Crystalline salts of rimegepant

Abstract

The invention relates to crystalline salts of Rimegepant and a preparation method thereof.

Description

Crystalline salts of Rimegepant

[0001] Priority is claimed of European patent application no. 24 204 195.2 that was filed on October 2, 2024.

[0002] The invention relates to crystalline salts of Rimegepant and a preparation method thereof.

[0003] Rimegepant (ATC N02CD06) has the systematic name [(5S,6S,9R)-5-amino-6-(2,3-difluoro- phenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl] 4-(2-oxo-3H-imidazo[4,5-b]pyridin-l-yl)pi- peridine-l-carboxylat and the following structure

[0004] Rimegepant is a potent, selective, competitive, orally active calcitonin gene-related peptide (CGRP) antagonist used for the acute treatment of migraine in adults. It was approved for marketing by the U.S. Food and Drug Administration (FDA) on February 27, 2020.

[0005] The marketed pharmaceutical crystalline form of Rimegepant is the hemisulfate sesquihydrate as known from WO 2013 / 130402 Al (US 8 759 372), wherein it is reported that the salt-forming process requires strict control of the dripping speed of the sulfuric acid solution and the addition of seed crystals. WO 2013 / 130402 Al further reports about attempts to form salts with other acids. The following acids were investigated: acetic acid, benzoic acid, benzenesulfonic acid, citric acid, fumaric acid, hydrochloric acid, E-lactic acid, maleic acid, E-malic acid, methanesulfonic acid, phosphoric acid, succinic acid, sulfuric acid, D-tartaric acid, and L-tartaric acid. The following solvents were used: methyl isobutyl ketone (MIBK), ethyl acetate (EA), toluene, tetrahydrofuran (THF), acetonitrile (MeCN), acetone, isopropanol, ethanol, methanol, 1,2-dichloroethylene, isopropanol / water (50:50), and water. Crystalline salt formation was not observed in the presence of acetic acid, benzoic acid benzene sulfonic acid, L-lactic acid, maleic acid, L-malic acid, phosphoric acid, and succinic acid.

[0006] WO 2023 / 175632 Al relates to solid state forms of (5S,6S,9R)-5-amino-6- (2,3-difluoro- phenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl-4-(2-oxo-2,3-dihydro-lH-imidazo[4,5-b] pyridin- 1 -yl)- 1 -piperidinecarboxylate hemisulfate .

[0007] WO 2024 / 180562 Al relates to a process for the preparation of (5S,6S,9R)-5-amino-6- (2,3difhiorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl-4-(2-oxo-2,3-dihydro-lH-imid- azo[4,5-b]pyridin-l-yl)-l -piperidine carboxylate compound with desfluro impurity at less than 0.1% level and in its crystalline form.

[0008] Bowker et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use, Wiley-VCH 2002, pages 162-173 relates to a procedure for salt selection and optimization.

[0009] In the pharmaceutical industry, it is often a big challenge to purify APIs with poor solubility to meet regulatory requirements (ICH regulations have strict requirements for known and unknown impurities in APIs).

[0010] Further, the marketed pharmaceutical crystalline form of Rimegepant is a lyophilizate . The preparation of lyophilizates is comparatively laborious and it would be desirable to find alternatives to lyophilizates that meet the regulatory requirements.

[0011] It is an object of the invention to provide Rimegepant in a solid physiologically acceptable form that has advantages compared to the known forms of Rimegepant. The solid form of Rimegepant should be obtainable in an economic manner on industrial scale and provide improved properties, especially in terms of high solubility, dissolution rate and low hygroscopicity.

[0012] This object has been achieved by the subject-matter of the patent claims.

[0013] Due to the presence of an amino group, Rimegepant has basic properties and can form a salt with a sufficiently strong acid. It has been found that with the formation of salts, the properties can be improved that are of key importance in the production of pharmaceutical compositions and dosage forms, especially orodispersible tablets, mainly due to the improved solubility and changed hygroscopicity of the active ingredient. Due to their specific physicochemical properties, the new salts can also represent a technological advantage in the preparation of orally dispersible tablet formulations.

[0014] Such physicochemical properties may include, for example, thermodynamic stability, crystal morphology [form, shape, structure, particle size, particle size distribution, degree of crystallinity, color], ripple behavior, flowability, density, bulk density, powder density, apparent density, vibrated density, hardness, deformability, grindability, compressibility, brittleness, elasticity, caloric properties [particularly melting point], solubility [particularly equilibrium solubility, pH dependence of solubility], dissolution [particularly dissolution rate, intrinsic dissolution rate], hygroscopicity, tackiness, adhesiveness, tendency to electrostatic charging, organoleptic properties [particularly taste] and the like.

[0015] The inventors tested different acids and prepared various crystalline salts of Rimegepant. Salt formation was achieved with acids already mentioned inW02013 / 130402 Al and with additional physiologically acceptable acids.

[0016] It has been surprisingly found that crystalline salt of Rimegepant with L-tartaric acid can be prepared and dried in a reproducible manner at elevated temperatures without partially losingcrystallinity. This is particularly surprising because in WO 2013 / 130402 Al it is reported that crystalline salts with different XRPD patterns for slurry and dried phase were obtained. For larger scale process, heated drying of slurry was needed to remove solvent efficiently, but heating resulted in partial loss of crystallinity and non-reproducibility of drying process. These problems according to WO 2013 / 130402 Al have been overcome by the present invention.

[0017] Further, it has been surprisingly found that crystalline salt of Rimegepant with L-tartaric acid has a dissolution rate that is more than twice as high as the dissolution rate of Rimegepant base and Rimegepant hemisulfate monohydrate.Brief description of the drawings:

[0018] Figure 1 shows an XRPD spectrum of a salt of Rimegepant formed with methanesulfonic acid.

[0019] Figure 2 shows an XRPD spectrum of a salt of Rimegepant formed with phosphoric acid.

[0020] Figure 3 shows an XRPD spectrum of another salt of Rimegepant formed with phosphoric acid.

[0021] Figure 4 shows an XRPD spectrum of a salt of Rimegepant formed with citric acid.

[0022] Figure 5 shows an XRPD spectrum of another salt of Rimegepant formed with citric acid.

[0023] Figure 6 shows an XRPD spectrum of a salt of Rimegepant formed with fumaric acid.

[0024] Figure 7 shows an XRPD spectrum of another salt of Rimegepant formed with fumaric acid.

[0025] Figure 8 shows an XRPD spectrum of a salt of Rimegepant formed with L-tartaric acid.

[0026] Figure 9 shows an XRPD spectrum of another salt of Rimegepant formed with L-tartaric acid.

[0027] Figure 10 shows an XRPD spectrum of a salt of Rimegepant formed with hydrochloric acid.

[0028] Figure 11 shows an XRPD spectrum of another salt of Rimegepant formed with hydrochloric acid.

[0029] Figure 12 shows an XRPD spectrum of a salt of Rimegepant formed with L-malic acid.

[0030] Figure 13 shows an XRPD spectrum of a salt of Rimegepant formed with acetic acid.

[0031] Figure 14 shows an XRPD spectrum of a salt of Rimegepant formed with hydrobromic acid.

[0032] Figure 15 shows an XRPD spectrum of a salt of Rimegepant formed with p-toluene sulfonic acid.

[0033] Figure 16 shows an XRPD spectrum of a salt of Rimegepant formed with adipic acid.

[0034] Figure 17 shows an XRPD spectrum of a salt of Rimegepant formed with propionic acid.

[0035] Figure 18 shows an XRPD spectrum of a salt of Rimegepant formed with formic acid.

[0036] Figure 19 shows an XRPD spectrum of a salt of Rimegepant formed with glutaric acid.

[0037] Figure 20 shows an XRPD spectrum of a salt of Rimegepant formed with maleic acid.

[0038] Figure 21 shows an XRPD spectrum of another salt of Rimegepant formed with maleic acid.

[0039] Figure 22 shows experimental results comparing intrinsic dissolution rate of Rimegepant hemisulfate sesquihydrate and Rimegepant tartrate.

