DESC:
FIELD OF THE INVENTION
The present invention relates to novel crystalline form of Tezacaftor and process for preparation thereof.

BACKGROUND OF THE INVENTION
Tezacaftor is indicated for the treatment of patients with cystic fibrosis, it is available in combination with ivacaftor as Symdeko ®. The chemical name for tezacaftor is 1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1Hindol-5-yl}cyclopropane-1-carboxamide.

The application US 2009/0131492 mentions tezacaftor and analogous compounds useful as modulators of ATP-Binding Cassette transporters or fragments, including cystic fibrosis transmembrane conductance regulator. The application WO 2011119984 A1 describes solid forms of tezacaftor.

The existence and possible number of solid forms for a given compound cannot be predicted, and there are no standard procedures that may be used to prepare solid forms of a substance. Discovery of new solid forms, hydrates or solvates of an active pharmaceutical ingredient is an important aspect as it provides broader scope to a formulation scientist for formulation optimization like better processing and handling, improved dissolution profile, improved shelf-life.

Hence, there is a persistent need for polymorphic forms of active pharmaceutical ingredient having better physicochemical properties. The present invention provides novel crystalline form of Tezacaftor.

SUMMARY OF THE INVENTION
The present invention provides novel crystalline form L of Tezacaftor characterized by diffraction peaks at 11.3, 18.2 and 21.3 ± 0.2 degree two theta in an X-ray diffraction pattern. The present invention further provides process for preparation of crystalline form L.

DESCRIPTION OF DRAWINGS
Figure 1 – X-ray powder diffraction pattern of crystalline form L of tezacaftor.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel crystalline form of tezacaftor and process for its preparation.

In one embodiment, the present invention provides crystalline form L of tezacaftor. The crystalline form L of tezacaftor having characteristic diffraction peaks at 11.3, 18.2 and 21.3 ± 0.2 degree two theta in an X-ray diffraction pattern. The crystalline form L of tezacaftor having addition characteristic diffraction peaks at 9.8 and 16.0 ± 0.2 degree two theta in an X-ray diffraction pattern.

The crystalline form L of tezacaftor having characteristic diffraction peaks at 9.8, 11.3, 18.2, 16.0 and 21.3 ± 0.2 degree two theta in an X-ray diffraction pattern. The crystalline form L of tezacaftor of the present invention is characterized by X-ray powder diffraction pattern as depicted in Figure 1.

The crystalline form L of tezacaftor having characteristic infrared absorption at 1075, 1234, 1492, 1677 and 3232± 2 cm-1.

The crystalline form L of tezacaftor is substantially pure. The term “substantially pure” refers to crystalline form L of tezacaftor that does not contain detectable levels of any other polymorphs of tezacaftor. Purity of the form can be determined by analytical methods known in the art. The present invention provides a substantially pure crystalline form L of tezacaftor characterized by diffraction peaks and X-ray powder diffraction pattern as described above.

In yet another embodiment, the present invention provides a process for the preparation of crystalline form L of tezacaftor comprising the steps of:
a) dissolving tezacaftor in a solvent,
b) adding an anti-solvent, and
c) isolating form L of tezacaftor.

The solvent can be selected from polar solvent. Polar solvent as ether like tetrahydrofuran, dioxane, dimethoxyethane; esters like ethyl acetate and ethyl chloroformate.

The antisolvent can be selected from non-polar solvents. Non-polar solvents can be selected from acyclic and cyclic hydrocarbon like hexane, cyclohexane, n-heptane, pentane, cyclopentane, toluene.

Process for the preparation of crystalline form L of tezacaftor comprises dissolving tezacaftor in the solvent by heating the mixture to a temperature of about 30°C to the reflux temperature of the solvent, adding anti-solvent at a temperature of below 30°C and isolating by techniques known in art like filtration, concentration, removal of solvent by evaporation, distillation, flash evaporation, drying on rotavapor.

Tezacaftor which is used for preparation of crystalline form L of the present invention can be prepared by methods known in the literature.

Crystalline form L of tezacaftor is suitable for preparation of pharmaceutical composition. The pharmaceutical composition of crystalline form L of tezacaftor along with pharmaceutically acceptable carriers, excipients or diluents can be prepared by methods known in the art. The pharmaceutical compositions containing crystalline form L of tezacaftor can be used for treatment of cystic fibrosis.

The X-ray powder diffraction pattern was recorded at room temperature using PANalytical X’Pert PRO diffractogram with Cu Ka radiation (? = 1.54060 Å), running at 45 kV and 40 mA.

The infrared absorption spectrum was obtained using a Perkin Elmer Precisely Spectrum 400 instrument using KBr pellet method.

The present invention is further illustrated by the following representative examples and does not limit the scope of the invention.

Examples
1. Process for preparation of crystalline form L of tezacaftor.
A mixture of tezacaftor (0.5 g) and ethyl chloroformate (4 ml) was stirred at 55°C. The mixture was cooled and cyclohexane (16 ml) was added and to it. The solid was collected by filtration and dried under vacuum.

2. Process for preparation of crystalline form L of tezacaftor.
A mixture of tezacaftor (1 g) and tetrahydrofuran (2 ml) was stirred at 65°C. The mixture was cooled and cyclohexane (64 ml) was added and to it. The solid was collected by filtration and dried under vacuum.
,CLAIMS:
1. A process for the preparation of crystalline form L of tezacaftor comprising the steps of:
a) dissolving tezacaftor in a solvent,
b) adding an anti-solvent, and
c) isolating form L of tezacaftor.

2. The crystalline form L of tezacaftor of claim 1, having characteristic diffraction peaks at 11.3, 18.2 and 21.3 ± 0.2 degree two theta in an X-ray diffraction pattern.

3. The crystalline form L of tezacaftor of claim 1, having additional characteristic diffraction peaks at 9.8 and 16.0 ± 0.2 degree two theta in an X-ray diffraction pattern.

4. The crystalline form L of tezacaftor of claim 1, having X-ray powder diffraction pattern as depicted in Figure 1.

5. The crystalline form L of tezacaftor of claim 1, having characteristic infrared absorption at 1075, 1234, 1492, 1677 and 3232± 2 cm-1.

6. The process according to claim 1, wherein solvent is a polar solvent.

7. The process according to claim 8, wherein polar solvent is tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate or ethyl chloroformate.

8. The process according to claim 1, wherein anti-solvent is a non-polar solvent.

9. The process according to claim 8, wherein non-polar solvent is hexane, cyclohexane, n-heptane, pentane, cyclopentane or toluene.