CN116456977A - Cinnimod salts and co-crystals - Google Patents

Abstract

The present invention relates to solid forms of cilnimod adipate and co-crystals.

Description

Sinimod Salts and Cocrystals

Background of the invention

The present invention relates to a salt or co-crystal of the compound sinimod and adipic acid.

Siponimod, 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl of formula (I) -Benzyl}-azetidine-3-carboxylic acid,

It is a lysophospholipid EDG1 (S1P1) receptor ligand and can be used to treat immune diseases. Sinimod fumarate is currently undergoing pre-registration for the treatment of secondary progressive multiple sclerosis.

Sinimod was first disclosed by Novartis in WO2004/103306. The hemifumarate salt of siinimod (i.e. the ratio of sinimod:fumaric acid 1:0.5) and the solid forms A, B, C, D and E of this hemifumarate (hemifurate) were obtained from Novartis is disclosed in WO2010/080409. Novartis discloses HCl salts, malates, oxalates, tartrates and crystalline forms thereof in WO2010/080455.

Prior art fumarates prepared according to WO2010/080409 form fine crystals which are easily charged. Processing such crystals into a final form, such as a tablet, is complex. On the other hand, the solid form of the present invention forms larger crystals which are less easily charged and thus have improved processability.

Summary of the invention

The present invention relates to sinimod adipate (adipate) salts and co-crystals in solid form.

The present invention relates to a solid form of sinimod form 11 co-crystallized with adipic acid (2:1), characterized by an XRPD pattern having 2Θ values of 6.7°, 12.7° and 13.5° 2Θ (±0.2 degrees 2Θ).

The present invention also relates to a process for the preparation of a solid form of sinimod in form 11 co-crystallized with adipic acid, the process comprising:

a, dissolving sinimod in ethyl acetate;

b, adding adipic acid;

c. Isolation of the solid form.

The present invention also relates to a solid form of sinimod adipate (1 :2) in form Q' characterized by an XRPD pattern having 2Θ values of 5.5°, 17.5° and 18.8° 2Θ (±0.2 degrees 2Θ).

The present invention also relates to a process for the preparation of a solid form of sinimod adipate in form Q' comprising:

a, dissolving Sinimod and adipic acid in methyl tert-butyl ether;

b. Separated solid form;

c. Expose the solid to moisture.

The present invention relates to a solid form of Form Q sinimod adipate (1 :2) characterized by an XRPD pattern having 2Θ values of 5.3°, 18.1° and 20.3° 2Θ (±0.2 degrees 2Θ).

The present invention also relates to a process for the preparation of a solid form of sinimod adipate in Form Q comprising:

a, dissolving Sinimod and adipic acid in methyl tert-butyl ether;

b. Isolation of the solid form.

The present invention also relates to a solid form of sinimod adipate (1 :1 ) in form P characterized by an XRPD pattern having 2Θ values of 5.6°, 7.5° and 19.2° 2Θ (±0.2 degrees 2Θ). Solid forms of sinimod adipate in Form P can be prepared by methods comprising:

a. Sinimod and adipic acid are dissolved in methanol and n-heptane;

b. Isolation of the solid form.

The present invention also relates to a solid form of sinimod adipate (1:2) in Form 1 characterized by an XRPD pattern having 2Θ values of 15.5°, 18.0°, 19.3 and 21.5° 2Θ (±0.2 degrees 2Θ) . Solid forms of sinimod adipate in Form 1 can be prepared by methods comprising:

a, suspending Sinimod and adipic acid in methyl tert-butyl ether;

b. Isolation of the solid form.

The present invention also relates to a solid form of Form 2 sinimod adipate (1:0.6) characterized by XRPD having 2Θ values of 4.0°, 7.4°, 17.8° and 19.3° 2Θ (±0.2 degrees 2Θ) Atlas. Solid forms of Form 2 sinimod adipic acid can be prepared by methods comprising:

a, dissolving sinimod and adipic acid in methanol;

b. Add n-heptane;

c. Isolation of the solid form.

Prior art fumarates prepared according to WO2010/080409 form fine crystals which are easily charged. Processing such crystals into a final form, such as a tablet, is complex. On the other hand, the solid form of the present invention forms larger crystals which are less easily charged and thus have improved processability. Furthermore, the water activity of Form 11 is better compared to the prior art forms.

