Solid state forms of Elacestrant dihydrochloride and their processes for the preparation

Abstract

The present invention relates to amorphous solid dispersions comprising 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 one or more pharmaceutically acceptable excipients; their process of preparation. Formula-1a.

Description

[0001] Solid state forms of Elacestrant dihydrochloride and their processes for the preparation

[0002] Related Applications:

[0003] This application claims the benefit of priority to our Indian patent application number 202441013791 filed on Feb 26, 2024, disclosures of all of which is incorporated by reference in their entirety.

[0004] Field of the invention:

[0005] The present invention relates to amorphous solid dispersions comprising of Elacestrant dihydrochloride which is represented by the following structural formula- la and one or more pharmaceutically acceptable excipients and processes for preparation thereof.

[0006] Background of the invention:

[0007] Elacestrant dihydrochloride is chemically known as (6R)-6-(2-(N-(4-(2- (ethylamino) ethyl)benzyl)-N-ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydro naphthalen-2-ol dihydrochloride 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.

[0008] US patent number US7612114B2 describes the process for the preparation of Elacestrant dihydrochloride. US patent number US10385008B2 describes Form 1, Form 2, Form 3 and mixture of Form 2 and Form 3. US patent number US11643385B2 describes Form IB. 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.

[0009] WO2023227029A1 describes Elacestrant dihydrochloride anhydrous crystalline form (CSII).

[0010] There is a still develop further solid state forms or polymorphs of Elacestrant dihydrochloride to meet the pharmaceuticals requirements.

[0011] 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.

[0012] 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.

[0013] The present inventors after significant efforts have surprisingly found amorphous solid dispersions of Elacestrant dihydrochloride which are useful for the preparation of various pharmaceutical compositions.

[0014] Brief description of the invention:

[0015] The first embodiment of the present invention provides amorphous solid dispersions comprising Elacestrant dihydrochloride of formula- la and one or more pharmaceutically acceptable excipients.

[0016] The second embodiment of the present invention provides a process for the preparation of amorphous solid dispersions comprising Elacestrant dihydrochloride of formula- la and one or more pharmaceutically acceptable excipients. Brief description of the drawings:

[0017] Figure-1: Illustrates the powder X-Ray diffraction {PXRD} pattern of amorphous solid dispersion comprising Elacestrant dihydrochloride and Povidone K-30.

[0018] Figure-2 Illustrates the PXRD pattern of amorphous solid dispersion comprising Elacestrant dihydrochloride and HPMCP-50.

[0019] Figure-3: Illustrates the PXRD pattern of amorphous solid dispersion comprising Elacestrant dihydrochloride and HPMC-E5.

[0020] Figure-4: Illustrates the PXRD pattern of amorphous solid dispersion comprising Elacestrant dihydrochloride and HPMC-AS.

[0021] Figure-5: Illustrates the PXRD pattern of amorphous solid dispersion comprising Elacestrant dihydrochloride and HPC-EF.

[0022] Detailed description of the invention:

[0023] The first embodiment of the present invention provides amorphous solid dispersion comprising Elacestrant dihydrochloride and one or more pharmaceutically acceptable excipients.

[0024] In the first aspect of the first embodiment, wherein the “excipient” is selected from but not limited to polyvinylpyrrolidone (povidone or PVP), polyvinyl polypyrrolidone, polysorbate, copovidone, cross linked polyvinyl pyrrolidone (crospovidone), polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulose, 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 (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P or HPMCP), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, 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-cyclodex trins, sulfobutylether beta-cyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates and the like and their respective grades which are suitable for bioavailability.

[0025] In the second aspect of the first embodiment, wherein the excipients are preferably chosen from Povidone (Povidone K-30), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose (HPMC) E5, hydroxypropyl methylcellulose (HPMC) AS, hydroxypropyl cellulose (HPC) EF, and their respective grades which are deemed more suitable for oral bioavailability.

[0026] In the third aspect of first embodiment of the present invention, the ratio of the weight of Elacestrant dihydrochloride to the weight of the excipient(s) within the solid dispersion ranges from about 1:0.05 to about 1:5, but is not limited to this range.

[0027] In the fourth aspect of first embodiment of the present invention provides a stable amorphous solid dispersion of Elacestrant dihydrochloride which is suitable for pharmaceutical preparations with having greater stability.

[0028] In the fifth aspect of first embodiment, wherein the amorphous solid dispersion is stable at 25-30°C. In the sixth aspect of first embodiment, wherein the amorphous solid dispersion is stable at 0-5 °C.

[0029] In the seventh aspect of first embodiment, wherein the amorphous solid dispersion is stable at 0-5 °C when stored at this temperature for a period of 12 months.

