A process for the preparation of solid forms of (6R)-6-(2-(n-(4-(2-(ethylamino) ethyl) benzyl)-n-ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-OL dihydrochloride

Abstract

The present invention relates to a process for the preparation of solid-state forms of (6R)- 6-(2-(N-(4-(2-(ethylamino)ethyl)benzyl)-N-ethylamino)-4-methoxyphenyl) 5,6,7,8- tetrahydr -onaphthalen-2-ol dihydrochloride (1). Formula (1) Elacestrant dlhydrochloride (1)

Description

[0001] "A PROCESS FOR THE PREPARATION OF SOLID FORMS OF (6R)-6- (2-(N-(4-(2-(ETHYLAMINO) ETHYL) BENZYL)-N-ETHYLAMINO)-4- METHOXYPHENYL)-5,6,7,8-TETRAHYDRONAPHTHALEN-2-OL DIHYDROCHLORIDE"

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a process for the preparation of solid forms of (6R)-6- (2-(N-(4-(2-(ethylamino) ethyl) benzyl)-N-ethylamino)-4-methoxyphenyl)-5, 6,7,8- tetrahydr -onaphthalen-2-ol dihydrochloride (1).

[0004] BACKGROUND OF THE INVENTION

[0005] Elacestrant dihydrochloride (1), is an estrogen receptor antagonist, for the treatment of postmenopausal women or adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2) -negative, ESRI -mutated advanced or metastatic breast cancer. It is chemically designated as (6R)-6-(2-(N-(4-(2-(ethylamino) ethyl) benzyl)-N-ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydro naphthal en-2-ol dihydrochloride and is chemically represented by the following structural Formula (1).

[0006] Elacestrant dihydrochloride (1)

[0007] US 7612114 B2 discloses Elacestrant and its salts for the first time which discloses a process for the preparation of Elacestrant, however in this patent does not disclose the polymorphism of this product.

[0008] US10385008B2 described crystalline Form 1, form 2 (anhydrous), form 3 (dihydrate) amorphous form & dispersion to matrix. However, this patent application has given no hint or suggestion to prepare solid dispersion / premix of Elacestrant dihydrochloride (1).

[0009] US11643385B2 described crystalline form IB its process for the preparation thereof. WO2023064519 described co-crystal of Elacestrant dihydrochloride and urea with (1 :2) named as Form A. Further this patent application disclosed Elacestrant form Bl, monohydrochloride salt Form HI, Elacestrant dihydrochloride form 6, form 7 & Form 9, Amorphous Elacestrant Dihydrochloride.

[0010] WO2023227029 described crystalline form CSII its process for the preparation thereof. Polymorphism is the occurrence of different crystalline forms of a single compound, and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and / or different X-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid-state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.

[0011] Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as infrared spectrometry or Differential Scanning Calorimetry (DSC). Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances.

[0012] OBJECTIVE OF THE INVENTION

[0013] Accordingly, one objective of the present invention is to provide a process for the preparation of solid forms of Elacestrant di hydrochloride (1).

[0014] In another objective, the present invention provides a process for the preparation of solid dispersion of Elacestrant dihydrochloride (1) with at least one pharmaceutically acceptable excipient. In another objective, the present invention provides a process for the preparation of solid dispersion Elacestrant free base with at least one pharmaceutically acceptable excipient.

[0015] The further objective of the present invention is to provide solid forms of Elacestrant dihydrochloride (1) is purity greater than 99% by HPLC, preferably greater than 99.5% by HPLC, more preferably greater than 99.9% by HPLC.

[0016] SUMMARY OF THE INVENTION

[0017] Accordingly, in the first aspect, the present invention provides a process for the preparation of solid forms of Elacestrant dihydrochloride (1)

[0018] In the second aspect, the present invention provides a process for the preparation of solid dispersion of Elacestrant dihydrochloride (1) comprising the steps of: a) dissolving Elacestrant dihydrochloride (1) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient to the solution obtained in step-a); and c) isolating the solid dispersion of Elacestrant dihydrochloride (1).

[0019] In the third aspect, the present invention provides a process for the preparation of solid dispersion of Elacestrant dihydrochloride (1) comprising the steps of: a) dissolving Elacestrant dihydrochloride (1) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient in a solvent to the mixture obtained in step a); and c) isolating the solid dispersion of Elacestrant dihydrochloride (1).

[0020] In the fourth aspect, the present invention provides an alternative process for the preparation of solid dispersion of Elacestrant dihydrochloride (1) comprising the steps of: a) dissolving Elacestrant free base (2) in a solvent or mixture of solvents, b) adding a solution of hydrochloric acid to the solution obtained in step a), c) adding at least one pharmaceutically acceptable excipient to the mixture obtained to step-b); d) optionally, adding second solvent to the reaction mixture obtained in step c), and e) isolating the solid dispersion of Elacestrant dihydrochloride (1).

[0021] In the fifth aspect, the present invention provides a process for the preparation of solid dispersion of Elacestrant dihydrochloride (1) comprising the steps of: a) dissolving Elacestrant free base (2) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient to the solution obtained in step-a), c) isolating the solid dispersion of Elacestrant free base, d) adding a solution of hydrochloric acid to step c), and e) isolating the solid dispersion of Elacestrant dihydrochloride (1).

