Field of the Invention:
The present invention relates to amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl) ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1, represented by the following structural formula:
9H3 9 H #CH3 f^ti
H2N. JLJ^C NH2 W
y ^ CH3 S^*N
Formula-1 The present invention also relates to novel crystalline forms of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl) ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 and process for its preparation thereof.
Background of the Invention:
5-[[[(2S)-2-Amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic known as Eluxadoline and is approved in US under the brand name VIBERZI. Eluxadoline is a mu-opioid receptor agonist; Eluxadoline is also a delta opioid receptor antagonist and a kappa opioid receptor agonist. The binding affinities (Ki) of eluxadoline for the human mu and delta opioid receptors are 1.8 nM and 430 nM, respectively. The binding affinity (Ki) of eluxadoline for the human kappa opioid receptor has not been determined; however, the Ki for guinea pig cerebellum kappa opioid receptor is 55 nM. In animals, eluxadoline interacts with opioid receptors in the gut.
5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid and process for its preparation was first disclosed in US7741356 B2 herein after referred as US’356 B2.

US7994206 B2 claims beta crystalline form of 5-[[[(2S)-2-amino-3-[4-(amino carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl] amino]methyl]-2-methoxybenzoic acid compound of formula-1.
US8691860 B2 claims alpha crystalline form of 5-[[[(2S)-2-amino-3-[4-(amino carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl] amino]methyl]-2-methoxybenzoic acid compound of formula-1.
IPCOM000245114D publication discloses crystalline forms of methyl 5-(((S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)-N-((S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl) propanamido)methyl)-2-methoxybenzoate dihydrochloride.
The said US’356 B2 discloses hydrochloric acid salt of 5-[[[(2S)-2-amino-3-[4-(amino carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl] amino]methyl]-2-methoxybenzoic acid compound of formula-1a but, does not gave any information about the free base of compound of formula-1.
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.

Brief description of the Invention:
The first aspect of the present invention is to provide novel crystalline form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1, herein after designated as Form-N1 and its preparation thereof.
The second aspect of the present invention is to provide novel crystalline form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1, herein after designated as Form-N2 and its preparation thereof.
The third aspect of the present invention is to provide novel crystalline form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1, herein after designated as Form-N3 and its preparation thereof.
The fourth aspect of the present invention is to provide amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 in combination with one or more pharmaceutical acceptable carrier.
The fifth aspect of the present invention is to provide process for the preparation of amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 in combination with one or more pharmaceutical acceptable carrier.
Brief description of the Drawings:
Figure 1: Illustrates the PXRD pattern of crystalline form-N1 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl) ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1.
Figure 2: Illustrates the PXRD pattern of crystalline form-N2 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl) ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1.

Figure 3: Illustrates the PXRD pattern of crystalline form-N3 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl) ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1.
Figure 4: Illustrates the PXRD pattern of amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl) ethyl]amino]methyl]-2-methoxybenzoic acid in combination with HPC.
Figure 5: Illustrates the PXRD pattern of amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl) ethyl]amino]methyl]-2-methoxybenzoic acid in combination with HPMC AS.
Figure 6: Illustrates the PXRD pattern of amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl) ethyl]amino]methyl]-2-methoxybenzoic acid in combination with HPMC.
Figure 7: Illustrates the PXRD pattern of amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl) ethyl]amino]methyl]-2-methoxybenzoic acid in combination with PVP K-30.
Figure 8: Illustrates the PXRD pattern of amorphous of 5-[[[(2S)-2-amino-3-[4-(amino carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl] amino]methyl]-2-methoxybenzoic acid.
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, methylcyclohexane, 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, 1,2-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), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, 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, propylene glycol, 2-methoxyethanol, l, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, anisole, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
The first aspect of the present invention provides novel crystalline form-N1 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1, characterized by its powder x-ray diffraction pattern having peaks at 6.3, 7.4, 9.0, 9.8, 10.4, 10.9, 11.1, 11.7, 12.2, 12.8, 13.7, 14.2, 14.9, 15.1, 15.7, 17.7, 18.1, 19.0, 19.4, 20.3, 21.1, 21.3, 21.9, 22.2, 22.5, 23.1, 23.8, 24.2, 24.8, 25.9, 27.1, 28.3, 31.9 and 32.6 ±0.2 degrees two theta and depicted in figure-1.
In an embodiment of the present invention provides a process for the preparation of
crystalline form-N1 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxo
propyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid
compound of formula-1, comprising of:
a) Adding a suitable solvent to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of fomula-1,
b) heating the reaction mixture to a suitable temperature,
c) stirring the reaction mixture,
d) cooling the reaction mixture,
e) filtering the solid to get the crystalline form-N1 of 5-[[[(2S)-2-amino-3-[4-(amino carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl) ethyl]amino]methyl]-2-methoxybenzoic acid.
Wherein, in step-a) the suitable solvent is selected from alcohol solvents, preferably
isopropanol;
in step-b) the suitable temperature is ranging from 25°C to the reflux temperature of the

