DESC:MULTI-COMPONENT SOLID FORMS OF FEVIPIPRANT
FIELD OF THE INVENTION
The present application relates to salt of Fevipiprant with L-Arginine, co-crystals of Fevipiprant with Nicotinamide and process for the preparation thereof.

BACKGROUND OF THE INVENTION:
Fevipiprant is the adopted name of drug compound having a chemical name: 1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-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, wherein the Fevipiprant is isolated from the reaction mixture by 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 recrystallization of a crude Fevipiprant from ethanol to give the pure Fevipiprant. No other physical characteristics of Fevipiprant is 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, crystalline state and multi-component solid forms.
The discovery of new polymorphs and complexes 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 salt of Fevipiprant with L-Arginine (Form FA), co-crystals of Fevipiprant with Nicotinamide (Form FN1 and Form FN2) with enhanced storage stability, solubility and processability.
SUMMARY OF THE INVENTION
In an aspect, the present application provides a salt of Fevipiprant with L-Arginine.
In another aspect, the present application provides a salt of Fevipiprant with L-Arginine (Form FA), characterized by a PXRD pattern comprising the peaks at about 3.81, 7.65, 10.89, 16.45, 19.07 and 23.07± 0.2° 2?.
In another aspect, the present application provides process for the preparation of the salt of Fevipiprant with L-Arginine, comprising the steps of:
a) suspending Fevipiprant and L-Arginine in methanol;
b) isolating the salt of Fevipiprant with L-Arginine.

In an aspect, the present application provides a co-crystal of Fevipiprant with Nicotinamide.
In another aspect, the present application provides a co-crystal of Fevipiprant with Nicotinamide (Form FN1).
In another aspect, the present application provides the co-crystal of Fevipiprant with Nicotinamide (Form FN1), characterized by a PXRD pattern comprising the peaks at about 8.21, 11.07, 13.87, 19.23, 20.26, 22.15 and 26.74± 0.2° 2?.
In another aspect, the present application provides process for the preparation of the co-crystal of Fevipiprant with Nicotinamide (Form FN1), comprising the steps of:
a) suspending Fevipiprant and Nicotinamide in acetonitrile;
b) isolating the co-crystal of Fevipiprant with Nicotinamide (Form FN1).

In an aspect, the present application provides a co-crystal of Fevipiprant with Nicotinamide (Form FN2).
In another aspect, the present application provides the co-crystal of Fevipiprant with Nicotinamide (Form FN2), characterized by a PXRD pattern comprising the peaks at about 8.69, 12.49, 14.93, 17.47, 17.92, 18.27, 19.45, 20.41, 21.45 and 24.37± 0.2° 2?.
In another aspect, the present application provides process for the preparation of the co-crystal of Fevipiprant with Nicotinamide (Form FN2), comprising the steps of:
a) dissolving Fevipiprant and Nicotinamide in acetonitrile;
b) maintaining the reaction mixture obtained in step a) at room temperature for about 3 hours;
c) isolating the co-crystal of Fevipiprant with Nicotinamide (Form FN2).

In another aspect, the present application provides a pharmaceutical composition comprising salt and co-crystals of Fevipiprant with atleast one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of salt of Fevipiprant with L-Arginine (Form FA) prepared by the method of Example No 1
Figure 2 is an illustrative X-ray powder diffraction pattern of co-crystal of Fevipiprant with Nicotinamide (Form FN1) prepared by the method of Example No 2
Figure 3 is an illustrative X-ray powder diffraction pattern of co-crystal of Fevipiprant with Nicotinamide (Form FN2) prepared by the method of Example No 3

