Crystallized form of a compound and method for generating the crystallized form of a compound.

Abstract

Disclosed herein are methods for crystallizing the compound of Formula I, and crystalline forms of the compound of Formula I. The disclosed crystalline forms of Formula I include a TBME solvate crystalline form, a toluene solvate crystalline form, an ethanol solvate crystalline form, a THF solvate crystalline form, an EtOAc solvate crystalline form, an acetone solvate crystalline form, and crystalline form C.

Description

Technical Field

[0001] This application relates to the fields of pharmaceutical chemistry, biochemistry, and medicine. In particular, it relates to the crystalline forms of compounds of Formula I, as well as methods for their production and methods for their use.

Background Art

[0002] Thyroid hormones (THs) play important roles in growth, development, metabolism, and homeostasis. They are produced by the thyroid gland as thyroxine (T4) and 3,5,3'-triiodo-L-thyronine (T3). T4 is the main secreted form in humans and is enzymatically deiodinated to the more active form T3 by deiodinases in peripheral tissues. THs exert their actions by interacting with thyroid hormone receptors (TRs) belonging to the nuclear hormone receptor superfamily and regulate the transcription of target genes.

[0003] TRs are expressed in most tissues and exist as two isoforms (TRα and TRβ). By tissue distribution studies, mouse knockout studies, and evaluation of patients with resistance to thyroid hormone (RTH), it has been demonstrated that TRα is the main isoform in the heart and regulates most cardiac functions, while the TRβ isoform predominates in the liver and pituitary gland and regulates cholesterol metabolism and thyroid-stimulating hormone (TSH) production, respectively. In addition, TRβ agonists can be used for the treatment of adrenoleukodystrophy (ALD) and lipid disorders such as hypercholesterolemia and fatty liver diseases, for example, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and glycogenosis (GSD).

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Non-Patent Documents

[0005] [Non-Patent Document 1] Fingl et al., 1975, “The Pharmacological Basis of Therapeutics” [Overview of the project] [Problems that the invention aims to solve]

[0006] While several promising phosphonate TRβ agonists have been discovered, there is a need for improved forms of these compounds to accelerate pharmaceutical development. [Means for solving the problem]

[0007] Some embodiments use formula I:

[0008] [ka]

[0009] The present invention provides a composition containing the crystalline form of a compound or its solvate.

[0010] Other embodiments include a method for producing a crystalline form of a compound of formula I or a solvate thereof, comprising the steps of: dissolving an amorphous form of the compound of formula I in a first solvent to produce a first solution; adding a second solvent to the first solution to produce a second mixture; and separating the crystalline form of the compound of formula I from the second mixture, wherein the compound of formula I is

[0011] [ka]

[0012] It provides a method to achieve this.

[0013] Yet another embodiment is a method for producing a crystalline form of a compound of formula I or a solvate thereof, comprising the steps of dissolving a compound of formula I in a first solvent to form a first solution; adding a seeding crystalline form of the compound of formula I or a solvate thereof to the first solution to form a seeded mixture; and separating the crystalline form of the compound of formula I or its solvate formed from the seeded mixture. where the compound of formula I is

[0014]

Chemical formula

[0015] is provided.

Brief Description of the Drawings

[0016] [Figure 1] It is a diagram showing the powder X-ray diffraction pattern of an amorphous form. [Figure 2] It is a diagram showing the powder X-ray diffraction pattern of the TBME solvate crystalline form. [Figure 3] It is a diagram showing the powder X-ray diffraction pattern of the toluene solvate crystalline form. [Figure 4] It is a diagram showing the powder X-ray diffraction pattern of the ethanol solvate crystalline form. [Figure 5] It is a diagram showing the powder X-ray diffraction pattern of the THF solvate crystalline form. [Figure 6a] It is a diagram showing the powder X-ray diffraction pattern of the EtOAc solvate crystalline form. [Figure 6b] It is a diagram showing the enlarged powder X-ray diffraction pattern of the EtOAc solvate crystalline form of Figure 6a. [Figure 7a] It is a diagram showing the powder X-ray diffraction pattern of the acetone solvate crystalline form. [Figure 7b] It is a diagram showing the enlarged powder X-ray diffraction pattern of the acetone solvate crystalline form of Figure 7a. [Figure 8a] It is a diagram showing the powder X-ray diffraction pattern of the THF solvate crystalline form. [Figure 8b] This figure shows the magnified powder X-ray diffraction pattern of the THF solvate crystal morphology shown in Figure 8a. [Figure 9] This figure shows the powder X-ray diffraction pattern of the crystalline form. [Figure 10a] This figure shows the powder X-ray diffraction pattern of the THF solvate crystal form. [Figure 10b] This figure shows the magnified powder X-ray diffraction pattern of the THF solvate crystal morphology in Figure 10a. [Figure 11] This figure shows the powder X-ray diffraction pattern of crystal form C. [Figure 12] This figure shows the powder X-ray diffraction pattern of crystal form C. [Figure 13] This graph shows the differential scanning calorimetry results for the crystalline morphology of TBME solvates. [Figure 14] This graph shows the differential scanning calorimetry results for the crystalline form of toluene solvate. [Figure 15] This graph shows the differential scanning calorimetry results for the crystalline form of ethanol solvate. [Figure 16] This graph shows the differential scanning calorimetry results for the crystalline form of alkylated solvates. [Figure 17] This graph shows the differential scanning calorimetry results for the crystalline form of acetone solvate. [Figure 18] This graph shows the differential scanning calorimetry results for the crystalline morphology of THF solvates. [Figure 19a] This graph shows the results of the first heating differential scanning calorimetry measurement for crystal form C. [Figure 19b] This graph shows the results of the second heating differential scanning calorimetry measurement for crystal form C, as shown in Figure 19a. [Figure 20a] This figure shows the powder X-ray diffraction pattern of a mixed crystalline form. [Figure 20b] This figure shows an enlarged powder X-ray diffraction pattern of the mixed crystal morphology shown in Figure 20a. [Figure 21] This figure shows the powder X-ray diffraction pattern of crystal form C. [Figure 22]This figure shows the powder X-ray diffraction pattern of crystal form C. [Figure 23] This figure shows the powder X-ray diffraction pattern of crystal form C. [Figure 24] This figure shows the powder X-ray diffraction pattern of crystal form C. [Figure 25] This figure shows the powder X-ray diffraction pattern of crystal form C. [Figure 26] This figure shows the powder X-ray diffraction pattern of crystal form C. [Figure 27] This figure shows the powder X-ray diffraction pattern of crystal form C. [Figure 28a] This graph shows the results of the first heating differential scanning calorimetry measurement for crystal form C. [Figure 28b] This graph shows the results of the second heating differential scanning calorimetry for crystal form C, as shown in Figure 28a. [Figure 29a] This graph shows the results of the dynamic vapor sorbation analysis of crystalline form C. [Figure 29b] This graph shows the results of the aqueous phase equilibrium analysis of crystalline form C. [Figure 30] This figure shows the powder X-ray diffraction pattern of crystalline form C, which exhibits observed peak values. [Modes for carrying out the invention]

