Crystal forms

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 crystalline polymorphs of Compound I, pharmaceutical compositions comprising said polymorphs, and methods of using said polymorphs for preparing pharmaceutical compositions. [Background technology]

[0002] Hepatitis C virus (HCV) is an RNA virus belonging to the genus Hepacivirus in the family Flaviviridae. Enveloped HCV virions contain a positive-stranded RNA genome that encodes all known virus-specific proteins in one 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 the core protein, the envelope proteins E1 and E2, the membrane-associated protein p7, and the nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A, and NS5B. Summary of the Invention

[0003] HCV infection is associated with progressive liver lesions, including cirrhosis and hepatocellular carcinoma. Chronic hepatitis C can be treated with pegylated interferon-α together with ribavirin. Efficacy and tolerability are still substantially limited, as many users suffer from adverse events, and viral clearance from the body is often incomplete.Therefore, new drugs are needed to treat HCV infection.

[0004] The drawings are presented by way of example, and not by way of limitation. [Brief description of the drawings]

[0005] [Figure 1] 1 shows the experimental PXRD pattern of crystalline form I of compound I. [Diagram 2] 1 shows the experimental PXRD pattern of Compound I trimethanol solvate. [Diagram 3] 1 shows an experimental PXRD of compound I dimethanol monohydrate. [Figure 4] 1 shows an experimental PXRD of Compound I desolvate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] The present invention relates to compound I (

[0007] [ka] 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] Crystalline forms 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 characteristic peaks in a powder X-ray diffraction (PXRD) pattern as shown in FIG.

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

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

[0012] In yet another aspect, the present invention relates to a crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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.

[0013] In yet another aspect, the present invention relates to a crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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.

[0014] In yet another aspect, the present invention relates to a crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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.

[0015] In yet another aspect, 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 FIG.

[0016] In yet another aspect, the present invention relates to a crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern at the 2θ values ​​(°2θ) as set out in Table 2a.

[0017] In yet another aspect, the present invention relates to a crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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.

[0018] In yet another aspect, the present invention relates to a crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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.

[0019] In yet another aspect, the present invention relates to a crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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.

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

[0021] In yet another aspect, the present invention relates to a crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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.

[0022] In yet another aspect, the present invention relates to a crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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.

[0023] In yet another aspect, the present invention relates to a crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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.

[0024] In yet another aspect, 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 FIG.

[0025] In yet another aspect, the present invention relates to a crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern at the 2θ values ​​(°2θ) as set out in Table 4a.

[0026] In yet another aspect, the present invention relates to a crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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.

[0027] In yet another aspect, the present invention relates to a crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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.

[0028] In yet another aspect, the present invention relates to a crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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.

[0029] The PXRD data used herein can be collected using a G3000 diffractometer (Inel Corp., Artenay, France) equipped with a curve position sensor and parallel beam optics. The diffractometer is operated at 40 kV and 30 mA with a copper anode tube (1.5 kW fine focus). The incident beam germanium monochromator is a monochromatic Cu-K α Radiation is applied. The diffractometer is calibrated at 1 degree intervals using an attenuated direct beam. Calibration is checked using a silicon powder linear position reference standard (NIST 640c). The instrument is computer controlled using Symphonix software (Inel Corp., Artenay, France) and data are analyzed using Jade software (Version 9.0, Materials Data, Inc., Livermore, Calif.). Samples are packed into aluminum sample holders and are flush with the glass slides. PXRD peak position measurement error is typically ±0.2 degrees two-theta (°2θ).

[0030] In another embodiment, the present invention relates to the above-mentioned crystalline form being substantially pure. As used herein, the term "substantially pure" refers to a crystalline form having a purity of at least about 90% when used in relation 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" refers to a crystalline form of compound I having a purity of at least about 95%. This 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" refers to a crystalline form having a purity of at least about 97%. This 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 substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern as shown in Figure 1. 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 substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern at the 2θ values ​​(°2θ) shown in Table 1a. 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 substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form may have a purity of at least 90%, preferably a purity of at least 95%, and more preferably a purity of at least 97%.

[0034] In another embodiment, the present invention relates to a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form may have a purity of at least 90%, preferably a purity of at least 95%, and more preferably a purity of at least 97%.

