FIELD OF INVENTION

The present application relates to amorphous lorcaserin hydrochloride, amorphous solid dispersion comprising lorcaserin hydrochloride and process for preparation thereof.

BACKGROUND

Lorcaserin is chemically described as (R)-8-chloro-1-methyl-2, 3, 4, 5-tetrahydro-1H-3-benzazepine. It has the chemical structure of formula (I).

(I)
Lorcaserin hydrochloride is an agonist of the 5-HT2C receptor and shows effectiveness at reducing obesity in animal models and humans. Further, 5-HT2C receptor is recognized as a well-accepted receptor target for the treatment of obesity, psychiatric, and other disorders.

The occurrence of different solid forms is possible for some compounds. A single compound may give rise to a variety of solid forms having distinct physical properties. This variation in solid forms may be significant and may result in differences in pharmaceutical products with respect to solubility, bioavailability, stability and other properties. Because solid forms may vary in their physical properties, regulatory authorities require that efforts shall be made to identify all possible solid forms, e.g., crystalline, amorphous, solvated, etc., of new drug substances.

The existence and possible number of solid forms for a given compound cannot be predicted, and there are no “standard” procedures that may be used to prepare solid forms of a substance. However, new forms of a pharmaceutically useful compound may provide an opportunity to improve the performance characteristics of pharmaceutical products. For example, in some cases, different forms of the same drug may exhibit very different solubility and dissolution rates. The discovery of new solid forms enlarges selection of materials with which formulation scientists may design a pharmaceutically acceptable dosage form of a drug with a targeted release profile or other desired characteristics.

Amorphous form of lorcaserin hydrochloride resulted in drug substance with limited physical stability. For example, amorphous lorcaserin hydrochloride tends to crystallize over a period of time. It has been surprisingly found that preparing amorphous solid dispersion comprising lorcaserin hydrochloride possesses significant physical stability improvements over amorphous lorcaserin hydrochloride alone.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an illustration of powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion comprising lorcaserin hydrochloride prepared in accordance with Example 8.

Figure 2 is an illustration of powder X-ray diffraction (PXRD) pattern of amorphous lorcaserin hydrochloride prepared in accordance with Example 12.

Figure 3 is an illustration of powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion comprising lorcaserin hydrochloride prepared in accordance with Example 13.

Figure 4 is an illustration of powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion comprising lorcaserin hydrochloride prepared in accordance with Example 14.

Figure 5 is an illustration of powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion comprising lorcaserin hydrochloride prepared in accordance with Example 15.

SUMMARY

In first embodiment, the present application provides an amorphous form of lorcaserin hydrochloride.

In second embodiment, the present application provides an amorphous form of lorcaserin hydrochloride characterized by X-ray powder diffraction pattern substantially as illustrated by Figure 2.

In third embodiment, the present application provides a process for the preparation of amorphous form of lorcaserin hydrochloride, comprising:

a) providing a solution of lorcaserin hydrochloride in a solvent; and

b) isolating amorphous form of lorcaserin hydrochloride.

In fourth embodiment, the present application provides pharmaceutical composition comprising amorphous form of lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers.

In fifth embodiment, the present application provides amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers.

In sixth embodiment, the present application provides amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers characterized by X-ray powder diffraction pattern substantially as illustrated by Figure 1, Figure 3 or Figure 4.

In seventh embodiment, the present application provides a process for preparing an amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers, comprising the steps of:

a) dissolving or dispersing lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers in a suitable solvent or mixture of solvents; and

b) isolating an amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers.

In eighth embodiment, the present application provides a process for preparing an amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers, comprising the steps of:

(a) dissolving or dispersing lorcaserin hydrochloride under heating in one or more pharmaceutically acceptable carriers; and

(b) cooling down the mixture.

In ninth embodiment, the present application provides a process for preparing an amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers, comprising the steps of:

(a) dissolving or dispersing lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers in a suitable solvent or mixture of solvents;

(b) spray drying the mixture to obtain the said amorphous solid dispersion.

