Related Applications:

This application claims the benefit of priority of our Indian patent applications 202241014804 filed on March 17, 2022 and 202241072602 filed on December 15, 2022 which are incorporated herein by reference.

Field of the Invention:

The present invention provides new solid state forms of (5S,6S,9R)-5-amino-6- (2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyri din-9-yl 4-(2-oxo-2,3-dihydro- lH-imidazo[4,5-b]pyridin-l-yl)-l-piperidinecarboxylate hemisulfate represented by the following structural formula- la and processes for preparation thereof.

Background of the Invention:

(5S,6S,9R)-5-Amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahy dro-5H-cyclohepta[b] pyridin-9-yl 4-(2-oxo-2, 3 -dihydro- 1 H-imidazo [4, 5 -b] pyridin- 1 -yl)- 1 -piperidinecarboxylate hemisulfate is commonly known as Rimeg epant sulfate. It is approved by USFDA on Feb 27, 2020 and is being marketed under the brand name NURTEC ODT

NURTEC ODT is a calcitonin gene-related peptide receptor antagonist indicated for the acute treatment of migraine with or without aura in adults and preventive treatment of episodic migraine in adults. US 8314117B2 describes Rimegepant, its analogs and process for preparation thereof.

US8759372B2 describes Rimegepant sulfate and its crystalline polymorphs namely Form Hl.5-1, Form P22C, Form P33, Form P35 and processes for preparation thereof.

Still, there is a need to develop novel solid state forms of Rimegepant sulfate which are suitable for the preparation of various pharmaceutical compositions.

The present inventors after significant efforts have surprisingly found new solid state forms of Rimegepant sulfate which are useful for the preparation of various pharmaceutical compositions.

Brief Description of the Invention:

The first embodiment of the present invention is to provide amorphous form of Rimegepant sulfate.

The second embodiment of the present invention is to provide a process for the preparation of amorphous form of Rimegepant sulfate.

The third embodiment of the present invention is to provide a solid dispersion comprising amorphous Rimegepant sulfate and one or more pharmaceutically acceptable excipients.

The fourth embodiment of the present invention is to provide a process for the preparation of solid dispersion comprising amorphous Rimegepant sulfate and one or more pharmaceutically acceptable excipients.

The fifth embodiment of the present invention provides a novel crystalline polymorph of Rimegepant sulfate, herein designated as Form-M.

The sixth embodiment of the present invention provides a process for the preparation of crystalline Form-M of Rimegepant sulfate. Brief Description of the Drawings:

Figure- 1: Illustrates the PXRD (powder X-Ray diffraction) pattern of amorphous form of Rimegepant sulfate

Figure-2: Illustrates the PXRD pattern of amorphous solid dispersion comprising

Rimegepant sulfate and HPMC AS

Figure-3: Illustrates the PXRD pattern of amorphous solid dispersion comprising

Rimegepant sulfate and copovidone

Figure-4: Illustrates the PXRD pattern of amorphous solid dispersion comprising

Rimegepant sulfate and povidone

Figure-5: Illustrates the PXRD pattern of amorphous solid dispersion comprising Rimegepant sulfate and HPC

Figure-6: Illustrates the PXRD pattern of amorphous solid dispersion comprising

Rimegepant sulfate and HPMC E3

Figure-7: Illustrates the PXRD pattern of amorphous solid dispersion comprising Rimegepant sulfate and Syloid

Figure-8: Illustrates the PXRD pattern of amorphous solid dispersion comprising

Rimegepant sulfate and Eudragit

Figure-9: Illustrates the PXRD pattern of Rimegepant sulfate crystalline Form-M obtained according to example-9.

Figure-10: Illustrates the PXRD pattern of Rimegepant sulfate crystalline Form-M obtained according to example- 10.

Detailed Description of the Invention:

The first embodiment of the present invention provides amorphous form of Rimegepant sulfate. The amorphous form of Rimegepant sulfate of the present invention is characterized by its PXRD pattern as illustrated in figure- 1.

The second embodiment of the present invention provides a process for the preparation of amorphous form of Rimegepant sulfate, comprising: a) providing a solution of Rimegepant sulfate in a solvent, b) obtaining amorphous form of Rimegepant sulfate. In one aspect of the present invention, providing a solution of Rimegepant sulfate in a solvent in step-a) can be carried out by combining Rimegepant sulfate with a solvent at a suitable temperature ranging from 0°C to 30°C and optionally heating the mixture to a temperature ranging from 30°C to 150°C based on the solvent used.

In another aspect of the present invention, the solution can also be obtained from the synthetic process in which Rimegepant sulfate is prepared.

The solvent for preparing amorphous form of Rimegepant sulfate by the above process is 2,2,2-trifluoroethanol.

Obtaining amorphous form of Rimegepant sulfate in step-b) of the above process can be done by removing the solvent from the mixture. The technique that is used for the removal of solvent from the mixture is distillation optionally under reduced pressure.

The Rimegepant sulfate compound of formula- 1 a which is used as input in the above process can be synthesized by any of the processes known in the art.

