WO2015044962A1

WO2015044962A1 - Amorphous form of levomilnacipran hydrochloride and hydrates thereof

Info

Publication number: WO2015044962A1
Application number: PCT/IN2014/000632
Authority: WO
Inventors: Shri Prakash Dhar Dwivedi; Brij Khera; Jayprakash Ajitsingh PARIHAR; Piyush Rajendra Sharma
Original assignee: Cadila Healthcare Limited
Priority date: 2013-09-30
Filing date: 2014-09-30
Publication date: 2015-04-02
Also published as: IN2013MU03122A

Abstract

The present invention provides an amorphous form of levomilnacipran hydrochloride and process of preparation thereof. The present invention also provides an amorphous solid dispersion comprising levomilnacipran hydrochloride and a polymer.

Description

AMORPHOUS FORM OF LEVOMILNACIPRAN HYDROCHLORIDE AND HYDRATES THEREOF

FIELD OF THE INVENTION

The field of the invention relates to an amorphous form of levomilnacipran hydrochloride. In particular, the invention relates to a process for the preparation of an amorphous form of levomilnacipran hydrochloride or hydrates thereof. The invention also relates to a pharmaceutical composition comprising an amorphous form of levomilnacipran hydrochloride or hydrates thereof for oral administration as an antidepressant agent.

BACKGROUND OF THE INVENTION

The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.

Levomilnacipran (CAS no. 96847-55- 1 ) is an antidepressant developed by Forest Laboratories and Pierre Fabre Group for the treatment of depression. Levomilnacipran is an active enantiomer of milnacipran. Levomilnacipran is highly potent selective norepinephrine (NE) and serotonin (5-HT) reuptake inhibitor with greater selectivity for NE reuptake inhibition than for 5-HT reuptake inhibition.

Levomilnacipran hydrochloride is chemically named as ( l S,2R)-2-(amino methyl)-N,N-diethyl- l -phenylcyclopropane-l -carboxamide hydrochloride, has the following structural Formul

(I)

US 7,005,452 (the US'452 patent) discloses novel therapeutics that are useful in the treatment of disorders that can be managed by inhibition of norepinephrine (NE) and serotonin (5-HT) reuptake, for example, anxiety disorders and depression (e.g., major depressive disorder). One of the compounds disclosed in the US'452 patent, which is believed to be particularly effective for treating these types of disorders is (lS,2R)-2- (aminomethyl)-N,N-diethyI- 1 -phenyl cyclopropane carboxamide.

US 4,478,836 (the US'836 patent) discloses l -aryl-2-aminomethyi cyclopropane carboxamide in crystalline form. The US'836 patent also discloses the process for preparation of such compound wherein said process discloses final crystallization in ethanol and ethyl ether to obtain crystalline compound.

U.S. 201 1 /01 12197 Al and 2013/0210919 A l discloses novel crystalline forms of (l S^R^-iaminomethy -iV.N-diethyl- l -phenyl cyclopropane carboxamide characterized by unit cell parameters.

WO 201 1/057176 Al discloses a novel crystalline form of (l S,2R)-2- (aminomethyl)-NN-diethyl-l-phenyl cyclopropane carboxamide characterized by unit cell parameters. It also discloses the process for preparation of different crystalline forms and pharmaceutical composition thereof.

Crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a noncrystalline form. It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form (Econno T., Chem. Pharm. Bull., 1990; 38: 2003-2007). For some therapeutic indications, one bioavailability pattern may be favoured over another. An amorphous form of rosuvastatin calcium, rabeprazole sodium are some of the examples of the amorphous drug exhibiting much higher bioavailability than the crystalline forms, which leads to the selection of the amorphous form as the final drug substance for pharmaceutical dosage form development. Therefore, it is desirable to have amorphous forms of drugs with high purity to meet the regulatory requirements and possesses good bioavailability.

