EA045751B1 - CRYSTAL FORMS AND METHODS FOR OBTAINING CRYSTAL FORMS OF THE COMPOUND - Google Patents

Description

State of the art

Field of technology

The present invention relates to the field of pharmaceutical chemistry, biochemistry and medicine. In particular, it relates to crystalline forms of the compound of formula (I) and methods for their preparation and use.

Description

Thyroid hormones (thyroid hormones, THs) play important roles in maintaining growth, development, metabolism, and homeostasis. They are produced by the thyroid gland in the form of thyroxine (T4) and 3,5,3'-triiodo-L-thyronine (T3). T4 is the major secreted form in humans, which in peripheral tissues is enzymatically deiodinated by deiodinases to the more active form, T3. THs exert their effects by interacting with thyroid hormone receptors (TR), which belong to the nuclear hormone receptor superfamily, and regulate the transcription of target genes.

TRs are expressed in most tissues and exist as two isoforms (TRa and TRe). Tissue distribution studies, gene knockout studies in mice, and studies of patients with resistance thyroid hormone (RTH) syndrome have shown that the TRa isoform is the predominant isoform in the heart and regulates most cardiac functions, while the TR3 isoform predominates in the liver and pituitary gland and regulates cholesterol metabolism and thyroid-stimulating hormone (TSH) production, respectively. In addition, TRe agonists can be used to treat adrenoleukodystrophy (ALD) and lipid disorders such as hypercholesterolemia and fatty liver disease, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and glycogen storage disease. Some promising phosphonate TR3 agonists have been discovered; however, there is a need for improved forms of such compounds to facilitate the development of pharmaceuticals.

Brief description of the invention

In some embodiments, a composition is provided containing a crystalline form of a compound of formula (I)

or its solvate.

In other embodiments, a method is provided for preparing a crystalline form of a compound of formula (I) or a solvate thereof, comprising: dissolving an amorphous form of a compound of formula (I) in a first solvent to form a first solution; adding a second solvent to the first solution to form a second mixture; isolating a crystalline form of a compound of formula (I) from a second mixture in which the compound of formula (I) is

Also provided in other embodiments is a method for obtaining a crystalline form of a compound of formula (I) or a solvate thereof, comprising: dissolving a compound of formula (I) in a first solvent to form a first solution; adding a seed crystal form of the compound of formula (I) or a solvate thereof to the first solution to form a seed mixture; isolating the resulting crystalline form of the compound of formula (I) or a solvate thereof from a seed mixture in which the compound of formula (I) is

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Brief description of drawings

Fig. 1 is a powder X-ray diffraction pattern of an amorphous shape.

Fig. 2 is an X-ray powder diffraction pattern of the crystalline form of tert-butyl methyl ether (MTBE) solvate.

Fig. 3 is a powder X-ray diffraction pattern of the crystalline form of toluene solvate.

Fig. 4 is a powder X-ray diffraction pattern of a crystalline form of ethanol solvate.

Fig. 5 is a powder X-ray diffraction pattern of a crystalline form of tetrahydrofuran (THF) solvate.

Fig. 6a is a powder X-ray diffraction pattern of the crystalline form of ethyl acetate solvate.

Fig. 6b is an enlarged X-ray powder diffraction pattern of the crystalline form of the ethyl acetate solvate shown in FIG. 6a.

Fig. 7a is a powder X-ray diffraction pattern of the crystalline form of acetone solvate.

Fig. 7b is an enlarged X-ray powder diffraction pattern of the crystalline form of the acetone solvate shown in FIG. 7a.

Fig. 8a is a powder X-ray diffraction pattern of the crystalline form of the THF solvate.

Fig. 8b is a scaled-up X-ray powder diffraction pattern of the THF crystalline form shown in FIG. 8a.

Fig. 9 is a powder X-ray diffraction pattern of the crystalline form.

Fig. 10a is a powder X-ray diffraction pattern of the crystalline form of the THF solvate.

Fig. 10b is an enlarged X-ray powder diffraction pattern of the crystalline form of THF shown in FIG. 10a.

Fig. 11 is a powder X-ray diffraction pattern of crystalline form C.

Fig. 12 is a powder X-ray diffraction pattern of crystalline form C.

Fig. 13 shows differential scanning calorimetry results for the crystalline form of MTBE solvate.

Fig. 14 shows differential scanning calorimetry results for the crystalline form of toluene solvate.

Fig. 15 shows differential scanning calorimetry results for the ethanol solvate crystalline form.

Fig. 16 shows differential scanning calorimetry results for the crystalline form of ethyl acetate solvate.

Fig. 17 shows differential scanning calorimetry results for the crystalline form of acetone solvate.

Fig. 18 shows differential scanning calorimetry results for the THF solvate crystalline form.

Fig. 19a shows the results of differential scanning calorimetry during primary heating for crystalline form C.

Fig. 19b shows secondary heating differential scanning calorimetry results for crystalline form C shown in FIG. 19a.

Fig. 20a is a powder X-ray diffraction pattern of a mixed crystalline form.

Fig. 20b is a scaled-up X-ray powder diffraction pattern of the mixed crystalline form shown in FIG. 20a.

Fig. 21 is a powder X-ray diffraction pattern of crystalline form C.

Fig. 22 is a powder X-ray diffraction pattern of crystalline form C.

Fig. 23 is a powder X-ray diffraction pattern of crystalline form C.

Fig. 24 is a powder X-ray diffraction pattern of crystalline form C.

Fig. 25 is a powder X-ray diffraction pattern of crystalline form C.

Fig. 26 is a powder X-ray diffraction pattern of crystalline form C.

Fig. 27 is a powder X-ray diffraction pattern of crystalline Form C.

Fig. 28a shows the results of differential scanning calorimetry during primary heating for crystalline form C.

Fig. 28b shows secondary heating differential scanning calorimetry results for crystalline form C shown in FIG. 28a.

Fig. Figure 29a shows the results of dynamic vapor sorption analysis for crystalline form C.

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Fig. Figure 29b shows the results of phase equilibrium analysis in water for crystalline form C.

Fig. 30 is an X-ray powder diffraction pattern of crystalline Form C with peak values identified.

Detailed Description of the Invention

The present invention discloses crystalline forms of the compound of formula (I) or solvates thereof and methods for crystallizing the compound of formula (I). The compound of formula (I) is shown below

Crystal forms of the compound of formula (I) include the tert-butyl methyl ether (MTBE) solvate crystal, the toluene solvate crystal, the ethanol solvate crystal, the tetrahydrofuran (THF) solvate crystal, the ethyl acetate solvate crystal, the acetone solvate crystal, and the C crystal (described in the present invention).

The present application relates to primary crystalline forms of compounds of formula (I), as well as methods for crystallizing various crystalline forms of compounds of formula (I). Crystalline forms advantageously exhibit improved stability, processability, and ease of preparation. As a result, the crystalline forms of the compounds of formula (I), in particular crystalline form C, provide long-term stability and low adsorption and desorption of water vapor. Consequently, crystalline forms provide significant clinical improvements in the treatment of ALD and lipid disorders such as hypercholesterolemia and fatty liver disease.

The present application also relates to various crystalline solvate forms and non-solvated form of the compound of formula (I), as well as methods for crystallizing the compound of formula (I).

Methods for crystallizing a compound of formula (I).

Methods for crystallizing a compound of formula (I) or a solvate thereof are disclosed. Crystalline forms of a compound of formula (I) can generally be isolated or prepared by crystallizing a compound of formula (I) under controlled conditions. In some embodiments, the method produces a crystalline form of the MTBE solvate. In some embodiments, the method produces a crystalline form of toluene solvate. In some embodiments, the method produces a crystalline form of ethanol solvate. In some embodiments, the method produces a crystalline form of the THF solvate. In some embodiments, the method produces a crystalline form of ethyl acetate solvate. In some embodiments, the method produces a crystalline form of acetone solvate. In some embodiments, the method produces crystalline Form C.

In some embodiments, the method includes dissolving an amorphous form of a compound of formula (I) in a first solvent to form a first solution. In some embodiments, the method includes dissolving a crystalline form of a compound of formula (I) or a solvate thereof in a first solvent to form a first solution. In some embodiments, the method includes dissolving a mixture of amorphous and crystalline forms of a compound of formula (I) in a first solvent to form a first solution. In some embodiments, the method includes adding a second solvent to the first solution to form a second mixture. In some embodiments, the second solvent is heptane.

In some embodiments, the method includes seeding a crystalline form of a compound of formula (I) or a solvate thereof into a first solution to form a seed mixture. In some embodiments, the method includes seeding a crystalline form of the MTBE solvate into the first solution to form a seed mixture. In some embodiments, the method includes seeding a crystalline form of toluene solvate into the first solution to form a seed mixture. In some embodiments, the method includes seeding a crystalline form of ethanol solvate into the first solution to form a seed mixture. In some embodiments, the method includes seeding a crystalline form of a THF solvate into the first solution to form a seed mixture. In some embodiments, the method includes seeding a crystalline form of ethyl acetate solvate into the first solution to form a seed mixture. In some embodiments, the method includes seeding a crystalline form of acetone solvate into the first solution to form a seed mixture. In some embodiments, the method includes seeding crystalline Form C into the first solution to form a seed mixture.

In some embodiments, the method includes seeding a crystalline

- 3 045751 form a compound of formula (I) or a solvate thereof into a second solution to form a seed mixture. In some embodiments, the method includes seeding a crystalline form of the MTBE solvate into a second solution to form a seed mixture. In some embodiments, the method includes seeding a crystalline form of toluene solvate into a second solution to form a seed mixture. In some embodiments, the method includes seeding a crystalline form of an ethanol solvate into a second solution to form a seed mixture. In some embodiments, the method includes seeding a crystalline form of a THF solvate into a second solution to form a seed mixture. In some embodiments, the method includes seeding a crystalline form of ethyl acetate solvate into a second solution to form a seed mixture. In some embodiments, the method includes seeding a crystalline form of an acetone solvate into a second solution to form a seed mixture. In some embodiments, the method includes seeding a crystalline Form C into a second solution to form a seed mixture.