The first aspect of the third embodiment of the present invention provides a process for the preparation of amorphous form of Rimegepant sulfate, comprising: a) providing a solution of Rimegepant sulfate in 2,2,2-trifluoroethanol, b) distilling off the solvent from the solution to provide amorphous form of Rimegepant sulfate.

The third embodiment of the present invention provides a solid dispersion comprising amorphous Rimegepant sulfate and one or more pharmaceutically acceptable excipients.

The third embodiment of the present invention further provides amorphous solid dispersion comprising Rimegepant sulfate and one or more pharmaceutically acceptable excipients.

The “excipient” is selected from but not limited to polyvinylpyrrolidone (povidone or PVP), polyvinylpolypyrrolidone, polysorbate, syloid, eudragit, 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), HPMC E3, hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), 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-cyclodextrins, 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 and the like.

In the present invention, the ratio of the weight of Rimegepant sulfate 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.

The fourth embodiment of the present invention provides a process for the preparation of a solid dispersion comprising amorphous Rimegepant sulfate and one or more pharmaceutically acceptable excipients, comprising: a) providing a solution of Rimegepant sulfate and one or more excipients in a solvent, b) obtaining a solid dispersion comprising amorphous Rimegepant sulfate and the corresponding excipient(s). The fourth embodiment of the present invention further provides a process for the preparation of amorphous solid dispersion comprising Rimegepant sulfate and one or more pharmaceutically acceptable excipients, comprising: a) providing a solution of Rimegepant sulfate and one or more excipients in a solvent, b) obtaining amorphous solid dispersion comprising Rimegepant sulfate and the corresponding excipient(s).

Providing a solution of Rimegepant sulfate and excipient(s) in a solvent in step-a) of the above processes can be carried out by combining Rimegepant sulfate and excipient(s) selected from those defined above with a solvent at a suitable temperature ranging from 0°C to 30°C and optionally heating the mixture to a temperature ranging from 30°C to 150°C based on the solvent used.

The excipient that is used in the above process is selected from HPMCAS, copovidone, povidone, HPC, HPMC E3, Syloid & Eudragit.

The solvent is 2,2,2-trifluoroethanol.

Obtaining a solid dispersion comprising amorphous Rimegepant sulfate and the corresponding excipient(s) or amorphous solid dispersion comprising Rimegepant sulfate and excipient in step-b) of the above processes can be done by removing the solvent from the mixture. The technique that is used for removal of the solvent from the mixture is distillation optionally under reduced pressure.

The first aspect of the fourth embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising Rimegepant sulfate and one or more excipient(s), comprising; a) providing a solution of Rimegepant sulfate and the excipient in 2,2,2-trifluoroethanol, b) distilling off the solvent from the solution to provide amorphous solid dispersion comprising Rimegepant sulfate and the corresponding excipient.

The excipient in the above process is selected from HPMCAS, copovidone, povidone, HPC, HPMC E3, Syloid & Eudragit. The fifth embodiment of the present invention provides a novel crystalline polymorph of Rimegepant sulfate, herein designated as Form-M.

The crystalline Form-M of Rimegepant sulfate of the present invention is characterized by its PXRD pattern as illustrated in figure-9 or figure- 10.

The sixth embodiment of the present invention provides a process for the preparation of crystalline Form-M of Rimegepant sulfate, comprising; a) providing a solution of Rimegepant sulfate in a solvent or mixture of solvents, b) obtaining crystalline Form-M of Rimegepant sulfate.

In one aspect of the present invention, providing a solution of Rimegepant sulfate in a solvent or mixture of solvents in step-a) can be carried out by combining Rimegepant sulfate with a solvent or mixture of solvents at a temperature ranging from 0°C to 30°C and optionally heating the mixture to a temperature ranging from 30°C to 100°C based on the solvent used.

In another aspect of the present invention, the solution can also be obtained from the synthetic process in which Rimegepant sulfate is prepared.

The solvent for preparing crystalline Form-M of Rimegepant sulfate by the above process is methanol: dichloromethane: water mixture.

Obtaining crystalline Form-M of Rimegepant sulfate in step-b) of the above process can be done by stirring the mixture and then removing the solvent from the mixture. The technique that is used for the removal of solvent from the mixture is filtration.

The first aspect of the sixth embodiment of the present invention provides a process for the preparation of crystalline Form-M of Rimegepant sulfate, comprising; a) providing a solution of Rimegepant sulfate in a mixture of methanol, dichloromethane and water, b) obtaining crystalline Form-M of Rimegepant sulfate. The Rimegepant sulfate compound of formula- 1 a which is used as input in the above processes can be synthesized by any of the processes known in the art.

The Rimegepant sulfate and the excipients which are used as inputs in the processes of the present invention can be in the form of crystalline or amorphous.

The solid state forms of compound of formula- la 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 where at least a portion of compound of formula- 1 a is present in the composition in at least one polymorphic form mentioned.

The seventh embodiment of the present invention provides the use of any of the solid state forms viz., amorphous form, amorphous solid dispersion and crystalline form-M of compound of formula- la of the present invention for the preparation of pharmaceutical formulations.