[0040] Figure 23 shows scanning electron microscopy (SEM) images of a salt of Rimegepant formed with L-tartaric acid at different resolution.Detailed description of the invention

[0041] A first aspect of the invention relates to a crystalline salt of Rimegepant with a physiologically acceptable acid, wherein the physiologically acceptable acid is(i) a saturated aliphatic mono- or dicarboxylic acid; preferably selected from formic acid, acetic acid, propionic acid, glutaric acid and adipic acid;(ii) an unsaturated aliphatic mono- or dicarboxylic acid; preferably selected from fumaric acid and maleic acid;(iii) a saturated aliphatic multicarboxylic mono- or dihydroxy acid; preferably selected from L-malic acid, citric acid, and L-tartaric acid;(iv) an inorganic acid selected from hydrobromic acid, phosphoric acid, and hydrochloric acid;(v) an aromatic sulfonic acid; preferably p-toluene sulfonic acid; or(vi) an aliphatic sulfonic acid; preferably methanesulfonic acid.

[0042] Preferably, the molar ratio of Rimegepant : physiologically acceptable acid is 1 : 1.

[0043] In preferred embodiments, the crystalline salt according to the invention is an ansolvate.

[0044] In other preferred embodiments, the crystalline salt according to the invention is a solvate; preferably wherein the solvent is selected from methanol, ethanol and isopropanol; more preferably methanol and ethanol.

[0045] Preferably, the crystalline salt according to the invention is obtainable by crystallization from alcoholic solution; preferably by cooling crystallization; more preferably from methanolic solution, from ethanolic solution or from isopropanolic solution; still more preferably from methanolic solution or from ethanolic solution.

[0046] In further preferred embodiments, the crystalline salt according to the invention is a hydrate.

[0047] Preferably, the crystalline salt according to the invention is obtainable by crystallization from aqueous solution; preferably by cooling crystallization; more preferably from aqueous methanolic solution; still more preferably from aqueous methanolic solution containing ethyl acetate.Crystalline salts of Rimegepant with methanesulfonic acid

[0048] Another aspect of the invention relates to a crystalline salt of Rimegepant with methane sulfonic acid, preferably in a molar ratio of Rimegepant : methanesulfonic acid of 1 : 1.

[0049] Preferably, the salt is Rimegepant methanesulfonate.

[0050] In preferred embodiments, the crystalline salt of Rimegepant with methanesulfonic acid is an ansolvate.

[0051] In other preferred embodiments, the crystalline salt of Rimegepant with methanesulfonic acid is a solvate; preferably wherein the solvent is selected from methanol and ethanol.

[0052] Preferably, the crystalline salt of Rimegepant with methanesulfonic acid is obtainable by crystallization from alcoholic solution; preferably by cooling crystallization; more preferably from methanolic solution or from ethanolic solution; still more preferably in accordance with Example 2n).

[0053] Preferably, the crystalline salt of Rimegepant with methanesulfonic acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 16.0 (±0.2), 17.1 (±0.2), 18.4 (±0.2), 20.0 (±0.2), and 21.6 (±0.2); preferably, one, two, three or all additional reflections selected from 12.1 (±0.2), 13.9 (±0.2), 24.3 (±0.2), 25.7 (±0.2), and 27.2 (±0.2).

[0054] Figure 1 shows an XRPD spectrum of a salt of Rimegepant formed with methanesulfonic acid from methanolic solution having the following XRPD reflections:Crystalline salts of Rimegepant with phosphoric acid

[0055] Another aspect of the invention relates to a crystalline salt of Rimegepant with phosphoric acid, preferably in a molar ratio of Rimegepant : phosphoric acid of 1 : 1.

[0056] Preferably, the salt is selected from Rimegepant dihydrogen phosphate, Rimegepant hydrogen phosphate, and Rimegepant phosphate (orthophosphate).

[0057] In preferred embodiments, the crystalline salt of Rimegepant with phosphoric acid is an ansolvate.

[0058] In other preferred embodiments, the crystalline salt of Rimegepant with phosphoric acid is a solvate; preferably wherein the solvent is selected from methanol, ethanol and isopropanol.

[0059] Preferably, the crystalline salt of Rimegepant with phosphoric acid is obtainable by crystallization from alcoholic solution; preferably by cooling crystallization; more preferably from methanolic solution, from ethanolic solution or from isopropanolic solution; still more preferably in accordance with Example 1c), 2f) or 3b).

[0060] Preferably, the crystalline salt of Rimegepant with phosphoric acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 15.1 (±0.2), 19.3 (±0.2), 19.8 (±0.2), 25.6 (±0.2), and 26.5 (±0.2); preferably, one, two, three or all additional reflections selected from 5.2 (±0.2), 13.2 (±0.2), 17.6 (±0.2), 21.1 (±0.2), 23.1 (±0.2), and 31.5 (±0.2).

[0061] Figure 2 shows an XRPD spectrum of a salt of Rimegepant formed with phosphoric acid from methanolic solution having the following XRPD reflections:

[0062] Preferably, the crystalline salt of Rimegepant with phosphoric acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 11.1 (±0.2), 12.0 (±0.2), 16.0 (±0.2), 19.2 (±0.2), and 20.6 (±0.2); preferably, one, two, three or all additional reflections selected from 8.0 (±0.2), 14.9 (±0.2), 18.6 (±0.2), 22.5 (±0.2), and 23.9 (±0.2).

[0063] Figure 3 shows an XRPD spectrum of another salt formed with phosphoric acid from ethanolic or isopropanolic solution having the following XRPD reflections:Crystalline salts of Rimegepant with citric acid

[0064] Another aspect of the invention relates to a crystalline salt of Rimegepant with citric acid, preferably in a molar ratio of Rimegepant : citric acid of 1 : 1.

[0065] Preferably, the salt is selected from Rimegepant dihydrogen citrate, Rimegepant hydrogen citrate, and Rimegepant citrate.

[0066] In preferred embodiments, the crystalline salt of Rimegepant with citric acid is an ansolvate.

[0067] In other preferred embodiments, the crystalline salt of Rimegepant with citric acid is a solvate; preferably wherein the solvent is selected from methanol and ethanol.

[0068] Preferably, the crystalline salt of Rimegepant with citric acid is obtainable by crystallization from alcoholic solution; preferably by cooling crystallization; more preferably from methanolic solution or from ethanolic solution; still more preferably in accordance with Example la) or 2a).

[0069] Preferably, the crystalline salt of Rimegepant with citric acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 13.2 (±0.2), 16.8 (±0.2), 18.4 (±0.2), 19.5 (±0.2), and 20.8 (±0.2); preferably, one, two, three or all additional reflections selected from 8.9 (±0.2), 12.1 (±0.2), 14.9 (±0.2), and 15.2 (±0.2).

[0070] Figure 4 shows an XRPD spectrum of a salt of Rimegepant formed with citric acid from methanolic solution having the following XRPD reflections:

[0071] Preferably, the crystalline salt of Rimegepant with citric acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 13.2 (±0.2), 17.0 (±0.2), 18.8 (±0.2), 20.9 (±0.2), and 21.7 (±0.2); preferably, one, two, three or all additional reflections selected from 8.6 (±0.2), 15.1 (±0.2), 15.6 (±0.2), 20.2 (±0.2), and 26.1 (±0.2).

[0072] Figure 5 shows an XRPD spectrum of another salt of Rimegepant formed with citric acid from ethanolic solution having the following XRPD reflections:Crystalline salts of Rimegepant with fumaric acid

[0073] Another aspect of the invention relates to a crystalline salt of Rimegepant with fumaric acid, preferably in a molar ratio of Rimegepant : fumaric acid of 1 : 1.

[0074] Preferably, the salt is Rimegepant fumarate.

[0075] In preferred embodiments, the crystalline salt of Rimegepant with fumaric acid is an ansolvate.

[0076] In other preferred embodiments, the crystalline salt of Rimegepant with fumaric acid is a solvate; preferably wherein the solvent is selected from methanol and ethanol.

