An amorphous solid dispersion of elacestrant dihydrochloride and process for the preparation thereof

Abstract

The present invention is to provide an amorphous solid dispersion comprising elacestrant dihydrochloride of formula (I), in combination with one or more pharmaceutically acceptable excipients such as a stabilizing agent including a polymer and / or an alkalizing agent. Additionally, the invention provides a process for the preparation of such amorphous solid dispersions and an amorphous form of elacestrant dihydrochloride. The resulting amorphous form or amorphous solid dispersions are advantageous for the formulation of pharmaceutical dosage forms and compositions, enhancing the bioavailability and stability of elacestrant dihydrochloride.

Description

[0001] AN AMORPHOUS SOLID DISPERSION OF ELACESTRANT DIHYDROCHLORIDE AND PROCESS FOR THE PREPARATION THEREOF

[0002] FIELD OF INVENTION:

[0003] The present invention relates to an amorphous solid dispersion comprising elacestrant dihydrochloride, as well as pharmaceutical compositions containing the same.

[0004] Additionally, the invention provides a novel process for the preparation of the amorphous form of elacestrant dihydrochloride and its amorphous solid dispersions.

[0005] BACKGROUND OF THE INVENTION:

[0006] Elacestrant dihydrochloride, the active ingredient, is an estrogen receptor (ER) antagonist and is used in the treatment of patients with postmenopausal and breast cancer. It is chemically known as (6R)-6-(2-(N-(4-(2-(ethylamino)ethyl)benzyl)-N- ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol dihydrochloride, having a structural formula as represented by formula I.

[0007] Formula I

[0008] Elacestrant was discovered by Eisai Co., Ltd. Radius Health, Inc. has an exclusive right and license from Eisai to research, develop, manufacture, and commercialize elacestrant worldwide. It was approved by the USFDA and EMA in 2023 for the treatment of breast cancer and marketed under the trade name ORSERDU® in the form of tablets with strengths of 345 mg and 86 mg. Elacestrant is an estrogen receptor antagonist that binds to estrogen receptor-alpha (ERa).

[0009] U.S. Patent no. 7,612,114 discloses the elacestrant or a salt and the preparation method thereof.

[0010] U.S. Patent no. 10,385,008 discloses three crystalline forms (1, 2, and 3) and an amorphous form of elacestrant dihydrochloride, along with pharmaceutical compositions, preparation methods, and uses thereof.

[0011] U.S. Patent no. 11,643,385 discloses the crystalline form IB of elacestrant dihydrochloride and the preparation method thereof.

[0012] PCT Publication No. 2023 / 227029 discloses the crystalline form CSII of elacestrant dihydrochloride and the preparation thereof.

[0013] The prior art discloses one or the other crystalline form or an amorphous form of elacestrant dihydrochloride. A drug substance is mostly used in its crystalline form when formulated into pharmaceutical products; crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice-like structures. An amorphous form generally provides better solubility and bioavailability than the crystalline form and may be useful for formulations. Amorphous solid dispersions of drugs are generally known to improve the stability and solubility of drug products. Therefore, it is desirable to have suitable amorphous solid dispersions of drugs with high purity and stability to meet the needs of regulatory agencies and also highly reproducible processes for their preparation.

[0014] The present invention is focuses on the preparation of an amorphous form and / or amorphous solid dispersions and / or premixes of elacestrant dihydrochloride. These forms offer enhanced purity, stability, and solubility, facilitating their formulation into pharmaceutical compositions with desirable release profiles. Accordingly, an amorphous and amorphous solid dispersion of elacestrant dihydrochloride, to aid in development of pharmaceutical composition.

[0015] OBJECTIVES OF THE INVENTION:

[0016] The main objective of the present invention is to provide an amorphous solid dispersion of elacestrant dihydrochloride with improved physicochemical properties.

[0017] In another objective of the present invention is to provide a process for the preparation of amorphous form and amorphous solid dispersions of elacestrant dihydrochloride .

[0018] The amorphous form and amorphous solid dispersion of elacestrant dihydrochloride obtained in this invention are useful in preparing pharmaceutical dosage forms and / or pharmaceutical compositions.

[0019] The amorphous form and amorphous solid dispersion of elacestrant dihydrochloride obtained in this invention are useful in the treatment of patients with postmenopausal and breast cancer.

[0020] SUMMARY OF THE INVENTION:

[0021] In one aspect, the present invention provides an amorphous solid dispersion comprising elacestrant dihydrochloride along with one or more pharmaceutically acceptable excipients, such as a polymer and / or an alkalizing agent.

[0022] In another aspect, the present invention provides an amorphous solid dispersion comprising elacestrant dihydrochloride prepared by freeze drying (lyophilization), solvent evaporation, spray drying, hot melt extrusion, co-grinding, rotary evaporation, co-precipitation, any suitable solvent removal process, the addition of a suitable antisolvent, or any combination thereof.

[0023] In another aspect, the present invention provides an amorphous form of elacestrant dihydrochloride prepared by freeze drying (lyophilization), solvent evaporation, spray drying, hot melt extrusion, co-grinding, rotary evaporation, coprecipitation, any suitable solvent removal process, the addition of a suitable antisolvent, or any combination thereof.

[0024] In another aspect, the present invention provides a pharmaceutical composition comprising an amorphous or an amorphous solid dispersion of elacestrant dihydrochloride along with one or more pharmaceutically acceptable excipients.

