WO2014076712A2

WO2014076712A2 - Lurasidone hydrochloride solid dispersion

Info

Publication number: WO2014076712A2
Application number: PCT/IN2013/000693
Authority: WO
Inventors: Bandi Parthasaradhi Reddy; Kura Rathnakar Reddy; Dasari Muralidhara Reddy; Itiyala Srinivas Reddy; Kesireddy Subash Chander Reddy; Bandi Vamsi Krishna
Original assignee: Hetero Research Foundation
Priority date: 2012-11-14
Filing date: 2013-11-12
Publication date: 2014-05-22
Also published as: WO2014076712A3

Abstract

The present invention provides a novel amorphous solid dispersion of lurasidone hydrochloride in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.

Description

LURASIDONE HYDROCHLORIDE SOLID DISPERSION

This application claims the benefit of Indian Provisional Patent Application No. 4762/CHE/2012, filed on November 14, 2012, which is incorporated herein by reference.

Filed of the Invention

Background of the Invention

Lurasidone hydrochloride is chemically, (3ai?,45,7i?,7a5)-2-[((li?,2i?)-2-{[4-(l ,2- benzisothiazol-3-yl)-piperazin-l-yl]methyl}cyclohexyl)methyl]hexahydro-lH-4,7- methanisoindol-l,3-dione hydrochloride and has the structural formula:

Lurasidone hydrochloride is a typical antipsychotic developed by Dainippon Sumitomo Pharma under the trade name Latuda^®.

Lurasidone and its salts were disclosed in US patent No. 5,532,372 ('372 patent). 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.

Lurasidone and its hydrochloride 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.

Process for the preparation of lurasidone hydrochloride was describes in '372 patent. According to the patent, crystalline solid of lurasidone hydrochloride was obtained by dissolving crude lurasidone in acetone at 20 to 30°C and then added a solution of hydrogen chloride in 2-propanol, and isolating. The crystalline lurasidone hydrochloride obtained by the process of the prior art is herein after designated as lurasidone hydrochloride crystalline Form I.

Crystalline Form of lurasidone free base was reported in IP.com Journal (2011), 1 1 (4A), 26.

International patent application publication no. WO 2012/063246 discloses an amorphous Form of lurasidone hydrochloride.

An unpublished application, PCT/IN2012/000548 assigned to Hetero Research Foundation discloses a novel amorphous Form of lurasidone hydrochloride. And also describes lurasidone hydrochloride crystalline Form I.

It was observed that the crystalline Forms and amorphous Form of lurasidone hydrochloride either not reproducible or not stable. We have also found a novel amorphous solid dispersion of lurasidone hydrochloride in combination with a pharmaceutically acceptable carrier. The amorphous solid dispersion of lurasidone hydrochloride is stable, reproducible and so, the amorphous solid dispersion of lurasidone hydrochloride is suitable for formulating lurasidone hydrochloride. Normally amorphous Forms are hygroscopic. Amorphous solid dispersion of lurasidone hydrochloride is found to be non-hygroscopic.

Thus, an object of the present invention is to provide amorphous solid dispersion of lurasidone hydrochloride 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 lurasidone hydrochloride 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 lurasidone hydrochloride in combination with a pharmaceutically acceptable carrier, which comprises:

a) preparing a solution comprising a mixture of lurasidone hydrochloride and one or more pharmaceutically acceptable carriers selected from copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, span-20 or soluplus in a solvent; and

b) removing the solvent to obtain amorphous solid dispersion of lurasidone hydrochloride 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 lurasidone hydrochloride 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 lurasidone hydrochloride 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 lurasidone hydrochloride in combination with a pharmaceutically acceptable carrier.

The powdered x-ray diffractogram (PXRD) of amorphous solid dispersion of lurasidone hydrochloride in combination with a pharmaceutically acceptable carrier is shown in figure 1.

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

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

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

Lurasidone hydrochloride used in step (a) may preferably be lurasidone hydrochloride obtained by the known process. The solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from methylene chloride, chloroform, carbontetrachloride, ethylene chloride, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol and n-pentanol, and more preferably the solvents are methylene chloride, dimethyl sulfoxide, methanol and ethanol.

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

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. The term "spray drying" refers to is a method of producing a dry powder from a liquid or slurry by rapidly drying with a hot gas.

According to another aspect of the present invention, there is provided pharmaceutical compositions comprising a therapeutically effective amount of amorphous solid dispersion of lurasidone hydrochloride along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient. The amorphous solid dispersion of lurasidone hydrochloride 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, 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, microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose excipietits, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners and the like.

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 palmitoy! 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.

