Methods for preparing crystalline forms of the monosulfate salt, compositions containing same, dosage forms containing same and pharmaceutical compositions

Abstract

Methods for making crystalline forms of resiquimod and methods for using these crystalline forms are provided. [Solution] A composition is provided comprising resiquimod in the form of a sulfate salt in crystalline form A, characterized by an X-ray powder diffraction spectrum including peaks at 2θ of about 7° to about 8°, 2θ of about 13.5° to about 14.5°, 2θ of about 19° to about 20°, and / or 2θ of about 19.5° to about 20.5°.

Description

[Technical field]

[0001] The present disclosure relates to crystalline forms of pharmaceutical compounds and formulations, methods of making these crystalline forms, and methods of using these crystalline forms. Summary of the Invention [Means for solving the problem]

[0002] Described herein are novel crystalline forms of pharmaceutical compounds. In one embodiment, the pharmaceutical compounds are included in pharmaceutical compositions useful for treating a disease or condition. In one embodiment, the disease or condition is cancer.

[0003] In some embodiments, the pharmaceutical composition comprises resiquimod in the form of a sulfate salt in crystalline form A. The sulfate salt may be a monosulfate salt and / or anhydrous. This crystalline form may be prepared into a suitable dosage form.

[0004] In one embodiment, crystalline form A of the Sulfate Salt is characterized by an X-ray powder diffraction spectrum that includes peaks at about 7° to about 8° 2θ, about 13.5° to about 14.5° 2θ, about 18° to about 19° 2θ, and / or about 15° to about 16° 2θ.

[0005] Crystalline form A of the Sulfate Salt can be stable at room temperature for at least about 2 days, or at least about 1 week.

[0006] Other embodiments describe pharmaceutical compositions comprising a crystalline form of the compound of formula I.

[0007] [ka]

[0008] Formula I may be a compound having the formula: 4-amino-α-butyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]-quinoline-2-methanol hemihydrate, 4-amino-α,α-dimethyl-2-ethoxymethyl-1H-imidazo-[4,5-c]-quinoline-1-ethanol, 2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]-quinolin-4-amine, or 4-amino-1-phenylmethyl-1H-imidazo-[4,5-c]-quinoline-2-methanol. In one embodiment, Formula I is resiquimod.

[0009] In some embodiments, the crystalline form of the compound of Formula I can be Form A and / or the sulfate salt. In one embodiment, the sulfate salt is the monosulfate salt and / or the anhydrate.

[0010] Other embodiments provide methods of treating a disease or condition. In one embodiment, a method of treating cancer is described. The method may include administering a pharmaceutical composition comprising a crystalline form of a compound having formula I.

[0011] [ka] [Brief description of the drawings]

[0012] [Figure 1] 1 shows the XRPD pattern of a batch of crystalline form A of the monohydrochloride salt. [Diagram 2] 1 shows a PLM image of crystalline form type A of the monohydrochloride salt (807919-16-A). [Diagram 3] 1 shows the TGA / DSC curve of crystalline form A of the monohydrochloride salt (807919-16-A). [Figure 4] 1 shows the XRPD pattern of crystalline form A of the dihydrochloride salt (807919-14-A). [Diagram 5] 1 shows a PLM image of crystalline form A of the dihydrochloride salt (807919-14-A). [Figure 6]1 shows the TGA / DSC curve of crystalline form A of the dihydrochloride salt (807919-14-A). [Figure 7] 1 shows the XRPD pattern of a batch of crystalline Form A of the Sulfate Salt. [Figure 8] 1 shows a PLM image of crystalline form type A of the sulfate salt (807919-11-A). [Figure 9] 1 shows the TGA / DSC curve of crystalline form A of the sulfate salt (807919-11-A). [Figure 10] 1 shows the XRPD pattern of a batch of crystalline Form A of the Phosphate Salt. [Figure 11] 1 shows a PLM image of crystalline form type A of the phosphate salt (807919-11-C). [Figure 12] 1 shows the TGA / DSC curve of crystalline form A of the phosphate salt (807919-11-C). [Figure 13] 1 shows the XRPD pattern of a batch of crystalline Form A of the Maleate Salt. [Figure 14] 1 shows a PLM image of crystalline form A of the maleate salt (807919-11-B). [Figure 15] 1 shows the TGA / DSC curve of crystalline form A of the maleate salt (807919-11-B). [Figure 16] 1 shows the XRPD pattern of a batch of crystalline Form A of the Malate Salt. [Figure 17] FIG. 1 shows a PLM image of crystalline form A of the malate salt (807919-11-E). [Figure 18] 1 shows the TGA / DSC curve of crystalline form A of the malate salt (807919-11-E). [Figure 19] 1 shows the XRPD pattern of a batch of crystalline form A of the adipate salt. [Figure 20] FIG. 1 shows a PLM image of crystalline form type A of the adipate salt (807919-12-A). [Figure 21] 1 shows the TGA / DSC curve of crystalline form A of the adipate salt (807919-12-A). [Figure 22] 1 shows a DVS plot of crystalline form A of the Sulfate Salt (807919-11-A). [Diagram 23] 1 shows an XRPD overlay of pre- and post-DVS testing of crystalline Form A of the Sulfate Salt (807919-11-A). [Figure 24] 1 shows a DVS plot of crystalline form A of the phosphate salt (807919-11-C). [Diagram 25] 1 shows an XRPD overlay of pre- and post-DVS testing of crystalline Form A of the Phosphate Salt (807919-11-C). [Figure 26] 1 shows a DVS plot of crystalline form A of the maleate salt (807919-11-B). [Figure 27] 1 shows an XRPD overlay of pre- and post-DVS testing of crystalline Form A of the maleate salt (807919-11-B). [Figure 28] 1 shows a DVS plot of crystalline form A of the Malate Salt (807919-11-E). [Figure 29] 1 shows an XRPD overlay of pre- and post-DVS testing of crystalline Form A of the Malate Salt (807919-11-E). [Diagram 30] 1 shows a DVS plot of crystalline form A of the adipate salt (807919-12-A). [Diagram 31] 1 shows an XRPD overlay of pre- and post-DVS testing of crystalline form A of the adipate salt (807919-12-A). [Diagram 32] 1 shows a DVS plot of crystalline form A of the monohydrochloride salt (807919-16-A). [Diagram 33] 1 shows an XRPD overlay of pre- and post-DVS testing of crystalline form A of the monohydrochloride salt (807919-16-A). [Diagram 34] 1 shows a DVS plot of crystalline form A of the dihydrochloride salt (807919-14-A). [Diagram 35] 1 shows an XRPD overlay of pre- and post-DVS testing of crystalline form A of the dihydrochloride salt (807919-14-A). [Diagram 36]4 shows the kinetic solubility of the seven crystalline forms described in this application and the crystalline form of the free base (short lines: clear solutions were observed during the evaluation). [Figure 37] 1 shows an XRPD overlay of crystalline form A of the free base (807919-05-A) after suspension for 24 hours. [Figure 38] 1 shows an XRPD overlay of crystalline form A of the adipate salt (807919-12-A) after 24 hours of suspension. [Figure 39] 1 shows an XRPD overlay of crystalline form A of the maleate salt (807919-11-B) after 24 hours of suspension. [Diagram 40] 1 shows an XRPD overlay of crystalline form A of the free base (807919-05-A) and after stability testing. [Diagram 41] 1 shows an XRPD overlay of pre- and post-stability testing of crystalline form A of the monohydrochloride salt (807919-16-A). [Diagram 42] 1 shows an XRPD overlay of pre- and post-stability testing of crystalline form A of the dihydrochloride salt (807919-14-A). [Diagram 43] 1 shows an XRPD overlay of pre- and post-stability testing of crystalline Form A of the Sulfate Salt (807919-11-A). [Diagram 44] 1 shows an XRPD overlay of pre- and post-stability testing of crystalline Form A of the Phosphate Salt (807919-11-C). [Diagram 45] 1 shows an XRPD overlay of pre- and post-stability testing of crystalline Form A of the maleate salt (807919-11-B). [Figure 46] 1 shows an XRPD overlay of pre- and post-stability testing of crystalline Form A of the Malate Salt (807919-11-E). [Figure 47] 1 shows an XRPD overlay of pre- and post-stability testing of crystalline form A of the adipate salt (807919-12-A). [Figure 48] 1 shows the XRPD pattern of crystalline form B of the Sulfate Salt (807919-25-A13). [Figure 49]1 shows the TGA / DSC curve of the crystalline form B of the sulfate salt (807919-25-A13). [Figure 50] 1 shows the XRPD pattern of crystalline form A of the hemisulfate salt (807919-34-A). [Figure 51] 1 shows the TGA / DSC curve of crystalline form A of the hemisulfate salt (807919-34-A). [Figure 52] 1 shows an XRPD overlay of a slurry experiment at room temperature. [Figure 53] 1 shows an XRPD overlay of crystalline form A of the Sulfate Salt (807919-21-A) before and after storage. [Figure 54] 1 shows the XRPD pattern of crystalline form A of the free base (807919-05-A). [Figure 55] 1 shows a PLM image of crystalline form A of the free base (807919-05-A). [Figure 56] 1 shows the TGA / DSC curve of crystalline form A of the free base (807919-05-A). [Figure 57] 1 shows a DVS plot of crystalline form A of the free base (807919-05-A). [Figure 58] 1 shows an XRPD overlay of pre- and post-DVS testing of crystalline form A of the free base (807919-05-A). [Figure 59] 1 shows the XRPD pattern of a batch of crystalline Form A of the Sulfate Salt. [Figure 60] 1 shows the TGA / DSC curve of crystalline form A of the sulfate salt (807919-21-A). [Figure 61] 1 shows the XRPD pattern of the crystalline form of the hydrochloride salt. [Figure 62] 1 shows the TGA / DSC curve of crystalline form B of the hydrochloride salt (807919-07-C2). [Figure 63] 1 shows the XRPD pattern of crystalline form A of the Sulfate Salt (807919-07-A3). [Figure 64] 1 shows the TGA / DSC curve of crystalline form A of the sulfate salt (807919-07-A3). [Figure 65]1 shows the XRPD pattern of crystalline form A of the Phosphate Salt (807919-07-E5). [Figure 66] 1 shows the TGA / DSC curve of crystalline form A of the phosphate salt (807919-07-E5). [Figure 67] 1 shows the XRPD pattern of crystalline form A of the glycolate salt (807919-07-B9). [Figure 68] 1 shows the TGA / DSC curve of crystalline form A of the glycolate salt (807919-07-B9). [Figure 69] 1 shows the XRPD pattern of crystalline form A of the maleate salt (807919-07-D4). [Figure 70] 1 shows the TGA / DSC curve of crystalline form A of the maleate salt (807919-07-D4). [Figure 71] 1 shows the XRPD pattern of crystalline form A of the Malate Salt (807919-07-B10). [Figure 72] 1 shows the TGA / DSC curve of crystalline form A of the malate salt (807919-07-B10). [Figure 73] 1 shows the XRPD pattern of crystalline form A of the adipate salt (807919-07-B14). [Figure 74] 1 shows the TGA / DSC curve of crystalline form A of the adipate salt (807919-07-B14). [Figure 75] 1 shows the XRPD pattern of crystalline form A of the hippurate salt (807919-07-B11). [Figure 76] 1 shows the TGA / DSC curve of crystalline form A of hippurate salt (807919-07-B11). [Figure 77] 1 shows the XRPD pattern of crystalline form A of the tartrate salt (807919-07-A6). [Figure 78] 1 shows the XRPD pattern of crystalline form B of the tartrate salt (807919-07-E6). [Figure 79] 1 shows the XRPD pattern of crystalline form C of the tartrate salt (807919-07-B6). [Figure 80]1 shows the TGA / DSC curve of crystalline form A of the tartrate salt (807919-07-A6). [Figure 81] 1 shows the TGA / DSC curve of crystalline form B of the tartrate salt (807919-07-E6). [Figure 82] 1 shows the TGA / DSC curve of crystalline form C of the tartrate salt (807919-07-B6). [Figure 83] 1 shows the XRPD pattern of crystalline form A of the fumarate salt (807919-07-A7). [Figure 84] 1 shows the XRPD pattern of crystalline form B of the fumarate salt (807919-07-E7). [Figure 85] 1 shows the XRPD pattern of crystalline form C of the fumarate salt (807919-07-C7). [Figure 86] 1 shows the TGA / DSC curve of crystalline form A of the fumarate salt (807919-07-A7). [Figure 87] 1 shows the TGA / DSC curve of crystalline form B of the fumarate salt (807919-07-E7). [Figure 88] 1 shows the TGA / DSC curve of crystalline form C of the fumarate salt (807919-07-C7). [Figure 89] 1 shows the XRPD pattern of crystalline form A of the Citrate Salt (807919-07-A8). [Figure 90] 1 shows the XRPD pattern of crystalline form B of the Citrate Salt (807919-07-B8). [Figure 91] 1 shows the TGA / DSC curve of crystalline form A of the Citrate Salt (807919-07-A8). [Figure 92] 1 shows the TGA / DSC curve of crystalline form B of the Citrate Salt (807919-07-B8). [Figure 93] 1 shows the XRPD pattern of crystalline form A of the Lactate Salt (807919-07-C12). [Figure 94] 1 shows the XRPD pattern of crystalline form B of the lactate salt (807919-07-A12). [Figure 95]1 shows the TGA / DSC curve of crystalline form A of the lactate salt (807919-07-C12). [Figure 96] 1 shows the TGA / DSC curve of crystalline form B of the lactate salt (807919-07-A12). [Figure 97] 1 shows the XRPD pattern of crystalline form A of the succinate salt (807919-07-C13). [Figure 98] 1 shows the XRPD pattern of crystalline form B of the succinate salt (807919-07-E13). [Figure 99] 1 shows the TGA / DSC curve of crystalline form A of the succinate salt (807919-07-C13). [Figure 100] 1 shows the TGA / DSC curve of crystalline form B of the succinate salt (807919-07-E13). [Figure 101] 1 shows the XRPD pattern of crystalline form A of the tosylate salt (807919-07-B15). [Figure 102] 1 shows the XRPD pattern of crystalline form B of the tosylate salt (807919-07-D15). [Figure 103] 1 shows the TGA / DSC curve of crystalline form A of the tosylate salt (807919-07-B15). [Figure 104] 1 shows the TGA / DSC curve of the crystalline form B of the tosylate salt (807919-07-D15). [Figure 105] 1 shows the XRPD pattern of crystalline form A of the mesylate salt (807919-07-A16). [Fig. 106] 1 shows the TGA / DSC curve of crystalline form A of the mesylate salt (807919-07-A16). [Figure 107] 1 shows the XRPD pattern of crystalline form A of the Oxalate Salt (807919-07-B17). [Figure 108] 1 shows the XRPD pattern of crystalline form B of the oxalate salt (807919-07-D17). [Fig. 109] 1 shows the TGA / DSC curve of crystalline form A of the oxalate salt (807919-07-B17). [Figure 110]1 shows the TGA / DSC curve of crystalline form B of the oxalate salt (807919-07-D17). [Figure 111] 1 shows the XRPD pattern of crystalline form A of the gentisate salt (807919-07-A18). [Figure 112] 1 shows the XRPD pattern of crystalline form B of gentisate salt (807919-07-E18). [Figure 113] 1 shows the TGA / DSC curve of crystalline form A of gentisate salt (807919-07-A18). [Fig. 114] 1 shows the TGA / DSC curve of crystalline form B of gentisate salt (807919-07-E18). [Figure 115] 1 shows the XRPD pattern of crystalline form A of the Benzoate salt (807919-07-A19). [Fig. 116] 1 shows the XRPD pattern of crystalline form B of the Benzoate salt (807919-07-E19). [Figure 117] 1 shows the TGA / DSC curve of crystalline form A of the benzoate salt (807919-07-A19). [Figure 118] 1 shows the TGA / DSC curve of crystalline form B of the benzoate salt (807919-07-E19). [Figure 119] 1 shows the XRPD pattern of crystalline form A of the Nitrate Salt (807919-07-D20). [Figure 120] 1 shows the XRPD pattern of crystalline form B of the Nitrate Salt (807919-07-B20). [Figure 121] 1 shows the TGA / DSC curve of crystalline form A of the nitrate salt (807919-07-D20). [Figure 122] 1 shows the TGA / DSC curve of the crystalline form B of the nitrate salt (807919-07-B20). [Figure 123] 1 shows the interconversion of crystalline forms of the free base. [Figure 124] 1 shows the XRPD pattern of crystalline form A (807920-05-A). [Fig. 125] 1 shows the TGA / DSC curve of crystalline morphology type A (807920-05-A). [Fig. 126] FIG. 1 shows the XRPD pattern of crystalline form C (807920-11-A11). [Figure 127] FIG. 1 shows the XRPD pattern of crystalline form F (807920-09-A4). [Figure 128] The XRPD pattern of isomorph Form B is shown. [Figure 129] FIG. 2 shows the TGA / DSC curve of the first batch of crystalline morphology B (807920-07-A13). [Fig. 130] FIG. 1 shows the TGA / DSC curve of the second batch of crystalline morphology type B (807920-07-A13). [Fig. 131] 1 shows the TGA / DSC curve of the third batch of crystalline morphology B (807920-07-A13). [Fig. 132] 1 shows the XRPD pattern of crystalline form D (807920-12-A9). [Fig. 133] FIG. 2 shows the TGA / DSC curve of crystalline morphology type D (807920-12-A9). [Fig. 134] Figure 2 shows the XRPD pattern of crystalline form E (807920-16-A3). [Fig. 135] 1 shows the TGA / DSC curve of crystalline form E (807920-16-A3). [Fig. 136] 1 shows the XRPD pattern of crystalline form G (807920-19-F). [Fig. 137] 1 shows the TGA / DSC curve of crystalline form G (807920-19-F). [Figure 138] The XRPD pattern of sample H (807920-22-A1) is shown. [Figure 139] The TGA / DSC curve of sample H (807920-22-A1) is shown. [Fig. 140] 1 shows the DVS plot of crystalline form A (807919-05-A). [Fig. 141] 1 shows an XRPD overlay of pre- and post-DVS testing of crystalline form A (807919-05-A). [Fig. 142]1 shows an XRPD overlay of pre- and post-stability testing of crystalline form A (807919-05-A). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Described herein are new crystalline forms of chemical compounds, formulations containing these crystalline forms, methods of making these crystalline forms, and methods of using these crystalline forms. In some embodiments, these new crystalline forms are referred to as polymorphs or isomorphs. Polymorphism of pharmaceuticals can have direct effects on the delivery of a given pharmacologic active agent, ingredient, or drug species. The polymorphic purity of a sample may be confirmed using techniques such as powder X-ray diffraction and IR / Raman spectroscopy, as well as by taking advantage of the differences in their optical properties.

[0014] Generally, active pharmaceutical ingredients (APIs) in pharmaceutical compositions can be prepared in a variety of different forms, including prodrugs, amorphous forms, solvates, hydrates, cocrystals, salts, etc. Discovery of new API forms may provide an opportunity to improve the performance characteristics of pharmaceutical compositions. In addition, discovery of drug forms opens up a number of possibilities for designing pharmaceutical dosage forms with targeted release or other desired properties.

[0015] Specific properties that can be targeted include the crystalline form of the API. Altering the crystalline form of a given API can result in changes in the targeted physical properties of the molecule. For example, various polymorphs of a given API may exhibit different solubilities, while a thermodynamically stable polymorph will exhibit lower solubility than a metastable polymorph. In addition, polymorphs of a pharmaceutical agent may differ in properties such as dissolution rate, shelf life, bioavailability, morphology, vapor pressure, density, color, and compressibility. Thus, for example, crystals, cocrystals, salts, solvates or hydrates with respect to aqueous solubility, dissolution rate, bioavailability, C max , T maxIt may be desirable to enhance the properties of an API by forming a molecular complex, for example, to improve physicochemical stability, processability in downstream manufacturing steps (e.g., flowability, compressibility, degree of friability, particle size manipulation), reduction in polymorphic form diversity, toxicity, taste, production costs, manufacturing process, or a combination thereof.

[0016] Disclosed are novel crystalline forms of compounds, and pharmaceutical compositions comprising these novel crystalline forms of compounds, which may be compounds having the structure of Formula I, or a pharma- ceutically acceptable salt thereof.

[0017] [ka]

[0018] In the formula, R 1 is hydrogen; substituted or unsubstituted C1-C 10 linear or branched alkyl, the substituent being C3-C6 cycloalkyl or C3-C6 cycloalkyl substituted with linear or branched C1-C4 alkyl; 10 Alkenyl; substituted straight or branched C2-C 10alkenyl, wherein the substituent is C3-C6 cycloalkyl or C3-C6 cycloalkyl substituted with straight or branched chain C1-C4 alkyl; C1-C6 hydroxyalkyl; alkoxyalkyl, wherein the alkoxy moiety contains from 1 to about 4 carbon atoms and the alkyl moiety contains from 1 to about 6 carbon atoms; acyloxyalkyl, wherein the acyloxy moiety is alkanoyloxy or benzoyloxy of 2 to about 4 carbon atoms and the alkyl moiety contains from 1 to about 6 carbon atoms; or benzyl; (phenyl)ethyl; or phenyl, wherein the benzyl, (phenyl)ethyl, or phenyl substituent is optionally substituted on the benzene ring with one or two moieties independently selected from C1-C4 alkyl, C1-C4 alkoxy, or halogen, with the proviso that when the benzene ring is substituted with two moieties, the two moieties contain a total of 6 or fewer carbon atoms; R 2 and R 3 is independently selected from hydrogen, C1-C4 alkyl, phenyl, or substituted phenyl, wherein the substituents are C1-C4 alkyl, C1-C4 alkoxy, or halogen; X is C1-C4 alkoxy, alkoxyalkyl where the alkoxy moiety contains 1 to about 4 carbon atoms and the alkyl moiety contains 1 to about 4 carbon atoms, alkoxyalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, alkylamido where the alkyl group contains 1 to about 4 carbon atoms, alkylamido, amino, substituted amino where the substituent is C1-C4 alkyl or C1-C4 hydroxyalkyl, amino, azido, chloro, hydroxy, 1-morpholino, 1-pyrrolidino, or C1-C4 alkylthio; and R is hydrogen, straight or branched chain C1-C4 alkoxy, halogen, or straight or branched chain C1-C4 alkyl.