In some embodiments, the seed mixture produces a crystalline form of the compound of formula (I) or a solvate thereof. In some embodiments, the seed mixture produces a crystalline form of the MTBE solvate. In some embodiments, the seed mixture produces a crystalline form of toluene solvate. In some embodiments, the seed mixture produces a crystalline form of ethanol solvate. In some embodiments, the seed mixture produces a crystalline form of the THF solvate. In some embodiments, the seed mixture produces a crystalline form of the ethyl acetate solvate. In some embodiments, the seed mixture produces a crystalline form of acetone solvate.

In some embodiments, a seed mixture produces crystalline form C. In some embodiments, a seed mixture seeded with a crystalline form of MTBE solvate produces crystalline form C. In some embodiments, a seed mixture seeded with a crystalline form of toluene solvate produces crystalline Form C. In some embodiments, a seed mixture seeded with a crystalline form of ethanol solvate produces crystalline Form C. In some embodiments, a seed mixture seeded with a crystalline form of THF solvate produces crystalline Form C. In some embodiments, a seed mixture seeded with an ethyl acetate solvate crystalline form produces crystalline Form C. In some embodiments, a seed mixture seeded with an acetone solvate crystalline form produces crystalline Form C. In some embodiments, a seed mixture seeded with an acetone solvate crystalline form produces crystalline Form C. In some embodiments, a seed mixture seeded with an ethyl acetate solvate crystalline form produces crystalline Form C. , containing crystalline form C as a seed, makes it possible to obtain crystalline form C.

In some embodiments, the method includes isolating a crystalline form of a compound of formula (I) or a solvate thereof. In some embodiments, the isolation is accomplished by filtration, such as hot filtration. In some embodiments, the isolated product may be dried, for example, by air drying.

In some embodiments, the first solvent may be the only solvent. In some embodiments, the first solvent may be a mixture of two or more solvents. In some embodiments, the first solvent may comprise ethyl acetate. In some embodiments, the first solvent may comprise ethanol. In some embodiments, the first solvent may comprise acetic acid. In some embodiments, the first solvent may contain octanol. In some embodiments, the first solvent may contain N-methyl-2-pyrrolidone (NMP). In some embodiments, the first solvent may contain MTBE. In some embodiments, the first solvent may contain toluene. In some embodiments, the first solvent may contain pyridine. In some embodiments, the first solvent may contain nitrobenzene. In some embodiments, the first solvent may comprise water. In some embodiments, the first solvent may contain heptane. In some embodiments, the first solvent may contain THF. In some embodiments, the first solvent may comprise acetone. In some embodiments, the first solvent may comprise acetonitrile.

In some embodiments, the second solvent may be the only solvent. In some embodiments, the second solvent may be a mixture of two or more solvents. In some embodiments, the second solvent may comprise ethyl acetate. In some embodiments, the second solvent may comprise ethanol. In some embodiments, the second solvent may comprise acetic acid. In some embodiments, the second solvent may contain octanol. In some embodiments, the second solvent may contain NMP. In some embodiments, the second solvent may contain MTBE. In some embodiments, the second solvent may contain toluene. In some embodiments, the second solvent may contain pyridine. In some embodiments, the second solvent may contain nitrobenzene. In some embodiments, the second solvent may comprise water. In some embodiments, the second solvent may comprise heptane. In some embodiments, the second solvent may contain THF. In some embodiments, the second solvent may comprise acetone. In some embodiments, the second solvent may comprise acetonitrile.

In some embodiments, the method further includes agitation. In some embodiments, agitation is accomplished by stirring. In some embodiments, agitation is accomplished by sonication.

In some embodiments, the method steps are performed at the same temperature. In some embodiments, the method steps are performed at different temperatures. In some embodiments, the method steps are performed at room temperature. In some embodiments, the method steps are performed at a temperature of from 0 to 100°C. In some embodiments, the method steps are performed at a temperature of 20 to 25°C. In some embodiments, the method steps are performed at a temperature of from 50 to 80°C. In some embodiments, the method steps are performed at a temperature of 50 to 60°C. In some embodiments, the method steps are performed at a temperature of 65 to 75°C. In some embodiments, the method steps are performed at a temperature of 23°C. In some embodiments, the method steps are performed at 55°C. In some embodiments, the method steps are performed at a temperature of 70°C. In some embodiments, the method steps may include a first solution, a second mixture, a seed mixture, isolation of a crystalline form, and agitation.

Crystalline forms of the compound of formula (I).

The present invention also discloses crystalline forms of the compound of formula (I) or solvates thereof, and in particular crystalline MTBE solvate, crystalline toluene solvate, crystalline ethanol solvate, crystalline THF solvate, crystalline ethyl acetate solvate, crystalline acetone solvate and crystalline Form C (described below).

Crystalline form of MTBE solvate.

The exact conditions for the formation of the crystalline form of the MTBE solvate can be determined empirically, and only a number of methods that have proven suitable in practice can be indicated.

The crystalline form of the MTBE solvate was characterized using various techniques, which are described in more detail in the experimental methods section. The crystal structure of the crystalline form of MTBE solvate determined by powder X-ray diffraction (pXRD) is shown in FIG. 2. The crystalline form of MTBE solvate, which can be prepared by the methods described below, exhibits characteristic peaks that can be identified from the XRD pattern.

Results obtained for the crystalline form of MTBE solvate using differential scanning calorimetry (DSC) are shown in FIG. 13. These results indicate a peak at 108°C for the MTBE solvate crystalline form, which indicates the melting point of the crystal. Therefore, in some embodiments, the crystalline form of the MTBE solvate has a melting point of about 103 to 113°C, about 106 to 110°C, or at about 108°C. The crystalline form of MTBE solvate was analyzed by thermogravimetric analysis (TGA), which showed a mass loss of 14.1% at temperatures ranging from 25 to 200 °C.

Crystalline form of toluene solvate.

The exact conditions for the formation of the crystalline form of toluene solvate can be determined empirically, and only a number of methods that have proven suitable in practice can be indicated.

The crystalline form of toluene solvate was characterized using various techniques, which are described in more detail in the experimental methods section. The crystal structure of the crystalline form of toluene solvate determined by powder X-ray diffraction (pXRD) is shown in FIG. 3. The crystalline form of toluene solvate, which can be prepared by the methods described below, exhibits characteristic peaks that can be identified from the XRD pattern.

The results obtained for the toluene solvate crystalline form by DSC are shown in FIG. 14. These results indicate a peak at 78°C for the toluene solvate crystalline form, which indicates the melting point of the crystal. Therefore, in some embodiments, the toluene solvate crystalline form has a melting point of about 73°C to 83°C, about 76°C to 80°C, or at about 78°C. The crystalline form of toluene solvate was analyzed by TGA, which showed a mass loss of 13.9% at temperatures ranging from 25°C to 200°C.

Crystalline form of ethanol solvate.

The exact conditions for the formation of the crystalline form of the ethanol solvate can be determined empirically, and only a number of methods can be indicated that have proven useful in practice.

The crystalline form of the ethanol solvate was characterized using various techniques, which are described in more detail in the experimental methods section. The crystal structure of the ethanol solvate crystalline form determined by powder X-ray diffraction (pXRD) is shown in FIG. 4. The crystalline form of ethanol solvate, which can be obtained by the methods described below, exhibits characteristic peaks that can be identified from the XRD pattern.

The results obtained for the ethanol solvate crystalline form by DSC are shown in FIG. 15. These results indicate a peak at 66°C for the ethanol solvate crystalline form, which indicates the melting point of the crystal. Therefore, in some embodiments, the crystalline form of the ethanol solvate has a melting point of about 61 to 71°C, about 64 to 68°C, or at about 66°C. The crystalline form of the ethanol solvate was analyzed by TGA, which showed a mass loss of 7.8% at temperatures ranging from 25 to 200 °C.

Crystalline form of THF solvate.

The exact conditions for the formation of the crystalline form of the THF solvate can be determined empirically, and only a number of methods that have proven suitable in practice can be indicated.

The crystalline form of the THF solvate was characterized using various techniques, which are described in more detail in the experimental methods section. The crystal structure of the crystalline form of the THF solvate determined by powder X-ray diffraction (pXRD) is shown in FIG. 5, 8a, 8b, 10a and 10b. The crystalline form of the THF solvate, which can be prepared by the methods described below, exhibits characteristic peaks that can be identified from the XRD pattern.

The results obtained for the THF solvate crystalline form by DSC are shown in FIG. 18. These results indicate a peak at 125°C for the THF solvate crystalline form, which indicates the melting point of the crystal. Therefore, in some embodiments, the crystalline form of the THF solvate has a melting point of about 120 to 130°C, about 123 to 127°C, or at about 125°C. The crystalline form of the THF solvate was analyzed by TGA, which showed a mass loss of 11.9% in one case and -12.1% in another case at temperatures ranging from 25 to 200°C.

Crystalline form of ethyl acetate solvate.

The exact conditions for the formation of the crystalline form of ethyl acetate solvate can be determined empirically, and only a number of methods can be indicated that have proven useful in practice.

The crystalline form of the ethyl acetate solvate was characterized using various techniques, which are described in more detail in the experimental methods section. The crystal structure of the crystalline form of ethyl acetate solvate determined by powder X-ray diffraction (pXRD) is shown in FIG. 6a and 6b. The crystalline form of ethyl acetate solvate, which can be prepared by the methods described below, exhibits characteristic peaks that can be identified from the XRD pattern.