Brief description of the drawings

Figure 1: XRPD pattern of solid Form Q of sinimod adipate (1:2) prepared according to Example 1

Figure 2: DSC profile of solid form Q of sinimod adipate (1:2) prepared according to Example 1

Figure 3: NMR spectrum of solid form Q of sinimod adipate (1:2) prepared according to Example 1

Figure 4: XRPD pattern of solid form Q' of Sinimod adipate (1:2) prepared according to Example 1

Figure 5: DSC profile of the solid form Q' of Sinimod adipate (1:2) prepared according to Example 1

Figure 6: NMR spectrum of the solid form Q' of Sinimod adipate (1:2) prepared according to Example 1

Figure 7: XRPD pattern of solid Form P of sinimod adipate (1:1) prepared according to Example 2

Figure 8: DSC profile of solid form P of sinimod adipate (1:1) prepared according to Example 2

Figure 9: NMR spectrum of solid form P of sinimod adipate (1:1) prepared according to Example 2

Figure 10: XRPD pattern of solid Form 1 of Sinimod adipate (1:2) prepared according to Example 3

Figure 11 : DSC profile of solid form 1 of sinimod adipate (1:2) prepared according to Example 3

Figure 12: NMR spectrum of solid form 1 of Sinimod adipate (1:2) prepared according to Example 3

Figure 13: XRPD pattern of solid form 2 of Sinimod adipate (1:0.6) prepared according to Example 4

Figure 14: DSC trace of solid form 2 of Sinimod adipate (1:0.6) prepared according to Example 4

Figure 15: NMR spectrum of solid form 2 of Sinimod adipate (1:0.6) prepared according to Example 4

Figure 16: XRPD pattern of solid form 4 of Sinimod adipate (1:2) prepared according to Example 5

Figure 17: Crystals of solid form Q' prepared according to Example 1

Figure 18: Crystals of solid Form Q prepared according to Example 1

Figure 19: Crystals of solid form P prepared according to Example 2

Figure 20: Crystals of solid Form 1 prepared according to Example 3

Figure 21 : Crystals of solid Form 2 prepared according to Example 4

Figure 22: Crystals in solid form of Sinimod fumarate prepared according to WO2010/080409

Figure 23: XRPD pattern of solid form 11 of Sinimod co-crystallized with adipic acid (2:1) prepared according to Example 7 or Example 8 or Example 9 or Example 10.

FIG. 24 : DSC trace of the solid form 11 of Sinimod co-crystallized with adipic acid (2:1 ) prepared according to Example 7 or Example 8 or Example 9 or Example 10.

FIG. 25 : Crystals of solid form 11 of Sinimod co-crystallized with adipic acid (2:1 ) prepared according to Example 8. FIG.

FIG. 26 : Crystals of solid form 11 of Sinimod co-crystallized with adipic acid (2:1 ) prepared according to Example 7. FIG.

FIG. 27 : Crystals of solid form 11 co-crystallized with adipic acid (2:1 ) of Sinimod prepared according to Example 9. FIG.

Figure 28: Crystals of solid Form A of Sinimod fumarate prepared according to WO2010/080409.

FIG. 29 : NMR spectrum of the solid form 11 of the co-crystal of Sinimod and adipic acid (2:1 ) prepared according to Example 7 or Example 8 or Example 9.

Detailed description of the invention

The present invention relates to sinimod adipate or its co-crystal and solid forms. A co-crystal can be defined as a binary compound in which two components (coformers) are in a solid state linked by nonionic intermolecular bonds.

The present invention relates to a solid form, Form 11, of sinimod co-crystallized with adipic acid (2:1). The solid form of Form 11 can be characterized by an XRPD pattern with 2Θ values of 6.7°, 12.7° and 13.5° 2Θ (±0.2 degrees 2Θ). Form 11 can also be characterized by an XRPD pattern with 2Θ values of 6.7°, 7.5°, 12.7°, 13.5°, 16.4° and 18.3° 2Θ (±0.2° 2Θ). Form 11 can be further characterized by the XRPD pattern described in the table below:

Form 11 can also be characterized by the XPRD spectrum depicted in Figure 23 or the DSC pattern depicted in Figure 24 or the NMR spectrum depicted in Figure 29.