[0019] In some embodiments, the crystalline form of the compound having the structure of Formula I is the hydrochloride, sulfate, phosphate, maleate, malate, adipate, glycolate, hippurate, tartrate, fumarate, citrate, lactate, succinate, tosylate, mesylate, oxalate, gentisate, benzoate, or nitrate salt of crystalline form A, B, C, D, E, F, or G.

[0020] In some embodiments, R 1 may contain from 2 to about 10 carbon atoms. In other embodiments, R 1 may contain from 2 to about 8 carbon atoms. In yet other embodiments, R 1 is 2-methylpropyl or benzyl.

[0021] In some embodiments, X may be azido, hydroxy, ethoxy, methoxy, 1-monofolino, or methylthio. 1 When is 2-methylpropyl, 2-hydroxy-2-methylpropyl or benzyl, X may be azio, hydroxy, ethoxy, methoxy, 1-monofolino or methylthio.

[0022] Other substituents in compounds of formula I that contain alkyl radicals (e.g., R when R is alkoxy or alkyl, or X when X is alkylamido) may contain two carbon atoms or, in some embodiments, one carbon atom in each alkyl radical.

[0023] In some embodiments, R is hydrogen.

[0024] Compounds of formula I may include 4-amino-α-butyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]-quinoline-2-methanol hemihydrate, 4-amino-α,α-dimethyl-2-ethoxymethyl-1H-imidazo-[4,5-c]-quinoline-1-ethanol, 2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]-quinolin-4-amine, and 4-amino-1-phenylmethyl-1H-imidazo-[4,5-c]-quinoline-2-methanol.

[0025] In one embodiment, the compound of formula I can be resiquimod (1-[4-amino-2-(ethoxymethyl)imidazo-[4,5-c]-quinolin-1-yl]-2-methylpropan-2-ol). Resiquimod has the structure [ka] may have the following structure:

[0026] The halogen or halo groups in any of the compounds described herein may be F, Cl, Br, I, or At. In some embodiments, the halogen or halo groups in any of the compounds described herein may be F, Cl, Br, or I.

[0027] These new crystalline forms of the compound of formula I may be the hydrochloride, sulfate, phosphate, maleate, malate, adipate, glycolate, hippurate, tartrate, fumarate, citrate, lactate, succinate, tosylate, mesylate, oxalate, gentisate, benzoate or nitrate salts of crystalline forms A, B, C, D, E, F or G.

[0028] One embodiment includes resiquimod in the form of the monosulfate salt in crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum comprising peaks at about 7° to about 8° 2θ, about 13.5° to about 14.5° 2θ, about 19° to about 20° 2θ, and / or about 19.5° to about 20.5° 2θ.

[0029] Other embodiments include resiquimod in the form of a sulfate salt in crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum including peaks at 2θ between about 7° and about 8°, 2θ between about 9° and about 10°, 2θ between about 11° and about 12°, 2θ between about 14° and about 14.5°, 2θ between about 15° and about 16°, 2θ between about 17° and about 20°, and / or 2θ between about 24° and about 26°. Resiquimod may also be formed as a sulfate salt in crystalline form A characterized by an X-ray powder diffraction spectrum including peaks at 2θ of about 7° to about 8°, 2θ of about 11.5° to about 12°, 2θ of about 14° to about 14.5°, 2θ of about 16° to about 16°, 2θ of about 17° to about 18.5°, 2θ of about 19.5° to about 20.5°, and / or 2θ of about 24° to about 25°.

[0030] Resiquimod may be formed as a sulfate salt in crystalline form B. Such crystalline form B may be characterized by an X-ray powder diffraction spectrum comprising peaks at about 7° to about 8° 2θ, about 9° to about 10° 2θ, and / or about 19° to about 20.5° 2θ.

[0031] Resiquimod may also be formed as a hemisulfate salt in crystalline form A. Such a crystalline form may be characterized by an X-ray powder diffraction spectrum that includes peaks at about 6° to about 6.5° 2θ, about 7° to about 8° 2θ, about 8° to about 9° 2θ, about 11° to about 12° 2θ, about 12.5° to about 13° 2θ, about 15° to about 15.5° 2θ, about 16° to about 17° 2θ, about 19° to about 19.5° 2θ, about 21° to about 21.5° 2θ, and / or about 23° to about 24° 2θ.

[0032] Other compounds of resiquimod may be formed in acetate / acetic acid co-crystals of the free base form of resiquimod. Such crystalline forms may be characterized by an X-ray powder diffraction spectrum that includes peaks at about 6° to about 7° 2θ, about 9° to about 10.5° 2θ, about 11° to about 12° 2θ, about 18° to about 19° 2θ, about 19° to about 20° 2θ, about 20.5° to about 21° 2θ, about 22° to about 23° 2θ, and / or about 25° to about 26° 2θ.

[0033] The Sulfate Salt may also be provided in crystalline forms C, D, E, F, G, and H. Form C of the Sulfate Salt may be interconverted to form A by storage at ambient temperature, e.g., overnight. Form D of the Sulfate Salt may be interconverted to form A by heating, e.g., to 100° C. Form E of the Sulfate Salt may be interconverted to form A by heating, e.g., to 120° C. Form F of the Sulfate Salt may be interconverted to form A by storage at ambient temperature, e.g., for 2 days. Form G of the Sulfate Salt may be interconverted to form A by heating, e.g., to 80° C. Since each metastable form and solvate interconverts to form A, in some embodiments, form A is the thermodynamically stable form at room temperature.

[0034] Resiquimod may be formed as a sulfate salt of the anhydrate (Form A). Such a crystalline form may be characterized by an X-ray powder diffraction spectrum that includes peaks at 2θ of about 8.5° to about 9°, 2θ of about 12° to about 13°, 2θ of about 16° to about 17°, 2θ of about 17.5° to about 18°, 2θ of about 19° to about 20.5°, 2θ of about 21° to about 22°, 2θ of about 23° to about 24°, and / or 2θ of about 29° to about 30°.

[0035] Resiquimod may be formed as a sulfate salt of a solvate (Form B). Such crystalline forms may be characterized by an X-ray powder diffraction spectrum that includes peaks at about 6° to about 6.5° 2θ, about 12° to about 12.5° 2θ, about 16° to about 16.5° 2θ, about 21° to about 22.5° 2θ, and / or about 24.5° to about 25° 2θ.

[0036] Resiquimod may be formed as sulfate Form C. Such a crystalline form may be characterized by an X-ray powder diffraction spectrum that includes peaks at about 9° to about 10° 2θ, about 12° to about 12.5° 2θ, about 14° to about 15° 2θ, about 18° to about 19° 2θ, about 19° to about 21.5° 2θ, and / or about 28° to about 29° 2θ.

[0037] Resiquimod may be formed as a sulfate salt of a DMAc solvate (Form D). Such a crystalline form may be characterized by an X-ray powder diffraction spectrum that includes peaks at about 8° to about 9° 2θ, about 11° to about 11.5° 2θ, about 16.5° to about 17° 2θ, about 17.5° to about 18° 2θ, about 21° to about 21.5° 2θ, about 22.5° to about 23° 2θ, and / or about 23.5° to about 24.5° 2θ.

[0038] Resiquimod may be formed as a sulfate salt of an NMP solvate (Form E). Such a crystalline form may be characterized by an X-ray powder diffraction spectrum that includes peaks at 2θ of about 8° to about 9°, 2θ of about 9° to about 9.5°, 2θ of about 11° to about 11.5°, 2θ of about 12° to about 13°, 2θ of about 16.5° to about 18°, 2θ of about 21° to about 21.5°, 2θ of about 22.5° to about 23°, and / or 2θ of about 23.5° to about 24°.

[0039] Resiquimod may be formed as sulfate Form F. Such a crystalline form may be characterized by an X-ray powder diffraction spectrum that includes peaks at 2θ of about 8° to about 8.5°, 2θ of about 10° to about 11°, 2θ of about 12° to about 13°, 2θ of about 16° to about 17°, 2θ of about 17° to about 18°, 2θ of about 20.5° to about 21.5°, 2θ of about 24.5° to about 25°, and / or 2θ of about 28.5° to about 29°.

[0040] Resiquimod may be formed as a sulfate salt of anisole solvate (Form G). Such a crystalline form may be characterized by an X-ray powder diffraction spectrum comprising peaks at about 8.5° to about 9° 2θ, about 9.5° to about 10° 2θ, about 13° to about 14° 2θ, about 19° to about 19.5° 2θ, and / or about 27.5° to about 28.5° 2θ.

[0041] Other compounds of formula I described in this application may be formed into similar salt structures.

[0042] The crystalline form of the compound of formula I may be Form A, Form B, Form C, Form D, Form E, Form F, Form G, and / or Form H. In some embodiments, the form may be Form A: anhydrous, Form B: solvate, Form C: metastable, Form D: dimethylacetamide (DMAc) solvate, Form E: N-methyl-2-pyrrolidone (NMP) solvate, Form F: metastable, Form G: anisole solvate, and Form H: acetate / acetic acid co-crystal.

[0043] Additionally, other compounds of formula I described herein may be formed as a sulfate salt in crystalline form B. The sulfate salt in crystalline form B may be a dimethylsulfoxide (DMSO) solvate. Additionally, other compounds of formula I described herein may be formed as a hemisulfate salt in crystalline form A.

[0044] In some embodiments, Form A can be stable at room temperature for at least about 1 day, at least about 2 days, at least about 3 days, at least about 1 week, at least about 2 weeks, at least about 1 month, at least about 6 months, or at least about 1 year.

[0045] Additionally, other compounds of formula I described herein may be formed as hydrochloride, sulfate, phosphate, maleate, malate, adipate salts, or combinations thereof. In some embodiments, the salts may be formed in the form or form A.

[0046] In one embodiment, the compound of formula I described herein may be formed as the monohydrochloride salt in crystalline form A. In one embodiment, the compound of formula I described herein may be formed as the dihydrochloride salt in crystalline form A. Either form of the hydrochloride salt may be formed as an anhydrate.

[0047] In one embodiment, the present invention comprises resiquimod in the form of a hydrochloride salt having crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum that includes peaks at 2θ from about 6° to about 7°, 2θ from about 9° to about 10°, 2θ from about 12° to about 13°, 2θ from about 14° to about 16°, 2θ from about 18° to about 23°, 2θ from about 23° to about 25°, 2θ from about 26° to about 27.5°, and / or 2θ from about 26° to about 27.5°.

[0048] Other embodiments include resiquimod in the form of the hydrochloride salt in crystalline form B. Crystalline form B may be characterized by an X-ray powder diffraction spectrum that includes peaks at 2θ from about 6° to about 8°, 2θ from about 19° to about 21°, 2θ from about 23° to about 24.5°, 2θ from about 26° to about 27°, and / or 2θ from about 28° to about 29°.

[0049] Other embodiments include resiquimod in the form of the monohydrochloride salt in crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum including peaks at 2θ from about 6° to about 7°, 2θ from about 9° to about 10°, 2θ from about 13° to about 14°, 2θ from about 17° to about 18°, 2θ from about 20° to about 21°, 2θ from about 27° to about 28°, and / or 2θ from about 34° to about 35°.

[0050] Other embodiments include resiquimod in the form of a dihydrochloride salt in crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum that includes peaks at 2θ from about 7° to about 8°, 2θ from about 8° to about 9°, 2θ from about 14° to about 15°, 2θ from about 15° to about 16°, 2θ from about 19° to about 20°, 2θ from about 25° to about 26°, and / or 2θ from about 26.5° to about 27.5°.

[0051] In one embodiment, the compound of formula I described herein may be formed as an anhydrous phosphoric acid salt in crystalline form A.

[0052] Other embodiments include resiquimod in the form of a phosphate salt having crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum that includes peaks at 2θ between about 7° and about 8°, at 2θ between about 10° and about 14.5°, at 2θ between about 15° and about 16°, at 2θ between about 20° and about 21°, and / or at 2θ between about 25° and about 26°. Other embodiments include resiquimod in the form of a phosphate salt having crystalline form A that is characterized by an X-ray powder diffraction spectrum that includes peaks at 2θ between about 7° and about 8.5°, at 2θ between about 10° and about 15.5°, at 2θ between about 16° and about 18.5°, at 2θ between about 19° and about 21°, at 2θ between about 22° and about 23°, at 2θ between about 23° and about 27°, and / or at 2θ between about 28° and about 29°.

[0053] In one embodiment, the compound of formula I described herein may be formulated as the anhydrous maleate salt in crystalline form A. In another embodiment, the compound of formula I described herein may be formulated as the anhydrous monomaleate salt in crystalline form A.

[0054] Other embodiments include resiquimod in the form of a maleate salt having crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum including peaks at 2θ between about 7° and about 8°, 2θ between about 9° and about 10°, 2θ between about 10° and about 11°, 2θ between about 15° and about 17°, 2θ between about 20° and about 21°, 2θ between about 21° and about 22°, 2θ between about 27° and about 28°, and / or 2θ between about 30° and about 31°. Other embodiments include resiquimod in the form of a maleate salt in crystalline form A characterized by an X-ray powder diffraction spectrum including peaks at 2θ of about 7° to about 8°, 2θ of about 9° to about 10°, 2θ of about 10° to about 11°, 2θ of about 11° to about 12°, 2θ of about 15° to about 16.5°, 2θ of about 17° to about 19°, 2θ of about 20° to about 21°, 2θ of about 21° to about 22°, 2θ of about 24° to about 25°, 2θ of about 27° to about 28°, and / or 2θ of about 30° to about 31°.

[0055] In one embodiment, the compound of formula I described herein may be formed as the anhydrous malate salt in crystalline form A.

[0056] Other embodiments include resiquimod in the form of a malate salt of crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum that includes peaks at about 6° to about 7° 2θ, about 8° to about 9° 2θ, about 13° to about 14° 2θ, about 17° to about 18° 2θ, and / or about 24° to about 25.5° 2θ. Other embodiments include resiquimod in the form of a malate salt of crystalline form A that is characterized by an X-ray powder diffraction spectrum that includes peaks at about 6° to about 7° 2θ, about 8° to about 9° 2θ, about 17° to about 18° 2θ, about 21.5° to about 23.5° 2θ, and / or about 25° to about 26° 2θ.

[0057] In one embodiment, the compound of formula I described herein may be formed as the anhydrous adipate salt in crystalline form A.

[0058] Other embodiments include resiquimod in the form of an adipate salt of crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum that includes peaks at 2θ from about 5.5° to about 6°, 2θ from about 11° to about 12°, 2θ from about 12° to about 13°, 2θ from about 13° to about 14°, 2θ from about 14° to about 15°, 2θ from about 18° to about 19°, 2θ from about 19° to about 20°, 2θ from about 21° to about 22°, 2θ from about 22° to about 23°, and / or 2θ from about 25° to about 28°. Other embodiments include resiquimod in the form of an adipate salt in crystalline form A, characterized by an X-ray powder diffraction spectrum including peaks at about 5° to about 6.5° 2θ, about 9° to about 11° 2θ, about 12° to about 13.5° 2θ, about 14° to about 15.5° 2θ, about 17° to about 18° 2θ, about 18° to about 19° 2θ, about 19.5° to about 22° 2θ, about 22° to about 25° 2θ, and / or about 26° to about 27.5° 2θ.

[0059] The compound of formula I may be formulated as a glycolic acid salt. In one embodiment, the compound of formula I described herein may be formulated as a glycolic acid salt in crystalline form A.

[0060] In one embodiment, resiquimod is in the form of the glycolic acid salt in crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum that includes peaks at 2θ from about 9° to about 10°, 2θ from about 11.5° to about 12.5°, 2θ from about 18° to about 19°, 2θ from about 19.5° to about 23°, 2θ from about 25° to about 26.5°, and / or 2θ from about 32° to about 33°.

[0061] The compound of formula I may also be formulated as a hippurate salt. In one embodiment, the compound of formula I described herein may also be formulated as a hippurate salt in crystalline form A.

[0062] In one embodiment, resiquimod is in the form of a hippurate salt in crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum that includes peaks at about 5.5° to about 6.5° 2θ, about 9° to about 10° 2θ, about 11.5° to about 12.5° 2θ, about 18.5° to about 19.5° 2θ, about 21° to about 22° 2θ, and / or about 25° to about 26° 2θ.

[0063] The compounds of formula I may also be formed as tartrate salts. In other embodiments, the compounds of formula I described herein may also be formed as tartrate salts in crystalline forms A, B and / or C.

[0064] One embodiment includes resiquimod in the form of a tartrate salt in crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum comprising peaks at about 6° to about 7° 2θ, about 9° to about 10° 2θ, about 18° to about 19° 2θ, about 20° to about 22° 2θ, and / or about 25° to about 26° 2θ.

[0065] One embodiment includes resiquimod in the form of a tartrate salt in crystalline form B. Crystalline form B may be characterized by an X-ray powder diffraction spectrum comprising peaks at about 8.5° to about 9° 2θ, about 11° to about 12° 2θ, about 13° to about 14° 2θ, about 14° to about 15° 2θ, about 16° to about 17° 2θ, and / or about 23° to about 24.5° 2θ.

[0066] One embodiment includes resiquimod in the form of a tartrate salt in crystalline form C. Crystalline form C may be characterized by an X-ray powder diffraction spectrum comprising peaks at about 7° to about 8° 2θ, about 10° to about 11.5° 2θ, and / or about 20° to about 21° 2θ.

[0067] The compounds of formula I may also be formulated as fumarate salts. In other embodiments, the compounds of formula I described herein may also be formulated as fumarate salts in crystalline forms A, B and / or C.

[0068] In one embodiment, the compound comprises resiquimod in the form of a fumarate salt having crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum comprising peaks at 2θ between about 6° and about 7°, 2θ between about 7° and about 8°, 2θ between about 9° and about 10.5°, 2θ between about 12° and about 14°, 2θ between about 18° and about 19°, 2θ between about 19° and about 20°, 2θ between about 23° and about 24.5°, and / or 2θ between about 25° and about 26°.

[0069] In one embodiment, the compound comprises resiquimod in the form of a fumarate salt in crystalline form B. Crystalline form B may be characterized by an X-ray powder diffraction spectrum comprising peaks at 2θ between about 9.5° and about 10.5°, 2θ between about 12° and about 13°, 2θ between about 15° and about 16°, 2θ between about 17° and about 18°, 2θ between about 19° and about 21°, and / or 2θ between about 25° and about 26°.

[0070] One embodiment comprises resiquimod in the form of a fumarate salt in crystalline form C. Crystalline form C may be characterized by an X-ray powder diffraction spectrum comprising peaks at 2θ between about 6° and about 7°, 2θ between about 9° and about 10°, 2θ between about 11° and about 12°, 2θ between about 15° and about 16°, 2θ between about 21° and about 22°, 2θ between about 26° and about 27°, and / or 2θ between about 27.5° and about 28.5°.

[0071] The compounds of formula I may also be formulated as citrate salts. In other embodiments, the compounds of formula I described herein may also be formulated as citrate salts in crystalline forms A and / or B.

[0072] In one embodiment, the composition comprises resiquimod in the form of a citrate salt having crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum comprising peaks at about 5° to about 6.5° 2θ, about 11° to about 12° 2θ, about 14.5° to about 15.5° 2θ, about 17° to about 18.5° 2θ, about 19° to about 20.5° 2θ, about 21° to about 22° 2θ, about 26° to about 27° 2θ, and / or about 27.5° to about 28.5° 2θ.

[0073] In one embodiment, the composition comprises resiquimod in the form of a citrate salt in crystalline form B. Crystalline form B may be characterized by an X-ray powder diffraction spectrum comprising peaks at about 5.5° to about 6.5° 2θ, about 8° to about 9° 2θ, about 9.5° to about 10.5° 2θ, about 11° to about 12.5° 2θ, about 18° to about 19.5° 2θ, and / or about 21° to about 24.5° 2θ.

[0074] The compounds of formula I may also be formulated as lactate salts. In other embodiments, the compounds of formula I described herein may also be formulated as lactate salts in crystalline forms A and / or B.

[0075] One embodiment comprises resiquimod in the form of a lactate salt in crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum comprising peaks at about 5° to about 8° 2θ, about 8° to about 9° 2θ, about 10° to about 11° 2θ, about 12.5° to about 13.5° 2θ, about 18.5° to about 19.5° 2θ, and / or about 22° to about 23° 2θ.

