WO2016034602A1

WO2016034602A1 - Solid forms of (2s,4r)-4-[4-(1-methyl-1h-pyrazol-4-yl)-2-trifluoromethyl-benzenesulfonyl]-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide

Info

Publication number: WO2016034602A1
Application number: PCT/EP2015/069982
Authority: WO
Inventors: Bjoern Bartels; Philipp CUENI; Olaf Grassmann; Anne Thérèse Gustaaf DE PAEPE
Original assignee: F. Hoffmann-La Roche Ag; Hoffmann-La Roche Inc.
Priority date: 2014-09-05
Filing date: 2015-09-02
Publication date: 2016-03-10
Also published as: AR101750A1; TW201625593A

Abstract

The invention relates to a solid form and to a process for the preparation of this solid form as defined in the description and in the claims.

Description

Solid forms of (2S,4R -4-r4-(l-methyl-lH-pyrazol-4-yl -2-trifluoromethyl- benzenesulfonyll - 1 -( 1 -trifluoromethyl-cvclopropanecarbonyl)-pyrrolidine-2-carboxylic acid ( 1 -cvano-cyclopropyP-amide

The present invention relates to solid forms of (2S,4R)-4- [4- (1 -methyl- lH-pyrazol-4- yl)-2-trifluoromethyl-benzenesulfonyl] - 1 - ( 1 -trifluoromethyl-cyclopropanecarbonyl)- pyrrolidine-2-carboxylic acid (l-cyano-cyclopropyl)-amide (hereinafter "compound of formula (I)").

The invention further relates to a process for the preparation of solid forms of the compound of formula (I). The compound of formula (I) can be used as a thearpeuticaly active substance. It is described in WO 2010/121918. Up to know, the compound of formula (I) has been described only in amorphous form. This form is not suitable for further drug development. The need still exists for a less hygroscopic and thermodinamicaly stable solid form at ambient conditions of the compound of formula (I). This problem was surprisingly solved by the crystalline Form A of the compound of formula (I) (hereinafter designated "Form A").

As used herein, "solid form" denotes a material in the solid state as understood by the skilled person, and comprises in particular the amorphous solid state and the crystalline solid state. As used herein, "amorphous form" denotes a material that lacks long range order and as such does not show sharp X-ray diffraction peaks in its XRPD pattern. The XRPD pattern of an amorphous material is characterized by one or more amorphous halos.

As used herein, "ambient conditions" are conditions as experienced in a standard laboratory, e.g. atmospheric pressure, air, temperature between 18 °C and 28 °C, humidity between 30 %-RH and 80 %-RH.

DP/17.08.15 "Room temperature" defines a temperature between 18 °C and 28 °C.

In the present description, temperatures are given with an uncertainty in the measurement of + 2 °C. In this context, "ca." means approximately and therefore means + 2 °C. The amorphous form of the compound of formula (I) (also called Form Amorphous) is hygroscopic.

Form A is a slightly-hygroscopic solvent-free crystal form and has a melting temperature of approximately 208 °C (extrapol. peak DSC). The crystal structure of Form A has been solved. No phase transformation was observed after storage at 100 %-RH at ambient temperature for 4 months.

Form A is the thermodynamically stable known crystalline form of the compound of formula (I) at ambient temperature.

No conversion of Form A could be observed upon cooling to -150 °C (10 °C/min) or -50 °C (1 °C/min) and by heating to the melting region. Form A can be prepared by dissolving the compound of formula (I) in ethanol at a temperature above room temperature, in particular above 30 °C, above 40 °C, above 50 °C or at around 65 °C, and by cooling the mixture below 25 °C, in particular at around 22 °C.

The above process can be done in a closed vial.

The temperature above room temperature can be advantageously above 60 °C, in particular at around 65 °C.

The temperature at the end of the cooling is advantageously around 22 °C or can also be around room temperature.

The cooling is idealy done linearly, for example within 8 hours.

