DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AMORPHOUS NALOXEGOL OXALATE AND SOLID DISPERSION OF NALOXEGOL OXALATE

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATER MARK BUILDING,
PLOT NO.11, SURVEY NO.9,
KONDAPUR, HITECH CITY,
HYDERABAD, 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which the same is to be performed.
FIELD OF THE INVENTION
The present invention relates to amorphous Naloxegol oxalate and process thereof. Further, the present invention relates to amorphous solid dispersion of Naloxegol oxalate with one or more pharmaceutically acceptable carriers, process for its preparation and pharmaceutical composition thereof.

BACKGROUND OF THE INVENTION
Naloxegol is a PEGylated derivative of Naloxone. Naloxegol oxalate, chemically known as (5a,6a)-17-allyl-6-(2,5,8,11,14,17,20heptaoxadocosan-22-yloxy)-4,5-epoxymorphinan-3,14-diol oxalate and has a structure of formula I:

I

Naloxegol, which is marketed in the form of its oxalate salt is an opioid antagonist drug approved in United States and several other countries under the trade name MOVANTIK®. Naloxegol oxalate is used in the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain.

US patent No. 7,786,133 B2 discloses Naloxegol and its pharmaceutically acceptable salts generically, and U.S. Patent No. 9,012,469 B2 discloses specifically Naloxegol oxalate and process for preparation thereof.

U.S. Patent No. 9,012,469 B2 describes crystalline Form A and Form B of Naloxegol oxalate and process for the preparation thereof.

The occurrences of different solid forms are possible for some compounds. A single compound may exist in different solid forms. Various solid forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution, and bioavailability. Thus, solid forms can affect the quality, safety, and efficacy of the drug product, regulatory authorities require that efforts shall be made to identify all solid forms, e.g., crystalline, amorphous, solvated, etc., of drug substances.

Therefore, there is a need to develop amorphous Naloxegol oxalate, which is stable, pure and industrially scalable.

OBJECTIVE OF THE INVENTION
The objective of the present invention is to provide amorphous Naloxegol oxalate.

Another objective of the present invention is to provide amorphous Naloxegol oxalate, which comprises Naloxegol oxalate and one or more pharmaceutically acceptable carriers.

SUMMARY OF THE IVENTION
In an embodiment of the present invention, there is provided amorphous Naloxegol oxalate.

In another embodiment, there is provided a solid dispersion of Naloxegol oxalate comprises Naloxegol oxalate in an amorphous and one or more pharmaceutically acceptable carrier.

In another embodiment, the present invention provides a process for the preparation solid dispersion of Naloxegol oxalate in an amorphous, which comprises:
a) providing a solution of dissolving Naloxegol oxalate in a solvent;
b) adding a pharmaceutically acceptable excipient; and
c) isolating amorphous solid dispersion of Naloxegol oxalate.

In another embodiment, the present invention provides a process for the preparation of amorphous Naloxegol oxalate, which comprises:
a) providing a solution of Naloxegol base and oxalic acid in a solvent;
b) adding pharmaceutically acceptable carrier to the solution of step a); and
c) isolating amorphous Naloxegol oxalate.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is powder X-ray power diffraction ("PXRD") pattern of solid dispersion of Naloxegol oxalate prepared according to the Example1.

Figure 2 is powder X-ray power diffraction ("PXRD") pattern of Amorphous Form of Naloxegol oxalate prepared according to the Example 2.

DETAILED DESCRIPTION OF THE IVENTION
When Naloxegol Oxalate is identified herein as “pure”, it generally means, unless specified otherwise, that the material is about 95.0% pure or more. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities and unreacted starting materials, and also means 95.0% of amorphous form is free from its crystalline forms, as appropriate.

The pure amorphous Naloxegol oxalate of the present invention may have a greater polymorphic purity as measured by XRPD of greater than about 99.0% or greater than about 99.5% or greater than about 99.7%.

The amorphous of the present invention may have a chemical purity by High Performance Liquid Chromatography (HPLC) of greater than about 96.0% or greater than about 98.0% or greater than about 99.0% or greater than about 99.5%.