[0022] In the sixth aspect, the present invention provides a process for the preparation of solid dispersion of Elacestrant free base comprising the steps of: a) dissolving Elacestrant free base (2) in a solvent or mixture of solvents b) adding at least one pharmaceutically acceptable excipient to the solution obtained in step-a), and c) isolating the solid dispersion of Elacestrant free base.

[0023] In the seventh aspect, the present invention provides solid-state forms of Elacestrant dihydrochloride (1) is having purity greater than 99% by HPLC, preferably greater than 99.5% by HPLC, more preferably greater than 99.9% by HPLC with total impurities less than 1.0%, more preferably less than 0.5%.

[0024] BRIEF DESCRIPTION OF THE DRAWINGS:

[0025] Figure 1: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Elacestrant dihydrochloride (1) with PVP. obtained Example 1

[0026] Figure 2: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Copovidone, obtained Example 2

[0027] Figure 3: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Elacestrant dihydrochloride (1) with HPMC-E3. obtained Example 3 Figure 4: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Elacestrant dihydrochloride (1) with PVP obtained Example 25

[0028] Figure 5: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Elacestrant dihydrochloride (1) with PVP obtained Example 26

[0029] Figure 6: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Copovidone, obtained Example 27.

[0030] Figure 7: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Elacestrant (1) with Copovidone obtained Example 28 Figure 8: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Elacestrant (1) with PVP obtained example 29

[0031] DETAILED DESCRIPTION OF THE INVENTION

[0032] As used herein, the term “solid dispersion” refers to dispersion of drug in a solid matrix where the matrix is either a small molecule or 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 or more 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.

[0033] As used herein, the term “excipient” refers to play a significant role in stabilizing solid dispersions, maximizing bioavailability, and overcoming absorption issues associated with poorly soluble drugs.

[0034] In the present application, solid dispersion and premix are used interchangeably to describe solid states disclosed herein.

[0035] Accordingly, in one embodiment the present invention provides a process for the preparation of solid forms of Elacestrant dihydrochloride (1). In the first embodiment, the present invention provides a process for the preparation of solid dispersion of Elacestrant dihydrochloride (1) comprising the steps of a) dissolving Elacestrant dihydrochloride (1) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient to the solution obtained in step-a); and c) isolating the solid dispersion of Elacestrant dihydrochloride (1)

[0036] In the process of the first embodiment, the suitable solvent used in step-a) is selected from alcohol solvents such as methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2- butanol, and the like; chloro solvents such as di chloromethane, 1, 2- di chloroethane, trichloroethylene, chloroform, carbon tetrachloride, and the like; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide and the like; water or its mixture thereof.

[0037] In the process of the first embodiment, the suitable pharmaceutically acceptable excipient used in step-b) selected from but not limited to polyvinylpyrrolidone, (povidone or PVP; PVP of different grades like K-IS, K-30, K-60, K-90 and K-120 may be used), polyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), copovidone, Eudragit, Soluplus, polyethylene glycol (macrogol or PEG), polyethylene glycol-6000 (PEG-6000), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethyl ethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC- AS), hydroxy ethyl methyl cellulose succinate (HEMCS), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), sulfo butyl ether-P-cyclodextrin (SBECD), hydroxypropyl beta cyclodextrin (HPpCD), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, Isomaltose, raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches such as maize starch or corn starch, sodium starch glycolate, sodium carboxymethyl starch, pregelatinized starch, gelatin, sodium dodecyl sulfate, edetate disodium, sodium phosphate, sodium lauryl sulfate, triacetin, sucralose, calcium phosphate, polydextrose, a,P,y-cyclodextrins, sulfo butyl ether betacyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, salcaprozate sodium, sodium caprylate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates and the like.

[0038] In the process of first embodiment, isolation of solid involve removal of solvent is carrying out by suitable techniques which includes but not limited to decantation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as Buchi rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration by gravity or suction, thin film drying, centrifugation or any other suitable techniques known in the art.

[0039] In the process of the first embodiment, drying solid dispersion of Elacestrant dihydrochloride (1) by a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying can be carried out for any time period required for obtaining the desired quality, such as from about 15 minutes to 10 hours or longer.

[0040] Solid dispersion of Elacestrant dihydrochloride (1) prepared according to the present invention can be further micronized or milled in conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but are not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or Micronization may be performed before drying, or after the completion of drying of the product.

[0041] In the process of the first embodiment, the present invention provides the ratio of the amount of Elacestrant dihydrochloride (1) within the solid form to the amount of the excipient which ranges from about 1 : 0.5 to about 1 : 10(w / w).

[0042] In the second embodiment, the present invention provides a process for the preparation of solid dispersion of Elacestrant dihydrochloride (1) with at least one pharmaceutically acceptable excipient, comprising the steps of a) dissolving Elacestrant dihydrochloride (1) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient in a solvent to the mixture obtained in step a), and c) isolating the solid dispersion of Elacestrant dihydrochloride (1).

