US20220298117A1 - Crystalline forms of [3-(4- {2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1h-imidazol-4-yl} -phenoxy)-propyl]-diethyl-amine - Google Patents

Abstract

The present invention relates to crystalline forms of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethylamine (“COMPOUND I”) useful in the treatment of RAGE mediated diseases.

Description

FIELD OF THE INVENTION
• The present invention relates to crystalline forms of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)- propyl]-diethylamine (“COMPOUND I”), and its use as a therapeutic agent.
BACKGROUND OF THE INVENTION
• The Receptor for Advanced Glycation Endproducts (RAGE) is a member of the immunoglobulin super family of cell surface molecules. Activation of RAGE in different tissues and organs leads to a number of pathophysiological consequences. RAGE has been implicated in a variety of conditions including: acute and chronic inflammation (Hofmann et al., Cell 97:889-901 (1999)), the development of diabetic late complications such as increased vascular permeability (Wautier et al., J. Clin. Invest. 97:238-243 (1995)), nephropathy (Teillet et al., J. Am. Soc. Nephrol. 11: 1488-1497 (2000)), atherosclerosis (Vlassara et. al., The Finnish Medical Society DUODECIM, Ann. Med. 28:419-426 (1996)), and retinopathy (Hammes et al., Diabetologia 42:603-607 (1999)). RAGE has also been implicated in Alzheimer's disease (Yan et al., Nature 382: 685-691, (1996)), erectile dysfunction, and in tumor invasion and metastasis (Taguchi et aL, Nature 405: 354-357, (2000)).
• Binding of ligands such as advanced glycation endproducts (AGEs), S100/calgranulin/EN-RAGE, ß-amyloid, CML (N^ϵ-Carboxymethyl lysine), and amphoterin to RAGE has been shown to modify expression of a variety of genes. For example, in many cell types interaction between RAGE and its ligands generates oxidative stress, which thereby results in activation of the free radical sensitive transcription factor NF-κB, and the activation of NF-κB regulated genes, such as the cytokines IL-1ß, TNF-α, and the like. In addition, several other regulatory pathways, such as those involving p21ras.
• MAP kinases, ERK1 and ERK2, have been shown to be activated by binding of AGEs and other ligands to RAGE. In fact, transcription of RAGE itself is regulated at least in part by NF-κB. Thus, an ascending, and often detrimental, spiral is fueled by a positive feedback loop initiated by ligand binding. Antagonizing binding of physiological ligands to RAGE, therefore, is our target, for down-regulation of the pathophysiological changes brought about by excessive concentrations of AGEs and other ligands for RAGE.
• Polymorphs of a given substance have the same chemical composition, but may differ from each other with respect to one or more physical properties, such as solubility and dissociation, true density, melting point, crystal shape, compaction behavior, flow properties, and/or solid state stability. These differences affect practical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in determining bio-availability). Although U.S. Pat. No. 7,884,219 discloses Form I and Form II of COMPOUND I, there is a need for additional drug forms that are useful for inhibiting RAGE activity in vitro and in vivo, and have properties suitable for large-scale manufacturing and formulation. Provided herein are new polymorphs of COMPOUND I, as well as methods of producing the polymorphs COMPOUND I.
SUMMARY OF THE INVENTION
• The preparation of [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine (“COMPOUND I”) and the use thereof, such as an antagonist of the receptor for advanced glycation endproducts (RAGE) and in the treatment of various medical conditions, are described in US Patent Publication No. 2004-0082542 and in US Patent Publication No. 2005-0026811. Such diseases or disease states may include, but are not limited to, acute and chronic inflammation, amyloidosis, Alzheimer's disease, cancer, tumor invasion and metastasis, kidney failure, or inflammation associated with autoimmunity, inflammatory bowel disease, rheumatoid arthritis, psoriasis, multiple sclerosis, hypoxia, stroke, heart attack, hemorrhagic shock, sepsis, organ transplantation, the development of diabetic late complications such as increased vascular permeability, diabetic nephropathy, diabetic retinopathy, a diabetic foot ulcer, a cardiovascular complication, diabetic neuropathy, impaired wound healing, erectile dysfunction, and osteoporosis. COMPOUND I and a method for its preparation are exemplified in US Patent Publication No. 2004-0082542 in Example 406.
• In one aspect, the present invention provides polymorphic forms of COMPOUND I. In one embodiment, the present invention provides a first polymorph, Form III, of COMPOUND I. In another embodiment, the present invention provides a second polymorph, Form IV, of COMPOUND I. In another aspect, the present invention provides methods for producing Form III and Form IV polymorphs of COMPOUND I.
• In another aspect, the present invention provides a pharmaceutical composition comprising one or more of Form I, Form II, Form III, and Form IV of COMPOUND I.
• In another aspect, the present invention provides a method of producing a pharmaceutical composition comprising one or more of Form I, Form II, Form III, and Form IV of COMPOUND I.
• In another aspect, the present invention provides a method of treating one or more RAGE mediated diseases comprising administering one or more of Form I, Form III, and
• Form IV of COMPOUND I to a subject in need thereof. Embodiments of the method of treatment of the present invention may comprise administering a pharmaceutical composition comprising a therapeutically effective amount of one or more polymorphs of COMPOUND I
• These and other embodiments of the present invention are described in greater detail in the detailed description of the invention which follows.
BRIEF DESCRIPTION OF DRAWINGS
• FIG. 1 is a Powder X-ray Powder Diffraction Pattern of Form III.
• FIG. 2 is a Differential Scanning Calorimetry (“DSC”) profile and a Thermogravimetric Analysis (“TGA”) of Form III.
• FIG. 3 is a Powder X-ray Powder Diffraction Pattern of Form IV.
• FIG. 4 is a Differential Scanning Calorimetry (“DSC”) profile and a Thermogravimetric Analysis (“TGA”) of Form IV.
DETAILED DESCRIPTION
• Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Moreover, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein. For example, a stated range of “1 to 10” should be considered to include any and all subranges between (and inclusive of) the minimum value of 1 and the maximum value of 10; that is, all subranges beginning with a minimum value of 1 or more, e.g. 1 to 6.1, and ending with a maximum value of 10 or less, e.g., 5.5 to 10.
• By percent by weight it is meant that a particular weight of one ingredient in a composition is divided by the total weight of all of the ingredients in that composition. Percent by weight may be used interchangeably and means approximately the same as weight/weight percent or % (weight/weight) or percent by mass or mass percent. When a liquid solute is used, it is often more practical to use volume/volume percent or % (vol/vol) or percent by volume, which are all considered to be synonymous. Ppm (parts per million), ppb (parts per billion), pph (parts per hundred) are often used to indicate a percentage based on quantity and not on mass (i.e., the quantity of a given type of atom or a given type of molecule in a composition with more atoms or molecules (be it gas, liquid or solid) is divided by the total quantity of atoms or molecules in the total composition). Other terms that are used are molarity, which is the number of moles of solute per liters of solution, and molality, which is the number of moles of solution per kilograms of solution. Another concentration unit is the mole fraction, which is the moles of a given component divided by the total moles of all solution components. Mole percent is related to the mole fraction and is the mole fraction multiplied by 100.
• It is further noted that, as used in this specification, the singular forms “a,” “an,” and “the” include plural referents unless expressly and unequivocally limited to one referent.
• The term “RAGE mediated disease” is used herein to refer to one or more conditions, diseases or disease states including, but not limited to, acute or chronic inflammation including skin inflammation such as psoriasis, rheumatoid arthritis, atopic dermatitis and lung inflammation including, asthma and chronic obstructive pulmonary disease, diabetes, diabetes related complications, renal failure, hyperlipidemic atherosclerosis associated with diabetes, neuronal cytotoxicity, restenosis, Down's syndrome, dementia associated with head trauma, amyotrophic lateral sclerosis, multiple sclerosis, amyloidosis, an autoimmune disease including inflammation associated with autoimmunity or organ, tissue, or cell transplant, impaired wound healing, periodontal disease, neuropathy, neuronal degeneration, vascular permeability, nephropathy, atherosclerosis, retinopathy, Alzheimer's disease, erectile dysfunction, tumor invasion and/or metastasis, osteoporosis, and the development of diabetic late complications such as increased vascular permeability, nephropathy, retinopathy, and neuropathy. The pharmaceutical compositions comprising a polymorphic form of COMPOUND I also may be used to antagonize RAGE in a subject.
• The term “therapeutically effective amount” is used herein to denote the amount of the polymorph of COMPOUND I that will elicit the therapeutic response of a subject that is being sought. In an embodiment, the therapeutic response may be antagonizing RAGE.
• Embodiments of the invention are directed to polymorphs of COMPOUND I, wherein the particular polymorph (e.g., Form III, Form IV) has at least a particular percentage of purity. In some embodiments of the invention, the polymorph of COMPOUND I (e.g., Form III, Form IV) is at least 80% pure. In some embodiments of the invention, the polymorph of COMPOUND I (e.g., Form III, Form IV) is at least 85% pure. In some embodiments of the invention, the polymorph of COMPOUND I (e.g., Form III, Form IV) is at least 90% pure. In some embodiments of the invention, the polymorph of COMPOUND I (e.g., Form III, Form IV) is at least 95% pure. In some embodiments of the invention, the polymorph of COMPOUND I (e.g., Form III, Form IV) is substantially free of other polymorphic forms. As used herein, a first polymorphic form that is “substantially pure” of other polymorphic forms includes the complete absence of the second form or an amount of the second form that is not readily detectable by ordinary analytical methods. Such ordinary analytical methods include DSC, solid state ¹³C NMR, Raman, X-ray powder diffraction, mid-IR (such as FT-IR) and near-IR. In an embodiment, an amount of a polymorphic form that is not readily detectable by one or more ordinary analytical methods is less than 5 percent by weight. In another embodiment, the amount of a polymorphic form that is not readily detectable by one or more ordinary analytical methods is less than 3 percent by weight. In another embodiment, the amount of a polymorphic form that is not readily detectable by one or more ordinary analytical methods is less than 2 percent by weight. In another embodiment, the amount of a polymorphic form that is not readily detectable by one or more ordinary analytical methods is less than 1 percent by weight. In another embodiment, the amount of a polymorphic form that is not readily detectable by one or more ordinary analytical methods is less than 0.5 percent by weight.
• In another embodiment, the dosage or blood level of COMPOUND I and administration may be sufficient for inhibition of the biological function of RAGE at a sufficient level for sufficient time to reverse amyloidosis.
• A therapeutically effective amount may be achieved in a subject by administering a dosage level of less 100 mg of compound per day. In another embodiment, the dosage level of administration is greater than 1 mg of compound per day. In another embodiment, the dosage level of administration is 5, 10 or 20 mg of compound per day.
• The term “treatment” as used herein, refers to the full spectrum of treatments for a given condition or disorder from which a subject is suffering, including alleviation or amelioration of one or more of the symptoms resulting from that disorder, to the delaying of the onset or progression of the disorder.
• In one aspect, the present invention provides polymorphs, or mixtures thereof, of COMPOUND I.
• One embodiment of the present invention is a solid state form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the solid state form is selected from the group consisting of:
• • a) a crystalline form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, characterized by an XRPD pattern having peaks at 2θ angles of 5.4°, 21.5°, and 22.0° ±0.2°; and
  • b) a crystalline form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, characterized by an XRPD pattern having peaks at 2θ angles of 19.7°, 22.0°, and 30.2° ±0.2°.
• In one embodiment, the solid state form is characterized by an XRPD pattern having peaks at 2θ angles of 5.4°, 21.5°, and 22.0° ±0.2°. In one embodiment, the solid state form is characterized by an XRPD pattern as shown in FIG. 1. In one embodiment, the solid state form is characterized by an endothermic peak at about 59° C., as determined by DSC. In one embodiment, the solid state form is characterized by a DSC profile as shown in FIG. 2. In one embodiment, the solid state form is characterized by an about 2.3 wt% loss between room temperature and about 150° C., as determined by TGA. In one embodiment, the solid state form is characterized by TGA profile as shown in FIG. 2. In one embodiment, the solid state form is characterized by at least two of the following features (i)-(iii):
• • i) an XRPD pattern having peaks at 2θ angles of 5.4°, 21.5°, and 22.0° ±0.2°;
  • ii) a DSC profile as shown in FIG. 2; or
  • iii) a TGA profile as shown in FIG. 2.
    In one embodiment, the solid state form is Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine.
• In another embodiment, the solid state form is characterized by an XRPD pattern having peaks at 2θ angles of 19.7°, 22.0°, and 30.2° ±0.2°. In another embodiment, the solid state form is characterized by an XRPD pattern having peaks at 2θ angles of 5.4, 19.7°, 21.8, 22.0°, and 30.2° ±0.2°. In another embodiment, the solid state form is characterized by an XRPD pattern as shown in FIG. 3. In another embodiment, the solid state form is characterized by an endothermic peak at about 51.9° C., as determined by DSC. In another embodiment, the solid state form is characterized by a DSC profile as shown in FIG. 4. In another embodiment, the solid state form is characterized by an about 4.2 wt% loss between room temperature and about 150° C., as determined by TGA. In another embodiment, the solid state form is characterized by a TGA profile as shown in FIG. 4. In another embodiment, the solid state form is characterized by at least two of the following features (i)-(iii):
• • (i) an XRPD pattern having peaks at 2θ angles of 19.7°, 22.0°, and 30.2° ±0.2°;
  • (ii) a DSC profile as shown in FIG. 4; or
  • (iii) a TGA profile as shown in FIG. 4.
    In another embodiment, the solid state form is Form IV.
• For all embodiments disclosed herein, a peak positional reproducibility is associated with the values of degree-2θ (XRPD), ppm (¹³C solid state NMR), and cm⁻¹ (IR and Raman). Accordingly, it will be understood that all peaks disclosed herein have the value disclosed ±the peak positional reproducibility associated with each analytical technique. The XRPD peak positional reproducibility is ±0.2 expressed in degree-2θ. The ¹³C NMR peak positional reproducibility is ±0.2 ppm. The IR peak positional reproducibility is ±2 cm⁻¹. The Raman peak positional reproducibility is ±2 cm⁻¹.
FORMS OF COMPOUND I Form I
• Crystalline Form I is characterized by the following X-ray powder diffraction pattern expressed in terms of the degree 2θ and relative intensities with a relative intensity of ≥3.4° measured on a Bruker D5000 diffractometer with CuKα radiation:
X-ray Powder Diffraction Peaks for Crystalline Form I