[0077] Preferably, the crystalline salt of Rimegepant with fumaric acid is obtainable by crystallization from alcoholic solution; preferably by cooling crystallization; more preferably from methanolic solution or from ethanolic solution; still more preferably in accordance with Example lb) or 2e).

[0078] Preferably, the crystalline salt of Rimegepant with fumaric acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 14.8 (±0.2), 15.1 (±0.2), 16.4 (±0.2), 20.4 (±0.2), and 25.8 (±0.2); preferably, one, two, three or all additional reflections selected from 11.6 (±0.2), 12.4 (±0.2), 19.0 (±0.2), 24.8 (±0.2), and 27.5 (±0.2).

[0079] Figure 6 shows an XRPD spectrum of a salt of Rimegepant formed with fumaric acid from methanolic solution having the following XRPD reflections:

[0080] Preferably, the crystalline salt of Rimegepant with fumaric acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 15.2 (±0.2), 18.3 (±0.2), 20.4 (±0.2), 20.8 (±0.2), and 21.4 (±0.2); preferably, one, two, three or all additional reflections selected from 8.4 (±0.2), 12.8 (±0.2), 16.3 (±0.2), 17.9 (±0.2), 19.8 (±0.2), and 25.7 (±0.2).

[0081] Figure 7 shows an XRPD spectrum of another salt of Rimegepant formed with fumaric acid from ethanolic solution having the following XRPD reflections:Crystalline salts of Rimegepant with L-tartaric acid

[0082] Another aspect of the invention relates to a crystalline salt of Rimegepant with L-tartaric acid, preferably in a molar ratio of Rimegepant : L-tartaric acid of 1 : 1.

[0083] Preferably, the salt is selected from Rimegepant hydrogen L-tartrate and Rimegepant L-tartrate.

[0084] In preferred embodiments, the crystalline salt of Rimegepant with L-tartaric acid is an ansolvate.

[0085] In other preferred embodiments, the crystalline salt of Rimegepant with L-tartaric acid is a solvate; preferably wherein the solvent is selected from methanol and ethanol.

[0086] In preferred embodiments, the crystalline salt of Rimegepant with L-tartaric acid is obtainable by crystallization from alcoholic solution; preferably by cooling crystallization; more preferably from methanolic solution or from ethanolic solution; still more preferably in accordance with Example 2c).

[0087] In other preferred embodiments, the crystalline salt of Rimegepant with L-tartaric acid is obtainable by crystallization from a solvent mixture of ethyl acetate (EA), methanol (MeOH) and water (preferably EA : MeOH : water = 6 : 5 : 1 (v / v / v)); preferably by cooling crystallization; still more preferably in accordance with Example 2d).

[0088] Preferably, the crystalline salt of Rimegepant with L-tartaric acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 16.3 (±0.2), 19.4 (±0.2), 20.4 (±0.2), 21.0 (±0.2), and 22.0 (±0.2); preferably, one, two, three or all additional reflections selected from 8.1 (±0.2), 13.6 (±0.2), 24.8 (±0.2), and 26.1 (±0.2).

[0089] Figure 8 shows an XRPD spectrum of a salt of Rimegepant formed with L-tartaric acid from methanolic solution having the following XRPD reflections:

[0090] Preferably, the crystalline salt of Rimegepant with L-tartaric acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 11.6 (±0.2), 13.2 (±0.2), 16.4 (±0.2), 19.5 (±0.2), and 20.9 (±0.2); preferably, one, two, three or all additional reflections selected from 4.2 (±0.2), 8.2 (±0.2), 12.5 (±0.2), 24.1 (±0.2) and 24.9 (±0.2).

[0091] Figure 9 shows an XRPD spectrum of another salt of Rimegepant formed with L-tartaric acid from solution in EA : MeOH : water = 6 : 5 : 1 (v / v / v) having the following XRPD reflections:Crystalline salts of Rimegepant with hydrochloric acid

[0092] Another aspect of the invention relates to a crystalline salt of Rimegepant with hydrochloric acid, preferably in a molar ratio of Rimegepant : hydrochloric acid of 1 : 1.

[0093] Preferably, the salt is Rimegepant hydrochloride.

[0094] In preferred embodiments, the crystalline salt of Rimegepant with hydrochloric acid is an an- solvate.

[0095] In other preferred embodiments, the crystalline salt of Rimegepant with hydrochloric acid is a solvate; preferably wherein the solvent is selected from methanol, ethanol and isopropanol.

[0096] Preferably, the crystalline salt of Rimegepant with hydrochloric acid is obtainable by crystallization from alcoholic solution; preferably by cooling crystallization; more preferably from methanolic solution, from ethanolic solution or from isopropanolic solution; still more preferably in accordance with Example If).

[0097] Preferably, the crystalline salt of Rimegepant with hydrochloric acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 15.0 (±0.2), 15.4 (±0.2), 19.3 (±0.2), 20.4 (±0.2), and 20.9 (±0.2); preferably, one, two, three or all additional reflections selected from 12.9 (±0.2), 21.6 (±0.2), 25.9 (±0.2), and 27.1 (±0.2).

[0098] Figure 10 shows an XRPD spectrum of a salt of Rimegepant formed with hydrochloric acid from methanolic or isopropanolic solution having the following XRPD reflections:

[0099] Preferably, the crystalline salt of Rimegepant with hydrochloric acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 4.7 (±0.2), 9.5 (±0.2), 12.5 (±0.2), 14.3 (±0.2), and 15.1 (±0.2); preferably, one, two, three or all additional reflections selected from 19.3 (±0.2), 20.2 (±0.2), 25.3 (±0.2), 27.6 (±0.2), and 27.7 (±0.2).

[0100] Figure 11 shows an XRPD spectrum of another salt of Rimegepant formed with hydrochloric acid from ethanolic solution having the following XRPD reflections:Crystalline salts of Rimegepant with L-malic acid

[0101] Another aspect of the invention relates to a crystalline salt of Rimegepant with L-malic acid, preferably in a molar ratio of Rimegepant : L-malic acid of 1 : 1.

[0102] Preferably, the salt is Rimegepant L-malate.

[0103] In preferred embodiments, the crystalline salt of Rimegepant with L-malic acid is an ansolvate.

[0104] In other preferred embodiments, the crystalline salt of Rimegepant with L-malic acid is a solvate; preferably wherein the solvent is selected from methanol, ethanol and isopropanol.

[0105] Preferably, the crystalline salt of Rimegepant with L-malic acid is obtainable by crystallization from alcoholic solution; preferably by cooling crystallization; more preferably from methanolic solution, from ethanolic solution or from isopropanolic solution; still more preferably in accordance with Example 2b).

[0106] Preferably, the crystalline salt of Rimegepant with L-malic acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 15.2 (±0.2), 15.7 (±0.2), 18.9 (±0.2), 19.9 (±0.2), and 20.3 (±0.2); preferably, one, two, three or all additional reflections selected from 12.4 (±0.2), 13.0 (±0.2), 21.0 (±0.2), 24.5 (±0.2), and 26.3 (±0.2).

[0107] Figure 12 shows an XRPD spectrum of a salt of Rimegepant formed with L-malic acid from methanolic solution having the following XRPD reflections:Crystalline salts of Rimegepant with acetic acid

[0108] Another aspect of the invention relates to a crystalline salt of Rimegepant with acetic acid, preferably in a molar ratio of Rimegepant : acetic acid of 1 : 1.

[0109] Preferably, the salt is Rimegepant acetate.

[0110] In preferred embodiments, the crystalline salt of Rimegepant with acetic acid is an ansolvate.

[0111] In other preferred embodiments, the crystalline salt of Rimegepant with acetic acid is a solvate; preferably wherein the solvent is selected from methanol and ethanol.

[0112] Preferably, the crystalline salt of Rimegepant with acetic acid is obtainable by crystallization from alcoholic solution; preferably by cooling crystallization; more preferably from methanolic solution or from ethanolic solution; still more preferably in accordance with Example 2m).

