DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

A PROCESS FOR THE PREPARATION OF ELEXACAFTOR

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed:
FIELD OF THE INVENTION

The present invention relates to a process for the preparation of amorphous Elexacaftor of Formula-I.

BACKGROUND OF THE INVENTION

Elexacaftor of Formula-I is chemically known as N-(1,3-dimethyl-1H-pyrazole-4-sulfonyl)-6-[3-(3,3,3­trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl] -2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide. Elexacaftor has been approved in combination with Tezacaftor and Ivacaftor under the brand name Trikafta®. Trikafta® is used for the treatment of cystic fibrosis (CF) in patients aged 12 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

US 10793547 (herein after referred as ‘547) disclosed a process for the preparation of Elexacaftor by reacting 2-chloro-N-(1,3-dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]pyridine-3-carboxamide of Formula-II with (4S)-2,2,4-trimethyl pyrrolidine hydrochloride of Formula-III in the presence of potassium carbonate to obtain Elexacaftor as white solid. The process is depicted below, as Scheme – I:

Scheme - I
Elexacaftor exist in different polymorphic forms. Polymorphism is often characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements of the molecules in the crystal lattice.

The US ‘547 patent disclosed different crystalline forms of Elexacaftor including crystalline Form – A; Form – E; Form – M; Form – X; Form – Y; Form – P2; Form – P1; Form – PA; Form – AN; Form – MK; Form – AA1; Form – AA2 and amorphous form.

“Amorphous" refers to a solid material having no long range order in the position of its molecules. Amorphous solids are generally super cooled liquids in which the molecules are arranged in a random manner so that there is no well-defined arrangement, e.g., molecular packing, and no long range order. Amorphous solids are generally isotropic, i.e. exhibit similar properties in all directions and do not have definite melting points. For example, an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid.

The present invention provides stable amorphous Elexacaftor, as well as a process for the preparation thereof. Amorphous Elexacaftor may provide different advantages in a variety of capacities, for example, in formulation, stability of the form, stability of the formulation, and in pharmacokinetic profiles.
OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide a process for the preparation of amorphous Elexacaftor.

SUMMARY OF THE INVENTION

In an embodiment, the present invention provides a process for the preparation of amorphous Elexacaftor,
which comprises:
a. providing a solution of Elexacaftor in a solvent;
b. optionally filtering the solution of step (a);
c. adding the above Elexacaftor filtrate to an anti-solvent or vice versa,
d. isolating amorphous Elexacaftor.

BRIEF DESCRIPTION OF THE DRAWINGS

Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing wherein:

FIG. 1 is a powder X-ray diffraction pattern of amorphous Elexacaftor.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for the preparation of amorphous Elexacaftor.

The process comprises by providing a solution of Elexacaftor in a solvent, optionally filtering the solution, adding the above Elexacaftor filtrate to an anti-solvent or vice versa and isolating amorphous Elexacaftor.
The solvent comprises “hydrocarbon solvents” selected form n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and mixtures thereof; “ether solvents” selected from dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and mixtures thereof; “ester solvents” selected from methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and mixtures thereof; “polar-aprotic solvents” selected from dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and mixtures thereof; “chloro solvents” selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride and mixtures thereof; “ketone solvents” selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and mixtures thereof; “nitrile solvents” selected from acetonitrile, propionitrile, isobutyronitrile and mixtures thereof; “alcohol solvents” selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, 2-butanol, tert-butanol, ethane-1,2-diol, propane-1,2-diol and mixtures thereof; “polar solvents” selected from formic acid, acetic acid and the like or mixture of any of the afore mentioned solvents.

The dissolution is carried out at a temperature ranging from about 10 – 50 °C.

Filtration of the Elexacaftor solution is carried out through a micro-filter or a nano-filter.

Anti-solvent used is capable of initiating precipitation of Elexacaftor from solution comprises water or an aqueous solution of solvent used in the first step.

The temperature of the solution with anti-solvent is maintained at a temperature of about -10 to 15 °C for 2 – 5 hours to obtain the solid.

The term vice versa is used to indicate that a statement is also true if anti-solvent is added to Elexacaftor filtrate in step c).