[0043] In the process of the second embodiment, the suitable solvent used in step-a) is same as defined in the first embodiment.

[0044] In the process of the second embodiment, the suitable pharmaceutically acceptable excipient used in step-b) is same as defined in the first embodiment.

[0045] In the process of the second embodiment, isolating involves removal of solvent from the mixture in step-c) is same as defined in the first embodiment.

[0046] In the present invention, the starting material Elacestrant dihydrochloride (1) can be used in the form of amorphous or crystalline or any other physical form

[0047] In the present invention, the pharmaceutically acceptable excipient used for the preparation of solid dispersion can be amorphous, crystalline or any other physical form.

[0048] In the process of the present invention the resulting solid dispersion of Elacestrant dihydrochloride (1) can be amorphous, crystalline or a mixture thereof. In the third embodiment, the present invention provides a process for the preparation of solid dispersion comprising Elacestrant dihydrochloride (1) with at least one pharmaceutically acceptable excipient, comprising the steps of: a) dissolving Elacestrant free base (2) in a solvent or mixture of solvents, b) adding a solution of hydrochloric acid to the mixture obtained in step a), c) adding at least one pharmaceutically acceptable excipient to the mixture obtained in step-b), and d) isolating the solid dispersion of Elacestrant dihydrochloride (1).

[0049] In the process of the third embodiment, the suitable solvent used in step-a) is selected from alcohol solvents such as methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2- butanol, and the like; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide and the like; or its mixture thereof.

[0050] In the process of the third embodiment, a solution of hydrochloric acid in step-b), comprises dissolving hydrochloric acid in a suitable solvent or a mixture of solvents.

[0051] In the process of the third embodiment, the solution of hydrochloric acid is selected from but not limited to alcoholic hydrochloride, aqueous hydrochloride, concentrated hydrochloride, ethyl acetate hydrochloride; wherein the alcoholic hydrochloride is selected from methanolic Hydrochloride, ethanolic Hydrochloride and the like.

[0052] In the process of third embodiment, the suitable pharmaceutically acceptable excipient used in step-c) is same as defined in the first embodiment.

[0053] In the process of the third embodiment, isolating involves removing the solvent from the mixture used in step-d) is same as defined in the first embodiment.

[0054] In the fourth embodiment, the present invention provides a process for the preparation of solid dispersion of Elacestrant dihydrochloride (1) comprising the steps of: a) dissolving Elacestrant free base (2) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient to the mixture obtained in step-a), c) isolating the solid dispersion of Elacestrant free base (2), d) adding a solution of hydrochloric acid to step c); and e) isolating the solid dispersion of Elacestrant dihydrochloride (1).

[0055] In the process of fourth embodiment, the suitable solvent used in step-a) is same as defined in the third embodiment.

[0056] In the process of the fourth embodiment, providing a solution of hydrochloric acid in step-d), comprises dissolving hydrochloric acid in a suitable solvent or a mixture of solvents.

[0057] In the process of the fourth embodiment, the suitable pharmaceutically acceptable excipient used in step-b) is same as defined in the first embodiment.

[0058] In the process of the fourth embodiment, isolating involves removing the solvent from the mixture used in step-c) and in step-e) is same as defined in the first embodiment.

[0059] In the fifth embodiment, the present invention provides a process for the preparation of solid dispersion comprising Elacestrant free base (2) with at least one pharmaceutically acceptable excipient, comprising the steps of: a) dissolving Elacestrant free base (2) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient to the mixture obtained in step-a); and c) isolating the solid dispersion of Elacestrant free base (2).

[0060] In the process of the fifth embodiment, the suitable solvent used in step-a) is same as defined in the third embodiment.

[0061] In the process of the fifth embodiment, the suitable pharmaceutically acceptable excipient used in step-b) is same as defined in the first embodiment.

[0062] In the process of the fifth embodiment, isolation of solid form involves removing the solvent from the mixture used in step-c) is same as defined in the first embodiment. In the process of the fifth embodiment, the Elacestrant free base (2) used in step-a) can be amorphous, crystalline or any other physical form.

[0063] In the sixth embodiment, the present invention provides solid-state forms of Elacestrant dihydrochloride (1) having purity greater than 99% by HPLC, preferably greater than 99.5% by HPLC, more preferably greater than 99.9% by HPLC with total impurities less than 1.0%, more preferably less than 0.5%.

[0064] In the seventh embodiment, the present invention provides solid forms of Elacestrant dihydrochloride (1) obtained according to the present invention is having loss on drying less than 10.0% (w / w), preferably less than 5.0% (w / w), preferably less than 3.0% (w / w).

[0065] In the eighth embodiment, the present invention provides solid forms of Elacestrant dihydrochloride (1) obtained in the present invention is free of any degradation impurities preferably less than 0.15% and more preferably less than 0.10%(w / w).

[0066] Elacestrant hydrochloride (1) used in the present invention is having greater purity than 99.5% purity by HPLC and particle size less than 200 microns and more preferably less than 100 microns.

