DESC:The following specification describes the invention and the manner in which it is to be performed:
AMORPHOUS ELUXADOLINE AND SOLID DISPERSION THEREOF

INTRODUCTION
The present invention provides amorphous eluxadoline, solid dispersion and processes for preparation thereof.
BACKGROUND OF THE INVENTION
Eluxadoline (I) is a mu-opioid receptor agonist and chemically known as 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid. It was approved by US FDA under the brand name of VIBERZI® for treating irritable bowel syndrome with diarrhea (IBS-D) in adults.

The US patent number 7741356 B2, in example-9, discloses a process for preparation of eluxadoline as a dihydrochloride salt.
The PCT publication WO2009009480A2 discloses a process for preparation of zwitter ion of eluxadoline. It also discloses eluxadoline crystalline zwitterionic Forms namely a and ß-Forms.
The US patent number 7629488B2, in example-5, discloses a process a process for preparation of eluxadoline as a dihydrochloride salt.
The discovery of further solid forms of an active pharmaceutical ingredient (API) can offer an opportunity to improve the performance profile of a pharmaceutical composition comprising the said API.
Processability of the API during manufacture of the pharmaceutical composition and characteristics of the finished dosage form, such as storage stability under difficult environmental conditions, such as high relative humidity and/or high temperature, can still be improved or optimized. The presence of the high energy form of the API in a pharmaceutical composition (amorphous form) usually improves the dissolution rate.
An object of the present invention is to provide a pharmaceutical composition comprising eluxadoline in a solid form, wherein the physicochemical stability and the dissolution characteristics of the solid form is improved, and wherein eluxadoline is rendered more suitable for use in a pharmaceutical composition.
SUMMARY
In a first aspect, the present invention provides amorphous eluxadoline.
In a second aspect, the present invention provides a process for the preparation of amorphous eluxadoline, comprising the steps;
a) providing a solution of eluxadoline in a solvent and,
b) isolating amorphous eluxadoline.
In a third aspect, the present invention provides a solid dispersion comprising amorphous eluxadoline and one or more pharmaceutically acceptable carriers.
In a fourth aspect, the present invention provides a process for the preparation of solid dispersion comprising amorphous eluxadoline and one or more pharmaceutically acceptable carriers, comprising the steps:
a) providing a solution comprising eluxadoline and one or more pharmaceutically acceptable carriers in a solvent,
b) removing the solvent from the solution obtained in step (a) and,
c) recovering a solid dispersion comprising amorphous eluxadoline and one or more pharmaceutically acceptable carriers.
In a fifth aspect, the present invention further provides a process for preparation of solid dispersion comprising amorphous eluxadoline and one or more pharmaceutically acceptable carriers, comprising;
a) grinding eluxadoline and one or more pharmaceutically acceptable carriers and
b) recovering a solid dispersion comprising amorphous eluxadoline and one or more pharmaceutically acceptable carriers.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 illustrates the PXRD pattern of amorphous eluxadoline, obtained by the procedure of Example 1.
Fig. 2 illustrates the PXRD pattern of amorphous eluxadoline, obtained by the procedure of Example 2.
Fig. 3 illustrates the PXRD pattern of solid dispersion comprising amorphous eluxadoline with PVPK-30 excipient, obtained by the procedure of Example 3.
Fig. 4 illustrates the PXRD pattern of solid dispersion comprising amorphous eluxadoline with HPMC-AS excipient, obtained by the procedure of Example 4.
Fig. 5 illustrates the PXRD pattern of solid dispersion comprising amorphous eluxadoline with HPC-L excipient, obtained by the procedure of Example 5.
Fig. 6 illustrates the PXRD pattern of solid dispersion comprising amorphous eluxadoline with eudragit excipient, obtained by the procedure of Example 6.
Fig. 7 illustrates the PXRD pattern of solid dispersion comprising amorphous eluxadoline with syloid excipient, obtained by the procedure of Example 7.
Fig. 8 illustrates the PXRD pattern of solid dispersion comprising amorphous eluxadoline with Eudragit & Syloid excipients, obtained by the procedure of Example 8.

DETAILED DESCRIPTION
In a first aspect, the present invention provides amorphous eluxadoline.
The amorphous eluxadoline is characterized by PXRD pattern provided in Fig.1 and Fig.2.
