The present invention provides amorphous form of viloxazine or its pharmaceutically acceptable salts, their process for the preparation and composition thereof.

The present invention further provides an amorphous solid dispersion of viloxazine, its pharmaceutically acceptable salt, isomers, and process for the preparation thereof, wherein said viloxazine, its pharmaceutically acceptable salt are either racemic or enantiomerically pure isomer selected from S(-) or R(+)-isomer. Moreover, there is provided a pharmaceutical composition comprising above said amorphous solid dispersion of viloxazine, pharmaceutically acceptable salts, or isomers thereof.

BACKGROUND OF THE INVENTION
Viloxazine hydrochloride having a chemical name; 2-[(2-ethoxyphenoxy)methyl]morpholine hydrochloride is a norepinephrine reuptake inhibitor (NRI) and is known as antidepressant in some European Countries and is under analysis for the treatment of ADHD (attention deficit hyperactivity disorder). Viloxazine is represented by the following chemical structure according to Formula (I):
.

Viloxazine has two stereoisomers, S(-)-isomer and R(+)-isomer and is also known to be used as racemic mixture.

US 3,714,161 discloses viloxazine and its pharmaceutically acceptable salts; and US 3,712,890 discloses process for the preparation of viloxazine hydrochloride.

US 9,403,783 (US’783) discloses anhydrous crystalline forms A and B of viloxazine hydrochloride and process of preparation thereof. US’783 further provides process for the preparation of viloxazine hydrochloride and its metabolites.

US 10,005,743 provides process for preparing viloxazine hydrochloride and its intermediates.

US 10,160,733 (US’733) provides methods of manufacture of viloxazine and its hydrochloride salts and polymorphs thereof. US’733 further discloses process for preparing various intermediates used for preparing viloxazine.

As it is apparent from disclosure(s), there are few polymorphs of viloxazine hydrochloride known from the prior published references. It is also known that viloxazine and its salts suffers from drawback such as presence of genotoxic impurities and is required to be re-crystallized in a particular solvent to improve its purity. Moreover, it is known that the bioavailability is the key determinant of a drug for its therapeutic effectiveness, which in turn depends upon the solubility of that drug in gastro intestinal fluid. The solubility of the drug in the vehicle determines its release rate and affects the absorption and therapeutic effectiveness.

The discovery of further solid forms of an active pharmaceutical ingredient (API) can offer an opportunity to improve the performance profile of a pharmaceutical composition comprising said API.

Preparing a solid dispersion increases the solubility of drug in the vehicle and also said solid dispersion can easily be formulated. The present invention is focussed on the preparation of amorphous form and/ or solid dispersions and/ or premix of viloxazine, pharmaceutically acceptable salts, and isomers thereof that possess high purity and solubility that can easily be formulated in a formulation having a desirable release profile.

OBJECTIVE OF THE INVENTION
The main object of the present invention is to provide amorphous form of viloxazine or pharmaceutically acceptable salt or isomers thereof.

Another object of the present invention is to provide an amorphous solid dispersion of viloxazine or pharmaceutically acceptable salt thereof, wherein said viloxazine or its pharmaceutically acceptable salt is either racemic, or enantiomerically pure which is selected from either S(-)-isomer or R(+)-isomer.

Another object of the present invention is to provide a amorphous form of viloxazine, pharmaceutically acceptable salt, and isomers thereof.

Another object of the present invention is to provide a process for the preparation of amorphous solid dispersion of viloxazine or pharmaceutically acceptable salt, with atleast one pharmaceutically acceptable carrier, wherein said viloxazine or its pharmaceutically acceptable salt is either anhydrous, hydrate or solvate in nature.

Another object of the present invention is to provide a process for the preparation of amorphous form of viloxazine, pharmaceutically acceptable salt, and isomers thereof, wherein said amorphous form is stable for atleast six months at 20±5oC and 30±5% RH, 25±5oC and 60±5% RH, as well as at 40±5oC and 75±5% RH and can be formulated easily for administering to patients.

Another object of the present invention is to provide a pharmaceutical composition comprising solid forms of viloxazine or its pharmaceutically acceptable salt, wherein the physicochemical stability and the dissolution characteristics of the solid form is improved, and wherein said viloxazine or its pharmaceutically acceptable salt is rendered more suitable for use in a pharmaceutical composition, and wherein said viloxazine or its pharmaceutically acceptable salt is either racemic, or enantiomerically pure which is selected from either S(-)-isomer or R(+)-isomer.