[0067] It is an object of the present invention to provide stable solid dispersions of Elacestrant dihydrochloride (1).

[0068] In the nineth embodiment, the physical stability of solid forms of Elacestrant dihydrochloride (1) with different ratio’s was determined by storing the samples at 40°C / 75% relative humidity (RH), 25°C / 60% RH and 2-8°C. The samples were tested by PXRD analysis. The solid dispersion of Elacestrant dihydrochloride (1) with different ratio’s were found to be physically stable at 40°C / 75% relative humidity (RH), 25°C / 60% RH conditions and 2-8°C up to 6 months and preferably more than 12 months.

[0069] In the tenth embodiment, pharmaceutical composition comprising solid forms of Elacestrant dihydrochloride (1) with at least one pharmaceutically acceptable excipient is formulated in a manner suitable for the route of administration to be used. As used herein, the term "pharmaceutical compositions" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

[0070] In the eleventh embodiment, the solid-state form of Elacestrant dihydrochloride (1), is characterized by particle size distribution wherein, d90 is less than 200 pm, preferably less than 100 pm and more preferably not more than 50 pm.

[0071] In the twelfth embodiment, the solid-state form of Elacestrant dihydrochloride (1), is characterized by particle size distribution wherein, d50 is less than 100 pm, preferably less than 50 pm and more preferably less than 25 pm.

[0072] In the thirteenth embodiment, the solid-state form of Elacestrant dihydrochloride (1), is characterized by particle size distribution wherein, dlO is less than 20 pm, preferably less than 10 pm and more preferably less than 5 pm.

[0073] P-XRD Method of Analysis:

[0074] PXRD analysis of solid dispersion of Elacestrant dihydrochloride (1) was carried out by using BRUKER / D8 ADVANCE diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03° / min.

[0075] The best mode of carrying out the present invention is illustrated by the examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.

[0076] Examples

[0077] Example 1: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Polyvinylpyrrolidone (PVP)

[0078] 1g of Elacestrant dihydrochloride (1) was added to 40 mL of Methanol at 25-30 °C and heated to 40-45 °C. lg of Polyvinylpyrrolidone (PVP) was then added to the reaction mass and stirred for 10-15 mins. The total reaction mass was transferred to a Buchi flask and solvent distilled off under vacuum. The obtained solid was dried in Vacuum Tray Dryer (VTD) below 45 °C to yield solid dispersion of Elacestrant dihydrochloride (1) with Polyvinylpyrrolidone (PVP). Yield: 90% (w / w), XRD: Figure 1. Example 2: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with copovidone

[0079] 1g of Elacestrant dihydrochloride (1) was added to 40 mL of Methanol at 25-30 °C and heated to 40-45 °C.lg of Copovidone was then added to the reaction mass and stirred for 10-15 mins. The total reaction mass was transferred to a Buchi flask and solvent distilled off under vacuum. The obtained solid was dried in Vacuum Tray Dryer (VTD) below 45 °C to yield solid dispersion of Elacestrant dihydrochloride

[0080] (1) with Copovidone. Yield: 91.5% (w / w), XRD: Figure 2.

[0081] Example 3: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3)

[0082] 1g of Elacestrant dihydrochloride (1) was added to 40 mL of Methanol at 25-30 °C and heated to 40-45 °C.lg of Hydroxypropyl methylcellulose-E3 (HPMC-E3) was then added to the reaction mass and stirred for 10-15 mins. The total reaction mass was transferred to a Buchi flask and solvent distilled off under vacuum. The obtained solid was dried in Vacuum Tray Dryer (VTD) below 45 °C to yield solid dispersion of Elacestrant dihydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3). Yield: 84% (w / w), XRD: Figure 3.

[0083] Example 4: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Polyvinylpyrrolidone (PVP)

[0084] 1g of Elacestrant dihydrochloride (1) was added to 40 mL of Methanol and Dichloromethane at 25-30 °C and heated to 40-45 °C.1g of Polyvinylpyrrolidone (PVP) was then added to the reaction mass and stirred for 10-15 mins. The total reaction mass was transferred to a Buchi flask and solvent distilled off under vacuum. The obtained solid was dried in Vacuum Tray Dryer (VTD) below 45 °C to yield solid dispersion of Elacestrant dihydrochloride (1) with Polyvinylpyrrolidone (PVP). Yield: 49.5% (w / w). Example 5: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with copovidone.

[0085] 1g of Elacestrant dihydrochloride (1) was added to 40 mL of Methanol and Dichloromethane (1 : 1) at 25-30 °C and heated to 40-45 °C.1g of Copovidone was then added to the reaction mass and stirred for 10-15 mins. The total reaction mass was transferred to a Buchi flask and solvent distilled off under vacuum. The obtained solid was dried in Vacuum Tray Dryer (VTD) below 45 °C to yield solid dispersion of Elacestrant dihydrochloride (1) with Copovidone. Yield: 59% (w / w). Example 6: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3)

[0086] 1g of Elacestrant dihydrochloride (1) was added to 40 mL of Methanol and Dichloromethane (1 : 1) at 25-30 °C and heated to 40-45 °C. lg of Hydroxypropyl methylcellulose-E3 (HPMC-E3) was then added to the reaction mass and stirred for 10- 15 mins. The total reaction mass was transferred to a Buchi flask and solvent distilled off under vacuum. The obtained solid was dried in Vacuum Tray Dryer (VTD) below 45 °C to yield solid dispersion of Elacestrant dihydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3). Yield: 53.3% (w / w).

