WO2018064585A1 - Odalasvir polymorphs and methods of manufacture thereof - Google Patents

Abstract

The invention provides Odalasvir polymorphs, hydrates, and solvates that exhibit advantageous properties, including purity, useful for the preparation of a therapeutic formulation.

Description

ODALASVIR POLYMORPHS AND METHODS OF MANUFACTURE THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of US Provisional Application No. 62/401,836 filed on September 29, 2016, and the entirety of the application is hereby incorporated by reference for all purposes.

BACKGROUND

Hepatitis C virus (HCV), a member of the Flaviviridae family of viruses in the hepacivirus genus, is the leading cause of chronic liver disease worldwide. Recent estimates report global hepatitis C prevalence of about 2.4%, and up to 170 million people are thought to be chronically infected. Although the development of diagnostics and blood screening has considerably reduced the rate of new infections, HCV remains a global health burden due to its chronic nature and potential for long-term liver damage. It is now known that HCV has the ability to incorporate into the host's genome.

The hepatitis C virus genome is a small positive-sense single stranded RNA that is enclosed in a nucleocapsid and lipid envelope. It consists of a 9.6 kb ribonucleotide that encodes a large polypeptide of about 3,000 amino acids (Dymock et al. Antiviral Chemistry & Chemotherapy 2000, 11, 79). Following maturation, this polypeptide is processed into at least ten proteins. NS3/4A serine protease is responsible for the cleavage of the non-structural downstream proteins. NS5A is a zinc-binding proline-rich hydrophilic phosphoprotein that has no apparent enzymatic activity, yet has an important function mediating the interaction with other nonstructural viral and cellular proteins. NS5B is an enzyme with polymerase activity and is involved in the synthesis of double-stranded RNA from the single-stranded viral RNA genome that serves as the template.

Odalasvir, also known as ACH-3102 and ODV (illustrated below), is an NS5A inhibitor with potent activity against HCV. Odalasvir is described in U.S. Patent No. 8,809,313. Odalasvir is currently in human clinical development for the treatment of HCV in combination with an NS5B inhibitor (AL-335) and a commercial NS3/4A protease inhibitor (Simeprevir). The triple combination therapy is described in PCT/US2016/54561 assigned to Janssen Pharmaceuticals, Inc. and Achillion Pharmaceuticals, Inc,.

The compound name of Odalasvir is dimethyl((2^,2'5)-((2^,2 ,3a^,3A ,7a^,7A'5)-2,2'- (5,5Htricyclo[8.2.2.2⁴'⁷]hexadeca-4,6,10, 12,13, 15-hexaene-5,l l-diyl)bis(lH- benzo[D]imidazole-5,2-diyl))bis(octahydro-lH-indole-2,l-diyl))bis(3-methyl-l-oxobutane- 2, 1 diyl))dicarbamate.

Given the activity of Odalasvir against HCV and other flaviviruses, it would be useful to prepare formulations and forms for in vivo administration that have advantageous properties, including purity, that may increase the safety or efficacy of the product or provide for improved manufacturing performance.

SUMMARY

It has been discovered that Odalasvir can be prepared in a highly purified form by recrystallization, and this results in a highly crystalline dihydrate that has advantageous properties in the preparation of a therapeutic formulation. This is an improvement over the preparation of amorphous Oldasavir that is described in U.S. Patent No. 8,809,313. In some aspects Odalasvir dihydrate has a higher purity than other Forms of solid Odalasvir, and this is beneficial for the manufacture of pharmaceutical formulations. It has also been discovered that the highly crystalline Odalasvir dihydrate has improved properties for manufacture, including easier handling and good stability.

The superior characteristics of the highly crystalline Odalasvir dihydrate were confirmed by comparative analysis in over 160 experiments across a diverse set of crystallization modes, solvents, and temperatures. In these investigations, three crystalline Forms, a highly crystalline dihydrate (Form A), a less crystalline mixed methanol/water solvate (Form B), and a class of structurally similar solvates (Forms C), were discovered and characterized. Both Form B and Form C convert to Form A in relative stability experiments. In contrast, amorphous solids were obtained from all evaporative and cooling crystallization experiments.

The highly crystalline Odalasvir dihydrate polymorph Form A is the most crystalline Form and has advantageous properties for high purity active pharmaceutical ingredient isolation. In one embodiment, Form A is produced by recrystallization from methanol, as described in more detail below. In one aspect, the present invention is directed to isolated Form A, and uses and methods of making thereof. In one embodiment, isolated Form A is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least the 2Theta values of 3.7° and 13.5°. In another embodiment, isolated polymorph Form A is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four 2Theta values selected from 3.7°, 7.5°, 10.8°, 13.5°, 13.7°, 15.3°, 16.4°, 19.5°, 19.8°, and 22.8°. In one embodiment, isolated Form A is characterized as having a differential scanning calorimetry (DSC) onset endotherm of about 96 °C, such as, for example, 96.13 °C.

Thus, the present invention provides a highly crystalline dihydrate polymorph of Odalasvir Form A and its use in manufacturing Odalasvir dosage forms. The present invention also includes a pharmaceutical composition containing such polymorph, and a method of using an effective amount of Form A polymorph to treat a patient in need thereof with a viral infection such as, for example, a flavivirus including HCV.

Odalasvir Form A can be produced, for example, by recrystallizing amorphous Odalasvir in methanol. In one embodiment, Odalasvir Form A is produced by the steps of adding methanol to amorphous Odalasvir at 50 °C, cooling the temperature to 25 °C and adding methanol, raising the temperature to 65 °C and stirring, washing with methanol, and spin drying for 30 minutes. In another embodiment, Odalasvir Form A is produced by the steps of adding methanol to amorphous Odalasvir, themo-cycling the slurry between 40 °C and 5 °C for 48 hours, and isolating the product by cooling the solution to 25 °C.

In an alternative embodiment, Odalasvir Form A is produced by repeated recrystallizations.

The present invention also includes Odalasvir Form B, a mixed methanol/water solvate with less crystallinity than Form A. It was produced from an amorphous slurry using methanol. According to the XRPD pattern that shows only a few weak diffraction peaks, Form B is not very crystalline. Thermal data indicates a desolvation event occurring with a broad endotherm that has an onset at 59.5°C. The corresponding thermogravimetric analysis (TGA) weight loss of 30.7% is confirmed as methanol and water evolving from the solid. A wet sample of Form B was placed on an XRPD plate and scanned for 10 consecutive scans (30 minutes) to determine if the sample is crystalline, but the sample lost crystallinity upon drying. The results shown in FIG. 16 indicate that Form B remains not very crystalline throughout the drying process.

In one embodiment, isolated Form B is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least the 2Theta values of 3.4° and 6.9°. In another embodiment, isolated Form B is characterized by an X-ray powder diffraction (XRPD) pattern comprising the 2Theta values of 3.4°, 6.9°, and 10.3°. In one embodiment, isolated Form B is characterized as having a differential scanning calorimetry (DSC) onset endotherm of about 59.50 °C.

Odalasvir Form B can be produced by recrystallizing amorphous Odalasvir in methanol and water. In one embodiment, Odalasvir Form B is produced by the steps of adding methanol: water to Odalasvir Form A, themo-cy cling the slurry between 40 °C and 5 °C for 48 hours, and isolating the product by cooling the solution to 25 °C.

Therefore, the present invention also provides Odalasvir Form B solvate and its use in manufacturing Odalasvir dosage forms. The present invention also includes a pharmaceutical composition containing such solvate, and a method of using an effective amount of this Form B solvate to treat a patient in need thereof with a viral infection such as, for example, a flavivirus including HCV.

In addition, the present invention provides Odalasvir Form C, which is a crystalline solvate that can be made from a range of solvents or solvent systems. The Form C solvate, for example, was found in 18 of 35 solids analyzed from slurry experiments. Form C is not observed in the solution phase. Odalasvir Form C is crystalline by XRPD and contains very small, irregular particles by polarized light microscopy (PLM). In one embodiment, isolated Form C is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least the 2Theta values of 7.7° and 12.9°. In one embodiment, isolated Form C is characterized by an XRPD pattern comprising at least four 2Theta values selected from 4.2°, 7.7°, 8.2°, 8.6°, 10.9°, 12.9°, 15.5°, 18.2°, 18.2° and 25.2°.

Odalasvir Form C was found using several different solvents including acetone, nitromethane, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, 2-propanol, dimethyl carbonate, and some water mixtures with acetone and acetonitrile. Although the FT-Raman spectra of the Form C samples are nearly identical, some differences were observed by XRPD as shown in FIG. 21, and this is likely due to the solvent used to form the solvate.

For example, Odalasvir Form C can be produced by recrystallizing Odalasvir Form A in acetone and water. In one embodiment, Odalasvir Form C is produced by the steps of adding acetone:water to Odalasvir Form A, themo-cycling the slurry between 40 °C and 5 °C for 48 hours, and isolating the product by cooling the solution to 25 °C.

In one example, a wet sample of Form C was placed on an XRPD plate and scanned for 10 consecutive scans (30 minutes) to observe the changes to the XRPD pattern upon drying. As shown in FIG. 23, significant shifting of various peaks was observed during the drying process. As shown in FIG. 24, when Form C was heated to 225°C and then cooled back to 25°C, some slight changes were observed in the XRPD pattern as the solvent was driven off. Other differences between various Form C samples include thermal analysis. A sample of Form C from methyl acetate was analyzed by DSC and TGA-IR, but did not show the desolvation endotherm in the DSC. However, residual ethyl acetate was detected (see FIG. 25).

In another example, Odalasvir Form C was tested and characterized as follows. Differential scanning calorimetry (DSC) indicated the sample was solvated showing a broad endotherm with an onset at 33.8°C. A final melting endotherm at 234.5°C was also observed. TGA collected on the sample revealed 3.1% weight loss associated with the broad endotherm in the DSC. Infrared analysis of the gas given off indicated that acetone and water were released.

Therefore, the present invention also provides Odalasvir Form C solvate and its use in manufacturing Odalasvir dosage forms. The present invention also includes a pharmaceutical composition containing such solvate, and a method of using an effective amount of this Form C solvate to treat a patient in need thereof with a viral infection such as, for example, a flavivirus including HCV.

In alternative embodiments, a combination of two or more Forms of Odalasvir is provided, such as Form A and Form B; Form A and Form C; or Form B and Form C. In another alternative embodiment, an isolated combination of three Forms is provided, for example, Form A, Form B and Form C. In other embodiments, Odalasvir Form A, Form B and/or Form C can be in admixture with amorphous Odalasvir, or other forms of Odalasvir.

In one embodiment, a pharmaceutical composition is provided comprising isolated Form A, Form B, and/or Form C and a pharmaceutically acceptable excipient. In one embodiment, the selected isolated Form of Odalasvir is administered in a pharmaceutical composition. In a further embodiment, a method is presented comprising administering an effective amount to the patient, typically a human, of the selected isolated form of Odalasvir and one or more additional therapeutic agents.

The present invention includes at least the following features:

(a) isolated Form A polymorph of Odalasvir;

(b) isolated Form B solvate of Odalasvir;

(c) isolated Form C solvate of Odalasvir;

(d) any mixture of (a), (b) and/or (c) with or without amorphous Odalasvir;

(e) any mixture comprising (a), (b) and/or (c);

(f) any of (a) through (e) in an effective amount for use in treating or preventing a flavivirus, such as hepatitis C virus, in a host, for example, a human;

(g) a pharmaceutical composition comprising any of (a) through (e) in combination with a pharmaceutically acceptable carrier;

(h) any of (a) through (e) wherein Odalasvir is in the form of a pharmaceutically acceptable salt;

(i) use of (a) through (e) in the manufacture of a medicament for use in treating a flavivirus in a host, for example a human;

(j) the use of (a) through (e) in the manufacture of Odalasvir active pharmaceutical ingredient into a dosage form;

(k) the use of (j) wherein the manufacture creates a spray-dried dispersion, a spray- dried solid, a granulo-layered solid dispersion, a particulate, a microparticle or a nanoparticle;

(1) a process for manufacturing a medicament intended for therapeutic use to treat a flavivirus, for example hepatitis C, as described herein wherein at least one of (a) through (e) is used in the manufacture;

(m) isolated Odalasvir Form A wherein Form A is in substantially pure form, (e.g., at least 90, 95, 98 or 99%);

(n) isolated Odalasvir Form B wherein Form B is in substantially pure form, (e.g., at least 90, 95, 98 or 99%); and (o) isolated Odalasvir Form C wherein Form C is in substantially pure form, (e.g., at least 90, 95, 98 or 99%).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts Odalasvir Form A as detected by polarized light microscopy (PLM) (200x in oil). A scale marker of 80 μιη is shown in the bottom left corner of the image.