In tenth embodiment, the present application provides pharmaceutical composition comprising amorphous solid dispersion of lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers.

In eleventh embodiment, the present application provides a pharmaceutical composition comprising amorphous form of lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers for treating disorders including depression, atypical depression, bipolar disorders, anxiety disorders, obsessive-compulsive disorders, social phobias or panic states, sleep disorders, sexual dysfunction, psychoses, schizophrenia, migraine and other conditions associated with cephalic pain or other pain, raised intracranial pressure, epilepsy, personality disorders, age-related behavioral disorders, behavioral disorders associated with dementia, organic mental disorders, mental disorders in childhood, aggressivity, agerelated memory disorders, chronic fatigue syndrome, drug and alcohol addiction, obesity, bulimia, anorexia nervosa and premenstrual tension.

In twelfth embodiment, the present application provides a pharmaceutical composition comprising amorphous solid dispersion of lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers for treating disorders including depression, atypical depression, bipolar disorders, anxiety disorders, obsessive-compulsive disorders, social phobias or panic states, sleep disorders, sexual dysfunction, psychoses, schizophrenia, migraine and other conditions associated with cephalic pain or other pain, raised intracranial pressure, epilepsy, personality disorders, age-related behavioral disorders, behavioral disorders associated with dementia, organic mental disorders, mental disorders in childhood, aggressivity, agerelated memory disorders, chronic fatigue syndrome, drug and alcohol addiction, obesity, bulimia, anorexia nervosa and premenstrual tension.

DETAILED DESCRIPTION

Unless indicated, the solid state forms of the present invention may be dried. Drying may be carried out, for example, at elevated temperature with or without reduced pressure.

Drying may be suitably carried out in a tray dryer, vacuum oven, Büchi® Rotavapor®, air oven, fluidized bed dryer, spin flash dryer, flash dryer, cone dryer, agitated nutsche filter cum dryer, nauta dryer or the like or any other suitable dryer.

The drying may be carried out at temperature of less than about 150°C, or less than about 120°C, or less than about 100°C, or less than about 70°C, or less than about 60°C, or less than about 50°C, or less than about 40°C, or less than about 20°C, or less than about 0°C, or less than about -20°C or any other suitable temperature. The drying may be carried out under reduced pressure, that is, less than standard atmospheric pressure or at atmospheric pressure or any other suitable pressure. The drying may take place over a period of about 30 minutes to about 12 hours, or about 2 hours to about 4 hours, or any other suitable time period.

The dried product may be optionally subjected to techniques such as sieving to get rid of lumps before or after drying. The dried product may be optionally milled to get desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer mills, and jet mills.

A solid that is in the "amorphous" solid state form means that it is in a non-crystalline state. Amorphous solids generally possess crystal-like short range molecular arrangement, but no long range order of molecular packing as are found in crystalline solids. The solid state form of amorphous solid can be determined by X-Ray Powder Diffraction (XPRD), or other standard techniques known to those skilled in the art.

In general, the term "solid dispersion" refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components.

The term "amorphous solid dispersion" as used herein, refers to solid dispersion which is substantially amorphous, that is, at least 80%, preferably at least 90%, most preferably at least 95%, is in amorphous form as determined by X-Ray Powder Diffraction (XPRD). Lorcaserin hydrochloride used for the preparation of amorphous solid dispersion can be crystalline or amorphous.

An “alcohol solvent” is an organic solvent containing a carbon bound to a hydroxyl group. “Alcoholic solvents” include, but are not limited to, 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, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, C1-6 alcohols, or mixtures thereof.

An “aliphatic or alicyclic hydrocarbon solvent” refers to a liquid, non-aromatic, hydrocarbon, which may be linear, branched, or cyclic. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of a hydrocarbon solvents include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, C5-C8 aliphatic hydrocarbons, petroleum ethers, or mixtures thereof.

“Aromatic hydrocarbon solvent” refers to a liquid, unsaturated, cyclic, hydrocarbon containing one or more rings which has at least one 6-carbon ring containing three double bonds. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of aromatic hydrocarbon solvents include, but are not limited to, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-C10aromatic hydrocarbons, or mixtures thereof.