• 	Angle (Degree 2θ)	Relative Intensity* %

  	4.6	5.7
  	5.5	3.9
  	6.8	67.0
  	9.1	12.3
  	10.2	35.4
  	11.2	4.5
  	11.6	8.3
  	13.1	3.4
  	13.7	21.9
  	14.6	5.3
  	15.0	6.3
  	15.4	5.9
  	15.9	10.8
  	16.5	16.5
  	17.4	70.6
  	18.4	11.5
  	19.0	13.9
  	20.7	100.0
  	21.3	77.3
  	21.7	37.4
  	22.4	22.0
  	22.8	11.2
  	23.1	8.2
  	23.4	8.2
  	23.7	7.8
  	24.2	8.0
  	24.7	32.8
  	24.9	37.5
  	25.3	30.1
  	26.3	28.9
  	26.8	9.5
  	27.2	10.6
  	28.0	9.5
  	29.8	7.9
  	30.9	6.8
  	32.1	11.0
  	33.0	6.0
  	34.1	8.4
  	34.8	5.9
  	37.3	9.5
  	38.0	4.9
  	38.7	5.8

• Representative values of degree 2θ for Form I are 13.1, 16.5, 22.4 and 26.8. Particularly representative values of degree 2θ for Form I are 16.5 and 26.8.
• Crystalline Form I is characterized by the following ¹³C Solid State NMR shifts.

• 	13C Chemical Shiftsa [ppm]	Intensityb

  	158.7	8.6
  	157.9	10.6
  	153.0	8.2
  	149.7	9.4
  	141.0	8.5
  	132.4	10.1
  	131.4	8.9
  	127.6	12.0
  	125.9	4.5
  	125.0	5.0
  	117.4	3.3
  	114.2	6.3
  	110.8	2.0
  	65.6	8.0
  	52.0	8.5
  	46.6	4.6
  	33.8	8.3
  	27.6	11.4
  	27.2 shoulder	—
  	24.1	10.4
  	16	11.9
  	13.9	10.2
  	aReferenced to external sample of solid phase adamantane at 29.5 ppm.
  	bDefined as peak heights. Intensities can vary depending on the actual setup of the CPMAS experimental parameters and the thermal history of the sample. CPMAS intensities are not necessarily quantitative.

• Representative ¹³C NMR chemical shifts for Form I are as follows:

• Form I 13C Chemical Shifts [ppm]

  157.9
  153.0
  149.7
  141.0
  131.4
  33.8
  27.6
  13.9

• Form I is characterized by the following FT-IR peaks:
FT-IR Peak List of Form I

• Wavelength (cm−1)

  652
  675
  697
  715
  749
  777
  829
  853
  870
  898
  919
  945
  958
  1016
  1067
  1086
  1105
  1162
  1200
  1223
  1236
  1279
  1294
  1318
  1353
  1379
  1408
  1429
  1444
  1465
  1486
  1503
  1563
  1576
  1588
  1617
  1882
  1899
  1981
  2051
  2163
  2276
  2324
  2391
  2672
  2731
  2803
  2813
  2869
  2900
  2927
  2961
  3033
  3061
  3093
  3133

• Representative FT-IR peaks for Form I are as follows:

• Form I Length (cm−1)

  697

  870

  1016

  1223

• Form I is characterized by the following Raman peaks:
Representative Raman Peaks of Form I

• Form I Wavenumber (cm−1)

  139
  192
  198
  208
  217
  266
  293
  335
  371
  389
  422
  448
  475
  511
  525
  571
  620
  633
  653
  677
  698
  724
  753
  787
  798
  821
  834
  855
  871
  880
  898
  947
  1004
  1010
  1024
  1055
  1075
  1088
  1106
  1170
  1197
  1250
  1274
  1293
  1318
  1354
  1362
  1410
  1430
  1444
  1497
  1510
  1563
  1586
  1618
  2571
  2871
  2902
  2932
  2962
  3063

• Particularly representative Raman peaks for Form I are as follows:

• Form I Wavenumber (cm−1)

  266

  293

  335

  653

  787

  1497

• Thermogravimetric analysis of Form I showed negligible weight loss of approximately 0.1% wt/wt or less from 25 to 250° C.
Form II
• Crystalline Form II is characterized by the following X-ray powder diffraction pattern expressed in terms of the degree 2θ and relative intensities with a relative intensity of ≥6.0° measured on a Bruker D5000 diffractometer with CuKα radiation:
X-ray Powder Diffraction Peaks for Crystalline Form II

• 	Angle (Degree 2-θ)	Relative Intensity* %

  	4.5	17.8
  	6.7	63.3
  	9.1	14.1
  	10.0	10.8
  	10.3	12.4
  	11.0	6.0
  	11.6	15.1
  	12.5	7.0
  	13.6	14.0
  	14.5	11.2
  	15.1	29.9
  	15.7	15.0
  	17.5	40.4
  	18.3	41.8
  	18.8	87.1
  	19.7	9.8
  	20.1	34.5
  	20.6	84.4
  	21.0	15.6
  	21.6	100.0
  	22.1	36.3
  	22.7	20.8
  	23.1	52.0
  	23.6	77.1
  	24.3	17.7
  	24.8	12.4
  	25.5	14.4
  	25.8	17.0
  	26.2	59.1
  	27.3	17.5
  	28.2	12.8
  	28.7	6.8
  	29.5	26.9
  	30.0	7.4
  	30.4	6.9
  	31.2	6.8
  	31.6	7.3
  	32.1	16.7
  	32.5	9.8
  	32.9	8.5
  	33.2	12.5
  	33.7	9.0
  	34.3	8.4
  	35.2	7.3
  	35.7	7.6
  	37.4	7.8
  	38.3	10.4
  	39.6	9.6
  	*The relative intensities may change depending on the crystal size and morphology.

