Crystal form, composition, solid dosage form, and method for preparing the composition of reximod in sulfate form.

Abstract

This invention provides a method for forming the crystalline form of resikimod and a method for using these crystalline forms. [Solution] A composition is provided comprising a reximod in the form of a sulfate of crystalline form A, characterized by an X-ray powder diffraction spectrum containing peaks at 2θ of approximately 7° to 8°, 2θ of approximately 13.5° to 14.5°, 2θ of approximately 19° to 20°, and / or 2θ of approximately 19.5° to 20.5°.

Description

Technical Field

[0001] The present disclosure relates to crystalline forms of pharmaceutical compounds and formulations, methods for forming these crystalline forms, and methods of using these crystalline forms.

Summary of the Invention

Means for Solving the Problems

[0002] In the present application, new crystalline forms of pharmaceutical compounds are described. In one embodiment, the pharmaceutical compound is included in a pharmaceutical composition that is beneficial for treating a disease or a symptom. In one embodiment, the disease or symptom is cancer.

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

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

[0005] The sulfate of crystalline form A can be stable at room temperature for at least about 2 days or at least about 1 week.

[0006] Other embodiments describe pharmaceutical compositions containing crystalline forms of the compound of formula I.

[0007]

Chemical Formula

[0008] Formula I may also 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]-quinoline-4-amine, or 4-amino-1-phenylmethyl-1H-imidazo-[4,5-c]-quinoline-2-methanol. In one embodiment, Formula I is a reximod.

[0009] In some embodiments, the crystalline form of the compound of formula I may be form A and / or a sulfate. In one embodiment, the sulfate is a monosulfate and / or an anhydride.

[0010] Other embodiments provide methods for treating diseases or symptoms. One embodiment describes a method for treating cancer. The method may include administering a pharmaceutical composition comprising a crystalline form of a compound having formula I.

[0011] [ka] [Brief explanation of the drawing]

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

[0013] This application describes novel crystalline forms of chemical compounds, formulations containing these crystalline forms, methods for forming these crystalline forms, and methods for using these crystalline forms. In some embodiments, these novel crystalline forms are referred to as polymorphs or isomorphs. The polymorphism of pharmaceuticals can have a direct efficacy with respect to the delivery of a given pharmaceutically active agent, component, or drug type. The purity of polymorphs in a sample may be confirmed using techniques such as powder X-ray diffraction and IR / Raman spectroscopy, and by taking advantage of their differences in 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, and salts. The discovery of new API forms may offer opportunities to improve the performance characteristics of pharmaceutical compositions. In addition, the discovery of drug forms expands the availability of numerous resources for designing drug dosage forms with target release properties or other desired characteristics.

[0015] Specific properties that may be targeted include the crystalline form of the API. Changing the crystalline form of a given API can result in changes to the physical properties of the target molecule. For example, different polymorphs of a given API may exhibit different solubility, while a thermodynamically stable polymorph may exhibit lower solubility than a metastable polymorph. In addition, polymorphs of a pharmaceutical may differ in properties such as dissolution rate, shelf life, bioavailability, form, vapor pressure, density, color, and compressibility. Therefore, for example, crystals, cocrystals, salts, solvates or hydrates with respect to water solubility, dissolution rate, bioavailability, C max , T maxIn some cases, it is desirable to enhance the properties of APIs by forming molecular complexes, taking into account physicochemical stability, processability in downstream manufacturing stages (e.g., fluidity, compressibility, degree of brittleness, particle size manipulation), reduction of polymorphic morphological diversity, toxicity, taste, production cost, manufacturing method, or a combination thereof.

[0016] Novel crystalline forms of compounds and pharmaceutical compositions comprising these novel crystalline forms of compounds are disclosed. The crystalline form may be a compound having the structure of formula I, or a pharmaceutically acceptable salt thereof.

[0017] [ka]

[0018] In the formula, R 1 hydrogen; substituted or unsubstituted C1-C 10 A linear or branched alkyl group, wherein the substituent is a C3-C6 cycloalkyl group or a C3-C6 cycloalkyl group substituted with a linear or branched C1-C4 alkyl group; a linear or branched C2-C 10 alkenyls; substituted linear or branched C2-C 10Alkenyls, wherein the substituent is a C3-C6 cycloalkyl or a C3-C6 cycloalkyl substituted with a linear or branched C1-C4 alkyl; C1-C6 hydroxyalkyl; alkoxyalkyl, wherein the alkoxy portion contains 1 to about 4 carbon atoms and the alkyl portion contains 1 to about 6 carbon atoms; acyloxyalkyl, wherein the acyloxy portion is an alkanoyloxy or benzoyloxy of 2 to about 4 carbon atoms and the alkyl portion contains 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 1 or 2 parts independently selected from C1-C4 alkyl, C1-C4 alkoxy, or halogen, provided that if the benzene ring is substituted in 2 parts, the 2 parts together contain 6 or fewer carbon atoms; R 2 and R 3 The substituent is independently selected from hydrogen, a C1-C4 alkyl, a phenyl, or a substituted phenyl, wherein the substituent is a C1-C4 alkyl, a C1-C4 alkoxy, or a halogen; X is an alkoxy, alkoxyalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, alkylamide, C1-C4 alkyl containing 1 to about 4 carbon atoms, an alkylamide, amino, substituted amino, amino whose substituent is C1-C4 alkyl or C1-C4 hydroxyalkyl; and, R is hydrogen, a linear or branched C1-C4 alkoxy, a halogen, or a linear or branched 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 of crystalline forms 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 still other embodiments, R 1 is 2-methylpropyl or benzyl.

[0021] In some embodiments, X may be azide, hydroxy, ethoxy, methoxy, 1-monopholino or methylthio. In some embodiments, when R 1 is 2-methylpropyl, 2-hydroxy-2-methylpropyl or benzyl, X may be azido, hydroxy, ethoxy, methoxy, 1-monopholino or methylthio.

[0022] Other substituents in the compound of Formula I containing an alkyl radical (e.g., R when R is alkoxy or alkyl, or X when X is alkylamide) may contain two carbon atoms, or, in some embodiments, each alkyl radical may contain one carbon atom.

[0023] In some embodiments, R is hydrogen.

[0024] The compound of formula I may also contain 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]-quinoline-4-amine, and 4-amino-1-phenylmethyl-1H-imidazo-[4,5-c]-quinoline-2-methanol.

[0025] In one embodiment, the compound of formula I may be reximod (1-[4-amino-2-(ethoxymethyl)imidazo-[4,5-c]-quinoline-1-yl]-2-methylpropan-2-ol). Reximod has a structure [ka] It may have.

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

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

[0028] One embodiment includes a reximod in the form of a monosulfate of crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum containing 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°.

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

[0030] The reximod may be formed as a sulfate of crystalline form B. Such crystalline form B may be characterized by an X-ray powder diffraction spectrum containing peaks at 2θ of about 7°–8°, 2θ of about 9°–10°, and / or 2θ of about 19°–20.5°.

[0031] Furthermore, the reximod may be formed as a hemisulfate in crystalline form A. Such crystalline forms may be characterized by an X-ray powder diffraction spectrum containing peaks at 2θ of approximately 6°–6.5°, 7°–8°, 8°–9°, 11°–12°, 12.5°–13°, 15°–15.5°, 16°–17°, 19°–19.5°, 21°–21.5°, and / or 2θ of approximately 23°–24°.

