DESC:INTRODUCTION
Aspects of the present application relates to crystalline forms of Fevipiprant process for the preparation thereof and pharmaceutical formulations of crystalline forms of Fevipiprant.
Fevipiprant is the adopted name of drug compound having a chemical name: 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid and structure as below.

Novartis is developing Fevipiprant, also known as QAW-039, a prostaglandin D2 receptor (PD2/CRTh2) antagonist, as an oral capsule formulation for the potential treatment of asthma and moderate to severe atopic dermatitis.
US 7666878 B2 discloses Fevipiprant [1-(4-Methanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid] its composition and use for treating inflammatory or allergic condition for which antagonism of the CRTh2 receptor is useful such as intrinsic asthma, extrinsic asthma, mild asthma, moderate asthma, severe asthma, bronchitis asthma, exercise-induced asthma, occupational asthma or bacterial infection induced asthma.
US 7666878 B2 discloses the preparation of Fevipiprant and the resultant product is isolated from the reaction mixture through removal of solvent in vacuo and the crude is triturated with diethyl ether, DCM and ethyl acetate. The resulting solid is dissolved in hot water (150 ml) and adjusted to pH 3-4 using 6M HCl. The suspension that forms is filtered and is further purified by dissolving in hot IPA (250 ml) and refluxing in the presence of charcoal for 5 minutes. The solution is filtered and the titled product is re-crystallized from water/IPA as a white/pale green crystals. Further, no other physical characteristics of Fevipiprant disclosed.
CN106188040A discloses Fevipiprant crude product was recrystallized from ethanol to give pure product. No other physical characteristics of Fevipiprant disclosed.
The physicochemical properties of a solid form is a critical parameter in the development of pharmaceutical dosage forms and these properties can affect the bioavailability, stability and processability of the active pharmaceutical ingredient. It is known that a solid active pharmaceutical ingredient can exist in amorphous and crystalline state. Crystalline solids may further exist as various polymorphs and solvates.
The discovery of new polymorphs and solvates of a pharmaceutical active compound provides an opportunity to improve the performance of a drug product in terms of its bioavailability or release profile in vivo, or it may have improved stability or advantageous handling properties. Polymorphism is an unpredictable property of any given compound. This subject has been reviewed in articles, including A. Goho, "Tricky Business," Science News, August 21, 2004. In general, one cannot predict whether there will be more than one form for a compound, how many forms will eventually be discovered, or how to prepare any previously unidentified form.
The discovery of new forms of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, storage stability, and ease of purification. Accordingly, the present inventors have found novel crystalline form of Fevipiprant (FP6, FP7 and FP8) with enhanced storage stability, solubility and processability.
SUMMARY
In an aspect, the present application provides a crystalline form of Fevipiprant (FP6), characterized by a PXRD pattern comprising the peaks at about 5.44, 8.18, 10.91, 15.35 and 16.44± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP6), characterized by a PXRD pattern comprising the peaks at about 5.44, 8.18, 10.91, 15.35 and 16.44± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with acetic acid;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding heptane as anti solvent to the solution obtained in step d);
f) isolating the crystalline form of Fevipiprant (FP6).

In an aspect, the present application provides a crystalline form of Fevipiprant (FP7), characterized by a PXRD pattern comprising the peaks at about 12.97, 13.88, 15.04 and 17.11 ± 0.2° 2?.
In an aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP7), comprising the steps of;
a) combining Fevipiprant with DMF;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding DIPE as anti solvent to the solution obtained in step d);
f) isolating the crystalline form of Fevipiprant (FP7).

In an aspect, the present application provides a crystalline form of Fevipiprant (FP8), characterized by a PXRD pattern comprising the peaks at about 10.20, 13.73 and 20.33± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP8), characterized by a PXRD pattern comprising the peaks at about 10.20, 13.73 and 20.33± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with 1,4-dioxane;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding anti solvent to the solution obtained in step d);
f) isolating the crystalline form of Fevipiprant (FP8).

In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP2), characterized by a PXRD pattern comprising the peaks at about 5.0, 13.7, 19.6, 20.3 and 21.8± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with acetone;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) isolating the crystalline form of Fevipiprant (FP2).

In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP2), characterized by a PXRD pattern comprising the peaks at about 5.0, 13.7, 19.6, 20.3 and 21.8± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with methanol;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding anti solvent selected from heptane, pentane or mixture thereof to the solution obtained in step d);
f) isolating the crystalline form of Fevipiprant (FP2).

In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP5), characterized by a PXRD pattern comprising the peaks at about 3.89 and 15.28 ± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with dimethyl sulfoxide;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) isolating the crystalline form of Fevipiprant (FP5)

In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP5), characterized by a PXRD pattern comprising the peaks at about 3.89 and 15.28 ± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with dimethyl sulfoxide;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding anti solvent to the solution obtained in step d);
f) isolating the crystalline form of Fevipiprant (FP5).

In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP1), characterized by a PXRD pattern comprising the peaks at about 12.07, 17.49, 19.85, 21.16 and 24.35 ± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with the solvent selected from formic acid, propionic acid, dimethylacetamide, tetrahydrofuran, ethanol, isopropyl alcohol, 1-propanol, benzyl alcohol, recemic propylene glycol, (R)-propylene glycol, 2-methoxy ethanol, N-methyl pyrrolidone, acetone or mixture thereof;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding anti solvent selected from MTBE, water, heptane, DIPE, cyclohexane, xylene, toluene, pentane or mixture thereof to the solution obtained in step d);
f) isolating the crystalline form of Fevipiprant (FP1).
In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP1), characterized by a PXRD pattern comprising the peaks at about 12.07, 17.49, 19.85, 21.16 and 24.35 ± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with the solvent selected from acetic acid, DMF or mixture thereof;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding anti solvent selected from MTBE, water or mixture thereof to the solution obtained in step d);
f) isolating the crystalline form of Fevipiprant (FP1).

In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP1), characterized by a PXRD pattern comprising the peaks at about 12.07, 17.49, 19.85, 21.16 and 24.35 ± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with methanol;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding water as anti solvent to the solution obtained in step d);
f) isolating the crystalline form of Fevipiprant (FP1).

In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP1), characterized by a PXRD pattern comprising the peaks at about 12.07, 17.49, 19.85, 21.16 and 24.35 ± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with the solvent selected from methanol, acetonitrile, IPA or mixture thereof ;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) isolating the crystalline form of Fevipiprant (FP1).

In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP1), characterized by a PXRD pattern comprising the peaks at about 12.07, 17.49, 19.85, 21.16 and 24.35 ± 0.2° 2?, comprising the steps of:
a) dissolving or suspending crystalline form of Fevipiprant selected from FP2, FP6 and FP7 in water;
b) isolating the crystalline form of Fevipiprant (FP1).