• Representative values of degree 2θ for Form II are 18.8 and ≥20.1 ±0.2.
Form II is characterized by the following ¹³C Solid State NMR chemical shifts:

• 	13C Chemical Shiftsa [ppm]	Intensityb

  	158.6	5.0
  	153.6	12.0
  	149.0	6.1
  	140.1	5.7
  	133.0	6.1
  	132.3	3.6
  	128.9	5.4
  	127.6	5.4
  	126.8	6.5
  	125.6	8.0
  	123.2	4.1
  	121.6	5.3
  	119.9	5.1
  	114.4	8.4
  	110.5	3.9
  	67.4	3.5
  	51.8	1.7
  	29.6	5.4
  	28.6	6.7
  	23.8	4.1
  	15.5	6.1
  	9.4	1.7
  	aReferenced to external sample of solid phase adamantane at 29.5 ppm.
  	bDefined as peak heights. Intensities can vary depending on the actual setup of the CPMAS experimental parameters and the thermal history of the sample. CPMAS intensities are not necessarily quantitative.

• Representative chemical shifts for Form II are as follows:

• Form II 13C Chemical Shifts [ppm]

  153.6
  149.0
  140.1
  123.2
  121.6
  119.9
  28.6

• Form II is characterized by the following FT-IR peaks:
FT-IR Peak Lists of Form II

• Wavelength (cm−1)

  660
  675
  690
  707
  717
  735
  750
  762
  783
  816
  824
  836
  848
  877
  899
  916
  928
  945
  969
  1004
  1024
  1046
  1062
  1075
  1088
  1105
  1115
  1135
  1159
  1178
  1202
  1239
  1274
  1290
  1316
  1325
  1368
  1395
  1412
  1425
  1455
  1462
  1482
  1502
  1563
  1576
  1587
  1617
  1773
  1898
  1981
  2022
  2038
  2052
  2070
  2164
  2191
  2259
  2288
  2324
  2677
  2725
  2774
  2783
  2823
  2865
  2881
  2898
  2926
  2950
  2958
  3030
  3047
  3061
  3078
  3090
  3140

• Representative FT-IR peaks for Form II are as follows:

• Form II Wavelength (cm−1)

  660
  707
  735
  816
  969
  1024
  1046
  1135
  1178

• Form II is characterized by the following Raman peaks:
Representative Raman Peaks of Form II

• Form II Wavenumber (cm−1)

  137
  156
  193
  257
  277
  300
  326
  374
  395
  419
  435
  443
  465
  474
  483
  506
  520
  536
  567
  590
  621
  634
  646
  660
  676
  693
  708
  722
  750
  772
  795
  825
  837
  852
  878
  900
  915
  947
  1005
  1027
  1061
  1089
  1106
  1134
  1160
  1180
  1196
  1223
  1243
  1277
  1298
  1324
  1348
  1370
  1412
  1441
  1454
  1467
  1507
  1563
  1575
  1589
  1617
  2728
  2783
  2825
  2868
  2879
  2917
  2931
  2957
  3014
  3031
  3066
  3137
  3174
  3226

• Particularly representative Raman peaks for Form II are as follows:

• Form II Wavenumber (cm−1)

  257
  300
  326
  590
  646
  1180
  1348
  1370

• Thermogravimetric analysis showed negligible weight loss of approximately 0.1% wt/wt or less for Form II from 25 to 250° C.
Form III
• Crystalline Form III is characterized by the following X-ray powder diffraction pattern expressed in terms of the degree 2θ:
X-ray Powder Diffraction Peaks for Crystalline Form III

• 	Angle (Degree 2-θ)	Relative Intensity* %

  	5.4	100.0
  	11.5	1.12
  	13.9	0.26
  	14.9	0.18
  	17.0	0.62
  	17.9	1.00
  	18.3	0.98
  	18.5	1.05
  	19.2	2.34
  	20.6	1.97
  	20.8	1.28
  	21.5	20.69
  	21.6	12.94
  	22.0	7.25
  	23.4	0.77
  	22.8	0.67
  	23.2	1.47
  	23.5	0.95
  	25.1	1.30
  	26.9	0.24
  	28.3	0.25
  	28.9	1.12
  	31.5	0.45
  	32.0	0.24
  	32.5	0.41
  	34.2	0.31
  	36.8	0.14
  	38.0	2.11
  	38.1	1.14
  	*The relative intensities may change depending on the crystal size and morphology.

• Representative values of degree 2θ for Form III are 5.4, 21.5, and 22.0 ±0.2.
• Thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC) data displayed in FIG. 2 indicated a weight loss of 2.3 up to 150° C. and one sharp melting peak at 59.3° C. (peak temperature).
Form IV
• Crystalline Form IV is characterized by the following X-ray powder diffraction pattern expressed in terms of the degree 2θ:
X-ray Powder Diffraction Peaks for Crystalline Form IV

• 	Angle (Degree 2-θ)	Relative Intensity* %

  	5.4	30.74
  	5.6	25.70
  	10.0	1.66
  	11.8	5.45
  	13.8	8.16
  	14.5	10.26
  	15.8	3.56
  	16.9	7.21
  	17.3	7.59
  	17.8	10.42
  	18.5	16.85
  	19.7	100.00
  	20.1	74.55
  	20.8	18.82
  	21.4	33.93
  	21.8	57.45
  	22.0	40.75
  	22.4	25.84
  	22.6	47.39
  	23.1	9.74
  	23.6	20.86
  	24.7	7.19
  	25.4	7.37
  	26.1	21.01
  	26.9	5.48
  	27.8	3.76
  	28.6	3.36
  	29.6	3.17
  	30.1	25.18
  	30.2	25.58
  	31.2	3.57
  	32.2	4.65
  	34.9	1.84
  	35.5	6.50
  	36.3	2.11
  	37.1	1.96
  	39.0	2.14
  	*The relative intensities may change depending on the crystal size and morphology.

