FIELD OF THE INVENTION

The present invention relates to pharmaceutically acceptable salts of [3-(4-{2-butyl- 1 - [4-(4-chloro-phenoxy)-phenyl]-1 H-imidazol-4-yl}-phenoxy)-propyl]-diethylamine

("COMPOUND I"), and their use as a therapeutic agent.

BACKGROUND OF THE INVENTION

The Receptor for Advanced Glycation Endproducts (RAGE) is a member of the immunoglobulin super family of cell surface molecules. Activation of RAGE in different tissues and organs leads to a number of pathophysiological consequences. RAGE has been implicated in a variety of conditions including: acute and chronic inflammation (Hofmann et al., Cell 97:889-901 (1999)), the development of diabetic late complications such as increased vascular permeability (Wautier et al., J. Clin. Invest. 97:238-243 (1995)), nephropathy (Teillet et al., J. Am. Soc. Nephrol. 11 : 1488- 1497 (2000)), atherosclerosis (Vlassara et. al., The Finnish Medical Society DUODECIM, Ann. Med. 28:419-426 (1996)), and retinopathy (Hammes et al., Diabetologia 42:603-607 (1999)). RAGE has also been implicated in Alzheimer's disease (Yan et al., Nature 382: 685-691 , (1996)), erectile dysfunction, and in tumor invasion and metastasis (Taguchi et al., Nature 405: 354-357, (2000)).

Binding of ligands such as advanced glycation endproducts (AGEs), S100/calgranulin/EN-RAGE, b-amyloid, CML (N ^e -Carboxymethyl lysine), and amphoterin to RAGE has been shown to modify expression of a variety of genes. For example, in many cell types interaction between RAGE and its ligands generates oxidative stress, which thereby results in activation of the free radical sensitive transcription factor NF-kB, and the activation of NF-kB regulated genes, such as the cytokines IL- 1 b, TNF- a, and the like. In addition, several other regulatory pathways, such as those involving p21 ras.

MAP kinases, ERK1 and ERK2, have been shown to be activated by binding of AGEs and other ligands to RAGE. In fact, transcription of RAGE itself is regulated at least in part by NF-kB. Thus, an ascending, and often detrimental, spiral is fueled by a positive feedback loop initiated by ligand binding. Antagonizing binding of physiological ligands to RAGE, therefore, is our target, for down-regulation of the pathophysiological changes brought about by excessive concentrations of AGEs and other ligands for RAGE. Pharmaceutically acceptable salts of a given compound may differ from each other with respect to one or more physical properties, such as solubility and dissociation, true density, melting point, crystal shape, compaction behavior, flow properties, and/or solid state stability. These differences affect practical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in determining bio-availability). Although U.S. Patent No. 7,884,219 discloses Form I and Form II of COMPOUND I as a free base, there is a need for additional drug forms that are useful for inhibiting RAGE activity in vitro and in vivo, and have properties suitable for large-scale manufacturing and formulation. Provided herein are new pharmaceutically acceptable salt forms of COMPOUND I, as well as methods of producing the pharmaceutically acceptable salt forms of COMPOUND I.

SUMMARY OF THE INVENTION

The preparation of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1 H-imidazol-4-yl}- phenoxy)-propyl]-diethyl-amine ("COMPOUND I") and the use thereof, such as an antagonist of the receptor for advanced glycation endproducts (RAGE) and in the treatment of various medical conditions, are described in US Patent Publication No. 2004-0082542 and in US Patent Publication No. 2005-002681 1. Such diseases or disease states may include, but are not limited to, acute and chronic inflammation, amyloidosis, Alzheimer's disease, cancer, tumor invasion and metastasis, kidney failure, or inflammation associated with autoimmunity, inflammatory bowel disease, rheumatoid arthritis, psoriasis, multiple sclerosis, hypoxia, stroke, heart attack, hemorrhagic shock, sepsis, organ transplantation, the development of diabetic late complications such as increased vascular permeability, diabetic nephropathy, diabetic retinopathy, a diabetic foot ulcer, a cardiovascular complication, diabetic neuropathy, impaired wound healing, erectile dysfunction, and osteoporosis. COMPOUND I and a method for its preparation are exemplified in US Patent Publication No. 2004-0082542 in Example 406.

In one aspect, the present invention provides pharmaceutically acceptable salt forms of COMPOUND I. In one embodiment, the present invention provides a crystalline or amorphous pharmaceutically acceptable salt of COMPOUND I. In one aspect, the pharmaceutically acceptable salt of COMPOUND I is anhydrous, a hydrate, or a solvate.

In another aspect, the present invention provides a pharmaceutical composition comprising one or more of the pharmaceutically acceptable salt forms of COMPOUND I. In another aspect, the present invention provides a method of producing a pharmaceutical composition comprising one or more pharmaceutically acceptable salt forms of COMPOUND I.

In another aspect, the present invention provides a method of treating one or more RAGE mediated diseases comprising administering one or more pharmaceutically acceptable salts COMPOUND I to a subject in need thereof. Embodiments of the method of treatment of the present invention may comprise administering a pharmaceutical composition comprising a therapeutically effective amount of one or more pharmaceutically acceptable salts of COMPOUND I

These and other embodiments of the present invention are described in greater detail in the detailed description of the invention which follows.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a Powder X-ray Powder Diffraction (XRPD) Pattern of saccharinate Type A.

FIG. 2 is a ¹ H NMR spectrum of saccharinate Type A.

FIG. 3 is a Differential Scanning Calorimetry (DSC) profile and a Thermogravimetric Analysis

(TGA) of saccharinate Type A.

FIG. 4 is a XRPD Pattern of vanillate Type A.

FIG. 5 is a ¹ H NMR spectrum of vanillate Type A.

FIG. 6 is a DSC profile and a TGA of vanillate Type A.

FIG. 7 is a XRPD Pattern of HCI Type A.

FIG. 8 is a DSC profile and a TGA of HCI Type A.

FIG. 9 is a XRPD Pattern of HCI Type B.

FIG. 10 is a DSC profile and a TGA of HCI Type B.

FIG. 1 1 is a XRPD Pattern of fumarate Type A.

FIG. 12 is a ¹ H NMR spectrum of fumarate Type A.

FIG. 13 is a DSC profile and a TGA of fumarate Type A.

FIG. 14 is a XRPD Pattern of maleate Type A.

FIG. 15 is a ¹ H NMR spectrum of maleate Type A.

FIG. 16 is a DSC profile and a TGA of maleate Type A.

FIG. 17 is a XRPD Pattern of galactarate Type A. FIG. 18 is a ¹ H NMR spectrum of galactarate Type A.

FIG. 19 is a DSC profile and a TGA of galactarate Type A. FIG. 20 is a XRPD Pattern of phosphate Type A.

FIG. 21 is a DSC profile and a TGA of phosphate Type A. FIG. 22 is a XRPD Pattern of L-tartrate Type A.

FIG. 23 is a ¹ H NMR spectrum of L-tartrate Type A.

FIG. 24 is a DSC profile and a TGA of L-tartrate Type A. FIG. 25 is a XRPD Pattern of L-tartrate Type B.

FIG. 26 is a DSC profile and a TGA of L-tartrate Type B. FIG. 27 is a XRPD Pattern of hippurate Type A.

FIG. 28 is a ¹ H NMR spectrum of hippurate Type A.

FIG. 29 is a DSC profile and a TGA of hippurate Type A. FIG. 30 is a XRPD Pattern of L-malate Type A.

FIG. 31 is a ¹ H NMR spectrum of L-malate Type A.

FIG. 32 is a DSC profile and a TGA of L-malate Type A. FIG. 33 is a XRPD Pattern of oxalate Type A.

FIG. 34 is a DSC profile and a TGA of oxalate Type A. FIG. 35 is a XRPD Pattern of gentisate Type A.

FIG. 36 is a ¹ H NMR spectrum of gentisate Type A.

FIG. 37 is a DSC profile and a TGA of gentisate Type A. FIG. 38 is a XRPD Pattern of gentisate Type B.

FIG. 39 is a ¹ H NMR spectrum of gentisate Type B.

FIG. 40 is a DSC profile and a TGA of gentisate Type B. FIG. 41 is a XRPD Pattern of mesylate Type A.

FIG. 42 is a XRPD Pattern of mesylate Type B.

FIG. 43 a DSC profile and a TGA of mesylate Type B.

FIG. 44 is a XRPD Pattern of HBr Type A.

FIG. 45 is a DSC profile and a TGA of HBr Type A. FIG 46 is a XRPD Pattern of HBr Type B.

FIG 47 is a DSC profile and a TGA of HBr Type B.

FIG 48 is a XRPD Pattern of 4-aminosalicylate Type A.

FIG 49 is a ¹ H NMR spectrum of 4-aminosalicylate Type A.

FIG 50 is a DSC profile and a TGA of 4-aminosalicylate Type A.

FIG 51 is a XRPD Pattern of 4-aminosalicylate Type B.

FIG 52 is a DSC profile and a TGA of 4-aminosalicylate Type B.

FIG 53 is a ¹³ C Solid-state Nuclear Resonance Spectroscopy (SSNMR) spectrum of

Saccharinate Type A.

FIG 54 is a ¹³ C SSNMR spectrum of vanillate Type A.

FIG 55 is a ¹³ C SSNMR spectrum of HCI Type A.

FIG 56 is a ¹³ C SSNMR spectrum of HCI Type B.

FIG 57 is a ¹³ C SSNMR spectrum of fumarate Type A.

FIG 58 is a ¹³ C SSNMR spectrum of maleate Type A.

FIG 59 is a ¹³ C SSNMR spectrum of galactarate Type A.

FIG 60 is a ¹³ C SSNMR spectrum of phosphate Type A.

FIG 61 is a ¹³ C SSNMR spectrum of L-tartrate Type B.

FIG 62 is a ¹³ C SSNMR spectrum of hippurate Type A.

FIG 63 is a ¹³ C SSNMR spectrum of malate Type A.

FIG 64 is a ¹³ C SSNMR spectrum of oxalate Type A.

FIG 65 is a ¹³ C SSNMR spectrum of gentisate Type A.

FIG 66 is a ¹³ C SSNMR spectrum of mesylate Type B.