In view of the above, it is therefore, desirable to provide an efficient, more economical, less hazardous and eco-friendly process for the preparation of an amorphous form of levomilnacipran hydrochloride and hydrates thereof. The amorphous form provided herein is atleast stable under ordinary stability conditions with respect to purity, storage and is a free flowing powder. SUMMARY OF THE INVENTION

In one general aspect, there is provided an amorphous form of levomilnacipran hydrochloride of Formula (I)

(I)

In general, the amorphous form of levomilnacipran hydrochloride has the x-ray powder diffraction pattern substantially as depicted in FIG.1

In another general aspect, there is provided the amorphous form of levomilnacipran hydrochloride having water content less than about 5% wt/wt.

In another general aspect, there is provided a process for the preparation of an amorphous form of levomilnacipran hydrochloride, the process comprising:

(a) providing a solution of levomilnacipran hydrochloride in one or more solvents; and

(b) obtaining the amorphous form of levomilnacipran hydrochloride by removal of the solvents.

In another general aspect, there is provided a stable amorphous form of levomilnacipran hydrochloride, which is atleast stable during storage and drying.

In another general aspect, there is provided the amorphous levomilnacipran hydrochloride having particle size distribution wherein the 10th volume percentile particle size (D 10) is about 50 μηι or. less, the 50th volume percentile particle size (D50) is about 200 μπι or less, or the 90th volume percentile particle size (D90) is about 400 μπι or less.

In another general aspect, there is provided a process for the preparation of the amorphous form of levomilnacipran hydrochloride, the process comprising:

(a) suspending levomilnacipran hydrochloride in one or more solvents; and

(b) obtaining the amorphous form levomilnacipran hydrochloride by removal of the solvents.

In another general aspect, there is provided an amorphous solid dispersion comprising levomilnacipran hydrochloride and a polymer as well as methods for production of such compositions from a solvent-based medium. In another general aspect, there is provided a process for preparing an amorphous solid dispersion, comprising the steps of:

(a) dissolving or dispersing levomilnacipran hydrochloride and a polymer in one or more organic solvents; and

(b) obtaining the amorphous solid dispersion of levomilnacipran hydrochloride and a polymer.

In another general aspect, there is provided an- amorphous form of levomilnacipran hydrochloride having a chiral purity jof about 98% or more, of about 99% or more, of about 99.5% or more, of about 99.8% or more, or of about 99.9% or more, as determined using high performance liquid chromatography (HPLC).

In another general aspect, there is provided an amorphous form of levomilnacipran hydrochloride having a HPLC purity of about 98% or more, of about 99% or more, of about 99.5% or more, of about 99.8% or more, or of about 99.9% or more, as determined using high performance liquid chromatography (HPLC).

In another general aspect, there is provided a pharmaceutical composition comprising an amorphous form of levomilnacipran hydrochloride together with one or more pharmaceutically acceptable carriers, excipients or diluents.

In another general aspect, there is provided a pharmaceutical composition comprising a stable amorphous form of levomilnacipran hydrochloride together with one or more pharmaceutically acceptable carriers, excipients or diluents.

BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS

FIG 1. Shows the X-ray diffractogram (XRD) of the amorphous form of levomilnacipran hydrochloride as per example- 1.

FIG 2. Shows the X-ray diffractogram (XRD) of the amorphous form of levomilnacipran as per example-2.

DETAILED DESCRIPTION OF THE INVENTION

The above and other objects of the present invention are achieved by the process of the present invention, which leads to greater stability of amorphous levomilnacipran hydrochloride. The invention provides a process for preparing an amorphous form of levomilnacipran hydrochloride and hydrates thereof in one or more of solvents.

Optionally, the solution, prior to any solids formation, can be filtered to remove any undissolved solids or solid impurities prior to removal of the solvent. Any filtration system and filtration techniques known in the art can be used. As used herein, the terms "suspending" herein means a process carried out in a heterogeneous mixture where complete dissolution does not occur. Also, heating the suspension or slurry can result in a homogenous mixture where complete or partial dissolution occurs at an elevated temperature or ambient temperature.

