Field of the Invention:
The present invention relates to amorphous form of 5-[[[(2S)-2-amino-3-[4-
(am1nocarbonyl)-2)6-dimethy!phenyi]-,-oxopropyi][(lS)-l-(4-phenyl-iH-imidazol-2-yl) ethyl]amino]methy^2-methoxybenzoic acid compound of formula-,, represented by the 5 following structural formula:
f"3 II H /CH3 l^li
HO^O Formula-1 Background of the Invention:
5-[[[C2S)-2-AminO-3-[4-(aminocarb0ny!)-2,6-dimethylPhenyl]-l-oxopropyl][(IS)-0 ,-(4-phenyl-lH-lmida2ol-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 a.so a delta opioid receptor antagonist and a kappa op.o.d receptor agonist. The binding affinities (Ki) of Eluxadoline for the human mu and delta op,01d 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 K, 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)-2J6-dimethylPhenyl]-l-0xopropyl][(IS)-l-(4-Phenyl-1H-imida2ol-2-yl)ethyl]amino]methyl]-2-meth0xybenZOic acid and process for its preparation was first disclosed in US774I356 B2 herein after referred as US'356 B2.
US7994206 B2 claims beta crystalline form of 5-[[[(2S)-2-amino-3-[4-Camino carbonyl)-236-dimethylPhenyl]-1 -oxopropyl jf(l S)-! -(4-phenyl-1 H-im idazo!-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)-216-dimethyIphenyl]-|-oxoProPyl][(IS)-l-(4-Phenyl-lH-imidazol-2-yl)ethyl]

amino]methyl]-2-methoxybenzoic acid compound of Formula-1.
FPCOM000245114D publication discloses crystalline forms of methyl 5-(((S)-2
ammo-3<4-carbamoyl-2)6-dimethylphenyl)-N-((S)-.-(4-phenyl-IH-imidazo!-2-yl)ethyl) 5 Propanamido)methyl)-2-methoxybenzoatedihydrochloride.
The said US'356 B2 discloses hydrochloric acid salt of 5-|f[(2S)-2-amino-3-,4-(am.no carbonyl)-2,6-d imethylphenyi]-1 -ox0propyl][(, S)-1 -(4-pheny,-1 H-imida7ol-2-yDethyl] aminojmethy^-methoxybcnzoic acid impound of formula-la but does not 10 have 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 d-st.nct solids sharing the same molecular formula, yet each polymorph may have distinct '5 physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physica, properties, such as different solubility profiles, different melting point temperatures and/or different x-ray d.ffracfon peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with 20 pred.cable solubility profiles. It is desirable to investigate all solid state forms of a drug mcludmg 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.
25 Add.fonal.y, polymorphic forms of the same drug substance or active pharmaceutical mgred.ent, 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.
30 An amorphous form of some of the drugs exhibit much higher bioavailability than
the crystalline forms, which leads to the selection of the amorphous form as the final drug substance for pharmaceutical dosage from development. Additionally, the aqueous solubihty of crystalline form is lower than its amorphous form in some of the drugs which may resulted in the difference in their in vivo bioavailability. Therefore, it is desirable to

have amorphous forms of drugs with high purity to meet the needs of regulatory agencies and also highly reproducible processes for their preparation. Accordingly, there remains a need to reproducibly obtain amorphous Eluxadoline of similar quality for use in a pharmaceutical preparation. 5
Brief description of the Invention:
The first aspect of the present invention is to provide an amorphous form of 5-[[[PSKHunino-S-^-CaminocarbonyO-^^imethylphenyl]-1 -oxopropyl][( 1 $). | -{4.
phenyl-m-imidazo]-2-yl)ethyl]amino]methyl]-2-methoxybenZoic acid compound of 10 formula-1.
The second aspect of the present invention is to provide a process for the preparation of amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyI)-2 6-d1methy.Pheny,]-l-oxo P~pyl]KlS>l.(4.phenyl-lH.imida2ol-2.yl)ethyl]amino]methyl]-15 2-methoxybenzoic acid compound of formula-1.
The third aspect of the present invention is to provide an alternative process for the
preparation of amorphous form of 5-[[r(2S)-2-amino-3-r4-(aminocarbonyl)-2,6-dimethy
lphenyl]-l-oxoproPyl][(IS)-l-(4-phenyl-IH-imidazol-2-yl)ethyl]amino]methyl]-2-20 methoxy benzoic acid compound of formula-1.
Brief description of the Drawings:
Figure 1: Illustrates the PXRD pattern of amorphous 5-[[[(2S)-2^mino-3Wamino
carbonyO-^e-dimethylphenylJ-I-oxopropylJKlSM^-phenyl-lH-imidazol^-yDethyl] 25 amino]methyl]-2-methoxybenzoic acid compound of formula-1. 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 cyciohexane, m-, o-, or p-xylene, and the like; "ether
30 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, isopropyi acetate, n-butyl acetate and the like; "polar-apro.ic
35 solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl
4

sulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as d.chloromethane, 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, propionic isobutyronitrile and the like; "alcoholic 5 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, !,2-ethoxyethanol, diethylene glycol. I. 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethy. ether, cyclohe*a„0|, benzyl alcohol phenol, or glycerol and the like; "polar solvents" such as water or mixtures thereof.
The first aspect of the present invention provides an amorphous form of 5-[[[(2S)-
2-amino-3-[4-(aminocarbonyl)-2>6-dimethylPhenyl]-.-oxoproPy,][(.S)-l-(4-phenyl-.H-im.dazol^-yDethyUaminoJmethylJ^-methoxybenzoic acid compound of formula-1.
The amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl
pheny!]-.-oxoproPyI][(lS)-l-(4-phenyl-lH-imidazol-2-y.)ethyl]amino]methyl]-2-methoxy benzo.c acid compound of formu.a-1 is further characterized by its powder x-ray diffraction pattern as depicted in figure 1.
The second aspect of the present invention provides a process for the preparation
of amorphous form of ^[[[(2S>2^mino.3-[4-(aminocaibonyl).2,Wimethylphenyl]-l.
oxopropy^dSM^-phenyl-lH-imidazol^-yDethylJaminojmethy.J^-methoxybenzoic acid compound of formula-1, comprising of the following steps:
a. Dissolving 5.[[[C2S).2-amino-3-[4Kami„ocaibonyl)-2,6-dimethylphenyl].ls,xo
Propyl][(lS)-l-(4-Phenyl-IH-imidazol-2-yl)ethy!]amino]methyl]-2-methoxy
benzoic acid addition salts compound of general formula-1 in a suitable solvent,
b. adding a suitable base to the reaction mixture,
c. stirring the reaction mixture,
d. isolating and drying to provide amorphous form of 5-[[[(2S)-2-amino-3-[4-(amino
carbonyl)-2,6-dimethylpheny|]-1 -oxopropyl][( 1S)-1 -(4-phenyl-1 H-im idazo!-2-yl)
ethyljamino] methyl]-2-methoxybenzoic acid compound of formula-].
Wherein,
In step-a) the suitable solvent is selected from alcohol solvents, chloro solvents, ester

solvents, polar aprotic solvents, ether solvents, ketone solvents, hydrocarbon solvents nitrile solvents and polar solvent like water or mixture thereof;
in step-b) the. suitable base is selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate and alkali metal bicarbonates such as
> sod.um bicarbonate, potassium bicarbonate and alkali metal hydroxides such as sodium hydrox.de, aqueous sodium hydroxide, potassium hydroxide, lithium hydroxide and alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide
__ potassium ethoxide, sodiumjert-butoxide, potassium-tert-butoxide, lithium tefrbutoxiae
or organic bases.
in step-d) the term isolating refers to the solvent removed by nitration or distillation of solvent or decanted the solvent from the reaction mixture or by spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), and the like or any other suitable techmque or by adding suitable anti-solvent. The suitable anti-solvent is selected from alcohol solvents, ester solvents, polar aprotic solvents, ketone solvents, hydrocarbon solvents and polar solvent like water or mixture thereof.
Amorphous 5-[[[C2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylPhenyl]-l-
oxopropylJtdSJ-l^-phenyl-lH-imidazol^-yDethylJaminoJmethylJ^-methoxybenzoic acid obtained according to the invention can be dried. Drying can be carried out in a tray dryer, vacuum oven, Buchi Rotavapor, air oven, fluidized bed dryer, spin Hash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures range of about 30°C to about 65°C; about 35°C to about 60°C" about 45-C to about 65'C. 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.
The preferred embodiment of the present invention provides a process for the preparation of amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl
phenyl]-l-oxoproPyU[(lS).l-(4-phenyl-.H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy benzoic acid compound of formula-!, comprising of the following steps:
a. Dissolving 5-t[K2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylPhenyl]-l-oxo
propyl][(IS)-l-(4-phenyl-lH-imidazol-2-yl)ethyl]amino]methyl]-2-methoxy
■benzoic acid hydrochloride compound of formula-1 a in water,
b. adding aqueous sodium hydroxide to the reaction mixture,
c. stirring the reaction mixture,