FIG 67 is a ¹³ C SSNMR spectrum of HBr salt Type A.

FIG 68 is a ¹³ C SSNMR spectrum of HBr salt Type B.

FIG 69 is a ¹³ C SSNMR spectrum of 4-aminosalicylate Type B.

DETAILED DESCRIPTION

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Moreover, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein. For example, a stated range of "1 to 10" should be considered to include any and all subranges between (and inclusive of) the minimum value of 1 and the maximum value of 10; that is, all subranges beginning with a minimum value of 1 or more, e.g. 1 to 6.1 , and ending with a maximum value of 10 or less, e.g., 5.5 to 10.

By percent by weight it is meant that a particular weight of one ingredient in a composition is divided by the total weight of all of the ingredients in that composition. Percent by weight may be used interchangeably and means approximately the same as weight/weight percent or %( weight/weight) or percent by mass or mass percent. When a liquid solute is used, it is often more practical to use volume/volume percent or % (vol/vol) or percent by volume, which are all considered to be synonymous. Ppm (parts per million), ppb (parts per billion), pph (parts per hundred) are often used to indicate a percentage based on quantity and not on mass (i.e., the quantity of a given type of atom or a given type of molecule in a composition with more atoms or molecules (be it gas, liquid or solid) is divided by the total quantity of atoms or molecules in the total composition). Other terms that are used are molarity, which is the number of moles of solute per liters of solution, and molality, which is the number of moles of solution per kilograms of solution. Another concentration unit is the mole fraction, which is the moles of a given component divided by the total moles of all solution components. Mole percent is related to the mole fraction and is the mole fraction multiplied by 100.

It is further noted that, as used in this specification, the singular forms "a," "an," and "the" include plural referents unless expressly and unequivocally limited to one referent.

The term "RAGE mediated disease" is used herein to refer to one or more conditions, diseases or disease states including, but not limited to, acute or chronic inflammation including skin inflammation such as psoriasis, rheumatoid arthritis, atopic dermatitis and lung inflammation including, asthma and chronic obstructive pulmonary disease, diabetes, diabetes related complications, renal failure, hyperlipidemic atherosclerosis associated with diabetes, neuronal cytotoxicity, restenosis, Down's syndrome, dementia associated with head trauma, amyotrophic lateral sclerosis, multiple sclerosis, amyloidosis, an autoimmune disease including inflammation associated with autoimmunity or organ, tissue, or cell transplant, impaired wound healing, periodontal disease, neuropathy, neuronal degeneration, vascular permeability, nephropathy, atherosclerosis, retinopathy, Alzheimer's disease, erectile dysfunction, tumor invasion and/or metastasis, osteoporosis, and the development of diabetic late complications such as increased vascular permeability, nephropathy, retinopathy, and neuropathy. The pharmaceutical compositions comprising a pharmaceutically acceptable salt of COMPOUND I also may be used to antagonize RAGE in a subject.

The term "therapeutically effective amount" is used herein to denote the amount of the pharmaceutically acceptable salt COMPOUND I that will elicit the therapeutic response of a subject that is being sought. In an embodiment, the therapeutic response may be antagonizing RAGE.

Embodiments of the invention are directed to pharmaceutically acceptable salts of COMPOUND I, wherein the particular pharmaceutically acceptable salt (e.g., HCI, HBr) has at least a particular percentage of purity. In some embodiments of the invention, the pharmaceutically acceptable salt of COMPOUND I (e.g., HCI, HBr) is at least 80% pure. In some embodiments of the invention, the pharmaceutically acceptable salt of COMPOUND I (e.g., HCI, HBr) is at least 85% pure. In some embodiments of the invention, the pharmaceutically acceptable salt of COMPOUND I (e.g., HCI, HBr) is at least 90% pure. In some embodiments of the invention, the pharmaceutically acceptable salt of COMPOUND I (e.g., HCI, HBr) is at least 95% pure. In some embodiments of the invention, the pharmaceutically acceptable salt of COMPOUND I is in crystalline (e.g., HCI Type A or HCI Type B) or amorphous form and is substantially free of other polymorphic forms. As used herein, a first polymorphic form that is "substantially pure" of another polymorphic form includes the complete absence of the second form or an amount of the second form that is not readily detectable by ordinary analytical methods. Such ordinary analytical methods include DSC, solid state ¹³ C NMR, Raman, X-ray powder diffraction, mid-IR (such as FT-IR) and near-IR. In an embodiment, an amount of a polymorphic form that is not readily detectable by one or more ordinary analytical methods is less than 5 percent by weight. In another embodiment, the amount of a polymorphic form that is not readily detectable by one or more ordinary analytical methods is less than 3 percent by weight. In another embodiment, the amount of a polymorphic form that is not readily detectable by one or more ordinary analytical methods is less than 2 percent by weight. In another embodiment, the amount of a polymorphic form that is not readily detectable by one or more ordinary analytical methods is less than 1 percent by weight. In another embodiment, the amount of a polymorphic form that is not readily detectable by one or more ordinary analytical methods is less than 0.5 percent by weight.

In another embodiment, the dosage or blood level of COMPOUND I and administration may be sufficient for inhibition of the biological function of RAGE at a sufficient level for sufficient time to reverse amyloidosis. A therapeutically effective amount may be achieved in a subject by administering a dosage level of less 100 mg of compound per day. In another embodiment, the dosage level of administration is greater than 1 mg of compound per day. In another embodiment, the dosage level of administration is 5, 10 or 20 mg of compound per day.

The term "treatment" as used herein, refers to the full spectrum of treatments for a given condition or disorder from which a subject is suffering, including alleviation or amelioration of one or more of the symptoms resulting from that disorder, to the delaying of the onset or progression of the disorder.

In one aspect, the present invention provides a pharmaceutically acceptable salt of COMPOUND I. In one embodiment, the present invention is a pharmaceutically acceptable salt is formed between [3-(4-{2-butyl-1 -[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4- yl}phenoxy)-propyl]-diethylamine and a pharmaceutically acceptable acid. In one embodiment, the pharmaceutically acceptable acid is selected from the group consisting of 1 -hydroxy-2-naphthoic acid, 4-aminosalicylic acid, adipic acid, L-aspartic acid, benzene sulfonic acid, benzoic acid, trans-cinnamic acid, citric acid, fumaric acid, galactaric acid, gentisic acid, gluconic acid, glutamic acid, glutaric acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid, L-lactic acid, maleic acid, L-malic acid, malonic acid, R- mandelic acid, methane sulfonic acid, naphthalene sulfonic acid, nicotinic acid, oxalic acid, palmitic acid, phosphoric acid, propionic acid, saccharin, salicyclic acid, stearic acid, succinic acid, sulfuric acid, L-tartaric acid, vanillic acid, and vanillin. In one embodiment, the pharmaceutically acceptable acid is selected from the group consisting of 4-aminosalicylic acid, fumaric acid, galactaric acid, gentisic acid, hippuric acid, hydrobromic acid, hydrochloric acid, L-lactic acid, maleic acid, L-malic acid, oxalic acid, phosphoric acid, saccharin, salicyclic acid, L-tartaric acid, and vanillin.

In one embodiment, the pharmaceutically acceptable salt of COMPOUND I is in a crystalline form. In one embodiment, the pharmaceutically acceptable salt of COMPOUND I is amorphous. In one embodiment, the pharmaceutically acceptable salt of COMPOUND I is anhydrous, a hydrate, or a solvate.

For all embodiments disclosed herein, a peak positional reproducibility is associated with the values of degree-20 (XRPD), ppm (NMR), and cm ^-1 (IR and Raman). Accordingly, it will be understood that all peaks disclosed herein have the value disclosed ± the peak positional reproducibility associated with each analytical technique. The XRPD peak positional reproducibility is ± 0.2 expressed in degree-20. The ¹³ C NMR peak positional reproducibility is ± 0.2 ppm. The IR peak positional reproducibility is + 2 cm ^-1 . The Raman peak positional reproducibility is + 2 cm ^-1 . PHARMACEUTICALLY ACCEPTABLE SALTS OF COMPOUND I

SACCHARINATE

In one aspect of the invention, the pharmaceutically acceptable salt of COMPOUND I is a saccharinate. In one embodiment, the saccharinate is crystalline. In one embodiment, the saccharinate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 18.1 °, 21.1 °, and 25.7° ±0.2°. In one embodiment, the saccharinate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 18.1 °, 18.8°, 19.6°, 21.1 °, 21.4°, and 23.1 ° ±0.2°. In one embodiment, the saccharinate is crystalline and is characterized by an XRPD pattern as shown in FIG. 1. In one embodiment, the saccharinate is crystalline and is characterized by a ¹ H-NMR substantially similar to FIG. 2. In one embodiment, the saccharinate is crystalline and is characterized by an endothermic peak at about 122 °C as determined by DSC. In one embodiment, the saccharinate is crystalline and is characterized by a DSC profile as shown in FIG. 3. In one embodiment, the saccharinate is crystalline and is characterized by a TGA profile as shown in FIG. 3. In one embodiment, the saccharinate is crystalline and is characterized by at least two of the following features (l-i)-(l-iv):

(l-i) an XRPD pattern having peaks at 2Q angles of 18.1 , 21.1 , and 25 1 ±0.2°; (l-ii) a 1 H-NMR substantially similar to FIG. 2;

(l-iii) a DSC profile as shown in FIG. 3; or

(l-iv) a TGA profile as shown in FIG. 3.

In one embodiment, the saccharinate is crystalline and is saccharinate Type A.

Saccharinate Type A is characterized by the following XRPD pattern expressed in terms of the degree 2Q and relative intensities:

The relative intensities may change depending on the crystal size and morphology.

In one embodiment, saccharinate Type A is characterized by the SSNMR of FIG. 53. In one embodiment, saccharinate Type is characterized by the following ¹³ C Solid State NMR shifts.

Representative ¹³ C NMR chemical shifts for saccharinate Type A are 158.04, 134.41 , 126.41 , and 29.80 ppm. Representative ¹³ C NMR chemical shifts for saccharinate Type A are also 158.04, 134.41 , and 126.41 ppm.