[0032] Other compounds of resikimod may be formed as acetate / acetic acid cocrystals of the free base form of resikimod. Such crystalline forms may be characterized by X-ray powder diffraction spectra containing peaks at 2θ of about 6°–7°, 9°–10.5°, 11°–12°, 18°–19°, 19°–20°, 20.5°–21°, 22°–23° and / or 25°–26°.

[0033] Furthermore, sulfates may be provided in crystalline forms C, D, E, F, G, and H. The transformation of sulfate form C may be interconverted to form A by storage at ambient temperature for, for example, overnight. The transformation of sulfate form D may be interconverted to form A by heating to, for example, 100°C. The transformation of sulfate form E may be interconverted to form A by heating to, for example, 120°C. The transformation of sulfate form F may be interconverted to form A by storage at ambient temperature for, for example, two days. The transformation of sulfate form G may be interconverted to form A by heating to, for example, 80°C. Since each metastable form and the solvated compound interconvert to form A, in some embodiments, form A is a thermodynamically stable form at room temperature.

[0034] The reximod may be formed as anhydrous (type A) sulfate. Such a crystalline form may be characterized by an X-ray powder diffraction spectrum containing peaks at 2θ of about 8.5°–about 9°, 2θ of about 12°–about 13°, 2θ of about 16°–about 17°, 2θ of about 17.5°–about 18°, 2θ of about 19°–about 20.5°, 2θ of about 21°–about 22°, 2θ of about 23°–about 24° and / or 2θ of about 29°–about 30°.

[0035] The reximod may be formed as a sulfate of the solvate (type B). Such a crystalline form may be characterized by an X-ray powder diffraction spectrum containing peaks at 2θ of about 6°–about 6.5°, 2θ of about 12°–about 12.5°, 2θ of about 16°–about 16.5°, 2θ of about 21°–about 22.5° and / or 2θ of about 24.5°–about 25°.

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

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

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

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

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

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

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

[0043] Furthermore, other compounds of formula I described herein may be formed as sulfates of crystalline form B. Sulfates of crystalline form B may be dimethyl sulfoxide (DMSO) solvates. Furthermore, other compounds of formula I described herein may be formed as hemisulfates of 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] Furthermore, other compounds of formula I described herein may be formed as hydrochlorides, sulfates, phosphates, maleates, malates, adipines, or combinations thereof. In some embodiments, the salts may be formed in form or type A.

[0046] In one embodiment, the compound of formula I described herein may be formed as a monohydrochloride of crystalline form A. In another embodiment, the compound of formula I described herein may be formed as a dihydrochloride of crystalline form A. Any form of the hydrochloride may be formed as an anhydride.

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

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

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

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

[0051] In one embodiment, the compound of formula I described herein may be formed as a phosphate anhydride in crystalline form A.

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

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

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

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

[0056] In other embodiments, the reximod is in the form of a malate of crystalline morphology A. Crystalline morphology A may be characterized by an X-ray powder diffraction spectrum containing peaks at 2θ of about 6°–about 7°, 2θ of about 8°–about 9°, 2θ of about 13°–about 14°, 2θ of about 17°–about 18° and / or 2θ of about 24°–about 25.5°. In other embodiments, the reximod is in the form of a malate of crystalline morphology A, characterized by an X-ray powder diffraction spectrum containing peaks at 2θ of about 6°–about 7°, 2θ of about 8°–about 9°, 2θ of about 17°–about 18°, 2θ of about 21.5°–about 23.5° and / or 2θ of about 25°–about 26°.

[0057] In one embodiment, the compound of formula I described herein may be formed as an adipinite anhydride in crystalline form A.

[0058] Other embodiments include a reximod in the form of an adipinate of crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum containing peaks at 2θ of about 5.5° to about 6°, 2θ of about 11° to about 12°, 2θ of about 12° to about 13°, 2θ of about 13° to about 14°, 2θ of about 14° to about 15°, 2θ of about 18° to about 19°, 2θ of about 19° to about 20°, 2θ of about 21° to about 22°, 2θ of about 22° to about 23° and / or 2θ of about 25° to about 28°. In other embodiments, the reximod is in the form of an adipinate of crystalline morphology A, characterized by an X-ray powder diffraction spectrum containing peaks at approximately 5°–6.5° 2θ, approximately 9°–11° 2θ, approximately 12°–13.5° 2θ, approximately 14°–15.5° 2θ, approximately 17°–18° 2θ, approximately 18°–19° 2θ, approximately 19.5°–22° 2θ, approximately 22°–25° 2θ, and / or approximately 26°–27.5° 2θ.

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

[0060] In one embodiment, the glycolate form in crystalline form A contains a reximod. Crystalline form A may be characterized by an X-ray powder diffraction spectrum containing peaks at 2θ of about 9° to about 10°, 2θ of about 11.5° to about 12.5°, 2θ of about 18° to about 19°, 2θ of about 19.5° to about 23°, 2θ of about 25° to about 26.5° and / or 2θ of about 32° to about 33°.

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

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

[0063] Furthermore, the compound of formula I may be formed as a tartrate. In other embodiments, the compound of formula I described herein may be formed as a tartrate of crystalline form A, B and / or C.

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

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

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

[0067] Furthermore, the compound of formula I may be formed as a fumarate. In other embodiments, the compound of formula I described herein may be formed as a fumarate of crystalline forms A, B and / or C.

[0068] One embodiment includes a reximod in the form of a fumarate of crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum containing peaks at 2θ of about 6° to about 7°, 2θ of about 7° to about 8°, 2θ of about 9° to about 10.5°, 2θ of about 12° to about 14°, 2θ of about 18° to about 19°, 2θ of about 19° to about 20°, 2θ of about 23° to about 24.5° and / or 2θ of about 25° to about 26°.

[0069] One embodiment includes a reximod in the form of a fumarate of crystalline form B. Crystalline form B may be characterized by an X-ray powder diffraction spectrum containing peaks at 2θ of about 9.5°–10.5°, 2θ of about 12°–13°, 2θ of about 15°–16°, 2θ of about 17°–18°, 2θ of about 19°–21° and / or 2θ of about 25°–26°.

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

[0071] Furthermore, the compound of formula I may be formed as a citrate. In other embodiments, the compound of formula I described herein may be formed as a citrate of crystalline form A and / or B.

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

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

[0074] Furthermore, the compound of formula I may be formed as a lactate. In other embodiments, the compound of formula I described herein may be formed as a lactate of crystalline form A and / or B.

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

[0076] In one embodiment, the lactate morphology of crystalline morphology B contains reximod. Crystalline morphology B may be characterized by an X-ray powder diffraction spectrum containing peaks at 2θ of about 5° to about 6°, 2θ of about 6.5° to about 8°, 2θ of about 9° to about 10.5° and / or 2θ of about 13.5° to about 14.5°.

[0077] Furthermore, the compound of formula I may be formed as a succinate. In other embodiments, the compound of formula I described herein may be formed as a succinate of crystalline form A and / or B.

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

[0079] One embodiment includes a reximod in the form of a succinate of crystalline form B. Crystalline form B may be characterized by an X-ray powder diffraction spectrum containing peaks at 2θ of about 8°–9°, 10°–11°, 12°–13°, 14°–15°, 16°–17°, 17°–18° and / or 2θ of about 23.5°–24.5°.

[0080] Furthermore, the compound of formula I may be formed as a tosylate. In other embodiments, the compound of formula I described herein may be formed as a tosylate of crystalline form A and / or B.

