DESC:
Field of the Invention:
The present invention relates to a crystalline form L1 and amorphous form of elexacaftor and process for their preparation. It also provides a pharmaceutical composition comprising elexacaftor.

Background of the Invention:
Elexacaftor (I) is chemically known as N-(1,3-dimethylpyrazol-4-yl) sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy) pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl] pyridine-3-carboxamide and is represented by the following structure.

(I)
Elexacaftor is a small molecule, next-generation corrector of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Elexacaftor in combination with tezacaftor and ivacaftor as the combination product TrikaftaTM is approved. Elexacaftor is considered a next-generation CFTR corrector as it possesses both a different structure and mechanism as compared to first generation correctors like tezacaftor. While dual corrector/potentiator combination therapy has proven useful in the treatment of a subset of CF patients, their use is typically limited to patients who are homozygous for the F508del-CFTR gene.

Several documents disclose different methods for crystallization of elexacaftor to prepare different crystalline forms by crystallization from various solvents.

Elexacaftor was first disclosed in patent US 20180162839 A1. The patent also discloses Form A, methanol solvate, ethanol solvate, 1-propanol solvate, sodium salt and potassium salt of elexacaftor. The patent also discloses the amorphous solid dispersion of elexacaftor. US 2019240197 A1 discloses pharmaceutical composition comprising of elexacaftor and solid dispersions of ivacaftor and tezacaftor.

The crystalline form L1 and amorphous form of elexacaftor obtained by the process of the present invention is different than reported in the above mentioned prior art documents and is the subject matter of the present invention.

Summary of the invention:
The present invention provides crystalline forms L1 of elexacaftor. The form L1 was obtained by crystallization of elexacaftor from methyl tertiary butyl and acetone. The amorphous form of elexacaftor was obtained by crystallization from methanol and water. The present invention further provides composition of elexacaftor with ivacaftor and tezacaftor.

Description of the Drawings:
Figure 1: X-ray powder diffractogram (XRPD) of crystalline form L1 of elexacaftor.
Figure 2: X-ray powder diffractogram (XRPD) of amorphous form of elexacaftor.

Detailed description of the invention:
Crystalline form L1 of elexacaftor:
One of the object of the present invention is related to crystalline form L1 of elexacaftor. The crystalline form L1 of elexacaftor obtained by the process of the present invention is characterized by XRPD pattern as shown in figure 1. The crystalline elexacaftor form L1 shows characteristic peaks in XRPD at 5.5, 10.3, 11.6 and 14.4 + 0.2 degree 2 ?.

Another object of the present invention is to provide a process for the preparation of elexacaftor crystalline form L1 which comprises dissolution of elexacaftor in ketone solvent followed by addition of an antisolvent.

The ketone solvent used is selected from acetone, dimethyl ketone, ethyl methyl ketone or methyl isobutyl ketone. The most preferred solvent is acetone. The antisolvent added is selected from group comprising of alcohols such as methanol, ethanol, isopropanol; esters such as ethyl acetate, methyl acetate; ethers such dioxane, methyl tertiary butyl ether, hydrocarbons such as toluene, tetrahydrofuran and chlorinated solvents such as dichloromethane, dichloromethane, carbon tetrachloride etc; the most preferred combination of solvents is acetone-methyl tertiary butyl ether.

The quantity of solvent and antisolvent for preparation of form L1 is 1-30 times quantity of elexacaftor, preferably 2-25 times.

The dissolution of elexacaftor is carried out at a temperature 10-80°C, preferably 20-40°C.

The solution obtained can be optionally stirred. The stirring can be done at a temperature of 0-40°C, more preferably at 15-30°C. The stirring can be carried out for 5 minutes to 2 hours.

Amorphous form of elexacaftor:
Another object of the present invention is related to amorphous form of elexacaftor. The amorphous form of elexacaftor obtained by the process of the present invention is characterized by XRPD pattern as shown in figure 2.

Another object of the present invention is to provide a process for the preparation of elexacaftor amorphous form which comprises dissolution of elexacaftor in alcohol solvent followed by addition of water. The alcohol solvent used is selected from methanol, ethanol, propanol, butanol, isopropanol.

The quantity of solvent for preparation of amorphous form of elexacaftor is 1-15 times quantity of elexacaftor. The amount of water added is 5-30 times of quantity of elexacaftor.

The dissolution of elexacaftor is carried out at a temperature 20-100°C, preferably 30-80°C. To the solution, water is added and stirred. The solution may be stirred for 5 minutes to 2 hours.

Preparation of composition of elexacaftor
Disclosed herein are pharmaceutical compositions comprising Compound I. The pharmaceutical composition can be of elexacaftor alone or in combination with tezacaftor and/or ivacaftor.

The elexacaftor used in the pharmaceutical composition can be crystalline form L1 or amorphous form.

In one embodiment, the pharmaceutical composition of the disclosure comprises polymers, one or more fillers, a disintegrant, and a lubricant.