The results obtained for the ethyl acetate solvate crystalline form by DSC are shown in FIG. 16. These results indicate a peak at 68°C for the ethyl acetate solvate crystalline form, which indicates the melting point of the crystal. Therefore, in some embodiments, the crystalline form of the ethyl acetate solvate has a melting point of about 63 to 73°C, about 66 to 70°C, or at about 68°C. The crystalline form of the ethyl acetate solvate was analyzed by TGA, which showed a mass loss of 10.8% at temperatures ranging from 25 to 200°C.

Crystalline form of acetone solvate.

The exact conditions for the formation of the crystalline form of acetone solvate can be determined empirically, and only a number of methods can be indicated that have proven useful in practice.

The crystalline form of the acetone solvate was characterized using various techniques, which are described in more detail in the experimental methods section. The crystal structure of the crystalline form of acetone solvate determined by powder X-ray diffraction (pXRD) is shown in FIG. 7a and 7b. The crystalline form of acetone solvate, which can be prepared by the methods described below, exhibits characteristic peaks that can be identified from the XRD pattern.

The results obtained for the acetone solvate crystalline form by DSC are shown in FIG. 17. These results indicate a peak at 96°C for the acetone solvate crystalline form, which indicates the melting point of the crystal. Therefore, in some embodiments, the crystalline form of the acetone solvate has a melting point of about 91 to 101°C, about 94 to 98°C, or about 96°C. The crystalline form of the acetone solvate was analyzed by TGA, which showed a mass loss of 9.0% at temperatures ranging from 25 to 200°C.

Crystalline form C.

Some embodiments include an unsolvated crystalline form of the compound of formula (I), referred to herein as crystalline form C. The exact conditions for the formation of crystalline form C can be determined empirically, and only a number of methods that have proven useful in practice can be indicated.

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Crystalline form C was characterized using various techniques, which are described in more detail in the experimental methods section. The crystal structure of crystal form C, determined by powder X-ray diffraction (pXRD), is shown in FIG. 11, fig. 12, fig. 21-27 and figs. 30. Crystalline Form C, which can be prepared by the methods described above, exhibits pronounced peaks at 2θ angles of approximately 9.1°, 12.4°, 13.8°, 16.0°, 16.6°, 17.1° , 18.6°, 19.1°, 21.6°, 21.7° and 23.7°. Thus, in some embodiments, the crystalline form of the compounds of formula (I) has at least one characteristic peak (e.g., one, two, three, four, five, six, seven, eight, nine, ten, or eleven characteristic peaks) with a value angle 2θ selected from the group consisting of approximately 9.1°, 12.4°, 13.8°, 16.0°, 16.6°, 17.1°, 18.6°, 19.1°, 21.6°, 21.7° and 23.7°. In some embodiments, the crystalline form of the compounds of formula (I) has at least three characteristic peaks occurring at 2θ angles selected from the group consisting of about 9.1°, 12.4°, 13.8°, 16. 0°, 16.6°, 17.1°, 18.6°, 19.1°, 21.6°, 21.7° and 23.7°.

Those skilled in the art should be well aware that due to experimental variability when diffraction patterns are taken on different setups, the peak positions are assumed to be equal if the 2θ angles coincide with a certain degree of variability. For example, according to the US Pharmacopoeia, diffraction patterns can be considered identical provided that the 2θ angles of the ten strongest diffraction peaks coincide with an accuracy of ±0.2° compared to the standard, and the relative intensities of the peaks do not change by more than 20%. Accordingly, in some embodiments, the peak positions provided in the present invention include a variability of 2θ angles within ±0.5°. In other embodiments, the peak positions provided in the present invention include a variation of 2θ angles within ±0.2°. In the present invention, the term approximately in relation to the values of the angles 2θ is defined as ±0.5°.

Results obtained for crystalline Form C by differential scanning calorimetry (DSC) are shown in FIG. 19a, 19b, 28a and 28b. These results indicate a peak at approximately 122°C for crystal form C, which indicates the melting point of the crystal.

Therefore, in some embodiments, crystalline Form C has a melting point of about 117 to 127°C, about 120 to 124°C, or at about 122°C. Crystalline form C was analyzed by thermogravimetric analysis (TGA), which showed a mass loss of 1.3% in one case and <0.1% in another case at temperatures ranging from 25 to 200°C.

Dynamic vapor sorption results for crystalline Form C showing water absorption of less than 0.2% by weight are shown in FIG. 29a. The results of powder X-ray diffraction analysis (pXRD) carried out after dynamic vapor sorption (Figs. 24 and 25) confirm that the crystalline form C does not transform into another polymorph. In fig. Figure 29b shows the results of a phase equilibrium experiment in water for three days, which did not show the transformation of crystalline form C, according to the XRD results shown in FIG. 26.

Thus, crystalline form C can be characterized as non-hygroscopic and stable over a wide range of humidity. Crystal form C also shows good crystallinity, relatively low residual solvent content (<0.1%), relatively high melting point (approximately 122°C), however crystal form C shows no evidence of hydrate formation. In contrast, solvate forms tend to desolvate to form mixtures of solvate and amorphous form. Such advantageous and useful properties as non-hygroscopicity and stability make the use of crystalline form C promising for commercial purposes. For example, treatments and pharmaceutical compositions based on crystalline form C may provide long-term stability and low water vapor adsorption and desorption, and may also provide significant clinical improvements in the treatment of ALD and lipid disorders such as hypercholesterolemia and fatty liver disease.

Treatment methods for adrenoleukodystrophy (ALD) and lipid metabolism disorders.

A compound of formula (I), and accordingly any of the compositions of a compound of formula (I) disclosed in the present invention, can be administered to a subject for the treatment or amelioration of ALD and lipid disorders such as hypercholesterolemia and fatty liver disease (non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) or glycogen storage disease). Thus, a compound of formula (I) can be administered to improve the condition of a subject, for example a subject suffering from ALD. Also, compounds of formula (I) can be administered for the treatment of lipid metabolism disorders such as hypercholesterolemia and fatty liver disease.

A compound of formula (I) can be administered in combination to a subject for the treatment of ALD and lipid disorders. The compounds of formula (I) can be administered to improve the condition of a patient suffering from hepatic encephalopathy. Compounds of formula (I) can be administered to relieve symptoms associated with ALD. The compounds of formula (I) can be administered to improve the condition of a patient suffering from hypercholesterolemia. Compounds of formula (I) can be administered to relieve symptoms associated with hypercholesterolemia. The compounds of formula (I) can be administered to improve the condition of a patient suffering from fatty liver disease. Compounds of formula (I) can be administered to relieve symptoms associated with fatty liver disease.

The subject is administered a therapeutically effective amount of compounds of formula (I). One skilled in the art will appreciate that the useful dose for in vivo administration and the particular route of administration will vary depending on the age, weight, severity of the disease and species of mammal being treated, the particular compounds used and the purposes for which the compounds are used. For example, see Fingl et al. The Pharmacological Basis of Therapeutics, 1975 (the present invention refers to this work, namely the reference to Chapter 1, p. 1). Determination of effective dosages, that is, the dosages required to achieve the desired result, can be performed by one skilled in the art using conventional pharmacological techniques. Typically, the use of the drug in medical practice begins with small dosages, and the dosage is increased until the desired effect is achieved. Alternatively, appropriate in vitro studies can be used to establish acceptable dosages and routes of administration of the compositions identified by the present methods using established pharmacological methods.

A single daily dose can be administered. Alternatively, multiple doses may be administered, such as two, three, four or five doses. Such multiple doses may be administered over one month, two weeks, or one week. In some embodiments, a single dose or multiple doses, such as two, three, four, or five doses, may be administered daily.

Compositions of compounds of formula (I).

The present invention also discloses compositions of a compound of formula (I). The compositions disclosed in the present invention are advantageously suitable for oral and/or intravenous administration to patients suffering from ALD or lipid disorders. In some embodiments, the compositions may be prepared by one of the methods disclosed in the present invention. For example, an amorphous crystallization method and/or a seeded crystallization method can produce the compositions disclosed in the present invention.

In some embodiments, the compositions may comprise a crystalline form of a compound of formula (I) (e.g., a MTBE solvate crystalline, a toluene solvate crystalline, an ethanol solvate crystalline, a THF solvate crystalline, an ethyl acetate solvate crystalline, an acetone solvate crystalline, and/or a crystalline form of Form C disclosed in the present invention). In some embodiments, the composition may contain at least about 20% by weight of the crystalline form of the compound of formula (I). In some embodiments, the composition may contain at least about 50% by weight of the crystalline form of the compound of formula (I). In some embodiments, the composition may contain at least about 80% by weight of the crystalline form of the compound of formula (I). In some embodiments, the composition may contain at least about 95% by weight of the crystalline form of the compound of formula (I). In some embodiments, the composition may contain at least about 50% by weight of crystalline Form C. In some embodiments, the composition may contain at least about 80% by weight of crystalline Form C. In some embodiments, the composition may contain at least about 95 % by weight of crystalline Form C. In some embodiments, the composition may contain at least about 99% by weight of crystalline Form C. In some embodiments, the composition consists essentially of a crystalline form of the compound of formula (I). In some embodiments, the composition consists essentially of crystalline Form C. In some embodiments, the composition contains a mixture of at least two (e.g., two, three, or four) crystalline forms, such as an MTBE solvate crystalline, a toluene solvate crystalline, a ethanol solvate crystal, THF solvate crystal, ethyl acetate solvate crystal, acetone solvate crystal and C crystal.

In some embodiments, the compositions contain crystalline Form C. For example, the compositions may contain at least about 20%, at least about 50%, at least about 90%, at least about 95%, or at least about 99% crystalline Form C. Likewise, the compositions may also contain, for example, a MTBE solvate crystal, a toluene solvate crystal, an ethanol solvate crystal, a THF solvate crystal, an ethyl acetate solvate crystal, or an acetone solvate crystal. The compositions may optionally contain at least about 20%, at least about 50%, at least about 90%, at least about 95%, or at least about 99% MTBE solvate crystalline, toluene solvate crystalline, ethanol solvate crystal, THF solvate crystal, ethyl acetate solvate crystal, acetone solvate crystal and/or C crystal.