solvent used in the reaction;
The preferred embodiment of the present invention provides a process for the preparation of crystalline form-N1 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1, comprising of:
a) Adding isopropanol to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl] -1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of fomula-1,
b) heating the reaction mixture to 60-65°C,
c) stirring the reaction mixture,
d) cooling the reaction mixture,
e) filtering the solid to get the crystalline form-N1 of 5-[[[(2S)-2-amino-3-[4-(amino carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl) ethyl]amino]methyl]-2-methoxybenzoic acid.
The second aspect of the present invention provides novel crystalline form-N2 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1, characterized by its powder x-ray diffraction pattern having peaks at 7.4, 7.6, 8.1, 8.7, 9.6, 9.8, 10.4, 10.7, 12.6, 14.1, 14.8, 15.4, 15.5, 16.1, 16.4, 17.6, 18.8, 19.3, 19.9, 21.2, 21.3, 21.7, 22.3, 22.5, 22.7, 23.8, 24.7, 25.0, 25.4, 25.6, 26.5, 27.2, 28.0, 28.4, 29.1, 29.3, 31.9, 36.3 and 38.5 ±0.2 degrees two theta and depicted in figure-2.
In an embodiment of the present invention provides a process for the preparation of
crystalline form-N2 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxo
propyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid
compound of formula-1, comprising of:
a) Adding a suitable solvent to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of fomula-1,
b) heating the reaction mixture to a suitable temperature,
c) adding a suitable solvent,

d) stirring the reaction mixture,
e) cooling the reaction mixture,
f) filtering the precipitated solid to get the crystalline form-N1 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl) ethyl]amino]methyl]-2-methoxybenzoic acid.
Wherein, in step-a) the suitable solvent is selected from alkyl formate; preferably ethyl formate; in step-b) the suitable temperature is ranging from 25°C to the reflux temperature of the solvent used in the reaction;
in step-c) the suitable solvent is selected from ketone solvents, ester solvents, chloro solvents, ether solvents, hydrocarbon solvents and polar solvent like water or mixture thereof.
The preferred embodiment of the present invention provides a process for the preparation of crystalline form-N2 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1, comprising of:
a) Adding ethyl formate to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of fomula-1,
b) heating the reaction mixture to 60-65°C,
c) adding a mixture of ethyl acetate and methyl tert-butyl ether,
d) stirring the reaction mixture,
e) cooling the reaction mixture,
f) filtering the precipitated solid to get the crystalline form-N2 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid.
The third aspect of the present invention provides novel crystalline form-N3 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1, characterized by its powder x-ray diffraction pattern having peaks at 6.2, 7.2, 8.9, 9.6, 10.2,
10.8, 12.6, 13.5, 13.9, 14.0, 14.6, 15.0, 15.4, 15.8, 17.9, 18.1, 19.0, 19.3, 20.0, 21.0, 21.6,
21.9, 22.9, 23.8, 24.4 and 27.7 ±0.2 degrees two theta and depicted in figure-3.