An “ester solvent” is an organic solvent containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “Ester solvents” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, C3-6 esters, or mixtures thereof.

A “halogenated hydrocarbon solvent” is an organic solvent containing a carbon bound to a halogen. “Halogenated hydrocarbon solvents” include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or mixtures thereof.

A “ketone solvent” is an organic solvent containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “Ketone solvents” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C3-6 ketones, 4-methyl-pentane-2-one or mixtures thereof.
A “nitrile solvent” is an organic solvent containing a cyano -(C?N) bonded to another carbon atom. “Nitrile solvents” include, but are not limited to, acetonitrile, propionitrile, C2-6 nitriles, or mixtures thereof.

A “polar aprotic solvent” has a dielectric constant greater than 15 and is at least one selected from the group consisting of amide-based organic solvents, such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), formamide, acetamide, propanamide, hexamethyl phosphoramide (HMPA), and hexamethyl phosphorus triamide (HMPT); nitro-based organic solvents, such as nitromethane, nitroethane, nitropropane, and nitrobenzene; pyridine-based organic solvents, such as pyridine and picoline; sulfone-based solvents, such as dimethylsulfone, diethylsulfone, diisopropylsulfone, 2-methylsulfolane, 3-methylsulfolane, 2,4-dimethylsulfolane, 3,4-dimethy sulfolane, 3-sulfolene, and sulfolane; and sulfoxide-based solvents such as dimethylsulfoxide (DMSO).
An “ether solvent” is an organic solvent containing an oxygen atom –O- bonded to two other carbon atoms. “Ether solvents” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, C2-6 ethers, or the like.

As used herein, “comprising” (open-ended) means the element or elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open-ended. As used herein, “consisting essentially of” means that the application may include elements in addition to those recited in the claim, but only if the additional elements do not materially alter the basic and novel characteristics. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

In third embodiment, the present application provides a process for the preparation of amorphous form of lorcaserin hydrochloride, comprising:
a) providing a solution of lorcaserin hydrochloride in a suitable solvent or mixtures thereof; and

b) isolating amorphous form of lorcaserin hydrochloride.
Providing a solution of lorcaserin hydrochloride in step a) includes:

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

ii) dissolving lorcaserin hydrochloride in a solvent.

Any physical form of lorcaserin hydrochloride may be utilized for providing the solution of lorcaserin hydrochloride in step a). The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 60°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 lorcaserin hydrochloride 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. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature precipitation.
In embodiments, lorcaserin hydrochloride may be dissolved in any suitable solvent. Suitable solvents include any solvents that have no adverse effect on the compound and may dissolve the starting material to a useful extent. Examples of such solvents include, but are not limited to: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, or diethyl ketone; esters, such as ethyl acetate, propyl acetate, isopropyl acetate, or butyl acetate; alcohols, such as methanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, cyclohexanol, glycerol, or C1-C6 alcohols; nitriles, such as acetonitrile or propionitrile; amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or hexamethyl phosphoric triamide; sulfoxides, such as dimethylsulfoxide; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, or chlorobenzene; aromatic hydrocarbons, such as toluene; or any mixtures of two or more thereof.

Step b) involves isolating amorphous form of lorcaserin hydrochloride from the solution obtained in step a). Isolation of amorphous form of lorcaserin hydrochloride in step b) may involve methods including removal of solvent, crash cooling, flash evaporation, rotational drying, spray drying, thin-film drying, agitated nutsche filter drying or any other suitable technique. The amorphous form of lorcaserin hydrochloride as isolated may carry some amount of occluded mother liquor and may have higher than desired levels of impurities. If desired, this amorphous form may be washed with a solvent or a mixture of solvents to wash out the impurities.

Suitable temperatures for isolation may be less than about 120°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -40°C or any other suitable temperatures.
The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or any other suitable dryer. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the lorcaserin hydrochloride is not degraded in its quality. Optionally drying may be carried out using an inert gas such as nitrogen or argon. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling.

