Novel crystalline forms of Elacestrant dihydrochloride and processes for their preparation

Abstract

The present invention relates to novel crystalline forms of Elacestrant dihydrochloride which is chemically known as (6R) -6- (2- (N- (4- (2-(ethyl amino) ethyl) benzyl) -N- ethyl amino) - 4- methoxy phenyl) - 5, 6, 7, 8- tetrahydrona phthalen-2-ol dihydrochloride of formula-1a and their processes for the preparation thereof Formula-1a. The present invention also relates to novel salts of Elacestrant of Formula- 1, represented by the following structural formula and processes for the preparation thereof. Formula-1.

Description

[0001] Novel crystalline forms of Elacestrant dihydrochloride and processes for their preparation

[0002] Related Applications:

[0003] This application claims the benefit of priority to our Indian patent application numbers 202441026692 filed on Mar 30, 2024, 202441047877 filed on Jun 21, 2024 and 202441083435 filed on Oct 30, 2024, the disclosures of all of which is incorporated by reference in their entirety.

[0004] Field of the invention:

[0005] The present invention relates to novel crystalline forms of Elacestrant dihydrochloride which is represented by the following structural formula- la and processes for the preparation thereof.

[0006] Formula- 1 a.

[0007] The present invention also relates to novel salts of Elacestrant of Formula- 1, represented by the following structural formula and processes for the preparation thereof.

[0008] Formula- 1.

[0009] Background of the invention:

[0010] Elacestrant dihydrochloride is chemically known as (6R)-6-(2-(N-(4-(2-

[0011] (ethylamino) ethyl)benzyl)-N-ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydro naphthalen-2-ol dihydrochloride compound of formula- la, which was approved in US under the brand name of ORSERDU™ for the treatment of postmenopausal women or adult men, with ER-positive, HER2-negative, ESRI -mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.

[0012] US patent number US7612114B2 describes the process for the preparation of Elacestrant dihydrochloride. US patent number US10385008B2 describes crystalline Form 1, Form 2, Form 3 and mixture of Form 2 and Form 3 of Elacestrant dihydrochloride. US patent number US11643385B2 describes crystalline Form IB of Elacestrant dihydrochloride.

[0013] W02022056100A1 describes the co-crystal of Elacestrant dihydrochloride and urea (form A); Elacestrant base (Form Bl), Elacestrant monohydrochloride salt (Form Hl), crystalline Elacestrant dihydrochloride Form 6 (DMSO solvate), crystalline Elacestrant dihydrochloride Form 7 (1 -propanol solvate), crystalline Elacestrant dihydrochloride Form 9.

[0014] WO2023227029A1 describes Elacestrant dihydrochloride anhydrous crystalline form (CSII).

[0015] WO2024104268 Al describes Co-crystal of Elacestrant dihydrochloride and Succinic acid (CSIV), Co-crystal of Elacestrant dihydrochloride and Tartaric acid (CSV), Co-crystal of Elacestrant dihydrochloride and Malic acid (CSVI).

[0016] 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.

[0017] 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.

[0018] Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. 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.

[0019] Still there is a need to develop further solid state forms or polymorphs of Elacestrant dihydrochloride to meet the pharmaceuticals requirements.

[0020] Since the development of new polymorphic forms of an active pharmaceutical ingredient provides new opportunity to improve the performance characteristics of pharmaceutical finished product, the development of new polymorphic forms is always encouraged.

[0021] Furthermore, solid state study of an active pharmaceutical ingredient aims to widen the variety of polymorphs that a formulation scientist has available for designing a pharmaceutical dosage form with desired characteristics.

[0022] The present inventors after significant efforts have surprisingly found crystalline forms of Elacestrant dihydrochloride and novel salts of Elacestrant which are useful for the preparation of various pharmaceutical compositions.

[0023] Brief description of the invention:

[0024] The first embodiment of the present invention provides a novel crystalline form of Elacestrant dihydrochloride of formula- la, herein after designated as crystalline form-M.

[0025] The second embodiment of the present invention provides a process for the preparation of crystalline form-M of Elacestrant dihydrochloride of formula- la.

[0026] The third embodiment of the present invention provides a novel crystalline form of Elacestrant dihydrochloride of formula- la, herein after designated as crystalline form-S.

[0027] The fourth embodiment of the present invention provides a process for the preparation of crystalline form-S of Elacestrant dihydrochloride of formula- la.

[0028] The fifth embodiment of the present invention provides a process for the micronization of crystalline form-S of Elacestrant dihydrochloride of formula- la.

[0029] The sixth embodiment of the present invention provides VH-PXRD (Variable humidity powder X-Ray diffraction) study of crystalline form-S of Elacestrant dihydrochloride of formula- la.

[0030] The seventh embodiment of the present invention provides VH-PXRD (Variable humidity powder X-Ray diffraction) study of micronized crystalline form-S of Elacestrant dihydrochloride of formula- 1 a.

[0031] The eighth embodiment of the present invention provides 0% RH in a desiccator under closed conditions and collected the PXRD study of crystalline form- S of Elacestrant dihydrochloride of formula- 1 a.

[0032] The ninth embodiment of the present invention provides 0% RH in a desiccator under closed conditions and collected the PXRD study of micronized crystalline form-S of Elacestrant dihydrochloride of formula- la.

[0033] The tenth embodiment of the present invention provides VT-PXRD (Variable temperature powder X-Ray diffraction) study of crystalline form-S of Elacestrant dihydrochloride of formula- la.

[0034] The eleventh embodiment of the present invention provides VT-PXRD (Variable temperature powder X-Ray diffraction) study of micronized crystalline form-S of Elacestrant dihydrochloride of formula- la.

[0035] The twelfth embodiment of the present invention provides a process for the preparation of crystalline form IB of Elacestrant dihydrochloride of formula- la. The thirteenth embodiment of the present invention provides a novel crystalline form of Elacestrant dihydrochloride of formula- la, herein after designated as crystalline form-N.