[0017] The crystalline forms of compounds of formula (I), or their solvates, and methods for crystallizing compounds of formula I are disclosed herein. Compounds of formula I are as follows:

[0018] [ka]

[0019] It is shown here.

[0020] The crystalline forms of Formula I include tert-butyl methyl ether (TBME) solvate crystalline form, toluene solvate crystalline form, ethanol solvate crystalline form, tetrahydrofuran (THF) solvate crystalline form, ethyl acetate (siRNA) solvate crystalline form, acetone solvate crystalline form, and crystalline form C (as described herein).

[0021] This application relates to a first crystalline form of the compound of formula I, and to a method for crystallizing various crystalline forms of the compound of formula I. The crystalline forms advantageously exhibit improved stability, processability, and ease of manufacture. As a result, the crystalline forms of formula I, particularly crystalline form C, offer long-term stability and low water vapor adsorption and desorption. Therefore, the crystalline forms offer significant clinical improvements in the treatment of ALD and lipid disorders, such as hypercholesterolemia and fatty liver disease.

[0022] This application also relates to various crystalline solvate and nonsolvated forms of the compound of formula I, as well as to methods for crystallizing the compound of formula I.

[0023] Method for crystallizing the compound of formula I A method for crystallizing a compound of formula I, or its solvate, is disclosed. The crystalline form of a compound of formula I can generally be obtained or produced by crystallizing the compound of formula I under controlled conditions. In some embodiments, this method produces the crystalline form of TBME solvate. In some embodiments, this method produces the crystalline form of toluene solvate. In some embodiments, this method produces the crystalline form of ethanol solvate. In some embodiments, this method produces the crystalline form of THF solvate. In some embodiments, this method produces the crystalline form of SiO solvate. In some embodiments, this method produces the crystalline form of acetone solvate. In some embodiments, this method produces the crystalline form C.

[0024] In some embodiments, the method includes the step of dissolving the amorphous form of the compound of formula I in a first solvent to produce a first solution. In some embodiments, the method includes the step of dissolving the crystalline form of the compound of formula I or its solvate in a first solvent to produce a first solution. In some embodiments, the method includes the step of dissolving a mixture of the amorphous and crystalline forms of the compound of formula I in a first solvent to produce a first solution. In some embodiments, the method includes the step of adding a second solvent to the first solution to produce a second mixture. In some embodiments, the second solvent is heptane.

[0025] In some embodiments, this method includes the step of seeding a crystalline form of a compound of formula I or its solvate into a first solution to produce a seed mixture. In some embodiments, this method includes the step of seeding a crystalline form of TBME solvate into a first solution to produce a seed mixture. In some embodiments, this method includes the step of seeding a crystalline form of toluene solvate into a first solution to produce a seed mixture. In some embodiments, this method includes the step of seeding a crystalline form of ethanol solvate into a first solution to produce a seed mixture. In some embodiments, this method includes the step of seeding a crystalline form of THF solvate into a first solution to produce a seed mixture. In some embodiments, this method includes the step of seeding a crystalline form of SiO2 solvate into a first solution to produce a seed mixture. In some embodiments, this method includes the step of seeding a crystalline form of acetone solvate into a first solution to produce a seed mixture. In some embodiments, this method includes the step of seeding a crystalline form of C into a first solution to produce a seed mixture.

[0026] In some embodiments, this method includes the step of seeding a crystalline form of the compound of formula I or its solvate into a second solution to produce a seed mixture. In some embodiments, this method includes the step of seeding a crystalline form of TBME solvate into a second solution to produce a seed mixture. In some embodiments, this method includes the step of seeding a crystalline form of toluene solvate into a second solution to produce a seed mixture. In some embodiments, this method includes the step of seeding a crystalline form of ethanol solvate into a second solution to produce a seed mixture. In some embodiments, this method includes the step of seeding a crystalline form of THF solvate into a second solution to produce a seed mixture. In some embodiments, this method includes the step of seeding a crystalline form of SiO solvate into a second solution to produce a seed mixture. In some embodiments, this method includes the step of seeding a crystalline form of acetone solvate into a second solution to produce a seed mixture. In some embodiments, this method includes the step of seeding a crystalline form of C into a second solution to produce a seed mixture.

[0027] In some embodiments, the seed mixture produces a crystalline form of the compound of formula I or its solvate. In some embodiments, the seed mixture produces a crystalline form of TBME 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 THF solvate. In some embodiments, the seed mixture produces a crystalline form of HCl solvate. In some embodiments, the seed mixture produces a crystalline form of acetone solvate.

[0028] In some embodiments, the seed mixture produces crystalline form C. In some embodiments, a seed mixture seeded with TBME solvate crystalline form produces crystalline form C. In some embodiments, a seed mixture seeded with toluene solvate crystalline form produces crystalline form C. In some embodiments, a seed mixture seeded with ethanol solvate crystalline form produces crystalline form C. In some embodiments, a seed mixture seeded with THF solvate crystalline form produces crystalline form C. In some embodiments, a seed mixture seeded with RINKAN solvate crystalline form produces crystalline form C. In some embodiments, a seed mixture seeded with acetone solvate crystalline form produces crystalline form C. In some embodiments, a seed mixture seeded with crystalline form C produces crystalline form C.