In another aspect, the present application provides a Fevipiprant co-crystal with Caffeine (Form FC), characterized by a PXRD pattern comprising the peaks at about 9.66, 13.20, 16.00, 17.23, 18.74, 20.49, 21.49 and 22.71 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of Fevipiprant co-crystal with Caffeine (Form FC), characterized by a PXRD pattern comprising the peaks at about 9.66, 13.20, 16.00, 17.23, 18.74, 20.49, 21.49 and 22.71 ± 0.2° 2?, comprising the steps of:
a) dissolving Fevipiprant and caffeine in tetrahydrofuran;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) adding water as anti solvent to the solution obtained in step b) or c);
e) cooling the solution obtained in step d);
f) isolating the Fevipiprant co-crystal with Caffeine (Form FC).

In another aspect, the present application provides a pharmaceutical composition comprising crystalline forms of Fevipiprant (FP1, FP2, FP5, FP6, FP7, FP8 and Form FC) with atleast one pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline form of Fevipiprant (FP6) prepared by the method of Example No 1
Figure 2 is an illustrative X-ray powder diffraction pattern of crystalline form of Fevipiprant (FP7) prepared by the method of Example No 2
Figure 3 is an illustrative X-ray powder diffraction pattern of crystalline form of Fevipiprant (FP8) prepared by the method of Example No 3
Figure 4 is an illustrative X-ray powder diffraction pattern of Fevipiprant co-crystals with caffeine (Form FC) prepared by the method of Example No 24
DETAILED DESCRIPTION
Aspects of the present application relates to crystalline forms of Fevipiprant process for the preparation thereof and pharmaceutical formulations of crystalline forms of Fevipiprant.
In an aspect, the present application provides a crystalline form of Fevipiprant (FP6), characterized by a PXRD pattern comprising the peaks at about 5.44, 8.18, 10.91, 15.35 and 16.44± 0.2° 2?. Crystalline form of Fevipiprant (FP6) further characterized by PXRD pattern comprising peaks at about 17.96, 19.33, 20.87, 21.93 and 24.78±0.2°2?. Crystalline form of Fevipiprant (FP6) is also characterized by its X-ray powder diffractogram as substantially shown in FIG. 1
In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP6), characterized by a PXRD pattern comprising the peaks at about 5.44, 8.18, 10.91, 15.35 and 16.44± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with acetic acid;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding heptane as anti solvent to the solution obtained in step d);
f) isolating the crystalline form of Fevipiprant (FP6).
In an embodiment of step a), combining Fevipiprant with acetic acid (or) by taking the reaction mixture containing Fevipiprant and acetic acid.
In an embodiment of step b), the heating may be carried out at temperature ranging from about 45°C to 100°C. The reaction mass may be maintained at the same temperature for any time period, such as from about 10 minutes to 5 hours or longer.
In embodiments of step c), the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In an embodiment of step d), cooling the solution may be carried out at temperature ranging from about -10°C to 15°C.
In embodiments of step e), adding heptane as anti solvent to the solution obtained in step d).
In embodiment of step e), the isolation may be effected by combining the solution of step d) with a suitable anti-solvent. Adding the solution obtained in step d) to the anti-solvent, or adding an anti-solvent to the solution obtained in step d), to effect the crystallization process are both within the scope of the present invention. After adding anti-solvent, the reaction mass may be maintained from 15 minutes to 15 hours or longer.
In embodiments of step f), the isolation of crystalline form of Fevipiprant (FP6) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline form of Fevipiprant (FP6) may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
The isolated product may be optionally further dried to afford crystalline form of Fevipiprant (FP6).
Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.

In an aspect, the present application provides a crystalline form of Fevipiprant (FP7), characterized by a PXRD pattern comprising the peaks at about 12.97, 13.88, 15.04 and 17.11 ± 0.2° 2?. Crystalline form of Fevipiprant (FP7) is characterized by its X-ray powder diffractogram as substantially shown in FIG. 2
In an aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP7), comprising the steps of;
a) combining Fevipiprant with DMF;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding DIPE as anti solvent to the solution obtained in step d);
f) isolating the crystalline form of Fevipiprant (FP7).
In an embodiment of step a), combining Fevipiprant with DMF (or) by taking the reaction mixture containing Fevipiprant and DMF.
In an embodiment of step b), the heating may be carried out at temperature ranging from about 45°C to 100°C. The reaction mass may be maintained at the same temperature for any time period, such as from about 10 minutes to 5 hours or longer.
In embodiments of step c), the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In an embodiment of step d), cooling the solution may be carried out at temperature ranging from about -10°C to 25°C.
In embodiments of step e), adding DIPE as anti solvent to the solution obtained in step d).
In embodiment of step e), the isolation may be effected by combining the solution of step d) with a suitable anti-solvent. Adding the solution obtained in step d) to the anti-solvent, or adding an anti-solvent to the solution obtained in step d), to effect the crystallization process are both within the scope of the present invention. After adding anti-solvent, the reaction mass may be maintained from 15 minutes to 15 hours or longer.
In embodiments of step f), the isolation of crystalline form of Fevipiprant (FP7) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline form of Fevipiprant (FP7) may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
The isolated product may be optionally further dried to afford crystalline form of Fevipiprant (FP7).
Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.

In an aspect, the present application provides a crystalline form of Fevipiprant (FP8), characterized by a PXRD pattern comprising the peaks at about 10.20, 13.73 and 20.33± 0.2° 2?. Crystalline form of Fevipiprant (FP8) is also characterized by its X-ray powder diffractogram as substantially shown in FIG. 3
In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP8), characterized by a PXRD pattern comprising the peaks at about 10.20, 13.73 and 20.33± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with 1,4-dioxane;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding anti solvent to the solution obtained in step d);
f) isolating the crystalline form of Fevipiprant (FP8).
In an embodiment of step a), combining Fevipiprant with 1,4-dioxane (or) by taking the reaction mixture containing Fevipiprant and 1,4-dioxane.
In an embodiment of step b), the heating may be carried out at temperature ranging from about 45°C to 90°C. The reaction mass may be maintained at the same temperature for any time period, such as from about 10 minutes to 5 hours or longer.
In embodiments of step c), the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In an embodiment of step d), cooling the solution may be carried out at temperature ranging from about -10°C to 10°C.
In embodiments of step e), adding suitable anti solvent to the reaction mass of step d), wherein the anti-solvent include, but are not limited to heptane, MTBE, water, DIPE, cyclohexane, xylene, toluene, pentane or mixture thereof.
In embodiment of step e), the isolation may be effected by combining the solution of step d) with a suitable anti-solvent. Adding the solution obtained in step d) to the anti-solvent, or adding an anti-solvent to the solution obtained in step d), to effect the crystallization process are both within the scope of the present invention. After adding anti-solvent, the reaction mass may be maintained from 15 minutes to 15 hours or longer.
In embodiments of step f), the isolation may be done using techniques such as direct filtration or by scraping, or by shaking the container.
The isolated product may be optionally further dried to afford crystalline form of Fevipiprant (FP8).
Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.

