CRYSTALLINE FORMS OF N-[5-[[[5-(l,l-DIMETHYLETHYL)-2-

OXAZOLYL]METHYL]THIO]-I-THIAZOLYLM-

PIPERIDINECARBOXAMIDE This application claims priority to U.S. Provisional No. 60/81 1 ,482 filed June 6,

2006, entitled Crystalline Forms Of N-[5-[[[5-(l,l-Dimethylethyl)-2-Oxazolyl]Methyl]- Thio]-2-Thiazolyl]-4-Piperidinecarboxamide, which is incorporated by reference in its entirety.

FIELD OF THE INVENTION The invention generally relates to crystalline forms of N-[5-[[[5-(l,l- dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperi dinecarboxamide. The invention also relates to a pharmaceutical composition comprising a crystalline form of N-[5-[[[5-(l,l-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thia zolyl]-4- piperidinecarboxamide, as well as a method of using a crystalline form of N-[5-[[[5-(l,l- dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperi dinecarboxamide in the treatment of proliferative diseases such as cancer, and of inflammation.

BACKGROUND OF THE INVENTION

N-[5-[[[5-(l,l-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-t hiazolyl]-4- piperidinecarboxamide, has the structure of formula I:

and is referred to herein as "Compound I". Compound I, salts of Compound I, and processes to prepare Compound I and salts are disclosed in U.S Patent 6,515,004 Bl , which is assigned to the present assignee and is incorporated herein by reference in its entirety. U.S. Patents 6,040,321, 6,214,852 Bl, 6,262,096 Bl, 6,392,053 B2, 6,414,156 B2, 6,515,004 Bl, 6,521,759, 6,613,911 B2, 6,639,074 B2, and 6,897,321 B2, which are assigned to the present assignee, are also incorporated herein by reference in their entirety. Compound I is suitable as an inhibitor of protein kinases such as the cyclin dependent kinases (cdks), for example, cdc2 (cdkl), cdk2, cdk3, cdk4, cdk5, cdkδ, cdk7, and cdk8. Compound I is expected to be useful in the therapy of proliferative diseases

such as cancer, and in the therapy of inflammation, arthritis, Alzheimer's disease, cardiovascular disease, and autoimmune disorders.

Typically, in the preparation of a pharmaceutical composition, a form of the active ingredient is sought that has a balance of desired properties such as dissolution rate, solubility, bioavailability, and/or storage stability. For example, it is desired that a form of the active ingredient, which has the requisite solubility and bioavailability, also has sufficient stability that it does not convert during manufacture or storage of the pharmaceutical composition to a different form, which has different solubility and/or bioavailability. One or more forms of Compound I or salt thereof are desired having properties and stability that allow the preparation of pharmaceutical compositions suitable for the treatment of diseases such as cancer. Further, one or more forms of Compound I or salt thereof are desired that allow the isolation and/or purification of Compound I, for example, during a preparative process.

SUMMARY OF THE INVENTION One aspect of the present invention provides a crystalline form of the hemi-L- tartrate salt of Compound I:

comprising Form N-3.

Another aspect of the present invention provides a crystalline form of the hemi-L- tartrate salt of Compound I comprising Form M-2.

Another aspect of the present invention provides a crystalline form of the hemi-L- tartrate salt of Compound I comprising Form FA-4.

Another aspect of the present invention provides a crystalline form of the dihydrogen chloride salt of Compound I comprising Form H3-1. Another aspect of the present invention provides a crystalline form of the hydrogen bromide salt of Compound I comprising Form H-I.

Another aspect of the present invention provides a crystalline form of the hydrogen iodide salt of Compound I comprising Form H-I .

Another aspect of the present invention provides a crystalline form of the trifluoroacetate salt of Compound I comprising Form N-I .

Another aspect of the present invention provides a crystalline form of the hemi-L- tartrate salt of Compound I comprising Form N-I .

Another aspect of the present invention provides a crystalline form of the hemi- fumarate salt of Compound I comprising Form E-I . Another aspect of the present invention provides a crystalline form of the hemi- succinate salt of Compound I comprising Form E-I.

Another aspect of the present invention provides a crystalline form of the free base of Compound I comprising Form H-I.

Another aspect of the invention provides a pharmaceutical composition comprising one or more of: Form N-3, Form N-I , Form M-2, and/or Form FA-4 of the hemi-L-tartrate salt of Compound I, Form H3-1 of the dihydrogen chloride salt of Compound I, Form H-I of the hydrogen bromide salt of Compound I, Form H-I of the hydrogen iodide salt of Compound I, Form N-I of the trifluoroacetate salt of Compound I, Form E-I of the hemi-fumarate salt of Compound I, Form E-I of the hemi-succinate salt of Compound I, and/or Form H-I of the free base of Compound I; and a pharmaceutically acceptable carrier or diluent.

Another aspect of the present invention provides a method for treating a proliferative disease, comprising administering to a mammalian species in need thereof, a therapeutically effect amount of Compound I, wherein Compound I is provided in a crystalline form comprising Form N-3, Form N-I , Form M-2, and/or Form FA-4 of the hemi-L-tartrate salt of Compound I, Form H3-1 of the dihydrogen chloride salt of Compound I, Form H-I of the hydrogen bromide salt of Compound I, Form H-I of the hydrogen iodide salt of Compound I, Form N-I of the trifluoroacetate salt of Compound I, Form E-I of the hemi-fumarate salt of Compound I, Form E-I of the hemi-succinate salt of Compound I, and/or Form H-I of the free base of Compound I.

The names used herein to characterize a specific form, e.g. "N-3" etc., should not be considered limiting with respect to any other substance possessing similar or identical physical and chemical characteristics, but rather it should be understood that these designations are mere identifiers that should be interpreted according to the characterization information also presented herein.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is illustrated by reference to the accompanying drawings described below.

FIG. 1 shows simulated and observed powder x-ray diffraction patterns (CuKa λ=1.5418 A) of the N-3 crystalline form of the hemi L-tartrate salt of N-[5-[[[5-(l,l- Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperi dinecarboxamide, at room temperature.

FIG. 2 shows simulated and observed powder x-ray diffraction patterns (CuKa λ=1.5418 A) of the M-2 crystalline form of the hemi L-tartrate salt of N-[5-[[[5-(l,l- dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperi dinecarboxamide, at room temperature.

FIG. 3 shows the simulated powder x-ray diffraction pattern (CuKa λ= 1.5418 A) of the FA-4 crystalline form of the hemi L-tartrate salt of N-[5-[[[5-(l,l-dimethylethyl)-2- oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, at a temperature of -50 ⁰ C. FIG. 4 shows simulated powder x-ray diffraction pattern (CuKa λ=l .5418 A) of the H3-1 crystalline form of the dihydrogen chloride salt of N-[5-[[[5-(l,l- Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperi dinecarboxamide, at a temperature of -33°C.

FIG. 5 shows simulated powder x-ray diffraction pattern (CuKa λ=1.5418 A) of the H-I crystalline form of the hydrogen bromide salt of N-[5-[[[5-(l,l-Dimethylethyl)-2- oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, at room temperature.

FIG. 6 shows simulated powder x-ray diffraction pattern (CuKa λ=1.5418 A) of the H-I crystalline form of the hydrogen iodide salt of N-[5-[[[5-(l,l-Dimethylethyl)-2- oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, at room temperature. FIG. 7 shows simulated powder x-ray diffraction pattern at room temperature

(CuKa λ=1.5418 A) of the N-I crystalline form of the trifluoroacetic acid salt of N- [5- [[[5-(l,l-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl ]-4-piperidinecarboxamide.

FIG. 8 shows simulated, observed, and observed at pH =9 powder x-ray diffraction patterns (CuKa λ=1.5418 A) of the H-I crystalline form of N-[5-[[[5-(l,l- Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperi dinecarboxamide, at room temperature

FIG. 9 shows simulated and observed powder x-ray diffraction patterns (CuKa λ=1.5418 A) of the E-I crystalline form of the hemi-fumarate salt of N-[5-[[[5-(l,l-

Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-pip eridinecarboxamide, at room temperature

FIG. 10 shows simulated and observed powder x-ray diffraction patterns (CuKa λ=1.5418 A) of the N-I crystalline form of hemi L-taitrate salt of N-[5-[[[5-(l,l- Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperi dinecarboxamide, at room temperature.

FIG. 11 shows simulated powder x-ray diffraction pattern (CuKa λ=1.5418 A) of the E-I crystalline form of the hemi-succinate salt of N-[5-[[[5-(l ,l-Dimethylethyl)-2- oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, at a temperature of -13°C. In FIG. 1 to FIG. 1 1 , the abscissa is in units of degrees 2θ, and the ordinate represents the intensity as the number of counts.

FIG. 12 shows a differential scanning calorimetry (DSC) thermogram of the N-3 crystalline form of the hemi L-tartrate salt of N-[5-[[[5-(l,l-dimethylethyl)-2- oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide. FIG. 13 shows a thermogravimetric analysis (TGA) thermogram of the N-3 crystalline form of the hemi L-tartrate salt of N-[5-[[[5-(l,l-dimethylethyl)-2- oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide.

FIG. 14 shows a differential scanning calorimetry thermogram of the M-2 crystalline form of the hemi L-tartrate salt of N-[5-[[[5-(l,l-dimethylethyl)-2- oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide.

FIG. 15 shows a thermogravimetric analysis (TGA) thermogram of the M-2 crystalline form of the hemi L-tartrate salt of N-[5-[[[5-(l,l-dimethylethyl)-2- oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide.

FIG. 16 shows a differential scanning calorimetry thermogram of the H-I crystalline form of N-[5-[[[5-(l,l-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thia zolyl]-4- piperidinecarboxamide.

FIG. 17 shows a thermogravimetric analysis (TGA) thermogram of the H-I crystalline form of N-[5-[[[5-(l , 1 -dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide. FIG. 18 shows a differential scanning calorimetry thermogram of the N-I crystalline form of hemi L-tartrate salt of N-[5-[[[5-(l,l-dimethylethyl)-2- oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide.

FIG. 19 shows a thermogravimetric analysis (TGA) thermogram of the N-I crystalline form of hemi L-tartrate salt of N-[5-[[[5-(l,l-dimethylethyl)-2- oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide.

