DESC:RELATED APPLICATION:
This application claims the benefit of priority of our Indian patent application number IN 201721004990 dated Feb. 13, 2017, which is incorporated herein by reference.
FIELD OF THE INVENTION
The present invention provides a novel crystalline polymorphic form of Lumacaftor and 5 process for preparation thereof.
BACKGROUND OF THE INVENTION
Lumacaftor of formula 1 (VX-809) acts as a chaperone during protein folding and increases the number of CFTR proteins that are trafficked to the cell surface. It is available in combination with ivacaftor (brand name Orkambi) which is used to treat people with cystic 10 fibrosis who have the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), the defective protein that causes the disease.
Formula-1
Patent US8993600B2 discloses Pharmaceutical composition of Lumacaftor. US8507534B2 15 discloses compound-1, Form-I of Lumacaftor which is substantially crystalline and salt free. US9314455B2 discloses compound-1, solvate Form A of Lumacaftor. However, Compound 1, Solvate Form A, as disclosed in that patent, comprises a crystalline lattice of Compound 1 in which voids in the crystalline lattice are empty, or occupied, or partially occupied by one or more molecules of a suitable solvent. Suitable solvents include to methanol, ethanol, 20 acetone, 2-propanol, acetonitrile, tetrahydrofuran, methyl acetate, 2-butanone, ethyl formate, and 2-methyl tetrahydrofuran. Further, certain physical characteristics of Compound 1 isostructural solvate form A, such as X-ray powder diffraction, melting point, and DSC, are not substantially affected by the particular solvent molecule.
Polymorphism is defined as "the ability of a substance to exist as two or more 25 crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules". Different
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polymorphs may differ in their physical properties such as melting point, solubility, X-ray
diffraction patterns, etc. Although those differences disappear once the
compound is dissolved, they can appreciably influence pharmaceutically relevant
properties of the solid form, such as handling properties, dissolution rate and
5 stability. Such properties can significantly influence the processing, shelf life, and
commercial acceptance of a polymorph. It is therefore important to investigate all
solid forms of a drug, including all polymorphic forms, and to determine the stability,
dissolution and flow properties of each polymorphic form. Polymorphic forms of a
compound can be distinguished in the laboratory by analytical methods such as Xray
10 diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared
spectrometry (IR). A solvate may be defined as a compound formed by solvation, for
example as a combination of solvent molecules with molecules or ions of a solute. Solvent
medium and mode of isolation play very important role in obtaining a polymorphic form over
the other.
15 The discovery of new polymorphic forms and solvates of a pharmaceutically useful
compound provides a new opportunity to improve the performance characteristics of a
pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has
available for designing.
SUMMARY OF THE INVENTION
20 One aspect of the present invention provides a novel crystalline polymorphic form Al-1 of
Lumacaftor of Formula-I:
N
CH3
NH
OH
O O
O
F
F O
Formula (1)
Another aspect of the invention provides preparation for process of novel crystalline
polymorphic form Al-1 of Lumacaftor of Formula-I.
25 Another aspect of the invention provides pharmaceutical compositions comprising a
crystalline polymorphic form Al-1 of Lumacaftor and at least one pharmaceutically
acceptable excipient.
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Another aspect of the invention provides pharmaceutical composition comprising crystalline polymorphic form Al-1 of Lumacaftor for the treatment of cystic fibrosis.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1 shows the X-ray powder diffractogram ("PXRD") pattern of Lumacaftor polymorphic form Al-1. 5
Fig 2 shows the X-ray powder diffractogram ("PXRD") pattern of Lumacaftor solvate form A from 1,3- dioxolane.
Fig 3 shows the X-ray powder diffractogram ("PXRD") pattern of Lumacaftor solvate form A from dichloromethane.
DETAILED DESCRIPTION OF THE INVENTION 10
One aspect of the present invention relates to novel crystalline polymorphic form Al-1 of Lumacaftor of formula (I):
Formula (1)
In an embodiment of the invention the novel crystalline polymorphic form Al-1 of 15 Lumacaftor is characterized by having one or more PXRD peaks (2 theta) at approximate positions: 5.38, 7.05, 8.58, 10.78, 12.52, 13.36, 14.15, 14.75, 14.81, 15.49, 16.24, 17.28, 18.50, 18.85, 19.99, 20.57, 21.30, 21.76, 22.38, 23.62, 24.66, 24.88, 25.73, 27.20, 28.19, 28.65, 29.41, 30.21, 31.56, 32.12, 32.93, 34.19, 36.64, 38.75 ± 0.2 degrees.
In an another embodiment of the invention the novel crystalline polymorphic form Al-1 of 20 Lumacaftor is characterized by having PXRD peaks as shown in fig-1.
The crystalline polymorphic form of the present invention has advantages relative to other known forms of Lumacaftor, including chemical stability, polymorphic stability and/or solubility.
Another aspect of the invention relates to preparation process of novel crystalline 25 polymorphic form Al-1 of Lumacaftor of formula (1).