VANILLATE

In one aspect of the invention, the pharmaceutically acceptable salt of COMPOUND I is a vanillate. In one embodiment, the vanillate is crystalline. In one embodiment, the vanillate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 7.6°, 15.2°, and 18.2° ±0.2°. In one embodiment, the vanillate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 7.6°, 15.2°, 18.2°, 19.5°, and 22.1 ° ±0.2°. In one embodiment, the vanillate is crystalline and is characterized by an XRPD pattern as shown in FIG. 4. In one embodiment, the vanillate is crystalline and is characterized by a ¹ H-NMR substantially similar to FIG. 5. In one embodiment, the vanillate is crystalline and is characterized by an endothermic peak at about 102 °C as determined by DSC. In one embodiment, the vanillate is crystalline and is characterized by a DSC profile as shown in FIG. 6. In one embodiment, the vanillate is crystalline and is characterized by a TGA profile as shown in FIG. 6. In one embodiment, the vanillate is crystalline and is characterized by at least two of the following features (l-i)-(l-iv):

(l-i) an XRPD pattern having peaks at 2Q angles of 7.6°, 15.2°, and 18.2° ±0.2;

(l-ii) a ¹ H-NMR substantially similar to FIG. 5;

(l-iii) a DSC profile as shown in FIG. 6; or

(l-iv) a TGA profile as shown in FIG. 6.

In one embodiment, the vanillate is crystalline and is vanillate Type A.

Vanillate Type A is characterized by the following XRPD pattern expressed in terms of the degree 2Q and relative intensities:

The relative intensities may change depending on the crystal size and morphology.

In one embodiment, vanillate Type A is characterized by the SSNMR of FIG. 54. In one embodiment, vanillate Type A is characterized by the following ¹³ C Solid State NMR shifts.

Representative ¹³ C NMR chemical shifts for vanillate Type A are 130.34, 1 18.84, 30.51 , and 9.76 ppm. Representative ¹³ C NMR chemical shifts for vanillate Type A are also 130.34, and 1 18.84 ppm.

HYDROCHLORIDE

In one aspect of the invention, the pharmaceutically acceptable salt of COMPOUND I is a hydrochloride. In one embodiment, the pharmaceutically acceptable salt of COMPOUND I is a mono-hydrochloride. In one embodiment, the hydrochloride is crystalline. In one embodiment, the hydrochloride is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 8.2°, 13.2°, and 19.8° ±0.2°. In one embodiment, the hydrochloride is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 8.2°, 13.2°, 18.9°, 19.8°, and 22.8° ±0.2°. In one embodiment, the hydrochloride is crystalline and is characterized by an XRPD pattern as shown in FIG. 7. In one embodiment, the hydrochloride is crystalline and is characterized by an endothermic peak at about 169 °C as determined by DSC. In one embodiment, the hydrochloride is crystalline and is characterized by a DSC profile as shown in FIG. 8. In one embodiment, the hydrochloride is crystalline and is characterized by a TGA profile as shown in FIG. 8. In one embodiment, the hydrochloride is crystalline and is characterized by at least two of the following features (l-i)-(l-iii):

(l-i) an XRPD pattern having peaks at 2Q angles of 8.2°, 13.2°, and 19.8° ±0.2°; (l-ii) a DSC profile as shown in FIG. 8; or

(l-iii) a TGA profile as shown in FIG. 8.

In one embodiment, the hydrochloride is crystalline and is hydrochloride Type A.

Hydrochloride Type A is characterized by the following XRPD pattern expressed in terms of the degree 2Q and relative intensities:

*The relative intensities may change depending on the crystal size and morphology.

In one embodiment, hydrochloride Type A is characterized by the SSNMR of FIG. 55. In one embodiment, hydrochloride Type A is characterized by the following ¹³ C Solid State NMR shifts.

Representative ¹³ C NMR chemical shifts for hydrochloride Type A are 126.39, 1 18.41 , 31.49, and 1 1.30 ppm. Representative ¹³ C NMR chemical shifts for hydrochloride Type A are also 126.39 and 1 18.41 ppm.

In one embodiment, the pharmaceutically acceptable salt of COMPOUND I is a dihydrochloride. In one embodiment, the hydrochloride is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 9.1 °, 14.1 °, and 20.9° ±0.2°. In one embodiment, the hydrochloride is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 9.1 °, 14.1 °, 18.4°, 20.9°, and 24.9° ±0.2°. In one embodiment, the hydrochloride is crystalline and is characterized by an XRPD pattern as shown in FIG. 8. In one embodiment, the hydrochloride is crystalline and is characterized by an endothermic peak at about 232 °C as determined by DSC. In one embodiment, the hydrochloride is crystalline and is characterized by a DSC profile as shown in FIG. 10. In one embodiment, the hydrochloride is crystalline and is characterized by a TGA profile as shown in FIG. 10. In one embodiment, the hydrochloride is crystalline and is characterized by at least two of the following features (l-i)-(l-iii):

(l-i) an XRPD pattern having peaks at 2Q angles of 9.1 °, 14.1 °, and 20.9° ±0.2°; (l-ii) a DSC profile as shown in FIG. 10; or

(l-iii) a TGA profile as shown in FIG. 10.

In one embodiment, the hydrochloride is crystalline and is hydrochloride Type B.

Hydrochloride Type B is characterized by the following XRPD pattern expressed in terms of the degree 2Q and relative intensities:

The relative intensities may change depending on the crystal size and morphology.

In one embodiment, hydrochloride Type B is characterized by the SSNMR of FIG. 56. In one embodiment, hydrochloride Type B is characterized by the following ¹³ C Solid State NMR shifts.

Representative ¹³ C NMR chemical shifts for hydrochloride Type B are 131.64, 120.91 , 50.16, and 24.89 ppm. Representative ¹³ C NMR chemical shifts for hydrochloride Type B are also 131.64 and 120.91 ppm.

FUMARATE

In one aspect of the invention, the pharmaceutically acceptable salt of COMPOUND I is a fumarate. In one embodiment, the pharmaceutically acceptable salt of COMPOUND I is a monofumarate. In one embodiment, the fumarate is crystalline. In one embodiment, the fumarate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 16.6°, 18.0°, and 21.5° ±0.2°. In one embodiment, the fumarate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 9.4°, 16.6°, 18.0°, 18.7°, and 21.5° ±0.2°. In one embodiment, the fumarate is crystalline and is characterized by an XRPD pattern as shown in FIG. 1 1. In one embodiment, the fumarate is crystalline and is characterized by a ¹ H-NMR substantially similar to FIG. 12. In one embodiment, the fumarate is crystalline and is characterized by an endothermic peak at about 117 °C as determined by DSC. In one embodiment, the fumarate is crystalline and is characterized by a DSC profile as shown in FIG. 13. In one embodiment, the fumarate is crystalline and is characterized by a TGA profile as shown in FIG. 13. In one embodiment, the fumarate is crystalline and is characterized by at least two of the following features (l-i)-(l-iv):

(l-i) an XRPD pattern having peaks at 2Q angles of 16.6°, 18.0°, and 21.5° ±0.2°;

(l-ii) a ¹ H-NMR substantially similar to FIG. 12;

(l-iii) a DSC profile as shown in FIG. 13; or

(l-iv) a TGA profile as shown in FIG. 13.

In one embodiment, the fumarate is crystalline and is fumarate Type A.

Fumarate Type A is characterized by the following XRPD pattern expressed in terms of the degree 2Q and relative intensities:

*The relative intensities may change depending on the crystal size and morphology.

In one embodiment, fumarate Type A is characterized by the SSNMR of FIG. 57. In one embodiment, fumarate Type A is characterized by the following ¹³ C Solid State NMR shifts.

Representative ¹³ C NMR chemical shifts for fumarate Type A are 172.38, 126.3, 51.14, and 25.36 ppm. Representative ¹³ C NMR chemical shifts for fumarate Type A are also 172.38 and 126.3 ppm.

MALEATE

In one aspect of the invention, the pharmaceutically acceptable salt of COMPOUND I is a maleate. In one embodiment, the pharmaceutically acceptable salt of COMPOUND I is a mono-maleate. In one embodiment, the maleate is crystalline. In one embodiment, the maleate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 4.1 °, 8.2°, and 20.1 ° ±0.2°. In one embodiment, the maleate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 4.1 °, 8.2°, 17.7°, and 20.1 ° ±0.2°. In one embodiment, the maleate is crystalline and is characterized by an XRPD pattern as shown in FIG. 14. In one embodiment, the maleate is crystalline and is characterized by a ¹ H-NMR substantially similar to FIG. 15. In one embodiment, the maleate is crystalline and is characterized by an endothermic peak at about 121 °C as determined by DSC. In one embodiment, the maleate is crystalline and is characterized by a DSC profile as shown in FIG. 16. In one embodiment, the maleate is crystalline and is characterized by a TGA profile as shown in FIG. 16. In one embodiment, the maleate is crystalline and is characterized by at least two of the following features (l-i)-(l-iv):

(l-i) an XRPD pattern having peaks at 2Q angles of 4.1 °, 8.2°, and 20.1 ° ±0.2°;

(l-ii) a ¹ H-NMR substantially similar to FIG. 15;

(l-iii) a DSC profile as shown in FIG. 16; or

(l-iv) a TGA profile as shown in FIG. 16.

In one embodiment, the maleate is crystalline and is maleate Type A.

Maleate Type A is characterized by the following XRPD pattern expressed in terms of the degree 2Q and relative intensities:

*The relative intensities may change depending on the crystal size and morphology.

In one embodiment, maleate Type A is characterized by the SSNMR of FIG. 58. In one embodiment, maleate Type A is characterized by the following ¹³ C Solid State NMR shifts.

Representative ¹³ C NMR chemical shifts for maleate Type A are 139.40, 127.34, 1 18.33, and 24.93 ppm. Representative ¹³ C NMR chemical shifts for maleate Type A are also 139.40, 127.34 and 1 18.33 ppm.