In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP2), characterized by a PXRD pattern comprising the peaks at about 5.0, 13.7, 19.6, 20.3 and 21.8± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with acetone;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) isolating the crystalline form of Fevipiprant (FP2).
In an embodiment of step a), combining Fevipiprant with acetone (or) by taking the reaction mixture containing Fevipiprant and acetone.
In an embodiment of step b), the heating may be carried out at temperature ranging from about 45°C to 80°C. The reaction mass may be maintained at the same temperature for any time period, such as from about 10 minutes to 5 hours or longer.
In embodiments of step c), the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In an embodiment of step d), cooling the solution may be carried out at temperature ranging from about -10°C to 10°C.
In embodiments of step e), the isolation of crystalline form of Fevipiprant (FP2) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline form of Fevipiprant (FP2) may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
The isolated product may be optionally further dried to afford crystalline form of Fevipiprant (FP2).
Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.

In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP2), characterized by a PXRD pattern comprising the peaks at about 5.0, 13.7, 19.6, 20.3 and 21.8± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with methanol;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding anti solvent selected from heptane, pentane or mixture thereof to the solution obtained in step d);
f) isolating the crystalline form of Fevipiprant (FP2).
In an embodiment of step a), combining Fevipiprant with methanol (or) by taking the reaction mixture containing Fevipiprant and methanol.
In an embodiment of step b), the heating may be carried out at temperature ranging from about 45°C to 80°C. The reaction mass may be maintained at the same temperature for any time period, such as from about 10 minutes to 5 hours or longer.
In embodiments of step c), the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In an embodiment of step d), cooling the solution may be carried out at temperature ranging from about -80°C to 10°C.
In embodiments of step e), adding anti solvent selected from heptane, pentane or mixture thereof to the solution obtained in step d).
In embodiment of step e), the isolation may be effected by combining the solution of step d) with a suitable anti-solvent. Adding the solution obtained in step d) to the anti-solvent, or adding an anti-solvent to the solution obtained in step d), to effect the crystallization process are both within the scope of the present invention. After adding anti-solvent, the reaction mass may be maintained from 15 minutes to 15 hours or longer.
In embodiments of step f), the isolation of crystalline form of Fevipiprant (FP2) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline form of Fevipiprant (FP2) may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
The isolated product may be optionally further dried to afford crystalline form of Fevipiprant (FP2).
Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.

In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP5), characterized by a PXRD pattern comprising the peaks at about 3.89 and 15.28 ± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with dimethyl sulfoxide;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) isolating the crystalline form of Fevipiprant (FP5).
In an embodiment of step a), combining Fevipiprant with dimethyl sulfoxide (or) by taking the reaction mixture containing Fevipiprant and dimethyl sulfoxide.
In an embodiment of step b), the heating may be carried out at temperature ranging from about 45°C to 100°C. The reaction mass may be maintained at the same temperature for any time period, such as from about 10 minutes to 5 hours or longer.
In embodiments of step c), the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In an embodiment, removal of the solvent at step d) may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using buchi rotavapor and the like.
The isolated product may be optionally further dried to afford crystalline form of Fevipiprant (FP5).
Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.

In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP5), characterized by a PXRD pattern comprising the peaks at about 3.89 and 15.28 ± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with dimethyl sulfoxide;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding anti solvent to the solution obtained in step d);
f) isolating the crystalline form of Fevipiprant (FP5).
In an embodiment of step a), combining Fevipiprant with dimethyl sulfoxide (or) by taking the reaction mixture containing Fevipiprant and dimethyl sulfoxide.
In an embodiment of step b), the heating may be carried out at temperature ranging from about 45°C to 90°C. The reaction mass may be maintained at the same temperature for any time period, such as from about 10 minutes to 5 hours or longer.
In embodiments of step c), the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In an embodiment of step d), cooling the solution may be carried out at temperature ranging from about -10°C to 30°C.
In embodiments of step e), adding suitable anti solvent to the reaction mass of step d), wherein the anti-solvent include, but are not limited to heptane, MTBE, water, DIPE, cyclohexane, xylene, toluene, pentane or mixture thereof.
In embodiment of step e), the isolation may be effected by combining the solution of step d) with a suitable anti-solvent. Adding the solution obtained in step d) to the anti-solvent, or adding an anti-solvent to the solution obtained in step d), to effect the crystallization process are both within the scope of the present invention. After adding anti-solvent, the reaction mass may be maintained from 15 minutes to 15 hours or longer.
In embodiments of step f), the isolation of crystalline form of Fevipiprant (FP5) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline form of Fevipiprant (FP5) may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
The isolated product may be optionally further dried to afford crystalline form of Fevipiprant (FP5).
Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.

