Field of the Invention:
The present invention relates to amorphous form of N-[6-(cis-2,6-dimethyl morpholin-
4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[l,r-biphenyl]-3-carboxamide
diphosphate compound of formula-la, represented by the following structural formula:
CH3
F3C ]| ^1 CH3 O f || — CH3
^J H .2H3P04
Formula-la
The present invention also relates to amorphous solid dispersions of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula-la and process for its preparation thereof. Background of the Invention:
Sonidegib (INN), also known as LDE225 and marketed as Odomzo, is a Hedgehog signaling pathway inhibitor (via smoothened antagonism) being developed as an anticancer agent by Novartis.
Sonidegib was approved by U.S Food and Drug Administration in 24* July 2015 for the treatment of patients with locally advanced basal cell carcinoma.
ODOMZO has also been approved by the European Commission for the Treatment of pediatric and adult patients with hedgehog pathway-activated medulloblastoma.
Sonidegib, chemically known as N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide compound of formula-1.
International (PCT) publication No. WO2007/131201 Al first disclosed Sonidegib and process for its preparation.
International (PCT) publication No. WO2010/033481 Al discloses various salts of Sonidegib and process for its preparation.
International (PCT) publication No. WO2011/009852 Al discloses the various crystalline forms of Sonidegib free base, Form-A, Form-B and Amorphous form.

International (PCT) publication No. WO2015/092720 Al discloses the various metabolites of Sonidegib.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.
Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.
Furthermore, amorphous materials do not exhibit the three-dimensional long-range order found in crystalline materials, but is structurally more similar to liquids where the arrangement of molecules is random. Amorphous solids do not give a definitive x-ray diffraction pattern (XRD). In addition, amorphous solids do not give rise to a melting point and tend to liquefy at some point beyond the glass transition point. Because amorphous solids do not have lattice energy, they usually dissolve in a solvent more rapidly and consequently may provide rapid bioavailability. Furthermore, amorphous forms of a drug may offer significant advantages over crystalline forms of the same drug in solid dosage form manufacturing process such as compressibility, economically or environmentally suitable solvents or process, or higher purity or yield of the desired product.

Brief description of the Invention:
The first aspect of the present invention is to provide amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,l'-biphenyl]-3-carboxamide diphosphate compound of formula-la and process for its preparation.
The second aspect of the present invention is to provide amorphous solid dispersions of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1'-biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with one or more pharmaceutical acceptable carriers.
The third aspect of the present invention is to provide process for the preparation of amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with one or more pharmaceutical acceptable carrier.
Brief description of the Drawings:
Figure 1: Illustrates the PXRD pattern of amorphous form of N-[6-(cis-2,6-dimethyl
morpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide
diphosphate compound of formula-la.
Figure 2: Illustrates the PXRD pattern of amorphous solid dispersion of N-[6-(cis-2,6-
dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-
carboxamide diphosphate in combination with HPMC.
Figure 3: Illustrates the PXRD pattern of amorphous solid dispersion of N-[6-(cis-2,6-
dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-
carboxamide diphosphate in combination with PVP K-30.
Figure 4: Illustrates the PXRD pattern of amorphous solid dispersion of N-[6-(cis-2,6-
dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-
carboxamide diphosphate in combination with HPMC AS.
Figure 5: Illustrates the PXRD pattern of amorphous solid dispersion of N-[6-(cis-2,6-
dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-
carboxamide diphosphate in combination with HPC.

Detailed description of the Invention:
As used herein the term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like; "ether solvents" such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, dimethoxy ethane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloro methane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; "polar solvents" such as water or mixtures thereof.
The first aspect of the present invention provides amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[l,r-biphenyl]-3-carboxamide diphosphate compound of formula-la and process for its preparation.
The amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[l,r-biphenyl]-3-carboxamide diphosphate of the present invention is characterized by its P-XRD diffractogram which is depicted in figure-1.
In an embodiment of the present invention provides a process for the preparation of amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula-la, comprising of:

