Particles of l-arginine salt of etrasimod

Abstract

The present invention relates to particles of L-arginine salt of compound of formula (1)

Description

[0001] P1828EP00

[0002] PARTICLES OF L- ARGININE SALT OF ETRASIMOD

[0003] The invention relates to particles of L-arginine salt of etrasimod, compound of the formula (1), and to a process for making particles of L-arginine salt of etrasimod:

[0004]

[0005] BACKGROUND OF THE PRESENT INVENTION

[0006] Etrasimod, (R)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydro-cyclopenta[b]indol-3-yl)acetic acid, is a potent sphingosine 1-phosphate (SIP) receptor modulator. Etrasimod is approved for use in the treatment of moderately to severely active ulcerative colitis in adults.

[0007] W02010011316 discloses etrasimod compound as well as its calcium and L-arginine salts and crystal form.

[0008] WO2011094008 discloses a method for preparation of L-arginine salt of etrasimod by a process employing enzymatic hydrolysis of etrasimod aliphatic ester.

[0009] WO2016209809 discloses methods for preparation of a crystalline plate morphology of the L-arginine salt of etrasimod using an enzymatic hydrolysis of the etrasimod aliphatic ester followed by a modified L-arginine salt-forming procedure compared to WO2011094008 disclosure. WO2016209809 teaches that procedures of WO2011094008 provide an L-arginine salt of etrasimod in crystal habit consisting of thin plates or flakes that are clustered in a radial manner around a nucleation site described as spherulites in reference examples with a BET surface area of from 10 m2g1to 13.5 m2g '. This particular morphology with such high BET surface area renders the material to be difficult to filter on a commercial scale,to be prone to degradation, particles are hygroscopic and provide for pharmaceutical formulations with reduced stability. WO2016209809 only partially addressed the dis-advantageous properties of the radial clusters by providing a lengthy method for preparation of nonassociated thin plates. However, the plate morphology described is very brittle to the extend that a complete unbroken plate is rarely seen and exhibits diminished flowability and poor pharmaceutical processability.

[0010] According to prescribing information for Velsipity® medicinal product, etrasimod is supplied as film-coated tablet containing L-arginine salt of etrasimod equivalent to 2 mg etrasimod.

[0011] The prior art discloses L-arginine salt of etrasimod in forms which are hygroscopic, difficult to isolate by filtration, chemically and mechanically unstable, and limit formulation of L-arginine salt of etrasimod into a stable low dose medicinal product.

[0012] Therefore, there is still a need for forms of L-arginine salt of etrasimod with advantageous properties for use in medicaments.

[0013] BRIEF DESCRIPTION OF THE INVENTION

[0014] The present invention is directed to an isometric particle of L-arginine salt of etrasimod characterized by a specific surface area of from 0.1 m2g1to 5 m2g1and process for making thereof.

[0015] BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of spray dried L-arginine salt of etrasimod according to the Example 3, spray dryer setting # 7.

[0017] Figure 2 depicts the optical microscope image of the spray dried L-arginine salt of etrasimod according to the Example 3, spray dryer setting # 7.Figure 3 depicts the scanning electron microscope image of the spray dried L-arginine salt of etrasimod according to the Example 3, spray dryer setting # 7.

[0018] Figure 4 depicts the scanning electron microscope image of the spray dried L-arginine salt of etrasimod according to the Example 3, spray dryer setting # 7.

[0019] Figure 5 depicts the scanning electron microscope image of the spray dried L-arginine salt of etrasimod according to the Example 3, spray dryer setting # 7 , which has been tapped.

[0020] Figure 6 depicts the scanning electron microscope image of L-arginine salt of etrasimod in the free-plate habit prepared according to WO2016209809 (Example 3), which has been tapped.

[0021] Figure 7 depicts the scanning electron microscope image of the suspended particles of L-arginine salt of etrasimod according to the

[0022] Example 1.

[0023] Figure 8 depicts the scanning electron microscope image of the suspended particles of L-arginine salt of etrasimod according to the

[0024] Example 1.

[0025] Figure 9 depicts the scanning electron microscope image of the spray dried L-arginine salt of etrasimod according to theExample 6 and spray drying setup according to

[0026] Table 2 entry # 3.

[0027] Figure 10 depicts the scanning electron microscope image of the spray dried L-arginine salt of etrasimod according to theExample 6 and spray drying setup according to

[0028] Table 2 entry # 4.

[0029] Figure 11 depicts the X-Ray Powder Diffractogram (XRPD) of spray dried L-arginine salt of etrasimod according to theExample 6, spray dryer setting # 10.

[0030] DETAILED DESCRIPTION OF THE INVENTION

[0031] The present invention is directed to an isometric particle of L-arginine salt of etrasimod and a processes for making thereof.

[0032] The compound with the international nonproprietary name etrasimod, chemically (R)-2-(7-(4-cyclopentyl-3- (trifluoromethyl)benzyloxy)-l,2,3,4- tetrahydrocyclopenta[b]indol-3-yl)acetic acid, is a potent therapeutically active compound. Typically, the potent therapeutic-cally active compounds are formulated into a medicinal product, which in majority consists of therapeutically inactive pharmaceutical inactive ingredient and in minority of the active ingredient. Etrasimod was formulated as a solid medicinal product, specifically as a film-coated tablet containing L-arginine salt of etrasimod equivalent to 2 mg etrasimod.