In fourth embodiment, the present application provides pharmaceutical composition comprising amorphous form of lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers.

In fifth embodiment, the present application provides amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers.

In sixth embodiment, the present application provides an amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers characterized by X-ray powder diffraction pattern substantially as illustrated by Figure 1, Figure 3 or Figure 4.

Pharmaceutically acceptable carriers include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol, inositol, trehalose, maltose, raffinose, a-, ß- and ?-cyclodextrins, gum arabic, sodium alginate, propylene glycol alginate, agar, gelatin, tragacanth, xanthan gum, starch, lectins, urea, chitosan, chitosan glutamate, hydroxypropyl ß-cyclodextrin chitosan, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose (MC), cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMC-P), hydroxylpropyl methylcellulose acetate succinate (HPMC-AS), carboxymethylethylcellulose (CMEC), carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate butyrate, hydroxyethyl cellulose, ethyl cellulose, co-(lactic/glycolic)copolymers, poly(orthoester), polyvinyl chloride, polyvinyl acetate, ethylene vinyl acetate, carbopols, silicon elastomers, polyacrylic polymers, polyvinylacetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, aminoalkyl methacryl copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, and carboxylvinyl polymer, polyvinylpyrrolidones (homopolymers or copolymers of N-vinyl pyrrolidone), polyethyleneglycols of various molecular weights, polyethylene-/polypropylene-/polyethylene-oxide block copolymers, polymethacrylates, polyvinylalcohol (PVA) and co-polymers thereof with PVP or with other polymers, polyacrylates, hypromellose phthalates, polyhydric alcohols, polyethylene glycols, polyethylene oxides, polyoxyethylene derivatives, 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; diluents such as starches and derivative thereof, e.g. dextrin, pullulan, corn startch and potato starch pregelatinized starches; lactose, sucrose, glucose, reduced maltose, mannitol, sorbitol, xylitol, trehalose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, crystalline cellulose/carmellose sodium, hydroxypropyl cellulose, magnesium aluminometasilicate, silicon dioxide, light anhydrous silicic acid or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches or the like;

disintegrants such as hydroxypropyl cellulose, low-substituted
hydroxypropyl cellulose, croscarmellose sodium, a starch, methylcellulose, sodium alginate, sodium carboxymethyl starch, carmellose calcium, carmellose sodium, crystalline cellulose and crystalline cellulose/carmellose sodium, sodium starch glycolate, pregelatinized starches, crospovidones, colloidal silicon dioxide or the like; lubricants such as stearic acid, magnesium stearate, talc, light anhydrous silicic acid, calcium stearate, zinc stearate, magnesium oxide, sodium lauryl sulfate, sodium stearyl fumarate, magnesium aluminometasilicate or the like; flavoring agents such as sucrose, aspartame, mannitol, dextran, saccharin, menthol, citric acid, tartaric acid, malic acid, ascorbic acid, sweet hydrangea leaves, fennel, ethanol, fructose, xylitol, glycyrrhizinic acid, purified sucrose, L-glutamine, cyclodextrin, peppermint, methyl salicylate or the like; surfactants such as sodium lauryl sulfate, polysolvate 80, sucrose fatty acid ester, polyoxyl 40 stearate, polyoxyethylene 60 hydrogenated castor oil, sorbitan monostearate, sorbitan monopalmitate or the like; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes or the like. Other pharmaceutically acceptable carriers that can be used include, but are not limited to, film formers, plasticizers, colorants, viscosity enhancers, preservatives, antioxidants, or the like.

The use of mixtures of more than one of the pharmaceutical acceptable carriers 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.

Any suitable quantity of pharmaceutical acceptable carriers can be used for the preparation of the said amorphous solid dispersion. For example, about 0.1, about 0.5, about 1.0, about 2.0, about 3.0, about 4.0, about 5.0, about 6.0, about 7.0, about 8.0, about 9.0 or about 10.0 portions by weight of pharmaceutical acceptable carriers can be used per one portion by weight of lorcaserin hydrochloride.