[0035] In another embodiment, the present invention relates to a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form may have a purity of at least 90%, preferably a purity of at least 95%, and more preferably a purity of at least 97%.

[0036] In yet another embodiment, the present invention relates to a substantially pure crystalline form of Compound I having 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 substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern at the 2θ values ​​(°2θ) shown in Table 2a. 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 substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form may have a purity of at least 90%, preferably a purity of at least 95%, and more preferably a purity of at least 97%.

[0039] In another embodiment, the present invention relates to a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form may have a purity of at least 90%, preferably a purity of at least 95%, and more preferably a purity of at least 97%.

[0040] In another embodiment, the present invention relates to a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form may have a purity of at least 90%, preferably a purity of at least 95%, and more preferably a purity of at least 97%.

[0041] In yet another embodiment, the present invention relates to a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern as shown in Figure 3. 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 substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern at the 2θ values ​​(°2θ) set out in Table 3a. 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 substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form may have a purity of at least 90%, preferably a purity of at least 95%, and more preferably a purity of at least 97%.

[0044] In another embodiment, the present invention relates to a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form may have a purity of at least 90%, preferably a purity of at least 95%, and more preferably a purity of at least 97%.

[0045] In another embodiment, the present invention relates to a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form may have a purity of at least 90%, preferably a purity of at least 95%, and more preferably a purity of at least 97%.

[0046] In yet another embodiment, the present invention relates to a substantially pure crystalline form of Compound I having 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 substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern at the 2θ values ​​(°2θ) set out in Table 4a. 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 substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form may have a purity of at least 90%, preferably a purity of at least 95%, and more preferably a purity of at least 97%.

[0049] In another embodiment, the present invention relates to a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form may have a purity of at least 90%, preferably a purity of at least 95%, and more preferably a purity of at least 97%.

[0050] In another embodiment, the present invention relates to a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form may have a purity of at least 90%, preferably a purity of at least 95%, and more preferably a purity of at least 97%.

[0051] In yet another aspect, the present invention relates to a method of using a crystalline form of the present invention to prepare a composition comprising Compound I. The method comprises dissolving a crystalline form of the present invention in a solvent.

[0052] Any crystalline form described herein, including any crystalline form described in any aspect, embodiment or example herein, may be used in the methods of the invention described herein.

[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, as described below, may be dissolved in the solvent. The resulting solution may then be dried, for example by spray drying, freeze drying or other solvent evaporation techniques, to remove the solvent and form a solid dispersion comprising Compound I and the excipient. Preferably, Compound I is present in an amorphous form in the solid dispersion. More preferably, the solid dispersion is a solid solution or glassy solution. In many cases, a pharma- ceutical acceptable surfactant, as described below, may be added to the solution before removing the solvent. As a result, the solid dispersion / solid solution / glassy solution formed according to this embodiment also comprises a 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 applied to facilitate dissolution and mixing of the crystalline form of Compound I in the molten or rubbery excipient. It is preferred to use melt extrusion to dissolve and mix the crystalline form of Compound I in the excipient. The resulting solution or melt may be cooled and solidified to form a solid dispersion comprising Compound I and the excipient. Preferably, Compound I is present in amorphous form in the solid dispersion. More preferably, the solid dispersion is a solid solution or glassy solution. The solid dispersion, solid solution or glassy solution may be ground, crushed, or granulated, and then compressed into a tablet or other suitable solid dosage form, optionally including other additives. The solid dispersion, solid solution, or glassy solution may be directly molded or formed into a tablet or other suitable solid dosage form. In many cases, a pharma- ceutical acceptable surfactant, as described below, may be added to the solution or melt before solidification. As a result, the solid dispersion / solid solution / glassy solution made according to this embodiment also contains a surfactant.

[0055] In yet another embodiment, a crystalline form of Compound I is dissolved in a solution containing suitable excipients using both heat and a volatile solvent.

[0056] The term "solid dispersion" as used herein defines a solid state (as opposed to a liquid or gaseous state) system that includes 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 of a pharma- ceutical acceptable hydrophilic polymer and a pharma- ceutical acceptable surfactant. The term "solid dispersion" encompasses systems in which small particles of one phase are dispersed in another phase. When a system is a solid dispersion of components that is chemically and physically uniform or homogeneous throughout one phase (as defined thermodynamically) or is composed of one phase, the solid dispersion is referred to as a "solid solution." A glassy solution is a solid solution in which the solute is dissolved in a glassy solvent.