The amorphous Naloxegol oxalate of the present invention may have a residual content within the ICH guidelines.

In an embodiment, there is provided amorphous solid dispersion of Naloxegol oxalate comprises Naloxegol oxalate and one or more pharmaceutically acceptable carrier.

The solid dispersion is characterized by X-ray powder diffraction pattern, which is depicted in Figure 1.

In another aspect, the present invention provides a process for the preparation solid dispersion of Naloxegol oxalate, which comprises:
a) providing a solution of dissolving Naloxegol oxalate in a solvent;
b) adding a pharmaceutically acceptable excipient; and
c) isolating amorphous solid dispersion of Naloxegol oxalate.

Any physical form of Naloxegol base may be utilized for providing the solution of Naloxegol in step a). Naloxegol that may be used as the input for the process of the present invention may be obtained by any process including the processes described in the art, for example, US 7,786,133, US 9,012,469 and the like.

The solution of Naloxegol Oxalate in step (a) may be provided either by dissolving Naloxegol Oxalate in a suitable solvent or it may be provided directly from a reaction mixture containing it that is obtained during the course of its manufacture. Suitable solvent that may be used in step a) may be selected from water; various classes of solvents, such as for example, alcoholic solvents, ketones, esters, ethers, halogenated solvents, hydrocarbons, nitriles, water aprotic polar solvents or mixtures thereof. Alcohol solvents such as for example methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and t-butanol; ketonic solvents such as acetone, propanone, and 2-butanone; halogenated solvents, such as dichloromethane, 1,2-dichloroethane and chloroform; ester solvents, such as ethyl acetate, n-propyl acetate, isopropylacetate and n-butyl acetate and the like; ether solvents such as for example dimethylether, diethylether, methyltertiarybutylether, ethylmethylether, diisopropylether, tetrahydrofuran, and dioxane; hydrocarbon such as toluene, xylene, cyclohexane, n-hexane, and n-heptane. The nitrile solvents may include acetonitrile, and propionitrile; aprotic polar solvents, such as N, N-dimethylformide (DMF), Dimethylsulfoxide (DMSO), and N, N-dimethylacetamide (DMA) or mixtures thereof.

Any physical form of Naloxegol oxalate may be utilized for providing the solution of Naloxegol oxalate in step a).

When the amorphous Naloxegol oxalate is prepared along with one or more pharmaceutically acceptable carriers, the pharmaceutically acceptable carrier may be added to a reaction solution containing Naloxegol oxalate to provide solution, dispersion or suspension. The solvent(s) for providing the solution, suspension or dispersion of Naloxegol oxalate along with one or more pharmaceutically acceptable carriers in step b) may be selected from the above list mentioned for providing solution.

Suitable Pharmaceutically acceptable carriers that may be used in step b) include, but not restricted to water soluble as well as water insoluble carriers. Typical water soluble carriers are polyvinylpyrrolidone (povidone K 30), copovidone, polyvinyl alcohol, hydroxypropyl methylcellulose (hypromellose; HPMC), hydroxypropylcellulose (HPC), polyvinyl caprolactam- polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus™), sugar and its derivatives, organic amines and similar. Typical water insoluble polymers are methylcellulose, ethylcellulose, hydroxypropyl cellulose and its derivatives, microcrystalline celluloses, polymethacrylates, hypromellose phthalate, hypromellose acetate succinate, cellulose acetate phthalate, carboxymethyl ethyl cellulose and crospovidone. Sugar and its derivatives mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins,lactitol, or the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives. The preferable pharmaceutically acceptable carriers include but not limited to Polyvinylpyrrolidone (PVP K-30),Copovidone, Hydroxypropyl cellulose (HPC) and Hydroxypropy methyl cellulose (HPMC).

The water-soluble forms of N-vinyl pyrrolidone are available in a variety of viscosity and molecular weight grades and may be chosen from but not limited to PVP K-12, PVP K-15, PVP K-17, PVP K-25, PVP K-30, PVP K-90, PVP K-120 and the like. Any of the above mentioned pharmaceutically acceptable carriers could be chosen or their mixtures or their mixtures.

