WO2013160916A1

WO2013160916A1 - Sunitinib malate solid dispersion

Info

Publication number: WO2013160916A1
Application number: PCT/IN2013/000280
Authority: WO
Inventors: Bandi Parthasaradhi Reddy; Kura Rathnakar Reddy; Dasari Muralidhara Reddy; Thungathurthy Srinivasa Rao; Bandi Vamsi Krishna
Original assignee: Hetero Research Foundation
Current assignee: Hetero Research Foundation
Priority date: 2012-04-25
Filing date: 2013-04-25
Publication date: 2013-10-31
Anticipated expiration: 2014-10-25

Description

SUNITINIB MALATE SOLID DISPERSION

This application claims the benefit of Indian Provisional Patent Application No. 1631 /CHE/2012, filed on April 25, 2012, which is incorporated herein by reference. Filed of the Invention

The present invention provides a novel amorphous solid dispersion of sunitinib malate in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it. Background of the Invention

Sunitinib and its salts are antineoplastic agents, which were disclosed in International application publication no. WO 01/60814 and U.S. Patent No. 6,573,293. Sunitinib is known by the chemical name N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-l ,2- dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-l H-pyrrole-3-carboxamide. Sunitinib is represented by the following structure.

Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid 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 the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).

Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.

Sunitinib and its malate salt can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.

U.S. patent application publication no. 2003/0069298 disclosed two crystal forms, Form I (characterized by an x-ray powder diffraction patterns having peaks expressed as 20 at 13.2, 19.4, 24.2 and 25.5 degrees) and Form II (characterized by an x-ray powder diffraction patterns having peaks expressed as 20 at 3.0, 12.1 , 14.5 and 27.7 degrees) of sunitinib malate.

International application publication no. WO 2009/156837 disclosed amorphous Form of sunitinib malate.

International application publication no. WO 2009/104021 disclosed crystalline Form 111 and Form IV of sunitinib malate.

Crystalline Form III of sunitinib malate was disclosed in International application publication no. WO 2010/076805.

International application publication no. WO 201 1/092664 disclosed crystalline Form V and Form VI of racemic sunitinib malate.

International application publication no. WO 201 1/100325 disclosed crystalline

Form A l , Form A2 and Form B of racemic sunitinib malate.

It was observed that the Form I, Form II, Form III, Form IV, Form V, Form VI, Form A l , Form A2, Form B and amorphous Form of sunitinib malate either not reproducible or not stable.

We have found a novel amorphous solid dispersion of sunitinib malate in combination with a pharmaceutically acceptable carrier. The amorphous solid dispersion of sunitinib malate is stable, reproducible and so, the amorphous solid dispersion of sunitinib malate is suitable for formulating sunitinib malate. Normally amorphous Forms are hygroscopic. Amorphous solid dispersion of sunitinib malate is found to be non- hygroscopic.

Thus, an object of the present invention is to provide amorphous solid dispersion of sunitinib malate in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.

Summary of the Invention

In one aspect, the present invention provides amorphous solid dispersion of sunitinib malate in combination with a pharmaceutically acceptable carrier.

In another aspect, the present invention there is provided a process for the preparation of amorphous solid dispersion of sunitinib malate in combination with a pharmaceutically acceptable carrier, which comprises:

a) preparing a solution comprising a mixture of sunitinib malate and one or more pharmaceutically acceptable carriers selected form copovidone, span 20, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus in water; and

b) subjecting the resulting solution to freeze drying to obtain amorphous solid dispersion of sunitinib malate in combination with a pharmaceutically acceptable carrier.

Yet in another aspect, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of amorphous solid dispersion of sunitinib malate along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.

Brief Description of the Drawing

Figure 1 is a powder X-ray diffractogram patterns of amorphous solid dispersion of sunitinib malate in combination with a pharmaceutically acceptable carrier.

Powder X-ray diffraction spectrum was measured on a bruker AXS D8 advance powder X-ray diffractometer having a copper-Κα radiation. Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two- theta, at 0.020 degrees two theta per step and a step time of 1 second. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 kV and current 35 mA.

Detailed Description of the Invention

The term "room temperature" refers to temperature at about 25 to 35°C.

According to one aspect of the present invention, there is provided amorphous solid dispersion of sunitinib malate in combination with a pharmaceutically acceptable carrier.

Amorphous solid dispersion of sunitinib malate in combination with a pharmaceutically acceptable carrier is found to be stable.

