WO2012080050A1

WO2012080050A1 - Solid forms of a phenoxybenzenesulfonyl compound

Info

Publication number: WO2012080050A1
Application number: PCT/EP2011/072020
Authority: WO
Inventors: Michael Thomas Brandl; Jeffrey Allen Campbell; Lawrence Emerson Fisher; Alfred Paul Spada
Original assignee: F. Hoffmann-La Roche Ag; Conatus Pharmaceuticals Inc.
Priority date: 2010-12-14
Filing date: 2011-12-07
Publication date: 2012-06-21

Abstract

Provided herein are solid forms of 4-[4-(4-chlorophenoxy)-benzenesulfonyl-methyl]- tetrahydropyran-4-carboxylic acid hydroxyamide, processes of preparation and pharmaceutical compositions thereof. Also provided are methods of their use for the treatment of a liver disease.

Description

SOLID FORMS OF A PHENOXYBENZENESULFONYL COMPOUND

Provided herein are solid forms of 4-[4-(4-chlorophenoxy)-benzenesulfonyl-methyl]- tetrahydropyran-4-carboxylic acid hydroxyamide, processes of preparation and pharmaceutical compositions thereof. Also provided are uses for the treatment of a liver disease.

4-[4-(4-chlorophenoxy)-benzenesulfonyl-methyl]-tetrahydropyran-4-carboxylic acid

hydroxyamide is characterized by formula:

It is well established that different polymorphs of the same chemical substance can have substantial impact on its oral bioavailability, and hence its therapeutic efficacy and safety profile. Additionally, different polymorphs often exhibit different solubility and stability that can impact the manufacturability and stability of a drug product. As such, it is essential to develop a controlled process for reliable preparation of a selected polymorph for a drug substance.

The preparation and selection of a solid form of a pharmaceutical compound is complex, given that a change in solid form may affect a variety of physical and chemical properties of the compound, such as its processability, stability, and bioavailability. Potential pharmaceutical solids include crystalline and amorphous solids. Amorphous solids are characterized by a lack of long-range structural order, whereas crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solid depends upon the specific application; amorphous solids are sometimes selected on the basis of, e.g., an enhanced dissolution profile, while crystalline solids may be desirable for properties such as, e.g., physical or chemical stability.

See, Vippagunta et al., Adv. Drug. Deliv. Rev. 2001, 48, 3-26; and Yu, Adv. Drug. Deliv. Rev. 2001, 48, 27-42.

Whether crystalline or amorphous, potential solid forms of a pharmaceutical compound include single-component and multiple-component solids. Single-component solids consist essentially of the pharmaceutical compound in the absence of other compounds. Variety among single- component crystalline materials may potentially arise, e.g., from the phenomenon of polymorphism, wherein multiple three-dimensional arrangements exist for a particular pharmaceutical compound. See, e.g., Byrn et ah, Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette. The importance of studying polymorphs was underscored by the case of Ritonavir, an HIV protease inhibitor that was formulated as soft gelatin capsules. About two years after the product was launched, the unanticipated precipitation of a new, less soluble polymorph in the formulation necessitated the withdrawal of the product from the market until a more consistent formulation could be developed. See, Chemburkar et ah, Org. Process Res. Dev. 2000, 4, 413-417. Additional diversity among the potential solid forms of a pharmaceutical compound may arise, e.g., from the possibility of multiple-component solids. Crystalline solids comprising two or more ionic species may be termed salts {see, e.g., Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, Eds., (2002), Wiley, Weinheim). Additional types of multiple-component solids that may potentially offer other property improvements for a pharmaceutical compound or salt thereof include, e.g., hydrates, solvates, co-crystals, and clathrates, among others {see, e.g., S. R. Byrn et ah, Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette). Moreover, multiple-component crystal forms may potentially be susceptible to polymorphism, wherein a given multiple-component composition may exist in more than one three-dimensional crystalline arrangement. Therefore, the preparation of solid forms is of great importance in the development of a safe, effective, stable and marketable pharmaceutical compound.

Liver disease is an acute or chronic damage to the liver, usually caused by infection, injury, exposure to drugs or toxic compounds, alcohol, impurities in foods, and the abnormal build-up of normal substances in the blood, an autoimmune process, or by a genetic defect (such as haemochromatosis). Sometimes the exact cause of the injury may not be known. Liver disease can be classified as acute or chronic liver disease based in the duration of the disease. In acute liver disease, such as acute hepatitis and acute liver failure (ALF), the history of the disease does not exceed six months. Liver diseases of longer duration are classified as chronic liver disease.

The common liver diseases include cirrhosis, liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic ischemia reperfusion injury, primary biliary cirrhosis (PBC), and hepatitis, including viral and alcoholic hepatitis. Most common forms of viral hepatitis are hepatitis B and C (HBV and HCV, respectively). Chronic hepatitis may result in cirrhosis. Chronic hepatitis B and/or chronic hepatitis C may lead to liver cancer (hepatocellular carcinoma, HCC). Cirrhosis caused by chronic hepatitis C infection accounts for 8,000-12,000 deaths per year in the United States, and HCV infection is the leading indication for liver transplantation. The death of liver cells through a process known as apoptosis is common in all forms of liver disease. Apoptosis of liver cells is linked to liver fibrosis and other liver disease. Prevention of excessive apoptosis liver cells is an important component in the treatment of acute and chronic liver disease (Guicciardi et al., Gut 2005, 54, 1024-1033; and Ghavami et al., Med. Sci. Monit. 2005, 11, RA337-345). The presence of active liver disease is often detected by the existence of elevated enzyme levels in the blood. Specifically, blood levels of ALT (alanine aminotransferase) and AST (aspartate aminotransferase), above clinically accepted normal ranges, are known to be indicative of ongoing liver damage. Routine monitoring of liver disease patients for blood levels of ALT and AST is used clinically to measure progress of the liver disease while on medical treatment. Reduction of elevated ALT and AST to within the accepted normal range is taken as clinical evidence reflecting a reduction in the severity of patient's on-going liver damage (Kim et al., Hepatology 2008, 47, 1363-1370).

In light of the fact that liver diseases affect a large patient population worldwide, and has tragic effects on the affected patient, there remains a strong need to provide new effective

pharmaceutical agents to treat liver diseases.

Provided herein are solid forms of a phenoxybenzenesulfonyl compound, 4-[4-(4- chlorophenoxy)-benzenesulfonyl-methyl]-tetrahydropyran-4-carboxylic acid hydroxyamide. In one embodiment, the solid form is crystalline Form A of 4-[4-(4-chlorophenoxy)- benzenesulfonyl-methyl]-tetrahydropyran-4-carboxylic acid hydroxyamide. In another embodiment, the solid form is crystalline Form B of 4-[4-(4-chlorophenoxy)-benzenesulfonyl- methyl]-tetrahydropyran-4-carboxylic acid hydroxyamide. In yet another embodiment, the solid form is amorphous 4-[4-(4-chlorophenoxy)-benzenesulfonyl-methyl]-tetrahydropyran-4- carboxylic acid hydroxyamide.

Also provided herein is a crystalline form of a phenoxybenzenesulfonyl compound, 4-[4-(4- chlorophenoxy)-benzenesulfonyl-methyl] -tetrahydropyran-4-carboxylic acid hydroxyamide. one embodiment, the crystalline form is unsolvated. In another embodiment, the crystalline form is solvated. In yet another embodiment, the crystalline form is a single-component crystalline form.

Further provided herein is a pharmaceutical composition, which comprises a solid form, e.g. , Form A, B, or an amorphous form, of 4-[4-(4-chlorophenoxy)-benzenesulfonyl-methyl]- tetrahydropyran-4-carboxylic acid hydroxyamide, and a pharmaceutically acceptable carrier.

Additionally provided herein is a method of treating or preventing a liver disease in a subject, which comprises administering to the subject a therapeutically effective amount of a solid form, e.g., Form A, B, or an amorphous form, of 4-[4-(4-chlorophenoxy)-benzenesulfonyl-methyl]- tetrahydropyran-4-carboxylic acid hydroxyamide.

In one embodiment, the liver disease is an acute and/or chronic liver disease. In certain embodiments, the liver disease is one resulted from an injury to the liver. In certain

embodiments, injury to the liver is caused by toxins, alcohol, some drugs, impurities in foods, and the abnormal build-up of normal substances in the blood. In certain embodiments, the injury to the liver is caused by infection or an autoimmune disorder. In certain embodiments, the exact cause of the injury to the liver is not known. In certain embodiments, the liver disease resulting from an injury to the liver include, but is not limited to, fatty liver, cirrhosis, primary biliary cirrhosis, primary sclerosing cholangitis, and al-antitrypsin deficiency.

In another embodiment, the liver disease includes, but is not limited to, cirrhosis, liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic ischemia reperfusion injury, hepatitis (viral and/or alcoholic hepatitis), hepatitis A, hepatitis B, hepatitis C, and primary biliary cirrhosis (PBC).

Provided herein is a method for treating a liver disease in a subject who has failed therapy for the liver disease, which comprises administering to the subject a therapeutically effective amount of a polymorph, e.g. , Form A, B, or an amorphous form, of 4-[4-(4-chlorophenoxy)- benzenesulfonyl-methyl]-tetrahydropyran-4-carboxylic acid hydroxyamide. In certain embodiments, the liver disease is hepatitis, hepatitis B, hepatitis C, or hepatitis D.

Provided herein is a method for reducing liver damage associated with a liver disease in a subject, which comprises administering to the subject a therapeutically effective amount of a solid form, e.g. , Form A, B, or an amorphous form, of 4-[4-(4-chlorophenoxy)-benzenesulfonyl- methyl] -tetrahydropyran-4-carboxylic acid hydroxyamide.

Provided herein is a method for treating or preventing an HCV infection, which comprises administering to a subject a therapeutically effective amount of a solid form, e.g. , Form A, B, or an amorphous form, of 4-[4-(4-chlorophenoxy)-benzenesulfonyl-methyl]-tetrahydropyran-4- carboxylic acid hydroxyamide.

Provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a liver disease or disorder associated with an HCV infection, comprising administering to a subject a therapeutically effective amount of a solid form, e.g. , Form A, B, or an amorphous form, of 4- [4-(4-chlorophenoxy)-benzenesulfonyl-methyl]-tetrahydropyran-4-carboxylic acid

hydroxyamide.

Provided herein is a method for inhibiting replication of a virus in a host, which comprises administering to the host an effective amount of a solid form, e.g. , Form A, B, or an amorphous form, of 4-[4-(4-chlorophenoxy)-benzenesulfonyl-methyl]-tetrahydropyran-4-carboxylic acid hydroxyamide. In one embodiment, the methods provided herein reduce liver damage associated with a chronic and/or acute liver disease. In another embodiment, the methods provided herein lower elevated levels of liver enzymes, such as elevated levels of ALT (alanine aminotransferase) and/or AST (aspartate aminotransferase) levels.

In one embodiment, the solid form, e.g., Form A, B, or an amorphous form, of 4-[4-(4- chlorophenoxy)-benzenesulfonyl-methyl]-tetrahydropyran-4-carboxylic acid hydroxyamide, is used as therapeutically active substance.

One embodiment provides the use of a solid form, e.g. , Form A, B, or an amorphous form, of 4- [4-(4-chlorophenoxy)-benzenesulfonyl-methyl]-tetrahydropyran-4-carboxylic acid

hydroxyamide, as therapeutically active substance for the treatment or prophylaxis of a liver disease in a subject.

hydroxyamide, for the treatment or prophylaxis of a liver disease in a subject.

One embodiment provides the use of a solid form, e.g. , Form A, B, or an amorphous form, of 4- [4-(4-chlorophenoxy)-benzenesulfonyl-methyl]-tetrahydropyran-4-carboxylic acid hydroxyamide, for preparation of a medicament for the treatment or prophylaxis of a liver disease in a subject.

One embodiment provides a solid form, e.g. , Form A, B, or an amorphous form, of 4-[4-(4- chlorophenoxy)-benzenesulfonyl-methyl]-tetrahydropyran-4-carboxylic acid hydroxyamide, for use in the treatment or prophylaxis of a liver disease in a subject.

Provided herein is a method of preparing a solid form, e.g. , Form A, B, or an amorphous form, of 4-[4-(4-chlorophenoxy)-benzenesulfonyl-methyl]-tetrahydropyran-4-carboxylic acid

hydroxyamide. FIG. 1 depicts an X-ray powder diffractogram (XRPD) of 4-[4-(4-chlorophenoxy)- benzenesulfonyl-methyl]-tetrahydropyran-4-carboxylic acid hydroxyamide in Form A.

FIG. 2 depicts an X-ray powder diffractogram (XPRD) of 4-[4-(4-chlorophenoxy)- benzenesulfonyl-methyl]-tetrahydropyran-4-carboxylic acid hydroxyamide in crystalline Form B. FIG. 3 depicts an X-ray powder diffractogram (XPRD) of 4-[4-(4-chlorophenoxy)- benzenesulfonyl-methyl]-tetrahydropyran-4-carboxylic acid hydroxyamide in an amorphous form.

To facilitate understanding of the disclosure set forth herein, a number of terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The term "subject" refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject, in one embodiment, a human. The term "host" refers to a unicellular or multicellular organism in which a virus can replicate, including, but not limited to, a cell, cell line, and animal, such as human.

The terms "treat," "treating," and "treatment" are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.

The terms "prevent," "preventing," and "prevention" are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.

The term "therapeutically effective amount" are meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term

"therapeutically effective amount" also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.

The term "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is

"pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The

Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of

Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007;

Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009. The term "about" or "approximately" means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or

"approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

The terms "active ingredient" and "active substance" refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease. As used herein, "active ingredient" and "active substance" may be an optically active isomer or an isotopic variant of a compound described herein.

The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease. The term "solid form", when used to refer to a compound(s), is intended to mean a physical form of the compound(s) which is not predominantly in a liquid or a gaseous state. A crystalline form and amorphous form of a compound(s) are examples of solid forms of the compound(s).

The term "crystalline", when used to describe a substance, component, or product, means that the substance, component, or product is substantially crystalline as determined by X-ray diffraction. See, e.g., Remington: The Science and Practice of Pharmacy, 20th ed.; page 173; Lippincott Williams & Wilkins: Philadelphia, PA, 2000; The United States Pharmacopeia, 26th ed.; pages 2233-2234; 2003.

The term "crystalline form" or "crystal form" refers to a crystalline solid form of a chemical compound, including, but not limited to, a single-component or multiple-component crystal form, e.g., a polymorph of a compound; or a solvate, hydrate, clathrate, a cocrystal, a salt of a compound, or a polymorph thereof.

The term "polymorph" or "polymorphic form" refers to two or more crystal forms that comprise the same compound(s). Different polymorphs may have different physical properties such as, for example, melting temperatures, heats of fusion, solubilities, dissolution rates, and/or vibrational spectra as a result of the arrangement or conformation of the molecules of the compound(s) in the crystal lattice. The differences in physical properties exhibited by polymorphs may affect pharmaceutical parameters, such as storage stability, compressibility, density, and dissolution rate. Differences in storage stability can result from changes in chemical reactivity (e.g. , differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e.g. , tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph), or both (e.g. , tablets of one polymorph are more susceptible to breakdown at high humidity). As a result of solubility/dissolution differences, in the extreme case, some polymorphic transitions may result in lack of potency or, at the other extreme, toxicity. In addition, the physical properties of a crystalline form may be important in processing; for example, one polymorph might be more likely to form solvates or might be difficult to filter and wash free of impurities (e.g. , particle shape and size distribution might be different between polymorphs).

The term "solvate" and "solvated" refers to a crystalline form of a substance which contains solvent. The term "hydrate" and "hydrated" refer to a solvate, wherein the solvent is water.

The term "polymorphs of solvate" refers to the existence of more than one crystalline form for a particular solvate composition. Similarly, the term "polymorphs of hydrate" refers to the existence of more than one crystalline form for a particular hydrate composition.

The term "amorphous" or "amorphous form" is intended to mean that the substance, component, or product in question is not substantially crystalline as determined by X-ray diffraction. In certain embodiments, a sample comprising an amorphous form of a substance may be substantially free of other amorphous forms and/or crystalline forms.