[0036] The fourteenth embodiment of the present invention provides a process for the preparation of crystalline form-N of Elacestrant dihydrochloride of formula- 1 a.

[0037] The fifteenth embodiment of the present invention provides Elacestrant Succinic acid of formula- lb.

[0038] The sixteenth embodiment of the present invention provides a process for the preparation of Elacestrant Succinic acid of formula- lb.

[0039] The seventeenth embodiment of the present invention provides Elacestrant Fumaric acid of formula- 1c.

[0040] The eighteenth embodiment of the present invention provides a process for the preparation of Elacestrant Fumaric acid of formula- 1c.

[0041] Brief description of the drawings:

[0042] Figure-1: Illustrates the powder X-Ray diffraction {PXRD} pattern of crystalline form-M of Elacestrant dihydrochloride.

[0043] Figure-2: Illustrates the PXRD pattern of crystalline form-S of Elacestrant dihydrochloride obtained according to example-2.

[0044] Figure-3: Illustrates the PXRD pattern of crystalline form-S of Elacestrant dihydrochloride obtained according to example-3.

[0045] Figure-4: Illustrates the PXRD pattern of micronized crystalline form-S of

[0046] Elacestrant dihydrochloride obtained according to example-4.

[0047] Figure-5: Illustrates overlay of VH-PXRD patterns of crystalline form-S collected at different % RH conditions.

[0048] Figure-6: Illustrates overlay of VT-PXRD patterns of crystalline form-S collected at different temperature.

[0049] Figure-7: Illustrates overlay of VH-PXRD patterns of micronized crystalline form-S collected at different % RH conditions. Figure-8: Illustrates overlay of VT- PXRD patterns of micronized crystalline form-S collected at different temperature.

[0050] Figure-9: Illustrates PXRD pattern for crystalline form-S after exposed to 0% RH for 2 hours.

[0051] Figure-10: Illustrates PXRD pattern for micronized crystalline form-S after exposed to 0% RH for 2 hours.

[0052] Figure-11: Illustrates the PXRD pattern of crystalline form IB of Elacestrant dihydrochloride obtained according to example-5 and example-6.

[0053] Figure-12: Illustrates the PXRD pattern of crystalline form-N of Elacestrant dihydrochloride .

[0054] Figure-13: Illustrates the PXRD pattern of crystalline form-M of Elacestrant Succinic acid.

[0055] Figure-14: Illustrates the PXRD pattern of crystalline form-S of Elacestrant Fumaric acid.

[0056] Detailed description of the invention:

[0057] As used herein the term “solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, pentane, cycloheptane, methyl cyclohexane, ethylbenzene, m-, o-, or p- xylene, or naphthalene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl t- butyl ether, diisopropyl ether, 1 ,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), diglyme, dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcohol solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2- fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1,2-propanediol (propylene glycol), 2-methoxyethanol, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.

[0058] As used herein the term “pharmaceutically acceptable salts” or “salts” include but are not limited to, hydrohalides like hydrochloride, hydrobromide and hydroiodide; inorganic acids such as nitrate, perchloric acid salt, sulfate or phosphate; lower-alkyl sulfonic acid salts such as methanesulfonate, or ethanesulfonate; arylsulfonic acid salts such as benzene sulfonate or p-toluenesulfoante; organic acid salts such as acteate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate or maleate; or an amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt, aspartic acid salt; salicylate salt, 1,5- naphthalenedisulfonic acid salt and the like.

[0059] The first embodiment of the present invention provides a novel crystalline form of Elacestrant dihydrochloride compound of formula- la, herein after designated as crystalline form-M.

[0060] In the first aspect of the first embodiment provides a crystalline form-M of Elacestrant dihydrochloride characterized by its PXRD pattern as depicted in Figure 1.

[0061] The second embodiment of the present invention provides a process for the preparation of crystalline form-M of Elacestrant dihydrochloride of formula- la, comprising: a) providing a solution of Elacestrant dihydrochloride in dimethylformamide, b) isolating a crystalline form-M of Elacestrant dihydrochloride of formula- la; wherein providing the solution in step-a) can be carried out by dissolving Elacestrant dihydrochloride in dimethylformamide at a suitable temperature ranging from about 25 °C to reflux temperature of the solvent used or solution in step-a) can also be obtained from the synthetic process in which Elacestrant dihydrochloride is prepared; isolating crystalline form-M of Elacestrant dihydrochloride in step-b) can be carried out by combining with an anti-solvent followed by filtering the compound; wherein anti-solvent is methyl tert-butyl ether.

[0062] The third embodiment of the present invention provides a novel crystalline form of Elacestrant dihydrochloride of formula- la, herein after designated as crystalline form-S.

[0063] The first aspect of the third embodiment provides a crystalline form-S of Elacestrant dihydrochloride of formula- la characterized by PXRD (powder X-Ray diffraction) pattern having peaks at about 3.0°, 6.1°, 9.6° and 24.1° ± 0.2° 20.

[0064] The second aspect of the third embodiment provides a crystalline form-S of Elacestrant dihydrochloride of formula- la characterized by PXRD (powder X-Ray diffraction) pattern having peaks at about 7.9° and 11.9° ± 0.2° 20.

[0065] The third aspect of the third embodiment provides a crystalline form-S of Elacestrant dihydrochloride of formula- la characterized by PXRD (powder X-Ray diffraction) peaks at about 7.9°, 9.6° and 11.9° ± 0.2° 20.

[0066] The fourth aspect of the third embodiment provides a crystalline form-S of Elacestrant dihydrochloride of formula- la characterized by PXRD (powder X-Ray diffraction) peaks at about 7.9°, 9.6° and 11.9° ± 0.2° 20 in a PXRD pattern as illustrated in Figure-2.

