DESC:The following specification particularly describes the invention and the manner in which it is to be performed.
INTRODUCTION
Aspects of the present application relate to solid forms of Fevipiprant and pharmaceutical compositions thereof. Specific aspect relate to amorphous and 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. The research, funded by Novartis Pharmaceuticals, National Institute for Health Research (NIHR) and the EU (AirPROM) and carried out by scientists at Leicester University, demonstrated that Fevipiprant pill significantly decreased the symptoms of asthma, improved lung function, reduced inflammation and repaired the lining of airways.
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 according the scheme-1 as depicted below 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 characteristics of Fevipiprant produced through the process disclosed therein are provided.

Prior art process may not suitable at a large scale to obtain the product with desired quality and yield. Hence, there remains need for the preparation of Fevipiprant with an inexpensive, environmentally friendly solvents and economical process that is better suited for industrial application. Further, there remains a need for a reproducible and stable solid form of Fevipiprant.
SUMMARY
In an aspect, the present application provides a crystalline form FP1 of Fevipiprant, characterized by a PXRD pattern comprising the peaks at about 12.07, 17.49, 19.85, 21.16 and 24.35 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline form FP1 of Fevipiprant, 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) treating Fevipiprant with solvent selected from ethyl acetate, methyl tert. butyl ether or a mixture thereof;
b) Isolating the crystalline form FP1of Fevipiprant.
In another aspect, the present application provides a crystalline form FP2 of Fevipiprant, characterized by a PXRD pattern comprising the peaks at about 5.0, 13.7, 19.6, 20.3 and 21.8 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline form FP2 of Fevipiprant, 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) treating Fevipiprant with solvent selected from methanol, dichloromethane or a mixtures thereof;
b) Isolating the crystalline form FP2 of Fevipiprant.
In another aspect, the present application provides a crystalline form FP3 of Fevipiprant, characterized by a PXRD pattern comprising the peaks at about 13.3, 17.7, 19.8, 20.5 and 25.3 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline form FP3 of Fevipiprant, characterized by a PXRD pattern comprising the peaks at about 13.3, 17.7, 19.8, 20.5 and 25.3 ± 0.2° 2?, comprising the steps of:
a) treating Fevipiprant with solvent selected from acetone or a mixture of acetone with any other solvent;
b) Isolating the crystalline form FP3 of Fevipiprant.
In an aspect, the present application provides an amorphous form of Fevipiprant.
In another aspect, the present application provides a process for the preparation of an amorphous form of Fevipiprant, comprising the steps of:
a) providing a solution of Fevipiprant or a salt thereof in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a); and
c) isolating the amorphous form of Fevipiprant or a salt thereof.
d) optionally, combining amorphous form of step c) with atleast one pharmaceutically acceptable excipient.
In another aspect, the present application provides amorphous solid dispersion of Fevipiprant together with atleast one pharmaceutically acceptable excipient.
In another aspect, the present application provides a process for the preparation of an amorphous solid dispersion of Fevipiprant, comprising the steps of:
a) providing a solution of Fevipiprant and atleast one pharmaceutically acceptable excipient in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a), and
c) isolating the amorphous solid dispersion of Fevipiprant or a salt thereof.
d) optionally, combining amorphous solid dispersion of step c) with atleast one additional pharmaceutically acceptable excipient.
In another aspect, the present application provides a pharmaceutical composition comprising crystalline or amorphous form of Fevipiprant, its solid dispersion together with atleast one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline form FP1 of Fevipiprant prepared by the method of Example No 1.
Figure 2 is an illustrative X-ray powder diffraction pattern of crystalline form FP2 of Fevipiprant prepared by the method of Example No 2.
Figure 3 is an illustrative X-ray powder diffraction pattern of crystalline form FP3 of Fevipiprant prepared by the method of Example No 4.
Figure 4 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Fevipiprant with povidone prepared by the method of Example No 5.
Figure 5 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Fevipiprant with hydroxy propyl cellulose prepared by the method of Example No 6.
Figure 6 is an illustrative X-ray powder diffraction pattern of amorphous Fevipiprant prepared by the method of Example No 7.