As used herein, a solid form (e.g. , a crystal form or amorphous form) that is "substantially pure" may comprise, in certain embodiments, less than about 20%, 15%, 10%, 5%, 3%, 2%, 1%, 0.75%, 0.5%, 0.25%, or 0.1% by weight of one or more other crystal forms, amorphous forms, and/or chemical compounds. In certain embodiments, a solid form that is substantially pure is substantially free of one or more other particular crystal forms, amorphous forms, and/or chemical compounds.

Solid Forms of a Phenoxybenzenesulfonyl Compound In one embodiment, provided herein is a solid form of a phenoxybenzenesulfonyl compound, 4- [4-(4-chlorophenoxy)-benzenesulfonyl-methyl]-tetrahydropyran-4-carboxylic acid hydroxyamide ("the phenoxybenzenesulfonyl compound"), which has the structure of:

The phenoxybenzenesulfonyl compound can be prepared according to the procedures as described in U.S. Pat. No. 5,932,595; 6,342,639; 6,420,537; or 6,518,460; the disclosure of each of which is incorporated herein by reference in its entirety.

In one embodiment, provided herein is a crystalline form of the phenoxybenzenesulfonyl compound. In certain embodiments, the crystalline form is unsolvated. In certain embodiments, the crystalline form is solvated. In one embodiment, the crystalline form is a single-component crystalline form of the phenoxybenzenesulfonyl compound. In another embodiment, the crystalline form is a multiple- component crystalline form of the phenoxybenzenesulfonyl compound. In certain embodiment, the multiple-component crystalline form is a solvate of the phenoxybenzenesulfonyl compound.

A. Form A of the Phenoxybenzenesulfonyl Compound In one embodiment, provided herein is crystalline Form A of 4-[4-(4-chlorophenoxy)- benzenesulfonyl-methyl]-tetrahydropyran-4-carboxylic acid hydroxyamide. In one embodiment, the crystalline Form A is a single-component crystalline form of 4-[4-(4-chlorophenoxy)- benzenesulfonyl-methyl] -tetrahydropyran-4-carboxylic acid hydroxyamide.

In certain embodiments, the crystalline Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 1. In certain embodiments, the crystalline Form A has a characteristic XRP diffraction peak at a two-theta angle of approximately 3.5, 13.3, 15.7, 16.7, 17.4, 18.8, 19.4, 21.3, 21.6, 21.9, 22.5, 22.8, 25.4, 26.3, 26.9, 27.5, 29.8, 30.9, 32.4, 33.9, 35.1, 36.1, 36.7, 37.2, or 38.8. In certain embodiments, the crystalline Form A has characteristic XRP diffraction peaks at two-theta angles of approximately 3.5, 15.7, 16.7, 17.4, 19.4, 21.3, 21.6, 21.9, 26.3, 26.9, and 29.8. In certain embodiments, the crystalline Form A has characteristic XRP diffraction peaks at two-theta angles of approximately 3.5, 13.3, 15.1, 15.7, 16.3, 16.7, 17.4, 18.7, 18.8, 19.4, 20.0, 20.5, 21.3, 21.6, 21.9, 22.5, 22.8, 23.4, 25.4, 26.3, 26.9, 27.5, 28.2, 29.0, 29.8, 30.5, 30.9, 32.4, 33.9, 34.9, 35.1, 36.1, 36.7, 37.2, and 38.8.

In certain embodiments, the crystalline Form A has an endotherm with an onset temperature of about 149 °C in a DSC thermogram. In certain embodiments, the crystalline Form A has an endotherm with a peak temperature of about 150 °C in a DSC thermogram. In certain embodiments, the crystalline Form A is non-hygroscopic. In certain embodiments, the crystalline Form A exhibits no greater than about 2%, no greater than about 1%, no greater than about 0.4%, no greater than about 0.2%, or no greater than about 0.1% weight gain upon equilibrium at about 11% RH for 8 weeks. In certain embodiments, the crystalline Form A exhibits no greater than about 2%, no greater than about 0.1%, no greater than about 0.4%, no greater than about 0.2%, or no greater than about 0.1% weight gain upon equilibrium at about 51% RH for 8 weeks. In certain embodiments, the crystalline Form A exhibits no greater than about 1%, no greater than about 0.5%, no greater than about 0.4%, no greater than about 0.3%, or no greater than about 0.25% weight gain upon equilibrium at about 93% RH for 8 weeks. In certain embodiments, the crystalline Form A exhibits about no greater than 0.1% weight gain upon equilibrium at about 11% RH for 8 weeks. In certain embodiments, the crystalline Form A exhibits about 0.1% weight gain upon equilibrium at about 51% RH for 8 weeks In certain embodiments, the crystalline Form A exhibits about 0.25% weight gain upon equilibrium at about 93% RH for 8 weeks.

In certain embodiments, the crystalline Form A exhibits no greater than about 10%, no greater than about 5%, no greater than about 4%, no greater than about 3%, or no greater than about 2% weight loss upon equilibrium at about 11% RH for 8 weeks. In certain embodiments, the crystalline Form A exhibits no greater than about 5%, no greater than about 2%, no greater than about 1%, no greater than about 0.5%, or no greater than about 0.4% weight loss upon equilibrium at about 51% RH for 8 weeks. In certain embodiments, the crystalline Form A exhibits no greater than about 0.5%, no greater than about 0.2%, or no greater than about 0.1% weight loss upon equilibrium at about 93% RH for 8 weeks. In certain embodiments, the crystalline Form A exhibits about no greater than 2% weight loss upon equilibrium at about 11% RH for 8 weeks. In certain embodiments, the crystalline Form A exhibits no greater than 0.4% weight loss upon equilibrium at about 51% RH for 8 weeks. In certain embodiments, the crystalline Form A exhibits no greater than 0.1% weight loss upon equilibrium at about 93% RH for 8 weeks. In certain embodiments, the crystalline Form A exhibits desirable characteristics for the synthesis, processing, and/or manufacture of a drug product containing the

phenoxybenzenesulfonyl compound. In certain embodiments, the phenoxybenzenesulfonyl compound in crystalline Form A surprisingly has an advantageous stability profile, which is an important characteristic for processing and manufacturing of a drug product. In certain embodiments, the crystalline Form A surprisingly is stable upon compression.

In certain embodiments, the crystalline Form A is substantially pure. In certain embodiments, the crystalline Form A is substantially free of other solid forms, e.g. , amorphous, and crystalline Form B. In certain embodiments, the purity of the crystalline Form A is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.

B. Form B of the Phenoxybenzenesulfonyl Compound

In one embodiment, provided herein is crystalline Form B of 4-[4-(4-chlorophenoxy)- benzenesulfonyl-methyl]-tetrahydropyran-4-carboxylic acid hydroxyamide. In one embodiment, the crystalline Form B is a single-component crystalline form of 4-[4-(4-chlorophenoxy)- benzenesulfonyl-methyl] -tetrahydropyran-4-carboxylic acid hydroxyamide.

In certain embodiments, the crystalline Form B has an X-ray powder diffraction pattern substantially as shown in FIG. 2. In certain embodiments, the crystalline Form B has a characteristic XRP diffraction peak at a two-theta angle of approximately 5.8, 13.8, 14.6, 17.7, 19.8, 20.9, 23.1, 23.7, 24.2, 24.9, 29.4, 31.3, 33.1, or 37.7. In certain embodiments, the crystalline Form B has characteristic XRP diffraction peaks at two-theta angles of approximately 5.8, 13.8, 14.6, 17.7, 23.1, 23.7, 24.2, 24.9, 29.4, 31.3, and 37.7. In certain embodiments, the crystalline Form B has characteristic XRP diffraction peaks at two-theta angles of approximately 5.8, 13.8, 14.6, 15.1, 16.4, 17.7, 18.6, 19.8, 20.8, 20.4, 20.9, 23.1, 23.4, 23.7, 24.2, 24.9, 28.1, 29.0, 29.4, 30.4, 31.3, 33.2, 34.8, and 37.7.

In certain embodiments, the crystalline Form B has an endotherm with an onset temperature of about 154 °C in a DSC thermogram. In certain embodiments, the crystalline Form B has an endotherm with a peak temperature of about 158 °C in a DSC thermogram.

In certain embodiments, the crystalline Form B is non-hygroscopic. In certain embodiments, the crystalline Form B exhibits no greater than about 1%, no greater than about 0.5%, no greater than about 0.3%, no greater than about 0.2%, or no greater than about 0.1% weight gain upon equilibrium at about 11% RH for 8 weeks. In certain embodiments, the crystalline Form B exhibits no greater than about 1%, no greater than about 0.5%, no greater than about 0.3%, no greater than about 0.2%, or no greater than about 0.1% weight gain upon equilibrium at about 51% RH for 8 weeks. In certain embodiments, the crystalline Form B exhibits no greater than about 1%, no greater than about 0.5%, no greater than about 0.4%, no greater than about 0.35%, or no greater than about 0.3% weight gain upon equilibrium at about 93% RH for 8 weeks. In certain embodiments, the crystalline Form B exhibits less than about 0.1% weight gain upon equilibrium at about 11% RH for 8 weeks. In certain embodiments, the crystalline Form B exhibits less than about 0.1% weight gain upon equilibrium at about 51% RH for 8 weeks. In certain embodiments, the crystalline Form B exhibits about 0.35% weight gain upon equilibrium at about 93% RH 8 weeks.

In certain embodiments, the crystalline Form B exhibits no greater than about 1%, no greater than about 0.5%, no greater than about 0.3%, no greater than about 0.2%, or no greater than about 0.1% weight loss upon equilibrium at about 11% RH for 8 weeks. In certain

embodiments, the crystalline Form B exhibits no greater than about 1%, no greater than about 0.5%, no greater than about 0.3%, no greater than about 0.2%, or no greater than about 0.1% weight loss upon equilibrium at about 51% RH for 8 weeks. In certain embodiments, the crystalline Form B exhibits no greater than about 1%, no greater than about 0.5%, no greater than about 0.3%, no greater than about 0.2%, or no greater than about 0.1% weight loss upon equilibrium at about 93% RH for 8 weeks. In certain embodiments, the crystalline Form B exhibits less than about 0.1% weight loss upon equilibrium at about 11% RH for 8 weeks. In certain embodiments, the crystalline Form B exhibits less than about 0.1% weight loss upon equilibrium at about 51% RH for 8 weeks. In certain embodiments, the crystalline Form B exhibits less than about 0.1% weight loss upon equilibrium at about 93% RH for 8 weeks.

In certain embodiments, the crystalline Form B exhibits desirable characteristics for the synthesis, processing, and/or manufacture of a drug product containing the

phenoxybenzenesulfonyl compound. In certain embodiments, the phenoxybenzenesulfonyl compound in crystalline Form B surprisingly has an advantageous stability profile, which is an important characteristic for processing and manufacturing of a drug product. In certain embodiments, the crystalline Form B surprisingly is stable upon compression.

In certain embodiments, the crystalline Form B is substantially pure. In certain embodiments, the crystalline Form B is substantially free of other solid forms, e.g. , amorphous, and crystalline Form A. In certain embodiments, the purity of the crystalline Form B is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%. C. Amorphous Form of the Phenoxybenzenesulfonyl Compound

In still another embodiment, provided herein is amorphous 4-[4-(4-chlorophenoxy)- benzenesulfonyl-methyl]-tetrahydropyran-4-carboxylic acid hydroxyamide. In certain

embodiments, the amorphous form has an exotherm with an onset temperature of about 103 °C in a DSC thermogram. In certain embodiments, the amorphous form has an endotherm with a peak temperature of about 151 °C in a DSC thermogram.

In certain embodiments, the amorphous form is unsolvated or solvated.

In certain embodiments, the amorphous form is non-hygroscopic. In certain embodiments, the amorphous form exhibits no greater than about 1%, no greater than about 0.5%, no greater than about 0.3%, no greater than about 0.2%, or no greater than about 0.1 % weight gain upon equilibrium at about 11% RH for 8 weeks. In certain embodiments, the amorphous form exhibits no greater than about 1%, no greater than about 0.5%, no greater than about 0.3%, no greater than about 0.2%, or no greater than about 0.1% weight gain upon equilibrium at about 22% RH for 8 weeks. In certain embodiments, the amorphous form exhibits no greater than about 1%, no greater than about 0.5%, no greater than about 0.3%, no greater than about 0.2%, or no greater than about 0.1% weight gain upon equilibrium at about 51% RH for 8 weeks. In certain embodiments, the amorphous form exhibits no greater than about 1%, no greater than about 0.5%, no greater than about 0.3%, no greater than about 0.2%, or no greater than about 0.1% weight gain upon equilibrium at about 75% RH for 8 weeks. In certain embodiments, the amorphous form exhibits no greater than about 1%, no greater than about 0.5%, no greater than about 0.3%, or no greater than about 0.2% or 0.25% weight gain upon equilibrium at about 93% RH for 8 weeks.

In certain embodiments, the amorphous form exhibits no greater than about 10%, no greater than about 5%, no greater than about 4%, no greater than about 3%, or no greater than about 2.5% weight loss upon equilibrium at about 11% RH for 8 weeks. In certain embodiments, the amorphous form exhibits no greater than about 5%, no greater than about 4%, no greater than about 3%, no greater than about 2%, or no greater than about 1.5% weight loss upon equilibrium at about 22% RH for 8 weeks. In certain embodiments, the amorphous form exhibits no greater than about 5%, no greater than about 4%, no greater than about 3%, or no greater than about 2% weight loss upon equilibrium at about 51% RH for 8 weeks. In certain embodiments, the amorphous form exhibits no greater than about 5%, no greater than about 4%, or no greater than about 3% weight loss upon equilibrium at about 75% RH for 8 weeks. In certain embodiments, the amorphous form exhibits no greater than about 5%, no greater than about 4%, no greater than about 3%, no greater than about 2%, or no greater than about 1.5% weight loss upon equilibrium at about 93% RH for 8 weeks. In certain embodiments, the amorphous form exhibits desirable characteristics for the synthesis, processing, and/or manufacture of a drug product containing the phenoxybenzenesulfonyl compound. In certain embodiments, the phenoxybenzenesulfonyl compound in amorphous form surprisingly has an advantageous stability profile, which is an important characteristic for processing and manufacturing of a drug product. In certain embodiments, the amorphous form surprisingly is stable upon compression.

In certain embodiments, the amorphous form is substantially pure. In certain embodiments, the amorphous form is substantially free of other solid forms, e.g. , crystalline Forms A and B. In certain embodiments, the purity of the amorphous form is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.

D. Characterization of the Solid Forms

Techniques suitable for characterizing a solid form of the phenoxybenzenesulfonyl compound, e.g. , crystalline Form A or B, or an amorphous form, include, but are not limited to, thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder

diffractometry (XRPD), single-crystal X-ray diffractometry, vibrational spectroscopy (e.g. , infrared (IR) and Raman spectroscopy), solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies. Without intending to be limited by any particular theory, in certain embodiments, the storage stability, compressibility, bulk density, or dissolution properties of the solid forms of the phenoxybenzenesulfonyl compound provided herein, e.g., Form A, B, or an amorphous form, are beneficial for manufacturing, formulation, and/or bioavailability of the phenoxybenzenesulfonyl compound. It should be understood that the numerical values of the peaks of the X-ray powder diffraction patterns may vary slightly from one machine to another or from one sample to another, and so the values quoted are not to be construed as absolute, but with an allowable variability, such as 0.1 or 0.2°, which is recommended in the United State Pharmacopeia (pages: 387-389, 2007). It should also be understood that peak intensities in an X-ray powder diffraction pattern for a solid form are generally not used to differentiate a polymorphic form from another, as intensities vary considerably due to a number of factors, including, but not limited to, the orientation of crystals in the X-ray beam, the purity of the ample being analyzed, and the degree of crystallinity of the sample.

Process of Preparation In one embodiment, provided herein is a method for preparing a solid form of the

phenoxybenzenesulfonyl compound provided herein, e.g., an amorphous form, or crystalline Form A or B. The method comprises the step of contacting the phenoxybenzenesulfonyl compound with a solvent, in which a solid form of the phenoxybenzenesulfonyl compound provided herein, e.g., an amorphous form, or crystalline Form A or B, is formed from a solution or converted from one solid form to another. In certain embodiments, the method further comprises the step of isolation, in which the solids can be isolated by a conventional method, such as filtration and centrifugation, optionally followed by washing with a solvent or a mixture of solvents and drying, e.g., vacuum oven drying, air drying, or desicator drying.