[0076] In one embodiment, resiquimod is in the form of the Lactate Salt in crystalline form B. Crystalline form B may be characterized by an X-ray powder diffraction spectrum comprising peaks at about 5° to about 6° 2θ, about 6.5° to about 8° 2θ, about 9° to about 10.5° 2θ, and / or about 13.5° to about 14.5° 2θ.

[0077] The compound of formula I may also be formulated as a succinate salt. In other embodiments, the compound of formula I described herein may also be formulated as a succinate salt in crystalline form A and / or B.

[0078] One embodiment comprises resiquimod in the form of a succinate salt in crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum comprising peaks at about 5° to about 8° 2θ, about 9° to about 11.5° 2θ, about 18° to about 19° 2θ, about 23° to about 24° 2θ, and / or about 24.5° to about 25.5° 2θ.

[0079] In one embodiment, the present invention comprises resiquimod in the form of a succinate salt in crystalline form B. Crystalline form B may be characterized by an X-ray powder diffraction spectrum that includes peaks at 2θ between about 8° and about 9°, 2θ between about 10° and about 11°, 2θ between about 12° and about 13°, 2θ between about 14° and about 15°, 2θ between about 16° and about 17°, 2θ between about 17° and about 18°, and / or 2θ between about 23.5° and about 24.5°.

[0080] The compounds of formula I may also be formed as tosylate salts. In other embodiments, the compounds of formula I described herein may also be formed as tosylate salts in crystalline forms A and / or B.

[0081] One embodiment comprises resiquimod in the form of a tosylate salt in crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum comprising peaks at about 4° to about 5° 2θ, about 9° to about 10° 2θ, about 16° to about 17° 2θ, about 19° to about 21° 2θ, and / or about 24° to about 28° 2θ.

[0082] In one embodiment, the compound comprises resiquimod in the form of a tosylate salt in crystalline form B. Crystalline form B may be characterized by an X-ray powder diffraction spectrum that includes peaks at about 5° to about 6° 2θ, about 7° to about 9° 2θ, about 9.5° to about 11.5° 2θ, about 12° to about 14° 2θ, about 15° to about 19° 2θ, about 19° to about 20.5° 2θ, and / or about 23° to about 24° 2θ.

[0083] The compound of formula I may also be formed as a mesylate salt. In one embodiment, the compound of formula I described herein may also be formed as a mesylate salt in crystalline form A.

[0084] In one embodiment, the compound comprises resiquimod in the form of a mesylate salt in crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum that includes peaks at 2θ from about 8° to about 9°, 2θ from about 12° to about 13°, 2θ from about 14° to about 15°, 2θ from about 16° to about 17°, 2θ from about 18° to about 19.5°, 2θ from about 21° to about 22°, and / or 2θ from about 25.5° to about 26.5°.

[0085] The compounds of formula I may also be formulated as oxalate salts. In one embodiment, the compounds of formula I described herein may also be formulated as oxalate salts in crystalline forms A and / or B.

[0086] One embodiment comprises resiquimod in the form of the oxalate salt in crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum that includes peaks at 2θ between about 9° and about 10°, 2θ between about 14° and about 15°, 2θ between about 17° and about 18°, 2θ between about 18.5° and about 20°, 2θ between about 21° and about 22°, 2θ between about 23° and about 25.5°, and / or 2θ between about 30° and about 31°.

[0087] In one embodiment, the composition comprises resiquimod in the form of the oxalate salt in crystalline form B. Crystalline form B may be characterized by an X-ray powder diffraction spectrum that includes peaks at 2θ between about 5° and about 6°, 2θ between about 9.5° and about 10°, 2θ between about 10.5° and about 11.5°, 2θ between about 13° and about 13.5°, 2θ between about 14.5° and about 15.5°, 2θ between about 16.5° and about 18°, 2θ between about 22° and about 24.5°, and / or 2θ between about 27° and about 28°.

[0088] The compound of formula I may also be formed as a gentisate salt. In other embodiments, the compound of formula I described herein may also be formed as a gentisate salt in crystalline form A and / or B.

[0089] In one embodiment, the compound comprises resiquimod in the form of a gentisate salt of crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum comprising peaks at about 6° to about 7.5° 2θ, about 8° to about 9° 2θ, about 10° to about 11° 2θ, about 14° to about 15° 2θ, about 16° to about 17° 2θ, about 18° to about 19° 2θ, about 20° to about 21.5° 2θ, and / or about 22.5° to about 23.5° 2θ.

[0090] In one embodiment, the compound comprises resiquimod in the form of a gentisate salt in crystalline form B. Crystalline form B may be characterized by an X-ray powder diffraction spectrum comprising peaks at 2θ between about 6° and about 7°, 2θ between about 10° and about 10.5°, 2θ between about 12° and about 13°, 2θ between about 20° and about 21°, 2θ between about 24° and about 24.5°, and / or 2θ between about 26° and about 26.5°.

[0091] The compounds of formula I may also be formulated as benzoate salts. In other embodiments, the compounds of formula I described herein may also be formulated as benzoate salts in crystalline forms A and / or B.

[0092] In one embodiment, the composition comprises resiquimod in the form of a benzoate salt in crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum that includes peaks at about 7° to about 9° 2θ, about 10° to about 11.5° 2θ, about 12° to about 12.5° 2θ, about 14° to about 16.5° 2θ, about 19° to about 22° 2θ, about 23.5° to about 24.5° 2θ, about 28.5° to about 29° 2θ, and / or about 29° to about 30° 2θ.

[0093] In one embodiment, the present invention comprises resiquimod in the form of a benzoate salt in crystalline form B. Crystalline form B may be characterized by an X-ray powder diffraction spectrum that includes peaks at 2θ between about 7° and about 8.5°, 2θ between about 12° and about 14°, 2θ between about 18° and about 19°, 2θ between about 19.5° and about 20.5°, 2θ between about 21° and about 23°, 2θ between about 24° and about 25°, and / or 2θ between about 26° and about 27°.

[0094] The compounds of formula I may also be formed as nitrate salts. In other embodiments, the compounds of formula I described herein may also be formed as nitrate salts in crystalline forms A and / or B.

[0095] One embodiment comprises resiquimod in the form of the nitrate salt in crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum including peaks at 2θ between about 9° and about 9.5°, 2θ between about 10° and about 10.5°, 2θ between about 11.5° and about 12.5°, 2θ between about 14° and about 15°, 2θ between about 16° and about 17.5°, 2θ between about 20° and about 22.5°, 2θ between about 25° and about 26°, and / or 2θ between about 28.5° and about 29.5°.

[0096] One embodiment comprises resiquimod in the form of the nitrate salt in crystalline form B. Crystalline form B may be characterized by an X-ray powder diffraction spectrum comprising peaks at 2θ between about 9° and about 10°, 2θ between about 12.5° and about 13°, 2θ between about 14° and about 16°, 2θ between about 19.5° and about 21°, 2θ between about 25° and about 26°, and / or 2θ between about 26° and about 27°.

[0097] In some embodiments, the monosulfate salt in crystalline form A can be converted to the hemisulfate salt at a water activity of 0.8. Additionally, the monosulfate salt in crystalline form A exhibits good physical stability at 80° C. for 24 hours or longer.

[0098] In some embodiments, a crystalline form of the compound described herein has an XRFD pattern in Figure 1, Figure 4, Figure 7, Figure 10, Figure 13, Figure 16, Figure 19, Figure 48, Figure 50, Figure 54, Figure 59, Figure 61, Figure 63, Figure 65, Figure 67, Figure 69, Figure 71, Figure 73, Figure 75, Figure 77, Figure 78, Figure 79, Figure 83, Figure 84, Figure 85, Figure 89, Figure 90, Figure 93, Figure 94, Figure 97, Figure 98, Figure 101, Figure 102, Figure 105, Figure 107, Figure 108, Figure 111, Figure 112, Figure 115, Figure 116, Figure 119, Figure 120, Figure 124, Figure 126, Figure 127, Figure 128, Figure 132, Figure 134, Figure 136 or Figure 138.

[0099] In some embodiments, the crystalline forms of the compound of formula I may be slightly hygroscopic. In other embodiments, the crystalline forms of the compound of formula I may be non-hygroscopic. Also, these crystalline forms may not show a change in morphology after dynamic vapor sorption (DVS) testing.

[0100] In other embodiments, the crystalline form exhibits improved or comparable solubility in water and biorelevant solvents at room temperature compared to the free base form of the compound of Formula I.

[0101] Additionally, the crystalline form may have physical and chemical stability as compared to the free base of the compound of Formula I. In some embodiments, no change in morphology and / or loss in purity may be exhibited at 25° C. / 60% relative humidity (RH) and 40° C. / 75% relative humidity (RH) as compared to the free base form. In some embodiments, the lack of change in morphology and / or loss in purity may persist for at least about 1 week, at least about 2 weeks, at least about 1 month, at least about 6 months, or at least about 1 year.

[0102] Another aspect provides improved aqueous solubility of the crystalline form of the compound of formula I as compared to the parent compound or its free base form. Another aspect provides improved aqueous solubility of the crystalline form of resiquimod as compared to the parent compound or its free base form.

[0103] Another aspect provides modified oral bioavailability values ​​of the crystalline forms of the compound of formula I as compared to the parent compound or its free base form delivered orally.Another aspect provides modified oral bioavailability values ​​of the crystalline forms of resiquimod as compared to the parent compound or its free base form delivered orally.

[0104] Additionally, the techniques and procedures of this disclosure may be used by one of skill in the art to prepare variants thereof, which variants are considered part of this disclosure.

[0105] The crystalline forms of the compound of formula I described herein may be used to treat a disease or condition. In some embodiments, the disease or condition is cancer. The cancer may include breast cancer, head and neck cancer, ovarian cancer, uterine cancer, skin cancer, brain cancer, bladder cancer, thyroid cancer, liver cancer, pancreatic cancer, lung cancer, eye cancer, throat cancer, esophageal cancer, stomach cancer, intestinal cancer, rectal cancer, testicular cancer, ovarian cancer, vaginal cancer, bone cancer, blood cancer, prostate cancer, and the like.

[0106] The crystalline forms of the compound of formula I described herein may be used to treat a tumor in a subject in need of such treatment, hi some embodiments, the tumor is a carcinoma, a sarcoma, a blastoma, or a combination thereof.

[0107] Carcinomas may include, but are not limited to, adrenal gland tumors, bone tumors, brain tumors, breast tumors, bronchial tumors, colon tumors, gallbladder tumors, kidney tumors, pharyngeal tumors, liver tumors, lung tumors, nerve tumors, pancreatic tumors, prostate tumors, parathyroid tumors, skin tumors, stomach tumors, and thyroid tumors. In another aspect of this embodiment, carcinomas include, but are not limited to, adenocarcinoma, squamous cell carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, and squamous cell carcinoma. In other aspects of this embodiment, the carcinoma may be, but is not limited to, small cell carcinoma, combined small cell carcinoma, verrucous carcinoma, squamous cell carcinoma, basal cell carcinoma, transitional cell carcinoma, inverted papilloma, plastic gastritis, familial adenomatous polyposis, insulinoma, glucagonoma, gastrinoma, VIPoma, somatostatinoma, cholangiocarcinoma, Kraskin tumor, hepatocellular adenoma, hepatocellular carcinoma, renal cell carcinoma, endometrioid tumor, renal oncocytoma, prolactinoma, multiple endocrine neoplasia, adrenal cortical adenoma, adrenal cortical tumor, adrenal duct ... carcinoma, Hürthle cell, neuroendocrine tumor, adenoid cystic carcinoma, eosinophilic adenoma, clear cell adenocarcinoma, apdoma, cylindroma, papillary hidradenoma, hydrocele, syringoma, papillary cystadenoma, cystadenoma, cystadenocarcinoma, signet ring cell carcinoma, mucinous cystadenoma, mucinous cystadenocarcinoma, mucoepidermoid carcinoma, ovarian serous cystadenoma, pancreatic serous cystadenoma, serous cystadenocarcinoma, papillary serous cystadenocarcinoma, breast ductal carcinoma, pancreatic ductal adenocarcinoma, comedocarcinoma of the breast, Paget's disease of the breast, extramammary Paget's disease, lobular carcinoma in situ, invasive lobular carcinoma, medullary carcinoma of the breast, medullary thyroid carcinoma, acinar cell carcinoma, Warthin's tumor, or thymoma.

[0108] Sarcomas may include, but are not limited to, soft tissue sarcoma, connective tissue sarcoma, lipomatous sarcoma, myomatous sarcoma, a complex mixed and stromal sarcoma, and mesothelial. In aspects of this embodiment, non-hematologic sarcomas include, but are not limited to, adenomatous tumor, adenomyoma, aggressive childhood fibromatosis, alveolar rhabdomyosarcoma, angiolipoleiomyoma, angiomyolipoma, angioleiomyoma, angiomyxoma, angiosarcoma, aponeurotic fibroma, Askin tumor, atypical fibroxanthoma, benign lipoblastomatosis, Brenner tumor, carcinosarcoma, chondroid lipoma, chondrosarcoma, clear cell sarcoma, renal clear cell sarcoma, collagenous fibroma ... fibroma, cystosarcoma phyllodes, dermal trunk fibrosarcoma, dermatofibrosarcoma protuberans (DFSP), dendroid fibroma, desmoplastic small round cell tumor, sporadic childhood fibromatosis, Ewing / PNET tumor, familial myxoid angiofibroma, fibroadenoma, tendon sheath fibroma, cervical fibromatosis, fibrous histiocytoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), genital leiomyoma, hemangioendothelioma, hepatoblastoma, brown lipoma, histiocytoma, juvenile digital fibromatosis, intradermal spindle cell lipoma, juvenile hyaline fibromatosis, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, mesodermal nephroma, mesothelioma, mixed Mullerian tumor, multiple cutaneous leiomyomas, a multiple cutaneous and uterine leiomyoma syndrome The tumor may include, for example, myelolipoma, myosarcoma, myxoid liposarcoma, myxosarcoma, neurogenic fibrolipoma, neurofibrosarcoma, orovaginal submucosal fibrosis, ossifying fibromyxoma, osteosarcoma, pancreatoblastoma, phyllodes tumor, footpad fibromatosis, pleomorphic adenoma, pleomorphic fibroma, pleomorphic lipoma, rhabdomyosarcoma, botryoid sarcoma, schwannoma sarcoma, solitary cutaneous leiomyoma, solitary fibrous tumor, spindle cell lipoma, smooth muscle tumor of unknown malignancy (STUMP), synovial sarcoma, angiosarcoma, or Wilms' tumor.

[0109] Blastomas may include, but are not limited to, chondroblastoma, hepatoblastoma, medulloblastoma, nephroblastoma, neuroblastoma, pancreatoblastoma, pleuroblastoma, retinoblastoma, or glioblastoma multiforme.

[0110] Resiquimod and related compounds of formula I described herein may be agonists of TLR / TLR8. Studies have found that many solid tumors, such as breast, head and neck, or ovarian cancer, have factors secreted by tumor cells that suppress pDC infiltration and DC maturation. These immature DC cells play no role in enhancing antitumor immunity. In contrast, DCs in the tumor microenvironment suppress antitumor immunity and promote angiogenesis, thereby promoting tumor growth. Imiquimod, a Toll-like receptor 7 agonist, and CpG drugs, a Toll-like receptor 9 agonist, stimulate pDCs in the tumor microenvironment to suppress tumor development.

[0111] Natural killer (NK) cells are a type of cytotoxic lymphocyte that constitutes a major component of the immune system. NK cells are a subset of peripheral blood lymphocytes defined by expression of CD56 or CD16 and lack of T cell receptor (CD3). They recognize and kill transformed cell lines in a non-MHC restricted manner and without priming. NK cells are primarily responsible for eliminating tumor and virus-infected cells. The process by which NK cells recognize target cells and deliver signals sufficient to induce lysis of the target is determined by a number of inhibitory and activating receptors on the cell surface. Discrimination of self from non-self by NK cells involves inhibitory receptors that recognize MHC-I molecules and non-MHC ligands, such as CD48 and Clr-1b. NK recognition of infected or damaged cells (non-self) works through stress-induced ligands (e.g., MICA, MICB, Rael, H60, Multl) or virus-derived ligands (e.g., m157, hemagglutinin) recognized by various activating receptors including NKG2D, Ly49H and NKp46 / Nc1.

[0112] NK cells represent the predominant lymphoid cells in peripheral blood for many months after allogeneic or autologous stem cell transplantation, and they are responsible for the majority of immunity against pathogens during this period.

[0113] Human NK cells mediate the lysis of tumor cells and virus-infected cells through natural cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC).

[0114] Human NK cells are regulated by positive and negative cytolytic signals. Negative (inhibitory) signals are transduced by the C-lectin domain containing receptor CD94 / NKG2A and some killer cell immunoglobulin-like receptors (KIRs). The regulation of NK lysis by inhibitory signals is known as the "missing self" hypothesis, whereby specific HLA-class I alleles expressed on the target cell surface ligate inhibitory receptors on NK cells. Downregulation of HLA molecules on tumor cells and some virus-infected cells (e.g. CMV) can reduce this inhibition below the target threshold and also make target cells susceptible to NK cell-mediated lysis if they carry NK-priming and activation molecules. TLR7, TLR8 or TLR9 agonists can activate both mDCs and pDCs to produce type I IFNs and express costimulatory molecules such as GITR-ligand, which can then activate NK cells to produce IFN-g and potently enhance the killing function of NK cells.

[0115] Inhibitory receptors are classified into two groups: the Ig-superfamily, called killer cell immunoglobulin-like receptors (KIRs), and the lectin family, NKG2, which dimerize with CD94 on the cell surface. KIRs have a two- or three-domain extracellular structure and bind to HLA-A, -B, or -C. The NKG2 / CD94 complex ligates HLA-E.

[0116] Inhibitory KIRs have up to four intracellular domains containing ITIMs, the best characterized of which are KIR2DL1, KIR2DL2, and KIR2DL3, which are known to bind to HLA-C molecules. KIR2DL1 binds to group 2 alleles, while KIR2DL2 and KIR2DL3 bind to group 1 HLA-C alleles. Certain leukemia / lymphoma cells express both group 1 and 2 HLA-C alleles and are known to be resistant to NK-mediated cytolysis.

[0117] With regard to positive activation signals, ADCC is thought to be mediated through CD16, and many triggering receptors responsible for natural cytotoxicity have been identified, including CD2, CD38, CD69, NKRP-1, CD40, B7-2, NK-TR, NKp46, NKp30, and NKp44. In addition, several KIR molecules with short cytoplasmic tails are stimulatory active. These KIRs (KIR2DS1, KIR2DS2, and KIR2DS4) are known to bind to HLA-C; their extracellular domains are identical to the inhibitory KIRs with which they are associated. The activating KIRs lack ITIMs and are instead associated with DAP12, which leads to the activation of NK cells. The mechanism of control of the expression of the inhibitory versus activating KIRs remains unclear.

[0118] Several reports have described the expression of TLRs in mouse or human cancers or cancer cell lines, for example, TLR1 through TLR6 are expressed by colon, lung, prostate and melanoma mouse tumor cell lines, TLR3 is expressed in human breast, liver and gastric cancer cells that express TLR2 and TLR4, TLR9 and TLR4 are expressed by human lung cancer cells, and TLR7 and TLR8 are found in human lung cancer tumor cells.

[0119] TLRs are a family of proteins that sense microbial products and / or initiate adaptive immune responses. TLRs activate dendritic cells (DCs). TLRs are conserved transmembrane molecules that contain a leucine-rich repeat ectodomain, a transmembrane domain, and an intracellular TIR (Toll / Interleukin Receptor) domain. TLRs recognize distinct structures on microbes, often referred to as "PAMPs" (pathogen-associated molecular structures). Ligand binding to TLRs triggers a cascade of intracellular signaling pathways that induce the production of inflammatory and immune-related factors.

[0120] TLR7 and TLR8 are phylogenetically and structurally related. TLR7 is selectively expressed by human pDCs and B cells. TLR8 is mainly expressed by mDCs, monocytes, macrophages and myeloid immune suppressor cells. TLR7-specific agonists activate plasmacytoid dendritic cells (pDCs) to produce large amounts of type 1 IFNs and express high levels of costimulatory molecules that promote activation of T cells, NK cells, B cells and mDCs. TLR8-specific agonists activate myeloid DCs, monocytes, macrophages or myeloid-derived suppressor cells to produce large amounts of type 1 IFNs, IL-12 and IL23 and express high levels of MHC class I, MHC class II and costimulatory molecules that promote activation of antigen-specific CD4 and CD8+ T cells.

[0121] Pharmaceutical compositions comprising crystalline forms of the compounds described herein may be administered to animals, such as mammals, which in some embodiments may be humans, cats, dogs, horses, pigs, cows, whales, or the like.

