Crystal form

Abstract

To provide new drugs for treating HCV infection.SOLUTION: The present invention provides crystalline forms of a compound I shown in the figure having characteristic peaks in a powder X-ray diffraction (PXRD) pattern. The compound I may be a potent HCV protease inhibitor. Also provided are compositions comprising the crystalline forms, and methods of preparing pharmaceutical compositions comprising the compound I, the methods comprising dissolving the crystalline form.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a crystalline polymorph of compound I, a pharmaceutical composition containing the polymorph, and a method for using the polymorph to produce the pharmaceutical composition. [Background technology]

[0002] Hepatitis C virus (HCV) is an RNA virus belonging to the genus Hepacivirus of the family Flaviviridae. The enveloped HCV virion contains a positive-strand RNA genome that encodes all known virus-specific proteins in a single continuous open reading frame. This open reading frame contains approximately 9500 nucleotides and encodes one large polyprotein of approximately 3000 amino acids. The polyprotein consists of a core protein, envelope proteins E1 and E2, membrane-bound protein p7, and non-structural proteins NS2, NS3, NS4A, NS4B, NS5A, and NS5B. [Overview of the project]

[0003] HCV infection is associated with progressive liver disease, including cirrhosis and hepatocellular carcinoma. Chronic hepatitis C can be treated with pegylated interferon-alpha in combination with ribavirin. However, its efficacy and tolerability remain substantially limited due to adverse events in many users, and viral elimination from the body is often incomplete. Therefore, new drugs for treating HCV infection are needed.

[0004] The drawings are presented as examples without limitation. [Brief explanation of the drawing]

[0005] [Figure 1] The experimental PXRD pattern of crystalline form I of compound I is shown. [Figure 2] The experimental PXRD pattern of compound I trimethanol solvate is shown. [Figure 3] The experimental PXRD of compound I-dimethanol monohydrate is shown. [Figure 4] The experimental PXRD of the desolvated compound I is shown. [Modes for carrying out the invention]

[0006] This invention relates to compound I (

[0007] [ka] This relates to the crystalline polymorphs of ). Compound 1 is a potent HCV protease inhibitor and is described in U.S. Patent Application Publication No. 2012 / 0070416, which is incorporated herein by reference in its entirety.

[0008] The crystalline form of compound I may be used to modulate / improve the physicochemical properties of the compound, including, but not limited to, physical properties (e.g., crystallinity, hygroscopicity, melting point, or hydration), pharmaceutical properties (e.g., solubility / dissolution rate, stability, or compatibility), and crystallization properties (e.g., purity, yield, or morphology).

[0009] In one embodiment, the present invention relates to a crystalline form of compound I having a characteristic peak in a powder X-ray diffraction (PXRD) pattern as shown in Figure 1.

[0010] In another embodiment, the present invention relates to a crystalline form of compound I having a characteristic peak at the 2θ value (°2θ) shown in Table 1a in a powder X-ray diffraction (PXRD) pattern.

[0011] The relative intensities and 2θ values ​​of each peak in Tables 1a, 2a, 3a, and 4a, and in Figures 1-4, can change or shift under certain conditions, even if the crystal form is the same. Those skilled in the art should be able to easily determine whether a given crystal form is the same as that described in Figures 1-4 or in one of Tables 1a, 2a, 3a, and 4a by comparing their PXRD data.

[0012] In yet another embodiment, the present invention relates to a crystalline form of compound I having characteristic peaks at 2θ values ​​(°2θ) of 8.4, 8.9, 11.1, 12.2, 14.5, 15, 15.9, 17.4, 17.8 and 22.2 in a powder X-ray diffraction (PXRD) pattern.

[0013] In yet another embodiment, the present invention relates to a crystalline form of compound I having characteristic peaks at 2θ values ​​(°2θ) of 8.4, 8.9, 10.2, 11.1, 12.2, 12.5, 13.2, 13.7, 14.5, 15, 15.5, 15.9, 17.4, 17.8, 19.6, 19.9, 21.1, 22.2, 22.7, and 23.9 in its powder X-ray diffraction (PXRD) pattern.

[0014] In yet another embodiment, the present invention relates to a crystalline form of compound I having characteristic peaks at 2θ values ​​(°2θ) of 6.7, 8.4, 8.9, 9.9, 10.2, 11.1, 12.2, 12.5, 13.2, 13.7, 14.5, 15, 15.5, 15.9, 17.4, 17.8, 18.1, 18.9, 19, 19.6, 19.9, 21.1, 21.8, 22.2, 22.7, 22.8, 23.2, 23.9, 24.6, and 25.1 in its powder X-ray diffraction (PXRD) pattern.

[0015] In yet another embodiment, the present invention relates to a crystalline form of compound I having a characteristic peak in the powder X-ray diffraction (PXRD) pattern as shown in Figure 2.

[0016] In yet another embodiment, the present invention relates to a crystalline form of compound I having a characteristic peak at the 2θ value (°2θ) shown in Table 2a in a powder X-ray diffraction (PXRD) pattern.

[0017] In yet another embodiment, the present invention relates to a crystalline form of compound I having characteristic peaks at 2θ values ​​(°2θ) of 8.2, 10.9, 14.1, 14.3, 14.9, 15.5, 15.8, 17.5, 21.8 and 22.2 in a powder X-ray diffraction (PXRD) pattern.

[0018] In yet another embodiment, the present invention relates to a crystalline form of Compound I having characteristic peaks at 2θ values (°2θ) of 8.2, 8.7, 10.9, 14.1, 14.3, 14.6, 14.9, 15.5, 15.8, 17.3, 17.5, 18.7, 19.7, 20.7, 21.4, 21.8, 22.2, 22.8, 23.5 and 23.7 in a powder X-ray diffraction (PXRD) pattern.

[0019] In yet another embodiment, the present invention relates to a crystalline form of Compound I having characteristic peaks at 2θ values (°2θ) of 6.4, 8.2, 8.7, 10.1, 10.9, 12, 12.3, 13, 13.4, 14.1, 14.3, 14.6, 14.9, 15.2, 15.5, 15.8, 17.3, 17.5, 18, 18.7, 19.4, 19.7, 20.2, 20.7, 20.9, 21.4, 21.8, 22.2, 22.8, 23.1, 23.5, 23.7, 24.2, 25, 25.4, 26.5 and 26.8 in a powder X-ray diffraction (PXRD) pattern.

[0020] In yet another embodiment, the present invention relates to a crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern as shown in Figure 3 In yet another embodiment, the present invention relates to a crystalline form of Compound I having characteristic peaks at 2θ values (°2θ) shown in Table 3a in a powder X-ray diffraction (PXRD) pattern.

[0021] In yet another embodiment, the present invention relates to a crystalline form of Compound I having characteristic peaks at 2θ values (°2θ) of 8.4, 8.8, 11.1, 14.4, 15, 15.8, 17.4, 17.7, 22.2 and 23.8 in a powder X-ray diffraction (PXRD) pattern.

[0022] In yet another embodiment, the present invention relates to a crystalline form of compound I having characteristic peaks at 2θ values ​​(°2θ) of 8.4, 8.8, 10.2, 11.1, 12.2, 13.2, 13.6, 14.4, 15, 15.4, 15.8, 17.4, 17.7, 18.8, 19.8, 21, 22.2, 22.7, 23.2 and 23.8 in its powder X-ray diffraction (PXRD) pattern.

[0023] In yet another embodiment, the present invention relates to a crystalline form of compound I having characteristic peaks at 2θ values ​​(°2θ) of 6.6, 8.4, 8.8, 9.8, 10.2, 11.1, 12.2, 12.4, 13.2, 13.6, 14.4, 15, 15.4, 15.8, 17.4, 17.7, 18.1, 18.8, 19.5, 19.8, 20.7, 21, 21.7, 22.2, 22.7, 23.2, 23.8, 24.5, 25, 26.8 and 27.4 in its powder X-ray diffraction (PXRD) pattern.

[0024] In yet another embodiment, the present invention relates to a crystalline form of compound I having a characteristic peak in a powder X-ray diffraction (PXRD) pattern, as shown in Figure 4.

