WO2017055935A1

WO2017055935A1 - Amorphous co-precipitates of flibanserin

Info

Publication number: WO2017055935A1
Application number: PCT/IB2016/050847
Authority: WO
Inventors: Dodda Mohan Rao; Vanga MALLA REDDY; Ambati Anna Reddy
Original assignee: Symed Labs Limited
Priority date: 2015-09-30
Filing date: 2016-02-17
Publication date: 2017-04-06

Abstract

Disclosed herein are stable amorphous co-precipitates of Flibanserin and a pharmaceutically acceptable excipient, methods for the preparation, pharmaceutical compositions, and method of treating thereof. We have carried out extensive research and experimentation to prepare amorphous co-precipitates (solid dispersions) of Flibanserin free base with various pharmaceutically acceptable excipients, in different ratios, such as hypromellose (also called as hydroxypropyl methylceiiulose or HPMC), lactose monohydrate, macrocrystalline cellulose, polyvinylpyrrolidone (also called as povidone or PVP), hydroxypropyl cellulose (HPC), hydroxypropyl methylceiiulose (HPMC), hypromellose phthalate (also called as hydroxypropyl methylceiiulose phthalate or HPMCP), maltodextrin, cyclodextrin, copovidone, and the like. It has been found that the Flibanserin forms amorphous co-precipitates with few specific excipients like hypromellose, lactose monohydrate and microcrystalline cellulose when a specific solvent or a solvent medium is employed.

Description

AMORPHOUS CO-PRECIPITATES OF FLIBANSERIN

CROSS REFERENCE TO RELATED APPLICATION

This patent application claims the benefit of priority to Indian Complete Patent Application No. 5214/CHE/2015 filed on September 30, 2015, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to stable amorphous co-precipitates of Flibanserin with pharmaceutically acceptable excipients, methods for the preparation, pharmaceutical compositions, and method of treating thereof.

BACKGROUND OF THE INVENTION

U.S. Patent No. 5,576,318 (hereinafter referred to as the '318 patent) discloses pharmacologically active benzimidazolone derivatives and their salts, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds possess central serotonergic activity and are useful in the treatment of central nervous system (CNS) disorders. Among them, Flibanserin, chemically named as l-[2-[4-[3-(trifluoromethyl)phenyl]-l- piperazinyl]ethyl]-2,3-dihydro- 1 H-benzimidazol-2-one, has agonist activity at 5-HTJA and antagonist activity at 5-HT₂A- Flibanserin also has moderate antagonist activities at the 5-HT₂B, 5-HT₂C, and D₄ receptors. Flibanserin is represented by the following structural formula I:

Flibanserin is sold by Sprout under the brand name ADDYI and it is orally administered as tablets containing 100 mg of Flibanserin. ADDYI is indicated for the treatment of premenopausal women with acquired or generalized hypoactive sexual desire disorder (HSDD). Various processes for the preparation of Flibanserin, its intermediates, and related compounds are disclosed in U.S. Patent No. 5,576,318; PCT Publication No. WO2010/128516; and Drugs of the Future 23(1), 9-16, 1998.

As per the process described in the U.S. Patent No. 5,576,318, Flibanserin is analogously prepared (as per the process exemplified in Example 1) by reacting l-(2- chloroethyl)-2,3-dihydro- 1 H-benzimidazol-2-one with 1 -(3-trifluoromethyl- phenyl)piperazine hydrochloride in the presence of potassium iodide and sodium carbonate in absolute ethanol at reflux temperature to produce a reaction mass. This reaction mass is then subjected to usual work-up procedures, followed extraction into ethyl acetate and then subjected to removal of solvent under vacuum to produce a solid. The resulting solid is then treated with diethylether, filtered and finally recrystallized from isopropanol to produce Flibanserin.

U.S. Patent No. 7,420,057 (hereinafter referred to as the '057 patent), assigned to Boehringer, discloses two crystalline forms (polymorph A and polymorph B) of Flibanserin, processes for their preparation, and characterizes the crystalline forms by powder X-ray diffraction (XRPD) peaks, and Differential Scanning Calorimetric thermogram (DSC).

According to Ό57 patent, polymorph A of Flibanserin is characterized by DSC having a melting point of about 161°C; and a powder X-ray diffraction spectrum having peaks expressed as 2-thcta angle positions at 5.19, 9.04, 9.33, 10.02, 10.59, 1 1.29, 13.22, 14.59, 15.46, 16.65, 17.08, 17.28, 17.42, 18.14, 18.65, 19.14, 19.82, 20.08, 20.38, 21.21, 21.89, 22.63, 23.21, 24.35, 24.61 , 24.99, 25.26, 26.57, 27.15, 27.31, 27.86, 28.21, 28.32, 28.65, 29.52, 30.25, 31.10 and 31.90 degrees. Polymorph B is characterized by a DSC thermogram having a melting point of about 120°C. The Ό57 patent also discloses that the polymorph B is less stable than polymorph A under the effects of mechanical stress produced by grinding.