All ranges recited herein include the endpoints, including those that recite a range "between" two values. Term "substantially" is to be construed as modifying a term or values such that it is not an absolute. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

As used herein, the term "stable" herein means an amorphous form of levomilnacipran hydrochloride that does not convert to any other solid forms when stored at a temperature of up to about 40°C and at a relative humidity of about 25% to about 75% for about three months or more.

As used herein, the term "solid dispersion" means any solid composition having at least two components. In certain embodiments, a solid dispersion as disclosed herein includes an active ingredient levomilnacipran hydrochloride dispersed among atleast one other component, for example a polymer.

The term "immobilize" as used herein with reference to the immobilization of the active compound i.e. levomilnacipran hydrochloride in the polymer matrix, means that molecules of the active compound interact with molecules of the polymer in such a way that the molecules of the levomilnacipran hydrochloride are held in the aforementioned matrix and prevented from crystal nucleation due to lack of mobility.

In one general aspect, there is provided an amorphous form of levomilnacipran hydrochloride of Formula (I).

(I)

In general, the amorphous form of levomilnacipran hydrochloride has the x-ray powder diffraction pattern substantially as depicted in FIG.1 In another general aspect, there is provided the amorphous form of levomilnacipran hydrochloride having water content less than about 5% wt/wt.

In another general aspect, there is provided amorphous form of levomilnacipran hydrochloride having purity by HPLC of about 98% or more and residual solvents less than 0.5%.

In another general aspect, there is provided amorphous form of levomilnacipran hydrochloride having a chiral purity of about 98% or more.

In general, the amorphous form of levomilnacipran hydrochloride is substantially free from residual solvents. The term "substantially free" means residual solvents within the permissible ICH limits suitable for pharmaceutical preparations. For example but not limited to less than 0.5%, particularly less than 0.3% or more particularly less than 0.2%, In another general aspect, there is provided a process for the preparation of an amorphous form of levomilnacipran hydrochloride, the process comprising:

(c) providing a solution of levomilnacipran hydrochloride in one or more solvents; and (d) obtaining the amorphous form of levomilnacipran hydrochloride by the removal of the solvents.

In general, a solution of levomilnacipran hydrochloride in one or more organic solvents is obtained by the known methods that include:

(i) direct use of a reaction mixture containing levomilnacipran hydrochloride that is obtained in the course of its synthesis; or

(ii) dissolving levomilnacipran hydrochloride in one or more organic solvents.

In general, in step a) any physical forms of levomilnacipran hydrochloride may be utilized for providing the solution of levomilnacipran hydrochloride in one or more solvents. The dissolution temperatures may be from 0°C to the reflux temperature of the solvent. In particular, the dissolution may be performed from 25°C to 120°C, more particularly, from about 40°C to about 100°C so as to obtain the clear solution of levomilnacipran hydrochloride.

One Or more solvent that may be used in step a) include water; alcohols selected from methanol, ethanol, isopropanol, 2-propanol, 1 -butanol and t-butyl alcohol; ketones such selected from acetone, butanone and methyl isobutyl ketone; esters selected from ethyl acetate, isopropyl acetate, t-butyl acetate and isobutyl acetate; chlorinated hydrocarbons selected form methylene dichloride, ethylene dichloride and chlorobenzene; nitriles selected form acetonitrile, and polar aprotic solvents selected from NN-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide.

Step b) involves isolation of an amorphous form of levomilnacipran hydrochloride from the solution of step a). The isolation may be affected by removing the solvent. Suitable techniques which may be used for the removal of solvent includes one or more of distillation using a rotational distillation device for example Buchi Rotavapor, distillation under vacuum, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), filtration, filtration under vacuum, decantation and centrifugation; or any other technique known in the art.

The solvent may be removed, optionally under reduced pressures, at temperatures less than 70°C, less than 60°C, less than 50°C.

In general, freeze drying (lyophilization) may be performed by freezing a solution of levomilnacipran hydrochloride at low temperatures and reducing the pressure to remove the solvent from the frozen solution of levomilnacipran hydrochloride. Temperatures that may be required to freeze the solution, depending on the solvent chosen to make the solution of levomilnacipran hydrochloride may range from 70°C to 10°C.