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Pharmaceutical compositions.

Compositions of compounds of formula (I) disclosed in the present invention may also be formulated for administration to a subject (eg, a human). The compound of formula (I) and accordingly the compositions disclosed herein can be formulated for administration with a pharmaceutically acceptable carrier or diluent. Thus, the compound of formula (I) can be formulated as a medicament with standard pharmaceutically acceptable carrier(s) and/or excipient(s) as is customary in the pharmaceutical art. The exact nature of the drug will depend on several factors, including the desired route of administration. Typically, the compound of formula (I) is prepared for oral, intravenous, intragastric, subcutaneous, intravascular or intraperitoneal administration.

The pharmaceutical carrier or diluent may be, for example, water or an isotonic solution such as 5% dextrose in water or saline. In addition to the active compound, solid oral forms may contain diluents (for example, lactose, dextrose, sucrose, cellulose, corn starch or potato starch), lubricants (for example, silicon dioxide, talc, stearic acid, magnesium stearate or calcium stearate, sodium lauryl sulfate and/or or polyethylene glycols), binding agents (for example, starches, gum arabic, gelatin, microcrystalline cellulose, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone), disaggregating agents (for example, starch, alginic acid, alginates or sodium starch glycolate), effervescent mixtures, dyes, sweeteners, wetting agents (lecithin, polysorbates, lauryl sulfates) and, as a rule, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations can be prepared by known methods, for example by mixing, granulating, tableting, glazing or spraying.

Liquid dispersions for oral administration may be syrups, emulsions or suspensions. Syrups may contain as carriers, for example, sucrose or sucrose with glycerol and/or mannitol and/or sorbitol.

Suspensions and emulsions may contain as a carrier, for example, natural gum, agar, sodium alginate, pectin, microcrystalline cellulose, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. In addition to the compounds of formula (I), suspensions or solutions for intramuscular injection may contain a pharmaceutically acceptable carrier, for example sterilized water, olive oil, ethyl oleate, glycols such as propylene glycol and sodium lauryl sulfate.

The drug may consist essentially of a compound of formula (I) and a pharmaceutically acceptable carrier.

Oral formulations may typically contain dosages of a compound of formula I in the range of from about 1 mg to 100 g. Accordingly, in some embodiments, the oral formulation contains compositions of a compound of formula (I) disclosed herein in the range of about 1 mg to 50 g. In some embodiments, the oral formulation contains compositions of a compound of Formula (I) disclosed herein in a range of from about 1 to 100 mg. In some embodiments, the oral formulation contains compositions of a compound of Formula (I) disclosed herein in a range of about 1 to 20 mg. In some embodiments, the oral formulation contains compositions of a compound of formula (I) disclosed herein in a range of from about 5 to 15 mg. In some embodiments, the oral formulation contains compositions of a compound of formula (I) disclosed herein in an amount of about 10 mg.

Formulations for intravenous administration may also typically contain dosages of a compound of formula (I) ranging from about 1 mg to 100 g (eg, about 10 mg). In some embodiments, the intravenous formulation contains a concentration of a compound of formula (I) from about 5 to 300 mg/ml (preferably from about 25 to 200 mg/ml, and more preferably from about 40 to 60 mg/ml).

The composition or medicinal product containing the specified composition may optionally be placed in a sealed package. Sealed packaging can reduce or prevent wetting of the composition or drug and/or its contact with ambient air. In some embodiments, the packaging includes an airtight seal. In some embodiments, the package is sealed under vacuum or with an inert gas (eg, argon) within a sealed package. Accordingly, the packaging may inhibit or reduce the rate of degradation of the composition or drug stored in the packaging. Various types of sealed packages are known in the art. For example, US Pat. No. 5,560,490, incorporated herein by reference in its entirety, discloses an example of sealed packaging for pharmaceuticals.

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Examples and experimental methods

Additional embodiments are disclosed in more detail in the following examples, which in no way limit the scope of the claims.

Powder X-ray diffraction analysis (pXRD).

pXRD was carried out on a Bruker D8 advance or Philips PW 1710 diffractometer. In embodiments using a Bruker D8 diffractometer, samples were scanned using Cu K _a radiation; tube power was 35 kV/45 mA; VANTEC1 detector; the step size along the 2θ angle was 0.017°; step time was 105 ± 5 seconds; the 2θ scanning range was 2°-50°. Samples in their original state or slightly crushed were used for analysis. Sample holders made of silicon single crystals were used. The diameter of the samples was 12 mm and the depth was 0.1 mm.

In embodiments using a Philips PW 1710 diffractometer, samples were scanned under Cu K _a radiation; the step size along the 2θ angle was 0.02°; stride time was 2.4 seconds; the 2θ scanning range was 2-50°. Sample holders of 0.1 mm size were used. The samples were scanned without any special treatment other than applying slight pressure to obtain a flat surface. The measurements were carried out in ambient air.

Thermogravimetric analysis (TGA).

Thermogravimetric measurements were carried out using a Perkin-Elmer TGS-2 thermobalance (aluminum sample cups, nitrogen atmosphere 50 ml/min, heating rate 10 K/min, range from 25°C to 200°C or 350°C).

Thermogravimetric analysis based on Fourier transform infrared spectroscopy (TG-FTIR).

Thermogravimetric analysis based on Fourier transform infrared spectroscopy was carried out using a Netzsch TG 209 microthermal balance connected to a Bruker FTIR Spectrometer Vector 22 spectrometer (sample cuvettes with a pinhole, nitrogen atmosphere, heating rate - 10 K/min, in the range from 25 to 250 °C).

Differential scanning calorimetric analysis (DSC).

In some embodiments, DSC was performed using Perkin Elmer DSC7 equipment under the following experimental conditions: sample weight - from 3.26 to 4.51 mg, closed gold cuvette for the sample, temperature range - from -50°C to 100°C/ 150°C/225°C, heating rate was 10 or 20 K/min. The samples were weighed in air.

In other embodiments, DSC was carried out using Perkin Elmer DSC7 equipment under the following experimental conditions: sample weight - 3.53 mg, closed gold cuvette for the sample, temperature range - from -50°C to 150°C, heating rate was 20 K /min. The sample was weighed in air.

Nuclear magnetic resonance (NMR) on 1H nuclei.

Samples were dissolved in CDCl ₃ . NMR spectra were recorded on a Bruker spectrometer (Ultrashield TM, B ACS 60, 300 MHz).

Determination of water content with Karl-Fischer titration.

Determination of water content with Karl-Fischer titration was carried out according to standard methods.

Dynamic vapor sorption.

A 9.869 mg sample was placed on a platinum dish and left at 25°C and 50% relative humidity (RH) before starting the humidity program. Humidity setting programs: 1.0 hour at 50% rel. vl., from 50% rel. ow. up to 0% rel. ow.; 5% rel. ow. per hour, 5 hours at 0% rel. vl., from 0% rel. ow. up to 93% rel. ow.; 5% rel. ow. per hour, 5 hours at rel. ow. 93%, from 93% rel. ow. up to 50% rel. ow.; 5% rel. ow. per hour, 1 hour at 50% rel. ow.

Solvents.

Fluka or Merck brand solvents were used. Fluka #95305, deionized water for appropriate experiments.

Determination of approximate solubility.

In some embodiments, a solvent is added stepwise to the solid to determine the approximate solubility at room temperature. After each addition, the sample was mixed well. Solvent was continued to be added until the sample was completely dissolved or until the amount of solvent exceeded 20 mL.

In other embodiments, aliquots of the test solvent were added to an accurately weighed amount of the compound of formula (I) in small portions (typically 100-1000 μl) and sonicated until completely dissolved, if possible. Dissolution was determined visually. Actual solubility may be higher than stated due to slow dissolution rates or use of excess solvent. Approximate solubility was determined in mg/mL, rounded to the nearest whole number.

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Crystallization experiments.

Crystallization experiments were carried out with compound weights ranging from 40 to 256 mg. Solutions or suspensions were stirred with a magnetic stirrer. Samples obtained after filtration (glass filter porosity P4) were air dried at ambient temperature for a short time to prevent possible desolvation of labile hydrates or solvates.

Source material A.

Starting material was provided by Metabasis Therapeutics Inc. The material was characterized as amorphous, which was confirmed by the XRD result (Fig. 1).

The approximate solubility at ambient temperature must be known to perform systematic crystallization experiments.

The approximate solubility of amorphous starting material A at 23°C is given in the table below. 1.

Table 1

Approximate solubility of starting material A

Solvent Solubility (mg/ml) 2,2,2-trifluoroethanol -195 acetonitrile >480 chloroform >388 dichloromethane >480 n-heptane <38 methyl ethyl ketone >480 methyl nonafluorobutyl ether <39 methylcyclohexane <40 THF >384 ethyl acetate -772 ethanol >200 acetic acid >200 1-octanol >200 M-methyl-2-pyrrolidone (NMP) >200 tert-butyl methyl ether (MTBE) >200 toluene >200 pyridine >200 nitrobenzene >200 ethanol/n-heptane 75:25 v/v >200 tetrahydrofuran (THF)/nheptane 75:25 rpm >200 ethyl acetate/n-heptane 75:25 v/v >200 acetone/n-heptane 75:25 v/v >200 ethanol/water 75:25 v/v >200 THF/water 75:25 v/v 190 acetone/water 75:25 v/v >200 acetonitrile/water 75:25 v/v >200

v/v = volume to volume.

Example 1. Attempts at crystallization from solution.