The cooling is also advantageously done without agitation. Form A can be isolated for example by filtration, rinsed with ethanol and dried.

In an alternative process, Form A can also be obtained by the crystallization of the compound of formula (I) from a mixture of ethanol/water.

The mixture of ethanol/water is advantageously l: l(v/v). The crystallization is advantageously done at ambient condition, in particular room temperature.

The crystals can be isolated by filtration, rinsed with the mixture of ethanol/water, in particular 1: 1 (v:v), and dried. Form A can also be prepared by evaporative crystallization, in particular as follows:

From ethanol, ethanol/water 95:5 (v/v), ethanol/water 85: 15 (v/v), ethanol/water 50:50 (v/v) or ethyl acetate, in particular at a temperature of around 65 °C;

From acetonitrile/water 50/50 (v/v) or dioxane, in particular at a temperature of around 60 °C; From ethanol, ethanol/water 90: 10 (v/v), ethanol/water 50:50 (v/v), ethyl acetate, acetone or dichloromethane, in particular at a temperature of around 30 °C; or

From methanol, DMF, NMP, nitromethane, acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, acetonitrile/water 85/15 (v/v), acetonitrile/water 80/20 (v/v), acetonitrile/water 50/50 (v/v), DMSO, THF, dioxane, dichloromethane, chloroform, dimethylcarbonate or acetic acid, in particular at ambient temperature.

Form A can also be prepared by anti-solvent crystallization with n-heptane, in particular at ambient temperature, from ethanol, acetone, methyl ethyl ketone, ethyl acetate, THF, dioxane, dichloromethane, chloroform or dimethylcarbonate.

The invention thus relates to a process for the manufacture of Form A comprising evaporating a solution of (2S,4R)-4-[4-(l-methyl-lH-pyrazol-4-yl)-2-trifluoromethyl- benzenesulfonyl] - 1 -( 1 -trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (l-cyano-cyclopropyl)-amide in a solvent selected from ethanol, ethanol/water 95:5 (v/v), ethanol/water 90: 10 (v/v), ethanol/water 85: 15 (v/v), ethanol/water 50:50 (v/v), ethyl acetate, acetonitrile/water 80/20 (v/v), acetonitrile/water 50/50 (v/v), dioxane, acetone, dichloromethane, methanol, DMF, NMP, nitromethane, methyl ethyl ketone, DMSO, THF, chloroform, dimethylcarbonate and acetic acid.

The evaporation can take place for example at a temperature between approximately 20 °C and approximately 60 °C, in particular at approximately 20 °C or 60 °C.

The invention thus further relates to a process for the manufacture of Form A comprising adding n-heptane to a solution of (2S,4R)-4-[4-(l-methyl-lH-pyrazol-4-yl)-2- trifluoromethyl-benzenesulfonyl] - 1 - ( 1 -trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine- 2-carboxylic acid (l-cyano-cyclopropyl)-amide in a solvent selected from ethanol, acetone, methyl ethyl ketone, ethyl acetate, THF, dioxane, dichloromethane, chloroform and dimethylcarbonate.

The addition of n-heptane can for example be done at room temperature.

The invention also relates to a solid form obtained by a process according to the invention.

Form A is characterized by by an X-ray powder diffraction pattern obtained with a Cu Kcc radiation having characteristic peaks expressed in degrees 2Theta at approximately (Cu Kcc radiation): 7.2, 8.7, 10.2, 15.3, 15.5, 16.1, 17.6, 17.7, 19.2, 20.5, 23.0, 23.7 and 24.3. The term "approximately" means in this context that there is an uncertainty in the measurements of the degrees 2Theta of + 0.2 (expressed in degrees 2Theta).