SUMMARY OF THE INVENTION
In an aspect, the present invention provides amorphous form of viloxazine or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides an amorphous form of viloxazine, or pharmaceutically acceptable salt thereof, wherein said amorphous form is stable for atleast six months at 20±5oC and 30±5% RH, 25±5oC and 60±5% RH, as well as at 40±5oC and 75±5% RH.

In another aspect, the present invention provides a process for the preparation of an amorphous form of viloxazine or pharmaceutically acceptable salt thereof comprising the steps of:
a) adding viloxazine or pharmaceutically acceptable salt thereof to a suitable solvent, wherein said viloxazine or pharmaceutically acceptable salt thereof is either racemic or enantiomerically pure isomer selected from S(-) and R(+)-isomer;
b) optionally heating at a suitable temperature; and
c) lyophilizing and isolating to get the amorphous form of viloxazine or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a process for the preparation of an amorphous form of S(-)-viloxazine hydrochloride comprising the steps of:
a) adding S(-)-viloxazine hydrochloride to a suitable solvent;
b) optionally heating at a suitable temperature; and
c) lyophilizing and isolating to get the amorphous form of S(-)-viloxazine hydrochloride.

In another aspect, the present invention provides a process for the preparation of amorphous viloxazine hydrochloride, comprising the steps of:
a) ball milling viloxazine hydrochloride under suitable milling conditions; and
b) isolating the amorphous form of viloxazine hydrochloride.

In another aspect, the present invention provides a process for the preparation of an amorphous form of viloxazine or pharmaceutically acceptable salt thereof, comprising the steps of:
a) adding viloxazine or pharmaceutically acceptable salt thereof in one or more suitable solvent;
b) optionally heating at a suitable temperature; and
c) isolating the amorphous form of viloxazine or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides amorphous form of viloxazine or pharmaceutically acceptable salt thereof substantially free from epichlorohydrin, 1-(2-ethoxyphenoxy)-2,3-epoxypropane, and 2-aminoethyl hydrogen sulfate wherein each impurity is less than about 0.5µg.

In another aspect, the present invention provides a process for the preparation of amorphous form of viloxazine or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of viloxazine or its pharmaceutically acceptable salt in a suitable solvent, wherein said viloxazine or its pharmaceutically acceptable salt is either racemic or enantiomerically pure isomer selected from S(-) or R(+)-isomer;
b) optionally heating the solution of step a); and
c) isolating the amorphous form of viloxazine or pharmaceutically acceptable salt or enantiomerically pure isomer thereof.

In another aspect, the present invention provides a process for the preparation of an amorphous solid dispersion of viloxazine, or pharmaceutically acceptable salt thereof, comprising the steps of:
a) adding viloxazine or its pharmaceutically acceptable salt in a suitable solvent, wherein said viloxazine or its pharmaceutically acceptable salt is either racemic or enantiomerically pure isomer selected from S(-) or R(+)-isomer;
b) adding atleast one pharmaceutically acceptable carrier to the solution obtained in step a); and
c) isolating to get amorphous solid dispersion of viloxazine or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a process for the preparation of an amorphous solid dispersion of S(-)-viloxazine or its pharmaceutically acceptable salt, comprising the steps of:
a) providing a solution of amorphous form of S(-)-viloxazine or its pharmaceutically acceptable salt in a suitable solvent;
b) adding atleast one pharmaceutically acceptable carrier; and
c) removing the solvent and isolating to get amorphous solid dispersion of S(-)-viloxazine or its pharmaceutically acceptable salt.

In another aspect, the present invention provides a process for the preparation of a premix of viloxazine or pharmaceutically acceptable salt thereof, comprising the steps of:
a) adding viloxazine or pharmaceutically acceptable salt thereof, to atleast one pharmaceutically acceptable carrier to get a solid mass;
b) optionally adding solvent to get a solution; and
c) isolating the premix of viloxazine or pharmaceutically acceptable salt thereof, either by removal of solvent from solution of step b) or by isolating the solid mass of step a), wherein said viloxazine or its pharmaceutically acceptable salt is either racemic or enantiomerically pure isomer selected from S(-) or R(+)-isomer.

In another aspect, the present invention provides a process for the preparation of an amorphous solid dispersion of viloxazine or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of viloxazine or pharmaceutically acceptable salt thereof in a suitable solvent;
b) adding at least one pharmaceutically acceptable carrier to the solution obtained in step a); and
c) isolating to get amorphous solid dispersion of viloxazine or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides substantially pure solid dispersion of viloxazine or its pharmaceutically acceptable salt wherein said viloxazine or its pharmaceutically acceptable salt is free from epichlorohydrin, 1-(2-ethoxyphenoxy)-2,3-epoxypropane, and 2-aminoethyl hydrogen sulfate wherein each impurity is less than about 0.5µg.