a) Dissolving N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,r-biphenyl]-3-carboxamide diphosphate in a suitable solvent,
b) stirring the reaction mixture,
c) isolating the amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[l,r-biphenyl]-3-carboxamide diphosphate compound of formula-la.
Wherein, in step-a) the suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents, nitrile solvents, polar solvents like water or mixtures thereof.
The preferred embodiment of the present invention provides a process for the preparation of amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula-la, comprising of:
a) Dissolving N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate in a mixture of methanol and dichloromethane,
b) stirring the reaction mixture,
c) isolating the amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4' -(trifluoromethoxy) [1,1' -biphenyl]-3-carboxamide diphosphate compound of formula-la.
In another embodiment of the presence invention provides a process for the preparation of amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula-la, comprising of:
a) Adding a suitable solvent to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide compound of formula-1,
b) stirring the reaction mixture,
c) adding phosphoric acid to the reaction mixture,

d) stirring the reaction mixture and isolating the amorphous form of N-[6-(cis-2,6-
dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1'-
biphenyl]-3-carboxamide diphosphate compound of formula-la.
Wherein, in step-a) the suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents, nitrile solvents and polar solvents like water or mixtures thereof.
The preferred embodiment of the present invention provides a process for the preparation of amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula-la, comprising of:
a) Adding methanol to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide compound of formula-1,
b) stirring the reaction mixture,
c) adding phosphoric acid to the reaction mixture,
d) stirring the reaction mixture and isolating the amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1'-biphenyl]-3-carboxamide diphosphate compound of formula-la.
The second aspect of the present invention provides amorphous solid dispersion of N-
[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1'-
biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with one or more pharmaceutical acceptable carriers.
Wherein, the term pharmaceutical acceptable carrier is preferably a polymeric carrier, and more preferably at least one from the group consisting of starches, modified starches, cellulose, methyl cellulose (MC), Microcrystalline cellulose (MCC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), polycarbophil, polyethylene glycol (PEG), polyethylene oxides, polyoxyalkylene derivatives, polymethacrylates, polyvinyl pyrrolidone (PVP), PVP K-30, polyvinyl acetate (PVAc), PVP

vinylacetate-copolymer (PVP-VA), Kollidon VA 64 (vinylpyrrolidone vinyl acetate copolymer), lactose, sorbitol, mannitol, maltitol, saccharose, isomalt, cyclodextrins such as cc-cyclodextrins, P-cyclodextrins, y-cyclodextrins, hydroxyl-propyl-cyclodextrins, hydroxyl propyl-cyclodextrin, sodium carboxymethyl cellulose cross-linked polyacrylic acid (carbipol), or a mixture thereof.
In an embodiment of the present invention provides amorphous solid dispersion of N-
[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1'-
biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with HPMC and the P-XRD pattern is depicted in figure-2.
The another embodiment of the present invention provides amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1'-biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with PVP K-30 and the P-XRD pattern is depicted in figure-3.
The another embodiment of the present invention provides amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1'-biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with HPMC AS and the P-XRD pattern is depicted in figure-4.
The another embodiment of the present invention provides amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1'-biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with HPC and the P-XRD pattern is depicted in figure-5.
In general, the term "solid dispersion" refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components.
The term "amorphous solid dispersion" as used herein, refers to solid dispersion which is substantially amorphous, that is, at least 80%, preferably at least 90%, most preferably at least 95%), is in amorphous form as determined by powder x-ray diffraction pattern.

The third aspect of the present invention provides a process for the preparation of amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,r-biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with one or more pharmaceutical acceptable carrier, comprising of:
a) Dissolving a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate and one or more pharmaceutical acceptable carrier in a suitable solvent,
b) stirring the reaction mixture,
c) isolating amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula-la with one or more pharmaceutical acceptable carrier.
Wherein, in step-a) the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, chloro solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents, nitrile solvents and polar solvents like water or mixture thereof and suitable pharmaceutical acceptable carrier is same as defined in the second aspect of the present invention.
The preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with HPMC, comprising of:
a) Dissolving a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate and HPMC in a mixture of methanol and dichloromethane,
b) stirring the reaction mixture,
c) isolating amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with HPMC.
The preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-