Alternatively, isolation can be effected by addition of an antisolvent to the solution obtain in step a), optionally by concentrating the solution obtained in step a). An anti-solvents that may be used can be selected from one or more of hydrocarbons selected from hexanes, n-heptane, n-pentane, cyclohexane and methylcyclohexane; aromatic hydrocarbons selected form toluene, xylene and ethylbenzene; ethers selected from diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran and 1 ,4-dioxane, 2-methoxyethanol or water.

In another general aspect, there is provided process for preparing amorphous levomilnacipran hydrochloride comprising spray drying a solution of levomilnacipran hydrochloride that involves the spray drying of feed stock, which is prepared as discussed below, wherein any solid forms of levomilnacipran hydrochloride may be used. In particular, the spray drying of levomilnacipran hydrochloride may be performed by dozing the feedstock into the spray-drying instrument JISL Mini Spray-drier LSD-48 by maintaining the inlet temperature in the range of 35°C-70°C, nitrogen pressure of 2-5 kg/cm², maintaining the outlet temperature in the range of 25°C to 60°C, at a feed rate of 10-60 rpm and maintaining the vacuum at 30-120 mm of Hg. In general, the feed stock of levomilnacipran hydrochloride may be conveniently prepared by dissolving any known forms or wet cake of levomilnacipran hydrochloride in the solvent comprises one or more water, alcohols, ketones, esters, chlorinated hydrocarbons, nitriles, N.N-dimethylformamide, . N,N-dimethylacetamide, . N- methylpyrrolidone, N,N-dimethylsulfoxide, or mixtures thereof.

In particular, alcohols are selected from methanol, ethanol, isopropanol, n- butanoi, and t-butanol; ketones are selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, and methyl tert-butyl ketone; esters selected from ethyl acetate, isopropyl acetate, butyl acetate, and isobutyl acetate, chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride, chloroform, and carbon tetrachloride; nitriles like acetonitrile; NN-dimethylformamide, N-dimethylacetamide, iV-methylpyrrolidone, NN-dimethylsulfoxide, water-methanol, water-ethanol, or water-acetone mixture are suitable solvents that evaporate easily to afford the dry product. Most particularly, acetone, methanol, ethanol, ethyl acetate or mixtures thereof are used.

In general aspect, the amorphous levomilnacipran hydrochloride obtained is formed into a finished dosage form.

In general, the finished dosage form comprises one or more of liquid, solid and semisolid dosage forms depending upon the route of administration. In particular, dosage forms are essentially pharmaceutical products in the form involving a mixture of amorphous levomilnacipran hydrochloride together alongwith the pharmaceutically acceptable carriers, excipients or diluents.

As used herein, the term "pharmaceutical products" includes pharmaceutical formulations selected from tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

According to another general aspect, any known solid forms of levomilnacipran hydrochloride is spray dried by dissolving or suspending or slurring in one or more solvents or mixture thereof with water to obtain amorphous form of levomilnacipran hydrochloride.

In general, the feedstock of levomilnacipran hydrochloride in one or more solvents or aqueous solvent system is spray-dried. Thus obtain spray-dried compound is in amorphous form characterized by the x-ray powder diffractogram of levomilnacipran hydrochloride. In another general aspect, there is provided a process for the preparation of the amorphous form of levomilnacipran hydrochloride, the process comprising:

(a) suspending levomilnacipran hydrochloride in one or more solvents; and

(b) obtaining the amorphous form of levomilnacipran hydrochloride by the removal of the solvent.

The suspension of levomilnacipran hydrochloride may be a clear solution with homogenous mixture or a suspension or slurry with a heterogeneous mixture in one or more organic solvent selected from water, alcohols, ketones, esters, chlorinated hydrocarbons, nitriles, NN-dimethylformamide, N/V-dimethyl acetamide, N- methylpyrrolidone, N./V-dimethylsulfoxide, or mixtures thereof.