[0122] A pharmaceutical composition may be prepared by combining a therapeutically effective amount of at least one crystalline form of a compound described herein with a commonly accepted pharmaceutical excipient and preparing a unit dosage form suitable for therapeutic use. As used herein, the term "pharmaceutical composition" refers to a therapeutically effective concentration of an active compound, such as any crystalline form of a compound described herein. Preferably, the pharmaceutical composition does not produce any toxic, allergic, or other untoward or undesired reaction when administered. The pharmaceutical compositions disclosed herein can be useful in medical and veterinary applications. The pharmaceutical composition may be administered alone or in combination with other co-active compounds, drugs, medicines, or hormones. The pharmaceutical composition may be manufactured using a number of different processes, including, but not limited to, conventional mixing, dissolving, granulating, dragee-making, wet milling, emulsifying, encapsulating, entrapping, and lyophilizing. Pharmaceutical compositions can take a variety of forms, including, but not limited to, sterile solutions, suspensions, emulsions, lyophilisates, tablets, pills, pellets, capsules, powders, syrups, elixirs, or other dosage forms suitable for administration.

[0123] The pharmaceutical compositions may be liquid, semi-solid or solid formulations, and the formulations disclosed herein may be prepared in a manner that forms one phase, such as an oil or a solid. Alternatively, the formulations disclosed herein may be prepared in a manner that forms two phases, such as an emulsion. Pharmaceutical compositions disclosed herein intended for such administration may be prepared by several methods known in the art of manufacturing pharmaceutical compositions.

[0124] Liquid preparations suitable for injection or topical (e.g., ocular) delivery may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols (propylene glycol, polyethylene glycol (PEG), glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in dispersions, and by the use of surfactants.

[0125] Semi-solid formulations suitable for topical administration include, but are not limited to, ointments, creams, salves and gels. The active compound in such solid formulations may be mixed with at least one inert conventional excipient (or carrier), such as lipids and / or polyethylene glycols.

[0126] Solid formulations suitable for topical administration include capsules, tablets, pills, powders, and granules. The active compound in such solid formulations may be mixed with at least one inert conventional excipient (or carrier) such as sodium citrate, or dicalcium phosphate, or (a) fillers or extenders, such as, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, such as, for example, glycerol; (d) disintegrants, such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution inhibitors, such as, for example, paraffin; (f) absorption accelerators, such as, for example, quaternary ammonium compounds; (g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (h) absorbents, such as, for example, potassium and bentonite; and (i) at least one inert conventional excipient (or carrier) such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0127] In liquid and semi-solid formulations, the concentration of the crystalline forms described herein may be between about 50 mg / mL and about 1000 mg / mL. In aspects of this embodiment, a therapeutically effective amount of a crystalline form of the compound described herein may be, for example, about 50 mg / mL to about 100 mg / mL, about 50 mg / mL to about 200 mg / mL, about 50 mg / mL to about 300 mg / mL, about 50 mg / mL to about 400 mg / mL, about 50 mg / mL to about 500 mg / mL, about 50 mg / mL to about 600 mg / mL, about 50 mg / mL to about 700 mg / mL, about 50 mg / mL to about 800 mg / mL, about 50 mg / mL to about 900 mg / mL, about 50 mg / mL to about 100 mg / mL, about 50 mg / mL to about 250 mg / mL, about 50 mg / mL to about 300 mg / mL, about 50 mg / mL to about 400 mg / mL, about 50 mg / mL to about 500 mg / mL, about 50 mg / mL to about 600 mg / mL, about 50 mg / mL to about 700 mg / mL, about 50 mg / mL to about 800 mg / mL, about 50 mg / mL to about 900 mg / mL, about 50 mg / mL to about 1000 mg / mL, about 50 mg / mL to about 1500 mg / mL, about 50 mg / mL to about 200 mg / mL, about 50 mg / mL to about 300 mg / mL, about 50 mg / mL to about 400 mg / mL, about 50 mg / mL to about 500 mg / mL, about 50 mg / mL to about 600 mg / mL, about 50 mg / mL to about 700 mg / mL, about 00mg / mL, about 100mg / mL to about 200mg / mL, about 100mg / mL to about 300mg / mL, about 100mg / mL to about 400mg / mL, about 100mg / mL to about 500mg / mL, about 100mg / mL to about 600mg / mL, about 100mg / mL to about 700mg / mL, about 100mg / mL to about 800mg / mL, about 100mg / mL to about 900mg / mL, about 100mg / mL to about 1000mg / mL, about 200mg / mL to about 300mg / mL, about 2 ... g / mL, about 200 mg / mL to about 500 mg / mL, about 200 mg / mL to about 600 mg / mL, about 200 mg / mL to about 700 mg / mL, about 200 mg / mL to about 800 mg / mL, about 200 mg / mL to about 900 mg / mL, about 200 mg / mL to about 1000 mg / mL, about 300 mg / mL to about 400 mg / mL, about 300 mg / mL to about 500 mg / mL, about 300 mg / mL to about 600 mg / mL, about 300 mg / mL to about 700 mg / mL, about 300 mg / mL to about 800 mg / mL L, about 300 mg / mL to about 900 mg / mL, about 300 mg / mL to about 1000 mg / mL, about 400 mg / mL to about 500 mg / mL, about 400 mg / mL to about 600 mg / mL, about 400 mg / mL to about 700 mg / mL, about 400 mg / mL to about 800 mg / mL, about 400 mg / mL to about 900 mg / mL, about 400 mg / mL to about 1000 mg / mL, about 500 mg / mL to about 600 mg / mL, about 500 mg / mL to about 700 mg / mL, about 500 mg / mL to about 800 mg / mL,It may be about 500 mg / mL to about 900 mg / mL, about 500 mg / mL to about 1000 mg / mL, about 600 mg / mL to about 700 mg / mL, about 600 mg / mL to about 800 mg / mL, about 600 mg / mL to about 900 mg / mL, or about 600 mg / mL to about 1000 mg / mL.

[0128] In semi-solid and solid formulations, the amount of the crystalline form described herein may be between about 0.01% and about 45% by weight. In aspects of this embodiment, the amount of the crystalline form of the compound described herein is between about 0.1% and about 45% by weight, about 0.1% and about 40% by weight, about 0.1% and about 35% by weight, about 0.1% and about 30% by weight, about 0.1% and about 25% by weight, about 0.1% and about 20% by weight, about 0.1% and about 15% by weight, about 0.1% and about 10% by weight, about 0.1% and about 5% by weight, about 1% and about 45% by weight, about 1% to about 40% by weight, about 1% to about 35% by weight, about 1% to about 30% by weight, about 1% to about 25% by weight, about 1% to about 20% by weight, about 1% to about 15% by weight, about 1% to about 10% by weight, about 1% to about 5% by weight, about 5% to about 45% by weight, about 5% to about 40% by weight, about 5% to about 35% by weight, about 5% to about 30% by weight, about 5% to about 25% by weight, about 5% to about to about 20% by weight, about 5% to about 15% by weight, about 5% to about 10% by weight, about 10% to about 45% by weight, about 10% to about 40% by weight, about 10% to about 35% by weight, about 10% to about 30% by weight, about 10% to about 25% by weight, about 10% to about 20% by weight, about 10% to about 15% by weight, about 15% to about 45% by weight, about 15% to about 40% by weight, about 15% to about 35% by weight, about It may be 15% to about 30% by weight, about 15% to about 25% by weight, about 15% to about 20% by weight, about 20% to about 45% by weight, about 20% to about 40% by weight, about 20% to about 35% by weight, about 20% to about 30% by weight, about 20% to about 25% by weight, about 25% to about 45% by weight, about 25% to about 40% by weight, about 25% to about 35% by weight, or about 25% to about 30% by weight.

[0129] The pharmaceutical compositions described herein may optionally include a pharma- ceutically acceptable carrier that facilitates processing of the active compound into a pharma- ceutically acceptable composition. Such a medium is generally mixed with the active compound or is permitted to dilute or encapsulate the active compound and may be a solid, semi-solid, or liquid. Any of a variety of pharma- ceutically acceptable carriers may be used, including, but not limited to, aqueous media such as water, saline, glycine, hyaluronic acid, and the like; solid media such as starch, magnesium stearate, mannitol, sodium saccharin, talcum, cellulose, glucose, sucrose, lactose, trehalose, magnesium carbonate, and the like; solvents; dispersion media; coatings; antibacterial and antifungal agents; isotonic and absorption delaying agents; or some other inactive ingredients.

[0130] The pharmaceutical compositions described herein may optionally contain other pharma- ceutically acceptable ingredients (or pharmaceutical ingredients), including, but not limited to, buffers, preservatives, tonicity adjusters, salts, antioxidants, osmolality adjusters, physiological substances, pharmaceutical substances, bulking agents, emulsifiers, wetting agents, sweeteners or flavoring agents, and the like. Various buffers and means for adjusting pH may be used to prepare the pharmaceutical compositions described herein, so long as the resulting preparation is pharma- ceutically acceptable. Such buffers include, but are not limited to, acetate buffers, borate buffers, citrate buffers, phosphate buffers, neutral buffered saline, and phosphate buffered saline. It is understood that acids or bases may be used to adjust the pH of the compositions, if necessary. Pharmaceutically acceptable antioxidants include, but are not limited to, sodium pyrosulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene. Useful preservatives include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, stabilized oxychloro compositions such as sodium chlorite, and chelating agents such as DTPA or DTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide. Tonicity adjusting agents useful in pharmaceutical compositions include, but are not limited to, salts such as sodium chloride, potassium chloride, mannitol or glycerin, and other pharma- ceutically acceptable tonicity adjusting agents.

[0131] A method for treating a disease or condition such as cancer includes administering the novel crystalline forms of Formula I, such as in pharmaceutical form. Administration may be once a day, twice a day, three times a day, four times a day or more. In other embodiments, administration may be once every other day, once every three days, once every four days, once every five days, once every six days, once a week, once every other week, once every three weeks, once a month, once every other month, once every six months, once a year, or the like.

[0132] (Example) Example 1 1. Overview A salt screen of the free base of resiquimod was performed to identify salt candidates with suitable physicochemical properties. In addition, a polymorphic screen was performed to identify the predominant crystalline form of the salt candidates.

[0133] An initial salt screening was performed under 100 conditions using 19 acids (HCl in two molar ratios) and five solvent systems. A total of 32 hit crystals were isolated and characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), with stoichiometry determined using proton nuclear magnetic resonance (1H NMR) or HPLC / IC. Considering the safety grade of the acids used, the number of polymorphs observed, and the physicochemical properties, seven crystalline salts, namely monohydrochloride, dihydrochloride, sulfate, phosphate, maleate, malate, and adipate, were selected as leading salts for further evaluation.

[0134] All seven salt leads were reconstituted in hundreds of milligrams (except dihydrochloride) and further evaluated for hygroscopicity, kinetic solubility and solid-state stability. As a result, 1) all derived salts except hydrochloride were slightly hygroscopic without morphological changes after DVS test, 2) compared to free base form A, all derived salts except maleate showed improved or equivalent solubility in water and biorelevant media (SGF, FaSSIF and FeSSIF) at room temperature (RT, 20±3°C), and 3) for the derived salts and free base form A, except dihydrochloride, no change in morphology and decrease in HPLC purity were detected under 25°C / 60% RH and 40°C / 75% RH for one week, showing good physical and chemical stability.

[0135] Based on the results of characterization and evaluation, sulfate salt was selected as the candidate salt and reconstituted in 6-g scale for polymorphic study. Polymorph screening was performed under 100 conditions using sulfate form A as the starting material. A total of three crystal forms were obtained, including one anhydrate (form A), one DMSO solvate (form B) and one hemisulfate. Thus, sulfate form A was selected as the predominant monosulfate form. Disproportionation risk and thermal stability were studied for sulfate form A, and the results showed that 1) sulfate form A transformed into hemisulfate at a water activity of 0.8, showing disproportionation risk at high relative humidity, and 2) sulfate form A showed good physicochemical stability at 80°C for 24 hours.

[0136] 2. Salt Screening 2.1 Experimental Overview According to the pKa value of 7.2 determined using Sirius T3 and the approximate solubility of the free base (807919-05-A) at room temperature, 19 salt forms and 5 solvent systems were used for screening. The free base was dispersed in the selected solvent in a glass vial and the corresponding salt form was added at a molar charge ratio of 1:1 (two ratios, both 1:1 and 2:1, for hydrochloric acid / free base, were used). The mixture of free base and acid was stirred at room temperature for 2.5 days. The resulting clear solution was suspended overnight at 5° C. to induce precipitation. If the samples were still clear, they would be evaporated to dryness at room temperature to maximize the chances of identifying as many crystalline hits as possible. The resulting solids were isolated and analyzed by XRPD.

[0137] A total of 32 crystal hits were obtained, as summarized in Table 2-1. 1 Characterization was performed by TGA and DSC, with stoichiometry determined by H NMR or HPLC / IC. Characterization data are summarized in Table 2-2, and detailed information is provided in Section 5.4.

[0138] [Table 2-1] ※※ FB: Free base. FB: Solid was produced via suspension at 5°C overnight. ※ : Samples were obtained via evaporation to dryness at room temperature. Blank experiments were set up to detect some possible variations in the free base.

[0139] [Table 2-2-1]

[0140] [Table 2-2-2] The samples were dried at 50° C. overnight before characterization.

[0141] 2.2 Reconstitution and characterization of major salts Based on the results of the characterization, seven major salts were selected and reconstituted in hundreds of milligrams (excluding dihydrochloride form A). Selection criteria included, but were not limited to: 1) low acid safety concerns (safety grade I), 2) sharp X-ray powder diffraction (XRPD) peaks without obvious amorphous halos, 3) negligible weight loss during thermogravimetric analysis (TGA), and 4) a suitable thermal event with a sharp melt during differential scanning calorimetry (DSC). Preparation procedures for the derived salts, as well as other salts described in this application, are described in Tables 2-3.

[0142] [Table 2-3-1]

[0143] [Table 2-3-2]

[0144] [Table 2-3-3]

[0145] [Table 2-3-4]

[0146] [Table 2-3-5]

[0147] [Table 2-3-6]

[0148] [Table 2-3-7]

[0149] [Table 2-3-8]

[0150] [Table 2-3-9]

[0151] [Table 2-3-10]

[0152] 2.2.1 Monohydrochloride Form A The monohydrochloride salt Form A was successfully reprepared as evidenced by the XRPD results in Figure 1. The XRPD data for the monohydrochloride salt Form A gives a first peak at 20.5, 6.9 and 27.3; a second peak at 9.8, 13.7 and 34.3; and a third peak at 17.4, 21.3 and 24.8 (peak shifts within ±0.2°).

[0153] The PLM image shown in Figure 2 shows a collection of small particles (<10 μm). As per the TGA and DSC data in Figure 3, the sample (807919-16-A) showed a weight loss of 1.1% up to 130°C and two endothermic peaks at 250.4°C and 266.2°C (peak temperatures) before decomposition, indicating the monohydrochloride salt form A anhydrate. A purity of 99.5 area% was detected by high performance liquid chromatography (HPLC) as shown in Tables 2-4. The stoichiometry of the reconstituted sample was also determined as 1.01 (acid / base) by HPLC / IC.

[0154] [Table 2-4]

[0155] 2.2.2 Dihydrochloride Form A The dihydrochloride salt form A was characterized by XRPD, TGA, DSC, polarized light microscopy (PLM) and HPLC / IC. Its XRPD pattern is shown in Figure 4 and the PLM image is shown in Figure 5. The XRPD data of the dihydrochloride salt form A gives a first peak at 7.1, 8.2 and 19.6; a second peak at 15.4, 16.4 and 25.6; a third peak at 7.3, 14.9 and 27.0 (peak shifts within ±0.2°).

[0156] The TGA and DSC results are shown in Figure 6 and show a weight loss of 1.2% up to 100°C, and four endothermic peaks at 99.5°C, 191.7°C, 250.7°C, and 261.9°C (peak temperatures) before decomposition, and a purity of 99.5 area% was detected by HPLC, as shown in Table 2-5, and the stoichiometry was calculated as 2.15 (acid / base) by HPLC / IC.

[0157] [Table 2-5]

[0158] 2.2.3 Sulfate type A Comparison of the XRPD patterns in Figure 7 indicates that the reproduced sample (807919-11-A) conforms to Sulfate Form A. The XRPD data for Sulfate Form A gives a first peak at 7.6, 11.7, and 18.2; a second peak at 15.5, 17.6, and 24.4; and a third peak at 9.6, 13.4, and 23.5 (peak shifts within ±0.2°).

[0159] Small particles (<10 μm) and aggregates are shown in FIG. 8. TGA and DSC results are shown in FIG. 9. A weight loss of 0.9% was observed up to 130° C. in TGA and the DSC curve shows a sharp melting peak at 214.4° C. (onset temperature) before decomposition. As per Table 2-6, a purity of 99.2% area was detected by HPLC and the stoichiometry was determined as 1.03 (acid / base) for the reconstituted batch. 1 A combination of 1 H NMR and TGA / DSC confirmed that sulfate Form A was an anhydrous monosulfate.

[0160] [Table 2-6]

[0161] 2.2.4 Phosphate type A Phosphate Form A was successfully reprepared as evidenced by the XRPD results in Figure 10. The XRPD data for phosphate Form A gives a first peak at 7.7, 15.3, and 20.6; a second peak at 12.4, 18.5, and 25.2; and a third peak at 14.3, 16.7, and 17.7 (peak shifts within ±0.2°).

[0162] The PLM image shown in Figure 11 shows a collection of small particles (<10 μm). As per the TGA and DSC data in Figure 12, phosphate form A (807919-11-C) shows a weight loss of 1.2% up to 130°C and an endothermic peak at 241.0°C (onset temperature) before decomposition. A purity of 99.4 area% was detected by HPLC as shown in Table 2-7. The stoichiometry of the reconstituted sample was also determined as 1.07 (acid / base) by HPLC / IC.

[0163] [Table 2-7]

[0164] 2.2.5 Maleate type A Maleate Form A (807919-D4) was prepared via reactive crystallization (1:1 molar ratio) in THF at room temperature. The XRPD results in FIG. 13 show that maleate Form A was successfully reprepared. The XRPD data of maleate Form A gives the first peak at 7.5, 10.3 and 24.7; the second peak at 9.3, 16.5 and 18.0; and the third peak at 15.7, 20.7 and 21.4 (peak shifts within ±0.2°).

[0165] Small particles (<10 μm) and aggregates are shown in Figure 14. TGA and DSC data showed a weight loss of 1.3% up to 130° C., and a possible melting endotherm at 224.1° C. (onset temperature) prior to decomposition was observed in the DSC (Figure 15). A purity of 99.2 area % was detected by HPLC as shown in Table 2-8. 1 H NMR results show a stoichiometry of 0.96 (acid / base) for the reprepared maleate form A (807919-11-B). 1 A combination of 1 H NMR and TGA / DSC identified maleate Form A as the monomaleate anhydrate.

[0166] [Table 2-8]

[0167] 2.2.6 Malate A Phosphate Form A was successfully reprepared as evidenced by the XRPD results in Figure 16. The XRPD data for phosphate Form A gives a first peak at 6.5, 8.5, and 23.2; a second peak at 12.0, 13.0, and 17.1; and a third peak at 8.8, 20.5, and 25.3 (peak shifts within ±0.2°).

[0168] The PLM image shown in Figure 17 shows a collection of irregularly shaped particles. As per the TGA and DSC data in Figure 18, Phosphate Form A (807919-11-E) shows a weight loss of 1.0% up to 130°C and a sharp endothermic peak at 192.9°C (onset temperature) before decomposition. A purity of 99.9 area% was detected by HPLC as per Table 2-9. Furthermore, the stoichiometry of the reconstituted sample was 1 Determined by 1 H NMR as 1.02 (acid / base).

[0169] [Table 2-9]

[0170] 2.2.7 Adipate type A Comparison of the XRPD patterns in Figure 19 indicates that the reproduced sample (807919-12-A) conforms to adipate form A. The XRPD data for adipate form A gives a first peak at 5.9, 12.5 and 21.3; a second peak at 13.9, 18.8 and 26.7; and a third peak at 14.4, 19.7 and 22.6 (peak shifts within ±0.2°).

[0171] Small particles (<10 μm) and severe aggregation are seen in FIG. 20. The TGA and DSC results are shown in FIG. 21. A weight loss of 0.9% was observed up to 130° C. in the TGA and the DSC curve shows a sharp melting peak at 218.0° C. (onset temperature) before decomposition. A purity of 99.9 area % was detected by HPLC as shown in Table 2-10. The stoichiometry was also determined as 0.52 (acid / base) for the reconstituted batch, indicating the formulation of hemiadipate salt.

[0172] [Table 2-10]

[0173] 2.3 Evaluation of major salts Additionally, evaluation studies of hygroscopicity, kinetic solubility, and solid-state stability were conducted to better understand the physicochemical properties of the seven derivatives. As a result, it was found that: 1) all derived salts, except for monohydrochloride form A and dihydrochloride form A, were slightly hygroscopic without any change in morphology after DVS evaluation; 2) compared to free base form A, all derived salts, except for maleate, showed improved or comparable solubility in water and biorelevant media; 3) all derived salts, except for dihydrochloride form A, showed good physical and chemical stability as evidenced by no substantial change in crystal morphology or HPLC purity.

[0174] 2.3.1 Hygroscopicity DVS isotherm plots were collected at 25° C. to investigate the solid form stability as a function of humidity. For the six anhydrous salts (monohydrochloride Form A, sulfate Form A, phosphate Form A, maleate Form A, malate Form A and adipate Form A), the solids were pre-dried at 0% relative humidity before starting to remove unbound solvent or water. For the dihydrochloride salt A of the considered hydrates / solvates, the solids were equilibrated at ambient humidity (approximately 30% RH) before testing.