[0025] In yet another embodiment, the present invention relates to a crystalline form of compound I having a characteristic peak at the 2θ value (°2θ) shown in Table 4a in its powder X-ray diffraction (PXRD) pattern.

[0026] In yet another embodiment, the present invention relates to a crystalline form of compound I having characteristic peaks at 2θ values ​​(°2θ) of 8.4, 9.1, 11.2, 14.5, 15.1, 15.6, 16, 16.3, 17.5, and 17.9 in a powder X-ray diffraction (PXRD) pattern.

[0027] In yet another embodiment, the present invention relates to a crystalline form of compound I having characteristic peaks at 2θ values ​​(°2θ) of 8.4, 9.1, 10.2, 11.2, 12.3, 13.3, 14.5, 15.1, 15.6, 16, 16.3, 17, 17.5, 17.9, 18.2, 19, 19.4, 20, 21.2, and 24 in its powder X-ray diffraction (PXRD) pattern.

[0028] In yet another embodiment, the present invention relates to a crystalline form of compound I having characteristic peaks at 2θ values ​​(°2θ) of 6.7, 8.4, 9.1, 9.6, 9.9, 10.2, 11.2, 12.3, 13.3, 13.7, 14.5, 15.1, 15.6, 16, 16.3, 17, 17.5, 17.9, 18.2, 19, 19.4, 20, 20.9, 21.2, 21.9, 22.4, 22.8, 23.3, 24, 24.6, 25.1, 25.6, 27 and 27.8 in its powder X-ray diffraction (PXRD) pattern.

[0029] The PXRD data used herein can be collected using a G3000 diffractometer (Inel Corp., Artonnet, France) equipped with a curve position sensor and parallel beam optics. The diffractometer is operated at 40 kV and 30 mA using a copper anode tube (1.5 kW fine focus). The incident beam germanium monochromator has a wavelength of 1.54178 Å and is monochromatic Cu-K α Radiation is applied. The diffractometer is calibrated at 1-degree intervals using a decayed direct beam. Calibration is checked using the silicon powder beam position reference standard (NIST 640c). The instrument is computer-controlled using Symphonix software (Inel Corp., Artonnet, France), and the data is analyzed using Jade software (version 9.0, Materials Data, Inc., Livermore, California). The sample is filled into an aluminum sample holder and brought to the same height as the glass slide. The PXRD peak position measurement error is typically ±0.2 degrees 2θ (°2θ).

[0030] In another embodiment, the present invention relates to the above-described crystalline forms that are substantially pure. As used herein, the term “substantially pure” means a crystalline form having a purity of at least about 90%, when used in reference to a given crystalline form. This means that the crystalline form does not contain more than about 10% of other forms of compound I. More preferably, the term “substantially pure” means a crystalline form of compound I having a purity of at least about 95%, which means that the crystalline form of compound I does not contain more than about 5% of other forms of compound I. Even more preferably, the term “substantially pure” means a crystalline form having a purity of at least about 97%, which means that the crystalline form of compound I does not contain more than about 3% of other forms of compound I.

[0031] In one embodiment, the present invention relates to a crystalline form of compound I that has a characteristic peak in a powder X-ray diffraction (PXRD) pattern as shown in Figure 1 and is substantially pure. For example, the crystalline form may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0032] In another embodiment, the present invention relates to a crystalline form of compound I that is substantially pure and has a characteristic peak at the 2θ value (°2θ) shown in Table 1a in its powder X-ray diffraction (PXRD) pattern. For example, the crystalline form may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0033] In another embodiment, the present invention relates to a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 8.4, 8.9, 11.1, 12.2, 14.5, 15, 15.9, 17.4, 17.8 and 22.2 in its powder X-ray diffraction (PXRD) pattern. For example, the crystalline form may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0034] In another embodiment, the present invention relates to a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 8.4, 8.9, 10.2, 11.1, 12.2, 12.5, 13.2, 13.7, 14.5, 15, 15.5, 15.9, 17.4, 17.8, 19.6, 19.9, 21.1, 22.2, 22.7, and 23.9 in its powder X-ray diffraction (PXRD) pattern. For example, the crystalline form may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0035] In another embodiment, the present invention relates to a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 6.7, 8.4, 8.9, 9.9, 10.2, 11.1, 12.2, 12.5, 13.2, 13.7, 14.5, 15, 15.5, 15.9, 17.4, 17.8, 18.1, 18.9, 19, 19.6, 19.9, 21.1, 21.8, 22.2, 22.7, 22.8, 23.2, 23.9, 24.6, and 25.1 in its powder X-ray diffraction (PXRD) pattern. For example, the crystalline form may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0036] In yet another embodiment, the present invention relates to a crystalline form of compound I that is substantially pure and has characteristic peaks in a powder X-ray diffraction (PXRD) pattern, as shown in Figure 2. For example, the crystalline form may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0037] In yet another embodiment, the present invention relates to a crystalline form of compound I that is substantially pure and has a characteristic peak at the 2θ value (°2θ) shown in Table 2a in its powder X-ray diffraction (PXRD) pattern. For example, the crystalline form may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0038] In another embodiment, the present invention relates to a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 8.2, 10.9, 14.1, 14.3, 14.9, 15.5, 15.8, 17.5, 21.8, and 22.2 in its powder X-ray diffraction (PXRD) pattern. For example, the crystalline form may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0039] In another embodiment, the present invention relates to a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 8.2, 8.7, 10.9, 14.1, 14.3, 14.6, 14.9, 15.5, 15.8, 17.3, 17.5, 18.7, 19.7, 20.7, 21.4, 21.8, 22.2, 22.8, 23.5 and 23.7 in its powder X-ray diffraction (PXRD) pattern. For example, the crystalline form may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0040] In another embodiment, the present invention relates to a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 6.4, 8.2, 8.7, 10.1, 10.9, 12, 12.3, 13, 13.4, 14.1, 14.3, 14.6, 14.9, 15.2, 15.5, 15.8, 17.3, 17.5, 18, 18.7, 19.4, 19.7, 20.2, 20.7, 20.9, 21.4, 21.8, 22.2, 22.8, 23.1, 23.5, 23.7, 24.2, 25, 25.4, 26.5, and 26.8 in its powder X-ray diffraction (PXRD) pattern. For example, the crystalline form may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0041] In yet another embodiment, the present invention relates to a crystalline form of compound I that has a characteristic peak in a powder X-ray diffraction (PXRD) pattern, as shown in Figure 3, and is substantially pure. For example, the crystalline form may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0042] In yet another embodiment, the present invention relates to a crystalline form of compound I that is substantially pure and has a characteristic peak at the 2θ value (°2θ) shown in Table 3a in its powder X-ray diffraction (PXRD) pattern. For example, the crystalline form may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0043] In another embodiment, the present invention relates to a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 8.4, 8.8, 11.1, 14.4, 15, 15.8, 17.4, 17.7, 22.2, and 23.8 in its powder X-ray diffraction (PXRD) pattern. For example, the crystalline form may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0044] In another embodiment, the present invention relates to a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 8.4, 8.8, 10.2, 11.1, 12.2, 13.2, 13.6, 14.4, 15, 15.4, 15.8, 17.4, 17.7, 18.8, 19.8, 21, 22.2, 22.7, 23.2, and 23.8 in its powder X-ray diffraction (PXRD) pattern. For example, the crystalline form may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0045] In another embodiment, the present invention relates to a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 6.6, 8.4, 8.8, 9.8, 10.2, 11.1, 12.2, 12.4, 13.2, 13.6, 14.4, 15, 15.4, 15.8, 17.4, 17.7, 18.1, 18.8, 19.5, 19.8, 20.7, 21, 21.7, 22.2, 22.7, 23.2, 23.8, 24.5, 25, 26.8 and 27.4 and 32.45 in its powder X-ray diffraction (PXRD) pattern. For example, the crystalline form may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0046] In yet another embodiment, the present invention relates to a crystalline form of compound I that is substantially pure and has characteristic peaks in a powder X-ray diffraction (PXRD) pattern, as shown in Figure 4. For example, the crystalline form may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0047] In yet another embodiment, the present invention relates to a crystalline form of compound I that is substantially pure and has a characteristic peak at the 2θ value (°2θ) shown in Table 4a in its powder X-ray diffraction (PXRD) pattern. For example, the crystalline form may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0048] In another embodiment, the present invention relates to a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 8.4, 9.1, 11.2, 14.5, 15.1, 15.6, 16, 16.3, 17.5, and 17.9 in its powder X-ray diffraction (PXRD) pattern. For example, the crystalline form may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0049] In another embodiment, the present invention relates to a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 8.4, 9.1, 10.2, 11.2, 12.3, 13.3, 14.5, 15.1, 15.6, 16, 16.3, 17, 17.5, 17.9, 18.2, 19, 19.4, 20, 21.2, and 24 in its powder X-ray diffraction (PXRD) pattern. For example, the crystalline form may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0050] In another embodiment, the present invention relates to a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 6.7, 8.4, 9.1, 9.6, 9.9, 10.2, 11.2, 12.3, 13.3, 13.7, 14.5, 15.1, 15.6, 16, 16.3, 17, 17.5, 17.9, 18.2, 19, 19.4, 20, 20.9, 21.2, 21.9, 22.4, 22.8, 23.3, 24, 24.6, 25.1, 25.6, 27 and 27.8 in its powder X-ray diffraction (PXRD) pattern. For example, the crystalline form may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0051] In yet another embodiment, the present invention relates to a method for using the crystalline form of the present invention to prepare a composition comprising compound I. This method includes dissolving the crystalline form of the present invention in a solvent.