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

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

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

[0084] One embodiment includes a reximod in the form of a mesylate of crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum containing peaks at 2θ of about 8°–9°, 12°–13°, 14°–15°, 16°–17°, 18°–19.5°, 2θ of about 21°–22°, and / or 2θ of about 25.5°–26.5°.

[0085] Furthermore, the compound of formula I may be formed as an oxalate. In one embodiment, the compound of formula I described herein may be formed as an oxalate of crystalline form A and / or B.

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

[0087] One embodiment includes a reximod in the form of an oxalate of crystalline form B. Crystalline form B may be characterized by an X-ray powder diffraction spectrum containing peaks at 2θ of about 5° to about 6°, about 9.5° to about 10°, about 10.5° to about 11.5°, about 13° to about 13.5°, about 14.5° to about 15.5°, about 16.5° to about 18°, about 22° to about 24.5° and / or about 27° to about 28°.

[0088] Furthermore, the compound of formula I may be formed as a gentisinate. In other embodiments, the compound of formula I described herein may be formed as a gentisinate of crystalline form A and / or B.

[0089] One embodiment includes a reximod in the form of a gentisinate of crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum containing peaks at 2θ of about 6° to about 7.5°, about 8° to about 9°, about 10° to about 11°, about 14° to about 15°, about 16° to about 17°, about 18° to about 19°, about 20° to about 21.5° and / or about 22.5° to about 23.5°.

[0090] One embodiment includes a reximod in the form of a gentisinate of crystalline form B. Crystalline form B may be characterized by an X-ray powder diffraction spectrum containing peaks at 2θ of about 6° to about 7°, 2θ of about 10° to about 10.5°, 2θ of about 12° to about 13°, 2θ of about 20° to about 21°, 2θ of about 24° to about 24.5° and / or 2θ of about 26° to about 26.5°.

[0091] Furthermore, the compound of formula I may be formed as a benzoate. In other embodiments, the compound of formula I described herein may be formed as a benzoate in crystalline form A and / or B.

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

[0093] One embodiment includes a reximod in the form of a benzoate in crystalline form B. Crystalline form B may be characterized by an X-ray powder diffraction spectrum containing peaks at 2θ of about 7° to about 8.5°, about 12° to about 14°, about 18° to about 19°, about 19.5° to about 20.5°, about 21° to about 23°, about 24° to about 25° and / or about 26° to about 27°.

[0094] Furthermore, the compound of formula I may be formed as a nitrate. In other embodiments, the compound of formula I described herein may be formed as a nitrate of crystalline form A and / or B.

[0095] In one embodiment, the reximod is contained in the form of a nitrate of crystalline form A. Crystalline form A may be characterized by an X-ray powder diffraction spectrum containing peaks at 2θ of about 9° to about 9.5°, 2θ of about 10° to about 10.5°, 2θ of about 11.5° to about 12.5°, 2θ of about 14° to about 15°, 2θ of about 16° to about 17.5°, 2θ of about 20° to about 22.5°, 2θ of about 25° to about 26° and / or 2θ of about 28.5° to about 29.5°.

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

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

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

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

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

[0101] Furthermore, the crystalline form may be physically and chemically stable compared to the free base of the compound of formula I. In some embodiments, the change in form and / or the decrease in purity may not be observed at 25°C / 60% relative humidity (RH) and 40°C / 75% relative humidity (RH) compared to the form of the free base. In some embodiments, the absence of change in form and / or the decrease in purity may last for at least about one week, at least about two weeks, at least about one month, at least about six months, or at least about one year.

[0102] Other aspects provide improved water solubility of the crystalline form of the compound of formula I compared to the form of the parent compound or its free base. Other aspects provide improved water solubility of the crystalline form of the reximod compared to the form of the parent compound or its free base.

[0103] Other aspects provide the value of the modified oral bioavailability of the crystalline form of the compound of formula I compared to the form of the parent compound or its free base delivered orally. Other aspects provide the value of the modified oral bioavailability of the crystalline form of the resikimod compared to the form of the parent compound or its free base delivered orally.

[0104] Furthermore, the techniques and methods of this disclosure can be used by those skilled in the art to prepare variants thereof, which are considered in part in this disclosure.

[0105] The crystalline form of the compound of formula I described herein may be used to treat a disease or symptom. In some embodiments, the disease or symptom is cancer. 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, hematological cancer, prostate cancer, and the like.

[0106] The crystalline form of the compound of formula I described herein may be used to treat tumors of subjects requiring treatment. In some embodiments, the tumor is a carcinoma, sarcoma, blastoma, or a combination thereof.

[0107] Carcinomas may include, but are not limited to, 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, and thyroid tumors. In other aspects of this embodiment, carcinomas may include, but are not limited to, adenocarcinomas, adenosquamous carcinomas, anaplastic carcinomas, large cell carcinomas, small cell carcinomas, and squamous cell carcinomas. In other aspects of this embodiment, carcinomas include, but are not limited to, small cell carcinoma, combined small cell carcinoma, vegetative carcinoma, squamous cell carcinoma, basal cell carcinoma, transitional cell carcinoma, inverted papilloma, plaque gastritis, familial adenomatous polyposis, insulinoma, glucagonoma, gastrinoma, VIP-producing tumor, somatostatinoma, cholangiocarcinoma, claskin tumor, hepatocellular adenoma, hepatocellular carcinoma, renal cell carcinoma, endometrial tumor, renal pallocyte tumor, prolactinoma, multiple endocrine tumors, adrenocortical adenoma, adrenocortical This includes cancer, Hürthle cells, neuroendocrine tumors, adenoid cystic carcinoma, eosinophilic adenoma, clear cell adenocarcinoma, apdoma, cystoma, papillary hidradenoma, hydrocystic cystoma, syringoma, papillary cystadenoma, cystadenoma, cystadenocarcinoma, signet ring cell carcinoma, mucinous cystadenoma, mucinous cystadenocarcinoma, mucosal epidermal carcinoma, ovarian serous cystadenoma, pancreatic serous cystadenoma, serous cystadenocarcinoma, papillary serous cystadenocarcinoma, mammary ductal carcinoma, pancreatic ductal adenocarcinoma, comedone breast carcinoma, mammary Paget's disease, extramammary Paget's disease, lobular carcinoma in situ, invasive lobular carcinoma, medullary carcinoma of the breast, medullary carcinoma of the thyroid, acinar cell carcinoma, Warthin's tumor, or thymoma.

