Crystalline form of an isoxazolidine derivative

Abstract

The present disclosure relates to a compound of formula (1) as an anhydrate which is in a crystalline Form 1, characterized by having a powder-X-ray diffractogram displaying a peak expressed as degree 2-Theta angles at about 8.3 and a solid form thereof. The present disclosure also relates to processes for its preparation, as well as a medicament and a pharmaceutical composition comprising it. The present disclosure further concerns the anhydrate crystalline Form 1 of compound of formula (1) for use as a medicine and more particularly in the treatment of Alzheimer disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS).

Description

[0001] CRYSTALLINE FORM OF AN ISOXAZOLIDINE DERIVATIVE

[0002] Herein is provided 3-Fluoro-5-[(3S)-2-[l-[6-(2-methylimidazol-l-yl)pyrimidin- 4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile (hereafter designated as compound of formula (1)) as an anhydrate which is in a crystalline Form 1. Herein are also provided processes for its preparation, and this anhydrate crystalline Form 1 for use as a medicine, and particularly in the treatment of Alzheimer disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS).

[0003] Compound of formula (1), depicted below, is a selective receptor-interacting protein kinase 1 inhibitor (RIPK1) which has receptor-interacting protein kinase 1 inhibitor properties and can be effective in therapies for diseases involving inflammation or cell death. It may be used in particular in the treatment of Alzheimer disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS). This compound, in amorphous form, is disclosed in the application WO2023 / 083847.

[0004] Besides its pharmaceutical efficacy, a pharmaceutically active agent has to comply with a variety of additional requirements. For instance, its stability under various environmental conditions, its stability during production of the pharmaceutical formulation, or its stability in the final medicament compositions. In addition, when a pharmaceutically active agent is used to prepare a pharmaceutical composition, it should be as pure as possible and its stability in long-term storage must be guaranteed under various environmental conditions. For example, this reduces or avoids the risk that the content of active substance in the medicament be less than that specified. Hence, there is a need to provide the compound of formula (1) under a form which is the most thermodynamically stable form at least under ambient conditions of temperature and pressure and which allows its use and storage at an industrial scale.

[0005] Furthermore, a pharmaceutically active agent should be only slightly hygroscopic. Indeed, the absorption of moisture decreases the amount of pharmaceutically active agent as a result of the increased weight caused by the uptake of water. Generally, pharmaceutical compositions that tend to absorb moisture must be protected from moisture during storage, for example by adding suitable drying agents or by storing the drug in an environment where it is protected from moisture.

[0006] Furthermore, a pharmaceutically active agent should be soluble for a good resorption in aqueous media of various pH and simulated gastrointestinal fluids like FeSSIF and FaSSIF.

[0007] Furthermore, a pharmaceutically active agent should not require an additional separate energy intensive preparation step to be obtained in an industrial process, as for example heat treatment.

[0008] There is also a need to provide the compound of formula (1) in a crystalline form which displays stability, low hygroscopicity, solubility in media of various pH and simulated gastrointestinal fluids like FeSSIF and FaSSIF and does not require an additional separate energy intensive preparation step to be obtained in an industrial process, as for example heat treatment.

[0009] Further, the availability of a well-defined crystalline form allows the purification of the drug substance by recrystallization.

[0010] The disclosure relates to a stable crystalline form of the compound of formula (1) which meets the important above-mentioned features.

[0011] Herein is provided a novel 3-Fluoro-5-[(3S)-2-[l-[6-(2-methylimidazol-l- yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile as an anhydrate which is in a crystalline Form 1, characterized by having a powder-X-ray diffractogram displaying peaks expressed as degree 2-Theta angles at about 6.7; 8.3; 10.1; 13.5; 15.5; 17.5; 18.3; and 20.3 (each time ± 0.2), which optionally further shows the following peaks expressed as degree 2-Theta angles at about: 15.8; 24.4; 25.6; 25.8; and 26.5 (each time ± 0.2), optionally further characterized by a powder X-ray diffractogram as substantially illustrated in figure 1. Herein is also provided a solid form, which is anhydrate crystalline Form 1 of the compound of formula (1).

[0012] Herein are further provided processes for the preparation of the anhydrate crystalline Form 1 of compound of formula (1).

[0013] Herein are also provided medicaments comprising the anhydrate crystalline Form 1 of compound of formula (1), and pharmaceutical compositions comprising the anhydrate crystalline Form 1 of compound of formula (1) and at least one pharmaceutically acceptable excipient.

[0014] In a particular embodiment, in said pharmaceutical composition, said anhydrate crystalline Form 1 is substantially pure and substantially free of alternative forms.

[0015] In another particular embodiment, in said pharmaceutical composition, said anhydrate crystalline Form 1 is at least 90 percent by weight of all forms.