Suitable solvents for use in preparing a solid form of the phenoxybenzenesulfonyl compound provided herein, e.g., an amorphous form, or crystalline Form A or B, include, but are not limited to, hydrocarbons, including, but not limited to, petroleum ether, pentane, hexane(s), heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, tetraline, and cumene; chlorinated hydrocarbons, including, but not limited to, dichloromethane (DCM), 1,2-dichloroethane, 1,1-dichloroethene, 1,2-dichloroethene, chloroform, trichloroethane, trichloroethene, carbon tetrachloride, chlorobenzene, and trifluoromethylbenzene; alcohols, including, but not limited to, methanol (MeOH), ethanol (EtOH), isopropanol (IP A), 1-propanol (PrOH), 1-butanol, 2-butanol, ί-butanol, 3-methyl-l- butanol (n-BuOH), 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol, and ethyleneglycol; ethers, including, but not limited to, diethyl ether, diisopropyl ether (DIPE), methyl i-butyl ether (MTBE), diphenyl ether, 1,2-dimethoxyethane, bi(2-methoxyethyl)ether, 1,1-dimethoxymethane, 2,2-dimethoxypropane, and anisole; ketones, including, but not limited to, acetone, butanone, methyl ethyl ketone (MEK), methyl isopropyl ketone, methyl butyl ketone, and methyl isobutyl ketone (MIBK); esters, including, but not limited to, methyl acetate, ethyl formate, ethyl acetate (EtOAc), propyl acetate, isopropyl acetate (IPA), isobutyl acetate, n-butyl acetate (n-BuOAc), and 5-butyl acetate (s-BuOAc); carbonates, including, but not limited to, ethylene carbonate and propylene carbonate; amides, including, but not limited to formamide, N,N-dimethylformamide (DMF), and N,N-dimethylacetamide (DMA); nitriles, including, but not limited to, acetonitrile (ACN or MeCN); sulfoxides, including, but not limited to, dimethyl sulfoxide (DMSO);

sulfones, including, but not limited to, sulfolane; nitro compounds, including, but not limited to, nitromethane and nitrobenzene; heterocycles, including, but not limited to, N-methyl

pyrrolindone, 2-methyl tetrahydrofuran, tetrahydrofuran (THF), 1,4-dioxane, and pyridine;

carboxylic acids, including, but not limited to, acetic acid, trichloroacetic acid, and

trifluoroacetic acid; phosphoramides, including, but not limited to, hexamethylphosphoramide; carbon sulfide; water; and mixtures thereof.

In one embodiment, provided herein is a method for preparing crystalline Form A of the phenoxybenzenesulfonyl compound, which comprises the steps of (a) preparing a solution of the phenoxybenzenesulfonyl compound in a solvent at a first temperature; and (b) generating crystalline Form A solids at a second temperature. In certain embodiments, to accelerate the formation of the crystalline Form A solids, the method comprises a seeding step by seeding the solution with crystals of Form A, prior to or during step (b). In certain embodiments, the method further comprises an isolation step as described herein.

In certain embodiments, the solution of the phenoxybenzenesulfonyl compound is prepared from any forms of the phenoxybenzenesulfonyl compound, including, but not limited to, oil;

semisolids; solids, including, but not limited to, an amorphous form, or Form A or B and mixtures thereof. In certain embodiments, the solution in step (a) is prepared as a saturated or nearly saturated solution at the first temperature. In certain embodiments, the saturated or nearly saturated solution is prepared by dissolving a sufficient amount of the phenoxybenzenesulfonyl compound in the solvent at a temperature that is higher than the first temperature, such that, when the solution is allowed to cool to the first temperature, a saturated or nearly saturated solution is obtained. The sufficient amount of the phenoxybenzenesulfonyl compound can be estimated based on the solubility of the phenoxybenzenesulfonyl compound in the solvent at the first temperature, which can be determined using a method known to a person skilled in the art. In certain embodiments, the saturated or nearly saturated solution is prepared by dissolving an amount of the phenoxybenzenesulfonyl compound in the solvent at the first temperature, followed by removing the solvent, e.g. , distillation.

The first temperature may range from room temperature to about the boiling point of the solvent, e.g. , from about 20 to about 250 °C, from about 20 to about 150 °C, from about 20 to about 120 °C, from about 50 to about 100 °C, or from about 60 to about 90 °C. The second temperature may range from -100 to 100 °C, from about -50 to about 50 °C, or from about - 10 to about 30 °C. The first temperature may be higher or lower than, or the same as the second temperature. To maximize the yield and the efficiency of the process, the second temperature is normally set to be lower than the first temperature.

In one embodiment, the crystalline Form A of the phenoxybenzenesulfonyl compound is formed by evaporating the solvent from the solution at the second temperature. The solvent evaporation can be facilitated by applying heat and/or vacuum to the solution. In one embodiment, the solvent is ethyl acetate, hexane, methylene chloride, methanol, water, or a mixture thereof. In another embodiment, the solvent is ethyl acetate, a mixture of ethyl acetate and hexane, a mixture of methylene chloride and hexane, a mixture of methanol and water, or water.

In another embodiment, the crystalline Form A of the phenoxybenzenesulfonyl compound is formed by cooling the solution to the second temperature. In this case, the second temperature is set to be lower than the first temperature. In one embodiment, the solvent is ethyl acetate, hexane, methylene chloride, methanol, water, or a mixture thereof. In another embodiment, the solvent is ethyl acetate a mixture of ethyl acetate and hexane, a mixture of methylene chloride and hexane, a mixture of methanol and water, or water.

In yet another embodiment, the crystalline Form A of the phenoxybenzenesulfonyl compound is formed by adding an anti-solvent to the solution at a second temperature.

Suitable anti-solvents include, but are not limited to, hydrocarbons, including, but not limited to, petroleum ether, pentane, hexane(s), heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, tetraline, and cumene; chlorinated hydrocarbons, including, but not limited to, dichloromethane (DCM), 1,2-dichloroethane, 1,1-dichloroethene, 1,2-dichloroethene, chloroform, trichloroethane, trichloroethene, carbon tetrachloride, chlorobenzene, and trifluoromethylbenzene; alcohols, including, but not limited to, methanol (MeOH), ethanol (EtOH), isopropanol (IP A), 1-propanol (PrOH), 1-butanol, 2-butanol, t- butanol, 3 -methyl- 1-butanol (n-BuOH), 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol, and ethyleneglycol; ethers, including, but not limited to, diethyl ether, diisopropyl ether (DIPE), methyl i-butyl ether (MTBE), diphenyl ether, 1,2-dimethoxyethane, bi(2-methoxyethyl)ether, 1,1-dimethoxymethane, 2,2-dimethoxypropane, and anisole; ketones, including, but not limited to, acetone, butanone, methyl ethyl ketone (MEK), methyl isopropyl ketone, methyl butyl ketone, and methyl isobutyl ketone (MIBK); esters, including, but not limited to, methyl acetate, ethyl formate, ethyl acetate (EtOAc), propyl acetate, isopropyl acetate (IPA), isobutyl acetate, n- butyl acetate (n-BuOAc), and s -butyl acetate (s-BuOAc); carbonates, including, but not limited to, ethylene carbonate and propylene carbonate; amides, including, but not limited to formamide, N,N-dimethylformamide (DMF), and N,N-dimethylacetamide (DMA); nitriles, including, but not limited to, acetonitrile (ACN or MeCN); sulfoxides, including, but not limited to, dimethyl sulfoxide (DMSO); sulfones, including, but not limited to, sulfolane; nitro compounds, including, but not limited to, nitromethane and nitrobenzene; heterocycles, including, but not limited to, N-methyl pyrrolindone, 2-methyl tetrahydrofuran, tetrahydrofuran (THF), 1,4- dioxane, and pyridine; carboxylic acids, including, but not limited to, acetic acid, trichloroacetic acid, and trifluoro acetic acid; phosphoramides, including, but not limited to,

hexamethylphosphoramide; carbon sulfide; water; and mixtures thereof.

When two solvents are used as a solvent/anti-solvent pair, the phenoxybenzenesulfonyl compound has a higher solubility in the solvent than in the anti-solvent. In certain embodiments, the solvent and the anti-solvent in a solvent/anti- solvent pair are at least partially miscible. In one embodiment, the solvent is ethyl acetate, methylene chloride, methanol, acetone, or a mixture thereof. In another embodiment, the anti-solvent is hexane, or water. In another embodiment, the solvent/anti- solvent pair is ethyl acetate/hexane, methylene chloride/hexane, ethyl acetate/toluene, or methanol/water. In yet another embodiment, the crystalline Form A of the phenoxybenzenesulfonyl compound is formed by adding the solution to an anti-solvent at the second temperature. In one embodiment, the solvent is ethyl acetate, methylene chloride, methanol, or a mixture thereof. In another embodiment, the anti-solvent is hexane or water. In another embodiment, the solvent/anti- solvent pair is ethyl acetate/hexane, methylene chloride/hexane, or methanol/water.

In yet another embodiment, the method for preparing the crystalline Form A of the

phenoxybenzenesulfonyl compound comprises the steps of (a) preparing a slurry of the phenoxybenzenesulfonyl compound in a solvent at a first temperature; and (b) forming the crystalline Form A by exposing the slurry to a second temperature. The slurry can be prepared from any forms of the phenoxybenzenesulfonyl compound, including, but not limited to, oil; semisolids; solids, including, but not limited to, an amorphous form, or Form A or B; and mixtures thereof. The process may further comprise a seeding step and/or an isolation step, as described herein. The first and second temperatures and the solvent are as defined herein. In one embodiment, the solvent is ethyl acetate, hexane, methylene chloride, methanol, isopropyl acetate, acetone, toluene, water, or a mixture thereof. In another embodiment, the solvent is ethyl acetate, acetone, a mixture of ethyl acetate and hexane, a mixture of methylene chloride and hexane, a mixture of methanol and water, or water.

In one embodiment, provided herein is a method for preparing crystalline Form B of the phenoxybenzenesulfonyl compound, which comprises the steps of (a) preparing a solution of the phenoxybenzenesulfonyl compound in a solvent at a first temperature; and (b) generating crystalline Form B solids at a second temperature. In certain embodiments, to accelerate the formation of the crystalline Form B solids, the method comprises a seeding step by seeding the solution with crystals of Form B, prior to or during step (b). In certain embodiments, the method further comprises an isolation step as described herein.

In one embodiment, the crystalline Form B of the phenoxybenzenesulfonyl compound is formed by evaporating the solvent from the solution at the second temperature. The solvent evaporation can be facilitated by applying heat and/or vacuum to the solution. In one embodiment, the solvent is ethyl acetate, hexane, methylene chloride, ethanol, isopropanol, isopropyl acetate, acetone, toluene, acetonitrile, water, or a mixture thereof. In another embodiment, the solvent is ethyl acetate, a mixture of ethyl acetate and hexane, a mixture of methylene chloride and hexane, isopropanol, isopropyl acetate, acetone, a mixture of acetone and water, a mixture of ethyl acetate and toluene, or acetonitrile.

In another embodiment, the crystalline Form B of the phenoxybenzenesulfonyl compound is formed by cooling the solution to the second temperature. In this case, the second temperature is set to be lower than the first temperature. In one embodiment, the solvent is ethyl acetate, hexane, methylene chloride, ethanol, isopropanol, isopropyl acetate, acetone, toluene, acetonitrile, water, or a mixture thereof. In another embodiment, the solvent is ethyl acetate, a mixture of ethyl acetate and hexane, a mixture of methylene chloride and hexane, isopropanol, isopropyl acetate, acetone, a mixture of acetone and water, a mixture of ethyl acetate and toluene, or acetonitrile.

In yet another embodiment, the crystalline Form B of the phenoxybenzenesulfonyl compound is formed by adding an anti-solvent to the solution at a second temperature.

hexamethylphosphoramide; carbon sulfide; water; and mixtures thereof.

When two solvents are used as a solvent/anti-solvent pair, the phenoxybenzenesulfonyl compound has a higher solubility in the solvent than in the anti-solvent. In certain embodiments, the solvent and the anti-solvent in a solvent/anti- solvent pair are at least partially miscible. In one embodiment, the solvent is ethyl acetate, methylene chloride, ethanol, isopropanol, isopropyl acetate, acetone, acetonitrile, or a mixture thereof. In another embodiment, the anti- solvent is hexane, toluene, or water. In another embodiment, the solvent/anti- solvent pair is ethyl acetate/hexane, methylene chloride/hexane, acetone/water, or ethyl acetate/toluene. In yet another embodiment, the crystalline Form B of the phenoxybenzenesulfonyl compound is formed by adding the solution to an anti-solvent at the second temperature. In one embodiment, the solvent is ethyl acetate, methylene chloride, ethanol, isopropanol, isopropyl acetate, acetone, acetonitrile, or a mixture thereof. In another embodiment, the anti-solvent is hexane, toluene, or water. In another embodiment, the solvent/anti- solvent pair is ethyl acetate/hexane, methylene chloride/hexane, acetone/water, or ethyl acetate/toluene.

In yet another embodiment, the method for preparing the crystalline Form B of the

phenoxybenzenesulfonyl compound comprises the steps of (a) preparing a slurry of the phenoxybenzenesulfonyl compound in a solvent at a first temperature; and (b) forming the crystalline Form B by exposing the slurry to a second temperature. The slurry can be prepared from any forms of the phenoxybenzenesulfonyl compound, including, but not limited to, oil; semisolids; solids, including, but not limited to, an amorphous form, or Form A or B; and mixtures thereof. The process may further comprise a seeding step and/or an isolation step, as described herein. The first and second temperatures and the solvent are as defined herein. In one embodiment, the solvent is ethyl acetate, hexane, methylene chloride, ethanol, isopropanol, isopropyl acetate, acetone, toluene, acetonitrile, water, or a mixture thereof. In another embodiment, the solvent is ethyl acetate, a mixture of ethyl acetate and hexane, a mixture of methylene chloride and hexane, isopropanol, isopropyl acetate, acetone, a mixture of acetone and water, a mixture of ethyl acetate and toluene, or acetonitrile.

In another embodiment, provided herein is a method for preparing crystalline Form B of the phenoxybenzenesulfonyl compound, which comprises the steps of (a) preparing a solution of the phenoxybenzenesulfonyl compound in a solvent at a first temperature; (b) seeding the solution with crystals of Form B; and (c) generating crystalline Form B solids at a second temperature. In certain embodiments, the method further comprises an isolation step as described herein. In one embodiment, the solvent is ethyl acetate, hexane, methylene chloride, ethanol, isopropanol, isopropyl acetate, acetone, toluene, acetonitrile, water, or a mixture thereof. In another embodiment, the solvent is ethyl acetate, a mixture of ethyl acetate and hexane, a mixture of methylene chloride and hexane, isopropanol, isopropyl acetate, acetone, a mixture of acetone and water, a mixture of ethyl acetate and toluene, or acetonitrile.

The solid forms of the phenoxybenzenesulfonyl compound provided herein can be prepared by the methods described herein, or by techniques known in the art, including, but not limited to, melt cooling, rapid melt cooling, freeze drying, lyophilization, quench cooling the melt, rapid solvent evaporation, slow solvent evaporation, solvent recrystallization, slurry recrystallization, crystallization from the melt, desolvation, sublimation, recrystallization in confined spaces ( e.g., in nanopores or capillaries), recrystallization on surfaces or templates (e.g. , on polymers), recrystallization in the presence of additives (e.g. , co-crystal counter- molecules), dehydration, rapid cooling, slow cooling, vapor diffusion, grinding, cryo-grinding, solvent-drop grinding, microwave-induced precipitation, ultrasonication-induced precipitation, laser-induced precipitation, and precipitation from a supercritical fluid. Pharmaceutical Compositions

Provided herein are pharmaceutical compositions comprising a solid form provided herein, e.g. , crystalline Form A or B or an amorphous form of the phenoxybenzenesulfonyl compound, as an active ingredient; in combination with a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a mixture thereof. Suitable excipients are well known to those skilled in the art, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the method of administration. For example, oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients that comprise primary or secondary amines are particularly susceptible to such accelerated decomposition. Consequently, provided herein are pharmaceutical compositions and dosage forms that contain little, if any, lactose other mono- or di- saccharides. As used herein, the term "lactose-free" means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient. In one embodiment, lactose-free compositions comprise an active ingredient provided herein, a binder/filler, and a lubricant. In another embodiment, lactose-free dosage forms comprise an active ingredient, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.