FIG. 20 shows the centro symmetric solvent site in the triclinic crystal structure of the base. The centrosymmetric solvent site (volume ~ 75 A ³ , violet net) in the triclinic crystal structure of the base, from aq. EtOH. Electron density corresponding to an oxygen atom was observed at the center of each site (black circle) but one water obviously does not fill the site, and the minimum (Nl 8 - center) distance of 3.40A is too long for any significant H-bond interaction. A molecule of acetonitrile (disordered end-for-end) may also fit in the site. One (ordered) chloride ion could fit in the site, suggesting the possible crystallization of an isostructural hemi- hydrochloride (i.e. 2 molecules of base + 1 HCl).

FIG. 21 shows the H-bonding in the pseudocentrosymmetric crystal structure of the (2: 1 ) L-tartrate salt, form N- 1.

FIG. 22 shows the H-bonding in the crystal structure of the (2:1) L-tartrate salt, form N-3.

FIG. 23 shows the structure of the hemitartrate (form M-2). The two independent cations of achiral Compound I adopt enantiomeric conformations which H-bond to the homochiral dianion of L-tartaric acid in a pseudo centrosymmetric arrangement. The two independent molecules of methanol are also pseudo centrically H-bonded to the two carboxylate anions. Other intermolecular H-bonds - between the amide NH and oxazole nitrogen -join neighboring, "centric" pairs of cations along the screw axes of space group P2), resulting in the overall arrangement observed.

FIGs. 24a-c. Modes of conformation and H-bonding in salts of Compound I.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, "polymorphs" refer to crystalline forms having the same chemical compositions but different spatial arrangements of the molecules and/or ions forming the crystals.

As used herein, "amorphous" refers to a solid form of a molecule and/or ions that is not crystalline. An amorphous solid does not display a definitive X-ray diffraction pattern with sharp maxima.

The crystal forms provided herein are provided in substantially pure form. In other embodiments, the crystal forms provided herein are provided as mixtures with either other crystal forms or amorphous material. In certain embodiments, the crystal

forms are present in such mixtures in an amount as low as the limit of detection. In other embodiments, the crystal forms are present in such mixtures at greater than about 0.1, 0.25, 0.5, 1, 5, 10, 25, 50, 75, 85, 90, 95, 96, 97, 98, 99 or 99.5 % by weight.

The compositions provided herein are comprised of crystal forms that are in substantially pure form. In other embodiments, the compositions provided herein are comprised of crystal forms in mixtures with either other crystal forms or amorphous material. In certain embodiments, the compositions are comprised of crystal forms that are present in such mixtures in an amount as low as the limit of detection. In other embodiments, the compositions are comprised of crystal forms that are present in such mixtures at greater than about 0.1, 0.25, 0.5, 1, 5, 10, 25, 50, 75, 85, 90, 95, 96, 97, 98, 99 or 99.5 % by weight.

As used herein, the parameter "molecules/asymmetric unit" refers to the number of molecules of Compound I in the asymmetric unit.

As used herein, the unit cell parameter "molecules/unit cell" refers to the number of molecules of Compound I in the unit cell.

When dissolved, the crystalline form of Compound I loses its crystalline structure, and is therefore referred to as a solution of Compound I. One or more of the crystalline forms of Compound I disclosed herein, may be used for the preparation of liquid formulations in which the compound is dissolved or suspended. A therapeutically effective amount of the crystalline Form N-3, Form N-I, Form

M-2, and/or Form FA-4 of the hemi-L-tartrate salt of Compound I, Form H3-1 of the dihydrogen chloride salt of Compound I, Form H-I of the hydrogen bromide salt of Compound I, Form H-I of the hydrogen iodide salt of Compound I, Form N-I of the trifluoroacetate salt of Compound I, Form E-I of the hemi-fumarate salt of Compound I, Form E-I of the hemi-succinate salt of Compound I, and/or Form H-I of the free base of Compound I may be combined with a pharmaceutically acceptable carrier or diluent to provide pharmaceutical compositions of this invention. By "therapeutically effective amount", it is meant an amount that, when administered alone or an amount when administered with an additional therapeutic agent, is effective to prevent, suppress, or ameliorate a disease or condition or the progression of a disease or condition.

The present invention provides crystalline forms of Compound I,

including salts of Compound I.

One aspect of the invention provides an anhydrous, non-solvated crystalline form of a hemi-L-tartrate salt of Compound I and is referred to herein as the "Form N-3" or "N-3 Form" of the hemi-L-tartrate salt of Compound I. The composition this hemi-L- tartrate salt form comprises one molecule of L-tartaric acid for each two molecules of Compound I.

In one embodiment, the N-3 Form of the hemi-L-tartrate salt of Compound I is characterized by unit cell parameters approximately equal to the following: Cell dimensions: a = 10.00 A b = 39.02 A c = 5.73 A α = 90.0° β = 94.6° γ = 90.0°

Space group: P2|

Molecules of Compound I/asymmetric unit: 2 Volume = 2226 A ³ Density (calculated) = 1.359 g/cm ³ wherein measurement of the crystalline form is at a temperature of about 22°C.

In a different embodiment, the N-3 Form of the hemi-L-tartrate salt of Compound I is characterized by a powder x-ray diffraction pattern substantially in accordance with the simulated powder x-ray diffraction pattern shown in Figure 1. In another embodiment, the N-3 Form of the hemi-L-tartrate salt of Compound I is characterized by a powder x- ray diffraction pattern substantially in accordance with the observed powder x-ray diffraction pattern shown in Figure 1. In another embodiment, the N-3 form of the hemi- L-tartrate salt is characterized by a powder x-ray diffraction pattern substantially in accordance with the simulated powder x-ray diffraction pattern shown in Figure 1 and with the observed powder x-ray diffraction pattern shown in Figure 1. In a still different embodiment, the N-3 Form of the hemi-L-tartrate salt of

Compound I is characterized by a powder x-ray diffraction pattern (CuKa λ=l .5418A at a

temperature of about 25°C) comprising one or more, in another embodiment, two, three, four or five or more, 2θ values selected from: 4.5±0.2, 8.9±0.2, 12.7±0.2, 18.0±0.2,19.3±0.2, 20.8±0.2, 21.7±0.2,24.5±0.2, 25.55±0.2 wherein measurement of the crystalline form is at a temperature of about 25°C.

In a further embodiment, the Form N-3 of the hemi-L-tartrate salt of Compound I is characterized by fractional atomic coordinates substantially as listed in Table 1. Table 1 : Fractional Atomic Coordinates for Form N-3 of the hemi-L-tartrate salt of

Compound I at room temperature

In a still further embodiment, the N-3 Form of the hemi-L-tartrate salt of Compound I is characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in Figure 12. In another embodiment, the N- 3 Form of the hemi-L-tartrate salt of Compound I is characterized by a melting temperature in the range of about 243-251 ⁰ C.

In another embodiment, the N-3 Form of the hemi-L-tartrate salt of Compound I is characterized by a thermogravimetric analysis (TGA) thermogram having no significant weight loss, in one embodiment, having weight loss of approximately -0.14 weight %, upon heating to a temperature of about 150 ⁰ C. The invention also provides the N-3 Form of the hemi-L-tartrate salt of Compound I that exhibits a TGA thermogram substantially the same as shown in Figure 13.

In still another embodiment, the N-3 Form of the hemi-L-tartrate salt of Compound T is provided in substantially pure form. This N-3 Form of the hemi-L-tartrate salt of Compound I in substantially pure form may be employed in pharmaceutical compositions which may optionally include one or more other components selected, for example, from excipients and carriers; and optionally, one or more other active pharmaceutical ingredients having active chemical entities of different molecular structures. In another embodiment, N-3 Form of the hemi-L-tartrate salt of Compound I is provided in substantially pure form as indicated by an analysis of the total peak area in the experimentally measured powder x-ray diffraction (PXRD) pattern arising from extra peaks that are absent from the simulated PXRD pattern. In another embodiment, N-3 Form of the hemi-L-tartrate salt of Compound I is provided with phase homogenicity as indicated by an analysis of the total peak area in the experimentally measured powder x- ray diffraction (PXRD) pattern arising from extra peaks that are absent from the

simulated PXRD pattern. One embodiment is a crystalline form having substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured PXR-D pattern arising from the extra peaks that are absent from the simulated PXRD pattern. For example, the N-3 Form of the hemi-L-tartrate salt of Compound I may be provided in substantially pure form, wherein substantially pure is greater than 90 weight % pure, in one embodiment greater than 95 weight % pure, and in another embodiment greater than 99 weight % pure.

In a different embodiment, a composition is provided consisting essentially of the N-3 Form of the hemi-L-tartrate salt of Compound I. In a different embodiment, a composition is provided comprising the N-3 Form of the hemi-L-tartrate salt of Compound I in substantially pure form. This Form N-3 of the hemi-L-tartrate salt of Compound I in substantially pure form may be employed in pharmaceutical compositions which may optionally include one or more other components selected, for example, from excipients and carriers; and optionally, one or more other active pharmaceutical ingredients having active chemical entities of different molecular structures.

The composition of this embodiment may comprise at least 90 weight % of Compound I in the N-3 Form of the hemi-L-tartrate salt of Compound I, based on the total weight of Compound I in the composition. In another embodiment, the composition comprises at least 95 weight % of Compound I in the N-3 Form of the hemi-L-tartrate salt of Compound I, based on the total weight of Compound I in the composition. In another embodiment, the composition comprises at least 99 weight % of Compound I in the N-3 Form of the hemi-L-tartrate salt of Compound I, based on the total weight of Compound I in the composition. Another aspect of the invention provides a crystalline form of a hemi-L-tartrate salt of Compound I and is referred to herein as the "Form M-2" or "M-2 Form" of the hemi-L-tartrate salt of Compound I. The composition of this hemi-L-tartrate salt form of Compound I comprises one molecule of L-tartaric acid for each two molecules of Compound I and about one molecule of methanol for each molecule of Compound I. In other embodiments, provided are compositions of the M-2 Form of the hemi-L-tartrate salt of Compound I which comprise less than one molecule of methanol for each molecule of Compound I. In other embodiments, provided are compositions of the M-2 Form of the hemi-L-tartrate salt of Compound I which comprise about 0.5 molecule of methanol for each molecule of Compound I.

In one embodiment, the Form M-2 of the hemi-L-tartrate salt of Compound I is characterized by unit cell parameters approximately equal to the following: Cell dimensions: a = 18.03 A b = 9.87 A c - 14.02 A α = 90.0° β = 92.7° γ = 90.0° Space group: P2i Molecules of Compound I/asymmetric unit: 2

Volume = 2492 A ³ Density (calculated) = 1.300 g/cm ³ wherein measurement of said crystalline form is at a temperature of about 22°C.