[0087] Example 7: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Polyvinylpyrrolidone (PVP)

[0088] 1g of Elacestrant dihydrochloride (1) was added to 40 mL of Methanol and acetone at 25-30 °C and heated to 40-45 °C. lg of Polyvinylpyrrolidone (PVP) was then added to the reaction mass and stirred for 10-15 mins. The total reaction mass was transferred to a Buchi flask and solvent distilled off under vacuum. The obtained solid was dried in Vacuum Tray Dryer (VTD) below 45 °C to yield solid dispersion of Elacestrant dihydrochloride (1) with Polyvinylpyrrolidone (PVP). Yield: 49.5% (w / w).

[0089] Example 8: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Copovidone

[0090] 1g of Elacestrant dihydrochloride (1) was added to 40 mL of Methanol and acetone at 25-30 °C and heated to 40-45 °C.1g of Copovidone was then added to the reaction mass and stirred for 10-15 mins. The total reaction mass was transferred to a Buchi flask and solvent distilled off under vacuum. The obtained solid was dried in Vacuum Tray Dryer (VTD) below 45 °C to yield solid dispersion of Elacestrant dihydrochloride (1) with Copovidone Yield: 53.5% (w / w).

[0091] Example 9: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3)

[0092] 1g of Elacestrant dihydrochloride (1) was added to 40 mL of Methanol and acetone at 25-30 °C and heated to 40-45 °C.lg of Hydroxypropyl methylcellulose-E3 (HPMC-E3) was then added to the reaction mass and stirred for 10-15 mins. The total reaction mass was transferred to a Buchi flask and solvent distilled off under vacuum. The obtained solid was dried in Vacuum Tray Dryer (VTD) below 45 °C to yield solid dispersion of Elacestrant dihydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3) Yield: 84% (w / w). Example 10: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Polyvinylpyrrolidone (PVP)

[0093] 1g of Elacestrant dihydrochloride (1) was added to 40 mL of Methanol and Tetrahydrofuran at 25-30 °C and heated to 40-45 °C. lg of Polyvinylpyrrolidone (PVP) was then added to the reaction mass and stirred for 10-15 mins. The total reaction mass was transferred to a Buchi flask and solvent distilled off under vacuum. The obtained solid was dried in Vacuum Tray Dryer (VTD) below 45 °C to yield solid dispersion of Elacestrant dihydrochloride (1) with Polyvinylpyrrolidone (PVP) Yield: 65.4% (w / w).

[0094] Example 11: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with copovidone

[0095] 1g of Elacestrant dihydrochloride (1) was added to 40 mL of Methanol and Tetrahydrofuran at 25-30 °C and heated to 40-45 °C.lg of Copovidone was then added to the reaction mass and stirred for 10-15 mins. The total reaction mass was transferred to a Buchi flask and solvent distilled off under vacuum. The obtained solid was dried in Vacuum Tray Dryer (VTD) below 45 °C to yield solid dispersion of Elacestrant dihydrochloride (1) with Copovidone Yield: 73.1% (w / w).

[0096] Example 12: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3)

[0097] 1g of Elacestrant dihydrochloride (1) was added to 40 mL of Methanol and Tetrahydrofuran at 25-30 °C and heated to 40-45 °C.lg of Hydroxypropyl methylcellulose-E3 (HPMC-E3) was then added to the reaction mass and stirred for 10- 15 mins. The total reaction mass was transferred to a Buchi flask and solvent distilled off under vacuum. The obtained solid was dried in Vacuum Tray Dryer (VTD) below 45 °C to yield solid dispersion of Elacestrant dihydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3) Yield: 73.5% (w / w).

[0098] Example 13: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Polyvinylpyrrolidone (PVP)

[0099] 3g of Elacestrant dihydrochloride (1) was added to 300 mL of Methanol at room temperature. 3g of Polyvinylpyrrolidone (PVP) was added to the reaction mixture and stirred for 15 to 30 minutes. Spray dried the obtained solution using spray dryer through following conditions:

[0100] Inlet Temperature: 50°C

[0101] Outlet Temperature: 30°C

[0102] Aspirator: 70% Feeding rate: 20 mL / min

[0103] N2 Pressure: 2.0 kg / cm2

[0104] Yield: 56.66%.

[0105] Example 14: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Copovidone

[0106] 3g of Elacestrant dihydrochloride (1) was added to 300 mL of Methanol at room temperature. 3g of Copovidone was added to the reaction mixture and stirred for 15 to 30 minutes. Spray dried the obtained solution using spray dryer through following conditions:

[0107] Inlet Temperature: 50°C

[0108] Outlet Temperature: 30°C

[0109] Aspirator: 70%

[0110] Feeding rate: 20 mL / min

[0111] N2 Pressure: 2.0 kg / cm2

[0112] Yield: 58.66%.