[0025] In another aspect, the present invention provides a process for the preparation of amorphous elacestrant dihydrochloride, comprising the steps of: a) dissolving elacestrant dihydrochloride in a suitable solvent or mixture of solvents at a suitable temperature; b) heating the resulting solution at a suitable temperature; c) removing the solvent from the solution obtained in step b); d) cooling the reaction mass obtained after solvent removal to a suitable temperature; e) adding a suitable anti-solvent to the cooled reaction mass obtained in step (d); and f) isolating the amorphous elacestrant dihydrochloride.

[0026] In yet another aspect, the present invention provides a process for the preparation of amorphous elacestr ant dihydrochloride, comprising the steps of: a) dissolving elacestrant dihydrochloride in a suitable solvent or mixture of solvents at a suitable temperature; and b) isolating the amorphous elacestrant dihydrochloride by spray drying.

[0027] In another aspect, the present invention provides an amorphous or amorphous solid dispersions comprising elacestrant dihydrochloride, wherein the content of N- ethyl impurity, a known related substance formed during synthesis or degradation, is less than 0.15% by weight.

[0028] In another aspect, the present invention provides the use of an amorphous or an amorphous solid dispersion of elacestrant dihydrochloride in the treatment of patients with postmenopausal and breast cancer.

[0029] BRIEF DESCRIPTION OF THE DRAWINGS:

[0030] Figure-1: Illustrates the PXRD pattern of an amorphous form of elacestrant dihydrochloride according to example- 1.

[0031] Figure-2: Illustrates the PXRD pattern of an amorphous form of elacestrant dihydrochloride according to example-2.

[0032] Figure-3: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with Povidone-K30 (1: 1) according to example- 10.

[0033] Figure-4: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with Povidone-K30 (1:2) according to example-11.

[0034] Figure-5: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with Povidone-K90 (1: 1) according to example- 12.

[0035] Figure-6: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with Povidone-K90 (1:2) according to example- 13.

[0036] Figure-7: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with PEG-400, Povidone-K30 and Meglumine according to example- 16.

[0037] Figure-8: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with PEG-400 and Povidone-K30 according to example- 19. Figure-9: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with PEG-400 according to example-20.

[0038] Figure-10: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with Povidone-K30 and Meglumine according to example-

[0039] 21.

[0040] Figure-11: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with Povidone-K30 and PEG- 1500 according to example-

[0041] 22.

[0042] Figure-12: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with Povidone-K30 according to example-23.

[0043] Figure-13: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with Povidone-K30 and Stearic acid according to example-

[0044] 24.

[0045] Figure-14: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with Povidone-K30 and Meglumine according to example-

[0046] 25.

[0047] Figure-15: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with Meglumine according to example-26.

[0048] Figure-16: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with Tromethamine according to example-27.

[0049] Figure-17: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with L-Arginine according to example-28.

[0050] Figure-18: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with PEG-200 according to example-29.

[0051] Figure-19: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with PEG-200 according to example-30.

[0052] Figure-20: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with Butylated hydroxytoluene according to example-31. Figure-21: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with TPGS according to example-32.

[0053] Figure-22: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with TPGS according to example-33.

[0054] Figure-23: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with PEG-400 according to example-34.

[0055] Figure-24: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with PEG-400 according to example-35.

[0056] Figure-25: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with PEG- 1500 according to example-36.

[0057] Figure-26: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with PEG- 1500 according to example-37.

[0058] Figure-27: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with PEG-400 according to example-38.

[0059] Figure-28: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with PEG-400 according to example-39.

[0060] Figure-29: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with Sucrose and Povidone-K30 according to example-40. Figure-30: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with Sucrose and Povidone-K30 according to example-41. Figure-31: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with Sucrose and Povidone-K30 according to example-42. Figure-32: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with HPC.EXF according to example-43.

[0061] Figure-33: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with Methocel VLV according to example-44.

[0062] Figure-34: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with Povidone-K30 according to example-45. Figure-35: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with HPC.EXF according to example-46.

[0063] Figure-36: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with Sucrose according to example-47.

[0064] Figure-37: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with PEG-4000 according to example-48.

[0065] Figure-38: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with PEG-4000 according to example-49.

[0066] Figure-39: Illustrates the PXRD pattern of an amorphous solid dispersion of elacestrant dihydrochloride with Succinic acid.

[0067] DETAILED DESCRIPTION:

[0068] The present invention provides an amorphous solid dispersion comprising elacestrant dihydrochloride along with one or more pharmaceutically acceptable excipients, such as a polymer and / or an alkalizing agent.

[0069] The present invention also provides a process for the preparation of an amorphous form and an amorphous solid dispersion comprising elacestrant dihydrochloride, along with one or more pharmaceutically acceptable excipients such as a polymer and / or an alkalizing agent. The oral solid dosage form of the amorphous form and / or amorphous dispersion provides enhanced bioavailability as well as stability.

[0070] The term “suitable solvent” used in the present invention is selected from the group comprising of water, alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons and halogenated hydrocarbons; wherein alcohol is selected from the group consisting of methanol, ethanol, n-propanol, iso-propanol, n-butanol, isobutanol and the like; ester is selected from the group consisting of ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate; ketone is selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone; ether is selected from the group consisting of methyl tert -butyl ether, diisopropyl ether, diethyl ether tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentyl methyl ether, dioxane and the like; halogenated solvent is selected from the group consisting of dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform, chlorobenzene, bromobenzene and the like; hydrocarbons is selected from the group consisting of toluene, xylene, n-pentane, n-hexane, n-heptane, anisole, ethyl benzene, cyclohexane and the like; nitrile is selected from the group consisting of acetonitrile, propionitrile and the like; amide is selected from the group consisting of N,N- dimethylformamide, N,N-dimethyl acetamide and the like; sulfoxide such as dimethyl sulfoxide; sulfone; or mixtures thereof.