In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP1), characterized by a PXRD pattern comprising the peaks at about 12.07, 17.49, 19.85, 21.16 and 24.35 ± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with the solvent selected from formic acid, propionic acid, dimethylacetamide, tetrahydrofuran, ethanol, isopropyl alcohol, 1-propanol, benzyl alcohol, recemic propylene glycol, (R)- propylene glycol, 2-methoxy ethanol, N-methyl pyrrolidone, acetone or mixture thereof;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding anti solvent selected from MTBE, water, heptane, DIPE, cyclohexane, xylene, toluene, pentane or mixture thereof to the solution obtained in step d);
f) isolating the crystalline form of Fevipiprant (FP1).
In an embodiment of step a), combining Fevipiprant with the solvent selected from formic acid, propionic acid, dimethylacetamide, tetrahydrofuran, ethanol, isopropyl alcohol, 1-propanol, benzyl alcohol, recemic propylene glycol, (R)- propylene glycol, 2-methoxy ethanol, N-methyl pyrrolidone, acetone or mixture thereof (or) by taking the reaction mixture containing Fevipiprant and the solvent selected from acetic acid, formic acid, propionic acid, DMF, dimethylacetamide, tetrahydrofuran, ethanol, isopropyl alcohol, 1-propanol, benzyl alcohol, recemic propylene glycol, (R)- propylene glycol, 2-methoxy ethanol, N-methyl pyrrolidone, acetone or mixture thereof.
In an embodiment of step b), the heating may be carried out at temperature ranging from about 45°C to 100°C. The reaction mass may be maintained at the same temperature for any time period, such as from about 10 minutes to 5 hours or longer.
In embodiments of step c), the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In an embodiment of step d), cooling the solution may be carried out at temperature ranging from about -80°C to 30°C.
In embodiments of step e), adding anti solvent selected from MTBE, water, heptane, DIPE, cyclohexane, xylene, toluene, pentane or mixture thereof to the solution obtained in step d).
In embodiment of step e), the isolation may be effected by combining the solution of step d) with a suitable anti-solvent. Adding the solution obtained in step d) to the anti-solvent, or adding an anti-solvent to the solution obtained in step d), to effect the crystallization process are both within the scope of the present invention. After adding anti-solvent, the reaction mass may be maintained from 15 minutes to 15 hours or longer.
In embodiments of step f), the isolation of crystalline form of Fevipiprant (FP1) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline form of Fevipiprant (FP1) may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
The isolated product may be optionally further dried to afford crystalline form of Fevipiprant (FP1).
Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.
In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP1), characterized by a PXRD pattern comprising the peaks at about 12.07, 17.49, 19.85, 21.16 and 24.35 ± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with the solvent selected from acetic acid, DMF or mixture thereof;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding anti solvent selected from MTBE, water or mixture thereof to the solution obtained in step d);
f) isolating the crystalline form of Fevipiprant (FP1).
In an embodiment of step a), combining Fevipiprant with the solvent selected from acetic acid, DMF or mixture thereof (or) by taking the reaction mixture containing Fevipiprant and the solvent selected from acetic acid, DMF or mixture thereof.
In an embodiment of step b), the heating may be carried out at temperature ranging from about 45°C to 100°C. The reaction mass may be maintained at the same temperature for any time period, such as from about 10 minutes to 5 hours or longer.
In embodiments of step c), the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In an embodiment of step d), cooling the solution may be carried out at temperature ranging from about -10°C to 30°C.
In embodiments of step e), adding anti solvent selected from MTBE, water or mixture thereof to the solution obtained in step d).
In embodiment of step e), the isolation may be effected by combining the solution of step d) with a suitable anti-solvent. Adding the solution obtained in step d) to the anti-solvent, or adding an anti-solvent to the solution obtained in step d), to effect the crystallization process are both within the scope of the present invention. After adding anti-solvent, the reaction mass may be maintained from 15 minutes to 15 hours or longer.
In embodiments of step f), the isolation of crystalline form of Fevipiprant (FP1) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline form of Fevipiprant (FP1) may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
The isolated product may be optionally further dried to afford crystalline form of Fevipiprant (FP1).
Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.

In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP1), characterized by a PXRD pattern comprising the peaks at about 12.07, 17.49, 19.85, 21.16 and 24.35 ± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with methanol;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding water as anti solvent to the solution obtained in step d);
f) isolating the crystalline form of Fevipiprant (FP1).
In an embodiment of step a), combining Fevipiprant with methanol (or) by taking the reaction mixture containing Fevipiprant and methanol.
In an embodiment of step b), the heating may be carried out at temperature ranging from about 45°C to 100°C. The reaction mass may be maintained at the same temperature for any time period, such as from about 10 minutes to 5 hours or longer.
In embodiments of step c), the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In an embodiment of step d), cooling the solution may be carried out at temperature ranging from about 15°C to 30°C.
In embodiments of step e), adding water as anti solvent to the solution obtained in step d)
In embodiment of step e), the isolation may be effected by combining the solution of step d) with a suitable anti-solvent. Adding the solution obtained in step d) to the anti-solvent, or adding an anti-solvent to the solution obtained in step d), to effect the crystallization process are both within the scope of the present invention. After adding anti-solvent, the reaction mass may be maintained from 15 minutes to 15 hours or longer.
In embodiments of step f), the isolation of crystalline form of Fevipiprant (FP1) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline form of Fevipiprant (FP1) may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
The isolated product may be optionally further dried to afford crystalline form of Fevipiprant (FP1).
Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.

In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP1), characterized by a PXRD pattern comprising the peaks at about 12.07, 17.49, 19.85, 21.16 and 24.35 ± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with the solvent selected from methanol, acetonitrile, IPA or mixture thereof ;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) isolating the crystalline form of Fevipiprant (FP1).
In an embodiment of step a), combining Fevipiprant with the solvent selected from methanol, acetonitrile, IPA or mixture thereof (or) by taking the reaction mixture containing Fevipiprant and the solvent selected from methanol, acetonitrile, IPA or mixture thereof.
In an embodiment of step b), the heating may be carried out at temperature ranging from about 45°C to 90°C. The reaction mass may be maintained at the same temperature for any time period, such as from about 10 minutes to 5 hours or longer.
In embodiments of step c), the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In an embodiment of step d), cooling the solution may be carried out at temperature ranging from about 15°C to 30°C.
In embodiments of step e), the isolation of crystalline form of Fevipiprant (FP1) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline form of Fevipiprant (FP1) may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
The isolated product may be optionally further dried to afford crystalline form of Fevipiprant (FP1).
Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.

In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP1), characterized by a PXRD pattern comprising the peaks at about 12.07, 17.49, 19.85, 21.16 and 24.35 ± 0.2° 2?, comprising the steps of:
a) dissolving or suspending crystalline form of Fevipiprant selected from FP2, FP6 and FP7 in water;
b) isolating the crystalline form of Fevipiprant (FP1).
In an embodiment, step a) may be carried out by dissolving or suspending crystalline form of Fevipiprant selected from FP2, FP6 and FP7 in water. Alternatively, the solution or suspension may be provided by taking the reaction mixture containing Fevipiprant in water.
In an embodiment, the crystalline form of Fevipiprant selected from FP2, FP6 and FP7 may be suspended in water at suitable temperature of about 25°C to reflux temperature.
In an embodiment, the crystalline form of Fevipiprant selected from FP2, FP6 and FP7 may be suspended in water for sufficient time to complete the formation of crystalline form of Fevipiprant (FP1) of about one hour or more.
In an embodiment, the crystalline form of Fevipiprant selected from FP2, FP6 and FP7 may be dissolved in water optionally by heating the mixture to obtain a homogenous solution. The solution may be filtered to make it particle free.
In an embodiment, the solution of crystalline form of Fevipiprant selected from FP2, FP6 and FP7 in water may be cooled to precipitate the solids to a suitable temperature at which crystalline form of Fevipiprant (FP1) is formed and / or is stable.
Isolation of crystalline form of Fevipiprant (FP1) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline form of Fevipiprant (FP1) may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In an embodiment, drying crystalline form of Fevipiprant (FP1) may be carried out at temperatures and times sufficient to achieve desired quality of product. Drying may be carried out at about 30°C or above at which crystalline form of Fevipiprant (FP1) is stable and for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP1) may be prepared from the solvent selected from
acetonitrile, chloroform, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, formamide, methanol, 2-methoxyethanol, N-methylpyrrolidone, nitromethane, tetrahydrofuran, acetic acid, acetone, 1-butanol, 2-butanol, butyl acetate, ethanol, ethyl acetate, ethyl formate, formic acid, isopropyl acetate, methyl acetate, methylethyl ketone, methylisobutyl ketone, 2-methyl-1-propanol, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, racemic propylene glycol, R-propylene glycol, S-propylene glycol, benzyl alcohol, MIPK, propionic acid or mixture thereof;
In an embodiment, the solution of Fevipiprant carried out by dissolving Fevipiprant in above solvents.
In an embodiment, the solution of Fevipiprant heating may be carried out at temperature ranging from about 45°C to 100°C. The reaction mass may be maintained at the same temperature for any time period, such as from about 10 minutes to 5 hours or longer.
In an embodiment, the solution of Fevipiprant optionally cooled to precipitate the solids to a suitable temperature at which crystalline Fevipiprant (FP1) is formed and / or is stable.
In embodiments, the isolation of crystalline form of Fevipiprant (FP1) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline form of Fevipiprant (FP1) may be isolated by employing any of the techniques, but not limited to: evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using buchi rotavapor, decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
The isolated product may be optionally further dried to afford crystalline form of Fevipiprant (FP1).
Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.