In seventh embodiment, the present application provides a process for preparing an amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers, comprising the steps of:

a) dissolving or dispersing lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers in a suitable solvent or mixtures thereof; and

b) isolating an amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers.
Lorcaserin hydrochloride used in step (a) includes, direct use of a reaction mixture containing lorcaserin hydrochloride obtained in the course of its manufacture, if desired, after addition of one or more pharmaceutically acceptable carriers. Optionally, lorcaserin hydrochloride can be dissolved or dispersed in a suitable solvent or mixture of solvent, either alone followed by addition of one or more pharmaceutically acceptable carriers, or in combination with one or more pharmaceutically acceptable carriers. Optionally, auxillaries such as diluents or disintegrant can be added during dissolution or dispersion.

Any physical form of lorcaserin hydrochloride, such as crystalline, amorphous or their mixtures can be utilized in step a.

The dissolution temperatures can range from about 0°C to about the reflux temperature of the solvent, less than about 100°C, less than about 90°C, less than about 80°C, less than about 70°C, less than about 60°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 lorcaserin hydrochloride is obtained without affecting its quality.

The solution can 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 can be filtered to remove any insoluble particles. The insoluble particles can be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution can 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. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus can need to be preheated to avoid premature precipitation.

When the solution or dispersion of lorcaserin hydrochloride is prepared together with a pharmaceutically acceptable carrier, the order of charging different materials to the solution is not critical for obtaining the desired solid dispersion. A specific order may be preferred with respect to the equipment being used and will be easily determined by a person skilled in the art. Lorcaserin hydrochloride or pharmaceutically acceptable carrier may be completely soluble in the solvent or they may form dispersion. In embodiments, lorcaserin hydrochloride and the pharmaceutically acceptable carrier may be separately dissolved either in the same solvent or in different solvents, and then combined to form a mixture.

Suitable solvents that can be used in step a) include, but are not limited to, water; alcohol; ketone; halogenated hydrocarbon; ester; ether; nitrile; polar aprotic; or mixtures thereof.

Isolation of an amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers in step

b) can involve methods including removal of solvent, crash cooling, flash
evaporation, rotational drying, spray drying, thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or any other suitable technique. An amorphous solid dispersion as isolated can carry some amount of occluded mother liquor and may have higher than desired levels of impurities. If desired, amorphous solid dispersion may be washed with a solvent or a mixture of solvents to wash out the impurities.

Suitable temperatures for isolation may be less than about 120°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -40°C or any other suitable temperatures.
Isolation may be carried out by freeze drying (lyophilization) the solution at low temperatures and reducing the pressure to remove the solvent from the frozen solution. Temperatures that may be required to freeze the solution, depending on the solvent chosen to make the solution, may range from about -80°C to about 20°C. Temperatures that may be required to remove the solvent from the frozen solution may be less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.

Optionally, isolation may be effected by combining a suitable anti-solvent with the solution obtained in step a). Anti-solvent as used herein refers to a liquid in which lorcaserin hydrochloride is less soluble or poorly soluble. An inert anti-solvent has no adverse effect on the reaction and it may assist in the solidification or precipitation of the dissolved starting material. Suitable anti-solvents that may be used include, but are not limited to: saturated or unsaturated, linear or branched, cyclic or acyclic, C1 to C10 hydrocarbons, such as heptanes, cyclohexane, or methylcyclohexane; water; or any mixtures thereof.

The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the lorcaserin hydrochloride is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling.

In eighth embodiment, the present application provides a process for preparing an amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers, comprising the steps of:

(a) dissolving or dispersing lorcaserin hydrochloride under heating in one or more pharmaceutically acceptable carriers; and

(b) cooling down the mixture.
The methods for dissolving or dispersing lorcaserin hydrochloride include stirring by heating up to or higher than the melting point or the softening point of lorcaserin hydrochloride or pharmaceutically acceptable carrier(s). Optionally, pressure can be applied using kneading machine along with heating. Plasticizers such as, polyethyleneglycol, sucrose fatty acid ester, glycerine fatty acid ester, propylene glycol, triethyl citrate, castor oil and triacetin; and surfactants, e.g. sodium lauryl sulfate, polysolvate 80, sucrose fatty acid ester, polyoxyl 40 stearate, polyoxyethylene 60 hydrogenated castor oil, sorbitan monostearate, and sorbitan monopalmitate can be added as additives.