[0071] The term “solid dispersion” used in the present invention is defined as the dispersion of a drug in a solid matrix where the matrix is either a small molecule or a polymer. Preferably, solid dispersion relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way. In other words, in a solid dispersion, the two components (polymer and API) form a homogeneous one-phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size. In a preferred embodiment, in the solid dispersion according to the present invention, no chemical bonds can be detected between the API and the polymer. In order to arrive at such a solid dispersion, preferably a solid solution, it is required to have a substantial amount of API dissolved in a suitable solvent at least at once during the preparation of said solid dispersion.

[0072] The polymer is selected from but not limited to polyvinylpyrrolidone (povidone or PVP; PVP of different grades like K-15, K-30, K-60, K-90 and K-120 may be used) and vinyl acetate (PVP / VA) copolymer, co-povidone, polyvinyl alcohol (PVA), polyvinyl acetate, polyvinylcaprolactam copolymer, polyacrylic acid (PAA), poly( ethylene glycol) (PEG; PEG of different grades like PEG-200, PEG-400, PEG- 1500 and PEG-4000 may be used), poly(ethylene oxide) (PEG), methyl cellulose, ethyl cellulose, carboxymethyl cellulose (CMC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC; HPC of different grades like LF and EXF may be used), hydroxypropyl cellulose acetate succinate (HPC-AS), hydroxypropylmethyl cellulose (hypromellose or HPMC or Methocel VLV), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxyethyl methyl cellulose succinate (HEMCS), cellulose acetate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate (HPMC- P), hydroxypropyl methyl cellulose phthalate, polyvinyl alcohols, propylene glycols, polyethylene glycol (macrogol or PEG), polysaccharides, heteropolysaccharides (pectins), poloxamers, poloxamines, and copolymers based on methacryalic acid and methacrylic / acrylic ester or derivatives, or a mixture thereof.

[0073] The alkalizing agent is selected from but not limited to meglumine, triethanolamine, diethanolamine, monoethanolamine, tromethamine, L-arginine, L-lysine, and L- histidine, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, sodium bicarbonate, calcium carbonate, magnesium oxide, magnesium carbonate, magnesium hydrogen carbonate, aluminum hydroxide, magnesium silicate, sodium citrate, magnesium aluminate, aluminum magnesium hydroxide, tribasic calcium phosphate or a mixture thereof.

[0074] In one embodiment, the present invention provides an amorphous solid dispersion comprising elacestrant dihydrochloride and one or more pharmaceutically acceptable excipients, such as a polymer and / or an alkalizing agent.

[0075] The starting compound elacestrant dihydrochloride is well known in the art and can be obtained according to the methods known in the art or the method exemplified herein in the present invention. Further, the starting compound elacestrant dihydrochloride may be in any form, such as crude obtained directly from the reaction mass, crystalline, amorphous, semi-solid in nature, and / or other forms, including various solvates and hydrates known in the art.

[0076] The pharmaceutically acceptable excipient such as polymer and / or an alkalizing agent is as defined above. The excipient used in the present invention refers to its ability to play a significant role in stabilizing solid dispersions, maximizing bioavailability, and overcoming absorption issues associated with poorly soluble drugs. Further, the excipient stabilizes the amorphous form of elacestrant dihydrochloride to prevent the conversion of the amorphous form to the crystal form. The excipients may be utilized with the elacestrant dihydrochloride and polymer composition in order to formulate the composition into tablets, capsules, suspensions, powders for suspension, creams, transdermal patches, depots, and the like.

[0077] In another embodiment, the present invention provides an amorphous solid dispersion comprising elacestrant dihydrochloride and one or more suitable pharmaceutically acceptable excipients, such as a polymer and / or an alkalizing agent. The excipient is selected from, but not limited to, polyvinylpyrrolidone (povidone or PVP; including various grades such as K-15, K-30, K-60, K-90, and K-120), copovidone, polyvinyl alcohol (PVA), polyvinyl acetate, poly(ethylene glycol) (PEG; including PEG-200, PEG-400, PEG- 1500, and PEG-4000), hydroxypropyl cellulose (HPC; including grades LF and EXF), hydroxypropyl methylcellulose (hypromellose, HPMC, or Methocel VLV), hydroxypropyl methylcellulose acetate succinate (HPMC- AS), meglumine, tromethamine, L-arginine, or mixtures thereof. The amorphous solid dispersion of elacestrant dihydrochloride described in the present invention demonstrates enhanced physical and chemical stability through the strategic selection of pharmaceutically acceptable excipients, such as polymers and alkalizing agents. These excipients play a critical role in inhibiting crystallization and maintaining the drug in its amorphous state, thereby preventing phase separation and recrystallization during storage. The stability of the formulation is further supported by strong drug- polymer interactions, optimal glass transition temperature, and careful control of environmental factors such as moisture and temperature. By maintaining the amorphous form and protecting against degradation pathways, the formulation ensures consistent therapeutic efficacy and extended shelf life under recommended storage conditions.

[0078] In another embodiment, the present invention provides an amorphous solid dispersion comprising elacestrant dihydrochloride along with one or more suitable pharmaceutically acceptable excipients, such as stabilizing agents including antioxidants such as butylated hydroxytoluene (BHT); lubricants such as stearic acid; solubilizers such as d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS); pH modifiers such as citric acid or succinic acid; and sweeteners such as sucrose. These excipients may be used individually or in combination to enhance the stability, processability, and palatability of the dispersion.

[0079] The amorphous solid dispersion may comprise elacestrant dihydrochloride and a pharmaceutically acceptable excipient, such as stabilizing agents including polymers and / or alkalizing agents, in a weight ratio ranging from about 1:0.01 to about 1:10 (elacestrant dihydrochloride to excipient). This ratio range is selected to optimize the physical stability, solubility, and bioavailability of the drug.