[0057] Non-limiting examples of excipients suitable for use in the methods of the invention include a number of hydrophilic polymers. The hydrophilic polymers used in the methods of the invention preferably have a T of at least 50° C., more preferably at least 60° C., and most preferably at least 80° C. (e.g., but not limited to, 80° C. to 180° C., or 100° C. to 150° C.). g The organic polymer T g The method for measuring the value is described in INTRODUCTION TO PHYSICAL POLYMER SCIENCE (2nd Edition, edited by LH Sperling, published by John Wiley & Sons, Inc., 1992). g The values ​​are the homopolymer T values ​​derived from each of the individual polymers. g It can be calculated as a weighted sum of the values ​​of polymer T g =ΣW i X i (Where, i is the weight percent of monomer i in the organic polymer, and X i is the T of the homopolymer derived from monomer i g (T is the value of homopolymer) g The values ​​can be taken from the POLYMER HANDBOOK (2nd Edition, edited by J. Brandrup and EH Immergut, published by John Wiley & Sons, Inc., 1975). g Hydrophilic polymers having a T of 50° C. or less can produce solid dispersions that are mechanically stable and sufficiently thermostable within normal temperature ranges that they can be used as a dosage form without further processing or compressed into tablets with only small amounts of tableting aids. g A hydrophilic polymer having the following formula may 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 a poorly water-soluble or water-insoluble polymer, such as a crosslinked polymer. The hydrophilic polymer contained in the solid composition of the present invention has an apparent viscosity of preferably 1 to 5000 mPa·s, more preferably 1 to 700 mPa·s, and most preferably 5 to 100 mPa·s when dissolved in an aqueous solution at 2% (w / v) at 20°C.

[0059] Hydrophilic polymers suitable for use in the method of the 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 and vinyl acetate or vinyl propionate); cellulose esters or ethers, such as alkylcelluloses (e.g. methylcellulose or ethylcellulose), hydroxyalkylcelluloses (e.g. hydroxypropylcellulose), hydroxyalkylalkylcelluloses (e.g. hydroxypropylmethylcellulose), and cellulose phthalates or succinates (e.g. cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate, or hydroxypropylmethylcellulose acetate succinate); high molecular weight polyalkylene oxides, such as polyethylene oxide, poly Examples of suitable polysaccharides include, but are not limited to, propylene oxide and copolymers of ethylene oxide and propylene oxide; polyacrylates or polymethacrylates, such as methacrylic acid / ethyl acrylate copolymers, methacrylic acid / methyl methacrylate copolymers, butyl methacrylate / 2-dimethylaminoethyl methacrylate copolymers, poly(hydroxyalkyl acrylates) and poly(hydroxyalkyl methacrylates); polyacrylamides; vinyl acetate polymers, such as copolymers of vinyl acetate and crotonic acid, and partially hydrolyzed polyvinyl acetate (also referred to as partially saponified "polyvinyl alcohol"); polyvinyl alcohol; oligo- or polysaccharides, such as carrageenan, galactomannan, and xanthan gum; polyhydroxyalkyl acrylates; polyhydroxyalkyl methacrylates; copolymers of methyl methacrylate and acrylic acid; polyethylene glycol (PEG); or mixtures thereof.

[0060] Non-limiting examples of preferred hydrophilic polymers for use in the methods of the 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, Ethocel 4, Ethocel 7, Ethocel 10, Ethocel 14, Ethocel 20, Copovidone (vinylpyrrolidone-vinyl acetate copolymer), 60 / 40), polyvinyl acetate, methacrylates / methacrylic acid 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 copolymers of N-vinylpyrrolidone and vinyl acetate, are preferred. A non-limiting example of a preferred polymer is a copolymer of 60% by weight N-vinylpyrrolidone and 40% by weight vinyl acetate. Other preferred polymers include, but are not limited to, hydroxypropyl methylcellulose (HPMC, also known in the United States Pharmacopeia as hypromellose), such as hydroxypropyl methylcellulose grade E5 (HPMC-E5); and hydroxypropyl methylcellulose acetate succinate (HPMC-AS).