In an embodiment of the present invention provides a process for the preparation of
crystalline form-N3 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxo
propyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid
compound of formula-1, comprising of:
a) Adding a suitable solvent to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of fomula-1,
b) heating the reaction mixture to a suitable temperature,
c) stirring the reaction mixture,
d) cooling the reaction mixture,
e) filtering the precipitated solid to get the crystalline form-N3 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl) ethyl]amino]methyl]-2-methoxybenzoic acid.
Wherein, in step-a) the suitable solvent is selected from ketone solvents, preferably methyl isobutyl ketone; in step-b) the suitable temperature is ranging from 25°C to the reflux temperature of the solvent used in the reaction;
The preferred embodiment of the present invention provides a process for the preparation of crystalline form-N3 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1, comprising of:
a) Adding methyl isobutyl ketone to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino] methyl]-2-methoxybenzoic acid compound of fomula-1,
b) heating the reaction mixture to 60-65°C,
c) stirring the reaction mixture,
d) cooling the reaction mixture,
e) filtering the precipitated solid to get the crystalline form-N3 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid.

The fourth aspect of the present invention provides amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 in combination with one or more pharmaceutical acceptable carrier.
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), hydroxyethylcellulose (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 (a vinylpyrrolidone-vinyl acetate copolymer), lactose, sorbitol, mannitol, maltitol, saccharose, isomalt, cyclodextrins such as cc-cyclodextrins, β-cyclodextrins, γ-cyclodextrins, hydroxyl-propyl-cyclodextrins, hydroxyl propyl-cyclodextrin, sodium carboxymethyl cellulose cross-linked polyacrylic acid (carbipol), or a mixture thereof.
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.
In an embodiment of the present invention provides amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 in combination with HPC and the P-XRD pattern is depicted in figure-4.
The another embodiment of the present invention provides amorphous solid dispersion
of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-
phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 in combination with HPMC AS and the P-XRD pattern is depicted in figure-5.

The another embodiment of the present invention provides amorphous solid dispersion
of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-
phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 in combination with HPMC and the P-XRD pattern is depicted in figure-6.
The another embodiment of the present invention provides amorphous solid dispersion
of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-
phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 in combination with PVP K-30 and the P-XRD pattern is depicted in figure-7.
The fifth aspect of the present invention provides process for the preparation of amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 in combination with one or more pharmaceutical acceptable carrier, comprising of:
a) Dissolving a mixture of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid and one or more pharmaceutical acceptable carrier in a suitable solvent,
b) stirring the reaction mixture,
c) isolating amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino] methyl]-2-methoxybenzoic acid compound of formula-1
Wherein, in step-a) the suitable solvent is selected from alcohol solvents, ketone solvents, ester 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 fourth aspect of the present invention.
The preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 in combination with HPC, comprising of:

a) Dissolving a mixture of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid and HPC in methanol,
b) stirring the reaction mixture,
c) isolating amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino] methyl]-2-methoxybenzoic acid compound of formula-1 in combination with HPC.
In another preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 in combination with HPMC, comprising of:
a) Dissolving a mixture of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid and HPMC in methanol,
b) stirring the reaction mixture,
c) isolating amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino] methyl]-2-methoxybenzoic acid compound of formula-1 in combination with HPMC.
In another preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 in combination with PVP K-30, comprising of:
a) Dissolving a mixture of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid and PVP K-30 in methanol,
b) stirring the reaction mixture,
c) isolating amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino] methyl]-2-methoxybenzoic acid compound of formula-1 in combination with PVP K-30.

In another preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 in combination with HPMC AS, comprising of:
a) Dissolving a mixture of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid and HPMC AS in methanol,
b) stirring the reaction mixture,
c) isolating amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino] methyl]-2-methoxybenzoic acid compound of formula-1 in combination with HPMC AS.
The amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid 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 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 to the amount of the pharmaceutical acceptable carrier is ranging from about 1:0.5 to 1:10 by weight.
5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 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.
5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 used for the preparation of crystalline forms and amorphous forms of 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 Kα 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 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid in combination with PVP K-30:
Methanol (30 ml) was added to a mixture of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid (1.0 gms) and polyvinyl pyrrolidone K-30 (1.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hy-flow bed. Distilled off the solvent completely from the obtained filtrate under reduced pressure to get the title compound. Yield: 1.5 gms. The P-XRD pattern of the obtained compound was depicted in figure-7.