In the following example, all vapors and suspensions produced oils. Suspension of samples containing trace amounts of birefringent and quenching solids in various solvents and antisolvents did not result in an increase in the number or size of crystals at elevated temperatures. Exposure of oils and starting materials to antisolvent vapors at elevated temperatures resulted in minor amounts of birefringent and quenching solids in the oils and gels. Temperature cycling experiments showed no evidence of crystallization. These results demonstrate the difficulty of crystallizing the compound of formula (I).

Details of various crystallization experiments from solutions and the results obtained are given below in table. 2.

table 2

Attempts at crystallization using solvents

No. Solvent system Way Results 1 tetrafluoroethylene/MTBE slow evaporation -> rapid evaporation oil 2 chloroform/heptane slow cooling oil 3 ethyl acetate/cyclohexane slow cooling oil 4 dioxane/methylcyclohexane slow cooling oil 5 methyl ethyl ketone/methyl cyclohexane slow evaporation —► rapid evaporation oil 6 dichloromethane/diisopropyl ether slow evaporation —► rapid evaporation oil 7 MTBE/perfluorohexanes suspension oil methyl nonafluorobutyl ether diffusion from vapor phase oil, small plates 8 oils (01/14/1981) at 40°С 70°С (+B/+E) 9 perfluorohexanes diffusion from vapor phase of oil (01/12/1981) at 40°С 70°С oil heptane diffusion from vapor phase oil, slight 10 oils (02/11/1981) at 40°С 70°С amount of sediment in the form of flakes (+B/+E) AND cyclohexane diffusion from vapor phase oil, slight oils (04/10/1981) at 40°С 70°С amount of sediment (+B/+E) 12 heptane suspension at ~70°С remaining oil 13 methylcyclohexane suspension at ~70°С remaining oil 14 methyl nonafluorobutyl ether suspension at ~70°С gel residue methyl nonafluorobutyl ether diffusion from fine particles 15 vapor phase at ~70°С (+B/+E), oil cyclohexane diffusion from particles 16 vapor phase at ~70°С (+B/+E), oil/gel 17 anisole temperature cycling 1060-10°C oil, without particulate matter 18 cumene temperature cycling 1060-10°C oil, without particulate matter 19 o-xylene temperature cycling 1060-10°C oil, without particulate matter

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20 methyl benzoate temperature cycling 1060-10°C oil, without particulate matter 21 acetonitrile suspension at ~70°С oil, without particulate matter 22 dioxane suspension at ~70°С oil, without particulate matter 23 methyl nonafluorobutyl ether suspension in oil (01/10/1981) oil, without particulate matter 24 methyl nonafluorobutyl ether suspension in oil (02/10/1981) oil, without particulate matter 25 methyl nonafluorobutyl ether suspension in oil (01/24/1981) oil, without particulate matter 26 methyl nonafluorobutyl ether suspension in oil (02/24/1984) at ~60°C oil, without particulate matter 27 methyl nonafluorobutyl ether suspension in oil (03/24/1984) at ~60°C oil, without particulate matter 28 methyl nonafluorobutyl ether suspension in oil (01/26/1984) at ~60°C oil, without particulate matter 29 ethanol/water deposition in antisolvent sticky gel-like solids

Example 2. Attempts at crystallization without the use of solvents.

Experiments at elevated temperature and relative humidity resulted in the production of oils containing small amounts of solids that exhibit birefringence and quenching. Ultrasonication did not provide any advantage over more common methods. These results further confirm the difficulty of crystallizing the compound of formula (I). Heteropriming using a diisopropyl ester analog was also ineffective.

The details of various solvent-free crystallization experiments and the results obtained are given below in Table. 3.

Table 3

Attempts at crystallization without application solvents No. Way Morphology thirty Ultrasonication (acetonitrile) oil, without crystallization 31 Ultrasonication (dichloromethane) oil, without crystallization 32 Ultrasonication (ethanol) oil, without crystallization 33 Ultrasonication (ethyl ether) oil, without crystallization 34 Ultrasonication (heptane) oil, without crystallization 35 Ultrasonic treatment (isopropyl alcohol) oil, without crystallization 36 Ultrasonication (methanol) oil, without crystallization 37 Ultrasonic treatment (methyl ethyl ketone) oil, without crystallization 38 Ultrasonication (methyl nonafluorobutyl ether) oil, without crystallization 39 Ultrasonication (MTBE) oil, without crystallization 40 Ultrasonication (THF) oil, without crystallization 41 Ultrasonication (toluene) oil, without crystallization

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42 At a temperature of ~100°C clear oil, two small crystalline fragments of irregular shape (+B/+E) 43 At relative humidity ~58% and temperature 40°C gelled solids (-B/-E) 44 At relative humidity ~75% and temperature 40°C oil, no solids 45 At relative humidity ~75% and temperature 60°C clear oil, no solids 46 At a temperature of ~80°C oil

Example 3: Crystallization experiments.

Spontaneous crystallization of the compound of formula (I) was observed when the amorphous form was dissolved in a mixture of THF and heptane (ratio 75:25 v/v) at room temperature. Heptane was additionally added until a cloudy solution was obtained. This solution was stirred with a magnetic stirrer at room temperature for 16 hours to obtain a white paste. The XRD results confirmed the crystalline form of the substance, Fig. 5 (test result 9 below). This crystalline substance has been used to seed amorphous solutions or suspensions in a number of other solvent systems. In most cases, a crystalline substance was obtained in a short time at room temperature. The solvates were always prepared using these crystallization conditions. Ethanol solvate (test 8) and THF solvate (test 14) were examined by solution NMR (not shown).

The first attempt at desolvation of the THF solvate at 80°C in heptane (test 15) resulted in the formation of a viscous sticky mass. After cooling to room temperature, the suspension was seeded with ethanol solvate and stirred for 20 hours at room temperature. After filtration and air drying at room temperature, the sample contained only a trace amount of residual solvent and xXRD confirmed the formation of a new crystalline form (i.e. crystalline form C), FIG. 9. The NMR spectrum of the solution (not shown) turned out to be identical to the spectrum of the starting material. This unsolvated crystalline form C was used as a seed in further crystallization experiments.

Various crystallization experiments resulted in large quantities of crystalline or solvate forms of the compound of formula (I). For example, THF solvate (test result 20) and unsolvated crystal form C (test results 21 and 23) were obtained at 200 mg.

The details of the various crystallization experiments and the results obtained are given below in Table. 4.

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Table 4

Crystallization experiments

Trial Raw material Solvent Concentration (mg/ml) Conditions Results 1 amorphous substance ethyl acetate 103/0.3 23°C crystals adding 0.4 ml n-heptane, 23°C, stirring (magnetic stirrer) at 23°C adding approx. 5 mg amorphous substance, room temperature temperature stirring for 135 min at 70°C cooling to room temperature temperature; addition substance obtained as a result of test 9 2 amorphous substance ethanol 62/0.2 23°С emulsion adding 0.1 ml water, 23 °C, stirring (magnetic stirrer) at 23 °C adding approx. 5 mg of amorphous substance,

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indoor temperature 3 amorphous substance acetic acid 65/0.2 23°С emulsion adding 0.1 ml water, 23 °C, stirring (magnetic stirrer) at 23 °C adding approx. 5 mg amorphous substance, room temperature temperature 4 amorphous substance 1-octanol 63/0.3 23°С emulsion adding 1.1 ml n-heptane, 23°C, stirring (magnetic stirrer) at 23°C adding approx. 5 mg amorphous substance, room temperature temperature 5 NMP 68/0.1 23°С emulsion

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amorphous substance adding 0.1 ml water, 23 °C, stirring (magnetic stirrer) at 23 °C adding approx. 5 mg amorphous substance, room temperature temperature 6 amorphous substance MTBE 54/0.2 23°С MTBE solvate adding 0.2 ml n-heptane, 23°C, stirring (magnetic stirrer) at 23°C adding the substance obtained from test 9; room temperature 7 amorphous substance toluene 60/0.2 23°С toluene solvate adding 0.1 ml n-heptane, 23°C, stirring

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(magnetic stirrer) at 23°C adding the substance obtained from test 9; room temperature 8 amorphous substance ethanol/nheptane 75:25 v/v 66/0.1 23°С ethanol solvate adding 0.09 ml n-heptane, 23 °C, stirring (magnetic stirrer) at 23 °C adding the substance obtained from test 9; room temperature 9 amorphous substance THF/n-heptane 75:25 rpm 63/0.1 23°С THF solvate adding 0.06 ml n-heptane, 23 °C, stirring

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(magnetic stirrer) at 23°C stirring at room temperature for 16 hours 10 amorphous substance ethyl acetate/nheptane 75:25 v/v 70/0.1 23°С solvate ethyl acetate adding 0.06 ml n-heptane, 23°C, stirring (magnetic stirrer) at 23°C adding the substance obtained from test 9; room temperature And amorphous substance acetone/nheptane 75:25 v/v 68/0.1 23°С acetone solvate adding 0.14 ml n-heptane, 23°C, stirring (magnetic stirrer) at 23°C

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adding the substance obtained from test 9; room temperature 12 amorphous substance acetone/water 75:25 rpm 60/0.2 23°С acetone solvate adding 0.02 ml water, 23°C, stirring (magnetic stirrer) at 23°C adding the substance obtained from test 9; room temperature 13 amorphous substance acetonitrile/water 75:25 v/v 67/0.1 23°С emulsion adding 0.02 ml water, 23°C, stirring (magnetic stirrer) at 23°C adding a substance

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obtained as a result of test 9; room temperature 14 amorphous substance THF/n-heptane 75:25 rpm 126/0.2 23°С THF solvate adding 0.1 ml n-heptane, 23°C, stirring (magnetic stirrer) at 23°C adding the substance obtained from test 9; room temperature adding 2.0 ml n-heptane, 23°C, stirring (magnetic stirrer) at 23°C filtration, air drying for 5 minutes. at