Polymorphism is the ability of a solid material to exist in more than one form or crystal structure. Amorphous solids consist of disordered arrangement of molecules and do not possess a distinguishable crystal lattice. The amorphous form is generally more soluble than the crystalline form and thus contributes more in the bioavailability.

An important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered pharmaceutical compound may reach the patient's bloodstream. The rate of dissolution is a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.

The discovery of new solid state forms of a pharmaceutical compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a pharmaceutical compound with a targeted release profile or other desired characteristics.

Amorphous co-precipitates, alternatively named as solid dispersions, of

Flibanserin have not been prepared, isolated and/or characterized in the literature.

Hence, there is a need in the art for highly pure and stable amorphous co- precipitates of Flibanserin having improved physiochemical characteristics that assist in the effective bioavailability of Flibanserin, a process for the preparation and a pharmaceutical composition thereof.

SUMMARY OF THE INVENTION

We have carried out extensive research and experimentation to prepare amorphous co-precipitates (solid dispersions) of Flibanserin free base with various pharmaceutically acceptable excipients, in different ratios, such as hypromellose (also called as hydroxypropyl methylcellulose or HPMC), lactose monohydrate, microcrystalline cellulose, polyvinylpyrrolidone (also called as povidone or PVP), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hypromellose phthalate (also called as hydroxypropyl methylcellulose phthalate or HPMCP), maltodextnn, cyclodextrin, copovidone, and the like. It has been found that the Flibanserin forms amorphous co-precipitates with few specific excipients like hypromellose, lactose monohydrate and microcrystalline cellulose when a specific solvent or a solvent medium is employed.

In one aspect, provided herein are amorphous co-precipitates of Flibanserin free base with a pharmaceutically acceptable excipient. Preferably, the pharmaceutically acceptable excipient is selected from the group consisting of hypromellose, lactose monohydrate and microcrystalline cellulose. The amorphous co-precipitates of Flibanserin disclosed herein have high purity, adequate stability and better solubility and dissolution properties.

The solubility of drugs in water and in buffer solutions with a pH of 6.8 and pH of 7.4 is fundamentally important for drug development and manufacturing. Drugs administered orally as a solid or in suspension have to dissolve in the aqueous gastric fluid before they can be absorbed and transported via the systemic circulation to their site of action. The rate and extent of dissolution of a drug is a major factor in controlling the absorption of that drug. This is because the concentration of the drug in the fluid in the gut lumen is one of the main factors governing the transfer of the drug through the membranes of the gastrointestinal tract (GIT). The rate of dissolution depends on the surface of the solid, which is dependent on both the physical nature of the dosage form of the drug and the chemical structure of the drug. However, the extent of dissolution depends only on the drug's solubility.

It has been surprisingly and unexpectedly found that the amorphous co- precipitates of Flibanserin with hypromellose as disclosed herein have excellent aqueous solubility and bioavailability when compared with that of the crystalline form of Flibanserin free base (Form A) as disclosed in the U.S. Patent No. 7,420,057.

The amorphous co-precipitate of Flibanserin with hypromellose of the present invention can be advantageously used for immediate release and extended release dosage forms as it shows better solubility in water as well as in the buffer solutions with a pH of 6.8 and pH of 7.4, and it is also having good solubility in 0.1N HC1, thereby having improved bioavailability when compared to the crystalline form of Flibanserin free base.

In another aspect, encompassed herein is a process for preparing the novel and stable amorphous co-precipitates of Flibanserin with pharmaceutically acceptable excipients.

In another aspect, provided herein are pharmaceutical compositions comprising the amorphous co-precipitates of Flibanserin and one or more pharmaceutically acceptable excipients.

In another aspect, encompassed herein is a process for preparing a pharmaceutical formulation comprising combining the amorphous co-precipitates of Flibanserin disclosed herein with one or more pharmaceutically acceptable excipients. In another aspect, the amorphous co-precipitates of Flibanserin disclosed herein for use in the pharmaceutical compositions has a D90 particle size of less than or equal to about 400 microns, specifically about 1 micron to about 300 microns, and most specifically about 10 microns to about 150 microns.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of Amorphous Co-precipitate of Flibanserin with Hypromellose (5 : 3) obtained according to the example 1.

Figure 2 is a characteristic powder X-ray diffraction (XRPD) pattern of Amorphous Co-precipitate of Flibanserin with Hypromellose (5 : 5) obtained according to the example 3.

Figure 3 is a characteristic Infrared (IR) spectrum of Amorphous Co-precipitate of Flibanserin with Hypromellose (5 : 3) obtained according to example 1.

Figure 4 is a characteristic Infrared (IR) spectrum of Amorphous Co-precipitate of Flibanserin with Hypromellose (5 : 5) obtained according to example 3.