The solid form 11 of sinimod co-crystallized with adipic acid (2:1) can be prepared by a method comprising:

a, dissolving sinimod in ethyl acetate;

b, adding adipic acid;

c. Isolation of the solid form.

Sinimod was dissolved in ethyl acetate. Ethyl acetate may optionally contain up to 3% (volume %) water. The concentration of sinimod in ethyl acetate can be between 0.02 g/ml and 0.65 g/ml. Add adipic acid to the solution. The molar ratio between siponimod and adipic acid may be between 1:0.5 and 1:1.1. The mixture is heated to a temperature between 55°C and 75°C and stirred at this temperature for 10 to 60 minutes. The mixture was cooled to a temperature between 35°C and 45°C. The mixture can optionally be seeded with a co-crystal of sinimod and adipate form 11. Seeds can be prepared, for example, by the method disclosed in Example 7. The mixture was stirred at this temperature for 1 to 5 hours. The mixture was cooled to 15°C to 25°C over 1.5 to 3 hours. The mixture was stirred at this temperature for 2 to 6 hours. The solid was filtered off, optionally washed and dried to obtain the solid form 11 as a cocrystal of siinemod and adipic acid (2:1).

The present invention also relates to solid forms of sinimod adipate (1:2) in forms Q and Q', and processes for their preparation.

Sinimod adipate (1:2) in Form Q' can be characterized by an XRPD pattern with 2Θ values of 5.5°, 17.5° and 18.8° 2Θ (±0.2 degrees 2Θ). Form Q' can also be characterized by an XRPD pattern with 2Θ values of 5.5°, 7.6°, 16.5°, 17.5° and 18.8° 2Θ (±0.2 degrees 2Θ). Form Q' can be further characterized by the XRPD pattern described in the table below:

2θ angle strength% 2θ angle strength% 2θ angle strength% 5.5 100.0 12.8 17.3 23.7 16.7 7.2 10.3 13.6 17.8 25.2 11.8 7.6 30.9 16.5 22.4 25.8 12.5 8.9 12.0 17.5 54.4 26.5 10.8 9.8 10.6 18.8 54.2 27.0 12.7 10.5 12.5 19.7 57.7 27.3 15.5 10.8 15.9 20.7 20.8 27.8 12.4 11.0 17.9 21.5 33.2 30.2 6.6 11.6 9.5 22.1 24.3 31.1 6.0 12.6 16.7 23.0 19.9

Form Q' can also be characterized by the XPRD spectrum depicted in FIG. 4 or the DSC pattern depicted in FIG. 5 or the NMR spectrum depicted in FIG. 6 .

Form Q sinimod adipate (1 :2) can be characterized by an XRPD pattern with 2Θ values of 5.3°, 18.1° and 20.3° 2Θ (±0.2 degrees 2Θ). Form Q can also be characterized by an XRPD pattern with 2Θ values of 5.3°, 12.8°, 18.1°, 19.6°, and 20.3° 2Θ (±0.2 degrees 2Θ). Form Q can be further characterized by the XRPD pattern described in the table below:

2θ angle strength% 2θ angle strength% 2θ angle strength% 3.7 24.3 14.9 17.9 24.6 21.0 5.3 100.0 16.1 16.6 25.7 13.2 7.7 39.3 17.3 74.1 26.8 17.2 8.6 11.5 18.1 56.4 27.6 15.2 8.8 11.1 18.4 39.5 28.3 15.3 10.4 11.4 18.9 44.2 28.7 13.0 10.7 16.8 19.6 47.4 29.3 9.4 11.5 10.8 20.3 76.0 30.7 9.5 12.8 42.8 21.5 42.4 31.1 7.1 13.5 19.1 21.9 30.6 32.3 7.1 14.0 14.6 23.8 28.8

Form Q can also be characterized by the XPRD spectrum depicted in FIG. 1 or the DSC pattern depicted in FIG. 2 or the NMR spectrum depicted in FIG. 3 .