[0033] The particles of L-arginine salt of etrasimod exhibit unique solid state properties, which render the use of the L-arginine salt of etrasimod in providing for a low dose medicament, suitable for a treatment of life threatening conditions, cumbersome and not straightforward, particularly on a commercial scale. The properties include but are not limited to a shape, a size, a specific surface area, and brittleness of particles of the L-arginine salt of etrasimod and a chemical instability of the L-arginine salt of etrasimod typically when heated or in the presence of water or air.

[0034] The L-arginine salt of etrasimod is poorly soluble in aqueous media across the physiological pH range and is regarded as BCS class II. Thus, the bioavailability of etrasimod is limited by a solvation rate of L-arginine salt of etrasimod. The solvation rate is most profoundly determined by a particle size and hence by a surface area of an active ingredient. On the one hand, a lower particle size and a higher surface area can improve the solvation rates and bioavailability of L-arginine salt of etrasimod. On the other, the particle size and thesurface area of the particles determine chemical and more importantly physical and mechanical properties of the medicaments. The brittleness refers to the tendency of a material to fracture or break easily under stress. A highly brittle particles of L-arginine salt of etrasi-mod are more likely to break into smaller fragments during processing, such as milling or grinding. Typically, the fractures occur along the planes of weakness in the particle structure. A high amount of small particles with a high surface area negatively influence stability and flow properties of L-arginine salt of etrasimod. Thus, the stability and the flow properties of L-arginine salt of etrasimod must be carefully managed to ensure that the final medicinal product with adequate bioavailability as well as low variability in bioavailability of etrasimod is obtained.

[0035] Surprisingly, despite of the teachings of the prior art the present inventors have found a process that provides an isometric particle of L-arginine salt of etrasimod with a BET surface area of 0.1 m2g1to

[0036]

[0037] 5 m2g which is on the one hand stable and resilient to chemical degradation and to mechanical stress and has powder properties allowing for straightforward pharmaceutical processing of a low dose medicament on a commercial scale, and on the other provides for the medicaments with desired and robust bioavailability.

[0038] Typically particle shapes are characterized as isometric or anisometric by relative ratios of the particle dimensions. The dimensions comprise a length, a width, and a thickness. The length in the context of the particle shape refers to the longest dimension from edge to edge of a particle oriented parallel to the ocular scale. The width and the thickness in the context of the particle shape refers to the longest dimensions of the particle measured at right angles to the length and at right angle to each other. The isometric particles have dimensions in each of the three axes of measurement which are approximately the same. For example, they have dimensions in the three axes such that the difference between the largest and the smallest measurement is not more than 50 % of the smallest. Typically, the isometric particles arespherical, cubical, and like in shape, but may be in the shape of less regular, but isometric, granules. The material of the particles can be arranged such that it fills the volume of the particle completely or partially. The anisometric particles can be for example rod like or needle-like with a similar width and thickness but with greater length, or plate-like with a similar length and width but with smaller thickness.

[0039] The present invention relates to an isometric particle of L-arginine salt of etrasimod. In a particular embodiment, the particle is spherical.

[0040] The flow properties as well as a chemical instability of particles can be related to a specific surface area of the particles. A higher specific surface area of the particles can exacerbate poor flow properties, since the increased surface area allows for higher interparticulate friction. Moreover, the increased surface area allows for an increased interaction with external environment including for example water and air, which can diminish the chemical instability of particles. The particles can be characterized by a specific surface area as for example measured by a gas absorption techniques using BET method for evaluation. The specific surface area could range from 0.1 m2g1to 20 m2g '. Accordingly, the specific surface area values disclosed in the present invention have been obtained by means of a specific surface area analysis technique based on the BET (Brunauer, Emmett and Teller) theory, which is a well-accepted theory known in the art for the calculation of surface areas of solids by means of measuring their physical adsorption of gas molecules (see: Brunauer, S.; Emmett, P. H.; and Teller, E.; / . Am. Chem. Soc, 1938, 60, 309). In particular, the specific surface area values measured in the present invention have been calculated from the BET surface area plot obtained by measuring the quantity of nitrogen gas molecules adsorbed by a weighted amount of solid at different relative pressures (P / Po) within the range 0.05-0.3 (P / Po), at 77.3 K. The measurement of the adsorption of gas molecules was carried out by means of a Quantachrome Autosorb iQ MP AG gas sorption analyzer or equivalent.Nitrogen gas was used for the adsorption measurement. The sample for each analysis was degassed at 25 °C for 960 minutes under vacuum (i.e.100 mm / Hg). The determination of the adsorption of nitrogen was measured at 77.3 K at eleven relative pressures (P / Po) sufficiently dispersed within the range of about 0.05 to about 0.30 (i.e. eleven absolute pressures in the range of about 36 mm Hg to about 223 mm Hg relative to the saturated pressure at the time of measurement that ranged from about 738 mmHg to about 743 mmHg).

[0041] The isometric particle of the present invention is characterized by a specific surface area of from 0.1 m2g1to 5 m2g1.

[0042] In one embodiment, the particle is characterized by a specific surface area of from 0.1 m2g1to 2 m2g '.

[0043] In another embodiment, the particle is characterized by a specific surface area of from 1 m2g1to 2 m2g '.

[0044] In another embodiment, the particle is characterized by a specific surface area of from 2 m2g1to 5 m2g '.