The dissolution temperature for providing the solution, suspension or dispersion of Naloxegol oxalate, optionally along with one or more pharmaceutically acceptable carriers may be less than about 130° C. or less than about 100° C. or less than about 80° C. or less than about 60° C. or less than about 40° C. or reflux temperature of the solvents used or any other suitable temperature.

When the solution is formed that may be filtered to remove any insoluble particles. The solution may be filtered by passing through paper, glass fiber, 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 isolation of solid may be performed by using techniques known in the art such as distillation, evaporation, oven drying, tray drying, rotational drying (such as the Buchi Rotavapor), spray drying, freeze-drying, fluid bed drying, flash drying, spin flash drying and Ultrafilm agitated thin film dryer-vertical (ATFD-V), hot melt extrusion (HME) and the like.

The solvent(s) may be removed using reduced pressure of less than about 100 mbar or less than about 60 mbar or less than about 30 mbar or less than about 10 mbar or any other suitable pressure. Suitable temperature that may be used for said removal of solvent(s) may be less than about 125° C. or less than about 100° C. or less than about 80° C. or less than about 60° C. or less than about 40° C. or any other suitable temperature.

The resultant amorphous Naloxegol oxalate of the present invention may be dried. The drying may be suitably carried out in a tray dryer, vacuum oven, rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In another embodiment, the present invention provides a process for the preparation of amorphous Naloxegol oxalate, which comprises:
a) providing a solution of Naloxegol base and oxalic acid in a solvent;
b) adding pharmaceutically acceptable carrier to the solution of step a); and
c) isolating amorphous Naloxegol oxalate.

The solution of step (a) may be provided by dissolving Naloxegol base and oxalic acid in a suitable solvent at a temperature of about less than about 100° C. or less than about 80° C. or less than about 60° C. or less than about 40° C. or reflux temperature of the solvents used or any other suitable temperature.

The pharmaceutically acceptable carrier may be selected from the above list mentioned for optionally, adding pharmaceutically acceptable carrier. The quantity of pharmaceutically acceptable carrier may be in the range of 0.5 to 5 grams or more per gram of Naloxegol or Naloxegol oxalate. The pharmaceutically acceptable carrier may be added to the solution of step a) to provide solution, suspension or dispersion, which may be subjected for removal of solvent or isolation of solid by using anti-solvent.

The amorphous Naloxegol oxalate of the present invention may be obtained by adding the anti-solvent to the solution obtained from step (a) or step (b). The anti-solvent may be selected from ether, alcohol and the like.

In another embodiment, the present invention provides a process for the preparation of amorphous Naloxegol oxalate, which comprises:
a) providing a solution of Naloxegol base and oxalic acid in a solvent;
b) adding pharmaceutically acceptable carrier to the solution of step a); and
c) isolating amorphous Naloxegol oxalate,
wherein pharmaceutically acceptable carrier is selected from selected from Polyvinylpyrrolidone (Povidone K 30) Copovidone, Hydroxypropyl cellulose (HPC) and Hydroxypropy methyl cellulose (HPMC).

The amorphous Naloxegol oxalate of the present invention may be converted to its pharmaceutical formulations which comprises amorphous form of Naloxegol, together with one or more pharmaceutically acceptable excipients. Amorphous form of Naloxegol oxalate together with one or more pharmaceutically acceptable excipients of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, or capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, or emulsions; or injectable preparations such as, but not limited to, solutions, dispersions, or freeze dried compositions.

Having described the invention with reference to certain aspects embodiments, embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing the preparation of the amorphous Naloxegol oxalate. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLE 1: Preparation of amorphous form Naloxegol Oxalate
Naloxegol oxalate (10 g) was dissolved in purified water (180 ml) and to it Povidone k-30 (10 g) was added at 20-30 °C and was stirred to get solution. This solution was filtered through hyflo bed to get clear filtrate. The resulting solution was subjected to lyophilization after freezing at -40 °C to afford white solid (19.8 g). The XPRD analysis shows the product is amorphous. Water content is 1.8%w/w.
Residual solvent by GC: methyl t-butylether: 146 ppm, n-propanol: 133 ppm. Purity: 99.52% by HPLC; Impurities: 0.04% (3-O-MEM ?Naloxegol), 0.05% (PEG-5 naloxol), 0.33% (PEG-6 naloxol), and 0.06% (oxidative dimer).