In another aspect, the present application provides a Fevipiprant co-crystal with Caffeine (Form FC), characterized by a PXRD pattern comprising the peaks at about 9.66, 13.20, 16.00, 17.23, 18.74, 20.49, 21.49 and 22.71 ± 0.2° 2?. Fevipiprant co-crystal with Caffeine (Form FC) is also characterized by its X-ray powder diffractogram as substantially shown in FIG.4
In another aspect, the present application provides a process for the preparation of Fevipiprant co-crystal with Caffeine (Form FC), characterized by a PXRD pattern comprising the peaks at about 9.66, 13.20, 16.00, 17.23, 18.74, 20.49, 21.49 and 22.71 ± 0.2° 2?, comprising the steps of:
a) dissolving Fevipiprant and caffeine in tetrahydrofuran;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) adding water as anti solvent to the solution obtained in step b) or c);
e) cooling the solution obtained in step d);
f) isolating the Fevipiprant co-crystal with Caffeine (Form FC).
In an embodiment step a) may be carried out by dissolving Fevipiprant and caffeine in tetrahydrofuran. Alternatively, the solution may be provided by taking the reaction mixture containing Fevipiprant and caffeine in tetrahydrofuran.
In an embodiment of step b), the heating may be carried out at temperature ranging from about 45°C to 100°C. The reaction mass may be maintained at the same temperature for any time period, such as from about 10 minutes to 5 hours or longer.
In embodiments of step c), the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In embodiments of step d), adding water as anti solvent to the solution obtained in step b) or c)
In embodiment of step d), the isolation may be effected by combining the solution of step d) with a suitable anti-solvent. Adding the solution obtained in step d) to the anti-solvent, or adding an anti-solvent to the solution obtained in step d), to effect the crystallization process are both within the scope of the present invention. After adding anti-solvent, the reaction mass may be maintained from 15 minutes to 15 hours or longer.
In an embodiment of step e), cooling the solution may be carried out at temperature ranging from about -10°C to 10°C.
In embodiments of step f), the isolation of Fevipiprant co-crystal with Caffeine (Form FC) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, Fevipiprant co-crystal with Caffeine (Form FC) may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
The isolated product may be optionally further dried to afford Fevipiprant co-crystal with Caffeine (Form FC).
Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.

Any physical form of Fevipiprant may be utilized for step a). Fevipiprant that may be used as the input for the process of the present invention may be obtained by the processes described in the art. For example Fevipiprant may be prepared by the processes described in US 7666878B2, WO2017056001?1 and CN106188040A.
The obtained crystalline forms of Fevipiprant (FP1, FP2, FP5, FP6, FP7, FP8 and Form FC) may be optionally milled to get 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 mills, and jet mills. etc., to produce a desired particle size distribution.
Crystalline forms of Fevipiprant (FP1, FP2, FP5, FP6, FP7, FP8 and Form FC) obtained according to certain processes of the present application has a particle size distribution wherein: d(0.5) is less than about 100 µm, or less than about 25 µm, or less than about 10 µm; and d(0.9) is less than about 200 µm, or less than about 50 µm, or less than about 30 µm. Particle size distributions can be determined using any means, including laser light diffraction equipment sold by Malvern Instruments limited, Malvern, Worcestershire, United Kingdom, Coulter counters, microscopic procedures, etc. The term d(x) means that a particular fraction has particles with a maximum size being the value given; 0.5 represents 50% of the particles and 0.9 represents 90% of the particles.
Any crystalline forms (or) amorphous form of Fevipiprant can be used as the input material for the process of the present invention.
A another aspect of the present application provides pharmaceutical formulation comprising crystalline forms of Fevipiprant (FP1, FP2, FP5, FP6, FP7, FP8 and Form FC) with one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins or resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, or the like.
In an aspect, the crystalline forms of Fevipiprant (FP1, FP2, FP5, FP6, FP7, FP8 and Form FC) may be used as an intermediate to produce amorphous form or alternate crystalline form or any targeted form.
In an aspect of the application, crystalline forms of Fevipiprant (FP1, FP2, FP5, FP6, FP7, FP8 and Form FC) prepared according to the processes of the present application can be substantially pure having a chemical purity greater than about 99%, or greater than about 99.5%, or greater than about 99.9%, by weight, as determined using high performance liquid chromatography (HPLC).
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
DEFINITIONS
As used herein, the term “isolated” refers to a compound that is at least 50%, preferably at least 90%, even more preferably at least 95%, and most preferably at least 99% pure, as judged by GC or HPLC.
The term "about" when used in the present invention preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1 .
As used herein, the term “DMF” refers to dimethylformamide.
As used herein, the term “DIPE” refers to diisopropyl ether.
As used herein, the term “MTBE” refers to methyl tert-butyl ether.
As used herein, the term “IPA” refers to Isopropyl alcohol.
Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following example, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present invention in any manner.

