Solid dispersion of elacestrant dihydrochloride and a process for the preparation thereof

Abstract

The present invention relates to a solid dispersion comprising elacestrant dihydrochloride, and a polymethacrylate polymer. The present invention also relates to a process for the preparation of the solid dispersion. The present invention further relates to a pharmaceutical composition comprising the solid dispersion and a pharmaceutical acceptable excipient, and its therapeutic uses thereof.

Description

ELACE-2026SOLID DISPERSION OF ELACESTRANT DIHYDROCHLORIDE AND A PROCESS FOR THE PREPARATION THEREOF PRIORITY

[0001] This application claims the benefit of Indian Provisional Application 202521014284 filed on February 19, 2025, entitled “Solid dispersion of elacestrant dihydrochloride and a process for the preparation thereof’, the contents of which are incorporated herein by reference.BACKGROUND OF THE INVENTIONTechnical Field

[0002] The present invention relates to a solid dispersion comprising elacestrant dihydrochloride, and a polymethacrylate polymer. The present invention also relates to a process for the preparation of the solid dispersion, a pharmaceutical composition comprising the solid dispersion, and therapeutic uses thereof.Description of the Related Art

[0003] Elacestrant, also known by its chemical name (6R)-6-(2-(N-(4-(2-(ethylamino)ethyl)benzyl)-N-ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydro-naphthalen-2-ol, is represented by the following compound of formula I,

[0004] Elacestrant dihydrochloride is represented by the following compound of formula la,ELACE-2026

[0005] Elacestrant and its pharmaceutically acceptable salts, including the dihydrochloride salt, are selective estrogen receptor modulators, indicated 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 with disease progression following at least one line of endocrine therapy.

[0006] The US Food and Drug Administration (the USFDA) approved elacestrant 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 with disease progression following at least one line of endocrine therapy in January 2023. Elacestrant is marketed in the USA under the brand name ORSERDU® as a tablet for oral use, in the dosage of 345 mg (equivalent to 400 mg elacestrant dihydrochloride) and 86 mg (equivalent to 100 mg elacestrant dihydrochloride) .

[0007] Elacestrant and its pharmaceutically acceptable salts are covered in a published International Application No. WO 2004 / 058682 (the WO ‘682 publication). Elacestrant dihydrochloride salt is specifically disclosed in a published International Application No. WO 2011 / 143469 (the WO ‘469 publication) and International Application No. WO 2016 / 176665 (the WO ‘665 publication). Polymorphic forms of elacestrant dihydrochloride such as the Crystalline Form 1, Form 2, Form 3 and an amorphous form are reported in published International Application No. WO 2018 / 0129419 (the WO ‘419 publication). Crystalline Form IB of elacestrant dihydrochloride is reported in published International Application No. WO 2020 / 010216 (the WO ‘216 publication).

[0008] Elacestrant dihydrochloride is classified as a BCS Class IV drug, indicating that the drug has low solubility and low permeability (Ref. Product Quality Review for Appln. No. 2176390rigls000, published by Center for Drug Evaluation and Research (CDER) of the U.S. FDA). Drugs with poor aqueous solubility typically exhibit a dissolution rate that limits absorption, while drugs with low membrane permeability tend to have a permeation rate that limits absorption. Formulating effective oral dosage forms for BCS Class IV drugs is challenging, as overcoming both solubility and permeability barriers is essential to enhance bioavailability and achieve desired pharmacokinetic profiles. Elacestrant as its dihydrochloride salt is administered orally, however, its oralELACE-2026bioavailability is approximately 10% only (Ref. Product Quality Review for Appln. No.2176390rigls000, published by the CDER of the U.S. FDA). Therefore, it is essential to find ways to overcome the solubility limitations of such drug substances so that the potential therapeutic benefits of drug substance are realized. Also, it is known in the art that selection of an appropriate polymer is important for preparing effective solid dispersion of a drug, and for the purpose, the critical attributes of a polymer needs to be taken into consideration for developing an effective solid dispersion. Accordingly, the present invention paves the way to address the challenges related to elacestrant dihydrochloride by providing solid dispersion of elacestrant dihydrochloride with a polymethacrylate polymer.SUMMARY OF THE INVENTION

[0009] The present invention provides a solid dispersion comprising elacestrant dihydrochloride, and a polymethacrylate polymer.