The solid form Q' of the salt of siinimod and adipic acid (1:2) can be prepared by a process comprising:

a, dissolving Sinimod and adipic acid in methyl tert-butyl ether;

b. Separated solid form;

c. Contacting the solid form with humidity to obtain Form Q'.

The solid form isolated in step b is preferably solid form Q of the salt of sinimod and adipic acid (1:2). Sinimod and adipic acid were dissolved in methyl tert-butyl ether. The concentration of sinimod in methyl tert-butyl ether can be between 0.02 g/ml and 0.06 g/ml. The concentration of adipic acid in methyl tert-butyl ether can be between 0.015 and 0.05 g/ml. The molar ratio between siinimod and adipic acid may be between 1:2 and 1:2.2. The mixture was kept at a temperature between 20°C and 25°C to evaporate the solvent until the final volume was between 25% and 30% (v/v) of the starting volume to obtain a suspension. Filter the suspension. The resulting solid can be dried to give Form Q sinimod adipate (1 :2). The resulting solid Form Q is exposed to a temperature of 40°C to 60°C and a humidity of 80% to 100%RH for 10 to 15 hours to provide Form Q' of sinimod adipate (1 :2).

The present invention also relates to a solid form of sinimod adipate (1 :1 ) in form P characterized by an XRPD pattern having 2Θ values of 5.6°, 7.5° and 19.2° 2Θ (±0.2 degrees 2Θ). Form P can also be characterized by an XRPD pattern with 2Θ values of 5.6°, 7.5°, 13.8°, 17.7°, and 19.2° 2Θ (±0.2 degrees 2Θ). Form P can be further characterized by the XRPD pattern described in the table below:

Form P can also be characterized by the XPRD spectrum depicted in FIG. 7 or the DSC pattern depicted in FIG. 8 or the NMR spectrum depicted in FIG. 9 .

The solid form of sinimod adipate (1:1) in Form P can be prepared by a process comprising:

a. Sinimod and adipic acid are dissolved in methanol and n-heptane;

b. Isolation of the solid form.

The volume ratio between methanol and n-heptane can be between 1:6 and 1:8. Sinimod and adipic acid were dissolved in methanol. The concentration of sinimod in methanol can be between 0.2 g/ml and 0.5 g/ml. The concentration of adipic acid in methanol can be between 0.07 g/ml and 0.15 g/ml. Add n-heptane to the mixture. About 10 drops were removed from the mixture and crystallized on a closed Petri dish at 20-25°C for 3 days to obtain crystals. Add the crystals to the previously prepared methanol and n-heptane solutions of siinimod and adipic acid. The mixture was then stirred at 20-25°C for 1 to 10 hours to obtain a suspension. The suspension is filtered and the resulting solid form P is optionally dried.

The present invention also relates to a solid form of sinimod adipate (1:2) in Form 1 characterized by XRPD having 2Θ values of 15.5°, 18.0°, 19.3° and 21.5° 2Θ (±0.2 degrees 2Θ) Atlas. Form 1 can also be characterized by an XRPD pattern with 2Θ values of 9.9°, 14.3°, 15.5°, 18.0°, 19.3°, 21.0°, and 21.5° 2Θ (±0.2 degrees 2Θ). Form 1 can be further characterized by the XRPD pattern described in the table below:

Form 1 can also be characterized by the XPRD spectrum depicted in FIG. 10 or the DSC pattern depicted in FIG. 11 or the NMR spectrum depicted in FIG. 12 .

The solid form of Form 1 sinimod adipate (1:2) can be prepared by a process comprising:

a, suspending Sinimod and adipic acid in methyl tert-butyl ether;

b. Isolation of the solid form.

The concentration of sinimod in methyl tert-butyl ether can be between 0.07 g/ml and 0.15 g/ml. The concentration of adipic acid in methyl tert-butyl ether can be between 0.04 g/ml and 0.07 g/ml. The molar ratio between siinimod and adipic acid may be between 1:2 and 1:2.2. Sinimod and adipic acid in contact with methyl tert-butyl ether. The suspension is stirred at a temperature of 20°C to 25°C for 10 to 20 hours. The suspension was filtered and optionally dried to give a solid, giving Sinimod adipate (1 :2) salt in Form 1 as a solid.