FIG. 2 is the X-ray powder diffraction (XRPD) pattern for Odalasvir Form A. The x-axis is 2Theta measured in degrees and the y-axis is intensity measured in counts. The diffraction pattern was measured by Optiform and collected using a continuous scan mode with a scan speed of 0.0008 on a Gonio scan axis with a range of 1.9990-40.0004. The X-ray wavelength was 1.5405980 angstroms from the Cu K-Alpha 1 emission line. Step Size: 0.0167. Time/step: 19.685.

FIG. 3 is a graph showing the thermal differential scanning calorimetry (DSC) data and thermal gravimetric analysis (TGA) data for Odalasvir Form A. For the DSC curve, the x-axis is temperature (°C) and the y-axis is heat flow (W/g). The TGA x-axis is temperature (°C) and the y-axis is weight percent.

FIG. 4 is a FT Raman spectrum obtained from a sample of Odalasvir Form A. The x-axis is wavenumbers measured in inverse cm (cm^"1) and the y-axis is the intensity measurement (counts).

FIG. 5 is a dynamic vapor sorption (DVS) isotherm plot obtained for Odalasvir Form A. The x-axis is the target % P/Po and the y-axis is the percent change in dry mass. The isotherm was collected at 25°C with a M(0) of 13.8747.

FIG. 6 is an image of amorphous Odalasvir as detected by polarized light microscopy (PLM) (lOOx in oil). A scale marker of 100 μιη is shown in the bottom left corner of the image.

FIG. 7 is the X-ray powder diffraction (XRPD) pattern spectrum for amorphous Odalasvir.The x-axis is 2Theta measured in degrees and the y-axis is intensity measured in counts. The diffraction pattern was measured by Optiform and collected using a continuous scan mode with a scan speed of 0.0008 on a Gonio scan axis with a range of 1.9990-40.0004. The X-ray wavelength was 1.5405980 angstroms from the Cu K- Alpha 1 emission line. Step Size: 0.0167. Time/step: 19.685. FIG. 8 is a graph of the thermal data (DSC/TGA) for amorphous Odalasvir. In the top DSC graph, the x-axis is temperature (°C) and the y-axis is heat flow (W/g). In the bottom inset TGA graph, the x-axis is temperature (°C) and the y-axis is weight percent.

FIG. 9 is a FT Raman spectrum obtained from a sample of amorphous Odalasvir. The x- axis is wavenumbers measured in inverse cm (cm^"1). The y-axis is intensity measurement (counts).

FIG. 10 is a graph of a modulated DSC (mDSC) conducted on amorphous Odalasvir to look for the glass transition temperature (t_g). Three plots are presented: Heat flow, Nonrev Heat Flow, and Rev Heat flow. The left most y-axis is heat flow (W/g), the second to right y-axis is nonrev heat flow (W/g), and the right most y-axis is rev heat flow (W/g). The x-axis in all cases is temperature (°C). A potential t_g was observed at 194.6 °C as shown.

FIG. 11 is a dynamic vapor sorption (DVS) isotherm plot for amorphous Odalasvir. The isotherm was collected at 25 °C with a M(0) of 13.3161. The graph indicates amorphous Odalasvir absorbs a maximum of 5% moisture from 0-90% RH. The x-axis is relative humidity and the y- axis is the percent change in dry mass.

FIG. 12 is an image of Odalasvir Form B as detected by polarized light microscopy (PLM) (200x in oil). A scale marker of 100 μιη is shown in the bottom left corner of the image.

FIG. 13 is the X-ray powder diffraction (XRPD) pattern for Odalasvir Form B. The x-axis is 2Theta measured in degrees and the y-axis is intensity measured in counts. The diffraction pattern was measured by Optiform and collected using a continuous scan mode with a scan speed of 0.0008 on a Gonio scan axis with a range of 1.9990-40.0004. The X-ray wavelength was 1.5405980 angstroms from the Cu K-Alpha 1 emission line. Step Size: 0.0167. Time/step: 19.685.

FIG.14 is a graph showing the thermal data (DSC/TGA) for Odalasvir Form B. In the top curve (DSC) the x-axis is temperature (°C) and the y-axis is heat flow (W/g). For the smaller inset TGA graph, the x-axis is temperature (°C) and the y-axis is weight percent.

FIG. 15 is a FT Raman spectrum obtained on a sample of Odalasvir Form B. The x-axis is wavenumbers measured in inverse cm (cm^"1). The y-axis is intensity measurement (counts).

FIG. 16 presents the XRPD data obtained from a slurry analysis of a wet group Odalasvir Form B sample. The x-axis is 2Theta measured in degrees and the y-axis is intensity measured in counts.

FIG. 17 is an image of Odalasvir Form C as detected by polarized light microscopy (PLM) (200x in oil). A scale marker of 100 μιη is shown in the bottom left corner of the image. FIG. 18 is the X-ray powder diffraction (XRPD) pattern for Odalasvir Form C. The x-axis is 2Theta measured in degrees and the y-axis is intensity measured in counts. The diffraction pattern was measured by Optiform and collected using a continuous scan mode with a scan speed of 0.0008 on a Gonio scan axis with a range of 1.9990-40.0004. The X-ray wavelength was 1.5405980 angstroms from the Cu K-Alpha 1 emission line. Step Size: 0.0167. Time/step: 19.685.

FIG.19 presents the thermal data (DSC/TGA) for Odalasvir Form C. In the main DSC graph, the x-axis is temperature (°C) and the y-axis is heat flow (W/g). For the smaller inset TGA graph, the x-axis is temperature (°C) and the y-axis is weight percent.

FIG. 20 is a FT Raman spectrum obtained of a sample of Odalasvir Form C. The x-axis is wavenumbers measured in inverse cm (cm^"1). The y-axis is in intensity units measured in counts.

FIG. 21 presents XRPD overlays for three Form C samples. The x-axis is 2Theta measured in degrees and the y-axis is intensity measured in counts. Odalasvir Form C was found from several different solvents: acetone, nitromethane, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, 2-propanol, dimethyl carbonate, and some water mixtures with acetone and acetonitrile. Although the FT-Raman spectra of the Form C samples are nearly identical, some differences are observed by XRPD, as shown.

FIG. 22 is a series of FT-Raman spectra of three Odalasvir Form C samples. The x-axis is wavenumbers measured in inverse cm (cm^"1). The y-axis is intensity (counts). Although the FT- Raman spectra of the Form C samples are nearly identical, some differences are observed by XRPD, as shown in FIG. 21.

FIG. 23 provides a XRPD slurry analysis of a wet Odalasvir Form C sample showing peaks that shift/change as the sample becomes increasingly anhydrous. The x-axis is wavenumbers measured in inverse cm (cm^"1). The y-axis is intensity (counts).

FIG. 24 provides a XRPD comparison of Odalasvir Form C at 25 °C and Form C heated to 225 °C. The x-axis is 2Theta measured in degrees and the y-axis is intensity measured in counts. As shown in Fig. 24, some differences were noted in the XRPD pattern.

FIG. 25 presents the thermal data and off-gas of a sample of Odalasvir Form C obtained from methyl acetate. In the main DSC graph, the x-axis is temperature (°C) and the y-axis is heat flow (W/g). For the smaller inset TGA graph, the x-axis is temperature (°C) and the y-axis is weight percent. FIG. 26 provides a XRPD comparison of Odalasvir Form A, Form B, and Form C. The x- axis is 2Theta measured in degrees and the y-axis is intensity measured in counts.

FIG. 27 is an FTIR spectrum of Odalasvir Form A. The x-axis is wavenumbers measured in inverse cm (cm^"1) and the y-axis is absorbance.

FIG. 28 is a comparison of FTIR spectrum of Odalasvir Form A before and after adsorption/desorption cycles of dynamic vapor sorption (DVS). The bottom (dark line) spectra is after DVS. The top (light line) spectra is before DVS. The x-axis is wavenumbers measured in inverse cm (cm^"1) and the y-axis is absorbance.

FIG. 29 is the X-ray powder diffraction (XRPD) pattern for Odalasvir Form A. The x-axis is 2Theta measured in degrees and the y-axis is intensity measured in counts. The analysis was carried out on a PANalytical X'PertPRO MPD diffractometer equipped with a Cu LFF X-ray tube. The instrument parameters are 45 kV generator voltage, 40 raA generator amperage, Bragg- Brentano geometry, and the stage was set to spin. The measurement conditions were set as follows: continuous scan mode, 3 to 50 degree scan range, .02 degrees per step counting time, 1 second per revolution spin time, CuKa radiation type, 15 mm divergence slit, .04 radian soller slit, 15 mm beam mask, 1 degree anti-scatter slit, beam knife, anti-scatter shield, nickel filter and X'Celerator detector used.

FIG. 30 presents the X-ray powder diffraction (XRPD) pattern for Odalasvir Form A before and after adsorption/desorption cycles of dynamic vapor sorption (DVS). The bottom spectra is after DVS and the top spectra is before DVS. The x-axis is 2Theta measured in degrees and the y- axis is intensity measured in counts. The analyses were carried out on a PANalytical X'PertPRO MPD diffractometer equipped with a Cu LFF X-ray tube. The instrument parameters are 45 kV generator voltage, 40 raA generator amperage, Bragg-Brentano geometry, and the stage was set to spin. The measurement conditions were set as follows: continuous scan mode, 3 to 50 degree scan range, .02 degrees per step counting time, 1 second per revolution spin time, CuKa radiation type, 15 mm divergence slit, .04 radian soller slit, 15 mm beam mask, 1 degree anti-scatter slit, beam knife, anti-scatter shield, nickel filter and X'Celerator detector used.

FIG. 31 is a differential scanning calorimetry (DSC) graph for Odalasvir Form A. In the DSC graph, the x-axis is temperature (°C) and the y-axis is heat flow (W/g). The analysis was carried out on a TA-Instruments Q2000 MTDSC equipped with a RCS cooling unit. The parameters were set to an initial temperature of 25 °C, a heating rate of 10 °C/min, a final temperature of 250 °C, and a nitrogen flow of 50 ml/min. Ten milligrams of compound were loaded into a Tzero sample pan for the experiment.

FIG. 32 is a differential scanning calorimetry (DSC) graph for Odalasvir Form A as it undergoes a heat cool cycle. The sample is first heated (he middle curve) and cooled (the top curve). The cooling cycle is followed by a second heat cycle (the bottom curve). The x-axis is temperature (°C) and the y-axis is heat flow (W/g). The analysis was carried out on a TA- Instruments Q2000 MTDSC equipped with a RCS cooling unit. The parameters were set to an initial temperature of 25 °C, a heating rate of 10 °C/min, a final temperature of 250 °C, and a nitrogen flow of 50 ml/min. Ten milligrams of compound were loaded into a Tzero sample pan for the experiment.

FIG. 33 provides a thermogravimetric analysis (TGA) curve for Odalasvir Form A. The x- axis is temperature measured in °C. The left y-axis is weight of Odalasvir measured as a percent. The right y-axis is the derived change in weight measured as a percent. The TGA curve was recorded on a TA Instruments Q500 thermogravimeter with a heating rate of 20 °C per minute, a resolution factor of 4, and a cutoff condition of 300 °C or 20% w/w mass loss.

FIG. 34 is a dynamic vapor sorption (DVS) isotherm plot obtained for Odalasvir Form A. The x-axis is target relative humidity (RH) measured in percent. The y-axis is change in mass measured in percent and measured as a function of the initial mass used (ref). The DVS was measured with a SMS dynamic vapor sorption using the following parameters: 60 minute dry time under nitrogen and equilibration for 60 minutes per step.

FIG. 35 is a dynamic vapor sorption (DVS) isotherm plot obtained for Odalasvir Form A. The x-axis is time measured in minutes. The left y-axis is change in mass measured in percent as a function of the initial mass used (ref). The right y-axis is target relative humidity (RH) measured in percent. The bottom curve corresponds to the right y-axis (RH). The top curve corresponds to the left y-axis (change in mass). The DVS was measured with a SMS dynamic vapor sorption using the following parameters: 60 minute dry time under nitrogen and equilibration for 60 minutes per step.