A solid form provided herein may be administered alone, or in combination with one or more other solid forms provided herein. The pharmaceutical compositions that comprise a solid form provided herein, e.g. , crystalline Form A or B or an amorphous form, can be formulated in various dosage forms for oral, parenteral, and topical administration. The pharmaceutical compositions can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd ed.; Rathbone et ah, Eds.; Marcel Dekker, Inc.: New York, NY, 2008). In one embodiment, the pharmaceutical compositions are provided in a dosage form for oral administration, which comprise a solid form provided herein, e.g., crystalline Form A or B or an amorphous form; and one or more pharmaceutically acceptable excipients or carriers.

In another embodiment, the pharmaceutical compositions are provided in a dosage form for parenteral administration, which comprise a solid form provided herein, e.g., crystalline Form A or B or an amorphous form; and one or more pharmaceutically acceptable excipients or carriers.

In yet another embodiment, the pharmaceutical compositions are provided in a dosage form for topical administration, which comprise a solid form provided herein, e.g., crystalline Form A or B or an amorphous form; and one or more pharmaceutically acceptable excipients or carriers.

The pharmaceutical compositions provided herein can be provided in a unit-dosage form or multiple-dosage form. A unit-dosage form, as used herein, refers to physically discrete a unit suitable for administration to a human and animal subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of an active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required

pharmaceutical carriers or excipients. Examples of a unit-dosage form include an ampoule, syringe, and individually packaged tablet and capsule. For example, a 100 mg unit dose contains about 100 mg of an active ingredient in a packaged tablet or capsule. A unit-dosage form may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit- dosage form. Examples of a multiple-dosage form include a vial, bottle of tablets or capsules, or bottle of pints or gallons.

The pharmaceutical compositions provided herein can be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.

In one embodiment, provided herein is a pharmaceutical composition, comprising a solid form provided herein, e.g. , crystalline Form A or B or an amorphous form of the

phenoxybenzenesulfonyl compound; and one or more pharmaceutically acceptable excipients selected from lactose anhydrous, croscarmellose sodium, povidone, microcrystalline cellulose, and magnesium stearate. In certain embodiments, the pharmaceutical composition is formulated as a tablet. In certain embodiments, the pharmaceutical composition is formulated as an immediate release tablet. In certain embodiments, the pharmaceutical composition is formulated as a capsule.

In another embodiment, provided herein is a pharmaceutical composition, comprising about 2.5 g of a solid form provided herein, e.g. , crystalline Form A or B or an amorphous form of the phenoxybenzenesulfonyl compound; and about 120 g of lactose anhydrous, about 12 g of croscarmellose sodium, about 6.5 g of povidone, about 8 g of microcrystalline cellulose, and about 1.5 g of magnesium stearate.

In yet another embodiment, provided herein is a pharmaceutical composition, comprising about 5 g of a solid form provided herein, e.g. , crystalline Form A or B or an amorphous form of the phenoxybenzenesulfonyl compound; and about 120 g of lactose anhydrous, about 6.5 g of povidone, about 8 g of microcrystalline cellulose, and about 1.5 g of magnesium stearate. In yet another embodiment, provided herein is a pharmaceutical composition, comprising about 10 g of a solid form provided herein, e.g., crystalline Form A or B or an amorphous form of the phenoxybenzenesulfonyl compound; and about 110 g of lactose anhydrous, about 12 g of croscarmellose sodium, about 6.5 g of povidone, about 8 g of microcrystalline cellulose, and about 1.5 g of magnesium stearate. In still another embodiment, provided herein is a pharmaceutical composition, comprising about 30 g of a solid form provided herein, e.g., crystalline Form A or B or an amorphous form of the phenoxybenzenesulfonyl compound; and about 90 g of lactose anhydrous, about 12 g of croscarmellose sodium, about 6.5 g of povidone, about 8 g of microcrystalline cellulose, and about 1.5 g of magnesium stearate. A. Oral Administration The pharmaceutical compositions provided herein for oral administration can be provided in solid, semisolid, or liquid dosage forms for oral administration. As used herein, oral

administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient(s), the pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.

Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g. , STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH- 105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. The amount of a binder or filler in the pharmaceutical

compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions provided herein. Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets. The amount of a diluent in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate;

polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre- gelatinized starch; clays; aligns; and mixtures thereof. The amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The amount of a disintegrant in the

pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL^® 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL^® (Cabot Co. of Boston, MA); and mixtures thereof. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.

Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB-O-SIL^® (Cabot Co. of Boston, MA), and asbestos-free talc. Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof. A color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN^® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN^® 80), and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serve a plurality of functions, even within the same formulation.

The pharmaceutical compositions provided herein for oral administration can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets. Enteric- coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.

The tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein for oral administration can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as the dry-filled capsule (DFC), consists of two sections, one slipping over the other, thus completely enclosing the active ingredient. The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient. The pharmaceutical compositions provided herein for oral administration can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil. Emulsions may include a pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent, and preservative. Suspensions may include a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and hydro alcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.

Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or poly-alkylene glycol, including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350- dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the

polyethylene glycol. These formulations can further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates .

The pharmaceutical compositions provided herein for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458. The pharmaceutical compositions provided herein for oral administration can be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosage forms.

The pharmaceutical compositions provided herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms. B. Parenteral Administration

The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration. Parenteral administration, as used herein, include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular,

intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.

The pharmaceutical compositions provided herein for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science {see, Remington: The Science and Practice of Pharmacy, supra).

The pharmaceutical compositions intended for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases. Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection. Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm seed oil. Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol {e.g., polyethylene glycol 300 and

polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N,N- dimethylacetamide, and dimethyl sulfoxide. Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride {e.g., benzethonium chloride), methyl- and propylparabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate.

Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents are those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including oc-cyclodextrin, β- cyclodextrin, hydroxypropyl- β-cyclodextrin, sulfobutylether- -cyclodextrin, and sulfobutylether 7- -cyclodextrin (CAPTISOL^®, CyDex, Lenexa, KS). When the pharmaceutical compositions provided herein are formulated for multiple dosage administration, the multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.

In one embodiment, the pharmaceutical compositions for parenteral administration are provided as ready-to-use sterile solutions. In another embodiment, the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical compositions are provided as ready-to-use sterile suspensions. In yet another embodiment, the pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle prior to use. In still another embodiment, the pharmaceutical compositions are provided as ready-to-use sterile emulsions.

The pharmaceutical compositions provided herein for parenteral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.

The pharmaceutical compositions provided herein for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions diffuse through. Suitable inner matrixes include, but are not limited to, polymethylmethacrylate, polybutyl- methacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include but are not limited to, polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated

polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber

epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer. C. Topical Administration

The pharmaceutical compositions provided herein can be administered topically to the skin, orifices, or mucosa. The topical administration, as used herein, includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration. The pharmaceutical compositions provided herein can be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and dermal patches. The topical formulation of the pharmaceutical compositions provided herein can also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, nonaqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical compositions can also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp., Emeryville, CA), and BIOJECT™ (Bioject Medical

Technologies Inc., Tualatin, OR).

The pharmaceutical compositions provided herein can be provided in the forms of ointments, creams, and gels. Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum;

emulsifiable or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water-soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water- in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see, Remington: The Science and Practice of Pharmacy, supra). These vehicles are emollient but generally require addition of antioxidants and preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Suitable cream vehicles may be water- washable, and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase is also called the "internal" phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers, such as carbomers,

carboxypolyalkylenes, and CARBOPOL^®; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose,

hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.

The pharmaceutical compositions provided herein can be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas. These dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices. Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which produce a melting point in the proximity of body temperature, when formulated with the pharmaceutical compositions provided herein; and antioxidants as described herein, including bisulfite and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di- and triglycerides of fatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid. Combinations of the various vehicles can also be used. Rectal and vaginal suppositories may be prepared by compressing or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.

The pharmaceutical compositions provided herein can be administered ophthalmically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants.

The pharmaceutical compositions provided herein can be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical compositions can be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3- heptafluoropropane. The pharmaceutical compositions can also be provided as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops. For intranasal use, the powder can comprise a bioadhesive agent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active ingredient provided herein; a propellant as solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of such sizes can be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

Capsules, blisters, and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the pharmaceutical compositions provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as /-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions provided herein for inhaled/intranasal administration can further comprise a suitable flavor, such as menthol and levomenthol; and/or sweeteners, such as saccharin and saccharin sodium. The pharmaceutical compositions provided herein for topical administration can be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release.

D. Modified Release

The pharmaceutical compositions provided herein can be formulated as a modified release dosage form. As used herein, the term "modified release" refers to a dosage form in which the rate or place of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route. Modified release dosage forms include, but are not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. The pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphorism of the active ingredient(s).

Examples of modified release include, but are not limited to, those described in U.S. Pat. Nos.:

3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767;

5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;

5,922,356; 5,958,458; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943;

6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,270,798; 6,375,987; 6,376,461; 6,419,961;

6,589,548; 6,613,358; 6,623,756; 6,699,500; 6,793,936; 6,827,947; 6,902,742; 6,958,161;

7,255,876; 7,416,738; 7,427,414; 7,485,322; Bussemer et al, Crit. Rev. Ther. Drug Carrier Syst.

2001, 18, 433-458; Modified-Release Drug Delivery Technology, 2nd ed.; Rathbone et al., Eds.;

Marcel Dekker AG: 2005; Maroni et al, Expert. Opin. Drug Deliv. 2005, 2, 855-871; Shi et al, Expert Opin. Drug Deliv. 2005, 2, 1039-1058; Polymers in Drug Delivery; Ijeoma et al, Eds.;

CRC Press LLC: Boca Raton, FL, 2006; Badawy et al, J. Pharm. Sci. 2007, 9, 948-959;

Modified-Release Drug Delivery Technology, supra; Conway, Recent Pat. Drug Deliv. Formul.

2008, 2, 1-8; Gazzaniga et al, Eur. J. Pharm. Biopharm. 2008, 68, 11-18; Nagarwal et al, Curr.

Drug Deliv. 2008, 5, 282-289; Gallardo et al, Pharm. Dev. Technol. 2008, 13, 413-423;

Chrzanowski, AAPS PharmSciTech. 2008, 9, 635-638; Chrzanowski, AAPS PharmSciTech.

2008, 9, 639-645; Kalantzi et al, Recent Pat. Drug Deliv. Formul. 2009, 3, 49-63; Saigal et al,

Recent Pat. Drug Deliv. Formul. 2009, 3, 64-70; and Roy et al, J. Control Release 2009, 134,

74-80.

1. Matrix Controlled Release Devices The pharmaceutical compositions provided herein in a modified release dosage form can be fabricated using a matrix controlled release device known to those skilled in the art. See, Takada et al. in Encyclopedia of Controlled Drug Delivery; Mathiowitz Ed.; Wiley: 1999; Vol 2.

In certain embodiments, the pharmaceutical compositions provided herein in a modified release dosage form is formulated using an erodible matrix device, which is water- swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins. Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid;

copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT^®, Rohm America, Inc.,

Piscataway, NJ); poly(2-hydroxyethyl-methacrylate); polylactides; copolymers of L- glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymers; poly-D-(-)-3- hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butylmethacrylate, methyl methacrylate, ethyl methacrylate, ethylacrylate, (2- dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride.

In certain embodiments, the pharmaceutical compositions provided herein are formulated with a non-erodible matrix device. The active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered. Materials suitable for use as a non-erodible matrix device include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene,

polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetate copolymers, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubbers, epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubbers, polydimethylsiloxanes, and silicone carbonate copolymers; hydrophilic polymers, such as ethyl cellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds, such as carnauba wax, microcrystalline wax, and triglycerides. In a matrix controlled release system, the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients or carriers in the compositions. The pharmaceutical compositions provided herein in a modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt-granulation followed by compression.

2. Osmotic Controlled Release Devices

The pharmaceutical compositions provided herein in a modified release dosage form can be fabricated using an osmotic controlled release device, including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS). In general, such devices have at least two components: (a) a core which contains an active ingredient; and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core. The semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s).

In addition to the active ingredient(s), the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device. One class of osmotic agents is water-swellable hydrophilic polymers, which are also referred to as "osmopolymers" and "hydrogels." Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate. The other class of osmotic agents is osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate;

sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof. Osmotic agents of different dissolution rates can be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form. For example, amorphous sugars, such as MANNOGEM EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.

The core can also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.

Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water-permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water- insoluble by chemical alteration, such as crosslinking. Examples of suitable polymers useful in forming the coating, include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly-(methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

Semipermeable membrane can also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes. The delivery port(s) on the semipermeable membrane can be formed post-coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat. Nos. 5,612,059 and 5,698,220. The total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.

The pharmaceutical compositions in an osmotic controlled-release dosage form can further comprise additional conventional excipients or carriers as described herein to promote performance or processing of the formulation.

The osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release 1995, 35, 1-21; Verma et ah, Drug Development and Industrial Pharmacy 2000, 26, 695-708; and Verma et al., J. Controlled Release 2002, 79, 7-27.

In certain embodiments, the pharmaceutical compositions provided herein are formulated as AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients or carriers. See, U.S. Pat. No. 5,612,059 and International Pat. Appl. Publ. No. WO 2002/17918. The AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.

In certain embodiments, the pharmaceutical compositions provided herein are formulated as ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxylethyl cellulose, and other pharmaceutically acceptable excipients or carriers.

3. Multiparticulate Controlled Release Devices

The pharmaceutical compositions provided herein in a modified release dosage form can be fabricated as a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 μιη to about 3 mm, about 50 μιη to about 2.5 mm, or from about 100 μιη to about 1 mm in diameter. Such multiparticulates can be made by the processes known to those skilled in the art, including wet-and dry-granulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores. See, for example, Multiparticulate Oral Drug Delivery; Ghebre-Sellassie Ed.; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Ghebre-Sellassie Ed.; Marcel Dekker: 1989.

Other excipients or carriers as described herein can be blended with the pharmaceutical compositions to aid in processing and forming the multiparticulates. The resulting particles can themselves constitute the multiparticulate device or can be coated by various film-forming materials, such as enteric polymers, water- swellable, and water-soluble polymers. The multiparticulates can be further processed as a capsule or a tablet.

4. Targeted Delivery

The pharmaceutical compositions provided herein can also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Examples include, but are not limited to, those disclosed in U.S. Pat. Nos. 5,709,874; 5,759,542; 5,840,674; 5,900,252; 5,972,366; 5,985,307; 6,004,534; 6,039,975; 6,048,736; 6,060,082; 6,071,495; 6,120,751;

6,131,570; 6,139,865; 6,253,872; 6,271,359; 6,274,552; 6,316,652; and 7,169,410.

In certain embodiments, the pharmaceutical compositions are formulated for single dose administration. Methods of Use

In one embodiment, provided herein is a method for treating, preventing, amiliorating a liver disease in a subject, which comprises administering to the subject a therapeutically effective amount of a solid form provided herein, e.g. , crystalline Form A or B or an amorphous form of the phenoxybenzenesulfonyl compound.

In another embodiment, provided herein is a method for reducing liver damage associated with a liver disease in a subject, which comprises administering to the subject a therapeutically effective amount of a solid form provided herein, e.g. , crystalline Form A or B or an amorphous form of the phenoxybenzenesulfonyl compound.

In certain embodiments, the liver disease is alcoholic fatty liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver fibrosis, cirrhosis, primary biliary cirrhosis, hepatic ischemia reperfusion injury, or hepatitis.

In certain embodiments, the subject has been pre-treated with other medication for liver disease. In certain embodiments, the subject being treated with other medication for a liver disease.

In certain embodiments, the subject has failed therapy for liver disease.

In certain embodiments, the liver disease is hepatitis B or hepatitis C.

In certain embodiments, the subject has failed therapy for hepatitis C.

In yet another embodiment, provided herein is a method for treating or preventing an HCV infection, which comprises administering to a subject a therapeutically effective amount of a solid form, e.g., Form A, B, or an amorphous form, of 4-[4-(4-chlorophenoxy)-benzenesulfonyl- methyl]-tetrahydropyran-4-carboxylic acid hydroxyamide.