Form A can be furher characterized by an infrared spectrum having sharp bands at (cm-1, Nujol): 3259, 3048, 2247, 1672, 1631, 1605, 1572, 1537, 1487, 1432, 1353, 1329, 1301, 1270, 1219, 1204, 1180, 1129, 1100, 1074, 1035, 1019, 984, 976, 958, 937, 924, 898, 850, 843, 816, 800, 741, 734, 702, 688, 676, 670 and 659 (+ 2 cm-1).

Form A can be furher characterized by a Raman spectrum having sharp bands at: 3096, 3021, 2999, 2950, 2248, 1675, 1607, 1574, 1558, 1489, 1452, 1433, 1394, 1348, 1311, 1272, 1222, 1147, 1102, 1036, 986, 977, 900, 878, 817, 801, 776, 734, 671, 657, 627, 584, 501, 447, 418, 305, 270, 211, 130 and 61 (+ 3 cm-1). These characteristics and others are shown on Figures 1 to 3.

Figure 1 shows the X-ray powder diffraction pattern (Cu Kcc) of Form A.

Figure 2 shows the Infrared spectra (Nujol) of Form A.

Figure 3 shows the Raman spectra of Form A.

The invention thus relates to: A solid form of (2S,4R)-4- [4- (1 -methyl- lH-pyrazol-4-yl)-2-trifluoromethyl- benzenesulfonyl] - 1 -( 1 -trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (l-cyano-cyclopropyl)-amide characterized by an X-ray powder diffraction pattern obtained with a Cu Kcc radiation having characteristic peaks expressed in degrees 2Theta at approximately 8.7, 15.5, 17.6, 19.2 and 20.5; A solid form as defined above having characteristic peaks expressed in degrees 2Theta at approximately 7.2, 15.3, 16.1, 17.7 and 23.7;

A solid form as defined above having characteristic peaks expressed in degrees 2Theta at approximately 10.2, 23.0 and 24.3; A solid form as defined above characterized by an X-ray powder diffraction pattern obtained with a Cu Kcc as shown in Figure 1 ;

A process for the manufacture of a solid form as defined above comprising dissolving (2S,4R)-4- [4- (1 -methyl- lH-pyrazol-4-yl)-2-trifluoromethyl-benzenesulfonyl]- 1- ( 1 -trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid ( 1 -cyano- cyclopropyl)-amide in ethanol at a temperature above room temperature and by cooling the mixture below 25 °C;

The process as defined above wherein the temperature above room temperature is above 60 °C, in particular at around 65 °C;

A process for the manufacture of a solid form as defined above comprising the crystallization of the compound of formula (I) from a mixture of ethanol/water;

The process as defined above, wherein the mixture of ethanol/water is l: l(v/v);

A process for the manufacture of a solid form as defined above comprising evaporating a solution of (2S,4R)-4-[4-(l-methyl-lH-pyrazol-4-yl)-2-trifluoromethyl- benzenesulfonyl] - 1 -( 1 -trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (l-cyano-cyclopropyl)-amide in a solvent selected from ethanol, ethanol/water 95:5 (v/v), ethanol/water 90: 10 (v/v), ethanol/water 85: 15 (v/v), ethanol/water 50:50 (v/v), ethyl acetate, acetonitrile/water 80/20 (v/v), acetonitrile/water 50/50 (v/v), dioxane, acetone, dichloromethane, methanol, DMF, NMP, nitromethane, methyl ethyl ketone, DMSO, THF, chloroform, dimethylcarbonate and acetic acid; A process for the manufacture of a solid form as defined above comprising adding n- heptane to a solution of (2S,4R)-4-[4-(l-methyl-lH-pyrazol-4-yl)-2-trifluoromethyl- benzenesulfonyl] - 1 -( 1 -trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (l-cyano-cyclopropyl)-amide in a solvent selected from ethanol, acetone, methyl ethyl ketone, ethyl acetate, THF, dioxane, dichloromethane, chloroform and dimethylcarbonate; and

A solid form obtained by a process according to the invention. Form A can be used in the treatment of kidney diseases, in particular in the treatment of lupus nephritis.