[0010] The present invention further provides a process for the preparation of a solid dispersion comprising elacestrant dihydrochloride and a polymethacrylate polymer, wherein the process comprises the steps of:(a) providing a solution or suspension of elacestrant dihydrochloride in a solvent;(b) adding a polymethacrylate to the solution or suspension obtained in the step (a) to obtain a reaction mixture; and(c) removing the solvent from the reaction mixture obtained in the step (b) to obtain the solid dispersion.

[0011] The present invention also provides a pharmaceutical composition comprising the solid dispersion of elacestrant dihydrochloride as described herein, and optionally a pharmaceutical acceptable excipient selected from a diluent, a disintegrant, a binder, a lubricant, a glidant, or a mixture thereof.

[0012] The present invention further provides a solid dispersion as described herein, or a pharmaceutical composition of the present invention for use in the treatment of breast cancer.

[0013] The present invention further provides a solid dispersion as described herein, or a pharmaceutical composition of the present invention for use in the treatment of ovarian cancer.ELACE-2026

[0014] These and other aspects of the present invention will be apparent from the following description.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 A illustrates the characteristic XRPD (X-Ray Powder Diffraction) pattern of the solid dispersion of elacestrant dihydrochloride as obtained in the Example 4.

[0016] Figure IB illustrates the characteristic XRPD patterns of the solid dispersion of elacestrant dihydrochloride, based on the stability study of the said solid dispersion conducted at variable temperatures as described in the Example 5.DETAILED DESCRIPTION OF THE INVENTION

[0017] In one aspect, the present invention relates to a solid dispersion comprising elacestrant dihydrochloride, and a polymethacrylate polymer.

[0018] As used herein the term “solid dispersion” refers to a system in a solid state comprising at least two components, and in the context of the present invention, one of the components is elacestrant dihydrochloride, which is dispersed throughout the other component, and the other component is a polymethacrylate polymer as described herein.

[0019] As used herein, the term “about” refers to any value which lies within the range defined by a number up to 10% of the value.

[0020] As used herein, the abbreviation “w / w” denotes weight by weight of the total contents.

[0021] In an embodiment, the elacestrant dihydrochloride contained in the solid dispersion of the present invention is in an amorphous form.

[0022] In an embodiment, the polymethacrylate polymer used in the solid dispersion of the present invention is selected from acrylic acid-ethyl acrylate copolymer; methacrylic acid-methyl methacrylate copolymer; methacrylic acid-ethyl acrylate copolymer; butyl methacrylate-(2-dimethylaminoethyl) methacrylate copolymer; butyl methacrylate-(2-dimethylaminoethyl)methacrylate-methyl methacrylate copolymer; ethyl acrylatemethyl methacrylate copolymer; methyl acrylate- methyl methacrylate-methacrylic acid copolymer; ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer; ethyl acrylate-methyl methacrylate-trimethylammonioethylELACE-2026methacrylate chloride copolymer; poly(hydroxyalkyl acrylate); poly(hydroxyalkyl methacrylate), or a mixture thereof.

[0023] The polymethacrylate polymers as described above are commercially available. The polymethacrylates polymers such as methacrylic acid-methyl methacrylate copolymer; methacrylic acid-ethyl acrylate copolymer; butyl methacrylate-(2-dimethylaminoethyl) methacrylate copolymer; butyl methacrylate- (2-dimethylaminoethyl)methacrylate-methyl methacrylate copolymer; ethyl acrylatemethyl methacrylate copolymer; methyl acrylate- methyl methacrylate-methacrylic acid copolymer; ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer; ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer are sold under the trade name Eudragit® by Evonik Industries AG. In the context of the present invention, the polymethacrylate polymers may also be referred to as “Eudragit® polymers” or “Eudragit polymers”.

[0024] In an embodiment, the polymethacrylate polymer used in the solid dispersion of the present invention is Eudragit polymer, which is selected from Eudragit E PO; Eudragit E100, Eudragit E 12,5; Eudragit NE 30 D, Eudragit FS 30D, Eudragit NE 40 D, Eudragit NM 30 D, Eudragit L 100, Eudragit L 12.5, Eudragit L 12.5 P, Eudragit L 30 D-55, Eudragit L 100-55, Eudragit S 100, Eudragit S 12.5, Eudragit S 12.5 P, Eudragit RL 100, Eudragit RL PO, Eudragit RL 30 D, Eudragit RL 12.5, Eudragit RS 100, Eudragit RS PO, Eudragit RS 30 D, or Eudragit RS 12.5.