GALACTARATE

In one aspect of the invention, the pharmaceutically acceptable salt of COMPOUND I is a galactarate. In one embodiment, the pharmaceutically acceptable salt of COMPOUND I is a mono-galactarate. In one embodiment, the galactarate is crystalline. In one embodiment, the galactarate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 8.0°, 14.6°, and 19.7° ±0.2°. In one embodiment, the galactarate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 8.0°, 14.6°, 19.7°, 21.5°, and 22.3° ±0.2°. In one embodiment, the galactarate is crystalline and is characterized by an XRPD pattern as shown in FIG. 17. In one embodiment, the galactarate is crystalline and is characterized by a ¹ H-NMR substantially similar to FIG. 18. In one embodiment, the galactarate is crystalline and is characterized by an endothermic peak at about 106°C and an endothermic peak at 162 °C as determined by DSC. In one embodiment, the galactarate is crystalline and is characterized by a DSC profile as shown in FIG. 19. In one embodiment, the galactarate is crystalline and characterized by an about 0.6 wt% loss between room temperature and about 130 °C as determined by TGA. In one embodiment, the galactarate is crystalline and is characterized by a TGA profile as shown in FIG. 19. In one embodiment, the galactarate is crystalline and is characterized by at least two of the following features (l-i)-(l-iv):

(l-i) an XRPD pattern having peaks at 2Q angles of 8.0°, 14.6°, and 19.7° ±0.2°;

(l-ii) a ¹ H-NMR substantially similar to FIG. 18;

(l-iii) a DSC profile as shown in FIG. 19; or

(l-iv) a TGA profile as shown in FIG. 19.

In one embodiment, the galactarate is crystalline and is galactarate Type A.

Galactarate Type A is characterized by the following XRPD pattern expressed in terms of the degree 2Q and relative intensities:

The relative intensities may change depending on the crystal size and morphology.

In one embodiment, galactarate Type A is characterized by the SSNMR of FIG. 58. In one embodiment, galactarate Type A is characterized by the following ¹³ C Solid State NMR shifts.

Representative ¹³ C NMR chemical shifts for galactarate Type A are 126.59, 74.71 , 31.19, and 22.76 ppm. Representative ¹³ C NMR chemical shifts for galactarate Type A are also 126.59 and 74.71 ppm.

PHOSPHATE

In one aspect of the invention, the pharmaceutically acceptable salt of COMPOUND I is a phosphate. In one embodiment, the pharmaceutically acceptable salt of COMPOUND I is a mono-phosphate. In one embodiment, the phosphate is crystalline. In one embodiment, the phosphate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 8.1 °, 14.7°, and 16.7° ±0.2°. In one embodiment, the phosphate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 8.1 °, 13.6°, 14.7°, 16.7°, and 22.5° ±0.2°. In one embodiment, the phosphate is crystalline and is characterized by an XRPD pattern as shown in FIG. 20. In one embodiment, the phosphate is crystalline and is characterized by an endothermic peak at about 108°C and an endothermic peak at about 138 °C as determined by DSC. In one embodiment, the phosphate is crystalline and is characterized by a DSC profile as shown in FIG. 21. In one embodiment, the phosphate is crystalline and is characterized by an about 0.3 wt% loss between room temperature and about 100 °C as determined by TGA. In one embodiment, the phosphate is crystalline and is characterized by a TGA profile as shown in FIG. 21. In one embodiment, the phosphate is crystalline and is characterized by at least two of the following features (l-i)-(l-iii):

(l-i) an XRPD pattern having peaks at 2Q angles of 8.1 °, 14.7°, and 16.7° ±0.2°;

(l-ii) a DSC profile as shown in FIG. 21 ; or (l-iii) a TGA profile as shown in FIG. 21.

In one embodiment, the phosphate is crystalline and is phosphate Type A.

Phosphate Type A is characterized by the following XRPD pattern expressed in terms of the degree 2Q and relative intensities:

The relative intensities may change depending on the crystal size and morphology.

In one embodiment, phosphate Type A is characterized by the SSNMR of FIG. 60. In one embodiment, phosphate Type A is characterized by the following ¹³ C Solid State NMR shifts.

Representative ¹³ C NMR chemical shifts for phosphate Type A are 159.04, 128.21 , 31.10, and 22.95 ppm. Representative ¹³ C NMR chemical shifts for phosphate Type A are 159.04 and 128.21 ppm.

L-TARTRATE

In one aspect of the invention, the pharmaceutically acceptable salt of COMPOUND I is a L-tartrate. In one embodiment, the L-tartrate is crystalline. In one embodiment, the L- tartrate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 4.2°, 18.4°, and 21.8° ±0.2°. In one embodiment, the L-tartrate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 4.2°, 12.4°, 18.4°, 20.7°, and 21.8° ±0.2°. In one embodiment, the L-tartrate is crystalline and is characterized by an XRPD pattern as shown in FIG. 22. In one embodiment, the L-tartrate is crystalline and is characterized by a ¹ H-NMR substantially similar to FIG. 23. In one embodiment, the L- tartrate is crystalline and is characterized by an endothermic peak at about 87 °C as determined by DSC. In one embodiment, the L-tartrate is crystalline and is characterized by a DSC profile as shown in FIG. 24. In one embodiment, the L-tartrate is crystalline and is characterized by an about 2.1 wt% loss between room temperature and about 60 °C as determined by TGA . In one embodiment, the L-tartrate is crystalline and is characterized by a TGA profile as shown in FIG. 24. In one embodiment, the L-tartrate is crystalline and is characterized by at least two of the following features (l-i)-(l-iv):

(l-i) an XRPD pattern having peaks at 2Q angles of 4.2°, 18.4°, and 21.8° ±0.2°;

(l-ii) a ¹ H-NMR as shown in FIG. 23; (l-ii) a DSC profile as shown in FIG. 24; or

(l-iii) a TGA profile as shown in FIG. 24.

In one embodiment, the L-tartrate is crystalline and is L-tartrate Type A.

L-tartrate Type A is characterized by the following XRPD pattern expressed in terms of the degree 2Q and relative intensities:

The relative intensities may change depending on the crystal size and morphology. In one embodiment, the L-tartrate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 18.5, 22.5°, and 32.1 ° ±0.2°. In one embodiment, the L-tartrate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 4.2°, 12.4°, 18.4°, 20.7°, and 21.8° ±0.2°. In one embodiment, the L-tartrate is crystalline and is characterized by an XRPD pattern as shown in FIG. 25. In one embodiment, the L- tartrate is crystalline and is characterized by an endothermic peak at about 102 °C as determined by DSC. In one embodiment, the L-tartrate is crystalline and is characterized by a DSC profile as shown in FIG. 26. In one embodiment, the L-tartrate is crystalline and is characterized by a TGA profile as shown in FIG. 26. In one embodiment, the L-tartrate is crystalline and is characterized by at least two of the following features (l-i)-(l-iii):

(l-i) an XRPD pattern having peaks at 2Q angles of 18.5, 22.5°, and 32.1 ° ±0.2°;

(l-ii) a DSC profile as shown in FIG. 26; or

(l-iii) a TGA profile as shown in FIG. 26.

In one embodiment, the L-tartrate is crystalline and is L-tartrate Type B.

L-tartrate Type B is characterized by the following XRPD pattern expressed in terms of the degree 2Q and relative intensities:

*The relative intensities may change depending on the crystal size and morphology.

In one embodiment, L-tartrate Type B is characterized by the SSNMR of FIG. 61. In one embodiment, L-tartrate Type B is characterized by the following ¹³ C Solid State NMR shifts.

Representative ¹³ C NMR chemical shifts for L-tartrate Type B are 127.29, 32.43, and 23.59 ppm. Representative ¹³ C NMR chemical shifts for L-tartrate Type B are also 179.26 and 127.29 ppm.

HIPPURATE In one aspect of the invention, the pharmaceutically acceptable salt of COMPOUND I is a hippurate. In one embodiment, the pharmaceutically acceptable salt of COMPOUND I is a mono-hippurate. In one embodiment, the hippurate is crystalline. In one embodiment, the hippurate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 3.4°, 20.2°, and 20.9° ±0.2°. In one embodiment, the hippurate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 3.4°, 13.0°, 20.2°, 20.9°, and 22.1 ° ±0.2°. In one embodiment, the hippurate is crystalline and is characterized by an XRPD pattern as shown in FIG. 27. In one embodiment, the hippurate is crystalline and is characterized by a ¹ H-NMR substantially similar to FIG. 28. In one embodiment, the hippurate is crystalline and is characterized by an endothermic peak at about 44.3°C and an endothermic peak at about 81.6 °C as determined by DSC. In one embodiment, the hippurate is crystalline and is characterized by a DSC profile as shown in FIG. 29. In one embodiment, the hippurate is crystalline and is characterized by a TGA profile as shown in FIG. 29. In one embodiment, the hippurate is crystalline and is characterized by at least two of the following features (l-i)-(l-iv):

(l-i) an XRPD pattern having peaks at 2Q angles of 3.4°, 20.2°, and 20.9° ±0.2°;

(l-ii) a ¹ H-NMR substantially similar to FIG. 28;

(l-iii) a DSC profile as shown in FIG. 29; or

(l-iv) a TGA profile as shown in FIG. 29.

In one embodiment, the hippurate is crystalline and is hippurate Type A.

Hippurate Type A is characterized by the following XRPD pattern expressed in terms of the degree 2Q and relative intensities:

The relative intensities may change depending on the crystal size and morphology.

In one embodiment, hippurate Type A is characterized by the SSNMR of FIG. 62. In one embodiment, hippurate Type A is characterized by the following ¹³ C Solid State NMR shifts.

Representative ¹³ C NMR chemical shifts for hippurate Type A are 159.46, 128.01 , 66.99, and 10.65 ppm. Representative ¹³ C NMR chemical shifts for hippurate Type A are 159.46 and 128.01 ppm.

L-MALATE

In one aspect of the invention, the pharmaceutically acceptable salt of COMPOUND I is a L-malate. In one embodiment, the L-malate is crystalline. In one embodiment, the L- malate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 3.7°, 17.2°, and 19.0° ±0.2°. In one embodiment, the L-malate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 3.7°, 17.2°, 19.0°, and 19.4° ±0.2°. In one embodiment, the L-malate is crystalline and is characterized by an XRPD pattern as shown in FIG. 30. In one embodiment, the L-malate is crystalline and is characterized by a ¹ H-NMR substantially similar to FIG. 31. In one embodiment, the L- malate is crystalline and is characterized by an endothermic peak at about 72°C as determined by DSC. In one embodiment, the L-malate is crystalline and is characterized by a DSC profile as shown in FIG. 32. In one embodiment, the L-malate is crystalline and is characterized by a TGA profile as shown in FIG. 32. In one embodiment, the L-malate is crystalline and is characterized by at least two of the following features (l-i)-(l-iv):

(l-i) an XRPD pattern having peaks at 2Q angles of 3.7°, 11.2°, and 19.0° ±0.2°; (l-ii) a ¹ H-NMR substantially similar to FIG. 31 ;

(l-iii) a DSC profile as shown in FIG. 32; or

(l-iv) a TGA profile as shown in FIG. 32.