[0113] Example 15: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3).

[0114] 3g of Elacestrant dihydrochloride (1) was added to 300 mL of Methanol at room temperature. 3g of Hydroxypropyl methylcellulose-E3 (HPMC-E3) was added to the reaction mixture and stirred for 15 to 30 minutes. Spray dried the obtained solution using spray dryer through following conditions:

[0115] Inlet Temperature: 50°C

[0116] Outlet Temperature: 30°C

[0117] Aspirator: 70%

[0118] Feeding rate: 20 mL / min

[0119] N2 Pressure: 2.0 kg / cm2

[0120] Yield: 66.66%.

[0121] Example 16: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Polyvinylpyrrolidone (PVP)

[0122] 3g of Elacestrant dihydrochloride (1) was added to 300 mL of Methanol and Acetone at room temperature. 3g of Polyvinylpyrrolidone (PVP) was added to the reaction mixture and stirred for 15 to 30 minutes. Spray dried the obtained solution using spray dryer through following conditions:

[0123] Inlet Temperature: 50°C Outlet Temperature: 30°C

[0124] Aspirator: 70%

[0125] Feeding rate: 20 mL / min

[0126] N2 Pressure: 2.0 kg / cm2

[0127] Yield: 56.66%.

[0128] Example 17: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Copovidone.

[0129] 3g of Elacestrant dihydrochloride (1) was added to 300 mL of Methanol and Acetone at room temperature. 3g of Copovidone was added to the reaction mixture and stirred for 15 to 30 minutes. Spray dried the obtained solution using spray dryer through following conditions:

[0130] Inlet Temperature: 50°C

[0131] Outlet Temperature: 30°C

[0132] Aspirator: 70%

[0133] Feeding rate: 20 mL / min

[0134] N2 Pressure: 2.0 kg / cm2

[0135] Yield: 48.66%.

[0136] Example 18: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3).

[0137] 3g of Elacestrant dihydrochloride (1) was added to 300 mL of Methanol and Acetone at room temperature. 3g of Hydroxypropyl methylcellulose-E3 (HPMC-E3) was added to the reaction mixture and stirred for 15 to 30 minutes. Spray dried the obtained solution using spray dryer through following conditions:

[0138] Inlet Temperature: 50°C

[0139] Outlet Temperature: 30°C

[0140] Aspirator: 70%

[0141] Feeding rate: 20 mL / min

[0142] N2 Pressure: 2.0 kg / cm2

[0143] Yield: 57.76%.

[0144] Example 19: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Polyvinylpyrrolidone (PVP)

[0145] 3g of Elacestrant dihydrochloride (1) was added to 300 mL of Methanol and Dichloromethane at room temperature. 3g of Polyvinylpyrrolidone (PVP) was added to the reaction mixture and stirred for 15 to 30 minutes. Spray dried the obtained solution using spray dryer through following conditions:

[0146] Inlet Temperature: 50°C

[0147] Outlet Temperature: 30°C

[0148] Aspirator: 70%

[0149] Feeding rate: 20 mL / min

[0150] N2 Pressure: 2.0 kg / cm2

[0151] Yield: 56.76%.

[0152] Example 20: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Copovidone.

[0153] 3g of Elacestrant dihydrochloride (1) was added to 300 mL of Methanol and Dichloromethane at room temperature. 3g of Copovidone was added to the reaction mixture and stirred for 15 to 30 minutes. Spray dried the obtained solution using spray dryer through following conditions:

[0154] Inlet Temperature: 50°C

[0155] Outlet Temperature: 30°C

[0156] Aspirator: 70%

[0157] Feeding rate: 20 mL / min

[0158] N2 Pressure: 2.0 kg / cm2

[0159] Yield: 76.26%.

[0160] Example 21: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3).

[0161] 3g of Elacestrant dihydrochloride (1) was added to 300 mL of Methanol and Dichloromethane at room temperature. 3g of Hydroxypropyl methylcellulose-E3 (HPMC-E3) was added to the reaction mixture and stirred for 15 to 30 minutes. Spray dried the obtained solution using spray dryer through following conditions:

[0162] Inlet Temperature: 50°C

[0163] Outlet Temperature: 30°C

[0164] Aspirator: 70%

[0165] Feeding rate: 20 mL / min

[0166] N2 Pressure: 2.0 kg / cm2

[0167] Yield: 76.66%.

[0168] Example 22: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Polyvinylpyrrolidone (PVP) 3g of Elacestrant dihydrochloride (1) was added to 300 mL of Methanol and Tetrahydrofuran at room temperature. 3g of Polyvinylpyrrolidone (PVP) was added to the reaction mixture and stirred for 15 to 30 minutes. Spray dried the obtained solution using spray dryer through following conditions:

[0169] Inlet Temperature: 50°C

[0170] Outlet Temperature: 30°C

[0171] Aspirator: 70%

[0172] Feeding rate: 20 mL / min

[0173] N2 Pressure: 2.0 kg / cm2

[0174] Yield: 76.86%.