[0067] The fifth aspect of the third embodiment provides a crystalline form-S of Elacestrant dihydrochloride of formula- la characterized by PXRD (powder X-Ray diffraction) peaks at about 7.9°, 9.6° and 11.9° ± 0.2° 20 and further having peaks at about 3.0°, 6.1° and 24.1° ± 0.2° 20. The sixth aspect of the third embodiment provides a crystalline form-S of Elacestrant dihydrochloride of formula- la characterized by PXRD (powder X-Ray diffraction) peaks at about 3.0°, 6.1°, 7.9°, 9.6°, 11.9° and 24.1° ± 0.2° 20.

[0068] The seventh aspect of the third embodiment provides a crystalline form-S of Elacestrant dihydrochloride characterized by its PXRD pattern substantially as shown in Figure 2.

[0069] The eighth aspect of the third embodiment provides a crystalline form-S of Elacestrant dihydrochloride characterized by its PXRD pattern substantially as shown in figure-3 and 4.

[0070] In ninth aspect of third embodiment, wherein the crystalline form-S of Elacestrant dihydrochloride is stable.

[0071] The fourth embodiment of the present invention provides a process for the preparation of crystalline form-S of Elacestrant dihydrochloride of formula- la, comprising: a) dissolving or suspending Elacestrant dihydrochloride in a solvent, b) isolating the crystalline form-S of Elacestrant dihydrochloride of formula- 1 a.

[0072] In the first aspect of the fourth embodiment, wherein dissolving or suspending Elacestrant dihydrochloride in step-a) can be carried out by mixing the Elacestrant dihydrochloride in a solvent at a suitable temperature ranging from about 0°C to reflux temperature of the solvent or can also be obtained from the synthetic process in which Elacestrant dihydrochloride is prepared.

[0073] In the second aspect of the fourth embodiment, wherein the solvent in step-a) is selected from ketone solvents, alcohol solvents, ester solvents, ethyl formate, water and / or mixtures thereof.

[0074] In the third aspect of the fourth embodiment, wherein the solvent is the mixture of ketone solvents and water.

[0075] In the fourth aspect of the fourth embodiment, wherein the ketone solvent is acetone. In the fifth aspect of the fourth embodiment, wherein isolating the crystalline form-S of Elacestrant dihydrochloride in step-b) is involves the removal of solvent by suitable techniques which includes but not limited to decantation, evaporation, flash evaporation, concentrating the mixture, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, cooling the mixture or solution to lower temperatures followed by filtration, thin film drying, combining with an anti-solvent or by any other suitable techniques known in the art.

[0076] In the sixth aspect of the fourth embodiment, wherein the isolating the crystalline form-S in step-b) can be carried out by evaporation, concentrating the mixture.

[0077] In the seventh aspect of the fourth embodiment, wherein the isolating the crystalline form-S in step-b) can be carried out by cooling the mixture obtained in step-a) to lower temperatures, followed by filtration.

[0078] In the eighth aspect of the fourth embodiment, wherein the second solvent optionally added to the mixture obtained in step-a) before isolating the crystalline form-S, wherein the second solvent is selected from ketone solvents.

[0079] In the ninth aspect of the fourth embodiment, wherein the isolating the crystalline form-S in step-b) can be carried out by combining with an anti-solvent wherein the anti-solvent is selected from ketone solvents, ester solvents.

[0080] In the tenth aspect of the fourth embodiment, wherein the anti-solvent is acetone.

[0081] In the eleventh aspect of the fourth embodiment of the present invention provides a process for the preparation of crystalline form-S of Elacestrant dihydrochloride of formula- la, comprising: a) providing a solution of Elacestrant dihydrochloride in the mixture of acetone and water, b) isolating a crystalline form-S of Elacestrant dihydrochloride of formula- la; wherein providing the solution in step-a) can be carried out by dissolving Elacestrant dihydrochloride in the mixture of acetone and water at a suitable temperature ranging from about 25°C to reflux temperature of the solvent or solution in step-a) can also be obtained from the synthetic process in which Elacestrant dihydrochloride is prepared; isolating crystalline form-S of Elacestrant dihydrochloride in step-b) can be carried out by the removal of the solvent from the solution by an anti-solvent crystallization, cooling crystallization, precipitation, evaporative crystallization, distillation, concentration optionally under reduced pressure.

[0082] The fifth embodiment of the present invention provides a process for the micronization of crystalline form-S of Elacestrant dihydrochloride of formula- la.

[0083] In the first aspect of the fifth embodiment, the micronization of crystalline form-S is performed by milling (and / or re-milling) using a jet-milling process with feed rates between 1 and 5 kg / cm2and milling pressures between 2.0 and 7.0 kg / cm2.

[0084] In the second aspect of the fifth embodiment, PXRD pattern for micronized crystalline form-S of Elacestrant dihydrochloride is illustrated in figure-4.

[0085] In the third aspect of the fifth embodiment of the present invention, wherein the crystalline Form-S of Elacestrant dihydrochloride of Formula la, produced by the present invention, is characterized by a particle size distribution wherein 90% of the particles have a size (D90) less than about 100 pm, preferably less than about 50 pm, 50% particles having particle size (D50) less than about 50 pm, preferably less than about 30 pm and 10% particles having particle size (D10) less than about 30 pm, preferably less than about 10 pm.

[0086] In the fourth aspect of the fifth embodiment the present invention, wherein the Micronized form-S of Elacestrant dihydrochloride of Formula- la, produced by the present invention, is characterized by a particle size distribution where 90% of the particles have a size (D90) less than about 15 pm, 50% particles having particle size (D50) less than about 10 pm and 10% particles having particle size (D10) less than about 5 pm. The sixth embodiment of the present invention, crystalline form-S obtained according to the present invention is taken and the sample exposed to different % RH conditions for 1 hour at each % RH by using DVS instrument and collected the PXRD pattern at each % of RH, which study herein is referred to as VH-PXRD (Variable humidity powder X-Ray diffraction) study.