In one embodiment, the L-malate is crystalline and is L-malate Type A.

L-malate Type A is characterized by the following XRPD pattern expressed in terms of the degree 2Q and relative intensities:

*The relative intensities may change depending on the crystal size and morphology.

In one embodiment, L-malate Type A is characterized by the SSNMR of FIG. 63. In one embodiment, L-malate Type A is characterized by the following ¹³ C Solid State NMR shifts.

Representative ¹³ C NMR chemical shifts for L-malate Type A are 128.47, 1 15.37, and 16.84 ppm. Representative ¹³ C NMR chemical shifts for L-malate Type A are and 1 15.37 ppm. OXALATE

In one aspect of the invention, the pharmaceutically acceptable salt of COMPOUND I is an oxalate. In one embodiment, the pharmaceutically acceptable salt of COMPOUND I is a mono-oxalate. In one embodiment, the oxalate is crystalline. In one embodiment, the oxalate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 16.1 °, 17.8°, and 21.9° ±0.2°. In one embodiment, the oxalate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 16.1 °, 17.8°, 21.5°, 22.5°, and 21.9° ±0.2°. In one embodiment, the oxalate is crystalline and is characterized by an XRPD pattern as shown in FIG. 33. In one embodiment, the oxalate is crystalline and is characterized by an endothermic peak at about 1 13 °C as determined by DSC. In one embodiment, the oxalate is crystalline and is characterized by a DSC profile as shown in FIG. 34. In one embodiment, the oxalate is crystalline and is characterized by a TGA profile as shown in FIG. 34. In one embodiment, the oxalate is crystalline and is characterized by at least two of the following features (l-i)-(l-iii):

(l-i) an XRPD pattern having peaks at 2Q angles of 16.1 °, 17.8°, and 21.9° ±0.2°;

(l-ii) a DSC profile as shown in FIG. 34; or

(l-iii) a TGA profile as shown in FIG. 34.

In one embodiment, the oxalate is crystalline and is oxalate Type A.

Oxalate Type A is characterized by the following XRPD pattern expressed in terms of the degree 2Q and relative intensities:

The relative intensities may change depending on the crystal size and morphology.

In one embodiment, oxalate Type A is characterized by the SSNMR of FIG. 64. In one embodiment, oxalate Type A is characterized by the following ¹³ C Solid State NMR shifts.

Representative ¹³ C NMR chemical shifts for oxalate Type A are 167.13, 129.67, 1 18.41 , and 30.88 ppm. Representative ¹³ C NMR chemical shifts for oxalate Type A are also 167.13, 129.67, and 1 18.41 ppm.

GENTISATE

In one aspect of the invention, the pharmaceutically acceptable salt of COMPOUND I is a gentisate. In one embodiment, the gentisate is crystalline. In one embodiment, the gentisate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 7.5°, 21.2°, and 24.7° ±0.2°. In one embodiment, the gentisate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 3.8°, 1.5°, 12.3°, 21.2°, and 24.7° ±0.2°. In one embodiment, the gentisate is crystalline and is characterized by an XRPD pattern as shown in FIG. 35. In one embodiment, the gentisate is crystalline and is characterized by a ¹ H-NMR substantially similar to FIG. 36. In one embodiment, the gentisate is crystalline and is characterized by an endothermic peak at about 103°C and an endothermic peak at about 131 °C as determined by DSC. In one embodiment, the gentisate is crystalline and is characterized by a DSC profile as shown in FIG. 37. In one embodiment, the gentisate is crystalline and is characterized by an about 1.8 wt% loss between room temperature and about 120 °C as determined by TGA. In one embodiment, the gentisate is crystalline and is characterized by a TGA profile as shown in FIG. 37. In one embodiment, the gentisate is crystalline and is characterized by at least two of the following features (l-i)-(l-iv):

(l-i) an XRPD pattern having peaks at 2Q angles of 1.5°, 21.2°, and 24.7° ±0.2°; (l-ii) a ¹ H-NMR substantially as shown in FIG. 36;

(l-iii) a DSC profile as shown in FIG. 37; or

(l-iv) a TGA profile as shown in FIG. 37.

In one embodiment, the gentisate is crystalline and is gentisate Type A. Gentisate Type A is characterized by the following XRPD pattern expressed in terms of the degree 2Q and relative intensities:

*The relative intensities may change depending on the crystal size and morphology.

In one embodiment, gentisate Type A is characterized by the SSNMR of FIG. 65. In one embodiment, gentisate Type A is characterized by the following ¹³ C Solid State NMR shifts.

Representative ¹³ C NMR chemical shifts for gentisate Type A are 128.12, 1 18.23, 23.22, and 9.69 ppm. Representative ¹³ C NMR chemical shifts for gentisate Type A are also 128.12, and 1 18.23 ppm.

In one embodiment, the gentisate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 13.3°, 18.4°, and 21.2° ±0.2°. In one embodiment, the gentisate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 7.1 °, 13.3°, 188.4°, and 21.2° ±0.2°. In one embodiment, the gentisate is crystalline and is characterized by an XRPD pattern as shown in FIG. 38. In one embodiment, the gentisate is crystalline and is characterized by a ¹ H-NMR substantially similar to FIG. 39. In one embodiment, the gentisate is crystalline and is characterized by an endothermic peak at about 129 °C as determined by DSC. In one embodiment, the gentisate is crystalline and is characterized by a DSC profile as shown in FIG. 40. In one embodiment, the gentisate is crystalline and is characterized by a TGA profile as shown in FIG. 40. In one embodiment, the gentisate is crystalline and is characterized by at least two of the following features (l-i)- (l-iv):

(l-i) an XRPD pattern having peaks at 2Q angles of 13.3°, 18.4°, and 21.2° ±0.2°; (l-ii) a ¹ H-NMR as shown in FIG. 39;

(l-iii) a DSC profile as shown in FIG. 40; or

(l-iv) a TGA profile as shown in FIG. 40.

In one embodiment, the gentisate is crystalline and is gentisate Type B.

Gentisate Type B is characterized by the following XRPD pattern expressed in terms of the degree 2Q and relative intensities:

The relative intensities may change depending on the crystal size and morphology.

MESYLATE

In one aspect of the invention, the pharmaceutically acceptable salt of COMPOUND I is a mesylate. In one embodiment, the mesylate is crystalline. In one embodiment, the mesylate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 8.0°, 13.3°, and 20.5° ±0.2°. In one embodiment, the mesylate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 8.0°, 13.3°, 16.3°, 20.5°, and 23.4° ±0.2°. In one embodiment, the mesylate is crystalline and is characterized by an XRPD pattern as shown in FIG. 41. In one embodiment, the mesylate is crystalline and is mesylate Type A.

Mesylate Type A is characterized by the following XRPD pattern expressed in terms of the degree 2Q and relative intensities:

The relative intensities may change depending on the crystal size and morphology.

In one embodiment, the mesylate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 20.3°, 22.4°, and 23.5° ±0.2°. In one embodiment, the mesylate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 10.6, 15.1 , 20.3°, 22.4°, and 23.5° ±0.2°. In one embodiment, the mesylate is crystalline and is characterized by an XRPD pattern as shown in FIG. 42. In one embodiment, the mesylate is crystalline and is characterized by an endothermic peak at about 96 °C as determined by DSC. In one embodiment, the mesylate is crystalline and is characterized by a DSC profile as shown in FIG. 43. In one embodiment, the mesylate is crystalline and is characterized by a TGA profile as shown in FIG. 43. In one embodiment, the mesylate is crystalline and is characterized by at least two of the following features (l-i)-(l-iii):

(l-i) an XRPD pattern having peaks at 2Q angles of 20.3°, 22.4°, and 23.5° ±0.2°; (l-ii) a DSC profile as shown in FIG. 43; or

(l-iii) a TGA profile as shown in FIG. 43.

In one embodiment, the mesylate is crystalline and is mesylate Type B.

Mesylate Type B is characterized by the following XRPD pattern expressed in terms of the degree 2Q and relative intensities:

*The relative intensities may change depending on the crystal size and morphology.

In one embodiment, mesylate Type B is characterized by the SSNMR of FIG. 66. In one embodiment, mesylate Type B is characterized by the following ¹³ C Solid State NMR shifts.

Representative ¹³ C NMR chemical shifts for mesylate Type B are 158.70, 127.58, 51.57, and 41.39 ppm. Representative ¹³ C NMR chemical shifts for mesylate Type B are also 158.70, and 127.58 ppm.

HYDROBROMIDE

In one aspect of the invention, the pharmaceutically acceptable salt of COMPOUND I is a hydrobromide. In one embodiment, the pharmaceutically acceptable salt of COMPOUND I is a mono-hydrobromide. In one embodiment, the hydrobromide is crystalline. In one embodiment, the hydrobromide is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 4.1 °, 13.1 °, and 16.4° ±0.2°. In one embodiment, the hydrobromide is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 4.1 °, 13.1 °, 16.4°, 19.7°, and 20.3° ±0.2°. In one embodiment, the hydrobromide is crystalline and is characterized by an XRPD pattern as shown in FIG. 44. In one embodiment, the hydrobromide is crystalline and is characterized by an endothermic peak at about 171 °C as determined by DSC. In one embodiment, the hydrobromide is crystalline and is characterized by a DSC profile as shown in FIG. 45. In one embodiment, the hydrobromide is crystalline and is characterized by a TGA profile as shown in FIG. 45. In one embodiment, the hydrobromide is crystalline and is characterized by at least two of the following features (l-i)-(l-iii):

(l-i) an XRPD pattern having peaks at 2Q angles of 4.1 °, 13.1 °, and 16.4° ±0.2°;

(l-ii) a DSC profile as shown in FIG. 45; or

(l-iii) a TGA profile as shown in FIG. 45.