[0030] The second embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising Elacestrant dihydrochloride and one or more pharmaceutically acceptable excipients, comprising: a) providing a solution of Elacestrant dihydrochloride and one or more excipients in a solvent or a mixture of solvents, b) isolating amorphous solid dispersion comprising Elacestrant dihydrochloride and the corresponding excipient(s).

[0031] In the first aspect of the second embodiment, providing a solution of Elacestrant dihydrochloride and excipient(s) in step-a) of the above process can be carried out by combining Elacestrant dihydrochloride and excipient(s) selected from those defined above with a solvent or mixture of solvents 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 and further combining with the excipient.

[0032] In the second aspect of the second embodiment, wherein the excipients are same as defined above; preferably chosen from Povidone (Povidone K-30), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose (HPMC) E5, hydroxypropyl methylcellulose (HPMC) AS, hydroxypropyl cellulose (HPC) EF, and their respective grades which are deemed more suitable for oral bioavailability.

[0033] In the third aspect of the second embodiment, wherein the solvent is selected from methanol, dichloromethane or mixture thereof. In the fourth aspect of the second embodiment, wherein the isolation of amorphous solid dispersion in step-b) can be done by removing the solvent from the mixture or solution by the 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 or by any other suitable techniques known in the art.

[0034] Elacestrant dihydrochloride used as an input for the preparation of amorphous solid dispersion of Elacestrant dihydrochloride obtained according to the present invention is prepared by any of the process disclosed in US 7612114 B2 or other references.

[0035] The amorphous solid dispersions of the present invention have a purity greater than about 98%, preferably greater than about 99%, more preferably greater than about 99.5% as determined by HPLC.

[0036] The amorphous solid dispersions of the present invention are useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used.

[0037] The third embodiment of the present invention provides the use amorphous solid dispersions of the present invention for the preparation of pharmaceutical formulations.

[0038] The fourth embodiment of the present invention provides pharmaceutical composition comprising amorphous solid dispersions of the present invention and at least one additional pharmaceutically acceptable excipient. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

[0039] In an aspect of the fourth embodiment, wherein the additional pharmaceutically acceptable excipient(s) selected from povidone, polyvinyl polypyrrolidone, polysorbate, copovidone, cross linked polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate, methyl cellulose, carboxymethyl cellulose, carboxymethylethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxy propyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose, cross linked sodium carboxymethyl cellulose, cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, talc, iron oxide, stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, 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, sulfobutylether beta-cyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates.

[0040] The fifth embodiment of the present invention provides a method of treating a patient in need thereof comprising administering to the said patient a therapeutically effective amount of amorphous solid dispersion of the present invention.

[0041] The solid dispersions produced by various processes of the present invention 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 includes 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 / micronization may be performed before drying or after drying of the product.

[0042] P-XRD Method of Analysis:

[0043] 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.

[0044] The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation of the scope of the invention.

[0045] Examples:

[0046] Example 1: Preparation of amorphous solid dispersion comprising Elacestrant dihydrochloride of formula- la and Povidone K-30.

[0047] Dissolved Elacestrant dihydrochloride (200 mg) in methanol (20 ml) at 25-30°C. Povidone K-30 (200 mg) added to the obtained solution and stirred at the same temperature. Filtered the obtained solution. Distilled off the solvent completely from the filtrate and dried to get title compound.

[0048] Yield: 320 mg. PXRD of the obtained compound is illustrated in figure- 1.

[0049] Example 2: Preparation of amorphous solid dispersion comprising Elacestrant dihydrochloride of formula-la and HPMCP HP-50. Dissolved Elacestrant dihydrochloride (200 mg) in methanol (10 ml) at 25-30°C. HPMC HP-50 (200 mg) added to the obtained solution at 25-30°C. Further, dichloromethane (10 ml) was added to the above mixture and stirred at the same temperature. Filtered the obtained solution. Distilled off the solvent completely from the filtrate and dried to get title compound.

[0050] Yield: 320 mg. PXRD of the obtained compound is illustrated in figure-2.

[0051] Example 3: Preparation of amorphous solid dispersion comprising Elacestrant dihydrochloride of formula-la and HPMC-E5.

[0052] Dissolved Elacestrant dihydrochloride (200 mg) in mixture of methanol (15 ml) and dichloromethane (15 ml) at 25-30°C. HPMC-E5 (200 mg) was added to the above solution and stirred at the same temperature. Filtered the obtained solution. Distilled off the solvent completely from the filtrate and dried to get title compound.

[0053] Yield: 310 mg. PXRD of the obtained compound is illustrated in figure-3.

[0054] Example 4: Preparation of amorphous solid dispersion comprising Elacestrant dihydrochloride of formula-la and HPMC-AS.