The amorphous solid dispersion by the melt method can be produced using agitation granulators with heating, for example. More concretely, a mixture of lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers can be prepared in advance. The above plasticizers or surfactants may be added to the mixture, if necessary. The conditions such as the treatment temperature and time vary depending on pharmaceutical carrier(s), additives and the like. The treatment temperature can be within the range of room temperature to about 300° C.; and the treatment time can be within the range of a few minutes to several hours. The cooling temperature can be within the range of about -100 °C to room temperature.

In ninth embodiment, the present application provides a process for preparing an amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers, comprising the steps of:

(c) dissolving or dispersing lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers in a suitable solvent or mixture of solvents;

(d) spray drying the mixture to obtain the said amorphous solid dispersion.

Suitable solvents that can be used during spray drying include, but are not limited to, water; alcohol; ketone; halogenated hydrocarbon; ester; ether; nitrile; polar aprotic; or mixtures thereof.

The spray drying technique involves dissolving lorcaserin hydrochloride and one or more pharmaceutically acceptable excipients in suitable solvent or mixtures thereof. The solution may be spray dried at 40 to 100°C inlet temperature, at a feed rate of 3 ml/min. to 15 ml/minute and at 4.5 to 6.5 kg/cm2 atomization pressure.

In tenth embodiment, the present application provides pharmaceutical composition comprising amorphous solid dispersion of lorcaserin hydrochloride and pharmaceutically acceptable carriers.

In an embodiment, the present application provides pharmaceutical composition comprising amorphous form of lorcaserin hydrochloride and pharmaceutically acceptable carriers.

Amorphous form of lorcaserin hydrochloride or amorphous solid dispersion comprising lorcaserin hydrochloride may be further formulated as: solid oral dosage forms such as, but not limited to: powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions.

Formulations may be in the forms of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The formulation may be prepared using techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Formulation may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.

Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided for purposes of illustration and should not be construed as limiting the scope of the present invention in any manner.

All PXRD data reported herein are obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer or a PANalytical X-ray Diffractometer, using copper Ka radiation wavelength 1.5418Å.

EXAMPLES
Example 1: Preparation of amorphous solid dispersion comprising lorcaserin hydrochloride and PVP-k-30:

Lorcaserin hydrochloride (1.0 g) and PVP-K-30 (1.0 g) were taken in methanol (50 ml) and stirred at room temperature for 15 minutes to obtain a clear solution. The resulting solution was subjected to distillation under reduced pressure at 70 to 80°C for 30-45 minutes and further dried at 90-95°C for 1 hour to obtain amorphous solid dispersion comprising lorcaserin hydrochloride.

Example 2: Preparation of amorphous solid dispersion comprising lorcaserin hydrochloride and PVP-k-30.

Lorcaserin hydrochloride (1.0 g) and PVP-K-30 (1.0 g) were taken in dichloromethane (25 ml) and stirred at room temperature for 10 minutes to obtain a clear solution. The resulting solution was subjected to distillation under reduced pressure at 50 to 70°C for 15-20 minutes and further dried at 90-95°C for 1 hour. Material was unloaded and dried in air tray drier at 90°C for 2 to 3 hours to obtain amorphous solid dispersion comprising lorcaserin hydrochloride.

Example 3: Preparation of amorphous solid dispersion comprising lorcaserin hydrochloride and PVP-k-30.

Lorcaserin Hydrochloride (12.5 g) and PVP-K-30 (37.5 gm) was taken in methanol (400 ml) and stirred at room temperature for 15 minutes to obtain a clear solution. The solution was filtered to obtain a particle free solution. The resulting solution was spray dried at below mentioned parameters to obtain amorphous solid dispersion comprising lorcaserin hydrochloride.