[0113] Preferably, the crystalline salt of Rimegepant with acetic acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 15.3 (±0.2), 19.1 (±0.2), 20.0 (±0.2), 20.5 (±0.2), and 26.6 (±0.2); preferably, one, two, three or all additional reflections selected from 9.6 (±0.2), 12.5 (±0.2), 14.8 (±0.2), 22.7 (±0.2), and 25.9 (±0.2).

[0114] Figure 13 shows an XRPD spectrum of a salt of Rimegepant formed with acetic acid from methanolic solution having the following XRPD reflections:Crystalline salts of Rimegepant with hydrobromic acid

[0115] Another aspect of the invention relates to a crystalline salt of Rimegepant with hydrobromic acid, preferably in a molar ratio of Rimegepant : hydrobromic acid of 1 : 1.

[0116] Preferably, the salt is Rimegepant hydrobromide.

[0117] In preferred embodiments, the crystalline salt of Rimegepant with hydrobromic acid is an ansolvate.

[0118] In other preferred embodiments, the crystalline salt of Rimegepant with hydrobromic acid is a solvate; preferably wherein the solvent is selected from methanol and ethanol.

[0119] Preferably, the crystalline salt of Rimegepant with hydrobromic acid is obtainable by crystallization from alcoholic solution; preferably by cooling crystallization; more preferably from methanolic solution or from ethanolic solution; still more preferably in accordance with Example 21).

[0120] Preferably, the crystalline salt of Rimegepant with hydrobromic acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 15.5 (±0.2), 16.3 (±0.2), 19.4 (±0.2), 20.5 (±0.2), and 21.0 (±0.2); preferably, one, two, three or all additional reflections selected from 13.1 (±0.2), 18.0 (±0.2), 24.7 (±0.2), and 26.0 (±0.2).

[0121] Figure 14 shows an XRPD spectrum of a salt of Rimegepant formed with hydrobromic acid from methanolic solution having the following XRPD reflections:Crystalline salts of Rimegepant with p-toluene sulfonic acid

[0122] Another aspect of the invention relates to a crystalline salt of Rimegepant with p-toluene sulfonic acid, preferably in a molar ratio of Rimegepant : p-toluene sulfonic acid of 1 : 1.

[0123] Preferably, the salt is Rimegepant p-toluene sulfonate.

[0124] In preferred embodiments, the crystalline salt of Rimegepant with p-toluene sulfonic acid is an ansolvate.

[0125] In other preferred embodiments, the crystalline salt of Rimegepant with p-toluene sulfonic acid is a solvate; preferably wherein the solvent is selected from methanol and ethanol.

[0126] Preferably, the crystalline salt of Rimegepant with p-toluene sulfonic acid is obtainable by crystallization from alcoholic solution; preferably by cooling crystallization; more preferably from methanolic solution or from ethanolic solution; still more preferably in accordance with Example 2k).

[0127] Preferably, the crystalline salt of Rimegepant with p-toluene sulfonic acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 16.0 (±0.2), 16.7 (±0.2), 18.1 (±0.2), 20.6 (±0.2), and 25.0 (±0.2); preferably, one, two, three or all additional reflections selected from 11.5 (±0.2), 13.1 (±0.2), 15.3 (±0.2), 19.3 (±0.2), and 26.4 (±0.2).

[0128] Figure 15 shows an XRPD spectrum of a salt of Rimegepant formed with p-toluene sulfonic acid from methanolic solution having the following XRPD reflections:Crystalline salts of Rimegepant with adipic acid

[0129] Another aspect of the invention relates to a crystalline salt of Rimegepant with adipic acid, preferably in a molar ratio of Rimegepant : adipic acid of 1 : 1.

[0130] Preferably, the salt is selected from Rimegepant adipate and Rimegepant hydrogenadipate.

[0131] In preferred embodiments, the crystalline salt of Rimegepant with adipic acid is an ansolvate.

[0132] In other preferred embodiments, the crystalline salt of Rimegepant with adipic acid is a solvate; preferably wherein the solvent is selected from methanol and ethanol.

[0133] Preferably, the crystalline salt of Rimegepant with adipic acid is obtainable by crystallization from alcoholic solution; preferably by cooling crystallization; more preferably from methanolic solution or from ethanolic solution; still more preferably in accordance with Example 2j).

[0134] Preferably, the crystalline salt of Rimegepant with adipic acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 15.3 (±0.2), 19.6 (±0.2), 20.0 (±0.2), 21.0 (±0.2), and 22.7 (±0.2); preferably, one, two, three or all additional reflections selected from 12.6 (±0.2), 13.3 (±0.2), 14.9 (±0.2), 15.7 (±0.2), and 26.6 (±0.2).

[0135] Figure 16 shows an XRPD spectrum of a salt of Rimegepant formed with adipic acid from methanolic solution having the following XRPD reflections:Crystalline salts of Rimegepant with propionic acid

[0136] Another aspect of the invention relates to a crystalline salt of Rimegepant with propionic acid, preferably in a molar ratio of Rimegepant : propionic acid of 1 : 1.

[0137] Preferably, the salt is Rimegepant propionate.

[0138] In preferred embodiments, the crystalline salt of Rimegepant with propionic acid is an ansolvate .

[0139] In other preferred embodiments, the crystalline salt of Rimegepant with propionic acid is a solvate; preferably wherein the solvent is selected from methanol and ethanol.

[0140] Preferably, the crystalline salt of Rimegepant with propionic acid is obtainable by crystallization from alcoholic solution; preferably by cooling crystallization; more preferably from methanolic solution or from ethanolic solution; still more preferably in accordance with Example 2h).

[0141] Preferably, the crystalline salt of Rimegepant with propionic acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 15.2 (±0.2), 15.9 (±0.2), 19.2 (±0.2), 20. 1 (±0.2), and 20.5 (±0.2); preferably, one, two, three or all additional reflections selected from 12.1 (±0.2), 12.9 (±0.2), 22.9 (±0.2), 25.2 (±0.2), and 26.8 (±0.2).

[0142] Figure 17 shows an XRPD spectrum of a salt of Rimegepant formed with propionic acid from methanolic solution having the following XRPD reflections:Crystalline salts of Rimegepant with formic acid

[0143] Another aspect of the invention relates to a crystalline salt of Rimegepant with formic acid, preferably in a molar ratio of Rimegepant : formic acid of 1 : 1.

[0144] Preferably, the salt is Rimegepant formate.

[0145] In preferred embodiments, the crystalline salt of Rimegepant with formic acid is an ansolvate.

[0146] In other preferred embodiments, the crystalline salt of Rimegepant with formic acid is a solvate; preferably wherein the solvent is selected from methanol and ethanol.

[0147] Preferably, the crystalline salt of Rimegepant with formic acid is obtainable by crystallization from alcoholic solution; preferably by cooling crystallization; more preferably from methanolic solution or from ethanolic solution; still more preferably in accordance with Example 2g).

[0148] Preferably, the crystalline salt of Rimegepant with formic acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 15.3 (±0.2), 19.3 (±0.2), 20.2 (±0.2), 20.7 (±0.2), and 25.5 (±0.2); preferably, one, two, three or all additional reflections selected from 12.2 (±0.2), 13.0 (±0.2), 16.0 (±0.2), 21.5 (±0.2), and 27.1 (±0.2).

[0149] Figure 18 shows an XRPD spectrum of a salt of Rimegepant formed with formic acid from methanolic solution having the following XRPD reflections:Crystalline salts of Rimegepant with glutaric acid

[0150] Another aspect of the invention relates to a crystalline salt of Rimegepant with glutaric acid, preferably in a molar ratio of Rimegepant : glutaric acid of 1 : 1 .

[0151] Preferably, the salt is selected from Rimegepant glutarate and Rimegepant hydrogenglutarate.

[0152] In preferred embodiments, the crystalline salt of Rimegepant with glutaric acid is an ansolvate.

[0153] In other preferred embodiments, the crystalline salt of Rimegepant with glutaric acid is a solvate; preferably wherein the solvent is selected from methanol and ethanol.

[0154] Preferably, the crystalline salt of Rimegepant with glutaric acid is obtainable by crystallization from alcoholic solution; preferably by cooling crystallization; more preferably from methanolic solution or from ethanolic solution; still more preferably in accordance with Example 2i).