DETAILED DESCRIPTION OF THE INVENTION

According to one aspect, the present invention provides amorphous co- precipitates (solid dispersions) comprising Flibanserin and a pharmaceutically acceptable excipient having improved physiochemical characteristics that assist in the effective bioavailability of Flibanserin.

In one embodiment, the pharmaceutically acceptable excipient is selected from the group consisting of hypromellose (also called as hydroxypropyl methylcellulose or HPMC), lactose monohydrate and microcrystalline cellulose.

According to another aspect, there are provided pharmaceutical compositions comprising the amorphous co-precipitates of Flibanserin disclosed herein, and one or more pharmaceutically acceptable excipients.

The amorphous co-precipitates of Flibanserin with a pharmaceutically acceptable carrier obtained by the processes disclosed herein may be characterized by one or more of their powder X-ray diffraction (XRD) pattern and Infrared absorption (IR) spectrum. In one embodiment, the amorphous co-precipitate of Flibanserin with hypromellose (5 : 3) is characterized by a powder XRD pattern substantially in accordance with Figure 1. The X-ray powder diffraction patterns show a plain halo with no well-defined peaks, thus demonstrating the amorphous nature of the product.

In another embodiment, the amorphous co-precipitate of Flibanserin with hypromellose (5 : 3) is further characterized by an infrared (FT-IR) spectrum having main bands at about 3444, 3199, 3068, 2941 , 2832, 1719, 1697, 1649, 1624, 1588, 1491, 1450, 1359, 1237, 1 165, 1 120, 992, 946, 786, 754, 730 and 693 ± 4 cm^'1 substantially in accordance with Figure 3.

In another embodiment, the amorphous co-precipitate of Flibanserin with hypromellose (5 : 5) is characterized by a powder XRD pattern substantially in accordance with Figure 2. The X-ray powder diffraction patterns show a plain halo with no well-defined peaks, thus demonstrating the amorphous nature of the product.

In another embodiment, the amorphous co-precipitate of Flibanserin with hypromellose (5 : 5) is further characterized by an infra red (FT-IR) spectrum having main bands at about 3447, 3068, 2939, 2836, 1734, 1613, 1495, 1452, 1 122, 947, 789, 755, 732 and 694 ± 4 cm^"1 substantially in accordance with Figure 4.

According to another aspect, there is provided a process for preparing an amorphous co-precipitate of Flibanserin and a pharmaceutically acceptable excipient, comprising:

a) providing a solution of Flibanserin and a pharmaceutically acceptable excipient in a solvent wherein the solvent is water, an organic solvent, or a solvent medium comprising water and an organic solvent; wherein the organic solvent is selected from the group consisting of an alcohol, a ketone, a halogenated hydrocarbon, a nitrile, an ester, an organic water-miscible solvent, and mixtures thereof;

b) optionally, filtering the solvent solution to remove insoluble matter; and

c) substantially removing the solvent from the solution to produce the amorphous co- precipitate of Flibanserin with the pharmaceutically acceptable excipient.

In one embodiment, the pharmaceutically acceptable excipient used in step-(a) is selected from the group consisting of hypromellose, lactose monohydrate and microcrystalline cellulose and mixtures thereof.

The use of other pharmaceutically acceptable excipients and mixtures of more than one of the pharmaceutical carriers for preparing amorphous co-precipitates of Flibanserin to provide desired release profiles or for the enhancement of stability is within the scope of this invention . Exemplary pharmaceutically acceptable excipients include, but are not limited to, polyvinylpyrrolidone (also called povidone), polyvinyl alcohol, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethylcellulose, polyvinyl acetate, maltodextrins, cyclodextrins, gelatins, hypromellose phthalate, sugars, and combinations comprising one or more of the foregoing hydrophilic carriers.

The process can produce amorphous co-precipitates of Flibanserin with the pharmaceutically acceptable excipient in substantially pure form.

The terms "co-precipitate" and "solid dispersions" as used in the present invention are synonymous and are intended to mean a dispersion of Flibanserin free base in an inert carrier or matrix in a solid state prepared by dissolving Flibanserin free base and one or more pharmaceutical excipients in a solvent or solvent mixture and removing the solvent or solvent mixture.

The term "substantially pure amorphous co-precipitate of Flibanserin with the pharmaceutically acceptable excipient" refers to the amorphous co-precipitate of Flibanserin having a purity greater than about 99%, specifically greater than about 99.5%, and more specifically greater than about 99.95% (measured by HPLC). For example, the total purity of the amorphous co-precipitate of Flibanserin obtained by the process disclosed herein can be about 99.5% to about 99.99% as measured by HPLC.

The amorphous co-precipitates of Flibanserin and hypromellose obtained by the process disclosed herein are stable, consistently reproducible and have good flow properties, and which are particularly suitable for bulk preparation and handling, and these solid dispersions are suitable for formulating Flibanserin free base.