DETAILED DESCRIPTION
Drawings:
Fig. 1 represents XRPD peaks of amorphous form of viloxazine hydrochloride
Fig. 2 represents XRPD peaks of solid dispersion of viloxazine prepared as per Example 4

Definitions:
The terms “amorphous form of viloxazine ,pharmaceutically acceptable salt or isomer thereof" indicate that viloxazine is present in substantially amorphous state and is substantially free from crystalline form. It may be present in the form of solid dispersion, adsorbate or pharmaceutical composition. "Substantially pure amorphous” denotes that atleast 90%, preferably atleast 95%, more preferably atleast 99% of the viloxazine hydrochloride is amorphous. In other words, “substantially free from crystalline form” preferably means that the amorphous form does not contain detectable amounts, of crystalline portions of viloxazine e.g. measurable upon X-ray powder diffraction analysis and/or Differential scanning calorimetry, and preferably the crystalline form is less than about 5% w/w of the amorphous form.

“Solid dispersion” as used herein refers to the dispersion of one or more active ingredients in an inert carrier, where the active ingredients could exist in finely crystalline, solubilized or amorphous state. Solid dispersion consists of two or more components, generally a carrier and drug optionally along with stabilizing agent (and/or surfactant or other additives). The most important role of the added carrier in solid dispersion is to reduce the molecular mobility of the drug to avoid the phase separation and re-crystallization of drug during storage. The resulting solid dispersions may have increased solubility. The increase in solubility of the drug in solid dispersion is mainly because drug remains in amorphous form which is associated with a higher energy state as compared to crystalline counterpart and due to that it requires very less external energy to dissolve. A solid dispersion is a molecular dispersion of a compound, particularly a drug substance within a carrier. Formation of a molecular dispersion provides a means of reducing the particle size to nearly molecular levels (i.e. there are no particles). As the carrier dissolves, the drug is exposed to the dissolution media as fine particles that are amorphous, which can dissolve and be absorbed more rapidly than larger particles. Further, the term " solid dispersion" as used in the context of the present invention, denotes a state where most of the viloxazine or a salt thereof, preferably 90%, 95% or all of the viloxazine or pharmaceutically acceptable salt thereof of the solid dispersion, is homogeneously molecularly dispersed in a solid carrier matrix. In a preferred embodiment, in the solid dispersion according to the present invention no chemical bonds can be detected between the API and the carrier. In order to arrive at such a solid dispersion, preferably solid solution, it is required to have a substantial amount of API dissolved in a suitable solvent at least at one time point during preparation of said solid dispersion.

The term "premix" is used herein to describe combinations of viloxazine or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier, wherein individual particles of the components cannot be distinguished using techniques such as optical microscopy. In embodiments, the drug is considered as being uniformly or non-uniformly distributed over surfaces of carrier particles.

The term "excipient" or "pharmaceutically acceptable excipient" means a component of a pharmaceutical product that is not an active ingredient, and includes but not limited to filler, diluent, disintegrants, glidants, stabilizers, surface active agents etc. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. One excipient can perform more than one function.

The terms “pharmaceutically acceptable salt” as used in the context of the present invention refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt, carbonate salts; organic acids such as succinic acid, formic acids, acetic acid, diphenyl acetic acid, palmoic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, dibenzoyl tartaric acid, oxalic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, methyl benzene sulfonate, p-toluenesulfonic acid and the like. The inorganic salts may further includes alkali metal and alkaline earth metal salts such as sodium, potassium, barium, lithium, calcium, magnesium, rhodium, zinc, cesium, selenium, and the like.

The term “stereomerically pure” or “enantiomercially pure” means substantially free of its counter stereoisomer or enantiomer. For example, a compound is stereomerically or enantiomerically pure, when the compound contains greater than or equal to 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of one stereoisomer, and 20%, 15%, 10%, 8%, 5%, 4%, 3%, 2%, 1% or less of the counter stereoisomer.

The term “substantially pure” as referred in the context of the present invention relates to substance that has purity preferably between about 95% and 100% by HPLC and total impurities between about 2%w/w to a non-detectable limit, more preferably between about 99% and 100% of purity by HPLC and between about 1%w/w and non-detectable limit of the total impurities, and, most preferably, between about 99.9% and 100% of purity by HPLC and about 0.25%w/w to a non-detectable limit of total impurities.