In a different embodiment, the Form M-2 of the hemi-L-tartrate salt of Compound I is characterized by a powder x-ray diffraction pattern substantially in accordance with the simulated powder x-ray diffraction pattern shown in Figure 2. In another embodiment, the Form M-2 of the hemi-L-tartrate salt of Compound I is characterized by a powder x- ray diffraction pattern substantially in accordance with the observed powder x-ray diffraction pattern shown in Figure 2. In another embodiment, the Form M-2 of the hemi- L-tartrate salt of Compound I is characterized by a powder x-ray diffraction pattern substantially in accordance with the simulated powder x-ray diffraction pattern and the observed powder x-ray diffraction pattern shown in Figure 2.

In a still different embodiment, the Form M-2 of the hemi-L-tartrate salt of Compound I is characterized by a powder x-ray diffraction pattern (CuKa λ= 1.5418A at a temperature of about 25°C) comprising one or more, in other embodiments two, three, four or five or more, 2θ values(CuKα λ=1.5418 A) selected from: 10.2±0.2, 12.1 ±0.2, 13.3 ±0.2, 14.8 ±0.2, 16.4±0.2, 18.7±0.2, 19.8 ±0.2,24.0±0.2 and 29.7±0.2 wherein measurement of the crystalline form is at a temperature of about 25°C.

In a further embodiment, the Form M-2 of the hemi-L-tartrate salt of Compound I is characterized by fractional atomic coordinates substantially as listed in Table 2.

Table 2: Fractional Atomic Coordinates for Form M-2 of the Hemi-L-Tartrate Salt of

Compound I at Room Temperature

In a still further embodiment, the Form M-2 of the hemi-L-tartrate salt of Compound I is characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in Figure 14. The Form M-2 of the hemi-L- tartrate salt of Compound I may be characterized by an endothermic event in the range of from about 132°C to about 160 ⁰ C, as measured by DSC.

In another embodiment, the Form M-2 of the hemi-L-tartrate salt of Compound I is characterized by a thermogravimetric analysis (TGA) thermogram having weight loss of approximately 2.9 weight % upon heating to a temperature of about 162°C. In another embodiment, the Form M-2 of the hemi-L-tartrate salt of Compound I is characterized by a thermogravimetric analysis (TGA) thermogram having weight loss of approximately 6.1 weight % upon heating to a temperature of about 200°C. The invention also provides the Form M-2 of the hemi-L-tartrate salt of Compound I that exhibits a TGA thermogram substantially the same as shown in Figure 15. In still another embodiment, the Form M-2 of the hemi-L-tartrate salt of

Compound I is provided in substantially pure form. This Form M-2 of the hemi-L- tartrate salt of Compound I in substantially pure form may be employed in pharmaceutical compositions which may optionally include one or more other components selected, for example, from excipients and carriers; and optionally, one or more other active pharmaceutical ingredients having active chemical entities of different molecular structures.

In another embodiment, the Form M-2 of the hemi-L-tartrate salt of Compound I is provided in substantially pure form has substantially pure phase homogeneity as indicated by an analysis of the total peak area in the experimentally measured powder x- ray diffraction (PXRD) pattern arising from extra peaks that are absent from the simulated PXRD pattern. In another embodiment, Form M-2 of the hemi-L-tartrate salt of Compound I has substantially pure phase homogeneity as indicated by less than 10%, in one embodiment less than 5%, and in another embodiment less than 2% of the total peak area in the experimentally measured powder x-ray diffraction (PXRD) pattern

arising from the extra peaks that are absent from the simulated PXRD pattern. In one embodiment, provided is a crystalline form having substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured PXRD pattern arising from the extra peaks that are absent from the simulated PXRD pattern. For example, the Form M-2 of the hemi-L-tartrate salt of Compound I may be provided in substantially pure form, wherein substantially pure is greater than 90 weight % pure, in one embodiment greater than 95 weight % pure, and in another embodiment greater than 99 weight % pure.

In a different embodiment, a composition is provided comprising the M-2 Form of the hemi-L-tartrate salt of Compound I in substantially pure form. In a different embodiment, a composition is provided consisting essentially of the Form M-2 of the hemi-L-tartrate salt of Compound I. The composition of this embodiment may comprise at least 90 weight % of Compound I in the Form M-2 of the hemi-L-tartrate salt of Compound I, based on the total weight of Compound I in the composition. In another embodiment, the composition comprises at least 95 weight % of Compound I in the Form M-2 of the hemi-L-tartrate salt of Compound I, based on the total weight of Compound I in the composition. In another embodiment, the composition comprises at least 99 weight % of Compound I in the Form M-2 of the hemi-L-tartrate salt of Compound I, based on the total weight of Compound I in the composition. Another aspect of the invention provides a crystalline form of a hemi-L-tartrate salt of Compound I and is referred to herein as the "Form FA-4" or "FA-4 Form" of the hemi-L-tartrate salt of Compound I. The composition of this hemi-L-tartrate salt form comprises one molecule of L-tartaric acid for each two molecules of Compound I; and about one molecule of formamide for each molecule of Compound 1. In other embodiments, provided are compositions of the FA-4 Form of the hemi-L-tartrate salt of Compound I which comprise less than one molecule of formamide for each molecule of Compound I. In other embodiments, provided are compositions of Form M-2 which comprise less than one molecule of methanol for each molecule of Compound I.

In one embodiment, the FA-4 Form of the hemi-L-tartrate salt of Compound I is characterized by unit cell parameters approximately equal to the following: Cell dimensions: a = 10.80 A b = 19.84 A c = 5.69 A α = 93.7°

β = 92.1° γ = 81.5° Space group: Pl

Molecules of Compound I/asymmetric unit: 2 Volume = 1202 A ³

Density (calculated) = 1.383 g/cm ³ wherein measurement of said crystalline form is at a temperature of about -50 ⁰ C.

In a different embodiment, the FA-4 Form of the hemi-L-tartrate salt of Compound I is characterized by a powder x-ray diffraction pattern substantially in accordance with the simulated powder x-ray diffraction pattern shown in Figure 3.

In a still different embodiment, the FA-4 Form of the hemi-L-tartrate salt of Compound I is characterized by a powder x-ray diffraction pattern (CuKa λ=l .5418A at a temperature of about 25°C) comprising one or more, in one embodiment, two, three, four or five or more, 2θ values (CuKa λ=1.5418 A) selected from: 4.5±0.2, 8.3±0.2, 9.0±0.2, 11.3±0.2, 16.6±0.2, 17.9±0.2, 20.1±0.2, 20.8±0.2 and 24.8±0.2 wherein measurement of said crystalline form is at a temperature of about 25°C.

In still another embodiment, FA-4 Form of the hemi-L-tartrate salt of Compound I is provided in substantially pure form. This FA-4 Form of the hemi-L-tartrate salt of Compound I in substantially pure form may be employed in pharmaceutical compositions which may optionally include one or more other components selected, for example, from excipients and carriers; and optionally, one or more other active pharmaceutical ingredients having active chemical entities of different molecular structures.

In another embodiment, the FA-4 Form of the hemi-L-tartrate salt of Compound I is provided in substantially pure form as indicated by an analysis of the total peak area in the experimentally measured powder x-ray diffraction (PXRD) pattern arising from the extra peaks that are absent from the simulated PXRD pattern. In another embodiment, the FA-4 Form of the hemi-L-tartrate salt of Compound I is provided in substantially pure phase homogeneity as indicated by less than 10%, in one embodiment less than 5%, in another embodiment less than 2% of the total peak area in the experimentally measured powder x-ray diffraction (PXRD) pattern arising from the extra peaks that are absent from the simulated PXRD pattern. In one embodiment, provided is a crystalline form having substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured PXRD pattern arising from the extra peaks that are absent from the simulated PXRD pattern.

For example, the FA-4 Form of the hemi-L-tartrate salt of Compound I may be provided in substantially pure form, wherein substantially pure is greater than 90 weight % pure, in one embodiment greater than 95 weight % pure, and in another embodiment greater than 99 weight % pure. In a different embodiment, a composition is provided consisting essentially of the

FA-4 Form of the hemi-L-tartrate salt of Compound I. In a different embodiment, a composition is provided comprising the FA-4 Form of the hemi-L-tartrate salt of Compound I in substantially pure form. The composition of this embodiment may comprise at least 90 weight % of Compound I in the FA-4 Form of the hemi-L-tartrate salt of Compound I, based on the total weight of Compound I in the composition. In another embodiment, the composition comprises at least 95 weight % of Compound I in the FA-4 Form of the hemi-L-tartrate salt of Compound I, based on the total weight of Compound I in the composition. In another embodiment, the composition comprises at least 99 weight % of Compound I in the FA-4 Form of the hemi-L-tartrate salt of Compound I, based on the total weight of Compound I in the composition. This Form FA-4 of the hemi-L-tartrate salt of Compound I in substantially pure form may be employed in pharmaceutical compositions which may optionally include one or more other components selected, for example, from excipients and carriers; and optionally, one or more other active pharmaceutical ingredients having active chemical entities of different molecular structures.

Another aspect of the invention provides a crystalline form of a trihydrate of Compound I dihydrogen chloride salt and is referred to herein as the "Form H3-1" or "H3-1 Form" of the dihydrogen chloride salt of Compound I. The composition of this dihydrogen chloride salt form comprises two molecules of hydrogen chloride for each molecule of Compound I and approximately three molecules of water for each molecule of Compound I. In other embodiments, the invention includes compositions of the H3-1 Form of the dihydrogen chloride salt of Compound I which comprise less than three molecules of water for each molecule of Compound I.

In one embodiment, the H3-1 Form of the dihydrogen chloride salt of Compound I is characterized by unit cell parameters approximately equal to the following: Cell dimensions: a = 9.32 A b = 10.15 A c = 26.19 A α = 90.0°

β = 94.2° γ = 90.0°

Space group: P2i/c

Molecules of Compound I/asymmetric unit: 1 Volume = 2471 A ³

Density (calculated) = 1.364 g/cm ³ wherein measurement of said crystalline form is at a temperature of about -33°C.

In a different embodiment, the H3-1 Form of the dihydrogen chloride salt of Compound I is characterized by a powder x-ray diffraction pattern substantially in accordance with the simulated powder x-ray diffraction pattern shown in Figure 4.