In a second aspect, the present invention provides a process for the preparation of amorphous eluxadoline, comprising the steps;
a) providing a solution of eluxadoline in a solvent and,
b) isolating amorphous eluxadoline.
Providing a solution of eluxadoline in step a) includes:
i) direct use of a reaction mixture containing eluxadoline that is obtained in the course of its synthesis; or
ii) dissolving eluxadoline in a solvent.
Any physical form of eluxadoline may be utilized for providing the solution of eluxadoline in step a). The dissolution temperatures may range from about 0 °C to about the reflux temperature of the solvent, or less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of eluxadoline is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In embodiments, eluxadoline can be dissolved in the following solvents. Examples of the solvents comprises alcohols, such as methanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, cyclohexanol, glycerol, or C1-C6 alcohols and the like; nitriles, such as acetonitrile or propionitrile; amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or hexamethyl phosphoric triamide and the like; sulfoxides, such as dimethylsulfoxide and the like; ethers such as dimethyl ether, diethyl ether, tetrahydrofuran (THF) and the like; water or any mixtures of two or more solvents thereof.
The quantity of solvent used for dissolution depends on the solvent and the dissolution temperature adopted. The concentration of eluxadoline in the solution may generally range from about 0.1 to about 10 g/ml in the solvent.
Step b) involves isolating amorphous eluxadoline from the solution obtained in step a). Isolation of amorphous eluxadoline in step b) may involve methods including removal of solvent, cooling, crash cooling, concentrating the mass, evaporation, flash evaporation, simple evaporation, fast solvent evaporation, rotational drying, spray drying, thin-film drying, agitated thin film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, rotary vacuum paddle dryer, adding anti-solvent or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation. The amorphous eluxadoline as isolated may carry some amount of occluded mother liquor and may have higher than desired levels of impurities. If desired, this amorphous form may be washed with a solvent or a mixture of solvents to wash out the impurities.
Suitable temperatures for isolation may be less than about 120 °C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -40°C or any other suitable temperatures.
Isolation of amorphous eluxadoline may be effected by combining a suitable anti-solvent with the solution obtained in step a). Anti-solvent as used herein refers to a liquid in which eluxadoline is less soluble or poorly soluble. An inert anti-solvent has no adverse effect on the reaction and it can assist in the solidification or precipitation of the dissolved starting material. Suitable anti-solvents that may be used include, but are not limited to: saturated or unsaturated, linear or branched, cyclic or acyclic, C1 to C10 hydrocarbons, such as heptanes, cyclohexane, or methylcyclohexane; water; or any mixtures thereof.
The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the eluxadoline is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling; or bead milling.
The amorphous form of eluxadoline is chemically and polymorphically stable up to three months at various storage conditions.
In a third aspect, the present invention provides a solid dispersion comprising amorphous eluxadoline and one or more pharmaceutically acceptable carriers.
The term "solid dispersion" defines a system in a solid state wherein one component is dispersed more or less evenly throughout the other component or components, e.g. in the context of the present invention amorphous eluxadoline within the polymer.
The absence of peaks on the X-ray powder diffractogram of the solid dispersion of the invention, suggests that the solid dispersion of the present invention is amorphous.
The absence of peaks on the X-ray powder diffractogram of the solid dispersion of the invention suggests that, in the solid dispersion of the present invention eluxadoline is in amorphous form.
The solid dispersion of the present invention is obtainable as a solid dispersion that is stable and pure with regard to the physical form of amorphous eluxadoline therein, and that is obtainable in an easy and reliable manner, e.g. even in large scale.
The present invention further describes processes for the preparation of the solid dispersion.
In a fourth aspect, the present invention provides a process for the preparation of solid dispersion comprising amorphous eluxadoline and one or more pharmaceutically acceptable carriers, comprising the steps:
a) providing a solution comprising eluxadoline and one or more pharmaceutically acceptable carriers in a solvent
b) removing the solvent from the solution obtained in step (a) and
c) recovering the solid dispersion comprising amorphous eluxadoline and one or more pharmaceutically acceptable carriers.
Step a) involves providing a solution of eluxadoline and at least one pharmaceutically acceptable carrier in a solvent;
Step a) may involve forming a solution of eluxadoline and one or more pharmaceutically acceptable carriers. In embodiments, the carrier enhances stability of the amorphous solid upon removal of solvent.