[0045] The particle size could be characterized by a median diameter D(50) of about 200 micrometers, of about 150 micrometers, of about 125 micrometers, of about 100 micrometers, of about 70 micrometers, of about 65 micrometers, of about 60 micrometers, of about 55 micrometers, of about 50 micrometers, of about 45 micrometers, of about 40 micrometers, of about 35 micrometers, of about 30 micrometers, of about 25 micrometers, or of about 20 micrometers. As used herein, the term D(50) has its conventional meaning as known to the person skilled in the art and can be measured by art-known particle size measuring techniques such as, for example, sedimentation field flow fractionation, photon correlation spectroscopy, laser diffraction or disk centrifugation. Specifically, a Malvern Instruments Mastersizer is used to determine the particle size distribution by laser diffraction. The D(50) mentioned herein may be related to volume distributions of the particles. In that instance, by "a D(50) of50 micrometers" it is meant that at least 50% of the volume of the particles has a particle size of less than 50 micrometers. The same applies to the other particle sizes mentioned. In a similar manner, the D(50) particle size may be related to weight distributions of the particles. In that instance, by "D(50) of 50 micrometers " it is meant that at least 50% of the weight of the particles has a particle size of less than 50 micrometers. The same applies to the other particle sizes mentioned. Usually volume and weight distribution result in the same or about the same value for the average particle size. The particle size could be an important factor determining the tableting speed, in particular the flowability and therefore the manufacturability on a large scale of a particular dosage form or formulation, and the quality of the final product. For instance, for capsules, the particle size may range preferably from about 100 to about 1500 micrometers (D(50)); for tablets the particle size is preferably less than 250 micrometers, more preferably less than 100 micrometers (D(50)). Typically, too small particles cause sticking on the tablet punches and manufacturability issues.

[0046] The particles obtained by spray drying have preferably a D(50) value falling in the range from about 10 micrometers to about 100 micrometers, more preferably in the range from about 15 micrometers to about 70 micrometers, even more preferably in the range of from about 20 micrometers, to about 60 micrometers.

[0047] The spherical particles can be also characterized by a diameter obtained for example by inspection of the particles by optical microscopy. The diameter can be from 5 micrometers to 100 micrometers, preferably from 10 micrometers to 75 micrometers, more preferably from 15 micrometers to 65 micrometers, even more preferably from 20 micrometers to 60 micrometers.

[0048] In one embodiment, the particle has a diameter from 10 to 75 micrometers.

[0049] The particle may be a single crystal, a part of single crystal, or an agglomeration of material with irregular internal structure of atoms or molecules.In one embodiment, the particle is crystalline.

[0050] In another embodiment, the particle is amorphous.

[0051] The particle can be characterized by XRPD pattern having 29 value of 2.8 degrees 2 theta (± 0.2 degrees 2 theta). The particle can be also characterized by XRPD pattern having 29 values of 2.8, 8.1, 11.9, 13.8, 19.0, and 20.1 degrees 2 theta (± 0.2 degrees 2 theta). The particle can be further characterized by XRPD pattern describe in the following table:

[0052] Angle (2-Theta °) Intensity (%) Angle (2-Theta °) Intensity (%) 2.40 100 16.66 53

[0053] 8.09 42 18.99 79 11.50 35 19.53 73 11.86 47 20.04 78 12.42 42 20.41 97 12.86 41 20.78 87 13.08 39 21.95 73 13.82 40 22.50 70 14.62 42 23.15 67 15.59 45 23.77 54 16.09 44 24.58 49 16.43 52 25.09 40

[0054]

[0055] The particle can be also characterized by XRPD pattern depicted in Figure 1.

[0056] When formulating a solid low dose medicament, ensuring good flow properties of pharmaceutical ingredients is essential for achieving consistent content uniformity in the final medicinal form. The anisometric particles of the rod-like shape and the plate-like shape influence the flow properties of the pharmaceutical ingredient negatively. Poor flowproperties of anisometric particles can lead to production issues, such as segregation of particles during blending of particulate pharmaceutical ingredient, resulting in uneven distribution of the active pharmaceutical ingredient within blends. The blended mixture inhomogeneities lead to poor contents uniformity of the final product. The particles of L-arginine salt of etrasimod can be mixed with one or more pharmaceutically acceptable excipients in accordance with the present invention. Those can be chosen from, for example, fillers, binders, disintegrants, lubricants and glidants.

[0057] The present invention also relates to a process for the preparation of a particle of L-arginine salt of etrasimod comprising:

[0058] a) Providing a mixture of a first solvent and water;

[0059] b) Mixing L-arginine salt of etrasimod with the mixture provided in the step a); c) Heating the mixture provided in the step b) to obtain a solution;

[0060] d) Adding a second solvent to the solution provided in the step c);

[0061] e) Spray-drying the mixture provided in the step d).

[0062] In one embodiment, the first solvent is miscible with water.

[0063] The firsts solvent can be mixed with water in a weight based ratio of water to the first solvent of from 1:1 to 1:10, preferably from 1:2 to 1:7, more preferably form 1:3 tol:6.

[0064] In one embodiment, water is mixed with the first solvent in water to the first solvent weight based ratio from 1 : 1 to 1 : 10.

[0065] The first solvent can be an alcohol, a ketone, or an ether or the mixture thereof. The alcohol can be selected from for example methanol, ethanol, 1 -propanol, 2-propanol, 1-butanol, 2-butanol, or tert-butyl alcohol, preferably 2-propanol. The ketone can be selected from for example acetone or 2-butanone, preferably acetone. The ether can be selected from for example tetrahydrofuran, 1,4-di oxane, or 1,2-dimethoxy ethane. The first solvent can be also acetonitrile, dimethylformamide, or dimethyl sulfoxide.In one embodiment, the first solvent is 2-propanol.