[0029] In some embodiments, the method includes a step of separating the crystalline form of the compound of formula I or its solvate. In some embodiments, the separation is carried out by filtration, for example, thermal filtration. In some embodiments, the separated product may be dried, for example, by air drying.

[0030] In some embodiments, the first solvent may be a single solvent. In some embodiments, the first solvent may be a mixture of two or more solvents. In some embodiments, the first solvent may contain SiO2. In some embodiments, the first solvent may contain ethanol. In some embodiments, the first solvent may contain 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 TBME. 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 contain 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 contain acetone. In some embodiments, the first solvent may contain acetonitrile.

[0031] In some embodiments, the second solvent may be a single solvent. In some embodiments, the second solvent may be a mixture of two or more solvents. In some embodiments, the second solvent may contain SiO2. In some embodiments, the second solvent may contain ethanol. In some embodiments, the second solvent may contain 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 TBME. 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 contain water. In some embodiments, the second solvent may contain heptane. In some embodiments, the second solvent may contain THF. In some embodiments, the second solvent may contain acetone. In some embodiments, the second solvent may contain acetonitrile.

[0032] In some embodiments, the method further includes stirring. In some embodiments, stirring is carried out by agitation. In some embodiments, stirring is carried out by ultrasonic treatment.

[0033] In some embodiments, part of this method is carried out at the same temperature. In some embodiments, part of this method is carried out at various temperatures. In some embodiments, part of this method is carried out at room temperature. In some embodiments, part of this method is carried out between 0°C and 100°C. In some embodiments, part of this method is carried out between 20°C and 25°C. In some embodiments, part of this method is carried out between 50°C and 80°C. In some embodiments, part of this method is carried out between 50°C and 60°C. In some embodiments, part of this method is carried out between 65°C and 75°C. In some embodiments, part of this method is carried out at 23°C. In some embodiments, part of this method is carried out at 55°C. In some embodiments, part of this method is carried out at 70°C. In some embodiments, part of this method may include a first solution, a second mixture, a seed mixture, separation of crystalline forms, and stirring.

[0034] Crystalline form of compound I The crystalline forms of the compounds of formula I, or their solvates, particularly the crystalline forms of TBME solvate, toluene solvate, ethanol solvate, THF solvate, RINKAN solvate, acetone solvate, and crystal form C (described below), are also disclosed herein.

[0035] TBME solvate crystal morphology The precise conditions for forming the TBME solvate crystal morphology can be determined empirically, and it is only possible to provide several methods that have been found to be practically suitable.

[0036] The crystalline morphology of TBME solvate was characterized using various techniques, which are described in more detail in the experimental methods section. Figure 2 shows the crystal structure of the TBME solvate crystalline morphology determined by powder X-ray diffraction (XRPD). The TBME solvate crystalline morphology obtained by the methods described below exhibits characteristic peaks that can be determined from the XRPD pattern.

[0037] Figure 13 shows the results obtained by differential scanning calorimetry (DSC) of the TBME solvate crystalline morphology. These results show a peak at a temperature of 108°C for the TBME solvate crystalline morphology, which indicates the melting point of the crystal. Therefore, in some embodiments, the TBME solvate crystalline morphology exhibits melting points of approximately 103°C–113°C, approximately 106°C–110°C, or approximately 108°C. When the TBME solvate crystalline morphology was analyzed by thermogravimetric analysis (TGA) performed from 25°C to 200°C, it showed a mass loss of 14.1%.

[0038] Toluene solvate crystal form The precise conditions for forming toluene solvate crystal forms can be determined empirically, and it is only possible to provide several methods that have been found to be practically suitable.

[0039] The crystalline morphology of toluene solvate was characterized using various techniques, which are described in more detail in the experimental methods section. Figure 3 shows the crystal structure of the toluene solvate crystalline morphology determined by powder X-ray diffraction (XRPD). The toluene solvate crystalline morphology obtained by the method described below exhibits characteristic peaks that can be determined from the XRPD pattern.

[0040] Figure 14 shows the results obtained by DSC of the toluene solvate crystalline form. These results show a peak at a temperature of 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 exhibits a melting point of approximately 73°C to 83°C, approximately 76°C to approximately 80°C, or approximately 78°C. When the toluene solvate crystalline form was analyzed by TGA and run from 25°C to 200°C, it showed a mass loss of 13.9%.

[0041] Ethanol solvate crystal form The precise conditions for forming ethanol solvate crystals can be determined empirically, and it is only possible to provide several methods that have been found to be practically suitable.

[0042] The crystalline morphology of ethanol solvate was characterized using various techniques, which are described in more detail in the experimental methods section. Figure 4 shows the crystal structure of the ethanol solvate crystalline morphology determined by powder X-ray diffraction (XRPD). The ethanol solvate crystalline morphology obtained by the methods described below exhibits characteristic peaks that can be determined from the XRPD pattern.

[0043] Figure 15 shows the results obtained by DSC of the ethanol solvate crystalline form. These results show a peak at a temperature of 66°C for the ethanol solvate crystalline form, which indicates the melting point of the crystal. Therefore, in some embodiments, the ethanol solvate crystalline form exhibits a melting point of approximately 61°C to 71°C, approximately 64°C to approximately 68°C, or approximately 66°C. When the ethanol solvate crystalline form was analyzed by TGA and run from 25°C to 200°C, it showed a mass loss of 7.8%.

[0044] THF solvate crystal form The precise conditions for forming the THF solvate crystal morphology can be determined empirically, and it is only possible to provide several methods that have been found to be practically suitable.

[0045] The THF solvate crystal morphology was characterized using various techniques, which are described in more detail in the experimental methods section. Figures 5, 8a and 8b, and 10a and 10b show the crystal structure of the THF solvate crystal morphology determined by powder X-ray diffraction (XRPD). The THF solvate crystal morphology obtained by the methods described below exhibits characteristic peaks that can be determined from the XRPD pattern.

[0046] Figure 18 shows the results obtained by DSC of the THF solvate crystalline form. These results show a peak at a temperature of 125°C for the THF solvate crystalline form, which indicates the melting point of the crystal. Therefore, in some embodiments, the THF solvate crystalline form exhibits melting points of approximately 120°C–130°C, approximately 123°C–127°C, or approximately 125°C. When the THF solvate crystalline form was analyzed by TGA and run from 25°C to 200°C, one case showed a mass loss of 11.9%, and another case showed a mass loss of 12.1%.