The term “suitable solvent” used in the context of the present invention, is selected from polar or non-polar solvents selected from, but not limited to, the group comprising of alcohol such as N-methyl pyrrolidine, dimethyl formamide, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, polyethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, t-amyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole; ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, methyl t-butyl ketone; esters solvents such as ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate; hydrocarbon such as toluene, xylene, hexane, n-heptane, n-pentane, anisole, ethyl benzene, cyclohexane and the like; nitriles such as acetonitrile, propionitrile, butanenitrile; acetic acid; water; and mixtures thereof.

According to one embodiment, the present invention provides an amorphous form of viloxazine, pharmaceutically acceptable salt, isomers thereof, wherein said amorphous form is stable for atleast six months at 20±5oC and 30±5% RH, 25±5oC and 60±5% RH, as well as at 40±5oC and 75±5% RH.

In another embodiment, the present invention provides a process for the preparation of an amorphous form of viloxazine or pharmaceutically acceptable salt thereof comprising the steps of:
a) adding viloxazine or pharmaceutically acceptable salt thereof to a suitable solvent, wherein said viloxazine or pharmaceutically acceptable salt thereof is either racemic or enantiomerically pure isomer selected from S(-) and R(+)-isomer;
b) optionally heating at a suitable temperature; and
c) lyophilizing and isolating to get the amorphous form of viloxazine or pharmaceutically acceptable salt thereof.

Between the two stereoisomers, the (S)-(-)-isomer is known to be five folds pharmacologically active than the (R)-(+)-isomer. See, e.g., “Optical Isomers of 2-(2-ethoxyphenoxymethyl)tetrahydro-1,4 oxazine (viloxazine) and Related Compounds” from Journal of Medicinal Chemistry, Jan. 9, 1976, 19(8); 1074.

In another embodiment, the amorphous form of viloxazine or pharmaceutically acceptable salt thereof comprises enantiomerically pure S(-)-isomer, wherein the counter R(+)-stereoisomer is less than about 15% w/w, preferably less than about 10% w/w, and more preferably less than about 8% w/w.

In another embodiment, the present invention provides a process for the preparation of an amorphous form of S(-)-viloxazine hydrochloride comprising the steps of:
a) adding S(-)-viloxazine hydrochloride to a suitable solvent;
b) optionally heating at a suitable temperature; and
c) lyophilizing and isolating to get the amorphous form of S(-)-viloxazine hydrochloride.

In another embodiment, the present invention provides a process for the preparation of amorphous form of viloxazine, or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of viloxazine or its pharmaceutically acceptable salt in a suitable solvent, wherein said viloxazine or its pharmaceutically acceptable salt is either racemic or enantiomerically pure isomer selected from S(-) or R(+)-isomer;
b) optionally heating the solution of step a); and
c) isolating the amorphous form of viloxazine or pharmaceutically acceptable salt or enantiomerically pure isomer thereof.

In another embodiment, the present invention provides a process for the preparation of an amorphous form of viloxazine or pharmaceutically acceptable salt thereof, comprising the steps of:
a) adding viloxazine or pharmaceutically acceptable salt thereof in one or more suitable solvent;
b) optionally heating at a suitable temperature; and
c) isolating the amorphous form of viloxazine hydrochloride.

In one another embodiment, the present invention provides a process for preparing amorphous form of viloxazine hydrochloride, wherein said process comprising of:
a) dissolving viloxazine hydrochloride in a suitable solvent and treating with suitable base to form viloxazine free base at a suitable temperature;
b) treating the viloxazine free base with aqueous or alcoholic hydrochloric acid to form viloxazine hydrochloride; and
c) removing the solvent to get amorphous form of viloxazine hydrochloride.

In another embodiment, the present application provides pharmaceutical composition comprising amorphous form of viloxazine hydrochloride, and atleast one pharmaceutically acceptable excipient, wherein said viloxazine hydrochloride is either racemic or enantiomerically pure isomer selected from S(-) and R(+)-isomer.

In one more embodiment, the present invention provides a substantially pure amorphous form of viloxazine and pharmaceutically acceptable salts thereof, wherein said amorphous form is substantially free from crystalline form.

In another embodiment, the present invention provides amorphous form of viloxazine or pharmaceutically acceptable salt thereof, substantially free from epichlorohydrin, 1-(2-ethoxyphenoxy)-2,3-epoxypropane, and 2-aminoethyl hydrogen sulfate wherein each impurity is less than about 0.5µg.