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

[0063] Non-limiting examples of pharma- ceutically acceptable surfactants suitable for use in the methods of the invention include polyoxyethylene castor oil derivatives, such as polyoxyethylene glycerol triricinoleate or polyoxy 35 castor oil (Cremophor® EL; BASF Corp.), or polyoxyethylene glycerol oxystearate, such as polyethylene glycol 40 hydrogenated castor oil (Cremophor® RH 40, also known as polyoxy 40 hydrogenated castor oil, or macrogol glycerol hydroxystearate), or polyethylene glycol 60 hydrogenated castor oil (Cremophor® RH 60); or mono fatty acid esters of polyoxyethylene sorbitan, such as mono fatty acid esters of polyoxyethylene (20) sorbitan, such as polyoxyethylene (20) sorbitan monooleate (Tween® 80), polyoxyethylene (20) sorbitan monostearate (Tween® 60), polyoxyethylene (20) sorbitan monopalmitate (Tween® 40) or polyoxyethylene (20) sorbitan monolaurate (Tween® 20).Other non-limiting examples of suitable surfactants include polyoxyethylene alkyl ethers, such as polyoxyethylene (3) lauryl ether, polyoxyethylene (5) cetyl ether, polyoxyethylene (2) stearyl ether, polyoxyethylene (5) stearyl ether; polyoxyethylene alkyl aryl ethers, such as polyoxyethylene (2) nonylphenyl ether, polyoxyethylene (3) nonylphenyl ether, polyoxyethylene (4) nonylphenyl ether, polyoxyethylene (3) octylphenyl ether; polyethylene glycol fatty acid esters, such as PEG-200 monolaurate, PEG-200 oleyl ether ... 0 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate; alkylene glycol fatty acid monoesters, such as propylene glycol monolaurate (Lauroglycol®); sucrose fatty acid esters, such as sucrose monostearate, sucrose distearate, sucrose monolaurate, sucrose dilaurate; sorbitan fatty acid monoesters, such as sorbitan monolaurate (Span® 20), sorbitan monooleate, sorbitan monopalmitate (Span® 40) or sorbitan stearate. Other suitable surfactants include, but are not limited to, block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers, or polyoxyethylene polypropylene glycols, such as Poloxamer® 124, Poloxamer® 188, Poloxamer® 237, Poloxamer® 388, or Poloxamer® 407 (BASF Wyandotte Corp.).

[0064] Non-limiting examples of preferred surfactants for use in the methods 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 pharma- ceutically acceptable surfactant used in the present invention may be a mixture of pharma-ceutically acceptable surfactants, for example a combination of a surfactant having an HLB value of less than 10 with another surfactant having an HLB value of 10 or greater.