Providing the solution in step a) includes:
i) direct use of a reaction mixture containing eluxadoline that is obtained in the course of its manufacture, if desired, after addition of one or more pharmaceutically acceptable carriers; or
ii) dissolution of eluxadoline in a solvent, either alone or in combination with one or more pharmaceutically acceptable carriers.
The quantity of solvent used for dissolution depends on the solvent and the dissolution temperature adopted. The concentration of eluxadoline in the solution may generally range from about 0.1 to about 10 g/ml in the solvent.
Any physical form of eluxadoline, such as crystalline, amorphous or their mixtures may be utilized for providing a solution in step a).
Pharmaceutically acceptable carriers that may be used in step a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones (PVP), Polyvinylpyrrolidone K 30 (PVPK-30), copovidone, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins or resins; release rate controlling agents such as hydroxypropyl celluloses (HPC), hydroxymethyl celluloses, hydroxyethylcellulose, hydroxyethylmethylcellulose (HEMC), carboxymethylcellulose (CMC), carboxymethylhydroxyethylcellulose (CMHEC), hydroxyethylcarboxymethylcellulose (HECMC), sodium carboxymethylcellulose, cellulose acetate phthalate (CAP), hydroxypropyl methylcelluloses (HPMC), hydroxypropylmethylcellulose acetate (HPMCA), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), Low-Substituted Hydroxypropyl Cellulose (HPC-L), ethylcelluloses, methylcelluloses, propylcellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, syloid cellulose, various grades of methyl methacrylates, poly(meth)acrylates (EUDRAGIT®), waxes, or the like. Other pharmaceutically acceptable excipients that are of use include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.
Eluxadoline and the pharmaceutically acceptable carrier may be dissolved either in the same solvent or they may be dissolved in different solvents and then combined to form a mixture. In embodiments, the solid dispersion described herein comprises amorphous eluxadoline and the carrier present in weight ratios ranging from about 5:95 to about 95:5. An example of a ratio is about 50:50.
The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of eluxadoline is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
The solvents that may be used in step a) include but are not limited to: alcohols, such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, cyclohexanol, or C1-C6 alcohols and the like; nitriles, such as acetonitrile or propionitrile; amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or hexamethyl phosphoric triamide and the like; sulfoxides, such as dimethylsulfoxide and the like;
Step b) involves removal of the solvent from the solution comprising eluxadoline and one or more pharmaceutically acceptable carriers. The solvent can be removed using the techniques such as evaporation, spray drying and other conventional techniques.
Step c) involves recovering the solid dispersion comprising amorphous eluxadoline and one or more pharmaceutically acceptable carriers.
A solid dispersion comprising amorphous eluxadoline and one or more pharmaceutically acceptable carriers may be isolated from a solution comprising eluxadoline and one or more pharmaceutically acceptable carriers in a solvent by using the conventional methods. The methods includes but not limited to cooling, crash cooling, concentrating the mass, evaporation, flash evaporation, simple evaporation, fast solvent evaporation, rotational drying, spray drying, thin-film drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation. The amorphous eluxadoline as isolated may carry some amount of occluded mother liquor and may have higher than desired levels of impurities. If desired, this amorphous form may be washed with a solvent or a mixture of solvents to wash out the impurities.
The recovered solid dispersion may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the eluxadoline is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling; or bead milling.
In a fifth aspect, the present invention further provides a process for preparation of solid dispersion comprising amorphous eluxadoline and one or more pharmaceutically acceptable carriers, comprising;
a) grinding eluxadoline and one or more pharmaceutically acceptable carriers and
b) recovering a solid dispersion comprising amorphous eluxadoline and one or more pharmaceutically acceptable carriers.
Any solid forms, either crystalline or amorphous form of eluxadoline can be used to grind it with one or more pharmaceutically acceptable carriers.
The present invention also provides a pharmaceutical composition comprising the solid dispersion as described above.