[0080] In another embodiment of the present invention is provide an amorphous solid dispersion comprising elacestrant dihydrochloride prepared by freeze drying (lyophilization), solvent evaporation, spray drying, hot melt extrusion, co-grinding, rotary evaporation, co-precipitation, any suitable solvent removal process, the addition of a suitable anti-solvent, or any combination thereof. In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of elacestrant dihydrochloride, comprising the steps of: a) dissolving a mixture of elacestrant dihydrochloride and one or more suitable excipients, such as stabilizing agents including polymers and / or alkalizing agents, in a suitable solvent or solvent mixture at an appropriate temperature; b) removing the solvent by freeze drying (lyophilization) of the resulting solution; and c) isolating the amorphous solid dispersion of elacestrant dihydrochloride.

[0081] In an embodiment, step a) involves dissolving elacestrant dihydrochloride together with a suitable excipient, such as a polymer and / or an alkalizing agent (e.g., a stabilizing agent), in a suitable solvent or mixture of solvents at a temperature ranging from about 10°C up to the reflux temperature of the solvent used. The mixture is stirred for a sufficient period to ensure complete dissolution. The resulting solution may be filtered to remove any undissolved particles or extraneous matter; Step (b) involves removing the solvent by freeze drying (lyophilization) of the solution. This process includes freezing the solution of elacestrant dihydrochloride at low temperatures and reducing the pressure to facilitate solvent removal from the frozen solution. The freezing temperature may range from about -80°C to about 0°C, or up to about 20°C, depending on the solvent system. The temperature for solvent removal (sublimation) may be less than about 20°C, 0°C, -20°C, -40°C, -60°C, -80°C, or any other suitable temperature as required by the specific process conditions; .and Step (c) involves collecting the solid obtained from step (b) by techniques such as scraping, shaking the container, or other methods appropriate to the equipment used. The isolated solid may optionally be further dried to yield an amorphous solid dispersion of elacestrant dihydrochloride.

[0082] The suitable pharmaceutically acceptable excipient, such as a polymer and / or an alkalizing agent (e.g., a stabilizing agent), is as defined above. Preferred excipients include polyvinylpyrrolidone (povidone or PVP), with various grades such as K-15, K- 30, K-60, K-90, and K-120; poly(ethylene glycol) (PEG), including grades PEG-200, PEG-400, PEG- 1500, and PEG-4000; hydroxypropyl cellulose (HPC), including grades LF and EXF; hydroxypropyl methylcellulose (hypromellose, HPMC, or Methocel VLV); hydroxypropyl methylcellulose acetate succinate (HPMC-AS); meglumine; tromethamine; L-arginine; or mixtures thereof.

[0083] The suitable solvent is selected from, but not limited to, alcohol solvents, ester solvents, nitrile solvents, ketone solvents, chloro solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, water, or mixtures thereof. Preferably, the solvent is an alcohol solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, or the like.

[0084] In another embodiment the present invention provides a process for the preparation of an amorphous solid dispersion of elacestrant dihydrochloride, comprising the steps of: a) dissolving a mixture of elacestrant dihydrochloride and one or more suitable excipients, such as stabilizing agents including polymers and / or alkalizing agents, in a suitable solvent or solvent mixture at an appropriate temperature; b) removing the solvent by evaporation; and c) isolating the amorphous solid dispersion of elacestrant dihydrochloride.

[0085] In an embodiment, step (a), which involves dissolving elacestrant dihydrochloride together with a suitable excipient, such as a polymer and / or an alkalizing agent (e.g., a stabilizing agent), can be performed in a manner similar to that described above;

[0086] Step (b) involves removing the solvent by evaporation, which may be carried out by slow evaporation or by distilling the solvent to near dryness using a rotary evaporator device, such as a Buchi Rotavapor, over a sufficient period of time. Evaporation, as used herein, refers to the removal of solvent almost completely at atmospheric pressure or under reduced pressure. Flash evaporation refers to solvent removal techniques including, but not limited to, tray drying and fluidized bed drying. Step (c) involves collecting the solid obtained from step (b) by techniques such as scraping, shaking the container, or other methods specific to the equipment used. The isolated solid may optionally be further dried to afford an amorphous solid dispersion of elacestrant dihydrochloride.

[0087] The pharmaceutically acceptable excipient, including polymers and / or alkalizing agents (such as stabilizing agents), as well as the suitable solvent, are as previously described.

[0088] In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of elacestrant dihydrochloride, comprising the steps of: a) dissolving a mixture of elacestrant dihydrochloride and one or more suitable excipients, such as stabilizing agents including polymers and / or alkalizing agents, in a suitable solvent or solvent mixture at an appropriate temperature; and b) isolating the amorphous solid dispersion of elacestrant dihydrochloride by spray drying.

[0089] In an embodiment, step (a), which involves dissolving elacestrant dihydrochloride together with a suitable excipient, such as a polymer and / or an alkalizing agent (e.g., a stabilizing agent), can be performed in a manner similar to that described above; and Step (b) involves removing the solvent by a spray drying process, which includes atomizing the liquid mixture into small droplets and rapidly evaporating the solvent within a spray-drying apparatus, such as a nozzle. The driving force for solvent evaporation is maintained by keeping the partial pressure of the solvent inside the spray dryer substantially below the solvent’s vapor pressure at the temperature of the drying droplets. The feed liquid may be a solution, slurry, emulsion, gel, or paste, provided it is pumpable and capable of atomization. Upon completion of spraying, the feed and atomization are stopped, and the resultant amorphous solid dispersion is collected.