The amorphous co-precipitate of Flibanserin with hypromellose as disclosed herein shows better solubility in water (107.14μg/ml) than the prior art crystalline form of Flibanserin free base which shows comparatively very low solubility in water (8.25μg/ml). This is a distinct advantage from a drug developing and manufacturing standpoint as the dissolution of a drug is directly related to its absorption when administered.

The amorphous co-precipitate of Flibanserin with hypromellose of the present invention also shows better solubility (16(^g/ml) in a buffer solution with a pH of 6.8 than the prior art crystalline form of Flibanserin free base which shows comparatively very low solubility (7.8μ^ηι1). The amorphous co-precipitate of Flibanserin with hypromellose of the present invention also shows better solubility (129.16μ§/πιΓ) in a buffer solution with a pH of 7.4 than the prior art crystalline form of Flibanserin free base which shows comparatively very low solubility (12.76μ /ηι1).

The amorphous co-precipitate of Flibanserin with hypromellose of the present invention also shows good solubility (952μ{¾/πι1) in 0.1N HCl solution with a pH of 1.2 when compared with that of the prior art crystalline form of Flibanserin free base (126( g/ml).

Moreover, the amorphous co-precipitate of Flibanserin with hypromellose as disclosed herein has better Partition Coefficient (log P) values in the solvent systems containing butanol/water and octanol/water 1.582 and 1.33 respectively when compared with that of the log P values (2.5 and 1.372 respectively) of crystalline Flibanserin free base. When partition coefficient value is between 1 and 2 the drug has good absorption throughout GIT. Hence, the amorphous co-precipitate of Flibanserin with hypromellose disclosed herein has better bioavailability than that of the crystalline Flibanserin free base.

The amorphous co-precipitate of Flibanserin with hypromellose of the present invention remains stable and it is in the same amorphous form when stored at a temperature of about 40±2°C and at a relative humidity of about 75±5% for a period of more than 3 months.

The amorphous co-precipitate of Flibanserin with hypromellose of the present invention remains stable and it is in the same amorphous form when stored at a temperature of about 30±2°C and at a relative humidity of about 65±5% for a period of more than 3 months.

The amorphous co-precipitate of Flibanserin with hypromellose of the present invention remains stable and it is in the same amorphous form when stored at a temperature of about 25±2°C and at a relative humidity of about 60±5% for a period of more than 3 months.

The term "remains stable", as used herein, refers to no formation of impurities, while being stored as described hereinabove.

The amorphous co-precipitates of Flibanserin disclosed herein are essentially free of crystalline forms, consistently reproducible, do not have the tendency to convert to crystalline forms, and are found to be more stable. The amorphous co-precipitates of Flibanserin disclosed herein exhibit properties making them suitable for formulating Flibanserin. More particularly, disclosed herein are amorphous co-precipitates of Flibanserin with improved physiochemical characteristics which help in the effective bioavailability of Flibanserin. Such pharmaceutical compositions may be administered easily to a mammalian patient in a dosage form with a high rate of bioavailability.

The term "amorphous co-precipitates of Flibanserin essentially free of crystalline forms" means that no crystalline forms of Flibanserin or the excipient can be detected within the limits of a powder X-ray diffractometer.

In one embodiment, the solvent used in step-(a) is selected from the group consisting of an alcohol, a ketone, a nitrile, an ester, and mixtures thereof. Specifically the solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, acetone, dichloromethane, acetonitrile, tetrahydrofuran, N,N- dimethylformamide, dimethoxyethane, and mixtures thereof. Most specifically, the solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetone, dichloromethane and mixtures thereof.

Step-(a) of providing a solution includes dissolving Flibanserin in the solvent, or such a solution may be obtained directly from a reaction in which Flibanserin is formed, and then combining the solution with a pharmaceutically acceptable excipient. The pharmaceutical excipient can be dissolved in a solution containing Flibanserin, or, Flibanserin can be dissolved in a solution containing a pharmaceutical excipient.

Alternatively, the solution in step-(a) is prepared by treating an acid addition salt of Flibanserin with a base to liberate Flibanserin free base, followed by extracting or dissolving Flibanserin free base in the solvent and then combining the solution with a pharmaceutically acceptable excipient.

The base used herein can be selected from the group consisting of inorganic and organic bases. Exemplary bases include, but are not limited to, methylamine, trimethylarnine, tributylamine, triethyl amine, diisopropylethylamine; and hydroxides, alkoxides, bicarbonates and carbonates of alkali or alkaline earth metals. Specific bases are collidine, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide. Acid addition salts of Flibanserin may be derived from organic and inorganic acids. For example, the acid addition salts are derived from a therapeutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, phosphoric acid, succinic acid, maleic acid, fumaric acid, citric acid, glutaric acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, malic acid, ascorbic acid, and the like. Exemplary acid addition salts include, but are not limited to, hydrochloride, hydrobromide, sulphate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, tartrate, and the like. A most specific acid addition salt of Flibanserin is hydrochloride salt.