[0066] In one embodiment, the surfactant used in the method of the present invention has an HLB value of at least 10. In another embodiment, the surfactant used in the method of the present invention has an HLB value of less than 10. In yet another embodiment, the mixture of two or more surfactants (e.g., a surfactant with an HLB value of at least 10 combined with another surfactant with 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, a hydrophilic polymer as described above, and a surfactant as described above to form a solution (e.g., melt). The hydrophilic polymer may be selected from the group consisting of homopolymers of N-vinyl lactams, copolymers of N-vinyl lactams, cellulose esters, cellulose ethers, polyalkylene oxides, polyacrylates, polymethacrylates, polyacrylamides, polyvinyl alcohols, vinyl acetate polymers, oligosaccharides, and polysaccharides. As non-limiting examples, the hydrophilic polymer may be homopolymers of N-vinyl pyrrolidone, copolymers of N-vinyl pyrrolidone, copolymers of N-vinyl pyrrolidone and vinyl acetate, copolymers of N-vinyl pyrrolidone and vinyl propionate, polyvinyl pyrrolidone, methylcellulose, ethylcellulose, hydroxyalkylcellulose, hydroxypropylcellulose, hydroxyalkylalkylcellulose, hydroxypropylmethylcellulose, cellulose phthalate, cellulose succinate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylsuccinate, hydroxypropylmethylcellulose ...methylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropyl The polyvinyl acetate copolymer is selected from the group consisting of methylcellulose, hydroxypropyl methylcellulose acetate succinate, polyethylene oxide, polypropylene oxide, copolymers 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), copolymers 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, ETHOCEL 4, ETHOCEL 7, ETHOCEL 10, ETHOCEL 14, ETHOCEL 20, Copovidone (vinylpyrrolidone-vinyl acetate copolymer 60 / 40), polyvinyl acetate, methacrylates / methacrylic acid 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 homopolymers of vinylpyrrolidone (e.g., PVP with a Fikentscher K value of 12 to 100, or PVP with a Fikentscher K value of 17 to 30), or copolymers 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 VP and 40% by weight VA). The surfactant may be selected, for example, from the group consisting of polyoxyethylene glycerol triricinoleate, polyoxyl 35 castor oil (Cremophor® 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® RH 40, also known as polyoxy 40 hydrogenated castor oil, or macrogol glycerol hydroxystearate), polyethylene glycol 60 hydrogenated castor oil (Cremophor® RH 60), mono fatty acid esters of polyoxyethylene (20) sorbitan (e.g., polyoxyethylene (20) sorbitan monooleate (Tween® 80), polyoxyethylene (20) sorbitan monostearate (Tween® 60), polyoxyethylene (20) sorbitan monopalmitate (Tween® 40) or polyoxyethylene (20) sorbitan monolaurate (Tween® 20)), polyoxyethylene (3) lauryl ether, polyoxyethylene (5) cetyl ether, polyoxyethylene (2) stearyl ether, polyoxyethylene (5) stearyl ether, polyoxyethylene (2) nonylphenyl ether, polyoxyethylene (5) oleyl ... ether, 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, a hydrophilic polymer as described above, and a surfactant as described above to form a solution (e.g., a melt). The hydrophilic polymer is a homopolymer or copolymer of N-vinylpyrrolidone (e.g., copovidone). The pharma-ceutically acceptable surfactant can be, for example, vitamin E TPGS, or sorbitan monolaurate.

[0069] The melt extrusion process of the present invention typically involves forming a melt from (1) the crystalline form of the present invention, (2) a hydrophilic polymer (or another suitable binder) as described above, and (3) preferably a surfactant as described above. The melt may then be cooled until solidified. The crystalline form of Compound I used initially disappears upon forming the melt. The melt may contain other additives. "Melting" refers to a transition to a liquid or rubbery state in which one component may be embedded, preferably homogeneously embedded, in one or more other components. In many cases, the polymeric components are melted and the crystalline form of Compound I and other components, including the surfactant, dissolve in the melt to form a solution. Melting usually involves heating above the softening point of the polymer. The formation of the melt may be performed in a variety of ways. The components may be mixed before, during, or after forming the melt. For example, the components may be first mixed and then melted, or mixed and melted simultaneously. The melt may be homogenized to efficiently disperse Compound I. In addition, it may be convenient to first melt the polymer and then mix and homogenize Compound I. In one example, all ingredients except the surfactant are mixed and fed into the extruder, with the surfactant being melted externally and forced in during extrusion.

[0070] In another example, the melt comprises Compound I and a hydrophilic polymer as described above, and the melt temperature is 100-170° C., preferably 120-150° C., and highly preferably 135-140° C. The melt may also comprise a pharma- ceutically acceptable surfactant as 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 a hydrophilic polymer as described above. The melt may also include a pharma- ceutically acceptable surfactant as described above.

[0072] To begin the melt extrusion process, compound I is used in a crystalline form of the invention, such as the crystalline form described in the aspects, embodiments, or examples herein. The crystalline form of the invention can first be dissolved in a suitable liquid solvent, such as an alcohol, an aliphatic hydrocarbon, an ester, or, optionally, liquid carbon dioxide. The solvent can be removed, such as evaporated, upon formation of the melt.

[0073] Various additives may also be incorporated into the melt, 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).

[0074] The melting and / or mixing may be carried out in equipment customary for this purpose. Particularly suitable equipment is an extruder or kneader. Suitable extruders include single-screw extruders, intermeshing screw extruders, or multi-screw extruders, preferably twin-screw extruders, which may rotate in the same or counter-rotating direction and may optionally be equipped with kneading disks. 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 may be provided by heating elements. However, friction and shear of the materials in the extruder may also provide a large amount of energy to the mixture, helping to form a homogeneous melt of the components.