In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of viloxazine, or pharmaceutically acceptable salt thereof, comprising the steps of:
a) adding viloxazine or its pharmaceutically acceptable salt in a suitable solvent, wherein said viloxazine or its pharmaceutically acceptable salt is either racemic or enantiomerically pure isomer selected from S(-) or R(+)-isomer;
b) adding atleast one pharmaceutically acceptable carrier to the solution obtained in step a); and
c) isolating to get amorphous solid dispersion of viloxazine or pharmaceutically acceptable salt thereof.

In another embodiment, the hydrates is a pseudo, mono-, di-, or trihydrate. Alternatively, the salt of the invention is anhydrous that includes, but are not limited to, viloxazine hydrochloride, viloxazine maleate salt, viloxazine sulfonate, viloxazine oxalate, viloxazine tartarate and viloxazine palmoate salt.

In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of S(-)-viloxazine or its pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of amorphous form of S(-)-viloxazine or its pharmaceutically acceptable salt in a suitable solvent;
b) adding atleast one pharmaceutically acceptable carrier; and
c) removing the solvent and isolating to get amorphous solid dispersion of viloxazine or its pharmaceutically acceptable salt thereof.

In a preferred embodiment, the amorphous solid dispersion of viloxazine or its pharmaceutically acceptable salt is prepared either by using amorphous or crystalline viloxazine or its pharmaceutically acceptable salt wherein said viloxazine or its salt is enantiomerically pure S(-)-isomer, wherein the counter R(+)-stereoisomer is less than about 15% w/w, preferably less than about 10% w/w, and more preferably less than about 8% w/w.

In another embodiment, the present invention provides a process for the preparation of a premix of viloxazine or pharmaceutically acceptable salt thereof, comprising the steps of:
a) adding viloxazine or pharmaceutically acceptable salt thereof, to atleast one pharmaceutically acceptable carrier to get a solid mass;
b) optionally adding solvent to get a solution; and
c) isolating the premix of viloxazine or pharmaceutically acceptable salt thereof, either by removal of solvent from solution of step b) or by isolating the solid mass of step a), wherein said viloxazine or its pharmaceutically acceptable salt is either racemic or enantiomerically pure isomer selected from S(-) or R(+)-isomer.

In another embodiment, the present invention provides a process for the preparation of a premix of viloxazine or pharmaceutically acceptable salt thereof, wherein said process comprises grinding of viloxazine or its pharmaceutically salt with atleast one pharmaceutically acceptable carrier, wherein said viloxazine or its salt is either racemic or enantiomerically isomer selected from S(-) or R(+)-isomer.

In another embodiment, the viloxazine and the pharmaceutically acceptable carriers may be dissolved either in the same solvent or they may be dissolved in different solvents and then combined to form a mixture. In embodiments, the solid dispersion described herein comprises amorphous or crystalline viloxazine or its salt, wherein viloxazine is either anhydrous, hydrate or solvate in nature; and the carrier present in weight ratios ranging from about 1:99 to about 99:1. Preferably, the ratio is about 50:50. In some embodiments, the solid dispersion described herein comprises one or more pharmaceutically acceptable carrier.

The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 100°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of viloxazine or its pharmaceutically acceptable salt is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow.

In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of viloxazine or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of viloxazine or pharmaceutically acceptable salt thereof in a suitable solvent;
b) adding at least one pharmaceutically acceptable carrier to the solution obtained in step a); and
c) isolating to get amorphous solid dispersion of viloxazine or pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of viloxazine or pharmaceutically acceptable salt thereof, wherein said viloxazine or its pharmaceutically acceptable salt is mixed with pharmaceutically acceptable water soluble carrier at ambient temperature.

In another embodiment, the present invention provides an amorphous solid dispersion wherein said viloxazine or its pharmaceutically acceptable salt is either anhydrous, hydrate or solvate in nature.

In preferred embodiment, the present invention provides a simple process which comprises mixing a viloxazine or its pharmaceutically acceptable salt and a water-soluble carrier together under no more than the usual agitation force with heating within the temperature region not melting them, making the water-soluble viloxazine or its pharmaceutically acceptable salt as amorphous in nature to thereby yield a solid dispersion insuring very high solubility and bioavailability which have never been achieved by any dry process heretofore known.

In preferred embodiment, the solid dispersion is a substance obtained by dispersing viloxazine or its pharmaceutically acceptable salt into a carrier in a mono-molecular state. In this dispersion, the viloxazine or its pharmaceutically acceptable salt remains in a completely amorphous state. Generally, the amorphous form is in a higher energetic state compared to the crystalline form and is therefore expected to have a higher absorptivity.