[0016] Herein are further disclosed the anhydrate crystalline Form 1 of compound of formula (1) for use as a medicine, for use as an inhibitor of RIPK1, and for use in the treatment of various diseases wherein RIPK1 is involved, more particularly Alzheimer disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS).

[0017] Herein is further disclosed use of the anhydrate crystalline Form 1 of compound of formula (1) for the manufacture of a medicament for treating a disease involving inhibition of receptor-interacting protein kinase 1 (RIPK1).

[0018] Herein is further disclosed use of the anhydrate crystalline Form 1 of compound of formula (1) for the manufacture of a medicament for treating Alzheimer disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS).

[0019] Herein is further disclosed method of treating a disease involving inhibition of receptor-interacting protein kinase 1 (RIPK1), comprising administering to a subject in need thereof a therapeutically effective amount of the anhydrate crystalline Form 1 of compound of formula (1).

[0020] Herein is further disclosed method of treating Alzheimer disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS), comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of the anhydrate crystalline Form 1 of compound of formula (1). BRIEF DESCRIPTION OF THE FIGURES

[0021] Figure 1 is a X-ray powder diagram of the anhydrate crystalline Form 1 of 3- Fluoro-5-[(3S)-2-[l-[6-(2-methylimidazol-l-yl)pyrimidin-4-yl]piperidine-4- carbonyl]isoxazolidin-3-yl]benzonitrile measured at room temperature.

[0022] Figure 2 is a thermogram of the anhydrate crystalline Form 1 of 3-Fluoro-5- [(3 S)-2-[l-[6-(2-methylimidazol-l-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3- yl]benzonitrile.

[0023] Figure 3 is a Dynamic Vapor Sorption (DVS) isotherm plot (2 sorption / desorption cycles) of the anhydrate crystalline Form 1 of3-Fluoro-5-[(3S)-2-[l-[6- (2-methylimidazol-l-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3- yl]benzonitrile measured at 25°C.

[0024] Figure 4 is a X-ray powder diagram of the anhydrate crystalline Form 2 of 3- Fluoro-5-[(3S)-2-[l-[6-(2-methylimidazol-l-yl)pyrimidin-4-yl]piperidine-4- carbonyl]isoxazolidin-3-yl]benzonitrile measured at room temperature.

[0025] Figure 5 is a thermogram of the anhydrate crystalline Form 2 of 3-Fluoro-5- [(3 S)-2-[l-[6-(2-methylimidazol-l-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3- yl]benzonitrile.

[0026] Figure 6 is a Dynamic Vapor Sorption (DVS) isotherm plot (2 sorption / desorption cycles) of the anhydrate crystalline Form 2 of3-Fluoro-5-[(3S)-2-[l-[6- (2-methylimidazol-l-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3- yl]benzonitrile measured at 25°C.

[0027] Figure 7 is a Temperature dependent X-ray powder diagram (deltaT-XRPD) of the anhydrate crystalline Form 1 of 3-Fluoro-5-[(3S)-2-[l-[6-(2-methylimidazol-l- yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile measured at temperatures from room temperature to 190°C in 5°C increments.

[0028] Definitions

[0029] As used herein, “a” or “an” entity refers to one or more of that entity, e.g., “a compound” refers to one or more compounds or at least one compound unless stated otherwise. As such, the terms “a” (or “an”), “one or more,” and “at least one” are used interchangeably herein. As used herein, the term “about” or “substantially as shown in” means approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 5 %.

[0030] As indicated typically, ±0.2° for XRPD peaks, and ±3°C for DSC.

[0031] As used herein, “Compound of formula (1)” refers to 3-Fluoro-5-[(3S)-2-[l-[6- (2-methylimidazol-l-yl)pyrimidin-4-yl]piperidine-4-carbonyl]isoxazolidin-3- yl]benzonitrile.

[0032] Herein, Compound of formula (1) may be referred to as a “drug,” “active agent,” “a therapeutically active agent,” or a “API.”

[0033] A “solvate” refers to an association or complex of one or more solvent molecules and a compound of formula (1).

[0034] “The amorphous phase of a compound” is a solid that lacks the long-range order that is characteristic of a crystal. Consequently, the X-ray diffraction pattern of an amorphous phase does not show diffraction peaks.

[0035] The term “crystalline” refers to any solid substance exhibiting three- dimensional order, which in contrast to an amorphous solid substance, gives a distinctive XRPD pattern with more or less sharp peaks.

[0036] The term “anhydrate” refers to a crystal form of a substance with no water in its structure. By extension, the term “anhydrate” usually refers to a crystal form of a substance with no water and / or solvent in its structure.

[0037] The term “heterosolvate” refers to a crystalline form with more than one type of solvent included in the lattice.