In yet another embodiment, provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a liver disease or disorder associated with an HCV infection, comprising administering to a subject a therapeutically effective amount of a solid form, e.g., Form A, B, or an amorphous form, of 4-[4-(4-chlorophenoxy)-benzenesulfonyl-methyl]- tetrahydropyran-4-carboxylic acid hydroxyamide. In yet another embodiment, provided herein is a method for treating or preventing an HBV infection, which comprises administering to a subject a therapeutically effective amount of a solid form, e.g. , Form A, B, or an amorphous form, of 4-[4-(4-chlorophenoxy)-benzenesulfonyl- methyl]-tetrahydropyran-4-carboxylic acid hydroxyamide. In yet another embodiment, provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a liver disease or disorder associated with an HBV infection, comprising administering to a subject a therapeutically effective amount of a solid form, e.g. , Form A, B, or an amorphous form, of 4-[4-(4-chlorophenoxy)-benzenesulfonyl-methyl]- tetrahydropyran-4-carboxylic acid hydroxyamide. In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

In certain embodiments, the liver disease is an acute liver disease. In certain embodiments, the liver disease is a chronic liver disease.

In certain embodiments, the liver disease is a disorder that results from an injury to the liver. In certain embodiments, the injury to the liver is caused by toxins, including, but not limited to, alcohol, some drugs, impurities in foods, and the abnormal build-up of normal substances in the blood. In certain embodiments, the injury to the liver is caused by an infection or by an autoimmune disorder. In certain embodiments, the exact cause of the injury is not known.

In certain embodiments, the liver disease includes, but is not limited to cirrhosis, liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatic ischemia reperfusion injury, hepatitis, viral hepatitis, alcoholic hepatitis, and primary biliary cirrhosis. In certain embodiments, the liver disease is manifested by raised liver enzymes (e.g., ALT and AST), pathological evidence of on going liver damage as a result of steatosis (fatty liver), fibrosis, and/or cirrhosis. In certain embodiments, NASH is manifested by raised liver enzymes (e.g., ALT and AST), pathological evidence of steatosis (fatty liver), fibrosis, and/or cirrhosis.

In certain embodiments, the liver disease is fatty liver (also called hepatic steatosis), including non-alcoholic fatty liver disease. As used herein, fatty liver is defined as an excessive accumulation of triglyceride inside the liver cells. In certain embodiments, in a subject with nonalcoholic fatty liver disease, the liver contains more that about 5% of the total weight of the liver or more than 30% of liver cells in a liver lobule are with fat deposit. The most common causes of non-alcoholic fatty liver are obesity, diabetes, and elevated serum triglyceride levels. Other causes include malnutrition, hereditary disorders of metabolism (such as the glycogen storage diseases,) and drugs (such as corticosteroids, tetracycline and aspirin). In certain embodiments, fatty liver produces no symptoms. In certain embodiments, fatty liver results in jaundice (a yellowish discoloration of the skin and the whites of the eyes), nausea, vomiting, pain, and abdominal tenderness.

In certain embodiments, the liver disease is NASH. Fatty liver with liver inflammation not caused by alcohol is known as non-alcoholic steatohepatitis or NASH. In certain embodiments, NASH can be caused by any of the causes mentioned above as possible causes of non-alcoholic fatty liver disease.

In certain embodiments, the liver disease is hepatitis or inflammation of the liver, including viral and alcoholic hepatitis. In certain embodiments, the viral hepatitis is caused by hepatitis B, C, D or E virus. In certain embodiments, the viral hepatitis is caused by hepatitis B or C virus.

Exemplary methods of treatment of hepatitis C are described in Strader et ah, Hepatology 2004, 39, 1147-1171.

In certain embodiments, the viral hepatitis is acute. In certain embodiments, the acute viral hepatitis is caused by hepatitis B, C, D or E virus. In certain embodiments, the acute viral hepatitis is caused by hepatitis B or C virus.

In certain embodiments, the viral hepatitis is chronic. In certain embodiments, the chronic viral hepatitis is caused by hepatitis B, C, D or E virus. In certain embodiments, the chronic viral hepatitis is caused by hepatitis B or C virus.

In certain embodiments, the liver disease is caused by HCV infection. In certain embodiments, the subject has never received therapy or prophylaxis for HCV infection. In certain

embodiments, the subject has previously received therapy or prophylaxis for HCV infection. In certain embodiments, the subject has not responded to HCV therapy. As known in the art, under current interferon therapy, up to 50% or more HCV patients do not respond to therapy (Genotype 1). In certain embodiments, the subject is a patient that received therapy but continued to suffer from HCV or one or more symptoms thereof. In certain embodiments, the subject is a patient that received therapy but failed to achieve a sustained response. In certain embodiments, the subject has received therapy for HCV infection but has failed show a 2 logio decline in HCV RNA levels after 12 weeks of therapy. It is believed that patients who have not shown more than 2 logio reduction in serum HCV RNA after 12 weeks of therapy have a 97- 100% chance of not responding.

In certain embodiments, the subject is a patient that discontinued HCV therapy because of one or more adverse events associated with the therapy. In certain embodiments, the subject is a patient where current therapy is not indicated. For instance, certain therapies for HCV are associated with neuropsychiatry events. Interferon (IFN)-a plus ribavirin is associated with a high rate of depression. Depressive symptoms have been linked to a worse outcome in a number of medical disorders. Life-threatening or fatal neuropsychiatry events, including suicide, suicidal and homicidal ideation, depression, relapse of drug addiction/overdose, and aggressive behavior have occurred in patients with and without a previous psychiatric disorder during HCV therapy.

Interferon-induced depression is a limitation for the treatment of chronic hepatitis C, especially for patients with psychiatric disorders. Psychiatric side effects are common with interferon therapy and responsible for about 10% to 20% of discontinuations of current therapy for HCV infection.

Accordingly, provided herein is a method of treating or preventing hepatitis C in a subject where the risk of neuropsychiatry events, such as depression, contraindicates treatment with current HCV therapy. Also provided is a method of treating hepatitis C in a subject where a

neuropsychiatric event, such as depression, or risk of such indicates discontinuation of treatment with current HCV therapy. Further provided herein is a method of treating hepatitis C in a subject where a neuropsychiatric event, such as depression, or risk of such indicates dose reduction of current HCV therapy.

Current therapy is also contraindicated in patients that are hypersensitive to interferon or ribavirin, or both, or any other component of a pharmaceutical product for administration of interferon or ribavirin. Current therapy is not indicated in patients with hemoglobinopathies (e.g. , thalassemia major, sickle-cell anemia) and other patients at risk from the hematologic side effects of current therapy. Common hematologic side effects include bone marrow suppression, neutropenia, and thrombocytopenia. Furthermore, ribavirin is toxic to red blood cells and is associated with hemolysis. Accordingly, the methods provided herein are useful in patients hypersensitive to interferon or ribavirin, or both, patients with a hemoglobinopathy, for instance thalassemia major patients and sickle-cell anemia patients, and other patients at risk from the hematologic side effects of current therapy. In certain embodiments, the subject has received HCV therapy and discontinued that therapy prior to administration of a method provided herein. In further embodiments, the patient has received therapy and continues to receive that therapy along with administration of a method provided herein. The methods provided herein can be co-administered with other therapy for HCV according to the judgment of one of skill in the art. In certain embodiments, the methods or compositions provided herein can be co-administered with a reduced dose of the other therapy for HCV.

In certain embodiments, provided are methods of treating a subject that is refractory to treatment with interferon. For instance, in some embodiments, the patient can be a patient that has failed to respond to treatment with one or more agents selected from the group consisting of interferon, interferon a, pegylated interferon a, interferon plus ribavirin, interferon a plus ribavirin and pegylated interferon a plus ribavirin. In some embodiments, the patient can be a patient that has responded poorly to treatment with one or more agents selected from the group consisting of interferon, interferon a, pegylated interferon a, interferon plus ribavirin, interferon a plus ribavirin and pegylated interferon a plus ribavirin.

In one embodiment, chronic HCV infection is manifested by raised liver enzymes (e.g., ALT, AST), persistent (e.g., greater than six months) HCV RNA levels, and/or histological evidence of liver damage, fibrosis, and/or cirrhosis. In one embodiment, the methods provided herein lower the elevated level of liver enzyme, such as ALT and AST levels. Methods for measuring the level of liver enzymes are well known in the art (Jeong et ah, Clin Chem. 2003, 49, 826-829; and Roziers et ah, Transfusion. 1995, 35, 331-334). In one embodiment, the elevated level or excess level of one or more liver enzyme, such as ALT or AST, or the total amount of elevated liver enzyme above the normal range is reduced to the normal levels of liver enzymes using the methods provided herein. In one embodiment, the elevated level or excess level of one or more liver enzyme, such as ALT or AST, or the total amount of elevated liver enzyme above the normal range is reduced by more than about 90% or more than 95%. In one embodiment, the elevated level of one or more liver enzyme, such as elevated levels of ALT or AST, or the total amount of elevated liver enzyme is reduced by at least about 95%, at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, at least about 10%, at least about 5%, at least about 2%, or at least about 1%.

In certain embodiment, provided herein is a method for treating a subject infected with hepatitis C virus and has a normal serum aminotransferase level. It has been reported that up to 60% of HCV-infected first-time blood donors and injection drug users have normal levels of ALT (Strader et ah, Hepatology, 2004, 39, 1147-1171). In one embodiment, a subject is considered to have normal ALT levels when there have been two or more determinations identified to be in the normal range of a licensed laboratory over six or more months. It is known in the art that biopsies of those with normal aminotransferase values have revealed bridging fibrosis or cirrhosis in 1% to 10% of cases, and at least portal fibrosis in a greater proportion (Strader et ah, Hepatology, 2004, 39, 1147-1171).

In certain embodiments, the liver disease is alcoholic hepatitis. Alcoholic hepatitis

(steatohepatitis) is a combination of fatty liver, diffuse liver inflammation, and liver necrosis, focal necrosis, all in various degrees of severity. In certain embodiments, the liver disease is liver fibrosis, lobular hepatitis, or periportal bridging necrosis. Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. In certain embodiments, an advanced liver fibrosis results in cirrhosis and liver failure.

In certain embodiments, provided herein is a method for reducing the level of fibrosis, lobular hepatitis, and/or periportal bridging necrosis in a subject, which comprises administering to the subject a therapeutically effective amount of a solid form provided herein, e.g., crystalline Form A or B or an amorphous form of the phenoxybenzenesulfonyl compound. Methods for measuring liver histologies such as changes in the extent of fibrosis, lobular hepatitis, and periportal bridging necrosis are well known in the art. For example, several non-invasive tests for liver fibrosis are described in Hepatology, 2006, 43, S 113-S 120; Hepatology, 2007, 45, 242- 249 (describing the measurement and treatment of liver fibrosis); Wright et ah, Gut. 2003, 52, 574 9 (describing measurement and determinants of the natural history of liver fibrosis in hepatitis C virus infection: a cross sectional and longitudinal study).

In certain embodiments, liver fibrosis is caused by hepatitis, chemical exposure, bile duct obstruction, autoimmune disease, obstruction of outflow of blood from the liver, heart and blood vessel disturbance, ocl -antitrypsin deficiency, high blood galactose level, high blood tyrosine level, glycogen storage disease, diabetes, malnutrition, Wilson Disease or hemochromatosis.

In one embodiment, the level of fibrosis, which is the formation of fibrous tissue, fibroid or fibrous degeneration, is reduced by more that about 90%. In one embodiment, the level of fibrosis, which is the formation of fibrous tissue, fibroid or fibrous degeneration, is reduced by at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, at least about 10%, at least about 5%, or at least about 2%. In certain embodiments, provided herein is a method for reducing the level of fibrogenesis in a subject, which comprises administering to the subject a therapeutically effective amount of a solid form provided herein, e.g. , crystalline Form A or B or an amorphous form of the phenoxybenzenesulfonyl compound. Liver fibrogenesis is the process leading to the deposition of an excess of extracellular matrix components in the liver known as fibrosis. It is observed in a number of conditions such as chronic viral hepatitis B and C, alcoholic liver disease, drug- induced liver disease, hemochromatosis, auto-immune hepatitis, Wilson disease, primary biliary cirrhosis, sclerosing cholangitis, liver schistosomiasis, and others. In certain embodiments, the level of fibrogenesis is reduced by more that about 90%. In one embodiment, the level of fibrogenesis is reduced by at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, at least about 10%, at least about 5% or at least about 2%.

In certain embodiments, the level of lobular hepatitis, wherein foci of inflammatory cells are also present in the sinusoids of the lobule is reduced by more that about 99% or about 95%. In another embodiment, the level of lobular hepatitis is reduced by at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, at least about 10%, at least about 5%, at least about 2% or at least about 1%.

In certain embodiments, the level of periportal bridging necrosis is reduced by more than about 90%. In yet another embodiment, the level of periportal bridging necrosis is reduced by at least about 90%, at least about 80%, at least about 70%, at least about 60%, at least about 50%, at least about 40%, at least about 30%, at least about 20%, at least about 10%, at least about 5%, at least about 2% or at least about 1%.

In certain embodiments, provided herein is a method for treating cirrhosis in a subject, which comprises administering to the subject a therapeutically effective amount of a solid form provided herein, e.g. , crystalline Form A or B or an amorphous form of the

phenoxybenzenesulfonyl compound. In certain embodiments, symptoms of cirrhosis include, but are not limited to, portal hypertension, abnormal nerve function, ascites (build-up of fluid in the abdominal cavity), breast enlargement in men, coughing up or vomiting blood, curling of fingers (Dupuytren contracture of the palms), gallstones, hair loss, itching, jaundice, kidney failure, liver encephalopathy, muscle loss, poor appetite, redness of palms, salivary gland enlargement in cheeks, shrinking of testes, small spider-like veins in skin, weakness, weight loss, spider angiomas (a central arteriole from which numerous small branching vessels radiate), encephalopathy, and asterixis (flapping tremor). Symptoms of cirrhosis vary, depending on severity and individuals. In certain embodiments, mild cirrhosis may not exhibit any symptoms at all.

In certain embodiments, the causes of cirrhosis include, but are not limited to, hepatitis and other viruses (e.g., HCV), use of certain drugs, chemical exposure, bile duct obstruction, autoimmune diseases, obstruction of outflow of blood from the liver (i.e., Budd-Chiari syndrome), heart and blood vessel disturbances, alphal-antitrypsin deficiency, high blood galactose levels, high blood tyrosine levels, glycogen storage disease, diabetes, malnutrition, hereditary accumulation of too much copper (Wilson Disease) or iron (hemochromatosis). In one embodiment, the cause of cirrhosis is alcohol abuse.

In certain embodiments, provided herein is a method for reducing the level of cirrhosis in a subject, which comprises administering to the subject a therapeutically effective amount of a solid form provided herein, e.g. , crystalline Form A or B or an amorphous form of the phenoxybenzenesulfonyl compound. In one embodiment, cirrhosis is characterized

pathologically by loss of the normal microscopic lobular architecture, with fibrosis and nodular regeneration. Methods for measuring the extent of cirrhosis are well known in the art. In one embodiment, the level of cirrhosis is reduced by about 5%-100%. In one embodiment, the level of cirrhosis is reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% in the subject.

In certain embodiments, provided herein is a method for treating primary biliary cirrhosis (PBC) in a subject, which comprises administering to the subject a therapeutically effective amount of a solid form provided herein, e.g., crystalline Form A or B or an amorphous form of the phenoxybenzenesulfonyl compound. Primary biliary cirrhosis begins with inflammation of the bile ducts inside the liver. The inflammation blocks the flow of bile out of the liver; thus, bile remains in the liver cells or spills over into the bloodstream. As inflammation spreads from the bile ducts to the rest of the liver, a latticework of scar tissue develops throughout the liver. In one embodiment, the method is for treatment of PBC in women aged 35 to 60. In certain embodiments, the PBC is caused by an autoimmune disorder. In one embodiment, primary biliary cirrhosis occurs in association with rheumatoid arthritis, scleroderma, or autoimmune thyroiditis. The method provided herein is useful in treating one or more of the symptoms of primary biliary cirrhosis.

In certain embodiments, provided herein is a method for treating hepatic ischemia reperfusion injury in a subject, which comprises administering to the subject a therapeutically effective amount of a solid form provided herein, e.g. , crystalline Form A or B or an amorphous form of the phenoxybenzenesulfonyl compound. Ischemia can occur in the liver due to several pathological conditions, such as liver transplantation, cardiogenic or hemodynamic shock, and liver resection for trauma or tumor. When the blood circulation is reestablished (reperfusion), the rapid increase in oxygen concentration leads to the production of reactive oxygen species, which in turn cause a generalized damage of hepatic cells (both necrosis and apoptosis) resulting in ischemia-reperfusion (IR) injury in the liver.