[0090] This spray drying process ensures the production of a physically and chemically stable amorphous solid dispersion of elacestrant dihydrochloride, suitable for pharmaceutical formulations with improved oral bioavailability and shelf life.

[0091] The pharmaceutically acceptable excipient, including polymers and / or alkalizing agents (such as stabilizing agents), as well as the suitable solvent, are as previously described.

[0092] In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of elacestrant dihydrochloride, comprising the steps of: a) mixing elacestrant dihydrochloride with a suitable excipient, such as a stabilizing agent including a polymer and / or an alkalizing agent; b) heating the resulting mixture obtained in step (a) at an appropriate temperature for a sufficient period to form a homogeneous reaction mass; and; c) isolating the amorphous solid dispersion of elacestrant dihydrochloride.

[0093] In an embodiment, step a) involves mixing elacestrant dihydrochloride with a suitable excipients such as a polymer and / or an alkalizing agent; step b) feed the blended mixture of step a) in the extruder and heat and convey the material from barrel at various suitable temperature of about 10°C to about 190°C, for a sufficient period of time till uniform molten mass obtained; step c) pass the molten mass from suitable die to form a strand or sheet followed by cooling, and step d) mill or powder the cooled extrudes to get the amorphous solid dispersion of elacestrant dihydrochloride and processed for the further downstream process. The isolated solid may be optionally further dried to afford an amorphous solid dispersion of elacestrant dihydrochloride. The pharmaceutically acceptable excipient, including polymers and / or alkalizing agents (such as stabilizing agents), used in Step a) are as previously described.

[0094] In another embodiment, the present invention provides a process for the preparation of amorphous solid dispersion of elacestrant dihydrochloride, comprising the steps of: a) dissolving elacestrant dihydrochloride in a suitable solvent or mixture of solvents at a suitable temperature; b) heating the resulting solution at a suitable temperature; c) adding a suitable excipient, such as a stabilizing agent including a polymer and / or an alkalizing agent to the heated solution obtained in step (b); d) removing the solvent from the solution or suspension obtained in step c); e) cooling the reaction mass to a suitable temperature; f) adding a suitable anti-solvent to the cooled reaction mass obtained in step e); and g) isolating the amorphous solid dispersion of elacestrant dihydrochloride.

[0095] In an embodiment, the process for preparing an amorphous solid dispersion of elacestrant dihydrochloride comprises the following steps: Step (a): Dissolving elacestrant dihydrochloride in a suitable solvent or mixture of solvents at a temperature ranging from about 10°C to the boiling point of the solvent, with stirring for a sufficient period to ensure complete dissolution. Step (b): Heating the solution obtained in step (a) at a temperature ranging from about 35 °C to the reflux temperature of the solvent used, for a sufficient period to achieve the desired reaction conditions. Step (c): Adding a suitable excipient, such as a stabilizing agent including a polymer and / or an alkalizing agent, to the heated solution from step (b). The resulting solution may be filtered to remove any undissolved particles or extraneous matter. Step (d): Removing the solvent by distillation, which may be conducted at atmospheric pressure, above atmospheric pressure, or under reduced pressure. The distillation temperature may be less than about 120°C, 100°C, 90°C, or any other suitable temperature, provided that the conditions do not cause an increase in impurity levels due to decomposition. Step (e): Cooling the reaction mass obtained from step (d) to a temperature ranging from about 0°C to about 30°C. Step (f): Adding a suitable anti-solvent to the cooled reaction mass from step (e) and maintaining the mixture for a sufficient period to complete the reaction or precipitation. Step (g): Isolating the amorphous solid dispersion of elacestrant dihydrochloride by filtration, which may be performed by gravity or suction filtration.

[0096] The suitable solvent and anti-solvent used in steps (a) and (f), are selected from, but are not limited to, alcohol solvents, ester solvents, nitrile solvents, ketone solvents, chloro solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, water, or mixtures thereof. Preferably, the alcohol solvents include methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, and the like. Preferred hydrocarbons include toluene, xylene, n-pentane, n-hexane, n-heptane, cyclohexane, and the like;

[0097] The pharmaceutically acceptable excipient, including polymers and / or alkalizing agents (such as stabilizing agents), used in Step c) are as previously described.

[0098] In another embodiment, the present invention provides a process for the preparation of amorphous elacestrant dihydrochloride, comprising the steps of: a) dissolving elacestrant dihydrochloride in a suitable solvent or mixture of solvents at a suitable temperature; b) heating the resulting solution at a suitable temperature; c) removing the solvent from the solution obtained in step b); d) cooling the reaction mass obtained after solvent removal to a suitable temperature; e) adding a suitable anti-solvent to the cooled reaction mass obtained in step (d); and f) isolating the amorphous elacestrant dihydrochloride.

[0099] In an embodiment, the process for preparing amorphous elacestrant dihydrochloride comprises the following steps: Step (a): Dissolving elacestrant dihydrochloride in a suitable solvent or mixture of solvents at a temperature ranging from about 10°C to the boiling point of the solvent, with stirring for a sufficient period to ensure complete dissolution. Step (b): Heating the solution obtained in step (a) at a temperature ranging from about 35°C to the reflux temperature of the solvent used, for a sufficient period. The solution may be filtered to remove any undissolved particles or extraneous matter. Step (c): Removing the solvent by distillation, which may be conducted at atmospheric pressure, above atmospheric pressure, or under reduced pressure. The distillation temperature may be less than about 120°C, 100°C, 90°C, or any other suitable temperature, provided that the conditions do not lead to increased impurity levels due to decomposition. Step (d): Cooling the reaction mass obtained from step (c) to a temperature ranging from about 0°C to about 30°C. Step (e): Adding a suitable antisolvent to the cooled reaction mass from step (d) and maintaining the mixture for a sufficient period to complete the reaction or precipitation. Step (f): Isolating the amorphous elacestrant dihydrochloride by filtration, which may be performed by gravity or suction.