[0038] As used herein, the term "substantially pure" means that the crystalline form contains at least 90 percent, preferably at least 95 percent, more preferably at least 97 percent, and most preferably at least 99 percent by weight of the indicated crystalline form. Alternatively, it will be understood that "substantially pure" means that the crystalline form contains less than 10 percent, preferably less than 5 percent, more preferably less than 3 percent, and most preferably less than 1 percent by weight of impurities, including other polymorphic, solvated, or amorphous forms. As used herein, a “pharmaceutically acceptable excipient” refers to a carrier or an excipient that is useful in preparing a pharmaceutical composition. For example, a pharmaceutically acceptable excipient is generally safe and includes carriers and excipients that are generally considered acceptable for mammalian pharmaceutical use.

[0039] As used herein, the terms “polymorph,” “crystal form,” “crystalline form,” and “Form” interchangeably refer to a solid having a particular molecular packing arrangement in the crystal lattice. Crystalline forms can be identified and distinguished from each other by at least one characterization technique including, e.g., X-ray powder diffraction (XRPD), single crystal X-ray diffraction, differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and / or thermogravimetric analysis (TGA). Accordingly, as used herein, the term “crystalline Form [X] of Compound of formula (1)” refers to a unique crystalline form that can be identified and distinguished from other forms by at least one characterization technique including, e.g., X-ray powder diffraction (XRPD), single crystal X-ray diffraction, differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and / or thermogravimetric analysis (TGA). In some embodiments, the novel crystalline forms of this disclosure are characterized by an X-ray powder diffractogram having at least one signal at least one specified two-theta value (° 29).

[0040] In the sense of the present disclosure and according to the European pharmacopoeia, the term "slightly hygroscopic" as used herein refers to compound showing a weight gain of less than 2 weight % and equal to or greater than 0.2 weight % based on the weight of the compound when measured in the range of from 0 to 80 % ( ± 2 %) relative humidity at about 25°C ( ± 1°C).

[0041] In the sense of the present disclosure and according to the European pharmacopoeia, the term "hygroscopic" as used herein refers to compound showing a weight gain of less than 15 weight % and equal to or greater than 2 weight % based on the weight of the compound when measured in the range of from 0 to 80 % ( ± 2 %) relative humidity at about 25°C ( ± 1°C).

[0042] Polymorphism is the ability of a single compound to exist in more than one form or crystal structure. Different polymorphs represent distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. A single compound may give rise to a variety of polymorphic forms wherein each form may have different and distinct physical properties, such as different solubility profiles, different thermodynamic stability, different crystallization behaviour, different filterability, different melting point temperatures and / or different X-ray diffraction peaks. The difference in the physical properties of different polymorphic forms results from different orientation and interm olecular interactions of adjacent molecules in the solid. Polymorphic forms of a compound can be distinguished, in particular, by X-ray diffraction.

[0043] Characterizations (XRPD, DSC, and DVS) and some properties of the herein described different anhydrate and solvates forms are detailed below.

[0044] As used herein, the term “DSC” refers to the analytical method of differential scanning calorimetry.

[0045] As used herein, the term “TGA” refers to the analytical method of thermo gravimetric (also referred to as thermogravimetric) analysis.

[0046] As used herein, the term “XRPD” refers to the analytical characterization method of X-ray powder diffraction. XRPD patterns can be recorded at ambient conditions in transmission or reflection geometry using a diffractometer.

[0047] As used herein, the term “deltaT-XRPD” refers to the analytical characterization method of X-ray powder diffraction recorded as multiple measurements at different temperatures, in particular recorded with elevating temperature increments, p.e. 5°C.

[0048] In the sense of the present disclosure, a “set temperature” means a temperature which remains the same during the corresponding step.

[0049] In the context of the present disclosure, the expression “almost complete evaporation” of a solvent means that the evaporation is not carried out in full, that is to say that the amount of solvent which is evaporated is decreased but nevertheless still present in a very low content. In other terms, the evaporation must not be carried out dry.

[0050] As used herein, the term “ambient temperature” or “room temperature” refers to a temperature ranging from 18°C to 25°C unless differently specified.

[0051] Anhydrate crystalline Form 1 of compound of formula (I), as well as comparative anhydrate form of compound of formula (1)

[0052] Anhydrate crystalline Form 1 of compound of formula (1)

[0053] As explained above, herein is provided an anhydrate crystalline form, which is Form 1 of a compound of formula (1)

[0054] According to one embodiment, the anhydrate crystalline Form 1 of compound of formula (1), has an X-ray power diffraction pattern comprising a peak, in terms of 2-theta angle, at about 8.3.