FIG. 36 is a graph showing the thermal differential scanning calorimetry (DSC) data for Odalasvir Form A. The x-axis is temperature (°C), the left y-axis is heat flow (W/g), the second to right y-axis is nonrev (non-reversing) heat flow (W/g), and the right most y-axis is rev (reversing) heat flow (W/g). FIG. 37 is the structure of ODV dihydrate used in Odalasvir Form A Polymorph, Odalasvir Form B Solvate, and Odalasvir Form C Solvate.

DETAILED DESCRIPTION OF THE INVENTION

Polymorphism is the ability of a compound to exist in more than one solid Form. An amorphous material is a non-crystalline solid that lacks the long-range order of a crystal. It cannot be predicted in advance whether a compound exists in more than one solid Form, what the various properties of any of those Forms might be if they do exist, or whether the properties are advantageous or not advantageous for the intended use.

Solid Forms of compounds can be characterized by analytical methods such as X-ray powder diffraction pattern (XRDP), thermogravimetric analysis (TGA), TGA with IR off-gas analysis, Differential Scanning Calorimetry (DSC), melting point, FT-Raman spectroscopy, Dynamic Vapor Sorption (DVS), polarized light microscopy (PLM) or other techniques known in the art.

The following Forms of Odalasvir have been discovered.

Odalasvir Form A Polymorph

Isolated Odalasvir Form A is provided in this invention.

In one embodiment, isolated Odalasvir Form A is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least the 2Theta values of 3.7° and 13.5°.

In one embodiment, Odalasvir Form A is characterized by an XRPD pattern comprising 2Theta values of 3.7°, 7.5°, 10.8°, 13.5°, 13.7°, 15.3°, 16.4°, 19.5°, 19.8°,and 22.8°.

In one embodiment, Form A is characterized by an XRPD pattern comprising at least two, three or four 2Theta values selected from 3.7°, 7.5°, 10.8°, 13.5°, 13.7°, 15.3°, 16.4°, 19.5°, 19.8°, and 22.8°, each combination of which is considered independently and individually described herein.

In one embodiment, Form A is characterized by an XRPD pattern substantially similar to that set forth in FIG. 2.

In one embodiment, Form A is characterized by a DSC onset endotherm of about 96 °C, including for example 96.13 °C. Odalasvir Form A can be produced, for example, by recrystallizing amorphous Odalasvir in methanol. In one embodiment, Odalasvir Form A is produced by the steps of adding methanol to amorphous Odalasvir at 50 °C, cooling the temperature to 25 °C and adding methanol, raising the temperature to 65 °C, and stirring, washing with methanol, and spin drying for 30 minutes. In another embodiment, Odalasvir Form A is produced by the steps of adding methanol to amorphous Odalasvir, themo-cycling the slurry between 40 °C and 5 °C for 48 hours, and isolating the product by cooling the solution to 25 °C. In an alternative embodiment Odalasvir Form A can be produced by repeated recrystallizations, for example, from TUF/methanol.

Detailed examples for how to prepare Odalasvir Form A are further described in the Examples section below.

Odalasvir Form B Solvate

Isolated Odalasvir Form B solvate is also provided in this invention. It is a mixed methanol/water solvate with less crystallinity than Form A.

In one embodiment, isolated Form B is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least the 2Theta values of 3.4° and 6.9°.

In one embodiment, Form B is characterized by an XRPD pattern comprising 2Theta values of 3.4°, 6.9°, and 10.3°. In one embodiment, Form B is characterized by an XRPD pattern comprising at least two 2Theta values selected from 3.4° and 6.9°. In one embodiment, Form B is characterized by an XRPD pattern substantially similar to that set forth in FIG. 13.

In one embodiment, Form B is characterized by a DSC onset endotherm of about 59 °C, for example, 59.50 °C.

Odalasvir Form B can be produced from an amorphous slurry using methanol. In one example, Odalasvir Form B is prepared by recrystallizing Odalasvir Form A in methanol and water. In one embodiment, Odalasvir Form B is produced by the steps of adding methanol: water to Odalasvir Form A, themo-cycling the slurry between 40 °C and 5 °C for 48 hours, and isolating the product by cooling the solution to 25 °C.

Form B is not very crystalline according to its XRPD pattern, showing only a few weak diffraction peaks. Thermal data indicates a desolvation event occurring with a broad endotherm with an onset at, for example, 59.5°C. The corresponding thermogravimetric analysis (TGA) weight loss of 30.7% is confirmed as methanol and water evolving from the solid. A wet sample of Form B was placed on an XRPD plate and scanned for 10 consecutive scans (30 minutes). The results shown in FIG. 16 indicate that Form B remains not very crystalline throughout the drying process.

Odalasvir Form C Solvate

Isolated Odalasvir Form C solvate is also provided in this invention. It includes structurally similar crystalline solvates of Odalasvir. It is observed from a range of solvents/solvent systems.

Odalasvir Form C is crystalline by XRPD and contains very small, irregular particles by polarized light microscopy (PLM).

In one embodiment, isolated Form C is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least the 2Theta values of 7.7° and 12.9°. In one embodiment, isolated Form C is characterized by an XRPD pattern comprising at least two, three or four 2Theta values selected from 4.2°, 7.7°, 8.2°, 8.6°, 10.9°, 12.9°, 15.5°, 18.2°, 18.2° and 25.2°, wherein each combination of 2Theta values is considered independently and individually presented herein.

The Form C solvate, for example, was found in 18 of 35 solids analyzed from slurry experiments. Form C is not observed in the solution phase.

Odalasvir Form C was found using several different solvents: acetone, nitromethane, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, 2-propanol, dimethyl carbonate, and some water mixtures with acetone and acetonitrile. Although the FT-Raman spectra of the Form C samples are nearly identical, some differences are observed by XRPD, as shown in FIG. 21, likely due to the solvent that forms the solvate.

As one example, Odalasvir Form C can be produced by recrystallizing Odalasvir Form A in acetone and water. In one embodiment, Odalasvir Form C is produced by the steps of adding acetone: water to Odalasvir Form A, thermo-cycling the slurry between 40 °C and 5 °C for 48 hours, and isolating the product by cooling the solution to 25 °C.

In an alternative embodiment Odalasvir Form C is produced by repeat recrystallizations.

In one embodiment, Form C is characterized by an XRPD pattern substantially similar to that set forth in FIG. 18. In one embodiment, Form C is characterized by a DSC onset endotherm of about 234.47 °C. Chemical Description and Terminology

Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term "or" means "and/or". Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable.

All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as"), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed.

The present invention includes polymorphs optionally with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.

By way of general example and without limitation, isotopes of hydrogen, for example, deuterium (²H) and tritium (³H) may be used anywhere in described structures so long as the polymorph remains the same. Alternatively or in addition, isotopes of carbon, e.g., ¹³C and ¹⁴C, may be used.

Isotopic substitutions, for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain embodiments, the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In one embodiment, deuterium is 90, 95 or 99% enriched at a desired location. Unless otherwise stated, the enrichment at any point is above natural abundance and enough to alter a detectable property of the drug in a human.

An "active agent" is a compound (including a compound disclosed herein), element, or mixture that when administered to a patient, alone or in combination with another compound, element, or mixture, confers, directly or indirectly, a physiological effect on the patient. The indirect physiological effect may occur via a metabolite or other indirect mechanism.

The term "carrier" means a diluent, excipient, or vehicle with which an active compound is provided.

A "dosage form" means a unit of administration of an active agent. Non-limiting examples of dosage forms include tablets, capsules, and the like.

The term "isolated" as used herein refers to the material in substantially pure form. An isolated compound does not have another component that materially affects the properties of the compound. In a particular embodiment, an isolated form is at least 95, 96%, 97%, 98 or 99% pure.

A "patient" or "host" is a human or non-human animal, including, but not limited to, simian, avian, feline, canine, bovine, equine or porcine in need of medical treatment. Medical treatment can include treatment of an existing condition, such as a disease or disorder, or a prophylactic or diagnostic treatment. In a particular embodiment, the patient or host is a human patient. In an alternative embodiment, the patient such as a host is treated to prevent a disorder or disease described herein.

A "pharmaceutically acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition/combination that is generally safe, is sufficiently non-toxic, and neither biologically nor otherwise undesirable. A "pharmaceutically acceptable excipient" as used in the present application includes both one and more than one such excipient.

A "pharmaceutically acceptable salt" is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. The pharmaceutically acceptable salt can be in the form of a pure crystal, or single polymorphic form, or can be used in non-crystalline or amorphic, glassy, or vitreous form, or a mixture thereof. In an alternative embodiment, the active compound can be provided in the form of a solvate. Salts of the present compounds further include solvates of the compounds and of the compound salts.

Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n- COOH where n is 0-4, and the like, or using a different acid that produces the same counterion. Lists of additional suitable salts may be found, e.g., in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

A "therapeutically effective amount" of a pharmaceutical composition/combination of this invention means an amount effective, when administered to a host, to provide a therapeutic benefit such as an amelioration of symptoms or reduction or diminution of the disease itself. In one embodiment, a therapeutically effective amount is an amount sufficient to prevent a significant increase or will significantly reduce the detectable level of complement Factor B in the patient's blood, serum, or tissues.

Use of Odalasvir Polymorphic Forms in the Manufacture of a Medicament

It has been discovered that Odalasvir Form A polymorph has unexpected and advantageous properties for the manufacture of pharmaceutical dosage forms. In particular, Odalasvir can be prepared in a highly purified form by recrystallization to a highly crystalline dihydrate. This is an improvement over the amorphous form of Odalasvir that is produced according to the method described in U.S. Patent No. 8,809,313. In particular, Odalasvir dihydrate has a higher purity in some aspects than other forms of solid Odalasvir. It has also been discovered that the highly crystalline Odalasvir dihydrate has improved properties for manufacture, including easier handling and/or good stability. In various embodiments, Odalasvir Form A is used in a spray-dried solid dispersion, a spray-dried solid or a granulo layered solid dispersion. In other embodiments, Odalasvir Form A is used in single or double emulsion solvent evaporation, solvent extraction, phase separation, milling, microemulsion, microfabrication, nanofabrication, sacrificial layers or a simple or complex coacervation process.

In certain embodiments, a composition is provided that includes Odalasvir Form A, Form B, or Form C or a combination thereof and comprises one or more of the following excipients: a phosphoglyceride; phosphatidylcholine; dipalmitoyl phosphatidylcholine (DPPC); dioleylphosphatidyl ethanolamine (DOPE); dioleyloxypropyltriethylammonium (DOTMA); dioleoylphosphatidylcholine; cholesterol; cholesterol ester; diacylglycerol; diacylglycerolsuccinate; diphosphatidyl glycerol (DPPG); hexanedecanol; fatty alcohol such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; a surface active fatty acid, such as palmitic acid or oleic acid; fatty acid; fatty acid monoglyceride; fatty acid diglyceride; fatty acid amide; sorbitan trioleate (Span®85) glycocholate; sorbitan monolaurate (Span®20); polysorbate 20 (Tween®20); polysorbate 60 (Tween®60); polysorbate 65 (Tween®65); polysorbate 80 (Tween®80); polysorbate 85 (Tween®85); polyoxyethylene monostearate; surfactin; a poloxomer; a sorbitan fatty acid ester such as sorbitan trioleate; lecithin; lysolecithin; phosphatidyl serine; phosphatidylinositol; sphingomyelin; phosphatidylethanolamine (cephalin); cardiolipin; phosphatidic acid; cerebroside; dicetylphosphate; dipalmitoylphosphatidylglycerol; stearylamine; dodecylamine; hexadecyl-amine; acetyl palmitate; glycerol ricinoleate; hexadecyl sterate; isopropyl myristate; tyloxapol; poly(ethylene glycol)5000-phosphatidylethanolamine; poly(ethylene glycol)400-monostearate; phospholipid; synthetic and/or natural detergent having high surfactant properties; deoxycholate; cyclodextrin; chaotropic salt; ion pairing agent; glucose, fructose, galactose, ribose, lactose, sucrose, maltose, trehalose, cellbiose, mannose, xylose, arabinose, glucoronic acid, galactoronic acid, mannuronic acid, glucosamine, galatosamine, and neuramic acid; pullulan, cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose (UPMC), hydroxycellulose (HC), methylcellulose (MC), dextran, cyclodextran, glycogen, hydroxy ethyl starch, carageenan, glycon, amylose, chitosan, Ν,Ο-carboxylmethylchitosan, algin and alginic acid, starch, chitin, inulin, konjac, glucommannan, pustulan, heparin, hyaluronic acid, curdlan, and xanthan, mannitol, sorbitol, xylitol, erythritol, maltitol, and lactitol, a pluronic polymer, polyethylene, polycarbonate (e.g. poly(l,3-dioxan-2one)), polyanhydride (e.g. poly(sebacic anhydride)), polypropylfumerate, polyamide (e.g. polycaprolactam), polyacetal, polyether, polyester (e.g., polylactide, polyglycolide, polylactide-co-glycolide, polycaprolactone, polyhydroxyacid (e.g. poly((P-hydroxyalkanoate))), poly(orthoester), polycyanoacrylate, polyvinyl alcohol, polyurethane, polyphosphazene, polyacrylate, polymethacrylate, polyurea, polystyrene, and polyamine, polylysine, polylysine-PEG copolymer, and poly(ethyleneimine), poly(ethylene imine)-PEG copolymer, glycerol monocaprylocaprate, propylene glycol, Vitamin E TPGS (also known as d-a-Tocopheryl polyethylene glycol 1000 succinate), gelatin, titanium dioxide, polyvinylpyrrolidone (PVP), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose (MC), block copolymers of ethylene oxide and propylene oxide (PEO/PPO), polyethyleneglycol (PEG), sodium carboxymethylcellulose (NaCMC), or hydroxypropylmethyl cellulose acetate succinate (HPMCAS).