Solubility comparison data for lurasidone hydrochloride and amorphous solid dispersion of lurasidone hydrochloride is shown below: Solvent Lurasidone hydrochloride Amorphous solid dispersion of lurasidone hydrochloride

Water Insoluble Insoluble

Methanol Slightly soluble Soluble

Dimethylformamide Slightly soluble Soluble

Dimethyl sulfoxide Insoluble Soluble

Ethanol Insoluble Slightly soluble

0.1N hydrochloride Insoluble Insoluble

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

Examples

Example 1 :

Preparation of lurasidone hydrochloride

Toluene (2250 ml) was added to trans-3a,7a-octahydroisoindolium-2-spiro-l'-[4'- (l,2-benisothiazol-3-yl)]piperazine methane sulfonate (150 gm) and then added potassium carbonate (75 gm) under stirring. To the reaction mixture was added bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide (100 gm) and 18-crown ether (1 1 gm). The contents were heated to reflux and maintained for 4 hours. To the reaction mass was added water (5000 ml) and then the separated aqueous layer was extracted with toluene. Combined organic layers were dried with sodium sulfate and then concentrated to obtain a residual solid. The residual solid obtained was dissolved in ethyl acetate (450 ml) and stirred for 30 minutes. The separated solid was filtered and then dried to obtain 120 gm of lurasidone.

Lurasidone (40 gm) as obtained above was dissolved in acetone (2000 ml) and stirred for 30 minutes at room temperature to obtain a clear solution. To the solution was added a solution of hydrochloric acid in isopropyl alcohol (40 ml) slowly and then cooled to 0 to 5°C. The contents were maintained for I hour at 0 to 5°C and filtered. The solid obtained was dried at 50°C under vacuum for 6 hours to give 30 gm of lurasidone hydrochloride. Example 2:

Preparation of amorphous lurasidone hydrochloride solid dispersion with copovidone

A mixture of lurasidone hydrochloride (10 gm) and copovidone (30 gm) was dissolved in a mixture of methanol (100 ml) and methylene chloride (100 ml) at room temperature. The solution was stirred for 30 minutes at room temperature and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 39 gm of amorphous lurasidone hydrochloride solid dispersion with copovidone.

Example 3:

A mixture of lurasidone hydrochloride (10 gm) and copovidone (10 gm) was dissolved in a mixture of methanol (60 ml) and methylene chloride (60 ml) at room temperature. The solution was stirred for 30 minutes at room temperature and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 19.5 gm of amorphous lurasidone hydrochloride solid dispersion with copovidone.

Example 4:

A mixture of lurasidone hydrochloride (10 gm) and copovidone (20 gm) was dissolved in a mixture of methanol (80 ml) and methylene chloride (80 ml) at room temperature. The solution was stirred for 30 minutes at room temperature and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 29 gm of amorphous lurasidone hydrochloride solid dispersion with copovidone. Example 5:

A mixture of lurasidone hydrochloride (10 gm) and copovidone (30 gm) was dissolved in a mixture of methanol (100 ml) and methylene chloride (100 ml) at room temperature. The solution was stirred for 30 minutes at room temperature and filtered through celite bed. The resulting filtrate was subjected to spray drying at 60 to 65°C to provide 38.5 gm of amorphous lurasidone hydrochloride solid dispersion with copovidone.

Example 6:

A mixture of lurasidone hydrochloride (10 gm) and copovidone (30 gm) was dissolved in dimethyl sulfoxide (150 ml) at room temperature. The solution was stirred for 30 minutes at room temperature and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 38 gm of amorphous lurasidone hydrochloride solid dispersion with copovidone. Example 7:

A mixture of lurasidone hydrochloride (10 gm), copovidone (20 gm) and span-20 (2 gm) was dissolved in a mixture of methanol (80 ml) and methylene chloride (80 ml) at room temperature. The solution was stirred for 30 minutes at room temperature and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 30 gm of amorphous lurasidone hydrochloride solid dispersion with copovidone. Example 8: Preparation of amorphous lurasidone hydrochloride solid dispersion with copovidone

Example 2 was repeated using ethanol solvent instead of methanol solvent to provide amorphous lurasidone hydrochloride solid dispersion with copovidone.

Example 9:

Example 2 was repeated using isopropanol solvent instead of methanol solvent to provide amorphous lurasidone hydrochloride solid dispersion with copovidone.

Example 10:

Example 2 was repeated using chloroform solvent instead of methylene chloride solvent to provide amorphous lurasidone hydrochloride solid dispersion with copovidone.

Example 1 1 :

Example 2 was repeated using ethylene chloride solvent instead of methylene chloride solvent to provide amorphous lurasidone hydrochloride solid dispersion with copovidone. Example 12:

Preparation of amorphous lurasidone hydrochloride solid dispersion with hydroxypropyl methylcellulose

A mixture of lurasidone hydrochloride (10 gm) and hydroxypropyl methylcellulose (20 gm) was dissolved in a mixture of methanol (90 ml) and methylene chloride (90 ml) at room temperature. The solution was stirred for 30 minutes at room temperature and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55 C and then dried to provide 28 gm of amorphous lurasidone hydrochloride solid dispersion with hydroxypropyl methylcellulose.

Example 13:

Example 12 was repeated using ethanol solvent instead of methanol solvent to provide amorphous lurasidone hydrochloride solid dispersion with hydroxypropyl methylcellulose.

Example 14:

Example 12 was repeated using isopropanol solvent instead of methanol solvent to provide amorphous lurasidone hydrochloride solid dispersion with hydroxypropyl methylcellulose.