[0066] In another embodiment, the first solvent is acetone.

[0067] The L-arginine salt of etrasimod is mixed with a mixture of the first solvent and water. The L-arginine salt of etrasimod can be mixed with the mixture in a weight based ratio of L-arginine salt of etrasimod to the mixture of from 1 :2 to 1:10, preferably from 1 :4 to 1:8, more preferably from 1:5 to 1:7.

[0068] In one embodiment, L-arginine salt of etrasimod is mixed with a mixture of the first solvent and water in a weight based ratio of L-arginine salt of etrasimod to the mixture of from 1:4 to 1:8.

[0069] The mixture of L-arginine salt of etrasimod is heated to obtain a solution. The mixture can be heated to from 30 °C to 90 °C, preferably from 35 °C to 85 °C, more preferably from 40 °C to 80 °C, and even more preferably from 50 °C to 75 °C.

[0070] In one embodiment, a mixture of mixture of L-arginine salt of etrasimod is heated at a temperature from 35 °C to 85 °C.

[0071] In another embodiment, a mixture of mixture of L-arginine salt of etrasimod is heated at a temperature from 40 °C to 80 °C.

[0072] In another embodiment, a mixture of mixture of L-arginine salt of etrasimod is heated at a temperature from 50 °C to 75 °C.

[0073] The second solvent is added to the mixture of L-arginine salt of etrasimod with the first solvent and water.

[0074] In one embodiment, the second solvent is miscible with the mixture of the first solvent and water.

[0075] The second solvent can be an alcohol, a ketone, or an ether or the mixture thereof. The alcohol can be selected from for example methanol, ethanol, 1 -propanol, 2-propanol, 1-butanol, 2-butanol, or tert-butyl alcohol, preferably 2-propanol. The ketone can be selectedfrom for example acetone or 2-butanone, preferably acetone. The ether can be selected from for example tetrahydrofuran, 1,4-di oxane, or 1,2-dimethoxy ethane. The second solvent can be also acetonitrile, dimethylformamide, or dimethyl sulfoxide.

[0076] In one embodiment, the second solvent is 2-propanol.

[0077] In another embodiment, the second solvent is acetone.

[0078] The second solvent is added to a stirred solution of L-arginine salt of etrasimod in the first solvent and water. The second solvent can be added at a rate of from 0.1 ml min1to 20 ml min preferably from 0.5 ml min1to

[0079]

[0080] 10 ml min more preferably from 1 ml min1to 2 ml min '.

[0081] In one embodiment, the second solvent is added to the solution of L-arginine salt of etrasimod in the first solvent and water at a rate from 0.5 ml min1to 10 ml min1.

[0082] In another embodiment, the second solvent is added to the solution of L-arginine salt of etrasimod in the first solvent and water at a rate from 1 ml min1to 2 ml min1.

[0083] The second solvent can be added at a temperature of the stirred solution or lower, preferably at the temperature of from 15 °C to 85 °C, preferably from 15°C to 75°C, more preferably at from 15°C to 55 °C, and even more preferably at from 15°C to 35°C.

[0084] In one embodiment, the second solvent is added at a temperature from 15°C to 75°C. In another embodiment, the second solvent is added at a temperature from 15°C to 55°C. In another embodiment, the second solvent is added at a temperature from 15°C to 45°C. The mixture of L-arginine salt of etrasimod, the first solvent, water, and the second solvent can be homogenous solution, heterogeneous suspension, or heterogeneous colloid suspension.

[0085] In one embodiment, the mixture of L-arginine salt of etrasimod, the first solvent, water, and the second solvent is heterogeneous suspension.The mixture of L-arginine salt of etrasimod, the first solvent, water, and the second solvent can be cooled to a temperature of from 15 °C to 85 °C, preferably from 15 °C to 75 °C, more preferably at from 15°C to 55 °C, and even more preferably at from 15 °C to 35 °C.

[0086] In one embodiment, the mixture of L-arginine salt of etrasimod, the first solvent, water, and the second solvent is cooled to a temperature from 15 °C to 75 °C.

[0087] In another embodiment, the mixture of L-arginine salt of etrasimod, the first solvent, water, and the second solvent is cooled to a temperature from 15 °C to 55 °C.

[0088] In another embodiment, the mixture of L-arginine salt of etrasimod, the first solvent, water, and the second solvent is cooled to a temperature from 15 °C to 35 °C.

[0089] The mixture of L-arginine salt of etrasimod, the first solvent, water, and the second solvent can be let to cool spontaneously or can be cooled at a rate of 0.1 °C min preferably 0.5 °C min more preferably 2 °C min and even more preferably 5 °C min '.

[0090] In one embodiment, the mixture of L-arginine salt of etrasimod, the first solvent, water, and the second solvent is cooled spontaneously.

[0091] The cooled mixture of L-arginine salt of etrasimod, the first solvent, water, and the second solvent can be stirred for from 0.1 h to 24 h, preferably from 0.5 h to 12 h, more preferably from 0.5 h to 6 h, even more preferably from 0.5 h to 3 h. The cooled mixture of L-arginine salt of etrasimod, the first solvent, water, and the second solvent can be stirred by all means known to the skilled person. The suspension can be also homogenized by highspeed dispersing instrument.

[0092] In one embodiment, the cooled mixture of L-arginine salt of etrasimod, the first solvent, water, and the second solvent is stirred for from 0.5 h to 12 h.