• Representative values of degree 2θ for Form IV are 19.7, 22.0, and 30.2 ±0.2.
• TGA and DSC data displayed in FIG. 4 indicated a weight loss of 4.2% up to 150° C. and one sharp possible desolvation/melting peak at 51.9° C. (peak temperature).
METHODS OF MAKING
• COMPOUND I and a method for its preparation are exemplified in US Patent Publication No. 2004-0082542 in Example 406, herein incorporated by reference. Additional methods to prepare COMPOUND I are described in U.S. Pat. No. 7,884,219, herein incorporated by reference. In another aspect, the present invention provides a method for producing a polymorph of COMPOUND I.
• In one embodiment, the method involves producing solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the method comprises:
• • a) dissolving a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent at room temperature to make a solution;
  • b) allowing the solution from step a) to evaporate at room temperature; and
  • c) collecting the solid produced from step b).
    In one embodiment, the suitable solvent in step a) is 2-methyltetrahydrofuran or tetrahydrofuran.
• In another embodiment, the present invention provides a method for producing solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the method comprises:
• • a) dissolving a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent at room temperature to make a solution;
  • b) stirring the solution from step a);
  • c) adding a suitable amount of a suitable anti-solvent; and
  • d) collecting the solid product produced from step c).
    In one embodiment, the suitable solvent in step a) is selected from the group consisting of ethanol, n-propyl alcohol, isopropyl alcohol, 2-methyltetrahydrofuran, isopropyl acetate, and methyl ethyl ketone. In one embodiment, the suitable anti-solvent in step c) is selected from the group consisting of water, hexane, and n-heptane.
• In yet another embodiment, the method involves producing of solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the method comprises:
• • a) slurrying a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propy]-diethylamine in a suitable amount of a suitable solvent system at a suitable temperature; and
  • b) collecting the solid produced from step a).
    In one embodiment, the suitable solvent system in step a) is selected from the group consisting of isopropyl alcohol, ethanol, ethyl acetate, cyclopentyl methyl ether, acetone, ethanol/water, n-propyl alcohol/heptane, ethanol/hexane, methyl ethyl ketone/hexane, 4-methyl-2-pentanone/hexane, isopropyl alcohol/hexane, ethyl acetate/hexane, toluene/hexane, 2-methyltetrahydrofuran/hexane, dioxane/hexane, cyclohexane, anisole, anisole/hexane, and methyl tert-butyl ether/hexane. In one embodiment, the suitable temperature is room temperature or 35° C.
• In still yet another embodiment, the method involves producing solid state form FormIII of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H- imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the method comprises:
• • a) dissolving a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent system at room temperature to make a solution;
  • b) adding a suitable amount of a polymer mixture to the solution from step a) to make a suspension;
  • c) allowing the suspension of step b) to evaporate at room temperature; and
  • d) collecting the solid produced from step c).
    In one embodiment, the suitable solvent system in step a) is selected from the group consisting of isopropyl alcohol, cyclohexane, ethyl acetate/hexane, acetone/hexane, isopropyl acetate/hexane, methyl ethyl ketone/hexane, and n-propyl alcohol/water. In one embodiment, the polymer mixture in step b) is selected from the group consisting of polyvinylpyrrolidone/polyvinyl alcohol/polyvinyl chloride/hypromellose/methyl cellulose or poly(methyl methacrylate)/sodium alginate/hydroxyethyl cellulose.
• In another embodiment, the method involves producing solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the method comprises:
• • a) dissolving a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent system at room temperature to make a solution in a vessel;
  • b) adding a suitable amount of a volatile solvent to the vessel of step a);
  • c) sealing the vessel after step b);
  • d) maintaining the vessel at room temperature for a sufficient amount of time for the volatile solvent to interact with the solution; and
  • e) collecting the solid produced from step c).
    In one embodiment, the suitable solvent system in step a) is methyl ethyl ketone and the suitable volatile solvent is hexane.
• In yet another embodiment, the method involves producing solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the method comprises:
• • a) suspending a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent system at room temperature to make a suspension;
  • b) heating the suspension from step a) to a suitable temperature and equilibrating for a suitable amount of time;
  • c) optionally filtering the suspension from step b);
  • d) slowly cooling to a suitable temperature over a suitable amount of time; and
  • e) collecting the solid produced from step d).
    In one embodiment, the suitable solvent system in step a) is selected from the group consisting of isopropyl alcohol, acetonitrile, cyclohexane, n-butanol, ethanol/n-heptane, methyl ethyl ketone/n-heptane, isopropyl alcohol/n-heptane, methyl tert-butyl ether/n-heptane, trichloromethane/hexane, isopropyl alcohol/hexane, methyl tert-butyl ether/hexane, ethyl acetate/hexane, toluene/hexane, and cyclopentyl methyl ether/hexane. In one embodiment the suitable temperature is about 40° C. and the suitable amount of time is about 1 hour in step b). In one embodiment, the suitable temperature is about 5° C. and the suitable time is about 5.5 hours in step d). In one embodiment, if no solid is obtained after cooling to about 5° C., a further cooling to −20° C. step is performed. In one embodiment, if no solid is obtained after cooling to about 5° C., an evaporation at room temperature step is performed.
• In still yet another embodiment, the method involves producing solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the method comprises:
• • a) adding a suitable amount of a volatile solvent to a suitable amount of solid [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a vessel;
  • b) sealing the vessel after step b);
  • c) maintaining the vessel at room temperature for a sufficient amount of time for the volatile solvent to interact with the solid [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine; and
  • d) collecting the solid form from the vessel.
    In one embodiment, the volatile solvent in step a) is isopropyl alcohol. In one embodiment, the suitable time in step c) is 5 to 10 days.
• One aspect of the present invention is the solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by any of the methods described herein.
• In one embodiment, the method involves producing solid state form Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the method comprises:
• • a) dissolving a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent at room temperature to make a solution;
  • b) stirring the solution from step a);
  • c) adding a suitable amount of a suitable anti-solvent; and
  • d) collecting the solid product produced from step c).
    In one embodiment, the suitable solvent in step a) is toluene. In one embodiment, the suitable anti-solvent in step c) is hexane.
• In another embodiment, the method involves producing solid state form Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the method comprises:
• • a) slurrying a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent system at a suitable temperature; and
  • b) collecting the solid produced from step a).
    In one embodiment, the suitable solvent system in step a) is selected from the group consisting of toluene, ethyl acetate, anisole, ethyl acetate/hexane, toluene/hexane, and ethanol/hexane. In one embodiment, the suitable temperature is room temperature or 35° C. in step a).
• In yet another embodiment, the method involves producing solid state form Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the method comprises:
• • a) dissolving a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent system at room temperature to make a solution;
  • b) adding a suitable amount of a polymer mixture to the solution from step a) to make a suspension;
  • c) allowing the suspension of step b) to evaporate at room temperature; and
  • d) collecting the solid produced from step c).
    In one embodiment, the suitable solvent system in step a) is isopropyl acetate/hexane. In one embodiment, the polymer mixture in step b) is poly(methyl methacrylate)/sodium alginate/hydroxyethyl cellulose.
• In still yet another embodiment, the method involves producing solid state form Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the comprises:
• • a) suspending a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent system at room temperature to make a suspension;
  • b) heating the suspension from step a) to a suitable temperature and equilibrating for a suitable amount of time;
  • c) optionally filtering the suspension from step b);
  • d) slowly cooling to a suitable temperature over a suitable amount of time; and
  • e) collecting the solid produced from step d).
    In one embodiment, the suitable solvent system in step a) is dioxane/water. In one embodiment, the suitable temperature is about 40° C. and the suitable amount of time is about 1 hour in step b). In one embodiment, the suitable temperature is about 5° C. and the suitable time is about 5.5 hours in step d). In one embodiment, if no solid is obtained after cooling to about 5° C., a further cooling to −20° C. step is performed. In one embodiment, if no solid is obtained after cooling to about 5° C., an evaporation at room temperature step is performed.
• One aspect of the present invention is the solid state form Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by any of the methods described herein.
• To ensure no chemical transformation or degradation has occurred, the purity of each polymorph may be confirmed using HPLC and then characterized by its physio-chemical properties such as DSC, X-ray powder diffraction, infrared spectrum, Raman spectrum, and/or solid state ¹³C NMR.
• In another aspect, the present invention provides mixtures comprising different polymorphs of COMPOUND I. In one embodiment, a mixture comprises a crystalline form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, characterized by an XRPD pattern having peaks at 2θ angles of 5.4°, 21.5°, and 22.0° ±0.2° and a second solid state form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the second solid state form is characterized by an XRPD pattern having peaks at 2θ angles of 18.8° and 20.1° ±0.2. In one embodiment, a mixture comprises b) a crystalline form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, characterized by an XRPD pattern having peaks at 2θ angles of 19.7°, 22.0°, and 30.2° ±0.2° and a second solid state form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the second solid state form is characterized by an XRPD pattern having peaks at 2θ angles of 18.8° and 20.1° ±0.2. In one embodiment, a mixture comprises a crystalline form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, characterized by an XRPD pattern having peaks at 2θ angles of 5.4°, 21.5°, and 22.0° ±0.2° and a second solid state form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the second solid state form is characterized by an XRPD pattern having peaks at 2θ angles of 16.5° and 26.8° ±0.2. In one embodiment, a mixture comprises b) a crystalline form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, characterized by an XRPD pattern having peaks at 2θ angles of 19.7°, 22.0°, and 30.2° ±0.2° and a second solid state form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]- diethylamine, wherein the second solid state form is characterized by an XRPD pattern having peaks at 2θ angles of 16.5° and 26.8° ±0.2. In one embodiment, a mixture comprises a crystalline form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, characterized by an XRPD pattern having peaks at 2θ angles of 5.4°, 21.5°, and 22.0° ±0.2° and a second solid state form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the second solid state form is characterized by an XRPD pattern having peaks at 2θ angles of 19.7°, 22.0°, and 30.2° ±0.2°. In one embodiment, a mixture comprises two or more of Form I, Form II, Form III, or Form IV of COMPOUND I. In one embodiment, ratio of one solid state form to a second solid state form by weight may be between 9:1 and 1:9, respectively. In an embodiment, the ratio by weight of one solid state form to a second solid state form is 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, or 1:9.
PHARMACEUTICAL COMPOSITIONS
• In another aspect, the present invention provides pharmaceutical compositions comprising one or more polymorphic forms of COMPOUND I. In one embodiment, a pharmaceutical composition comprises Form III of COMPOUND I and a pharmaceutically acceptable excipient, diluent, carrier, or mixture thereof. In one embodiment, a pharmaceutical composition comprises Form IV of COMPOUND I and a pharmaceutically acceptable excipient, diluent, carrier, or mixture thereof. In one embodiment, a pharmaceutical composition comprises Form III and Form IV of COMPOUND I and a pharmaceutically acceptable excipient, diluent, carrier, or mixture thereof. In one embodiment, a pharmaceutical composition comprises Form I and Form III of COMPOUND I and a pharmaceutically acceptable excipient, diluent, carrier, or mixture thereof. In one embodiment, a pharmaceutical composition comprises Form II and Form III of COMPOUND I and a pharmaceutically acceptable excipient, diluent, carrier, or mixture thereof. In one embodiment, a pharmaceutical composition comprises Form I and Form IV of COMPOUND I and a pharmaceutically acceptable excipient, diluent, carrier, or mixture thereof. In one embodiment, a pharmaceutical composition comprises Form II and Form IV of COMPOUND I and a pharmaceutically acceptable excipient, diluent, carrier, or mixture thereof. In one embodiment, a pharmaceutical composition comprises one or more of Form I, Form II, Form III, or Form IV of COMPOUND I and a pharmaceutically acceptable excipient, diluent, carrier, or mixture thereof.
• In another aspect, the present invention also provides methods of producing a pharmaceutical composition comprising one or polymorphs of COMPOUND I. In one embodiment, a method of producing a pharmaceutical composition comprises combining Form III of COMPOUND I with a pharmaceutically acceptable excipient, diluent, carrier, or a mixture thereof. In one embodiment, a method for producing a pharmaceutical composition comprises combining Form IV of COMPOUND I with a pharmaceutically acceptable excipient, diluent, carrier, or a mixture thereof. In one embodiment, a method for producing a pharmaceutical composition comprises combining Form III and Form IV of COMPOUND I with a pharmaceutically acceptable excipient, diluent, carrier, or a mixture thereof. In one embodiment, a method for producing a pharmaceutical composition comprises combining Form III and Form I of COMPOUND I with a pharmaceutically acceptable excipient, diluent, carrier, or a mixture thereof. In one embodiment, a method for producing a pharmaceutical composition comprises combining Form III and Form II of COMPOUND I with a pharmaceutically acceptable excipient, diluent, carrier, or a mixture thereof. In one embodiment, a method for producing a pharmaceutical composition comprises combining Form IV and Form I of COMPOUND I with a pharmaceutically acceptable excipient, diluent, carrier, or a mixture thereof. In one embodiment, a method for producing a pharmaceutical composition comprises combining Form IV and Form II of COMPOUND I with a pharmaceutically acceptable excipient, diluent, carrier, or a mixture thereof. In one embodiment, a method for producing a pharmaceutical composition comprises combining one or more of Form I, Form II, Form III, or Form IV of COMPOUND I and a pharmaceutically acceptable excipient, diluent, carrier, or mixture thereof.
• Pharmaceutical compositions of the present invention comprising a Form I, Form II, Form III, Form IV or mixtures thereof of COMPOUND I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, dispersible powders or granules, or hard or soft capsules. Compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
• Tablets, tronches, lozenges, dispersible powders or granules, or hard or soft capsules may contain one or more polymorphs of COMPOUND I in admixture with non-toxic pharmaceutically-acceptable excipients which are suitable for the manufacture of such tablets, tronches, lozenges, dispersible powders or granules, or hard or soft capsules. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, croscarmelose sodium, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents or glidants, for example magnesium stearate, stearic acid, colloidal silicon dioxide, or talc. Hard gelatin capsules may include one or more polymorphs of COMPOUND I in combination with an inert solid excipient, diluent, carrier, or mixture thereof.
• A “pharmaceutically acceptable carrier, diluent, or excipient” is a medium generally accepted in the art for the delivery of biologically active agents to mammals, e.g., humans. Such carriers are generally formulated according to a number of factors well within the purview of those of ordinary skill in the art to determine and account for. These include, without limitation, the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers and excipients include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources, e.g., Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa. 1985, the contents of which are incorporated herein by reference.
METHODS OF TREATMENT
• In another embodiment, the present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of COMPOUND I wherein a therapeutically effective amount of COMPOUND I comprises a sufficient amount for the treatment of a RAGE mediated disorder. In another embodiment, a pharmaceutical composition may comprise a therapeutically effective amount of Form I of COMPOUND I. In another embodiment, a pharmaceutical composition may comprise a therapeutically effective amount of Form II of COMPOUND I. In another embodiment, a pharmaceutical composition may comprise a therapeutically effective amount of Form III of COMPOUND I. In another embodiment, a pharmaceutical composition may comprise a therapeutically effective amount of Form IV of COMPOUND I. In another embodiment, a pharmaceutical composition may comprise a therapeutically effective amount of a mixture of one or more of Form I, II, III, or IV of COMPOUND I.
• In another aspect, the present invention provides a method for treating a RAGE mediated disease comprising administering one or more polymorphic forms of COMPOUND I to a subject in need thereof. The method may comprise administering a pharmaceutical composition comprising a therapeutically effective amount of COMPOUND I to a subject in need thereof.
• A pharmaceutical composition of the present invention may be administered at a dosage level of less than 100 mg of compound per day. In another embodiment, the dosage level of administration is greater than 1 mg of compound per day. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage will vary depending upon the host treated and the particular mode of administration. For example, in one non-limiting embodiment, a dosage unit forms, such as a tablet or capsule, intended for oral administration to humans may contain less than 100 mg of COMPOUND I with an appropriate and convenient amount of carrier material. In another embodiment, the dosage level of administration is greater than 1 mg of compound per day. In another embodiment, the dosage level of administration is 5, 10 or 20 mg of compound per day.
• The dosage may be individualized by the clinician based on the specific clinical condition of the subject being treated. Thus, it will be understood that the specific dosage level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
EXAMPLES Analytical Methods Used To Characterize Forms I and II
• Methods used to collect XRPD, solid state ¹³C NMR, FT-IR, Raman, TGA, and DSC data for Forms I and II of COMPOUND I are provided in U.S. Pat. No. 7,884,219.
Analytical Methods Used To Characterize Forms III and IV X-ray Powder Diffraction (XRPD) Analysis
• XRPD analysis was performed with a Panalytical X'Pert³ Powder XRPD on a Si zero-background holder. The 2θ position was calibrated against Panalytical Si reference standard disc. The XRPD parameters used are listed in Table 1.