[0100] The suitable solvent and anti-solvent used in steps (a) and (e), are selected from, but are not limited to, alcohol solvents, ester solvents, nitrile solvents, ketone solvents, chloro solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, water, or mixtures thereof. Preferably, the alcohol solvents include methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, and the like. Preferred hydrocarbons include toluene, xylene, n-pentane, n-hexane, n-heptane, cyclohexane and the like.

[0101] In another embodiment, the present invention provides a process for the preparation of amorphous elacestrant dihydrochloride, comprising the steps of: a) dissolving elacestrant dihydrochloride in a suitable solvent or mixture of solvents at a suitable temperature; and b) isolating the amorphous elacestrant dihydrochloride by spray drying. In an embodiment, step (a) involves dissolving elacestrant dihydrochloride in a suitable solvent or mixture of solvents at a temperature ranging from about 10°C to the reflux temperature of the solvent used, with stirring for a sufficient period to ensure complete dissolution. The resulting solution may be filtered to remove any undissolved particles or extraneous matter. Step (b) involves removing the solvent by a spray drying process, which includes atomizing the liquid mixture into small droplets and rapidly evaporating the solvent within a spray-drying apparatus (e.g., a nozzle). The driving force for solvent evaporation is maintained by keeping the partial pressure of the solvent inside the spray dryer substantially below the vapor pressure of the solvent at the temperature of the drying droplets. The feed liquid may be a solution, slurry, emulsion, gel, or paste, provided it is pumpable and capable of being atomized. Upon completion of the spraying process, the feed and atomization are stopped, and the resultant amorphous solid dispersion is collected.

[0102] The suitable solvent is selected from but are not limited to alcohol solvent, ester solvent, nitrile solvent, ketone solvent, chloro solvent, ether solvent, hydrocarbon solvent, polar aprotic solvent, water, or a mixture thereof; preferably alcohol solvent such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol and the like.

[0103] In another embodiment, an amorphous or an amorphous solid dispersion of elacestrant dihydrochloride prepared according to the present invention may be micronized or milled using conventional particle size reduction techniques to achieve the desired particle size and solubility profile, tailored to the requirements of various pharmaceutical compositions. Suitable techniques for particle size reduction include, but are not limited to, ball milling, roll milling, hammer milling, and jet milling. The milling or micronization step may be performed either prior to drying or after the completion of the drying process. It was found that the amorphous solid dispersion of elacestrant dihydrochloride described herein is stable and exhibits excellent physicochemical properties. Furthermore, the amorphous solid dispersion of the present invention can be readily formulated into pharmaceutical compositions comprising elacestrant dihydrochloride.

[0104] Amorphous and amorphous solid dispersions of elacestrant dihydrochloride produced by the method of the present invention, along with their purity and relative content of N-ethyl impurity, are summarized below in Table 1.

[0105] The present invention recognizes the critical importance of controlling the levels of N- ethyl impurity in amorphous and amorphous solid dispersions of elacestrant dihydrochloride. The N-ethyl impurity, being a known related substance formed during synthesis or degradation, directly impacts the chemical purity and overall quality of the pharmaceutical composition. Maintaining low levels of this impurity is essential to ensure the safety and efficacy of the drug product, as elevated impurity concentrations may pose potential toxicological risks. Furthermore, the control of N-ethyl impurity levels is necessary to comply with regulatory guidelines and pharmacopeial standards governing drug purity and quality. Monitoring the N-ethyl impurity also serves as an indicator of the chemical stability of the amorphous solid dispersion, with stable and minimal impurity levels reflecting the robustness of the formulation and manufacturing process. Accordingly, the methods described herein provide amorphous solid dispersions of elacestrant dihydrochloride with controlled and acceptable N-ethyl impurity content, thereby ensuring a safe, effective, and regulatory-compliant pharmaceutical composition. The content of N-ethyl impurity amorphous solid dispersions of elacestrant dihydrochloride, preferably is less than 0.15% by weight Table 1:

[0106] Amorphous forms and amorphous solid dispersions of elacestrant dihydrochloride produced by the method of the present invention, tested at various stability conditions along with their purity and relative levels of N-ethyl impurity, are summarized in Table 2 below. Table 2:

[0107]

[0108] In another embodiment of the present invention provides a pharmaceutical composition comprising an amorphous or an amorphous solid dispersion of elacestrant dihydrochloride, along with one or more pharmaceutically acceptable excipients.

[0109] The pharmaceutical composition comprising amorphous or amorphous solid dispersion of elacestrant dihydrochloride and one or more pharmaceutically acceptable excipients selected from but not limited to fillers, binders, disintegrators, lubricants, coloring agents, stabilizing agents, buffers, antioxidants, glidants, polymers and the like.

[0110] The pharmaceutical composition as used herein 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 that results, directly or indirectly, from the combination, complexation, or aggregation of any two or more of the ingredients. Accordingly, pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.

[0111] The composition of the present application may be a solid oral dosage form such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage form 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. The composition of the present application may be in the forms of immediate release, delayed release, or modified release.

[0112] In another embodiment of the present invention provides the use of amorphous or amorphous solid dispersion of elacestrant dihydrochloride in the treatment of patients with postmenopausal and breast cancer.