[0108] Sarcoma may include, without limitation, soft tissue sarcoma, connective tissue sarcoma, liposarcoma, myomatous sarcoma, a complex mixed and stromal sarcoma, and mesothelial sarcoma. In this embodiment, nonhematological sarcoma may include, without limitation, adenomatous tumor, adenomyoma, invasive pediatric fibromatosis, alveolar rhabdomyosarcoma, angiolipid leiomyoma, angiomyolipoma, angioleiomyoma, angiomyxoma, angiosarcoma, aponeurotic fibroma, Askin tumor, atypical fibroxanthoma, benign lipoblastoma, Brenner tumor, carcinosarcoma, chondroid lipoma, chondrosarcoma, clear cell sarcoma, renal clear cell sarcoma, collagenous fibroma Fibromas, phyllodes cystic sarcoma, dermatofibrosarcoma, dermatofibrosarcoma protuberans (DFSP), tendonoid fibroma, fibroplastic small round cell tumor, scattered juvenile fibromatosis, Ewing / PNET tumor, familial myxoid angiofibroma, fibroadenoma, tenosynovial fibroma, cervical fibromatosis, fibrous histiocytoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), genital leiomyoma, hemangioendothelioma, hepatoblastoma, pheochromocytoma, histiocytoma, juvenile digital fibromatosis, intradermal spindle cell lipoma, juvenile hyaline fibromatosis, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, mesodermal nephroma, mesothelioma, mixed Müller tumor, multiple cutaneous and uterine leiomyoma syndrome This may include leiomyomatosis, myelolipoma, myosarcoma, myxoid liposarcoma, myxosarcoma, neurofibrolipoma, neurofibrosarcoma, submucosal fibrosis of the oral and vaginal walls, ossifying fibromyxoma, osteosarcoma, pancreaticblastoma, phyllodes tumor, plantar fibromatosis, pleomorphic adenoma, soft fibroma, pleomorphic lipoma, rhabdomyosarcoma, staphyloid sarcoma, schwannoma sarcoma, solitary cutaneous leiomyoma, solitary fibrous tumor, spindle cell lipoma, leiomyoma of unknown grade (STUMP), synovial sarcoma, angiosarcoma, or Wilms' tumor.

[0109] Blastoma may include, without limitation, chondroblastoma, hepatoblastoma, medulloblastoma, nephroblastoma, neuroblastoma, pancreaticblastoma, pleuroblastoma, retinoblastoma, or glioblastoma multiforme.

[0110] The reximod and related compounds of formula I described herein may also be TLR / TLR8 agonists. Studies have found that many solid tumors, such as breast cancer, head and neck cancer, or ovarian cancer, have factors secreted by tumor cells that suppress pDC invasion and DC maturation. These immature DC cells did not play a role in enhancing antitumor immunity. In contrast, DCs within the tumor microenvironment promote tumor growth by suppressing antitumor immunity and promoting angiogenesis. Imiquimod, a Toll-like receptor 7 agonist, and CpG drugs, a Toll-like receptor 9 agonist, stimulate pDCs within the tumor microenvironment to suppress tumorigenesis.

[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 the expression of CD56 or CD16 and the deficiency of the T cell receptor (CD3). They recognize and kill transformed cell lines without priming in an MHC-unrestricted form. NK cells primarily play a role in eliminating tumor and virus-infected cells. The process by which NK cells recognize target cells and deliver sufficient signals to induce target lysis is determined by a number of inhibitory and activating receptors on the cell surface. NK cell recognition of self from non-self includes inhibitory receptors that recognize MHC-I molecules and non-MHC ligands such as CD48 and Clr-1b. NK cell 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, hemagglutinins) recognized by various activating receptors, including NKG2D, Ly49H, and NKp46 / Nc1.

[0112] NK cells constitute the majority of lymphoid cells in the peripheral blood for several months after allogeneic or autologous stem cell transplantation, and they play a major role in immunity against pathogens during this period.

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

[0114] Human NK cells are regulated by positive and negative cytolytic signals. Negative (inhibitory) signals are converted by C-lectin domains, including the receptor CD94 / NKG2A, and several killer cell immunoglobulin-like receptors (KIRs). The regulation of NK lysis by inhibitory signals is known as the “missing self” hypothesis, which posits that specific HLA-class I alleles are expressed on ligation-inhibitory receptors on the target cell surface of NK cells. Downregulation of HLA molecules on tumor cells and certain virus-infected cells (e.g., CMV) reduces this inhibition below a target threshold, and if target cells carry NK-priming and activating molecules, they may become more susceptible to NK cell-mediated lysis. TLR7, TLR8, or TLR9 agonists can activate both mDCs and pDCs to produce type I IFNs and express costimulatory molecules such as GITR-ligands, subsequently activating NK cells to produce IFN-γ, thereby potently enhancing 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 dimerizes with CD94 on the cell surface. KIRs have a 2- or 3-domain extracellular structure and bind to HLA-A, -B, or -C. The NKG2 / CD94 complex ligates HLA-E.

[0116] Repressive KIRs possess up to four intracellular domains, including ITIMs, the most distinctive of which are KIR2DL1, KIR2DL2, and KIR2DL3, known for binding to HLA-C molecules. KIR2DL2 and KIR2DL3 bind to group 1 HLA-C alleles, while KIR2DL1 binds to group 2 alleles. Certain leukemia / lymphoma cells are known to express both group 1 and 2 HLA-C alleles and resist NK-mediated cytolysis.

[0117] Regarding positive activation signals, ADCC is thought to be mediated via CD16, and many trigger receptors responsible for innate 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 stimulative. These KIRs (KIR2DS1, KIR2DS2, and KIR2DS4) are known to bind to HLA-C; their extracellular domains are identical to those of the repressive KIRs they are associated with. The activating KIRs lack ITIMs and instead are associated with DAP12, which leads to NK cell activation. The mechanism of regulation of the expression of these repressive KIRs versus activating KIRs remains unclear.

[0118] Several reports describe the expression of TLRs in mouse or human cancer or cancer cell lines. For example, TLR1 through TLR6 are expressed in mouse tumor cell lines of colon, lung, prostate, and melanoma; TLR3 is expressed in human breast, liver, and gastric cancer cells that express TLR2 and TLR4; TLR9 and TLR4 are expressed in 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 containing a leucine-rich, repeating external domain, a transmembrane domain, and an intracellular TIR (Toll / interleukin receptor) domain. TLRs recognize individual microbial structures, often referred to as “PAMPs” (pathogen-associated molecular structures). Ligands bound to TLRs trigger a cascade of intracellular signaling pathways that induce the production of factors involved in inflammation and immunity.

[0120] TLR7 and TLR8 are systematically and structurally related. TLR7 is selectively expressed by human pDCs and B cells. TLR8 is primarily expressed by mDCs, monocytes, macrophages, and myeloimmunosuppressor cells. TLR7-specific agonists activate plasmacytoid dendritic cells (pDCs) to produce large amounts of type 1 IFNs and activate high levels of costimulatory molecules that promote the activation of T cells, NK cells, B cells, and mDCs. TLR8-specific agonists activate myeloid DCs, monocytes, macrophages, or myeloid suppressor cells to produce large amounts of type 1 IFNs, IL-12, and IL-23 and activate high levels of MHC class I, MHC class II, and costimulatory molecules that promote the activation of antigen-specific CD4 and CD8+ T cells.

[0121] Pharmaceutical compositions containing the crystalline forms of the compounds described herein may be administered to animals such as mammals. In some embodiments, the mammals may be humans, cats, dogs, horses, pigs, cattle, whales, or other similar animals.

[0122] Pharmaceutical compositions may be prepared by a therapeutically effective amount of at least one crystalline form of the compounds described herein, in combination with commonly accepted pharmaceutical excipients, and by the preparation of dosage forms in units suitable for therapeutic use. As used herein, the term “pharmaceutical composition” means a therapeutically effective concentration of an active compound, such as, for example, some of the crystalline forms of the compounds described herein. Preferably, the pharmaceutical composition does not produce adverse, allergic, or other undesirable or unwanted reactions when administered. The pharmaceutical compositions disclosed herein can be used for medical and veterinary applications. Pharmaceutical compositions may be administered alone or in combination with other co-active compounds, drugs, medicines, or hormones. Pharmaceutical compositions may be manufactured using several different processes, including, but not limited to, conventional mixing, dissolution, granulation, sugar-coated tablet production, wet grinding, emulsification, encapsulation, sealing, and dry freezing. Pharmaceutical compositions can take various forms, without limitation, including sterile solutions, suspensions, emulsions, lyophilized products, tablets, pills, small pills, capsules, powders, syrups, panaceas, or other dosage forms suitable for administration.