In other embodiments, a composition is provided that includes Odalasvir Form A, Form B, or Form C or a combination thereof and comprises one or more of the following surfactants: polyoxyethylene glycol, polyoxypropylene glycol, decyl glucoside, lauryl glucoside, octyl glucoside, polyoxyethylene glycol octylphenol, Triton X-100, glycerol alkyl ester, glyceryl laurate, cocamide MEA, cocamide DEA, dodecyldimethylamine oxide, and poloxamers. Examples of poloxamers include, poloxamers 188, 237, 338 and 407. These poloxamers are available under the trade name Pluronic® (available from BASF, Mount Olive, N.J.) and correspond to Pluronic® F-68, F-87, F-108 and F-127, respectively. Poloxamer 188 (corresponding to Pluronic® F-68) is a block copolymer with an average molecular mass of about 7,000 to about 10,000 Da, or about 8,000 to about 9,000 Da, or about 8,400 Da. Poloxamer 237 (corresponding to Pluronic® F-87) is a block copolymer with an average molecular mass of about 6,000 to about 9,000 Da, or about 6,500 to about 8,000 Da, or about 7,700 Da. Poloxamer 338 (corresponding to Pluronic® F-108) is a block copolymer with an average molecular mass of about 12,000 to about 18,000 Da, or about 13,000 to about 15,000 Da, or about 14,600 Da. Poloxamer 407 (corresponding to Pluronic® F-127) is a polyoxyethylene-polyoxypropylene triblock copolymer in a ratio of between about E101 P56 E101 to about E106 P70 E106, or about E101 P56E101, or about E106 P70 E106, with an average molecular mass of about 10,000 to about 15,000 Da, or about 12,000 to about 14,000 Da, or about 12,000 to about 13,000 Da, or about 12,600 Da. Additional examples of surfactants that can be used in the invention include, but are not limited to, polyvinyl acetate, cholic acid sodium salt, dioctyl sulfosuccinate sodium, hexadecyltrimethyl ammonium bromide, saponin, sugar esters, Triton X series, sorbitan trioleate, sorbitan mono-oleate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and oxypropylene, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, cetylpyridinium chloride, benzalkonium chloride, olive oil, glyceryl monolaurate, corn oil, cotton seed oil, and sunflower seed oil.

Use of Odalasvir Polymorphs for Medical Treatment

In one embodiment, a method for the treatment of a host infected with a Flavivirus such as hepatitis C viral infection is provided. In another embodiment, a method is provided for a host suffering from a disorder related to such infection that includes administration to the host, such as a human, an effective amount of Form A, Form B, or Form C of Odalasvir, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In one embodiment, Form A, Form B, or Form C of Odalasvir is provided in an isolated form of at least 90% purity (meaning the Form altogether with any included hydrate or solvate molecules, and not treating such hydrates or solvates as impurities, and/or free from other polymorphic forms). In other embodiments, Form A, Form B, or Form C of Odalasvir is provided in at least 95%, 96%, 97%, 98%, or 99% pure form.

In another embodiment, Form A, Form B, or Form C of Odalasvir is administered as a single stereoisomer of Odalasvir, wherein the single stereoisomer is at least in 90% pure form (i.e., free from other isomers), and typically, at least 95%, 96%, 97%, 98%, or 99% pure form.

In one embodiment, an effective amount of Form A, Form B, or Form C of Odalasvir or its pharmaceutically acceptable salt, optionally in a pharmaceutically acceptable carrier, is provided to a host in need of hepatitis C therapy, or another therapy as disclosed herein.

In alternative embodiments, the material used in treatment of a host comprises a combination of two Forms, such as Forms A and B; Forms B and C; or Forms A and C. In another alternative embodiment, the material used in treatment of a host comprises a combination of three Forms, for example, Form A, Form B and Form C. In an alternative embodiment, the material used in treatment comprises a mixture of the amorphous form of Odalasvir in combination with one or more of Form A, Form B, and Form C.

In one embodiment, the viral infection is caused by a Flaviviridae (such as flavivirus, hepacivirus (HCV), and pestivirus); a respiratory virus (such as adenovirus, avian influenza, Influenza virus type A and B, respiratory syncytial virus, rhinovirus, and SARS); a gastro-enteric virus (such as coxsackie, enterovirus, poliovirus, and rotavirus); herpes simplex 1 and 2; cytomegalovirus; varicella; or a Caliciviridae (such as norovirus).

In one embodiment, the infection is hepatitis C.

In another embodiment, an effective amount of Form A, Form B, or Form C as described herein, optionally as a pharmaceutically acceptable salt and optionally in a pharmaceutically acceptable carrier, can be used to treat a host, typically a human, with a secondary condition associated with hepatitis C, or another disorder described herein, including but not limited to those disorders described below.

An effective amount of a pharmaceutical composition/combination as described herein may be an amount sufficient to (a) inhibit the progression of hepatitis C or other disorder described herein; (b) cause a regression of the hepatitis C infection or other disorder described herein; or (c) cause a cure of a hepatitis C infection, or other disorder described herein, for example such that HCV virus or HCV antibodies can no longer be detected in a previously infected patient's blood or plasma. An amount of a pharmaceutical composition/combination as described herein effective to inhibit the progress or cause a regression of hepatitis C, or other disorder described herein, includes an amount effective to stop the worsening of symptoms of hepatitis C, or other disorder described herein, or reduce the symptoms experienced by a patient infected with the hepatitis C virus, or other disorder described herein. Alternatively, a halt in progression or regression of a disorder described herein, for example hepatitis C, may be accomplished. For example, a lack of increase or reduction in the hepatitis C viral load or a lack of increase or reduction in the number of circulating HCV antibodies in a patient's blood are markers of a halt in progression or regression of hepatitis C infection. Other hepatitis C disease markers include aminotransferase levels, particularly levels of the liver enzymes AST and ALT. Normal levels of AST are from 5 to 40 units per liter of serum (the liquid part of the blood) and normal levels of ALT are from 7 to 56 units per liter of serum. These levels will typically be elevated in a HCV infected patient. Disease regression is usually marked by the return of AST and ALT levels to the normal range.

In yet another embodiment, an effective amount of Form A, Form B, or Form C described herein, optionally as a pharmaceutically acceptable salt and optionally in a pharmaceutically acceptable carrier can be used as a prophylaxis to ward off or prevent a host, typically a human, from having a disorder described herein, for example the hepatitis C infection. In an alternative embodiment, an effective amount of Form A, Form B, or Form C described herein, optionally as a pharmaceutically acceptable salt and/or optionally in a pharmaceutically acceptable carrier can be used to treat a secondary condition associated with a disorder described herein, for example hepatitis C, including but not limited to those disorders described below in (i) through (viii):

(i) Cryoglobulinemia, a condition in which the blood contains abnormal antibodies (called cryoglobulins) that come from hepatitis C virus stimulation of lymphocytes. These antibodies can deposit in small blood vessels, thereby causing inflammation of the vessels (vasculitis) in tissues throughout the body including the skin, joints and kidneys (glomerulonephritis).

(ii) B-cell non-Hodgkin's lymphoma associated with hepatitis C, which is considered to be caused by excessive stimulation by hepatitis C virus of B-lymphocytes and results in abnormal reproduction of the lymphocytes.

(iii) Skin conditions such as lichen planus and porphyria cutanea tarda.

(iv) Cirrhosis, a disease in which normal liver cells are replaced with scar or abnormal tissue. Hepatitis C is one of the most common causes of liver cirrhosis.

(v) Ascites, the accumulation of fluid in the abdominal cavity commonly caused by cirrhosis of the liver, which can be caused by hepatitis C infection.

(vi) Hepatocellular carcinoma, of which 50% of the cases in the U.S. are currently caused by chronic hepatitis C infection.

(vii) Hepatitis C related jaundice, which is a yellowish pigmentation caused by increased bilirubin.

(viii) Thrombocytopenia, often found in patients with hepatitis C and may be the result of bone marrow inhibition, decrease in liver thrombopoietin production and/or an autoimmune mechanism. In many patients, as hepatitis C advances, the platelet count decreases and both bone marrow viral inhibition and antiplatelet antibodies increase. Other symptoms and disorders associated with hepatitis C that may be treated by an effective amount of a pharmaceutical composition/combination of the disclosure include decreased liver function; fatigue; flu-like symptoms: fever, chills, muscle aches, joint pain, and headaches; nausea; aversion to certain foods; unexplained weight loss; psychological disorders including depression; and, tenderness in the abdomen.

The active compounds presented herein can also be used to enhance liver function, a problem generally associated with hepatitis C infection. For example the active compounds presented herein can be used to enhance synthetic functions, including the synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'-nucleosidases, and y glutaminyltranspeptidases, etc.). The compounds of the present invention can be used to enhance the synthesis of bilirubin, the synthesis of cholesterol, or the synthesis of bile acids. Compounds presented herein can also be used to enhance liver metabolic function, including carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism. Compounds can be used to enhance the detoxification of exogenous drugs or to enhance hemodynamic function, including splanchnic and portal hemodynamics.

Symptoms of hepatitis C that may be affected by an effective amount of Form A, Form B, or Form C include decreased liver function; fatigue; flu-like symptoms, such as fever, chills, muscle aches, joint pain, and headaches; nausea; aversion to certain foods; unexplained weight loss; psychological disorders including depression; tenderness in the abdomen; and, jaundice.

"Liver function" refers to a normal function of the liver, including, but not limited to, a synthetic function including synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'-nucleosidase, y glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; and a hemodynamic function, including splanchnic and portal hemodynamics.

An effective amount of a Form A, Form B, or Form C described herein should provide a sufficient concentration of Odalasvir when administered to a patient. A sufficient concentration of Odalasvir is a concentration in the patient's body necessary to prevent or combat the infection or the symptom to be treated. Such an amount may be ascertained experimentally, for example by assaying blood concentration of the agent, or sometimes theoretically, by calculating bioavailability. The amount of Form A, Form B, or Form C sufficient to inhibit viral infection in vitro may be determined with a conventional assay for viral infectivity such as a replicon based assay that has been described in the literature.

Methods of treatment include providing certain dosage amounts of Odalasvir Form A, Form B, or Form C to a patient. Dosage levels of Odalasvir Form A, Form B, or Form C of about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single unit dosage form will vary depending upon the patient treated and the particular mode of administration. In certain embodiments, the amount of active ingredient can be from about 0.1 mg to about 2000 mg, from about 10 mg to about 1500 mg, from about 100 mg to about 1000 mg, from about 200 mg to about 800 mg, or from about 300 to about 600 mg of Form A, Form B, or Form C. Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most infectious disorders, a dosage regimen of 4 times daily or less is preferred and a dosage regimen of 1 or 2 times daily are particularly preferred.