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room temperature 15 Trial 19 n-heptane 40/2.0 23°С crystalline form C + small amount of THF solvate stirring at 80°C (magnetic stirrer) cooling to room temperature temperature, addition of substance obtained from test 8; indoor temperature stirring at room temperature (magnetic stirrer) for 20 hours, 23°C filtration, air drying for 5 minutes. at room temperature temperature

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16 amorphous substance n-heptane 59/2.0 23°C addition of substance obtained from test 14; room temperature stirring at room temperature (magnetic stirrer) for 18 hours, 23°C filtration, air drying for 5 minutes. at room temperature amorphous substance + small amount of THF solvate 17 amorphous substance water 51/2.0 23°C addition of substance obtained from test 14; room temperature amorphous substance

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stirring at room temperature (magnetic stirrer) for 18 hours, 23°C filtration, air drying for 5 minutes. at room temperature temperature 18 amorphous substance n-heptane 54/2.0 23°С amorphous substance adding the substance obtained from test 8; room temperature stirring at room temperature (magnetic stirrer) for 18 hours, 23°C filtration, drying

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air for 5 minutes. at room temperature temperature 19 amorphous substance water 53/2.0 23°С amorphous substance adding the substance obtained from test 8; room temperature stirring at room temperature (magnetic stirrer) for 18 hours, 23°C filtration, air drying for 5 minutes. at room temperature temperature 20 amorphous substance THF 253/0.3 23°С THF solvate (238 mg) adding 30 ml n-heptane, 23°C, stirring (magnetic

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stirrer) for 30 minutes. at 23 °C sonication at room temperature for 3 min. stirring for 30 minutes. at 55°C hot filtration, air drying for 5 minutes. at room temperature 21 amorphous substance pure ethanol 252/0.3 23°C adding 30 ml of n-heptane, 23°C, stirring (magnetic stirrer) for 55 minutes. at 23 °C sonication at room temperature crystalline form C (198 mg)

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temperature for 3 minutes. stirring for 38 minutes. at 23 °C stirring for 47 min. at 55°C stirring for 70 minutes. at 23 °C add approx. 5 mg crystalline form C (test 23), stirring at 23°C for 10 minutes. sonication at room temperature temperature for 3 minutes. stirring for 50 minutes. at 55°C hot filtration, drying at

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air for 5 minutes. at room temperature temperature 22 amorphous substance MTBE 256/0.3 23°С crystalline form C + small amount of MTBE solvate (191 mg) adding 30 ml of n-heptane, 23°C, stirring (magnetic stirrer) for 45 minutes. at 23 °C sonication at room temperature temperature for 3 minutes. stirring for 45 minutes. at 23°C stirring for 47 minutes. at 55°С stirring for 78 minutes. at 23°C adding approx. 5 mg crystal form C

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(test result 23), stirring at 23°C stirring for 4 minutes. at 23 °C stirring for 8 minutes. at 55°C sonication at room temperature for 3 minutes. stirring for 80 minutes. at 55°C sonication at room temperature for 3 minutes. stirring for 22 minutes. at 55°C sonication at room temperature

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23 amorphous substance n-heptane + 0.5% THF 199/10 temperature for 3 minutes. crystalline form C (144 mg) stirring for 10 minutes. at 55°C hot filtration, air drying for 5 minutes. at room temperature temperature 23°С stirring (magnetic stirrer) for 25 minutes. at 55°C adding approx. 5 mg crystalline shape C (test result 15), stirring at 55°C for 25 minutes ultrasonic treatment at room temperature for 3 minutes. stirring for 24 minutes. at 55°C hot filtration, air drying for 5 minutes. at room temperature temperature

v/v = volume to volume.

Example 4. Characteristics of crystalline samples.

Crystalline solid forms were examined using pXRD, TGA, DSC, and selected samples were examined using solution NMR.

pXRD results of unsolvated crystalline Form C (Figures 11, 12, 21-27 and 30) show good crystallinity, relatively low residual solvent content (<0.1%), melting point of 122°C (sealed sample cuvettes; peak temperature DSC), Fig. 19a and 19b. NMR of the solution revealed a spectrum of the starting material (not shown).

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Study of solvates using DSC, Fig. 13-18, allowed us to determine their stability, assessed by the peak temperature measured in hermetically sealed sample cuvettes. The peak temperatures of solvates vary widely. The highest temperature was observed for the THF solvate (125°C), Fig. 18, which confirms its high stability. For ethanol solvate (66°C), Fig. 15, and ethyl acetate solvate (68°C), FIG. 16, the peak temperatures are much lower and significantly lower than the boiling points of the corresponding solvents. Ethanol solvate (test result 8) and THF solvate (test result 14) were examined by solution NMR (not shown) and showed spectra identical to those of the starting material and solvent of the corresponding solvate.

Thermogravimetric (TG) mass loss and DSC peak temperatures for Example 4 are shown in Table 1 below. 5.

Table 5 Solid Form Study

Connection or test Solid form Weight loss during TG at temperatures from 25°C to 200°C (%) Peak Temperature (°C) A amorphous substance no data no data 6 MTBE solvate 14.1 108 7 toluene solvate 13.9 78 8 ethanol solvate 7.8 66 10 ethyl acetate solvate 10.8 68 eleven acetone solvate 9.0 96 14 THF solvate 12.1 125 15 crystalline form C + small amount of THF solvate 0.7 117 20 THF solvate 11.9 125 21 crystal form C <0.1 122 23 crystal form C 1.3 no data

Example 5 Additional crystallization experiments using seeds.

Phase equilibration experiments in solvent mixtures at various temperatures and seed crystallization experiments were carried out to search for other unsolvated crystalline forms of the compound of formula (I). A number of typical crystallization methods (for example, recrystallization from a melt or crystallization by cooling solutions) are unacceptable, since under these conditions the nucleation of the compound is difficult. In turn, desolvation of solvates tends to form an amorphous form.

Seeding concentrated solutions of the amorphous form in ethanol and THF using unsolvated crystalline form C at room temperature yields ethanol solvate (test result 26) and THF solvate (test result 29), respectively. DSC examination of various solvates allowed their stability to be determined, as assessed by peak temperatures measured in sealed sample cuvettes.

Crystalline Form C was obtained directly under test conditions 30: the amorphous form was dissolved in ethyl acetate and heated to 75°C. Heptane was added slowly until the ethyl acetate/heptane ratio was 1:7 v/v. The system was seeded with crystalline Form C and stirred for additional time at 77°C. The solid was isolated by hot filtration of the suspension. The pRSA result showed unsolvated cre

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For crystallization of unsolvated crystalline Form C, a solvent/antisolvent mixture is desired that does not yield the corresponding solvate or oil but still allows acceptable solubility to be determined. In ethyl acetate/heptane mixtures at a ratio below 1:7 v/v. at 76°C, oil was obtained even when crystalline form C was introduced as a seed (test result 34).

The unsolvated crystalline form C shows high physical and chemical stability in ethyl acetate/heptane 1:7 v/v. Phase equilibration experiments for three days at room temperature and at a temperature of 78°C showed no transformation of the crystalline form C obtained in test 37. The NMR spectrum of the solution was identical to the spectrum of the starting material (not shown).

Mixing a suspension of amorphous form with seeds in the form of crystalline form C in a mixture of ethyl acetate/heptane 1:7 v/v. at room temperature for 18 hours also gave crystalline form C (test 42). However, at 2°C, ethyl acetate solvate was formed (test 43). The stability ranges of ethyl acetate solvate in solvent/antisolvent mixtures at different temperatures need to be tested. Crystalline Form C appears to be physically more stable over a wider range of solvent/antisolvent ratios when using ethyl acetate/heptane than when using ethanol/heptane (tests 33 and 34).

For several samples, the peak at a 2Θ angle of 18° in the diffraction pattern was wider, as follows from tests 44 and 45, Fig. 23. Therefore, the supersaturated solution was seeded (test 47) with a sample that showed a relatively broad peak at a 2Θ angle of 18°, FIG. 27. The solid obtained from this stability experiment indicated that this broader peak does not indicate a physically more stable form.

Details of additional crystallization experiments using seeds and the results for the solid state of samples from example 5 are given below in table. 6.

Table 6 Additional crystallization experiments using seeds

Pepe Tanie Raw material Solvent Concentration (mg/ml) Conditions Results 24 amorphous substance THF 119/0.15 shaking at 23 °C THF solvate adding approx. 5 mg THF solvate (test result 20), shaking at 23°C

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25 amorphous substance ethanol 125/0.15 shaking at 23 °C ethanol solvate adding approx. 5 mg THF solvate (test result 20), shaking at 23°C 26 amorphous substance ethanol 125/0.15 23°С ethanol solvate adding approx. 5 mg crystalline form C (test result 21), shake at 23°C 27 amorphous substance ethanol + nheptane 75:25 v/v 67/0.19 23°С ethanol solvate adding approx. 5 mg THF solvate (test result 20), shaking at 23°C storage at 23°C for 17 days

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28 amorphous substance ethanol + nheptane 75:25 v/v 66/0.19 23°С ethanol solvate adding approx. 5 mg crystalline form C (test result 21), shaking at 23°C storage at 23°C for 17 days 29 amorphous substance THF 124/0.15 23°С THF solvate adding approx. 5 mg crystalline form C (test result 21), shake at 23°C storage at 23°C for 17 days thirty amorphous substance ethyl acetate 251/2.0 23°С crystal form C stirring at 75 °C 251/5.5 adding 3.5 ml n-heptane

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ethyl acetate + n-heptane 1:1.75 rpm adding approx. 12 mg crystalline form C (test result 21) ethyl acetate + n-heptane 251/16 adding 10.5 ml n-heptane and approx. 5 mg crystalline form C (test result 21) stirring at 77°C for 20 minutes. deletion solid with glass walls stirring at 77°C for 5 minutes. hot filtration, air drying for 3 minutes.