• TABLE 1
  Parameters for XRPD test

  	Parameters	Reflection Mode
  	X-Ray wavelength	Cu, kα
  	Kα1 (Å)	1.540598
  	Kα2 (Å)	1.544426
  	Kα2/Kα1 intensity ratio	0.50
  	X-Ray tube setting	45 kV, 40 mA
  	Divergence slit	Fixed ⅛°
  	Scan mode	Continuous
  	Scan range	(° 2TH)3-40
  	Scan step time [s]	18.87
  	Step size (° 2TH)	0.0131
  	Test Time	4 min 15 s

Thermogravimetry Analysis (TGA) and Differential Scanning Calorimetry (DSC)
• TGA data were collected using a TA Q500 and Q550 from TA Instruments. DSC was performed using a TA Q2000 from TA Instruments. DSC was calibrated with Indium reference standard and the TGA was calibrated using nickel reference standard. Detailed parameters used are listed in Table 2.

• TABLE 2
  Parameters for TGA and DSC test

  Parameters	TGA	DSC
  Method	Ramp	Ramp
  Sample pan	Aluminum, open	Aluminum, crimped
  Temperature	RT - desired temperature	25° C. - desired temperature
  Heating rate
  	10° C./min	10° C./min
  Purge gas	N2	N2

• Crystalline Form II was used as the starting material in each of the following Examples.
Example 1
• Solid vapor diffusion experiments were conducted using 16 different solvents. Approximate 30 mg of starting material was weighed into a 3-mL vial, which was placed into a 20-mL vial with 2 mL of volatile solvent. The 20-mL vial was sealed with a cap and kept at RT for 7 days allowing solvent vapor to interact with sample. The solids were tested by
• XRPD and the results summarized in Table 3 showed that Type II, gel or mixture of forms were generated.

• TABLE 3
  Summary of solid vapor diffusion experiments

  	Solvent	Solid Form
  	H2O	Form II
  	Ethanol	Form II
  	Isopropanol	Forms II + III
  	Acetone	Form II
  	4-Methyl-2-pentanone	Form II
  	Ethyl acetate	Form II
  	Isopropyl Acetate	Form II
  	Methyl tert-butyl ether	Form II
  	Tetrahydrofuran	Gel
  	Dichloromethane	Form II
  	Toluene	Form II
  	Acetonitrile	Form II
  	Cyclopentyl methyl ether	Form II
  	2-Methyltetrahydrofuran	Form II
  	CH3COOH	Gel
  	CHCl3	Gel

Example 2
• Slow evaporation experiments were performed under six conditions. Briefly, 30 mg of starting material was dissolved in 1˜6 mL of solvent in a 20-mL glass vial. If no dissolution was achieved, suspensions were filtered using a PTFE (pore size of 0.2 μm) and the filtrates were used for the following steps. The visually clear solutions were covered by Parafilm® with 5˜10 pinholes and subjected to evaporation at RT. The solids were isolated for XRPD analysis. The results summarized in Table 4 indicated that Type II, gel or mixture of forms were obtained.

• TABLE 4
  Summary of slow evaporation experiments

  Solvent (v:v)	Solid Form	Solvent (v:v)	Solid Form
  2-Methyltetra-	Form III	Methyl ethyl ketone	Form II
  hydrofuran
  Acetic acid	Gel	Methanol	Gel
  Acetone	Form II	Methyl tert-butyl	Form II
  		ether
  Acetonitrile	Form II	N-Methyl-2-	Gel
  		pyrrolidone+
  CHCl3	Form II	Tetrahydrofuran	Forms II + III
  Cyclohexane	Form II	Toluene	Gel
  Dichloromethane	Form II	Acetone/H2O	—
  Dioxane	Gel	Methanol/H2O	Form II
  Dimethylacetamide*	Gel	Ethanol/H2O	Gel
  Ethyl acetate	Form II	Isopropyl	Gel
  		alcohol/H2O
  Ethanol	Form II	Tetrahydro-	Gel
  		furan/H2O
  Isopropyl alcohol	Form II	Dioxane/H2O	Form II
  Isopropyl Acetate	Form II	Acetonitrile/H2O	Gel
  *Solid was obtained via vacuumed evaporation at RT.
  +Gel was obtained via vacuumed evaporation at 40° C.
  —: Limited solid for XRPD test.

Example 3
• A total of 42 anti-solvent addition experiments were carried out. About 30 mg of starting material was dissolved in 0.2-2.0 mL solvent to obtain a clear solution. The solution was magnetically stirred followed by addition of 0.2 mL anti-solvent stepwise till precipitate appeared or the total amount of anti-solvent reached 15.0 mL. The obtained precipitate was isolated for XRPD analysis. Results in Table 5 showed that Types I, II, gel or mixture of forms were obtained.