[0175] Example 23: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Copovidone.

[0176] 3g of Elacestrant dihydrochloride (1) was added to 300 mL of Methanol and Tetrahydrofuran at room temperature. 3g of Copovidone was added to the reaction mixture and stirred for 15 to 30 minutes. Spray dried the obtained solution using spray dryer through following conditions:

[0177] Inlet Temperature: 50°C

[0178] Outlet Temperature: 30°C

[0179] Aspirator: 70%

[0180] Feeding rate: 20 mL / min

[0181] N2 Pressure: 2.0 kg / cm2

[0182] Yield: 73.66%.

[0183] Example 24: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3).

[0184] 3g of Elacestrant dihydrochloride (1) was added to 300 mL of Methanol and Tetrahydrofuran at room temperature. 3g of Hydroxypropyl methylcellulose-E3 (HPMC-E3) was added to the reaction mixture and stirred for 15 to 30 minutes. Spray dried the obtained solution using spray dryer through following conditions:

[0185] Inlet Temperature: 50°C

[0186] Outlet Temperature: 30°C

[0187] Aspirator: 70%

[0188] Feeding rate: 20 mL / min

[0189] N2 Pressure: 2.0 kg / cm2

[0190] Yield: 71.36%. Example 25: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Polyvinylpyrrolidone (PVP).

[0191] Elacestrant free base (3.0 g) was added to methanol (300 mL) at room temperature and stirred to get a clear solution. To this Polyvinylpyrrolidone (PVP) 20% W / W (3 g) was added and stirred to get amorphous solid dispersion of Elacestrant free base, then methanol was added to the obtained solid to get clear solution. To this Methanolic hydrochloric acid was added. Spray dried the obtained solution using spray dryer through following conditions:

[0192] Inlet Temperature: 50°C

[0193] Outlet Temperature: 30°C

[0194] Aspirator: 70%

[0195] Feeding rate: 20 mL / min

[0196] N2 Pressure: 2.0 kg / cm2

[0197] Yield: 60%, XRD: Figure 4.

[0198] Example 26: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Polyvinylpyrrolidone (PVP)

[0199] Elacestrant free base (3.0 g) was added to methanol (300 mL) at room temperature and stirred to get a clear solution. To this Polyvinylpyrrolidone (PVP) 10% W / W (3 g) was added and stirred to get amorphous solid dispersion of Elacestrant free base, then methanol was added to the obtained solid to get clear solution. To this aqueous hydrochloric acid was added. Spray dried the obtained solution using spray dryer through following conditions:

[0200] Inlet Temperature: 50°C

[0201] Outlet Temperature: 30°C

[0202] Aspirator: 70%

[0203] Feeding rate: 20 mL / min

[0204] N2 Pressure: 2.0 kg / cm2

[0205] Yield: 60%, XRD: Figure 5.

[0206] Example 27: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with Copovidone.

[0207] Elacestrant free base (5.0 g) was added to methanol (15 vol) at room temperature and stirred to get a clear solution. To the obtained solution, aqueous hydrochloric acid (1.1 eq) was added. To this, methylene dichloride (25 vol) was added and stirred, then Copovidone (4.0 g) was added to the reaction mixture and stirred to get a clear solution. Spray dried the obtained solution using spray dryer through following conditions: Inlet Temperature: 75°C

[0208] Outlet Temperature: 45°C

[0209] Aspirator: 70%

[0210] Feeding rate: 20 mL / min

[0211] N2 Pressure: 2.0 kg / cm2

[0212] Yield: 75%, XRD: Figure 6

[0213] Example 28: Preparation of amorphous solid dispersion of Elacestrant with Copovidone.

[0214] 3g of Elacestrant was added to 300 mL of Methanol and Dichloromethane at room temperature. 3g of Copovidone was added to the reaction mixture and stirred for 15 to 30 minutes. Spray dried the obtained solution using spray dryer through following conditions:

[0215] Inlet Temperature: 50°C

[0216] Outlet Temperature: 30°C

[0217] Aspirator: 70%

[0218] Feeding rate: 20 mL / min

[0219] N2 Pressure: 2.0 kg / cm2

[0220] Yield: 78%., XRD: Figure 7

[0221] Example 29: Preparation of amorphous solid dispersion of Elacestrant with Polyvinylpyrrolidone (PVP).

[0222] Elacestrant free base (3.0 g) was added to methanol (300 mL) at room temperature and stirred to get a clear solution. To this Polyvinylpyrrolidone (PVP) (3 g) was added and stirred to get amorphous solid dispersion of Elacestrant free base, then methanol was added to the obtained solid to get clear solution. Spray dried the obtained solution using spray dryer through following conditions:

[0223] Inlet Temperature: 50°C

[0224] Outlet Temperature: 30°C

[0225] Aspirator: 70%

[0226] Feeding rate: 20 mL / min

[0227] N2 Pressure: 2.0 kg / cm2

[0228] Yield: 60%, XRD: Figure 8 Example 30: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with hydroxypropyl cellulose (HPC)