[0123] The pharmaceutical composition may be a liquid formulation, a semi-solid formulation, or a solid formulation. The formulations disclosed herein may be manufactured in a way that forms a single phase, such as an oil or a solid. Alternatively, the formulations disclosed herein may be manufactured in a way that forms a two-phase phase, such as an emulsion. The pharmaceutical composition disclosed herein, intended for such administration, may be prepared by some methods known in the art of manufacturing pharmaceutical compositions.

[0124] Liquid formulations suitable for injection or topical (e.g., ocular) delivery may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injection 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 others of the same kind), suitable mixtures thereof, vegetable oils (such as olive oil), and organic esters for injection such as ethyl oleate. Adequate fluidity may be maintained, for example, by using coatings such as lecithin, by maintaining the particle size required during dispersion, and by using surfactants.

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

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

[0127] In liquid and semi-solid formulations, the concentration of the crystalline form described herein may be between approximately 50 mg / mL and approximately 1000 mg / mL. In this embodiment, the therapeutically effective amount of the crystalline form of the compound described herein may be, for example, approximately 50 mg / mL to approximately 100 mg / mL, approximately 50 mg / mL to approximately 200 mg / mL, approximately 50 mg / mL to approximately 300 mg / mL, approximately 50 mg / mL to approximately 400 mg / mL, approximately 50 mg / mL to approximately 500 mg / mL, approximately 50 mg / mL to approximately 600 mg / mL, approximately 50 mg / mL to approximately 700 mg / mL, approximately 50 mg / mL to approximately 800 mg / mL, approximately 50 mg / mL to approximately 900 mg / mL, and approximately 50 mg / mL to approximately 10 00 mg / mL, approximately 100 mg / mL to approximately 200 mg / mL, approximately 100 mg / mL to approximately 300 mg / mL, approximately 100 mg / mL to approximately 400 mg / mL, approximately 100 mg / mL to approximately 500 mg / mL, approximately 100 mg / mL to approximately 600 mg / mL, approximately 100 mg / mL to approximately 700 mg / mL, approximately 100 mg / mL to approximately 800 mg / mL, approximately 100 mg / mL to approximately 900 mg / mL, approximately 100 mg / mL to approximately 1000 mg / mL, approximately 200 mg / mL to approximately 300 mg / mL, approximately 200 mg / mL to approximately 400 mg g / mL, approximately 200 mg / mL to approximately 500 mg / mL, approximately 200 mg / mL to approximately 600 mg / mL, approximately 200 mg / mL to approximately 700 mg / mL, approximately 200 mg / mL to approximately 800 mg / mL, approximately 200 mg / mL to approximately 900 mg / mL, approximately 200 mg / mL to approximately 1000 mg / mL, approximately 300 mg / mL to approximately 400 mg / mL, approximately 300 mg / mL to approximately 500 mg / mL, approximately 300 mg / mL to approximately 600 mg / mL, approximately 300 mg / mL to approximately 700 mg / mL, approximately 300 mg / mL to approximately 800 mg / m L, approximately 300 mg / mL to approximately 900 mg / mL, approximately 300 mg / mL to approximately 1000 mg / mL, approximately 400 mg / mL to approximately 500 mg / mL, approximately 400 mg / mL to approximately 600 mg / mL, approximately 400 mg / mL to approximately 700 mg / mL, approximately 400 mg / mL to approximately 800 mg / mL, approximately 400 mg / mL to approximately 900 mg / mL, approximately 400 mg / mL to approximately 1000 mg / mL, approximately 500 mg / mL to approximately 600 mg / mL, approximately 500 mg / mL to approximately 700 mg / mL, approximately 500 mg / mL to approximately 800 mg / mL,The dosage may be approximately 500 mg / mL to approximately 900 mg / mL, approximately 500 mg / mL to approximately 1000 mg / mL, approximately 600 mg / mL to approximately 700 mg / mL, approximately 600 mg / mL to approximately 800 mg / mL, approximately 600 mg / mL to approximately 900 mg / mL, or approximately 600 mg / mL to approximately 1000 mg / mL.

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

[0129] The pharmaceutical compositions described herein may optionally include a pharmaceutically acceptable carrier that facilitates the treatment of the active compound into a pharmaceutically acceptable composition. Such a medium is generally permitted to be mixed with the active compound, or to dilute or encapsulate the active compound, and may be a solid, semi-solid, or liquid. Any variety of pharmaceutically acceptable carriers may be used, and such carriers may include, but are not limited to, aqueous media such as water, saline, glycine, hyaluronic acid, and others of the same kind; solid media such as starch, magnesium stearate, mannitol, sodium saccharin, talcum, cellulose, glucose, sucrose, lactose, trehalose, magnesium carbonate, and others of the same kind; solvents; dispersion media; coatings; antimicrobial and antifungal agents; isotonic and absorption retarders; or several other inert components.

[0130] The pharmaceutical compositions described herein may, if necessary, contain other pharmaceutically acceptable ingredients (or pharmaceutical ingredients), including, but not limited to, buffers, preservatives, tonicity modifiers, salts, antioxidants, osmotic pressure modifiers, physiological substances, pharmaceutical substances, bulking agents, emulsifiers, wetting agents, sweeteners or flavorings, and other similar substances. Various buffers and means for adjusting pH may be used to prepare the pharmaceutical compositions described herein, provided that the resulting preparation is pharmaceutically 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, if necessary, to adjust the pH of the composition. 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, phenylmercury acetate, phenylmercury nitrate, stabilized oxychloro compositions such as sodium chlorite, and chelating agents such as DTPA or DTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide. Useful tonic modifiers for pharmaceutical compositions include, but are not limited to, salts such as sodium chloride and potassium chloride, mannitol or glycerin, and other pharmaceutically acceptable tonic modifiers.

[0131] A method of treating a disease or condition such as cancer involves administering a new crystalline form of Formula I, such as in the form of a pharmaceutical drug. The administration may be once daily, twice daily, three times daily, four times daily, or more. In other embodiments, it 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 week, once every three weeks, once a month, once every six months, once a year, or similar.

[0132] (Examples) (Example 1) 1. Overview Salt screening of the free base of the reximod was performed to identify candidate salts with suitable physicochemical properties. In addition, polymorphic screening was performed to identify the main crystalline form of the candidate salt.

[0133] An initial salt screening was performed under 100 conditions using 19 acids (hydrochloric acid in 2 molar ratios) and 5 solvent systems. A total of 32 hit crystals were isolated and characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC), along with stoichiometry determined using proton nuclear magnetic resonance (1H NMR) or HPLC / IC. Considering the safety grade of the acid used, the number of polymorphs observed, and the physicochemical properties, seven crystalline salts—mono-hydrochloride, di-hydrochloride, sulfate, phosphate, maleate, malate, and adipinate—were selected as leading salts for further evaluation.