DETAILED DESCRIPTION
Aspects of the present application provide amorphous and crystalline forms of Fevipiprant and processes thereof.

In an aspect, the present application provides a crystalline form FP1 of Fevipiprant, characterized by a PXRD pattern comprising the peaks at about 12.07, 17.49, 19.85, 21.16 and 24.35 ± 0.2° 2?. In an embodiment, the application provides crystalline form FP1 of Fevipiprant, characterized by a PXRD pattern having one or more additional peaks at about 14.3, 15.75, 17.93 and 19.85 ± 0.2° 2?.
In an embodiment, the present application provides crystalline form FP1 of Fevipiprant, characterized by a PXRD pattern substantially as shown in figure 1.
In another aspect, the present application provides a process for the preparation of crystalline form 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) treating Fevipiprant with solvent selected from ethyl acetate, methyl tert. butyl ether or a mixture thereof;
b) Isolating the crystalline form of Fevipiprant.
In embodiments, crystalline form FP1 of Fevipiprant may be obtained by treating Fevipiprant with solvent selected from ethyl acetate, methyl tert. butyl ether or a mixture thereof; wherein the mixture of Fevipiprant and the solvent is either heterogeneous or homogeneous.
In an embodiment, crystalline form FP1 of Fevipiprant may be obtained by suspending Fevipiprant in a solvent selected from ethyl acetate, methyl tert. butyl ether or a mixture thereof at suitable temperature and sufficient time.
In an embodiment, crystalline form FP1 of Fevipiprant may be obtained by crystallizing it from the solution comprising Fevipiprant and solvent ethyl acetate, methyl tert. butyl ether or a mixture thereof.
In embodiments, crystallization of Fevipiprant may be carried out according to any method known in the art for the reduction of solubility of Fevipiprant such as lowering the temperature (i.e., cooling crystallization) of the solution; adding anti-solvent to the solution; evaporating the solvent from the solution; or the combinations thereof. Crystallization may be carried out by any method described in any aspect or according to procedures exemplified in the instant application.
In an embodiment, crystallization of Fevipiprant may be carried out by lowering the temperature of the solution comprising Fevipiprant and solvent selected from the group comprising of ethyl acetate, methyl tert. butyl ether or a mixture thereof to a suitable temperature of about 25°C and below. In an embodiment, crystallization may be carried out by lowering the temperature of the solution to 0°C and below.
In an embodiment, temperature lowering may be carried out slowly or drastically. In an embodiment, drastic lowering of temperature may be effected by placing the solution in a pre-cooled bath. In further embodiments, temperature lowering may be carried out in gradually in single step or stepwise in multiple steps.
In an embodiment, after lowering the temperature, the solution comprising Fevipiprant and solvent may be stirred at the same temperature for time sufficient to obtain crystalline form of Fevipiprant.
In an embodiment, the crystallization of Fevipiprant may be carried out by evaporation of the solvent from the solution comprising Fevipiprant and solvent selected from the group comprising of ethyl acetate, methyl tert. butyl ether or a mixture thereof. In an embodiment, the solvent may be evaporated under optionally under reduced pressure by fast solvent evaporation. Fast solvent evaporation may be carried out in suitable equipment such as Buchi rotavapour, Spray drying, thin film drier, freez drier or the like.
Isolation of crystalline form FP1 of Fevipiprant may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline form 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, isolated crystalline form FP1 of Fevipiprant may be optionally dried in suitable drying equipment for times sufficient to achieve desired quality of product at suitable temperatures.
In another aspect, the present application provides a crystalline form FP2 of Fevipiprant, characterized by a PXRD pattern comprising the peaks at about 5.0, 13.7, 19.6, 20.3 and 21.8 ± 0.2° 2?.
In an embodiment, the present application provides crystalline form FP2 of Fevipiprant, characterized by a PXRD pattern substantially as shown in figure 2.
In another aspect, the present application provides a process for the preparation of crystalline form FP2 of Fevipiprant, 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) treating Fevipiprant with solvent selected from methanol, dichloromethane or a mixtures thereof;
b) isolating the crystalline form FP2 of Fevipiprant.