[0055] According to one embodiment, the anhydrate crystalline Form 1 of compound of formula (1), is characterized by having a powder-X-ray diffractogram displaying peaks expressed as degree 2-Theta angles at about 6.7; 8.3; 10.1; 13.5; 15.5; 17.5; 18.3; and 20.3 (each time ± 0.2). According to another embodiment, the anhydrate crystalline Form 1 of compound of formula (1), is characterized by having a powder-X-ray diffractogram displaying peaks expressed as degree 2-Theta angles at about 6.7; 8.3; 10.1; 13.5; 15.5; 17.5; 18.3; and 20.3 (each time ± 0.2), which further shows the following peaks expressed as degree 2-Theta angles at: about 15.8; 24.4; 25.6; 25.8; and 26.5 (each time ± 0.2), optionally further characterized by a powder X-ray diffractogram as substantially illustrated in figure 1.

[0056] More particularly, a characteristic X-ray powder diffractogram of the anhydrate crystalline Form 1 of compound of formula (1) can be given substantially in figure 1, and its characteristic signals are summarized in the following table I:

[0057] Table I

[0058] In one embodiment, the anhydrate crystalline Form 1 of compound of formula (1) has a differential scanning calorimetry (DSC) showing 2 overlapped endothermic peaks the first at about 163 °C (160°C onset) (± 2°C) and the second at about 169°C (onset 168°C) (± 2°C) and is optionally further characterized by a thermogram as substantially illustrated in figure 2.

[0059] As indicated in the figure 2, these temperatures are associated with an enthalpy AHf of about 11 J / g for the first peak and about 74 J / g for the second peak. The third broad peak at about 288°C is associated with the decomposition of the compound.

[0060] In another embodiment, the anhydrate crystalline Form 1 of compound of formula (1) is characterized by showing a weight gain of about 0.16 weight % at 40 % RH, about 0.26 % at 60 % RH, and about 0.58 % at 80 % RH in the sorption cycle, and showing a weight gain of about 0.18 weight % at 40 % RH, about 0.58 % at 60 % RH, and about 1.89 % at 80 % RH in the desorption cycle, as determined by Dynamic Vapor Sorption (DVS) in the range of from 0 % to 95 % relative humidity at a temperature of about 25°C (± 0.2°C), and is optionally further characterized by a DVS isotherm plot shown substantially in figure 3.

[0061] The characteristic data corresponding substantially to figure 3 are summarized in the following table II:

[0062] Table II

[0063] The sharp rise of the sorption isotherm between 80 and 95 % RH for the first and second sorption cycle of about 3.6 % by weight and the subsequent release of water in the desorption cycle between 95 % RH and 50 % RH indicate the formation of a hydrate (Table II). The hydrate formation is reversible.

[0064] Considering the molecular mass of the compound of formula (1) of 461.5 g / mol, a molar amount of 0.96 mol water can be calculated. This indicates the formation of a monohydrate.

[0065] According to the European pharmacopoeia definition, the anhydrate crystalline Form 1 of compound of formula (1) displays a slightly hygroscopicity.

[0066] The 2 overlapped endothermic peaks in the DSC thermogram of the anhydrate crystalline Form 1 of compound of formula (1) as substantially illustrated in figure 2 indicate a structural transition. deltaT-XRPD was performed on anhydrate crystalline Form 1 of compound of formula (1) as substantially illustrated in figure 7. The peaks shown as bright band areas up to about 160°C (a temperature covered by the first endothermic peak in the DSC illustrated in figure 2) can be associated with the anhydrate crystalline Form 1.

[0067] Above about this temperature and below about 173°C (a temperature covered by the second endothermic peak in the DSC illustrated in figure 2), the bright band areas can be associated with a new polymorphic form of the compound of formula (1), which is described as the anhydrate crystalline Form 2 of the compound of formula (1).

[0068] Above about 173 °C, the peaks vanish, which indicates the amorphous melt.

[0069] Shown in the experimental part is the potential of compound of formula (1) to form polymorphs (anhydrous forms and more particularly anhydrate crystalline form 2).

[0070] Characterizations (XRPD, DSC, and DVS) and some properties of this comparative anhydrate form 2 is detailed below.

[0071] A preparation of the anhydrate crystalline Form 1 of compound of formula (1) is detailed below in example 1 and 2.

[0072] Anhydrate crystalline Form 2 of compound of formula (1)

[0073] A preparation of the anhydrate crystalline Form 2 of compound of formula (1) is detailed below in comparative example 3.

[0074] Anhydrate crystalline Form 2 of compound of formula (1) was characterized by XRPD, DSC, and DVS and the results are detailed below.