[0052] In the methods of the present invention described herein, crystal forms described herein, including any of the crystal forms described herein, may be used.

[0053] In one embodiment, the solvent is a volatile solvent, such as ethanol or methanol. A suitable excipient, such as a hydrophilic polymer or sugar alcohol described below, may be dissolved in the solvent. The resulting solution can then be dried to remove the solvent, for example by spray drying, freeze-drying, or other solvent evaporation techniques, to prepare a solid dispersion containing compound I and the excipient. Preferably, compound I exists in an amorphous form in the solid dispersion. More preferably, the solid dispersion is a solid solution or a glassy solution. Often, a pharmaceutically acceptable surfactant described below may be added to the solution before removing the solvent. As a result, the solid dispersion / solid solution / glassy solution prepared according to this embodiment also contains the surfactant.

[0054] In another embodiment, the solvent is a molten or rubbery excipient, such as a hydrophilic polymer or sugar alcohol as described below. The crystalline form of compound I is dissolved in the molten or rubbery excipient. Heating may be used to facilitate the dissolution and mixing of the crystalline form of compound I in the molten or rubbery excipient. It is preferable to use melt extrusion to dissolve and mix the crystalline form of compound I in the excipient. The resulting solution or melt can be cooled and solidified to form a solid dispersion containing compound I and the excipient. Preferably, compound I exists in an amorphous form in the solid dispersion. More preferably, the solid dispersion is a solid solution or a glassy solution. The solid dispersion, solid solution or glassy solution may be rubbed, crushed, or granulated and then compressed into a tablet or another suitable solid dosage form, optionally containing other additives. The solid dispersion, solid solution or glassy solution may be directly molded or formed into a tablet or another suitable solid dosage form. Often, pharmaceutically acceptable surfactants as described below may be added to the solution or melt before solidification. As a result, the solid dispersion / solid solution / glassy solution prepared according to this embodiment also contains a surfactant.

[0055] In yet another embodiment, both heating and a volatile solvent are used to dissolve the crystalline form of compound I in a solution containing a suitable excipient.

[0056] As used herein, the term “solid dispersion” refers to a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, one of which is dispersed throughout one or more other components. For example, an active ingredient or combination of active ingredients may be dispersed in a matrix consisting of a pharmaceutically acceptable hydrophilic polymer and a pharmaceutically acceptable surfactant. The term “solid dispersion” encompasses systems in which small particles of one phase are dispersed in another phase. If a solid dispersion of components is chemically and physically uniform or homogeneous throughout one phase (as thermodynamically defined), or consists of one phase, then that solid dispersion is referred to as a “solid solution.” A glassy solution is a solid solution in which a solute is dissolved in a glassy solvent.

[0057] Non-limiting examples of excipients suitable for use in the methods of the present invention include a large number of hydrophilic polymers. The hydrophilic polymers used in the methods of the present invention preferably have a T of at least 50°C, more preferably at least 60°C, very preferably at least 80°C (for example, without limitation, 80°C to 180°C, or 100°C to 150°C may be mentioned) g The organic polymer has the T g value measurement method described in INTRODUCTION TO PHYSICAL POLYMER SCIENCE (2nd Edition, edited by L.H. Sperling, John Wiley & Sons, Inc., published in 1992). The T g value can be calculated as the weighted sum of the T g values of the homopolymers derived from each of the individual polymers. That is, the polymer T g = ΣW i ·X i (where W i is the weight percentage of monomer i in the organic polymer, and X i is the T g value of the homopolymer derived from monomer i). The T g values of homopolymers can be taken from POLYMER HANDBOOK (2nd Edition, edited by J. Brandrup and E.H. Immergut, John Wiley & Sons, Inc., published in 1975). The hydrophilic polymer having the above-mentioned T g can be used to prepare a solid dispersion that is mechanically stable and sufficiently temperature-stable within the normal temperature range, and this solid dispersion can be used as a dosage form without further processing, or can be compressed into tablets using only a very small amount of tableting aids. Hydrophilic polymers having a T of 50°C or lower g may also be used.

[0058] Preferably, the hydrophilic polymer used in the present invention is water-soluble. The solid composition of the present invention may also contain poorly water-soluble or water-insoluble polymers, such as crosslinked polymers. When the hydrophilic polymer contained in the solid composition of the present invention is dissolved in an aqueous solution at 2% (w / v) at 20°C, it preferably has an apparent viscosity of 1 to 5000 mPa·s, more preferably 1 to 700 mPa·s, and most preferably 5 to 100 mPa·s.

[0059] Hydrophilic polymers suitable for use in the method of the present invention include homopolymers or copolymers of N-vinyl lactams, such as homopolymers or copolymers of N-vinylpyrrolidone (e.g., polyvinylpyrrolidone (PVP), or copolymers of N-vinylpyrrolidone with vinyl acetate or vinyl propionate); cellulose esters or cellulose ethers, such as alkylcellulose (e.g., methylcellulose or ethylcellulose), hydroxyalkylcellulose (e.g., hydroxypropylcellulose), hydroxyalkylalkylcellulose (e.g., hydroxypropylmethylcellulose), and phthalic acid or succinate cellulose (e.g., cellulose phthalate acetate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate, or hydroxypropylmethylcellulose succinate acetate); and high molecular weight polyalkylene oxides, such as polyethylene oxide, poly This includes, but is not limited to, propylene oxide and copolymers of ethylene oxide and propylene oxide; polyacrylates or polymethacrylates, e.g., methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, butyl methacrylate / 2-dimethylaminoethyl methacrylate copolymer, poly(hydroxyalkyl acrylate) and poly(hydroxyalkyl methacrylate); polyacrylamide; vinyl acetate polymers, e.g., copolymers of vinyl acetate and crotonic acid, and partially hydrolyzed polyvinyl acetate (also called partially saponified "polyvinyl alcohol"); polyvinyl alcohol; oligosaccharides or polysaccharides, e.g., carrageenan, galactomannan and xanthan gum; polyhydroxyalkyl acrylates; polyhydroxyalkyl methacrylates; copolymers of methyl methacrylate and acrylic acid; polyethylene glycol (PEG); and mixtures thereof.

[0060] Non-limiting examples of preferred hydrophilic polymers for use in the method of the present invention include polyvinylpyrrolidone (PVP) K17, PVP K25, PVP K30, PVP K90, hydroxypropyl methylcellulose (HPMC) E3, HPMC E5, HPMC E6, HPMC E15, HPMC K3, HPMC A4, HPMC A15, HPMC acetate succinate (AS) LF, HPMC AS MF, HPMC AS HF, HPMC AS LG, HPMC AS MG, HPMC AS HG, HPMC phthalate (P) 50, HPMC P 55, etocell 4, etocell 7, etocell 10, etocell 14, etocell 20, and copovidone (vinylpyrrolidone-vinyl acetate copolymer). This includes 60 / 40), polyvinyl acetate, methacrylate / methacrylate copolymer (Eudragit) L100-55, Eudragit L100, Eudragit S100, polyethylene glycol (PEG) 400, PEG 600, PEG 1450, PEG 3350, PEG 4000, PEG 6000, PEG 8000, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407.