Amorphous Elexacaftor may then be isolated. Isolation may be carried out by methods well known in the art, for example, by filtering and drying the obtained solid.

The amorphous Elexacaftor disclosed herein may be incorporated into oral pharmaceutical dosage forms, for example, a capsule or tablet. Dosage forms that include the amorphous Elexacaftor herein may be useful for treatment of cystic fibrosis transmembrane conductance regulator (CFTR) gene.

The oral dosage forms containing amorphous Elexacaftor may further comprise one or more additional pharmaceutically acceptable excipients such as, for example, hypromellose, hypromellose acetate succinate, sodium lauryl sulfate, croscarmellose sodium, microcrystalline cellulose and magnesium stearate.

The following examples are provided to illustrate the process of the present invention. They, are however, not intended to limit the scope of the present invention in any way and several variants of these examples would be evident to person ordinarily skilled in the art.

EXAMPLE-1:

Preparation of amorphous form of Elexacaftor [Formula-I]:

Elexacaftor (95 grams) was dissolved in acetone (190 mL) at 20 to 30 °C and the solution was filtered through micro filter. The filtrate was added to a pre-cooled mixture of 90% v/v aqueous acetone (1710 mL) at -2 to -5 °C. The resulting suspension was stirred at this temperature for 3 hours. The solid was filtered, washed with water and dried to obtain amorphous form of Elexacaftor (90 grams) as white powder.

Yield: 95%;
Purity: 99.9% by HPLC.

EXAMPLE-2:

Preparation of amorphous form of Elexacaftor [Formula-I]:

Elexacaftor (5 grams) was dissolved in N,N-dimethylformamide (10 mL) at 20 to 30 °C and the solution was filtered through micro filter. The filtrate was added to a pre-cooled mixture of 90% v/v aqueous N,N-dimethylformamide (100 mL) at 0 to -5 °C. The resulting suspension was stirred at this temperature for 4 hours. The solid was filtered, washed with water and dried to obtain amorphous form of Elexacaftor (4.7 grams) as white powder.

Yield: 95%;
Purity: 99.84% by HPLC.

EXAMPLE-3:

Preparation of amorphous form of Elexacaftor [Formula-I]:

Elexacaftor (5 grams) was dissolved in acetic acid (10 mL) at 20 to 30 °C and the solution was filtered through micro filter. The filtrate was added to a pre-cooled water (100 mL) at 0 to 5 °C. Thereafter, the resulting suspension was stirred at this temperature for 4 hours. The solid was filtered, washed with water and dried to obtain amorphous form of Elexacaftor (3.5 grams) as white powder.
,CLAIMS:CLAIMS:
We claim,
1. A process for the preparation of amorphous elexacaftor, which comprises
a. providing a solution of elexacaftor in a solvent;
b. optionally, filtering the solution from step (a);
c. adding the above elexacaftor filtrate to an anti-solvent or vice versa;
d. isolating amorphous elexacaftor.

2. The process as claimed in claim 1, wherein the solvent in step (a) comprises hydrocarbon solvents selected from benzene, toluene, xylene or mixture there of; ether solvents selected from dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether or mixture thereof; ester solvents selected from methyl acetate, ethyl acetate, n-propyl acetate or mixture thereof; polar aprotic solvents selected from dimethylacetamide, dimethylformamide, dimethyl sulfoxide or mixture thereof; chloro solvents selected from dichloromethane, dichloroethane, chloroform or mixture thereof , ketone solvents selected from acetone, methyl ethyl ketone, methyl isobutyl ketone or mixture thereof; alcohol solvents selected from methanol, ethanol, n-propanol, isopropanol or mixture thereof; polar solvents selected from formic acid, acetic acid or mixtures thereof.

3. The process as claimed in claim 1, wherein the anti-solvent in step (c) comprises water or an aqueous solution of solvent used in step (a).

4. The process as claimed in claim 1, wherein filtration at step (b) is carried-out through micro-filter or nano-filter.

5. The process as claimed in claim 1, wherein the isolation of elexacaftor in step (d) is carried out by cooling the reaction mixture.