Example-2: Preparation of Amorphous 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid in combination with HPC:
Methanol (30 ml) was added to a mixture of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid (1.0 gms) and hydroxypropyl cellulose (1.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed. Distilled off the solvent completely from the obtained filtrate under reduced pressure to get the title compound. Yield: 1.2 gms. The P-XRD pattern of the obtained compound was depicted in figure-4.
Example-3: Preparation of Amorphous 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid in combination with HPMC:
Methanol (30 ml) was added to a mixture of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid (1.0 gms) and hydroxypropyl methylcellulose (1.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed. Distilled off the solvent completely from the obtained filtrate under reduced pressure to get the title compound. Yield: 1.5 gms. The P-XRD pattern of the obtained compound was depicted in figure-6.
Example-4: Preparation of Amorphous 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid in combination with HPMC AS:
Methanol (30 ml) was added to a mixture of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid (1.0 gms) and hydroxypropyl methylcellulose acetate succinate (1.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction

mixture through hyflow bed. Distilled off the solvent completely from the obtained filtrate
under reduced pressure to get the title compound.
Yield: 1.0 gms.
The P-XRD pattern of the obtained compound was depicted in figure-5.
Example-5: Preparation of Amorphous Eluxadoline: (Formula-1)
Methanol (30 ml) was added to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid (1.0 gms) at 25-30°C and stirred for 30 minutes. Filtered the reaction mixture through hyflow bed. Distilled off the solvent completely from the obtained filtrate under reduced pressure to get the title compound. Yield: 0.7 gms. The P-XRD pattern of the obtained compound was depicted in figure-8.
Example-6: Preparation of Amorphous Eluxadoline: (Formula-1)
Methanol (200 ml) was added to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid (5 gms) at 25-30°C and stirred for 20 minutes at the same temperature. Filtered the reaction mixture through hyflow bed. The obtained filtrate was spray dried at below mentioned parameters to obtain amorphous 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid.
Operation parameters:
Labultima Instrument.
Aspirator: 70%
Feed Rate: 10 ml/min
Inlet temperature: 55°C to 60°C.
Gas flow N2: 2 kg/ cm2.
Yield: 2.0 gms; The P-XRD pattern of the obtained compound was depicted in figure-8.
Example-7: Preparation of crystalline form-N1 of Eluxadoline: (Formula-1)
A mixture of isopropanol (60 ml) and 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-

methoxy benzoic acid (3.0 gms) were heated to 60-65°C and stirred for 6 hours at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hour at the same temperature. Filtered the solid, washed with isopropanol and dried to get the title compound. Yield: 2.8 gms; The P-XRD pattern of the obtained compound was depicted in figure-1.
Example-8: Preparation of crystalline form-N2 of Eluxadoline: (Formula-1)
Ethyl formate (5.0 ml) was added to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid (0.5 gms) at 25-30°C. Heated the reaction mixture to 60-65°C. Ethyl acetate (5.0 ml) added to the reaction mixture at 60-65°C and stirred for 10 minutes. Methyl tert-butyl ether (5.0 ml) was added to the reaction mixture at 60-65°C and stirred for 6 hours at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 15 minutes at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 0.3 gms. The P-XRD pattern of the obtained compound was depicted in figure-2.
Example-9: Preparation of crystalline form-N3 of Eluxadoline: (Formula-1)
A mixture of methyl isobutyl ketone (60 ml) and 5-[[[(2S)-2-amino-3-[4-(amino carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl] amino]methyl]-2-methoxybenzoic acid (3.0 gms) were heated to 60-65°C and stirred for 6 hours at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hour at the same temperature. Filtered the solid and dried to get the title compound. Yield: 2.6 gms; The P-XRD pattern of the obtained compound was depicted in figure-3.