[0175] The five salt forms (sulfate A, phosphate A, maleate A, malate A, and adipate A) were slightly hygroscopic as evidenced by 0.2-1.1% water uptake at up to 80% relative humidity. No changes in solid morphology were observed in all five derivatives after DVS evaluation (FIGS. 22-31).

[0176] The DVS plots shown in Figures 32 and 34 indicate that both hydrochloride salt forms are hygroscopic. For monohydrochloride form A (807919-16-A), 2.9% water uptake was observed up to 80% relative humidity and no change in morphology was detected after DVS testing (Figure 33). For dihydrochloride form A (807919-14-A), 12.2% water uptake was detected up to 80% relative humidity and one plateau was observed at about 20% relative humidity, suggesting the possible presence of hydrate. In addition, dihydrochloride form A transformed into a new form containing the diffraction peaks of monohydrochloride form A after DVS evaluation (Figure 35), indicating the risk of disproportion of dihydrochloride form A at high relative humidity.

[0177] 2.3.2 Kinetic solubility The kinetic solubilities of the seven main salts were measured in water and three biorelevant media (SGF, FaSSIF and FeSSIF) at room temperature using free base form A (807919-05-A) as a control. All solubility samples (initial solid loading of about 5 mg / mL) were rotated at 25 rpm in a rolling incubator and sampled at 1, 2, 4 and 24 hours, respectively. After centrifugation and separation using a 0.45 μm nylon filter, the filtrate was collected for HPLC and pH testing, and the wet cake was collected for XRPD characterization. If a clear solution was obtained after 24 hours, the exact concentration and purity were determined for that solution.

[0178] The results are summarized in Table 2-11 and the kinetic solubility summary is shown in Figure 36A-D. Comparison with free base form A, monohydrochloride form A, dihydrochloride form A, sulfate form A, phosphate form A, malate form A and adipate form A shows improved or comparable solubility in water and biorelevant buffers. Also, the residual solids after 24 hours of suspension showed no change in morphology (Figures 37-38). Meanwhile, a decrease in solubility was observed in SGF, FaSSIF and FeSSIF after the formation of the monomaleate salt (maleate form A), while no change in morphology was detected after the evaluation of kinetic solubility (Figure 39). In addition, no degradation was observed for the clear solutions after 24 hours, as evidenced by the HPLC results in Table 2-12.

[0179] [Table 2-11-1]

[0180] [Table 2-11-2] S: solubility, pH: final pH of supernatant, FC: change in solid form C: Transparent, N / A: Data not available, N / A ※ :Limited solids for analysis ※ :Concentration and pH data of the clear solution were collected.

[0181] [Table 2-12-1]

[0182] [Table 2-12-2]

[0183] 2.3.3 Physical and chemical stability The physicochemical stability of the seven major salts was evaluated under 25°C / 60% relative humidity and 40°C / 75% relative humidity for one week using free base form A (807919-05-A) as a control. Stability samples were characterized by XRPD and HPLC, and the results are summarized in Tables 2-13. XRPD patterns show no change in the investigated forms except for dihydrochloride form A, as shown in Figures 40-47. Also, no substantial purity change was observed for the seven derived and free base forms A. All data indicated physical and chemical stability of monohydrochloride form A, sulfate form A, phosphate form A, maleate form A, malate form A, adipate form A and free base form A at the conditions tested for at least one week.

[0184] [Table 2-13]

[0185] 2.4 Conclusion A total of 32 hit crystals were produced through salt screening. Based on the characterization results, seven derived salts, namely, monohydrochloride A, dihydrochloride A, sulfate A, phosphate A, maleate A, malate A and adipate A, were selected to be reformulated for further evaluation including hygroscopicity, kinetic solubility and solid-state stability. Considering the results summarized in Tables 2-14 and 2-15, the sulfate salt was recommended as the candidate salt for further polymorphic investigation.

[0186] [Table 2-14] ※ : Safety grades of acids used, according to Handbook of Pharmaceutical Salts: Properties, Selection and Uses, Wiley-VCH: Zurich, 2002. ※※ : Peak temperature

[0187] [Table 2-15] ※ : Safety grades of acids used, according to Handbook of Pharmaceutical Salts: Properties, Selection and Uses, Wiley-VCH: Zurich, 2002.

[0188] 3. Polymorphic investigation of sulfate salts 3.1 Summary of Polymorph Screening Using the reconstituted sulfate form A (807919-21-A) as starting material, polymorph screening experiments were carried out under 100 conditions with different crystallization or solid-state transfer methods, the detailed procedures of which can be found in Section 5.5.

[0189] As the results are summarized in Tables 3-1 and 3-2, three crystalline forms were obtained, initially sulfate Form A as an anhydrate, sulfate Form B as a DMSO solvate, and hemisulfate Form A as a hydrate.

[0190] [Table 3-1]

[0191] [Table 3-2] ※ : Peak temperature

[0192] 3.1.1 Sulfate type B A sample of sulfate Form B (807919-25-A13) was obtained via solid vapor diffusion in DMSO at room temperature and its XRPD pattern is shown in Figure 48. The XRPD data for sulfate Form B gives a first peak at 7.0, 9.6 and 20.0; a second peak at 18.2, 19.6 and 25.2; a third peak at 14.0, 24.6 and 28.3 (peak shifts within ±0.2°).

[0193] The TGA and DSC results are shown in Figure 49. A weight loss of 11.7% is observed up to 130°C, and the DSC shows two endothermic peaks at 111.2°C and 202.2°C (onset temperature) before decomposition, firstly due to desolvation and secondly due to melting. Sulfate form B transforms into anhydrous sulfate form A after heating at 120°C. Also, the DMSO content of 11.3% is observed. 1 1 H NMR was detected and was consistent with the weight loss in TGA. Taking into account all characterization data, the sulfate form B was calculated as a DMSO solvate.

[0194] 3.1.2 Hemisulfate type A Hemisulfate type A is acetone / H2O(a w The hemisulfate A sample (807919-34-A) was obtained in the acetone / H2O (a = 0.8) system at room temperature. w =0.8) with a molar charge ratio of 0.5:1 (acid / base). The XRPD pattern is shown in Figure 50 and the TGA / DSC data is shown in Figure 51. The XRPD data for hemisulfate Form A gives a primary peak at 8.5, 11.4 and 12.7; a secondary peak at 6.3, 16.6 and 19.2; a tertiary peak at 7.6, 15.3 and 23.4 (peak shifts within ±0.2°).

[0195] In TGA and DSC, a weight loss of 5.9% was observed up to 80° C., and it shows two endothermic peaks at 105.3° C. and 219.2° C. (peak temperatures) before decomposition, firstly due to dehydration and secondly due to melting. A purity of 99.6 area % was detected by HPLC (Table 3-3). 1 H NMR results show that traces of acetone were detected. Combined with the stoichiometry of 0.50 (acid / base) detected by HPLC / IC, the sample (807919-34-A) was assumed to be a hydrate of the hemisulfate salt.

[0196] [Table 3-3]

[0197] 3.2 Study of the stability of sulfate form A 3.2.1 Research on disequilibrium risks A series of suspension experiments were carried out at various water activities (0–0.8) to assess the risk of imbalance. In detail, approximately 15 mg of sulfate A sample was w The suspension was weighed into 0.5 mL of acetone / H2O with a pH ranging from 0 to 0.8. After the suspension was stirred at room temperature for 5 days, the remaining solid was characterized by XRPD. As shown in Tables 3-4 and FIG. 52, a w When is lower than 0.6, no change in morphology was observed, but when hemisulfate type A is a w = 0.8, indicating a risk of disequilibrium of sulfate type A at high relative humidity.

[0198] [Table 3-4] ※ : Calculated value

[0199] 3.2.2 Thermal stability studies To understand the thermal stability at high temperatures, a sample of Sulfate Form A (807919-21-A) was stored at 80°C for 24 hours and tested by XRPD and HPLC. As shown in Tables 3-5 and Figure 53, no change in solid form or increase in HPLC impurities was observed, indicating good physical and chemical stability under the conditions tested.

[0200] [Table 3-5]

[0201] 3.3 Conclusion A total of three crystalline forms, including two monosulfate salts (anhydrous form A / DMSO solvate form B) and a hemisulfate salt form A, were obtained through polymorph screening.

[0202] In addition, the disequilibrium risk and thermal stability were evaluated for sulfate type A. As a result, 1) sulfate type A is a w = 0.8, indicating the risk of disequilibrium at high relative humidity, and 2) sulfate form A showed no substantial change in crystal form or HPLC purity and good thermal stability after storage at 80°C for 24 hours. Based on the polymorph screening and evaluation results, sulfate form A was predicted as the thermodynamically stable form of the monosulfate at room temperature.

[0203] 4. Conclusion Screening of resiquimod free base salts was performed under 100 conditions, and a total of 32 hit crystalline substances were isolated. Based on the characterization results, seven major salts, mono-HCl, di-HCl, sulfate, phosphate, maleate, malate, and adipate, were selected as the primary salts for further evaluation, including hygroscopicity, kinetic solubility, and solid-state stability. As evidenced by the results, sulfate salt with good physicochemical properties was recommended as the salt candidate. Using sulfate form A as the starting material, polymorph screening was performed under 100 conditions, and three crystal forms were observed, including one anhydrate (form A), one DMSO solvate, and one hemisulfate, indicating sulfate form A as the major form of monosulfate. In addition, sulfate form A showed good physicochemical properties under 80°C for 24 hours, but could be converted to hemisulfate at high relative humidity.

[0204] 5.1 Characterization of starting materials 5.1.1 Starting Free Base Salt Screening The starting free base (sample resiquimod, CP ID of 807919-05-A) was characterized by XRPD, PLM, TGA, DSC, HPLC and DVS.

[0205] XRPD results in Figure 54 show that the sample (807919-05-A) is crystalline and defined as free base form A. PLM image shown in Figure 55 shows a collection of small particles (<10 μm). As shown in the TGA and DSC results in Figure 56, a weight loss of 0.3% was observed up to 150°C in the TGA and the DSC curve shows one endothermic peak at 193.3°C (onset temperature). A purity of 99.1 area% was detected by HPLC (Table 5-1). The DVS plot in Figure 57 shows a water uptake of 0.1% up to 80% relative humidity, indicating that free base form A is non-hygroscopic. Also, no change in morphology was observed after DVS evaluation as shown in Figure 58.

[0206] As received, free base Form A (807919-05-A) was used as the starting material for the salt screen. The solubility of Form A was evaluated in nine solvents at room temperature. Approximately 2 mg of solid was weighed into each 3 mL glass vial and each solvent from Table 5-2 was added to the vial in 100 μL increments until the solid was completely dissolved or the total volume reached 1 mL. The solubility range of the starting material summarized in Table 5-2 was used to guide the selection of solvents for the salt screen.

[0207] [Table 5-1]

[0208] [Table 5-2]

[0209] 5.1.2 Starting sulfate for polymorph screening The XRPD comparison in Figure 59 indicates that sulfate Form A (807919-21-A) was successfully reconstituted in a 6-g scale. The detailed procedure is provided in Table 5-3. As shown in the TGA and DSC results in Figure 60, a weight loss of 2.0% was observed up to 100°C, and the DSC data showed a sharp melting peak at 209.6°C (onset temperature). Also, a purity of 99.4 area% was detected via HPLC (Table 5-4), and the stoichiometry was determined as 1.11 (acid / base) by HPLC / IC.

[0210] Reconstituted sulfate Form A (807919-21-A) was used as the starting material for the polymorph screen. The solubility data in Table 5-5 were collected employing the same procedures as in Section 5.1.1 and were incorporated to guide the selection of solvents in the design of the polymorph screen.

[0211] [Table 5-3]

[0212] [Table 5-4]

[0213] [Table 5-5]

[0214] 5.2 Abbreviations for Solvents Used The solvent abbreviations used are listed in Table 5-6.

[0215] [Table 5-6]

[0216] 5.3 Equipment and Methods 5.3.1 XRPD For XRPD analysis, a PANalytical Empyrean X-ray powder diffractometer was used, and the parameters used are listed in Tables 5-7.

[0217] [Table 5-7]

[0218] 5.3.2 TGA / DSC TGA data was collected using a TA Instruments TA Q500 / Q5000 TGA. DSC was performed using a TA Instruments TA Q200 / Q2000 DSC. Detailed parameters are listed in Tables 5-8.

[0219] [Table 5-8]

[0220] 5.3.3 HPLC Agilent 1100 HPLC was used to analyze purity and solubility, and the detailed method is listed in Tables 5-9 and 5-10.

[0221] [Table 5-9]

[0222] [Table 5-10]

[0223] 5.3.4 IC The IC method for measurement of counterion content is listed in Table 5-11 below.

[0224] [Table 5-11]

[0225] 5.3.5 PLM Polarized light microscopy photographs were captured with an Axio Lab. A1 upright microscope at room temperature.

[0226] 5.3.6 DVS DVS was measured via SMS (Surface Measurement System) DVS Intrinsic. Relative humidity at 25°C was calculated for the melting points of LiCl, Mg(NO3)2, and KCl. The actual parameters of the DVS test are listed in Table 5-12.

[0227] [Table 5-12]

[0228] 5.3.7 1 H NMR 1 H NMR spectra were collected on a Bruker 400M NMR Spectometer using DMSO-d6 as the solvent.

[0229] 5.3.8 pKa The pKa was determined using a Sirius T3™ according to the product instructions and the parameters of the pKa test are listed in Table 5-13.

[0230] [Table 5-13]

[0231] 5.4 Characterization of crystalline hits from salt screening 5.4.1 Hydrochloride type B A total of two salt crystalline forms were obtained from the screening. Hydrochloride salt form A (807919-07-D1) was obtained via solution crystallization in THF (1:1 molar charge) and form B (807919-07-C2) was produced via reactive crystallization with EtOAc (2:1 molar ratio, acid / base) at room temperature. The XRPD patterns are displayed in Figure 69. XRPD data for hydrochloride salt form B shows a first peak at 7.4, 24.3 and 26.2; a second peak at 6.7, 15.4 and 20.3; and a third peak at 12.7, 19.1 and 28.5 (peak shifts within ±0.2°).

[0232] For the hydrochloride salt Form B, the TGA and DSC data (Figure 62) show a two step weight loss of 10.8% up to 150°C, multiple endotherms before decomposition, and five endotherms at 103.5°C, 110.2°C, 181.1°C, 249.8°C, and 266.0°C (peak temperatures) before decomposition. A stoichiometry of 1.73 (acid / base) was determined by HPLC / IC and a purity of 99.2 area% was determined by HPLC as shown in Table 5-15.

[0233] [Table 5-14]

[0234] [Table 5-15]

[0235] One sulfate crystalline form was produced through screening. Sulfate Form A (807919-07-A3) was produced through solution crystallization in acetone (1:1 molar ratio) at room temperature and its XRPD pattern is shown in Figure 63. As per the TGA and DSC data shown in Figure 64, a weight loss of 0.4% was observed up to 130°C and the DSC curve shows an endothermic peak at 210.1°C (onset temperature). An area of ​​99.3% purity was detected by HPLC as shown in Table 5-16 and the stoichiometry of sulfate Form A (807919-07-A3) was determined as 0.98 (acid / base) by HPLC / IC.

[0236] [Table 5-16]

[0237] 5.4.3 Phosphates One phosphate crystalline form was obtained through screening. Phosphate form A (807919-07-E5) was obtained through solution crystallization (1:1 molar ratio) in MeOH / H2O (9:1, v / v) at room temperature, and its XRPD pattern was shown in Figure 65. TGA and DSC curves (Figure 66) showed a weight loss of 0.5% up to 150°C and an endotherm at 254.5°C (onset temperature) possibly due to melting accompanied by decomposition. Also, an area of ​​99.9% purity was detected by HPLC, as shown in Table 5-17, and the stoichiometry was determined as 0.92 (acid / base) for phosphate form A (807919-07-E5) via HPLC / IC.

[0238] [Table 5-17]

[0239] 5.4.4 Glycolate salts One glycolate crystalline form was obtained through screening. Glycolate Form A (807919-07-B9) was produced via reactive crystallization (1:1 molar ratio) in ethanol at room temperature. Its XRPD pattern is displayed in FIG. 67. XRPD data of glycolate Form A gives a first peak at 9.3, 11.8 and 22.5; a second peak at 14.4, 19.7 and 25.6; a third peak at 13.1, 18.0 and 21.5 (peak shifts within ±0.2°).

[0240] From the TGA and DSC data in Figure 68, a weight loss of 0.9% was observed up to 130°C, and the DSC results show a sharp endothermic peak at 206.0°C (onset temperature) before decomposition. Also, a purity of 99.7 area% was detected by HPLC in Table 5-18, and the stoichiometry of Glycolate Salt Form A (807919-07-B9) is: 1 Determined by 1 H NMR as 1.04 (acid / base).

[0241] [Table 5-18]

[0242] 5.4.5 Maleate One maleate crystalline form was obtained through screening. Maleate Form A (807919-07-D4) was produced via reactive crystallization (1:1 molar ratio) in THF at room temperature. The XRPD pattern is displayed in Figure 69.

[0243] The TGA and DSC results in Figure 70 show a weight loss of 1.4% up to 150°C, and an endothermic peak at 223.8°C (onset temperature) as near melting. Also, a purity of 99.3 area% was detected by HPLC as shown in Table 5-19, and the stoichiometry was: 1 Calculated by 1 H NMR as 0.98 (acid / base).

[0244] [Table 5-19]

[0245] 5.4.6 Malate One malate crystalline form was obtained via screening. Malate Form A (807919-07-B10) was produced via reactive crystallization (1:1 charge molar ratio) in EtOH at room temperature. The XRPD pattern is displayed in Figure 71.

[0246] According to the TGA and DSC data in Figure 72, a weight loss of 0.8% was observed up to 130°C, and the DSC results show a sharp endotherm at 193.3°C (onset temperature) likely due to melting. Also, a purity of 99.9 area% was detected by HPLC in Table 5-20, with the stoichiometry being: 1 Determined by 1 H NMR as 1.04 (acid / base).

[0247] [Table 5-20]

[0248] 5.4.7 Adipates One crystalline form of adipate was obtained through screening. Adipate form A (807919-07-B14) was produced via reactive crystallization (1:1 molar ratio) in EtOH at room temperature. The XRPD pattern and TGA / DSC curves are shown in Figure 73 and Figure 74, respectively.

[0249] A weight loss of 1.0% was observed in TGA up to 130°C, and the DSC results show an endothermic peak at 217.7°C (onset temperature) possibly due to melting. Also, a purity of 100.0 area% was detected by HPLC as shown in Table 5-21, and the stoichiometry of Adipate A (807919-07-B14) is: 1 Calculated by 1 H NMR as 0.52 (acid / base).

[0250] [Table 5-21]

[0251] 5.4.8 Hippurate One crystalline form of hippurate was obtained through screening. Hippurate Form A (807919-07-B11) was produced through reactive crystallization (1:1 molar ratio) in EtOH at room temperature. The XRPD pattern is displayed in Figure 75. The XRPD data of hippurate Form A gives the first peak at 5.9, 9.5 and 12.1; the second peak at 18.9, 21.2 and 25.2; and the third peak at 10.8, 23.3 and 29.2 (peak shifts within ±0.2°).

[0252] The TGA and DSC results in Figure 76 show a weight loss of 2.8% before 130°C and an endothermic peak at 213.9°C (onset temperature) before decomposition. Also, a purity of 99.6 area% was detected by HPLC as shown in Table 5-22. The stoichiometry is: 1 Determined by 1 H NMR as 1.00 (acid / base).

[0253] [Table 5-22]

[0254] 5.4.9 Tartrates A total of three tartrate salt crystal forms were obtained through screening. Tartrate salt form A (807919-07-A6), form B (807919-07-E6), and form C (807919-07-B6) were produced via reactive crystallization in acetone, MeOH / H2O (9:1, v / v), and EtOH, respectively, with a molar charge ratio of 1:1. The XRPD pattern of tartrate salt form A is shown in Figure 77. The XRPD data of tartrate salt form A gives a first peak at 6.3, 18.2, and 20.9; a second peak at 9.1, 19.4, and 25.9; and a third peak at 16.3, 23.1, and 23.6 (peak shifts within ±0.2°).

[0255] The XRPD pattern of tartrate salt form B is shown in Figure 78. The XRPD data for tartrate salt form B gives a primary peak at 8.9, 14.5 and 23.5; a secondary peak at 11.3, 16.9 and 24.2; a tertiary peak at 9.9, 13.4 and 15.4 (peak shifts within ±0.2°).

[0256] The XRPD pattern of tartrate Form C is shown in Figure 79. The XRPD data for tartrate Form C gives a primary peak at 7.2, 10.2, and 11.1; a secondary peak at 9.3, 13.8, and 18.9; and a tertiary peak at 8.7, 20.4, and 23.5 (peak shifts within ±0.2°).

[0257] For Form A, a weight loss of 2.1% was observed up to 130° C. and the DSC data (Figure 80) shows an endothermic peak at 161.4° C. (onset temperature) before decomposition. For Form B, the TGA and DSC results shown in Figure 81 show a weight loss of 3.2% up to 130° C. and two endothermic peaks at 144.9° C. and 245.8° C. (peak temperature) before decomposition. For Form C, a weight loss of 2.1% was observed up to 150° C. and the DSC results (Figure 82) show an endothermic at 72.2° C. (peak temperature) before melting at 240.9° C. (onset temperature) before decomposition.