DETAILED DESCRIPTION
Aspects of the present application relates to salt of Fevipiprant with L-Arginine, co-crystals of Fevipiprant with Nicotinamide and process for the preparation thereof.
In an aspect, the present application provides a salt of Fevipiprant with L-Arginine.
In an aspect, the present application provides the salt of Fevipiprant with L-Arginine (Form FA), characterized by a PXRD pattern comprising the peaks at about 3.81, 7.65, 10.89, 16.45, 19.07 and 23.07± 0.2° 2?. The salt of Fevipiprant with L-Arginine (Form FA) is also characterized by its X-ray powder diffractogram as substantially shown in FIG. 1
In another aspect, the present application provides process for the preparation of the salt of Fevipiprant with L-Arginine, comprising the steps of:
a) suspending Fevipiprant and L-Arginine in methanol;
b) isolating the salt of Fevipiprant with L-Arginine.
In an embodiment, step a) may be carried out by suspending mixture of Fevipiprant and L-Arginine in methanol. Alternatively, the suspension may be provided by taking the reaction mixture containing Fevipiprant and L-Arginine in methanol.
In an embodiment, the mixture of Fevipiprant and L-Arginine may be suspending in methanol optionally by heating the reaction mixture.
In an embodiment, the suspension of Fevipiprant and L-Arginine in methanol may be cooled to precipitate the solids at a suitable temperature.
In an embodiment, optionally the solution of step a) may be contacted with an anti-solvent. Anti-solvent may include, but not limited to hydrocarbons such as n-hexane, n-heptane, cyclohexane or the like; ethers such as diethyl ether, di isopropyl ether, methyl tert-butyl ether or the like; water; or any mixtures thereof.
Isolation of the salt of Fevipiprant with L-Arginine may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, the salt of Fevipiprant with L-Arginine 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 the salt of Fevipiprant with L-Arginine.
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 co-crystal of Fevipiprant with Nicotinamide.
In an aspect, the present application provides a co-crystal of Fevipiprant with Nicotinamide (Form FN1).
In an aspect, the present application provides the co-crystal of Fevipiprant with Nicotinamide (Form FN1), characterized by a PXRD pattern comprising the peaks at about 8.21, 11.07, 13.87, 19.23, 20.26, 22.15 and 26.74± 0.2° 2?. The co-crystal of Fevipiprant with Nicotinamide (Form FN1) is also characterized by its X-ray powder diffractogram as substantially shown in FIG. 2.
In another aspect, the present application provides process for the preparation of the co-crystal of Fevipiprant with Nicotinamide (FN1), comprising the steps of:
a) suspending Fevipiprant and Nicotinamide in acetonitrile;
b) isolating the co-crystal of Fevipiprant with Nicotinamide (Form FN1).
In an embodiment, step a) may be carried out by suspending mixture of Fevipiprant and Nicotinamide in acetonitrile. Alternatively, the suspension may be provided by taking the reaction mixture containing Fevipiprant and Nicotinamide in acetonitrile.
In an embodiment, the mixture of Fevipiprant and Nicotinamide may be suspended in acetonitrile optionally by heating the reaction mixture. In a specific embodiment, the mixture of Fevipiprant and Nicotinamide may be suspended in acetonitrile at 70°C.
In an embodiment, the suspension of Fevipiprant and Nicotinamide in acetonitrile may be cooled to precipitate the solids at a suitable temperature.
In an embodiment, optionally the solution of step a) may be contacted with an anti-solvent. Anti-solvent may include, but not limited to hydrocarbons such as n-hexane, n-heptane, cyclohexane or the like; ethers such as diethyl ether, di isopropyl ether, methyl tert-butyl ether or the like; water; or any mixtures thereof.
Isolation of the co-crystal of Fevipiprant with Nicotinamide (Form FN1) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, the co-crystal of Fevipiprant with Nicotinamide (Form FN1) 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 the co-crystal of Fevipiprant with Nicotinamide (Form FN1).
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 co-crystal of Fevipiprant with Nicotinamide (Form FN2).
In another aspect, the present application provides the co-crystal of Fevipiprant with Nicotinamide (Form FN2), characterized by a PXRD pattern comprising the peaks at about 8.69, 12.49, 14.93, 17.47, 17.92, 18.27, 19.45, 20.41, 21.45 and 24.37± 0.2° 2?. Co-crystal of Fevipiprant with Nicotinamide (Form FN2) is also characterized by its X-ray powder diffractogram as substantially shown in FIG. 3
In another aspect, the present application provides process for the preparation of the co-crystal of Fevipiprant with Nicotinamide (Form FN2), comprising the steps of:
a) dissolving Fevipiprant and Nicotinamide in acetonitrile;
b) maintaining the reaction mixture obtained in step a) at room temperature for about 3 hours;
c) isolating the co-crystal of Fevipiprant with Nicotinamide (Form FN2).
In an embodiment, step a) may be carried out by dissolving Fevipiprant and Nicotinamide in acetonitrile. Alternatively, the solution may be provided by taking the reaction mixture containing Fevipiprant and Nicotinamide in acetonitrile.
In an embodiment, the mixture of Fevipiprant and Nicotinamide may be dissolved in acetonitrile optionally by heating the reaction mixture. In a specific embodiment, the mixture of Fevipiprant and Nicotinamide may be dissolved in acetonitrile at 70°C.
In an embodiment, the dissolution of Fevipiprant and Nicotinamide in acetonitrile may be cooled to precipitate the solids to a suitable temperature.
In an embodiment, the solution of step a) may be maintain the reaction mixture at room temperature for about 3 hours or longer.
Isolation of the co-crystal of Fevipiprant with Nicotinamide (Form FN2) may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, the co-crystal of Fevipiprant with Nicotinamide (Form FN2) 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 co-crystal of Fevipiprant with Nicotinamide (Form FN2).
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.
Another aspect of the present application provides pharmaceutical formulation comprising salt or co-crystals of Fevipiprant (Form FA, Form FN1 or Form FN2) 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 salt and the co-crystals of Fevipiprant (Form FA, Form FN1 or Form FN2) may be used as an intermediate to produce amorphous form or alternate crystalline form or any targeted form.
In an aspect of the application, the salt and the co-crystals of Fevipiprant (Form FA, Form FN1 and Form FN2) 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.
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 salt of Fevipiprant with L-Arginine (Form FA)
Fevipiprant (250 mg) and L-Arginine (204 mg) were dissolved in methanol (5 ml) at 25°C. The reaction mass was stirred for 3 hours at 25°C. The resultant suspension was filtered under vacuum and further dried in VTD at 60°C to obtain the title compound.