• TABLE 5
  Summary of anti-solvent addition experiments

  	Solvent	Anti-solvent	Solid Form
  	Ethanol	H2O	Form III
  	Ethanol	n-Heptane	Gel
  	Ethanol	Hexane	Forms II + III
  	n-Propyl alcohol	H2O	Form II
  	n-Propyl alcohol	n-Heptane	Form II
  	n-Propyl alcohol	Hexane	Forms II + III
  	Isopropyl alcohol	H2O	Form II
  	Isopropyl alcohol	n-Heptane	Forms II + III
  	Isopropyl alcohol	Hexane	Forms II + III
  	Tetrahydrofuran	H2O	Form III
  	Tetrahydrofuran	n-Heptane	Form II
  	Tetrahydrofuran	Hexane	Form II
  	Acetone	H2O	Form II
  	Acetone	n-Heptane	Form II
  	Acetone	Hexane	Form II
  	2-Methyltetrahydrofuran	H2O	Form II
  	2-Methyltetrahydrofuran	n-Heptane	Form II
  	2-Methyltetrahydrofuran	Hexane	Form II
  	Dioxane	H2O	Forms II + III
  	Dioxane	n-Heptane	Form II
  	Dioxane	Hexane	Form II
  	Methanol	H2O	Form II
  	Acetonitrile	H2O	Form II
  	N-Methyl-2-pyrrolidone	H2O	Form II
  	Dimethylacetamide	H2O	Form II
  	Dimethyl sulfoxide	H2O	Low crystallinity
  	Ethyl acetate	n-Heptane	Form II
  	Ethyl acetate	Hexane	Form II
  	Isopropyl Acetate	n-Heptane	Form II
  	Isopropyl Acetate	Hexane	Forms II + III
  	Methyl tert-butyl ether	n-Heptane	Form II
  	Methyl tert-butyl ether	Hexane	Form II
  	Methyl ethyl ketone	n-Heptane	Form II
  	Methyl ethyl ketone	Hexane	Form III
  	CH2Cl2	n-Heptane	Form II
  	CH2Cl2	Hexane	Form II
  	CHCl3	n-Heptane	Form II
  	CHCl3	Hexane	Form II
  	Toluene	n-Heptane	Form II
  	Toluene	Hexane	Forms II + IV
  	Cyclopentyl methyl ether	n-Heptane	Form II
  	Cyclopentyl methyl ether	Hexane	Form II

Example 4
• Slurry experiments were conducted at RT in different solvent systems. About 30 mg of starting material was suspended in 0.1˜0.2 mL of solvent in a 3-mL glass vial. After the suspension was stirred magnetically for 7 days at RT, the remaining solids were isolated for XRPD analysis. Results summarized in Table 6 indicated that Type II, III, IV, or mixture of forms were obtained.

• TABLE 6
  Summary of slurry conversion experiments at RT

  	Solvent (v:v)	Solid Form
  	Isopropyl alcohol	Form III
  	Ethanol	Form III
  	Acetonitrile	Form II
  	Toluene	Form IV
  	Cyclohexane	Form II
  	n-Heptane	Form II
  	Hexane	Form II
  	Ethyl Acetate	Forms III + IV
  	Cyclopentyl methyl ether	Form III
  	Acetone	Form III
  	Anisole	Form IV
  	H2O	Form II
  	Ethanol/H2O (0.97/0.03, aw = 0.2)	Form III
  	Ethanol/H2O (0.927/0.073, aw = 0.4)	Form III
  	Ethanol/H2O (0.855/0.145, aw = 0.6)	Low crystallinity
  	Ethanol/H2O (0.704/0.296, aw = 0.8)	Low crystallinity
  	N-propyl alcohol/n-Heptane (1:3)	Form III
  	Ethanol/Hexane (1:3)	Form III
  	Methyl ethyl ketone/Hexane (1:3)	Form III
  	4-Methyl-2-pentanone/Hexane (1:3)	Forms II + III
  	Isopropyl alcohol/Hexane (1:3)	Form III
  	CHCl3/Hexane (1:3)	Form II
  	Anisole/Hexane(1:3)	Form II
  	Methyl tert-butyl ether/Hexane (1:3)	Form II
  	Acetone/Hexane (1:3)	Form II
  	Ethyl acetate/Hexane (1:3)	Forms III + IV
  	Isopropyl acetate/Hexane (1:3)	Form II
  	Toluene/Hexane(1:3)	Form IV
  	2-Methyltetrahydrofuran/Hexane (1:3)	Forms II + III
  	Dioxane/Hexane (1:3)	Form III

Example 5
• Slurry experiments were also conducted at 35° C. in different solvent systems. About 30 mg of starting material was suspended in 0.1˜0.3 mL of solvent in a 3 mL glass vial. After the suspension was stirred for about 7 days at 35° C., the remaining solids were isolated for XRPD analysis. Results summarized in Table 7 indicated that Form II, III, IV, or mixture of forms were obtained.

• TABLE 7
  Summary of slurry conversion experiments at 35° C.

  	Solvent	Solid Form
  	Isopropyl alcohol	Forms II + III
  	Ethanol	Forms II + III
  	Acetonitrile#	Form II
  	Toluene	Form IV
  	Cyclohexane	Form III
  	Heptane	Form II
  	Hexane	Form II
  	Ethyl acetate	Form III
  	Cyclopentyl methyl ether	Forms II + III
  	Acetone	Forms II + III
  	Anisole*	Forms III + IV
  	H2O	Form II
  	Ethanol/H2O (0.97/0.03, aw = 0.2)*	Form III
  	Ethanol/H2O (0.927/0.073, aw = 0.4)*	Form III
  	Ethanol/H2O (0.855/0.145, aw = 0.6)#	Form III
  	Ethanol/H2O (0.704/0.296, aw = 0.8)*	Form III
  	N-propyl alcohol/Heptane (1:6)*	Form III
  	Ethanol/Hexane (1:6)*	Forms III + IV
  	Methyl ethyl ketone/Hexane (1:6)	Forms II + III
  	4-Methyl-2-pentanone/Hexane (1:6)	Forms II + III
  	Isopropyl alcohol/Hexane (1:6)	Forms II + III
  	CHCl3/Hexane (1:6)	Form II
  	Anisole/Hexane(1:6)*	Forms II + III
  	Methyl tert-butyl ether/Hexane (1:6)	Forms II + III
  	Acetone/Hexane (1:6)	Form II
  	Ethyl acetate/Hexane (1:6)	Forms II + III
  	Isopropyl acetate/Hexane (1:6)	Forms II + III
  	Toluene/Hexane(1:6)*	Form III
  	2-Methyltetrahydrofuran/Hexane (1:6)	Forms II + III
  	Dioxane/Hexane (1:6)	Forms II + III
  	Up to 150 mg starting material were added to prepare suspension due to the large solubility at 35° C.
  	*, #After adding 150 mg starting material the solution was clear.
  	*Solid precipitated when the sample was removed from hot plate to RT.
  	#Solid precipitated when the sample was removed from hot plate to 5° C.

Example 6
• Polymer-induced crystallization experiments were also conducted at 30 conditions with two polymer mixtures. About 30 mg of starting material was dissolved in 1˜2 mL of solvent in a 3 mL glass vial. If no dissolution was achieved, suspensions were filtered using a PTFE (pore size of 0.2 μm) and the filtrates were used for the following steps. About 2 mg of polymer mixture added into clear solutions. Suspensions were covered by Parafilm® with 5˜10 pinholes and subjected to evaporation at RT. The solids were isolated for XRPD analysis. Results summarized in Table 8 indicated that Type II, III, gel or mixture of forms were obtained.