[0258] Also, the stoichiometric ratio is 1 It was determined by 1 H NMR as 1.02 (acid / base) for Form A, and 0.52 (acid / base) for Forms B and C.

[0259] 5.4.10 Fumarate A total of three crystalline forms of fumarate salt were obtained through screening. Fumarate salt form A (807919-07-A7), form B (807919-07-E7), and form C (807919-07-C7) were produced via reactive crystallization (1:1 molar ratio) in acetone, MeOH / H2O (9:1, v / v), and EtOAc, respectively, at room temperature. The XRPD pattern of fumarate salt form A is shown in Figure 83. The XRPD data of fumarate salt form A gives the first peak at 6.4, 9.9, and 18.4; the second peak at 7.9, 23.7, and 26.0; and the third peak at 7.2, 13.3, and 25.2 (peak shifts within ±0.2°).

[0260] The XRPD pattern of fumarate salt form B is shown in Figure 84. The XRPD data for fumarate salt form B gives a primary peak at 10.0, 12.4, and 17.2; a secondary peak at 15.3, 19.1, and 20.3; and a tertiary peak at 17.2, 22.6, and 24.9 (peak shifts within ±0.2°).

[0261] The XRPD pattern of fumarate Form C is shown in Figure 85. The XRPD data for fumarate Form C gives a primary peak at 6.7, 9.1, and 26.6; a secondary peak at 11.2, 15.4, and 20.1; and a tertiary peak at 13.7, 19.4, and 21.1 (peak shifts within ±0.2°).

[0262] For Form A, the TGA and DSC data show a 0.8% weight loss up to 150° C. and three endothermic peaks at 229.9° C., 238.0° C., and 252.9° C. (peak temperatures) before decomposition (Figure 86). For Form B, the TGA and DSC data show a 4.2% weight loss up to 100° C. and four endothermic peaks at 109.6° C., 226.8° C., 237.9° C., and 255.9° C. (peak temperatures) before decomposition (Figure 87). For Form C, the TGA and DSC data show a 0.4% weight loss up to 100° C. and four endothermic peaks at 156.3° C., 237.8° C., and 248.8° C. (peak temperatures) before decomposition (Figure 88).

[0263] Also, the stoichiometry is1 The H NMR was determined to be 0.81, 0.61 and 1.03 (acid / base) for Forms AC.

[0264] 5.4.11 Citrate Two citrate crystalline forms were obtained through screening. Citrate form A (807919-07-A8) and form B (807919-07-B8) were produced via reactive crystallization (1:1 molar ratio) in acetone and EtOH, respectively, at room temperature. The XRPD pattern of citrate form A is shown in Figure 89. The XRPD data of citrate form A gives the first peak at 6.3, 11.5, and 21.3; the second peak at 14.9, 17.6, and 19.6; and the third peak at 5.7, 10.0, and 26.3 (peak shifts within ±0.2°).

[0265] The XRPD pattern of citrate form B is shown in Figure 90. The XRPD data for citrate form B gives a first peak at 6.0, 10.0 and 18.2; a second peak at 8.2, 12.1 and 21.5; and a third peak at 11.0, 13.4 and 19.2 (peak shifts within ±0.2°).

[0266] For Form A, a weight loss of 0.3% was observed up to 100° C., and the DSC (FIG. 91) results show a sharp endothermic peak at 163.1° C. (onset temperature) before decomposition. For Form B, the TGA and DSC data in FIG. 92 show a weight loss of 2.3% before 100° C., and a sharp endothermic peak at 195.3° C. (onset temperature) before decomposition.

[0267] The stoichiometric ratios are shown in Figures 108 and 109, respectively. 1 By 1 H NMR it was determined to be 1.02 and 0.53 (acid / base) for forms A and B.

[0268] 5.4.12 Lactate Two crystalline forms of lactate salt were obtained through screening. Lactate salt form A (807919-07-C12) and form B (807919-07-A12) were produced through reactive crystallization (1:1 molar ratio) in EtOAc and acetone, respectively, at room temperature. The XRPD pattern of lactate salt form A is shown in Figure 93. The XRPD data of lactate salt form A gives the first peak at 5.6, 7.5 and 9.0; the second peak at 6.7, 10.1 and 22.3; and the third peak at 8.4, 13.2 and 19.2 (peak shifts within ±0.2°).

[0269] The XRPD pattern of lactate salt form B is shown in Figure 94. The XRPD data for lactate salt form B gives a primary peak at 5.8, 7.6 and 9.4; a secondary peak at 6.8, 11.6 and 14.0; and a tertiary peak at 8.5, 18.8 and 25.6 (peaks vary within ±0.2°).

[0270] For Form A, a weight loss of 0.4% was observed in the TGA up to 100° C., and the DSC results in FIG. 95 show endothermic peaks at 85.4° C., 159.5° C., and 169.4° C. (peak temperatures) before decomposition. For Form B, the TGA and DSC results in FIG. 96 show a weight loss of 0.6% up to 100° C., and two endothermic peaks at 142.9° C. and 160.2° C. (peak temperatures) before decomposition.

[0271] The stoichiometric ratio is: 1 H NMR was determined to be 1.07 and 0.96 (acid / base) for lactate salt forms A and B.

[0272] 5.4.13 Succinate Two succinate crystalline forms were obtained through screening. Succinate Form A (807919-07-C13) and Form B (807919-07-E13) were produced through reactive crystallization (1:1 molar ratio) in EtOAc and MeOH / H2O at room temperature. The XRPD pattern of succinate Form A is shown in Figure 97. The XRPD data of succinate Form A gives a first peak at 6.4, 7.1, and 9.9; a second peak at 11.3, 18.4, and 23.1; and a third peak at 5.0, 20.1, and 24.9 (peak shifts within ±0.2°).

[0273] The XRPD pattern of succinate form B is shown in Figure 98. The XRPD data for succinate form B gives a first peak at 10.5, 17.5 and 23.9; a second peak at 8.7, 12.2 and 14.1; a third peak at 16.6, 19.7 and 22.3 (peak shifts within ±0.2°).

[0274] For Form A, the TGA and DSC results in Figure 99 show a 2.0% weight loss up to 130°C, with a sharp endothermic peak at 174.4°C (onset temperature) before decomposition. For Form B, the data (Figure 100) show a 4.6% weight loss up to 100°C, with three endothermic peaks at 103.5°C, 188.4°C, and 209.6°C (peak temperatures) before decomposition. The stoichiometry is also: 1 Determined by 1 H NMR as 1.00 and 0.52 (acid / base).

[0275] 5.4.14 Tosylate Two tosylate crystalline forms were obtained through screening. Tosylate Form A (807919-07-B15) and Form B (807919-07-D15) were produced through reactive crystallization (1:1 molar ratio) in EtOH and THF at room temperature. The XRPD pattern of tosylate Form A is shown in Figure 101. The XRPD data of tosylate Form A gives the first peak at 4.8, 9.3 and 19.2; the second peak at 14.9, 16.3 and 19.7; and the third peak at 20.7, 24.6 and 27.9 (peak shifts within ±0.2°).

[0276] The XRPD pattern of tosylate salt form B is shown in Figure 102. The XRPD data for tosylate salt form B gives a first peak at 7.7, 8.6 and 10.0; a second peak at 13.5, 15.5 and 19.9; a third peak at 17.4, 23.3 and 27.8 (peak shifts within ±0.2°).

[0277] For Form A, the TGA and DSC results in Figure 103 show a 1.3% weight loss up to 130°C, with a sharp endothermic peak at 201.5°C (onset temperature) before decomposition. For Form B, the data (Figure 104) show a 5.3% weight loss up to 150°C, with four endothermic peaks at 61.1°C, 185.4°C, 189.9°C, and 201.9°C (peak temperatures) before decomposition. The stoichiometry is also: 1 1 H NMR was determined to be 0.89 and 0.92 (acid / base) for Forms A and B.

[0278] 5.4.15 Mesylate One mesylate crystalline form was obtained through screening. Mesylate Form A was produced via reactive crystallization (1:1 molar ratio) in acetone at room temperature. The XRPD pattern is shown in Figure 105. The XRPD data of mesylate Form A gives a first peak at 8.6, 12.7, and 25.8; a second peak at 14.2, 18.6, and 19.5; and a third peak at 16.4, 17.4, and 21.3 (peak shifts within ±0.2°).

[0279] As shown in the TGA and DSC data in Figure 106, it shows a weight loss of 1.5% up to 130°C and a sharp endothermic peak at 206.6°C (onset temperature) before decomposition. 1 Determined by 1 H NMR as 0.93 (acid / base).

[0280] 5.4.16 Oxalates Two oxalate crystalline forms were obtained through screening. Oxalate Form A (807919-07-B17) and Form B (807919-07-D17) were produced via reactive crystallization (1:1 molar ratio) in EtOH and THF, respectively, at room temperature. The XRPD pattern of oxalate Form A is shown in Figure 107. The XRPD data of oxalate Form A gives the first peak at 9.2, 19.1, and 23.4; the second peak at 14.5, 17.7, and 25.0; and the third peak at 11.5, 22.6, and 30.2 (peak shifts within ±0.2°).

[0281] The XRPD pattern of oxalate Form B is shown in Figure 108. The XRPD data for oxalate Form B gives a first peak at 5.4, 18.0 and 23.1; a second peak at 9.9, 10.9 and 27.8; and a third peak at 13.0, 16.9 and 24.2 (peak shifts within ±0.2°).

[0282] For Form A, the TGA and DSC data (Figure 109) show a 0.7% weight loss up to 130°C, with a sharp endothermic peak at 227.3°C (onset temperature) before decomposition. For Form B, the TGA and DSC results (Figure 110) show a 1.8% weight loss up to 130°C, with two endothermic peaks at 190.5°C and 218.2°C (peak temperature) before decomposition. The stoichiometry was also calculated by HPLC / IC as 0.92 and 1.02 (acid / base) for Forms A and B.

[0283] 5.4.17 Gentisate A total of two crystalline forms of gentisate were obtained through screening. Gentisate form A (807919-07-A18) and form B (807919-07-E18) were produced through reactive crystallization (1:1 molar ratio) in acetone and MeOH / H2O (9:1, v / v) at room temperature, respectively. The XRPD pattern of gentisate form A is shown in Figure 111. The XRPD data of gentisate form A gives the first peak at 6.7, 10.0 and 22.9; the second peak at 7.1, 8.4 and 16.4; and the third peak at 14.4, 18.4 and 20.5 (peak shifts within ±0.2°).

[0284] The XRPD pattern of gentisate form B is shown in Figure 112. The XRPD data of gentisate form B gives a first peak at 6.3, 10.1 and 24.2; a second peak at 12.7, 20.6 and 26.2; a third peak at 11.1, 14.8 and 15.8 (peak shifts within ±0.2°).

[0285] For Form A, the TGA and DSC data (Figure 113) show a weight loss of 4.9% up to 150°C, an endothermic peak at 210.4°C (onset temperature) and an exothermic peak at 145.5°C (peak temperature) before decomposition. For Form B, the TGA and DSC results shown in Figure 114 show a weight loss of 1.7% up to 150°C, an endothermic peak at 208.2°C (onset temperature) and an exothermic peak at 148.5°C (peak temperature) before decomposition. Also, the stoichiometry is 1 By 1 H NMR it was determined to be 0.99 and 1.00 (acid / base) for Forms A and B.

[0286] 5.4.18 Benzoates A total of two benzoate crystal forms were obtained through screening. Benzoate form A (807919-07-A19) and form B (807919-07-E19) were produced via reactive crystallization (1:1 molar ratio) in acetone and MeOH / H2O (9:1, v / v) at room temperature. The XRPD pattern of benzoate form A is shown in Figure 115. The XRPD data of benzoate form A gives the first peak at 7.9, 20.8 and 21.5; the second peak at 12.0, 15.6 and 23.9; and the third peak at 8.7, 19.9 and 29.2 (peak shifts within ±0.2°).

[0287] The XRPD pattern of benzoate form B is shown in Figure 116. The XRPD data for benzoate form B gives a primary peak at 7.7, 12.5, and 18.8; a secondary peak at 13.5, 22.6, and 26.7; and a tertiary peak at 19.8, 21.4, and 24.4 (peak shifts within ±0.2°).

[0288] For Form A, the TGA and DSC results (Figure 117) show a weight loss of 0.6% up to 130°C, and an endothermic peak at 199.0°C (onset temperature) before decomposition. For Form B, the TGA and DSC data shown in Figure 118 show a weight loss of 4.0% up to 100°C, and two endothermic peaks at 102.2°C and 199.8°C (onset temperature) before decomposition. Also, the stoichiometry is 1 By 1 H NMR it was calculated as 0.98 and 0.99 (acid / base) for forms A and B.

[0289] 5.4.19 Nitrates Two nitrate crystalline forms were obtained through screening. Nitrate Form A (807919-07-D20) and Form B (807919-07-B204) were produced through solution crystallization (1:1 molar ratio) in THF and EtOH at room temperature. The XRPD pattern of Nitrate Form A is shown in Figure 119. The XRPD data of Nitrate Form A gives a first peak at 17.2, 20.5, and 21.6; a second peak at 9.1, 10.1, and 12.0; and a third peak at 14.5, 16.2, and 25.0 (peak shifts within ±0.2°).

[0290] The XRPD pattern of nitrate form B is shown in Figure 120. The XRPD data for nitrate form B gives a primary peak at 6.7, 9.1 and 25.5; a secondary peak at 9.7, 12.7 and 15.6; and a tertiary peak at 14.4, 20.1 and 26.8 (peak shifts within ±0.2°).

[0291] For Form A, the TGA and DSC results in Figure 121 show a weight loss of 1.6% up to 130°C, with a sharp endothermic peak at 212.5°C (onset temperature) before decomposition. For Form B, the TGA and DSC results (Figure 122) show a weight loss of 0.6% up to 130°C, with a sharp endothermic peak at 217.6°C (onset temperature) before decomposition. The stoichiometry was also determined by HPLC / IC as 1.04 (acid / base) for both Forms A and B.

[0292] 5.5 Sulfate polymorph screening experiment 5.5.1 Addition of anti-solvent A total of 18 anti-solvent addition experiments were performed. Approximately 15 mg of starting sulfate salt (807919-21-A) was dissolved in 0.1-2.5 mL of solvent to obtain a clear solution, the solution was stirred with a magnetic stirrer, and then 0.2 mL of anti-solvent was added stepwise until a precipitate formed or the total amount of anti-solvent reached 15.0 mL. The resulting precipitate was isolated for XRPD analysis. The results in Table 5-23 show that no new forms were obtained.

[0293] [Table 5-23] ※ : A solid was observed after stirring the clear solution after addition of the anti-solvent for 2 days at 5°C. ※※ : No solid was obtained via stirring the clear solution at 5° C., evaporation was employed.

[0294] 5.5.2 Solid-state vapor diffusion Solid vapor diffusion experiments were conducted using 13 different solvents. Approximately 10 mg of the starting sulfate salt (8079-21-A) was weighed into a 3-mL glass vial and placed in a 20-mL glass vial with 2 mL of volatile solvent. The 20-mL glass vial was sealed with a cap and stored at room temperature for 7 days to allow the solvent vapor to interact with the sample. The solid was examined by XRPD and the results, summarized in Table 5-24, show that sulfate forms A and B were produced.

[0295] [Table 5-24]

[0296] 5.5.3 Liquid vapor diffusion Ten liquid vapor diffusion experiments were performed. Approximately 15 mg of the starting sulfate salt (807919-21-A) was dissolved in a suitable solvent in a 3-mL glass vial to obtain a clear solution. This solvent was then placed in a 20-mL glass vial along with 3 mL of a volatile solvent. The 20-mL glass vial was sealed with a cap and stored at room temperature for sufficient time for the organic vapors to interact with the solution. The precipitate was isolated for XRPD analysis. After 7 days, a solid was isolated for XRPD analysis. The results, summarized in Table 5-25, indicate that only sulfate form A was obtained.

[0297] [Table 5-25]

[0298] 5.5.4 Slow evaporation Slow evaporation experiments were performed under eight conditions. Briefly, approximately 15 mg of starting sulfate (807919-21-A) was dissolved in 0.1-2.5 mL of solvent in a 3-mL glass vial. If not completely dissolved, the suspension was filtered using a nylon membrane (0.45 μm pore size) and the filtrate would be used as a substitute for the subsequent steps. A visually clear solution was allowed to evaporate at the desired temperature with the vial sealed with PARAFILM®. The solid was isolated for XRPD analysis and the results summarized in Tables 5-26 indicate that a mixture of sulfate Form A and hemisulfate Form A was produced.

[0299] [Table 5-26]

[0300] 5.5.5 Polymer-induced crystallization Polymer-induced crystallization experiments were conducted in two sets of polymer mixtures in three solvents. Approximately 15 mg of starting sulfate (807919-21-A) was dissolved in the appropriate solvent to obtain a clear solution in a 3-mL vial. Approximately 2 mg of the polymer mixture was added to a 3-mL glass vial. All samples were subjected to evaporation at room temperature to induce precipitation. The solids were isolated for XRPD analysis. The results, summarized in Table 5-27, show that only sulfate form A was produced.

[0301] [Table 5-27] Polymer mixture A: polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl chloride (PVC), polyvinyl acetate (PVAC), hypromellose (HPMC), methylcellulose (MC) (1:1:1:1:1:1 mass ratio) Polymer blend B: polycaprolactone (PCL), polyethylene glycol (PEG), poly(methyl methacrylate) (PMMA), sodium alginate (SA) and hydroxyethyl cellulose (HEC) (1:1:1:1:1 mass ratio)

[0302] 5.5.6 Suspension at room temperature Suspension conversion experiments were carried out in different solvent systems at room temperature. Approximately 15 mg of starting sulfate (807919-21-A) was suspended in 0.5 mL of solvent in a 1.5-mL glass vial. After the suspension was stirred magnetically at room temperature for 5 days, the remaining solid was isolated for XRPD analysis. The results, summarized in Table 5-28, show that hemisulfate form A was produced alongside sulfate form A.

[0303] [Table 5-28]

[0304] 5.5.7 Suspension at 50°C Suspension conversion experiments were conducted at 50° C. in different solvent systems. Approximately 15 mg of starting sulfate salt (807919-21-A) was suspended in 0.3 mL of solvent in a 1.5-mL glass vial. After the suspension was stirred at 50° C. for 6 days, the remaining solid was isolated for XRPD analysis. The results, summarized in Table 5-29, indicate that only sulfate Form A was produced.

[0305] [Table 5-29]

[0306] 5.5.8 Slow Cooling Slow cooling experiments were conducted with seven solvent systems. Approximately 20 mg of starting sulfate (807919-21-A) was suspended in 1.0 mL of solvent in a 3-mL glass vial at room temperature. The suspension was then heated to 50°C, equilibrated for approximately 2 hours, and filtered into a new vial using a nylon membrane (0.45 μm pore size). The filtrate was cooled slowly to 5°C at a rate of 0.1°C / min. The clear solution was transferred to cooling at -20°C for 2 days, and the final clear solution was allowed to evaporate at room temperature. The results, summarized in Table 5-30, show that sulfate forms A and B were produced.

[0307] [Table 5-30] N / A: Few solids for XRPD analysis ※ : The solid was obtained at -20°C.

[0308] Example 2 1. Summary Polymorphic screening of resiquimod free base was performed and the crystalline polymorphism was evaluated to identify suitable crystalline forms for further pharmaceutical development.

[0309] The received starting material (Batch No.: 1444875-48-9) was characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Characterization results indicate that the starting material is consistent with the anhydrous form of free base A.

[0310] Polymorph screening was carried out under 100 conditions using form A as the starting material through the methods of antisolvent addition, evaporation, slow cooling, suspension conversion, vapor diffusion and polymer-induced crystallization. Based on the comparison of XRPD, a total of eight crystal forms were isolated, including one anhydrate (form A), two metastable forms (forms C and F), four solvates (forms B, D, E and G) and one acetate / acetic acid co-crystal (sample H). The characterization results were summarized in Table 2-1. As shown in the interconversion diagram in Figure 144, all metastable forms and solvates converted to form A after storage at ambient conditions or heating experiments, indicating that form A is the thermodynamically stable form at room temperature (RT, 20±3°C).

[0311] Form A was selected as the major form and further evaluated for hygroscopicity and solid state stability. Hygroscopicity was evaluated using water vapor sorption measurements (DVS) at 25°C, and the results show that form A is non-hygroscopic. Physicochemical stability was investigated under conditions of 25°C / 60% RH and 40°C / 75% RH for one week, and at 80°C for 24 hours. No change in crystal morphology or decrease in HPLC purity was observed, indicating good physical and chemical stability of form A under the tested conditions.

[0312] 2. Characterization of Crystal Morphology Polymorph screening was performed under 100 experimental conditions, resulting in eight crystalline forms, including one anhydrate (Form A), two metastable forms (Forms C / F), four solvates (Forms B / D / E / G) and one acetate / acetic acid co-crystal (Sample H). The interconversion relationships between these forms were investigated via storage and heating experiments, the results of which are shown in Figure 144.