d. filtering the solid and drying to provide amorphous form of 5-[[[(2S)-2-amino-3-[4-(am inocarbonyl)-2,6-dirnethylphenyl]- I -oxopropyl][( 1S)-1 -(4-phenyl-1H-
imidazol-2-y])ethy!]amino]methyl]-2-methoxybenzoiC acid compound of formula-1.
5
Amorphous 5-[[[(2S)-2.amino-3-[4-(aminocarbonyl)-2,6-dimethylPhenyi]-l-oxo ProPyl][(lS)-l-(4-Phenyl-IH-imidazoi-2-yl)ethy0amino]methyl]-2-methoxyben2oic acid compound of formula-l obtained according to the present invention is substantially free of crystalline forms. 10
Amorphous 5-[[[(2S)-2-amino-3.[4-(aminocarbonyl)-2s6-dimethylphenyl]-l-oxo propyl][(]S)-l-(4-phenyl-lH-imidaZol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-I obtained according to the present invention is substantially free from residual solvents. 15
The third aspect of the present invention provides an alternative process for the preparation of amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethyl
phenylJ-UoxopropylJtdSM^-phenyl-IH-imidazol^-yDethylJaminoJmethyO^-methoxy benzoic acid compound of formula-l comprising of
0 a. Treating 5-(((S)-2-(tert-butoxycarbonylamino).3-(4-carbamoyl-2,6-dimethyl
phenyl)-N-(CS)-l-(4-phenyl-lH-imidazol-2.yl)ethyl)propanamido)methyl)-2-methoxybenzoic acid compound of formu!a-2 with a suitable acid in a suitable solvent,
b. treating the reaction mixture obtained in step-a) with a suitable base,
> c. stirring the reaction mixture,
d. isolating and drying to provide amorphous 5-[[[(2S)-2-amino-3-[4-(amino
carbonyl>2J6-dimethylPhenyl]-l-oxoPropyl][(lS)-l-(4-phenyl-lH-imidazol-2-yi) ' ethyl]amino]methyl]-2-methoxybenzoic acid compound of formula-l.
1 Wherein,
In step-a) the suitable acid is selected from hydrochloric acid, aqueous hydrochloric acid, tnfluoro acetic acid, formic acid, methane sulfonic acid and the suitable solvent is selected from alcohol solvents, chloro solvents, ester solvents, polar aprotic solvents, ketone ' solvents, hydrocarbon solvents/ether solvents, nitrile solvents and polar solvent like water or mixture thereof;

in step-b) the suitable base is selected from organic or inorganic base;
in step-d) the isolation of the compound is same as defined in step-(d) of the second aspect
of the present invention.
5 The preferred embodiment of the present invention provides an alternative process
for the preparation of amorphous form of 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2 6-
d.methy.phenyn-l-oxopropylJfdSM^phenyMHHmidazol^-yDethylJaminolmethyl]; 2-methoxy benzoic acid compound of formula-1 comprising of
a. Treating 5-(C(S)-2-(tert-butoxycarbonylamino)-3-(4-carbamoyl-2,6-dimethyl
> phen>',>N-^-I-f4-phenyi-lH-imidazol-2-yl)ethyl)propanamido)methyl)-2-
methoxybenzoic acid compound of formula-2 with a suitable acid in a suitable solvent,
b. treating the reaction mixture obtained in step-a) with a suitable base,
c. stirring the reaction mixture,
d. filtering the solid and drying to provide amorphous 5-[[[(2S)-2-amino-3-[4-(amino
carbony i)-2,6-dimethylphenyl]-1 -oxopropyI][( 1S)-1 -(4-phenyl-1 H-imidazol-2-yl)
ethyl]amino]methyI]-2-methoxyben2oic acid compound of formula-1.
5-((4S)-4-(tert-butoxycarbonylamino)-5-(4-carbamoyl-2,6-dimethylphenyl)-3-oxo-2-((R)-l-(4-phenyl-iH-imidazo.-2-yl)ethyl)Pentyl)-2-methoxy benzoic acid compound of
formula-2 or 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2J6-dimethylphenyl]-1-oxoPropy,]
r(lS)-l-(4-phenyl-lH-imida20]-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid
hydrochloride compound of formula-la used in the present invention can be prepared from the process known in the art.
5-[[[(2S)-2-amino-3-[4-(amin0carbonyl)-2)6-dimethylphenyl]-l-oxopropyl][(lS)-l-(4-phenyl-]H-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.
• The invention also encompasses pharmaceutical compositions comprising