EXAMPLES
Example-1: Preparation of crystalline form of Fevipiprant (FP6)
Fevipiprant (2 g) was dissolved in acetic acid (16 ml) at 70°C. The obtained clear solution was cooled to 2°C. Heptane (50 ml) was added to the clear solution at 2°C. The reaction mass was stirred at 2°C for 2 hours. The resultant suspension was filtered under vacuum to obtain the title compound.
Example-2: Preparation of crystalline form of Fevipiprant (FP7)
Fevipiprant (2 g) was dissolved in dimethylformamide (8 ml) at 70°C. The obtained clear solution was cooled to 25°C. DIPE (40 ml) was added to the clear solution at 25°C. The reaction mass was stirred at 25°C for 2 hours. The resultant suspension was filtered under vacuum to obtain the title compound.
Example-3: Preparation of crystalline form of Fevipiprant (FP8)
Fevipiprant (1.5 g) was dissolved in 1,4-dioxane (6 ml) at 70°C. The obtained clear solution was cooled to 25°C. Heptane (18 ml) was added to the clear solution at 25°C. The reaction mass was stirred at 2°C for 3 hours. The resultant suspension was filtered under vacuum to obtain the title compound.
Example-4: Preparation of crystalline form of Fevipiprant (FP2)
Fevipiprant (1 g) was dissolved in acetone (20 ml) at 70°C. The obtained clear solution was cooled to 25°C and stirred for 1 hr. The reaction mass was stirred at 2°C for 3 hours. The resultant suspension was filtered under vacuum to obtain the title compound.
Example-5: Preparation of crystalline form of Fevipiprant (FP2)
Fevipiprant (2 g) was dissolved in methanol (50 ml) at 70°C. The obtained clear solution was cooled to 2°C. Heptane (150 ml) was added to the clear solution at 2°C. The reaction mass was stirred at 2°C for 1 hour. The resultant suspension was filtered under vacuum to obtain the title compound.
Example-6: Preparation of crystalline form of Fevipiprant (FP2)
Fevipiprant (500 mg) was dissolved in methanol (10 ml) at 60°C. The obtained clear solution was cooled to -78°C. Pre cooled pentane (30 ml) was added to the clear solution at -78°C. The reaction mass was stirred at -78°C for 3 hours. The resultant suspension was filtered under vacuum to obtain the title compound.
Example-7: Preparation of crystalline form of Fevipiprant (FP5)
Fevipiprant (50 mg) was dissolved in dimethyl sulfoxide (0.5 ml) at 60°C. The obtained clear solution was slowly evaporated to obtain the title compound.
Example-8: Preparation of crystalline form of Fevipiprant (FP5)
Fevipiprant (250 mg) was dissolved in dimethyl sulfoxide (1 ml) at 70°C. The obtained clear solution was cooled to 25°C. Heptane (5 ml) was added to the clear solution at 25°C. The reaction mass was stirred at 25°C for 3 hour. The resultant suspension was filtered under vacuum to obtain the title compound.
Example-9: Preparation of crystalline form of Fevipiprant
Fevipiprant (0.5 g) was dissolved in a solvent at 90°C. The obtained clear solution was cooled to 25°C. Anti solvent was added to the clear solution at 25°C. The reaction mass was stirred at 25°C for 3 hour. The resultant suspension was filtered under vacuum to obtain the title compound.
Example No. Solvent Name Solvent quantity Anti solvent Name Anti solvent quantity Resulted form
9a Acetic acid 2 ml MTBE 5 ml FP1
9b Formic acid 0.5 ml MTBE 5 ml FP1
9c Propionic acid 2 ml MTBE 5 ml FP1
9d DMAc 1 ml MTBE 5 ml FP1
9e DMF 0.5 ml MTBE 5 ml FP1

Example-10: Preparation of crystalline form of Fevipiprant
Fevipiprant (0.25 g) was dissolved in a solvent at 70°C. The obtained clear solution was cooled to 25°C. Anti solvent was added to the clear solution at 25°C. The reaction mass was stirred at 25°C for 3 hour. The resultant suspension was filtered under vacuum to obtain the title compound.
Example No. Solvent Name Solvent quantity Anti solvent Name Anti solvent quantity Resulted form
10a Formic acid 1 ml Water 10 ml FP1
10b Propionic acid 3 ml Water 10 ml FP1
10c Acetic acid 2 ml Water 10 ml FP1
10d DMF 1 ml Water 10 ml FP1
10e DMA 1 ml Water 10 ml FP1
Example-11: Preparation of crystalline form of Fevipiprant
Fevipiprant (250 mg) was dissolved in solvent at 70°C. The obtained clear solution was cooled to 2°C. Anti solvents was added to the clear solution at 2°C. The reaction mass was stirred at 2°C for 3 hour. The resultant suspension was filtered under vacuum to obtain the title compound.
Example No. Solvent Name Solvent quantity Anti solvent Name Anti solvent quantity Resulted form
11a Formic acid 1 ml Heptane and DIPE 12 ml and 10 ml FP1
11b Acetic acid 2 ml Heptane and DIPE 12 ml and 10 ml FP6

11c Propionic acid 4 ml Heptane and DIPE 12 ml and 10 ml FP1
11d DMF 1 ml Heptane and DIPE 12 ml and 10 ml FP7

11e DMA 1 ml Heptane and DIPE 12 ml and 10 ml FP1
Example-12: Preparation of crystalline form of Fevipiprant
Fevipiprant (250 mg) was dissolved in solvent at 70°C. The obtained clear solution was cooled to 25°C. Anti solvent was added to the clear solution at 25°C. The reaction mass was stirred at 25°C for 6 hour. The resultant suspension was filtered under vacuum to obtain the title compound.
Example No. Solvent Name Solvent quantity Anti solvent Name Anti solvent quantity Resulted form
12a 2-methoxy ethanol 2 ml Heptane and DIPE 10 ml and 10 ml FP1
12b N-methyl pyrrolidone 1 ml Heptane, DIPE, MIBK and water 5 ml, 5 ml, 10 ml and 10ml FP1
12c 1,4-dioxane 1 ml Heptane 5 ml FP8