3-yl]-2-methyl-4'-(trifluoromethoxy) [l,r-biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with PVP K-30, comprising of:
a) Dissolving a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate and PVP K-30 in a mixture of methanol and dichloromethane,
b) stirring the reaction mixture,
c) isolating amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with PVP K-30.
The preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with HPMC AS, comprising of:
a) Dissolving a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate and HPMC AS in a mixture of methanol and dichloromethane,
b) stirring the reaction mixture,
c) isolating amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[l,r-biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with HPMC AS.
The preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with HPC, comprising of:
a) Dissolving a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate and HPC in a mixture of methanol and dichloromethane,
b) stirring the reaction mixture,

c) isolating amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[l,r-biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with HPC.
The amorphous and amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[l,r-biphenyl]-3-carboxamide diphosphate obtained according to the present invention can be isolated using a rotational distillation device such as a Buchi Rotavapor, vacuum drying, spray drying, spray granulating, freeze drying and spray-freeze drying, agitated thin film drying (ATFD) or melt extrusion or freeze drying (lyophilization) or by any other suitable techniques.
In the present invention, the composition of the solid dispersion containing of a mole ratio of the amount of the N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula-la to the amount of the pharmaceutical acceptable carrier is ranging from about 1:0.5 to 1:10 by weight.
N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula-la produced by the present invention can be further micronized or milled in a conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide compound of formula-1 used in the present invention is prepared according to any of the process known in the art.
The invention also encompasses pharmaceutical compositions comprising compound of formula-1 or salts thereof of the present invention. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills,

powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection
preparations.
P-XRD Method of Analysis:
PXRD analysis of compounds produced by the present invention were carried out using BRUKER D8 ADVANCE/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples Example-1:
Preparation of Amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate (Formula-la)
A mixture of dichloromethane (100 ml) and methanol (100 ml) was added to N-[6-
(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1'-
biphenyl]-3-carboxamide diphosphate (5.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature. The reaction mixture was spray dried at below mentioned parameters to obtain amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate: Operation parameters: Labultima Instrument Inlet temperature: 40°C Feed rate: lOml/min Aspirator flow rate: 70% Gas flow N2 pressure: 5.0 kg/ cm
Yield: 2.5 gms; The P-XRD pattern of the obtained compound was depicted in figure-1. Particle size distribution: (PSD): D(0.9) is 30.5 urn; D[4.3] is 15.4 urn. Example-2: Preparation of Amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)

pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide
diphosphate in combination with HPMC: (1:1)
A mixture of dichloromethane (150 ml) and methanol (150 ml) was added to N-[6-
(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1'-
biphenyl]-3-carboxamide diphosphate (5.0 gms) and HPMC (5.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature. The reaction mixture was spray dried at below mentioned parameters to obtain amorphous solid dispersion of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate with HPMC: Operation parameters: Labultima Instrument Inlet temperature: 55°C Feed rate: lOml/min Aspirator flow rate: 70% Gas flow N2 pressure: 5.0 kg/ cm Yield: 5.0 gms; The P-XRD pattern of the obtained compound was depicted in figure-2.
Example-3: Preparation of Amorphous solid dispersion of N-[6-(cis-2,6-dimethyl
morpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-
carboxamide diphosphate in combination with PVPK-30: (1:1)
A mixture of dichloromethane (150 ml) and methanol (150 ml) was added to N-[6-
(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1'-
biphenyl]-3-carboxamide diphosphate (5.0 gms) and PVP K-30 (5.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature. The reaction mixture was spray dried at below mentioned parameters to obtain amorphous solid dispersion of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate with PVP K-30: Operation parameters: Labultima Instrument Inlet temperature: 55°C Feed rate: lOml/min