In a still different embodiment, the H3-1 Form of the dihydrogen chloride salt of Compound I is characterized by a powder X-ray diffraction pattern (CuKa λ=l .5418 A at a temperature of about 25°C) comprising one or more, in one embodiment two, three, four or five or more, 2θ values (CuKa λ=1.5418 A) selected from: 9.5±0.2, 11.3±0.2, 14.3±0.2, 17.5±0.2,21.0±0.2, 21.7±0.2, 22.7±0.2, 24.3±0.2, and 30.4±0.2, wherein measurement of said crystalline form is at a temperature of about 25°C.

In still another embodiment, the H3-1 Form of the dihydrogen chloride salt of Compound I is provided in substantially pure form. In one embodiment, the H3-1 Form of the dihydrogen chloride salt of Compound I has substantially pure phase homogeneity as indicated by less than 10%, in one embodiment less than 5%, and in another embodiment less than 2% of the total peak area in the experimentally measured powder x- ray diffraction (PXRD) pattern arising from the extra peaks that are absent from the simulated PXRD pattern. In still another embodiment, the H3-1 Form of the dihydrogen chloride salt of Compound I is provided in substantially pure form as indicated by an analysis of the total peak area in the experimentally measured powder x-ray diffraction (PXRD) pattern arising from the extra peaks that are absent from the simulated PXRD pattern. In one embodiment, provided is a crystalline form having substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured PXRD pattern arising from the extra peaks that are absent from the simulated PXRD pattern.

In still another embodiment, the H3-1 Form of the dihydrogen chloride salt of Compound I is provided in substantially pure form. For example, the H3-1 Form of the dihydrogen chloride salt of Compound I may be provided in substantially pure form, wherein substantially pure is greater than 90 weight % pure, in another embodiment

greater than 95 weight % pure, and in another embodiment greater than 99 weight % pure.

In a different embodiment, a composition is provided consisting essentially of the H3-1 Form of the dihydrogen chloride salt of Compound I. In a different embodiment, a composition is provided comprising the H3-1 Form of the dihydrogen chloride salt of Compound I in substantially pure form. This Form H3-1 of the dihydrogen chloride salt of Compound I in substantially pure form may be employed in pharmaceutical compositions which may optionally include one or more other components selected, for example, from excipients and carriers; and optionally, one or more other active pharmaceutical ingredients having active chemical entities of different molecular structures. The composition of this embodiment may comprise at least 90 weight % of Compound I in the H3-1 Form of the dihydrogen chloride salt of Compound I, based on the total weight of Compound I in the composition. In another embodiment, the composition comprises at least 95 weight % of Compound I in the H3-1 Form of the dihydrogen chloride salt of Compound I, based on the total weight of Compound I in the composition. In another embodiment, the composition comprises at least 99 weight % of Compound I in the H3-1 Form of the dihydrogen chloride salt of Compound I, based on the total weight of Compound I in the composition.

Another aspect of the invention provides a crystalline form of the monohydrate of the Compound I hydrogen bromide salt and is referred to herein as the "Form H-I" or "H- 1 Form" of the hydrogen bromide salt of Compound I. The composition of this hydrogen bromide salt form comprises one molecule of hydrogen bromide for each molecule of Compound I and about one molecule of water for each molecule of Compound I. In other embodiments, the invention includes compositions of the H-I Form of the hydrogen bromide salt of Compound I comprising less than one molecule of water for each molecule of Compound I.

In one embodiment, the Form H-I of the hydrogen bromide salt of Compound I is characterized by unit cell parameters approximately equal to the following:

Cell dimensions: a = 16.82 A' b = 9.36 A c = 14.69 A α = 90.0° β = 96.3° γ = 90.0°

Space group: P2i/c

Molecules of Compound I/asymmetric unit: 1

Volume = 2298 A ³

Density (calculated) = 1.386 g/cm ³ wherein measurement of said crystalline form is at a temperature of about 22°C.

In a different embodiment, the Form H-I of the hydrogen bromide salt of Compound I is characterized by a powder x-ray diffraction pattern substantially in accordance with the simulated powder x-ray diffraction pattern shown in Figure 5.

In a still different embodiment, the Form H-I of the hydrogen bromide salt of Compound I is characterized by a powder x-ray diffraction pattern (CuKa λ=1.5418A at a temperature of about -30 ⁰ C) comprising one or more, in one embodiment two, three, four or five or more 2θ values (CuKa λ=1.5418 A) selected from: 10.8±0.2, 12.7±0.2, 14.2±0.2, 17±0.2, 20.8±0.2, ±0.2, 23.3±0.2, and 29.7±0.2, wherein measurement of said crystalline form is at a temperature of about +25°C. In another embodiment, the Form H-I of the hydrogen bromide salt of Compound

I is provided in substantially pure phase homogeneity form as indicated by less than 10%, in one embodiment less than 5%, and in another embodiment less than 2% of an analysis of the total peak area in the experimentally measured powder x-ray diffraction (PXRD) pattern arising from the extra peaks that are absent from the simulated PXRD pattern. In another embodiment, the Form H-I of the hydrogen bromide salt of Compound I is provided in substantially pure form as indicated by an analysis of the total peak area in the experimentally measured powder x-ray diffraction (PXRD) pattern arising from the extra peaks that are absent from the simulated PXRD pattern. In one embodiment, provided is a crystalline form having substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured PXRD pattern arising from the extra peaks that are absent from the simulated PXRD pattern.

In still another embodiment, the Form H-I of the hydrogen bromide salt of Compound I is provided in substantially pure form. For example, the Form H-I of the hydrogen bromide salt of Compound I may be provided in substantially pure form, wherein substantially pure is greater than 90 weight % pure, in one embodiment greater than 95 weight % pure, and in another embodiment greater than 99 weight % pure.

In a different embodiment, a composition is provided consisting essentially of the Form H-I of the hydrogen bromide salt of Compound I. In a different embodiment, a composition is provided comprising the Form H-I of the hydrogen bromide salt of

Compound I in substantially pure form. The composition of this embodiment may comprise at least 90 weight % of Compound I in Form H-I of the hydrogen bromide salt of Compound I, based on the total weight of Compound I in the composition. In another embodiment, the composition comprises at least 95 weight % of Compound I in Form H- 1 of the hydrogen bromide salt of Compound I, based on the total weight of Compound I in the composition. In another embodiment, the composition comprises at least 99 weight % of Compound I in Form H-I of the hydrogen bromide salt of Compound I, based on the total weight of Compound I in the composition. The Form H-I of the hydrogen bromide salt of Compound I in substantially pure form may be employed in pharmaceutical compositions which may optionally include one or more other components selected, for example, from excipients and carriers; and optionally, one or more other active pharmaceutical ingredients having active chemical entities of different molecular structures.

Another aspect of the invention provides a crystalline form of the monohydrate of the hydrogen iodide salt of Compound I and is referred to herein as the "Form H-I" or "H-I Form" of the hydrogen iodide salt of Compound I. The composition of this hydrogen iodide salt form comprises one molecule of hydrogen iodide for each molecule of Compound I and about one molecule of water for each molecule of Compound I. In other embodiments, the invention includes compositions of the H-I Form of the hydrogen iodide salt of Compound I which comprise less than one molecule of water for each molecule of Compound I. In still other embodiments, the invention includes compositions of the H-I Form of the hydrogen iodide salt of Compound I which comprise about 0.75 molecules of water for each molecule of Compound I.

In one embodiment, the Form H-I of the hydrogen iodide salt of Compound I is characterized by unit cell parameters approximately equal to the following: Cell dimensions: a = 16.81 A b = 9.48 A c = 14.92 A α = 90.0° β = 96.7° γ = 90.0°

Space group: P2i/c

Molecules of Compound I/asymmetric unit: 1 Volume = 2362 A ³

Density (calculated) = 1.480 g/cm ³ wherein measurement of said crystalline form is at a temperature of about 22°C. In a different embodiment, the Form H-I of the hydrogen iodide salt of Compound I is characterized by a powder x-ray diffraction pattern substantially in accordance with the simulated powder x-ray diffraction pattern shown in Figure 6. In a still different embodiment, the Form H-I of the hydrogen iodide salt of Compound I is characterized by a powder x-ray diffraction pattern (CuKa λ=1.5418A at a temperature of about 25°C) comprising one or more, in another embodiment, two, three, four or five, 2θ values (CuKa λ=1.5418 A) selected from: 5.3±0.2,14.1±0.2, 15.0±0.2, 16.9±0.2, 18.8±0.2, 19.5±0.2, 20.6±0.2, and 24.0±0.2, wherein measurement of said crystalline form is at a temperature of about 25°C.

In still another embodiment, the Form H-I of the hydrogen iodide salt of Compound I is provided in substantially pure form. In one embodiment, the Form H- 1 of the hydrogen iodide salt of Compound I has substantially pure phase homogeneity as indicated by less than 10%, less than 5%, and less than 2% of the total peak area in the experimentally measured powder x-ray diffraction (PXRD) pattern arising from the extra peaks that are absent from the simulated PXRD pattern. In still another embodiment, the Form H-I of the hydrogen iodide salt of Compound I is provided in substantially pure form, as indicated by analysis of the total peak area in the experimentally measured powder x-ray diffraction (PXRD) pattern arising from the extra peaks that are absent from the simulated PXRD pattern. In one embodiment, provided is a crystalline form having substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured PXRD pattern arising from the extra peaks that are absent from the simulated PXRD pattern. For example, the Form H-I of the hydrogen iodide salt of Compound I may be provided in substantially pure form, wherein substantially pure is greater than 90 weight % pure, in one embodiment greater than 95 weight % pure, and in another embodiment greater than 99 weight % pure.

In a different embodiment, a composition is provided consisting essentially of the Form H-I of the hydrogen iodide salt of Compound I. In a different embodiment, a composition is provided comprising the Form H-I of the hydrogen iodide salt of Compound I in substantially pure form. The composition of this embodiment may comprise at least 90 weight % of Compound I in the Form H-I of the hydrogen iodide salt of Compound I, based on the total weight of Compound I in the composition. In another

embodiment, the composition comprises at least 95 weight % of Compound I in the Form H-I of the hydrogen iodide salt of Compound 1, based on the total weight of Compound I in the composition. In another embodiment, the composition comprises at least 99 weight % of Compound I in the Form H-I of the hydrogen iodide salt of Compound I, based on the total weight of Compound I in the composition. This Form H-I of the hydrogen iodide salt of Compound I in substantially pure form may be employed in pharmaceutical compositions which may optionally include one or more other components selected, for example, from excipients and carriers; and optionally, one or more other active pharmaceutical ingredients having active chemical entities of different molecular structures.