[0093] The mixture of L-arginine salt of etrasimod in the first solvent, water, and the second solvent is spray dried in a flow of an inert gas, preferably nitrogen. The temperature of thegas inlet can be from 70 °C to 140 °C, preferably from 80 °C to 130 °C, more preferably from 90 °C to 120 °C.

[0094] In one embodiment, a temperature of the gas inlet is from 70 °C to 140 °C.

[0095] In another embodiment, a temperature of the gas inlet is from 80 °C to 130 °C.

[0096] The temperature of the gas outlet can be from 50 °C to 130 °C, preferably from 65 °C to 115 °C, more preferably from 80 °C to 105 °C.

[0097] In one embodiment, a temperature of the gas outlet is from 50 °C to 130 °C.

[0098] In another embodiment, a temperature of the gas outlet is from 65 °C to 115 °C.

[0099] The present invention also relates to a process for the preparation of a particle of L-arginine salt of etrasimod comprising:

[0100] a) Providing a mixture of a solvent and water;

[0101] b) Mixing L-arginine salt of etrasimod with the mixture provided in the step a); c) Spray-drying the mixture provided in the step b).

[0102] In one embodiment, the solvent is miscible with water.

[0103] The solvent can be mixed with water in a weight based ratio of water to the solvent of from 1:1 to 1:20, preferably from 1:2 to 1:10, more preferably form 1:3 tol:6.

[0104] In one embodiment, water is mixed with the solvent in water to the solvent weight based ratio from 1 : 1 to 1 :20.

[0105] In another embodiment, water is mixed with the solvent in water to the solvent weight based ratio from 1:2 to 1:10.

[0106] In another embodiment, water is mixed with the solvent in water to the solvent weight based ratio from 1 :3 to 1 :6.

[0107] The solvent can be an alcohol, a ketone, or an ether or the mixture thereof. The alcohol can be selected from for example methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol, 2-butanol, or tert-butyl alcohol, preferably 2-propanol. The ketone can be selected from forexample acetone or 2-butanone, preferably acetone. The ether can be selected from for example tetrahydrofuran, 1,4-di oxane, or 1,2-dimethoxy ethane. The first solvent can be also acetonitrile, dimethylformamide, or dimethyl sulfoxide.

[0108] In one embodiment, the solvent is 2-propanol.

[0109] In another embodiment, the solvent is acetone.

[0110] The mixture of the solvent and water can be set to a temperature of from 0 °C to 60 °C, preferably from 10 °C to 50 °C, more preferably from 15 °C to 45 °C, and even more preferably from 20 °C to 40 °C.

[0111] In one embodiment, the mixture of the solvent and water is set to a temperature of from 10 °C to 50 °C.

[0112] The L-arginine salt of etrasimod is mixed with the mixture of the solvent and water to form a mixture having a weight-based concentration of the L-arginine salt of etrasimod of from 1 % to 15 %, preferably from 4 % to 12 %, more preferably from 5 % to 10 %.

[0113] In one embodiment, L-arginine salt of etrasimod is mixed with the mixture of the solvent and water to form the mixture having a weight-based concentration of the L-arginine salt of etrasimod of from 4 % to 12 %.

[0114] The mixture of L-arginine salt of etrasimod with the mixture of the solvent and water can be set to a temperature of from 0 °C to 60 °C, preferably from 10 °C to 50 °C, more preferably from 15 °C to 45 °C, and even more preferably from 20 °C to 40 °C.

[0115] In one embodiment, the mixture of L-arginine salt of etrasimod with the mixture of the solvent and water is set to a temperature of from 10 °C to 50 °C.

[0116] The mixture of L-arginine salt of etrasimod, the solvent, and water can be homogenous solution, heterogeneous suspension, or heterogeneous colloid suspension.

[0117] In one embodiment, the mixture of L-arginine salt of etrasimod, the solvent, and water is heterogeneous suspension.In one embodiment, the mixture of L-arginine salt of etrasimod, the solvent, and water is homogeneous solution.

[0118] The mixture of L-arginine salt of etrasimod, the solvent, and water can be stirred for from 0.1 h to 24 h, preferably from 0.5 h to 12 h, more preferably from 0.5 h to 6 h, even more preferably from 0.5 h to 3 h. The mixture of L-arginine salt of etrasimod, the first solvent, water, and the second solvent can be stirred by all means known to the skilled person. The mixture of L-arginine salt of etrasimod, the solvent, and water can be also homogenized by high-speed dispersing instrument.

[0119] In one embodiment, the mixture of L-arginine salt of etrasimod, the solvent, and water is homogenized by high-speed instrument.

[0120] The mixture of L-arginine salt of etrasimod, the solvent, and water is spray dried in a flow of an inert gas, preferably nitrogen. The temperature of the gas inlet can be from 70 °C to 140 °C, preferably from 80 °C to 130 °C, more preferably from 90 °C to 120 °C.

[0121] In one embodiment, a temperature of the gas inlet is from 70 °C to 140 °C.

[0122] In another embodiment, a temperature of the gas inlet is from 80 °C to 130 °C.

[0123] In another embodiment, a temperature of the gas inlet is from 90 °C to 120 °C.

[0124] The temperature of the gas outlet can be from 35 °C to 75 °C, preferably from 40 °C to 65 °C, more preferably from 40 to 60 °C.

[0125] In one embodiment, a temperature of the gas outlet is from 35 °C to 75 °C.

[0126] In another embodiment, a temperature of the gas outlet is from 40 °C to 65 °C.

[0127] In another embodiment, a temperature of the gas outlet is from 40 °C to 60 °C.