[0113] EXAMPLES:

[0114] The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

[0115] Example-1: Preparation of amorphous form of elacestrant dihydrochloride by distillation:

[0116] To a clean and dry RBF, elacestrant dihydrochloride (1 g) was dissolved in methanol (5 ml) at 20 to 30°C, heated to 40 to 50°C, stirred for up to a clear solution, and maintained for 20 to 30 min at the same temperature. Distilled off methanol followed by co-distilled with n-heptane (1 ml) under vacuum at 40 to 50°C. Cooled the reaction mass to 20 to 30°C under a nitrogen atmosphere, n-heptane (5 ml) was added and stirred for 30 to 40 min at the same temperature. The solid obtained was filtered, washed with n-heptane ( 1 ml) under nitrogen atmosphere, and dried under reduced pressure at 40 to 45°C to obtain the title compound. Yield: 0.95 g.

[0117] Example-2: Preparation of amorphous form of elacestrant dihydrochloride by Spray Drying:

[0118] Elacestrant dihydrochloride (65 g) was dissolved in methanol (1300 mL) at 20 to 30°C, and stirred for 20 to 30 mins at the same temperature until a clear solution was obtained. Filtered the solution through 0.2-micron filter to remove undissolved particulates. The resulting clear solution was subjected to spray drying in a laboratory Spray Dryer (Model Buchi-S300) with feed rate of the solution 6 mL / min and inlet temperature at 60°C to obtain the title compound. Yield: 50.0 g.

[0119] Example-3: Preparation of amorphous solid dispersion of elacestrant dihydrochloride by freeze drying (lyophilization):

[0120] To a clean and dry RBF, elacestrant dihydrochloride (1 g) and Povidone-K30 (1 g) were dissolved in methanol (10 ml) at 40 to 50°C, and stirred for 20 to 30 mins at the same temperature until a clear solution was obtained. Filtered the solution through hyflo to remove undissolved particulates. The resulting clear solution was subjected to Eyophilisation using Labocon lyophilizer (ModeLFD-BT-104) to obtain the title compound. Yield: 1.5 g.

[0121] Example-4: Preparation of amorphous solid dispersion of elacestrant dihydrochloride by freeze drying (lyophilization):

[0122] To a clean and dry RBF, elacestrant dihydrochloride (1 g) and HPMC-AS (1 g) were dissolved in methanol (10 ml) at 40 to 50°C, and stirred for 20 to 30 mins at the same temperature until a clear solution was obtained. Filtered the solution through hyflo to remove undissolved particulates. The resulting clear solution was subjected to Lyophilisation using Labocon lyophilizer (ModeLFD-BT-104) to obtain the title compound. Yield: 1.6 g.

[0123] Example-5: Preparation of amorphous solid dispersion of elacestrant dihydrochloride by evaporation (rotary evaporator):

[0124] Elacestrant dihydrochloride (1 g) and Povidone-K30 (1 g) were dissolved in methanol (10 ml) at 40 to 50°C, and stirred for 20 to 30 mins at the same temperature until a clear solution was obtained. Filtered the solution through hyflo to remove undissolved particulates. The resulting clear solution was distilled completely under vacuum using rotary evaporation at 65 to 70°C to obtain the title compound. Yield: 1.4 g.

[0125] Example-6: Preparation of amorphous solid dispersion of elacestrant dihydrochloride by evaporation (rotary evaporator):

[0126] Elacestrant dihydrochloride (1 g) and HPMC-AS (1 g) were dissolved in methanol (10 ml) at 40 to 50°C, and stirred for 20 to 30 mins at the same temperature until a clear solution was obtained. Filtered the solution through hyflo to remove undissolved particulates. The resulting clear solution was distilled completely under vacuum using rotary evaporation at 65 to 70°C to obtain the title compound. Yield: 1.5 g.

[0127] Example 7: Preparation of amorphous solid dispersion of elacestrant dihydrochloride by evaporation (rotary evaporator):

[0128] Elacestrant dihydrochloride (5 g), Succinic acid (0.65 g, 0.5 eq.) were dissolved in methanol (100 mL) at 20 to 30°C, and stirred for 20 to 30 mins at the same temperature until a clear solution was obtained. Filtered the solution through 0.2-micron filter to remove undissolved particulates. The resulting clear solution was distilled by using rotary evaporator at below 45°C and obtained the title compound. Yield: 5.0 g. Example-8: Preparation of amorphous solid dispersion of elacestrant dihydrochloride by Hot Melt Extrusion:

[0129] Elacestrant dihydrochloride (1 g) and Povidone-K30 (2 g) were mixed uniformly. After passing through a 40-mesh filter, the mixture was fed to a Thermo MiniCTW extruder for amorphous solid dispersion preparation at a temperature of 150 to 160°C and a speed of 30 rpm. The collected solid was grinded and passed through a 40-mesh filter to obtain the title compound. Yield: 2.20 g.

[0130] Example-9: Preparation of amorphous solid dispersion of elacestrant dihydrochloride by Hot Melt Extrusion:

[0131] Elacestrant dihydrochloride (1 g) and HPMC-AS (2 g) were mixed uniformly. After passing through a 40-mesh filter, the mixture was fed to a Thermo MiniCTW extruder for amorphous solid dispersion preparation at a temperature of 150 to 160°C and a speed of 30 rpm. The collected solid was grinded and passed through a 40-mesh filter to obtain the title compound. Yield: 2.38 g.