In other embodiments, provided is a crystal form in substantially pure form which has a PXRX) pattern substantially similar to the patterns in Figures 5 and 6, and which contains Compound I as a mixture of the hydrogen bromide salt and the hydrogen iodide salt. The crystal form contains the bromide ion in an amount between 0.1% and 99.9%, in another embodiment between 50.0% and 99.9%, in another embodiment between

50.1%, 60%, 70%, 80%, 90%, 95%, 97%, 98% or 99%, and 99.9%, of the total quantity of anions in the crystal lattice. This crystal form may be described as a solid solution of the hydrogen iodide and hydrogen bromide salts of Compound I.

Another aspect of the invention provides an anhydrous, non-solvated crystalline form of the trifluoroacetic acid salt of the Compound I and is referred to herein as the "Form N-I" or "N-I Form" of the trifluoroacetic acid salt of Compound I. The composition of this trifluoroacetic acid salt form comprises one molecule of trifluoroacetic acid for each molecule of Compound I.

In one embodiment, the Form N-I of the trifluoroacetic acid salt of Compound I is characterized by unit cell parameters approximately equal to the following: Cell dimensions: a = 34.30 A b = 16.86 A c = 8.14 A α = 90.0° β = 90.0° γ = 90.0°

Space group: Pbca

Molecules of Compound I/asymmetric unit: 1 Volume = 471 1 A ³

Density (calculated) = 1.395 g/cm ³ wherein measurement of said crystalline form is at a temperature of about 22°C.

In a different embodiment, the Form N-I of the trifluoroacetic acid salt of Compound I is characterized by a powder x-ray diffraction pattern substantially in accordance with the simulated powder x-ray diffraction pattern shown in Figure 7.

In a still different embodiment, the Form N-I of the trifluoroacetic acid salt of Compound I is characterized by a powder x-ray diffraction pattern (CuKa λ=1.5418A at a temperature of about 25°C) comprising one or more, in another embodiment two, three, four or five or more, 2θ values (CuKa λ=1.5418 A) selected from: 7.4±0.2, 1 1.6±0.2, 14.4±0.2, 15.9±0.2, 17.7±0.2, 19.9±0.2, 21.1±0.2, 21.8±0.2 and 26.9±0.2, wherein measurement of said crystalline form is at a temperature of about 25°C.

In still another embodiment, the Form N-I of the trifluoroacetic acid salt of Compound I is provided in substantially pure form. In one embodiment, the Form N-I of the trifluoroacetic acid salt of Compound I has substantially pure phase homogeneity as indicated by less than 10%, in one embodiment less than 5%, and in another embodiment less than 2% of the total peak area in the experimentally measured powder x-ray diffraction (PXRD) pattern arising from the extra peaks that are absent from the simulated PXRD pattern.

In still another embodiment, the Form N-I of the trifluoroacetic acid salt of Compound I is provided in substantially pure form as indicated by an analysis of the total peak area in the experimentally measured powder x-ray diffraction (PXRD) pattern arising from the extra peaks that are absent from the simulated PXRD pattern. In one embodiment, provided is a crystalline form having substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured PXRD pattern arising from the extra peaks that are absent from the simulated PXRD pattern.

For example, the Form N-I of the trifluoroacetic acid salt of Compound I may be provided in substantially pure form, wherein substantially pure is greater than 90 weight % pure, in one embodiment greater than 95 weight % pure, and in another embodiment greater than 99 weight % pure. In a different embodiment, a composition is provided consisting essentially of the

Form N-I of the trifluoroacetic acid salt of Compound I. In a different embodiment, a composition is provided comprising the Form N-I of the trifluoroacetic acid salt of Compound I in substantially pure form. The composition of this embodiment may comprise at least 90 weight % of Compound 1 in Form N-I of the trifluoroacetic acid salt

of Compound I, based on the total weight of Compound I in the composition. In another embodiment, the composition comprises at least 95 weight % of Compound I in Form N- 1 of the trifluoroacetic acid salt of Compound I, based on the total weight of Compound I in the composition. In another embodiment, the composition comprises at least 99 weight % of Compound I in Form N-I of the trifluoroacetic acid salt of Compound I, based on the total weight of Compound I in the composition. This Form N-I of the trifluoroacetic acid salt of Compound I in substantially pure form may be employed in pharmaceutical compositions which may optionally include one or more other components selected, for example, from excipients and carriers; and optionally, one or more other active pharmaceutical ingredients having active chemical entities of different molecular structures.

Another aspect of the invention provides a monohydrate crystalline form of Compound I, which is referred to herein as the "Form H-I" or "H-I Form" of Compound I. The composition of this form, Form H-I of Compound I, comprises about one molecule of water for each molecule of Compound I. In other embodiments, provided are compositions of the H-I Form of Compound I which comprise less than one molecule of water for each molecule of Compound I. In other embodiments, provided are compositions of the H-I Form of Compound I which comprise between about 0.3 and 1 molecule of water for each molecule of Compound I. In other embodiments, the invention includes compositions of a dehydrated hydrate H-I Form of Compound I which contains essentially no water in the crystal lattice.

In one embodiment, the Form H-I of Compound I is characterized by unit cell parameters approximately equal to the following:

Cell dimensions: a = 10.82 A b = 16.72 A c = 5.72 A α = 98.9° β = 92.4° γ = 97.4° Space group: Pl bar

Molecules of Compound I/asymmetric unit: 1 Volume = 1013 A ³ Density (calculated) = 1.277 g/cm ³ wherein measurement of said crystalline form is at a temperature of about 22°C.

In a different embodiment, the Form H-I of Compound I is characterized by a powder x-ray diffraction pattern substantially in accordance with the simulated powder x- ray diffraction pattern shown in Figure 8.

In a still different embodiment, the Form H- 1 of Compound I is characterized by a powder x-ray diffraction pattern (CuKa λ=1.5418A at a temperature of about 25°C) comprising one or more, in another embodiment two, three, four or five or more, 20 values (CuKa λ=1.5418 A) selected from: 5.6±0.2, 15.8±0.2, 17.3±0.2, 18.2±0.2, 21.1±0.2, and 30.1±0.2, wherein measurement of said crystalline form is at a temperature of about 25°C.

In a further embodiment, the Form H-I of Compound I is characterized by fractional atomic coordinates substantially as listed in Table 3. Table 3: Fractional Atomic Coordinates for Form H-I of Compound I at Temperature

+22°C

In a still further embodiment, the Form H-I of Compound I is characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in Figure 16.

In another embodiment, the Form H-I of Compound I is characterized by a thermogravimetric analysis (TGA) thermogram having weight loss in the range of from

about 0 to about 2 weight % upon heating to a temperature of about 125°C. In another embodiment, the Form H-I of Compound I is characterized by a TGA having weight loss of approximately 1.6 weight % upon heating to a temperature of about 125°C. The invention also provides the H-I Form of Compound I that exhibits a TGA thermogram substantially the same as shown in Figure 17.

In still another embodiment, the Form H-I of Compound I is provided in substantially pure form. In one embodiment, the Form H-I of Compound I has substantially pure phase homogeneity as indicated by less than 10%, in one embodiment less than 5%, and in another embodiment less than 2% of the total peak area in the experimentally measured powder x-ray diffraction (PXRD) pattern arising from the extra peaks that are absent from the simulated PXRD pattern. In still another embodiment, the Form H-I of Compound I is provided in substantially pure form, as indicated by an analysis of the total peak area in the experimentally measured powder x-ray diffraction (PXRD) pattern arising from the extra peaks that are absent from the simulated PXRD pattern. In one embodiment, provided is a crystalline form having substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured PXRD pattern arising from the extra peaks that are absent from the simulated PXRD pattern.

For example, the Form H- 1 of Compound I may be provided in substantially pure form, wherein substantially pure is greater than 90 weight % pure, in one embodiment greater than 95 weight % pure, and in another embodiment greater than 99 weight % pure.

In a different embodiment, a composition is provided consisting essentially of the Form H-I of Compound I. In a different embodiment, a composition is provided comprising the Form H-I of Compound I in substantially pure form. The composition of this embodiment may comprise at least 90 weight % of the Form H-I of Compound I, based on the weight of Compound I in the composition. In another embodiment, the composition comprises at least 95 weight % of the Form H-I of Compound I, based on the weight of Compound I in the composition. In another embodiment, the composition comprises at least 99 weight % of the Form H-I of Compound I, based on the weight of Compound I in the composition. This Form H-I of Compound I in substantially pure form may be employed in pharmaceutical compositions which may optionally include one or more other components selected, for example, from excipients and carriers; and

optionally, one or more other active pharmaceutical ingredients having active chemical entities of different molecular structures.

Another aspect of the invention provides a crystalline form of an ethanolate of the hemi-fumaric acid salt of Compound I and is referred to herein as the "Form E-I" or "E-I Form" of the hemi-fumarate salt of Compound I. The composition of this hemi-fumaric acid salt form comprises one molecule of fumaric acid for each two molecules of Compound I and about one molecule of ethanol for each molecule of Compound I. In other embodiments, provided are compositions of the E-I Form of the hemi-fumarate salt of Compound I comprising less than one molecule of ethanol for each molecule of Compound I. In other embodiments, provided are compositions of the E-I Form of the hemi-fumarate salt of Compound I comprising between about 0.8 and about 1.0 molecule of ethanol for each molecule of Compound I.

In one embodiment, the Form E-I of the hemi-fumaric acid salt of Compound I is characterized by unit cell parameters approximately equal to the following: Cell dimensions: a = 19.69 A b = 7.91 A c = 16.83 A α = 90.0° β = 101.7° γ = 90.0°

Space group: P2|/c

Molecules of Compound I/asymmetric unit: 1 Volume = 2567 A ³ Density (calculated) = 1.254 g/cm ³ wherein measurement of said crystalline form is at a temperature of about 22°C. In a different embodiment, the Form E- 1 of the hemi-fumaric acid salt of Compound I is characterized by a powder x-ray diffraction pattern substantially in accordance with the simulated powder x-ray diffraction pattern shown in Figure 9. In another embodiment, the Form E-I of the hemi-fumaric acid salt of Compound I is characterized by a powder x-ray diffraction pattern substantially in accordance with the observed powder x-ray diffraction pattern shown in Figure 9. In another embodiment, the Form E-I of the hemi-fumaric salt of Compound I is characterized by a powder x-ray diffraction pattern substantially in accordance with the simulated powder x-ray diffraction pattern and the observed powder x-ray diffraction pattern shown in Figure 9.