[0055] Dissolved Elacestrant dihydrochloride (200 mg) in mixture of methanol (15 ml) and dichloromethane (15 ml) at 25-30°C. HPMC-AS (200 mg) was added to the above solution and stirred at the same temperature. Filtered the obtained solution. Distilled off the solvent completely from the filtrate and dried to get title compound.

[0056] Yield: 321 mg. PXRD of the obtained compound is illustrated in figure-4.

[0057] Example 5: Preparation of amorphous solid dispersion comprising Elacestrant dihydrochloride of formula- la and HPC-EF.

[0058] Dissolved Elacestrant dihydrochloride (200 mg) in mixture of methanol (15 ml) and dichloromethane (15 ml) at 25-30°C. HPC-EF (200 mg) was added to the above solution and stirred at the same temperature. Filtered the obtained solution. Distilled off the solvent completely from the filtrate and dried to get title compound.

[0059] Yield: 322 mg. PXRD of the obtained compound is illustrated in figure-5.

Claims

Claims1. Amorphous solid dispersion comprising Elacestrant dihydrochloride and one or more pharmaceutically acceptable excipients.

2. The amorphous solid dispersion as claimed in claim 1, wherein the “excipient” selected from povidone, polyvinylpolypyrrolidone, polysorbate, copovidone, cross linked polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate, methyl cellulose, carboxymethyl cellulose, carboxymethylethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose, cross linked sodium carboxymethyl cellulose, cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, talc, iron oxide, stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, 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-cyclodex trins, sulfobutylether betacyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates.

3. The amorphous solid dispersion as claimed in claim 1, wherein the pharmaceutically acceptable excipient(s) is selected from povidone, hydroxy propyl methylcellulose phthalate, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl cellulose.

4. The Amorphous solid dispersion as claimed in claim 1, wherein the ratio of the weight of Elacestrant dihydrochloride to the weight of the excipient(s) within the solid dispersion ranges from but not limited to about 1:0.05 to about 1:5.

5. The Amorphous solid dispersion as claimed in claim 1, which is stable.

6. The Amorphous solid dispersion as claimed in claim 1, which is stable at 25- 30°C.

7. The Amorphous solid dispersion as claimed in claim 1, which is stable at 0-5 °C.

8. The Amorphous solid dispersion as claimed in claim 1, which is stable at 0-5 °C when stored at this temperature for a period of 12 months.

9. The Amorphous solid dispersion as claimed in claim 1, which does not convert to any other solid forms when stored at a temperature at 0-5 °C for a period of 12 months.

10. A process for the preparation of amorphous solid dispersion comprising Elacestrant dihydrochloride and one or more pharmaceutically acceptable excipients, comprising: a) providing a solution of Elacestrant dihydrochloride and one or more pharmaceutically acceptable excipients in a solvent or a mixture of solvents, b) isolating amorphous solid dispersion comprising Elacestrant dihydrochloride and corresponding pharmaceutically acceptable excipient(s).

11. The process as claimed in claim 10, wherein providing a solution of Elacestrant dihydrochloride and excipient(s) in step-a) is carried out by combining Elacestrant dihydrochloride and excipient(s) with a solvent or mixture of solvents 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 and further combining with the excipient.

12. The process as claimed in claim 10, wherein the pharmaceutically acceptable excipient(s) is selected from povidone, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl cellulose.

13. The process as claimed in claim 10, wherein the solvent is selected from methanol, dichloromethane or mixture thereof.

14. The process as claimed in claim 10, wherein isolation of amorphous solid dispersion in step-b) is carried out by removing the solvent from the mixture or solution.

15. The process as claimed in claim 14, wherein the techniques which includes 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, melt extrusion, spray drying, freeze drying, spray-freeze drying.

16. Use of amorphous solid dispersions comprising Elacestrant dihydrochloride and one or more pharmaceutically acceptable excipients for the preparation ofpharmaceutical formulation.

17. A pharmaceutical composition comprising amorphous solid dispersions of the Elacestrant dihydrochloride of claim 16 and at least one additional pharmaceutically acceptable excipient.

18. The pharmaceutical composition as claimed in claim 17, wherein the additional pharmaceutically acceptable excipient(s) selected from povidone, polyvinyl polypyrrolidone, polysorbate, copovidone, cross linked polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate, methyl cellulose, carboxymethyl cellulose, carboxymethylethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose, cross linked sodium carboxymethyl cellulose, cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, talc, iron oxide, stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, 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, sulfobutylether beta-cyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid,succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates.

19. A method of treating a patient in need thereof comprising administering to the said patient a therapeutically effective amount of amorphous solid dispersion comprising Elacestrant dihydrochloride and one or more pharmaceutically acceptable excipients.

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