[0061] Among these, homopolymers or copolymers of N-vinylpyrrolidone, such as a copolymer of N-vinylpyrrolidone and vinyl acetate, are preferred. An unspecified example of a preferred polymer is a copolymer of 60% by weight of N-vinylpyrrolidone and 40% by weight of vinyl acetate. Other preferred polymers include, but are not limited to, hydroxypropyl methylcellulose (HPMC, also known as hypromellose in the United States Pharmacopeia), such as hydroxypropyl methylcellulose grade E5 (HPMC-E5); and hydroxypropyl methylcellulose succinate acetate (HPMC-AS).

[0062] The pharmaceutically acceptable surfactant used in the method of the present invention is preferably a nonionic surfactant. More preferably, the nonionic surfactant has an HLB value of 2 to 20. The HLB system (Fiedler, HB, ENCYLOPEDIA OF EXCIPIENTS, 5th edition, Aulendorf: ECV-Editio-Cantor-Verlag (2002)) assigns numerical values ​​to surfactants, with lipophilic substances being assigned lower HLB values ​​and hydrophilic substances being assigned higher HLB values.

[0063] Non-limiting examples of pharmaceutically acceptable surfactants suitable for use in the methods of the present invention include polyoxyethylene castor oil derivatives, e.g., polyoxyethylene glycerol trilicinolate or polyoxy 35 castor oil (Cremophor(R) EL; BASF Corp.), or polyoxyethylene glycerol oxystearate, e.g., polyethylene glycol 40 hydrogenated castor oil (Cremophor(R) RH 40, also known as polyoxy 40 hydrogenated castor oil, or macrogol glycerol hydroxystearate), or polyethylene glycol 60 hydrogenated castor oil (Cremophor(R) RH 60); or mono fatty acid esters of polyoxyethylene (20) sorbitan, such as polyoxyethylene (20) sorbitan monooleate (Tween(R) 80), polyoxyethylene (20) sorbitan monostearate (Tween(R) 60), polyoxyethylene (20) sorbitan monopalmitate (Tween(R) 40), or polyoxyethylene (20) sorbitan monolaurate (Tween(R) 20).Other non-limiting examples of suitable surfactants include polyoxyethylene alkyl ethers, e.g., polyoxyethylene(3) lauryl ether, polyoxyethylene(5) cetyl ether, polyoxyethylene(2) stearyl ether, polyoxyethylene(5) stearyl ether; polyoxyethylene alkylaryl ethers, e.g., polyoxyethylene(2) nonylphenyl ether, polyoxyethylene(3) nonylphenyl ether, polyoxyethylene(4) nonylphenyl ether, polyoxyethylene(3) octylphenyl ether; polyethylene glycol fatty acid esters, e.g., PEG-200 monolaurate, PEG-20 This includes dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate; alkylene glycol fatty acid monoesters, e.g., propylene glycol monolaurate (Lauroglycol(R)); sucrose fatty acid esters, e.g., sucrose monostearate, sucrose distearate, sucrose monolaurate, sucrose dilaurate; sorbitan fatty acid monoesters, e.g., sorbitan monolaurate (Span(R)20), sorbitan monooleate, sorbitan monopalmitate (Span(R)40), or sorbitan stearate. Other suitable surfactants include, but are not limited to, ethylene oxide and propylene oxide block copolymers, also known as polyoxyethylene polyoxypropylene block copolymers, or polyoxyethylene polypropylene glycols, such as Poloxamer(R) 124, Poloxamer(R) 188, Poloxamer(R) 237, Poloxamer(R) 388, or Poloxamer(R) 407 (BASF Wyandotte Corp.).

[0064] Non-limiting examples of preferred surfactants for use in the method of the present invention include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, Cremophor RH 40, Cremophor EL, Gelucire 44 / 14, Gelucire 50 / 13, D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS), propylene glycol laurate, sodium lauryl sulfate, and sorbitan monolaurate.

[0065] The pharmaceutically acceptable surfactant used in the present invention may be a mixture of pharmaceutically acceptable surfactants, for example, a combination of a surfactant having an HLB value of less than 10 and another surfactant having an HLB value of 10 or more.

[0066] In one embodiment, a surfactant having an HLB value of at least 10 is used in the method of the present invention. In another embodiment, a surfactant having an HLB value of less than 10 is used in the method of the present invention. In yet another embodiment, a mixture of two or more surfactants (for example, a combination of a surfactant having an HLB value of at least 10 and another surfactant having an HLB value of less than 10) is used in the method of the present invention.

[0067] In one embodiment, the method of the present invention comprises dissolving the crystalline form of the present invention, the hydrophilic polymer described above, and the surfactant described above to form a solution (e.g., a molten product). The hydrophilic polymer may be selected from the group consisting of, for example, homopolymers of N-vinyl lactam, copolymers of N-vinyl lactam, cellulose esters, cellulose ethers, polyalkylene oxides, polyacrylates, polymethacrylates, polyacrylamides, polyvinyl alcohols, vinyl acetate polymers, oligosaccharides, and polysaccharides. In non-limiting examples, the hydrophilic polymer may be homopolymers of N-vinylpyrrolidone, copolymers of N-vinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl acetate, copolymers of N-vinylpyrrolidone and vinyl propionate, polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxyalkylcellulose, hydroxypropylcellulose, hydroxyalkylalkylcellulose, hydroxypropylmethylcellulose, cellulose phthalate, cellulose succinate, cellulose phthalate acetate, hydroxypropylmethylcellulose phthalate, hydroxypropyl succinate The following are selected from the group consisting of methylcellulose, hydroxypropyl methylcellulose succinate acetate, polyethylene oxide, polypropylene oxide, copolymer of ethylene oxide and propylene oxide, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, butyl methacrylate / 2-dimethylaminoethyl methacrylate copolymer, poly(hydroxyalkyl acrylate), poly(hydroxyalkyl methacrylate), copolymer of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate, carrageenan, galactomannan, and xanthan gum.Preferably, the hydrophilic polymer is polyvinylpyrrolidone (PVP) K17, PVP K25, PVP K30, PVP K90, hydroxypropyl methylcellulose (HPMC) E3, HPMC E5, HPMC E6, HPMC E15, HPMC K3, HPMC A4, HPMC A15, HPMC acetate succinate (AS) LF, HPMC AS MF, HPMC AS HF, HPMC AS LG, HPMC AS MG, HPMC AS HG, HPMC phthalate (P) 50, HPMC P 55, etocell 4, etocell 7, etocell 10, etocell 14, etocell 20, or copovidone (vinylpyrrolidone-vinyl acetate copolymer). Selected from 60 / 40), polyvinyl acetate, methacrylate / methacrylate copolymer (Eudragit) L100-55, Eudragit L100, Eudragit S100, polyethylene glycol (PEG) 400, PEG 600, PEG 1450, PEG 3350, PEG 4000, PEG 6000, PEG 8000, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, or poloxamer 407. More preferably, the hydrophilic polymer is selected from a homopolymer of vinylpyrrolidone (e.g., PVP having a Fikenture K value of 12 to 100, or PVP having a Fikenture K value of 17 to 30), or a copolymer of 30 to 70% by weight of N-vinylpyrrolidone (VP) and 70 to 30% by weight of vinyl acetate (VA) (e.g., a copolymer of 60% by weight of VP and 40% by weight of VA). The surfactant may be selected from the group consisting of, for example, polyoxyethylene glycerol trilicinolate, polyoxyl 35 castor oil (Cremophor(R)EL; BASF Corp.) or polyoxyethylene glycerol oxystearate, mono-fatty acid esters of polyoxyethylene sorbitan, polyoxyethylene alkyl ethers, polyoxyethylene alkylaryl ethers, polyethylene glycol fatty acid esters, alkylene glycol fatty acid monoesters, sucrose fatty acid esters, and sorbitan fatty acid monoesters.Non-limiting examples of surfactants include polyethylene glycol 40 hydrogenated castor oil (Cremophor(R) RH 40, also known as polyoxy 40 hydrogenated castor oil, or macrogol glycerol hydroxystearate), polyethylene glycol 60 hydrogenated castor oil (Cremophor(R) RH 60), mono fatty acid esters of polyoxyethylene(20) sorbitan (e.g., polyoxyethylene(20) sorbitan monooleate (Tween(R) 80), polyoxyethylene(20) sorbitan monostearate (Tween(R) 60), polyoxyethylene(20) sorbitan monopalmitate (Tween(R) 40), or polyoxyethylene(20) sorbitan monolaurate (Tween(R) 20)), polyoxyethylene(3) lauryl ether, polyoxyethylene(5) cetyl ether, polyoxyethylene(2) stearyl ether, polyoxyethylene(5) stearyl ether, and polyoxyethylene(2) nonylphenyl Selected from the group consisting of ethers, polyoxyethylene(3) nonylphenyl ether, polyoxyethylene(4) nonylphenyl ether, polyoxyethylene(3) octylphenyl ether, PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate, propylene glycol monolaurate, sucrose monostearate, sucrose distearate, sucrose monolaurate, sucrose dilaurate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, and sorbitan stearate. Preferably, the surfactant is selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, Cremophor RH 40, Cremophor EL, Gelucire 44 / 14, Gelucire 50 / 13, D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS), propylene glycol laurate, sodium lauryl sulfate, or sorbitan monolaurate.More preferably, the surfactant is selected from sorbitan monolaurate or D-α-tocopheryl polyethylene glycol 1000 succinate.