[0087] In an aspect of the sixth embodiment, the overlay of VH-PXRD pattern for crystalline form-S after exposed to different % RH for 1 hr at each % RH is illustrated in figure-5.

[0088] The seventh embodiment of the present invention, micronized crystalline form-S obtained according to the present invention is taken and the sample exposed to different % RH conditions for 1 hour at each % RH by using DVS instrument and collected the PXRD pattern at each % of RH, which study herein is referred to as VH- PXRD study.

[0089] In an aspect of the seventh embodiment, the overlay of VH-PXRD pattern for micronized crystalline form-S after exposed to different % RH conditions for 1 hour at each % RH is illustrated in figure-7.

[0090] The eighth embodiment of the present invention, crystalline form-S obtained according to the present invention is taken and the sample exposed to 0% RH conditions for 2 hours by using P2O5 to generate the 0% RH in a desiccator under closed conditions and collected the PXRD.

[0091] In an aspect of the eighth embodiment, PXRD pattern for crystalline form-S after exposed to 0% RH for 2 hours is illustrated in figure-9.

[0092] The ninth embodiment of the present invention, micronized crystalline form-S obtained according to the present invention is taken and the sample exposed to 0% RH conditions for 2 hours by using P2O5 to generate the 0% RH in a desiccator under closed conditions and collected the PXRD. In an aspect of the ninth embodiment, PXRD pattern for micronized crystalline form-S after exposed to 0% RH for 2 hours is illustrated in figure- 10.

[0093] The tenth embodiment of the present invention, crystalline form-S obtained according to the present invention is taken and the sample exposed to different temperatures ranging from 25 °C - 205 °C and collected the PXRD pattern at each temperature, which study herein is referred to as VT-PXRD (Variable temperature powder X-Ray diffraction) study.

[0094] In an aspect of the tenth embodiment, the overlay of VT-PXRD pattern for crystalline form-S after exposed to different temperatures ranging from 25 °C- 205 °C is illustrated in figure-6.

[0095] The eleventh embodiment of the present invention, micronized crystalline form-S obtained according to the present invention is taken and the sample exposed to different temperatures ranging from 25 °C - 205 °C and collected the PXRD pattern at each temperature, which study herein is referred to as VT-PXRD (Variable temperature powder X-Ray diffraction) study.

[0096] In an aspect of the eleventh embodiment, the overlay of VT-PXRD pattern for micronized crystalline form-S after exposed to different temperatures ranging from 25°C- 205°C is illustrated in figure-7.

[0097] The twelfth embodiment of the present invention provides a process for the preparation of crystalline form IB of Elacestrant dihydrochloride of formula- la, comprising: a) providing a solution of Elacestrant dihydrochloride in a solvent, b) isolating a crystalline form IB of Elacestrant dihydrochloride of formula- la; wherein providing the solution of Elacestrant dihydrochloride in step-a) can be carried out by combining Elacestrant dihydrochloride with a solvent at a suitable temperature ranging from about 25 °C to reflux temperature of the solvent used or solution in step-a) can also be obtained from the synthetic process in which Elacestrant dihydrochloride is prepared; the solvent is selected from propylene glycol, dimethyl sulfoxide and the like; isolating crystalline form IB of Elacestrant dihydrochloride in step-b) can be carried out by combining with an anti-solvent followed by filtering the compound; wherein the anti-solvent is selected from hydrocarbon solvents, ether solvents and the like.

[0098] The thirteenth embodiment of the present invention provides a novel crystalline form of Elacestrant dihydrochloride of formula- la, herein after designated as crystalline form-N.

[0099] In the first aspect of the thirteenth embodiment provides a crystalline form-N of Elacestrant dihydrochloride of formula- 1 a, characterized by PXRD (powder X-Ray diffraction) pattern having peaks at about 5.7°, 7.9°, 9.9° and 21.0° ± 0.2° 20.

[0100] In the second aspect of the thirteenth embodiment provides a crystalline form- N of Elacestrant dihydrochloride of formula- la, characterized by PXRD (powder X- Ray diffraction) pattern having peaks at about 5.7°, 7.9°, 9.9°, 12.1°, 13.0°, 14.4° and 21.0° ± 0.2° 20.

[0101] In the third aspect of the thirteenth embodiment provides a crystalline form-N of Elacestrant dihydrochloride characterized by its PXRD pattern as depicted in Figure- 12.

[0102] The fourteenth embodiment of the present invention provides a process for the preparation of crystalline form-N of Elacestrant dihydrochloride of formula- la, comprising: a) providing a solution of Elacestrant in an ether solvent, b) combining the solution with Hydrochloric acid source, c) isolating a crystalline form-N of Elacestrant dihydrochloride of formula- 1 a; wherein providing the solution in step-a) can be carried out by dissolving Elacestrant in an ether solvent at a suitable temperature ranging from about 25 °C to reflux temperature of solvent used or solution in step-a) can also be obtained from the synthetic process in which Elacestrant is prepared; hydrochloric acid source in step-b) is selected from concentrated hydrochloric acid, hydrochloric acid gas and like; isolating crystalline form-N of Elacestrant dihydrochloride in step-c) is by the solvent removal by known techniques which are selected from combining with an antisolvent or cooling the mixture to lower temperatures followed by filtration of the mixture or crystallization.

[0103] The fifteenth embodiment of the present invention provides Elacestrant

[0104] Succinic acid of formula- lb

[0105] Formula- lb.

[0106] In the first aspect of the fifteenth embodiment, wherein the compound of formula- lb can be isolated as solid.

[0107] In the second aspect of the fifteenth embodiment, wherein the solid is obtained as crystalline solid and the said crystalline form is designated as crystalline form-M.

[0108] In the third aspect of the fifteenth embodiment, wherein the compound of formula- lb is characterized by its PXRD pattern as illustrated in figure- 13.