The pharmaceutical composition of the present invention may be formulated in accordance with conventional methods, and may be prepared in the form of oral formulations such as tablets, pills, powders, capsules, syrups, emulsions, micro emulsions, and others, or formulation for parenteral injection, e.g., intramuscular, intravenous, or subcutaneous administration. The pharmaceutical composition of the present invention may comprise the inventive solid dispersion, and any possible carrier and excipient

EXAMPLES
Example 1: Preparation of amorphous eluxadoline
4 g of eluxadoline and 210 mL of methanol were charged into a round bottom flask at 30oC. The contents were stirred for dissolution and filtered. The filtrate was spray dried at 70oC to afford the title compound.
Example 2: Preparation of amorphous eluxadoline
0.5 g of eluxadoline and 20 mL of methanol were charged into a round bottom flask at 30oC. The contents were stirred for dissolution and filtered. The filtrate was heated to 70oC and then vacuum was applied at the same temperature followed by drying at 70°C to get the title compound.
Example 3: Preparation of solid dispersion of eluxadoline
0.25 g of eluxadoline and 0.25 g of PVPK-30 were added to 20 mL of methanol at 30°C. The contents were stirred for dissolution and filtered. The filtrate was distilled under reduced pressure at 65oC in rotavapor to afford the title compound.
Example 4: Preparation of solid dispersion of eluxadoline
0.25 g of eluxadoline and 0.25 g of HPMC-AS were added to 20 mL of methanol at 30°C. The contents were stirred for dissolution and filtered. The filtrate was heated to 70oC and then vacuum was applied at the same temperature followed by drying at 70°C to get the title compound.
Example 5: Preparation of solid dispersion of eluxadoline
0.25 g of eluxadoline and 0.25 g of HPC-L were added to 20 mL of methanol at 30°C. The contents were stirred for dissolution and filtered. The filtrate was distilled under reduced pressure at 65oC in rotavapor to afford the title compound.
Example 6: Preparation of solid dispersion of eluxadoline
0.4 g of eluxadoline and 0.4 g of eudragit were added to 32 mL of methanol at 30°C. The contents were stirred for dissolution and filtered. The filtrate was heated to 70oC and then vacuum was applied at the same temperature followed by drying at 70°C to get the title compound.
Example 7: Preparation of solid dispersion of eluxadoline
0.25 g of eluxadoline and 0.25 g of Syloid were added into Mortar and pestle. The contents were grinded for five minutes to get the title compound.
Example 8: Preparation of solid dispersion of eluxadoline
0.25 g of premix of amorphous eluxadoline and eudragit and 0.125 g of Syloid were added into Mortar and pestle. The contents were grinded for five minutes to get the title compound.
,CLAIMS:1. Amorphous eluxadoline.
2. The amorphous eluxadoline as claimed in claim 1, wherein the amorphous eluxadoline characterized by powder X-ray diffraction pattern as depicted in Fig.1.
3. A process for the preparation of amorphous eluxadoline comprising
a) providing a solution of eluxadoline in a solvent and
b) isolating the amorphous eluxadoline.
4. The process as claimed in claim 3, wherein the solvent is selected from alcohol, ether and water.
5. The process as claimed in claim 4, wherein the alcohol is selected from methanol, ethanol, propanol, isopropanol and n-butanol.
6. The process as claimed in claim 3, wherein the ether solvent is selected from dimethyl ether, diethyl ether and tetrahydrofuran.
7. A solid dispersion comprising amorphous eluxadoline and one or more pharmaceutically acceptable carriers.
8. The solid dispersion as claimed in claim 7, wherein the pharmaceutically acceptable carrier is selected from PVPK-30, HPMC-AS, HPC-L, Eudragit, Syloid and the mixture thereof.
9. A process for the preparation of solid dispersion comprising amorphous eluxadoline and one or more pharmaceutically acceptable carriers, comprising the steps:
a) providing a solution comprising eluxadoline and one or more pharmaceutically acceptable carriers in a solvent
b) removing the solvent from the solution obtained in step (a) and
c) recovering the solid dispersion comprising amorphous eluxadoline and one or more pharmaceutically acceptable carriers.

10. A process for the preparation of solid dispersion comprising amorphous eluxadoline and one or more pharmaceutically acceptable carriers, comprising
a) grinding eluxadoline and one or more pharmaceutically acceptable carriers and
b) recovering a solid dispersion comprising amorphous eluxadoline and one or more pharmaceutically acceptable carriers.