Alternatively, a solution containing Flibanserin can be combined with a solution containing a pharmaceutically acceptable excipient, and the solvents used for preparing the different solutions need not be the same as long as the solvents have mutual solubility and form a single phase. In any event, Flibanserin should be completely soluble in the solvents used and should provide a clear solution. The presence of insoluble crystals could lead to the formation of a material that is not completely amorphous.

In one embodiment, the dissolution is carried out at a temperature of about 20°C to about 100°C, specifically at about 25°C to about 80°C, and more specifically at about 25°C to about 65°C.

In another embodiment, the solution obtained in step-(a) is optionally be subjected to carbon treatment or silica gel treatment. The carbon treatment or silica gel treatment may be carried out by methods known in the art, for example by stirring the solution with finely powdered carbon or silica gel at a temperature of below about 70°C for at least 5 minutes, specifically at a temperature of about 40°C to about 70°C for at least 30 minutes; and filtering the resulting mixture through hyflo bed to obtain a filtrate containing Flibanserin by removing charcoal or silica gel. Preferably, a finely powdered carbon is an active carbon. In one embodiment, a specific mesh size of silica gel is 40-500 mesh, and more specifically 60-120 mesh.

The solution obtained in step-(a) is stirred at a temperature of about 20°C to the reflux temperature of the solvent used for at least 10 minutes, and specifically at a temperature of about 20°C to about 60°C for about 20 minutes to about 2 hours. Removal of solvent in step-(c) is accomplished, for example, by substantially complete evaporation of the solvent, concentrating the solution, or distillation of solvent, under inert atmosphere to obtain amorphous co-precipitate comprising Flibanserin and the pharmaceutically acceptable excipient.

In one embodiment, the removal of solvent in step-(c) is carried out by distillation. The distillation process can be performed at atmospheric pressure or at reduced pressure.

Specifically the distillation process is performed at reduced pressure. In one embodiment, the solvent is removed at a pressure of about 760 mm Hg or less, specifically at about 400 mm Hg or less, more specifically at about 80 mm Hg or less, and most specifically from about 30 to about 80 mm Hg.

In a preferred embodiment, the distillation process is performed under reduced pressure and at a temperature of about 50°C to about 120°C, and most specifically at a temperature of about 60°C to about 90°C.

In another embodiment, the solvent is removed by evaporation. Evaporation can be achieved at sub-zero temperatures by lyophilisation or freeze-drying techniques. The solution may also be completely evaporated in, for example, a pilot plant Rota vapor, a Vacuum Paddle Dryer or in a conventional reactor under vacuum above about 720 mm Hg by flash evaporation techniques by using an agitated thin film dryer ("ATFD").

In another embodiment, the removal of solvent in step-(c) may also be accomplished by spray-drying. The air inlet temperature to the spray drier used may range from^* about 50°C to about 150°C, specifically from about 60°C to about 120°C and most specifically from about 70°C to about 100°C; and the outlet air temperature used may range from about 30°C to about 90°C.

The dried product obtained by the process disclosed herein above can optionally be milled to get desired particle sizes. Milling or micronization can be performed prior to drying, or after the completion of drying of the product. The milling operation reduces the size of particles and increases surface area of particles. Drying is more efficient when the particle size of the material is smaller and the surface area is higher, hence milling will frequently be performed prior to the drying operation.

Flibanserin as used herein as starting materials can be obtained by the processes described in the prior art, for example, the processes described in the U.S. Patent No. 5,576,318. Milling can be done suitably using jet milling equipment like an air jet mill, or using other conventional milling equipment.

The resulting amorphous powder compositions disclosed herein have improved solubility properties and hence also have improved bioavailability.

The amorphous co-precipitates of Flibanserin with the pharmaceutically acceptable excipients obtained by the process disclosed herein are a random distribution of the Flibanserin and the pharmaceutically acceptable excipient in a particle matrix. Without being held to any particular theory, the co-precipitates have the characteristics of solid dispersions at a molecular level, being in the nature of solid solutions. The solid solutions, or molecular dispersions, provide homogeneous particles in which substantially no discrete areas of only amorphous Flibanserin and/or only pharmaceutically acceptable excipient can be observed.

Further encompassed herein is the use of the amorphous co-precipitates of Flibanserin and the pharmaceutically acceptable excipients for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.

A specific pharmaceutical composition of the amorphous co-precipitates of Flibanserin is selected from a solid dosage form and an oral suspension.

In one embodiment, the amorphous co-precipitate of Flibanserin and the pharmaceutically acceptable excipient, has a D90 particle size of less than or equal to about 400 microns, specifically about 1 micron to about 300 microns, and most specifically about 10 microns to about 150 microns.