[0313] [Table 2-1] N / A: data not collected due to morphological conversion to type A. N / A: Data not available.

[0314] Procedures for the preparation of the following crystalline forms are set forth in Table 2-1a.

[0315] [Table 2-3-1]

[0316] [Table 2-3-2]

[0317] 2.1 Anhydride (type A) The starting material (Batch No: 144875-48-9, CP ID 807920-05-A) was characterized by XRPD, TGA, DSC and HPLC. The XRPD results in Figure 124 match the Form A reference (807919-05-A). The XRPD pattern is displayed in Figure 141 and gives the primary peak at 8.9, 12.4 and 17.7; secondary peaks at 19.7, 21.5 and 23.4; and a tertiary peak at 16.5, 20.1 and 26.7 (peak shifts within ±0.2°).

[0318] For the anhydrous Form A crystalline form, TGA and DSC data show a weight loss of 2.5% up to 100°C and a sharp endothermic peak at 193.0°C (onset temperature) before decomposition (Figure 125). Also, a purity of 99.4 area% was detected by HPLC in Table 2-2. Considering all the results, Form A was considered anhydrous.

[0319] [Table 2-2]

[0320] 2.2 Metastable form 2.2.1 Type C Form C was produced in a 1,4-dioxane system. A sample of Form C (807920-11-A11) was obtained via solid vapor diffusion in 1,4-dioxane. As per the XRPD pattern shown in Figure 126, Form C transformed to Form A after drying overnight at ambient conditions, indicating a metastable form of Form C at ambient conditions. The XRPD pattern gives the first peak at 9.6, 18.7 and 19.8; a second peak at 12.1, 14.5 and 21.2; and a third peak at 17.4, 20.7 and 28.5 (peak shifts within ±0.2°).

[0321] 2.2.2 Type F A sample of Form F (807929-09-A4) was obtained via slow cooling in MEK, and the XRPD pattern gives a first peak at 10.4, 16.5, and 21.2; a second peak at 8.3, 20.7, and 28.8; and a third peak at 12.5, 17.7, and 24.8 (peak shifts within ±0.2°), as shown in Figure 127.

[0322] After storage at ambient temperature for 2 days, form F transformed into form A, indicating that form F is metastable at ambient temperature.

[0323] 2.3 Solvates 2.3.1 type B Isomorphism occurred for Form B, which was prepared in several solvent systems including IBA / toluene, EtOAc, THF / H2O, etc. The XRPD pattern of Form B is displayed in Figure 128. The XRPD pattern gives a primary peak at 6.2, 16.3, and 21.4; a secondary peak at 12.3, 22.3, and 24.7; and a tertiary peak at 20.4, 27.0, and 28.4 (peak shifts within ±0.2°).

[0324] Three batches of isomorphous Form B crystalline form were produced. Batch 1: TGA and DSC data (Figure 129) show a 10.8% weight loss up to 165°C, with two endothermic peaks at 158.4°C and 192.9°C (peak temperatures) before decomposition. Batch 2: TGA and DSC data (Figure 130) show a 9.3% weight loss up to 150°C, with two endothermic peaks at 146.7°C and 191.9°C (peak temperatures) before decomposition. Batch 3: TGA and DSC data (Figure 131) show a 6.5% weight loss up to 160°C, with two endothermic peaks at 143.7°C and 194.4°C (peak temperatures) before decomposition.

[0325] Also, 1 H NMR confirmed a 5.2% EtOAc content in the sample of form B (807920-08-A7), indicating a solvate of EtOAc for form B (807920-08-A7). 1 H NMR confirmed a THF content of 6.1% in the sample of Form B (807920-12-A2), indicating a solvate of THF for Form B (807920-12-A2).

[0326] [Table 2-3]

[0327] 2.3.2 Type D A sample of Form D (807920-12-A9) was prepared via solution vapor diffusion in DMAc / MTBE. The XRPD pattern is displayed in Figure 157. The XRPD pattern gives a primary peak at 8.7, 17.6, and 23.9; a secondary peak at 11.2, 21.2, and 22.8; and a tertiary peak at 9.1, 15.5, and 16.9 (peak shifts within ±0.2°). The TGA and DSC data (Figure 133) show a weight loss of 18.4% up to 90°C, and two endothermic peaks at 87.2°C and 190.2°C (onset temperature) before decomposition. Also, 1 H NMR confirmed the content of 18.3% DMAc in the sample of Form D, indicating a solvate of DMC for Form D.

[0328] 2.3.3 Type E Form E was produced in an NMP / MTBE system. A sample of Form E was obtained via suspension in NMP / MTBE (1:2, v / v) at room temperature. The XRPD pattern is disclosed in Figure 134. The XRPD pattern gives a primary peak at 8.7, 17.9 and 23.9; a secondary peak at 16.9, 21.3 and 22.9; and a tertiary peak at 9.2, 11.2 and 12.5 (peak shifts within ±0.2°). The TGA and DSC data (Figure 135) show a weight loss of 25.5% up to 120°C, and two endothermic peaks at 134.0°C and 187.4°C (peak temperatures) before decomposition. Also, 1 H NMR showed that a content of 22.9% NMP was detected, consistent with the weight loss by TGA, indicating that Form E is an NMP solvate.

[0329] 2.3.4 Type G Form G was produced in an anisole system. A sample of Form G (807920-19-F) was obtained by rapid cooling from 50° C. to −20° C., and the XRPD pattern is shown in FIG. 136. The XRPD pattern gives a primary peak at 9.7, 13.3, and 19.2; a secondary peak at 8.9, 13.8, and 28.0; and a tertiary peak at 12.4, 20.6, and 23.4 (peak shifts within ±0.2°). TGA and DSC data (FIG. 137) show a weight loss of 14.6% up to 100° C., and two endothermic peaks at 64.5° C. and 193.0° C. (onset temperature) before decomposition. Also, 1 H NMR results showed that 12.4% anisole was detected, consistent with the second order weight loss in TGA, indicating an anisole solvate for Form G.

[0330] 2.4 Salts / co-crystals (Sample H) Sample H (807920-22-A1) was obtained via addition of anti-solvent in ethyl lactate / n-heptane with the addition of acetic acid (0.4:1 molar ratio, acid / base), and a mixture of Form A and Sample H was produced via addition of anti-solvent in ethyl lactate / n-heptane (acetic acid content is detected in ethyl lactate). The XRPD pattern shown in Figure 138 gives a first peak at 9.7, 13.3 and 19.2; a second peak at 8.9, 13.8 and 28.0; a third peak at 12.4, 20.6 and 23.4 (peak shifts within ±0.2°). TGA and DSC data (Figure 139) show a weight loss of 14.6% up to 100°C, and two endothermic peaks at 64.5°C and 193.0°C (onset temperature) before decomposition. Also, the acetic acid content is 0.47:1 (molar ratio, acid / base). 1 The combined characterization data was determined by H NMR and suggested that sample H was an acetate / acetic acid cocrystal.

[0331] 3. Evaluation of the main type A Since all solvates and metastable forms were converted to Form A after storage and heating experiments, anhydrous Form A is the thermodynamically stable form at room temperature and was chosen to further evaluate hygroscopicity and solid state stability. Results: 1) Form A is non-hygroscopic as evidenced by limited uptake of water in DVS, and 2) Form A shows good physicochemical properties under 25°C / 60% RH and 40°C / 75% RH for 1 week and under 80°C for 24 hours.

[0332] 3.1 Hygroscopicity DVS isotherm plots were collected at 25° C. to investigate the solid morphology stability as a function of humidity for anhydrous Form A (807919-05-A). The solids were pre-dried at 0% RH to remove any unbound solvent or water before initiation. As shown in the DVS plot in Figure 140, 0.1% water uptake was observed up to 80% RH, indicating that Form A (807919-05-A) is non-hygroscopic. Also, no change in morphology was observed after the DVS test (Figure 140).

[0333] 3.2 Solid-state stability The physicochemical stability of Form A (807919-05-A) was evaluated under 25°C / 60%RH and 40°C / 75%RH for one week, and under 80°C (closed section) for 24 hours. Stability samples were characterized by XRPD and HPLC, with the results summarized in Table 3-1 and Figure 142. No changes in HPLC purity or crystal morphology were observed, indicating good physicochemical stability of Form A (807919-05-A) under the conditions tested.

[0334] [Table 3-1] ※ : Data was collected during the salt screening section.

[0335] 4. Conclusion Using the free base form A of compound 001 as the starting material, a total of 100 polymorph screening experiments were prepared, and solid-state XRPD analysis revealed that eight crystalline forms were obtained. The form identification results show that one anhydrate (form A), two metastable forms (forms C / F), four solvates (forms B / D / E / G) and one acetate / acetic acid cocrystal (sample H) were present. The interconversion results show that all of forms B-G were converted to form A after heating or storage, indicating good physical stability of form A. Furthermore, form A was evaluated by hygroscopicity and solid-state stability. The results show that form A is non-hygroscopic and has good physicochemical properties under 25°C / 60% RH and 40°C / 75% RH for one week, and under 80°C for 24 hours. Combined with the characterization results, form A is recommended for further pharmaceutical development.

[0336] 5.Other 5.1 Sample Information The starting material as received was used directly for polymorph screening and evaluation experiments, the detailed information of which is shown in Table 5-1.

[0337] [Table 5-1] NA: The information was not used.

[0338] 5.2 Abbreviations for Solvents Used Solvent abbreviations are listed in Table 5-2.

[0339] [Table 5-2]

[0340] 5.3 Equipment and Methods 5.3.1 XRPD For XRPD analysis, a PANalytical Empyrean X-ray powder diffractometer was used. The XRPD parameters used are listed in Table 5-3.

[0341] [Table 5-3]

[0342] 5.3.2 TGA and DSC TGA data was collected using a TA Instruments TAQ500 / Q5000TGA. DSC was performed using a TA Instruments TAQ200 / Q2000DSC. Detailed parameters used are listed in Table 5-4.

[0343] [Table 5-4]

[0344] 5.3.3 HPLC An Aglient 1100 HPLC was utilized for purity analysis, the detailed method of which is listed in Table 5-5.

[0345] [Table 0-1]

[0346] 5.3.4 DVS DVS was measured via SMS (Surface Measurement System) DVS Intrinsic. Relative humidity at 25°C was calibrated against the melting points of LiCl, Mg(NO3)2 and KCl. The actual parameters for the DVS test are listed in Table 5-6.

[0347] [Table 5-6]

[0348] 5.3.5 Solution NMR Solution NMR was collected on a Bruker 400M NMR Spectrometer using DMSO-d6.

[0349] 5.4 Polymorphism Screening The solubility of the starting material (807920-05-A) was evaluated at room temperature. Approximately 2 mg of solid was added to a 3-mL glass vial. Solvent was then added stepwise (100 μL per step) until the solid dissolved or until a total volume of 1 mL was reached. The results, summarized in Tables 5-7, were used to guide the selection of solvents in the polymorph screening.

[0350] Polymorph screening experiments were performed using different crystallization or solid state transformation methods. The methods employed and the identified crystalline forms are summarized in Tables 5-8.

[0351] [Table 5-7]

[0352] [Table 5-8]

[0353] 5.4.1 Addition of anti-solvent A total of 20 anti-solvent addition experiments were performed. Approximately 15 mg of starting material (807920-05-A) was dissolved in 0.1-2.3 mL of solvent to obtain a clear solution, which was stirred with a magnetic stirrer, followed by the addition of 0.2 mL of anti-solvent in steps until a precipitate formed or until a total amount of anti-solvent reached 15.0 mL. The resulting precipitate was isolated for XRPD analysis. The results in Table 5-9 show that Forms B, G and Sample H were produced alongside Form A.

[0354] [Table 5-9] ※ : A solid was observed after stirring the clear solution for 2 days at 5° C. followed by addition of anti-solvent. ※※ : No solid was obtained by stirring the clear solution at 5°C and evaporation was performed.

[0355] 5.4.2 Slow evaporation Slow evaporation experiments were carried out under 10 conditions. Briefly, about 15 mg of starting material (807920-05-A) was dissolved in 1.0-2.0 mL of solvent in a 3-mL glass vial. If not completely dissolved, the suspension was filtered using a nylon membrane (0.45 μm pore size) and the filtrate would be used as a substitute for the subsequent steps. The visually clear solution was exposed to evaporation at room temperature with the vial sealed with PARAFILM®. The solid was isolated for XRPD analysis and the results summarized in Tables 5-10 show that Forms A and B were obtained.

[0356] [Table 5-10]

[0357] 5.4.3 Slow Cooling Slow cooling experiments were conducted with 10 solvent systems. Approximately 15 mg of starting material (807920-05-A) was suspended in 1.0 mL of solvent in a 3-mL glass vial at room temperature. The suspension was then heated to 50°C, equilibrated for 2 h, and filtered using a nylon membrane (0.45 μm pore size). The filtrate was slowly cooled to 5°C at a rate of 0.1°C / min. The resulting solid was kept isothermal at 5°C before being isolated for XRPD analysis. The clear solution was transferred to -20°C and, if still clear, exposed to evaporation at room temperature. The results, summarized in Tables 5-11, show that Forms B, F, and G were produced alongside Form A.

[0358] [Table 5-11] No solids were obtained upon slow cooling and all samples were transferred to -20°C. ※ A small amount of solid was obtained and the system was allowed to evaporate at room temperature.

[0359] 5.4.4 Polymer-induced crystallization Polymer-induced crystallization experiments were conducted in two sets of polymer mixtures in seven solvents. Approximately 15 mg of starting material (807920-05-A) was dissolved in the appropriate solvent to obtain a clear solution in a 3-mL vial. Approximately 2 mg of the polymer mixture was added to a 3-mL glass vial. All samples were subjected to evaporation at room temperature to induce precipitation. The solids were isolated for XRPD analysis. The results, summarized in Tables 5-12, show that Forms A and B were produced.

[0360] [Table 5-12] Polymer mixture A: polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl chloride (PVC), polyvinyl acetate (PVAC), hypromellose (HPMC), methylcellulose (MC) (1:1:1:1:1:1 mass ratio) Polymer mixture B: polycaprolactone (PCL), polyethylene glycol (PEG), poly(methyl methacrylate) (PMMA) sodium alginate (SA), and hydroxyethyl cellulose (HEC) (1:1:1:1:1 mass ratio).

[0361] 5.4.5 Solid-state vapor diffusion Solid vapor diffusion experiments were conducted using 13 different solvents. Approximately 10 mg of starting material (807920-05-A) was weighed into a 3-mL glass vial and placed in a 20-mL glass vial with 2 mL of volatile solvent. The 20-mL glass vial was sealed with a cap and stored at room temperature for 7 days to allow the solvent vapor to interact with the sample. The solids were examined by XRPD and the results, summarized in Table 5-13, show that Forms A and C were produced.

[0362] [Table 5-13]

[0363] 5.4.6 Liquid vapor diffusion Ten liquid vapor diffusion experiments were performed. Approximately 15 mg of starting material (807920-05-A) was dissolved in an appropriate solvent in a 3-mL glass vial to obtain a clear solution. This solution was then placed in a 20-mL glass vial along with 3 mL of a volatile solvent. The 20-mL glass vial was sealed with a cap and stored at room temperature for sufficient time for the organic vapors to interact with the solution. The precipitate was isolated for XRPD analysis. After 6 days, a solid was isolated for XRPD analysis. The results, summarized in Table 5-14, show that Forms B, D, and E were produced alongside Form A.

[0364] [Table 5-14]

[0365] 5.4.7 Suspension at room temperature Suspension conversion experiments were carried out at room temperature in different solvent systems. Approximately 15 mg of starting material (807920-05-A) was suspended in 0.5 mL of solvent in a 1.5-mL glass vial. After the suspension was stirred on a magnetic stirrer for 3 days at room temperature, the remaining solid was isolated for XRPD analysis. The results, summarized in Table 5-15, show that only Form A was obtained.

[0366] [Table 5-15]

[0367] 5.4.8 Suspension at 50°C Suspension conversion experiments were carried out at 50° C. in different solvent systems. Approximately 15 mg of starting material (807920-05-A) was suspended in 0.3 mL of solvent in a 1.5-mL glass vial. After the suspension was stirred at 50° C. for 3 days, the remaining solid was isolated for XRPD analysis. The results, summarized in Tables 5-16, show that Forms A and C were obtained.

[0368] [Table 5-16]

[0369] The above disclosure is illustrative. It should be recognized by those skilled in the art that the techniques disclosed herein describe representative techniques that serve to implement the teachings of the present application. However, those skilled in the art, in light of the teachings of the present application, may make many changes to the specific embodiments disclosed and still obtain the same or similar results without departing from the spirit and scope of the present invention.

[0370] Unless otherwise noted, all numbers expressing quantities of ingredients, properties such as molecular weights, and reaction conditions used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may be varied depending on the desired properties sought to be obtained by the present invention. Without attempting to limit the scope of the claims to the theory of equivalents in the specification, each numerical parameter should, at the very least, be construed in light of the number of recited significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values ​​are reported and described as precisely as possible in the specific examples. However, some numerical values ​​inherently contain certain variations necessarily resulting from the standard deviation found in their respective testing measurements.

[0371] As used in the context of describing the invention (particularly in the context of the claims that follow), "a," "an," "the," and similar references are to be construed as covering both one and more than one, unless otherwise indicated herein or otherwise clearly contradicted by context. Value ranges described herein are merely a shorthand way of referring to each individual value within the range separately. Unless otherwise indicated, each individual value is incorporated herein as if set forth herein. All methods described herein can be performed in any suitable order, unless otherwise indicated or otherwise clearly contradicted by context. The use of any or all of the examples or representative language described herein (e.g., "such as") is merely intended to better illuminate the invention and does not limit the scope of the invention as described in the claims. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0372] Groups of alternative elements or embodiments of the invention disclosed herein should not be construed as limiting. Each member of a group may be set forth and referred to in the claims individually or in combination with other members of the group or other elements described herein. One or more members of a group may be included in or deleted from a group for reasons of convenience and / or patentability. When such inclusion or deletion occurs, the appended claim is considered modified to satisfy all Markush group descriptions used in the appended claim.

[0373] The specific embodiments of the invention described herein include the best mode known to the inventors for carrying out the invention. Of course, variations of these described embodiments will become apparent to those of skill in the art upon reading the foregoing description. The inventors expect those of skill in the art to make such appropriate variations and intend to modify the matters specifically described herein. Accordingly, the present invention includes all modifications and equivalents of the subject matter recited in the claims to the extent permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is included in this application unless otherwise indicated or otherwise clearly contradicted by context.

[0374] Additionally, numerous references are made throughout this specification to patents and printed publications. Each of the references and printed publications mentioned above is individually incorporated by reference in its entirety into this application.

[0375] Additionally, certain embodiments disclosed herein may be limited in the claims using the terms "consising of" or "consisting essentially of." When used in a claim as submitted or as amended, the transitional term "consising of" excludes any element, step, or ingredient not specifically recited in the claim. The transitional term "consising essentially of" limits the scope of the claim to certain materials or steps that do not materially affect the basic and novel characteristics. Thus, the claimed embodiments of the invention are inherently or explicitly set forth and enabled in the present application.

[0376] In conclusion, the embodiments of the invention disclosed herein are illustrative of the principles of the invention. Thus, by way of example, but not of limitation, alternative configurations of the invention may be utilized in accordance with the present disclosure. Accordingly, the invention is not limited to the exact details described and illustrated.

[0377] (Additional Note) (Appendix 1) A composition comprising resiquimod in the form of a sulfate salt in crystalline form A.

[0378] (Appendix 2) The sulfate is a monosulfate. 2. The composition of claim 1.

[0379] (Appendix 3) The sulfate salt is anhydrous. 2. The composition of claim 1.

[0380] (Appendix 4) Crystalline form A is characterized by an X-ray powder diffraction spectrum containing peaks at about 7° to about 8° 2θ, about 13.5° to about 14.5° 2θ, about 19° to about 20° 2θ, and about 19.5° to about 20.5° 2θ. 2. The composition of claim 1.

[0381] (Appendix 5) The crystalline form A is stable at room temperature for at least about 2 days. 2. The composition of claim 1.

[0382] (Appendix 6) The crystalline form A is stable at room temperature for at least about one week. 2. The composition of claim 1.

[0383] (Appendix 7) A dosage form comprising the composition of claim 1.