We Claim:
1. Crystalline forms of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxo
propyl][(1S)-1-(4-phenyl-1H-imidazol-2yl)ethyl]amino]methyl]-2-methoxybenzoic acid
compound of formula-1:
a) Crystalline form-N1 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid, characterized by its powder x-ray diffraction pattern having peaks at 6.3, 7.4, 9.0, 9.8, 10.4, 10.9, 11.1, 11.7, 12.2, 12.8, 13.7, 14.2, 14.9, 15.1, 15.7, 17.7, 18.1, 19.0, 19.4, 20.3, 21.1, 21.3, 21.9, 22.2, 22.5, 23.1, 23.8, 24.2, 24.8, 25.9, 27.1, 28.3, 31.9 and 32.6 ±0.2 degrees two theta and P-XRD pattern as depicted in figure-1.
b) Crystalline form-N2 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid, characterized by its powder x-ray diffraction pattern having peaks at 7.4, 7.6, 8.1, 8.7, 9.6, 9.8, 10.4, 10.7, 12.6, 14.1, 14.8, 15.4, 15.5, 16.1, 16.4, 17.6, 18.8, 19.3, 19.9, 21.2, 21.3, 21.7, 22.3, 22.5, 22.7, 23.8, 24.7, 25.0, 25.4, 25.6, 26.5, 27.2, 28.0, 28.4, 29.1, 29.3, 31.9, 36.3 and 38.5 ±0.2 degrees two theta and P-XRD pattern as depicted in figure-2.
c) Crystalline form-N3 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-
1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy
benzoic acid, characterized by its powder x-ray diffraction pattern having peaks at 6.2,
7.2, 8.9, 9.6, 10.2, 10.8, 12.6, 13.5, 13.9, 14.0, 14.6, 15.0, 15.4, 15.8, 17.9, 18.1, 19.0,
19.3, 20.0, 21.0, 21.6, 21.9, 22.9, 23.8, 24.4 and 27.7 ±0.2 degrees two theta and P-
XRD pattern as depicted in figure-3.
2. A process for the preparation of crystalline form-N1 of 5-[[[(2S)-2-amino-3-[4-(amino
carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]
amino]methyl]-2-methoxybenzoic acid compound of formula-1, comprising of:
a) Adding a suitable solvent to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of fomula-1,
b) heating the reaction mixture to a suitable temperature,

c) stirring the reaction mixture,
d) cooling the reaction mixture,
e) filtering the solid to get the crystalline form-N1 of 5-[[[(2S)-2-amino-3-[4-(amino carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl) ethyl]amino]methyl]-2-methoxybenzoic acid.
Wherein, in step-a) the suitable solvent is selected from alcohol solvents, preferably isopropanol; in step-b) the suitable temperature is ranging from 25°C to the reflux temperature of the solvent used in the reaction.
3. A process for the preparation of crystalline form-N1 of 5-[[[(2S)-2-amino-3-[4-(amino
carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]
amino]methyl]-2-methoxy benzoic acid compound of formula-1, comprising of:
a) Adding isopropanol to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl] -1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of fomula-1,
b) heating the reaction mixture to 60-65°C,
c) stirring the reaction mixture,
d) cooling the reaction mixture,
e) filtering the solid to get the crystalline form-N1 of 5-[[[(2S)-2-amino-3-[4-(amino carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl) ethyl]amino]methyl]-2-methoxybenzoic acid.
4. A process for the preparation of crystalline form-N2 of 5-[[[(2S)-2-amino-3-[4-(amino
carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]
amino]methyl]-2-methoxybenzoic acid compound of formula-1, comprising of:
a) Adding a suitable solvent to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of fomula-1,
b) heating the reaction mixture to a suitable temperature,
c) adding a suitable solvent,
d) stirring the reaction mixture,
e) cooling the reaction mixture,