[0109] The sixteenth embodiment of the present invention provides a process for the preparation of Elacestrant Succinic acid of formula- lb comprising: a) providing a solution of Elacestrant and Succinic acid in a solvent, b) isolating Elacestrant Succinic acid; wherein providing the solution in step-a) can be carried out by dissolving Elacestrant in a solvent at a suitable temperature ranging from about 25 °C to reflux temperature of the solvent used and by adding Succinic acid or dissolving Elacestrant and succinic acid in a solvent at a suitable temperature ranging from about 25 °C to reflux temperature of the solvent used or solution in step-a) can also be obtained from the synthetic process in which Elacestrant is prepared and followed by adding succinic acid; the solvent is selected from alcohol solvents such as isopropyl alcohol, isolating Elacestrant Succinic acid in step-b) can be carried out by known techniques which are selected from combining with an anti-solvent or cooling the mixture to lower temperatures followed by filtration of the mixture or crystallization.

[0110] In an aspect of the sixteenth embodiment, wherein Elacestrant Succinic acid of formula- lb further used for the preparation of pure Elacestrant of formula- 1 or its pharmaceutically acceptable salts.

[0111] The seventeenth embodiment of the present invention provides Elacestrant Fumaric acid of formula- 1c

[0112] In the first aspect of the seventeenth embodiment, wherein the compound of formula- 1c isolated as solid.

[0113] In the second aspect of the seventeenth embodiment, wherein the solid is obtained as crystalline solid and the said crystalline form is designated as crystalline form-S.

[0114] In the third aspect of the seventeenth embodiment, wherein the crystalline form-S of formula- 1c is characterized by its PXRD pattern as illustrated in figure- 14.

[0115] The eighteenth embodiment of the present invention provides a process for the preparation of Elacestrant Fumaric acid of formula- 1c comprising: a) providing a solution of Elacestrant and Fumaric acid in a solvent, b) isolating Elacestrant Succinic acid; wherein providing the solution in step-a) can be carried out by dissolving Elacestrant in a solvent at a suitable temperature ranging from about 25 °C to reflux temperature of the solvent used and by adding fumaric acid or dissolving Elacestrant and succinic acid in a solvent at a suitable temperature ranging from about 25 °C to reflux temperature of the solvent used or solution in step-a) can also be obtained from the synthetic process in which Elacestrant is prepared and followed by adding fumaric acid; the solvent is selected from alcohol solvents such as isopropyl alcohol, isolating Elacestrant Fumaric acid in step-b) can be carried out by known techniques which are selected from combining with an anti-solvent or cooling the mixture to lower temperatures followed by filtration of the mixture or crystallization.

[0116] In an aspect of the eighteenth embodiment, wherein Elacestrant Fumaric acid of formula- 1c further used for the preparation of pure Elacestrant of formula- 1 or its pharmaceutically acceptable salts.

[0117] Elacestrant dihydrochloride used as an input in the present invention can be prepared by any of the process disclosed in literature such as US 7612114 B2 or by the process described in the literature or the common general knowledge of person skilled in art.

[0118] Crystalline forms of Elacestrant dihydrochloride, Elacestrant Succinic acid and Elacestrant Fumaric acid obtained according to the present invention having purity of greater than about 99%, preferably greater than about 99.5%, more preferably greater than about 99.7%, most preferably greater than about 99.8% measured by HPLC {High Performance Liquid Chromatography}.

[0119] Crystalline forms of Elacestrant dihydrochloride, Elacestrant Succinic acid and Elacestrant Fumaric acid can be further micronized or milled to get 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 not limited to single or multi-stage micronization using cutting mills, pin / cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling or micronization may be performed before drying or after drying of the product.

[0120] The nineteenth embodiment of the present invention crystalline forms obtained according to the present invention such as crystalline form-M, form-S and form-N of Elacestrant dihydrochloride of formula- la used for the preparation of various pharmaceutical formulations.

[0121] The twentieth embodiment of the present invention provides a pharmaceutical composition comprising crystalline forms obtained according to the present invention such as crystalline form-M, form-S and form-N of Elacestrant dihydrochloride of formula- la and at least one pharmaceutically acceptable excipient.

[0122] The twenty-first embodiment of the present invention Elacestrant Succinic acid and Elacestrant Fumaric acid used for the preparation of various pharmaceutical formulations.

[0123] The twenty-second embodiment of the present invention provides a pharmaceutical composition comprising Crystalline forms of Elacestrant dihydrochloride, Elacestrant Succinic acid and Elacestrant Fumaric acid obtained according to the present invention and at least one pharmaceutically acceptable excipient.

[0124] As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations. Suitable pharmaceutically acceptable excipients are selected from but not limited to binders, diluents, disintegrants, surfactants and lubricants. Suitable binders that can be include polyvinylpyrolidone, copovidone, starches such as pregelatinized starch, cellulose derivatives such as hydroxypropylmethyl cellulose, ethylcellulose, hydroxypropylcellulose and carboxymethylcellulose, gelatine, acacia, agar, alginic acid, carbomer, chitosan, dextrates, cyclodextrin, dextrin, glycerol dibehenate, guargum, hypromellose, maltodextrin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, sodium alginate, sucrose, mixtures thereof; suitable diluents that can be include anhydrous lactose, lactose monohydrate, modified lactose, dibasic calcium phosphate, tribasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, maize starch, pregelatinized starch, calcium carbonate, sucrose, glucose, dextrates, dextrins, dextrose, fructose, lactitol, mannitol, sorbitol starch, calcium lactate or mixtures thereof; suitable disintegrants that can be include magnesium aluminometa silicate (or magnesium aluminum silicate), starch, pregelatinized starch, sodium starch glycolate, crospovidone, croscarmellose sodium, low- substituted hydroxypropyl cellulose, alginic acid, carboxy methyl cellulose sodium, sodium alginate, calcium alginate and chitosan; suitable lubricants that can be include (but are not limited to) magnesium stearate, stearic acid, palmitic acid, talc, and aerosil. Suitable surfactants that can be include (but are not limited to) polysorbate 80, polyoxyethylene sorbitan, polyoxyethylene -polyoxy-propylene copolymer and sodium lauryl sulphate; beta-cyclodextrin include (but are not limited to) sulfobutylalkyl ether-beta-cyclodextrin, betadex-sulfobutylether sodium, or hydroxypropyl-beta-cyclodextrin.