[0075] The melt may range from low viscosity, pasty to viscous. Shaping of the extrudate may be accomplished by a calendar, usually with two counter-rotating rollers having mutually matching depressions on their surfaces. The extrudate may be cooled and solidified. The extrudate may be cut into pieces either before (hot cut) or after solidification (cold cut).

[0076] The solidified extrusion product may be further milled, ground, or otherwise reduced into granules. The solidified extrusion product and each resulting granule comprise a solid dispersion, preferably a solid solution, of Compound I in a matrix of a hydrophilic polymer and, optionally, a pharma- ceutical acceptable surfactant. If the granule does not contain a surfactant, a pharma- ceutical acceptable surfactant as described above may be added to the granule and mixed. Before being milled or ground into granules, the extrusion product may be mixed with other active ingredients (e.g., ritonavir) and / or excipients. The granules may be further processed into a suitable solid oral dosage form.

[0077] In one example, copovidone and the above-mentioned surfactant 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, which may contain, for example, 5% by weight of Compound I, is then milled. The mixture is then extruded, and the resulting extrudate can be milled and sieved for further processing to make capsules or tablets. The surfactant used in this example may be added during extrusion via liquid injection.

[0078] The process of solvent evaporation, for example by spray drying, offers the advantage of being able to process at lower temperatures if desired, and other modifications to the process can be made to further improve powder properties. The spray dried powder can then be further processed if desired, and the final drug product is flexible as to whether a capsule, tablet, or other solid dosage form is desired.

[0079] Examples of spray drying methods and spray drying equipment 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 manufactured by Niro Inc., or GEA Process Engineering Inc., Buchi Labortechnik AG, and Spray Drying Systems, Inc. Spray drying methods typically involve dividing a liquid mixture into small droplets in a vessel (spray drying apparatus) where there is a strong driving force for the evaporation of the solvent from the droplets, and then rapidly removing the solvent from the droplets. Atomization techniques include, for example, two-fluid or pressure nozzles or rotary atomizers. A strong driving force for solvent evaporation can be provided, for example, by maintaining the partial pressure of the solvent in the spray drying apparatus well below the evaporation pressure of the solvent at the temperature of the dried droplets. This can be done by (1) maintaining the pressure in the spray drying apparatus under a 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 so that the droplets are sufficiently dry by the time they reach the walls of the equipment. This ensures that the dried droplets are essentially solid, can form a fine powder, and do not stick to the walls of the equipment. The spray-dried product can be collected by removing the material manually, pneumatically, mechanically, or by other suitable means. The actual time to obtain the desired level of dryness depends on the droplet size, formulation, and operation of the spray dryer. After solidification, the solid powder may be allowed to remain in the spray-drying chamber for an additional time (e.g., 5-60 seconds) to allow further evaporation of the solvent from the solid powder. It is preferred that the final solvent content in the solid dispersion leaving the dryer is at a sufficiently low level so that the stability of the final product is improved. For example, the residual solvent content of the spray-dried powder can be less than 2% by weight. Highly preferably, the residual solvent content is within the limits set forth in the International Conference on Harmonization (ICH) guidelines. In addition, it may be useful to further dry the spray-dried composition to reduce the residual solvent to even lower levels. 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] Like the solid extrudate described above, the spray-dried product contains a solid dispersion, preferably a solid solution, of Compound I in a matrix consisting of a hydrophilic polymer as described above and optionally a pharma- ceutically acceptable surfactant as described above. If the spray-dried product does not contain a surfactant, a pharma- ceutically acceptable surfactant as described above may be added and mixed into the spray-dried product prior to further processing.

[0082] Before being fed into the spray dryer, the crystalline form of Compound I of the present invention, the hydrophilic polymer described above, and any other active ingredient or excipient, such as the pharma- ceutical acceptable surfactant described above, can 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 can be preheated before being fed into the spray dryer. In many cases, ritonavir is dissolved together with the crystalline form of Compound I.