[0134] All seven main salt leads were re-prepared into several hundred milligrams (except for 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 testing; 2) all derived salts except maleate showed improved or equivalent solubility in water and bio-related media (SGF, FaSSIF, and FeSSIF) at room temperature (RT, 20±3℃) compared to free base type A; and 3) all derived salts except dihydrochloride and free base type A showed good physical and chemical stability, with no morphological changes or decrease in HPLC purity detected over a week at 25℃ / 60%RH and 40℃ / 75%RH.

[0135] Based on the results of characterization and evaluation, sulfate was selected as a candidate salt and re-prepared on a 6-g scale for polymorphism studies. Polymorphism screening was performed using sulfate type A as the starting material under 100 conditions. A total of three crystalline forms were obtained, including one anhydrous (type A), one DMSO solvated compound (type B), and one hemisulfate. Thus, sulfate type A was selected mainly as the monosulfate form. Disproportionation risk and thermal stability were studied for sulfate type A, and the results showed that 1) sulfate type A converts to hemisulfate with a water activity of 0.8 and shows a risk of disproportionation at high relative humidity, and 2) sulfate type A exhibits good physicochemical stability for 24 hours at 80°C.

[0136] 2. Salt screening 2.1 Experiment Overview Nineteen salt forms and five solvent systems were used for screening, 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. The free base was dispersed in a selected solvent in a glass vial, and the corresponding salt form was added in a molar charge ratio of 1:1 (two ratios were used for hydrochloric acid / free base: both 1:1 and 2:1). 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 opportunity to identify as many crystalline hits as possible. The resulting solids were isolated and analyzed by XRPD.

[0137] As summarized in Table 2-1, a total of 32 crystal hits were obtained. 1 The samples were characterized by TGA and DSC, along with stoichiometry determined by 1H NMR or HPLC / IC. The characterization data are summarized in Table 2-2, and detailed information is provided in Section 5.4.

[0138] [Table 2-1] ※※ : The solid was produced via suspension at 5°C overnight. FB: Free base ※ The sample was obtained by evaporation through drying at room temperature. A blank experiment was prepared to detect several possible changes in free bases.

[0139] [Table 2-2-1]

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

[0141] 2.2 Re-preparation and characterization of major salts Based on the results of the characterization, seven main salts were selected and re-prepared into several hundred milligrams (except for dihydrochloride type A). The selection criteria, but not limited to, included: 1) low safety concerns of the acid (safety class I), 2) a sharp X-ray powder diffraction (XRPD) peak without a distinct amorphous halo, 3) negligible weight loss during thermogravimetric analysis (TGA), and 4) a suitable thermal event with sharp melting during differential scanning calorimetry (DSC). The preparation procedures for the derived salts, as with the other salts described herein, are described in Table 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] [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​The PLM image shown in Figure 2 shows an aggregate of small particles (<10 μm). As shown by the TGA and DSC data in Figure 3, the sample (807919-16-A) shows a weight loss of 1.1% up to 130 °C, shows two endothermic peaks at 250.4 °C and 266.2 °C (peak temperatures) before decomposition, and shows the anhydride of monohydrochloride type A. As shown in Table 2-4, a purity of 99.5 area % was detected by high performance liquid chromatography (HPLC). Also, the stoichiometric ratio of the re-prepared sample was determined to be 1.01 (acid / base) by HPLC / IC.

[0154]

Table 2-4

[0155] 2.2.2 Dihydrochloride type A Dihydrochloride type 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 dihydrochloride type A gives the first peak at 7.1, 8.2 and 19.6; the second peak at 15.4, 16.4 and 25.6; the third peak at 7.3, 14.9 and 27.0 (peak shifts within ±0.2°).

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

[0157]

Table 2-5

[0158] 2.2.3 Sulfate type A The comparison of XRPD patterns in Figure 7 shows that the reproduced sample (807919-11-A) conforms to sulfate type A. The XRPD data for sulfate type 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 Figure 8. The TGA and DSC results are shown in Figure 9. A weight loss of 0.9% was observed up to 130°C by TGA, and the DSC curve shows a steep melting peak at 214.4°C (starting temperature) before decomposition. As shown in Table 2-6, purity in the 99.2% range was detected by HPLC, and the stoichiometric ratio was determined to be 1.03 (acid / base) for the re-prepared batch. 1 Based on the combined results of 1H NMR and TGA / DSC, sulfate type A was identified as an anhydride of the monosulfate.

[0160] [Table 2-6]

[0161] 2.2.4 Phosphate type A Phosphate type A was successfully re-prepared, as demonstrated by the XRPD results in Figure 10. The XRPD data for phosphate type A yielded 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 an aggregate of small particles (<10 μm). As shown in the TGA and DSC data in Figure 12, phosphate type A (807919-11-C) shows a weight loss of 1.2% up to 130°C and exhibits an endothermic peak at 241.0°C (start temperature) before decomposition. As shown in Table 2-7, a purity in the 99.4% range was detected by HPLC. Furthermore, the stoichiometry of the re-prepared sample was determined to be 1.07 (acid / base) by HPLC / IC.

[0163]

Table 2-7

[0164] 2.2.5 Maleate Type A Maleate Type A (807919-D4) was produced via reaction crystallization (1:1 molar ratio) in THF at room temperature. The XRPD results in Figure 13 indicate that Maleate Type A was successfully re-prepared. The XRPD data for Maleate Type A give a first peak at 7.5, 10.3 and 24.7; a second peak at 9.3, 16.5 and 18.0; and a third peak at 15.7, 20.7 and 21.4 (peak shift within ±0.2°).

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

[0166]

Table 2-8

[0167] 2.2.6 Malate Type A Malate Type A was successfully re-prepared, as evidenced by the XRPD results in Figure 16. The XRPD data for Malate Type A give 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 shift within ±0.2°).

[0168] The PLM image shown in Figure 17 shows an aggregate of irregularly shaped particles. As shown in the TGA and DSC data in Figure 18, phosphate type A (807919-11-E) shows a weight loss of 1.0% up to 130°C and exhibits a sharp endothermic peak at 192.9°C (start temperature) before decomposition. As shown in Table 2-9, a purity in the 99.9% range was detected by HPLC. Furthermore, the stoichiometry of the re-prepared sample was: 1 The acid / base ratio was determined to be 1.02 by 1H NMR.

[0169] [Table 2-9]

[0170] 2.2.7 Adipine type A The comparison of XRPD patterns in Figure 19 shows that the reproduced sample (807919-12-A) conforms to adipinate type A. The XRPD data for adipinate type 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 are within ±0.2°).

[0171] Small particles (<10 μm) and vigorous aggregation are shown in Figure 20. The TGA and DSC results are shown in Figure 21. A weight loss of 0.9% was observed in TGA up to 130°C, and the DSC curve shows a sharp melting peak at 218.0°C (starting temperature) before decomposition. A purity of 99.9% was detected by HPLC, as shown in Table 2-10. The stoichiometric ratio was determined to be 0.52 (acid / base) for the re-prepared batch, indicating the hemiadipate formulation.

[0172] [Table 2-10]

[0173] 2.3 Evaluation of the main salts Furthermore, 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, 1) all derived salts, except for monohydrochloride type A and dihydrochloride type A, were slightly hygroscopic without morphological changes after DVS evaluation; 2) all derived salts, except for maleate, showed improved or equivalent solubility in water and bio-related media compared to free base type A; and 3) all derived salts, except for dihydrochloride type A, exhibited good physical and chemical stability, as evidenced by the fact that no substantial changes occurred in crystalline form or HPLC purity.