The present invention also relates to a solid form of Form 2 sinimod adipate (1:0.6) characterized by XRPD having 2Θ values of 4.0°, 7.4°, 17.8° and 19.3° 2Θ (±0.2 degrees 2Θ) Atlas. Form 2 can also be characterized by an XRPD pattern having 2Θ values of 4.0°, 5.7°, 7.4°, 17.8°, 19.3°, 20.0°, and 21.0° 2Θ (±0.2 degrees 2Θ). Form 2 can be further characterized by the XRPD pattern described in the table below:

Form 2 can also be characterized by the XPRD spectrum depicted in Figure 13 or the DSC pattern depicted in Figure 14 or the NMR spectrum depicted in Figure 15.

Solid Form 2 can be prepared by methods comprising:

a, dissolving sinimod and adipic acid in methanol;

b. Add n-heptane;

c. Isolation of the solid form.

The concentration of sinimod in methanol can be between 0.3 and 0.6 g/ml. The concentration of adipic acid in methanol can be between 0.04 g/ml and 0.08 g/ml. The molar ratio between siinimod and adipic acid may be between 1:0.5 and 1:0.7. Sinimod and adipic acid were dissolved in methanol. Add n-heptane to the mixture. The volume ratio between n-heptane and methanol can be between 7:1 and 9:1. The mixture was heated to a temperature of 35°C to 50°C to obtain a solution. The mixture is then cooled to a temperature of -5°C to 5°C and stirred at this temperature for 15 to 120 minutes to obtain a suspension. The solid obtained may be isolated by any suitable technique, for example using filtration and optionally dried.

The present invention also relates to a solid form of sinimod adipate (1:2) in Form 4 characterized by XRPD having 2Θ values of 12.6°, 18.4°, 21.5° and 23.16° 2Θ (±0.2 degrees 2Θ) Atlas. Form 4 can also be characterized by an XRPD pattern with 2Θ values of 12.6°, 13.0°, 15.3°, 18.4°, 21.5°, and 23.2° 2Θ (±0.2 degrees 2Θ). Form 4 can be further characterized by the XRPD pattern described in the table below:

2θ angle strength% 2θ angle strength% 2θ angle strength% 3.8 6.3 16.6 21.5 24.7 6.9 7.5 17.5 17.0 13.6 25.1 8.4 8.8 9.4 17.6 11.5 25.3 19.2 10.6 11.4 18.1 13.7 25.8 28.6 11.3 8.3 18.4 44.9 26.6 6.8 11.6 7.9 18.9 10.4 26.9 13.4 12.6 48.2 19.2 10.0 27.0 11.2 13.0 18.8 20.1 10.6 28.4 4.0 13.3 4.3 20.5 10.3 29.8 3.2 14.5 11.3 20.9 13.7 30.3 4.0 15.1 6.9 21.5 100.0 30.8 4.9 15.3 15.9 22.7 20.8 31.2 14.3 15.5 13.2 23.2 41.5 32.1 3.9 16.0 11.0 24.0 8.1 33.6 4.2

Form 4 can also be characterized by the XPRD diagram shown in FIG. 16 .

The solid form of sinimod adipate (1 :2) in form 4 can be prepared by a process comprising exposing sinimod adipate (1 :2) in form 1 to 35°C to 50°C °C temperature, humidity 60% to 100% relative humidity, lasts 1 to 6 months.

Example

The XRPD spectrum of the solid compound was obtained using the following measurement conditions:

Panalytical Empyrean diffractometer with Θ/2Θ geometry (transmition mode) with PixCell 3D detector

Use the following conditions to obtain the DCS graph: 10°C/min->250°C

Photographs of crystals were obtained by SEM Jeol JCM-6000.

Nuclear magnetic resonance spectroscopy (NMR) was performed using an Avance III 400MHz NMR spectrometer.