In certain embodiment, provided herein is a method for inhibiting replication of a virus in a host, which comprises administering to the host an effective amount of a solid form provided herein, e.g. , crystalline Form A or B or an amorphous form of the phenoxybenzenesulfonyl compound. In one embodiment, the host is a cell. In another embodiment, the host is a human cell. In yet another embodiment, the host is a mammal. In still another embodiment, the host is human.

In certain embodiments, the subject is a patient that has received therapy for HCV infection but failed to show a 2 logio decline in HCV RNA level after 12 weeks of therapy. In certain embodiments, administration of a therapeutically effective amount of a solid form provided herein results in a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more reduction in the replication of the virus relative to a subject without administration of the compound, as determined at 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 14 days, 15 days, or 30 days after the administration by a method known in the art, e.g., determination of viral titer. In certain embodiments, administration of a therapeutically effective amount of a solid form provided herein results in a 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100-fold or more reduction in the replication of the virus relative to a subject without administration of the compound, as determined at 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 14 days, 15 days, or 30 days after the administration by a method known in the art. In certain embodiments, administration of a therapeutically effective amount of a solid form provided herein results in reduction of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more logio in the replication of the virus relative to a subject without administration of the compound, as determined at 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 14 days, 15 days, or 30 days after the administration by a method known in the art.

In certain embodiments, administration of a therapeutically effective amount of a solid form provided herein results in a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or more reduction in the viral titer relative to a subject without administration of the compound, as determined at 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 14 days, 15 days, or 30 days after the administration by a method known in the art.

In certain embodiments, administration of a therapeutically effective amount of a solid form provided herein results in a 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100 or more fold reduction in the viral titer relative to a subject without administration of the compound, as determined at 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 14 days, 15 days, or 30 days after the administration by a method known in the art. In certain embodiments, administration of a therapeutically effective amount of a solid form provided herein results in reduction of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more logio in the viral titer relative to a subject without administration of the compound, as determined at 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 14 days, 15 days, or 30 days after the administration by a method known in the art.

Depending on the condition, disorder, or disease, to be treated and the subject' s condition, a solid form of the phenoxybenzenesulfonyl compound provided herein may be administered by oral, parenteral (e.g. , intramuscular, intraperitoneal, intravenous, intracerebroventricular (ICV), intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g. , transdermal or local) routes of administration, and may be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In certain embodiments, a solid form of the phenoxybenzenesulfonyl compound provided herein is administered orally. In certain embodiments, a solid form of the phenoxybenzenesulfonyl compound provided herein is administered orally as a tablet. In certain embodiments, a solid form of the phenoxybenzenesulfonyl compound provided herein is administered orally as a capsule. In certain embodiments, a solid form of the phenoxybenzenesulfonyl compound provided herein is administered orally as an elixir. In certain embodiments, a solid form of the

phenoxybenzenesulfonyl compound provided herein is administered parenterally. In certain embodiments, a solid form of the phenoxybenzenesulfonyl compound provided herein is administered intravenously.

The dose may be in the form of one, two, three, four, five, six, or more sub-doses that are administered at appropriate intervals per day. The dose or sub-doses can be administered in the form of dosage units containing from about 0.1 to about 1,000 milligram, from about 0.1 to about 500 milligrams, or from 0.5 about to about 100 milligram active ingredient(s) per dosage unit, and if the condition of the patient requires, the dose can, by way of alternative, be administered as a continuous infusion. In certain embodiments, a solid form of the

phenoxybenzenesulfonyl compound provided herein is administered to a subject in the amount ranging from about 1 to about 1,000, from about 10 to about 500, from about 20 to about 400, or from about 50 to about 400 mg/day. In one embodiment, a solid form of the

phenoxybenzenesulfonyl compound provided herein is administered to a subject in the amount of about 25, about 50, about 100, about 150, about 200, about 250, about 300, about 350, or about 400 mg/day. In another embodiment, a solid form of the phenoxybenzenesulfonyl compound provided herein is administered to a subject in the amount of about 25 or about 200 mg/day as a single dose. In yet another embodiment, a solid form of the

phenoxybenzenesulfonyl compound provided herein is administered to a subject in the amount of about 50 mg, about 100, about 150, about 200, about 250, about 300, about 350, or about 400 mg once a day (QD). In yet another embodiment, a solid form of the phenoxybenzenesulfonyl compound provided herein is administered to a subject in the amount of about 50, about 100, about 150, or about 200 mg twice a day (BID).

In certain embodiments, an appropriate dosage level is about 0.01 to about 100 mg per kg patient body weight per day (mg/kg per day), about 0.01 to about 50 mg/kg per day, about 0.01 to about 25 mg/kg per day, or about 0.05 to about 10 mg/kg per day, which may be administered in single or multiple doses. A suitable dosage level may be about 0.01 to about 100 mg/kg per day, about 0.05 to about 50 mg/kg per day, or about 0.1 to about 10 mg/kg per day. Within this range the dosage may be about 0.01 to about 0.1, about 0.1 to about 1.0, about 1.0 to about 10, or about 10 to about 50 mg/kg per day. In certain embodiments, a solid form of the phenoxybenzenesulfonyl compound provided herein is administered to a subject at a dosage level ranging from about 0.1 to about 1,000, from about 1 to about 500, from about 2 to about 250 mg/kg per day. In certain embodiments, a solid form of the phenoxybenzenesulfonyl compound provided herein is administered to a subject at a dosage level ranging from about 5 to about 10 mg/kg per day. In certain embodiments, a solid form of the phenoxybenzenesulfonyl compound provided herein is administered to a subject at a dosage level of about 2 or 250 mg/kg per day.

Combination Therapy

The solid forms of the phenoxybenzenesulfonyl compounds provided herein may also be combined or used in combination with other therapeutic agents useful in the treatment and/or prevention of a liver disease.

As used herein, the term "in combination" includes the use of more than one therapy (e.g. , one or more prophylactic and/or therapeutic agents). However, the use of the term "in combination" does not restrict the order in which therapies (e.g. , prophylactic and/or therapeutic agents) are administered to a subject with a disease or disorder. A first therapy (e.g. , a prophylactic or therapeutic agent such as a compound provided herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g. , 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g. , a prophylactic or therapeutic agent) to the subject.

Triple therapy is also contemplated herein.

As used herein, the term "synergistic" includes a combination of a solid form of the

phenoxybenzenesulfonyl compound provided herein and another therapy (e.g., a prophylactic or therapeutic agent) which has been or is currently being used to prevent, treat, or manage a condition, disorder, or disease, which is more effective than the additive effects of the therapies. A synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a subject with a condition, disorder, or disease. The ability to utilize lower dosages of a therapy (e.g., a prophylactic or therapeutic agent) and/or to administer said therapy less frequently reduces the toxicity associated with the administration of said therapy to a subject without reducing the efficacy of said therapy in the prevention, treatment, or management of a condition, disorder, or disease). In addition, a synergistic effect can result in improved efficacy of agents in the prevention, treatment, or management of a condition, disorder, or disease. Finally, a synergistic effect of a combination of therapies (e.g. , a combination of prophylactic or therapeutic agents) may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone.

A solid form of the phenoxybenzenesulfonyl compound provided herein can be administered in combination or alternation with another therapeutic agent, such as an anti-HCV agent. In combination therapy, effective dosages of two or more agents are administered together, whereas in alternation or sequential-step therapy, an effective dosage of each agent is administered serially or sequentially. The dosages given will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

For example, it has been recognized that drug-resistant variants of HCV can emerge after prolonged treatment with an antiviral agent. Drug resistance most typically occurs due to the mutation of a gene that encodes for an enzyme used in viral replication. The efficacy of a drug against the viral infection can be prolonged, augmented, or restored by administering a compound in combination or alternation with a second, and perhaps third, antiviral compound that induces a different mutation from that caused by the principle drug. Alternatively, the pharmacokinetics, biodistribution, or other parameters of the drug can be altered by such combination or alternation therapy. In general, combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the virus.

In certain embodiments, the pharmaceutical compositions provided herein further comprise a second antiviral agent as described herein. In certain embodiments, the compound provided herein is combined with one or more agents selected from the group consisting of an interferon, ribavirin, amantadine, an interleukin, an NS3 protease inhibitor, an NS5A inhibitor, a HCV polymerase inhibitor, a cyclophyllin inhibitor, a therapeutic vaccine, a cysteine protease inhibitor, a thiazolidine, a benzanilide, a helicase inhibitor, a gliotoxin, a cerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES -dependent translation, and a ribozyme. In one embodiment, the second antiviral agent is an interferon. In another

embodiment, the interferon is selected from the group consisting of pegylated interferon alpha 2a, pegylated interferon alpha 2b, pegylated interferon lambda, interferon alfacon-1, natural interferon, ALBUFERON^®, interferon beta- la, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta, interferon lambda, and interferon gamma- lb.

In certain embodiments, a solid form of the phenoxybenzenesulfonyl compound provided herein is combined with a HCV protease inhibitor, including, but not limited to, Telaprevir (VX-950), Boceprevir (SCH-603034), TMC435, BI 201335, Vaniprevir, Narlaprevir (SCH-900518), Danoprevir (ITMN-191, RG7227), BMS-850032, ACH-1625, GS 9256, ABT-450, IDX320, GS- 9451, ACH-2684, and MK-6172.

Other suitable protease inhibitors for the treatment of HCV include those disclosed in, for example, U.S. Pat. No. 6,004,933, which discloses a class of cysteine protease inhibitors of HCV endopeptidase 2. Other protease inhibitors include thiazolidine derivatives, such as RD-1-6250, RD4 6205, and RD4 6193, which show relevant inhibition in a reverse-phase HPLC assay with an NS3/4A fusion protein and NS5A/5B substrate (Sudo et al., Antiviral Research 1996, 32, 9-18); and thiazolidines and benzanilides identified in Kakiuchi et ah, FEBS Lett. 1998, 421, 217-220; and Takeshita et al, Analytical Biochemistry 1997, 247, 242-246. In certain embodiments, a solid form of the phenoxybenzenesulfonyl compound provided herein is combined with a HCV polymerase inhibitor, including, but not limited to, R7128, PSI-7977, PSI-938, INX-184, GS-9190, Filibuvir I, ANA-598, ABT-333, and IDX375.

In certain embodiments, a solid form of the phenoxybenzenesulfonyl compound provided herein is combined with an NS5A inhibitor, including, but not limited to, BMS-790052, PPI-461, GS- 5885, and BMS-824393.

In certain embodiments, a solid form of the phenoxybenzenesulfonyl compound provided herein is combined with a cyclophillin inhibitor, including, but not limited to, Debio 025 and SCY-635

In certain embodiments, a solid form of the phenoxybenzenesulfonyl compound provided herein is combined with a therapeutic vaccine, including, but not limited to, GI5005. In certain embodiments, the compound provided herein is combined with one or more agents selected from the group consisting of adefovir dipivoxil (Hepsera), tenofovir dipivoxil (Viread), lamivudine (Epivir), entecavir (Baraclude), and telbivudine (Tyzeka).

Suitable helicase inhibitors include, but are not limited to, those disclosed in U.S. Pat. No.

5,633,358; and International Pat. Appl. Publ. No. WO 97/36554.

Suitable nucleotide polymerase inhibitors include, but are not limited to, gliotoxin (Ferrari et al, Journal of Virology 1999, 73, 1649-1654) and cerulenin (Lohmann et al., Virology 1998, 249, 108-118).

Suitable interfering RNA (iRNA) based antivirals include, but are not limited to, short interfering RNA (siRNA) based antivirals, such as Sirna-034 and those described in International Pat. Appl. Publ. Nos. WO/03/070750 and WO 2005/012525, and U.S. Pat. Appl. Publ. No. 2004/0209831.

Suitable antisense phosphorothioate oligodeoxynucleotides (S-ODN) complementary to sequence stretches in the 5' non-coding region (NCR) of HCV virus include, but are not limited to those described in Alt et al., Hepatology 1995, 22, 707-717, and nucleotides 326-348 comprising the 3' end of the NCR and nucleotides 371-388 located in the core coding region of HCV RNA (Alt et al, Archives of Virology 1997, 142, 589-599; and Galderisi et al, Journal of Cellular Physiology 1999, 181, 251-257).

Suitable inhibitors of IRES -dependent translation include, but are not limited to, those described in Japanese Pat. Appl. Publ. Nos.: JP 08268890 and JP 10101591. Suitable ribozymes include those disclosed in, for example, U.S. Pat. Nos. 6,043,077; 5,869,253; and 5,610,054.

Suitable nucleoside analogs include, but are not limited to, the compounds described in U.S. Pat. Nos.: 6,660,721; 6,777,395; 6,784,166; 6,846,810; 6,927,291; 7,094,770; 7,105,499; 7,125,855; and 7,202,224; U.S. Pat. Appl. Publ. Nos. 2004/0121980; 2005/0009737; 2005/0038240; and 2006/0040890; and International Pat. Appl. Publ. Nos: WO 99/43691; WO 01/32153; WO 01/60315; WO 01/79246; WO 01/90121, WO 01/92282, WO 02/18404; WO 02/32920, WO 02/48165, WO 02/057425; WO 02/057287; WO 2004/002422, WO 2004/002999, and WO 2004/003000.

Other miscellaneous compounds that can be used as second agents include, for example, 1- amino-alkylcyclohexanes (U.S. Pat. No. 6,034,134), alkyl lipids (U.S. Pat. No. 5,922,757), vitamin E and other antioxidants (U.S. Pat. No. 5,922,757), squalene, amantadine, bile acids (U.S. Pat. No. 5,846,964), N-(phosphonacetyl)-L-aspartic acid (U.S. Pat. No. 5,830,905), benzenedicarboxamides (U.S. Pat. No. 5,633,388), polyadenylic acid derivatives (U.S. Pat. No. 5,496,546), 2',3'-dideoxyinosine (U.S. Pat. No. 5,026,687), benzimidazoles (U.S. Pat. No.

5,891,874), plant extracts (U.S. Pat. Nos. 5,725,859; 5,837,257; and 6,056,961), and piperidines (U.S. Pat. No. 5,830,905).

In certain embodiments, one or more of the solid forms of the phenoxybenzenesulfonyl compound provided herein are administered in combination or alternation with an anti-hepatitis C virus interferon, including, but not limited to, INTRON^® A (interferon alfa-2b), PEGASYS^® (Peginterferon alfa-2a) ROFERON^® A (recombinant interferon alfa-2a), INFERGEN^®

(interferon alfacon-1), and PEG-INTRON^® (pegylated interferon alfa-2b). In one embodiment, the anti-hepatitis C virus interferon is INFERGEN^®, IL-29 (PEG-Interferon lambda), R7025 (Maxy-alpha), BELEROFON^®, oral interferon alpha, BLX-883 (LOCTERON^®), omega interferon, MULTIFERON^®, medusa interferon, ALBUFERON^®, or REBIF^®.

In certain embodiments, one or more of the solid forms of the phenoxybenzenesulfonyl compound provided herein are administered in combination or alternation with an anti-hepatitis C virus polymerase inhibitor, such as ribavirin, viramidine, NM 283 (valopicitabine), PSI-6130, R1626, HCV-796, R7128, IDX184, and IDX375. In certain embodiments, one or more of the solid forms of the phenoxybenzenesulfonyl compound provided herein are administered in combination with ribavirin and an anti-hepatitis C virus interferon, such as INTRON^® A (interferon alfa-2b), PEGASYS^® (Peginterferon alfa-2a), ROFERON^® A (recombinant interferon alfa-2a), INFERGEN^® (interferon alfacon-1), and PEG- INTRON^® (pegylated interferon alfa-2b). In certain embodiments, one or more of the solid forms of the phenoxybenzenesulfonyl compound provided herein are administered in combination or alternation with an anti-hepatitis C virus protease inhibitor, such as ITMN-191, SCH 503034, VX950 (telaprevir), and Medivir HCV protease inhibitor.

In certain embodiments, one or more of the solid forms of the phenoxybenzenesulfonyl compound provided herein are administered in combination or alternation with an anti-hepatitis C virus vaccine, including, but not limited to, TG4040, PEVIPRO™, CGI-5005, HCV/MF59, GV1001, IC41, and INNO0101 (El).