The eighth embodiment of the present invention provides a pharmaceutical composition comprising any of the solid state forms viz., amorphous form, amorphous solid dispersion and crystalline form-M of compound of formula- la of the present invention and at least one pharmaceutically acceptable excipient.

The ninth embodiment of the present invention provides a method of treating a patient in need thereof comprising administering to the said patient a pharmaceutical composition comprising a therapeutically effective amount of any of the solid state forms viz., amorphous form, amorphous solid dispersion and crystalline form-M of compound of formula- 1 a of the present invention.

The compound of formula- la produced by the processes of the present invention may have particle size distribution of D90 less than about 400 pm, preferably less than about 300 pm, more preferably less than about 200 pm.

In one aspect of the present invention, the compound of formula- la may have particle size distribution of D90 less than about 100 pm, preferably less than about 50 pm. The compound of formula- la 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.

P-XRD Method of Analysis:

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 1.5406A ⁰ and at a continuous scan speed of 0.03°/min.

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

Examples:

Example-1: Preparation of amorphous form of Rimegepant sulfate (Formula-la)

A mixture of Rimegepant sulfate (0.5 gm) and 2,2,2-trifluoroethanol (60 ml) was stirred for 15 min at 25-30°C. Distilled off the solvent completely from the solution and dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure- 1. Yield: 425 mg.

Example-2: Preparation of amorphous solid dispersion comprising Rimegepant sulfate and HPMC AS

A mixture of Rimegepant sulfate (200 mg) and 2,2,2-trifluoroethanol (25 ml) was stirred for 25 min at 25-30°C. HPMC AS (200 mg) was added to the solution at 25-30°C and stirred for 20 min at the same temperature. Distilled off the solvent completely from the solution and dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-2. Yield: 298 mg.

Example-3: Preparation of amorphous solid dispersion comprising Rimegepant sulfate and copovidone

A mixture of Rimegepant sulfate (200 mg) and 2,2,2-trifluoroethanol (25 ml) was stirred for 25 min at 25-30°C. Copovidone (200 mg) was added to the solution at 25-30°C and stirred the mixture for 15 min at the same temperature. Distilled off the solvent completely from the solution and dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-3. Yield: 350 mg.

Example-4: Preparation of amorphous solid dispersion comprising Rimegepant sulfate and povidone

A mixture of Rimegepant sulfate (200 mg) and 2,2,2-trifluoroethanol (25 ml) was stirred for 25 min at 25-30°C. Povidone (200 mg) was added to the solution at 25-30°C and stirred for 15 min at the same temperature. Distilled off the solvent completely from the solution and dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-4. Yield: 375 mg. Example-5: Preparation of amorphous solid dispersion comprising Rimegepant sulfate and HPC

A mixture of Rimegepant sulfate (200 mg) and 2,2,2-trifluoroethanol (25 ml) was stirred for 20 min at 25-30°C. HPC (200 mg) was added to the solution at 25-30°C and stirred for 20 min at the same temperature. Distilled off the solvent completely from the solution and dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-5. Yield: 313 mg.

Example-6: Preparation of amorphous solid dispersion comprising Rimegepant sulfate and HPMC E3

A mixture of Rimegepant sulfate (200 mg) and 2,2,2-trifluoroethanol (25 ml) was stirred for 30 min at 25-30°C. HPMC E3 (200 mg) was added to the solution at 25-30°C and stirred for 20 min at the same temperature. Distilled off the solvent completely from the solution and dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-6. Yield: 328 mg.

Example-7: Preparation of amorphous solid dispersion comprising Rimegepant sulfate and Syloid

A mixture of Rimegepant sulfate (200 mg) and 2,2,2-trifluoroethanol (25 ml) was stirred for 25 min at 25-30°C. Syloid (200 mg) was added to the solution at 25-30°C and stirred for 5 min at the same temperature. Distilled off the solvent completely from the solution and dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-7. Yield: 348 mg.

Example-8: Preparation of amorphous solid dispersion comprising Rimegepant sulfate and Eudragit

A mixture of Rimegepant sulfate (200 mg) and 2,2,2-trifluoroethanol (25 ml) was stirred for 25 min at 25-30°C. Eudragit (200 mg) was added to the solution at 25-30°C and stirred for 10 min at the same temperature. Distilled off the solvent completely from the solution and dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-8. Yield: 360 mg. Example-9: Preparation of crystalline Form-M of compound of formula-la

Methanol: dichloromethane: water (37.5 ml; 1:1:1) mixture was added to Rimegepant sulfate (500 mg) at 25-30°C. Heated the mixture to 80-85°C and stirred for 2 hr at the same temperature. Filtered the solid and dried to get the title compound. The PXRD pattern of the obtained compound is shown in figure-9. Yield: 300 mg.

Example-10: Preparation of crystalline Form-M of compound of formula-la

Methanol: dichloromethane: water (112.5 ml; 1: 1:1) mixture was added to Rimegepant sulfate (1.5 gm) at 25-30°C. Heated the mixture to 80-85°C and stirred for 5 hr at the same temperature. Filtered the solid and dried to get the title compound. The PXRD pattern of the obtained compound is shown in figure- 10. Yield: 0.95 gm.