WO2013164857A1

WO2013164857A1 - Desvenlafaxine succinate solid dispersion

Info

Publication number: WO2013164857A1
Application number: PCT/IN2013/000285
Authority: WO
Inventors: Bandi Parthasaradhi Reddy; Kura Rathnakar Reddy; Dasari Muralidhara Reddy; Kesireddy Subash Chander Reddy; Bandi Vamsi Krishna
Original assignee: Hetero Research Foundation
Priority date: 2012-04-30
Filing date: 2013-04-29
Publication date: 2013-11-07

Abstract

The present invention provides a novel amorphous solid dispersion of desvenlafaxine succinate in combination with soluplus, process for its preparation and pharmaceutical compositions comprising it. In one aspect, the present invention provides amorphous solid dispersion of desvenlafaxine succinate in combination with soluplus. In another aspect, the present invention there is provided a process for the preparation of amorphous solid dispersion of desvenlafaxine succinate in combination with soluplus, which comprises: a) preparing a solution comprising a mixture of desvenlafaxine succinate and soluplus in a solvent; and b) removing the solvent to obtain amorphous solid dispersion of desvenlafaxine succinate in combination with soluplus. Yet in another aspect, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of amorphous solid dispersion of desvenlafaxine succinate along with soluplus, and at least one pharmaceutically acceptable excipient.

Description

DESVENLAFAXINE SUCCINATE SOLID DISPERSION

This application claims the benefit of Indian Provisional Patent Application No. 1679/CHE/2012, filed on April 30, 2012, which is incorporated herein by reference.

Filed of the Invention

The present invention provides a novel amorphous solid dispersion of desvenlafaxine succinate in combination with soluplus, process for its preparation and pharmaceutical compositions comprising it.

Background of the Invention

Desvenlafaxine, chemically l-[2-dimethylamine(4-hydroxyphenyl)ethyl]cyclo- hexanol and has the structure formula:

Desvenlafaxine succinate also known as 0-desmethylvenlafaxine succinate, is an antidepressant of the serotonin-norepinephrine reuptake inhibitor. The generic name Desvenlafaxine is marketed by Wyeth under the brand name Pristiq^®.

Desvenlafaxine and its salts were disclosed in U.S. patent no. 4,535,186.

Desvenlafaxine succinate was disclosed in U.S. patent no. 6,673,838 ('838 patent). The '838 patent also disclosed crystalline Form I, Form II, Form III, Form IV and amorphous Form of desvenlafaxine succinate.

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.

Desvenlafaxine and its succinate 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. application publication no. 2008/188567 disclosed crystalline Form V and

Form F of desvenlafaxine succinate.

Crystalline Form V of desvenlafaxine succinate was disclosed in International application publication no. WO 2008/1 10338.

Crystalline monohydrate Form of desvenlafaxine succinate was disclosed in

International application publication no. WO 2008/156748 and also disclosed another crystalline Form of desvenlafaxine succinate.

International application publication no. WO 2008/17886 disclosed desvenlafaxine succinate hydrate.

International application publication no. WO 2008/047167 disclosed crystalline

Form I and Form II of desvenlafaxine succinate substantially free of other polymorphs.

Crystalline Form V and Form VI of desvenlafaxine succinate were disclosed in International application publication no. WO 2009/009665. ^~ U.S. application publication no. 2010/0210719 disclosed an amorphous solid dispersion comprising desvenlafaxine succinate and at least one pharmaceutical acceptable carries such as povidone, gum, ethylcellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cyclodextrin, gelatin, hypromellose phthalate, sugar, polyhydric alcohol, polyethylene glycol, polyethylene oxide, polyoxyalkylene derivative, methacrylic acid copolymer, polyvinyl alcohol or propylene glycol derivative.

We have also found a novel amorphous solid dispersion of desvenlafaxine succinate in combination with soluplus. The amorphous solid dispersion of desvenlafaxine succinate with soluplus is stable, reproducible and so, the amorphous solid dispersion of desvenlafaxine succinate with soluplus is suitable for formulating desvenlafaxine succinate. Normally amorphous Forms are hygroscopic. Amorphous solid dispersion of desvenlafaxine succinate with soluplus is found to be non-hygroscopic.

Thus, an object of the present invention is to provide amorphous solid dispersion of desvenlafaxine succinate in combination with soluplus, process for its preparation and pharmaceutical compositions comprising it.

Summary of the Invention

In one aspect, the present invention provides amorphous solid dispersion of desvenlafaxine succinate in combination with soluplus.

In another aspect, the present invention there is provided a process for the preparation of amorphous solid dispersion of desvenlafaxine succinate in combination with soluplus, which comprises:

a) preparing a solution comprising a mixture of desvenlafaxine succinate and soluplus in a solvent; and

b) removing the solvent to obtain amorphous solid dispersion of desvenlafaxine succinate in combination with soluplus.

Yet in another aspect, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of amorphous solid dispersion of desvenlafaxine succinate along with soluplus, 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 desvenlafaxine succinate in combination with soluplus.

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 another aspect of the present invention, there is provided amorphous solid dispersion of desvenlafaxine succinate in combination with soluplus.

The powdered x-ray diffractogram (PXRD) of amorphous solid dispersion of desvenlafaxine succinate in combination with soluplus is shown in figure 1.

Amorphous solid dispersion of desvenlafaxine succinate in combination with soluplus is found to be stable.

According to another aspect of the present invention, there is provided a process for the preparation of amorphous solid dispersion of desvenlafaxine succinate in combination with soluplus, which comprises:

Desvenlafaxine succinate used in step (a) may preferably be desvenlafaxine succinate obtained by the known process.

The solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol and n-pentanol, and more preferably the solvents are dimethyl sulfoxide, dimethylacetamide, dimethylformamide and ethanol. The solvent may be removed from the solution in step (b) by known methods, for example, distillation or spray drying.

The distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is almost completely distilled off.

As used herein, "reduced pressure" refers to a pressure of less than 100 mmHg.

According to another aspect of the present invention, there is provided pharmaceutical compositions comprising a therapeutically effective amount of amorphous solid dispersion of desvenlafaxine succinate along with soluplus, and at least one pharmaceutically acceptable excipient. The amorphous solid dispersion of desvenlafaxine succinate with soluplus 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 methy!cellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullulan, 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, microcrystaliine 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 palmitoyi carnitine; and the like and mixtures thereof.

Specific examples of disintegrants include low-substituted hydro xypropylcellulose (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 Desvenlafaxine succinate

l-[2-(DimethyIamino)-l-(4-benzyloxyphenyl)ethyl]cyclohexanol ( 1 10 gm), methanol (2200 ml) and palladium carbon (10%, 1 1 gm) were added at room temperature and then heated to 45°C. To the reaction mass was applied hydrogen gas for 3 to 4 hours and then cooled to 30°C. To the reaction mass was added ethyl acetate (1320 ml) and filtered through hi-flow bed. The solvent was distilled off from the filtrate thus obtained and then added isopropyl alcohol (220 ml). The contents were stirred for 2 hours at 0 to 5°C, filtered and then dried to obtain 60 gm of desvenlafaxine.

Desvenlafaxine (60 gm) was dissolved in isopropyl alcohol (600 ml) and then added succinic acid (27 gm). The contents were heated to reflux and stirred for 30 minutes. The reaction mass was then cooled to 60°C and then treated with activated carbon. The reaction mass was stirred for 30 minutes at 60°C and filtered. The solid obtained was dried to obtain 80 gm of desvenlafaxine succinate.

Example 2:

Preparation of amorphous desvenlafaxine succinate solid dispersion with soluplus

A mixture of desvenlafaxine succinate (10 gm), soluplus (10 gm) and span-20 (2 gm) was dissolved in methanol (200 ml) at room temperature. The solution was stirred for 45 minutes and filtered through hi-flow bed. The solvent was distilled off from the filtrate thus obtained under reduced pressure at 65°C to obtain 21 gm of amorphous desvenlafaxine succinate solid dispersion with soluplus.

Example 3:

Example 2 was repeated using dimethyl sulfoxide solvent instead of methanol solvent to obtain amorphous desvenlafaxine succinate solid dispersion with soluplus.

Example 4:

Example 2 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous desvenlafaxine succinate solid dispersion with soluplus.

Example 5:

Example 2 was repeated using dimethylacetamide solvent instead of methanol solvent to obtain amorphous desvenlafaxine succinate solid dispersion with soluplus. Example 6:

Example 2 was repeated using dimethylformamide solvent instead of methanol solvent to obtain amorphous desvenlafaxine succinate solid dispersion with soluplus.

Example 7:

Preparation of amorphous desvenlafaxine succinate solid dispersion with soluplus l -[2-(Dimethylamino)- l -(4-benzyloxyphenyl)ethyl]cyclohexanol ( 1 10 gm), methanol (2200 ml) and palladium carbon ( 10%, 1 1 gm) were added at room temperature and then heated to 45°C. To the reaction mass was applied hydrogen gas for 3 to 4 hours and then cooled to 30°C. To the reaction mass was added ethyl acetate (1320 ml) and filtered through hi-flow bed. The solvent was distilled off from the filtrate thus obtained and then added isopropyl alcohol (220 ml). The contents were stirred for 2 hours at 0 to 5°C and then added isopropyl alcohol (600 ml) and succinic acid (27 gm). The contents were heated to reflux and stirred for 30 minutes. The reaction mass was then cooled to 60°C and then treated with activated carbon. The reaction mass was stirred for 30 minutes at 60°C. To the reaction mass was added a mixture of soluplus (80 gm) and span-20 (16 gm) and then added methanol ( 1600 ml) at room temperature. The solution was stirred for 45 minutes and filtered through hi-flow bed. The solvent was distilled off from the filtrate thus obtained under reduced pressure at 65°C to obtain 165 gm of amorphous desvenlafaxine succinate solid dispersion with soluplus.

Claims

We claim:

1. An amorphous solid dispersion of desvenlafaxine succinate in combination with soluplus.

2. The amorphous solid dispersion of desvenlafaxine succinate in combination with soluplus of claim 1 , having a powder X-ray diffractogram as shown in figure 1.

3. A process for the preparation of amorphous solid dispersion of desvenlafaxine succinate in combination with soluplus of claim 1 , which comprises:

a. preparing a solution comprising a mixture of desvenlafaxine succinate and soluplus in a solvent; and

b. removing the solvent to obtain amorphous solid dispersion of desvenlafaxine succinate in combination with soluplus.

4. The process as claimed in claim 3, wherein the solvent used in step (a) is a solvent or a mixture of solvents selected from dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol and n-pentanol.

5. The process as claimed in claim 4, wherein the solvents are dimethyl sulfoxide, dimethylacetamide, dimethylformamide and ethanol.

6. Pharmaceutical compositions comprising a therapeutically effective amount of amorphous solid dispersion of desvenlafaxine succinate along with soluplus, and at least one pharmaceutically acceptable excipient.

7. The pharmaceutical composition as claimed in claim 6, wherein the amorphous solid dispersion of desvenlafaxine is formulated into tablets, capsules, suspensions, dispersions or injectables.