f) filtering the precipitated solid to get the crystalline form-N2 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid. Wherein, in step-a) the suitable solvent is selected from alkyl formate; preferably ethyl formate; in step-b) the suitable temperature is ranging from 25°C to the reflux temperature of the solvent used in the reaction; in step-c) the suitable solvent is selected from ketone solvents, ester solvents, chloro solvents, ether solvents, hydrocarbon solvents and polar solvent like water or mixture thereof.
5. A process for the preparation of crystalline form-N2 of 5-[[[(2S)-2-amino-3-[4-(amino
carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]
amino]methyl]-2-methoxy benzoic acid compound of formula-1, comprising of:
a) Adding ethyl formate to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of fomula-1,
b) heating the reaction mixture to 60-65°C,
c) adding a mixture of ethyl acetate and methyl tert-butyl ether,
d) stirring the reaction mixture,
e) cooling the reaction mixture,
f) filtering the precipitated solid to get the crystalline form-N2 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid.
6. A process for the preparation of crystalline form-N3 of 5-[[[(2S)-2-amino-3-[4-(amino
carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]
amino]methyl]-2-methoxybenzoic acid compound of formula-1, comprising of:
a) Adding a suitable solvent to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of fomula-1,
b) heating the reaction mixture to a suitable temperature,
c) stirring the reaction mixture,
d) cooling the reaction mixture,

e) filtering the precipitated solid to get the crystalline form-N3 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl) ethyl]amino]methyl]-2-methoxybenzoic acid. Wherein, in step-a) the suitable solvent is selected from ketone solvents, preferably methyl isobutyl ketone; in step-b) the suitable temperature is ranging from 25°C to the reflux temperature of the solvent used in the reaction.
7. A process for the preparation of crystalline form-N3 of 5-[[[(2S)-2-amino-3-[4-(amino
carbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]
amino]methyl]-2-methoxy benzoic acid compound of formula-1, comprising of:
a) Adding methyl isobutyl ketone to 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino] methyl]-2-methoxybenzoic acid compound of fomula-1,
b) heating the reaction mixture to 60-65°C,
c) stirring the reaction mixture,
d) cooling the reaction mixture,
e) filtering the precipitated solid to get the crystalline form-N3 of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl) ethyl]amino]methyl]-2-methoxybenzoic acid.
8. Amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl
phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-
methoxy benzoic acid compound of formula-1 in combination with one or more
pharmaceutical acceptable carrier.
Wherein, the pharmaceutical acceptable carrier is selected from 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, β-cyclodextrins, γ-cyclodextrins, hydroxyl-propyl-cyclodextrins, hydroxyl propyl-cyclodextrin, sodium carboxymethyl cellulose cross-linked polyacrylic acid (carbipol), or a mixture thereof.
9. Amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl
phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-
methoxy benzoic acid compound of formula-1 in combination with one or more
pharmaceutical acceptable carrier, which includes:
a) Amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 in combination with HPC and the P-XRD pattern is depicted in figure-4.
b) Amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 in combination with HPMC AS and the P-XRD pattern is depicted in figure-5.
c) Amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 in combination with HPMC and the P-XRD pattern is depicted in figure-6.
d) Amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethy lphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-1 in combination with PVP K-30 and the P-XRD pattern is depicted in figure-7.
10. A process for the preparation of amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-
(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)
ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-1 in combination with
one or more pharmaceutical acceptable carrier, comprising of:
a) Dissolving a mixture of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl phenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-

methoxybenzoic acid and one or more pharmaceutical acceptable carrier in a suitable solvent,
b) stirring the reaction mixture,
c) isolating amorphous solid dispersion of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino] methyl]-2-methoxybenzoic acid in combination with one or more pharmaceutical acceptable carrier compound of formula-1.
Wherein, in step-a) the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents, chloro solvents, nitrile solvents and polar solvents like water or mixture thereof and suitable pharmaceutical acceptable carrier is selected from 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, β-cyclodextrins, γ-cyclodextrins, hydroxyl-propyl -cyclodextrins, hydroxyl propyl-cyclodextrin, sodium carboxymethyl cellulose cross-linked polyacrylic acid (carbipol), or a mixture thereof.