[0025] Other commercially available polymethacrylate polymers of the type methacrylic acid-ethyl acrylate copolymer such as Kollicoat® MAE 30 DP, Kollicoat® MAE 100 P, Acryl-EZE®, Acryl-EZE® 93 A, Acryl-EZE® MP, and Eastacryl® 30 D can also be used in the solid dispersion of the present invention.

[0026] The polymethacrylate polymers namely Kollicoat® MAE 30 DP and Kollicoat® MAE 100 P are commercially available from BASF Fine Chemicals.

[0027] The polymethacrylate polymers namely Acryl-EZE®, Acryl-EZE® 93 A, and Acryl-EZE® MP are commercially available from Colorcon.

[0028] The polymethacrylate polymer namely Eastacryl® 30 D is commercially available from Eastman Chemicals.

[0029] In an embodiment, the polymethacrylate polymer used in the solid dispersion of the present invention is selected from Eudragit E PO; Eudragit El 00, Eudragit E 12,5,ELACE-2026Eudragit FS 30D , Eudragit NE 30 D, Eudragit NE 40 D, Eudragit NM 30 D, Eudragit L 100, Eudragit L 12.5, Eudragit L 12.5 P, Eudragit L 30 D-55, Eudragit L 100-55, Eudragit S 100, Eudragit S 12.5, Eudragit S 12.5 P, Eudragit RL 100, Eudragit RL PO, Eudragit RL 30 D, Eudragit RL 12.5, Eudragit RS 100, Eudragit RS PO, Eudragit RS 30 D, Eudragit RS 12.5, Kollicoat MAE 30 DP, Kollicoat MAE 100 P, Acryl-EZE, Acryl-EZE 93A, Acryl-EZE MP, or Eastacryl 30 D.

[0030] In an embodiment, the polymethacrylate polymer used in the solid dispersion of the present invention is selected from Eudragit L 100-55, Eudragit L 100, Eudragit L 30 D-55, Eudragit FS 30D, Kollicoat MAE 30 DP, Kollicoat MAE 100 P, Acryl-EZE, Acryl-EZE 93A, Acryl-EZE MP, or Eastacryl 30 D.

[0031] In an embodiment, the polymethacrylate polymer used in the solid dispersion of the present invention is selected from Eudragit L 100-55, Eudragit L 100, Eudragit L 30 D-55, or Eudragit FS 30D.

[0032] In an embodiment, as may be combined with any of the preceding paragraphs, the solid dispersion of the present invention comprising elacestrant dihydrochloride and polymethacrylate polymer, may further comprise a surfactant.

[0033] In an embodiment, as may be combined with any of the preceding paragraphs, the surfactant used in the solid dispersion of the present invention is selected from polysorbate 20 (Tween® 20), polysorbate 80 (Tween® 80), sorbitan monolaurate (Span 20®), Sorbitan monooleate (Span 80®), sodium docusate, sodium lauryl sulfate, or vitamin E TPGS (D-a-Tocopherol polyethylene glycol succinate).

[0034] In an embodiment, as may be combined with any of the preceding paragraphs, the surfactant used in the solid dispersion of the present invention is selected from sodium lauryl sulfate, or vitamin E TPGS.

[0035] In an embodiment as may be combined with any of the preceding paragraphs, the ratio of elacestrant dihydrochloride to the polymethacrylate polymer ranges from about 1: 0.1 to about 1:10 [w / w].

[0036] In another embodiment as may be combined with any of the preceding paragraphs, the ratio of elacestrant dihydrochloride to the polymethacrylate polymer ranges from about 1: 0.1 to about 1:5 [w / w].

[0037] In an embodiment, the present invention provides a solid dispersion comprising elacestrant dihydrochloride and Eudragit L100-55, wherein the solid dispersion isELACE-2026characterized by the X-Ray Powder Diffraction (XRPD) pattern as substantially illustrated in Figure 1A.

[0038] In an aspect, the present invention provides a process for the preparation of a solid dispersion comprising elacestrant dihydrochloride and a polymethacrylate polymer, wherein the process comprises the steps of:(a) providing a solution or suspension of elacestrant dihydrochloride in a solvent;(b) adding a polymethacrylate polymer to the solution or suspension obtained in the step (a) to obtain a reaction mixture; and(c) removing the solvent from the reaction mixture obtained in the step (b) to obtain the solid dispersion.