In a still different embodiment, the Form E-I of the hemi-fumaric acid salt of Compound I is characterized by a powder x-ray diffraction pattern (CuKa λ=l .5418 A at a temperature of about 25°C) comprising one or more, in one embodiment two, three, four or five or more, 2θ values (CuKa λ= 1.5418 A) selected from: 4.6±0.2, 9.2±0.2, 10.7±0.2, 12.6±0.2, 13.8±0.2, 16.1 ±0.2, 17.8±0.2, 19.4±0.2, and 21.8±0.2, wherein measurement of said crystalline form is at a temperature of about 25 ⁰ C.

In still another embodiment, the Form E-I of the hemi-fumaric acid salt of Compound I is provided in substantially pure form. In one embodiment, the Form E-I of the hemi-fumaric acid salt of Compound I has substantially pure phase homogeneity as indicated by less than 10%, in one embodiment less than 5%, and in another embodiment less than 2% of the total peak area in the experimentally measured powder x-ray diffraction (PXRD) pattern arising from the extra peaks that are absent from the simulated PXRD pattern. In still another embodiment, the Form E-I of the hemi-fumaric acid salt of Compound I is provided in substantially pure form, as indicated by an analysis of the total peak area in the experimentally measured powder x-ray diffraction (PXRD) pattern arising from the extra peaks that are absent from the simulated PXRD pattern. In another embodiment, provided is a crystalline form having substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured PXRD pattern arising from the extra peaks that are absent from the simulated PXRD pattern. For example, the Form E-I of the hemi-fumaric acid salt of Compound I may be provided in substantially pure form, wherein substantially pure is greater than 90 weight % pure, in one embodiment greater than 95 weight % pure, and in another embodiment greater than 99 weight % pure.

In a different embodiment, a composition is provided consisting essentially of the Form E-I of the hemi-fumaric acid salt of Compound I. In a different embodiment, a composition is provided comprising the Form E-I of the hemi-fumaric acid salt of Compound I in substantially pure form. This Form E-I of the hemi-fumaric acid salt of Compound I in substantially pure form may be employed in pharmaceutical compositions which may optionally include one or more other components selected, for example, from excipients and carriers; and optionally, one or more other active pharmaceutical ingredients having active chemical entities of different molecular structures. The composition of this embodiment may comprise at least 90 weight % of Compound I in the Form E-I of the hemi-fumaric acid salt of Compound I, based on the total weight Compound I in the composition. In another embodiment, the composition comprises at

least 95 weight % in the Form E-I of the hemi-fumaric acid salt of Compound I, based on the total weight Compound I in the composition. In another embodiment, the composition comprises at least 99 weight % of Compound I in the Form E-I of the hemi- fumaric acid salt of Compound I, based on the total weight Compound I in the composition.

Another aspect of the invention provides a crystalline form of the hemi-L-tartaric acid salt of Compound I, which is referred to herein as the "Form N-I" or "N-I Form" of the hemi-L-tartaric acid salt of Compound I. The composition of this form comprises one molecule of L-tartaric acid for each two molecules of Compound I. In one embodiment, the Form N- 1 of the hemi-L-tartaric acid salt of Compound I is characterized by unit cell parameters approximately equal to the following: Cell dimensions: a = 9.96 A b = 19.65 A c = 5.71 A α = 93.5° β = 94.2° γ = 92.4° Space group: Pl

Molecules of Compound I/asymmetric unit: 2 Volume = 11 1 1 A ³

Density (calculated) = 1.362 g/cm ³ wherein measurement of said crystalline form is at a temperature of about 22°C.

In a different embodiment, the Form N-I of the hemi-L-tartaric acid salt of Compound I is characterized by a powder x-ray diffraction pattern substantially in accordance with the simulated powder x-ray diffraction pattern shown in Figure 10. In another embodiment, the Form N-I of the hemi-L-tartaric acid salt of Compound I is characterized by a powder x-ray diffraction pattern substantially in accordance with the observed powder x-ray diffraction pattern shown in Figure 10. In another embodiment, the Form N-I of the hemi-L-tartaric acid salt of Compound I is characterized by a powder x-ray diffraction pattern substantially in accordance with the simulated powder x-ray diffraction pattern and the observed powder x-ray diffraction pattern shown in Figure 10.

In a still different embodiment, the Form N-I of the hemi-L-tartaric acid salt of Compound I is characterized by a powder x-ray diffraction pattern (CuKa λ=1.5418A at a temperature of about 25°C) comprising one or more, in one embodiment two, three, four

or five or more 2θ values (CuKa λ=1.5418 A) selected from: 4.5±0.2, 8.9±0.2, 12.4±0.2, 13.0±0.2, 15.9±0.2, 18.2±0.2, 20.0±0.2, 24.7±0.2 and 29.2±0.2, wherein measurement of said crystalline form is at a temperature of about 25°C.

In a further embodiment, the Form N-I of the hemi-L-tartaric acid salt of Compound I is characterized by fractional atomic coordinates substantially as listed in Table 4.

Table 4: Fractional Atomic Coordinates for Form N-I of the Hemi-L-Tartaric Acid Salt of Compound I at Room Temperature

In a still further embodiment, the Form N-I of the hemi-L-tartaric acid salt of Compound I is characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in Figure 18. In another embodiment, the Form N-I of the hemi-L-tartaric acid salt of

Compound I is characterized by a thermogravimetric analysis (TGA) thermogram having a smooth baseline until ca. 225°C when a steep weight loss, due to decomposition, is observed. The invention also provides the N-I Form of the hemi L-tartaric acid salt of Compound I that exhibits a TGA thermogram substantially the same as shown in Figure 19.

In still another embodiment, the Form N-I of the hemi-L-tartaric acid salt of Compound I is provided in substantially pure form. In one embodiment, the Form N-I of the hemi-L-tartaric acid salt of Compound I has substantially pure phase homogeneity as indicated by less than 10%, in one embodiment less than 5%, and in another embodiment less than 2% of the total peak area in the experimentally measured powder x-ray diffraction (PXRD) pattern arising from the extra peaks that are absent from the simulated PXRD pattern. In still another embodiment, the Form N-I of the hemi-L-tartaric acid salt of Compound I is provided in substantially pure form, as indicated by an analysis of the total peak area in the experimentally measured powder x-ray diffraction (PXRD) pattern arising from the extra peaks that are absent from the simulated PXRD pattern. In one embodiment, provided is a crystalline form having substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured PXRD pattern arising from the extra peaks that are absent from the simulated PXRD pattern.

For example, the Form N-I of the hemi-L-tartaric acid salt of Compound I may be provided in substantially pure form, wherein substantially pure is greater than 90 weight

% pure, in one embodiment greater than 95 weight % pure, and in another embodiment greater than 99 weight % pure.

In a different embodiment, a composition is provided consisting essentially of the Form N-I of the hemi-L-tartaric acid salt of Compound I. In a different embodiment, a composition is provided comprising the Form N-I of the hemi-L-tartaric acid salt of

Compound I in substantially pure form. This Form N-I of the hemi-L-tartaric acid salt of Compound I may be employed in pharmaceutical compositions which may optionally include one or more other components selected, for example, from excipients and carriers; and optionally, one or more other active pharmaceutical ingredients having active chemical entities of different molecular structures. The composition of this embodiment may comprise at least 90 weight % of Compound I in Form N-I of the hemi- L-tartaric acid salt of Compound I, based on the total weight of Compound I in the composition. In another embodiment, the composition comprises at least 95 weight % of Compound I in Form N-I of the hemi-L-tartaric acid salt of Compound I, based on the total weight of Compound I in the composition. In another embodiment, the composition comprises at least 99 weight % of Compound I in Form N-I of the hemi-L-tartaric acid salt of Compound I, based on the total weight of Compound I in the composition.

Another aspect of the invention provides an ethanolate of the hemi-succinate salt of Compound I and is referred to herein as the "Form E-I" or "E-I Form" of the hemi- succinate salt of Compound I. The composition of this hemi-succinate salt form comprises one molecule of succinic acid for each two molecules of Compound I and about one molecule of ethanol for each molecule of Compound I. In another embodiment, provided are compositions comprising less than one molecule of ethanol for each molecule of Compound I. In one embodiment, the Form E-I of the hemi-succinate salt of Compound I is characterized by unit cell parameters approximately equal to the following: Cell dimensions: a = 19.79 A b = 7.90 A c = 16.74 A α = 90.0° β = 102.0° γ = 90.0°

Space group: P2i/c Molecules of Compound I/asymmetric unit: 1

Volume = 2562 A ³ Density (calculated) = 1.259 g/cm ³ wherein measurement of said crystalline form is at a temperature of about -13°C.

In another embodiment, the Form E-I of the hemi-succinate salt of Compound I is characterized by unit cell parameters approximately equal to the following: Cell dimensions: a = 19.83 A b = 7.90 A c = 16.78 A α = 90.0° β = 102.0° γ = 90.0°

Space group: P2i/c

Molecules of Compound I/asymmetric unit: 1 Volume = 2572 A ³ Density (calculated) = 1.254 g/cm ³ wherein measurement of said crystalline form is at a temperature of about 22 ⁰ C.

In a different embodiment, the Form E-I of the hemi-succinate salt of Compound I is characterized by a powder X-ray diffraction pattern substantially in accordance with the simulated powder x-ray diffraction pattern shown in Figure 11. In a still different embodiment, the Form E-I of the hemi-succinate salt of

Compound I is characterized by a powder x-ray diffraction pattern (CuKa λ=l .5418 A at a temperature of about 25°C) comprising one or more, in one embodiment two, three, four or five or more, 2θ values (CuKa λ= 1.5418 A) selected from: 4.6±0.2, 9.1 ±0.2, 10.8±0.2, 13.7±0.2, 16.1±0.2, 17.7±0.2, 19.3±0.2, and 23.3±0.2, wherein measurement of said crystalline form is at a temperature of about 25°C.