Preferably, the pharmaceutically acceptable carriers may be one or more of copovidone, span 20, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus.

According to another aspect of the present invention, there is provided a process for the preparation of amorphous solid dispersion of sunitinib malate in combination with a pharmaceutically acceptable carrier, which comprises:

Sunitinib malate used in step (a) may preferably be sunitinib malate obtained by the known process.

Preferably, the pharmaceutically acceptable carriers used in step (a) may be selected form copovidone or hydroxypropyl methylcellulose.

The term "Freeze drying" refers to a sublimation process that removes free water or other solvent in the form of solid.

Freeze drying in step (b) may preferably be carried out at room temperature According to another aspect of the present invention, there is provided pharmaceutical compositions comprising a therapeutically effective amount of amorphous solid dispersion of sunitinib malate along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient. The amorphous solid dispersion of sunitinib malate may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.

Preferably the present invention provides a pharmaceutical composition containing said solid dispersion along with the pharmaceutically acceptable excipients such as diluents, chelating agents, disintegrant, glidant, binders, surfactants, coloring agents and/or luricants.

Specific examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, puUulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.

Specific examples of diluents include calcium carbonate, calcium phosphate- dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like and mixtures thereof.

Surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical dosage forms. These include polyethoxylated fatty acids and its derivatives, for example, polyethylene glycol 400 distearate, polyethylene glycol-20 dioleate, polyethylene glycol 4 - 150 mono dilaurate, and polyethylene glycol - 20 glyceryl stearate; alcohol - oil transesterification products, for example, polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example, polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example, propylene glycol monocaprylate; mono and diglycerides, for example, glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example, polyethylene glycol - 20 sorbitan monooleate and sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example, polyethylene glycol - 20 cetyl ether and polyethylene glycol - 10 - 100 nonyl phenol; sugar esters, for example, sucrose monopalmitate; polyoxyethylene - polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for example, sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, and palmitoyl carnitine; and the like and mixtures thereof.

Specific examples of disintegrants include low-substituted hydroxypropylcellulose

(L-HPC), sodium starch glycollate, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium A-type (Ac-di-sol), starch, crystalline cellulose, hydroxypropyl starch, pregelatinized starch, and the like and mixtures thereof.

Specific examples of lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like and mixtures thereof.

Coloring agents include any FDA approved colors for oral use.

The invention will now be further described by the following examples, which are illustrative rather than limiting.

Examples

Example 1 :

Preparation of sunitinib

5-Formyl-2,4-dimethyl-lH-pyrrole-3-carboxylicacid-(2-diethylamino-ethyl)amide (100 gm) was dissolved in ethanol ( 1500 ml) and then added 5-fluoro-l ,3-dihydro-indol- 2-one (54 gm) and pyrrolidine (1.57 ml). The contents were then heated to reflux and stirred for 3 hours. The reaction mass was then cooled to room temperature, stirred for 1 hour and filtered. To the wet solid thus obtained was added ethanol (1200 ml) and then heated to 50°C. The solution was stirred for 1 hour at 50°C and then cooled to room temperature. The contents were stirred for 1 hour at room temperature and filtered. The solid obtained was dried at 55 to 60°C for 9 hours to obtain 1 15 gm of sunitinib.

Example 2:

Preparation of amorphous sunitinib malate solid dispersion with copovidone Sunitinib (10 gm) as obtained in example 1 was dissolved in water (200 ml) and then added L-malic acid (3.58 gm) and copovidone (20 gm) at room temperature. The contents were then heated to 75°C and stirred for 30 minutes at 75°C. The solution was then cooled to room temperature and filtered. The resulting filtrate was subjected to freeze drying at room temperature for 36 hours to obtain 33 gm of amorphous sunitinib malate solid dispersion with copovidone.

Example 3:

Preparation of amorphous sunitinib malate solid dispersion with copovidone

A mixture of sunitinib malate (10 gm) and copovidone (20 gm) was dissolved in water (200 ml) at room temperature. The contents were then heated to 70 to 80°C and stirred for 30 minutes to obtain a clear solution. The solution was then cooled to room temperature and filtered. The resulting filtrate was subjected to freeze drying at room temperature for 36 hours to obtain 23 gm of amorphous sunitinib malate solid dispersion with copovidone.