The invention therefore also relates to Form A for use in the treatment of

autoimmune disorders or kidney diseases, in particular lupus nephritis.

The invention also relates to a method for the treatment of autoimmune disorders or kidney diseases, in particular lupus nephritis, comprising the administration of an effective amount of Form A to a patient in need thereof.

The invention further relates to the use of Form A in the treatment of autoimmune disorders or kidney diseases, in particular lupus nephritis.

The invention thus relates to a pharmaceutical composition comprising Form A.

The invention relates also to a solid form obtained by a process as described above.

The invention will now be illustrated by the following examples which have no limiting character.

Examples

X-ray analysis

X-ray diffraction patterns were recorded at ambient conditions in transmission geometry with a STOE STADI P diffractometer (Cu Ka radiation, primary monochromator, silicon strip detector, angular range 3° to 42° 2Theta, approximately 30 minutes total

measurement time). The samples were prepared and analyzed without further processing (e.g. grinding or sieving) of the substance.

IR analysis

The Nujol mull FTIR spectrum was collected using a ThermoNicolet 6700 FTIR spectrometer. The sample was prepared as a film of a Nujol suspension consisting of approximately 5 mg of sample and approximately 5 mg of Nujol (mineral oil) between two sodium chloride plates.

The spectral range is between 4000 cm-1 and 650 cm-1, resolution 2 cm-1 and at least 300 co-added scans are collected. Happ-Genzel apodization was used. Raman analysis

The FT- Raman spectrum was collected in the spectral range of 4000-50 cm-1 with a Bruker MultiRam FT- Raman spectrometer, equipped with a NdYAG 1064 nm laser and a liquid nitrogen cooled Germanium detector. The laser power at the sample was about 200mW, 2 cm-1 resolution was used and 512 scans were co-added. The apodization used was Blackman-Harris 4-term.

Example 1

Preparation of Form A

785 g of crude material (compound of formula (I)) were suspended in 3.12 L of ethanol at ambient temperature for 30 minutes. Then, 3.12 L of water were slowely added and the resulting mixture was agitated for 5 h at ambient temperature. The product was isolated by filtration and rinsed in multiple steps with a mixture of 1.01 L of ethanol and 1.01 L of water. The crystals were dried at 50 °C/<10 mbar for 65 h.

Example 2

Preparation of Form A 15 mg of the compound of formula (I) were dissolved in 0.3 mL of a mixture of ethanol/water 1: 1 at 65 °C in a closed vial. The clear solution was linearly cooled from 65 °C to 22 °C within 8 h without agitation. The product was isolated by removing the mother liquor with a pipette and analyzed in wet stage and after drying (50 °C/<20 mbar for >24 h).

Example 3

Evaporative crystallization experiments

Form A was dissolved in selected solvents and solvent mixtures at 20 °C and 60 °C.

Subsequently, the solvent or solvent mixture was allowed to evaporate at the respective temperature (20 °C or 60 °C). The experiment details and results are shown in Table 1.

All experiments led to Form A.

Table 1

drying conditions: 24 h @ 50 °C/<20 mbar

High humidity exposure

Form A was exposed to 100 %-RH at ambient temperature for 16 weeks. No phase transformation was observed by XRPD. The results are shown in Table 2.

Form Amorphous was exposed to 100 %-RH at ambient temperature for 6 weeks. Small amounts of crystalline Form A could be detected by XRPD. The results are shown in Table 12. Table 2

Example 5

Vapor-induced recrystallization of amorphous material Form Amorphous was exposed to ethanol vapor at ambient temperature for 6 weeks. Phase transformation into Form A was observed by XRPD (shown in Table 3).