[0075] More particularly, a characteristic X-ray powder diffractogram of the anhydrate crystalline Form 2 of compound of formula (1) can be given substantially in figure 4 and its characteristic signals are summarized in the following table III:

[0076] Table III

[0077] As substantially indicated in figure 5, the anhydrate crystalline Form 2 of compound of formula (1) has a differential scanning calorimetry showing one melting endotherm peak at about 168°C ± 2°C (onset at about 166°C ± 2°C). This melting point temperature is associated with an enthalpy of fusion AHf of about 69 J / g. The second broad peak at about 288°C is associated with the decomposition of the compound.

[0078] In addition, as substantially illustrated in figure 6 and specified in the table IV below, the anhydrate crystalline Form 2 of compound of formula (1) is characterized by showing a weight gain of about 0.33 weight % at 40 % RH, about 0.51 % at 60 % RH, and about 0.96 % at 80 % RH in the sorption cycle, and showing a weight gain of about 0.42 weight % at 40 % RH, about 0.89 % at 60 % RH, and about 2.37 % at 80 % RH in the desorption cycle, as determined by Dynamic Vapor Sorption (DVS) in the range of from 0 % to 95 % relative humidity at a temperature of about 25°C (± 0.2°C), and is optionally further characterized by a DVS isotherm plot shown substantially in figure 6. The characteristic data corresponding to substantially figure 6 are summarized in the following table IV:

[0079] Table IV

[0080] The sharp rise of the sorption isotherm between 80 and 95 % RH for the first and second sorption cycle of about 3.8 % in weight and the subsequent release of water in the desorption cycle between 95 % RH and 50 % RH indicate the formation of a hydrate (Table IV). The hydrate formation is reversible.

[0081] Considering the molecular mass of the compound of formula (1) of 461.5 g / mol, a molar amount of 1.09 mol water can be calculated. This indicates the formation of a monohydrate. In conclusion the DVS isotherms of the anhydrate crystalline Form 1 of compound of formula (1) and the anhydrate crystalline Form 2 of compound of formula (1) show the water uptake of Form 1 and Form 2 is comparable in the range up to 95 % RH.

[0082] Solubility in aqueous media of different pH and simulated gastrointestinal fluids like FeSSIF and FaSSIF

[0083] The solubility crystalline anhydrates of Form 1 and Form 2 of compound of formula (1) was tested in buffers of pH ranging from 1.2 to 7.4 and the simulated gastrointestinal fluids FeSSIF and FaSSIF. This is detailed in example 4. The data indicate that no significant differences were observed between Form 1 and Form 2. Conclusion

[0084] In view of the results provided above, it has been demonstrated that the anhydrate crystalline Form 1 of compound of formula (1) and the anhydrate crystalline Form 2 of compound of formula (1) possess similar properties particularly in terms of stability at least under ambient conditions of temperature and pressure, water sorption under humidity conditions (hygroscopicity), and solubility in aqueous media.

[0085] However, anhydrate crystalline Form 2 of compound of formula (1) is obtained from the anhydrate crystalline Form 1 of compound of formula (1) by tempering at 160°C, which requires energy. Therefore, the anhydrate crystalline Form 1 of compound of formula (1) is advantageous from an environmental and economic point of view for manufacturing and use at an industrial scale.

[0086] Processes for the preparation of anhydrate crystalline Form 1 of compound of formula (1)

[0087] As indicated above, herein are also provided processes for preparing anhydrate crystalline Form 1 of 3-Fluoro-5-[(3S)-2-[l-[6-(2-methylimidazol-l-yl)pyrimidin-4- yl]piperidine-4-carbonyl]isoxazolidin-3-yl]benzonitrile .

[0088] Anhydrate crystalline Form 1 of compound of formula (1) may be obtained by conventional crystallization techniques known to one of skill in the Art, such as crystallization by evaporation, crystallization by cooling, or crystallization by adding a nonsolvent such as methyl tert-butyl ether.

[0089] Crystallization by cooling

[0090] According to one embodiment, a process for the preparation of anhydrate crystalline Form 1 of the compound of formula (1) comprises at least the following steps:

[0091] 1) solubilizing or suspending the compound of formula (1) in amorphous form in a solvent selected from alcohols, ketones, and acetates, at a set temperature which is room temperature;

[0092] 2) optionally purifying the solution or suspension obtained in step 1) by heating at a set temperature ranging from 50°C to 80°C, stirring, and filtering the solution or suspension; 3) heating the solution or suspension obtained in step 1) or in step 2) at a set temperature ranging from 50°C to 80°C;

[0093] 4) cooling the solution or suspension obtained in step 2) to a set temperature ranging from -20°C to 25°C; and

[0094] 5) isolating the anhydrate crystalline Form 1 of compound of formula (1) formed in step 4).

[0095] The optional step 2) allows advantageously the elimination of impurities or germs that may be present in the solution or suspension.