The disclosure includes a method of treating HCV in a patient comprising administering a therapeutically effective amount of any of the dosage forms disclosed herein. The disclosure includes a method of treating HCV comprising administering a dosage form of the disclosure comprising from about 10 mg to about 150 mg Odalasvir Form A, Form B, or Form C (by weight of active compound without regard to weight of hydrate or solvate included). The disclosure includes a method of treating HCV comprising administering from about 1 mg to about 1 g, from about 10 mg to about 500 mg, from about 10 mg to about 250 mg, from about 10 to about 25 mg, from about 7.5 to about 20 mg, from about 10 to 12.5 or 15 mg, from about 25 mg to about 50 mg, or from about 10 mg to about 50 mg of Odalasvir Form A, Form B, or Form C to the patient in a single dosage form. In one embodiment, the disclosure includes a method of treating HCV comprising administering about 5 mg of Odalasvir Form A, Form B, or Form C to the patient daily. In one embodiment, the disclosure includes a method of treating HCV comprising administering about 7.5 mg of Odalasvir Form A, Form B, or Form C to the patient daily. In one embodiment, the disclosure includes a method of treating HCV comprising administering about 10 mg of Odalasvir Form A, Form B, or Form C to the patient daily. In one embodiment, the disclosure includes a method of treating HCV comprising administering about 12.5 mg of Odalasvir Form A, Form B, or Form C to the patient daily. In one embodiment, the disclosure includes a method of treating HCV comprising administering about 15 mg of Odalasvir Form A, Form B, or Form C to the patient daily. In one embodiment, the disclosure includes a method of treating HCV comprising administering about 20 mg of Odalasvir Form A, Form B, or Form C to the patient daily. In one embodiment, the disclosure includes a method of treating HCV comprising administering about 25 mg of Odalasvir Form A, Form B, or Form C to the patient daily. The administration may be once per day.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, as well as drug combination and the severity of the particular disease in the patient undergoing therapy.

The pharmaceutical compositions contemplated here can optionally include a carrier. Carriers must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, fillers, flavorants, glidents, lubricants, pH modifiers, preservatives, stabilizers, surfactants, solubilizers, tableting agents, and wetting agents. Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin, talc, and vegetable oils. Examples of other matrix materials, fillers, or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and starch. Examples of surface active agents include sodium lauryl sulfate and polysorbate 80. Examples of drug complexing agents or solubilizers include the polyethylene glycols, caffeine, xanthene, gentisic acid and cylodextrins. Examples of disintegrants include sodium starch gycolate, sodium alginate, carboxymethyl cellulose sodium, methyl cellulose, colloidal silicon dioxide, and croscarmellose sodium. Examples of binders include methyl cellulose, microcrystalline cellulose, starch, and gums such as guar gum, and tragacanth. Examples of lubricants include magnesium stearate and calcium stearate. Examples of pH modifiers include acids such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, and the like; bases such as sodium acetate, potassium acetate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide, and the like, and buffers generally comprising mixtures of acids and the salts of said acids. Optional other active agents may be included in a pharmaceutical composition that do not substantially interfere with the activity of the compound of the present invention.

Abbreviations

Ac: acetyl

ACN: acetonitrile

aq: aqueous

DCM: dichloromethane

DIEA: N,N-diisopropylethylamine

DMF: N,N-dimethylformamide

dppf : 1 , 1 '-bi s(diphenylphosphino)ferrocene

EDCI: ^-(S-Dimethylaminopropy^-jV-ethylcarbodiimide hydrochloride

Et: ethyl

HOBt: 1-hydroxybenzotriazole

MeOH: methanol

MTBE: methyl fert-butyl ether

NaOH: sodium hydroxide

Na₂S₂0₃: sodium thiosulfate

Pd(dppf)Cl2: [l,l '-bis(diphenylphosphino)ferrocene]dichloropalladium

rt: room temperature

THF: tetrahydrofuran

TPP: triphenylphosphine General Methods

All nonaqueous reactions were performed under an atmosphere of dry argon gas using oven-dried glassware and anhydrous solvents. The progress of reactions and the purity of target compounds were determined using one of the following two HPLC methods: (1) Waters AQUITY HPLC BEH C18 1.7 μιη 2.1 x50 mm column with an isocratic elution of 0.24 min at 90: 10 water: acetonitrile containing 0.05% formic acid followed by a 4.26-min linear gradient elution from 90: 10 to 10:90 at a flow rate of 1.0 mL/min with UV (PDA), ELS, and MS (SQ in APCI mode) detection (method 1); and (2) Waters AQUITY HPLC BEH C18 1.7 μιη 2.1 x50 mm column with an isocratic elution of 0.31 min at 95:5 water: acetonitrile containing 0.05% formic acid followed by a 17.47-min linear gradient elution from 95:5 to 5:95 at a flow rate of 0.4 mL/min with UV (PDA), ELS, and MS (SQ in APCI mode) detection (method 2).

Target compounds were purified via preparative reverse-phase HPLC using a YMC Pack Pro C18 5 μπι 150x20 mm column with an isocratic elution of 0.35 min at 95:5 water: acetonitrile containing 0.1% trifluoroacetic acid followed by a 23.3-min linear gradient elution from 95:5 to 5:95 at a flow rate of 18.9 mL/min with UV and mass-based fraction collection.

Analytical Techniques

FT-Raman Spectroscopy: Raman spectra were collected with a Nicolet NXR9650 or NXR960 spectrometer (Thermo Electron) equipped with 1064 nm Nd:YV0₄ excitation laser, InGaAs and liquid-N2 cooled Ge detectors, and a MicroStage. All spectra were acquired at 4 cm^"1 resolution, 64-128 scans using Happ-Genzel apodization function and 2-level zero-filling, unless noted otherwise.

Polarized-Light Microscopy (PLM): The photomicrographs were collected using Olympus BX60 polarized-light microscope equipped with Olympus DP70 camera.

Powder X-ray Diffraction (XRPD): XRPD diffractograms were acquired using PANalytical X'Pert Pro diffractometer on Si zero-background wafers. All diffractograms were collected using a monochromatic Cu Koc (45 kV/40 raA) radiation and a step size of 0.02° 2Theta.

Differential Scanning Calorimetry (DSC): DSC was conducted with a TA Instruments Q100 differential scanning calorimeter equipped with an autosampler and a refrigerated cooling system under 40 mL/min N2 purge. DSC thermograms were obtained at 15 °C/min in crimped Al pans. Thermogravimetric Analysis (TGA): TGA thermograms were obtained with a TA Instruments Q500 thermogravimetric analyzer under 40 mL/min N2 purge at 15 °C/min in Pt or Al pans.

Thermogravimetric Analysis with IR off-gas detection (TGA-IR): TGA-IR was conducted with a TA Instruments Q5000 thermogravimetric analyzer interfaced to a Nicolet 6700 FT-IR spectrometer (Thermo Electron) equipped with an external TGAIR module with a gas flow cell and DTGS detector. TGA was conducted with 60 mL/min N2 flow and heating rate of 15 °C/min in Pt or Al pans. IR spectra were collected at 4 cm^"1 resolution and 32 scans at each time point.

Dynamic Vapor Sorption (DVS): DVS experiments were conducted on a Surface Measurement Systems DVS-HT at 25 °C. The instrument was operated in step mode and the relative humidity was increased in 10% RH increments from 40% RH to 90% RH, then decreased from 90% RH to 0% RH, then increased a second time from 0% RH to 90% RH, then decreased from 90%) RH to 0% RH. An extra step at 75% RH was included in each cycle. The mass equilibrium criterion was set at 0.005%) change in mass over time (dm/dt). A minimum step time of 10 minutes and a maximum step time of 240 minutes were specified.

EXAMPLES

Example 1. Synthesis of dimethyl((2S,2'S)-((2S,2'S,3aS,3A'S,7aS,7A'S)-2,2'-(5,5'- (tricyclo[8.2.2.2⁴'⁷]hexadeca-4,6 0 2 3 5-hexaene-5 1-diyl)bis(lH-benzo[D]imidazole- 5,2-diyl))bis(octahydro-lH-indole-2,l-diyl))bis(3-methyl-l-oxobuta ne-2,ldiyl))dicarbamate

Amorphous Odalasvir can be synthesized with the procedures described in U.S. Patent 8,809,313, hereby incorporated by reference. An example synthesis provided therein is provided below.

Ste 1 : Preparation of Compound 2

To a stirred solution of (2R,3aS,7aS)-octahydro-lH-indole-2-carboxylic acid (250 g, 1.0 equiv) (1) in THF (3 L) and water (1.5 L) at 0 °C was added dropwise a cooled aqueous solution of 2.5 M NaOH (1 L). The reaction mixture was stirred for 15 minutes at the same temperature. Di-tert-butyl dicarbonate (1.3 equiv) was added dropwise, maintaining the temperature at 0 °C. The resulting reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was washed with MTBE (3 times). The aqueous phase was acidified with IM aqueous citric acid and extracted with ethyl acetate (3 times). The combined organic layers were dried over sodium sulfate and concentrated to dryness to afford (2R,3a,S',7a₎S)-l-(tert-butoxycarbonyl)octahydro-lH- indole-2-carboxylic acid (368 g) (2).

Ste 2. Preparation of Compound 3

To a stirred solution of 4-bromo-l,2-diaminobenzene (23.1 g, 1.2 equiv), (2R,3a,S',7a₎S)-l- (tert-butoxycarbonyl)octahydro-lH-indole-2-carboxylic acid (26.9 g, 1.0 equiv) (2), and EDCI (23.6 g, 1.2 equiv) in ACN (600 mL) at 0 °C was added DIEA (21.5 mL, 1.3 equiv) dropwise. The reaction mixture was stirred for 1 hour after the addition was complete. Water (1.2 L) was added and the reaction mixture was stirred overnight. The solid powder (3) was collected, washed with water, and dried for use in the next step without further purification (39.1 g).

Ste 3. Preparation of Compound 4

An isomeric mixture (3) of (2,S',3a₎S',7a₎S)-tert-butyl 2-((2-amino-4- bromophenyl)carbamoyl)octahydro-lH-indole-l-carboxylate and (2S,3aS,7aS)-tert-buty\ 2-((2- amino-5-bromophenyl)carbamoyl)octahydro-lH-indole-l-carboxylate (160 g, 0.36 mol) was dissolved in acetic acid (480 mL) and the reaction mixture was stirred at 65 °C until the starting materials were consumed (as judged by LC-MS analysis). The reaction was cooled to room temperature and the solvent was removed under vacuum. The remaining residue was dissolved in ethyl acetate (500 mL) and aqueous ammonia (100 mL) was added carefully. Additional water (100 mL) was added and the organic layer was separated and collected. The aqueous phase was extracted with ethyl acetate (2x300 mL). The combined organic phase was washed with water (200 mL), washed with by brine (200 mL), and dried over MgSCk The solution was concentrated and the remaining residue was purified by silica gel column chromatography (hexanes/ethyl acetate) to afford (2,S',3a₎S',7a₎S)-tert-butyl 2-(6-bromo-lH-benzo[d]imidazol-2-yl)octahydro-lH- indole-l-carboxylate (4) (140 g).

Ste 4. Preparation of Compound 5

Under an atmosphere of argon, a mixture of (2,S',3a₎S',7a₎S)-tert-butyl 2-(6-bromo-lH- benzo[d]imidazol-2-yl)octahydro-lH-indole-l-carboxylate (4) (30 g, 1.0 equiv), bis(pinacolato)diborane (27.2 g, 1.5 equiv), potassium acetate (21 g, 3.0 equiv), and Pd(dppf)Cl2 (5.7 g, 0.098 equiv) in anhydrous 1,4-dioxane (300 mL) was heated at 80-90 °C for approximately 4 hours (until the reaction was complete as judged by LC-MS). The cooled (room temperature) reaction mixture was diluted with ethyl acetate (300 mL), stirred with activated carbon (60 g) for 1 hour, and filtered through a pad of Celite^®. The filtrate was concentrated under reduced pressure and the resulting brown foam was purified by silica gel column chromatography (hexanes/ethyl acetate, 5: 1→1 :2 v/v) to afford (2S,3aS,7aS)-tert-butyl 2-(6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-benzo[d]imidazol-2-yl)octahydro-lH-indole-l-carboxylate) as an off- white solid (5).