[0132] Example-10: Preparation of amorphous solid dispersion of elacestrant dihydrochloride by Distillation:

[0133] Elacestrant dihydrochloride (1 g) was dissolved in methanol (5 ml) at 20 to 30°C, heated to 40 to 50°C, and stirred for up to a clear solution. Povidone-K30 (1 g) was added and stirred for 20 to 30 min at the same temperature. Distilled off methanol followed by co-distilled with n-heptane (1 ml) under vacuum at 40 to 50°C. Cooled the reaction mass to 20 to 30°C under a nitrogen atmosphere, n-heptane (5 ml) was added and stirred for 30 to 40 min at the same temperature. The solid obtained was filtered, washed with n-heptane ( 1 ml) under a nitrogen atmosphere, and dried under reduced pressure at 40 to 45°C to obtain the title compound. Yield: 1.85 g. The following table summarizes amorphous solid dispersions of elacestrant dihydrochloride prepared analogously using the distillation process described above. Example-16: Preparation of amorphous solid dispersion of elacestrant dihydrochloride by Spray Drying:

[0134] Elacestrant dihydrochloride (20 g), PEG-400 (4 g), Povidone-K30 (10 g) and Meglumine (1g) were dissolved in methanol (700 mL) at 20 to 30°C, and stirred for 20 to 30 mins at the same temperature until a clear solution was obtained. Filtered the solution through 0.2-micron filter to remove undissolved particulates. The resulting clear solution was subjected to spray drying in a laboratory Spray Dryer (Model labultima- LU200) with feed rate of the solution 6 mL / min and inlet temperature at 60°C to obtain the title compound. Yield: 12.0 g. The following table summarizes amorphous solid dispersions of elacestrant dihydrochloride prepared analogously using the spray drying process described above.

[0135]

[0136] Example-51: Tablets Containing amorphous solid dispersion of elacestrant dihydrochloride Amorphous solid dispersion of elacestrant dihydrochloride tablets were prepared by dry granulation, using the formulations detailed in Table 3 and 4. Table 3

[0137] Table 4 Tablet fabrication procedure:

[0138] 1. The required quantities of the API as well as the excipients were weighed according to the batch formula.

[0139] 2. Co-sifting of the API and intra granular materials was performed using a #30 mesh sieve, except for the lubricant, which was sifted through #60 mesh sieve. 3. The materials from steps 1 and 2 were combined in a double-lined polybag and mixed manually. The premixed material was subjected to a slugging process using suitable punches to achieve the desired hardness. The slugs obtained in step 4 were manually crushed using a stainless -steel pestle and mortar, then passed through ASTM #20 / 60 sieves. The fraction passing through ASTM #20 / 60 should be no less than 70%. If necessary, step 5 was repeated until at least 70% of the material passed through ASTM #20 / 60 sieves. The resulting material was manually mixed in a double-lined polybag. The extragranular materials, except the lubricant, were passed through a #40 mesh sieve; the lubricant was passed through a #60 mesh sieve. Materials from steps 7 and 8 were combined and mixed manually in a polybag. The compression was carried out using the lubricated blend prepared in step 9.

Claims

1. CLAIMS:

1. An amorphous solid dispersion comprising elacestrant dihydrochloride and one or more pharmaceutically acceptable excipients, such as stabilizing agents including polymers and / or alkalizing agents.

2. The amorphous solid dispersion according to claim 1 , wherein the polymer and / or an alkalizing agent is selected from polyvinylpyrrolidone (povidone or PVP; PVP of different grades like K-15, K-30, K-60, K-90 and K-120), poly(ethylene glycol) (PEG; PEG of different grades like PEG-200, PEG-400, PEG- 1500 and PEG- 4000), hydroxypropyl cellulose (HPC; HPC of different grades like LF and EXF), hydroxypropylmethyl cellulose (hypromellose or HPMC or Methocel VLV), hydroxypropyl methylcellulose acetate succinate (HPMC -AS), meglumine, tromethamine, L-arginine or a mixture thereof.

3. The amorphous solid dispersion according to claim 1 to 2, wherein the ratio of elacestrant dihydrochloride to the pharmaceutically acceptable excipient ranges from about 1:0.01 to about 1: 10.

4. A process for the preparation of an amorphous solid dispersion of elacestrant dihydrochloride, according to claim 1 to 3, wherein the amorphous solid dispersion is prepared by one or more methods selected from the group consisting of freeze drying (lyophilization), solvent evaporation, spray drying, hot melt extrusion, cogrinding, rotary evaporation, co-precipitation, solvent removal processes, addition of a suitable anti-solvent, or any combination thereof.

5. A process for the preparation of amorphous elacestrant dihydrochloride, comprising the steps of: a) dissolving elacestrant dihydrochloride in a suitable solvent or mixture of solvents at a suitable temperature;b) heating the resulting solution at a suitable temperature; c) removing the solvent from the solution obtained in step b); d) cooling the reaction mass obtained after solvent removal to a suitable temperature; e) adding a suitable anti-solvent to the cooled reaction mass obtained in step (d); and f) isolating the amorphous elacestrant dihydrochloride.

6. The process as claimed in claim 5, wherein the suitable solvent of step a) is selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol and iso-butanol; and the suitable anti-solvent of step e) is selected from toluene, xylene, n-pentane, n- hexane, n-heptane, anisole, ethyl benzene and cyclohexane.

7. A process for the preparation of amorphous elacestrant dihydrochloride, comprising the steps of: a) dissolving elacestrant dihydrochloride in a suitable solvent or mixture of solvents at a suitable temperature; and b) isolating the amorphous elacestrant dihydrochloride by spray drying.

8. The process as claimed in claim 7, wherein the suitable solvent of step a) is selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol and iso-butanol.

9. An Amorphous or amorphous solid dispersions comprising elacestrant dihydrochloride wherein the content of N-ethyl impurity is less than 0.15% by weight.

10. A pharmaceutical composition comprising an amorphous solid dispersion of elacestrant dihydrochloride according to claim 1 , and one or more pharmaceutically acceptable excipients.

Images