[0039] In an embodiment, the solvent used in the step (a) of the process for the preparation of the solid dispersion of the present invention, is selected from an alcohol solvent, an ether solvent, an ester solvent, a ketone solvent, a hydrocarbon solvent, a haloalkane solvent, a nitrile solvent, a sulfoxide solvent, an amide solvent, or a mixture thereof.

[0040] In yet another embodiment, the alcohol solvent is selected from methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secbutyl alcohol, tert-butyl alcohol, or a mixture thereof; the ether solvent is selected from diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, or a mixture thereof; the ester solvent is selected from methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate, or a mixture thereof; the hydrocarbon solvent is selected from toluene, xylene, chlorobenzene, heptane, hexane, or a mixture thereof; the ketone solvent is selected from acetone, ethyl methyl ketone, methyl isobutyl ketone, or a mixture thereof; the haloalkane solvent is selected from dichloromethane, chloroform, dichloroethane, or a mixture thereof; the nitrile solvent is selected from acetonitrile, propionitrile, butyronitrile, or a mixture thereof; the sulfoxide solvent is selected from dimethyl sulfoxide, diethyl sulfoxide, or a mixture thereof; the amide solvent is selected from dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, or a mixture thereof.

[0041] In another embodiment, the solvent used in the step (a) of the process for the preparation of the solid dispersion of the present invention, is selected from an alcohol solvent, a haloalkane solvent, or a mixture thereof.ELACE-2026

[0042] In another embodiment, the solvent used in the step (a) of the process for the preparation of the solid dispersion of the present invention, is an alcohol solvent, which is selected from methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec -butyl alcohol, tert-butyl alcohol, or a mixture thereof.

[0043] In yet further embodiment, the solvent used in the step (a) of the process for the preparation of the solid dispersion of the present invention, is a haloalkane solvent, which is selected from dichloromethane, chloroform, dichloroethane, or a mixture thereof.

[0044] In an embodiment, as may be combined with any of the preceding paragraphs, the polymethacrylate polymer used the step (b) of the process for the preparation of the solid dispersion of the present invention, is as described above.

[0045] In an embodiment, in the step (b) of the process for the preparation of the solid dispersion of the present invention, the polymethacrylate polymer is dissolved in a solvent prior to addition to the solution or suspension, which is obtained in the step (a).

[0046] In an embodiment, the solvent used for dissolving the polymethacrylate polymer may be the same solvent or a different solvent as used in the step (a) of the above process, and the same may be selected from the solvents described herein above.

[0047] In an embodiment, the solvent used for dissolving the polymethacrylate polymer may be selected from an alcohol solvent, a haloalkane solvent, or a mixture thereof.

[0048] In an embodiment, the reaction mixture obtained in the step (b) for the preparation of the solid dispersion of the present invention, may be stirred at a suitable temperature.

[0049] In another embodiment, the reaction mixture obtained in the step (b) is stirred at a temperature ranging from about 35°C to about 75°C.

[0050] In an embodiment, the reaction mixture obtained in the step (b) for the preparation of the solid dispersion of the present invention, may be stirred for a suitable time.

[0051] In another embodiment, the reaction mixture obtained in the step (b) is stirred for about 5 minutes to about 5 hours.

[0052] In another further embodiment, the reaction mixture obtained in the step (b) is stirred for about 30 minutes to about 3 hours.

[0053] In an embodiment, in the step (c) of the process for the preparation of the solid dispersion of the present invention, the solvent is removed by a method selected from the group consisting of evaporation, distillation, lyophilization, filtration, spray drying, agitated thin film drying (ATFD), air tray drying, and vacuum tray drying.ELACE-2026

[0054] In an embodiment, the step (b) of the above process further comprises the step of adding a surfactant to the reaction mixture containing elacestrant dihydrochloride and a polymethacrylate polymer.

[0055] In another embodiment, the step (b) of the above process further comprises the step of adding a surfactant, wherein the surfactant is added together with the polymethacrylate polymer to the solution or suspension obtained in the step (a).

[0056] In an embodiment, in the step (b) of the above process, the polymethacrylate polymer and the surfactant are dissolved in a solvent prior to addition to the solution or suspension of the step (a).

[0057] In an embodiment, the surfactant used in the step (b) of the above process may be selected from the surfactants described herein above.