Step 5. Preparation of Compound 6

6 A mixture of Br₂ (82.8 g) and iron powder (4.6 g) in DCM (1.6 L) was stirred at room temperature for 1 hour. A slurry of [2.2]paracyclophane (200 g, 1.0 equiv) in DCM was added in one portion to the mixture. The resulting mixture was heated to reflux, and a solution of Br₂ (228 g) in DCM (400 mL) was added slowly over a 3 hour period. After this addition was complete, the reaction mixture continued to reflux for 3 hours and was allowed to cool to room temperature with stirring overnight. The mixture was washed with 5% w/v aqueous Na₂S₂Cb (2 L) and water (2 L), dried (MgS0₄), and evaporated to dryness. The isolated crude solid was dissolved in hot toluene (1.2 L, approximately 100 °C), allowed to cool slowly overnight to room temperature with stirring, and further cooled to 5 °C for 3 hours. The resulting solid was collected and washed with cold toluene (approximately 100 mL) to afford 4,16-dibromo[2.2]paracyclophane (6) (83 g). ¾ ΝΜΚ (300 MHz, CDCh): 5 2.79-3.00 (m, 4H), 3.10-3.21 (m, 2H), 3.44-3.54 (m, 2H), 6.44 (d, J=8.0 Hz, 2H), 6.51 (d, J=2.0 Hz, 2H), 7.14 (dd, J=8.0 Hz, 2.0 Hz, 2H).

Step 6. Preparation of Compound 7

Under an atmosphere of argon, a mixture of 4,16-dibromo[2.2]paracyclophane (6) (20 g, 1.0 equiv), (2S,3aS,7aS)-tert-butyl 2-(6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- benzo[d]imidazol-2-yl)octahydro-lH-indole-l-carboxylate (64 g, 2.5 equiv), Cs₂CCb (44.5 g, 2.5 equiv), Pd(PPh₃ (3.16 g, 0.05 equiv), DMF (500 mL), and water (25 mL) was heated at 130 °C for approximately 2-3 hours (until the reaction was complete as judged by LC-MS). The reaction mixture was allowed to cool to room temperature and filtered through a pad of silica gel (30 g) layered with Celite^®. This pad was washed with DMF (2x50 mL) and the combined filtrates were added to stirred water (2.5 L) to afford a pale yellow precipitate. This solid was collected by filtration, washed with water (1 L) and ACN (500 mL), and dissolved in a mixture of DCM (250 mL) and MeOH (25 mL). To this solution was added ACN (250 mL) to generate a fine slurry, which was then concentrated under reduced pressure at 30-35° C to remove approximately 150 mL of solvent. Another portion of ACN (500 mL) was added and additional solvent (approximately 100 mL) was removed under reduced pressure at 40-45 °C. The solid was collected by filtration and dried under vacuum to afford (2S,2 ,3aS,3a ,7aS,7a'5)-di-tert-butyl 2,2'-(5,5'-(tricyclo[8.2.2.2⁴'⁷]hexadeca-4,6,10, 12,13, 15-hexaene-5,l l-diyl)bis(lH- benzo[d]imidazole-5,2-diyl))bis(octahydro-lH-indole-l-carboxylate) (7) as a pale yellow powder (33.8 g).

Step 7. Preparation of Compound 8

To a cooled (0 °C) solution of (2S,2 ,3aS,3a ,7aS,7a\S)-di-fer/-butyl 2,2'-(5,5'- (tricyclo[8.2.2.2⁴'⁷]hexadeca-4,6, 10,12, 13,15-hexaene-5, l l-diyl)bis(lH-benzo[d]imidazole-5,2- diyl))bis(octahydro-lH-indole-l-carboxylate) (7) (20.33 g, 1.0 equiv) in DCM/MeOH (4/1 v/v, 200 mL) was added a 4N HCl/dioxane solution (100 mL). The reaction mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure to afford a pale yellow powder (21.7 g). The solid was dried under vacuum until residual MeOH was undetectable by ¾ MR spectroscopic analysis. This thoroughly dried material was used directly in the next step.

Step 8. Preparation of Compound 9

To a mixture of (,S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acid (10 g, 2.3 equiv) and HOBt monohydrate (8.8 g, 2.3 equiv) in ACN (50 mL) at room temperature was added EDCI (11.14 g, 2.3 equiv). After stirring for 5 minutes, this activated acid mixture was added to a solution of the hydrochloride salt, compound 8 (21.7 g), and DIEA (32 mL, 7.2 equiv) in DMF (250 mL). The reaction mixture was stirred at room temperature until the reaction was judged as complete by LC-MS analysis (approximately 4 hours) and then poured into water (1.2 L) with stirring. The precipitate was collected by filtration, stirred in ACN/water (4: 1 v/v, 500 mL) overnight, collected again by filtration, and dried in vacuo to afford dimethyl (( ^ '_^S)- ((2^,2 ,3a^,3a ,7a^,7a'^-2,2'-(5,5'-(tricyclo[8.2.2.2⁴'⁷]hexadeca-4,6,10, 12,13, 15-hexaene-5,l l- diyl)bis(lH-benzo[d]imidazole-5,2-diyl))bis(octahydro-lH-indole-2,l-diyl))bis(3-methyl-l- oxobuta ne-2,l-diyl))dicarbamate (9) (22.62 g). ¾ MR (300 MHz, DMSO-de, 120 °C): δ 0.87 (d, J=6.5 Hz, 6H), 0.92 (d, J=6.5 Hz, 6H), 1.20-1.60 (m, 6H), 1.65-2.10 (m, 12H), 2.31 (m, 2H), 2.38-2.52 (m, 2H), 2.54-2.76 (m, 4H), 2.85 (m, 2H), 3.07 (m, 2H), 3.45 (m, 2H), 3.57 (br s, 6H), 4.07 (t, j=8.0 Hz, 2H), 4.34 (m, 2H), 5.28 (t, J=8.5 Hz, 2H), 6.51 (br, 2H), 6.57 (d, J=8.0 Hz, 2H), 6.73 (s, 2H), 6.76 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H), 7.72 (s, 2H).

Example 2. Preparation of Odalasvir Form A

To a solution of moc-valine methyl ester (0.626 wt. equi) in dichloromethane was added HOBt (0.56 wt. equiv) followed by EDCI (0.7 wt. equiv). The reaction mixture was cooled between 0°C- 5°C before cyclophane (1 wt. equiv) followed by DIPEA (N,N- diisopropylethylamine, 1.5 vol. equiv) was added. The reaction was allowed to warm to room temperature and stirred until completion as analyzed by HPLC. Activated charcoal was added to the reaction mixture and stirring continued for about 30 minutes before the reaction was filtered over a pad of celite. The filtrate was washed with brine containing sodium hydroxide to remove any traces of HOBT. The filtrate was then dried over anhydrous sodium sulfate and evaporated to dryness. Methanol was added to the residue and the mixture was heated to about 55°C until crystalline Odalasvir precipitated from the reaction mixture. The solid was filtered to afford Form A of Odalasvir in about 75% yield.

Example 3. Characterization of Odalasvir Form A

Material made similarly to Example 2 was used without further purification or pre- treatment (e.g., drying). The polarized light microscopy (PLM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric with IR off-gas analysis (TGA-IR) and FT-Raman spectroscopy data are shown in FIG. 1, FIG. 2, FIG. 3, and FIG. 4, respectively. The material was determined to be crystalline by XRPD and PLM and was designated as Form A. Form A was found to be a dihydrated crystal by thermal analysis. DSC showed a broad melting endotherm at 98.1°C that was associated with 3.6% water (theoretical dihydrate=3.4%) observed by TGA-IR. In a separate experiment, Form A was heated to 190°C in the TGA instrument and cooled back to room temperature. The sample was amorphous by XRPD analysis. Dynamic Vapor Sorption (DVS) analysis was completed on Form A indicating that the sample was a stable and non-hygroscopic dihydrate. The maximum water uptake from 0-90% RH was about 0.3%, which can be attributed to surface water adsorption. No change to the crystal Form or reduction in crystallinity in the post-DVS analysis sample was observed by XRPD. The DVS isotherm plot is shown in FIG. 5.

Example 4. Visual Solubility Assessment of Odalasvir Form A

Solubility estimates were conducted using Form A in a range of solvents. The solubility of Form A was visually estimated in eight solvents at about 25°C by dosing small aliquots of the solvent into a fixed amount of the Odalasvir Form A (10.0 mg) until the dissolution point or a maximum volume of 10 mL was reached. The approximate solubility values are summarized in Table 1.

Table 1. Approximate Solubility of Odalasvir Form A in Common Solvents at 25°C

Example 5. Preparation and Characterization of Amorphous Odalasvir

Results of the visual solubility assessment of Form A indicated 1,4-dioxane possessed adequate solubility to be used in lyophilization experiments. Additional experiments utilizing acetone (solvent) and water (anti- solvent) also generated amorphous Odalasvir. Both techniques were used in several small-scale experiments and both were successful in generating amorphous material. However, the residual 1,4-dioxane in the solids generated by lyophilization was 4.5%. Residual water was found in the anti-solvent addition experiments, but was managed by filtering under nitrogen and vacuum drying the solids at 40°C. The characterization data for amorphous amorphous Odalasvir is shown in FIG. 6, FIG. 7, FIG. 8, FIG. 9, FIG. 10, and FIG. 11.

Example 6. Preparation of Amorphous Odalasvir

Odalasvir (Form A, 4.02 g) was combined with acetone (40 mL) in a 250 mL round bottom flask. The sample was stirred and vortexed until complete dissolution was observed (about 3 minutes). Water (120 mL) was added to the flask and solids crashed out immediately. The thick slurry was filtered on a Buchner funnel under a nitrogen hood. Additional water was added and used to remove the rest of the slurry from the flask. The sample was dried on the filter under vacuum for 1 hour. The solids were isolated and dried in a vacuum oven at 40 °C overnight.

Example 7. Characterization of Amorphous Odalasvir

The XRPD pattern and PLM image confirmed that the material was amorphous as shown in FIG. 6 and FIG. 7. Amorphous Odalasvir was physically stable when stored in a sealed vial at 25°C for at least 2 weeks. Also, the amorphous material was exposed to ambient conditions for three days and no change to the sample was detected by XRPD. TGA indicated that the material lost 2.5% water between 25°C and 175°C. A potential t_g was observed at 194.6°C as shown in FIG. 10. The value is unusually high for a glass transition, however, the observed physical stability of the amorphous material is also consistent with a higher t_g. DVS analysis indicated that amorphous Odalasvir absorbed a maximum of 5% moisture from 0-90%RH (shown in the isotherm plot in FIG. 1 1). No change (crystallization) to the amorphous XRPD pattern was observed in the sample analyzed after DVS analysis.

Example 8. Solvent Selection/ Crystallization

Crystallization experiments using amorphous Odalasvir were conducted in 48 solvents/solvent mixtures (Table 2A and Table 2B). Solvents and aqueous mixtures were selected based on a diverse range of properties that are important to crystallization and polymorph discovery, including dielectric constants, boiling points, and H-bonding. Crystallization experiments were conducted in these solvents using the following three crystallization modes: stirring amorphous Odalasvir slurries while cycling the temperature between 5 °C and 40 °C for 48 hours (heat to 40 °C at 2 °C/min; hold for two hours; cool to 5 °C at 1 °C/min; hold for two hours; and repeat for 48 hours); cooling of solutions saturated at 25 °C to -15 °C; and, evaporation of solutions saturated at 25 °C. The experiments were conducted by stirring Odalasvir amorphous slurries while cycling the temperature between 5 °C and 40 °C for 48 hours (same parameters as mentioned above). The solvents used for the amorphous Odalasvir solvent selection are listed in Table 2A and the solvents used for the crystalline amorphous material solvent selection are displayed in Table 2B.

Table 2A. List of 48 Solvents/Mixtures Included in the Amorphous Input Form Solvent

Selection

23 2-Propanol 47 EtO Ac: Toluene (1 :2)

24 Trifluoroethanol 48 MIBK:Heptane (l :2)

Table 2B. List of 48 Solvents/Mixtures Included in the Solvent Selection for Form A Studies

Example 9. Results from Solvent Selection

All solids obtained from the screen were isolated and analyzed by FT-Raman spectroscopy. The samples were then grouped based on FT-Raman spectral match. Representative samples from each of the Forms were further characterized by additional analytical techniques where appropriate and sample quantities permitted. Three Forms were identified and characterized:

The slurry experiments utilizing amorphous Odalasvir primarily produced Form C. Form C was observed in 15 of the 27 solids analyzed. Form B was produced in all methanol containing experiments in the amorphous input slurries. In the crystalline input slurries, samples containing methanol remained as Form A. Form A was also the predominant output of experiments using Form A as input material. Form A was found in five of the eight solids analyzed. The solution phase experiments, especially evaporation, led to all amorphous products. No crystalline solids were obtained from solution phase experiments.