[0174] 2.3.1 Hygroscopicity DVS isotherm plots were collected at 25°C to investigate solid morphological stability as a function of humidity. For the six anhydrous salts (monohydrochloride type A, sulfate type A, phosphate type A, maleate type A, malate type A, and adipinate type A), the solids were pre-dried at 0% relative humidity before starting to remove unbound solvent or water. For the possible hydrate / solvate dihydrochloride A, the solids were brought to equilibrium at ambient humidity (approximately 30% RH) before testing.

[0175] The five salt forms (sulfate type A, phosphate type A, maleate type A, malate type A, and adipine type A) were slightly hygroscopic, as evidenced by the uptake of 0.2–1.1% water up to 80% relative humidity. No changes in solid morphology were observed in any of the five induced forms after DVS evaluation (FIG. 22–31).

[0176] The DVS plots shown in Figures 32 and 34 indicate that both hydrochloride forms are hygroscopic. For monohydrochloride type A (807919-16-A), 2.9% moisture uptake was observed up to 80% relative humidity, and no morphological changes were detected after the DVS test (Figure 33). For dihydrochloride type A (807919-14-A), 12.2% moisture uptake was detected up to 80% relative humidity, with one plateau observed at approximately 20% relative humidity, suggesting the possibility of hydrate presence. In addition, dihydrochloride type A transformed into a new morphology containing diffraction peaks of monohydrochloride type A after the DVS evaluation (Figure 35), indicating a risk of dihydrochloride type A imbalance at high relative humidity.

[0177] 2.3.2 Kinetic solubility The kinetic solubility of the seven main salts was measured at room temperature, using free base form A (807919-05-A) as a control, in water and three bio-related media (SGF, FaSSIF, and FeSSIF). Samples of all solubility (initial solid load of approximately 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 of that solution were measured.

[0178] The results are summarized in Table 2-11, and an overview of the kinetic solubility is shown in Figures 36A-D. Comparisons with free base type A, monohydrochloride type A, dihydrochloride type A, sulfate type A, phosphate type A, malate type A, and adipinate type A show improved or equivalent solubility in water and biological buffers. Furthermore, the residual solid after 24 hours of suspension showed no morphological changes (Figures 37-38). During this time, a decrease in solubility was observed in SGF, FaSSIF, and FeSSIF after the formation of monomaleate (maleate type A), while no morphological changes were detected after the evaluation of kinetic solubility (Figure 39). In addition, as demonstrated by the HPLC results in Table 2-12, no degradation was observed in the clear solution after 24 hours.

[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 unavailable, N / A ※ Limited solids for analysis ※ Concentration and pH data for 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 main salts was evaluated for one week under 25°C / 60% relative humidity and 40°C / 75% relative humidity conditions, 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 Table 2-13. The XRPD patterns, as shown in Figures 40-47, indicate no change in the investigated forms, except for dihydrochloride form A. Furthermore, no substantial change in purity was observed for the seven derived salts and free base form A. All data demonstrate the physical and chemical stability of monohydrochloride form A, sulfate form A, phosphate form A, maleate form A, malate form A, adipinate form A, and free base form A under the tested conditions 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—monohydrochloride type A, dihydrochloride type A, sulfate type A, phosphate type A, maleate type A, malate type A, and adipinate type A—were selected to be re-prepared for further evaluation, including hygroscopicity, kinetic solubility, and solid-state stability. Considering the results summarized in Tables 2-14 and 2-15, sulfate was recommended as a candidate salt for further investigation of crystalline polymorphism.

[0186] [Table 2-14] ※ Based on the safety rating of the acid used, Handbook of Pharmaceutical Salt: Properties, Selection and Uses, Wiley-VCH: Zurich, 2002. ※※ : Peak temperature

[0187] [Table 2-15] ※ Based on the safety rating of the acid used, Handbook of Pharmaceutical Salt: Properties, Selection and Uses, Wiley-VCH: Zurich, 2002.

[0188] 3. Polymorphism of sulfates 3.1 Summary of Polymorph Screening Using a reformulated sulfate type A (807919-21-A) as the starting material, polymorph screening experiments were conducted under 100 conditions, along with different crystallization or solid transfer methods. The detailed procedures can be found in Section 5.5.

[0189] As summarized in Tables 3-1 and 3-2, three crystalline forms were obtained: sulfate type A as an anhydrous form, sulfate type B as a DMSO solvate, and hemisulfate type 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 type 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 type B gives a first peak at 7.0, 9.6, and 20.0; a second peak at 18.2, 19.6, and 25.2; and a third peak at 14.0, 24.6, and 28.3 (peak shifts are within ±0.2°).

[0193] The TGA and DSC results are shown in Figure 49. A weight loss of 11.7% was observed up to 130°C, and the DSC showed two endothermic peaks at 111.2°C and 202.2°C (starting temperature) before decomposition, firstly due to desolvation and secondly due to melting. Sulfate type B deforms to anhydrous sulfate type A after being heated at 120°C. Also, the DMSO content of 11.3% 1 It was detected by 1H NMR and was consistent with the weight loss in TGA. Considering all characterization data, sulfate type B was calculated as the DMSO solvate.

[0194] 3.1.2 Hemisulfate type A Hemisulfate type A is acetone / H2O(a w The sample of hemisulfate type A (807919-34-A) was obtained using the acetone / H2O (a) system at room temperature. w The reaction crystallization in (0.8) was produced 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 type A gives a first peak at 8.5, 11.4, and 12.7; a second peak at 6.3, 16.6, and 19.2; and a third peak at 7.6, 15.3, and 23.4 (peak shifts are within ±0.2°).

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

[0196] [Table 3-3]

[0197] 3.2 Stability study of sulfate type A 3.2.1 Research on disequilibrium risks A series of suspension experiments were conducted at various water activity levels (0-0.8) to assess the risk of imbalance. Specifically, approximately 15 mg of sulfate type A sample was used in a w The sample was weighed into 0.5 mL of acetone / H2O, 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 Table 3-4 and Figure 52, a w When the value was lower than 0.6, no morphological changes were observed, but hemisulfate type A was a w It is produced at =0.8, and a risk of sulfate-type A imbalance is shown at high relative humidity.

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

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

[0200] [Table 3-5]

[0201] 3.3 Conclusion A total of three crystalline forms, including two monosulfates (anhydrous type A / DMSO solvate type B) and hemisulfate type A, were obtained through polymorphic screening.

[0202] In addition, the risk of imbalance and thermal stability were evaluated for sulfate type A. As a result, 1) Sulfate type A is a w At =0.8, it transformed into hemisulfate type A, showing a risk of imbalance at high relative humidity. 2) Sulfate type A showed no substantial change in crystalline form or HPLC purity and exhibited good thermal stability after storage at 80°C for 24 hours. Based on the polymorph screening and evaluation results, sulfate type A was inferred to be the thermodynamically stable form of monosulfate at room temperature.

[0203] 4. Conclusion Screening of salts of the free base of reximod was performed under 100 conditions, and a total of 32 hit crystalline substances were isolated. Based on the results of characterization, seven main salts—monoHCl, diHCl, sulfate, phosphate, maleate, malate, and adipicate—were selected as major salts for further evaluation, including hygroscopicity, kinetic solubility, and solid-state stability. As demonstrated by the results, sulfate, with good physicochemical properties, was recommended as a salt candidate. Using sulfate type A as the starting material, polymorph screening was performed under 100 conditions, and three crystalline forms were observed, including one anhydrous (type A), one DMSO solvated compound, and one hemisulfate, with sulfate type A being indicated as the major form of monosulfate. In addition, sulfate type A exhibited good physicochemical properties at 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 Salt screening of the starting free base The starting free base (the sample's reciquimod, with CP ID 807919-05-A) was characterized by XRPD, PLM, TGA, DSC, HPLC, and DVS.