[0155] Preferably, the crystalline salt of Rimegepant with glutaric acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 14.6 (±0.2), 15.8 (±0.2), 19.2 (±0.2), 20.0 (±0.2), and 25.7 (±0.2); preferably, one, two or all additional reflections selected from 12.2 (±0.2), 23.4 (±0.2), and 24.6 (±0.2).

[0156] Figure 19 shows an XRPD spectrum of a salt of Rimegepant formed with glutaric acid from methanolic solution having the following XRPD reflections:Crystalline salts of Rimegepant with maleic acid

[0157] Another aspect of the invention relates to a crystalline salt of Rimegepant with maleic acid, preferably in a molar ratio of Rimegepant : maleic acid of 1 : 1.

[0158] Preferably, the salt is Rimegepant maleate.

[0159] In preferred embodiments, the crystalline salt of Rimegepant with maleic acid is an ansolvate.

[0160] In other preferred embodiments, the crystalline salt of Rimegepant with maleic acid is a solvate; preferably wherein the solvent is selected from methanol, ethanol and isopropanol.

[0161] Preferably, the crystalline salt of Rimegepant with maleic acid is obtainable by crystallization from alcoholic solution; preferably by cooling crystallization; more preferably from methanolic solution, from ethanolic solution or from isopropanolic solution; still more preferably in accordance with Example le) or 3a).

[0162] Preferably, the crystalline salt of Rimegepant with maleic acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 16.3 (±0.2), 18.6 (±0.2), 19.0 (±0.2), 20.3 (±0.2), and 20.7 (±0.2); preferably, one, two, three or all additional reflections selected from 11.9 (±0.2), 13.2 (±0.2), 14.9 (±0.2), 15.3 (±0.2), 21.8 (±0.2), 24.5 (±0.2), and 26.0 (±0.2).

[0163] Figure 20 shows an XRPD spectrum of a salt formed with maleic acid from ethanolic solution having the following XRPD reflections:

[0164] Preferably, the crystalline salt of Rimegepant with maleic acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 14.7 (±0.2), 15.8 (±0.2), 18.9 (±0.2), 20.3 (±0.2), and 20.6 (±0.2); preferably, one, two, three or all additional reflections selected from 11.2 (±0.2), 12.8 (±0.2), 21.7 (±0.2), 23.5 (±0.2), and 27.2 (±0.2).

[0165] Figure 21 shows an XRPD spectrum of another salt formed with maleic acid from isopropanolic solution having the following XRPD reflections having the following XRPD reflections:Pharmaceutical compositions and dosage forms

[0166] Another aspect of the invention relates to a pharmaceutical composition or dosage form comprising a crystalline salt of Rimegepant according to the invention as described above.

[0167] The pharmaceutical compositions preferably comprise a therapeutically effective amount of the crystalline salt of Rimegepant according to the invention, and one or more pharmaceutically acceptable excipients. Excipients may include but are not limited to fdlers, diluents, binders, wetting agents, disin- tegrants, flavors, sweeteners, taste enhancers, and the like.

[0168] A therapeutically effective amount is the amount needed to provide a meaningful patient benefit as determined by practitioners in that art. Pharmaceutically acceptable excipients are those conventionally known carriers having acceptable safety profiles.

[0169] Suitable pharmaceutical compositions encompass all common solid and liquid forms including capsules, tablets, lozenges, and powders as well as liquid suspensions, syrups, elixirs, and solutions. Solid compositions may by formed in timed or sustained released formulations. Pharmaceutical compositions can be made using common formulation techniques and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols).

[0170] Solid pharmaceutical compositions are normally formulated in dosage units providing from about 1 to about 1000 mg of the active ingredient per dose. Some examples of solid dosage units are 0.1 mg, 1 mg, 10 mg, 100 mg, 500 mg, and 1000 mg, expressed as equivalents to Rimegepant. Liquid compositions are generally in a unit dosage range of 1-100 mg / mL. Some examples of liquid dosageunits are 0.1 mg / mL, 1 mg / mL, 10 mg / mL, 25 mg / mL, 50 mg / mL, and 100 mg / mL, expressed as equivalents to Rimegepant.

[0171] Preferably, an oral dosage form provides 70 to 750 mg of the crystalline salt of Rimegepant according to the invention. Included in this embodiment are oral dosage forms having 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 500 mg, and 750 mg of the crystalline salt of Rimegepant according to the invention, expressed as equivalents to Rimegepant.

[0172] In one embodiment, the crystalline salt of Rimegepant according to the invention is administered once a day. Suitable doses include 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 500 mg, and 750 mg of the crystalline salt of Rimegepant according to the invention, expressed as equivalents to Rimegepant.

[0173] In one embodiment, the crystalline salt of Rimegepant according to the invention is administered twice a day. Suitable doses include 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 500 mg, and 750 mg of the crystalline salt of Rimegepant according to the invention, expressed as equivalents to Rimegepant.

[0174] The invention encompasses all conventional modes of administration including oral, parenteral, intranasal, sublingual, and transdermal methods. Typically, the daily dose will be 0.01-100 mg / kg body weight daily, expressed as equivalents to Rimegepant. Generally, more compound is required orally and less parenterally. The specific dosing regimen, however, should be determined by a physician using sound medical judgment.

[0175] In preferred embodiments, the pharmaceutical composition or dosage form according to the invention is an orodispersible tablet, preferably for sublingual or oral use.

[0176] The orodispersible tablet may contain the crystalline salt of Rimegepant according to the invention as a lyophilizate.

[0177] The orodispersible tablet may contain gelatin, mannitol, mint flavor, and sucralose.Medical uses

[0178] Another aspect of the invention relates to a pharmaceutical composition or dosage form according to the invention for use in the treatment or prevention of migraine. Another aspect of the invention relates to the use of a crystalline salt of Rimegepant according to the invention as described above for the manufacture of a pharmaceutical composition or dosage form according to the invention as described above for the treatment or prevention of migraine. Another aspect of the invention relates to a method of treating or preventing migraine comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline salt of Rimegepant according to the invention as described above.

[0179] Preferably, treatment or prevention of migraine includes acute treatment of migraine with or without aura in adults.

[0180] Preferably, treatment or prevention of migraine includes preventive treatment of episodic migraine in adults who have at least 4 migraine attacks per monthGeneral description of the screening process:

[0181] Rimegepant was dissolved while being stirred in methanol at 70 ± 5 °C. In case of using solid acids, a solution of the acid in water or a mixture of water / MeOH was prepared. When Rimegepant base dissolved, the slow addition of the respective acid or acid solution was started. The mixture was cooled to room temperature (around 25 °C) in 2 hours. At the final temperature, the material was stirred for an additional 16 hours. The precipitate was isolated by vacuum filtration and washed with MeOH. If the precipitate did not fall out, the mixture was cooled to 0 °C and, if necessary, the solvent was also evaporated. The isolated precipitate was dried in a vacuum dryer at 40 °C and 50 mbar.

[0182] Spontaneous nucleation upon cooling the crystallization mixture after the addition of acid was achieved in the case of phosphoric, citric, fumaric, L-tartaric and malic acids. The precipitated products were characterized by XRPD to verify crystallinity. The obtained salts were further characterized (XRPD, TG / MS, DSC, hydration according to Ph. Eur.).EXAMPLES

[0183] The following examples further illustrate the invention but are not to be construed as limiting its scope:

[0184] Example 1 : solvent ethanol

[0185] la) Salt with citric acid in ethanol

[0186] Rimegepant (0.4 g) was dissolved in ethanol (22 mL) at 75 °C under stirring. Solution of citric acid (0.14 g / 2 mL) was slowly added. The mixture was cooled to 25 °C in 2 hours and stirred for additional 16 hours. Material was filtered by vacuum filtration and washed with 2 mL of ethanol. Obtained material was dried in vacuum dryer at 40 °C. 370 mg of Rimegepant salt with citric acid was obtained.