The results are summarized in Table 3. An overlay of the XRPD patterns of the observed Forms are shown in FIG. 26. A peak table of the unique XRPD peaks for each Form is shown in Table 4. Detailed analysis and scale-up information can be found in the subsequent sections for each Form (including amorphous). Form A is the polymorph of the input ODV. The characterization data can be found in FIG. 1, FIG. 2, FIG. 3, FIG. 4, and FIG. 5.

The Form assignments as they relate to each of the tested solvents with various conditions are provided in Table 3.

Table 3. Form Assignments vs. Solvent Selection

Example 10. An Alternative Preparation of Form A Odalasvir Dihydrate

Step 1 : Preparation Amorphous Odalasvir

A round bottomed flask was charged with dichloromethane (10 vol.), N-moc-J-valine (3.0 eq.) and O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluorob orate (TBTU, 3.0 eq.) at 25±5 °C under a nitrogen atmosphere and the reaction was stirred for 5-10 minutes. The reaction was cooled to 0±5°C under a nitrogen atmosphere and stirred for 5-10 minutes. The cyclophane (1.0 eq.) was added to the reaction at 0±5 °C and stirred for 20-30 minutes under a nitrogen atmosphere. Diisopropylethylamine (7.1 eq.) was slowly added to the reaction through an addition vessel while maintaining the temperature at 0±5 °C over a period of 2 hours under a nitrogen atmosphere. The reaction temperature was raised to 25±5 °C and the reaction was stirred for 24 hours. The reaction was diluted with dichloromethane (10 vol.) and stirred for 10 minutes. Activated charcoal (0.1 w/w) was added at 25±5 °C and stirred for 30-40 minutes. The reaction was filtered through a Celite^® bed before the Celite^® bed was washed with dichloromethane (5 vol.) and vacuum dried for 20-30 minutes. The organic layer was washed with sodium hydroxide in 13% sodium chloride solution (10 vol. x 3). The organic layer was washed with water (10 vol.), diluted with citric acid monohydrate solution (10 vol. x 2) and stirred for 1 hour. The organic layer was separated, washed with water (10 vol.), washed with 8% sodium bicarbonate solution (10 vol.) and washed with water (10 vol.). The organic layer was dried over anhydrous sodium sulphate (0.5 w/w), filtered through a Celite^®bed and the Celite^® bed was washed with dichloromethane (4 vol.). The organic layer was passed through a cartridge filter and the cartridge was washed with dichloromethane (3 vol.). The filtrate was concentrated under vacuum below 55 °C until the ratio of product: dichloromethane was 1 : approximately 2.0 (w/w stage).

Step 2: Preparation of Odalasvir Form A Dihydrate

Methanol (6 vol.) was added at a temperature below 55 °C and the reaction was concentrated at a temperature below 55 °C under vacuum until the ratio of product: solvent was 1 : approximately 3.0 (w/w stage). The reaction was cooled to 25±5 °C and cartridge filtered methanol (15 vol.) was added. The reaction temperature was raised to 65± 5°C and the reaction was stirred for 6 hours. The reaction was cooled to 25±5 °C and stirred for 1 hour. The product was collected, washed with methanol (2 vol.) and spin-dried for 20-30 minutes. The purity was not less than 97.0%. MR: Single peak between 3.5δ to 3.7δ. XRPD: Crystalline Example 11. Preparation of Amorphous Odalasvir from Form A

Odalasvir Form A (4.02 g) was combined with acetone (40 mL) in a 250 mL round bottom flask. The sample was stirred and vortexed until complete dissolution was observed (approximately 3 minutes). Water (120 mL) was added to the flask and the solids precipitated out immediately. The thick slurry was filtered on a Buchner funnel under a nitrogen hood. Additional water was added and used to remove the rest of the slurry from the flask. The sample was dried on the filter under vacuum for 1 hour. The solids were isolated and dried in a vacuum oven at 40 °C overnight to form amorphous Odalasvir.

Example 12. Preparation of Form B (Mixed Methanol/Water Solvate)

Form B is a partially crystalline mixed methanol/water solvate. It was produced from three amorphous slurry experiments involving methanol. Physical characterization data for Form B is found in FIG. 12, FIG. 13, FIG. 14, and FIG. 15. An original preparation is provided:

Form A (50.8 mg) was combined with methanol (1.2 mL) in a 2 mL UPLC vial containing a stir disk and this resulted in a slurry. The suspension was then thermo-cycled between 40°C and 5°C for 48 hours (in two hour periods). The sample was isolated at 25°C on a stainless steel filter plate and dried under vacuum on the filter for 20 minutes.

Example 13. Characterization of Form B

Form B was characterized by XRPD, showing only a few weak diffraction peaks. Thermal data indicated a desolvation event occurring with a broad endotherm with an onset at 59.5°C. The corresponding TGA weight loss of 30.7% was confirmed as methanol and water evolving from the solids. A wet sample of Form B was placed on an XRPD plate and scanned for 10 consecutive scans (30 minutes). The results shown in FIG. 16 indicate that Form B remains partially crystalline throughout the drying process.

Example 14. Preparation of Form C (Structurally Similar Solvate Class)

Form C is a class of solvates observed during the course of the crystallization experiments. The similar solvates were observed in 18 of 35 solids analyzed from the slurry experiments. Form C was not observed in solution phase. Physical characterization data for Form C is shown in FIG. 17, FIG. 18, FIG. 19, and FIG. 20. Odalasvir (Form A, 105.4 mg) was combined with acetone:20 vol% water (1 mL) in a 2 mL HPLC vial containing a stir disk. The suspension was then thermo-cycled between 40°C and 5°C for 48 hours (in two hour periods). The suspension was then stirred at 25°C for 30 minutes. The sample was isolated at 25°C on a 0.45um Vericel^® filter and dried under vacuum on the filter for 60 minutes.

Example 15. Characterization of Odalasvir Form C Solvate

Odalasvir Form C was crystalline by XRPD and contained very small, irregular particles by PLM. DSC showed a broad endotherm with an onset at 33.8°C, indicating that the sample was solvated. A final melting endotherm at 234.5°C was also observed. TGA collected on the sample revealed that a 3.1% weight loss associated with the broad endotherm in the DSC. IR analysis of the off-gas indicated that acetone and water were being released. Form C was found from several different solvents: acetone, nitromethane, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, 2-propanol, dimethyl carbonate, and some water mixtures with acetone and acetonitrile. Although the FT-Raman spectra of the Form C samples were nearly identical, some differences were observed by XRPD, as shown in FIG. 21 and FIG. 22. The variations are likely due to the solvent type forming the solvate. A wet sample of Form C was placed on an XRPD plate and scanned for 10 consecutive scans (30 minutes) to observe the changes to the XRPD pattern upon drying. As shown in FIG. 23, significant shifting of various peaks was observed during the drying process. When Form C was heated to 225°C and then cooled back to 25°C, some slight changes were observed in the XRPD pattern as the solvent was driven off (FIG. 24). Other differences between various Form C samples include thermal analysis. A sample of Form C from methyl acetate was analyzed by DSC and TGA-IR, but did not show the desolvation endotherm in the DSC. However, residual ethyl acetate was detected as shown in FIG. 25.

Example 16: Comparison of Odalasvir Form A, Form B, and Form C

The XRPD data for Form A, Form B, and Form C are summarized in Table 4 below.

Table 4. XRPD Peak Table for Odalasvir Form A, Form B, and Form C

All values are in degrees two-theta. The ten most intense peaks (1= high intensity) for each Form are provided. *Form B was partially crystalline with only three distinguishable peaks. The three Forms have distinctly different fingerprints as shown in the overlay of XRPD graphs (FIG. 26).

Example 17. Relative Stability

The polymorph screen produced three different types of crystal Forms: a dihydrate (Form A), a partially crystalline mixed methanol/water solvate (Form B), and a class of structurally similar solvates (Form C). Experiments were performed to give relative stability information between Form B/ Form A and Form CI Form A at specific conditions.

Example 18. Relative Stability of Form B vs. Form A at 25 °C

A slurry containing Form B in methanol/ 10 vol% water was seeded with Form A and stirred at 25°C. A sample analyzed by FT-Raman after six days indicated complete conversion to Form A. Form A is more stable than Form B in the given conditions at 25°C. This is also supported by the crystalline Form A slurry experiments. When Form A was used as an input material and thermo-cycled in methanol or methanol/10 vol% water, Form A was returned. The process utilizes a hot methanol crystallization to produce Form A from the crude API which contains water from a prior sodium hydroxide wash. Relative stability experiments were not conducted at higher temperatures. However, with the presence of water to maintain a moderate level of water activity and the partial crystallinity and stability of Form B, the risk of formation of Form B in the process at higher temperatures is likely minimal.

Example 19. Relative Stability of Form C vs. Form A

A slurry containing Form C in acetone/10 vol% water was seeded with Form A and stirred at 25 °C. A sample analyzed by FT-Raman after six days indicated the slurry remained as Form C. The sample was then heated to 50 °C for 2 days and as analyzed by Raman IR, the sample had completely converted to Form A. Form A is more stable than Form C at 50 °C in acetone/10 vol% water. Heating a slurry of Form C to 50 °C likely destabilizes the solvate and converts it to the crystalline Form A. The sample studied contained 10% water and dihydrate formation was likely favored.

Example 20. Additional Preparation of Odalasvir Dihydrate

Step 1 : Preparation of di-tert-Butyl (2^,3a^,7a^,2 ,3a ,7a'5)-2,2'-[tricyclo[8.2.2.2⁴'⁷]hexadeca- 1 ( 12),4,6, 10, 13 , 15-hexaene-5, 11 -diylbis( lH-benzimidazole-6,2-diyl)]bisoctahydro- lH-indole- 1 - carboxylate.

fert-Butyl (2S,3aS,7aS)-2-[6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- benzimidazol-2-yl]octahydro-lH-indole-l -carboxylate and pseudo-para-5,11- dibromotricyclo[8.2.2.2⁴'⁷]hexadeca-l(12),4,6,10, 13,15-hexaene can be prepared as described in U.S Patent No.: 8,809,313 to Wiles et al.

fert-Butyl (2£,3aSJaS)-2-[6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- benzimidazol-2-yl]octahydro-lH-indole-l -carboxylate was coupled with pseudo-para-5, 11- dibromotricyclo[8.2.2.2⁴'⁷]hexadeca-l(12),4,6,10, 13,15-hexaene in the presence of a palladium catalyst, such as Pd(PPh₃)4, and cesium carbonate in aqueous dimethyl sulfoxide (DMSO) as the solvent. After completion of the reaction, the reaction mixture was added to water, and the precipitated product was isolated and washed with water and acetonitrile. Subsequently, the crude product was dissolved in dichloromethane and the organic layer was separated and washed with water. Then, the dichloromethane was chased out with methanol and acetonitrile, which was followed by the addition of acetonitrile. The resulting precipitate was isolated, washed with acetonitrile, and dissolved in a dichloromethane/methanol mixture. A solvent switch to ^-heptane was performed and the crystallized product was isolated, washed with ^-heptane, and dried. Step 2. Preparation of 6,6'-Tricyclo[8.2.2.2⁴'⁷]hexadeca-l(12),4,6, 10,13, 15-hexaene-5, l l- diylbis[2-[(2,S',3a₎S',7a₎S)-octahydro-lH-indol-2-yl]-lH-benzimidazole] tetrahydrochloride.

To di-fert-butyl (2^,3a^,7a^,2 ,3a ,7a'5)-2,2'-[tricyclo[8.2.2.2⁴'⁷]hexadeca-

1 ( 12),4,6, 10, 13 , 15-hexaene-5, 11 -diylbis( lH-benzimidazole-6,2-diyl)]bisoctahydro- lH-indole- 1 - carboxylate in dichloromethane and methanol, a solution of hydrogen chloride in 1,4-dioxane was added. After completion of the reaction, a solvent switch to methanol was performed. Subsequently, the precipitate was isolated, washed with methanol, and dried. Optionally, the precipitate was then treated with dichloromethane, isolated, washed with dichloromethane, and dried.