In embodiments, crystalline form FP2 of Fevipiprant may be obtained by treating Fevipiprant with solvent selected from methanol, dichloromethane or mixtures thereof; wherein the mixture of Fevipiprant and the solvent is either heterogeneous or homogeneous.
In an embodiment, crystalline form FP2 of Fevipiprant may be obtained by suspending Fevipiprant in a solvent selected from methanol, dichloromethane or mixtures thereof at suitable temperature and sufficient time.
In an embodiment, crystalline form of Fevipiprant may be obtained by crystallizing it from the solution comprising Fevipiprant and solvent selected from methanol, dichloromethane or mixtures thereof.
In embodiments, crystallization of Fevipiprant may be carried out according to any method known in the art for the reduction of solubility of Fevipiprant such as lowering the temperature (i.e., cooling crystallization) of the solution; adding anti-solvent to the solution; evaporating the solvent from the solution; or the combinations thereof. Crystallization may be carried out by any method described in any aspect or according to procedures exemplified in the instant application.
In an embodiment, the crystallization of Fevipiprant may be carried out by evaporation of the solvent from the solution comprising Fevipiprant and solvent selected from the group comprising of methanol, dichloromethane or a mixtures thereof. In an embodiment, the solvent may be evaporated under optionally under reduced pressure by fast solvent evaporation. Fast solvent evaporation may be carried out in suitable equipment such as Buchi rotavapour, Spray drying, thin film drier, freez drier or the like.
In an embodiment, crystallization of Fevipiprant may be carried out by lowering the temperature of the solution comprising Fevipiprant and solvent selected from the group comprising of methanol, dichloromethane or a mixtures thereof to a suitable temperature of about 25°C and below. In an embodiment, crystallization may be carried out by lowering the temperature of the solution to 0°C and below.
In an embodiment, temperature lowering may be carried out slowly or drastically. In an embodiment, drastic lowering of temperature may be effected by placing the solution in a pre-cooled bath. In further embodiments, temperature lowering may be carried out in gradually in single step or stepwise in multiple steps.
In an embodiment, after lowering the temperature, the solution comprising Fevipiprant and solvent may be stirred at the same temperature for time sufficient to obtain crystalline form FP2 of Fevipiprant.
Isolation of crystalline form FP2 of Fevipiprant may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline form 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, isolated crystalline form FP2 of Fevipiprant may be optionally dried in suitable drying equipment for times sufficient to achieve desired quality of product at suitable temperatures.

In another aspect, the present application provides a crystalline form FP3 of Fevipiprant, characterized by a PXRD pattern comprising the peaks at about 13.3, 17.7, 19.8, 20.5 and 25.3 ± 0.2° 2?.
In an embodiment, the present application provides crystalline form FP3 of Fevipiprant, characterized by a PXRD pattern substantially as shown in figure 3.
In another aspect, the present application provides a process for the preparation of crystalline form FP3 of Fevipiprant, characterized by a PXRD pattern comprising the peaks at about 13.3, 17.7, 19.8, 20.5 and 25.3 ± 0.2° 2?, comprising the steps of:
a) treating Fevipiprant with solvent selected from acetone or a mixture of acetone with any other solvent;
b) isolating the crystalline form FP3 of Fevipiprant.
In embodiments, crystalline form FP3 of Fevipiprant may be obtained by treating Fevipiprant with solvent selected from acetone or a mixture of acetone with any other solvent; wherein the mixture of Fevipiprant and the solvent is either heterogeneous or homogeneous.
In an embodiment, crystalline form FP3 of Fevipiprant may be obtained by suspending Fevipiprant in a solvent selected from acetone or a mixture of acetone with any other solvent at suitable temperature and sufficient time.
In an embodiment, crystalline form FP3 of Fevipiprant may be obtained by crystallizing it from the solution comprising Fevipiprant and solvent selected from acetone or a mixture of acetone with any other solvent.
In embodiments, crystallization of Fevipiprant may be carried out according to any method known in the art for the reduction of solubility of Fevipiprant such as lowering the temperature (i.e., cooling crystallization) of the solution; adding anti-solvent to the solution; evaporating the solvent from the solution; or the combinations thereof. Crystallization may be carried out by any method described in any aspect or according to procedures exemplified in the instant application.