Operation parameters:
Aspirator : 80%
Feed rate : 20 %
Inlet nitrogen temperature : 70°C
Outlet temperature : 47-48°C
Atomisation Pressure : 5.0 kg/cm2

Example 4: Preparation of amorphous solid dispersion comprising lorcaserin hydrochloride and PVP-k-30.

Lorcaserin hydrochloride (500 mg) and PVP-K-30 (1.5 g) were taken in methanol (30 ml) and stirred at room temperature for 10 minutes to obtain a clear solution. The resulting solution was subjected to distillation under reduced pressure at 70°C for 30-45 minutes to obtain amorphous solid dispersion comprising lorcaserin hydrochloride.

Example 5: Preparation of amorphous solid dispersion comprising lorcaserin hydrochloride and HPMC-AS.

Lorcaserin hydrochloride (1.0 g) and HPMC-AS (1.0 g) were taken in methanol (100 ml) and stirred at room temperature for 15 minutes to obtain a clear solution. The resulting solution was subjected to distillation under reduced pressure at 70-80°C for 15-20 minutes and further dried at 90-95°C for 1 hour to obtain amorphous solid dispersion comprising lorcaserin hydrochloride.

Example 6: Preparation of amorphous solid dispersion comprising lorcaserin hydrochloride and HPMC-AS.

Lorcaserin hydrochloride (500 mg) and HPMC-AS (500 mg) were taken in dichloromethane (25 ml) and stirred at room temperature for 10 minutes to obtain a clear solution. The resulting solution was subjected to distillation under reduced pressure at 60-70°C for 10-15 minutes and further dried at 80°C for 1 hour to obtain amorphous solid dispersion comprising lorcaserin hydrochloride.

Example 7: Preparation of amorphous solid dispersion comprising lorcaserin hydrochloride and HPMC-AS.

Lorcaserin hydrochloride (500 mg) and HPMC-AS (1.0 g) were taken in methanol (80 ml) and stirred at room temperature for 10 minutes to obtain a clear solution. The resulting solution was subjected to distillation under reduced pressure at 70°C for 75-80 minutes to obtain amorphous solid dispersion comprising lorcaserin hydrochloride.

Example 8: Preparation of amorphous solid dispersion comprising lorcaserin hydrochloride and HPMC 3CPS.

Lorcaserin hydrochloride (500 mg) and HPMC 3CPS (500 mg) were taken in dichloromethane (25 ml) and stirred at room temperature for 10 minutes to obtain a clear solution. The resulting solution was subjected to distillation under reduced pressure at 60-70°C for 10-15 minutes and further dried at 80°C for 1 hour to obtain amorphous solid dispersion comprising lorcaserin hydrochloride.

PXRD Pattern is shown as Figure 1.
Example 9: Preparation of amorphous solid dispersion comprising lorcaserin hydrochloride and HPMC 3CPS.

Lorcaserin hydrochloride (1.0 g) and HPMC 3CPS (1.0 g) were taken in methanol (100 ml) and stirred at room temperature for 10 minutes to obtain a clear solution. The resulting solution was subjected to distillation under reduced pressure at 70-85°C for 15-20 minutes and further dried at 95°C for 1 hour to obtain amorphous solid dispersion comprising lorcaserin hydrochloride.

Example 10: Preparation of amorphous solid dispersion comprising lorcaserin hydrochloride and HPC EF.

Lorcaserin hydrochloride (1.0 g) and HPC EF (1.0 g) were taken in dichloromethane (50 ml) and stirred at room temperature for 10 minutes to obtain a clear solution. The resulting solution was subjected to distillation under reduced pressure at 60-70°C for 10-15 minutes and further dried at 80°C for 1 hour to obtain amorphous solid dispersion comprising lorcaserin hydrochloride.

Example 11: Preparation of amorphous solid dispersion comprising lorcaserin hydrochloride and HPC EF.