[0128] EXAMPLES

[0129] Nuclear magnetic resonance spectroscopy (NMR) was performed using Avance III 400 MHz NMR spectrometer.XRPD spectrum was obtained using the following measurement conditions: Panalytical Empyrean diffractometer with 0 / 20 geometry (transmission mode), equipped with a PixCell 3D detector:Start angle (20): 2.0°

[0130] End angle (20): 35.0°

[0131] Step size: 0.026°

[0132] Scan speed: 0.0955 “ / seconds

[0133] Radiation type: Cu

[0134] Radiation wavelengths: 1.5406A (Kai), primary monochromator used

[0135] Divergence slit: 1 / 2°

[0136] Antiscatter slit: 1 / 2°

[0137] Seller slit: 0.02 rad

[0138] Detector slit: 7.5 mm

[0139] Rotation speed: 30 rpm

[0140] Spray drying was done using Biichi Mini Spray Dryer B-290. All operations were carried over under a protective atmosphere of an inert gas. Typically nitrogen gas was employed. The solvents were deoxygenated prior use by methods known to a person skilled in the art.

[0141] The L-arginine salt of etrasimod was obtained by reworking the examples of the prior art WO2011094008.

[0142] Example 1 2-propanol / water mixture for spray-drying

[0143] The L-arginine salt of etrasimod (5 g, 7.915 mmol) was charged into three-neck 250 mL round bottom flask and a mixture of 2-propanol (31.8 mL) and water (7.00 mL) was added. The mixture was heated to 75 °C and yellowish solution was obtained. To the solution, 2-propanol (96 mL) was added such that the solution temperature of 70 °C is maintained. After the addition, the mixture was stirred and let to reach ambient temperature. The resultingsuspension was homogenized by overhead homogenizer (IKA Turrax) set to 20000 revolutions per minute for 5 min and then was used directly for spray drying. The suspended particles have been analyzed and subjected to the stability test according to Example 7.

[0144] Example 2 Acetone / water mixture for spray-drying

[0145] The L-arginine salt of etrasimod (10 g) was charged into three-neck 250 mL round bottom flask and a mixture of acetone (65 ml) and water (9.5 ml) was added. The mixture was heated to 50 °C and yellowish solution was obtained. To the solution, acetone (76.6 ml) was added yielding yellow solution at the end of addition. The mixture was seeded with crushed starting L-arginine salt of etrasimod, stirred, and let to reach ambient temperature. The resulting suspension was used directly for spray drying. The suspended particles have been analyzed and subjected to the stability test according to Example 7.

[0146] Example 3 Spray drying

[0147] The settings for each experiment are provided in Table 1. The mixtures of L-arginine salt of etrasimod in solvent mixtures prepared according to

[0148] Example 1 or Example 2 were used as an input for spray drying. The suspensions were sprayed by two-fluid nozzle into a chamber, which is supplied with an additional hot nitrogen flow. The droplets were transported by the nitrogen, while getting dried. The particles were collected in product collection vessel when the solvent within the droplets was fully vaporized. Condenser was set to 0 °C, aspiration to 100% for all experiments.

[0149] Table 1

[0150] Spray dryer setting # Solvent Tin / °C Tout / °C Pump / % Flow / mm 1 2-propanol 110 93 20 30 2 2-propanol 110 92 20 20 3 2-propanol 110 90 30 30

[0151]

[0152] Spray dryer setting # Solvent Tin / °C Tout / °C Pump / % Flow / mm 4 2-propanol 110 92 15 25 5 2-propanol 110 91 20 20 6 acetone 100 82 25 30 7 acetone 100 83 25 25 8 acetone 105 87 25 20 9 2-propanol 125 102 25 22 10 2-propanol 120 95 25 22

[0153]

[0154] The particles prepared using spray drier settings # 7 and # 8 had specific surface area of 1.67 m2g1and 1.55 m2g1as found by BET analysis.

[0155] Example 4

[0156] Water (62.5 g) was mixed with 2-propanol (187.5 g). The solvent mixture (45.2 g) was heated to 39°C and L-arginine salt of etrasimod (5.0 g) was added. The obtained solution was spray dried at the spray dryer setting according to

[0157] Table 2 entry # 14. The spray dried material was collected and dried under vacuum at 80°C for 18 hours. The product was analyzed by XRPD, HPLC, SEM and BET.

[0158] Example 5

[0159] Water (50.0 g) was mixed with 2-propanol (200.2 g). The solvent mixture (45.0 g) was mixed with L-arginine salt of etrasimod (5.0 g). The mixture was heated to 45°C and was homogenized by overhead homogenizer (IKA Turrax) set to 10000 revolutions per minute for 10 min. The obtained suspension was spray dried at the spray dryer setting according toTable 2 entry # 18. The spray dried material was collected and dried under vacuum at 80°C for 18 hours. The product was analyzed by XRPD, HPLC, SEM and BET.Example 6 Spray drying

[0160] The settings for each experiment are provided in

[0161] Table 2. The mixtures of L-arginine salt of etrasimod, solvent, and water according to

[0162] Table 2 entries # 1-17, and according to

[0163] Table 2 entry # 19 were prepared by adapting the procedure of The particles prepared using spray drier settings # 7 and # 8 had specific surface area of 1.67 m2 g1and 1.55 m2 g1as found by BET analysis.