[0083] The solid dispersions prepared by melt extrusion, spray drying or other techniques can be made into suitable solid oral dosage forms. In one embodiment, the solid dispersions prepared by melt extrusion, spray drying or other techniques (e.g., extrudates or spray dried powders) can be compressed into tablets. The solid dispersions can be compressed directly or milled or pulverized into granules or powders before compression. Compression can be done using a tablet press, such as a steel die between two moving punches. When the solid composition includes Compound I and another anti-HCV agent, solid dispersions of the individual active ingredients can be made separately and optionally milled or pulverized solid dispersions can be mixed and then compressed. Compound I and another anti-HCV agent can be made in the same solid dispersion, optionally milled and / or mixed with other additives and then compressed into tablets. Also, when the solid composition includes Compound I and ritonavir, solid dispersions of the individual active ingredients can be made separately and optionally milled or pulverized solid dispersions can be mixed and then compressed. Compound I and ritonavir may be made into the same solid dispersion, optionally milled and / or mixed with other excipients, and then compressed into tablets.

[0084] At least one additive may be used during compression of the solid dispersion, such as a flow regulator, a lubricant, a filler, a disintegrant or a plasticizer. These additives may be mixed with the milled or ground solid dispersion before compression. The disintegrant promotes rapid disintegration of the compact in the stomach and keeps the loose granules separated from each other. Non-limiting examples of suitable disintegrants are cross-linked polymers, such as 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, microcrystalline 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 fats and oils. Non-limiting examples of suitable lubricants include polyethylene glycol (eg, those having a molecular weight of 1000 to 6000), magnesium and calcium stearate, sodium stearyl fumarate, and the like.

[0085] Various other additives may also be used in preparing the solid compositions according to the process of the present invention, for example dyes such as azo dyes, organic or inorganic pigments such as aluminum oxide or titanium dioxide, or dyes of natural origin; stabilizers, for example light stabilizers, radical scavengers, stabilizers against microbial attack.

[0086] In one embodiment, the methods of the invention described above (including those described in any aspect, embodiment, example or preference) use a substantially pure crystalline form of Compound I having characteristic peaks in a 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 invention described above (including those described in any aspect, embodiment, example or preference) use a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern at the 2θ values ​​(°2θ) shown in Table 1a. For example, the crystalline form used may have a purity of at least 90%, preferably at least 95%, more preferably at least 97%.

[0088] In another embodiment, the methods of the invention described above (including those described in any aspect, embodiment, example or preference) employ a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form employed may have a purity of at least 90%, preferably a purity of at least 95%, more preferably a purity of at least 97%.

[0089] In another embodiment, the methods of the invention described above (including those described in any aspect, embodiment, example or preference) use a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form used may have a purity of at least 90%, preferably a purity of at least 95%, more preferably a purity of at least 97%.

[0090] In another embodiment, the methods of the invention described above (including those described in any aspect, embodiment, example or preference) use a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form used may have a purity of at least 90%, preferably a purity of at least 95%, more preferably a purity of at least 97%.

[0091] In yet another embodiment, the methods of the invention described above (including those described in any aspect, embodiment, example or preference) employ a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern as shown in Figure 2. For example, the crystalline form employed 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 invention described above (including those described in any aspect, embodiment, example or preference) use a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern at the 2θ values ​​(°2θ) shown in Table 2a. For example, the crystalline form used may have a purity of at least 90%, preferably at least 95%, more preferably at least 97%.

[0093] In another embodiment, the methods of the invention described above (including those described in any aspect, embodiment, example or preference) employ a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form employed may have a purity of at least 90%, preferably a purity of at least 95%, more preferably a purity of at least 97%.

[0094] In another embodiment, the methods of the invention described above (including those described in any aspect, embodiment, example or preference) use a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form used may have a purity of at least 90%, preferably a purity of at least 95%, more preferably a purity of at least 97%.

[0095] In another embodiment, the methods of the invention described above (including those described in any aspect, embodiment, example or preference) utilize a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form used may have a purity of at least 90%, preferably at least 95%, more preferably at least 97%.

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

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

[0098] In another embodiment, the methods of the invention described above (including those described in any aspect, embodiment, example or preference) employ a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form employed may have a purity of at least 90%, preferably a purity of at least 95%, more preferably a purity of at least 97%.