In another embodiment, the amorphous co-precipitate of Flibanserin and the pharmaceutically acceptable excipient, disclosed herein for use in the pharmaceutical compositions has a D90 particle size of less than or equal to about 400 microns, specifically about 1 micron to about 300 microns, and most specifically about 10 microns to about 150 microns.

In another embodiment, the particle sizes of the amorphous co-precipitate of Flibanserin and the pharmaceutically acceptable excipient, can be achieved by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range. According to another aspect, there is provided a method for treating a premenopausal women with acquired or generalized hypoactive sexual desire disorder (HSDD), comprising administering a therapeutically effective amount of the amorphous co-precipitate of Flibanserin, or a pharmaceutical composition that comprises a therapeutically effective amount of amorphous co-precipitate of Flibanserin along with pharmaceutical ly acceptable excipients.

According to another aspect, there are provided pharmaceutical compositions comprising amorphous co-precipitate of Flibanserin prepared according to the processes disclosed herein and one or more pharmaceutically acceptable excipients.

According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining amorphous co-precipitate of Flibanserin prepared according to the process disclosed herein, with one or more pharmaceutically acceptable excipients.

In another embodiment, the pharmaceutical compositions comprise at least a therapeutically effective amount of the amorphous co-precipitate of Flibanserin. Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, elixir, aerosol, syrups, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes or any other acceptable route of administration. Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, troches, sachets, suspensions, powders, lozenges, elixirs and the like.

The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinafter.

In one embodiment, capsule dosage forms contain the amorphous co-precipitate of Flibanserin within a capsule which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. Suitable enteric coating agents include phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxy methyl ethyl cellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, the coating agents may be employed with suitable plasticizers and/or extending agents. A coated capsule or tablet may have a coating on the surface thereof or may be a capsule or tablet comprising a powder or granules with an enteric-coating.

Tableting compositions may have few or many components depending upon the tableting method used, the release rate desired and other factors. For example, the compositions described herein may contain diluents such as cellulose-derived materials like powdered lactose monohydrate, cellulose, microcrystalline cellulose, micro fine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols such as mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.

Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.

INSTRUMENTAL DETAILS:

X-Ray Powder Diffraction (P-XRD):

The X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X-ray powder diffractometer equipped with a Cu-anode (copper-Κα radiation). Approximately 1 gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees 2-theta, at 0.03 degrees to theta per step and a step time of 38.4 seconds. The sample was simply placed on the sample holder. The sample was applied with a voltage of 40 KV and current of 35 mA.

Infra-Red Spectroscopy (FT-IR):

FT-IR spectroscopy was carried out with a Bruker vertex 70 spectrometer. For the production of the KBr compacts approximately 5 mg of sample was powdered with 200 mg of KBr. The spectra were recorded in transmission mode ranging from 3800 cm^" to 650 cm^"1.

The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.

EXAMPLES

Example 1

Preparation of Amorphous Co-precipitate of Flibanserin with Hydroxypropyl methylcellulose (Hypromellose)

Flibanserin (5 g) and hydroxypropyl methylcellulose (3 g) were added to methanol (240 ml), followed by heating the mixture at 60-65 °C to form a clear solution. The resulting solution was stirred for 10-15 minutes at the same temperature, followed by removal of the solvent by distillation under reduced pressure at 50-60°C to produce 7.8 g of amorphous co-precipitate of Flibanserin with hydroxypropyl methylcellulose (5 : 3) as a white colored powder.

Characterization Data:

The resulting amorphous co-precipitate of Flibanserin with hydroxypropyl methylcellulose (5 : 3) is characterized by an X-ray powder diffraction pattern, showing a plain halo with no peaks, as shown in Figure 1.

Example 2

Flibanserin (5 g) and hydroxypropyl methylcellulose (4 g) were added to methanol (270 ml), followed by heating the mixture at 60-65 °C to form a clear solution. The resulting solution was stirred for 10-15 minutes at the same temperature, followed by removal of the solvent by distillation under reduced pressure at 50-60°C to produce 8.5 g of amorphous co-precipitate of Flibanserin with hydroxypropyl methylcellulose (5 : 4) as a white colored powder. Example 3

Preparation of Amorphous Co-precipitate of Flibanserin with Hydroxypropyl methylcellulose

Flibanserin (5 g) and hydroxypropyl methylcellulose (5 g) were added to methanol (270 ml), followed by heating the mixture at 60-65°C to form a clear solution. The resulting solution was stirred for 10-15 minutes at the same temperature, followed by removal of the solvent by distillation under reduced pressure at 50-60°C to produce 9.7 g of amorphous co-precipitate of Flibanserin with hydroxypropyl methylcellulose (5 ; 5) as a white colored powder.