[0047] alkyl crystalline form of alkyl ammonium compounds The precise conditions for forming the toluene solvate crystal form can be determined empirically, and it is only possible to provide several methods that have been found to be practically suitable.

[0048] The crystalline morphology of the siRNA solvate was characterized using various techniques, which are described in more detail in the experimental methods section. Figures 6a and 6b show the crystal structure of the siRNA solvate morphology determined by powder X-ray diffraction (XRPD). The siRNA solvate morphology obtained by the methods described below exhibits characteristic peaks that can be determined from the XRPD pattern.

[0049] Figure 16 shows the results obtained by DSC of the toluene solvate crystalline form. These results show a peak at a temperature of 68°C for the toluene solvate crystalline form, which indicates the melting point of the crystal. Therefore, in some embodiments, the toluene solvate crystalline form exhibits a melting point of approximately 63°C–73°C, approximately 66°C–70°C, or approximately 68°C. When the toluene solvate crystalline form was analyzed by TGA and run from 25°C to 200°C, it showed a mass loss of 10.8%.

[0050] Crystalline form of acetone solvate The precise conditions for forming the acetone solvate crystal form can be determined empirically, and it is only possible to provide several methods that have been found to be practically suitable.

[0051] The crystalline morphology of acetone solvate was characterized using various techniques, which are described in more detail in the experimental methods section. Figures 7a and 7b show the crystalline structure of the acetone solvate crystalline morphology determined by powder X-ray diffraction (XRPD). The acetone solvate crystalline morphology obtained by the methods described below exhibits characteristic peaks that can be determined from the XRPD pattern.

[0052] Figure 17 shows the results obtained by DSC of the acetone solvate crystalline form. These results show a peak at a temperature of 96°C for the acetone solvate crystalline form, which indicates the melting point of the crystal. Therefore, in some embodiments, the acetone solvate crystalline form exhibits a melting point of approximately 91°C to 101°C, approximately 94°C to approximately 98°C, or approximately 96°C. When the acetone solvate crystalline form was analyzed by TGA and run from 25°C to 200°C, it showed a mass loss of 9.0%.

[0053] Crystal form C Some embodiments include a non-solvated crystalline form of formula (I), which is referred to herein as crystalline form C. The exact conditions for forming crystalline form C can be determined empirically, and it is only possible to provide several methods that have been found to be practically suitable.

[0054] Crystal form C was characterized using various techniques, which are described in more detail in the experimental methods section. Figures 11, 12, 21-27, and 30 show the crystal structure of form C as determined by powder X-ray diffraction (XRPD). Crystal form C, obtainable by the methods disclosed above, shows prominent peaks at approximately 9.1°, 12.4°, 13.8°, 16.0°, 16.6°, 17.1°, 18.6°, 19.1°, 21.6°, 21.7°, and 23.7° at 2 theta (2θ). Therefore, in some embodiments, the crystalline form of the compound of formula I has at least one characteristic peak (e.g., characteristic peaks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11) selected from 2θ 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 compound of formula I has at least three characteristic peaks selected from 2θ 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°.

[0055] As is well understood in the art, due to experimental variability when X-ray diffraction patterns are measured with different instruments, peak positions are considered identical if the 2θ values ​​coincide within a certain degree of variability. For example, the United States Pharmacopeia states that identity is confirmed if the angle settings of the 10 strongest diffraction peaks coincide with the angle settings of a standard substance within ±0.2° and the relative intensity of the peaks does not vary by more than 20%. Therefore, in some embodiments, the peak positions listed herein include a 2θ variation of within ±0.5°. In other embodiments, the peak positions listed herein include a 2θ variation of within ±0.2°. When disclosed herein, the term “approximately” when referring to a value of 2θ is defined as 2θ of ±0.5°.

[0056] Figures 19a and 19b, and 28a and 28b, show the results obtained by DSC of crystalline form C. These results show a peak at a temperature of approximately 122°C for crystalline form C, which indicates the melting point of the crystal. Therefore, in some embodiments, crystalline form C exhibits melting points of approximately 117°C–127°C, approximately 120°C–124°C, or approximately 122°C. When crystalline form C was analyzed by TGA and run from 25°C to 200°C, one case showed a mass loss of 1.3%, and another case showed a mass loss of <0.1%.

[0057] On the other hand, Figure 29a shows the results of dynamic vapor sorption (DVS) of crystalline form C, indicating water uptake of less than 0.2 mass%. Figures 24 and 25, which are XRPD results following the DVA analysis, confirm that morphology C did not transition to a different polymorph. Figure 29b shows a 3-day phase equilibrium experiment in water, which did not show the transformation of crystalline form C seen in the XRPD in Figure 26.

[0058] Therefore, crystalline form C can be characterized as non-hygroscopic and stable over a wide range of humidity. Crystalline form C also exhibits good crystallinity, has a very low residual solvent content (<0.1%), a relatively high melting point (approximately 122°C), and shows no evidence of hydrate formation. In contrast, the solvate form tends to desolvate, producing a mixture of the solvate and amorphous forms. This advantageous and unexpected non-hygroscopicity and stability demonstrated by crystalline form C can be utilized. For example, in therapeutic methods and pharmaceutical compositions, crystalline form C can offer long-term stability and low water vapor adsorption and desorption, potentially providing significant clinical improvements in the treatment of ALD, as well as lipid disorders, such as hypercholesterolemia and fatty liver disease.

[0059] Treatment methods for adrenoleukodystrophy (ALD) and dyslipidemia Compounds of formula I, and therefore any composition of compounds of formula I disclosed herein, may be administered to patients to treat or reverse ALD, as well as dyslipidemia, such as hypercholesterolemia and fatty liver disease, such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or glycogen storage disease (GSD). Therefore, compounds of formula I may be administered to improve the condition of a patient, for example, a patient suffering from ALD. As another example, compounds of formula I may be administered to treat dyslipidemia, such as hypercholesterolemia and fatty liver disease.