[0164] Example 4 and were used for spray drying. The mixture of L-arginine salt of etrasimod, solvent, and water according to

[0165] Table 2 entry # 18 was prepared according to Example 5 and was used for spray drying. The mixtures were sprayed by two-fluid nozzle into a chamber, which was supplied with an additional hot nitrogen flow. The droplets were transported by the nitrogen, while getting dried. The particles were collected in product collection vessel when the solvent within the droplets was fully vaporized. Condenser was set to 0 °C, aspiration to 100% for all experiments.

[0166] Table 2# Mixture of L-arginine salt of Spray drying SSA / etrasimod (1 Arg), solvent (S), and 2 -1mg water (W)

[0167] Solvent Ratio w(l Arg) Tl °C Zin / °C Tout / Flow / Pump /

[0168] (S) W S / % (w / w) °C 1 h'1ml min'1

[0169] (w / w)

[0170] R - - - - - - - 13.76 1 THF 1 : 17 10 10 100 50 800 5 - 2 THF 1 : 8 10 10 100 55 800 5 - 3 THF 1 : 4 10 10 100 48 800 5 3.32 4 IPA 1 : 3 10 25 100 55 800 5 3.62 5 DMK 1 : 3 10 10 100 45 800 5 5.03 6 ACN 1 : 3 5 25 110 55 800 5 4.61 7 IPA 1 : 2 10 40 100 50 600 5 3.13 8 IPA 1 : 2 10 40 100 55 600 5 2.02 9 THF 1 : 4 10 10 100 48 600 5 2.66 10 THF 1 : 4 10 10 100 55 600 5 1.52 11 ACN 1 : 2 5 40 100 45 600 5 4.67 12 ACN 1 : 2 5 40 110 55 600 5 3.49 13 IPA 1 : 4 5 45 100 - 600 5 2.41 14 IPA 1 : 3 10 40 100 - 600 5 2.89 15 IPA 1 : 3 5 30 100 - 600 5 2.27 16 IPA 1 : 4 10 50 100 - 600 5 2.98 17 DMK 1 : 9 10 10 80 - 600 5 2.93

[0171]

[0172] # Mixture of L-arginine salt of Spray drying SSA / etrasimod (1 Arg), solvent (S), and 2 -1mg water (W)

[0173] Solvent Ratio w(l Arg) T / °C Zin / °C Tout / Flow / Pump / (S) W S / % (w / w) °C 1 h'1ml min'1

[0174] (w / w)

[0175] 18 IPA 1 : 4 10 45 100 - 600 5 2.06 19 IPA 1 : 3 5 40 100 - 600 5 2.28

[0176]

[0177] R: reference L-arginine salt of etrasimod material obtained by reworking the examples of the prior art WO2011094008; THF: tetrahydrofuran; ACN: acetonitrile; DMK: acetone; IPA: 2-propanol.

[0178] Example 7 Stability of particles obtained by spray drying

[0179] The particle samples (about 50 mg) were packed in LDPE bags and put into the stability chamber set to the temperature of 55 °C and relative humidity of 90 %. Materials were analyzed by HPLC after 1 month storage.

[0180] Table 3

[0181] # Particles Spray dryer 55 °C 90 % RH LDPE

[0182] setting # T(0) T(1 m)

[0183] AreaIN(etrasimod) / % AreaIN(etrasimod) / % 1 N / A 98.70 62.52 Example 1

[0184] 2 Example 3 7 97.32 84.11

[0185] 3 Example 3 8 96.37 79.44

[0186] 4 Example 3 9 97.68 82.75

[0187]

[0188] 5 15 99.84 84.11 Example 6

[0189]

[0190] Example 8 Tablet formulation

[0191] The tablet formulation according to Table 4 was made by adjusting L-Arginine salt of etrasimod (spray dried) and the filler into a bin of a diffusion blender and the mixture was blended for suitable time (e.g. 15 min). The resulting blend was sifted using a screening mill. The disintegrant was sifted through a screening mill, added together with the previous blend to an adequate bin of a diffusion blender, and blended for a suitable time (e.g. 20 minutes). The lubricant was sifted and blended with the bulk resulting from previous blends into a diffusion blender (e.g. bin blender) for a suitable time (e.g. 5 minutes). The resulting blend was compressed on a rotary tablet press using appropriate punches (e.g. 6 mm round punches). The coating agent and purified water were adjusted into an adequate container and agitated for suitable time (e.g. 1 hour) or until complete homogenization. The tablets are coated with the coating agent suspension until a suitable weight gain (e.g. 4 % weight gain related to core tablet).

[0192] Table 4

[0193] Ingredient % (w / w)

[0194] L-Arginine salt of etrasimod (spray dried) 1.40

[0195] Filler 94.10 Disintegrant 4.00

[0196] Lubricant 0.50

[0197] Total core tablet 100

[0198] Coating agent 4.00

[0199]

[0200] Total coated tablet 104

[0201]

Claims

CLAIMS1. An isometric particle of L-arginine salt of etrasimod characterized by a specific surface area of from 0.1 to 5 m2g '.

2. A process for the preparation of an isometric particle of L-arginine salt of etrasimod comprising:a) Providing a mixture of a first solvent and water;b) Mixing L-arginine salt of etrasimod with the mixture provided in step a); c) Heating the mixture provided in the step b) to obtain a solution; d) Adding a second solvent to the solution provided in the step c); e) Spray-drying the mixture provided in the step d).

3. The process according to the claim 2 wherein a weight based ratio of water to the first solvent is from 1:1 to 1:10.

4. The process according to the claim 2 or 3 wherein a weight based ratio of water to the first solvent is from 1 :2 to 1:

75. The process according to the claims 2 to 4 wherein a weight based ratio of water to the first solvent is from 1 :3 to 1 :6.