In further aspect, the stable amorphous levomilnacipran hydrochloride can be stored under nitrogen atmosphere and packed in a double polythene bag tied with a thread, keeping primary packing containing amorphous levomilnacipran hydrochloride inside a black color polyethylene bag containing oxygen busters and sealing it, placing above the double polyethylene bag inside a triple laminated bag optionally containing oxygen busters and sealing it, and placing the sealed triple laminated bag inside a closed high density polyethylene (HDPE) container and storing in controlled environment chamber at 25°C and/or 40°C.

In another general aspect, there is provided an amorphous form of levomilnacipran hydrochloride having a chiral purity of about 98% or more, of about 99% or more, of about 99.5% or more, of about 99.8% or more, or of about 99.9% or more, as determined using high performance liquid chromatography (HPLC).

In another general aspect, there is provided an amorphous solid dispersion comprising levomilnacipran hydrochloride and a polymer.

In another general aspect, the amorphous solid dispersion is characterized by x- ray powder diffraction pattern substantially as depicted in FIG.2

In another general -aspect there is provided a process for the preparation of an amorphous solid dispersion of levomilnacipran hydrochloride, the process comprising: (a) dissolving or dispersing levomiinacipran hydrochloride and a polymer in one or more solvents; and

(b) obtaining the amorphous solid dispersion of levomiinacipran hydrochloride and a polymer.

In general, the polymer or carriers may be a non-ionic polymer or an ionic polymer. The polymer or pharmaceutically acceptable carriers comprises of hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose, methacrylic acid copolymers or polyvinylpyrrolidone (PVP). In particular, PVP of different grades like - 15, K-30, K-60, -90 and K- 120 may be used for the preparation of amorphous composition. More particular, hydroxypropylmethyl cellulose or its acetate, succinate and PVP K-30 may be used.

In some embodiments, the levomiinacipran hydrochloride may be dispersed within a matrix formed by a polymer in its solid state such that it is immobilized in its amorphous form. The polymer may prevent intramolecular hydrogen bonding or weak dispersion forces between two or more drug molecules of levomiinacipran hydrochloride. The solid dispersion provides for a large surface area, thus further allowing for improved dissolution and bioavailability of levomiinacipran.

In some embodiments, the ratio of the amount of weight of levomiinacipran hydrochloride within the solid dispersion to the amount by weight of the polymer therein is from about 1 : 1 to 1 : 10. The composition of levomiinacipran hydrochloride with polymer, preferably PVP K-30 or HPMC-AC may be prepared by using 1 : 1 to 1 : 10 polymers with respect to levomiinacipran hydrochloride. The usage of higher molar amount of polymer increases the amorphous character of the drug substance.

The solvent comprises one or more of low boiling solvents selected from methanol, ethanol, isopropanol, acetone, isopropyl ^"acetate, methylene chloride and ethyl acetate or mixture thereof with water.

The compound levomiinacipran hydrochloride and a polymer (for example HPMC-AC or PVP K-30) may be dissolved in one or more organic solvent having a low boiling point, e.g. methanol, ethanol, isopropanol, acetone or ethyl acetate. The amorphous solid dispersion may be obtained by removal of solvent (for example by spray drying, lyophilization, flash evaporation or vacuum distillation.) thereby leaving the amorphous solid dispersion precipitated in a matrix formed by the polymer. In another general aspect, there is provided a pharmaceutical composition comprising an amorphous form of levomilnacipran hydrochloride together with one or more pharmaceutically acceptable carriers, diluents and excipients.

In another general aspect, there is provided a pharmaceutical composition comprising an amorphous solid dispersion of levomilnacipran hydrochloride and a polymer together with one or more pharmaceutically acceptable carriers, diluents and excipients.

In another general aspect, there is provided a pharmaceutical composition comprising the amorphous form of levomilnacipran hydrochloride substantially free residual solvents as measured by GC together with one or more pharmaceutically acceptable carriers, diluents and excipients.