Characterization Data:

The resulting amorphous co-precipitate of Flibanserin with hydroxypropyl methylcellulose (5 : 5) is characterized by an X-ray powder diffraction pattern, showing a plain halo with no peaks, as shown in Figure 2.

Example 4

Preparation of Amorphous Co-precipitate of Flibanserin with Microcrystalline cellulose

Flibanserin (5 g) and microcrystalline cellulose (3 g) were added to methanol (270 ml), followed by heating the mixture at 60-65 °C to form a clear solution. The resulting solution was stirred for 10-15 minutes at the same temperature, followed by removal of the solvent by distillation under reduced pressure at 50-60°C to produce 7.5 g of amorphous co-precipitate of Flibanserin with microcrystalline cellulose (5 : 3) as a white colored powder. Example 5

Preparation of Amorphous Co-precipitate of Flibanserin with Hydroxypropyl methylcellulose and Microcrystalline cellulose

Hydroxypropyl methylcellulose (3 g) and microcrystalline cellulose (3 g) were added to a solution of Flibanserin (5 g) and methanol (330 ml), followed by heating the resulting solution at reflux temperature to form a clear solution. The resulting solution was maintained for 10-15 minutes at the same temperature, followed by removal of the solvent by distillation under reduced pressure at 50-60°C to produce 10.5 g of amorphous co-precipitate of Flibanserin as a white colored powder. Example 6

Hydroxypropyl methylcellulose (3 g) and microcrystalline cellulose (1 g) were added to a solution of Flibanserin (5 g) and methanol (270 ml), followed by heating the resulting solution at reflux temperature to form a clear solution. The resulting solution was maintained for 10-15 minutes at the same temperature, followed by removal of the solvent by distillation under reduced pressure at 50-60°C to produce 8.8 g of amorphous co-precipitate of Flibanserin as a white colored powder.

Example 7

Solubility Studies:

Solubility of the amorphous co-precipitate of Flibanserin with hypromellose (obtained in Example 1) and the crystalline form of Flibanserin free base (Form A, obtained as per the processes described in U.S. Patent No. 7,420,057) was studied in water, buffer solution with pH 6.8, buffer solution with pH 7.4 and 0.1N HC1 solution (pH 1.2), and the resulting solubility data is depicted in the below table:

The above solubility data clearly shows that the amorphous co-precipitate of Flibanserin with hypromellose has better solubility, in water as well as in the buffer solutions with a pH of 6.8 and pH of 7.4, than the crystalline form of Flibanserin, and it is also having good solubility in 0.1N HCl (pH 1.2), thereby having better bioavailability when compared to the crystalline form of Flibanserin free base.

General Procedure:

Four separate 250 ml beakers were taken and 100 mg of drug substance was added into each beaker respectively, followed by the addition of water (250 ml) into the first beaker, 6.8 pH buffer solution (250 ml) into the second beaker, 7.4 pH buffer solution (250 ml) into the third beaker and 0.1N HC1 solution (250 ml) into the fourth beaker respectively. The beakers were placed on magnetic stirrers separately for 24 hours. After completion of 24 hours, the supernatant solutions were taken and scanned for the maximum absorption in the UV spectrophotometer.

The above buffer solutions were prepared according to the standard procedures reported in the United States Pharmacopeia (USP) under general chapter titled "buffer solutions".

Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.

The term "micronization" used herein means a process or method by which the size of a population of particles is reduced.

As used herein, the term "micron" or "μιη" both are equivalent and refer to "micrometer" which is 1 x 10^"6 meter.

As used herein, "Particle Size Distribution (P.S.D)" means the cumulative volume size distribution of equivalent spherical diameters as determined by laser diffraction in Malvern Master Sizer 2000 equipment or its equivalent.

The important characteristics of the PSD are the (D90), which is the size, in microns, below which 90% of the particles by volume are found, and the (D₅₀), which is the size, in microns, below which 50% of the particles by volume are found. Thus, a D90 or d(0.9) of less than 300 microns means that 90 volume-percent of the particles in a composition have a diameter less than 300 microns.

The term "pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and includes that which is acceptable for human pharmaceutical use.

The term "pharmaceutical composition" is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients. The term "therapeutically effective amount" as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.

The term "delivering" as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host.

The term "buffering agent" as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate and other such materials known to those of ordinary skill in the art.

The term "sweetening agent" as used herein is intended to mean a compound used to impart sweetness to a formulation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.

The term "binders" as used herein is intended to mean substances used to cause adhesion of powder particles in granulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethy 1 cellulose sodium, polyvinylpyrrolidone, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch, starch, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers, collagen, albumin, celluloses in non-aqueous solvents, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, microcrystalline cellulose, combinations thereof and other material known to those of ordinary skill in the art.

The term "diluents" or "filler" as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage formulations. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "glidant" as used herein is intended to mean agents used in solid dosage formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "lubricant" as used herein is intended to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "disintegrant" as used herein is intended to mean a compound used in solid dosage formulations to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pregelatinized, sweeteners, clays, such as bentonite, microcrystalline cellulose, carsium, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.