Example 4:

Preparation of amorphous sunitinib malate solid dispersion with hydroxypropyl methylcellulose

A mixture of sunitinib malate (50 gm) and hydroxypropyl methylcellulose (75 gm) was dissolved in water (500 ml) at room temperature. The contents were then heated to 70 to 80°C and stirred for 30 minutes to obtain a clear solution. The solution was then cooled to room temperature and filtered. The resulting filtrate was subjected to freeze drying at room temperature for 42 hours to obtain 1 15 gm of amorphous sunitinib malate solid dispersion with hydroxypropyl methylcellulose.

Example 5:

Preparation of amorphous sunitinib malate solid dispersion with polyethylene glycol

A mixture of sunitinib malate (25 gm) and polyethylene glycol (25 gm) was dissolved in water (300 ml) at room temperature. The contents were then heated to 70 to 80°C and stirred for 30 minutes to obtain a clear solution. The solution was then cooled to room temperature and filtered. The resulting filtrate was subjected to freeze drying at room temperature for 40 hours to obtain 40 gm of amorphous sunitinib malate solid dispersion with polyethylene glycol. Example 6:

Preparation of amorphous sunitinib malate solid dispersion with ethyl cellulose

A mixture of sunitinib malate (10 gm) and ethyl cellulose (15 gm) was dissolved in water (200 ml) at room temperature. The contents were then heated to 70 to 80°C and stirred for 30 minutes to obtain a clear solution. The solution was then cooled to room temperature and filtered. The resulting filtrate was subjected to freeze drying at room temperature for 36 hours to obtain 20 gm of amorphous sunitinib malate solid dispersion with ethyl cellulose.

Example 7:

Preparation of amorphous sunitinib malate solid dispersion with soluplus

A mixture of sunitinib malate (25 gm) and soluplus (50 gm) was dissolved in water (400 ml) at room temperature. The contents were then heated to 70 to 80°C and stirred for 30 minutes to obtain a clear solution. The solution was then cooled to room temperature and filtered. The resulting filtrate was subjected to freeze drying at room temperature for 40 hours to obtain 60 gm of amorphous sunitinib malate solid dispersion with soluplus.

Example 8:

Preparation of amorphous sunitinib malate solid dispersion with copovidone

5-Formyl-2,4-dimethyl-l H-pyrrole-3-carboxylic acid-(2-diethylamino-ethyl)- amide (100 gm) was dissolved in ethanol (1500 ml) and then added 5-fluoro-l,3-dihydro- indol-2-one (54 gm) and pyrrolidine (1.57 ml). The contents were then heated to reflux and stirred for 3 hours. The reaction mass was then cooled to room temperature, stirred for 1 hour and filtered. To the wet solid thus obtained was added ethanol (1200 ml) and then heated to 50°C. The solution was stirred for 1 hour at 50°C and then cooled to room temperature. The contents were stirred for 1 hour at room temperature and then added water (2300 ml). To the reaction mass was added L-malic acid (41 gm) and copovidone (230 gm) and then heated to 75°C. The solution was then cooled to room temperature and filtered. The resulting filtrate was subjected to freeze drying at room temperature for 40 hours to obtain 378 gm of amorphous sunitinib malate solid dispersion with copovidone.

Claims

We claim:

1. An amorphous solid dispersion of sunitinib malate in combination with a pharmaceutically acceptable carrier.

2. The amorphous solid dispersion of claim 1, wherein the pharmaceutically acceptable carrier comprises one or more of copovidone, span 20, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus.

3. The amorphous solid dispersion of claim 1 , having a powder X-ray diffractogram as shown in figure 1 .

4. A process for the preparation of amorphous solid dispersion of sunitinib malate in combination with a pharmaceutically acceptable carrier of claim 1 , which comprises: a. preparing a solution comprising a mixture of sunitinib malate and one or more pharmaceutically acceptable carriers selected form copovidone, span 20, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol or soluplus in water; and

b. subjecting the resulting solution to freeze drying to obtain amorphous solid dispersion of sunitinib malate in combination with a pharmaceutically acceptable carrier.

5. The process as claimed in claim 4, wherein the pharmaceutically acceptable carriers used in step (a) is selected form copovidone or hydroxypropyl methylcellulose.

6. The process as claimed in claim 4, wherein the freeze drying in step (b) is carried out at room temperature.

7. Pharmaceutical compositions comprising a therapeutically effective amount of amorphous solid dispersion of sunitinib malate along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.

8. The pharmaceutical composition as claimed in claim 7, wherein the amorphous solid dispersion of sunitinib malate is formulated into tablets, capsules, suspensions, dispersions or injectables.