Example 1: Preparation of Sinimod Adipate (1:2) Solid Form, Forms Q and Q'

0.64 g of sinimod and 0.36 g of adipic acid were dissolved in 18 mL of methyl tert-butyl ether (MTBE). The solution was filtered and left at a temperature of 20°C to 25°C to evaporate the solvent to a final volume of about 5 ml to obtain a suspension. Filter the suspension. Cake 1 was dried (25 °C/1 h/vacuum) to afford 0.62 g of Sinimod adipate (1 :2) salt, Form Q. The XRPD pattern of the obtained solid corresponds to the XRPD pattern shown in FIG. 1 , the DSC pattern of the obtained solid corresponds to the DSC pattern shown in FIG. 2 , and the NMR pattern of the obtained solid corresponds to the NMR pattern shown in FIG. 3 . The obtained solid was exposed to 50° C. and 100% relative humidity for 12 hours to obtain 0.62 g of Sinimod adipate (1 :2) salt, Form Q′. The XRPD pattern of the obtained solid corresponds to the XRPD pattern shown in Figure 4, the DSC pattern of the obtained solid corresponds to the DSC pattern shown in Figure 5, and the NMR pattern of the obtained solid corresponds to the NMR spectrum shown in Table 6.

Example 2: Preparation of Sinimod Adipate (1:1), Form P in Solid Form

Dissolve 2 g of sinimod and 0.64 g of adipic acid in 6 mL of methanol. The solution was diluted with 40 ml of n-heptane. Crystals were obtained by placing 10 drops in a closed Petri dish for crystallization at 20°C–25°C for 3 days. Add the crystals to the previously prepared solution. The mixture was stirred at 20°C - 25°C for 75 minutes to obtain a suspension. The suspension was filtered and the solid obtained was washed with 5 ml of n-heptane and dried (25°C/3h/vacuum) to afford 2.105g of Sinimod adipate (1:1), Form P. The XRPD spectrum of the solid obtained corresponds to the XRPD spectrum shown in Figure 7, the DSC spectrum of the solid obtained corresponds to the DSC spectrum shown in Figure 8, and the NMR spectrum of the solid obtained corresponds to the NMR spectrum shown in Table 9.

Example 3: Preparation of Sinimod Adipate (1:2), Form 1 in Solid Form

Mix 2 g of sinimod and 1.14 g of adipic acid with 20 mL of methyl tert-butyl ether (MTBE). The suspension was stirred overnight at 20-25°C, filtered and the filter cake washed with 5ml MTBE (5ml). The powder material was dried (25°C/1 h/vacuum) to afford 2.4 g of sinimod adipate (1 :2), Form 1, as a solid. The XRPD pattern of the obtained solid corresponds to the XRPD pattern shown in Figure 10, the DSC pattern of the obtained solid corresponds to the DSC pattern shown in Figure 11, and the NMR pattern of the obtained solid corresponds to the NMR spectrum shown in Figure 12.

Example 4: Preparation of Sinimod Adipate (1:0.6), Form 2 in Solid Form

Mix 2 g of Sinimod and 0.28 g of adipic acid with 5 mL of methanol. The solution was diluted with 40 ml of n-heptane, and heated to 40°C to obtain a solution. The solution was cooled to 0°C and stirred at (-2)-0°C for 30 minutes. The suspension was filtered and the resulting solid was washed with 2 ml of n-heptane and dried (25 °C/3 h/vacuum) to yield 1.8 g of Sinimod adipate (1 :0.6), Form 2.

The XRPD spectrum of the solid obtained corresponds to the XRPD spectrum shown in Figure 13, the DSC spectrum of the solid obtained corresponds to the DSC spectrum shown in Figure 14, and the NMR spectrum of the solid obtained corresponds to the NMR spectrum shown in Figure 15

Example 5: Preparation of Sinimod Adipate (1:2), Form 4 in Solid Form

0.5 g of sinimod adipate in form 1 (1:2) was exposed to a temperature of 40° C. and a relative humidity of 75% for 1 month to provide 0.5 g of sinimod adipate in form 4 salt (1:2). The XRPD pattern of the obtained solid corresponds to the XRPD pattern shown in FIG. 16 .

Embodiment 6: comparative example

The prior art fumarate was prepared according to the procedure described in WO2010/080409. In Figures 17-22, crystals of a salt of the prior art (Figure 22) and a salt of the present invention (Figures 17-21) are shown. State-of-the-art salts form small crystals that are easily charged, and processing such crystals into final forms, such as tablets, is therefore challenging. In contrast, the salts of the present invention form larger crystals, are less likely to be charged, and have improved processability.