In another embodiment, the present application provides a pharmaceutical composition comprising a solid dispersion of viloxazine or pharmaceutically acceptable salt thereof, together with atleast one pharmaceutically acceptable excipient.

In another embodiment, the present invention provides substantially pure solid dispersion of viloxazine or its pharmaceutically acceptable salt wherein said viloxazine or its pharmaceutically acceptable salt is free from epichlorohydrin, 1-(2-ethoxyphenoxy)-2,3-epoxypropane, and 2-aminoethyl hydrogen sulfate wherein each impurity is less than about 0.5µg.

The pharmaceutical composition of the present invention may be formulated in accordance with conventional methods, and may be prepared in the form of oral formulations such as tablets, pills, powders, capsules, syrups, emulsions, micro emulsions, and others, or formulation for parenteral injection, e.g., intramuscular, intravenous, or subcutaneous administration. The pharmaceutical composition of the present invention may comprise the inventive solid dispersion or premix, and any possible excipient.

In another embodiment, the present application provides a solid dispersion of viloxazine, or pharmaceutically acceptable salt thereof, with less than 5% of crystallinity, preferably with less than 1% crystallinity and more preferably with less than 0.5% crystallinity as per X-ray diffraction analysis.

In another embodiment, a solution of viloxazine or pharmaceutically acceptable salt thereof used to prepare amorphous solid dispersion/ premix/ amorphous form of viloxazine or its pharmaceutically acceptable salt, may be prepared by dissolving viloxazine or pharmaceutically acceptable salt thereof in a suitable solvent or by taking the reaction mixture containing viloxazine or a salt thereof directly.

In preferred embodiment, amorphous form of viloxazine or pharmaceutically acceptable salt thereof may be combined with carrier either by physical blending of both the solid components or by suspending both the components in a suitable solvent and conditions, such that both the components remain unaffected. Blending may be carried out using techniques known in art such as rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure / vacuum or inert atmosphere such nitrogen at suitable temperature and sufficient time to obtain uniform composition of amorphous form of viloxazine or pharmaceutically acceptable salt thereof and atleast one pharmaceutically acceptable carrier.

In another embodiment, pharmaceutically acceptable carrier used for preparing solid dispersion may include, but not limited to, an inorganic oxide such as SiO2, TiO2, ZnO2, ZnO, Al2O3 and zeolite; a water insoluble carrier is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene glycol, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolat, and cross-linked styrene divinyl benzene or any other carrier at any aspect of present application. In an embodiment, atleast one pharmaceutically acceptable carrier may be selected from the group consisting of Eudragit FS 30 D (poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid)), Eudragit L 30 D-55 (methacrylic acid-ethyl acrylate copolymer), Eudragit RL (poly(ethyl acrylate-co-methyl methacrylate-cotrimethylammonioethyl methacrylate chloride)), Eudragit NE 30 D and Eudragit NM 30 D (poly(ethyl acrylate-co-methyl methacrylate)), Eudragit L and S (poly(methacrylic acid-co-methyl methacrylate), polyvinyl pyrrolidone, PEG glyceryl esters, glyceryl behenate; glyceryl palmitostearate, poly(ethyl acrylate-co-methyl methacrylate) ethyl acrylate methyl methacrylate copolymer, povidone K-30, povidone K-60, Povidone K-90, L-HPC, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, acacia, carrageenan, xanthan gum, tragacanth, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxy methyl ethyl cellulose and the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, shellac, zein, alginic acid, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other carrier at any aspect of present invention. The pharmaceutical acceptable carrier further includes Hydrophobic compounds such as ethyl cellulose, cellulose acetate, cellulose acetate butyrate, waxes (e.g., carnauba wax,microcrystalline wax), hydrogenated vegetable oils, Compritol 888 ATO (glyceryl behenate), Precirol ATO 5 (glyceryl palmitostearate), PEG glyceryl esters such as Gelucire 50/1. EUDRAGITR NE 30 D or EUDRAGITR NM 30 D (poly(ethyl acrylate-co-methyl methacrylate) ethyl acrylate methyl methacrylate copolymer), EUDRAGITR) RS and EUDRAGITR) RL (poly(ethyl acrylate-co-methyl methacrylate-cotrimethylammonioethyl methacrylate chloride)), polyvinyl acetate, cellulose acetate propionate, and combinations thereof.

The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention.

Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation.