In certain embodiments, one or more of the solid forms of the phenoxybenzenesulfonyl compound provided herein are administered in combination or alternation with an anti-hepatitis C virus monoclonal antibody, such as AB68 and XTL-6865 (formerly HepX-C); or an anti- hepatitis C virus polyclonal antibody, such as cicavir.

In certain embodiments, one or more of the solid forms of the phenoxybenzenesulfonyl compound provided herein are administered in combination or alternation with an anti-hepatitis C virus immunomodulator, such as ZADAXIN^® (thymalfasin), NOV-205, and oglufanide. In certain embodiments, one or more of the solid forms of the phenoxybenzenesulfonyl compound provided herein are administered in combination or alternation with NEXAVAR^®, doxorubicin, PI-88, amantadine, JBK- 122, VGX-410C, MX-3253 (celgosivir), SUVUS^® (BIVN- 401 or virostat), PF-03491390 (formerly IDN-6556), G126270, UT-231B, DEBIO-025, EMZ702, ACH-0137171, MitoQ, ANA975, AVI-4065, bavituximab (tarvacin), ALINIA^® (nitrazoxanide), and PYN17.

The solid forms of the phenoxybenzenesulfonyl compounds provided herein can also be administered in combination with other classes of compounds, including, but not limited to, (1) alpha- adrenergic agents; (2) antiarrhythmic agents; (3) anti- atherosclerotic agents, such as ACAT inhibitors; (4) antibiotics, such as anthracyc lines, bleomycins, mitomycin, dactinomycin, and plicamycin; (5) anticancer agents and cytotoxic agents, e.g. , alkylating agents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes; (6) anticoagulants, such as acenocoumarol, argatroban, bivalirudin, lepirudin, fondaparinux, heparin, phenindione, warfarin, and ximelagatran; (7) anti-diabetic agents, such as biguanides (e.g. , metformin), glucosidase inhibitors (e.g. , acarbose), insulins, meglitinides (e.g. , repaglinide), sulfonylureas (e.g. , glimepiride, glyburide, and glipizide), thiozolidinediones (e.g. , troglitazone, rosiglitazone, and pioglitazone), and PPAR-gamma agonists; (8) antifungal agents, such as amorolfine, amphotericin B, anidulafungin, bifonazole, butenafine, butoconazole, caspofungin, ciclopirox, clotrimazole, econazole, fenticonazole, filipin, fluconazole, isoconazole, itraconazole,

ketoconazole, micafungin, miconazole, naftifine, natamycin, nystatin, oxyconazole,

ravuconazole, posaconazole, rimocidin, sertaconazole, sulconazole, terbinafine, terconazole, tioconazole, and voriconazole; (9) antiinflammatories, e.g. , non-steroidal anti-inflammatory agents, such as aceclofenac, acemetacin, amoxiprin, aspirin, azapropazone, benorilate, bromfenac, carprofen, celecoxib, choline magnesium salicylate, diclofenac, diflunisal, etodolac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicyl salicylate, sulindac,

sulfinpyrazone, suprofen, tenoxicam, tiaprofenic acid, and tolmetin; (10) antimetabolites, such as folate antagonists, purine analogues, and pyrimidine analogues; (11) anti-platelet agents, such as GPIIb/IIIa blockers (e.g. , abciximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g. , clopidogrel, ticlopidine and CS-747), cilostazol, dipyridamole, and aspirin; (12)

antiproliferatives, such as methotrexate, FK506 (tacrolimus), and mycophenolate mofetil; (13) anti-TNF antibodies or soluble TNF receptor, such as etanercept, rapamycin, and leflunimide; (14) aP2 inhibitors; (15) beta-adrenergic agents, such as carvedilol and metoprolol; (16) bile acid sequestrants, such as questran; (17) calcium channel blockers, such as amlodipine besylate; (18) chemotherapeutic agents; (19) cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib; (20) cyclosporins; (21) cytotoxic drugs, such as azathioprine and cyclophosphamide; (22) diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzothiazide, ethacrynic acid, ticrynafen, chlorthalidone, furosenide, muzolimine, bumetanide, triamterene, amiloride, and spironolactone; (23) endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; (24) enzymes, such as L-asparaginase; (25) Factor Vila Inhibitors and Factor Xa Inhibitors; (26) farnesyl-protein transferase inhibitors; (27) fibrates; (28) growth factor inhibitors, such as modulators of PDGF activity; (29) growth hormone secretagogues; (30) HMG CoA reductase inhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known as rosuvastatin, atavastatin, or visastatin); neutral endopeptidase (NEP) inhibitors; (31) hormonal agents, such as

glucocorticoids (e.g. , cortisone), estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; (32)

immunosuppressants; (33) mineralocorticoid receptor antagonists, such as spironolactone and eplerenone; (34) microtubule-disruptor agents, such as ecteinascidins; (35) microtubule- stabilizing agents, such as pacitaxel, docetaxel, and epothilones A-F; (36) MTP Inhibitors; (37) niacin; (38) phosphodiesterase inhibitors, such as PDE III inhibitors (e.g. , cilostazol) and PDE V inhibitors (e.g. , sildenafil, tadalafil, and vardenafil); (39) plant-derived products, such as vinca alkaloids, epipodophyllotoxins, and taxanes; (40) platelet activating factor (PAF) antagonists; (41) platinum coordination complexes, such as cisplatin, satraplatin, and carboplatin; (42) potassium channel openers; (43) prenyl-protein transferase inhibitors; (44) protein tyrosine kinase inhibitors; (45) renin inhibitors; (46) squalene synthetase inhibitors; (47) steroids, such as aldosterone, beclometasone, betamethasone, deoxycorticosterone acetate, fludrocortisone, hydrocortisone (Cortisol), prednisolone, prednisone, methylprednisolone, dexamethasone, and triamcinolone; (48) TNF-alpha inhibitors, such as tenidap; (49) thrombin inhibitors, such as hirudin; (50) thrombolytic agents, such as anistreplase, reteplase, tenecteplase, tissue

plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated plasminogen streptokinase activator complex (APSAC); (51) thromboxane receptor antagonists, such as ifetroban; (52) topoisomerase inhibitors; (53) vasopeptidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilat and gemopatrilat; and (54) other miscellaneous agents, such as, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, and gold compounds.

The solid forms of the phenoxybenzenesulfonyl compound provided herein can also be provided as an article of manufacture using packaging materials well known to those of skill in the art. See, e.g. , U.S. Pat. Nos. 5,323,907; 5,052,558; and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. In certain embodiments the methods of use comprise administering to the subject a second agent, in combination or alteration.

In certain embodiments, the second agents are selected from the group consisting of an interferon, ribavirin, amantadine, an interleukin, an NS3 protease inhibitor, an NS5A inhibitor, a HCV polymerase inhibitor, a cyclophyllin inhibitor, a therapeutic vaccine, a cysteine protease inhibitor, a thiazolidine, a benzanilide, a helicase inhibitor, a gliotoxin, a cerulenin, an antisense

phosphorothioate oligodeoxynucleotide, an inhibitor of IRES -dependent translation, and a ribozyme.

In one embodiment, the second agent is an interferon.

In another embodiment, the interferon is selected from the group consisting of pegylated interferon alpha 2a, pegylated interferon alpha 2b, pegylated interferon lambda, interferon alfacon- 1, natural interferon, ALBUFERON^®, interferon beta- la, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta, interferon lambda, and interferon gamma- lb.

In some embodiments of the aforementioned method the subject is a patient that has received therapy for HCV infection but failed to achieve a sustained response.

In some embodiments of the aforementioned method the subject is a patient that has received therapy for HCV infection but failed to show a 2 logio decline in HCV RNA level after 12 weeks of therapy.

Provided herein also are kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a subject. In certain embodiments, the kit provided herein includes a container and a dosage form of a solid form of the

phenoxybenzenesulfonyl compound provided herein, e.g., crystalline Form A or B or an amorphous form.

In certain embodiments, the kit includes a container comprising a dosage form of a solid form of the phenoxybenzenesulfonyl compound provided herein, e.g., crystalline Form A or B or an amorphous form, in a container comprising one or more other therapeutic agent(s) described herein.

Kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needle-less injectors drip bags, patches, and inhalers. The kits provided herein can also include condoms for administration of the active ingredients.

Kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

The disclosure will be further understood by the following non-limiting examples.

EXAMPLES Example 1

General Methods

X-Ray Powder Diffraction (XRPD)

X-Ray powder diffraction patterns were collected on a Scintag X-ray Diffractometer (Model XI) with a Peltier detector, using CuKa radiation (wavelength = 1.540600A). The scanning angle (2Θ) was from 2° to 40° at 2° per minute. All samples were finely ground with an agate mortar and pestle prior to measurements.

Differential Scanning Calorimetry (DSC)

DSC data were recorded on a Perkin-Elmer DSC-7 interfaced to an IBM PC computer, and analyzed with Thermal Analysis software from MC2 Thermal Systems. The heating rate was 10 °C/minute and the sensitivity range set at 2 °C /second. A purge of nitrogen gas was maintained throughout each experimental run.

HYGROSCOPICITY

Briefly, approximately 15-20 mg of Form A solid were accurately weighed into small weighing bottles fitted with round glass top and placed in 11%, 22%, 51%, 75%, and 93% relative humidity chambers at ambient temperature. Relative humidity was maintained with saturated solutions of LiCl, KC₂H₃0₂, Ca(N0 )₂-4H₂0, NaCl, and NH₄H₂P0₄, respectively. At several intervals, the samples were removed from the chamber, weighed, and compared to the initial weights.

Example 2

Preparation of Form B of 4-[4-(4-chlorophenoxy)-benzenesulfonylmethyl]-tetrahydropyran-4- carboxylic acid hydroxyamide with seeding

To a solution of 4-[4-(4-chlorophenoxy)-benzenethiomethyl]-tetrahydropyran-4-carboxylic acid hydroxyamide (55.9 Kg) in NMP (365 L) was added a solution of OXONE^® (134 Kg) in water (313 L). The rate of addition was maintained such that the internal temperature of the reaction mixture was maintained at approximately 40 °C. The reaction mixture was agitated at approximately 35 °C. The reaction was complete after approximately 3 hrs as determined by TLC. Water (163 L) was added to the reaction mixture, and the mixture was cooled and stirred overnight at approximately 0 - 5 °C. The resulting precipitates were collected and divided into approximately 4 equal portions. Each portion was washed with water (1 X 60 L) and

centrifuged, and washed with hexane (43 Kg) and centrifuged. The solids were combined to afford 180.4 Kg of damp 4-[4-(4-chlorophenoxy)-benzenesulfonylmethyl]-tetrahydropyran-4- carboxylic acid hydroxyamide. The combined solids were suspended in ethyl acetate (469 Kg) and heated to reflux with agitation. A solution of 5% aqueous NaHC0₃ was added and agitated for approximately 1 hr at approximately 40 °C. The agitation was stopped and the aqueous NaHC0₃ phase was removed. Water (208 L) was added to ethyl acetate phase with agitation at approximately 60 °C for approximately 10 min. The aqueous phase was removed and the ethyl acetate was heated to 70 °C. The solution was filtered and collected. This solution was concentrated by distillation under vacuum to approximately 1/3 of the initial volume. The vacuum was released and seed crystals (25 g) of Form B were added. Distillation under vacuum was continued and the seeding procedure was repeated two more time (25 g of form B seed crystals each time) once each after the removal of 50 L of ethyl acetate. The distillation continued to the point that product began to crystalize out of solution. The temperature was reduced to 0 °C with agitation. The crystallized product was collected, washed with cold ethyl acetate, and dried to afford 4-[4-(4-chlorophenoxy)-benzenesulfonylmethyl]-tetrahydropyran-4- carboxylic acid hydroxyamide (34.8 Kg, 99.6% HPLC purity) as Form B as determined by XRPD analysis. Example 3

Characterization of Form A of 4-[4-(4-chlorophenoxy)-benzenesulfonylmethyl]-tetrahydropyran-

4-carboxylic acid hydroxyamide

Form A was analyzed by X-ray diffractometry and a representative XRPD pattern of crystalline Form A is shown in FIG. 1. Some XRPD peaks of crystalline Form A are summarized in Table 1. TABLE 1. X-Ray Diffraction Peaks for Form A

Two-theta angle (°) d Space (A) Intensity (%)

13.33 6.64 8

15.10 5.86 10

15.70 5.64 27

16.27 5.44 58

16.66 5.32 35

17.44 5.08 53

18.65 4.75 8

18.78 4.72 11

19.39 4.57 60

20.03 4.43 100

20.52 4.32 32

21.29 4.17 33

21.64 4.10 45

21.94 4.05 24

22.54 3.94 11

22.78 3.90 10

23.44 3.79 64

25.39 3.51 16

26.25 3.39 67

26.91 3.31 29

27.46 3.25 16

28.16 3.17 22

29.01 3.08 9

29.83 2.99 20

30.49 2.29 16

30.91 2.89 13

32.41 2.76 12

33.87 2.64 12

34.87 2.57 8

35.06 2.56 7

36.12 2.48 9

36.73 2.44 6

37.17 2.42 10

38.82 2.32 17

Form A was also analyzed by DSC. Form A shows a sharp endothermic peak with an onset temperature of about 149 °C and a maximum temperature of about 150 °C.

Example 4

Characterization of Form B of 4-[4-(4-chlorophenoxy)-benzenesulfonylmethyl]-tetrahydropyran- 4-carboxylic acid hydroxyamide

Form B was analyzed by X-ray diffractometry and a representative XRPD pattern of crystalline Form B is shown in FIG. 2. Some XRPD peaks of crystalline Form B are summarized in Table 2.

TABLE 2. X-Ray Diffraction Peaks for Form B

Form B was also analyzed by DSC. Form B shows a sharp endothermic peak with an onset temperature of about 154 °C and a maximum temperature of about 158 °C. Example 5

Characterization of 4-[4-(4-chlorophenoxy)-benzenesulfonylmethyl]-tetrahydropyran-4- carboxylic acid hydroxyamide in an amorphous form

The powder x-ray diffraction of the amorphous form is shown in FIG. 3. The amorphous form was also analyzed by DSC. The amorphous form shows an exotherm with an onset temperature of about 103 °C, which represents a transition of the amorphous form to a crystalline form. The amorphous form also shows an endotherm observed at an onset temperature of approximately 151 °C, corresponding to melting of a crystalline form.

Example 6

Stability of Form A

Samples of Form A were suspended in various solvents, including ethyl acetate, ethanol/water (1: 1), and water for 5 days. After exposure to each of these conditions, the samples were analyzed by x-ray powder diffractometry. Form A was found to be converted to Form B, when suspended in ethyl acetate or ethanol/water (1: 1) for prolonged periods. Form A was found to be physically stable when suspended in water for 7 days at 25 °C.

Additionally, samples of Form A were also tested at ambient temperature for 8 weeks under various controlled humidity conditions ranging from 11 % to 93% relative humidity. The results for hygroscopicity of Form A are summarized in Table 3.

TABLE 3

RH (%) Time (wks) Weight Change (%)

4 -0.368

11 6 -0.703

8 -2.00

4 -0.329

51 6 -0.277

8 -0.364

4 0.179

93 6 0.133

8 0.212 Samples of Form A were also tested for 10 months under conditions of elevated temperature and humidity (40 °C/75% RH). Samples from the studies were analyzed by DSC, TGA, and powder x-ray diffractometry. Form A was found to be physically stable in relative humidity at ambient temperature ranging from 11 % to 93%, at 40 °C in 75% relative humidity for 10 months, at 60 °C in 75% relative humidity for 1 week, and at 80 °C in 75% relative humidity for 3 weeks.

Furthermore, samples of Form A were tested for stability in a hydroxypropyl methylcellulose suspending vehicle for 3 days at 25°C, and then analyzed by x-ray powder diffractometry. Form A was found to be physically stable after suspension in the hydroxypropyl methylcellulose suspending vehicle at 25 °C for 3 days.

Example 7

Stability of Form B

Samples of Form B were suspended in various solvents including ethyl acetate, ethanol/water (1: 1), and water for 5 days. After exposure to each of these conditions, the samples were analyzed by x-ray powder diffractometry. Form B was found to be physically stable when suspended in water for 7 days at 25 °C.

Additionally, samples of Form B were tested at ambient temperature for 8 weeks under various controlled humidity conditions ranging from 11 % to 93% relative humidity. The results for hygroscopicity of Form B are summarized in Table 4.