[0096] In a particular embodiment, the solvent of step 1) is selected from methanol, 2- propanol, 1 -butanol, 1 -pentanol, acetone, ethyl acetate, isopropyl acetate, and isobutyl acetate.

[0097] In an embodiment, the solvent of step 1) is ethyl acetate.

[0098] According to one variant, the set temperature of step 1) is the same as the one of step 4).

[0099] According to another variant, the set temperature of step 1) is the same as the one of step 4) and the set temperature of step 2) is the same as the one of step 3).

[0100] Crystallization by adding methyl tert-butyl ether (also named MTBE) as a non-solvent.

[0101] According to another embodiment, a process for the preparation of the anhydrate crystalline Form 1 of compound of formula (1), comprises at least the following steps:

[0102] 1) solubilizing or suspending the compound of formula (1) in amorphous form in a solvent selected from alcohols, ketones, and acetates, at a set temperature which is room temperature;

[0103] 2) optionally filtering the solution or suspension obtained in step 1);

[0104] 3) adding MTBE as a non-solvent; and

[0105] 4) isolating the anhydrate crystalline Form 1 of compound of formula (1) formed in step 3).

[0106] The optional step 2) of filtering allows advantageously to remove impurities or germs that may be present in the solution or suspension.

[0107] In a particular embodiment, the solvent of step 1) is selected from methanol, 2- propanol, 1 -butanol, 1 -pentanol, acetone, ethyl acetate, isopropyl acetate, and isobutyl acetate. In a particular embodiment, the solvent of step 1) is methanol.

[0108] Optionally, after step 3) the solvent is left to evaporate.

[0109] EXAMPLES

[0110] MATERIAL AND METHODS

[0111] I, DIFFERENTIAL SCANNING CALORIMETRY (DSC)

[0112] Differential scanning calorimetry (DSC) was measured with a Mettler Toledo DSC3+ Instrument using a heating rate of 10°C / min from 25°C to 350°C. A sample of approx. 3-4mg of compound was prepared in a 40 pl Aluminium pan.

[0113] II, X-RAY POWDER DIFFRACTION (XRPD)

[0114] XRPD measurements were performed with STOE Stadi-P transmission diffractometer (S2: flatbed preparation or S3: preparation in capillaries) fitted with a Cu- anticathode tube (X Kai = 1.540598 A), at a voltage of 45 kV and a current of 35 mA. The Cu-radiation is monochromized with a curved germanium crystal ((H I) reflection). Reflection intensities were detected with a Mythen detector. The solid compound was prepared in a 2 or 8mm discs (S2) (depending on the amount of substance) or in 0.7mm capillaries (S3). XRPD diffraction pattern was recorded according to the following conditions:

[0115] • Scanning initial angle: 2.0 degrees 29

[0116] • Scanning final angle: 34 degrees 29 at least

[0117] • Detector mode: moving

[0118] • Exposure time: 240 or 120 seconds

[0119] • Sample rotation: on

[0120] The measured data was visualized and evaluated with the Software WinXPOW Version 3.12.1 deltaT - XRPD measurements: The solid compound was prepared in a 0.7 mm glass capillary at the STOE diffractometer equipped with temperature control and an IP -PSD detector. The temperature dependent recordings were made in 5°C steps.

[0121] III, WATER SORPTION ISOTHERMS USING DYNAMIC VAPOR SORPTION (DVS) The adsorption of water to the solid compound of formula (1) was measured with a Dynamic Vapour Sorption (DVS) Resolution Instrument from Surface Measurement Systems. Approx. 5mg of compound of formula (1) was transferred to an aluminium pan of the ultrabalance and the exact mass was measured at different water partial pressure values (P / PO). At the beginning of the measurements, a drying period of 9 hours at 0 % water partial pressure was performed. Then, a method with two cycles was used ranking from 0 % to 95 % P / PO in 10 % steps (a 5 % step from 90 % RH to 95 % RH) at a controlled temperature of 25°C. P / PO was increased to the next step, when no further mass changes occur (dm / dt mode). Then followed by a desorption cycle with decreasing relative humidity by steps of 10 % RH, from 95 to 0 % RH, followed by a second sorption cycle with increasing relative humidity raised by steps of 10 % RH, from 0 to 95 % RH then followed by a second desorption cycle with decreasing relative humidity lowered by steps of 10 % RH, from 95 to 0 % RH.

[0122] Data were evaluated with the DVS Standard Analysis Suite v7.4 in Excel.

[0123] IV. HPLC method A

[0124] Apparatus: Liquid chromatographic gradient pump system with UV detector and column thermostate, equipped with an autosampler and a data acquisition system (e.g. HPLC, Waters).