In still another embodiment, the Form E-I of the hemi-succinate salt of Compound I is provided in substantially pure form. In one embodiment, the Form E- 1 of the hemi-succinate salt of Compound I has substantially pure phase homogeneity as indicated by less than 10%, in one embodiment less than 5%, and in another embodiment less than 2% of the total peak area in the experimentally measured powder x-ray diffraction (PXRD) pattern arising from the extra peaks that are absent from the simulated PXRD pattern. In still another embodiment, the Form E-I of the hemi-succinate salt of Compound I is provided in substantially pure form, as indicated by an analysis of the total peak area in the experimentally measured powder x-ray diffraction (PXRD) pattern

arising from the extra peaks that are absent from the simulated PXRD pattern. In one embodiment, provided is a crystalline form having substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured PXRD pattern arising from the extra peaks that are absent from the simulated PXRD pattern. For example, the Form E-I of the hemi-succinate salt of Compound I may be provided in substantially pure form, wherein substantially pure is greater than 90 weight % pure, in one embodiment greater than 95 weight % pure, and in another embodiment greater than 99 weight % pure.

In a different embodiment, a composition is provided consisting essentially of the Form E-I of the hemi-succinate salt of Compound I. In a different embodiment, a composition is provided comprising the Form E-I of the hemi-succinate salt of Compound I in substantially pure form. This Form E-I of the hemi-succinate salt of Compound I may be employed in pharmaceutical compositions which may optionally include one or more other components selected, for example, from excipients and carriers; and optionally, one or more other active pharmaceutical ingredients having active chemical entities of different molecular structures.

In other embodiments, the invention provides a crystal form in substantially pure form which has a PXRD pattern substantially similar to the patterns in Figures 9 and 11, and which contains Compound I as a mixture of the fumarate salt and the succinate salt, and which contains about one molecule of ethanol per molecule of Compound I. The crystal form contains the fumarate ion in an amount between 0.1% and 99.9%, in another embodiment between 50.1%, 60%, 70%, 80%, 90%, 95%, 97%, 98% or 99%, and 99.9%, of the total quantity of anions in the crystal lattice. This crystal form may be described as a solid solution of the fumarate and succinate salts of Compound I. The composition of this embodiment may comprise at least 90 weight % of

Compound I in Form E-I of the hemi-succinate salt of Compound I, based on the total weight of Compound I in the composition. In another embodiment, the composition comprises at least 95 weight % of Compound I in Form E-I of the hemi-succinate salt of Compound I, based on the total weight of Compound I in the composition. In another embodiment, the composition comprises at least 99 weight % of Compound I in Form E-I of the hemi-succinate salt of Compound I, based on the total weight of Compound I in the composition.

USE AND UTILITY

Compound I is an inhibitor of protein kinases such as the cyclin dependent kinases (cdks), for example, cdc2 (cdkl), cdk2, cdk3, cdk4, cdk5, cdkβ, cdk7 and cdk8. Compound I is expected to be useful in the therapy of proliferative diseases such as cancer, and of inflammation, arthritis, Alzheimer's disease, and cardiovascular disease. More specifically, Compound I is useful in the treatment of a variety of cancers, including (but not limited to) the following:

-carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin; -hematopoietic tumors of lymphoid lineage, including acute lymphocytic leukemia (ALL), B-cell lymphoma, Burkett's lymphoma, Hodgkin's disease, Non- Hodgkin's lymphoma (NHL) including mantle cell lymphoma (MCL), and cutaneous T- cell lymphoma (CTCL);

-hematopoietic tumors of myeloid lineage, including acute myelogenous leukemia (AML), chronic myelogenous leukemia CML, promyelocytic leukemia (PML), myelodysplasia syndrome (MDS), and multiple myeloma (MM);

-tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; and

-other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, neuroblastoma, and glioma.

For example, Compound I provided in one or more of the crystalline forms disclosed herein may be useful in the treatment of breast, lung, and/or colorectal cancers. In another embodiment, Compound I is provided as a hemi-L- tartrate salt in Form N-3. Due to the key role of cdks in the regulation of cellular proliferation in general, inhibitors could act as reversible cytostatic agents which may be useful in the treatment of any disease process which features abnormal cellular proliferation, e.g., neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis following angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, angiogenesis, and endotoxic shock. Compound I may also be useful in the treatment of Alzheimer's disease, as suggested by the finding that cdk5 is involved in the phosphorylation of tau protein (J. Biochem, 117, 741-749 (1995)).

Compound I may also act as an inhibitor of other protein kinases, e.g., protein kinase C, her2, rafl, MEKl, MAP kinase, EGF receptor, PDGF receptor, IGF receptor,

PI3 kinase, weel kinase, Src, AbI, VEGF, and lck, and thus be effective in the treatment of diseases associated with other protein kinases.

Compound I may also induce or inhibit apoptosis, a physiological cell death process critical for normal development and homeostasis. Alterations of apoptotic pathways contribute to the pathogenesis of a variety of human diseases. Compound I, as a modulator of apoptosis, may be useful in the treatment of a variety of human diseases with aberrations in apoptosis including cancer (including, but not limited to, follicular lymphomas, carcinomas with p53 mutations, hormone dependent tumors of the breast, prostate and ovary, and precancerous lesions such as familial adenomatous polyposis), viral infections (including, but not limited to, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), autoimmune diseases (including, but not limited to, systemic lupus, erythematosus, immune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel diseases, and autoimmune diabetes mellitus), neurodegenerative disorders (including, but not limited to, Alzheimer's disease, AIDS- related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), AIDS, myelodysplastic syndromes, aplastic anemia, ischemic injury associated myocardial infarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol induced liver diseases, hematological diseases (including, but not limited to, chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including, but not limited to, osteoporosis and arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases, and cancer pain.

The crystal forms provided herein possess improved chemical and physical properties, such as purity profile, stability, solubility, dissolution rate and/or hygroscopicity profile, may be formulated more easily and/or may be manufactured more easily.

The invention also provides pharmaceutical compositions which comprise Compound I, wherein Compound I is in one or more of the crystalline forms disclosed herein, and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention may further comprise one or more pharmaceutically acceptable additional ingredient(s) such as alum, stabilizers, antimicrobial agents, buffers, coloring agents, flavoring agents, and the like.

Daily dosages for human administration of Compound I will normally be determined by the prescribing physician with the dosages generally varying according to

the age, weight, route of administration, and response of the individual patient, as well as the severity of the patient's symptoms. For example, Compound I may be administered to humans in an amount from about 0.001 mg/kg of body weight to about 100 mg/kg of body weight per day, in one embodiment, from about 0.01 mg/kg of body weight to about 50 mg/kg of body weight per day, and in another embodiment, from about 0.1 mg/kg of body weight to about 20 mg/kg of body weight per day.

Typically, the solid form of a pharmaceutically active material is important in the preparation of a solid dosage form, such as tablets or capsules as the manufacturing, stability, and/or the performance of the pharmaceutically active material can be dependent upon the solid form. Generally, a crystalline form provides pharmaceutically active material with uniform properties, such as solubility, density, dissolution rate, and stability. For example, Compound I provided as a hemi-L-tartrate salt in Form N-3 has properties suitable for the manufacture of tablets or capsules, for providing a stable oral dosage form, and/or for delivery of Compound I to a patient in need thereof.

METHODS OF PREPARATION AND CHARACTERIZATION Crystalline forms may be prepared by a variety of methods, including for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and/or salt, freeze drying the solvent mixture, and addition of antisolvents (countersolvents) to the solvent mixture. High throughput crystallization techniques may be employed to prepare crystalline forms including polymorphs.

Crystals of drugs, including polymorphs, methods of preparation, and characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, S. R. Byrn, R.R. Pfeiffer, and J.G. Stowell, 2 ^nd Edition, SSCI, West Lafayette, Indiana (1999). For crystallization techniques that employ solvent, the choice of solvent or solvents is typically dependent upon one or more factors, such as solubility of the compound, crystallization technique, and vapor pressure of the solvent. Combinations of solvents may be employed, for example, the compound may be solubilized into a first solvent to afford a solution, followed by the addition of an antisolvent to decrease the solubility of

the compound in the solution and to afford the formation of crystals. An antisolvent is a solvent in which the compound has low solubility.

In one method to prepare crystals, a compound is suspended and/or stirred in a suitable solvent to afford a slurry, which may be heated to promote dissolution. The term "slurry", as used herein, means a saturated solution of the compound, which may also contain an additional amount of the compound to afford a heterogeneous mixture of the compound and a solvent at a given temperature.

Seed crystals may be added to any crystallization mixture to promote crystallization. Seeding may be employed to control growth of a particular polymorph or to control the particle size distribution of the crystalline product. Accordingly, calculation of the amount of seeds needed depends on the size of the seed available and the desired size of an average product particle as described, for example, in "Programmed Cooling of Batch Crystallizers," J.W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971,26, 369-377. In general, seeds of small size are needed to control effectively the growth of crystals in the batch. Seed of small size may be generated by sieving, milling, or micronizing of large crystals, or by micro-crystallization of solutions. Care should be taken that milling or micronizing of crystals does not result in any change in crystallinity from the desired crystal form (i.e., change to amorphous or to another polymorph). A cooled crystallization mixture may be filtered under vacuum, and the isolated solids may be washed with a suitable solvent, such as cold recrystallization solvent, and dried under a nitrogen purge to afford the desired crystalline form. The isolated solids may be analyzed by a suitable spectroscopic or analytical technique, such as solid state nuclear magnetic resonance, differential scanning calorimetry, powder x-ray diffraction, or the like, to assure formation of the preferred crystalline form of the product. The resulting crystalline form may be produced in an amount of greater than about 70 weight % isolated yield, in one embodiment, greater than 90 weight % isolated yield, based on the weight of the compound originally employed in the crystallization procedure. The product may be comilled or passed through a mesh screen to delump the product, if necessary.

Crystalline forms may be prepared directly from the reaction medium of the final process for preparing Compound I. This may be achieved, for example, by employing in the final process step a solvent or a mixture of solvents from which Compound I may be crystallized. Alternatively, crystalline forms may be obtained by distillation or solvent

addition techniques. Suitable solvents for this purpose include, for example, the aforementioned nonpolar solvents and polar solvents, including protic polar solvents such as alcohols, and aprotic polar solvents such as ketones.

The presence of more than one crystalline form and/or polymorph in a sample may be determined by techniques such as powder x-ray diffraction (PXRD) or solid state nuclear magnetic resonance spectroscopy. For example, the presence of extra peaks in the comparison of an experimentally measured PXRD pattern with a simulated PXRD pattern may indicate more than one crystalline form and/or polymorph in the sample. The simulated PXRD may be calculated from single crystal x-ray data, see Smith, D.K., "A FOR TRAN Program for Calculating X-Ray Powder Diffraction Patterns, " Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963).