In one embodiment, the hydrobromide is crystalline and is hydrobromide Type A.

Hydrobromide Type A is characterized by the following XRPD pattern expressed in terms of the degree 2Q and relative intensities:

*The relative intensities may change depending on the crystal size and morphology.

In one embodiment, hydrobromide Type A is characterized by the SSNMR of FIG. 67. In one embodiment, hydrobromide Type A is characterized by the following ¹³ C Solid

State NMR shifts.

Representative ¹³ C NMR chemical shifts for hydrobromide Type A are 1 18.47, 65.63, 31.66, and 1 1.06 ppm. Representative ¹³ C NMR chemical shifts for hydrobromide Type A are also 159.17 and 1 18.47 ppm.

In one embodiment, the pharmaceutically acceptable salt is a di-hydrobromide. In one embodiment, the hydrobromide is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 9.3°, 20.9°, and 23.0° ±0.2°. In one embodiment, the hydrobromide is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 9.3°, 12.4°, 20.2°, 20.9°, and 23.0° ±0.2°. In one embodiment, the hydrobromide is crystalline and is characterized by an XRPD pattern as shown in FIG. 46. In one embodiment, the hydrobromide is crystalline and is characterized by melting peak at about 231.5 °C (onset temperature) as determined by DSC. In one embodiment, the hydrobromide is crystalline and is characterized by a DSC profile as shown in FIG. 47. In one embodiment, the hydrobromide is crystalline and is characterized by a TGA profile as shown in FIG. 47. In one embodiment, the hydrobromide is crystalline and is characterized by at least two of the following features (l-i)-(l-iii):

(l-i) an XRPD pattern having peaks at 2Q angles of 9.3°, 20.9°, and 23.0° ±0.2°;

(l-ii) a DSC profile as shown in FIG. 47; or

(l-iii) a TGA profile as shown in FIG. 47.

In one embodiment, the hydrobromide is crystalline and is hydrobromide Type B.

Hydrobromide Type B is characterized by the following XRPD pattern expressed in terms of the degree 2Q and relative intensities:

*The relative intensities may change depending on the crystal size and morphology.

In one embodiment, hydrobromide Type B is characterized by the SSNMR of FIG. 68. In one embodiment, hydrobromide Type B is characterized by the following ¹³ C Solid

State NMR shifts.

Representative ¹³ C NMR chemical shifts for hydrobromide Type B are 160.62, 132.22, 29.34, and 23.71 ppm. Representative ¹³ C NMR chemical shifts for hydrobromide Type B are also 160.62 and 132.22 ppm.

4-AMINOSALICYLATE

In one aspect of the invention, the pharmaceutically acceptable salt of COMPOUND I is a 4-aminosalicylate. In one embodiment, the pharmaceutically acceptable salt of COMPOUND I is a mono-4-aminosalicylate. In one embodiment, the 4-aminosalicylate is crystalline. In one embodiment, the 4-aminosalicylate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 17.1 °, 19.2°, and 21.5° ±0.2°. In one embodiment, the 4-aminosalicylate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 3.5°, 1 1.2°, 17.1 °, 19.2°, and 21.5° ±0.2°. In one embodiment, the 4-aminosalicylate is crystalline and is characterized by an XRPD pattern as shown in FIG. 48. In one embodiment, the 4-aminosalicylate is crystalline and is crystalline and is characterized by a ¹ H-NMR substantially similar to FIG. 49. In one embodiment, the 4- aminosalicylate is crystalline and is characterized by an endothermic peak at about 87°C as determined by DSC. In one embodiment, the 4-aminosalicylate is crystalline and is characterized by a DSC profile as shown in FIG. 50. In one embodiment, the 4- aminosalicylate is crystalline and is characterized by a TGA profile as shown in FIG. 50. In one embodiment, the 4-aminosalicylate is crystalline and is characterized by at least two of the following features (l-i)-(l-iv):

(l-i) an XRPD pattern having peaks at 2Q angles of 17.1 °, 19.2°, and 21.5° ±0.2°; (l-ii) a ¹ H-NMR as shown in FIG. 49;

(l-iii) a DSC profile as shown in FIG. 50; or

(l-iii) a TGA profile as shown in FIG. 51.

In one embodiment, the 4-aminosalicylate is crystalline and is 4-aminosalicylate Type A.

4-Aminosalicylate Type A is characterized by the following XRPD pattern expressed in terms of the degree 2Q and relative intensities:

The relative intensities may change depending on the crystal size and morphology.

In one embodiment, the 4-aminosalicylate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 7.1 °, 19.2°, and 20.9° ±0.2°. In one embodiment, the 4-aminosalicylate is crystalline and is characterized by an XRPD pattern having peaks at 2Q angles of 7.1 °, 17.1 °, 17.6°, 19.2°, and 20.9° ±0.2°. In one embodiment, the 4-aminosalicylate is crystalline and is characterized by an XRPD pattern as shown in FIG. 51. In one embodiment, the 4-aminosalicylate is crystalline and is characterized by an endothermic peak at about 131 ° C as determined by DSC. In one embodiment, the 4- aminosalicylate is crystalline and is characterized by a DSC profile as shown in FIG. 52. In one embodiment, the 4-aminosalicylate is crystalline and is characterized by a TGA profile as shown in FIG. 52. In one embodiment, the 4-aminosalicylate is crystalline and is characterized by at least two of the following features (l-i)-(l-iii):

(l-i) an XRPD pattern having peaks at 2Q angles of 7.1 °, 19.2°, and 20.9° ±0.2°;

(l-ii) a DSC profile as shown in FIG. 52; or

(l-iii) a TGA profile as shown in FIG. 52.

In one embodiment, the 4-aminosalicylate is crystalline and is 4-aminosalicylate Type B.

4-Aminosalicylate Type B is characterized by the following XRPD pattern expressed in terms of the degree 2Q and relative intensities:

The relative intensities may change depending on the crystal size and morphology.

In one embodiment, 4-aminosalicylate Type B is characterized by the SSNMR of FIG. 69. In one embodiment, 4-aminosalicylate Type B is characterized by the following ¹³ C Solid State NMR shifts.

Representative ¹³ C NMR chemical shifts for 4-aminosalicylate Type B are 126.54, 1 18.29, 49.18, and 39.15 ppm. Representative ¹³ C NMR chemical shifts for 4- aminosalicylate Type B are also 126.54 and 1 18.29 ppm. PHARMACEUTICAL COMPOSITIONS

In another aspect, the present invention provides pharmaceutical compositions comprising one or more pharmaceutically acceptable salts of COMPOUND I. In one embodiment, a pharmaceutical composition comprises a pharmaceutically acceptable salt of COMPOUND I selected from the group consisting of 1-hydroxy-2-naphthate, 4- aminosalicyate, adipate, L-aspartate, benzene sulfonate, benzoate, trans-cinnamate, citrate, fumarate, galactarate, gentisate, gluconate, glutamate, glutarate, hexanoate, hippurate, hydrobromide, hydrochloride, L-lactate, maleate, L-malate, malonate, R-mandelate, methane sulfonate, naphthalene sulfonate, nicotinate, oxalate, palmitate, phosphorate, propionate, saccharinate, salicyclate, stearate, succinate, sulfurate, L-tartarate, vanillate, and vanillin and a pharmaceutically acceptable excipient, diluent, carrier, or mixture thereof. In one embodiment, a pharmaceutical composition comprises a pharmaceutically acceptable salt of COMPOUND I is selected from the group consisting of 4-aminosalicylate, fumarate, galactarate, gentisate, hippurate, hydrobromide, hydrochloride, L-lactate, maleate, L-malate, oxalate, phosphorate, saccharinate, salicyclate, L-tartarate, and vanillinate and a pharmaceutically acceptable excipient, diluent, carrier, or mixture thereof.

In another aspect, the present invention also provides methods of producing a pharmaceutical composition comprising a pharmaceutically acceptable salt of COMPOUND I. In one embodiment, a method of producing a pharmaceutical composition comprises combining a pharmaceutically acceptable salt of COMPOUND I with a pharmaceutically acceptable excipient, diluent, carrier, or a mixture thereof. In one embodiment, a method for producing a pharmaceutical composition comprises a pharmaceutically acceptable salt of COMPOUND I selected from the group consisting of selected from the group consisting of 1- hydroxy-2-naphthate, 4-aminosalicyate, adipate, L-aspartate, benzene sulfonate, benzoate, trans-cinnamate, citrate, fumarate, galactarate, gentisate, gluconate, glutamate, glutarate, hexanoate, hippurate, hydrobromide, hydrochloride, L-lactate, maleate, L-malate, malonate, R-mandelate, methane sulfonate, naphthalene sulfonate, nicotinate, oxalate, palmitate, phosphorate, propionate, saccharinate, salicyclate, stearate, succinate, sulfurate, L-tartarate, vanillate, and vanillin with a pharmaceutically acceptable excipient, diluent, carrier, or a mixture thereof. In one embodiment, a method for producing a pharmaceutical composition comprises combining a pharmaceutically acceptable salt of COMPOUND I is selected from the group consisting of 4-aminosalicylate, fumarate, galactarate, gentisate, hippurate, hydrobromide, hydrochloride, L-lactate, maleate, L-malate, oxalate, phosphorate, saccharinate, salicyclate, L-tartarate, and vanillinate with a pharmaceutically acceptable excipient, diluent, carrier, or a mixture thereof. Pharmaceutical compositions of the present invention comprising a pharmaceutically acceptable salt of COMPOUND I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, dispersible powders or granules, or hard or soft capsules. Compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations.

Tablets, tranches, lozenges, dispersible powders or granules, or hard or soft capsules may contain a pharmaceutically acceptable salt of COMPOUND I in admixture with non-toxic pharmaceutically-acceptable excipients which are suitable for the manufacture of such tablets, tranches, lozenges, dispersible powders or granules, or hard or soft capsules. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, croscarmelose sodium, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents or glidants, for example magnesium stearate, stearic acid, colloidal silicon dioxide, or talc. Hard gelatin capsules may include a pharmaceutically acceptable salt of COMPOUND I in combination with an inert solid excipient, diluent, carrier, or mixture thereof.