[0099] In another embodiment, the methods of the invention described above (including those described in any aspect, embodiment, example or preference) use a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form used may have a purity of at least 90%, preferably a purity of at least 95%, more preferably a purity of at least 97%.

[0100] In another embodiment, the methods of the invention described above (including those described in any aspect, embodiment, example or preference) use a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form used may have a purity of at least 90%, preferably a purity of at least 95%, more preferably a purity of at least 97%.

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

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

[0103] In another embodiment, the methods of the invention described above (including those described in any aspect, embodiment, example or preference) employ a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form employed may have a purity of at least 90%, preferably at least 95%, more preferably at least 97%.

[0104] In another embodiment, the methods of the invention described above (including those described in any aspect, embodiment, example or preference) employ a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form employed may have a purity of 90%, preferably at least 95%, more preferably at least 97%.

[0105] In another embodiment, the methods of the invention described above (including those described in any aspect, embodiment, example or preference) use a substantially pure crystalline form of Compound I having characteristic peaks in a powder X-ray diffraction (PXRD) pattern 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. For example, the crystalline form used may have a purity of at least 90%, preferably a purity of at least 95%, more preferably a purity of at least 97%.

[0106] In yet another aspect, the present invention relates to a composition comprising a crystalline form of Compound I of the present invention. The crystalline forms described herein (including those described in any aspect, embodiment or example) can be used to make the compositions of the present invention. Preferably, the crystalline form is substantially pure, e.g., can have a purity of at least 90%, preferably at least 95%, 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] Preparation of crystalline form I (hydrate) Crude compound I and methanol (12 volumes) were charged to a reactor and heated to 55±10° C. to dissolve the solids. Water (12 volumes) was added to the solution at a rate to maintain a temperature of >50° C. The product was cooled to room temperature (RT) at approximately 10° C. / hr 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 volumes). The product was dried in a vacuum oven at 50° C. using a humidified nitrogen (approximately 30-90% relative humidity) oven.

[0108] The powder X-ray diffraction patterns and relative intensities of the PXRD peaks of the crystalline forms thus prepared 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 about 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 thus prepared are shown in Figure 2 and Table 2a, respectively. The crystal profile of the crystalline forms is summarized in Table 2b.

[0113] [Table 3] TIFF2025004239000006.tif49162

[0114] [Table 4]

[0115] [Example 3] Preparation of Compound I Dimethanol Monohydrate Crude Compound I and methanol (12 volumes) were charged to a reactor and heated to 55±10° C. to dissolve the solids. Water (12 volumes) was added to the solution at a rate to maintain a temperature of >50° C. The product was cooled to room temperature at approximately 10° C. / hr 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 volumes).

[0116] The powder X-ray diffraction patterns and relative intensities of the PXRD peaks of the crystalline forms thus prepared 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 Desolvates of Compound I Crude compound I and methanol (12 volumes) were charged to a reactor and heated to 55±10° C. to dissolve the solids. Water (12 volumes) was added to the solution at a rate to maintain a temperature of >50° C. The product was cooled to room temperature at approximately 10° C. / hr 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 volumes). The product was dried in a vacuum oven at 50° C. with a dry nitrogen purge.

[0120] The powder X-ray diffraction patterns and relative intensities of the PXRD peaks of the crystalline forms thus prepared 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 invention provides illustration and description, but is not intended to be exhaustive or to limit the invention to the precise form disclosed. Modifications and variations are possible in light of the above teachings or may be acquired from practice of the invention. It is therefore intended that the scope of the invention be defined by the appended claims and their equivalents.

Claims

1. A crystalline form of Compound I having characteristic peaks in a PXRD pattern at 2θ values ​​set forth in any one of Tables 1a, 2a, 3a and 4a.

2. A crystalline form of Compound I having characteristic peaks in a PXRD pattern as depicted in any one of Figures 1-4.

3. A crystalline form of Compound I having the characteristic peaks in its PXRD pattern as described herein.

4. A crystalline form of Compound I having characteristic peaks in the PXRD pattern 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.

5. 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 the PXRD pattern.

6. 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 a PXRD pattern.

7. A composition comprising the crystalline form according to any one of claims 1 to 6.

8. A method for making a pharmaceutical composition comprising Compound I, comprising dissolving a crystalline form according to any one of claims 1 to 6.

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