compound of formula-. 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. 5
Amorphous 5-[[[(2S)-2-amino-3-r4-(aminocarbonyl)-2,6-dimethylPhenyl]-l-oxo
propyOtdSJ-l^-phenyl-lH-imidazol^-yOethynaminoimethylJ^-methoxybenzoic acid
compound of formula-, obtained according to the present invention is having purity
greater than 99.9%; preferably greater than 99.93%; more preferably greater than 99.96%
10 as measured by HPLC.
Amorphous form of 5-[[[(2S>2^mmo.3-[4Kamirrocarbonyl).2>6mimethylphenyl].
l-oxopropylJCC.SJ-l^phenyl-lH-imidazol^-yDethylJaminoJmethyU^-methoxybenzoic acd is useful in the preparation of pharmaceutical composition.
15 The process of the present invention is schematically represented below: o OCH3
III O OCHj
HcrsY'^ JL jL
(I 1 HO-^^V^X
CH ^V^N^v /^\ HC1. Water , [ f"3
x-xX I>\J ^™*~ a, W/V-O
H2NL JL JL NH-Boc If T T °
y X^ CH3 H2N\J^\^5sL NH2
o I CW3
Formula-2
Formula-1
Formula-la = HO salt
P-XRD Method of Analysis: PXRD analysis of compounds produced by the
present invention were carried out using BRUKER D8 ADVANCE/AXS X-Ray d,ffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed 20 of0.03°/min.
PSD method of Analysis:
Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument.
!5 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-I: Preparation of Amorphous 5-[[f(2S)-2-amin0-3-[4-(ami„ocarbony.)-2 6-
dimeehylPheny!]-l-oxoproPyI][(lS)-l-(4-Pheny]-lH-imidaZoI-2-yl)ethyl|amino) methyIJ-2-methoxybenzoic acid: (Formula-1)
S-t^SJ^-amino-S-^-faminocarbonyO^.e-dimethylphenylJ-l-oxopropylJftlS)-
]-(4-Phenyl-lH-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenZoic acid hydrochloride compound of formu!a-la (2.0 gms) was added to water (10.0 ml) and stirred for 10 mmutcs at the *»ne temperature. Aqueous sodium hydroxide solution was slowly added to 10 the reaction mixture at 25-30X and stirred for 30 minutes at the same temperature F.ltered the precipitated solid, washed with water and dried to get the title compound: Yield: 1.2 gms; Purity by HPLC: 99.97%.
Particle Size Distribution (PSD): D(0.l) is 3.1 urn; D(0.5) is 41.6 urn; D(0.9) is 479 9 unr D[4.3] is 156.3 urn.
15 The P-XRD pattern of the obtained compound is depicted in figure-1.
ExampIe-2: Preparation of Amorphous 5-[[[(2S)-2-amino-3-[4.(aminocarb0nyl)-2,6-
dimethylpheny]].l-oxoProPyl][(lS).l.(4.phenyl.lH-imidazoN2-yl)ethyl]amino] methyl]-2-methoxybenzoic acid: (Formula-1)
20 Water (2.0 ml) was added to 5-((4S)-4-(tert-butoxycarbonylamino)-5-(4-
carbamoyl-2J6-dimethylPhenyl)-3-oxo-2-((R)-,-(4-phenyl-lHrimidaZol-2-yl)ethyl)pentyl) -2-methoxy benzoic acid compound of formula-2 (2.0 gms) at 25-30X. Aqueous hydrochloric acid solution (4.0 ml) was slowly added to the reaction mixture at 15-20'C. Raised the temperature of the reaction mixture to 25-30X and stirred for 30 minutes at the 25 same temperature. Basifying the reaction mixture using aqueous sodium hydroxide solution at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 0.9 gms; Purity by HPLC: 99.98%.
Particle Size Distribution (PSD): D(0.1) is 7.6 um; D(0.5) is 76.0 u.m; D(0.9) is 330.0 unr
30 D[4.3] is 127.2 u.m. '
The P-XRD pattern of the obtained compound is depicted.in figure-1.