[0187] lb) Salt with fumaric acid in ethanol

[0188] Rimegepant (0.4 g) was dissolved in ethanol (22 mL) at 75 °C under stirring. Solution of fumaric acid (87 mg / 2 mL water / 3 mL EtOH) was slowly added. The mixture was cooled to 25 °C in 2 hours and stirred for additional 16 hours. Material was filtered by vacuum filtration and washed with 2 mL of ethanol. Obtained material was dried in vacuum dryer at 40 °C. 280 mg of Rimegepant salt with fumaric acid was obtained.

[0189] 1c) Salt with phosphoric acid in ethanol

[0190] Rimegepant (0.4 g) was dissolved in ethanol (22 mL) at 75 °C under stirring. Solution of phosphoric acid (46 pL) was slowly added. The mixture was cooled to 25 °C in 2 hours and stirred for additional 16 hours. Material was filtered by vacuum filtration and washed with 2 mL of ethanol.Obtained material was dried in vacuum dryer at 40 °C. 460 mg of Rimegepant salt with phosphoric acid was obtained.

[0191] Id) Salt with hydrochloric acid in ethanol

[0192] Rimegepant (0.4 g) was dissolved in ethanol (22 mL) at 75 °C under stirring. Solution of IM hydrochloric acid (0.75 mL) was slowly added. The mixture was cooled to 25 °C in 2 hours and stirred for additional 16 hours. Material was filtered by vacuum filtration and washed with 2 mL of ethanol. Obtained material was dried in vacuum dryer at 40 °C. 230 mg of Rimegepant salt with hydrochloric acid was obtained.

[0193] le) Salt with maleic acid in ethanol

[0194] Rimegepant (0.240 g) was dissolved in mixture ethanol : water = 3: 1 (3 mL) at 70 °C under stirring. Solution of maleic acid (52 mg) in ethanol : water = 3 : 1 (1 mL) was slowly added. The mixture was cooled to 25 °C in 2 hours and stirred for additional 16 hours. Material was filtered by vacuum filtration and washed with 1 mL of mixture ethanol : water = 3: 1. Obtained material was dried in vacuum dryer at 40 °C. 96 mg of Rimegepant salt with maleic acid was obtained.

[0195] Example 2: solvent methanol or solvent mixtures including methanol

[0196] 2a) Salt with citric acid in methanol

[0197] Rimegepant (0.4 g) was dissolved in methanol (15 mL) at 75 °C under stirring. Solution of citric acid (0.14 g / 0.7mL water) was slowly added. The mixture was cooled to 25 °C in 2 hours and stirred for additional 16 hours. Material was filtered by vacuum filtration and washed with 2 mL of methanol. Obtained material was dried in vacuum dryer at 40 °C. 320 mg of Rimegepant salt with citric acid was obtained.

[0198] 2b) Salt with L-malic acid in methanol

[0199] Rimegepant (0.4 g) was dissolved in methanol (15 mL) at 75 °C under stirring. Solution of L- malic acid (0.10 g / 0.3 mL water) was slowly added. The mixture was cooled to 25 °C in 2 hours and stirred for additional 16 hours. Material was filtered by vacuum filtration and washed with 2 mL of methanol. Obtained material was dried in vacuum dryer at 40 °C. 330 mg of Rimegepant salt with L- malic acid was obtained.

[0200] 2c) Salt with L-tartaric acid in methanol

[0201] Rimegepant (0.4 g) was dissolved in methanol (15 mL) at 75 °C under stirring. Solution of L- tartaric acid (0. 11 g / 0.2 mL water / 5 mL MeOH) was slowly added. The mixture was cooled to 25 °C in 2 hours and stirred for additional 16 hours. Material was filtered by vacuum filtration and washed with 2 mL of methanol. Obtained material was dried in vacuum dryer at 40 °C. 400 mg of Rimegepant salt with L-tartaric acid was obtained.

[0202] 2d) Salt with L-tartaric acid in EA : MeOH : water

[0203] 12 g of Rimegepant and 258 mL of a solvent mixture EA : MeOH : water = 6 : 5 : 1 (vol%) were charged into a 400 mL reactor. The crystallization mixture was heated to Tr = 60 °C. The mixture was stirred until Rimegepant was dissolved. In a separate flask, a solution of 3.37 g of L-tartaric acid in water was prepared. Adding the acid solution to the crystallization mixture was started. After adding half the amount of acid, cleavage was performed with Rimegepant tartrate. The inoculum was set. Addition of the remaining tartaric acid was continued. The entire amount of acid was added within 10 min. The suspension thickened. After adding the acid, cooling the crystallization system to Tr = 0 °C within 2.5 h was started. Stirring was continued at the final temperature for 1 h. The product was collected and washed with 2 x 60 mL ethyl acetate (EA). The precipitate was dried for 5 hours at 30 °C, 5 hours at 50 °C and then for 10 hours at 70 °C at 50 mbar. m(dried product) = 13.98 g. Due to the excessive residual solvent content, the salt was additionally dried for 16 hours at 75 °C at 50 mbar.

[0204] Comparative tests revealed that the thus obtained L-tartaric acid salt of Rimegepant has more than twice the dissolution rate of Rimegepant base and Rimegepant hemisulfate monohydrate . The experimental results of the intrinsic dissolution rate tests (n=3) are shown in Eigure 22 (0.001 M HC1, 900 ml, 37°C, ap2, 100 rpm, 0.5 cm2, HPLC).

[0205] Further, the thus obtained L-tartaric acid salt of Rimegepant crystallizes in needle-like crystals as shown on the SEMs in Figure 23 A and B at different resolution.

[0206] 2e) Salt with fumaric acid in methanol

[0207] Rimegepant (0.4 g) was dissolved in methanol (15 mL) at 75 °C under stirring. Solution of fumaric acid (88 mg / 0.5 mL water / 2 mL MeOH) was slowly added. The mixture was cooled to 25 °C in 2 hours and stirred for additional 16 hours. Material was filtered by vacuum filtration and washed with 2 mL of methanol. Obtained material was dried in vacuum dryer at 40 °C. 370 mg of Rimegepant salt with fumaric acid was obtained.

[0208] 2f) Salt with phosphoric acid in methanol

[0209] Rimegepant (0.4 g) was dissolved in methanol (15 mL) at 75 °C under stirring. Solution of phosphoric acid (46 pL) was slowly added. The mixture was cooled to 25 °C in 2 hours and stirred for additional 16 hours. Material was filtered by vacuum filtration and washed with 2 mL of methanol. Obtained material was dried in vacuum dryer at 40 °C. 240 mg of Rimegepant salt with phosphoric acid was obtained.

[0210] 2g) Salt with formic acid in methanol

[0211] Rimegepant (0.4 g) was dissolved in methanol (15 mL) at 70 °C under stirring. Solution of formic acid (280 pL) was slowly added. The mixture was cooled to 25 °C in 2 hours and stirred for additional 16 hours. Solvent was additionally evaporated under reduced pressure. Material was filtered by vacuum filtration and washed with 2 mL of methanol. Obtained material was dried in vacuum dryer at 40 °C. 420 mg of Rimegepant salt with formic acid was obtained.

[0212] 2h) Salt with propionic acid in methanol

[0213] Rimegepant (0.4 g) was dissolved in methanol (15 mL) at 70 °C under stirring. Solution of propionic acid (56 pL) was slowly added. The mixture was cooled to 25 °C in 2 hours and stirred for additional 16 hours. Solvent was additionally evaporated under reduced pressure. Material was fdtered by vacuum fdtration and washed with 2 mL of methanol. Obtained material was dried in vacuum dryer at 40 °C. 220 mg of Rimegepant salt with propionic acid was obtained.

[0214] 2i) Salt with glutaric acid in methanol

[0215] Rimegepant (0.4 g) was dissolved in methanol (15 mL) at 70 °C under stirring. Solution of glutaric acid (99.1 mg) in water (0.5 mL) was slowly added. The mixture was cooled to 25 °C in 2 hours and stirred for additional 16 hours. Solvent was additionally evaporated under reduced pressure. Material was fdtered by vacuum fdtration and washed with 2 mL of methanol. Obtained material was dried in vacuum dryer at 40 °C. 270 mg of Rimegepant salt with glutaric acid was obtained.