[0058] In the context of the present invention elacestrant dihydrochloride used in the preparation of the solid amorphous dispersion of the present invention can be prepared by following any method of preparation known in the art, for instance, elacestrant dihydrochloride can be prepared using a method described in the published International Application No. WO 2020 / 167855.

[0059] Also, the polymethacrylate polymers, as described above, used in the solid dispersion of the present invention, are commercially available.

[0060] The solid dispersion of the present invention comprising elacestrant dihydrochloride and a polymethacrylate polymer as described herein, meets the stability criteria under a variety of accelerated stability conditions, such as elevated temperature and relative humidity.

[0061] The stability of the solid dispersion of the present invention under a variety of accelerated stability conditions, such as elevated temperature and relative humidity was determined by evaluating the change in the physical state of elacestrant dihydrochloride contained in the solid dispersion, and the evaluation was performed by measuring whether there is any change in the amorphous state / non-crystalline state of elacestrant dihydrochloride during the stability study using any standard physical measurement, such as X-ray powder diffraction method.

[0062] The solid dispersion containing elacestrant dihydrochloride and Eudragit LI GO-55 obtained as per the Example 4 was subjected to a variety of accelerated stability conditions, such as elevated temperature and relative humidity. The X-ray powderELACE-2026diffraction (XRPD) pattern of the specified solid dispersion subjected to variable temperatures is illustrated in the Figure IB.

[0063] Further, a stability study was carried out for the solid dispersion of the present invention as per the method described in the experimental section. The results of stability study as presented in the experimental section confirms that the solid dispersion of the present invention is stable over a period of 3 months under the storage conditions specified therein.

[0064] In an aspect, the present invention provides a pharmaceutical composition comprising the solid dispersion of elacestrant dihydrochloride as described herein, and optionally a pharmaceutical acceptable excipient selected from a diluent, a disintegrant, a binder, a lubricant, a glidant, a surfactant or a mixture thereof.

[0065] In an embodiment, the present invention provides a pharmaceutical composition comprising the solid dispersion, wherein the solid dispersion is present in an amount ranging from about 10 % to about 70 % w / w.

[0066] In an embodiment, the pharmaceutical composition comprising the solid dispersion is in solid oral dosage form selected from a tablet or a capsule.

[0067] In an embodiment, the pharmaceutical composition comprising the solid dispersion is in the form of a tablet.

[0068] In an aspect, the present invention provides a method for the treatment of breast cancer comprising administering a therapeutically effective amount of the solid dispersion of the present invention, or a pharmaceutical composition comprising the solid dispersion, to a patient in need thereof.

[0069] In another aspect, the present invention provides a solid dispersion of the present invention, or a pharmaceutical composition of the solid dispersion, for use in the treatment of breast cancer.

[0070] In an aspect, the present invention provides a method for the treatment of ovarian cancer comprising administering a therapeutically effective amount of the solid dispersion of the present invention, or a pharmaceutical composition comprising the solid dispersion, to a patient in need thereof.

[0071] In another aspect, the present invention provides a solid dispersion of the present invention, or a pharmaceutical composition of the solid dispersion, for use in the treatment of ovarian cancer.ELACE-2026

[0072] In an embodiment, the present invention provides pharmaceutical composition comprising the solid dispersion of elacestrant dihydrochloride, having a D50 and D90 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns, and most preferably less than about 10 microns.