[0125] In an embodiment of the present invention discloses a method for treating a patient in need thereof. The method involves administering a therapeutically effective amount of crystalline forms of Elacestrant dihydrochloride or Elacestrant Succinic acid or Elacestrant Fumaric acid obtained in accordance with the present invention. The crystalline forms are utilized in the treatment of postmenopausal women or adult men, with ER-positive, HER2-negative, ESRI -mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.

[0126] P-XRD Method of Analysis:

[0127] The PXRD analysis of compound of formula- la of the present invention was carried out by using BRUKER / D8 ADVANCE diffractometer using CuKa radiation of wavelength 1.5406A0.

[0128] VH-PXRD Method of Analysis:

[0129] The PXRD analysis of compound of formula- la of the present invention was carried out by using Bruker D8 diffractometer using Cu Ka radiation (40 kV, 30 mA), 0-20 goniometer, and divergence of V4 and receiving slits, a Ge monochromator and a Lynxeye XE (ID mode) detector. The instrument was performance checked using a certified Corundum standard (NIST 1976). The software used for data collection was Diffrac Plus XRD Commander v2.6.1 and the data were analyzed and presented using Diffrac Plus EVA vl5.0.0.0.

[0130] Samples are exposed to different % RH conditions from 10% RH to 95% RH using DVS instrument for 1-2 hr and collected the PXRD pattern. The PXRD data were collected at 298.15 K with water temperature of 35.0° C., in an angular range of 2 to 49°, with a step size of 0.03°, a collection time of 28.6 sec / step, and a collection time at each % RH was 6 min 29 sec.

[0131] VT-PXRD sample analysis method parameters:

[0132] The PXRD analysis of compound of formula- la of the present invention was carried out by using PANalytical Empyrean diffractometer using Cu Ka radiation (45 kV, 40 mA), 0-20 goniometer, and divergence of V4 and receiving slits, a Ge monochromator and a PIXcel detector. The instrument was performance checked using a certified Corundum standard (NIST 1976). The software used for data collection was Xpert software and the data were analyzed and presented using Diffrac

[0133] Plus EVA V15.0.0.0.

[0134] Samples run under non-ambient conditions were mounted on a silicon wafer with a heat-conducting compound. The sample was then heated from ambient to the appropriate temperature at 20°C / min and subsequently held isothermally for 1 minute before data collection was initiated. The PXRD data were collected in an angular range of 5° to 39.9°, with a step size of 0.013°, a collection time of 18.8 sec / step, and a collection time at each % RH was 3 min 37 sec.

[0135] The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided for illustration only and hence should not be considered as limitation of the scope of the invention.

[0136] Examples:

[0137] Example-1: Preparation of crystalline form-M of Elacestrant dihydrochloride of formula-la

[0138] Dissolved Elacestrant dihydrochloride (1 g) in dimethylformamide (30 ml) at 60- 65 °C. Cooled the obtained solution to 25-30°C, methyl tert-butyl ether (90 ml) was added to the solution and stirred at the same temperature. Filtered the solid, washed with methyl tert-butyl ether and dried to get the title compound.

[0139] Yield: 0.96 g. PXRD of the obtained compound is illustrated in figure- 1.

[0140] Example-2: Preparation of crystalline form-S of Elacestrant dihydrochloride of formula-la

[0141] Dissolved Elacestrant dihydrochloride (1 g) in the mixture of acetone (20 ml) and water (40 ml) at 25-30°C. Filtered the obtained solution. Evaporated the solvent completely from the filtrate and dried to get title compound.

[0142] Yield: 0.85 g. PXRD of the obtained compound is illustrated in figure-2.

[0143] Example-3: Preparation of crystalline form-S of Elacestrant dihydrochloride of formula-la Dissolved Elacestrant dihydrochloride (5 g) in the mixture of acetone (50 ml) and water (10 ml) at 45-55°C. The solution was slowly Cooled to 0-5°C and stirred at the same temperature. Acetone was added to the mixture at 0-5°C, raised the temperature of the mixture to 25-30°C and stirred at the same temperature. Filtered the solid, washed with acetone and dried get the titled compound.

[0144] Yield: 4.5 g. PXRD of the obtained compound is illustrated in figure-3.

[0145] Example-4: Micronization of crystalline form-S of Elacestrant dihydrochloride of formula-la

[0146] Crystalline form-S of Elacestrant dihydrochloride was subjected to micronization using a micronizer. Crystalline form-S of Elacestrant dihydrochloride (25 g) was charged into micronizer. Micronization was started slowly through the product feed funnel from micronizer through the hopper at the feed rate of 3 to 4 kgs / hour, applied the pressure for milling. Finally the collector was removed from the micronizer and the material was unloaded to get the micronized crystalline form-S. Yield: 21.3 g. PXRD of the obtained compound is illustrated in figure-4.

[0147] Example-5: Preparation of crystalline form IB of Elacestrant dihydrochloride of formula-la

[0148] Dissolved Elacestrant dihydrochloride (1 g) in dimethyl sulfoxide (10 ml) at 75-80°C. Toluene (50 ml) was added to the above solution and stirred at the same temperature. Cooled the mixture to 25-30°C and stirred at the same temperature. Filtered the solid, washed with toluene and dried to get the title compound.

[0149] Yield: 0.87 g. PXRD of the obtained compound is illustrated in figure- 11.