As discussed herein, the polymer can be a pH-dependent enteric polymer. Such pH-dependent enteric polymers include, but are not limited to, cellulose derivatives (e.g., cellulose acetate phthalate (CAP)), hydroxypropyl methyl cellulose phthalates (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), carboxymethylcellulose (CMC) or a salt thereof (e.g., a sodium salt such as (CMC-Na)); cellulose acetate trimellitate (CAT), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethyl-cellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP), or polymethacrylates (e.g., Eudragit® S). In some embodiments, the polymer is hydroxypropyl methyl cellulose acetate succinate (HPMCAS). In some embodiments, the polymer is hydroxypropyl methyl cellulose acetate succinate HG grade (HPMCAS-HG). [0140] Fillers suitable for the pharmaceutical compositions disclosed herein are compatible with the other ingredients of the pharmaceutical compositions, i.e., they do not substantially reduce the solubility, the hardness, the chemical stability, the physical stability, or the biological activity of the pharmaceutical compositions. Exemplary fillers include: celluloses, modified celluloses, (e.g. sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose), cellulose acetate, microcrystalline cellulose, calcium phosphates, dibasic calcium phosphate, starches (e.g. corn starch, potato starch), sugars (e.g., mannitol, lactose, sucrose, or the like), or any combination thereof. In one embodiment, the filler is microcrystalline cellulose.

In some embodiments, the pharmaceutical compositions comprises one or more fillers selected from microcrystalline cellulose, for example MCC Avicel PH102 or Avicel PH101, by weight of the pharmaceutical composition.

Disintegrants suitable for the pharmaceutical compositions disclosed herein can enhance the dispersal of the pharmaceutical compositions and are compatible with the other ingredients of the pharmaceutical compositions, i.e., they do not substantially reduce the chemical stability, the physical stability, the hardness, or the biological activity of the pharmaceutical compositions. Exemplary disintegrants include croscarmellose sodium, sodium starch glycolate, crospovidone or a combination thereof. In one embodiment, the disintegrant is croscarmellose sodium.

In some embodiments, the pharmaceutical compositions disclosed herein comprise a lubricant. A lubricant can prevent adhesion of a mixture component to a surface (e.g., a surface of a mixing bowl, a granulation roll, a compression die and/or punch). A lubricant can also reduce interparticle friction within the granulate and improve the compression and ejection of compressed pharmaceutical compositions from a granulator and/or die press. A suitable lubricant for the pharmaceutical compositions disclosed herein is compatible with the other ingredients of the pharmaceutical compositions, i.e., they do not substantially reduce the solubility, the hardness, or the biological activity of the pharmaceutical compositions. Exemplary lubricants include magnesium stearate, sodium stearyl fumarate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil or any combination thereof. In embodiment, the lubricant is magnesium stearate.

In some embodiments, the pharmaceutical compositions disclosed herein are tablets. Another aspect of the disclosure provides a spray dried dispersion comprising one or more APIs, wherein the dispersion is substantially free of a polymer, and wherein the spray dried dispersion is generated by (i) providing a mixture that consists essentially of one or more APIs and a solvent; and (ii) forcing the mixture through a nozzle under spray drying conditions to generate the spray dried dispersion.

Any suitable spray dried dispersions of ivacaftor and tezacaftor can be used for the pharmaceutical compositions disclosed herein.

The methods of present invention have been described in the foregoing examples.

Examples
The XRPD patterns were recorded on PANanalytical of model PW/3040/60X’Pert Pro.
Preparation of form L1

Example 1: Preparation of form L1

Elexacaftor (0.44 g) was dissolved in acetone (0.8 ml) at 55°C. The solution was cooled to 25°C. The above solution was dumped to pre chilled methyl tertiary butyl ether (8 ml) and stirred for 15 minutes at -20°C. The crystalline product obtained was filtered and dried at 40°C. The product was further dried under reduced pressure.
Weight: 0.30 g
Example 2: Preparation of amorphous form of elexacaftor

Elexacaftor (0.4 g) was dissolved in methanol (3.2ml) and the mixture was heated at 65°C for 25 minutes to get a clear solution. The solution was cooled to 25°C. This solution was added to pre chilled water (8 ml) at 0°C. The precipitate was stirred for 15 minutes and filtered. The solid was dried at 40°C and further dried under reduced pressure.

Weight: 0.23 g
,CLAIMS:
1) A crystalline form L1 of elexacaftor having 2 theta values at 5.5, 10.3, 11.6, 14.4 + 0.2 °.

2) The crystalline form L1 of elexacaftor according to 1, having XRPD as shown in Figure 1.

3) A Process for the preparation of elexacaftor crystalline form L1 comprising dissolving elexacaftor in ketone solvent followed by addition of the solution in an antisolvent.

4) The process of claim 3 wherein ketone solvent used is selected from acetone, dimethyl ketone, ethyl methyl ketone or methyl isobutyl ketone.

5) The process of claim 3 wherein antisolvent added is selected from alcohols such as methanol, ethanol, isopropanol; esters such as ethyl acetate, methyl acetate; ethers such dioxane, methyl tertiary butyl ether, hydrocarbons such as toluene, tetrahydrofuran and chlorinated solvents such as dichloromethane, dichloromethane, carbon tetrachloride.

6) A process for the preparation of elexacaftor amorphous form which comprises dissolution of elexacaftor in alcohol solvent followed by addition of the solution in water.

7) The process of claim 6 wherein alcohol solvent used is selected from methanol, ethanol, propanol, butanol, isopropanol.

8) The amorphous form of elexacaftor obtained by the process of claim 6, having XRPD as shown in Fig 2.