[0216] 2j) Salt with adipic acid in methanol

[0217] Rimegepant (0.4 g) was dissolved in methanol (15 mL) at 70 °C under stirring. Solution of adipic acid (110 mg) in water (2 mL) was slowly added. The mixture was cooled to 25 °C in 2 hours and stirred for additional 16 hours. Solvent was additionally evaporated under reduced pressure. Material was fdtered by vacuum fdtration and washed with 2 mL of methanol. Obtained material was dried in vacuum dryer at 40 °C. 300 mg of Rimegepant salt with adipic acid was obtained.

[0218] 2k) Salt with p-toluene sulfonic acid in methanol

[0219] Rimegepant (0.4 g) was dissolved in methanol (15 mL) at 65 °C under stirring. Solution of p- toluene sulfonic acid (140 mg) in water (0.3 mL) was slowly added. The mixture was cooled to 0 °C in 2 hours and stirred for additional 16 hours. Solvent was additionally evaporated under reduced pressure. Material was fdtered by vacuum fdtration and washed with 2 mL of methanol. Obtained material was dried in vacuum dryer at 40 °C. 560 mg of Rimegepant salt with p-toluene sulfonic acid was obtained.

[0220] 21) Salt with hydrobromic acid in methanol

[0221] Rimegepant (0.4 g) was dissolved in methanol (15 mL) at 70 °C under stirring. Solution of hydrobromic acid (38.7 pL) was slowly added. The mixture was cooled to 20 °C in 2 hours and stirred for additional 16 hours. Solvent was additionally evaporated. Material was fdtered by vacuum fdtration and washed with 2 mL of methanol. Obtained material was dried in vacuum dryer at 40 °C. 120 mg of Rimegepant salt with hydrobromic acid was obtained.

[0222] 2m) Salt with acetic acid in methanol

[0223] Rimegepant (0.4 g) was dissolved in methanol (15 mL) at 70 °C under stirring. Acetic acid (45 pL) was slowly added. The mixture was cooled to 20 °C in 2 hours and stirred for additional 16 hours. Solvent was additionally evaporated. Material was fdtered by vacuum fdtration and washed with 2 mLof methanol. Obtained material was dried in vacuum dryer at 40 °C. 350 mg of Rimegepant salt with acetic acid was obtained.

[0224] 2n) Salt with methanesulfonic acid in methanol

[0225] Rimegepant (0.4 g) was dissolved in methanol (15 mL) at 70 °C under stirring. Methanesulfonic acid (50 pL) was slowly added. The mixture was cooled to 0 °C in 2 hours and stirred for additional 16 hours. Solvent was additionally evaporated. Material was fdtered by vacuum fdtration and washed with 2 mL of methanol. Obtained material was dried in vacuum dryer at 40 °C. 170 mg of Rimegepant salt with methanesulfonic acid was obtained.

[0226] Example 3 : solvent isopropanol

[0227] 3a) Salt with maleic acid in isopropanol

[0228] Rimegepant (0.270 g) was dissolved in mixture isopropanol : water = 3: 1 (3 mL) at 70 °C under stirring. Solution of maleic acid (58.6 mg) in isopropanol : water= 3: 1 (1 mL) was slowly added. The mixture was cooled to 25 °C in 2 hours and stirred for additional 16 hours. Material was fdtered by vacuum fdtration and washed with 1 mL of mixture isopropanol : water = 3: 1. Obtained material was dried in vacuum dryer at 40 °C. 140 mg of Rimegepant salt with maleic acid was obtained.

[0229] 3b) Salt with phosphoric acid in isopropanol

[0230] Rimegepant (0.240 g) was dissolved in mixture isopropanol : water = 3: 1 (3 mL) at 70 °C under stirring. Solution of phosphoric acid (30.8 pL) in isopropanol : water = 3: 1 (1 mL) was slowly added. The mixture was cooled to 25 °C in 2 hours and stirred for additional 16 hours. Material was fdtered by vacuum fdtration and washed with 1 mL of mixture isopropanol : water = 3: 1. Obtained material was dried in vacuum dryer at 40 °C. 90 mg of Rimegepant salt with phosphoric acid was obtained.

Claims

Patent claims:

1. A crystalline salt of Rimegepant with a physiologically acceptable acid, wherein the physiologically acceptable acid is(i) a saturated aliphatic mono- or dicarboxylic acid; preferably selected from formic acid, acetic acid, propionic acid, glutaric acid and adipic acid;(ii) an unsaturated aliphatic mono- or dicarboxylic acid; preferably selected from fumaric acid and maleic acid;(iii) a saturated aliphatic multicarboxylic mono- or dihydroxy acid; preferably selected from L- malic acid, citric acid, and L-tartaric acid;(iv) an inorganic acid selected from hydrobromic acid, phosphoric acid, and hydrochloric acid;(v) an aromatic sulfonic acid; preferably p-toluene sulfonic acid; or(vi) an aliphatic sulfonic acid; preferably methanesulfonic acid.

2. The crystalline salt according to claim 1, wherein the molar ratio of Rimegepant : physiologically acceptable acid is 1 : 1.

3. The crystalline salt according to claim 1 or 2, which is an ansolvate.

4. The crystalline salt according to claim 1 or 2, which is a solvate; preferably wherein the solvent is selected from methanol, ethanol and isopropanol; more preferably methanol and ethanol.

5. The crystalline salt according to claim 1 or 2, which is a hydrate.

6. The crystalline salt according to any of claims 1 to 5, wherein the physiologically acceptable acid is formic acid; preferably wherein the crystalline salt of Rimegepant with formic acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 15.3 (±0.2), 19.3 (±0.2), 20.2 (±0.2), 20.7 (±0.2), and 25.5 (±0.2); preferably, one, two, three or all additional reflections selected from 12.2 (±0.2), 13.0 (±0.2), 16.0 (±0.2), 21.5 (±0.2), and 27.1 (±0.2).

7. The crystalline salt according to any of claims 1 to 5, wherein the physiologically acceptable acid is acetic acid; preferably wherein the crystalline salt of Rimegepant with acetic acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 15.3 (±0.2), 19.1 (±0.2), 20.0 (±0.2), 20.5 (±0.2), and 26.6 (±0.2); preferably, one, two, three or alladditional reflections selected from 9.6 (±0.2), 12.5 (±0.2), 14.8 (±0.2), 22.7 (±0.2), and 25.9 (±0.2).

8. The crystalline salt according to any of claims 1 to 5, wherein the physiologically acceptable acid is propionic acid; preferably wherein the crystalline salt of Rimegepant with propionic acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 15.2 (±0.2), 15.9 (±0.2), 19.2 (±0.2), 20.1 (±0.2), and 20.5 (±0.2); preferably, one, two, three or all additional reflections selected from 12.1 (±0.2), 12.9 (±0.2), 22.9 (±0.2), 25.2 (±0.2), and 26.8 (±0.2).

9. The crystalline salt according to any of claims 1 to 5, wherein the physiologically acceptable acid is glutaric acid; preferably wherein the crystalline salt of Rimegepant with glutaric acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 14.6 (±0.2), 15.8 (±0.2), 19.2 (±0.2), 20.0 (±0.2), and 25.7 (±0.2); preferably, one, two or all additional reflections selected from 12.2 (±0.2), 23.4 (±0.2), and 24.6 (±0.2).

10. The crystalline salt according to any of claims 1 to 5, wherein the physiologically acceptable acid is adipic acid; preferably wherein the crystalline salt of Rimegepant with adipic acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 15.3 (±0.2), 19.6 (±0.2), 20.0 (±0.2), 21.0 (±0.2), and 22.7 (±0.2); preferably, one, two, three or all additional reflections selected from 12.6 (±0.2), 13.3 (±0.2), 14.9 (±0.2), 15.7 (±0.2), and 26.6 (±0.2).