[0060] Compound I may be administered to patients in combination for the treatment of ALD and dyslipidemia. Compound I may be administered to improve the condition of patients with hepatic encephalopathy. Compound I may be administered to alleviate symptoms associated with ALD. Compound I may be administered to improve the condition of patients with hypercholesterolemia. Compound I may be administered to alleviate symptoms associated with hypercholesterolemia. Compound I may be administered to improve the condition of patients with fatty liver disease. Compound I may be administered to alleviate symptoms associated with fatty liver disease.

[0061] A therapeutically effective dose of the compound of formula I is administered to the patient. As will be readily apparent to those skilled in the art, the useful in vivo dose and specific mode of administration will vary depending on age, body weight, severity of pain, and the mammalian species being treated, the specific compound used, and the specific application in which these compounds are used (see, for example, Fingl et al., 1975, "The Pharmacological Basis of Therapeutics," which is incorporated herein by reference in its entirety, particularly with reference to Chapter 1, page 1). Determining the effective dose level, which is the dose level required to achieve the desired result, can be achieved by those skilled in the art using conventional pharmacological methods. Typically, human clinical application of the product begins at a lower dose level, with the dose level increasing until the desired effect is achieved. Alternatively, acceptable in vitro studies can be used with established pharmacological methods to establish useful doses and routes of administration of the compositions identified by this method.

[0062] A once-daily dose may be administered. Alternatively, multiple doses, such as two, three, four, or five doses, may be administered. These multiple doses may be administered over a period of 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.

[0063] Compound composition of formula I Compositions of compounds of formula I are also disclosed herein. The compositions of this application are advantageously particularly suitable for oral and / or intravenous administration to patients with ALD or dyslipidemia. In some embodiments, the compositions can be obtained by one of the methods disclosed herein. For example, amorphous crystallization and / or seeding crystallization can produce the compositions of this application.

[0064] In some embodiments, the composition may contain crystalline forms of the compound of formula I (e.g., TBME solvate crystalline form, toluene solvate crystalline form, ethanol solvate crystalline form, THF solvate crystalline form, toluene solvate crystalline form, acetone solvate crystalline form, and / or crystalline form C, as disclosed herein). In some embodiments, the composition may contain at least about 20% by mass of the crystalline form of the compound of formula I. In some embodiments, the composition may contain at least about 50% by mass of the crystalline form of the compound of formula I. In some embodiments, the composition may contain at least about 80% by mass of the crystalline form of the compound of formula I. In some embodiments, the composition may contain at least about 95% by mass of the crystalline form of the compound of formula I. In some embodiments, the composition may contain at least about 50% by mass of crystalline form C. In some embodiments, the composition may contain at least about 80% by mass of crystalline form C. In some embodiments, the composition may contain at least about 95% by mass of crystalline form C. In some embodiments, the composition may contain at least about 99% by mass of crystalline form C. In some embodiments, the composition essentially consists of crystalline forms of the compound of formula I. In some embodiments, the composition essentially consists of crystalline form C. In some embodiments, the composition comprises a mixture of at least two (e.g., two, three, or four) forms of TBME solvate crystalline form, toluene solvate crystalline form, ethanol solvate crystalline form, THF solvate crystalline form, siRNA solvate crystalline form, acetone solvate crystalline form, and crystalline form C.

[0065] In some embodiments, the composition contains crystalline form C. For example, the composition may contain at least about 20%, at least about 50%, at least about 90%, at least about 95%, or at least about 99% of crystalline form C. Similarly, the composition may also contain, for example, TBME solvate crystalline form, toluene solvate crystalline form, ethanol solvate crystalline form, THF solvate crystalline form, toluene solvate crystalline form, or acetone solvate crystalline form. The composition may optionally contain at least about 20%, at least about 50%, at least about 90%, at least about 95%, or at least about 99% of TBME solvate crystalline form, toluene solvate crystalline form, ethanol solvate crystalline form, THF solvate crystalline form, toluene solvate crystalline form, acetone solvate crystalline form, and / or crystalline form C.

[0066] Pharmaceutical composition Compositions of the compound of Formula I of this application may also be formulated for administration to a patient (e.g., a human). Compounds of Formula I, and therefore compositions disclosed herein, may be formulated for administration with a pharmaceutically acceptable carrier or diluent. Thus, compounds of Formula I may be formulated as pharmaceuticals, as is customary in the pharmaceutical art, with standard pharmaceutically acceptable carriers and / or excipients. The exact nature of the formulation will depend on several factors, including the desired route of administration. Typically, compounds of Formula I are formulated for oral, intravenous, intragastric, subcutaneous, intravascular, or intraperitoneal administration.

[0067] The pharmaceutical carrier or diluent may be, for example, water or an isotonic solution, such as 5% dextrose in water or physiological saline. The solid oral form may contain, together with the active compound, diluents such as lactose, dextrose, sucrose, cellulose, corn starch or potato starch; lubricants such as silica, talc, stearic acid, magnesium stearate or calcium stearate, sodium lauryl sulfate, and / or polyethylene glycol; binders such as starch, gum arabic, gelatin, crystalline cellulose, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; de-agglomerating agents such as starch, alginic acid, alginate or sodium starch glycolate; foaming agents (effervescing mixture); colorants; sweeteners; humectants such as lecithin, polysorbate, lauryl sulfate; and generally non-toxic and pharmacologically inert substances used in pharmaceutical formulations. Such pharmaceuticals can be manufactured by known methods, for example, by processes such as mixing, granulation, tableting, sugar coating, or film coating.

[0068] Liquid dispersions for oral administration may be syrups, emulsions, or suspensions. Syrups may contain, for example, sucrose as a carrier, or sucrose together with glycerin and / or mannitol and / or sorbitol.

[0069] The suspensions and emulsions may contain carriers, such as natural rubber, agar, sodium alginate, pectin, crystalline cellulose, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. Suspensions or solutions for intramuscular injection may contain, together with the compound of formula I, pharmaceutically acceptable carriers, such as sterile water, olive oil, ethyl oleate, glycol, such as propylene glycol, and sodium lauryl sulfate.

[0070] A pharmaceutical product may essentially consist of a compound of formula I and a pharmaceutically acceptable carrier.