A "pharmaceutically acceptable carrier, diluent, or excipient" is a medium generally accepted in the art for the delivery of biologically active agents to mammals, e.g., humans. Such carriers are generally formulated according to a number of factors well within the purview of those of ordinary skill in the art to determine and account for. These include, without limitation, the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers and excipients include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources, e.g., Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa. 1985, the contents of which are incorporated herein by reference.

METHODS OF TREATMENT In another aspect, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a pharmaceutically acceptable salt of COMPOUND I wherein a therapeutically effective amount of COMPOUND I comprises a sufficient amount for the treatment of a RAGE mediated disorder.

In another aspect, the present invention provides a method for treating a RAGE mediated disease comprising administering a pharmaceutically acceptable salt of COMPOUND I to a subject in need thereof. The method may comprise administering a pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable salt of COMPOUND I to a subject in need thereof.

A pharmaceutical composition of the present invention may be administered at a dosage level of less than 100 mg of compound per day. In another embodiment, the dosage level of administration is greater than 1 mg of compound per day. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage will vary depending upon the host treated and the particular mode of administration. For example, in one non-limiting embodiment, a dosage unit forms, such as a tablet or capsule, intended for oral administration to humans may contain less than 100 mg of COMPOUND I with an appropriate and convenient amount of carrier material. In another embodiment, the dosage level of administration is greater than 1 mg of compound per day. In another embodiment, the dosage level of administration is 5, 10 or 20 mg of compound per day.

The dosage may be individualized by the clinician based on the specific clinical condition of the subject being treated. Thus, it will be understood that the specific dosage level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

EXAMPLES

Analytical Methods

X-ray Powder Diffraction (XRPD) Analysis

XRPD analysis was performed with a Panalytical X’Pert ³ Powder XRPD on a Si zero- background holder. The 2Q position was calibrated against Panalytical Si reference standard disc. The XRPD parameters used are listed in Table 1. T able 1 : Parameters for XRPD test

¹ H NMR

Solution NMR was collected on Bruker 500M NMR Spectrometer using DMSO-c/6 and CD ₃ OD as solvents.

HPLC

Agilent 1 100 HPLC was utilized to analyze the purity and stoichiometry, with detailed method listed in below.

Item Value

Column Gemini C18 1 10A , 250x4.6 mm, 5 pm

A: 0.05% TFA in H ₂ 0

Mobile phase

B: 0.05% TFA in H2O acetonitrile

Purity Stoichiometry

Time (min) %B Time (min) %B

Gradient table

0.0 25 0.0 20

20.0 40 6.0 95 Item Value

25.0 55 7.0 95

35.0 95 7.1 20

40.0 95 10.0 20

40.1 25

50.0 25

Run time 50.0 min 10.0 min

Post time 0.0 min

Flow rate 1 .0 mL/min

Injection volume 5 pL

Detector wavelength UV at 255 nm

Column temperature 40 °C

Sampler temperature RT

Diluent Acetonitrile

1C

IC method for counter-ion content measurement is listed below.

Item Value

Column lonPac AS18 Analytical Column (4 ^c 250 mm) Mobile Phase 25 mM NaOH

Injection volume 25 pL

Flow rate 1 .0 mL/min

Cell temperature 35 °C

Column temperature 35 °C

Current 80 mA

6 mins (Cl ), 8 mins (Br), 10 mins

Run Time

14 mins (PC ^3- )

Thermogravimetry Analysis (TGA) and Differential Scanning Calorimetry (DSC)

TGA data were collected using a TA Q500 and Q550 from TA Instruments. DSC was performed using a TA Q2000 from TA Instruments. DSC was calibrated with Indium reference standard and the TGA was calibrated using nickel reference standard. Detailed parameters used are listed in Table 2. Table 2: Parameters for TGA and DSC test

Solid-state Nuclear Magnetic Resonance (SSNMR)

Experiments were performed on a Bruker NEO spectrometer (Bruker, Billerica, MA) operating at 100.47 MHz for 13C and 399.50 MHz for ¹ H. Data acquisition, collection, and processing was preformed using the Bruker Topspin 4.0.1 software package. Each sample was packed into a 4 mm zirconia rotor. Teflon end spacers were used to contain the sample in the central part of the rotor. All experiments were acquired using Cross Polarization / Magic Angle Spinning (CP/MAS). Data was acquired with a magic angle spinning speed of 10 kHz (high quality spectra) and at 9 kHz (quick spectrum) to identify isotropic shifts vs spinning sidebands. A Revolution NMR HX widebore probe (Revolution NMR, Fort Collins, CO) was used, with a 4mm magic angle spinning module. ¹ H decoupling was used, and was applied at 100 kHz (2.5 us H90). Proton decoupling was applied during acquisition.

Chemical shifts were reported relative to TMS via a secondary reference of the methyl peak of 3-methylglutaric acid (MGA) at 18.84 ppm with an accuracy of ±0.2 ppm.

Crystalline Form II of COMPOUND I, described in U.S. Patent No. 7,884,219, was used as the starting material in each of the following Examples. U.S. Patent No. 7,884,219, herein incorporated by reference, provides a method for preparing Crystalline Form II of COMPOUND I.

EXAMPLE 1

A total of 320 salt/co-crystal screening experiments were conducted using 38 acids (two molar ratios for HCI and HBr) and eight solvent systems. Specifically, freebase stock solutions of ~100 mg/mL were first prepared in each solvent system. For each experiment, 0.2 mL stock solution and the corresponding acids were mixed in a molar charge ratio of 1 :1 (acid/freebase, 2:1 for HCI/freebase and HBr/freebase as well), and then stirred at RT. After stirring for 3~5 days, if precipitation was observed, the precipitate was isolated. It no precipitation, the clear solutions were first transferred to slurry at 5 °C to introduce precipitation. Solutions without any precipitation were further subjected to anti-solvent addition (for solvents in column B/D, 0.5 mL hexane was added; for solvents in column G/H, 0.5 mL water was added; for solvent in column F, 0.5 mL n-heptane was added). If still no precipitation, the final clear solutions were transferred to evaporation at RT to induce precipitation. All solids isolated were vacuum dried at RT for 2 hrs before XRPD analysis.

As summarized in Table 1 , a total of 17 crystalline salt/co-crystal hits were obtained from the screening, namely saccharinate Type A, vanillate Type A, HCI salt Type A, fumarate Type A, maleate Type A, galactarate Type A, phosphate Type A, L-tartrate Type A, hippurate Type A, L-malate Type A, oxalate Type A, gentisate Type A/B, mesylate Type A, HBr salt Type A/B, and 4-aminosalicylate Type A. T able 1 : Summary of salt screening experiments

#: obtained via 5 °C slurry;

&: obtained via anti-solvent addition; *: obtained via evaporation. EXAMPLE 2

All hits were further characterized by TGA and DSC, with the stoichiometry determined by ¹ H NMR or HPLC/IC. Based on the characterization data in Table 2 below, most of them were considered to be anhydrates.

Table 2: Characterization summary of crystalline hits

*: peak temperature

+: sample converted to gel after storage at ambient conditions.

EXAMPLE 3

One saccharinate crystal form was obtained via screening. Saccharinate Type A was generated via stirring the freebase and saccharin in ethyl acetate/hexane (1 :2, v/v) at RT, with a molar charge ratio of 1 :1 (acid/freebase). The XRPD pattern was displayed in FIG. 1. Negligible weight loss was observed before decomposition in TGA and DSC data (FIG. 3) showed a single sharp endotherm at 120.0 °C (onset temperature) possibly due to melting. Based on the integration of the phenyl protons (2H) of freebase at ~7.1 ppm and the phenyl protons (4H) of saccharin at ~7.6 ppm, the ratio of saccharin to freebase was determined as 1.22:1 by ¹ H NMR using CD ₃ OD as shown in FIG. 2. Based on the characterization results, saccharinate Type A was considered to be an anhydrate.

EXAMPLE 4

One vanillate crystal form was generated via screening. Vanillate Type A was obtained via stirring the freebase and vanillic acid in ethyl acetate/hexane (1 :2, v/v) at RT, with a molar charge ratio of 1 :1 (acid/freebase). The XRPD pattern was shown in FIG. 4. As per TGA and DSC results in FIG. 6, negligible weight loss was observed before decomposition and DSC result showed a sharp endothermic peak at 99.6 °C (onset temperature) possibly due to melting. Based on the integration of the phenyl protons (2H) of freebase at ~7.1 ppm and the phenyl protons (3H) of vanillic acid at ~6.8/7.5/7.6 ppm, the ratio of counter ion to freebase was determined as 1.04:1 by ¹ H NMR using CD ₃ OD as shown in FIG. 5. Based on the characterization results, Type A was considered to be an anhydrate of mono-vanillate.

EXAMPLE 5

One HCI salt crystal form was obtained from screening. HCI salt Type A was obtained via reactive crystallization (molar charge of 2:1 , acid/freebase) in ethyl acetate/hexane (1 :2, v/v) at RT. The XRPD pattern of Type A is displayed in FIG. 7. Negligible weight loss was observed before decomposition in TGA and DSC results (FIG. 8) showed a sharp endothermic peak at 167.0 °C (onset temperature) possibly due to melting. Also, the stoichiometry was determined as 1.33 (acid/base) for the sample by HPLC/IC. Therefore, HCI salt Type A was speculated to be an anhydrate.

A second HCI salt crystal form (Type B) was obtained by stirring free base in ethanol at 5 °C (molar charge ratio of 2:1 , acid/freebase). The XRPD of Type B is displayed in FIG. 9. Negligible weight loss was observed before decomposition in TGA and DSC results (FIG. 10) show an endothermic peak at 232.4 °C. HCI salt Type B was speculated to be an anhydrate. HCI salt Type B is a di-hydrochloride.

EXAMPLE 6

One fumarate crystal form was obtained via screening. Fumarate Type A was generated via stirring the freebase with fumaric acid in acetone/hexane (1 :2, v/v) at RT, with a molar charge ratio of 1 :1 (acid/freebase). The XRPD pattern was shown in FIG. 1 1. TGA and DSC data in FIG. 13 showed negligible weight loss before decomposition and a sharp endothermic peak at 1 15.0 °C (onset temperature) possibly due to melting. Based on the integration of the phenyl proton (2H) of freebase at ~7.7 ppm and CH proton (2H) of fumaric acid at ~6.6 ppm, the ratio of counter ion to freebase was determined as 1.00:1 by ¹ H NMR using DMSO -d6 as shown in FIG. 12. Therefore, Type A was speculated to be an anhydrate of mono-fumarate.