Example 15:

Example 12 was repeated using chloroform solvent instead of methylene chloride solvent to provide amorphous lurasidone hydrochloride solid dispersion with hydroxypropyl methylcellulose.

Example 16:

Example 12 was repeated using ethylene chloride solvent instead of methylene chloride solvent to provide amorphous lurasidone hydrochloride solid dispersion with hydroxypropyl methylcellulose. Example 17:

Preparation of amorphous lurasidone hydrochloride solid dispersion with soluplus

A mixture of lurasidone hydrochloride (10 gm) and soluplus (20 gm) was dissolved in a mixture of methanol (80 ml) and methylene chloride (80 ml) at room temperature. The solution was stirred for 30 minutes at room temperature and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 28 gm of amorphous lurasidone hydrochloride solid dispersion with soluplus. Example 18:

A mixture of lurasidone hydrochloride (20 gm) and soluplus . (60 gm) was dissolved in ethanol (300 ml) at room temperature. The contents were heated to 70 to 75°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 74 gm of amorphous lurasidone hydrochloride solid dispersion with soluplus.

Example 19:

Preparation of amorphous lurasidone hydrochloride solid dispersion with soluplus Example 17 was repeated using ethanol solvent instead of methanol solvent to provide amorphous lurasidone hydrochloride solid dispersion with soluplus.

Example 20:

Preparation of amorphous lurasidone hydrochloride solid dispersion with soluplus Example 17 was repeated using isopropanol solvent instead of methanol solvent to provide amorphous lurasidone hydrochloride solid dispersion with soluplus.

Example 21 :

Preparation of amorphous lurasidone hydrochloride solid dispersion with soluplus Example 17 was repeated using chloroform solvent instead of methylene chloride solvent to provide amorphous lurasidone hydrochloride solid dispersion with soluplus. Example 22:

Preparation of amorphous Iurasidone hydrochloride solid dispersion with soluplus

Example 17 was repeated using ethylene chloride solvent instead of methylene chloride solvent to provide amorphous Iurasidone hydrochloride solid dispersion with soluplus.

Example 23:

Preparation of amorphous Iurasidone hydrochloride solid dispersion with polyethylene glycol

A mixture of Iurasidone hydrochloride (10 gm) and polyethylene glycol (10 gm) was dissolved in a mixture of methanol (60 ml) and methylene chloride (60 ml) at room temperature. The contents were heated to 70 to 75°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 18 gm of amorphous Iurasidone hydrochloride solid dispersion with polyethylene glycol.

Example 24:

Preparation of amorphous Iurasidone hydrochloride solid dispersion with ethyl cellulose

A mixture of Iurasidone hydrochloride (10 gm) and ethyl cellulose (10 gm) was dissolved in a mixture of methanol (60 ml) and methylene chloride (60 ml) at room temperature. The contents were heated to 70 to 75°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 18 gm of amorphous Iurasidone hydrochloride solid dispersion with ethyl cellulose. Example 25:

Preparation of amorphous Iurasidone hydrochloride solid dispersion with copovidone

Lurasidone (40 gm) was dissolved in acetone (2000 ml) and stirred for 30 minutes at room temperature to obtain a clear solution. To the solution was added a solution of hydrochloric acid in isopropyl alcohol (40 ml) slowly and then cooled to 0 to 5°C. The contents were maintained for 1 hour at 0 to 5 C and then added copovidone (90 gm) and a mixture of methanol (300 ml) and methylene chloride (300 ml) at room temperature. The solution was stirred for 30 minutes at room temperature and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 116 gm of amorphous lurasidone hydrochloride solid dispersion with copovidone.

Example 26:

Lurasidone (40 gm) was dissolved in acetone (2000 ml) and stirred for 30 minutes at room temperature to obtain a clear solution. To the solution was added a solution of hydrochloric acid in isopropyl alcohol (40 ml) slowly and then cooled to 0 to 5°C. The contents were maintained for 1 hour at 0 to 5°C and then added hydroxypropyl methylcellulose (60 gm) and a mixture of methanol (250 ml) and methylene chloride (250 ml) at room temperature. The solution was stirred for 30 minutes at room temperature and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 74 gm of amorphous lurasidone hydrochloride solid dispersion with hydroxypropyl methylcellulose.

Claims

We claim:

1. Amorphous solid dispersion of lurasidone hydrochloride in combination with a pharmaceutically acceptable carrier.

2. The amorphous solid dispersion of claim 1, wherei the pharmaceutically acceptable carrier comprises one or more of copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, span-20 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 lurasidone hydrochloride in combination with a pharmaceutically acceptable carrier, which comprises:

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

6. The process as claimed in claim 5, wherein the solvents are methylene chloride, dimethyl sulfoxide, methanol and ethanol.

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

8. Pharmaceutical compositions comprising a therapeutically effective amount of amorphous solid dispersion of lurasidone hydrochloride along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient. The pharmaceutical composition as claimed in claim 8, wherein the amorphous solid dispersion of lurasidone hydrochloride is formulated into tablets, capsules, suspensions, dispersions or injectables.