[0068] In another embodiment, the method of the present invention comprises dissolving the crystalline form of the present invention, the hydrophilic polymer described above, and the surfactant described above to form a solution (e.g., a melt). The hydrophilic polymer is a homopolymer or copolymer of N-vinylpyrrolidone (e.g., copovidone). A pharmaceutically acceptable surfactant may be, for example, vitamin E TPGS or sorbitan monolaurate.

[0069] The melt extrusion method of the present invention typically comprises preparing a melt from (1) the crystalline form of the present invention, (2) the hydrophilic polymer described above (or another suitable binder), and (3) preferably the surfactant described above. The melt may then be cooled until it solidifies. The crystalline form of compound I used initially disappears during the formation of the melt. The melt may contain other additives. "Melting" means a transition to a liquid or rubbery state in which one component can be embedded, preferably uniformly, within one or more other components. Often, the polymer component melts, and the other components, including the crystalline form of compound I and the surfactant, dissolve in the melt to form a solution. Melting usually involves heating above the softening point of the polymer. The preparation of the melt can be carried out in various ways. The components may be mixed before, during, or after the formation of the melt. For example, the components may be mixed first and then melted, or mixing and melting may be carried out simultaneously. The melt may be homogenized to efficiently disperse compound I. In addition, it may be convenient to melt the polymer first, then mix in compound I, and then homogenize. In one example, all materials except the surfactant are mixed and fed into the extruder, while the surfactant is melted externally and injected under pressure during extrusion.

[0070] In another example, the molten material comprises compound I and the hydrophilic polymer described above, with a melting temperature of 100-170°C, preferably 120-150°C, and very preferably 135-140°C. The molten material may also contain the pharmaceutically acceptable surfactant described above.

[0071] In yet another example, the melt comprises compound I, at least another anti-HCV agent (e.g., an HCV polymerase inhibitor, an NS5A inhibitor, or a combination of an HCV polymerase inhibitor and an NS5A inhibitor), and the hydrophilic polymer described above. The melt may also contain the pharmaceutically acceptable surfactant described above.

[0072] To initiate the melt extrusion method, compound I is used in the crystalline form of the present invention, for example, the crystalline form described herein in the embodiments, examples, or examples. The crystalline form of the present invention may first be dissolved in a suitable liquid solvent, such as an alcohol, aliphatic hydrocarbon, ester, or optionally liquid carbon dioxide. The solvent may be removed, for example, by evaporation, during the preparation of the melt.

[0073] Various additives, such as flow regulators (e.g., colloidal silica), lubricants, fillers, disintegrants, plasticizers, colorants, or stabilizers (e.g., antioxidants, light stabilizers, radical scavengers, and stabilizers against microbial attack), may also be incorporated into the molten material.

[0074] Melting and / or mixing can be carried out in apparatus commonly used for this purpose. Particularly suitable apparatus are extruders or kneaders. Suitable extruders include single-screw extruders, meshing-screw extruders, or multi-screw extruders, preferably twin-screw extruders that can rotate in the same or opposite direction and may optionally be equipped with a kneading disc. It is understood that the operating temperature may be determined by the type of extruder or the type of configuration within the extruder used. Part of the energy required to melt, mix and dissolve the components in the extruder can be supplied by a heating element. However, friction and shear of the material in the extruder can also supply a considerable amount of energy to the mixture, which can help form a homogeneous molten material of the components.

[0075] The molten material can range from low viscosity, paste-like to viscous. The extruded material is typically formed using a calender equipped with two counter-rotating rollers having mutually aligned grooves on its surface. The extruded material can be cooled and solidified. The extruded material may be cut into pieces before solidification (hot cut) or after solidification (cold cut).

[0076] The solidified extruded product may be further reduced to granules by grinding, pulverizing, or other methods. The solidified extruded product and each resulting granule consist of a solid dispersion, preferably a solid solution, of compound I in a matrix comprising a hydrophilic polymer and optionally a pharmaceutically acceptable surfactant. If the granules do not contain a surfactant, the above-mentioned pharmaceutically acceptable surfactant may be added to and mixed with the granules. The extruded product may be mixed with other active ingredients (e.g., ritonavir) and / or additives before grinding or pulverizing to form granules. The granules may be further processed into a suitable solid oral administration form.

[0077] In one example, copovidone and the surfactant described above are mixed and granulated, and then aerosil and the crystalline form of compound I of the present invention are added. The mixture may also contain ritonavir. The mixture is then ground, which may contain, for example, 5% by weight of compound I. The mixture is then extruded, and the resulting extruded material may be ground and sieved for further processing to create capsules or tablets. The surfactant used in this example may be added during extrusion via liquid addition.

[0078] For example, the solvent evaporation method by spray drying offers the advantage of being able to process at low temperatures if required, and other modifications can be made to the method to further improve the powder properties. The spray-dried powder can then be further processed as required, and the final drug product may be in the form of capsules, tablets, or other solid dosage forms as desired.

[0079] Examples of spray drying methods and spray drying apparatuses are described in K. Masters, SPRAY DRYING HANDBOOK (Halstead Press, New York, 4th edition, 1985). Non-limiting examples of spray drying devices suitable for the present invention include spray dryers from Niro Inc., or GEA Process Engineering Inc., Buchi Labortechnik AG, and Spray Drying Systems, Inc. A spray drying method typically involves dividing a liquid mixture into small droplets in a container (spray dryer) that provides a strong propulsion force for the evaporation of a solvent from droplets, and rapidly removing the solvent from those droplets. Atomization techniques include, for example, two-fluid or pressure nozzles or rotary atomizers. A strong propulsion force for solvent evaporation can be provided, for example, by maintaining the partial pressure of the solvent in the spray dryer far below the evaporation pressure of the solvent at the temperature of the drying droplets. This can be done by (1) maintaining the pressure in the spray dryer under partial vacuum; (2) mixing the droplets with a warm drying gas (e.g., heated nitrogen); or (3) both.

[0080] The temperature and flow rate of the drying gas, as well as the design of the spray dryer, can be selected to ensure that droplets are sufficiently dry before reaching the walls of the apparatus. This ensures that the dried droplets are essentially solid, capable of forming a fine powder, and do not adhere to the walls of the apparatus. The spray-dried product can be collected by removing the material manually, pneumatically, mechanically, or by other suitable means. The actual time required to obtain a preferred level of dryness depends on the size of the droplets, the formulation, and the operation of the spray dryer. After solidification, the solid powder may be left in the spray-drying chamber for an additional time (e.g., 5-60 seconds) to further evaporate the solvent from the solid powder. It is preferable that the final solvent content in the solid dispersion after leaving the dryer is sufficiently low to improve the stability of the final product. For example, the residual solvent content of the spray-dried powder may be less than 2% by weight. Very preferably, the residual solvent content is within the limits specified in the International Conference on Harmonisation of Regulations (ICH) guidelines. In addition, it may be useful to further dry the spray-dried composition to further reduce the residual solvent to an even lower level. Methods for further reducing solvent levels include, but are not limited to, fluidized bed drying, infrared drying, tumble drying, vacuum drying, and combinations thereof, as well as other methods.