EXAMPLE 7

One maleate crystal form was obtained via screening. Maleate Type A was generated via stirring the freebase with maleic acid in ethyl acetate/hexane (1 :2, v/v) at RT, with a molar charge ratio of 1 :1 (acid/freebase). The XRPD pattern is displayed in FIG. 14. As per TGA and DSC data shown in FIG. 16, negligible weight loss was observed before decomposition and DSC result showed a sharp melting peak 120.2 °C (onset temperature). Based on the integration of the phenyl proton (2H) of freebase at ~7.7 ppm and CH proton (2H) of maleic acid at ~6.0 ppm, the ratio of counter ion to freebase was determined as 0.97:1 by ¹ H NMR using DMSO -d6 as shown in FIG. 15. Therefore, Type A was speculated to be an anhydrate of mono-maleate.

EXAMPLE 8

One galactarate crystal form was obtained via screening. Galactarate Type A was generated via stirring the freebase with galactaric acid in dioxane/H20 (9:1 , v/v) at RT, with a molar charge ratio of 1 :1 (acid/freebase). The XRPD pattern is displayed in FIG. 17. A weight loss of 0.6% was observed up to 130 °C and DSC data (FIG. 19) showed a broad endotherm at 106.3 °C (peak temperature) possibly due to moisture/solvent loss, followed by melting at 158.4 °C (onset temperature). Based on the integration of the phenyl proton (2H) of freebase at ~7.7 ppm and CH proton (4H) of galactaric acid at ~3.7/4.2 ppm, the ratio of counter ion to freebase was determined as 0.98:1 by ¹ H NMR using DMSO -d6 as shown in FIG. 18. Based on with the results, Type A was considered to be an anhydrate of mono- galactarate.

EXAMPLE 9

One phosphate crystal form was obtained from screening. Phosphate Type A was obtained via reactive crystallization (molar ratio of 1 :1) in acetone/hexane (1 :2, v/v) at RT, and its XRPD pattern is shown in FIG. 20. TGA and DSC curves (FIG. 21) showed a weight loss of 0.3% up to 100 °C and two sharp endotherms at 107.5 °C and 138.0 °C (peak temperature). Also, the stoichiometry was determined as 0.91 (acid/base) for the sample via HPLC/IC. Therefore, Type A was considered to be an anhydrate of mono-phosphate.

EXAMPLE 10 One tartrate crystal form was obtained via screening. L-Tartrate Type A was generated via stirring the freebase with L-tartaric acid in ethyl acetate/hexane (1 :2, v/v) at RT, with a molar charge ratio of 1 :1 (acid/freebase). The XRPD pattern is displayed in FIG. 22. A weight loss of 2.1 % was observed up to 60 °C, and DSC data (FIG. 24) showed an endotherm at 76.4 °C (onset temperature) before decomposition. Based on the integration of the phenyl proton (2H) of freebase at ~7.7 ppm and CH proton (2H) of L-tartaric acid at ~4.0 ppm, the ratio of counter ion to freebase was determined as 1.00:1 by ¹ H NMR using DMSO -d6 as shown in FIG. 23. Also, no ethyl acetate and limited hexane content was observed by ¹ H NMR. Based on the results, L-tartrate Type A was possibly a hydrate.

EXAMPLE 1 1

One hippurate crystal form was obtained via screening. Hippurate Type A was generated via stirring the freebase with hippuric acid in ethyl acetate/hexane (1 :2, v/v) at 5 °C, with a molar charge ratio of 1 :1 (acid/freebase). The XRPD pattern is displayed in FIG. 27. As per TGA and DSC results in FIG. 29, negligible weight loss was observed before decomposition and DSC data showed a minor endotherm at 44.3 °C (peak temperature) before possible melting peak at 72.7 °C (onset temperature). Based on the integration of the phenyl proton (2H) of freebase at ~7.1 ppm and the phenyl proton (5H) of hippuric acid at ~7.5/7.6 ppm, the ratio of counter ion to freebase was determined as 0.98:1 by ¹ H NMR using CD ₃ OD as shown in FIG. 28. Therefore, Type A was considered to be an anhydrate of mono-hippurate.

EXAMPLE 12

One malate crystal form was obtained via screening. L-Malate Type A was produced via stirring the freebase with L-malic acid in ethyl acetate/hexane (1 :2, v/v) at RT, with a molar charge ratio of 1 :1 (acid/freebase). The XRPD pattern is displayed in FIG. 30. As per TGA and DSC results in FIG. 32, negligible weight loss was observed before decomposition, and DSC result showed a sharp meting peak at 67.8 °C (onset temperature). Based on the integration of the phenyl proton (2H) of freebase at ~7.1 ppm and the CH2 and CH proton (3H) of L-malic acid at ~2.4/2.6/4.2 ppm, the ratio of counter ion to freebase was determined as 1.1 1 : 1 by ¹ H NMR using CD ₃ OD as shown in FIG. 31. Based on the characterization results, L-malate Type A was speculated to be an anhydrate.

EXAMPLE 13

One oxalate crystal form was obtained via screening. Oxalate Type A was generated via stirring the freebase with oxalic acid in methyl tert-butyl ether at RT, with a molar charge ratio of 1 :1 (acid/freebase). The XRPD pattern was shown in FIG. 33. Negligible weight loss was observed before decomposition in TGA and DSC data (FIG. 34) showed a sharp endotherm at 109.5 °C (onset temperature) possibly due to melting. Also, the stoichiometry was determined as 1.12 (acid/base) for the sample by HPLC/IC. Therefore, Type A was speculated to be an anhydrate of mono-oxalate.

EXAMPLE 14

A total of two gentisate crystal forms were obtained via screening. Gentisate Type A and Type B were generated via stirring the freebase with gentisic acid in methyl tert-butyl ether and toluene at RT, respectively, with a molar charge ratio of 1 :1 (acid/freebase). The XRPD patterns are displayed in FIG. 35 (Type A) and Fig. 38 (Type B).

For gentisate Type A, a weight loss of 1.8% was observed up to 120 °C and DSC data (FIG. 37) showed two endotherms at 89.9 °C and 129.2 °C (onset temperature), with the first due to the dehydration/desolvation and the second due to melting. For gentisate Type B, negligible weight loss was observed before decomposition and DSC result (FIG. 40) showed a sharp endotherm at 122.9 °C (onset temperature). Based on the integration of the phenyl proton (2H) of freebase at ~7.7 ppm and the phenyl proton (3H) of gentisic acid at ~6.7/6.8/7.3 ppm, the ratio of counter ion to freebase was determined as 1.01 :1 and 1.03:1 by ¹ H NMR using CD ₃ OD for gentisate Type A and Type B samples, respectively, with the ¹ H NMR spectra shown in FIG. 36 (Type A) and FIG. 39 (Type B). Also, no methyl tert-butyl ether signal was detected for gentisate Type A sample by ¹ H NMR. Therefore, gentisate Type A was possibly a hydrate and Type B was considered as an anhydrate.

EXAMPLE 15

One mesylate crystal form was obtained via screening. Mesylate Type A was generated via reactive crystallization (molar ratio of 1 :1) in ethyl acetate/hexane (1 :2, v/v) at RT. The XRPD pattern is displayed in FIG. 41. No further characterization was performed due to the sample converted to gel after storage at ambient conditions. This suggested the mesylate was most likely highly hygroscopic and unstable under ambient conditions.

EXAMPLE 16

Two HBr salt crystal forms were obtained via screening. HBr salt Type A was generated via reactive crystallization in ethanol at RT, with a molar charge ratio of 1 :1 (acid/freebase). HBr salt Type B was generated via stirring the freebase with the acid solution in methyl tert-butyl ether at RT, with a molar charge ratio of 2:1 (acid/freebase). The XRPD patterns were displayed in FIG. 44 (Type A) and Fig. 46 (Type B). For HBr salt Type A, negligible weight loss was observed before decomposition and DSC result (FIG. 45) showed a sharp endotherm at 169.9 °C (onset temperature) possibly due to melting. For HBr salt Type B, negligible weight loss was observed before decomposition and DSC result (FIG. 47) showed a minor endotherm at 167.5 °C (onset temperature) possibly due to the presence of small amount of HBr salt Type A or a solid to solid phase transition, followed by a sharp melting peak at 231.5 °C (onset temperature). Also, the stoichiometry of HBr salt Type A and Type B samples were determined as 1.05 and 2.07 (acid/base) by HPLC/IC respectively. Therefore, Type A was considered to be an anhydrate of mono-HBr salt and Type B was speculated to be an anhydrate of di-HBr salt.

EXAMPLE 17

One 4-aminosalicylate crystal form was obtained via screening. 4-Aminosalicylate Type A was generated via stirring the freebase with 4-aminosalicylic acid in methyl tert-butyl ether at RT, with a molar charge ratio of 1 :1 (acid/freebase). The XRPD pattern is displayed in FIG. 48. Negligible weight loss was observed before decomposition in TGA and DSC result showed a sharp endotherm at 81.7 °C (onset temperature) possibly due to melting (FIG. 50). Based on the integration of the phenyl proton (2H) of freebase at ~7.7 ppm and the phenyl proton (3H) of 4-aminosalicylate acid at ~6.1/6.2/7.6 ppm, the ratio of counter ion to freebase was determined as 1.01 by 1 H NMR using CD ₃ OD for the sample, as shown in FIG. 49. Therefore, Type A was considered to be an anhydrate of mono-4-aminosalicylate.

EXAMPLE 18

Three new forms were obtained during the sample preparation for ssNMR test: L- tartrate Type B, mesylate Type B, and 4-aminosalicylate Type B. All forms were further characterized by TGA and DSC, with the results summarized in the table below and details provided subsequently.

Various embodiments of the invention have been described in fulfillment of the various objects of the invention. It should be recognized that these embodiments are merely illustrative of the principles of the present invention. Numerous modifications and adaptations thereof will be readily apparent to those skilled in the art without departing from the spirit and scope of the present invention.