In an embodiment, the crystallization of Fevipiprant may be carried out by evaporation of the solvent from the solution comprising Fevipiprant and solvent selected from acetone or a mixture of acetone with any other solvent. In an embodiment, the solvent may be evaporated under optionally under reduced pressure by fast solvent evaporation. Fast solvent evaporation may be carried out in suitable equipment such as Buchi rotavapour, Spray drying, thin film drier, freez drier or the like.
In an embodiment, crystallization of Fevipiprant may be carried out by lowering the temperature of the solution comprising Fevipiprant and solvent selected from acetone or a mixture of acetone with any other solvent to a suitable temperature of about 25°C and below. In an embodiment, crystallization may be carried out by lowering the temperature of the solution to 0°C and below.
In an embodiment, temperature lowering may be carried out slowly or drastically. In an embodiment, drastic lowering of temperature may be effected by placing the solution in a pre-cooled bath. In further embodiments, temperature lowering may be carried out in gradually in single step or stepwise in multiple steps.
In an embodiment, after lowering the temperature, the solution comprising Fevipiprant and solvent may be stirred at the same temperature for time sufficient to obtain crystalline form FP3 of Fevipiprant.
Isolation of crystalline form FP3 of Fevipiprant may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline form 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, isolated crystalline form FP3 of Fevipiprant may be optionally dried in suitable drying equipment for times sufficient to achieve desired quality of product at suitable temperatures.
In another aspect, the present application provides an amorphous form of Fevipiprant or a salt thereof.
The present application provides a stable amorphous form of Fevipiprant suitable for powder handling and downstream processes. Amorphous form of Fevipiprant of the present application was surprisingly found to be highly stable under mechanical stress such as grinding and milling and stable under hygroscopic conditions such as higher relative humidity conditions of more than 60% RH.
In an embodiment, the present application provides a stable amorphous form of Fevipiprant with less than 5% of crystallinity, preferably with less than 1% crystallinity and more preferably with less than 0.5% crystallinity as per X-ray diffraction analysis.
In an embodiment, the present application provides an amorphous form of Fevipiprant characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 6.
In another aspect, the present application provides a process for the preparation of an amorphous form of Fevipiprant, comprising the steps of:
a) providing a solution of Fevipiprant in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a); and
c) isolating the amorphous form of Fevipiprant.
d) optionally, combining amorphous form of step c) with atleast one pharmaceutically acceptable excipient.
In an embodiment, the present aspect provides a process for the preparation of an amorphous form of Fevipiprant.
In an embodiment, suitable solvent at step a) of this aspect may be selected from C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic ethers, C2-C6 nitriles, halogenated hydrocarbons, water or mixtures thereof. In preferred embodiment, the suitable solvent may be selected from the group comprising of alcohol solvents such as methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol; dichloromethane; tetrahydrofuran; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; esters solvents such as methyl acetate, ethyl acetate, isopropyl acetate; water and mixtures thereof.
In an embodiment, providing a solution at step a) may be carried out by dissolving Fevipiprant in a suitable solvent or by taking the reaction mixture containing Fevipiprant directly.
In an embodiment, a solution of Fevipiprant can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In an embodiment, a solution of Fevipiprant may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent at step b) 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 Büchi® Rotavapor®, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD) and the like. In preferred embodiment, the solvent may be removed under reduced pressures and at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.
In an embodiment, the isolation of an amorphous form of at step c) involves recovering the solid obtained in step b). The solid obtained from step b) may be recovered using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used. In an embodiment, the amorphous form of Fevipiprant obtained from step b) may be optionally dried before or after isolating it at step c).
Amorphous form of Fevipiprant obtained at step c) may be optionally combined with atleast one pharmaceutically acceptable excipient at step d).
In an embodiment, amorphous form of Fevipiprant may be combined with excipient using a technique known in art or by the procedures disclosed in the present application.