Table 3

Exposure time

Starting material Solvent Amount of API [mg] XRPD Result

[weeks]

Form Amorphous Ethanol 90.0 approx. 6 Form A

Claims

1. A solid form of (2S,4R)-4- [4- (1 -methyl- lH-pyrazol-4-yl)-2-trifluoromethyl- benzenesulfonyl] - 1 -( 1 -trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2- carboxylic acid (l-cyano-cyclopropyl)-amide characterized by an X-ray powder diffraction pattern obtained with a Cu Kcc radiation having characteristic peaks expressed in degrees 2Theta at approximately 8.7, 15.5, 17.6, 19.2 and 20.5.

2. A solid form according to claim 1 having characteristic peaks expressed in degrees 2Theta at approximately 7.2, 15.3, 16.1, 17.7 and 23.7.

3. A solid form according to claim 1 or 2 having characteristic peaks expressed in

degrees 2Theta at approximately 10.2, 23.0 and 24.3.

4. A solid form according to any one of claims 1 to 3 characterized by an X-ray powder diffraction pattern obtained with a Cu Kcc as shown in Figure 1.

5. A process for the manufacture of a solid form according to any one of claims 1 to 4 comprising dissolving (2S,4R)-4- [4- (1 -methyl- lH-pyrazol-4-yl)-2-trifluoromethyl- benzenesulfonyl] - 1 -( 1 -trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2- carboxylic acid (l-cyano-cyclopropyl)-amide in ethanol at a temperature above room temperature and by cooling the mixture below 25 °C.

6. A process according to claim 5, wherein the temperature above room temperature is above 60 °C, in particular at around 65 °C.

7. A process for the manufacture of a solid form according to any one of claims 1 to 4 comprising the crystallization of the compound of formula (I) from a mixture of ethanol/water.

8. The process according to claim 7, wherein the mixture of ethanol/water is l: l(v/v).

9. A process for the manufacture of a solid form according to any one of claims 1 to 4 comprising evaporating a solution of (2S,4R)-4-[4-(l-methyl-lH-pyrazol-4-yl)-2- trifluoromethyl-benzenesulfonyl] - 1 - ( 1 -trifluoromethyl-cyclopropanecarbonyl)- pyrrolidine-2-carboxylic acid (l-cyano-cyclopropyl)-amide in a solvent selected from ethanol, ethanol/water 95:5 (v/v), ethanol/water 90: 10 (v/v), ethanol/water 85: 15 (v/v), ethanol/water 50:50 (v/v), ethyl acetate, acetonitrile/water 80/20 (v/v), acetonitrile/water 50/50 (v/v), dioxane, acetone, dichloromethane, methanol, DMF,

NMP, nitromethane, methyl ethyl ketone, DMSO, THF, chloroform,

dimethylcarbonate and acetic acid.

10. A process for the manufacture of a solid form according to any one of claims 1 to 4 comprising adding n-heptane to a solution of (2S,4R)-4-[4-(l-methyl-lH-pyrazol-4- yl)-2-trifluoromethyl-benzenesulfonyl] - 1 - ( 1 -trifluoromethyl-cyclopropanecarbonyl)- pyrrolidine-2-carboxylic acid (l-cyano-cyclopropyl)-amide in a solvent selected from ethanol, acetone, methyl ethyl ketone, ethyl acetate, THF, dioxane, dichloromethane, chloroform and dimethylcarbonate.

11. A solid form obtained by a process according to any one of claims 5 to 10.

12. A solid form according to any one of claims 1 to 4 for use in the treatment of

autoimmune disorders or kidney diseases, in particular lupus nephritis.

13. A pharmaceutical composition comprising a solid form according to any one of claims 1 to 4.

14. A method for the treatment of autoimmune disorders or kidney diseases, in particular lupus nephritis, comprising the administration of an effective amount of a solid form according to any one of claims 1 to 4 to a patient in need thereof.

15. The use of a solid form according to any one of claims 1 to 4 in the treatment of autoimmune disorders or kidney diseases, in particular lupus nephritis.

16. The invention as hereinbefore described.

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