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In one embodiment of the invention, the process for preparation of Lumacaftor polymorphic form Al-1 comprising:
a. providing a solution of Lumacaftor in suitable solvent or mixture of solvents; b. isolating crystalline polymorph form Al-1 of Lumacaftor from the solution.
In certain embodiments, providing a solution of Lumacaftor in suitable solvent means 5 the solution of Lumacaftor may be obtained by dissolving Lumacaftor in suitable solvent at a suitable temperature, or such a solution may be obtained directly from a chemical synthesis in which Lumacaftor is formed. Then optionally, filtering the solvent solution to remove any extraneous matter; and finally isolating by removing the solvent from the solution to afford Lumacaftor crystalline polymorph form Al-1. Removal of solvent is accomplished by, for 10 example, filtering the solid, substantially complete evaporation of the solvent, concentrating the solution and filtering the solid.
In some embodiments, the suitable temperature may range from RT to about the reflux temperature of the solvent used, or from about 30 °C to about 110 °C or any temperatures range that doesn’t affect the quality of the product to be obtained. 15
In some embodiment of the invention, wherever applicable, the reaction solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material.
In few embodiments of the invention, the dried product or product obtained may 20 optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.
In certain embodiments, the suitable solvent is selected from water, methanol, 25 ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, toluene, xylene, methylene dichloride, ethylene dichloride, chlorobenzene, acetonitrile, benzonitrile, diethyl ether, diisopropyl ether, t-butyl methyl 30
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ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine, formic acid, acetic acid, propionic acid, hexane, heptanes, cyclohexane, cycloheptane and cyclooctane or mixtures thereof. More preferably benzonitrile is used. 5
Yet another aspect of the invention relates to pharmaceutical compositions comprising a substantially pure crystalline polymorphic form Al-1 of Lumacaftor and at least one pharmaceutically acceptable excipient.
Still another aspect of the invention relates to pharmaceutical composition comprising crystalline polymorphic form Al-1 of Lumacaftor for the treatment of cystic fibrosis. 10
Another aspect of the present invention relates to preparation of Lumacaftor solvate of form A using solvents such as propylene glycol, 1,3-dioxolane, dichloromethane, benzyl alcohol, DMSO, etc. The solvate form obtained by using the said solvents, is similar XRD pattern of solvate form A.
The invention is further exemplified by the following non-limiting examples, which are 15 illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.
Examples 20
XPRD (X-ray powder diffraction)
The X-Ray diffraction (XRD) data of Form Al-1 were collected on a PANalytical P-XRD powder diffractometer with x’celerator detector. Cu sealed tube with Ka radiation was used at 45 kV. The samples were placed on zero-background at 25° C. The data were integrated with High score plus software. Uncertainties for the reported peak positions are ±0.2 degrees. 25
Example 1: Preparation of Lumacaftor polymorphic form Al-1 Lumacaftor (5 g) was added to a stirred solution of benzonitrile (100 mL) at 25-30°C, reaction mixture was heated to 100-110°C and stirred for 1 hour at 100-110°C then cooled to 25-30°C. Then reaction mixture stirred for 24 hours at 25-30°C and precipitated material
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filtered, dried for 12 hours at 50-55°C in a vacuum tray drier to obtain 4 g of Lumacaftor polymorph (AL-1) with PXRD as shown in fig-1.
Example 2: Preparation of Lumacaftor solvate form A Lumacaftor (2 g) was added to a stirred solution of 1,3-dioxolane (30 ml) at 25-30°C, reaction mixture was heated to 100-110°C and stirred for 1 hour at 100-110°C then cooled to 5 25-30°C. Then reaction mixture stirred for 24 hours at 25-30°C and precipitated material filtered, dried for 12 hours at 50-55°C in a vacuum tray drier to obtain 1. g of Lumacaftor solvate form A with PXRD as shown in fig-2.
Example 3: Preparation of Lumacaftor solvate form A Lumacaftor (2 g) was added to a stirred solution of dichloromethane (125 ml) at 25-30°C, 10 reaction mixture was heated to 35-40°C and stirred for 1 hour at 35-40°C then cooled to 25-30°C. Then reaction mixture stirred for 24 hours at 25-30°C and precipitated material filtered, dried for 8 hours at 50-55°C in a vacuum tray drier to obtain 1.8 g of solvate form A with PXRD as shown in fig-3. ,CLAIMS:solution of Lumacaftor in a suitable solvent or mixture of solvents at a suitable temperature; and 5
b. isolating the crystalline form Al-1 Lumacaftor.
wherein, the suitable solvent solvent is benzonitrile and the suitable temperature is in the range 30 °C to about 110 °C.
2. The crystalline form AI-1 obtained according to process claimed in claim 1, is characterized having X-ray powder diffractogram peak comprising at least one 10 peak at diffraction 2? angle (2? ±0.2) selected from 7.05, 12.52, 14.81, 15.49, 16.24, 17.28 and 18.50 ± 0.2.
3. A pharmaceutical composition comprising crystalline form Al-1 obtained according to claim 1, and one or more pharmaceutically acceptable excipients.