[0229] Elacestrant free base (3.0 g) was added to methanol (300 mL) at room temperature and stirred to get a clear solution. To this hydroxypropyl cellulose (HPC) (3 g) was added and stirred to get amorphous solid dispersion of Elacestrant free base, then methanol was added to the obtained solid to get clear solution. To this aqueous hydrochloric acid was added. Spray dried the obtained solution using spray dryer through following conditions:

[0230] Inlet Temperature: 50°C

[0231] Outlet Temperature: 30°C

[0232] Aspirator: 70%

[0233] Feeding rate: 20 mL / min

[0234] N2 Pressure: 2.0 kg / cm2

[0235] Yield: 60%,

[0236] Example 31: Preparation of amorphous solid dispersion of Elacestrant dihydrochloride (1) with hydroxypropyl beta cyclodextrin (HPpCD).

[0237] Elacestrant free base (3.0 g) was added to methanol (300 mL) at room temperature and stirred to get a clear solution. To this hydroxypropyl beta cyclodextrin (HPpCD) (3 g) was added and stirred to get amorphous solid dispersion of Elacestrant free base, then methanol was added to the obtained solid to get clear solution. To this aqueous hydrochloric acid was added. Spray dried the obtained solution using spray dryer through following conditions:

[0238] Inlet Temperature: 50°C

[0239] Outlet Temperature: 30°C

[0240] Aspirator: 70%

[0241] Feeding rate: 20 mL / min

[0242] N2 Pressure: 2.0 kg / cm2

[0243] Yield: 60%,

Claims

1. We claim:

1. A process for the preparation of solid dispersion of Elacestrant dihydrochloride (1) comprising the steps of: a) dissolving Elacestrant dihydrochloride (1) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient to step-a), and c) isolating solid dispersion of Elacestrant dihydrochloride (1).

2. A process for the preparation of solid dispersion of Elacestrant dihydrochloride (1) comprising the steps of: a) dissolving Elacestrant free base (2) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient to the solution obtained in step-a), c) isolating the solid dispersion of Elacestrant free base, d) adding a solution of hydrochloric acid to step c), and e) isolating the solid dispersion of Elacestrant dihydrochloride (1).

3. A process for the preparation of solid dispersion of Elacestrant dihydrochloride (1) comprising the steps of: a) dissolving Elacestrant free base (2) in a solvent or mixture of solvents, b) adding PVP (polyvinylpyrrolidone) at 10 & 20% w / w relative to the total weight of PVP to the solution obtained in step a), c) optionally isolating the solid dispersion of Elacestrant free base, d) adding a solution of hydrochloric acid to step c), and e) isolating the solid dispersion of Elacestrant dihydrochloride (1).

4. The process as claimed in claim 2, wherein the solution of hydrochloric acid is selected from but not limited to alcoholic Hydrochloride, aqueous Hydrochloride, concentrated Hydrochloride, ethyl acetate Hydrochloride; wherein the alcoholic Hydrochloride is selected from methanolic Hydrochloride, ethanolic Hydrochloride.

5. A process for the preparation of solid dispersion comprising Elacestrant free base with at least one pharmaceutically acceptable excipient, comprising the steps of: a) dissolving Elacestrant free base (2) in a solvent or mixture of solvents, b) adding at least one pharmaceutically acceptable excipient to the solution obtained in step-a), and c) isolating the solid dispersion of Elacestrant free base.

6. The process as claimed in any of the proceeding claims, the suitable solvent is selected from alcohol solvents such as methanol, ethanol, 1 -propanol, 2- propanol, 1 -butanol, 2-butanol, and the like; chloro solvents such as di chloromethane, 1, 2-di chloroethane, trichloroethylene, chloroform, carbon tetrachloride, and the like; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide and the like; water or its mixture thereof.

7. The process as claimed in any of the proceeding claims, pharmaceutically acceptable excipient is selected from polyvinylpyrrolidone, (povidone or PVP; PVP of different grades like K-IS, K-30, K-60, K-90 and K-120 may be used), polyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), copovidone, Eudragit, Soluplus, polyethylene glycol (macrogol or PEG), polyethylene glycol-6000 (PEG-6000), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethyl ethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl cellulose acetate succinate (HPC AS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), sulfo butyl ether-P-cyclodextrin (SBECD), hydroxypropyl beta cyclodextrin (HPpCD), cross linked sodium carboxymethyl cellulose (croscarmellose sodium).

8. The process as claimed in any of the proceeding claims, removal of solvent is carrying out by suitable techniques selected from decantation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as Buchi rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray -freeze drying, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration by gravity or suction, thin film drying, centrifugation.

9. The process as claimed in any of the proceeding claims, Elacestrant dihydrochloride (1), is characterized by particle size distribution wherein, d50 is less than 200 pm, preferably less than 100 pm and more preferably not more than 50 pm.

10. The process as claimed in any of the proceeding claims, wherein Elacestrant or its dihydrochloride (1) or its solid dispersion is having purity greater than 99% by HPLC, preferably greater than 99.5% by HPLC, more preferably greater than 99.9% by HPLC with total impurities less than 1.0%, more preferably less than 0.5%.

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