémélange.
PCT/IB2017/050679 2016-02-10 2017-02-08 Lumacaftor amorphe et sa dispersion solide Ceased WO2017137900A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
IN201621004780 2016-02-10
IN201621004780 2016-02-10
IN201621016845 2016-05-13
IN201621016845 2016-05-13
IN201621029378 2016-08-29
IN201621029378 2016-08-29

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4434581A2 (fr) 2017-01-09 2024-09-25 Laurus Labs Limited Procédé et formes cristallines de lumacaftor

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007056341A1 (fr) 2005-11-08 2007-05-18 Vertex Pharmaceuticals Incorporated MODULATEURS HÉTÉROCYCLIQUES DE TRANSPORTEURS À CASSETTE LIANT l’ATP
WO2009073757A1 (fr) * 2007-12-07 2009-06-11 Vertex Pharmaceuticals Incorporated Formes solides d'acide 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-méthylpyridin-2-yl)benzoïque
WO2011127290A2 (fr) * 2010-04-07 2011-10-13 Vertex Pharmaceuticals Incorporated Formes solides de l'acide 3-(6-(1-(2,2-difluorobenzo [d] [1,3] dioxol-5-yle) cyclopropane carboxamido)-3-méthylpyridin-2-yle) benzoïque
US8124781B2 (en) 2007-12-07 2012-02-28 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US8461342B2 (en) 2007-12-07 2013-06-11 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007056341A1 (fr) 2005-11-08 2007-05-18 Vertex Pharmaceuticals Incorporated MODULATEURS HÉTÉROCYCLIQUES DE TRANSPORTEURS À CASSETTE LIANT l’ATP
WO2009073757A1 (fr) * 2007-12-07 2009-06-11 Vertex Pharmaceuticals Incorporated Formes solides d'acide 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-méthylpyridin-2-yl)benzoïque
US8124781B2 (en) 2007-12-07 2012-02-28 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US8461342B2 (en) 2007-12-07 2013-06-11 Vertex Pharmaceuticals Incorporated Processes for producing cycloalkylcarboxamido-pyridine benzoic acids
US8507534B2 (en) 2007-12-07 2013-08-13 Vertex Pharmaceuticals Incorporated Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid
WO2011127290A2 (fr) * 2010-04-07 2011-10-13 Vertex Pharmaceuticals Incorporated Formes solides de l'acide 3-(6-(1-(2,2-difluorobenzo [d] [1,3] dioxol-5-yle) cyclopropane carboxamido)-3-méthylpyridin-2-yle) benzoïque

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Title
BERNSTEIN J: "Polymorphism of pharmaceuticals", POLYMORPHISM IN MOLECULAR CRYSTALS, 2002, pages 253 - 255, XP002308143 *
HANCOCK B C ET AL: "CHARACTERISTICS AND SIGNIFICANCE OF THE AMORPHOUS STATE IN PHARMACEUTICAL SYSTEMS", JOURNAL OF PHARMACEUTICAL SCIENCES, AMERICAN PHARMACEUTICAL ASSOCIATION, WASHINGTON, US, vol. 86, no. 1, 1 January 1997 (1997-01-01), pages 1 - 12, XP000929450, ISSN: 0022-3549, DOI: 10.1021/JS9601896 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4434581A2 (fr) 2017-01-09 2024-09-25 Laurus Labs Limited Procédé et formes cristallines de lumacaftor

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