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at room temperature 31 amorphous substance ethyl acetate 251/2.0 23°С crystal form C stirring at 75°C ethyl acetate + n-heptane 1:7 v/v 251/16 adding nheptane and approx. 5 mg crystal form C (test result 30) deletion solid with glass walls stirring at 76°C for 5 minutes. removal of solids substances from the glass wall stirring at 76°C for 75 minutes.

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removal of solids substances from the glass wall stirring at 76°C for 35 minutes. hot filtration, air drying for 3 minutes. at room temperature 32 amorphous substance ethanol 248/2.0 23°С crystal form C stirring at 76°C ethanol + nheptane 1:7 v/v 248/16 adding 14 ml n-heptane and approx. 5 mg crystalline form C (test result 30) ethanol + nheptane 1:10 v/v 248/22 adding 6 ml n-heptane and approx. 5 mg crystalline

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y form C (test result 30) cool to room temperature over one night adding approx. 5 mg of crystalline form C (test result 30), stirring at room temperature for 50 minutes. removal of solid matter from the glass wall, stirring at 23°C for 3 days, filtration, air drying in

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for 3 minutes at room temperature 33 amorphous substance ethanol 250/0.5 23°С crystal form C stirring at 76°C ethanol + nheptane 1:10 v/v 250/5.5 adding 5.0 ml n-heptane and approx. 5 mg crystalline form C (test result 31) ethanol + nheptane 1:20 v/v 250/10.5 adding 5.0 ml n-heptane and approx. 5 mg crystalline form C (test result 31) ethanol + nheptane 1:30 v/v 250/15.5 adding 5.0 ml n-heptane and approx. 5 mg crystalline form C (test result 31) cooling to room temperature

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temperatures for one night adding approx. 5 mg of crystalline form C (test result 31), stirring at room temperature for 43 minutes. deletion solid from glass wall stirring at 23°C for 3 days filtration, air drying for 3 minutes. at room temperature 34 ethyl acetate 251/2.0 23°C

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amorphous substance stirring at 76°C crystal form C ethyl acetate + n-heptane 1:1 v/v 251/4.0 adding 2.0 ml n-heptane and approx. 5 mg crystalline form C (test result 31) ethyl acetate + n-heptane 1:2 v/v 251/6.0 adding 2.0 ml n-heptane and approx. 5 mg crystalline form C (test result 31) ethyl acetate + n-heptane 1:3 v/v 251/8.0 adding 2.0 ml n-heptane and approx. 5 mg crystalline form C (test result 31) ethyl acetate + n-heptane 1:4 v/v 251/10 adding 2.0 ml n-heptane and approx. 5 mg crystalline form C

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(test result 31) ethyl acetate + n-heptane 1:5 v/v 251/12 adding 2.0 ml n-heptane and approx. 5 mg crystalline form C (test result 31) ethyl acetate + n-heptane 1:6 v/v 251/14 adding 2.0 ml n-heptane and approx. 5 mg crystalline form C (test result 31) ethyl acetate + n-heptane 1:7 v/v 251/16 adding 2.0 ml n-heptane and approx. 5 mg crystalline form C (test result 31) stirring at 78°C for 20 minutes. removing solids from

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glass wall stirring at 78°C for 20 minutes. hot filtration, air drying for 3 minutes. at room temperature 35 amorphous substance ethyl acetate 253/2.0 23°С crystal form C adding solution to 14 ml n-heptane + approx. 5 mg crystalline form C (test result 34), stirring at 78°C for 20 minutes. removal of solids substances from the glass wall

- 43 045751

stirring at 78°C for 25 minutes. hot filtration, air drying for 3 minutes. at room temperature 36 amorphous substance ethyl acetate 250/1.0 23°С crystal form C adding the solution to 15 ml of ethyl acetate + nheptane in a ratio of 1:14 v/v. + 57 mg starting material B + approx. 5 mg crystalline form C (test result 34), stirring at 78°C for 15 minutes. removal of solids

- 44 045751

substances from the glass wall cooling to room temperature temperature, stirring at room temperature for 3 days filtration, air drying for 3 minutes. at room temperature 37 Tested e 34 ethyl acetate + n-heptane 1:7 v/v 110/7.0 23°С crystal form C stirring at 78°C for 3.5 hours deletion solid with glass walls stirring at 78°C in

- 45 045751

within 5.5 hours removal of solids from the glass wall stirring at 78°C for 3 days removing solid matter from glass wall hot filtration, drying air for 3 minutes. at room temperature 38 amorphous substance ethyl acetate 127/0.15 23°C adding approx. 5 mg crystalline form C (test result 30), solvate ethyl acetate

- 46 045751

shaking at 23°C storage at 23°C, 17 hours 39 amorphous substance ethyl acetate 124/0.15 23°С crystal form C adding approx. 5 mg crystalline form C (test result 30), shaking at 23°C adding 3.0 ml n-heptane 50°C, 2 min. 23°C, add approx. 5 mg MTBE solvate (test result 6), stirring at 23°C for 10 minutes. deletion solid substances with

- 47 045751

glass wall 50°C, 2 min filtration, air drying for 3 minutes. at room temperature 40 amorphous substance ethanol 125/0.15 23°С ethanol solvate adding approx. 5 mg crystalline form C (test result 30), shaking at 23°C 50°C, 2 min. adding 3.0 ml n-heptane 23°C, add approx. 5 mg MTBE solvate (test result 6), stirring

- 48 045751

at 23°C for 10 minutes. deletion solid with glass walls stirring for 11 hours, 23°C filtration, air drying for 3 minutes. at room temperature 41 amorphous substance butyl acetate 127/0.15 23°С crystal form C adding approx. 5 mg crystalline form C (test result 30), shaking at 23°C adding 3.0 ml n-heptane 50°C, 2 min.

- 49 045751

removal of solids substances from the glass wall stirring for 15 minutes, 23°C 50°C, 2 min. stirring for 23 hours, 23°C filtration, air drying for 3 minutes. at room temperature 42 amorphous substance ethyl acetate + n-heptane 1:7 v/v 252/16 23°С crystal form C adding approx. 5 mg crystalline form C (test result 31) stirring for 18 hours, 23°C

- 50 045751

filtration, air drying for 3 minutes. at room temperature 43 amorphous substance ethyl acetate + n-heptane 1:7 v/v 252/16 23°С solvate ethyl acetate adding approx. 5 mg crystalline form C (test result 31) stirring for 18 hours, 2°C filtration, air drying for 3 minutes. at room temperature 44 amorphous substance ethyl acetate 112/0.15 23°С crystal form C adding 3.0 ml n-heptane adding approx. 5 mg toluene solvate

- 51 045751

(result tests 7) stirring for 6 days, 23 °C removing solids from glass walls, filtration, air drying for 3 minutes. at room temperature 45 amorphous substance ethyl acetate 117/0.15 23°С crystal form C adding 3.0 ml n-heptane adding approx. 5 mg ethanol solvate (test result 40) stirring for 6 days, 23 °C removal of solids

- 52 045751

substances with glass walls, filtration, air drying for 3 minutes. at room temperature 46 amorphous substance ethanol 120/0.15 23°С ethanol solvate adding 3.0 ml n-heptane adding approx. 5 mg toluene solvate (test result 7) stirring for 55 minutes, 23°C removal of solids substances from the glass wall stirring for 6 days, 23 °C

- 53 045751

removing solids from glass walls, filtration, air drying for 3 minutes. at room temperature temperature 47 Test e 14 ethyl acetate 129/1.0 23°С crystal form C adding 7.0 ml n-heptane adding approx. 15 mg crystalline form C (test result 45) stirring for 7 minutes, 23°C deletion solid with glass walls stirring for 3 days, 23 °C filtration, air drying for 3 minutes. at room temperature temperature

v/v = volume to volume.

Example 6. Stability of THF solvate.

Desolvation of solvates tends to produce an amorphous form. When the THF solvate was stored for eight weeks at 96% relative humidity and room temperature (Test 48), a mixture of the solvate and the amorphous form was formed, as confirmed by xXRD, FIG. 20a and 20b.

The stability test results for the THF solvate from Example 6 are shown in Table 1 below. 7.

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Table 7

Stability of THF solvate

Trial Raw material Solvent Concentration (mg/ml) Conditions Results 48 14 - approx. 13 mg storage in a humidity chamber with rel. ow. 96% at 23 °C Mixture of THF solvate + amorphous form storage in a humidity chamber with rel. ow. 96% at 23°C for eight weeks

Example 7: Hydrate formation.

Crystalline form C shows no evidence of hydrate formation. Dynamic vapor sorption at 25°C showed very low water vapor adsorption/desorption when increasing RH from 50% to 93% or decreasing RH from 50% to 0% (approx. ±0.1%). After storage for three days at 96% relative humidity and room temperature (Test 49), FIG. 29a, and at 40°C (test 50), pXRD showed no transformation of the crystalline form. Water absorption measured by the Karl-Fischer method was found to be relatively low (<0.2%). In addition, a phase equilibration experiment in water for three days at room temperature showed no transformation of the crystalline form (test 51), FIG. 29b. Wide background in the XRD diffraction pattern, Fig. 26 is due to water remaining in the sample after gentle drying at room temperature after filtering the suspension. The result obtained by the Karl-Fischer method shows a water content of 45%.

The results of the hydrate formation test from Example 7 are shown in Table 1 below. 8.

Table 8 Hydrate Form Tests

Trial Original material Solvent Concentration (mg/ml) Conditions Results 49 33 - approx. 50 mg storage in a humidity chamber with rel. ow. 96% at 23 °C form C

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storage in a humidity chamber with rel. ow. 96% at 23°C for three days 50 33 - approx. 50 mg storage in a humidity chamber with rel. ow. 96% at 40°C form C storage in a humidity chamber with rel. ow. 96% at 40°C for three days 51 33 water 71/2.0 23°С form C stirring for three days, 23°C, filtration and air drying

Example 8. Studies of the compound of formula (I) by powder X-ray diffraction analysis (pXRD).