The term "wetting agent" as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrol idone (PVP).

Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above- described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

We claim:

1. An amorphous co-precipitate (solid dispersion) comprising Flibanserin free base and a pharmaceutically acceptable excipient.

2. The amorphous co-precipitate of Flibanserin of claim 1, wherein the pharmaceutically acceptable excipient is selected from the group consisting of hypromellose, lactose monohydrate, microcrystalline cellulose and mixtures thereof.

3. An amorphous co-precipitate (solid dispersion) comprising Flibanserin free base and hypromellose.

4. The amorphous co-precipitate of Flibanserin of claim 3 , wherein

a) the amorphous co-precipitate of Flibanserin with hypromellose (5 : 3) is characterized by a powder XRD pattern, showing no peaks, substantially in accordance with Figure 1, and

b) the amorphous co-precipitate of Flibanserin with hypromellose (5 : 5) is characterized by a powder XRD pattern, showing no peaks, substantially in accordance with Figure 2.

5. The amorphous co-precipitate of Flibanserin of claim 4, wherein

a) the amorphous co-precipitate of Flibanserin with hypromellose (5 : 3) is further characterized by an infrared (FT-IR) spectrum having main bands at about 3444, 3199, 3068, 2941, 2832, 1719, 1697, 1649, 1624, 1588, 1491, 1450,

1359, 1237, 1165, 1 120, 992, 946, 786, 754, 730 and 693 ± 4 cm^"1 substantially in accordance with Figure 3, and

b) the amorphous co-precipitate of Flibanserin with hypromellose (5 : 5) is further characterized by an infrared (FT-IR) spectrum having main bands at about 3447, 3068, 2939, 2836, 1734, 1613, 1495, 1452, 1122, 947, 789, 755, 732 and

694 ± 4 cm^"1 substantially in accordance with Figure 4.

6. A process for the preparation of the amorphous co-precipitate of Flibanserin of claim 1 , comprising:

b) optionally, filtering the solvent solution to remove insoluble matter; and c) substantially removing the solvent from the solution to produce the amorphous co-precipitate of Flibanserin with the pharmaceutically acceptable excipient.

7. The process of claim 6, wherein the pharmaceutically acceptable excipient used in step-(a) is hypromellose, microcrystalline, lactose monohydrate, and a mixture thereof; wherein the solvent used in step-(a) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, acetone, dichloromethane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethoxyethane, and mixtures thereof; and wherein the removal of the solvent in step-(c) is accomplished by distillation or complete evaporation of the solvent, spray drying, vacuum drying, lyophilization or freeze drying, agitated thin-film drying, or a combination thereof.

8. The process of claim 7, wherein the solvent used in step-(a) is selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetone, dichloromethane and mixtures thereof; and wherein the removal of the solvent in step-(c) is accomplished by distillation.

9. The process of claim 8, wherein the distillation is performed under reduced pressure at a temperature of about 50°C to about 120°C.

10. A pharmaceutical composition comprising the amorphous co-precipitate of Flibanserin of claim 1, and one or more pharmaceutically acceptable excipients.

1 1. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is a solid dosage form, an oral suspension, a liquid, a powder, an elixir, an aerosol, or an injectable solution.

12. A method for treating a premenopausal women with acquired or generalized hypoactive sexual desire disorder (HSDD), comprising administering a therapeutically effective amount of the amorphous co-precipitate of Flibanserin, or a pharmaceutical composition that comprises a therapeutically effective amount of amorphous co-precipitate of Flibanserin of claim 1 along with pharmaceutically acceptable excipients.

13. A pharmaceutical composition comprising the amorphous co-precipitate of Flibanserin with hypromellose of claim 3, and one or more pharmaceutically acceptable excipients.

14. The pharmaceutical composition of claim 13, wherein the amorphous co-precipitate of Flibanserin with hypromellose has a D90 particle size of less than or equal to about 400 microns.

15. The pharmaceutical composition of claim 13, wherein the amorphous co-precipitate of Flibanserin with hypromellose has a D 0 particle size of about 1 micron to about

300 microns.

16. The pharmaceutical composition of claim 13, wherein the amorphous co-precipitate of Flibanserin with hypromellose has a D90 particle size of about 10 microns to about 150 microns.

17. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition is a solid dosage form, an oral suspension, a liquid, a powder, an elixir, an aerosol, or an injectable solution.

18. A method for treating a premenopausal women with acquired or generalized hypoactive sexual desire disorder (HSDD), comprising administering a therapeutically effective amount of the amorphous co-precipitate of Flibanserin, or a pharmaceutical composition that comprises a therapeutically effective amount of the amorphous co-precipitate of Flibanserin with hypromellose of claim 3 along with pharmaceutically acceptable excipients.