Aspirator flow rate: 70%
Gas flow N2 pressure: 5.0 kg/ cm
Yield: 6.0 gms; The P-XRD pattern of the obtained compound was depicted in figure-3.
Example-4: Preparation of Amorphous solid dispersion of N-[6-(cis-2,6-dimethyl
morpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-
carboxamide diphosphate in combination with HPMC AS: (1:1)
A mixture of dichloromethane (150 ml) and methanol (150 ml) was added to N-[6-
(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1'-
biphenyl]-3-carboxamide diphosphate (5.0 gms) and HPMC AS (5.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature. The reaction mixture was spray dried at below mentioned parameters to obtain amorphous solid dispersion of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate with HPMC AS: Operation parameters: Labultima Instrument Inlet temperature: 55°C Feed rate: lOml/min Aspirator flow rate: 70% Gas flow N2 pressure: 5.0 kg/ cm Yield: 5.0 gms; The P-XRD pattern of the obtained compound was depicted in figure-4.
Example-5: Preparation of Amorphous solid dispersion of N-[6-(cis-2,6-dimethyl
morpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-
carboxamide diphosphate in combination with HPC: (1:1)
A mixture of dichloromethane (150 ml) and methanol (150 ml) was added to N-[6-
(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1'-
biphenyl]-3-carboxamide diphosphate (5.0 gms) and HPC (5.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature. The reaction mixture was spray dried at below mentioned parameters to obtain amorphous solid dispersion of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide

diphosphate with HPC: Operation parameters:
Labultima Instrument
Inlet temperature: 55°C
Feed rate: lOml/min
Aspirator flow rate: 70%
Gas flow N2 pressure: 5.0 kg/ cm2
Yield: 5.0 gms. The P-XRD pattern of the obtained compound was depicted in figure-5.
Example-6: Preparation of Amorphous N-(6-(cis-2,6-dimethylmorpholino)pyridin-3-yl) -
2-methyl-4'-(trifluoromethoxy)-[l,l'-biphenyl]-3-carboxamide diphosphate:
(Formula-la)
Methanol (150 ml) was added to N-(6-(cis-2,6-dimethylmorpholino)pyridin-3-yl) -2-methyl-4'-(trifluoromethoxy)-[l,r-biphenyl]-3-carboxamide (5.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature. Phosphoric acid (3.0 gms) was added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. The reaction mixture was spray dried at below mentioned parameters to obtain amorphous N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate: Operation parameters: Labultima Instrument Inlet temperature: 65°C Feed rate: lOml/min Aspirator flow rate: 65% Gas flowN2pressure: 3.0 kg/ cm2 Yield: 3.0 gms; The P-XRD pattern of the obtained compound was depicted in figure-1.

We Claim:
1. Amorphous N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoro
methoxy) [l,r-biphenyl]-3-carboxamide diphosphate.
CH3
l^J H .2H3P04
Formula-la
2. A process for the preparation of amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-
yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1 '-biphenyl]-3-carboxamide
diphosphate compound of formula-la, comprising of:
a) Dissolving N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoroomethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate in a suitable solvent selected from alcohol solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents, nitrile solvents and polar solvents like water or mixtures thereof,
b) stirring the reaction mixture,
c) isolating the amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4' -(trifluoromethoxy) [1,1' -biphenyl]-3-carboxamide diphosphate compound of formula-la by filtration, solvent dry distillation, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), and the like or any other suitable technique or by adding suitable anti-solvent.
3. A process for the preparation of amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-
yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1 '-biphenyl]-3-carboxamide
diphosphate compound of formula-la, comprising of:
a) Dissolving N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-
(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate in a mixture of methanol and dichloromethane,

b) stirring the reaction mixture,
c) isolating the amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4' -(trifluoromethoxy) [1,1' -biphenyl]-3-carboxamide diphosphate compound of formula-la.

4. Amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with one or more pharmaceutical acceptable carriers.
5. Amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate according to claim-4, wherein, the pharmaceutical acceptable carrier is a polymeric carrier, starches, modified starches, cellulose, methyl cellulose (MC), Microcrystalline cellulose (MCC), ethyl cellulose (EC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC-AS), polycarbophil, polyethylene glycol (PEG), polyethylene oxides, polyoxy alkylene derivatives, polymethacrylates, polyvinyl pyrrolidone (PVP), PVP K-30, polyvinyl acetate (PVAc), PVP vinylacetate-copolymer (PVP-VA), Kollidon VA 64 (vinylpyrrolidone-vinyl acetate copolymer), lactose, sorbitol, mannitol, maltitol, saccharose, isomalt, cyclodextrins such as cc-cyclodextrins, P-cyclodextrins, y-cyclodextrins, hydroxyl-propyl-cyclodextrins, hydroxyl propyl-cyclodextrin, sodium carboxymethyl cellulose cross-linked polyacrylic acid (carbipol), or a mixture thereof.
6. Amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with one or more pharmaceutical acceptable carrier, which includes:
a) Amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4' -(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate in combination with HPMC which is characterized by its P-XRD pattern as depicted in figure-2.

b) Amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,r-biphenyl]-3-carboxamide diphosphate in combination with PVP K-30 which is characterized by its P-XRD pattern as depicted in figure-3.
c) Amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate in combination with HPMC AS which is characterized by its P-XRD pattern as depicted in figure-4.
d) Amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate in combination with HPC which is characterized by its P-XRD pattern as depicted in figure-5.
7. A process for the preparation of amorphous solid dispersion of N-[6-(cis-2,6-dimethyl
morpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-
carboxamide diphosphate compound of formula-la in combination with one or more
pharmaceutical acceptable carrier, comprising of:
a) Dissolving a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate and one or more pharmaceutical acceptable carrier in a suitable selected from alcohol solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents, nitrile solvents and polar solvents like water or mixture thereof
b) stirring the reaction mixture,
c) isolating amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula-la with one or more pharmaceutical acceptable carrier.
8. A process for the preparation of amorphous solid dispersion of N-[6-(cis-2,6-dimethyl
morpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-

carboxamide diphosphate compound of formula-la in combination with one or more pharmaceutical acceptable carrier, comprising of: i). amorphous solid dispersion of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl]-
2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate in
combination with HPMC, comprising of:
a) Dissolving a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate and HPMC in a mixture of methanol and dichloromethane,
b) stirring the reaction mixture,
c) isolating amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1, l'-biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with HPMC.
ii). amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-
2-methyl-4'-(trifluoromethoxy) [1, l'-biphenyl]-3-carboxamide diphosphate
compound of formula-la in combination with PVP K-30, comprising of:
a) Dissolving a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate and PVP K-30 in a mixture of methanol and dichloromethane,
b) stirring the reaction mixture,
c) isolating amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with PVP K-30.
iii). amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-
2-methyl-4'-(trifluoromethoxy) [1, l'-biphenyl]-3-carboxamide diphosphate
compound of formula-la in combination with HPMC AS, comprising of:
a) Dissolving a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate and HPMC AS in a mixture of methanol and dichloromethane,
b) stirring the reaction mixture,

c) isolating amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)
pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,r-biphenyl]-3-carboxamide
diphosphate compound of formula-la in combination with HPMC AS.
iv). amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-
2-methyl-4'-(trifluoromethoxy) [1, l'-biphenyl]-3-carboxamide diphosphate
compound of formula-la in combination with HPC, comprising of:
a) Dissolving a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate and HPC in a mixture of methanol and dichloromethane,
b) stirring the reaction mixture,
c) isolating amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with HPC.
9. A process for the preparation of amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-
yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1, l'-biphenyl]-3-carboxamide
diphosphate compound of formula-la, comprising of:
a) Adding a suitable solvent selected from alcohol solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents, nitrile solvents and polar solvents like water or mixture thereof to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1'-biphenyl]-3-carboxamide compound of formula-1,
b) stirring the reaction mixture,
c) adding phosphoric acid to the reaction mixture,
d) stirring the reaction mixture and isolating the amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1'-biphenyl]-3-carboxamide diphosphate compound of formula-la.
10. A process for the preparation of amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-
yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1, l'-biphenyl]-3-carboxamide
diphosphate compound of formula-la, comprising of:

a) Adding methanol to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide compound of formula-1,
b) stirring the reaction mixture,
c) adding phosphoric acid to the reaction mixture,
d) stirring the reaction mixture and isolating the amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1'-biphenyl]-3-carboxamide diphosphate compound of formula-la.

The present invention relates to amorphous form of N-[6-(cis-2,6-dimethylmorpholin-
4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide
diphosphate compound of formula-la and process for its preparation thereof, which is represented by the following structural formula
CH3
F3C (i ^ CH3 ° r HT ^^ CH3
l^J H . 2 H3P04
Formula-la