In preferred embodiment, amorphous form of Fevipiprant may be combined with excipient either by physical blending of both the solid components or by suspending both the components in a suitable solvent and conditions, such that both the components remain unaffected. Blending may be carried out using techniques known in art such as rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure / vacuum or inert atmosphere such nitrogen at suitable temperature and sufficient time to obtain uniform composition of amorphous form of Fevipiprant and atleast one pharmaceutically acceptable excipient.
In an embodiment, amorphous form of Fevipiprant may be combined with the excipient by evaporating the suspension or solution of amorphous form of Fevipiprant and atleast one pharmaceutically acceptable excipient.
In an embodiment, pharmaceutically acceptable excipient may include, but not limited to an inorganic oxide such as SiO2, TiO2, ZnO2, ZnO, Al2O3 and zeolite; a water insoluble polymer is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolat, and cross-linked styrene divinyl benzene or any other excipient at any aspect of present application.
In preferred embodiment, pharmaceutically acceptable excipient may be selected from the group consisting of silicon dioxide, e.g. colloidal or fumed silicon dioxide or porous silica or Syloid; copolymers, such as polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer; and cellulose, preferably microcrystalline cellulose.
Amorphous form of Fevipiprant isolated at step c) or d) may be dried in suitable drying equipment such as vacuum oven, rotatory cone dryer, 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, less than about 60°C, less than about 40°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 10 hours or longer.
In an aspect, the present application provides pharmaceutical composition comprising amorphous form of Fevipiprant and atleast one pharmaceutically acceptable excipient.
In an aspect, the present application provides amorphous solid dispersion of Fevipiprant together with atleast one pharmaceutically acceptable excipient. In an embodiment, the present aspect provides amorphous solid dispersion of Fevipiprant and atleast one pharmaceutically acceptable excipient.
In an embodiment, atleast one pharmaceutically acceptable excipient of this aspect may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcellulose and the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other excipient at any aspect of present application. The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation. Solid dispersions of the present application also include the solid dispersions obtained by combining Fevipiprant with a suitable non-polymeric excipient by employing techniques known in the art or procedures described or exemplified in any aspect of the instant application.
In an embodiment, the present application provides amorphous solid dispersion of Fevipiprant together with atleast one pharmaceutically acceptable excipient characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 4 & 5.
In another aspect, the present application provides a process for the preparation of an amorphous solid dispersion of Fevipiprant, comprising the steps of:
a) providing a solution of Fevipiprant and atleast one pharmaceutically acceptable excipient in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a), and
c) isolating the amorphous solid dispersion of Fevipiprant.
d) optionally combining amorphous solid dispersion of step c) with atleast one additional pharmaceutically acceptable excipient.
In an embodiment, the present aspect provides a process for the preparation of amorphous solid dispersion of Fevipiprant and atleast one pharmaceutically acceptable excipient.
In an embodiment, suitable solvent at step a) of this aspect may be selected from C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic ethers, C2-C6 nitriles, halogenated hydrocarbons, water or mixtures thereof.
In preferred embodiment, the suitable solvent may be selected from the group consisting of alcohol solvents such as methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol; dichloromethane, tetrahydrofuran; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; esters solvents such as methyl acetate, ethyl acetate, isopropyl acetate; water and mixtures thereof.
In an embodiment, atleast one pharmaceutically acceptable excipient of these aspects may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxy propyl cellulose hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcelluloseand the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other excipient at any aspect of present application. The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation. Solid dispersions of the present application also include the solid dispersions obtained by combining Fevipiprant with a suitable non-polymeric excipient by employing techniques known in the art or procedures described or exemplified in any aspect of the instant application.
In an embodiment, providing a solution at step a) may be carried out by dissolving Fevipiprant and atleast one pharmaceutically acceptable excipient in a suitable solvent simultaneously or by dissolving components in a suitable solvent separately to form individual solutions and combining those solutions later.
In an embodiment, providing a solution at step a) may be carried out by dissolving Fevipiprant and atleast one pharmaceutically acceptable excipient. In an embodiment, providing a solution at step a) may be carried out by dissolving a salt of Fevipiprant and atleast one pharmaceutically acceptable excipient.