In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of viloxazine or its pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of amorphous form of viloxazine or its pharmaceutically acceptable salt in a suitable solvent, wherein said viloxazine is either racemic, or enatiomerically pure S(-) or R(+)-isomer;
b) adding poly(ethyl acrylate-co-methyl methacrylate) ethyl acrylate methyl methacrylate copolymer; and
c) removing the solvent and isolating to get amorphous solid dispersion of viloxazine its pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of viloxazine or its pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of amorphous form of viloxazine or its pharmaceutically acceptable salt in a suitable solvent, wherein said viloxazine is either racemic, or enatiomerically pure S(-) or R(+)-isomer;
b) adding poly (ethyl acrylate-co-methyl methacrylate-cotrimethylammonioethyl methacrylate chloride); and
c) removing the solvent and isolating to get amorphous solid dispersion of viloxazine its pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a solid dispersion which is stable at a temperature of about 40oC and at a relative humidity of about 25% to about 75% for about six months and more.

Solid dispersions of the present application also include the solid dispersions obtained by combining viloxazine or pharmaceutically acceptable salt thereof with a suitable non-polymeric carrier by employing techniques known in the art or procedures described or exemplified in any aspect of the instant application.

In another embodiment, the present invention provides amorphous form of viloxazine or pharmaceutically acceptable salt thereof, its solid dispersion comprising viloxazine or pharmaceutically acceptable salt thereof, wherein said viloxazine or pharmaceutically acceptable salt thereof is having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.

In another embodiment, the amorphous solid dispersion of viloxazine or pharmaceutically acceptable salt thereof, obtained by the process of the present invention is characterized by particle size distribution (D90) of less than about 2000µm, preferably less than about 1000µm, more preferably less than about 500 µm, and most preferably about 100µm.

In another embodiment, viloxazine or pharmaceutically acceptable salt thereof, as described in present invention can be used in any form selected from R-isomer , S-isomer or racemic mixture thereof.

In another embodiment, the amorphous form of viloxazine or pharmaceutically acceptable salt thereof, obtained by the process of the present invention is characterized by particle size distribution (D90) of less than about 200µm, preferably less than about 150µm, more preferably less than about 50 µm, and most preferably about 20µm.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

EXAMPLES
Example-1: Preparation of amorphous form of Viloxazine hydrochloride
Viloxazine hydrochloride (0.4 g) was dissolved in ethanol (20 mL) at 40°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C. The obtained product was re-dissolved in ethanol (20 mL) at 40°C and added n-heptane to get precipitates. The precipitates were washed with n-heptane and dried under reduced pressure at 50°C for 20 minutes to obtain title compound.

Example-2: Preparation of amorphous form of Viloxazine hydrochloride
Charged Viloxazine hydrochloride (0.4 g) in water (20 mL) and heated at 70oC. Cooled the solution to room temperature and lyophilized to get the title compound.
Example-2: Preparation of amorphous form of (S)-Viloxazine hydrochloride
Viloxazine hydrochloride (0.4 g) was dissolved in ethyl acetate (50 mL) at 25°C and stirred at60oC to get the reaction mixture for 4-6h. Lyophilized the solution so obtained to get title compound.

Example-3: Preparation of amorphous form of Viloxazine hydrochloride
Charged Viloxazine hydrochloride (0.4 g) in dimethyl formamide (4 mL) at room temperature. Stirred for 1 h and water added dropwise. The precipitated solid was stirred for 15 min. Filtered the precipitates washed with cyclohexane and dried under reduced pressure to get the title compound.

Example-4: Preparation of amorphous solid dispersion of Viloxazine free with poly(ethyl acrylate-co-methyl methacrylate) ethyl acrylate methyl methacrylate copolymer:
A mixture of Viloxazine free base (0.5 g) and poly(ethyl acrylate-co-methyl methacrylate) ethyl acrylate methyl methacrylate copolymer (0.5 g) was dissolved in ethanol (25 mL) at 40°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C to obtain title compound.

Example-5: Preparation of amorphous solid dispersion of Viloxazine with poly (ethyl acrylate-co-methyl methacrylate-cotrimethylammonioethyl methacrylate chloride):
A mixture of viloxazine free base (1.0 g) and poly (ethyl acrylate-co-methyl methacrylate-cotrimethylammonioethyl methacrylate chloride) (1.5 g) was dissolved in water (25 mL) at room temperature and stirred for 1.5 h. The solvent was evaporated in rotavapour under reduced pressure to obtain title compound.