[0150] Example-6: Preparation of crystalline form IB of Elacestrant dihydrochloride of formula-la

[0151] Dissolved Elacestrant dihydrochloride (0.5 g) in propylene glycol (5 ml) at 25-30°C. Methyl tert-butyl ether (15 ml) was added to the above solution at 25-30°C and stirred at the same temperature. Filtered the solid, washed with methyl tert-butyl ether and dried to get the title compound. Yield: 0.36 g. PXRD of the obtained compound is illustrated in figure- 11.

[0152] Example-7: Preparation of Elacestrant

[0153] Dissolved Elacestrant dihydrochloride (2 g) in water (30 ml) at 45-50°C and cooled the obtained solution to 25-30°C. Aqueous sodium bicarbonate solution was added to the above solution and stirred at the same temperature. Filtered the solid, washed with water to get wet solid. The obtained wet solid was slurried in water and filtered the solid, washed with water and dried to get the title compound. Yield: 1.5 g.

[0154] Example-8: Preparation of crystalline form-N of Elacestrant dihydrochloride of formula-la

[0155] Dissolved Elacestrant (1.4 g) in tetrahydrofuran (28 ml) at 60-65 °C. Hydrochloric acid (0.57 ml) was added to the above solution at 60-65°C and stirred at the same temperature. Cooled the mixture to 25-30°C and stirred at the same temperature. Filtered the solid, washed with tetrahydrofuran and dried to get the title compound. Yield: 1.5 g. PXRD of the obtained compound is illustrated in figure- 12.

[0156] Example-9: Preparation of crystalline form-M of Elacestrant Succinic acid

[0157] Dissolved Elacestrant (0.3 g) in isopropyl alcohol (10 ml) at 60-65°C. Succinic acid (0.154 g) was added to the above solution at 60-65°C and stirred at the same temperature. Cooled the obtained solution to 25-30°C and stirred at the same temperature. Filtered the solid, washed with isopropyl alcohol and dried to get the title compound.

[0158] Yield: 0.210 g. PXRD of the obtained compound is illustrated in figure-13.

[0159] Example-10: Preparation of crystalline form-S of Elacestrant Fumaric acid

[0160] Dissolved Elacestrant (0.3 g) in isopropyl alcohol (10 ml) at 60-65 °C. Fumaric acid (0.151 gm) was added to the above solution at 60-65 °C and stirred at the same temperature. Cooled the obtained mixture to 25-30°C and stirred at the same temperature. Filtered the solid, washed with isopropyl alcohol and dried to get the title compound.

[0161] Yield: 0.250 g. PXRD of the obtained compound is illustrated in figure- 14.

Claims

Claims1. A crystalline form-S of Elacestrant dihydrochloride of formula- laFormula- 1 a characterized by its PXRD peaks at about 7.9°, 9.6° and 11.9° ± 0.2° 26.

2. The crystalline form-S of Elacestrant dihydrochloride according to claim 1 is further characterized by its PXRD peaks at about 3.0°, 6.1° and 24.1° ± 0.2° 20.

3. The crystalline form-S of Elacestrant dihydrochloride according to claim 1 is further characterized by its XRPD pattern substantially as shown in Figure-2.

4. The crystalline form-S of Elacestrant dihydrochloride according to claim 1, further characterized by its XRPD pattern substantially as shown in Figures-3 and 4.

5. A crystalline form-S of Elacestrant dihydrochloride is characterized by its PXRD peaks at about 3.0°, 6.1°, 7.9°, 9.6°, 11.9° and 24.1° ± 0.2° 26.

6. A process for the preparation of crystalline form-S of Elacestrant dihydrochloride of formula- la,comprising: a) dissolving or suspending Elacestrant dihydrochloride in a solvent, b) isolating a crystalline form-S of Elacestrant dihydrochloride of formula- 1 a.

7. The process according to claim 6, wherein dissolving or suspending Elacestrant dihydrochloride in step-a) can be carried out by mixing the Elacestrant dihydrochloride in a solvent at a suitable temperature ranging from about 0°C to reflux temperature of the solvent or can also be obtained from the synthetic process in which Elacestrant dihydrochloride is prepared.

8. The process according to claim 7, wherein the solvent is selected from ketone solvents, alcohol solvents, ester solvents, ethyl formate, water and / or mixtures thereof.

9. The process according to claim 8, wherein the solvent is the mixture of ketone solvents and water.

10. The process according to claim 9, wherein the ketone solvent is acetone.

11. The process according to claim 6, wherein isolating the crystalline form-S of Elacestrant dihydrochloride in step-b) can be carried out by the removal of solvent by suitable techniques which includes but not limited to decantation, evaporation, flash evaporation, concentrating the mixture, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, cooling the mixture or solution to lower temperatures followed by filtration, thin film drying, combining with an anti-solvent.

12. The process according to claim 11, wherein the isolating the crystalline form-S is carried out by evaporation, concentrating the mixture.

13. The process according to claim 11, wherein the isolating the crystalline form-S is carried out by combining with an anti-solvent followed by filtering the compound; wherein the anti-solvent is selected from ketone solvents, ester solvents.

14. The process according to claim 13, wherein the anti-solvent is acetone.

15. Elacestrant dihydrochloride characterized by a particle size distribution with a D90 less than about 100 pm.

16. Elacestrant dihydrochloride according to claim 15, wherein the Elacestrant dihydrochloride is in crystalline form-S.

17. A micronized Elacestrant dihydrochloride characterized by a particle size distribution with a D90 less than about 15 pm.

18. A micronized Elacestrant dihydrochloride according to claim 17, wherein the Elacestrant dihydrochloride is in crystalline form-S.

19. A process for the preparation of crystalline form-M of Elacestrant dihydrochloride of formula- la,comprising: a) providing a solution of Elacestrant dihydrochloride in dimethylformamide, b) isolating a crystalline form-M of Elacestrant dihydrochloride of formula- 1 a.

20. The process according to claim 19, wherein the solution in step-a) can be carried out by dissolving Elacestrant dihydrochloride in dimethylformamide at a temperature ranging from about 25 °C to reflux temperature of the solvent used or solution in step-a) can also be obtained from the synthetic process in which Elacestrant dihydrochloride is prepared.