In another general aspect, there is provided a pharmaceutical composition comprising the amorphous form of levomilnacipran hydrochloride substantially free from crystalline forms together with one or more pharmaceutical y acceptable carriers, diluents and excipients.

In another general aspect, there is provided a pharmaceutical composition comprising a stabilized amorphous solid dispersion of levomilnacipran hydrochloride and a polymer together with one or more pharmaceutically acceptable carrier, excipients and diluents.

In another general aspect, there is provided a pharmaceutical composition comprising an amorphous levomilnacipran hydrochloride having particle size distribution, wherein the 10th volume percentile particle size (D IO) is about 50 μπι or less, the 50th volume percentile particle size (D50) is about 200 μιτι or less, the 90th volume percentile particle size (D90) is about 400 μιη or less.

Powder X-ray diffraction of amorphous levomilnacipran hydrochloride can be obtained under following conditions,

(i) Characterization by Powder X-ray Diffraction

Analytical method: Powder X-ray Diffractioncan be performed using a Rigaku D MAX 2200 VPC diffraction meter or PANALYTICAL ExpertPro DY2408 or other suitable machines in practice, the powder X-ray diffraction pattern was measured at room temperature using a Cu Ka filled tube (40kV, 40 mA) as the X-ray. source with a wide- angle goniometer, a 1° scattering slit, an diverging slit, a graphite secondary monochromatof and a scintillation counter. Data collection was done in 2Θ continuous scan mode at a scan speed of 3 minute in scan steps of 0.02° in the range of 2° to 40°.

The invention also encompasses pharmaceutical compositions comprising levomilnacipran or its pharmaceutically acceptable salts of the invention. As used herein, the term "pharmaceutical compositions" includes pharmaceutical Formulations like tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

Pharmaceutical compositions containing the levomilnacipran hydrochloride or hydrates thereof may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants. Various modes of administration of the pharmaceutical compositions of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES

Example-1 :

Preparation of amorphous levomilnacipran hydrochloride (1)

10.0 g of levomilnacipran hydrochloride was dissolved in 100.0 mL of water at 25°C to 30°C. The content was stirred for 30 minutes at 25°C to 30°C. To this, 1.0 g charcoal was added and stirred for 30 minutes at 80°C. The content was filtered through Hyflosupercel, and the Hyflosupercel pad was washed with 50 mL water. The filtrate was concentrated partially under vacuum below 45°C till 50 mL water remains. 50 mL water was added and stirred at 80°C to get clear solution. The clear solution was spray dryied in JISL Mini spray drier LSD-48 by maintaining the inlet temperature in the range of 60°C under nitrogen pressure of 2 kg/cm² at a feed rate of 30 rpm and maintaining the outlet temperature in the range of 40°C. The product was collected from cyclone and was further dried at 40°C±5°C . under vacuum for 10 hours to get 6.0 g of amorphous levomilnacipran hydrochloride. Example-2:

. Preparation of amorphous levomilnacipran hydrochloride (D

5 g of levomilnacipran hydrochloride and 100 mL methanol were taken in round bottom ■ flask at 25-30°C. The reaction mixture was heated at 55-60°C to obtain clear solution. 5 g of PVP- 30 polymer was added and stirred at 55-60°C for 2 hours. The reaction mixture was distilled under vacuum at 60-65°C. The product was dried under vacuum at 55-60°C to obtain 8 g amorphous levomilnacipran hydrochloride composition.

Example-3:

Preparation of amorphous levomilnacipran hydrochloride (D

25 g levomilnacipran hydrochloride and 250 mL acetonitrile were combined and stirred at 25°C for 15 minutes to suspend levomilnacipran hydrochloride in a 250 mL Buchi flask. The suspension was heated to 75°C for 2 hours and filtered. The filtrate was distilled completely under reduced pressure at 45°C to afford 15 g of amorphous levomilnacipran hydrochloride.