6. The process according to any one of the claims 2 to 5 wherein the first solvent is acetone or 2-propanol.

7. The process according to any one of the claims 2 to 6 wherein L-arginine salt of etrasimod is mixed with a mixture of the first solvent and water in a weight based ratio of L-arginine salt of etrasimod to the mixture of from 1 :4 to 1:8.

8. The process according to any one of the claims 2 to 7 wherein the mixture in step c) is heated at a temperature from 35 °C to 85 °C.

9. The process according to any one of the claims 2 to 8 wherein the mixture in step c) is heated at a temperature from 40 °C to 80 °C.

10. The process according to any one of the claims 2 to 9 wherein the mixture in step c) is heated at a temperature from 50 °C to 75 °C.

11. The process according to any one of the claims 2 to 10 wherein the second solvent is acetone or 2-propanol.

12. The process according to any one of the claims 2 to 11 wherein the second solvent is added in step d) at a rate from 0.5 ml min1to 10 ml min '.

13. The process according to any one of the claims 2 to 12 wherein the second solvent is added in step d) at a rate from 1 ml min1to 2 ml min '.

14. The process according to any one of the claims 2 to 13 wherein the second solvent is added in step d) at a temperature from 15 °C to 75 °C.

15. The process according to any one of the claims 2 to 14 wherein the second solvent is added in step d) at a temperature from 15 °C to 55 °C.

16. The process according to any one of the claims 2 to 15 wherein the second solvent is added in step d) at a temperature from 15 °C to 45 °C.

17. The process according to any one of the claims 2 to 16 wherein the mixture in step e) is suspension.

18. The process according to any one of the claims 2 to 17 wherein the mixture in step e) is cooled at a temperature from 15 to 75 °C.

19. The process according to any one of the claims 2 to 18 wherein the mixture in step e) is cooled at a temperature from 15 to 55 °C.

20. The process according to any one of the claims 2 to 19 wherein the mixture in step e) is cooled at a temperature from 15 to 35 °C.

21. The process according to any one of the claims 2 to 20 wherein the mixture in step e) is stirred for from 0.5 to 12 h.

22. The process according to any one of the claims 2 to 21 wherein the mixture in step e) is spray dried at a temperature of the gas inlet from 70 to 140 °C.

23. The process according to any one of the claims 2 to 22 wherein the mixture in step e) is spray dried at a temperature of the gas inlet from 80 to 130 °C.

24. The process according to any one of the claims 2 to 23 wherein the mixture in step e) is spray dried at a temperature of the gas outlet from 50 to 130 °C.

25. The process according to any one of the claims 2 to 24 wherein the mixture in step e) is spray dried at a temperature of the gas outlet from 65 to 115 °C.

26. The particle of L-arginine salt of etrasimod obtainable by the process according to claims 2 to 25.

27. A process for the preparation of an isometric particle of L-arginine salt of etrasimod comprising:a) Providing a mixture of a solvent and water;b) Mixing L-arginine salt of etrasimod with the mixture provided in step a); c) Spray-drying the mixture provided in the step b).

28. The process according to the claim 27 wherein a weight based ratio of water to the first solvent is from 1:1 to 1 :20.

29. The process according to the claim 27 or 28 wherein a weight based ratio of water to the first solvent is from 1 :2 to 1:1030. The process according to the claims 27 to 29 wherein a weight based ratio of water to the first solvent is from 1:3 to 1:6.

31. The process according to any one of the claims 27 to 30 wherein the first solvent is acetone or 2-propanol.

32. The process according to any one of the claims 27 to 31 wherein the mixture of the solvent and water is set to a temperature of from 10 °C to 50 °C.

33. The process according to any one of the claims 27 to 32 wherein L-arginine salt of etrasimod is mixed with the mixture of the solvent and water to form the mixture having a weight-based concentration of the L-arginine salt of etrasimod of from 4 % to 12 %.

34. The process according to any one of the claims 27 to 33 wherein the mixture of the L- arginine salt of etrasimod, the solvent, and water is set to a temperature of from 10 °C to 50 °C.

35. The process according to any one of the claims 27 to 34 wherein the mixture in step c) is heterogeneous suspension or homogeneous solution.

36. The process according to any one of the claims 27 to 35 wherein the mixture in step c) is homogenized by high-speed dispersing instrument.

37. The process according to any one of the claims 27 to 36 wherein the mixture in step c) is spray dried at a temperature of the gas inlet from 70 °C to 140 °C.

38. The process according to any one of the claims 27 to 37 wherein the mixture in step c) is spray dried at a temperature of the gas inlet from 80 °C to 130 °C.

39. The process according to any one of the claims 27 to 38 wherein the mixture in step c) is spray dried at a temperature of the gas inlet from 90 °C to 120 °C.

40. The process according to any one of the claims 27 to 39 wherein the mixture in step c) is spray dried at a temperature of the gas outlet from 35 °C to 75 °C.

41. The process according to any one of the claims 27 to 40 wherein the mixture in step c) is spray dried at a temperature of the gas outlet from 40 °C to 65 °C.

42. The process according to any one of the claims 27 to 41 wherein the mixture in step c) is spray dried at a temperature of the gas outlet from 40 °C to 60 °C.

43. The particle of L-arginine salt of etrasimod obtainable by the process according to claims 27 to 42.

44. A pharmaceutical composition comprising the particle according to the claims 1, 26, or 43 and one or more pharmaceutically acceptable excipients.

Images