[0125] Column: XBridge BEH C18, 2.5pm, 4.6*150mm, Waters or suitable

[0126] Mobile phases: A 95 % dem. H2O / 5 % ACN / 0.05 % TFA

[0127] B 5 % dem. H2O / 95 % ACN / 0.05 % TFA

[0128] Diluent: 67 % dem. H2O / 33 % Acetonitrile

[0129] Gradient:

[0130] Time [min] A B

[0131] 0.0 92.0 % 8.0 %

[0132] 0.0 to 1.0 92.0 % 8.0 %

[0133] 1.0 to 15.0 linear to 50.0 % 50.0 %

[0134] 15.0 to 19.0 linear to 0.0 % 100.0 % 19.0 to 20.0 0.0 % 100.0 %

[0135] 20.0 to 20.5 linear to 92.0 % 8.0 %

[0136] 20.5 to 29.0 92.0 % 8.0 %

[0137] Flow: l.O mL / min

[0138] Injection volume: 15 .L

[0139] Column temperature: +40°C

[0140] Sample temperature: +10°C

[0141] Detection: 257 nm (UV)

[0142] Samples: 1 mg / 10.0 mL Diluent

[0143] Example 1 : Preparation of crystalline anhydrate Form 1 of compound of formula (1) via recrystallization in methanol by adding methyl-tert-butyl ether as a non-solvent.

[0144] Protocol 1 : A 150 mg / mL solution of amorphous compound of Formula (1) in methanol was prepared at 50°C. The latter was cooled down to 0°C, and the non-solvent methyl tert-butyl ether was added dropwise over several hours (20 volumes of methyl tertbutyl ether for each 1g of amorphous compound of Formula (1)). The crystalline anhydrate Form 1 of compound of formula (1) thus obtained was washed with methyl tert-butyl ether, filtered, and then dried.

[0145] Example 2: Preparation of crystalline anhydrate Form 1 of compound of formula (1) via recrystallization in ethyl acetate by cooling.

[0146] Protocol 2: A 100 mg / mL slurry suspension of amorphous compound of Formula (1) in ethyl acetate under nitrogen was prepared at room temperature. The slurry suspension was then heated to 55°C. The latter was stirred at 55°C for 16 hours. The solution was then cooled to room temperature, and the slurry suspension was stirred further for 2 hours. The anhydrate Form 1 of compound of Formula (1) thus obtained was filtered and then dried.

[0147] Characterization of crystalline anhydrate Form 1

[0148] The crystalline anhydrate Form 1 of compound of formula (1) was characterized by XRPD as substantially presented in figure 1, by DSC as substantially illustrated by figure 2, and DVS as substantially illustrated by figure 3. Comparative Example 3: Preparation of crystalline anhydrate Form 2 of compound of formula (1) via heating

[0149] Protocol 3: Anhydride Form 1 of compound of Formula (1) in an opened glass container covered by a semi-permeable filter paper was tempered slowly to 160°C under vacuum in a drying oven over 2 hours. The crystalline anhydrate Form 2 of compound of formula (1) was then slowly cooled down to room temperature.

[0150] The crystalline anhydrate Form 2 of compound of formula (1) was characterized by XRPD as substantially presented in figure 4, by DSC as substantially illustrated by figure 5, and DVS as substantially illustrated by figure 6.

[0151] The emergence of crystalline anhydrate Form 2 of compound of formula (1) from the tempering of crystalline anhydrate Form 1 of compound of formula (1) was demonstrated by deltaT-XRPD as substantially presented in figure 7.

[0152] Example 4: Solubility of crystalline anhydrates of Form 1 and Form 2 of compound of formula (1) in aqueous media of various pH and simulated gastrointestinal fluids like FeSSIF and FaSSIF,

[0153] Protocol 4: Solutions / suspensions of 4mg / ml crystalline anhydrates of Form 1 and Form 2 of compound of formula (1) were prepared in the respective buffers listed in Table V by mixing for 2 hours and 2000 rpm at 25°C in the dark (Eppendorf ThermoMixer C). For analyzing the concentration of dissolved compound of formula (1), the solutions / suspensions were centrifugated for 15 minutes at 17500 rpm, and samples of the supernatant were analyzed by HPLC method A. Then the solutions / suspensions were stored in the dark for 24 hours at 25°C. After centrifugation for 15 minutes at 17500 rpm, the supernatant was analyzed for the concentration of compound of formula (1) by HPLC method A.

[0154] Table V

[0155] The data of Table V shows that complete solubility is given at pH 1.2 and 3.0. The lower amount at pH 1.2 is due to strong degradation. No significant differences observed were between Form 1 and Form 2. Form 2 was slightly more soluble at pH 4.5 and pH 6.5, and Form 1 was slightly more soluble at pH 7.4.