11. The crystalline salt according to any of claims 1 to 5, wherein the physiologically acceptable acid is fumaric acid; preferably wherein the crystalline salt of Rimegepant with fumaric acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at(i) 14.8 (±0.2), 15.1 (±0.2), 16.4 (±0.2), 20.4 (±0.2), and 25.8 (±0.2); preferably, one, two, three or all additional reflections selected from 11.6 (±0.2), 12.4 (±0.2), 19.0 (±0.2), 24.8 (±0.2), and 27.5 (±0.2); or(ii) 15.2 (±0.2), 18.3 (±0.2), 20.4 (±0.2), 20.8 (±0.2), and 21.4 (±0.2); preferably, one, two, three or all additional reflections selected from 8.4 (±0.2), 12.8 (±0.2), 16.3 (±0.2), 17.9 (±0.2), 19.8 (±0.2), and 25.7 (±0.2).

12. The crystalline salt according to any of claims 1 to 5, wherein the physiologically acceptable acid is maleic acid; preferably wherein the crystalline salt of Rimegepant with maleic acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at(i) 16.3 (±0.2), 18.6 (±0.2), 19.0 (±0.2), 20.3 (±0.2), and 20.7 (±0.2); preferably, one, two, three or all additional reflections selected from 11.9 (±0.2), 13.2 (±0.2), 14.9 (±0.2), 15.3 (±0.2),21.8 (±0.2), 24.5 (±0.2), and 26.0 (±0.2); or(ii) 14.7 (±0.2), 15.8 (±0.2), 18.9 (±0.2), 20.3 (±0.2), and 20.6 (±0.2); preferably, one, two, three or all additional reflections selected from 11.2 (±0.2), 12.8 (±0.2), 21.7 (±0.2), 23.5 (±0.2), and 27.2 (±0.2).

13. The crystalline salt according to any of claims 1 to 5, wherein the physiologically acceptable acid is malic acid; preferably wherein the crystalline salt of Rimegepant with L-malic acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 15.2 (±0.2), 15.7 (±0.2), 18.9 (±0.2), 19.9 (±0.2), and 20.3 (±0.2); preferably, one, two, three or all additional reflections selected from 12.4 (±0.2), 13.0 (±0.2), 21.0 (±0.2), 24.5 (±0.2), and 26.3 (±0.2).

14. The crystalline salt according to any of claims 1 to 5, wherein the physiologically acceptable acid is citric acid; preferably wherein the crystalline salt of Rimegepant with citric acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at(i) 13.2 (±0.2), 16.8 (±0.2), 18.4 (±0.2), 19.5 (±0.2), and 20.8 (±0.2); preferably, one, two, three or all additional reflections selected from 8.9 (±0.2), 12.1 (±0.2), 14.9 (±0.2), and 15.2 (±0.2); or(ii) 13.2 (±0.2), 17.0 (±0.2), 18.8 (±0.2), 20.9 (±0.2), and 21.7 (±0.2); preferably, one, two, three or all additional reflections selected from 8.6 (±0.2), 15.1 (±0.2), 15.6 (±0.2), 20.2 (±0.2), and 26.1 (±0.2).

15. The crystalline salt according to any of claims 1 to 5, wherein the physiologically acceptable acid is L-tartaric acid; preferably wherein the crystalline salt of Rimegepant with L-tartaric acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at(i) 16.3 (±0.2), 19.4 (±0.2), 20.4 (±0.2), 21.0 (±0.2), and 22.0 (±0.2); preferably, one, two, three or all additional reflections selected from 8.1 (±0.2), 13.6 (±0.2), 24.8 (±0.2), and 26. 1 (±0.2); or(ii) 11.6 (±0.2), 13.2 (±0.2), 16.4 (±0.2), 19.5 (±0.2), and 20.9 (±0.2); preferably, one, two, three or all additional reflections selected from 4.2 (±0.2), 8.2 (±0.2), 12.5 (±0.2), 24.1 (±0.2), and24.9 (±0.2).

16. The crystalline salt according to any of claims 1 to 5, wherein the physiologically acceptable acid is hydrobromic acid; preferably wherein the crystalline salt of Rimegepant with hydrobromic acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20at 15.5 (±0.2), 16.3 (±0.2), 19.4 (±0.2), 20.5 (±0.2), and 21.0 (±0.2); preferably, one, two, three or all additional reflections selected from 13.1 (±0.2), 18.0 (±0.2), 24.7 (±0.2), and 26.0 (±0.2).

17. The crystalline salt according to any of claims 1 to 5, wherein the physiologically acceptable acid is phosphoric acid; preferably wherein the crystalline salt of Rimegepant with phosphoric acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at(i) 15.1 (±0.2), 19.3 (±0.2), 19.8 (±0.2), 25.6 (±0.2), and 26.5 (±0.2); preferably, one, two, three or all additional reflections selected from 5.2 (±0.2), 13.2 (±0.2), 17.6 (±0.2), 21.1 (±0.2), 23.1 (±0.2), and 31.5 (±0.2); or(ii) 11.1 (±0.2), 12.0 (±0.2), 16.0 (±0.2), 19.2 (±0.2), and 20.6 (±0.2); preferably, one, two, three or all additional reflections selected from 8.0 (±0.2), 14.9 (±0.2), 18.6 (±0.2), 22.5 (±0.2), and 23.9 (±0.2).

18. The crystalline salt according to any of claims 1 to 5, wherein the physiologically acceptable acid is hydrochloric acid; preferably wherein the crystalline salt of Rimegepant with hydrochloric acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at(i) 15.0 (±0.2), 15.4 (±0.2), 19.3 (±0.2), 20.4 (±0.2), and 20.9 (±0.2); preferably, one, two, three or all additional reflections selected from 12.9 (±0.2), 21.6 (±0.2), 25.9 (±0.2), and 27.1 (±0.2); or(ii) 4.7 (±0.2), 9.5 (±0.2), 12.5 (±0.2), 14.3 (±0.2), and 15.1 (±0.2); preferably, one, two, three or all additional reflections selected from 19.3 (±0.2), 20.2 (±0.2), 25.3 (±0.2), 27.6 (±0.2), and 27.7 (±0.2).

19. The crystalline salt according to any of claims 1 to 5, wherein the physiologically acceptable acid is p-toluene sulfonic acid; preferably wherein the crystalline salt of Rimegepant with p-toluene sulfonic acid has reflections in an XRPD spectrum, measured at 23 °C with Cu ka2 radiation (1.5406 A) in 20 at 16.0 (±0.2), 16.7 (±0.2), 18.1 (±0.2), 20.6 (±0.2), and 25.0 (±0.2); preferably, one, two, three or all additional reflections selected from 11.5 (±0.2), 13.1 (±0.2), 15.3 (±0.2), 19.3 (±0.2), and 26.4 (±0.2).

20. The crystalline salt according to any of claims 1 to 5, wherein the physiologically acceptable acid is methanesulfonic acid; preferably wherein the crystalline salt of Rimegepant with methanesulfonic acid has reflections in an XRPD spectrum, measured at 23°C with Cu ka2 radiation (1.5406 A) in 20 at 16.0 (±0.2), 17.1 (±0.2), 18.4 (±0.2), 20.0 (±0.2), and 21.6 (±0.2); preferably, one,two, three or all additional reflections selected from 12.1 (±0.2), 13.9 (±0.2), 24.3 (±0.2), 25.7 (±0.2), and 27.2 (±0.2).

21. The crystalline salt according to any of the preceding claims, which is obtainable by crystallization from alcoholic solution; preferably by cooling crystallization; more preferably from methanolic solution, from ethanolic solution or from isopropanolic solution; still more preferably from methanolic solution or from ethanolic solution.

22. The crystalline salt according to any of the preceding claims, which is obtainable by crystallization from aqueous solution; preferably by cooling crystallization; more preferably from aqueous methanolic solution; still more preferably from aqueous methanolic solution containing ethyl acetate.

23. A pharmaceutical composition or dosage form comprising a crystalline salt according to any of the preceding claims.

24. The pharmaceutical composition or dosage form according to claim 23, which is an orodispersible tablet.

25. The pharmaceutical composition or dosage form according to claim 23 or 24 for use in the treatment or prevention of migraine.

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