Step 3. Preparation of the Dihydrate of methyl [(2S)-\-[(2S,3aS,7aS)-2-[6-[\ l-[2-[(2^,3a^,7a5)-l- [(2,S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl]octahydro-lH-indol-2-yl]-lH- benzimidazol-6-yl]tricyclo[8.2.2.2⁴'⁷]hexadeca-l(12),4,6,10, 13,15-hexaen-5-yl]-lH- benzimidazol-2-yl]octahydro- lH-indol- 1 -yl]-3 -methyl- 1 -oxobutan-2-yl]carbamate.

To N-(methoxycarbonyl)-L-valine and l-[bis(dimethylamino)methylene]-lH- benzotriazol-l-ium 3-oxide tetrafluorob orate (TBTU) in dichloromethane, 6,6'- tricyclo[8.2.2.2⁴'⁷]hexadeca-l(12),4,6, 10,13, 15-hexaene-5, l l-diylbis[2-[(2^,3a^,7a5)-octahydro- lH-indol-2-yl]-lH-benzimidazole] tetrahydrochloride was added. Subsequently, N-ethyl-N- isopropylpropan-2-amine (DIPEA) was added slowly to the reaction mixture. After completion of the reaction, dichloromethane was added and the mixture was washed with an aqueous solution of sodium chloride and sodium hydroxide to remove traces of lH-benzotriazol-l-ol (HOBt) and N- (methoxycarbonyl)-L-valine. Subsequently, the mixture was washed consecutively with water, aqueous citric acid solution, water, aqueous sodium hydrogen carbonate solution, and water. After the mixture was partially concentrated, a solvent switch to methanol was performed and the crystallized product was isolated, washed with methanol, and dried. Optionally, the crystallization from methanol may be repeated if required to meet the acceptance criteria, and/or the product may be recrystallized from dichloromethane/methanol, isolated, washed with methanol, and dried. The product was obtained as the dihydrate. Ex mple 21. Recrystallization of Odalasvir Dihydrate

EasyMax laboratory reactors (Mettler Toledo, USA) equipped with 100 mL vessels were charged with Odalasvir dihydrate and THF at a ratio of 1 mol Odalasvir dihydrate/2.766 L THF. The reactions were stirred at 250 to 350 rpm using Agitators equipped with four-blade 451 angle impellers and heated to 40 °C for about 20 to 30 minutes or until the Odalasvir dihydrate was dissolved. Methanol (0.9605 LMeOH/ Odalasvir dihydrate) was added over a 10 minute period and the reactions were stirred for an additional 5 to 10 minutes. The reactions were seeded with 3wt% of Odalasvir dihydrate (0.031kg/mol API) at 40 °C and secondary nucleation appeared. The reactions were stirred for an additional 20 minutes. Methanol (6.264 LMeOH/mol Odalasvir dihydrate) was added according to Table 5 using a non-linear profile over 2-3 hours.

Table 5. Methanol added to Reaction Vessel using a Non-linear Profile over 2-3 Hours

20 1.253 0.313 1.75

25 1.566 0.313 1.9

30 1.879 0.313 2.02

35 2.192 0.313 2.11

40 2.506 0.313 2.19

45 2.819 0.313 2.24

50 3.132 0.313 2.29

60 3.758 0.626 2.36

70 4.385 0.626 2.41

80 5.011 0.626 2.45

90 5.638 0.626 2.48

100 6.264 0.626 2.5

The suspensions were heated to 60 °C over a 60 minute period. The reactions were cooled to 5 °C over a 120 minute period. The reactions were stirred at 5 °C for 90-120 minutes and filtered at the lab temperature. The products were washed once with methanol (2.3051 LMeOH/mol API), once with 80/20 methanol/water (2.3051 L H₂0 /mol API), and dried at 45-50 °C with a trace of water in the oven for 24 hours. The products were sampled and the solid Form was analyzed by XRD. The water content was determined by KF. The residual solvent content of MeOH and TUF were determined by GC head space (GCHS). Drying of the product was complete when the residual MeOH concentration was below 50 ppm and the water content was between 2.9-3.7 wt%. (Theoretical yield 93-96%)

Example 22. Characterization of Odalasvir Dihydrate

Odalasvir dihydrate was characterized with DSC, TGA, XRDP, IR, and DVS. The DSC (FIG. 31) showed a broad endotherm due to the loss of the crystalline water (dihydrate) and the resulting collapse of the product. The glass transition of the amorphous material corresponded to a signal at approximately 200 °C. Decomposition began at about 250 °C. A heat-to-cool experiment (FIG. 32) was performed to further investigate the collapsing of the product. The first heating cycle showed the DSC curve as shown in FIG. 31. During the cooling cycle, the signal at about 193 °C can be attributed to the glass transition. Heating cycle 2 showed only the glass transition temperature of Odalasvir dihydrate at 200 °C. An amorphous material is formed due to the collapsing of the crystal lattice as this material transitions from a glassy to a rubbery state. The modulated DSC (FIG. 36) showed Tg at 200 °C. The TGA (FIG. 33) showed a weight loss of 3.5% (room temperature - 150 °C) corresponding to the release of the dihydrate. The TGA also showed that degradation starts at + 250 °C. The DVS isotherm plot (FIG. 34) and the DVS kinetic plot (FIG. 35) showed that the dihydrate was slightly hygroscopic (+ 1% water at high relative humidity). The XRPD (FIG. 29) showed diffraction peaks without the presence of a halo, indicating that Odalasvir was present as a crystalline product. The XRPD was performed on the product before and directly after the adsorption desorption cycles of the DVS experiment (FIG. 30), and the XRPD confirmed that the product remained crystalline after exposure to high humidity. The IR (FIG. 27) reflected the vibrational modes of Odalasvir dihydrate. The IR (FIG. 28) was performed before and after the adsorption desorption cycles in the DVS experiment, and the IR in both cases was comparable.

Example 23. Preparation of ODV Spray-dried Product (SDP)

Acetone is transferred into a suitable container and stirred using a suitable mixer. While stirring, copovidone is added into the container. The mixture is stirred until dissolved. The poloxamers are added to the solution with stirring. The mixture is stirred until dissolved. Form A, Form B, or Form C Odalasvir dihydrate is added with stirring to the solution. The mixture is stirred until dissolved. The mixture is spray dried with spray solution using a suitable spray dryer and the resulting spray dry product is collected in a suitable container. The spray dried product is dried in a suitable dryer. The SDP is collected and packaged in a suitable container.

Example 24. A Fixed Dose Combination of ODV, Simeprevir, and AL-335

PCT/US2016/54561 describes a composition, including the fixed-dose composition, of Odalasvir, AL-335 (an NS5B inhibitor), and Simeprevir (a NS3/4A protease inhibitor).

Simeprevir AL-335

In one embodiment, the process for manufacturing a fixed-dose combination of ODV, Simeprevir, and AL-335 includes blending Simeprevir spray dried product, Odalasvir spray dried product, Compound III, croscarmellose sodium and silicified microcrystalline cellulose. Magnesium stearate is added and blended and the product is compressed into tablets and packaged.

This specification has been described with reference to embodiments of the invention. However, one of ordinary skill in the art appreciates that various modifications and changes can be made without departing from the scope of the invention as set forth in the claims below. Accordingly, the specification is to be regarded in an illustrative rather than a restrictive sense, and all such modifications are intended to be included within the scope of invention.

Claims

What is claimed is:

1. Isolated crystalline Odalasvir dihydrate Form A characterized by an X-ray powder diffraction (XRPD) pattern comprising at least the 2 Theta values of 3.7° and 13.5°.

2. The crystalline Odalasvir dihydrate Form A of claim 1, wherein the XRPD pattern further comprises at least two 2 Theta values selected from 7.5°, 10.8°, 13.7°, 15.3°, 16.4°, 19.5°, 19.8°, and 22.8°.

3. The crystalline Odalasvir dihydrate Form A of claim 1 that has a differential scanning calorimetry (DSC) onset endotherm of about 96 °C.

4. The crystalline Odalasvir dihydrate Form A of claim 1 produced by recrystallization from methanol.

5. A pharmaceutical composition comprising the crystalline Odalasvir dihydrate Form A of any one of claims 1-4 and a pharmaceutically acceptable excipient.

6. Odalasvir Form B methanol/water solvate characterized by an X-ray powder diffraction (XRPD) pattern comprising at least the 2 Theta values of 3.4° and 6.9°.

7. The Odalasvir Form B methanol/water solvate of claim 6, wherein the XRPD pattern further comprises the 2 Theta values of 3.4°, 6.9°, 10.3°.

8. The Odalasvir Form B methanol/water solvate of claim 6, that has a differential scanning calorimetry (DSC) onset endotherm of about 59 °C.

9. A pharmaceutical composition comprising the Odalasvir Form B methanol/water solvate of any one of claims 6-8 and a pharmaceutically acceptable excipient.

10. Isolated Odalasvir Form C solvate characterized by an X-ray powder diffraction (XRPD) pattern comprising at least the 2theta values of 7.7° and 12.9°.

11. The Odalasvir Form C solvate of claim 10, wherein the XRPD pattern further comprises at least two 2theta values selected from 4.2°, 8.2°, 8.6°, 10.9°, 15.5°, 18.2°, 18.2°, and 25.2°.

12. The Odalasvir Form C solvate of claim 10 that has a differential scanning calorimetry (DSC) onset endotherm of about 234 °C.

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13. A pharmaceutical composition comprising the Odalasvir Form C solvate of any one of claims 10-12 and a pharmaceutically acceptable excipient.

14. Use of the crystalline Odalasvir dihydrate Form A of any one of claims 1-4 in the manufacture of a medicament for treatment of a hepatitis C virus infection in a host in need thereof.

15. The crystalline Odalasvir dihydrate Form A of any one of claims 1-4 for use in the treatment of a hepatitis C virus infection in a host.

16. The crystalline Odalasvir dihydrate Form A of claim 15, wherein the host is a human.

17. Use of Odalasvir Form B methanol/water solvate of any one of claims 6-8 in the manufacture of a medicament for treatment of a hepatitis C virus infection in a host in need thereof.

18. Odalasvir Form B methanol/water solvate of any one of claims 6-8 for use in the treatment of a hepatitis C virus infection in a host.

19. The Odalasvir Form B methanol/water solvate of claim 18, wherein the host is a human.

20. Use of Odalasvir Form C solvate of any one of claims 10-12 in the manufacture of a medicament for treatment of a hepatitis C virus infection in a host in need thereof.

21. Odalasvir Form C solvate of any one of claims 10-12 for use in the treatment of a hepatitis C virus infection in a host.

22. The Odalasvir Form C solvate of claim 21, wherein the host is a human.

23. The use of any one of claims 14, 17, or 20, wherein the host is a human.

24. A method for the treatment of a host infected with hepatitis C virus, comprising administering the crystalline Odalasvir dihydrate Form A of any one of claims 1-4.

25. A method for the treatment of a host infected with hepatitis C virus, comprising administering the Odalasvir Form B methanol/water solvate of any one of claims 6-8.

26. A method for the treatment of a host infected with hepatitis C virus, comprising administering the Odalasvir Form C solvate of any one of claims 10-12.

27. The method of any one claim 24-26, wherein the host is a human.

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28. A spray-dry dispersion made from crystalline Odalasvir dihydrate Form A.

29. The spray-dry dispersion of claim 28 that contains 10 mg to 50 mg of Odalasvir.

30. The spray-dry dispersion of claim 28 that contains 25 mg of Odalasvir.

31. The spray-dry dispersion of claim 28 that contains 12.5 mg of Odalasvir.

32. A method for the manufacture of the spray-dry dispersion of any of claims 28-31.

33. A pharmaceutical composition comprising the spray-dry dispersion of any one of claims 28-31 in a pharmaceutically acceptable carrier.

34. Use of the spray-dry dispersion of any one of claims 28-31 in the manufacture of a medicament for treatment of a hepatitis C virus infection in a host in need thereof.

35. The use of claim 34, wherein the host is a human.

36. The spray-dry dispersion of any one of claims 28-31 for use in the treatment of a hepatitis C virus infection in a host.

37. The spray-dry dispersion of claim 36, wherein the host is a human.

38. A method for the treatment of a host infected with hepatitis C virus, comprising administering the spray-dry dispersion of any one of claims 28-31.

39. The method of claim 38, wherein the host is a human.

40. A method for manufacturing a dosage form comprising a spray-dry dispersion of any one of claims 28-31.

41. The method of claim 40, wherein the dosage form further comprises a compound or pharmaceutically acceptable salt thereof of Simprevir and AL-335:

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The method of claim 40, wherein Simeprevir is present in the dosage form as a spray-dried

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