DESC:The following specification particularly describes the invention and the manner in which it is to be performed.
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 (FP4 and FP5) with enhanced storage stability, solubility and processability.
SUMMARY
In an aspect, the present application provides a crystalline form of Fevipiprant (FP4), characterized by a PXRD pattern comprising the peaks at about 13.52, 18.44, 19.09, 20.17 and 21.7 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP4), characterized by a PXRD pattern comprising the peaks at about 13.52, 18.44, 19.09, 20.17 and 21.7± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with benzyl alcohol;
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 (FP4).
In an aspect, the present application provides a crystalline form of Fevipiprant (FP5), characterized by a PXRD pattern comprising the peaks at about 3.89 and 15.28 ± 0.2° 2?.
In an aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP5), comprising the steps of;
a) combining Fevipiprant with dimethyl sulfoxide;
b) heating the reaction mixture obtained in step a);
c) cooling the solution obtained in step (b);
d) obtaining the crystalline form of Fevipiprant (FP5).
In another aspect, the present application provides a pharmaceutical composition comprising crystalline forms of Fevipiprant 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 (FP4) prepared by the method of Example No 1.
Figure 2 is an illustrative X-ray powder diffraction pattern of crystalline form of Fevipiprant (FP5) prepared by the method of Example No 2.
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 (FP4), characterized by a PXRD pattern comprising the peaks at about 13.52, 18.44, 19.09, 20.17 and 21.7 ± 0.2° 2?. Crystalline form of Fevipiprant (FP4) further characterized by PXRD pattern comprising peaks at about 12.58, 19.53, 20.96 and 25.81±0.2°2?. Crystalline form of Fevipiprant (FP4) is also characterized by its X-ray powder diffractogram as substantially shown in FIG. 1
In some embodiments, crystalline form of Fevipiprant (FP4) may be a benzyl alcohol solvate.
In another aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP4), characterized by a PXRD pattern comprising the peaks at about 13.52, 18.44, 19.09, 20.17 and 21.7± 0.2° 2?, comprising the steps of:
a) combining Fevipiprant with benzyl alcohol;
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 (FP4).
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.
In an embodiment of step a), combining Fevipiprant with benzyl alcohol (or) by taking the reaction mixture containing Fevipiprant and benzyl alcohol.
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 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 ether, water and hydrocarbon solvents. In specific embodiment of step e), suitable antisolvent is diisopropylether.
In embodiment of step f), 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 (FP4).
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 (FP5), characterized by a PXRD pattern comprising the peaks at about 3.89 and 15.28 ± 0.2° 2?. Crystalline form of Fevipiprant (FP5) further characterized by PXRD pattern comprising peaks at about 10.84, 13.63, 15.60, 16.89, 18.68 and 19.54±0.2°2?. Crystalline form of Fevipiprant (FP5) is also characterized by its X-ray powder diffractogram as substantially shown in FIG. 2
In some embodiments, crystalline form of Fevipiprant (FP5) may be a dimethyl sulfoxide solvate.
In an aspect, the present application provides a process for the preparation of crystalline form of Fevipiprant (FP5), comprising the steps of;
a) combining Fevipiprant with dimethyl sulfoxide;
b) heating the reaction mixture obtained in step a);
c) cooling the solution obtained in step (b);
d) obtaining the crystalline form of Fevipiprant (FP5).
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.
In an embodiment of step a), the 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. 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 c), cooling the solution may be carried out at temperature ranging from about 20°C to 30°C. The reaction mass may be maintained at the same temperature for any time period, such as from about 5 minutes to 10 hours or longer. Optionally adding suitable anti solvent to the reaction mass of step c), wherein the anti-solvent include, but are not limited to ether, water and hydrocarbon solvents.
In embodiments of step d), the obtained product is crystalline form of Fevipiprant (FP5).
The obtained crystalline forms of Fevipiprant (FP4 and FP5) 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 (FP4 and FP5) 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 fourth aspect of the present application provides pharmaceutical formulation comprising crystalline forms of Fevipiprant (FP4 and FP5) 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 (FP4 and FP5) 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 (FP4 and FP5) 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).
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 “solvate” refers to a complex formed by the combining Fevipiprant and a solvent.
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 crystalline form of Fevipiprant (FP4)
Fevipiprant (1 g) was dissolved in benzyl alcohol (20 ml) at about 70°C and the solution was filtered to make it particle free. The obtained clear solution was cooled to 0°C. Diisopropylether (60 ml) was added to the clear solution at 0°C. The reaction mass was stirred at 0°C for 13 hours. The resultant suspension was filtered under vacuum and dried in air tray dryer at 50°C for 2 hours to obtain crystalline form of Fevipiprant (FP4).

Example-2: Preparation of crystalline form of Fevipiprant (FP5)
Fevipiprant (350 mg) was dissolved in dimethyl sulfoxide (0.1 ml) at about 75°C. The obtained clear solution was cooled to 25°C to obtain the title compound.

Example-3: Preparation of crystalline form of Fevipiprant (FP4)
Fevipiprant (3 g) was dissolved in benzyl alcohol (60 ml) at about 70°C and the solution was filtered to make it particle free. The obtained clear solution was cooled to 0°C. Diisopropylether (60 ml) was added to the clear solution at 0°C. The reaction mass was stirred at -5°C for 4 hours. The resultant suspension was filtered under vacuum and dried in air tray dryer at 50°C for 4 hours to obtain crystalline form of Fevipiprant (FP4).
,CLAIMS:We claim
1. A crystalline form of Fevipiprant (FP4), characterized by a PXRD pattern comprising the peaks at about 13.52, 18.44, 19.09, 20.17 and 21.7 ± 0.2° 2?.
2. The process for the preparation of crystalline form of Fevipiprant (FP4) according to claim 1, the process comprising the steps of:
a) combining Fevipiprant with benzyl alcohol;
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); and
f) isolating the crystalline form of Fevipiprant (FP4).
3. The process according to claim 2, wherein the anti-solvent is selected from ether, water or hydrocarbon solvents.
4. A crystalline form of Fevipiprant (FP5), characterized by a PXRD pattern comprising the peaks at about 3.89 and 15.28 ± 0.2° 2?.
5. The process for the preparation of crystalline form of Fevipiprant (FP5) according to claim 4, the process comprising the steps of:
a) combining Fevipiprant with dimethyl sulfoxide;
b) heating the reaction mixture obtained in step a);
c) cooling the solution obtained in step (b); and
d) obtaining the crystalline form of Fevipiprant (FP5).
6. A pharmaceutical composition comprising crystalline form of Fevipiprant (FP4) with atleast one pharmaceutically acceptable excipient.
7. A pharmaceutical composition comprising crystalline form of Fevipiprant (FP5) with atleast one pharmaceutically acceptable excipient.