Claims

CLAIMS1. An anhydrate crystalline form, which is Form I of compound of formula (1):

2. The anhydrate crystalline Form 1 of compound of formula (1) according to claim 1, characterized by having a powder-X-ray diffractogram comprising a peak expressed as degree 2-Theta angles at about 8.3.

3. The anhydrate crystalline Form 1 of compound of formula (1) according to claim 1 or claim 2, having a powder-X-ray diffractogram displaying peaks expressed as degree 2- Theta angles at about 6.7; 8.3; 10.1; 13.5; 15.5; 17.5; 18.3; and 20.3.

4. The anhydrate crystalline Form 1 of compound of formula (1) according to any one of claims 1, 2, or 3, which further shows the following peaks expressed as degree 2-Theta angles: at about 15.8; 24.4; 25.6; 25.8; and 26.5.

5. The anhydrate crystalline Form 1 of compound of formula (1) according to any one of claims 1 to 4, further characterized by a powder X-ray diffractogram as substantially illustrated in figure 1.

6. The anhydrate crystalline form 1 of compound of formula (1) according to any one of claims 1 to 5, wherein a differential scanning calorimetry DSC shows 2 overlapped endothermic peaks the first at about 163°C (160°C onset) (± 2°C) and the second at about 169°C (onset 168°C) and is optionally further characterized by a thermogram as substantially illustrated in figure 2.

7. The anhydrate crystalline Form 1 of compound of formula (1) according to any one of claims 1 to 6, characterized by showing a weight gain of about 0.16 weight % at 40 % RH, about 0.26 % at 60 % RH, and about 0.58 % at 80 % RH in the sorption cycle, and showing a weight gain of about 0.18 weight % at 40 % RH, about 0.58 % at 60 % RH, and about 1.89 % at 80 % RH in the desorption cycle, as determined by Dynamic Vapor Sorption (DVS) in the range of from 0 % to 95 % relative humidity at a temperature of about 25°C, optionally further characterized by a DVS isotherm plot as substantially shown in figure 3.

8. A solid form, which is anhydrate crystalline Form 1 of the compound of formula (1) according to any one of claims 1 to 7.

9. A process for the preparation of the anhydrate crystalline Form 1 of compound of formula (1) as defined in any one of claims 1 to 7, comprising at least the following steps:1) solubilizing or suspending the compound of formula (1) in amorphous form in a solvent selected from alcohols, ketones and acetates, at a set temperature which is room temperature;2) optionally purifying the solution or suspension obtained in step 1) by heating at a set temperature ranging from 50°C to 80°C, stirring and filtering the solution or suspension;3) heating the solution or suspension obtained in step 1) or in step 2) at a set temperature ranging from 50°C to 80°C;4) cooling the solution or suspension obtained in step 2) to a set temperature ranging from -20°C to 25°C; and5) isolating the anhydrate crystalline Form 1 of compound of formula (1) formed in step 4).

10. The process according to claim 9, wherein the solvent is selected from methanol, 2- propanol, 1 -butanol, 1 -pentanol, acetone, ethyl acetate, isopropyl acetate, and isobutyl acetate.

11. The process according to claim 9, wherein the solvent is ethyl acetate.

12. A process for the preparation of the anhydrate crystalline Form 1 of compound of formula (1) as defined in any one of claims 1 to 7, comprising at least the following steps:1) solubilizing or suspending the compound of formula (1) in amorphous form in a solvent selected from alcohols, ketones and acetates, at a set temperature which is room temperature;2) optionally filtering the solution or suspension obtained in step 1);3) adding methyl-tert-butyl ether as a non-solvent;4) isolating the anhydrate crystalline Form 1 of compound of formula (1) formed in step 3).

13. The process according to claim 12, wherein the solvent is selected from methanol, 2- propanol, 1 -butanol, 1 -pentanol, acetone, ethyl acetate, isopropyl acetate, and isobutyl acetate.

14. The process according to claim 12, wherein the solvent is selected from methanol.

15. A medicament, characterized in that it comprises the anhydrate crystalline Form 1 of compound of formula (1) as defined in any one of claims 1 to 7.

16. A pharmaceutical composition comprising the anhydrate crystalline Form 1 of compound of formula (1) as defined in any one of claims 1 to 7, and at least one pharmaceutically acceptable excipient.

17. The pharmaceutical composition according to claim 16, wherein said anhydrate crystalline Form 1 is substantially pure and substantially free of alternative forms.

18. The pharmaceutical composition according to claim 16, wherein said anhydrate crystalline Form 1 is at least 90 percent by weight of all forms.

19. The anhydrate crystalline Form 1 of compound of formula (1) as defined in any one of claims 1 to 7 for use as a medicine.

20. The anhydrate crystalline Form 1 of compound of formula (1) as defined in any one of claims 1 to 7 for use in the treatment of Alzheimer disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS).

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