[0071] Oral formulations may generally contain a dosage of the compound of formula I in the range of about 1 mg to about 100 g. Therefore, in some embodiments, the oral formulation contains a composition of the compound of formula I disclosed herein in the range of about 1 mg to about 50 g. In some embodiments, the oral formulation contains a composition of the compound of formula I disclosed herein in the range of about 1 mg to about 100 mg. In some embodiments, the oral formulation contains a composition of the compound of formula I disclosed herein in the range of about 1 mg to about 20 mg. In some embodiments, the oral formulation contains a composition of the compound of formula I disclosed herein in the range of about 5 mg to about 15 g. In some embodiments, the oral formulation contains about 10 mg of the composition of the compound of formula I disclosed herein.

[0072] Intravenous formulations may also generally contain dosages of the compound of formula I in the range of about 1 mg to about 100 g (e.g., about 10 mg). In some embodiments, intravenous formulations have concentrations of the compound of formula I of about 5 to about 300 mg / mL (preferably about 25 to about 200 mg / mL, more preferably about 40 to about 60 mg / mL).

[0073] A composition, or a pharmaceutical containing the composition, may be placed in optionally sealed packaging. Sealed packaging can reduce or prevent moisture and / or ambient air from coming into contact with the composition or pharmaceutical. In some embodiments, the packaging includes a hermetic seal. In some embodiments, the packaging is sealed within the sealed package under vacuum or using an inert gas (e.g., argon). Thus, the packaging can suppress or reduce the rate of decomposition of the composition or pharmaceutical stored within the packaging. Various types of sealed packaging are known in the art. For example, U.S. Patent No. 5,560,490, which is incorporated herein by reference in its entirety, discloses an exemplary sealed package for pharmaceuticals.

[0074] Examples and experimental methods Additional embodiments are disclosed in further detail in the following embodiments, but these do not limit the scope of the claims.

[0075] Powder X-ray diffraction (XRPD) XRPD analysis was performed using either a Bruker D8 advance or a Philips PW 1710. In embodiments using the Bruker D8 instrument, the sample was scanned using CuKα radiation, 35kV / 45mA tube power, a VANTEC1 detector, a step size of 0.017°²θ, a step time of 105±5 seconds, and a scanning range of 2°–50°²θ. Samples were prepared either as received or slightly ground. A silicon single-crystal sample holder with a sample diameter of 12 mm and a depth of 0.1 mm was used.

[0076] In embodiments using a Philips PW instrument, the sample was scanned using copper Kα radiation, a step size of 0.02°²θ, a step time of 2.4 seconds, and a scanning range of 2° to 50°²θ. A 0.1 mm sample holder was used. The sample was measured without any special treatment, except for applying light pressure to obtain a flat surface. The measurements were performed in an ambient air atmosphere.

[0077] Thermogravimetric analysis (TGA) Thermogravimetric analysis was performed using a Perkin-Elmer Thermobalance TGS-2 (aluminum sample dish, N2 atmosphere 50 ml / min, heating rate 10 K / min, range 25-200 or 25-350°C).

[0078] Thermogravimetric Fourier Transform Infrared Spectroscopy (TG-FTIR) Thermogravimetric Fourier transform infrared spectroscopy measurements were performed using a Netzsch Thermo-Microbalance TG 209 (sample dish with pinhole, N2 atmosphere, heating rate 10 K / min, range 25-250°C) coupled to a Bruker FTIR Spectrometer Vector 22.

[0079] Differential Scanning Calorimetry (DSC) In some embodiments, DSC was performed using a Perkin Elmer DSC7 under the following experimental conditions: sample mass of 3.26–4.51 mg, closed gold sample dish, temperature range -50°C to 100°C / 150°C / 225°C, heating rate of 10 or 20 K / min. The sample was weighed in air.

[0080] In other embodiments, DSC was performed using a Perkin Elmer DSC7 under the following experimental conditions: sample mass of 3.53 mg, closed gold sample dish, temperature range of -50°C to 150°C, heating rate of 20 K / min. The sample was weighed in air.

[0081] 1 H nuclear magnetic resonance (NMR) The sample was dissolved in CDCl3. NMR spectra were recorded using a Bruker spectrometer (Ultrashield™, B ACS 60, 300 MHz).

[0082] Karl Fischer moisture analysis Karl Fischer moisture analysis was performed according to standard procedures.

[0083] Dynamic vapor sorption (DVS) The sample (9.869 mg) was placed on a Pt dish and equilibrated at 25°C and 50% relative humidity (rh) before starting the predetermined humidity program. The predetermined humidity program included 1.0 hour at 50% rh from 50% rh to 0% rh; 5 hours at 5% rh / hour and 0% rh from 0% rh to 93% rh; 5 hours at 5% rh / hour and 93% rh from 93% rh to 50% rh; and 1 hour at 5% rh / hour and 50% rh.

[0084] solvent Fluka or Merck grade solvents were used. Fluka No. 95305 deionized water was used for the relevant experiment.

[0085] Approximate measurement of solubility In some embodiments, a solvent was added to the solid material during the process to determine the approximate solubility at room temperature. After all additions were made, the sample was thoroughly stirred. The addition of the solvent was continued until the material was completely dissolved or until 20 ml of solvent had been added.

[0086] In other embodiments, an aliquot of the test solvent was added to a precisely weighed amount of the compound of formula I, increasing slightly (typically 100–1000 μL) while sonicating until complete dissolution was achieved, if possible. Dissolution was determined visually. Actual solubility may be higher than reported due to slower dissolution rates or the use of excess solvent. Approximate solubility was determined to the nearest integer in mg / mL.

[0087] Crystallization experiment Crystallization experiments were performed using 40 mg to 256 mg of the compound. The solution or slurry was stirred with a magnetic stirrer. After filtration (using a P4 porosity glass filter), the obtained sample was air-dried briefly at room temperature to prevent potential desolvation of unstable hydrates or solvates.

[0088] Starting material A The starting material was obtained from Metabasis Therapeutics Inc. The material was characterized as amorphous, as confirmed by the XRPD in Figure 1.

[0089] To conduct systematic crystallization experiments, the approximate solubility at room temperature should be known. The approximate solubility of amorphous starting material A at 23°C is shown in Table 1 below.