Example 7: Preparation of solid form 11 of co-crystal of siinimod and adipic acid (2:1)

Dissolve 360 mg of sinimod in 0.6 mL of ethyl acetate. To the mixture was added 51 mg of adipic acid. The mixture was sonicated for 5 minutes. The solid material was filtered off to obtain 380 mg of sinimod co-crystallized with adipic acid as solid form 11. The XRPD pattern of the obtained solid corresponds to the XRPD pattern shown in FIG. 23 . The DSC spectrum of the obtained solid corresponds to that shown in FIG. 24 . The crystals of the obtained solid are shown in FIG. 26 .

Example 8: Preparation of solid form 11 of sinimod co-crystallized with adipic acid (2:1)

Mix 380 mg of sinimod-adipic acid adduct with 1.1 mL of ethyl acetate. The solution was heated to 70°C and then naturally cooled to 40°C to obtain a suspension. It was then reheated to 60°C and cooled to ambient temperature (20-25°C) within 8 hours, decanted and the remainder was dried in a vacuum desiccator at 25°C under nitrogen for 3 hours to obtain 330 mg Sidney Solid form 11 of Maud co-crystallized with adipic acid (2:1). The XRPD pattern of the obtained solid corresponds to the XRPD pattern shown in FIG. 23 . The DSC spectrum of the obtained solid corresponds to that shown in FIG. 24 . The crystals of the obtained solid are shown in FIG. 25 .

Example 9: Preparation of solid form 11 of sinimod co-crystallized with adipic acid (2:1)

33 g of sinimod were dissolved in 1237.5 ml of ethyl acetate. The mixture was heated to 57°C and 10.2 g of adipic acid were added. The mixture was cooled to 40°C and stirred at this temperature for 2 hours. The mixture was cooled to 20° C. within 2 hours and stirred at this temperature for 3 hours. The solid obtained was filtered off to afford 29.04 g of siinimod co-crystallized with adipic acid (2:1 ) as a solid form 11 (88% of theoretical yield) with a purity of 99.9% (HPLC IN). The XRPD pattern of the obtained solid corresponds to the XRPD pattern shown in FIG. 23 . The DSC spectrum of the obtained solid corresponds to that shown in FIG. 24 . The crystals of the obtained solid are shown in FIG. 27 .

Example 10: Preparation of Sinimod Adipic Acid (2:1) Cocrystalline Solid Form 11, Isolation from Reaction Mixture

30 grams of (E)-4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy) imino) ethyl)-2-ethylbenzaldehyde with 10.5 grams Azetidine-3-carboxylic acid and 600 ml of methanol were mixed. The mixture was stirred for 30 minutes. To the mixture was added 7 _ml of _Et3N.BH3 complex over 30 minutes. The mixture was heated to 30°C and stirred at this temperature for 3 hours. The mixture was cooled to 10-15°C and filtered using celite. 750 g of water were added to the filtrate. The mixture was distilled until a suspension was obtained. The mixture was cooled to 45°C, and 750 g of ethyl acetate and 3 g of acetic acid were added. Phase. The organic phase was filtered using celite. 600 g EtOAc was added to the filtrate. 500 ml of solvent was distilled off from the mixture, and 500 ml of ethyl acetate was added to the mixture. 500 ml of solvent was distilled off from the mixture, and 500 ml of ethyl acetate was added to the mixture. The mixture was concentrated to a final volume of 1350ml. The remainder was heated to 55°C and 10.2 g of adipic acid were added. The mixture was cooled to 40°C and stirred at this temperature for 2 hours. The mixture was cooled to 20°C within 2 hours. The mixture was stirred at 20°C for 3 hours. The solid form 11 co-crystallized with siinemod and adipic acid (2:1) was filtered off. The yield was 85% of theory with a purity of 99.9% (HPLC IN). The XRPD pattern of the obtained solid corresponds to the XRPD pattern shown in FIG. 23 . The DSC spectrum of the obtained solid corresponds to that shown in FIG. 24 .

Embodiment 11: comparative example

Prior art Sinimod fumarate (1:0.5), Form A was prepared according to the procedure disclosed in WO2010/080409.