[0073] The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.ELACE-2026EXAMPLESGeneral methods:X-Ray Powder Diffraction (XRPD) (Instrumental settings):The measurements were performed on X-Ray Diffractometer model Empyrean (PANalytical) Detector: PIXcel1D[1] using Cu lamp with type and wavelength of the X-ray radiation: K-ai 1.54060[A], K-a.2 1.5444 [A] under the following conditions: The measurements were carried out with a Fixed module programmable divergence slit and anti-scatter Slit (Offset 0.00°); Generator settings: 40 mA / 45 kV, Time per step: 50s, Step size: , 0.013 and start angle (°) 2.0 and End angle: 50.0; Scan type: continuous; measurement performed at 25°C. The XRPD instrument is calibrated using NIST SRM 6-40E silicon standard and NIST SRM 1976 Alumina.Sample preparation: Take an adequate amount of the sample to fill the sample holder using back-loading technique. Then load the sample holder between the X-ray optics-path and scan using the above described parameters. Integrate the obtained X-ray powder diffraction profiles using HighScore Plus Software.Example 1: Preparation of solid dispersion of elacestrant dihydrochloride with Eudragit L 100-55To a solution of elacestrant dihydrochloride (1.8g) in methyl alcohol (27mL) and dichloromethane (27mL) was added Eudragit L 100-55 (0.2g). The reaction mixture was heated at about 50°C to about 55°C for about 30min. The reaction mixture was distilled under vacuum at a temperature below 50°C, and then degassed under vacuum at a temperature ranging from about 55 °C to about 60°C to obtain the solid dispersion.Example 2: Preparation of solid dispersion of elacestrant dihydrochloride with Eudragit L 100-55To a solution of elacestrant dihydrochloride (1.6g) in methyl alcohol (24mL) and dichloromethane (24mL) was added Eudragit L 100-55 (0.4g). The reaction mixture was heated at about 50°C to about 55°C for about 30min. The reaction mixture was distilled under vacuum at a temperature below 50°C, and then degassed under vacuum at a temperature ranging from about 55 °C to about 60°C to obtain the solid dispersion.ELACE-2026Example 3: Preparation of solid dispersion of elacestrant dihydrochloride with Eudragit L 100-55To a solution of elacestrant dihydrochloride (1.4g) in methyl alcohol (21mL) and dichloromethane (21mL) was added Eudragit L 100-55 (0.6g). The reaction mixture was heated at about 50°C to about 55°C for about 30 min. The reaction mixture was distilled under vacuum at a temperature below 50°C, and then degassed under vacuum at a temperature ranging from about 55 °C to about 60°C to obtain the solid dispersion.Example 4: Preparation of solid dispersion of elacestrant dihydrochloride with Eudragit L 100-55A solution of elacestrant dihydrochloride (1.8g) in methyl alcohol (80mL) and dichloromethane (80mL) was stirred at a temperature of about 20°C to about 30°C for about 15 minutes to obtain clear solution. To this solution, was added Eudragit L 100-55 (1.2g) and stirred at a temperature of about 20°C to about 30°C for about 15 minutes to 30 minutes to obtain clear solution. The reaction mass was filtered and clear filtrate was subjected to spray dryer (Parameters for spray drying: inlet temp 87°C, outlet temp 47°C, aspirator speed 1400RPM, feed pump speed 25RPM & pressure 2kg / cm2). After completion of spray drying, material is dried under vacuum at a temperature of about 50°C for 12 hours to obtain the solid dispersion.Yield: 2.17 g (0.72 w / w).XRPD: Figure 1A.Particle Size: D10: 3.51pm, D50: 6.09pm, D90: 11.2pm.Example 5: Stability study of solid dispersion of elacestrant dihydrochloride with Eudragit L 100-55 conducted at variable temperatureStability study of solid dispersion of elacestrant dihydrochloride with Eudragit L 100-55 obtained in the Example 4 was determined through XRPD analysis of solid dispersion of elacestrant dihydrochloride with Eudragit L 100-55 conducted at variable temperatures of 20°C, 50°C, 70°C, 90°C and 110°C and the results of this study are presented in the Figure IB.ELACE-2026Example 6: Stability data of solid dispersion of elacestrant dihydrochloride with Eudragit L 100-55 conducted at variable relative humidity and temperature conditionsThe stability study for the solid dispersion of elacestrant dihydrochloride with Eudragit L 100-55 was carried out by storing the solid dispersion of elacestrant dihydrochloride with Eudragit L 100-55 obtained by the process of the present invention over a period of 3 months at temperature and relative humidity (RH) storage conditions of 5 °C ± 3 °C; 25°C± 2°C / 60% ± 5% RH; 40°C± 2°C / 75% ± 5% RH; and 60°C / 95% RH.The stability of the solid dispersion of elacestrant dihydrochloride with Eudragit L 100-55 was assessed by monitoring changes in the physical state of the polymorph after a 1 -month and 3 -month stability study. The physical state of the stored polymorph was evaluated using X-ray Powder Diffraction (XRPD) method, and the XRPD pattern obtained at the end of the stability study was compared with the initial XRPD data generated prior to subjecting the solid dispersion of elacestrant dihydrochloride with Eudragit L 100-55 to the stability study. This comparison was used to determine whether any physical changes occurred during the storage period.Results of the stability study:The results of the stability study conducted on the solid dispersion of elacestrant dihydrochloride with Eudragit L 100-55, prepared according to the process of the present invention, are presented in Table 1 below. As described herein above, the stability of this solid dispersion was evaluated based on any change in its physical state, as determined by the XRPD method.Table 1ELACE-2026The results of the stability study presented in the above Table 1 indicates that the solid dispersion of elacestrant dihydrochloride with Eudragit L 100-55 is found to be stable over a period of 3 months at the specified temperature and relative humidity storage conditions.