Crystalline forms of Compound I according to the invention may be characterized using various techniques, the operation of which are well known to those of ordinary skill in the art. The crystalline forms of Compound I may be characterized and distinguished using single crystal x-ray diffraction performed under standardized operating conditions and temperatures, which is based on unit cell measurements of a single crystal of the form at a fixed analytical temperature. The approximate unit cell dimensions in Angstroms (A), as well as the crystalline cell volume, space group, molecules per cell, and crystal density may be measured, for example at a sample temperature of 25°C. A detailed description of unit cells is provided in Stout & Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), Chapter 3, which is herein incorporated by reference.

Alternatively, the unique arrangement of atoms in spatial relation within the crystalline lattice may be characterized according to the observed fractional atomic coordinates. Another means of characterizing the crystalline structure is by powder x-ray diffraction analysis in which the diffraction profile is compared to a simulated profile representing pure powder material, preferably both run at the same analytical temperature, and measurements for the subject form characterized as a series of 2θ values (usually four or more). Other means of characterizing the form may be used, such as solid state nuclear magnetic resonance (NMR), differential scanning calorimetry, thermography, and gross examination of the crystalline or amorphous morphology. These parameters may also be used in combination to characterize the subject form.

EXAMPLES EXAMPLE 1 -Methods of Analysis

The crystalline forms described herein were analyzed using one or more of the testing methods described below. Single Crystal X-Ray Measurements

Data were collected on a Bruker-Nonius CAD4 serial diffractometer Bruker AXS, Inc. Madison, WI). Unit cell parameters were obtained through least-squares analysis of the experimental diffractometer settings of 25 high-angle reflections. Intensities were measured using Cu Ka radiation (λ = 1.5418 A) at a constant temperature with the θ-2θ variable scan technique and were corrected only for Lorentz-polarization factors. Background counts were collected at the extremes of the scan for half of the time of the scan. Alternately, single crystal data were collected on a Bruker-Nonius Kappa CCD 2000 system using Cu Ka radiation (λ = 1.5418 A). Indexing and processing of the measured intensity data were carried out with the HKL2000 software package

(Otwinowski, Z. and Minor, W., in Macromolecular Crystallography, eds. Carter, W. C. Jr. and Sweet, R.M., Academic Press, NY, 1997) in the Collect program suite (Collect: Data collection software, R. Hooft, Nonius B.V., 1998). When indicated, crystals were cooled in the cold stream of an Oxford Cryosystems Cryostream Cooler (Oxford Cryosystems, Inc., Devens, MA) during data collection.

The structures were solved by direct methods and refined on the basis of observed reflections using either the SDP software package (SDP Structure Determination Package, Enraf-Nonius, Bohemia, NY) with minor local modifications or the crystallographic package, maXus (maXus Solution and Refinement Software Suite: S. Mackay, CJ. Gilmore, C. Edwards, M. Tremayne, N. Stewart, and K. Shankland).

The derived atomic parameters (coordinates and temperature factors) were refined through full matrix least-squares. The function minimized in the refinements was Iw(IFoI - IFcI) ² - R is defined as ∑ ||F _O | - |F _C ||/∑ |F _O | while R _w = [∑w( |F ₀ | - |F _C |) ² /∑ _W |F _O | ² ] ^I/2 where w is an appropriate weighting function based on errors in the observed intensities. Difference maps were examined at all stages of refinement. Hydrogen atoms were introduced in idealized positions with isotropic temperature factors, but no hydrogen parameters were varied.

Simulated powder x-ray diffraction patterns were generated from the single crystal atomic parameters at the data collection temperature, unless noted otherwise. (Yin. S.; Scaringe, R. P.; DiMarco, J.; Galella, M. and Gougoutas, J. Z., American Pharmaceutical Review, 2003, 6, 2, 80).

Powder X-Ray Diffraction Measurements - Method A

About 200 mg were packed by the backloading method into a Philips powder X- ray diffraction (PXRD) sample holder. The sample was transferred to a Philips MPD unit (45 KV, 40 mA, Cu Ka). Data were collected at room temperature in the 2 to 32 2-theta range (continuous scanning mode, scanning rate 0.03 degrees/sec, auto divergence and anti scatter slits, receiving slit: 0.2 mm, sample spinner : ON)

Powder X-Ray Diffraction Measurements- Method B

X-ray powder diffraction data were obtained using a Bruker C2 GADDS. The radiation was Cu Ka (40 KV, 50mA). The sample-detector distance was 15 cm. Powder samples were placed in sealed glass capillaries of lmm or less in diameter; the capillary was rotated during data collection. Data were collected for 3<2θ<35° with a sample exposure time of at least 2000 seconds. The resulting two-dimensional diffraction arcs were integrated to create a traditional 1 -dimensional PXRD pattern with a step size of 0.02 degrees 2θ in the range of 3 to 35 degrees 20.

Powder X-Ray Diffraction Measurements- Method C

X-ray powder diffraction (PXRD) data were obtained using a Bruker GADDS (General Area Detector Diffraction System) manual chi platform goniometer. Powder samples were placed in thin walled glass capillaries of lmm or less in diameter; the capillary was rotated during data collection. The sample-detector distance was 17 cm. The radiation was Cu Ka (λ = 1.5418 A). Data were collected for 3<2θ <35° with a sample exposure time of at least 300 seconds.

DSC

Differential scanning calorimetry (DSC) experiments were performed in a TA Instruments™ model QlOOO or 2920. The sample (about 2-6 mg) was weighed in an aluminum pan onto which a lid had been crimped and pinpricked, and recorded accurately

recorded to a hundredth of a milligram, and transferred to the DSC. The instrument was purged with nitrogen gas at 50 mL/min. Data were collected between room temperature and 350 ⁰ C at 10°C/min heating rate. The plot was made with the endothermic peaks pointing down.

TGA

Thermal gravimetric analysis (TGA) experiments were performed in a TA Instruments™ model Q500 or 2950. The sample (about 10-30 mg) was placed in an aluminum pan, onto which a Hd had been crimped and pinpricked, and then placed on a platinum pan, both of which had been previously tared. The weight of the sample was measured accurately and recorded to a thousand of a milligram by the instrument. The furnace was purged with nitrogen gas at 100 mL/min. Data were collected between room temperature and 350 ⁰ C at 10°C/min heating rate.

Example 2: Form N-3 of the Hem i-L-Tart rate Salt of Compound I

The hemi-L-tartrate salt of Compound I was crystallized in Form N-3 from aqueous acetone to provide colorless elongated plates: mp 243-251°C. Example 3: Form M-2 of the Hemi-L-Tartrate Salt of Compound I

The hemi-L-tartrate salt of Compound I was crystallized in Form M-2 from methanol/water to provide colorless elongated plates: mp ~130 (darken), -175 (opaque), 247-255 ⁰ C. Example 4: Form FA-4 of the Hemi-L-Tartrate Salt of Compound I

The hemi-L-tartrate salt of Compound I was crystallized in Form FA-4 from formamide to provide colorless thin plates. Example S: Form H3-1 of the Dihydrogen Chloride Salt of Compound I

The dihydrochloride trihydrate salt of Compound I was crystallized in Form H3-1 from methyl ethyl ketone/methanol/ethanol/aqueous hydrochloric acid to provide colorless intergrown plates: mp 83 (crack), 88-100 (birefringent changes), -135-235 (recryst.) ⁰ C. Example 6: Form H-I of the Hydrogen Bromide Salt of Compound I

The hydrobromide monohydrate salt of Compound I was crystallized in Form H-I from KBr/acetone/water to provide colorless rods: mp 166-168 ⁰ C.

Example 7: Form H-I of the Hydrogen Iodide Salt of Compound I

The hydroiodide monohydrate salt of Compound I was crystallized in Form H-I from acetone/acetonitrile/water to provide colorless rods: mp 86 (crack), 244-252 ⁰ C. Example 8: Form N-I of the Trifluoroacetic Acid Salt of Compound I The trifluoroacetic acid salt of Compound I was crystallized in Form N-I from ethanol/methanol/water to provide colorless rods: mp 185-212 ⁰ C. Example 9: Form H-I of Compound I

The monohydrate of Compound I was crystallized in Form H-I : mp 210-215 ⁰ C. Example 10: Form E-I of the Hemi-Fumarate Salt of Compound I The hemi-fumarate salt of Compound I was crystallized in Form E-I from 95% ethanol to provide colorless hexagonal plates: mp ~142 (crack), 160 (opaque), 185 (needles develop), 208-218 ⁰ C. Example 11 : Form N-I of the Hemi-L-Tartrate Salt of Compound I

The hemi-L-tartrate salt of Compound I was crystallized in Form N-I from 1 :1 aqueous acetone: mp 240-245 (dec) ⁰ C.

Example 12: Form E-I of the Hemi-Succinate Salt of Compound I

The hemi-succinate salt of Compound I was crystallized in Form E-I from 95% ethanol to provide colorless hexagonal plates: mp 128-144, 192-195 ⁰ C. Example 13: Conversion of Form N-I of the Hemi-L-Tartrate Salt of Compound I to Form N-3

Form N-I of the hemi-L-tartrate salt of Compound I converts to Form N-3. Conversion was observed when a 1 : 1 mixture of 1 :1 Nl :N3 was slurried in 1 :1 acetone: water at room temperature for six days, or at 55 ⁰ C for 20 h.

Alternatively, Form N-I can be converted to N-3 by the following procedure. In a reaction vessel equipped with mechanical stirrer, thermometer and condenser, a mixture of dried Compound I (free base) and 0.55 equivalent of L-tartaric acid or Compound I (tartrate salt) in 1:1 water acetone (6.4 mL/g of free base) is heated to gentle reflux 64-67 ⁰ C) until a solution is obtained. More 1 :1 acetone-water is optionally added. The solution is polish filtered into a reaction vessel and re-heated to 53-56 ⁰ C. Seeds of N-3 form are added to induce crystallization of the right crystalline form, and after the slurry developed, a slow addition of acetone (three times the volume of acetone- water used) is performed. The slurry of Compound I, which is then stirred at 53-56 ⁰ C for 3 h and then allowed to cool at room temperature. The solid is collected by filtration and dried in a vacuum oven at room temperature, then at 55-60 ⁰ C to constant weight to give Compound

I in approximately 92-95% yield from the free base or approximately 93-98% from the salt.

All publications and patent, applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. While the claimed subject matter has been described in terms of various embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions, and changes may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the subject matter limited solely by the scope of the following claims, including equivalents thereof.