In an embodiment, a solution of Fevipiprant and the excipient may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In an embodiment, a solution of Fevipiprant and the excipient may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent at step b) 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 Büchi® Rotavapor®, spray drying, freeze drying, agitated thin film drying and the like.
In preferred embodiment, the solvent may be removed under reduced pressures, at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.
In an embodiment, the isolation of an amorphous solid dispersion of Fevipiprant and excipient at step c) involves recovering the solid obtained in step b). The solid obtained from step b) may be recovered using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used.
In an embodiment, the amorphous solid dispersion of Fevipiprant and excipient obtained from step b) may be optionally dried before or after isolating at step c).
Amorphous solid dispersion of Fevipiprant obtained at step c) may be optionally combined with atleast one additional pharmaceutically acceptable excipient at step d).
In an embodiment, amorphous solid dispersion of Fevipiprant may be combined with additional excipient using a technique known in art or by the procedures disclosed in the present application.
In preferred embodiment, amorphous solid dispersion of the present application may be combined with additional excipient either by physical blending of both the solid components or by suspending both the components in a suitable solvent and conditions, such that both the components remain unaffected. Blending may be carried out using techniques known in art such as rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure / vacuum or inert atmosphere such nitrogen at suitable temperature and sufficient time to obtain uniform composition of amorphous solid dispersion of Fevipiprant with pharmaceutically acceptable excipient and atleast one additional pharmaceutically acceptable excipient.
In an embodiment, amorphous solid dispersion of the present application may be combined with additional excipient by evaporating the suspension or solution of amorphous solid dispersion of Fevipiprant and additional excipient.
In an embodiment, pharmaceutically acceptable additional excipient may be same or different from the excipient used in the preparation of amorphous solid dispersion of Fevipiprant. Additional excipient may include, but not limited to an inorganic oxide such as SiO2, TiO2, ZnO2, ZnO, Al2O3 and zeolite; a water insoluble polymer is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolat, and cross-linked styrene divinyl benzene or any other excipient at any aspect of present application.
In preferred embodiment, pharmaceutically acceptable additional excipient may be selected from the group consisting of silicon dioxide, e.g. colloidal or fumed silicon dioxide or porous silica or Syloid; copolymers, such as polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer; and cellulose, preferably microcrystalline cellulose.
Amorphous solid dispersion of Fevipiprant isolated at step c) or d) may be dried in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, 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, less than about 60°C, less than about 40°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 10 hours or longer.
In an aspect, the present application provides pharmaceutical composition comprising amorphous solid dispersion of Fevipiprant with atleast one pharmaceutically acceptable excipient and atleast one additional pharmaceutically acceptable excipient.
In an aspect, the present application provides pharmaceutical compositions comprising amorphous Fevipiprant and atleast one pharmaceutically acceptable excipient, in particular in the form of solid dispersions and adsorbates, and a process for preparing the same. In embodiments, the pharmaceutically acceptable excipient is selected from the excipients at any aspect of present application.
In embodiments, the present application provides adsorbates, wherein Fevipiprant or a salt thereof is associated with a suitable substrate. Suitable substrate may be a particulate and/or porous substrate, wherein this substrate has an outer and/or inner surface onto which the API may be adsorbed. This means that if the substrate has pores, these pores are filled by the Fevipiprant and the substrate remains unaffected, it does not, at least not essentially, change during and / or after the adsorption. In embodiments, the suitable substrate is selected from the excipients at any aspect of present application.
Amorphous form of Fevipiprant or its solid dispersion may be obtained alternatively either by employing a melt-extrusion technique or by combining a solution of Fevipiprant as obtained any of the aspects of present application with a suitable anti-solvent. In embodiment, amorphous product may be obtained by employing suitable melt-extrusion conditions or any of the procedures known in the art for obtaining amorphous product by melt-extrusion technique. In embodiment, solution of Fevipiprant may be combined with the anti-solvent at suitable temperature and for sufficient time to obtain amorphous product.
In another aspect, the present application provides crystalline and amorphous Fevipiprant, its solid dispersion or pharmaceutical composition comprising Fevipiprant or a salt thereof having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by 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
The term "about" when used in the present application 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.