[0081] As with the solid extruded product described above, the spray-dried product contains a solid dispersion, preferably a solid solution, of compound I in a matrix consisting of the hydrophilic polymer and optionally the pharmaceutically acceptable surfactant described above. If the spray-dried product does not contain a surfactant, the pharmaceutically acceptable surfactant described above may be added to and mixed with the spray-dried product before further processing.

[0082] Before supplying to a spray dryer, the crystalline form of compound I of the present invention, the hydrophilic polymer described above, and any other active ingredients or excipients, such as the pharmaceutically acceptable surfactant described above, may be dissolved in a solvent. Suitable solvents include, but are not limited to, alkanols (e.g., methanol, ethanol, 1-propanol, 2-propanol, or mixtures thereof), acetone, acetone / water, alkanol / water mixtures (e.g., ethanol / water mixtures), or combinations thereof. The solution may be preheated before supplying to a spray dryer. In many cases, ritonavir is dissolved together with the crystalline form of compound I.

[0083] Solid dispersions prepared by melt extrusion, spray drying, or other methods can be prepared into a suitable solid oral administration form. In one embodiment, a solid dispersion prepared by melt extrusion, spray drying, or other methods (e.g., an extruded or spray-dried powder) can be compressed into a tablet. The solid dispersion may be compressed directly, or it may be ground or pulverized into granules or powder before compression. Compression can be performed using a tablet press such as a steel die between two movable punches. If the solid composition contains compound I and another anti-HCV agent, solid dispersions of the individual active ingredients may be prepared separately, and the optionally ground or pulverized solid dispersions may be mixed and then compressed. Compound I and another anti-HCV agent may be prepared in the same solid dispersion, optionally ground, and / or mixed with other additives and then compressed into a tablet. Alternatively, if the solid composition contains compound I and ritonavir, solid dispersions of the individual active ingredients may be prepared separately, and then optionally ground or pulverized and then compressed. Compound I and ritonavir may be prepared as a solid dispersion, optionally ground, and / or mixed with other additives, and then compressed into tablets.

[0084] At least one additive, selected from flow regulators, lubricants, fillers, disintegrants, or plasticizers, may be used during the compression of the solid dispersion. These additives may be mixed with the solid dispersion, which may have been pulverized or ground before compression. Disintegrants promote rapid disintegration in the stomach of the compression, keeping the free granules separated from each other. Non-limiting examples of suitable disintegrants are cross-linked polymers, e.g., cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, or croscarmellose sodium. Non-limiting examples of suitable fillers (also called bulking agents) are lactose monohydrate, calcium hydrogen phosphate, crystalline cellulose (e.g., Avicel), silicates, especially silicon dioxide, magnesium oxide, talc, potato or corn starch, isomalt, or polyvinyl alcohol. Non-limiting examples of suitable flow regulators include highly dispersible silica (e.g., colloidal silica such as Aerosil), and animal or vegetable oils and fats. Suitable lubricants, though not limited to specific examples, include polyethylene glycol (e.g., those with a molecular weight of 1,000 to 6,000), magnesium and calcium stearate, and sodium stearyl fumarate.

[0085] When producing a solid composition according to the method of the present invention, various other additives may be used, such as dyes like azo dyes, organic or inorganic pigments like aluminum oxide or titanium dioxide, or dyes of natural origin; stabilizers, such as light stabilizers, radical scavengers, and stabilizers against microbial attack.

[0086] In one embodiment, the methods of the present invention described above (including the methods described in any aspect, embodiment, example, or preferred method) use a crystalline form of compound I that is substantially pure and has characteristic peaks in the powder X-ray diffraction (PXRD) pattern as shown in Figure 1. For example, the crystalline form used may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0087] In another embodiment, the methods of the present invention described above (including the methods described in any aspect, embodiment, example, or preference) use a crystalline form of compound I that is substantially pure and has a characteristic peak at the 2θ value (°2θ) shown in Table 1a in the powder X-ray diffraction (PXRD) pattern. For example, the crystalline form used may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0088] In another embodiment, the methods of the present invention described above (including the methods described in any aspect, embodiment, example, or preferred method) use a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 8.4, 8.9, 11.1, 12.2, 14.5, 15, 15.9, 17.4, 17.8, and 22.2 in a powder X-ray diffraction (PXRD) pattern. For example, the crystalline form used may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0089] In another embodiment, the methods of the present invention described above (including the methods described in any aspect, embodiment, example, or preferred method) use a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 8.4, 8.9, 10.2, 11.1, 12.2, 12.5, 13.2, 13.7, 14.5, 15, 15.5, 15.9, 17.4, 17.8, 19.6, 19.9, 21.1, 22.2, 22.7, and 23.9 in a powder X-ray diffraction (PXRD) pattern. For example, the crystalline form used may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0090] In another embodiment, the methods of the present invention described above (including the methods described in any aspect, embodiment, example, or preferred method) use a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 6.7, 8.4, 8.9, 9.9, 10.2, 11.1, 12.2, 12.5, 13.2, 13.7, 14.5, 15, 15.5, 15.9, 17.4, 17.8, 18.1, 18.9, 19, 19.6, 19.9, 21.1, 21.8, 22.2, 22.7, 22.8, 23.2, 23.9, 24.6, and 25.1 in a powder X-ray diffraction (PXRD) pattern. For example, the crystalline form used may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0091] In yet another embodiment, the methods of the present invention described above (including the methods described in any aspect, embodiment, example, or preference) use a crystalline form of compound I that is substantially pure and has characteristic peaks in the powder X-ray diffraction (PXRD) pattern as shown in Figure 2. For example, the crystalline form used may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0092] In yet another embodiment, the methods of the present invention described above (including the methods described in any aspect, embodiment, example, or preference) use a crystalline form of compound I that is substantially pure and has a characteristic peak at the 2θ value (°2θ) shown in Table 2a in the powder X-ray diffraction (PXRD) pattern. For example, the crystalline form used may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0093] In another embodiment, the methods of the present invention described above (including the methods described in any aspect, embodiment, example, or preferred method) use a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 8.2, 10.9, 14.1, 14.3, 14.9, 15.5, 15.8, 17.5, 21.8, and 22.2 in the powder X-ray diffraction (PXRD) pattern. For example, the crystalline form used may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0094] In another embodiment, the methods of the present invention described above (including the methods described in any aspect, embodiment, example, or preferred method) use a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 8.2, 8.7, 10.9, 14.1, 14.3, 14.6, 14.9, 15.5, 15.8, 17.3, 17.5, 18.7, 19.7, 20.7, 21.4, 21.8, 22.2, 22.8, 23.5, and 23.7 in a powder X-ray diffraction (PXRD) pattern. For example, the crystalline form used may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0095] In another embodiment, the methods of the present invention described above (including the methods described in any aspect, embodiment, example, or preference) use a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 6.4, 8.2, 8.7, 10.1, 10.9, 12, 12.3, 13, 13.4, 14.1, 14.3, 14.6, 14.9, 15.2, 15.5, 15.8, 17.3, 17.5, 18, 18.7, 19.4, 19.7, 20.2, 20.7, 20.9, 21.4, 21.8, 22.2, 22.8, 23.1, 23.5, 23.7, 24.2, 25, 25.4, 26.5, and 26.8 in a powder X-ray diffraction (PXRD) pattern. For example, the crystal form used may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0096] In yet another embodiment, the methods of the present invention described above (including the methods described in any aspect, embodiment, example, or preference) use a crystalline form of compound I that is substantially pure and has characteristic peaks in the powder X-ray diffraction (PXRD) pattern as shown in Figure 3. For example, the crystalline form used may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0097] In yet another embodiment, the methods of the present invention described above (including the methods described in any aspect, embodiment, example, or preference) use a crystalline form of compound I that is substantially pure and has a characteristic peak at the 2θ value (°2θ) shown in Table 3a in the powder X-ray diffraction (PXRD) pattern. For example, the crystalline form used may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0098] In another embodiment, the methods of the present invention described above (including the methods described in any aspect, embodiment, example, or preferred method) use a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 8.4, 8.8, 11.1, 14.4, 15, 15.8, 17.4, 17.7, 22.2, and 23.8 in the powder X-ray diffraction (PXRD) pattern. For example, the crystalline form used may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0099] In another embodiment, the methods of the present invention described above (including the methods described in any aspect, embodiment, example, or preferred method) use a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 8.4, 8.8, 10.2, 11.1, 12.2, 13.2, 13.6, 14.4, 15, 15.4, 15.8, 17.4, 17.7, 18.8, 19.8, 21, 22.2, 22.7, 23.2, and 23.8 in a powder X-ray diffraction (PXRD) pattern. For example, the crystalline form used may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0100] In another embodiment, the methods of the present invention described above (including the methods described in any aspect, embodiment, example, or preferred method) use a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 6.6, 8.4, 8.8, 9.8, 10.2, 11.1, 12.2, 12.4, 13.2, 13.6, 14.4, 15, 15.4, 15.8, 17.4, 17.7, 18.1, 18.8, 19.5, 19.8, 20.7, 21, 21.7, 22.2, 22.7, 23.2, 23.8, 24.5, 25, 26.8, and 27.4 in a powder X-ray diffraction (PXRD) pattern. For example, the crystalline form used may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0101] In yet another embodiment, the methods of the present invention described above (including the methods described in any aspect, embodiment, example, or preference) use a crystalline form of compound I that is substantially pure and has characteristic peaks in the powder X-ray diffraction (PXRD) pattern as shown in Figure 4. For example, the crystalline form used may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0102] In yet another embodiment, the methods of the present invention described above (including the methods described in any aspect, embodiment, example, or preference) use a crystalline form of compound I that is substantially pure and has a characteristic peak at the 2θ value (°2θ) shown in Table 4a in the powder X-ray diffraction (PXRD) pattern. For example, the crystalline form used may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0103] In another embodiment, the methods of the present invention described above (including the methods described in any aspect, embodiment, example, or preferred method) use a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 8.4, 9.1, 11.2, 14.5, 15.1, 15.6, 16, 16.3, 17.5, and 17.9 in the powder X-ray diffraction (PXRD) pattern. For example, the crystalline form used may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0104] In another embodiment, the methods of the present invention described above (including the methods described in any aspect, embodiment, example, or preferred method) use a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 8.4, 9.1, 10.2, 11.2, 12.3, 13.3, 14.5, 15.1, 15.6, 16, 16.3, 17, 17.5, 17.9, 18.2, 19, 19.4, 20, 21.2, and 24 in a powder X-ray diffraction (PXRD) pattern. For example, the crystalline form used may have a purity of 90%, preferably at least 95%, and more preferably at least 97%.