Example-2: Preparation of co-crystal of Fevipiprant with Nicotinamide (Form FN1)
Fevipiprant (300 mg) and Nicotinamide (171 mg) were dissolved in acetonitrile (6 ml) at 70°C. The reaction mass was stirred for 3 hours at 70°C. The resultant suspension was filtered under vacuum to obtain the title compound.

Example-3: Preparation of co-crystal of Fevipiprant with Nicotinamide (Form FN2)
Fevipiprant (500 mg) and Nicotinamide (143 mg) were dissolved in acetonitrile (7.5 ml) at 70°C. The reaction mass was stirred for 3 hours at 25°C. The resultant suspension was filtered under vacuum and further dried in VTD at 60°C to obtain the title compound.
The melting point of the co-crystal was determined at 146.29°C, as measured by differential scanning calorimetry (DSC).
,CLAIMS:We Claim:
1. A salt of Fevipiprant with L-Arginine.
2. The salt of Fevipiprant with L-Arginine as claimed in claim 1, characterized by a PXRD pattern comprising the peaks at about 3.81, 7.65, 10.89, 16.45, 19.07 and 23.07± 0.2° 2?.
3. A process for the preparation of the salt of Fevipiprant with L-Arginine, comprising the steps of:
a) suspending Fevipiprant and L-Arginine in methanol;
b) isolating the salt of Fevipiprant with L-Arginine.
4. A co-crystal of Fevipiprant with Nicotinamide.
5. A co-crystal of Fevipiprant with Nicotinamide (Form FN1).
6. The co-crystal of Fevipiprant with Nicotinamide (Form FN1) as claimed in claim 5, characterized by a PXRD pattern comprising the peaks at about 8.21, 11.07, 13.87, 19.23, 20.26, 22.15 and 26.74± 0.2° 2?.
7. A process for the preparation of the co-crystal of Fevipiprant with Nicotinamide (Form FN1), comprising the steps of:
a) suspending Fevipiprant and Nicotinamide in acetonitrile;
b) isolating the co-crystal of Fevipiprant with Nicotinamide (Form FN1).
8. A co-crystal of Fevipiprant with Nicotinamide (Form FN2).
9. The co-crystal of Fevipiprant with Nicotinamide (Form FN2) as claimed in claim 7, characterized by a PXRD pattern comprising the peaks at about 8.69, 12.49, 14.93, 17.47, 17.92, 18.27, 19.45, 20.41, 21.45 and 24.37± 0.2° 2?.
10. A process for the preparation of the co-crystal of Fevipiprant with Nicotinamide (Form FN2), comprising the steps of:
a) dissolving Fevipiprant and Nicotinamide in acetonitrile;
b) maintaining the reaction mixture obtained in step a) at room temperature for about 3 hours;
c) isolating the co-crystal of Fevipiprant with Nicotinamide (Form FN2).