[0090] [Table 1] [Examples]

[0091] Crystallization trials based on solutions In the following examples, all evaporation and slurry yielded oil. Slurrying of high-temperature samples containing trace amounts of birefringent and extinctive solids in various solvents and antisolvents did not result in an increase in yield or crystal size. Applying pressure to the oil and starting materials at high temperatures and under antisolvent vapor yielded trace amounts of birefringent and extinctive solids embedded in the oil and gel. Temperature circulation experiments showed no signs of crystallization. These results demonstrate the difficulty of crystallizing the compound of formula I.

[0092] Details of various crystallization experiments based on solutions and their results are shown in Table 2 below.

[0093] [Table 2A]

[0094] [Table 2B] [Examples]

[0095] Non-solvent crystallization trials High temperature and humidity stress experiments yielded an oil containing small amounts of solids exhibiting birefringence and quenching. Sonication did not appear to offer any advantages beyond more common techniques. These results further confirm the difficulty of crystallizing the compound of formula I. Heteroseeding using diisopropyl ester analogs was also ineffective.

[0096] Details of various non-solvent crystallization experiments and their results are shown in Table 3 below.

[0097] [Table 3] [Examples]

[0098] Crystallization experiment When the amorphous form was dissolved in a mixture of THF and heptane (ratio 75:25 v / v) at room temperature, spontaneous crystallization of the compound of formula (I) was observed. Additional heptane was added until a turbid “solution” was obtained. This turbid “solution” was stirred in a magnetic stirrer at room temperature for 16 hours to produce a white paste. XRPD measurement confirmed the crystalline material, Figure 5 (Test 9 below). This first crystalline material was used to seed solutions or slurries of the amorphous form in several other solvent systems. In most cases, the crystalline material was produced at room temperature within a short time. Solvates were always produced using these crystallization conditions. Ethanol solvate (Test 8) and THF solvate (Test 14) were confirmed by solution NMR (not shown).

[0099] A first attempt (Test 15) to desolvate the THF solvate in heptane at 80°C yielded a viscous, sticky mass. After cooling to room temperature, the slurry was seeded with ethanol solvate and stirred at room temperature for 20 hours. After filtration and air drying at room temperature, the sample contained only a very small amount of residual solvent, and XRPD confirmed the formation of a new crystalline form (i.e., crystal form C), Figure 9. The solution NMR spectrum (not shown) showed the same spectrum as the starting material. This unsolvated crystal form C was used to seed for further crystallization experiments.

[0100] Various crystallization experiments produced larger quantities of the compound of formula I in either crystalline or solvate form. For example, THF solvate (test result 20) and non-solvated crystalline form C (test results 21 and 23) were produced in quantities of 200 mg.

[0101] Details of various crystallization experiments and their results are shown in Table 4 below.

[0102] [Table 4A]

[0103] [Table 4B]

[0104] [Table 4C]

[0105] [Table 4D]

[0106] [Table 4E]

[0107] [Table 4F]

[0108] [Table 4G] [Examples]

[0109] Characterization of crystalline samples The crystalline solid form was characterized by XRPD, TGA, and DSC, and the sample was selected by solution NMR.

[0110] Figures 11, 12, 21-27, and 30 show the XRPD results for non-solvated crystalline form C, indicating good crystallinity, very low residual solvent content (<0.1%), and a melting temperature of 122°C (sealed and closed sample dish; DSC peak temperature), as shown in Figures 19a and 19b. The solution NMR spectrum shows the spectrum of the starting material (not shown).

[0111] Figures 13–18, which characterize the solvates by DSC, provide an overview of the solvate stability, as estimated by the peak temperatures measured in sealed, closed sample dishes. The peak temperatures of the solvates vary considerably. The highest temperature observed is for THF solvate (125°C) in Figure 18, reflecting its high stability. For ethanol solvate (66°C) in Figure 15 and toluene solvate (68°C) in Figure 16, the peak temperatures are much lower, well below the boiling points of the corresponding solvents. Ethanol solvate (test result 8) and THF solvate (test result 14) were confirmed by solution NMR (not shown), and the solvent spectra of the starting materials and the corresponding solvates are shown.

[0112] The TG mass loss and DSC peak temperature results for Example 4 are shown in Table 5 below.

[0113] [Table 5] [Examples]

[0114] Additional seeding crystallization experiment To search for other non-solvated crystalline forms of the compound of formula I, phase equilibrium and seeding experiments were used in solvent mixtures at different temperatures. Several typical crystallization techniques (e.g., recrystallization from melt or crystallization by cooling of solution) were not applicable because nucleation of the compound was inhibited under these conditions. Subsequently, desolvation of the solvate tends to produce an amorphous form.

[0115] Using non-solvated crystalline form C at room temperature, ethanol solvate (test result 26) and THF solvate (test result 29) were produced by seeding concentrated solutions of the amorphous form in ethanol and THF, respectively. Characterization of the different solvates by DSC provided an overview of the solvate stability, as estimated by the peak temperature measured in a sealed, closed sample dish.

[0116] Crystalline form C was generated directly under the conditions of Experiment 30. The amorphous form was dissolved in siRNA and heated to 75°C. Heptane was slowly added until a ratio of 1:7 v / v siRNA / heptane was reached. Crystalline form C was seeded into the system and stirred for a further time at 77°C. The solid was separated by thermal filtration of the suspension. XRPD showed that non-solvated crystalline form C was generated, Figure 21.

[0117] For the crystallization of non-solvated crystalline form C, a solvent / reverse solvent mixture is desirable that does not produce the corresponding solvate or oil, but still exhibits acceptable solubility. Even when crystalline form C was seeded in an  / heptane mixture at a ratio of less than 1:7 v / v at 76°C, oil was formed (Test Result 34).

[0118] The non-solvated crystalline form C exhibits high physical and chemical stability in siRNA / heptane 1:7v / v. Phase equilibrium experiments at room temperature and 78°C for 3 days did not show any transformation of crystalline form C from Test 37. Solution NMR showed the same spectrum as the starting material (not shown).