Example-4:

Preparation of amorphous solid dispersion of levomilnacipran hydrochloride (I)

In 50 mL three necked round bottom flask equipped with mechanical stirrer, thermometer and an addition funnel, I g of levomilnacipran hydrochloride and 20 mL methanol were taken at 25-30°C. The reaction mixture was heated at 50-55°C to obtain clear solution. 1 g of HPMC (3cps) polymer was added and stirred at 50-55°C for 15 minutes. The reaction mixture was distilled under vacuum at 60-65°C. The product was dried under vacuum at 55-60°C to obtain 1.3 g amorphous solid dispersion of levomilnacipran hydrochloride.

While the preseht invention has been described in terms of its specific embodiments, certain modification and equivalents will be apparent to those skilled in art and the intended to be included within the scope of the invention.

Claims

We Claim:

1. An amorphous form of levomilnacipran hydrochloride.

2. The amorphous form of levomilnacipran hydrochloride according to claim 1 , wherein the levomilnacipran hydrochloride has the x-ray powder diffraction pattern substantially as depicted in FIG. I .

3. The amorphous form of levomilnacipran hydrochloride according to claim 1 , having water content less than about 5% w/w.

4. The amorphous form of levomilnacipran hydrochloride according to claim 1 having a purity by HPLC of about 98% or more and residual solvent less than 0.5%.

5. The amorphous form of levomilnacipran hydrochloride according to claim 1 having a chiral purity of about 98% or more.

6. A process for the preparation of an amorphous form of levomilnacipran hydrochloride, the process comprising:

(b) obtaining the amorphous form of levomilnacipran hydrochloride by the removal of the solvents.

7. The process according to claim 6, wherein the solvent comprises one or more of water, alcohols, ketones, esters, chlorinated hydrocarbons, nitriles, N,N- dimethylformamide, N,N-dimethyIacetamide, N-methylpyrrolidone, N,N- dimethylsulfoxide, or mixtures thereof.

8. The process according to claim 6, wherein removing the solvent comprises one or more of distillation, distillation under vacuum, spray drying, agitated thin film dyring ("ATFD"), freeze drying (lyophilization), filtration, filtration under vacuum, decantation and centrifugation.

9. The process according to claim 6, further comprising forming the product obtained into a finished dosage form.

10. An amorphous solid dispersion comprising levomilnacipran hydrochloride and a polymer.

1 1. The amorphous solid dispersion according to claim 10, wherein the polymer is a non- ionic polymer or an ionic polymer.

12. The amorphous solid dispersion according to claim 1 1 , wherein the polymer comprises one or more of hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose, methacrylic acid copolymers, and polyvinyl pyrrolidone.

13. The amorphous solid dispersion according to claim 10, characterized by x-ray powder diffraction pattern substantially as depicted in FIG. 2.

14. The amorphous solid dispersion according to claim 10, wherein the ratio of the amount of weight of levominlacipran hydrochloride within the solid dispersion to the amount by weight of the polymer therein is from about 1 : 1 to 1 : 10.

15. A process for the preparation of an amorphous solid dispersion of levomilnacipran hydrochloride, the process comprising:

(a) dissolving or dispersing levomilnacipran hydrochloride and a polymer in one or more solvents; and

16. The process according to claim 15, wherein the solvent is selected form methanol, ethanol, isopropanol, acetone isopropylacetate, methylene dichloride and ethyl acetate or mixture thereof with water.

17. A pharmaceutical composition comprising an amorphous form of levomilnacipran hydrochloride together with one or more of pharmaceutically acceptable carriers, diluent and excipients.

18. A pharmaceutical composition comprising an amorphous solid dispersion of levomilnacipran hydrochloride, and a polymer together with one or more of pharmaceutically acceptable carriers, excipients or diluents.

19. A pharmaceutical composition comprising an amorphous levomilnacipran hydrochloride having particle size distribution, wherein the 10th volume percentile particle size (D 10) is about 50 μπι or less, the 50th volume percentile particle size (D50) is about 200 μπι or less, the 90th volume percentile particle size (D90) is about 400 μπι or less.