[0105] In another embodiment, the methods of the present invention described above (including the methods described in any aspect, embodiment, example, or preferred method) use a crystalline form of compound I that is substantially pure and has characteristic peaks at 2θ values ​​(°2θ) of 6.7, 8.4, 9.1, 9.6, 9.9, 10.2, 11.2, 12.3, 13.3, 13.7, 14.5, 15.1, 15.6, 16, 16.3, 17, 17.5, 17.9, 18.2, 19, 19.4, 20, 20.9, 21.2, 21.9, 22.4, 22.8, 23.3, 24, 24.6, 25.1, 25.6, 27 and 27.8 in a powder X-ray diffraction (PXRD) pattern. For example, the crystalline form used may have a purity of at least 90%, preferably at least 95%, and more preferably at least 97%.

[0106] In yet another embodiment, the present invention relates to compositions comprising a crystalline form of compound I of the present invention. Crystalline forms described herein (including those described in any aspect, embodiment, or example) may be used to prepare compositions of the present invention. Preferably, the crystalline forms are substantially pure and may have a purity of, for example, at least 90%, preferably at least 95%, and more preferably at least 97%. In one embodiment, the composition of the present invention comprises at least 5% by weight of a substantially pure crystalline form of the present invention. In another embodiment, the composition of the present invention comprises at least 10% by weight of a substantially pure crystalline form of the present invention. In yet another embodiment, the composition of the present invention comprises at least 5% by weight of one or more crystalline forms of the present invention. In yet another embodiment, the composition of the present invention comprises at least 10% by weight of one or more crystalline forms of the present invention. [Examples]

[0107] [Example 1] Production of Crystal Form I (Hydrate) Crude compound I and methanol (12 vols) were charged into a reactor and heated to 55 ± 10°C to dissolve the solid. Water (12 vols) was added to this solution at a rate maintaining a temperature of >50°C. The product was cooled to room temperature (RT) at approximately 10°C / hour and mixed at RT for 30 minutes. The product was isolated by filtration, and the wet cake was washed with 1:2 (v / v) methanol:water (2 vols). The product was dried in a vacuum oven using a humidified nitrogen oven (approximately 30-90% relative humidity) at 50°C.

[0108] The powder X-ray diffraction patterns and relative intensities of the PXRD peaks of the crystalline forms produced in this way are shown in Figure 1 and Table 1a, respectively. The crystal profile of the crystalline forms is summarized in Table 1b.

[0109] [Table 1]

[0110] [Table 2]

[0111] [Example 2] Preparation of compound I trimethanol solvate Compound I (532 mg) was dissolved in MeOH (7.67 g) at approximately 55°C. The resulting solution was allowed to cool to room temperature. Crystals formed from the solution, and the product was isolated by filtration.

[0112] The powder X-ray diffraction patterns and relative intensities of the PXRD peaks of the crystalline forms produced in this way are shown in Figure 2 and Table 2a, respectively. The crystal profile of the crystalline forms is summarized in Table 2b.

[0113] [Table 3] TIFF0007943886000005.tif49162

[0114] [Table 4]

[0115] [Example 3] Preparation of Compound I Dimethanol Monohydrate Crude compound I and methanol (12 vols) were charged into a reactor and heated to 55 ± 10°C to dissolve the solid. Water (12 vols) was added to this solution at a rate maintaining a temperature of >50°C. The product was cooled to room temperature at approximately 10°C / hour and mixed in RT for 30 minutes. The product was isolated by filtration and the wet cake was washed with 1:2 (v / v) methanol:water (2 vols).

[0116] The powder X-ray diffraction patterns and relative intensities of the PXRD peaks of the crystalline forms produced in this way are shown in Figure 3 and Table 3a, respectively. The crystal profile of the crystalline forms is summarized in Table 3b.

[0117] [Table 5]

[0118] [Table 6]

[0119] [Example 4] Preparation of the desolvated compound I Crude compound I and methanol (12 vols) were charged into a reactor and heated to 55 ± 10°C to dissolve the solid. Water (12 vols) was added to this solution at a rate maintaining a temperature of >50°C. The product was cooled to room temperature at approximately 10°C / hour and mixed in RT for 30 minutes. The product was isolated by filtration, and the wet cake was washed with 1:2 (v / v) methanol:water (2 vols). The product was dried in a vacuum oven at 50°C while purging with dry nitrogen.

[0120] The powder X-ray diffraction patterns and relative intensities of the PXRD peaks of the crystalline forms produced in this way are shown in Figure 4 and Table 4a, respectively. The crystal profile of the crystalline forms is summarized in Table 4b.

[0121] [Table 7]

[0122] [Table 8]

[0123] The foregoing description of the present invention provides examples and explanations, but is not intended to be exhaustive or to limit the invention to what is disclosed. Modifications and alterations are possible in accordance with the above teachings or can be learned from the practice of the invention. Therefore, it should be noted that the scope of the invention is defined by the claims and their equivalents.