The term “inert solvent” when used in the present application is a solvent that does not react with the reactants or reagent s under conditions that cause the chemical reaction indicated to take place.
The terms “crystalline form" indicates that the Fevipiprant is present in substantially crystalline Form. "Substantially" crystalline denotes that atleast 80 %, preferably 90 % or 95 %, more preferably all of the Fevipiprant is crystalline form. In other words, "crystalline form of Fevipiprant” denotes Fevipiprant, which does not contain substantial amounts, preferably does not contain noticeable amounts, of any other crystalline portions of Fevipiprant e.g. measurable upon X-ray powder diffraction analysis.
The terms “amorphous form of Fevipiprant " and “amorphous Fevipiprant or a salt thereof” indicate that the Fevipiprant is present in substantially amorphous state in the composition (e.g. solid dispersion, adsorbate or pharmaceutical composition). "Substantially" amorphous denotes that 90 %, preferably 95 % or 99 %, more preferably all of the Fevipiprant being present in the solid dispersion, on the adsorbate or in the pharmaceutical composition is amorphous. In other words, an "amorphous" Fevipiprant composition denotes a Fevipiprant -containing composition, which does not contain substantial amounts, preferably does not contain noticeable amounts, of crystalline portions of Fevipiprant e.g. measurable upon X-ray powder diffraction analysis.
The term "solid dispersion" when used in the present application, denotes a state where most of the Fevipiprant, preferably 90%, 95% or all of the Fevipiprant of the solid dispersion, is homogeneously molecularly dispersed in a solid polymer matrix. Preferably solid dispersion, relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way. In other words, in a solid dispersion, the two components (polymer and API) form a homogeneous one-phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size. In a preferred embodiment, in the solid dispersion according to the present invention no chemical bonds can be detected between the API and the polymer. In order to arrive at such a solid dispersion, preferably solid solution, it is required to have a substantial amount of API dissolved in a suitable solvent at least at one time point during preparation of said solid dispersion.
The term "adsorbate" when used in the present application, specifies that the Fevipiprant is, preferably evenly, and preferably homogeneously, distributed on the inner and/or outer surface of the particulate substrate.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include, but are not limited to, methanol, ethanol, 2-nitroethanol,2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
An “aliphatic hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called“aromatic.” Examples of “C5-C8aliphatic or aromatic hydrocarbons” include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6esters” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6Nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.
EXAMPLES
Example-1: Preparation of crystalline Form FP1 of Fevipiprant
A solution of sodium hydroxide (2.64 g) in water (75 mL) was added to a mixture of Ethyl 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate (15 g), etrahydrofuran (150 mL) and water (225 mL) at 27°C and stirred the reaction mixture for 16 hours at the same temperature . After the completion of the reaction, the solvent was removed from the mixture under reduced pressure at 45°C and the pH of reaction mixture was adjusted to 2.0 with 6N HCl at 20°C. The reaction mixture was then extracted with dichloromethane (3 x 200 mL) and the combined organic layer was dried over sodium sulphate. The solvent was removed under reduced pressure at 40°C and added ethyl acetate (20 mL) and methyl tert.butyl ether (20 mL). Stirred the mixture at 27°C for 15 minutes and the solid was filtered. The solid was washed with methyl tert. butyl ether (10 mL) and dried under reduced pressure at 40°C for 2 hours to obtain the title compound as off-white solid.
Yield: 11.2 g and Purity by HPLC: 99.88 %
Example-2: Preparation of crystalline Form-FP2 of Fevipiprant
Fevipiprant (500 mg) was dissolved in methanol (50 mL) at 40°C and the solution was filtered to make it particle free. The clear solution was taken in Buchi rotavapour and evaporated under reduced pressure at 60°C to obtain the title compound.
Example-3: Preparation of crystalline Form-FP2 of Fevipiprant
Fevipiprant (500 mg) was dissolved in a mixture of dichloromethane (40 mL) and methanol (10 mL) at 25°C and the solution was filtered to make it particle free. The clear solution was taken in Buchi rotavapour and evaporated under reduced pressure at 40°C to obtain the title compound.