12d Tetrahydrofuran 1 ml Heptane 5 ml FP1
12e Acetone 4 ml Heptane 20 ml FP1
Example-13: Preparation of crystalline form of Fevipiprant
Fevipiprant (250 mg) was dissolved in solvent at 90°C. The obtained clear solution was cooled to 2°C. Anti solvent was added to the clear solution at 2°C. The reaction mass was stirred at 2°C for 3 hour. The resultant suspension was filtered under vacuum to obtain the title compound.
Example No. Solvent Name Solvent quantity Anti solvent Name Anti solvent quantity Resulted form
13a Ethanol 10 ml Heptane 20 ml FP1
13b Isopropyl alcohol 10 ml Heptane 20 ml FP1
13c Methanol 5ml Heptane 15 ml FP2
Example-13d: Preparation of crystalline form of Fevipiprant (FP1)
Fevipiprant (250 mg) was dissolved in benzyl alcohol (2 ml) at 90°C. The obtained clear solution was cooled to 2°C. Heptane (6 ml) was added to the clear solution at 2°C. The reaction mass was stirred at 2°C for 3 hour. MTBE (20 ml) and water (10 ml) were added to the solution at 25°C. The resultant suspension was filtered under vacuum to obtain the title compound.
Example-13e: Preparation of crystalline form of Fevipiprant (FP1)
Fevipiprant (250 mg) was dissolved in racemic propylene glycol (10 ml) at 95°C. The obtained solution was cooled to 2°C. Heptane (20 ml) was added to the clear solution at 2°C. The reaction mass was stirred at 2°C for 3 hour. MTBE (20 ml) was added to the solution at 25°C. Water (10 ml) was added to the solution at 2°C. The resultant suspension was filtered under vacuum to obtain the title compound.
Example-13f: Preparation of crystalline form of Fevipiprant (FP1)
Fevipiprant (250 mg) was dissolved in R-propylene glycol (10 ml) at 95°C. The obtained solution was cooled to 2°C. Heptane (20 ml) was added to the clear solution at 2°C. The reaction mass was stirred at 2°C for 3 hour. MTBE (20 ml) was added to the solution at 25°C. Water (10 ml) was added to the solution at 2°C. The resultant suspension was filtered under vacuum to obtain the title compound.
Example-14: Preparation of crystalline form of Fevipiprant
Fevipiprant (250 mg) was dissolved in solvent at 90°C. The obtained solution was cooled to 25°C. Anti solvent was added to the clear solution at 25°C. The reaction mass was stirred at 25°C for 3 hour. The resultant suspension was filtered under vacuum to obtain the title compound.
Example No. Solvent Name Solvent quantity Anti solvent Name Anti solvent quantity Resulted form
14a Ethanol 10 ml Water 30 FP1
14b Methanol 5 ml Water 15 FP1
14c IPA 10 ml Water 30 FP1
Example-15a: Preparation of crystalline form of Fevipiprant (FP1)
Fevipiprant (250 mg) was dissolved in formic acid (1 ml) at 90°C. The obtained solution was cooled to 25°C. Cyclohexane (5 ml) was added to the clear solution at 25°C. The reaction mass was stirred at 2°C for 3 hour. Xylene (5 ml) and toluene (5 ml) were added to the clear solution at 2°C. The reaction mass was stirred at 2°C for 3 hour. MTBE (20 ml) and n-heptane (20 ml) were added to the clear solution at 25°C. The reaction mass was stirred at 25°C for 1 hour. The resultant suspension was filtered under vacuum to obtain the title compound.
Example-15b: Preparation of crystalline form of Fevipiprant (FP1)
Fevipiprant (250 mg) was dissolved in propionic acid (4 ml) at 90°C. The obtained solution was cooled to 25°C. Cyclohexane (12 ml) was added to the clear solution at 25°C. The reaction mass was stirred at 2°C for 3 hour. The resultant suspension was filtered under vacuum to obtain the title compound.
Example-15c: Preparation of crystalline form of Fevipiprant (FP1)
Fevipiprant (250 mg) was dissolved in DMAc (1 ml) at 90°C. The obtained solution was cooled to 25°C. Cyclohexane (5 ml) was added to the clear solution at 25°C. The reaction mass was stirred at 2°C for 3 hour. Xylene (5 ml) and toluene (5 ml) were added to the clear solution at 2°C. The reaction mass was stirred at 2°C for 3 hour. MTBE (5 ml) and n-heptane (20 ml) were added to the clear solution at 25°C. The reaction mass was stirred at 2°C for 4 hour. The resultant suspension was filtered under vacuum to obtain the title compound.
Example-16: Preparation of crystalline form of Fevipiprant
Fevipiprant (250 mg) was dissolved in solvent at 90°C. The obtained solution was cooled to 25°C. Anti solvent was added to the clear solution at 25°C. The reaction mass was stirred at 25°C for 3 hour. The resultant suspension was filtered under vacuum to obtain the title compound.
Example No. Solvent Name Solvent quantity Anti solvent Name Anti solvent quantity Resulted form
16a 2-methoxy ethanol 1 ml Water 5 ml FP1
16b THF 1 ml Water 5 ml FP1
16c Acetone 4 ml Water 20 ml FP1
Example-17: Preparation of crystalline form of Fevipiprant (FP1)
Fevipiprant (250 mg) was dissolved in acetone (4 ml) at 90°C. The obtained solution was cooled to 2°C. Heptane (20 ml) was added to the clear solution at 2°C. The reaction mass was stirred at 2°C for 3 hour. The resultant suspension was filtered under vacuum to obtain the title compound.
Example-18: Preparation of crystalline form of Fevipiprant
Fevipiprant (250 mg) was dissolved in solvent at 60°C. The obtained solution was cooled to 25°C. The resultant suspension was filtered under vacuum to obtain the title compound.
Example No. Solvent Name Solvent quantity Resulted form
18a Methanol 10 ml FP1
18b Acetonitrile 8 ml FP1
18c Acetone 4 ml FP2
Example-18d: Preparation of crystalline form of Fevipiprant (FP1)
Fevipiprant (250 mg) was dissolved in IPA (20 ml) at 90°C. The obtained solution was cooled to 25°C. The resultant suspension was filtered under vacuum to obtain the title compound.
Example-19: Preparation of crystalline form of Fevipiprant (FP1)
Crystalline form of Fevipiprant-FP6 (250 mg) was dissolved in water (5 ml) at 25°C. The obtained solution was stirred for 2 hours. The resultant suspension was filtered under vacuum to obtain the title compound.
Example-20: Preparation of crystalline form of Fevipiprant (FP1)
Crystalline form of Fevipiprant-FP7 (250 mg) was dissolved in water (5 ml) at 25°C. The obtained solution was stirred for 2 hours. The resultant suspension was filtered under vacuum to obtain the title compound.
Example-21: Preparation of crystalline form of Fevipiprant (FP1)
Crystalline form of Fevipiprant-FP2 (200 mg) was dissolved in water (5 ml) at 25°C. The obtained solution was stirred for 2 hours. The resultant suspension was filtered under vacuum to obtain the title compound.
Example-22: Preparation of crystalline form of Fevipiprant (FP1)
Fevipiprant (500 mg) was dissolved in 2-propanol (30 ml) at 90°C. The obtained solution was cooled to -78°C. Precooled pentane (100 ml) was added to the clear solution at-78°C. The reaction mass was stirred at -78°C for 3 hour. The resultant suspension was filtered under vacuum to obtain the title compound.
Example-23: Preparation of crystalline form of Fevipiprant (FP1)