Measure the water activity of the prior art form and the solid form of the invention: DVS machine ProUmid SPX-1 μAdvance, 25°C, 0-90-0% relative humidity, 10% steps, maximum time 10 hours per step. Balance bandwidth 0.05%/60 minutes.

Water Activity: The difference between the weight of a sample at a constant temperature between 0 and 90% relative humidity. It corresponds to the amount of water absorbed by the tested compound when the humidity varies from 0% to 90% at a constant temperature. The higher the water activity, the more water the compound can absorb, which can lead to a lower purity compound because hydrolyzed impurities can form. It can also lead to mechanical stress in the final product, such as a tablet, as the compound absorbs water increasing its volume, and the volume of the final product, such as a tablet, also increases, which causes the product to break.

In the table below, the water activity (at 25°C) of sinimod with adipic acid (2:1) co-crystal form 11 and sinimod fumarate (1:0.5) form A is compared:

SIM.fum Sinimod with Fumaric Acid, Form A

SIM.adi Cocrystal of sinimod with adipic acid, Form 11

dm poor mass (corresponds to water activity)

It can be concluded that Form 11, co-crystallized with sinimod with adipic acid (2:1), exhibits lower water activity than sinimod fumarate form A.

Crystals of solid form 11 co-crystallized with siinimod and adipic acid (2:1) are shown in Figures 25-27. Crystals of Sinimod fumarate, Form A, are shown in FIG. 28 . It can be concluded that Form 11 crystals are much larger and less easily charged than Form A crystals and have improved properties in terms of processability.

Claims (15)

1. A salt or co-crystal of siinimod and adipic acid. 2. A solid form of a salt or co-crystal of sinimod with adipic acid. 3. The solid form according to claim 2, cocrystal of sinimod with adipic acid (2:1), Form 11, characterized by having 2Θ values of 6.7°, 12.7° and 13.5° 2Θ (± 0.2 degrees 2Θ ) XRPD pattern. 4. The solid form according to claim 3, characterized by an XRPD pattern having 2Θ values of 6.7°, 7.5°, 12.7°, 13.5°, 16.4° and 18.3° 2Θ (±0.2 degrees 2Θ). 5. A process for preparing a solid form according to claim 3 or 4, comprising: a, dissolving sinimod in ethyl acetate; b, adding adipic acid; c. Isolation of the solid form. 6. The method according to claim 5, wherein the ethyl acetate contains at most 3% (volume %) water. 7. The solid form of claim 2, the salt of sinimod with adipic acid (1:0.6), Form 2, characterized by having 2Θ values of 4.0°, 7.4°, 17.8° and 19.3° 2Θ ( ±0.2 degrees 2θ) XRPD pattern. 8. A method of preparing a solid form according to claim 7, comprising: a, dissolving sinimod and adipic acid in methanol; b. Add n-heptane; c. Isolation of the solid form. 9. The solid form of claim 2, the salt of sinimod and adipic acid (1:2), Form 1, characterized by having 2Θ values of 15.5°, 18.0°, 19.3 and 21.5° 2Θ (± 0.2 degrees 2θ) XRPD patterns. 10. A method of preparing a solid form according to claim 9, comprising: a, suspending Sinimod and adipic acid in methyl tert-butyl ether; b. Isolation of the solid form. 11. The solid form of claim 2, the salt of sinimod with adipic acid (1:1), Form P, characterized by having 2Θ values of 5.6°, 7.5° and 19.2° 2Θ (±0.2 degrees 2θ) XRPD patterns. 12. A method of preparing a solid form according to claim 11 comprising: a. Sinimod and adipic acid are dissolved in methanol and n-heptane; b. Isolation of the solid form. 13. The solid form of claim 2, the salt of sinimod with adipic acid (1:2), Form Q', characterized by having 2Θ values of 5.5°, 17.5° and 18.8° 2Θ (±0.2 Degree 2θ) XRPD patterns. 14. A method of preparing a solid form according to claim 12, comprising: a, siinimod and adipic acid are dissolved in methyl tert-butyl ether; b. Separated solid form; c. Expose the solid to moisture. 15. The method according to claim 14, wherein said humidity is between 80% and 100% RH.