[0119] Crystalline form C was also formed by stirring an amorphous slurry containing seeds of crystalline form C in RINKAN / heptane 1:7 v / v at room temperature for 18 hours (Test 42). However, at 2°C, the RINKAN solvate was formed (Test 43). The stability range of the RINKAN solvate in solvent / reverse solvent mixtures needs to be tested at different temperatures. When using the RINKAN / heptane process, crystalline form C appears to be physically more stable over a wider range of solvent / reverse solvent ratios than when using the ethanol / heptane process (Tests 33 and 34).

[0120] As seen in tests 44 and 45 in Figure 23, the XRPD peak near approximately 18°2θ was broader for a small number of samples. Therefore, samples showing a relatively broad peak near 18°2θ in Figure 27 were seeded into a supersaturated solution (test 47). The solids produced in this stability experiment revealed that this broader peak does not represent a physically more stable morphology.

[0121] Details of the additional seeding crystallization experiment and the results for the solid state of the sample in Example 5 are shown in Table 6 below.

[0122] [Table 6A]

[0123] [Table 6B]

[0124] [Table 6C]

[0125] [Table 6D]

[0126] [Table 6E]

[0127] [Table 6F]

[0128] [Table 6G]

[0129] [Table 6H]

[0130] [Table 6I] [Examples]

[0131] Stability of THF solvate Desolvation of solvates tends to produce amorphous forms. Storing THF solvates at 96% rh at room temperature for 8 weeks (Test 48) produced a mixture of solvates and amorphous forms, as confirmed by XRPD, Figures 20a and 20b.

[0132] The results of the THF solvate stability test for Example 6 are shown in Table 7 below.

[0133] [Table 7] [Examples]

[0134] hydrate formation Crystalline form C shows no evidence of hydrate formation. DVS analysis at 25°C showed very little water vapor adsorption / desorption when humidity was increased from 50 to 93%rh or decreased from 50%rh to 0%rh (approximately ±0.1%). XRPD showed no change in crystal morphology after storage for 3 days at 96%rh at room temperature (test 49) and 40°C (test 50) in Figure 29a. Water uptake measured by the Karl Fischer method was very low (<0.2%). In addition, phase equilibrium experiments in water for 3 days at room temperature showed no change in crystal morphology (test 51), Figure 29b. The broad background in the XRPD figure 26 is due to water remaining in the sample after thorough drying at room temperature following suspension filtration. The Karl Fischer result shows a water content of 45%.

[0135] The results of the hydrate formation test in Example 7 are shown in Table 8 below.

[0136] [Table 8] [Examples]

[0137] Powder X-ray diffraction (XRPD) measurement of Equation I XRPD measurements were performed on the crystalline form C of the compound of formula I. The observed peaks are shown in Figure 30 and Table 9. Prominent peaks are listed in Table 10. Please note that since the preferred orientation state of this sample is unknown, it cannot be said that any of the peaks are representative or characteristic of this material.

[0138] The range of data collected may depend on the instrument. In most cases, peaks within a range of approximately 30°2θ were selected. A rounding algorithm was used to round each peak to the nearest 0.01°2θ, based on the instrument used to collect the data and / or its inherent peak resolution. In both figures and tables, the peak positions along the x-axis (°2θ) were determined using proprietary software and rounded to one or two significant figures based on the above criteria. The variation in peak positions is given within ±0.2°2θ. For the d-interval list, the wavelength used to calculate the d-interval was 1.5405929 Å, the CuKα1 wavelength.

[0139] [Table 9]

[0140] Table 10 provides XRPD data identified as “outstanding peaks.” Outstanding peaks are a subset of the entire list of observed peaks. Outstanding peaks are selected from the observed peaks by identifying low-angle peaks with strong intensity that preferably do not overlap.

[0141] [Table 10]

Claims

1. Formula I: 【Chemistry 1】 A composition comprising the compound crystals of, The crystal is of crystal form C, and the crystal exhibits the following characteristic peaks: 9.1°±0.2°2θ, 12.4°±0.2°2θ, 13.8°±0.2°2θ, 16.0°±0.2°2θ, 16.6°±0.2°2θ, 17.1°±0 .2°2θ, 18.6°±0.2°2θ, 19.1°±0.2°2θ, 21.6°±0.2°2θ, 21.7°±0.2°2θ, and 23.7°±0.2°2θ A composition exhibiting a powder X-ray diffraction pattern containing [a specific component].

2. The crystal exhibits the following characteristic peaks: 9.1°, 12.4°, 13.8°, 16.0°, 16.6°, 17.1°, 18.6°, 19.1°, 21.6°, 21.7°, and 23.7°²θ The composition according to claim 1, which exhibits a powder X-ray diffraction pattern containing the following:

3. The composition according to claim 1 or 2, comprising more than 50% by mass of crystals.

4. The composition according to claim 1 or 2, comprising more than 80% by mass of crystals.

5. The composition according to claim 1 or 2, comprising more than 95% by mass of crystals.

6. The composition according to claim 1 or 2, which is essentially composed of crystals.

7. A method for producing a compound crystal of formula I, The compound of formula I, 【Chemistry 2】 And, The crystal is of crystal form C, and the crystal exhibits the following characteristic peaks: 9.1°±0.2°2θ, 12.4°±0.2°2θ, 13.8°±0.2°2θ, 16.0°±0.2°2θ, 16.6°±0.2°2θ, 17.1°±0 .2°2θ, 18.6°±0.2°2θ, 19.1°±0.2°2θ, 21.6°±0.2°2θ, 21.7°±0.2°2θ, and 23.7°±0.2°2θ The powder X-ray diffraction pattern includes the following: The method described above is The process involves dissolving the compound of formula I in a first solvent to produce a first solution, The process involves adding crystals of crystalline form C, ethanol solvate crystals, or toluene solvate crystals to a first solution to produce a seed mixture as seeding for the compound of formula I, The process involves separating the generated crystals of compound I from the seed mixture. including, method.

8. The resulting crystal exhibits the following characteristic peaks: 9.1°, 12.4°, 13.8°, 16.0°, 16.6°, 17.1°, 18.6°, 19.1°, 21.6°, 21.7°, and 23.7°²θ The method according to claim 7, which shows a powder X-ray diffraction pattern including the following.

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