[0384] (Appendix 8) Formula I [ka] (In the formula, R 1 is hydrogen; substituted or unsubstituted C1-C 10 linear or branched alkyl, the substituent being C3-C6 cycloalkyl or C3-C6 cycloalkyl substituted with linear or branched C1-C4 alkyl; 10 Alkenyl; substituted straight or branched C2-C 10alkenyl, wherein the substituent is C3-C6 cycloalkyl or C3-C6 cycloalkyl substituted with straight or branched chain C1-C4 alkyl; C1-C6 hydroxyalkyl; alkoxyalkyl, wherein the alkoxy moiety contains from 1 to about 4 carbon atoms and the alkyl moiety contains from 1 to about 6 carbon atoms; acyloxyalkyl, wherein the acyloxy moiety is alkanoyloxy or benzoyloxy of 2 to about 4 carbon atoms and the alkyl moiety contains from 1 to about 6 carbon atoms; or benzyl; (phenyl)ethyl; or phenyl, wherein the benzyl, (phenyl)ethyl, or phenyl substituent is optionally substituted on the benzene ring with one or two moieties independently selected from C1-C4 alkyl, C1-C4 alkoxy, or halogen, with the proviso that when the benzene ring is substituted with two moieties, the two moieties contain a total of 6 or fewer carbon atoms; R 2 and R 3 is independently selected from hydrogen, C1-C4 alkyl, phenyl, or substituted phenyl, wherein the substituents are C1-C4 alkyl, C1-C4 alkoxy, or halogen; X is C1-C4 alkoxy, alkoxyalkyl where the alkoxy moiety contains 1 to about 4 carbon atoms and the alkyl moiety contains 1 to about 4 carbon atoms, alkoxyalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, alkylamido where the alkyl group contains 1 to about 4 carbon atoms, alkylamido, amino, substituted amino where the substituent is C1-C4 alkyl or C1-C4 hydroxyalkyl, amino, azido, chloro, hydroxy, 1-morpholino, 1-pyrrolidino, or C1-C4 alkylthio; and R is hydrogen, a straight or branched chain C1-C4 alkoxy, halogen, or a straight or branched chain C1-C4 alkyl. The compound of formula (I) comprises a crystalline form of the crystalline form being the hydrochloride, sulfate, phosphate, maleate, malate, adipate, glycolate, hippurate, tartrate, fumarate, citrate, lactate, succinate, tosylate, mesylate, oxalate, gentisate, benzoate or nitrate salt of crystalline form A, B, C, D, E, F or G; composition.

[0385] (Appendix 9) R1 is 2-methylpropyl or benzyl; 9. The composition of claim 8.

[0386] (Appendix 10) X is azido, hydroxy, ethoxy, methoxy, 1-morpholino or methylthio; 9. The composition of claim 8.

[0387] (Appendix 11) R is hydrogen; 9. The composition of claim 8.

[0388] (Appendix 12) The compound is 4-amino-α-butyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]-quinoline-2-methanol hemihydrate, 4-amino-α,α-dimethyl-2-ethoxymethyl-1H-imidazo-[4,5-c]-quinoline-1-ethanol, 2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]-quinolin-4-amine, or 4-amino-1-phenylmethyl-1H-imidazo-[4,5-c]-quinoline-2-methanol, 9. The composition of claim 8.

[0389] (Appendix 13) The compound is resiquimod. 9. The composition of claim 8.

[0390] (Appendix 14) The crystalline form is Form A. 9. The composition of claim 8.

[0391] (Appendix 15) The crystalline form is a sulfate salt. 9. The composition of claim 8.

[0392] (Appendix 16) The sulfate is a monosulfate. 16. The composition of claim 15.

[0393] (Appendix 17) The sulfate salt is anhydrous. 16. The pharmaceutical composition of claim 15.

[0394] (Appendix 18) A method of treating cancer in a subject in need of such treatment, comprising administering to a subject in need of such treatment a composition comprising a crystalline form of a compound of the formula set forth in Appendix 8.

[0395] (Appendix 19) A method of treating a tumor in a subject in need of such treatment, comprising administering to a subject in need of such treatment a composition comprising a crystalline form of a compound of the formula described in Appendix 8.

[0396] (Appendix 20) The tumor is a carcinoma, a sarcoma, or a blastoma. Tumor That is, 19. The method according to claim 18.

Claims

1. The monosulfate salt of resiquimod in crystalline form.

2. Anhydrous, The monosulfate salt of resiquimod in crystalline form according to claim 1.

3. characterized by an X-ray powder diffraction spectrum exhibiting peaks at 7.6±0.2°2θ, 11.7±0.2°2θ, 15.5±0.2°2θ, 17.6±0.2°2θ, 18.2±0.2°2θ, and 24.4±0.2°2θ; The monosulfate salt of resiquimod in crystalline form according to claim 1.

4. characterized by an X-ray powder diffraction spectrum exhibiting peaks at 7.6±0.2°2θ, 9.6±0.2°2θ, 11.7±0.2°2θ, 13.4±0.2°2θ, 15.5±0.2°2θ, 17.6±0.2°2θ, 18.2±0.2°2θ, 23.5±0.2°2θ, and 24.4±0.2°2θ; The monosulfate salt of resiquimod in crystalline form according to claim 1.

5. Characterized by a DSC curve exhibiting a melting peak having an onset temperature at 209.6° C., 210.1° C. or 214.4° C.; The monosulfate salt of resiquimod in crystalline form according to claim 1.

6. Characterized by a DSC curve showing a melting peak with an onset temperature at 210° C. and an endothermic peak at 213° C. The monosulfate salt of resiquimod in crystalline form according to claim 1.

7. characterized by an X-ray powder diffraction spectrum exhibiting peaks at 7.6±0.2 degrees 2θ, 11.7±0.2 degrees 2θ, 15.5±0.2 degrees 2θ, 17.6±0.2 degrees 2θ, 18.2±0.2 degrees 2θ, and 24.4±0.2 degrees 2θ; and Characterized by a DSC curve exhibiting a melting peak having an onset temperature at 209.6° C., 210.1° C. or 214.4° C.; The monosulfate salt of resiquimod in crystalline form according to claim 1.

8. characterized by an X-ray powder diffraction spectrum exhibiting peaks at 7.6±0.2°2θ, 9.6±0.2°2θ, 11.7±0.2°2θ, 13.4±0.2°2θ, 15.5±0.2°2θ, 17.6±0.2°2θ, 18.2±0.2°2θ, 23.5±0.2°2θ, and 24.4±0.2°2θ; and Characterized by a DSC curve exhibiting a melting peak having an onset temperature at 209.6° C., 210.1° C. or 214.4° C.; The monosulfate salt of resiquimod in crystalline form according to claim 1.

9. A crystalline form of resiquimod monosulfate according to any one of claims 1 to 8; at least one pharma- ceutically acceptable carrier or excipient; A composition comprising:

10. 9. A method for the treatment of a rheumatoid arthritis comprising administering to a patient a crystalline form of resiquimod monosulfate according to any one of claims 1 to 8 in combination with a pharma- ceutically acceptable carrier or excipient. A method for preparing a pharmaceutical composition.

11. A dosage form comprising the composition of claim 9.

12. For the treatment of cancer, 9. The monosulfate salt of resiquimod in a crystalline form according to any one of claims 1 to 8.

13. The cancer is selected from breast cancer, head and neck cancer, ovarian cancer, uterine cancer, skin cancer, brain cancer, bladder cancer, thyroid cancer, liver cancer, pancreatic cancer, lung cancer, eye cancer, throat cancer, esophageal cancer, stomach cancer, intestinal cancer, rectal cancer, testicular cancer, ovarian cancer, vaginal cancer, bone cancer, blood cancer and prostate cancer. The monosulfate salt of resiquimod in crystalline form according to claim 12.

14. For the treatment of tumors, 9. The monosulfate salt of resiquimod in a crystalline form according to any one of claims 1 to 8.

15. The tumor is a carcinoma, a sarcoma, a blastoma, or a combination thereof; 15. The crystalline form of resiquimod monosulfate according to claim 14.

16. The tumors include adrenal tumors, bone tumors, brain tumors, breast tumors, bronchial tumors, colon tumors, gallbladder tumors, kidney tumors, pharyngeal tumors, liver tumors, lung tumors, nerve tumors, pancreatic tumors, prostate tumors, parathyroid tumors, skin tumors, gastric tumors, thyroid tumors, adenocarcinoma, squamous cell carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, squamous cell carcinoma, combined small cell carcinoma, verrucous carcinoma, basal cell carcinoma, transitional cell carcinoma, inverted papilloma, plastic gastritis, familial adenomatous polyposis, insulinoma, glucagonoma, gastrinoma, VIP-producing tumor, somatostatinoma, cholangiocarcinoma, Kraskin tumor, hepatocellular adenoma, hepatocellular carcinoma, renal cell carcinoma, Endometriotic tumor, renal oncocytoma, prolactinoma, multiple endocrine neoplasm, adrenal cortical adenoma, adrenal cortical carcinoma, Hürthle cell, neuroendocrine tumor, adenoid cystic carcinoma, eosinophilic adenoma, clear cell adenocarcinoma, apdoma, cylindroma, papillary hidradenoma, hydrocele, syringoma, papillary cystadenoma, cystadenoma, cystadenocarcinoma, signet ring cell carcinoma, mucinous cystadenoma, mucinous cystadenocarcinoma, mucoepidermoid carcinoma, ovarian serous cystadenoma, pancreatic serous cystadenoma, serous cystadenocarcinoma, papillary serous cystadenocarcinoma, breast ductal carcinoma, pancreatic ductal adenocarcinoma, comedocarcinoma of the breast, Paget's disease of the breast, extramammary Paget's disease, lobular carcinoma in situ, invasive lobular carcinoma, medullary carcinoma of the breast carcinoma of the breast), medullary thyroid carcinoma, acinic cell carcinoma, Warthin's tumor, and thymoma; or The tumors include soft tissue sarcoma, connective tissue sarcoma, liposarcoma, myomatous sarcoma, complex mixed and stromal sarcoma, adenomatous tumor, adenomyoma, aggressive childhood fibromatosis, alveolar rhabdomyosarcoma, angiolipoleiomyoma, angiomyolipoma, angioleiomyoma, angiomyxoma, angiosarcoma, aponeurotic fibroma, Askin tumor, atypical fibroxanthoma, benign lipoblastomatosis, Brenner tumor, carcinosarcoma, chondroid lipoma, chondrosarcoma, clear cell sarcoma, renal clear cell sarcoma, collagenous fibroma, and collagenous fibroma. fibroma), cystosarcoma phyllodes, dermal trunk fibrosarcoma, dermatofibrosarcoma protuberans (DFSP), dendroid fibroma, desmoplastic small round cell tumor, sporadic childhood fibromatosis, Ewing / PNET tumor, familial myxoid angiofibroma, fibroadenoma, tendon sheath fibroma, cervical fibromatosis, fibrous histiocytoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), genital leiomyoma, hemangioendothelioma, hepatoblastoma, brown lipoma, histiocytoma, childhood digital fibromatosis, intradermal spindle cell lipoma, juvenile hyalin fibromatosis, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, mesoblastic nephroma, mesothelioma, mixed Mullerian tumor, multiple cutaneous leiomyomas, multiple skin and uterine leiomyoma syndrome (a multiple cutaneous and uterine leiomyoma syndrome) and uterine leiomyomatosis, myelolipoma, myosarcoma, myxoid liposarcoma, myxoid sarcoma, neurogenic fibrolipoma, neurofibrosarcoma, oral-vaginal submucosal fibrosis, ossifying fibromyxoma, osteosarcoma, pancreatoblastoma, phyllodes tumor, footpad fibromatosis, pleomorphic adenoma, pleomorphic fibroma, fatty tumor, rhabdomyosarcoma, botryoid sarcoma, Schwannoma sarcoma, solitary cutaneous leiomyoma a sarcoma selected from the group consisting of leiomyoma, solitary fibrous tumor, spindle cell lipoma, smooth muscle tumor of uncertain malignant potential (STUMP), synovial sarcoma, angiosarcoma, and Wilms' tumor; or The tumor is a blastoma selected from chondroblastoma, hepatoblastoma, medulloblastoma, nephroblastoma, neuroblastoma, pancreatoblastoma, pleuroblastoma, retinoblastoma, and glioblastoma multiforme; 16. The monosulfate salt of resiquimod in crystalline form according to claim 15.

17. For the treatment of cancer, The composition of claim 9.

18. The cancer is selected from breast cancer, head and neck cancer, ovarian cancer, uterine cancer, skin cancer, brain cancer, bladder cancer, thyroid cancer, liver cancer, pancreatic cancer, lung cancer, eye cancer, throat cancer, esophageal cancer, stomach cancer, intestinal cancer, rectal cancer, testicular cancer, ovarian cancer, vaginal cancer, bone cancer, blood cancer and prostate cancer.

18. The composition of claim 17.

19. For the treatment of tumors, The composition of claim 9.

20. The tumor is a carcinoma, a sarcoma, a blastoma, or a combination thereof; 20. The composition of claim 19.

21. The tumors include adrenal tumors, bone tumors, brain tumors, breast tumors, bronchial tumors, colon tumors, gallbladder tumors, kidney tumors, pharyngeal tumors, liver tumors, lung tumors, nerve tumors, pancreatic tumors, prostate tumors, parathyroid tumors, skin tumors, gastric tumors, thyroid tumors, adenocarcinoma, squamous cell carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, squamous cell carcinoma, combined small cell carcinoma, verrucous carcinoma, basal cell carcinoma, transitional cell carcinoma, inverted papilloma, plastic gastritis, familial adenomatous polyposis, insulinoma, glucagonoma, gastrinoma, VIP-producing tumor, somatostatinoma, cholangiocarcinoma, Kraskin tumor, hepatocellular adenoma, hepatocellular carcinoma, renal cell carcinoma, Endometriotic tumor, renal oncocytoma, prolactinoma, multiple endocrine neoplasm, adrenal cortical adenoma, adrenal cortical carcinoma, Hürthle cell, neuroendocrine tumor, adenoid cystic carcinoma, eosinophilic adenoma, clear cell adenocarcinoma, apdoma, cylindroma, papillary hidradenoma, hydrocele, syringoma, papillary cystadenoma, cystadenoma, cystadenocarcinoma, signet ring cell carcinoma, mucinous cystadenoma, mucinous cystadenocarcinoma, mucoepidermoid carcinoma, ovarian serous cystadenoma, pancreatic serous cystadenoma, serous cystadenocarcinoma, papillary serous cystadenocarcinoma, breast ductal carcinoma, pancreatic ductal adenocarcinoma, comedocarcinoma of the breast, Paget's disease of the breast, extramammary Paget's disease, lobular carcinoma in situ, invasive lobular carcinoma, medullary carcinoma of the breast carcinoma of the breast), medullary thyroid carcinoma, acinic cell carcinoma, Warthin's tumor, and thymoma; or The tumors include soft tissue sarcoma, connective tissue sarcoma, liposarcoma, myomatous sarcoma, complex mixed and stromal sarcoma, adenomatous tumor, adenomyoma, aggressive childhood fibromatosis, alveolar rhabdomyosarcoma, angiolipoleiomyoma, angiomyolipoma, angioleiomyoma, angiomyxoma, angiosarcoma, aponeurotic fibroma, Askin tumor, atypical fibroxanthoma, benign lipoblastomatosis, Brenner tumor, carcinosarcoma, chondroid lipoma, chondrosarcoma, clear cell sarcoma, renal clear cell sarcoma, collagenous fibroma, and collagenous fibroma. fibroma), cystosarcoma phyllodes, dermal trunk fibrosarcoma, dermatofibrosarcoma protuberans (DFSP), dendroid fibroma, desmoplastic small round cell tumor, sporadic childhood fibromatosis, Ewing / PNET tumor, familial myxoid angiofibroma, fibroadenoma, tendon sheath fibroma, cervical fibromatosis, fibrous histiocytoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), genital leiomyoma, hemangioendothelioma, hepatoblastoma, brown lipoma, histiocytoma, childhood digital fibromatosis, intradermal spindle cell lipoma, juvenile hyalin fibromatosis, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, mesoblastic nephroma, mesothelioma, mixed Mullerian tumor, multiple cutaneous leiomyomas, multiple skin and uterine leiomyoma syndrome (a multiple cutaneous and uterine leiomyoma syndrome) and uterine leiomyomatosis, myelolipoma, myosarcoma, myxoid liposarcoma, myxoid sarcoma, neurogenic fibrolipoma, neurofibrosarcoma, oral-vaginal submucosal fibrosis, ossifying fibromyxoma, osteosarcoma, pancreatoblastoma, phyllodes tumor, footpad fibromatosis, pleomorphic adenoma, pleomorphic fibroma, fatty tumor, rhabdomyosarcoma, botryoid sarcoma, Schwannoma sarcoma, solitary cutaneous leiomyoma a sarcoma selected from the group consisting of leiomyoma, solitary fibrous tumor, spindle cell lipoma, smooth muscle tumor of uncertain malignant potential (STUMP), synovial sarcoma, angiosarcoma, and Wilms' tumor; or The tumor is a blastoma selected from chondroblastoma, hepatoblastoma, medulloblastoma, nephroblastoma, neuroblastoma, pancreatoblastoma, pleuroblastoma, retinoblastoma, and glioblastoma multiforme; 21. The composition of claim 20.

22. For the treatment of cancer, The dosage form of claim 11.

23. The cancer is selected from breast cancer, head and neck cancer, ovarian cancer, uterine cancer, skin cancer, brain cancer, bladder cancer, thyroid cancer, liver cancer, pancreatic cancer, lung cancer, eye cancer, throat cancer, esophageal cancer, stomach cancer, intestinal cancer, rectal cancer, testicular cancer, ovarian cancer, vaginal cancer, bone cancer, blood cancer and prostate cancer.

23. The dosage form of claim 22.

24. For the treatment of tumors, The dosage form of claim 11.

25. The tumor is a carcinoma, a sarcoma, a blastoma, or a combination thereof; 25. The dosage form of claim 24.

26. The tumors include adrenal tumors, bone tumors, brain tumors, breast tumors, bronchial tumors, colon tumors, gallbladder tumors, kidney tumors, pharyngeal tumors, liver tumors, lung tumors, nerve tumors, pancreatic tumors, prostate tumors, parathyroid tumors, skin tumors, gastric tumors, thyroid tumors, adenocarcinoma, squamous cell carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, squamous cell carcinoma, combined small cell carcinoma, verrucous carcinoma, basal cell carcinoma, transitional cell carcinoma, inverted papilloma, plastic gastritis, familial adenomatous polyposis, insulinoma, glucagonoma, gastrinoma, VIP-producing tumor, somatostatinoma, cholangiocarcinoma, Kraskin tumor, hepatocellular adenoma, hepatocellular carcinoma, renal cell carcinoma, Endometriotic tumor, renal oncocytoma, prolactinoma, multiple endocrine neoplasm, adrenal cortical adenoma, adrenal cortical carcinoma, Hürthle cell, neuroendocrine tumor, adenoid cystic carcinoma, eosinophilic adenoma, clear cell adenocarcinoma, apdoma, cylindroma, papillary hidradenoma, hydrocele, syringoma, papillary cystadenoma, cystadenoma, cystadenocarcinoma, signet ring cell carcinoma, mucinous cystadenoma, mucinous cystadenocarcinoma, mucoepidermoid carcinoma, ovarian serous cystadenoma, pancreatic serous cystadenoma, serous cystadenocarcinoma, papillary serous cystadenocarcinoma, breast ductal carcinoma, pancreatic ductal adenocarcinoma, comedocarcinoma of the breast, Paget's disease of the breast, extramammary Paget's disease, lobular carcinoma in situ, invasive lobular carcinoma, medullary carcinoma of the breast carcinoma of the breast), medullary thyroid carcinoma, acinic cell carcinoma, Warthin's tumor, and thymoma; or The tumors include soft tissue sarcoma, connective tissue sarcoma, liposarcoma, myomatous sarcoma, complex mixed and stromal sarcoma, adenomatous tumor, adenomyoma, aggressive childhood fibromatosis, alveolar rhabdomyosarcoma, angiolipoleiomyoma, angiomyolipoma, angioleiomyoma, angiomyxoma, angiosarcoma, aponeurotic fibroma, Askin tumor, atypical fibroxanthoma, benign lipoblastomatosis, Brenner tumor, carcinosarcoma, chondroid lipoma, chondrosarcoma, clear cell sarcoma, renal clear cell sarcoma, collagenous fibroma, and collagenous fibroma. fibroma), cystosarcoma phyllodes, dermal trunk fibrosarcoma, dermatofibrosarcoma protuberans (DFSP), dendroid fibroma, desmoplastic small round cell tumor, sporadic childhood fibromatosis, Ewing / PNET tumor, familial myxoid angiofibroma, fibroadenoma, tendon sheath fibroma, cervical fibromatosis, fibrous histiocytoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), genital leiomyoma, hemangioendothelioma, hepatoblastoma, brown lipoma, histiocytoma, childhood digital fibromatosis, intradermal spindle cell lipoma, juvenile hyalin fibromatosis, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, mesoblastic nephroma, mesothelioma, mixed Mullerian tumor, multiple cutaneous leiomyomas, multiple skin and uterine leiomyoma syndrome (a multiple cutaneous and uterine leiomyoma syndrome) and uterine leiomyomatosis, myelolipoma, myosarcoma, myxoid liposarcoma, myxoid sarcoma, neurogenic fibrolipoma, neurofibrosarcoma, oral-vaginal submucosal fibrosis, ossifying fibromyxoma, osteosarcoma, pancreatoblastoma, phyllodes tumor, footpad fibromatosis, pleomorphic adenoma, pleomorphic fibroma, fatty tumor, rhabdomyosarcoma, botryoid sarcoma, Schwannoma sarcoma, solitary cutaneous leiomyoma a sarcoma selected from the group consisting of leiomyoma, solitary fibrous tumor, spindle cell lipoma, smooth muscle tumor of uncertain malignant potential (STUMP), synovial sarcoma, angiosarcoma, and Wilms' tumor; or The tumor is a blastoma selected from chondroblastoma, hepatoblastoma, medulloblastoma, nephroblastoma, neuroblastoma, pancreatoblastoma, pleuroblastoma, retinoblastoma, and glioblastoma multiforme; 26. The dosage form of claim 25.

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