TABLE 4

RH (%) Time (wks) Weight Change (%)

4 0.000

11 6 0.028

8 -0.035

4 0.022

51 6 0.088

8 -0.055

4 0.030

93 6 0.301

8 0.321 Samples of Form B were also tested for 10 months under conditions of elevated temperature and humidity (40 °C/75% RH). Samples from the studies were analyzed by DSC, TGA, and powder x-ray diffractometry. Form B was found to be physically stable at ambient temperature at relative humidity ranging from 11% to 93%, at 40 °C in 75% relative humidity for at least 10 months, at 60 °C in 75% relative humidity for 1 week, and at 80 °C in 75% relative humidity for 3 weeks.

Furthermore, samples of Form B were also tested for stability in a in hydroxypropyl

methylcellulose suspending vehicle for 3 days at 25°C, then analyzed by x-ray powder diffractometry. Form B was found to be physically stable after suspension in the hydroxypropyl methylcellulose suspending vehicle at 25 °C for 3 days.

Example 8

Stability of the amorphous form

The amorphous form was exposed to 93% relative humidity at ambient temperature for 44 hrs and suspended in water for 4 days at 25°C. A hot stage x-ray powder diffractometry experiment was conducted to determine crystal form conversion at elevated temperature.

Additionally, samples of an amorphous form were tested at ambient temperature for 8 weeks under various controlled humidity conditions ranging from 11 % to 93% relative humidity. The results for hygroscopicity of the amorphous form are summarized in Table 5.

TABLE 5

The amorphous form was found to be converted primarily to Form A with a small amount of Form B, when exposed to 93% relative humidity and after suspension in water. The amorphous form was found to be converted to either Form A or Form B, when heated during hot stage x-ray powder diffraction experiments.

Example 9

Preparation of Form A of 4-[4-(4-chlorophenoxy)-benzenesulfonylmethyl]-tetrahydropyran-4- carboxylic acid hydroxyamide

To a solution of 4-[4-(4-chlorophenoxy)-benzenethiomethyl]-tetrahydropyran-4-carboxylic acid hydroxyamide (7.6 g) in methanol (200 mL) was added a solution of OXONE^® (19 g) in water (128 mL). The reaction mixture was stirred at approximately 25 °C for 7.5 hrs at which time was determined to be complete by TLC. The reaction mixture was diluted with water and extracted 3 times with ethyl acetate. The ethyl acetate extracts were dried over MgS0₄. The product was crystallized from dry ethyl acetate and collected by vacuum filtration. The crystals were dried overnight at 70 °C under vacuum to afford 4-[4-(4-chlorophenoxy) benzenesulfonylmethyl]-tetrahydropyran-4-carboxylic acid hydroxyamide (6.43 g) as Form A as determined by XRPD analysis.

Example 10

To a solution of 4-[4-(4-chlorophenoxy)-benzenethiomethyl]-tetrahydropyran-4-carboxylic acid hydroxyamide (8.7 Kg) in l-methyl-2-pyrrolidinone (NMP) (71 L) was added a solution of OXONE^® (22.1 Kg) in water (78 L). The rate of addition was maintained such that the internal temperature of the reaction mixture was maintained at approximately 20 °C. The reaction mixture was stirred at approximately 25 °C. The reaction was complete after 1.5 hrs as determined by TLC to produce 4-[4-(4-chlorophenoxy)-benzenesulfonylmethyl]- tetrahydropyran-4-carboxylic acid hydroxyamide (97% HPLC purity). Water (230 L) was added to the reaction mixture and the resulting mixture was stirred overnight at 5 °C. The resulting precipitate was filtered and the filter cake was washed with water (3 X 40 L), which was followed by washing with hexane (25 Kg). The solids were dried over a stream of nitrogen for 72 hrs. The solids were collected to afford 8.86 Kg of crude 4-[4-(4-chlorophenoxy)- benzenesulfonylmethyl]-tetrahydropyran-4-carboxylic acid hydroxyamide. This product was dissolved in ethyl acetate (approximately 240 Kg) and heated to approximately 75 °C, and the solution was filtered. The collected filtrate was concentrated under vacuum to approximately 30 L. This mixture was stirred overnight at 5 °C. The solids were filtered and dried over nitrogen for 14 hrs to afford 7.64 Kg of material. This material was dissolved in 172 Kg of ethyl acetate, heated to reflux, and filtered. Ethyl acetate was concentrated under vacuum to approximately 30 L. Hexane (30 Kg) was added, and the mixture concentrated in vacuo to a total volume of approximately 25 L. The mixture was cooled to 5 °C and stirred under nitrogen overnight. The solids were filtered and the filter cake dried under a stream of nitrogen for 48 hrs to afford 4- [4- (4-chlorophenoxy)-benzenesulfonylmethyl] -tetrahydro-pyran-4-carboxylic acid hydroxyamide (7.2 Kg, 99.6% HPLC purity) as Form A as determined by XRPD analysis.

Example 11

Preparation of Form B of 4-[4-(4-chlorophenoxy)-benzenesulfonylmethyl]-tetrahydropyran-4- carboxylic acid hydroxyamide

To a solution of 4-[4-(4-chlorophenoxy)-benzenethiomethyl]-tetrahydropyran-4-carboxylic acid hydroxyamide (240 g) in methanol (4.8 L) was added a solution of OXONE^® (609 g) in water (2.99 L). The reaction mixture was stirred at approximately 25 °C. The reaction was complete after 2.1 hrs as determined by TLC. The reaction mixture was diluted with ethyl acetate (3 L). The precipitated solids were filtered and washed with ethyl acetate (5 X 100 mL). The combined solvent was concentrated in vacuo to a total volume of approximately 4 L. The resulting precipitate was filtered and washed with water, followed by hexane. The filtrate was dissolved in ethyl acetate (1 L). The aqueous wash was extracted with ethyl acetate (3 X 500 mL). The ethyl acetate solution and extracts were combined to afford a total volume of approximately 2.4 L, and washed with 5% aqueous NaHC0₃ (1 X 300 mL). The ethyl acetate was heated to 55 °C and the solvent was concentrated in vacuo to approximately 1 L. The solution was allowed to stir at room temperature overnight. The solution was cooled to approximately -5 °C and an equal volume of hexane (approximately 1 L) was added. The ethyl acetate/hexane mixture was stirred and filtered to afford 4-[4-(4-chlorophenoxy)-benzenesulfonylmethyl]-tetrahydropyran-4- carboxylic acid hydroxyamide (215 g, 98% HPLC purity) as Form B as determined by XRPD analysis.

Example 12

Preparation of Form B of 4-[4-(4-chlorophenoxy)-benzenesulfonylmethyl]-tetrahydropyran-4- carboxylic acid hydroxyamide without seeding

To a solution of 4-[4-(4-chlorophenoxy)-benzenethiomethyl]-tetrahydropyran-4-carboxylic acid hydroxyamide (24 Kg) in l-methyl-2-pyrrolidinone (NMP) (240 L) was added a solution of OXONE^® (61 Kg) in water (219 L). The rate of addition was maintained such that the internal temperature was maintained at approximately 20 °C. The reaction mixture was stirred at approximately 25 °C. The reaction was complete after approximately 3 hrs as determined by TLC. Water (300 L) was added to the reaction mixture and the resulting mixture was stirred overnight at approximately 10 - 15 °C. The resulting precipitate was filtered and the filter cake was washed with water (3 X 40L), followed with hexane (35 Kg). The solids were dried over a stream of nitrogen overnight to afford 42.5 Kg of crude 4-[4-(4-chlorophenoxy)- benzenesulfonylmethyl]-tetrahydropyran-4-carboxylic acid hydroxyamide. This product was dissolved in ethyl acetate (approximately 146 L) and heated to reflux with agitation. The ethyl acetate solution was washed with deionized water (142 L). The water wash was separated and the ethyl acetate solution was washed with approximately 5% aqueous NaHC0₃ (100 L). The NaHC0₃ phase was separated. To the ethyl acetate solution was added approximately 50 L of ethyl acetate and 50 L of deionized water. The resulting mixture was agitated and heated to approximately 55 °C. The aqueous layer was removed and the ethyl acetate solution was heated to reflux and filtered. The ethyl acetate was removed by distillation to a volume of

approximately 75 L. The resulting mixture was cooled to approximately 5 °C and allowed to stir over night under nitrogen purge. The solids were filtered and washed with ethyl acetate (2 X ~ 20L) and dried at 40 °C under a purge of nitrogen to yield 4-[4-(4-chlorophenoxy)- benzenesulfonylmethyl]-tetrahydropyran-4-carboxylic acid hydroxyamide (16.98 Kg, 99.7% HPLC purity) as Form B as determined by XRPD analysis.

Example 13

Preparation of 4-[4-(4-chlorophenoxy)-benzenesulfonylmethyl]-tetrahydropyran-4-carboxylic acid hydroxyamide in an amorphous form

A solution of 4-[4-(4-chlorophenoxy)-benzenesulfonylmethyl]-tetrahydropyran-4-carboxylic acid hydroxyamide in ie/ -butanol is lyophilized to form amorphous 4-[4-(4-chlorophenoxy)- benzenesulfonylmethyl] -tetrahydropyran-4-carboxylic acid hydroxyamide. Example 14

Pharmaceutical Formulations

Pharmaceutical formulations (tablets) comprising a solid form (e.g., Form B) of 4-[4-(4- chlorophenoxy)-benzenesulfonylmethyl]-tetrahydropyran-4-carboxylic acid hydroxyamide are illustrated in Table 6.

TABLE 6.

Ingredients Amount Per Tablet (mg)

Phenoxybenzenesulfonyl compound 2.50 5.00 10.00 30.00

Lactose Anhydrous 119.9 117.4 112.4 92.40

Croscarmellose Sodium 11.90 11.90 11.90

Povidone 6.400 6.400 6.400 6.400

Microcrystalline Cellulose 8.000 8.000 8.000 8.000

Magnesium Stearate 1.300 1.300 1.300 1.300

Purified Water Q.S. Q.S. Q.S. Q.S. Reference 1

Preparation of a mixture of Forms A and B of 4-[4-(4-chlorophenoxy)-benzenesulfonylmethyl]- tetrahydropyran-4-carboxylic acid hydroxyamide

To a solution of 4-[4-(4-chlorophenoxy)-benzenethiomethyl]-tetrahydropyran-4-carboxylic acid hydroxyamide (236 g) in methanol (3.14 L) was added a solution of OXONE^® (potassium peroxymonosulfate) (599 g) in water (2.36 L). The reaction mixture was stirred at approximately 25 °C. The reaction was complete as determined by thin layer chromatography (TLC) after 3.5 hrs. The resulting reaction mixture was diluted with water and extracted 3 times with ethyl acetate. The ethyl acetate phase was separated, dried over MgS0₄ and concentrated under vacuum to approximately 50% volume where crystals began to form. The solution was allowed to stand at room temperature overnight. The crystallized solids were collected and dried under vacuum to afford 4-[4-(4-chlorophenoxy)-benzenesulfonylmethyl]-tetrahydropyran-4- carboxylic acid hydroxyamide as a 55% to 45% mixture of Forms A and B (221 g), respectively, as determined by XRPD analysis.

The examples set forth above are provided to give those of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of what is disclosed herein. Modifications that are obvious to persons of skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited in this specification are incorporated herein by reference as if each such publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference.

Claims

1. A crystalline or amorphous form of 4-[4-(4-chlorophenoxy)-benzenesulfonyl- methyl]-tetrahydropyran-4-carboxylic acid hydroxyamide, or a pharmaceutically acceptable salt, solvate, or hydrate of such amorphous form.

2. A crystalline form of the compound according to claim 1, wherein the crystalline form is Form A, having an X-ray powder diffraction pattern with a peak expressed in two-theta at approximately 3.5, 13.3, 15.7, 16.7, 17.4, 18.8, 19.4, 21.3, 21.6, 21.9, 22.5, 22.8, 25.4, 26.3, 26.9, 27.5, 29.8, 30.9, 32.4, 33.9, 35.1, 36.1, 36.7, 37.2, or 38.8. 3. A crystalline form of the compound according to claim 1, wherein the crystalline form is Form B, having an X-ray powder diffraction pattern with a peak expressed in two-theta at approximately 5.8, 13.8, 14.6, 17.7, 19.8, 20.9, 23.1, 23.7, 24.2, 24.9, 29.4, 31.

3, 33.1, or 37.7.

4. An amorphous form of the compound according to claim 1, having an exotherm with an onset temperature of about 103 °C and with a peak temperature of about 151 °C in a differential scanning calorimetry thermogram.

5. The amorphous form of claim 4, wherein the amorphous form has a purity of no less than about 95%.

6. A pharmaceutical composition comprising the crystalline form of claim 1 or 2 and one or more pharmaceutically acceptable carriers.

7. A pharmaceutical composition comprising the crystalline form of claim 1 or 3 and one or more pharmaceutically acceptable carriers.

8. A pharmaceutical composition comprising the amorphous form of claim 1 or 4 and one or more pharmaceutically acceptable carriers.

9. The pharmaceutical composition of any of claims 6 to 8, further comprising a second antiviral agent.

10. The pharmaceutical composition of claim 9, wherein the second antiviral agent is selected from the group consisting of an interferon, ribavirin, an interleukin, an NS3 protease inhibitor, an NS5A inhibitor, a HCV polymerase inhibitor, a cyclophyllin inhibitor, a therapeutic vaccine, a cysteine protease inhibitor, a, thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, , acerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES -dependent translation, and a ribozyme.

11. The pharmaceutical composition of claim 10, wherein the second antiviral agent is an interferon.

12. The pharmaceutical composition of claim 11, wherein the interferon is selected from the group consisting of pegylated interferon alpha 2a, pegylated interferon alpha 2b, pegylated interferon lambda, interferon alfahcon-1, natural interferon, albuferon, interferon beta- la, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta, and interferon gamma- lb.

13. A method of treating, preventing, or ameliorating one or more symptoms of a liver disease in a subject, comprising administering to the subject the crystalline form of any of claims 1, 2 and 3 or the amorphous form of any of claims 1, and 4 or 5.

14. The method of any of claim 13, wherein the liver disease is an acute liver disease, or wherein the liver disease is a chronic liver disease.

15. The method of any of claims 13 and 14, wherein the liver disease is alcoholic fatty liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver fibrosis, cirrhosis, primary biliary cirrhosis, hepatic ischemia reperfusion injury, or hepatitis.

16. The method of any of claims 13 to 15, wherein the liver disease is hepatitis B, or hepatitis C.

17. The method of claim 13 to 16, wherein the method comprises administering to the subject a second agent, in combination or alternation.

18. The method of claim 17, wherein the second agent is selected from the group consisting of an interferon, ribavirin, amantadine, an interleukin, a NS3 protease inhibitor, a cysteine protease inhibitor, a phenathrenequinone, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a liotoxin, acerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES -dependent translation, and a ribozyme.

19. The method of claim 18, wherein the second agent is an interferon.

20. The method of claim 19, wherein the interferon is selected from the group consisting of pegylated interferon alpha 2a, interferon alfacon-1, natural interferon, albuferon, interferon beta- la, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta, and interferon gamma- lb.

21. The method of any of claims 16 to 20, wherein the subject is a patient that has received therapy for HCV infection but failed to achieve a sustained response.

22. The method of any of claims 16 to 21, wherein the subject is a patient that has received therapy for HCV infection but failed to show a 2 logio decline in HCV RNA level after 12 weeks of therapy.

23. A method for inhibiting replication of a virus in a host, which comprises administering to the host with the crystalline form of any of claims 1, 2 and 3 or the amorphous form of claim 4 or 5.

24. The method of claim 23, wherein the host is a human or a cell.

25. The crystalline form of any of claims 1, 2 and 3 or the amorphous form of claim 4 or 5 for use as therapeutically active substance.

26. The use of the crystalline form of any of claims 1, 2 and 3 or the amorphous form of claim 4 or 5 for use as therapeutically active substance for the treatment or prophylaxis of a liver disease.

27. The use of the crystalline form of any of claims 1, 2 and 3 or the amorphous form of claim 4 to 5 for use as therapeutically active substance for the preparation of a medicament for the treatment or prophylaxis of a liver disease.

28. The crystalline form of any of claims 1, 2 and 3 or the amorphous form of claim 4 or 5 for use in the treatment or prophylaxis of a liver disease.

29. The invention as hereinbefore described.