Fevipiprant (500 mg) was dissolved in 1-propanol (35 ml) at 95°C. The obtained solution was cooled to -78°C. Precooled pentane (100 ml) was added to the clear solution at-78°C. The reaction mass was stirred at -78°C for 4 hour. The resultant suspension was filtered under vacuum to obtain the title compound.
Example-24: Preparation of Fevipiprant co-crystal with Caffeine (Form FC)
Fevipiprant (250 mg) and caffeine (227.7 mg) were dissolved in tetrahydrofuran (10 ml) at 65°C. The obtained solution was cooled to 25°C. Water (30 ml) was added to the solution at 25°C. The reaction mass was stirred at -2 2 to 8 °C for 3 hour. The resultant suspension was filtered under vacuum to obtain the title compound.
,CLAIMS:We claim
1. A crystalline form of Fevipiprant (FP6), characterized by a PXRD pattern comprising the peaks at about 5.44, 8.18, 10.91, 15.35 and 16.44± 0.2° 2?.
2. The process for the preparation of crystalline form of Fevipiprant (FP6) according to claim 1, the process comprising the steps of:
a) combining Fevipiprant with acetic acid;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding heptane as anti solvent to the solution obtained in step d); and
f) isolating the crystalline form of Fevipiprant (FP6).
3. A crystalline form of Fevipiprant (FP7), characterized by a PXRD pattern comprising the peaks at about 12.97, 13.88, 15.04 and 17.11 ± 0.2° 2?.
4. The process for the preparation of crystalline form of Fevipiprant (FP7) according to claim 3, the process comprising the steps of;
a) combining Fevipiprant with DMF;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding DIPE as anti solvent to the solution obtained in step d); and
f) isolating the crystalline form of Fevipiprant (FP7).
5. A crystalline form of Fevipiprant (FP8), characterized by a PXRD pattern comprising the peaks at about 10.20, 13.73 and 20.33± 0.2° 2?.
6. The process for the preparation of crystalline form of Fevipiprant (FP8) according to claim 5, the process comprising the steps of:
a) combining Fevipiprant with 1,4-dioxane;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding anti-solvent selected from heptane, MTBE, water, DIPE, cyclohexane, xylene, toluene, pentane or mixtures thereof to the solution obtained in step d); and
f) isolating the crystalline form of Fevipiprant (FP8).
7. A process for the preparation of crystalline form of Fevipiprant (FP2), characterized by a PXRD pattern comprising the peaks at about 5.0, 13.7, 19.6, 20.3 and 21.8± 0.2° 2?, the process comprising the steps of:
a) combining Fevipiprant with acetone;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c); and
e) isolating the crystalline form of Fevipiprant (FP2).
8. A process for the preparation of crystalline form of Fevipiprant (FP2), characterized by a PXRD pattern comprising the peaks at about 5.0, 13.7, 19.6, 20.3 and 21.8± 0.2° 2?, the process comprising the steps of:
a) combining Fevipiprant with methanol;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding anti solvent selected from heptane, pentane or mixture thereof to the solution obtained in step d); and
f) isolating the crystalline form of Fevipiprant (FP2).
9. A process for the preparation of crystalline form of Fevipiprant (FP5), characterized by a PXRD pattern comprising the peaks at about 3.89 and 15.28 ± 0.2° 2?, the process comprising the steps of:
a) combining Fevipiprant with dimethyl sulfoxide;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b); and
d) isolating the crystalline form of Fevipiprant (FP5)
10. A process for the preparation of crystalline form of Fevipiprant (FP5), characterized by a PXRD pattern comprising the peaks at about 3.89 and 15.28 ± 0.2° 2?, the process comprising the steps of:
a) combining Fevipiprant with dimethyl sulfoxide;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding anti solvent selected from heptane, MTBE, water, DIPE, cyclohexane, xylene, toluene, pentane or mixtures thereof to the solution obtained in step d); and
f) isolating the crystalline form of Fevipiprant (FP5).
11. A process for the preparation of crystalline form of Fevipiprant (FP1), characterized by a PXRD pattern comprising the peaks at about 12.07, 17.49, 19.85, 21.16 and 24.35 ± 0.2° 2?, the process comprising the steps of:
a) combining Fevipiprant with the solvent selected from formic acid, propionic acid, dimethylacetamide, tetrahydrofuran, ethanol, isopropyl alcohol, 1-propanol, benzyl alcohol, recemic propylene glycol, (R)-propylene glycol, 2-methoxy ethanol, N-methyl pyrrolidone, acetone or mixtures thereof;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding anti solvent selected from MTBE, water, heptane, DIPE, cyclohexane, xylene, toluene, pentane or mixture thereof to the solution obtained in step d); and
f) isolating the crystalline form of Fevipiprant (FP1).
12. A process for the preparation of crystalline form of Fevipiprant (FP1), characterized by a PXRD pattern comprising the peaks at about 12.07, 17.49, 19.85, 21.16 and 24.35 ± 0.2° 2?, the process comprising the steps of:
a) combining Fevipiprant with the solvent selected from methanol, acetic acid, DMF or mixtures thereof;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c);
e) adding anti solvent selected from MTBE, water or mixtures thereof to the solution obtained in step d); and
f) isolating the crystalline form of Fevipiprant (FP1).
13. A process for the preparation of crystalline form of Fevipiprant (FP1), characterized by a PXRD pattern comprising the peaks at about 12.07, 17.49, 19.85, 21.16 and 24.35 ± 0.2° 2?, the process comprising the steps of:
a) combining Fevipiprant with the solvent selected from methanol, acetonitrile, IPA or mixtures thereof ;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) cooling the solution obtained in step b) or c); and
e) isolating the crystalline form of Fevipiprant (FP1).
14. A process for the preparation of crystalline form of Fevipiprant (FP1), characterized by a PXRD pattern comprising the peaks at about 12.07, 17.49, 19.85, 21.16 and 24.35 ± 0.2° 2?, the process comprising the steps of:
a) dissolving or suspending crystalline form of Fevipiprant selected from FP2, FP6 and FP7 in water; and
b) isolating the crystalline form of Fevipiprant (FP1).
15. A Fevipiprant co-crystal with Caffeine (Form FC), characterized by a PXRD pattern comprising the peaks at about 9.66, 13.20, 16.00, 17.23, 18.74, 20.49, 21.49 and 22.71 ± 0.2° 2?.
16. The process for the preparation of Fevipiprant co-crystal with Caffeine (Form FC), according to claim 15, the process comprising the steps of:
a) dissolving Fevipiprant and caffeine in tetrahydrofuran;
b) heating the reaction mixture obtained in step a);
c) optionally filtering the reaction mixture obtained in step b);
d) adding water as anti solvent to the solution obtained in step b) or c);
e) cooling the solution obtained in step d); and
f) isolating the Fevipiprant co-crystal with Caffeine (Form FC).