EXAMPLE 2: Preparation of amorphous Naloxegol oxalate
A mixture of Naloxegol Oxalate (2 g) and Povidone K 30 (2 g) was dissolved in a mixture of acetone (188 ml) and methanol (12 ml). This solution was subjected to spray drying on BÜCHI mini spray dryer B-290 using inlet temperature 77 °C, Aspiration 60%. The obtained solid was dried at 32-37 °C under reduced pressure (~20 mm Hg) till constant weight to get titled compound (2.8 g).
The XPRD analysis showed that the product is amorphous.
Residual solvent by GC: Acetone: Not detected, Methanol: 63 ppm.

EXAMPLE 3: Preparation of amorphous form Naloxegol oxalate
A mixture of Naloxegol Base (2 g, HPLC purity > 99.5%), Oxalic acid (0.27 g) and Povidone K 30 (1.9 g) were dissolved in methanol (150 ml) to get solution. This solution was filtered through hyflo bed to get clear filtrate, which was subjected to spray drying on BÜCHI mini spray dryer B-290 using inlet temperature 80 °C, Aspiration 60%. The resultant solid was dried at 32-37 °C under reduced pressure (=20 mm Hg) till constant weight to get titled compound (2.96 g).
The XPRD analysis showed that the product is amorphous.
Residual solvent by GC: Methanol: 125 ppm

EXAMPLE 4: Preparation of amorphous form Naloxegol oxalate
A mixture of Naloxegol Base (2 g, HPLC purity > 99.5%), Oxalic acid (0.28 g) and Povidone K 30 (1.2 g) were dissolved in a mixture of acetone (188 ml) and methanol (12 ml). This solution was filtered through hyflo bed to get clear filtrate, which was subjected to spray drying on BÜCHI mini spray dryer B-290 using inlet temperature 80 °C, Aspiration 60%. The resultant solid was dried at 32-37 °C under reduced pressure (=20 mm Hg) till constant weight to get titled compound (2.48 g).
The XPRD analysis showed that the product is amorphous.
Residual solvent by GC: Acetone: Not detected; Methanol: 75 ppm. ,CLAIMS:WE CLAIM:

1. A solid dispersion of Naloxegol oxalate comprising Naloxegol oxalate in an amorphous and at least one pharmaceutically acceptable carrier.

2. The solid dispersion as claimed in claim 1, wherein the pharmaceutically acceptable carrier is selected from water soluble and/or water insoluble carriers.

3. The compound as claimed in claim 1, wherein the solid dispersion of Naloxegol oxalate is characterized by X-ray diffraction pattern of Figure 1.

4. The process as claimed in claim 2, wherein the pharmaceutically acceptable excipient is Povidone K-30.

5. A process for the preparation solid dispersion of Naloxegol oxalate in an amorphous, which comprises:
a) providing a solution of Naloxegol oxalate in solvent;
b) adding a pharmaceutically acceptable excipient; and
c) isolating solid dispersion of Naloxegol oxalate in an amorphous.

6. The process as claimed in claim 5, wherein the solvent is selected from water, alcoholic solvents, ketones, esters, ethers, halogenated solvents, hydrocarbons, nitriles, aprotic polar solvents or mixtures thereof.

7. The process as claimed in claim 5, wherein the isolation is by the technique of distillation, evaporation, oven drying, tray drying, rotational drying, spray drying, freeze-drying (lyophilization), fluid bed drying, flash drying, spin flash drying, Ultrafilm agitated thin film dryer-vertical or hot melt extrusion.

8. The process as claimed in claim 5, wherein the isolation is by lyophilization.

9. The process as claimed in claim 5, wherein the solvent is water.

10. A process for the preparation amorphous Naloxegol oxalate, which comprises:
a) providing a solution of Naloxegol base and oxalic acid in a solvent;
b) adding pharmaceutically acceptable carrier to the solution of step a); and
c) isolating amorphous solid dispersion of Naloxegol oxalate.