Crystalline form C of the compound of formula (I) was examined by xXRD. The identified peaks are shown in Fig. 30 and in table. 9. Pronounced peaks are given in table. 10. It should be noted that none of the peaks are known to be representative or characteristic of this substance, since the preferred orientation state in this sample is unknown.

The range of data collected may vary depending on the diffractometer. In most cases, peaks were selected in the 2Θ angle range up to approximately 30°. Rounding algorithms were used to round each peak to 0.01° based on the instrument used to collect the data and/or the native resolution of the peaks. Peak locations along the x axis (2θ angle, deg) in both the figures and tables were determined using proprietary software and rounded to one or two decimal places based on the above criteria. Peak position variations are presented with an accuracy of ±0.2°. To calculate the d value, the Cu-Ka1 wavelength was used, which was 1.5405929 A.

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Table 9

Identified peaks

Angle 2Θ, (deg.) *(A) Intensity, (%) 7.15 ±0.20 12.347 ± 0.345 22 9.06 ± 0.20 9.753 ±0.215 85 10.99 ±0.20 8.042 ±0.146 8 12.35 ±0.20 7.164 ±0.116 60 13.62 ±0.20 6.498 ± 0.095 31 13.82 ±0.20 6.401± 0.092 88 14.34 ±0.20 6.172 ±0.086 19 15.99 ±0.20 5.537 ±0.069 62 16.63 ±0.20 5.326 ± 0.064 43 17.14 ±0.20 5.168 ±0.060 80 18.19 ±0.20 4.872 ± 0.053 28 18.62 ±0.20 4.760 ±0.051 75 19.06 ±0.20 4.652 ± 0.048 65 19.82 ±0.20 4.475 ± 0.045 10 19.98 ±0.20 4.440 ± 0.044 9 20.09 ± 0.20 4.416 ±0.044 AND 21.56 ±0.20 4.119 ±0.038 89 21.65 ±0.20 4.102 ±0.037 100 22.09 ± 0.20 4.021 ± 0.036 22 23.67 ± 0.20 3.756 ±0.031 53 24.04 ± 0.20 3.699 ± 0.030 20 24.68 ± 0.20 3.605 ± 0.029 9 24.85 ± 0.20 3.580 ±0.028 27 25.54 ± 0.20 3.484 ± 0.027 9 26.12 ±0.20 3.409 ± 0.026 26 26.65 ± 0.20 3.343 ± 0.025 7 26.80 ± 0.20 3.324 ± 0.024 7 26.89 ± 0.20 3.313 ±0.024 9 27.49 ± 0.20 3.242 ± 0.023 16 27.62 ± 0.20 3.227 ± 0.023 AND 27.87 ± 0.20 3.199 ±0.022 9 28.72 ± 0.20 3.106 ±0.021 10 29.08 ± 0.20 3.068 ± 0.021 4

In table Figure 10 shows the pSAR data, indicated as pronounced peaks. The pronounced peaks represent a subset of the entire set of identified peaks. Pronounced peaks are selected from the identified peaks by identifying preferentially non-overlapping, flat peaks with high intensity.

Claims (25)

1. Composition containing a crystalline form of the compound of formula (I): wherein the crystalline form is crystalline form C, wherein the crystalline form exhibits a powder x-ray diffraction pattern containing at least three characteristic peaks, said characteristic peaks occurring at 2θ angles selected from the group consisting of about 9.1°, 12 ,4°, 13.8°, 16.0°, 16.6°, 17.1°, 18.6°, 19.1°, 21.6°, 21.7° and 23.7°. 2. The composition of claim 1, wherein the crystalline form exhibits a powder x-ray diffraction pattern containing at least three characteristic peaks, said characteristic peaks occurring at 2θ angles selected from the group consisting of 9.1°, 12.4 °, 13.8°, 16.0°, 16.6°, 17.1°, 18.6°, 19.1°, 21.6°, 21.7° and 23.7°, ± 0, 5° 2θ. 3. The composition of claim 1, wherein the crystalline form exhibits a powder x-ray diffraction pattern containing at least three characteristic peaks, said characteristic peaks occurring at 2θ angles selected from the group consisting of 9.1°, 12.4 °, 13.8°, 16.0°, 16.6°, 17.1°, 18.6°, 19.1°, 21.6°, 21.7° and 23.7°. 4. The composition of claim 2, wherein the crystalline form has a melting point of about 122°C. 5. The composition according to any one of claims 1 to 4, characterized in that the composition contains more than 50% by weight of the crystalline form. 6. Composition according to any one of claims 1 to 4, characterized in that the composition contains more than 80% by weight of the crystalline form. 7. The composition according to any one of claims 1 to 4, characterized in that the composition contains more than 95% by weight of the crystalline form. 8. Composition according to any one of claims 1 to 4, characterized in that the composition mainly consists of a crystalline form. 9. A method for obtaining a crystalline form of a compound of formula (I), comprising: dissolving the amorphous form of the compound of formula (I) in a first solvent to form a first solution, wherein the first solvent is selected from the group consisting of ethyl acetate, ethanol, tert-butyl methyl ether (MTBE), heptane, tetrahydrofuran (THF), butyl acetate, and mixtures thereof; adding a second solvent to the first solution to form a second mixture, where the second solvent is selected from the group consisting of ethyl acetate, ethanol, tert-butyl methyl ether, heptane, tetrahydrofuran, butyl acetate, and mixtures thereof; and isolating a crystalline form of the compound of formula (I) from the second mixture, wherein the compound of formula (I) is - 58 045751 wherein the crystalline form is crystalline form C, wherein the crystalline form exhibits a powder x-ray diffraction pattern containing at least three characteristic peaks, said characteristic peaks occurring at 2θ angles selected from the group consisting of about 9.1°, 12. 4°, 13.8°, 16.0°, 16.6°, 17.1°, 18.6°, 19.1°, 21.6°, 21.7° and 23.7°. 10. The method of claim 9, wherein the crystalline form exhibits a powder x-ray diffraction pattern containing at least three characteristic peaks, said characteristic peaks occurring at 2θ angles selected from the group consisting of 9.1°, 12.4 °, 13.8°, 16.0°, 16.6°, 17.1°, 18.6°, 19.1°, 21.6°, 21.7° and 23.7°, ± 0, 5° 2θ. 11. The method of claim 9, wherein the crystalline form exhibits a powder X-ray diffraction pattern containing at least three characteristic peaks, said characteristic peaks occurring at 2θ angles selected from the group consisting of 9.1°, 12.4 °, 13.8°, 16.0°, 16.6°, 17.1°, 18.6°, 19.1°, 21.6°, 21.7° and 23.7°. 12. The method of claim 9, wherein the first solvent is selected from the group consisting of ethyl acetate, ethanol, tert-butyl methyl ether, heptane, THF, and mixtures thereof. 13. The method according to claim 12, wherein the first solvent contains THF. 14. The method according to claim 13, wherein the first solvent further contains heptane. 15. The method according to claim 14, in which the first solvent contains THF and heptane in a ratio of 75:25 v/v. 16. The method of claim 9, wherein the second solvent is selected from the group consisting of ethyl acetate, ethanol, tert-butyl methyl ether, heptane, THF, and mixtures thereof. 17. The method of claim 16, wherein the second solvent is heptane. 18. The method of claim 9, wherein the method further comprises agitating the second mixture. 19. The method of claim 9, wherein isolating the crystalline form includes filtering the second mixture. 20. A method for obtaining a crystalline form of a compound of formula (I), comprising: dissolving a compound of formula (I) in a first solvent to form a first solution, wherein the first solvent is selected from the group consisting of ethyl acetate, ethanol, tert-butyl methyl ether, heptane, tetrahydrofuran, butyl acetate and mixtures thereof; adding a seed crystal form of the compound of formula (I) or a solvate thereof to the first solution to form a seed mixture; and isolating the resulting crystalline form of the compound of formula (I) or a solvate thereof from the seed mixture, wherein the compound of formula (I) is wherein the crystalline form is crystalline form C, wherein the crystalline form exhibits a powder x-ray diffraction pattern containing at least three characteristic peaks, said characteristic peaks occurring at 2θ angles selected from the group consisting of about 9.1°, 12. 4°, 13.8°, 16.0°, 16.6°, 17.1°, 18.6°, 19.1°, 21.6°, 21.7° and 23.7°. 21. The method of claim 20, wherein the resulting crystalline form exhibits a powder x-ray diffraction pattern containing at least three characteristic peaks, said characteristic peaks occurring at 2θ angles selected from the group consisting of 9.1°, 12. 4°, 13.8°, 16.0°, 16.6°, 17.1°, 18.6°, 19.1°, 21.6°, 21.7° and 23.7°, ± 0 .5° 2θ. 22. The method of claim 20, wherein the resulting crystalline form exhibits a powder X-ray diffraction pattern containing at least three characteristic peaks, said characteristic peaks occurring at 2θ angles selected from the group consisting of 9.1°, 12. 4°, 13.8°, 16.0°, 16.6°, 17.1°, 18.6°, 19.1°, 21.6°, 21.7° and 23.7°. 23. The method of claim 20, wherein the seed crystalline form is selected from the group consisting of an MTBE solvate crystalline form, a toluene solvate crystalline form, a crystalline form - 59 045751 ethanol solvate form, THF solvate crystalline form, ethyl acetate solvate crystalline form, acetone solvate crystalline form, crystalline form C and mixtures thereof. 24. The method of claim 23, wherein the seed crystal form is crystal form C. 25. The method of claim 23, wherein the seed crystal form is a THF solvate crystal form.