Claims

1. Compound I in the form of (i) hydrate crystalline form, (ii) trimethanol solvate crystalline form, (iii) dimethanol monohydrate crystalline form, or (iv) desolvated crystalline form: 【Chemistry 1】 The hydrate crystal form has characteristic peaks in the PXRD pattern at the 2θ values ​​listed in Table 1, with each peak position being ±0.2°2θ, as shown in Table 1: Table 1 The trimethanol solvate crystalline form exhibits characteristic peaks in the PXRD pattern at the 2θ values ​​listed in Table 2, with each peak position being ±0.2°2θ, as shown in Table 2: Table 2 The dimethanol monohydrate crystalline form exhibits characteristic peaks in the PXRD pattern at the 2θ values ​​listed in Table 3, with each peak position being ±0.2°2θ, as shown in Table 3: Table 3 The desolvated crystalline form exhibits characteristic peaks in the PXRD pattern at the 2θ values ​​listed in Table 4, with each peak position being ±0.2°2θ, as shown in Table 4: Table 4 Compound I.

2. Compound I according to claim 1, wherein the PXRD pattern has characteristic peaks at the 2θ values ​​listed in Table 1, and the position of each peak is ±0.2°2θ.

3. Compound I according to claim 1, wherein the PXRD pattern has characteristic peaks at the 2θ values ​​listed in Table 2, and the position of each peak is ±0.2°2θ.

4. Compound I according to claim 1, wherein the PXRD pattern has characteristic peaks at the 2θ values ​​listed in Table 3, and the position of each peak is ±0.2°2θ.

5. Compound I according to claim 1, wherein the PXRD pattern has characteristic peaks at the 2θ values ​​listed in Table 4, and the position of each peak is ±0.2°2θ.

6. Compound I in hydrate crystalline form: 【Chemistry 2】 Compound I, wherein the hydrate crystal form has characteristic peaks at 2θ values ​​(°2θ) of 8.4, 8.9, 11.1, 12.2, 14.5, 15, 15.9, 17.4, 17.8 and 22.2 in the PXRD pattern, with each peak position being ±0.2°2θ.

7. Compound I according to claim 6, wherein the hydrate crystal form has characteristic peaks at 2θ values ​​(°2θ) of 8.4, 8.9, 10.2, 11.1, 12.2, 12.5, 13.2, 13.7, 14.5, 15, 15.5, 15.9, 17.4, 17.8, 19.6, 19.9, 21.1, 22.2, 22.7, and 23.9 in the PXRD pattern, with each peak position being ±0.2°2θ.

8. Compound I according to claim 6, wherein the hydrate crystal form has characteristic peaks at 2θ values ​​(°2θ) of 6.7, 8.4, 8.9, 9.9, 10.2, 11.1, 12.2, 12.5, 13.2, 13.7, 14.5, 15, 15.5, 15.9, 17.4, 17.8, 18.1, 18.9, 19, 19.6, 19.9, 21.1, 21.8, 22.2, 22.7, 22.8, 23.2, 23.9, 24.6, and 25.1 in the PXRD pattern, with each peak position being ±0.2°2θ.

9. Compound I in trimethanol solvate crystalline form: 【Transformation 3】 Compound I, wherein the trimethanol solvate crystal form has characteristic peaks at 2θ values ​​(°2θ) of 8.2, 10.9, 14.1, 14.3, 14.9, 15.5, 15.8, 17.5, 21.8, and 22.2 in the PXRD pattern, with each peak position being ±0.2°2θ.

10. Compound I according to claim 9, wherein the trimethanol solvate crystal form has characteristic peaks at 2θ values ​​(°2θ) of 8.2, 8.7, 10.9, 14.1, 14.3, 14.6, 14.9, 15.5, 15.8, 17.3, 17.5, 18.7, 19.7, 20.7, 21.4, 21.8, 22.2, 22.8, 23.5 and 23.7 in the PXRD pattern, with each peak position being ±0.2°2θ.

11. Compound I according to claim 9, wherein the trimethanol solvate crystal form has characteristic peaks at 2θ values ​​(°2θ) of 6.4, 8.2, 8.7, 10.1, 10.9, 12, 12.3, 13, 13.4, 14.1, 14.3, 14.6, 14.9, 15.2, 15.5, 15.8, 17.3, 17.5, 18, 18.7, 19.4, 19.7, 20.2, 20.7, 20.9, 21.4, 21.8, 22.2, 22.8, 23.1, 23.5, 23.7, 24.2, 25, 25.4, 26.5, and 26.8, with each peak position being ±0.2°2θ.

12. Compound I of dimethanol monohydrate crystalline form: 【Chemistry 4】 Compound I, wherein the dimethanol monohydrate crystalline form has characteristic peaks at 2θ values ​​(°2θ) of 8.4, 8.8, 11.1, 14.4, 15, 15.8, 17.4, 17.7, 22.2, and 23.8 in the PXRD pattern, with each peak position being ±0.2°2θ.

13. Compound I according to claim 12, wherein the dimethanol monohydrate crystalline form has characteristic peaks at 2θ values ​​(°2θ) of 8.4, 8.8, 10.2, 11.1, 12.2, 13.2, 13.6, 14.4, 15, 15.4, 15.8, 17.4, 17.7, 18.8, 19.8, 21, 22.2, 22.7, 23.2, and 23.8 in the PXRD pattern, with each peak position being ±0.2°2θ.

14. Compound I according to claim 12, wherein the dimethanol monohydrate crystalline form has characteristic peaks at 2θ values ​​(°2θ) of 6.6, 8.4, 8.8, 9.8, 10.2, 11.1, 12.2, 12.4, 13.2, 13.6, 14.4, 15, 15.4, 15.8, 17.4, 17.7, 18.1, 18.8, 19.5, 19.8, 20.7, 21, 21.7, 22.2, 22.7, 23.2, 23.8, 24.5, 25, 26.8, and 27.4, with each peak position being ±0.2°2θ.

15. Compound I in desolvated crystalline form: 【Transformation 5】 Compound I, wherein the desolvated crystalline form has characteristic peaks at 2θ values ​​(°2θ) of 8.4, 9.1, 11.2, 14.5, 15.1, 15.6, 16, 16.3, 17.5, and 17.9 in the PXRD pattern, with each peak position being ±0.2°2θ.

16. Compound I according to claim 15, wherein the desolvated crystalline form has characteristic peaks at 2θ values ​​(°2θ) of 8.4, 9.1, 10.2, 11.2, 12.3, 13.3, 14.5, 15.1, 15.6, 16, 16.3, 17, 17.5, 17.9, 18.2, 19, 19.4, 20, 21.2, and 24 in the PXRD pattern, with each peak position being ±0.2°2θ.

17. Compound I according to claim 15, wherein the desolvated crystalline form has characteristic peaks at 2θ values ​​(°2θ) of 6.7, 8.4, 9.1, 9.6, 9.9, 10.2, 11.2, 12.3, 13.3, 13.7, 14.5, 15.1, 15.6, 16, 16.3, 17, 17.5, 17.9, 18.2, 19, 19.4, 20, 20.9, 21.2, 21.9, 22.4, 22.8, 23.3, 24, 24.6, 25.1, 25.6, 27 and 27.8, with each peak position being ±0.2°2θ.

18. A composition comprising compound I as described in any one of claims 1 to 17 and a pharmaceutically acceptable carrier.

19. A method for preparing a pharmaceutical composition containing compound I, comprising dissolving compound I as described in any one of claims 1 to 17.

20. A method for preparing a pharmaceutical composition containing compound I, comprising dissolving compound I according to any one of claims 1 to 17 in a volatile solvent to form a solution.

21. The method according to claim 20, wherein the solution further comprises an excipient.

22. The method according to claim 20, wherein the solution further comprises a surfactant.

23. The method according to claim 20, further comprising spray-drying the solution to form a solid dispersion.

24. The method according to claim 20, further comprising freeze-drying the solution to form a solid dispersion.

25. A method for preparing a pharmaceutical composition containing compound I, comprising dissolving compound I according to any one of claims 1 to 17 in a molten hydrophilic polymer to form a molten product.

26. The method according to claim 25, wherein the molten material further comprises an excipient.

27. The method according to claim 25, wherein the molten material further contains a surfactant.

28. The method according to claim 25, further comprising solidifying a molten material to form a solid dispersion.

29. The method according to claim 25, wherein the hydrophilic polymer is copovidone.

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