21. The process according to claim 19, wherein isolating crystalline form-M of Elacestrant dihydrochloride in step-b) can be carried out by combining with an anti-solvent followed by filtering the compound; wherein anti-solvent is methyl tert-butyl ether.

22. A process for the preparation of crystalline form-N of Elacestrant dihydrochloride of formula- la, comprising: a) providing a solution of Elacestrant in an ether solvent, b) combining the solution with Hydrochloric acid source, c) isolating a crystalline form-N of Elacestrant dihydrochloride of formula- 1 a.

23. The process according to claim 22, wherein providing the solution in step-a) can be carried out by dissolving Elacestrant in an ether solvent at a suitable temperature ranging from about 25 °C to reflux temperature of solvent used or solution in step-a) can also be obtained from the synthetic process in which Elacestrant is prepared; hydrochloric acid source in step-b) is selected from concentrated hydrochloric acid, hydrochloric acid gas; isolating crystalline form- N of Elacestrant dihydrochloride in step-c) is by the solvent removal by known techniques which are selected from combining with an anti-solvent or cooling the mixture to lower temperatures followed by filtration of the mixture or crystallization.

24. Elacestrant Succinic acid of formula- lbFormula- lb.

25. Elacestrant Succinic acid according to claim 24, wherein the compound of formula- lb isolated as solid.

26. Elacestrant Succinic acid according to claim 25, wherein the solid is obtained as crystalline solid and the said crystalline form is designated as crystalline form-M.

27. Elacestrant Succinic acid according to claim 26, wherein the crystalline form-M of formula- lb is characterized by its PXRD pattern as illustrated in figure- 13.

28. A process for the preparation of Elacestrant Succinic acid of formula- lb comprising: a) providing a solution of Elacestrant and Succinic acid in a solvent, b) isolating Elacestrant Succinic acid.

29. The process according to claim 28, wherein providing the solution in step-a) can be carried out by dissolving Elacestrant in a solvent at a suitable temperature ranging from about 25 °C to reflux temperature of the solvent used and by adding Succinic acid or dissolving Elacestrant and succinic acid in a solvent at a suitable temperature ranging from about 25 °C to reflux temperature of the solvent used or solution in step-a) can also be obtained from the synthetic process in which Elacestrant is prepared and followed by adding succinic acid; the solvent is selected from alcohol solvents such as isopropyl alcohol, isolating Elacestrant Succinic acid in step-b) can be carried out by known techniques which areselected from combining with an anti-solvent or cooling the mixture to lower temperatures followed by filtration of the mixture or crystallization.

30. The process according to claim 28, wherein Elacestrant Succinic acid of formula- 1b further used for the preparation of pure Elacestrant of formula- 1 or its pharmaceutically acceptable salts.

31. Elacestrant Fumaric acid of formula- 1c32. Elacestrant Fumaric acid according to claim 31, wherein the compound of formula- 1c isolated as solid.

33. Elacestrant Fumaric acid according to claim 32, wherein the solid is obtained as crystalline solid and the said crystalline form is designated as crystalline form-S.

34. Elacestrant Fumaric acid according to claim 33, wherein the crystalline form-S of formula- 1c is characterized by its PXRD pattern as illustrated in figure- 14.

35. A process for the preparation of Elacestrant Fumaric acid of formula- 1c comprising: a) providing a solution of Elacestrant and Fumaric acid in a solvent, b) isolating Elacestrant Succinic acid.

36. The process according to claim 35, wherein providing the solution in step-a) can be carried out by dissolving Elacestrant in a solvent at a suitable temperature ranging from about 25 °C to reflux temperature of the solvent used and by addingfumaric acid or dissolving Elacestrant and succinic acid in a solvent at a suitable temperature ranging from about 25 °C to reflux temperature of the solvent used or solution in step-a) can also be obtained from the synthetic process in which Elacestrant is prepared and followed by adding fumaric acid; the solvent is selected from alcohol solvents such as isopropyl alcohol, isolating Elacestrant Fumaric acid in step-b) can be carried out by combining with an anti-solvent or cooling the mixture to lower temperatures followed by filtration of the mixture or crystallization.

37. The process according to claim 35, wherein Elacestrant Fumaric acid of formulaic further used for the preparation of pure Elacestrant of formula- 1 or its pharmaceutically acceptable salts.

38. The crystalline Form-M and Form-N of Elacestrant dihydrochloride of formula- 1 a obtained according to the preceding claims used for the preparation of various pharmaceutical formulations.

39. The crystalline Form-S of Elacestrant dihydrochloride of formula- la obtained according to the preceding claims used for the preparation of various pharmaceutical formulations.

40. The pharmaceutical composition comprising crystalline form selected from one or more of crystalline Form-M and Form-N of Elacestrant dihydrochloride of formula- la according the preceding claims and at least one pharmaceutically acceptable excipient.

41. The pharmaceutical composition comprising crystalline Form-S of Elacestrant dihydrochloride of formula- la according the preceding claims and at least one pharmaceutically acceptable excipient.

42. Use of crystalline Form-M and Form-N of Elacestrant dihydrochloride of formula- la and one or more pharmaceutically acceptable excipients for the preparation of pharmaceutical formulation.

43. Use of crystalline Form-S of Elacestrant dihydrochloride of formula-la and one or more pharmaceutically acceptable excipients for the preparation of pharmaceutical formulation.

44. A method of treating a patient in need thereof comprising administering to the said patient a therapeutically effective amount of crystalline Form-M and Form-N of Elacestrant dihydrochloride of formula- la and one or more pharmaceutically acceptable excipients.

45. A method of treating a patient in need thereof comprising administering to the said patient a therapeutically effective amount of crystalline Form-S of Elacestrant dihydrochloride of formula- la and one or more pharmaceutically acceptable excipients.

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