• TABLE 8
  Summary of polymer-induced crystallization experiments

  Solvent	Polymer Mixture	Solid Form
  Isopropyl alcohol	polyvinyl pyrrolidone (PVP),	Form III
  	polyvinyl alcohol (PVA),
  	polyvinylchloride (PVC),
  	hypromellose (HPMC),
  	methyl cellulose (MC) (mass
  	ratio of 1:1:1:1:1)
  Ethanol	polyvinyl pyrrolidone (PVP),	Form II
  	polyvinyl alcohol (PVA),
  	polyvinylchloride (PVC),
  	hypromellose (HPMC),
  	methyl cellulose (MC) (mass
  	ratio of 1:1:1:1:1)
  Acetonitrile	polyvinyl pyrrolidone (PVP),	Form II
  	polyvinyl alcohol (PVA),
  	polyvinylchloride (PVC),
  	hypromellose (HPMC),
  	methyl cellulose (MC) (mass
  	ratio of 1:1:1:1:1)
  Toluene	polyvinyl pyrrolidone (PVP),	Form II
  	polyvinyl alcohol (PVA),
  	polyvinylchloride (PVC),
  	hypromellose (HPMC),
  	methyl cellulose (MC) (mass
  	ratio of 1:1:1:1:1)
  Cyclohexane	polyvinyl pyrrolidone (PVP),	Forms II + III
  	polyvinyl alcohol (PVA),
  	polyvinylchloride (PVC),
  	hypromellose (HPMC),
  	methyl cellulose (MC) (mass
  	ratio of 1:1:1:1:1)
  Ethyl acetate/	polyvinyl pyrrolidone (PVP),	Form III
  hexane	polyvinyl alcohol (PVA),
  	polyvinylchloride (PVC),
  	hypromellose (HPMC),
  	methyl cellulose (MC) (mass
  	ratio of 1:1:1:1:1)
  Acetone/hexane	polyvinyl pyrrolidone (PVP),	Form III
  	polyvinyl alcohol (PVA),
  	polyvinylchloride (PVC),
  	hypromellose (HPMC),
  	methyl cellulose (MC) (mass
  	ratio of 1:1:1:1:1)
  Tetrahydrofuran/hexane	polyvinyl pyrrolidone (PVP),	Form II
  	polyvinyl alcohol (PVA),
  	polyvinylchloride (PVC),
  	hypromellose (HPMC),
  	methyl cellulose (MC) (mass
  	ratio of 1:1:1:1:1)
  Methanol/H2O	polyvinyl pyrrolidone (PVP),	Form II
  	polyvinyl alcohol (PVA),
  	polyvinylchloride (PVC),
  	hypromellose (HPMC),
  	methyl cellulose (MC) (mass
  	ratio of 1:1:1:1:1)
  Ethanol/H2O	polyvinyl pyrrolidone (PVP),	Form II
  	polyvinyl alcohol (PVA),
  	polyvinylchloride (PVC),
  	hypromellose (HPMC),
  	methyl cellulose (MC) (mass
  	ratio of 1:1:1:1:1)
  Isopropyl alcohol	poly(methyl methacrylate)	Forms II + III
  	(PMMA) sodium alginate
  	(SA), and hydroxyethyl
  	cellulose (HEC) (mass ratio
  	of 1:1:1)
  Ethanol	poly(methyl methacrylate)	Gel
  	(PMMA) sodium alginate
  	(SA), and hydroxyethyl
  	cellulose (HEC) (mass ratio
  	of 1:1:1)
  Acetonitrile	poly(methyl methacrylate)	Form II
  	(PMMA) sodium alginate
  	(SA), and hydroxyethyl
  	cellulose (HEC) (mass ratio
  	of 1:1:1)
  Toluene	poly(methyl methacrylate)	Gel
  	(PMMA) sodium alginate
  	(SA), and hydroxyethyl
  	cellulose (HEC) (mass ratio
  	of 1:1:1)
  Cyclohexane	poly(methyl methacrylate)	Form II
  	(PMMA) sodium alginate
  	(SA), and hydroxyethyl
  	cellulose (HEC) (mass ratio
  	of 1:1:1)
  Isopropyl acetate/	poly(methyl methacrylate)	Forms III + IV
  hexane	(PMMA) sodium alginate
  	(SA), and hydroxyethyl
  	cellulose (HEC) (mass ratio
  	of 1:1:1)
  Methyl ethyl ketone/	poly(methyl methacrylate)	Form III
  hexane	(PMMA) sodium alginate
  	(SA), and hydroxyethyl
  	cellulose (HEC) (mass ratio
  	of 1:1:1)
  Dioxane/hexane	poly(methyl methacrylate)	Gel
  	(PMMA) sodium alginate
  	(SA), and hydroxyethyl
  	cellulose (HEC) (mass ratio
  	of 1:1:1)
  Isopropyl alcohol/	poly(methyl methacrylate)	Form II
  H2O	(PMMA) sodium alginate
  	(SA), and hydroxyethyl
  	cellulose (HEC) (mass ratio
  	of 1:1:1)
  N-propyl alcohol/	poly(methyl methacrylate)	Forms II + III
  H2O	(PMMA) sodium alginate
  	(SA), and hydroxyethyl
  	cellulose (HEC) (mass ratio
  	of 1:1:1)

Example 7
• Fifteen liquid vapor diffusion experiments were conducted. Approximate 30 mg of starting material was dissolved in appropriate solvent to obtain a clear solution in a 3-mL vial. This solution was then placed into a 20-mL vial with 3 mL of volatile solvents. The 20-mL vial was sealed with a cap and kept at RT allowing sufficient time for organic vapor to interact with the solution. The precipitates were isolated for XRPD analysis. The results summarized in Table 9 showed that Form II or mixture of forms was generated.

• TABLE 9
  Summary of liquid vapor diffusion experiments

  	Solvent	Anti-solvent	Solid Form
  	2-Methyltetrahydrofuran*	Hexane	Form II
  	Acetone*	n-heptane	Form II
  	CHCl3*	n-heptane	Form II
  	Cyclohexane*	n-heptane	Form II
  	Dichloromethane*	Hexane	Form II
  	Ethyl acetate*	Hexane	Form II
  	Ethanol*	Hexane	Form II
  	Isopropyl alcohol*	Hexane	Form II
  	Isopropyl acetate*	n-heptane	Form II
  	Methyl ethyl ketone*	Hexane	Forms II + III
  	4-Methyl-2-pentanone*	n-heptane	Form II
  	Methyl tert-butyl ether	Hexane	Form II
  	N-propyl alcohol*	n-heptane	Form II
  	Tetrahydrofuran	n-heptane	Form II
  	Toluene*	n-heptane	Form II
  	*Solids were obtained via evaporation at RT.

Example 8
• Slow cooling experiments were conducted in 25 solvent systems. About 50-100 mg of starting material was suspended in 0.3-0.4 mL of solvent in a 4-mL glass vial at RT. The suspension was then heated to 40° C., equilibrated for one hour and filtered using a PTFE membrane (pore size of 0.20 μm). For the systems which were still clear solution, filtration skipped. Filtrates were slowly cooled down to 5° C. within 5.5 hrs. For the systems which no solid obtained either cooling to −20° C. or evaporation at RT were employed. Results summarized in Table 10 indicated Form II, Form III, Form IV or mixture of forms were observed.

• TABLE 10
  Summary of slow cooling experiments

  	Solvent (v:v)	Solid Form
  	Isopropyl alcohol*	Form III
  	Ethanol	Form II
  	Acetonitrile*	Form III
  	Cyclohexane	Form III
  	n-Butanol*	Form III
  	Ethanol/n-Heptane (1:6)	Form III
  	Methyl ethyl ketone/n-Heptane (1:6)*	Form III
  	CHCl3/n-Heptane*	Form II
  	Isopropyl alcohol/n-Heptane (1:6)	Form III
  	Methyl tert-butyl ether/n-heptane (1:6)*	Forms II + III
  	Acetone/n-Heptane (1:6)	Form II
  	CHCl3/n-Hexane (1:6)*	Form III
  	Isopropyl alcohol/Hexane(1:6)	Form III
  	Methyl tert-butyl ether/Hexane (1:6)	Form III
  	Ethyl acetate/Hexane (1:6)	Form III
  	Isopropyl acetate/Hexane (1:6)	Form II
  	Toluene/Hexane(1:6)*	Forms II + III
  	Cyclopentyl methyl ether/Hexane (1:6)*	Form III
  	Acetonitrile/H2O (1:2)+	Gel
  	Acetone/H2O (1:2)+	—
  	Tetrahydrofuran/H2O (1:2)+	Gel
  	2-Methyltetrahydrofuran/H2O (1:6)+	Form II
  	Dioxane/H2O (1:2)+	Form III
  	Dimethylacetamide/H2O (1:2)+	Gel
  	n-Propyl alcohol/H2O (1:2)+	Gel
  	The first 18 solutions were still clear after adding about 100 mg starting material, filtration skipped.
  	*Solids were obtained via cooling to −20° C.
  	+Solids were obtained via evaporation at RT
  	—: No solid precipitated

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

Claims (76)

1. A solid state form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the solid state form is selected from the group consisting of:

a) a crystalline form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, characterized by an XRPD pattern having peaks at 2θ angles of 5.4°, 21.5°, and 22.0° ±0.2°; and

b) a crystalline form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, characterized by an XRPD pattern having peaks at 2θ angles of 19.7°, 22.0°, and 30.2° ±0.2°.

2. The solid state form of claim 1, characterized by an XRPD pattern having peaks at 2θ angles of 5.4°, 21.5°, and 22.0° ±0.2°.

3. The solid state form of claim 2, characterized by an XRPD pattern as shown in FIG. 1.

4. The solid state form of claim 2, characterized by an endothermic peak at about 59° C., as determined by DSC.

5. The solid state form of claim 2, characterized by a DSC profile as shown in FIG. 2.

6. The solid state form of claim 2, characterized by an about 2.3 wt% loss between room temperature and about 150° C., as determined by TGA.

7. The solid state form of claim 2, characterized by TGA profile as shown in FIG. 2.

8. The solid state form of claim 2, characterized by at least two of the following features (I-i)-(I-iii):

(I-i) an XRPD pattern having peaks at 2θ angles of 5.4°, 21.5°, and 22.0° ±0.2°;

(I-ii) a DSC profile as shown in FIG. 2; or

(I-iii) a TGA profile as shown in FIG. 2.

9. The solid state form of claim 2, which is Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)- propyl]-diethylamine.

10. The solid state form of any one of claims 2-9, wherein the solid state form is at least 80% pure.

11. The solid state form of any one of claims 2-10, wherein the solid state form is substantially pure.

12. A mixture comprising the solid state form of any one of claims 2-9 and a second solid state form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the solid state form is characterized by an XRPD pattern having peaks at 2θ angles of 18.8° and 20.1° ±0.2.

13. The solid state form of claim 1, characterized by an XRPD pattern having peaks at 2θ angles of 19.7°, 22.0°, and 30.2° ±0.2°.

14. The solid state form of claim 13, characterized by an XRPD pattern having peaks at 2θ angles of 5.4, 19.7°, 21.8, 22.0°, and 30.2° ±0.2°.