Lorcaserin hydrochloride (1.0 g) and HPC EF (1.0 g) were taken in methanol (50 ml) and stirred at room temperature for 10 minutes to obtain a clear solution. The resulting solution was subjected to distillation under reduced pressure at 70-80°C for 10-15 minutes and further dried at 90°C for 1 hour to obtain amorphous solid dispersion comprising lorcaserin hydrochloride.

Example 12: Preparation of amorphous lorcaserin hydrochloride.

Lorcaserin Hydrochloride (7.0 g) was taken in Methanol (70 ml) and stirred at room temperature to obtain a clear solution. The solution was filtered on filter paper to obtain a particle free solution. The resulting solution was spray dried at below mentioned parameters to obtain the amorphous lorcaserin hydrochloride.

Operation parameters:
Aspirator : 70%;
Feed rate : 10 %( 3 ml/min)
Inlet nitrogen temperature : 70°C to 75°C
Atomisation Pressure : 5.0 kg/cm2
PXRD Pattern is shown as Figure 2.

Example 13: Preparation of amorphous solid dispersion comprising lorcaserin hydrochloride and HPMC.

Lorcaserin hydrochloride (500 mg) and Hydroxypropyl methylcellulose (HPMC) (500mg) were taken in Methanol (100 ml) and stirred at room temperature to obtain a clear solution. The resulting solution was subjected to distillation under reduced pressure at 60 to 65°C for 30-45 minutes to obtain the amorphous form comprising lorcaserin hydrochloride.
PXRD Pattern is shown as Figure 3.

Example 14: Preparation of amorphous solid dispersion comprising lorcaserin hydrochloride and PVP-K-30.

Lorcaserin hydrochloride (1000 mg) and PVP-K-30 (1000mg) were taken in Methanol (30 ml) and stirred at room temperature to obtain a clear solution. The resulting solution was subjected to distillation under reduced pressure at 60 to 65°C for 30-45 minutes to obtain amorphous form comprising lorcaserin hydrochloride.

PXRD Pattern is shown as Figure 4.
Example 15: Preparation of amorphous solid dispersion comprising lorcaserin hydrochloride and PVP-K-30.

Lorcaserin Hydrochloride (1000 mg) and PVP-K-30 (500 mg) were taken in Methanol (25 ml) and stirred at room temperature to obtain a clear solution. The resulting solution was subjected to distillation under reduced pressure at 60 to 65°C for 30-45 minutes to obtain amorphous form comprising lorcaserin hydrochloride.

PXRD Pattern is shown as Figure 5.

CLAIMS:WE CLAIM:

1. A process for the preparation of amorphous form of lorcaserin hydrochloride, comprising:

a) providing a solution of lorcaserin hydrochloride in a suitable solvent or mixtures thereof; and

b) isolating amorphous form of lorcaserin hydrochloride.

2. A process for preparing an amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers, comprising the steps of:

a) dissolving or dispersing lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers in a suitable solvent or mixtures thereof; and

b) isolating an amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers.

3. A process for preparing an amorphous solid dispersion, comprising the steps of:

(a) dissolving or dispersed lorcaserin hydrochloride under heating in one or more pharmaceutically acceptable carriers; and

(b) cooling down the mixture.

4. A process for preparing an amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers, comprising the steps of:

(a) dissolving or dispersing lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers in a suitable solvent or mixture of solvents;

(b) spray drying the mixture to obtain the said amorphous solid dispersion.

5. A pharmaceutical composition comprising amorphous form of lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers for treating disorders including depression, atypical depression, bipolar disorders, anxiety disorders, obsessive-compulsive disorders, social phobias or panic states, sleep disorders, sexual dysfunction, psychoses, schizophrenia, migraine and other conditions associated with cephalic pain or other pain, raised intracranial pressure, epilepsy, personality disorders, age-related behavioral disorders, behavioral disorders associated with dementia, organic mental disorders, mental disorders in childhood, aggressivity, agerelated memory disorders, chronic fatigue syndrome, drug and alcohol addiction, obesity, bulimia, anorexia nervosa and premenstrual tension.