Example-6: Preparation of amorphous solid dispersion of Viloxazine hydrochloride with poly (ethyl acrylate-co-methyl methacrylate-cotrimethylammonioethyl methacrylate chloride):
A mixture of viloxazine hydrochloride (1.0 g) and poly (ethyl acrylate-co-methyl methacrylate-cotrimethylammonioethyl methacrylate chloride) (1.0 g) was dissolved in water (25 mL) at room temperature and stirred for 2 h. The solvent was evaporated in rotavapour under reduced pressure to obtain title compound.

Example-7: Preparation of amorphous solid dispersion of Viloxazine hydrochloride with co-povidone
A mixture of viloxazine free base (1.0 g) and co-povidone (1.0 g) was dissolved in methanol (25 mL) at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C to obtain title compound.

Example-8: Ball mill mixed-grinding process
Using a ball mill (SPEX Industries), a mixture of viloxazine free base (1g), hydroxypropylmethylcellulose (5 g), low-substituted hydroxypropylcellulose (3g) and crystalline cellulose (12 g) was mix-ground for 4 hours to provide a solid dispersion.

Example 9: Preparation of solid dispersion of Viloxazine hydrochloride with more than one pharmaceutically acceptable carrier
To a mixture of hydroxypropylmethylcellulose (1g), low-substituted hydroxypropylcellulose (3 g) and PEG glyceryl esters (5 g) was added a solution of viloxazine hydrochloride (1 g) in absolute ethanol and after stirring at 50oC for two hours, the ethanol was evaporated in vacuum to provide a solid dispersion.

Example 10: Preparation of solid dispersion of Viloxazine hydrochloride with microcrystalline cellulose:
To a mixture of microcrystalline cellulose (1g) in water was added a solution of viloxazine hydrochloride (1 g) in absolute ethanol and after stirring, the solvents were evaporated in vacuum to provide a solid dispersion.

WE CLAIM

1. Amorphous form of viloxazine or pharmaceutically acceptable salt thereof.

2. A process for preparing amorphous form of viloxazine, or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of viloxazine or its pharmaceutically acceptable salt in a suitable solvent, wherein said viloxazine or its pharmaceutically acceptable salt is either racemic or enantiomerically pure isomer selected from S(-) or R(+)-isomer;
b) optionally heating the solution of step a); and
c) isolating the amorphous form of viloxazine or pharmaceutically acceptable salt or enantiomerically pure isomer thereof.

3. The amorphous form as claimed in claim 1, wherein said amorphous form is
stable at a temperature of about 40oC and at a relative humidity of about 25% to
about 75% for about six months and more.

4. Amorphous solid dispersion of viloxazine or pharmaceutically acceptable salt
or isomer thereof, with at least one pharmaceutically acceptable carrier.

5. A process for the preparation of an amorphous solid dispersion of viloxazine or pharmaceutically acceptable salt or isomer thereof as claimed in claim 4, wherein said process comprising the steps of:
a) providing a solution of viloxazine, pharmaceutically acceptable salt, or isomer thereof in a suitable solvent;
b) adding at least one pharmaceutically acceptable carrier to the solution obtained in step a); and
c) isolating to get amorphous solid dispersion of viloxazine or pharmaceutically acceptable salt or isomer thereof.

6. The process as claimed in claim 5, wherein said process further comprising the
steps of:
a) providing a solution of amorphous form of viloxazine or its pharmaceutically acceptable salt in a suitable solvent, wherein said viloxazine is either racemic, or enatiomerically pure S(-) or R(+)-isomer;
b) adding poly(ethyl acrylate-co-methyl methacrylate) ethyl acrylate methyl methacrylate copolymer; and
c) removing the solvent and isolating to get amorphous solid dispersion of viloxazine its pharmaceutically acceptable salt thereof.

7. The process as claimed in claims 5 or 6, wherein said solution of viloxazine or pharmaceutically acceptable salt or isomer thereof may be obtained by dissolving viloxazine or pharmaceutically acceptable salt or isomer thereof in a suitable solvent or by directly taking the reaction mixture containing viloxazine or its pharmaceutically acceptable salt.

8. The amorphous solid dispersion as claimed in claim 4, wherein said solid dispersion is stable at a temperature of about 40oC and at a relative humidity of about 25% to about 75% for about six months and more.

9. Composition comprising viloxazine or pharmaceutically acceptable salt or isomer thereof, and atleast one pharmaceutically acceptable excipient, wherein said viloxazine or pharmaceutically acceptable salt thereof is selected from amorphous form or solid dispersion of viloxazine.

10. A method for preparation of composition comprising viloxazine or pharmaceutically acceptable salt or isomer thereof as claimed in claim 9, wherein said composition is prepared by combining either amorphous form or solid dispersion of viloxazine.