15. The solid state form of claim 13, characterized by an XRPD pattern as shown in FIG. cm 3.

16. The solid state form of claim 13, characterized by an endothermic peak at about 51.9° C., as determined by DSC.

17. The solid state form of claim 13, characterized by a DSC profile as shown in FIG. 4.

18. The solid state form of claim 13, characterized by an about 4.2 wt% loss between room temperature and about 150° C., as determined by TGA.

19. The solid state form of claim 13, characterized by a TGA profile as shown in FIG. 4.

20. The solid state form of claim 13, characterized by at least two of the following features (I-i)-(I-iii):

(I-i) an XRPD pattern having peaks at 2θ angles of 19.7°, 22.0°, and 30.2° ±0.2°;

(I-ii) a DSC profile as shown in FIG. 4; or

(I-iii) a TGA profile as shown in FIG. 4.

21. The solid state form of claim 13, which is Form IV.

22. The solid state form of any one of claims 13-21, wherein the solid state form is at least 80% pure.

23. The solid state form of any one of claims 13-22, wherein the solid state form is substantially pure.

24. A mixture comprising the solid state form of any one of claims 13-21 and a second solid state form of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine, wherein the solid state form is characterized by an XRPD pattern having peaks at 2θ angles of 18.8° and 20.1° ±0.2

25. A mixture comprising forms Form III and Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)- propyl]-diethylamine.

26. A method for producing solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:

a) dissolving a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent at room temperature to make a solution;

b) allowing the solution from step a) to evaporate at room temperature; and

c) collecting the solid produced from step b).

27. The method of claim 26, wherein the suitable solvent is 2-methyltetrahydrofuran or tetrahydrofuran.

28. Solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of claim 26 or 27.

29. A method for producing solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:

a) dissolving a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyI]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent at room temperature to make a solution;

b) stirring the solution from step a);

c) adding a suitable amount of a suitable anti-solvent; and

d) collecting the solid product produced from step c).

30. The method of claim 29, wherein the suitable solvent in step a) is selected from the group consisting of ethanol, n-propyl alcohol, isopropyl alcohol, 2-methyltetrahydrofuran, isopropyl acetate, and methyl ethyl ketone.

31. The method of claim 29 or 30, wherein the suitable anti-solvent is selected from the group consisting of water, hexane, and n-heptane.

32. Solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of any of claims 29-31.

33. A method for producing solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:

a) slurrying a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent system at a suitable temperature; and

b) collecting the solid produced from step a).

34. The method of claim 33, wherein the suitable solvent system is selected from the group consisting of isopropyl alcohol, ethanol, ethyl acetate, cyclopentyl methyl ether, acetone, ethanol/water, n-propyl alcohol/heptane, ethanol/hexane, methyl ethyl ketone/hexane, 4-methyl-2-pentanone/hexane, isopropyl alcohol/hexane, ethyl acetate/hexane, toluene/hexane, 2-methyltetrahydrofuran/hexane, dioxane/hexane, cyclohexane, anisole, anisole/hexane, and methyl tert-butyl ether/hexane.

35. The method of claim 33 or 34, wherein the suitable temperature is room temperature or 35° C.

36. Solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of any of claims 33-35.

37. A method for producing solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:

a) dissolving a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent system at room temperature to make a solution;

b) adding a suitable amount of a polymer mixture to the solution from step a) to make a suspension;

c) allowing the suspension of step b) to evaporate at room temperature; and

d) collecting the solid produced from step c).

38. The method of claim 37, wherein the suitable solvent system is selected from the group consisting of isopropyl alcohol, cyclohexane, ethyl acetate/hexane, acetone/hexane, isopropyl acetate/hexane, methyl ethyl ketone/hexane, and n-propyl alcohol/water.

39. The method of claim 37 or 38, wherein the polymer mixture is selected from the group consisting of polyvinylpyrrolidone/polyvinyl alcohol/polyvinyl chloride/hypromellose/methyl cellulose or poly(methyl methacrylate)/sodium alginate/hydroxyethyl cellulose.

40. Solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of any of claims 37-39.

41. A method for producing solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:

a) dissolving a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent system at room temperature to make a solution in a vessel;

b) adding a suitable amount of a volatile solvent to the vessel of step a);

c) sealing the vessel after step b);

d) maintaining the vessel at room temperature for a sufficient amount of time for the volatile solvent to interact with the solution; and

e) collecting the solid produced from step c).

42. The method of claim 41, wherein the suitable solvent system is methyl ethyl ketone and the suitable volatile solvent is hexane.

43. Solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of claim 41 or 42.

44. A method for preparing solid state form Form Ill of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:

a) suspending a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent system at room temperature to make a suspension;

b) heating the suspension from step a) to a suitable temperature and equilibrating for a suitable amount of time;

c) optionally filtering the suspension from step b);

d) slowly cooling to a suitable temperature over a suitable amount of time; and

e) collecting the solid produced from step d).

45. The method of claim 44, wherein the suitable solvent system is selected from the group consisting of isopropyl alcohol, acetonitrile, cyclohexane, n-butanol, ethanol/n-heptane, methyl ethyl ketone/n-heptane, isopropyl alcohol/n-heptane, methyl tert-butyl ether/n-heptane, trichloromethane/hexane, isopropyl alcohol/hexane, methyl tert-butyl ether/hexane, ethyl acetate/hexane, toluene/hexane, and cyclopentyl methyl ether/hexane.

46. The method of claim 44 or 45, wherein in step b), the suitable temperature is about 40° C. and the suitable amount of time is about 1 hour.

47. The method of any of claims 44-46, wherein in step d), the suitable temperature is about 5° C. and the suitable time is about 5.5 hours.

48. The method of claim 47, wherein if no solid is obtained after cooling to about 5° C., a further cooling to −20° C. step is performed.

49. The method of claim 47, wherein if no solid is obtained after cooling to about 5° C., an evaporation at room temperature step is performed.

50. Solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of any of claims 44-49.

51. A method for preparing solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:

a) adding a suitable amount of a volatile solvent to a suitable amount of solid [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a vessel;

b) sealing the vessel after step b);

c) maintaining the vessel at room temperature for a sufficient amount of time for the volatile solvent to interact with the solid [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]- diethylamine; and

d) collecting the solid form from the vessel.

52. The method of claim 51, wherein the volatile solvent is isopropyl alcohol.

53. The method of claim 50 or 51, wherein the suitable time is 5 to 10 days.

54. Solid state form Form III of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of any of claims 51-53.

55. A method for preparing solid state form Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:

a) dissolving a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent at room temperature to make a solution;

b) stirring the solution from step a);

c) adding a suitable amount of a suitable anti-solvent; and

d) collecting the solid product produced from step c).

56. The method of claim 55, wherein the suitable solvent in step a) is toluene.

57. The method of claim 55 or 56, wherein the suitable anti-solvent hexane.

58. Solid state form Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of any of claims 55-57.

59. A method for preparing solid state form Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:

a) slurrying a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent system at a suitable temperature; and

b) collecting the solid produced from step a).

60. The method of claim 59, wherein the suitable solvent system is selected from the group consisting of toluene, ethyl acetate, anisole, ethyl acetate/hexane, toluene/hexane, and ethanol/hexane.

61. The method of claim 59 or 60, wherein the suitable temperature is room temperature or 35° C.

62. Solid state form Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of any of claims 59-61.

63. A method for preparing solid state form Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:

a) dissolving a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyI]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent system at room temperature to make a solution;

b) adding a suitable amount of a polymer mixture to the solution from step a) to make a suspension;

c) allowing the suspension of step b) to evaporate at room temperature; and

d) collecting the solid produced from step c).

64. The method of claim 63, wherein the suitable solvent system is isopropyl acetate/hexane.

65. The method of claim 63 or 64, wherein the polymer mixture is poly(methyl methacrylate)/sodium alginate/hydroxyethyl cellulose.

66. Solid state form Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of any of claims 63-65.

67. A method for preparing solid state form Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1 H-imidazol-4-yl}phenoxy)- propyl]-diethylamine, comprising:

a) suspending a suitable amount of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine in a suitable amount of a suitable solvent system at room temperature to make a suspension;

b) heating the suspension from step a) to a suitable temperature and equilibrating for a suitable amount of time;

c) optionally filtering the suspension from step b);

d) slowly cooling to a suitable temperature over a suitable amount of time; and

e) collecting the solid produced from step d).

68. The method of claim 67, wherein the suitable solvent system is dioxane/water.

69. The method of claim 67 or 68, wherein in step b), the suitable temperature is about 40° C. and the suitable amount of time is about 1 hour.

70. The method of any of claims 67-69, wherein in step d), the suitable temperature is about 5° C. and the suitable time is about 5.5 hours.

71. The method of claim 70, wherein if no solid is obtained after cooling to about 5° C., a further cooling to −20° C. step is performed.

72. The method of claim 70, wherein if no solid is obtained after cooling to about 5° C., an evaporation at room temperature step is performed.

73. Solid state form Form IV of [3-(4-{2-butyl-1-[4-(4-chlorophenoxy)phenyl]-1H-imidazol-4-yl}phenoxy)-propyl]-diethylamine prepared by the method of any of claims 67-72.

74. A pharmaceutical composition comprising one or more of the solid state forms of claims 1-73 and one or more pharmaceutically acceptable carriers or diluents.

75. A method for treating Alzheimer's disease comprising administering the pharmaceutical composition of claim 74 to a patient in need thereof.

76. A method for treating Alzheimer's disease comprising administering one or more of the solid state forms of claims 1-73.

Images