Claims

ELACE-2026CLAIMS1. A solid dispersion comprising elacestrant dihydrochloride and a polymethacrylate polymer.

2. The solid dispersion of the claim 1, wherein the polymethacrylate polymer is selected from acrylic acid-ethyl acrylate copolymer; methacrylic acid-methyl methacrylate copolymer; methacrylic acid-ethyl acrylate copolymer; butyl methacrylate -(2-dimethylaminoethyl) methacrylate copolymer; butyl methacrylate- (2-dimethylaminoethyl)methacrylate-methyl methacrylate copolymer; ethyl acrylatemethyl methacrylate copolymer; methyl acrylate- methyl methacrylate-methacrylic acid copolymer; ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer; ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer; poly(hydroxyalkyl acrylate); poly(hydroxyalkyl methacrylate), or a mixture thereof.

3. The solid dispersion of the claim 1 or the claim 2, wherein the polymethacrylate polymer is selected from Eudragit E PO; Eudragit E100, Eudragit E 12,5, Eudragit FS 30D , Eudragit NE 30 D, Eudragit NE 40 D, Eudragit NM 30 D, Eudragit L 100, Eudragit L 12.5, Eudragit L 12.5 P, Eudragit L 30 D-55, Eudragit L 100-55, Eudragit S 100, Eudragit S 12.5, Eudragit S 12.5 P, Eudragit RL 100, Eudragit RL PO, Eudragit RL 30 D, Eudragit RL 12.5, Eudragit RS 100, Eudragit RS PO, Eudragit RS 30 D, Eudragit RS 12.5, Kollicoat MAE 30 DP, Kollicoat MAE 100 P, Acryl-EZE, Acryl-EZE 93A, Acryl-EZE MP, or Eastacryl 30 D.

4. The solid dispersion of any one of the claims 1, 2 and 3, wherein the solid dispersion further comprises a surfactant.

5. The solid dispersion of the claim 4, wherein the surfactant is selected from polysorbate 20 (Tween® 20), polysorbate 80 (Tween® 80), sorbitan monolaurate (Span 20®), Sorbitan monooleate (Span 80®), sodium docusate, sodium lauryl sulfate, or vitamin E TPGS (D-a-Tocopherol polyethylene glycol succinate).ELACE-20266. The solid dispersion of any of the claims 1 , 2 and 3 , wherein the ratio of elacestrant dihydrochloride to the polymethacrylate polymer ranges from about 1: 0.1 to about 1:10 [w / w].

7. A process for the preparation of a solid dispersion comprising elacestrant dihydrochloride and a polymethacrylate polymer, comprising the steps of:(a) providing a solution or suspension of elacestrant dihydrochloride in a solvent;(b) adding a polymethacrylate polymer to the solution or suspension obtained in the step (a) to obtain a reaction mixture; and(c) removing the solvent from the reaction mixture obtained in the step (b) to obtain the solid dispersion.

8. The process of the claim 7, wherein the solvent used in the step (a) is selected from an alcohol solvent, an ether solvent, an ester solvent, a ketone solvent, a hydrocarbon solvent, a haloalkane solvent, a nitrile solvent, a sulfoxide solvent, an amide solvent, or a mixture thereof.

9. The process of the claim 7 or the claim 8, wherein the solvent used in the step (a) is an alcohol solvent selected from methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec -butyl alcohol, tert-butyl alcohol, or a mixture thereof.

10. The process of the claim 7 or the claim 8, wherein the solvent used in the step (a) is a haloalkane solvent selected from dichloromethane, chloroform, dichloroethane, or a mixture thereof.

11. A pharmaceutical composition comprising the solid dispersion of any one of the claims 1 to 6, and a pharmaceutical acceptable excipient selected from a diluent, a disintegrant, a binder, a lubricant, a glidant, a surfactant or a mixture thereof.

12. A solid dispersion of any one of the claims 1 to 6 for use in the treatment of breast cancer.ELACE-202613. A solid dispersion of any one of the claims 1 to 6 for use in the treatment of ovarian cancer.

Images