Example-4: Preparation of crystalline Form-FP3 of Fevipiprant
Fevipiprant (500 mg) was dissolved in acetone (50 mL) at 25°C and the solution was filtered to make it particle free. The clear solution was taken in Buchi rotavapour and evaporated under reduced pressure at 50°C to obtain the title compound.
Example-5: Preparation of amorphous solid dispersion of Fevipiprant with povidone.
Fevipiprant (250 mg) and povidone (PVP K30) (750 mg) were dissolved in methanol (50 mL) at 25°C and the solution was filtered to make it particle free. The clear solution was taken in Buchi rotavapour and evaporated under reduced pressure at 60°C to obtain the title compound.
Example-6: Preparation of amorphous solid dispersion of Fevipiprant with HPC.
Fevipiprant (250 mg) and hydroxy propyl cellulose (HPC) (750 mg) were dissolved in methanol (50 mL) at 60°C and the solution was filtered to make it particle free. The clear solution was taken in Buchi rotavapour and evaporated under reduced pressure at 60°C to obtain the title compound.
Example-7: Preparation of amorphous Fevipiprant
Fevipiprant (3 g) was dissolved in a mixture of dichloromethane (80 mL) and methanol (80 mL) at 25°C and the solution was filtered to make it particle free. The clear solution spray dried with a feed rate of 5 mL/minute and 75% aspiration at 60°C to obtain the title compound.
,CLAIMS:We claim
1. A crystalline form of Fevipiprant, wherein the crystalline form is:
(A) A crystalline form FP1 of Fevipiprant, characterized by a PXRD pattern comprising the peaks at about 12.07, 17.49, 19.85, 21.16 and 24.35 ± 0.2° 2? (or) (B) A crystalline form FP2 of Fevipiprant, characterized by a PXRD pattern comprising the peaks at about 5.0, 13.7, 19.6, 20.3 and 21.8 ± 0.2° 2? (or) (C) A crystalline form FP3 of Fevipiprant, characterized by a PXRD pattern comprising the peaks at about 13.3, 17.7, 19.8, 20.5 and 25.3 ± 0.2° 2?.
2. A process for the preparation of crystalline form FP1 of Fevipiprant, 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) treating Fevipiprant with solvent selected from ethyl acetate, methyl tert. butyl ether or a mixture thereof;
b) Isolating the crystalline form FP1of Fevipiprant.
3. A process for the preparation of crystalline form FP2 of Fevipiprant, 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) treating Fevipiprant with solvent selected from methanol, dichloromethane or a mixtures thereof;
b) Isolating the crystalline form FP2 of Fevipiprant.
4. A process for the preparation of crystalline form FP3 of Fevipiprant, characterized by a PXRD pattern comprising the peaks at about 13.3, 17.7, 19.8, 20.5 and 25.3 ± 0.2° 2?, comprising the steps of:
a) treating Fevipiprant with solvent selected from acetone or a mixture of acetone with any other solvent;
b) Isolating the crystalline form FP3 of Fevipiprant.
5. An amorphous form of Fevipiprant.
6. A process for the preparation of an amorphous form of Fevipiprant, comprising the steps of:
a) providing a solution of Fevipiprant or a salt thereof in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a), and;
c) isolating the amorphous form of Fevipiprant or a salt thereof.
7. An amorphous solid dispersion of Fevipiprant together with atleast one pharmaceutically acceptable excipient.
8. A process for the preparation of an amorphous solid dispersion of Fevipiprant, comprising the steps of:
a) providing a solution of Fevipiprant and atleast one pharmaceutically acceptable excipient in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a), and;
c) isolating the amorphous solid dispersion of Fevipiprant or a salt thereof.
9. The process of claim 6 or 8, wherein the solvent selected from methanol, dichloromethane, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, water and mixtures thereof.
10. The amorphous solid dispersion of Fevipiprant according to claim 7 or 8, wherein the pharmaceutically acceptable excipient selected from povidone K-30, hydroxy propyl cellulose (HPC), polyvinyl pyrrolidone, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL, hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer), ethyl cellulose, cellulose acetate phthalate, carboxymethylethylcellulose, hypromellose phthalates or mixture thereof.