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

[0206] The received free base type A (807919-05-A) was used as a starting material for salt screening. The solubility of type A was evaluated in nine solvents at room temperature. Approximately 2 mg of the solid was weighed into each 3 mL glass vial, and each solvent listed in 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 ranges of the starting materials summarized in Table 5-2 were used to guide the selection of solvents for salt screening.

[0207] [Table 5-1]

[0208] [Table 5-2]

[0209] 5.1.2 Starting Sulfates for Polymorphic Screening The XRPD comparison in Figure 59 shows that sulfate type A (807919-21-A) was successfully re-prepared on a 6-g scale. Detailed procedures are provided in Table 5-3. As shown in the TGA and DSC results in Figure 60, a 2.0% weight loss was observed up to 100°C, and the DSC data showed a sharp melting peak at 209.6°C (start temperature). Furthermore, a purity in the 99.4% range was detected via HPLC (Table 5-4), and the stoichiometry was determined to be 1.11 (acid / base) by HPLC / IC.

[0210] The re-prepared sulfate type A (807919-21-A) was used as the starting material for polymorphism screening. The solubility data in Table 5-5 were collected using the same procedure as in Section 5.1.1 and were incorporated to guide solvent selection in the design of the polymorphism screening.

[0211] [Table 5-3]

[0212] [Table 5-4]

[0213] [Table 5-5]

[0214] 5.2 Abbreviations for solvents used The abbreviations for the solvents used are listed in Table 5-6.

[0215] [Table 5-6]

[0216] 5.3 Apparatus and Methods 5.3.1 XRPD A PANalytical Empyrean X-ray powder diffractometer was used for XRPD analysis. The parameters used are listed in Table 5-7.

[0217] [Table 5-7]

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

[0219] [Table 5-8]

[0220] 5.3.3 HPLC The Agilent 1100 HPLC was used to analyze purity and solubility, and detailed methods are shown in Tables 5-9 and 5-10.

[0221] [Table 5-9]

[0222] [Table 5-10]

[0223] 5.3.4 IC The IC methods for measuring counterion content are listed in Table 5-11 below.

[0224] [Table 5-11]

[0225] 5.3.5 PLM Polarized light microscope images were captured at room temperature using an upright microscope at Axio Lab. A1.

[0226] 5.3.6 DVS DVS was measured via SMS (Surface Measurement System) DVS Intrinsic. Relative humidity at 25°C was calculated for the dissolution 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 1H NMR 1 The 1H NMR spectrum was collected using a Bruker 400M NMR Spectometer with DMSO-d6 as the solvent.

[0229] 5.3.8 pKa pKa was determined using Sirius T3™ according to the product's instructions for use, and the parameters for the pKa test are listed in Table 5-13.

[0230] [Table 5-13]

[0231] 5.4 Characterization of crystalline materials found through salt screening 5.4.1 Hydrochloride type B A total of two salt crystalline forms were obtained from the screening. Hydrochloride type A (807919-07-D1) was obtained via crystallization in solution in THF (1:1 molar charge), and type B (807919-07-C2) was produced at room temperature via reaction crystallization with siRNA (2:1 molar ratio, acid / base). The XRPD patterns are shown in Figure 69. The XRPD data for hydrochloride type 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 hydrochloride type B, TGA and DSC data (Figure 62) show a two-step weight loss of 10.8% up to 150°C, multiple endothermic reactions before decomposition, and five endothermic reactions before decomposition at 103.5°C, 110.2°C, 181.1°C, 249.8°C, and 266.0°C (peak temperatures). The stoichiometry of 1.73 (acid / base) was determined by HPLC / IC, and the purity in the 99.2% range 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 type A (807919-07-A3) was produced at room temperature in acetone (1:1 molar ratio) via solution crystallization, and its XRPD pattern is shown in Figure 63. As shown in the TGA and DSC data 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 (start temperature). The 99.3% purity region was detected by HPLC as shown in Table 5-16, and the stoichiometry of sulfate type A (807919-07-A3) was determined to be 0.98 (acid / base) by HPLC / IC.

[0236] [Table 5-16]

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

[0238] [Table 5-17]

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

[0240] As shown in Figure 68, TGA and DSC data indicate a 0.9% weight loss up to 130°C, and the DSC results show a sharp endothermic peak at 206.0°C (starting temperature) before decomposition. Furthermore, a purity in the 99.7% range was detected by HPLC in Table 5-18, and the stoichiometry of glycolate type A (807919-07-B9) is as follows: 1 The acid / base ratio was determined to be 1.04 by 1H NMR.

[0241] [Table 5-18]

[0242] 5.4.5 Maleate One maleate crystal morphology was obtained through screening. Maleate type A (807919-07-D4) was produced at room temperature in THF via reactive crystallization (1:1 molar ratio). The XRPD pattern is shown 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 (starting temperature) indicating that melting is minimized. Furthermore, a purity in the 99.3% range was detected by HPLC as shown in Table 5-19, and the stoichiometric ratio was... 1 The ratio was calculated as 0.98 (acid / base) by 1H NMR.

[0244] [Table 5-19]

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

[0246] As shown in Figure 72, TGA and DSC data indicate a 0.8% weight loss up to 130°C, and the DSC results show a sharp endothermic reaction at 193.3°C (starting temperature), likely due to melting. Furthermore, a purity in the 99.9% range was detected by HPLC in Table 5-20, and its stoichiometric ratio is... 1 The acid / base ratio was determined to be 1.04 by 1H NMR.

[0247] [Table 5-20]

[0248] 5.4.7 Adipine salts One adipinate crystal morphology was obtained through screening. Adipinate type A (807919-07-B14) was produced at room temperature in EtOH via reaction crystallization (1:1 molar ratio). The XRPD pattern and TGA / DSC curve are shown in Figures 73 and 74, respectively.

[0249] A weight loss of 1.0% was observed in TGA up to 130°C, and the DSC results showed an endothermic peak at 217.7°C (start temperature), likely due to melting. Furthermore, a purity in the 100.0% range was detected by HPLC as shown in Table 5-21, and the stoichiometric ratio of adipinate A (807919-07-B14) was: 1 The ratio was calculated as 0.52 (acid / base) by 1H NMR.

[0250] [Table 5-21]

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

[0252] The TGA and DSC results in Figure 76 show a 2.8% weight loss before 130°C and an endothermic peak at 213.9°C (start temperature) before decomposition. Furthermore, a purity in the 99.6% range was detected by HPLC as shown in Table 5-22. Its stoichiometric ratio is: 1 The acid / base ratio was determined to be 1.00 by 1H NMR.

[0253] [Table 5-22]

[0254] 5.4.9 Tartrates A total of three crystalline forms of tartrate were obtained through screening. Tartrate types A (807919-07-A6), B (807919-07-E6), and C (807919-07-B6) were produced by reaction crystallization in acetone, MeOH / H2O (9:1, v / v), and EtOH, respectively, at a molar charge ratio of 1:1. The XRPD pattern of tartrate type A is shown in Figure 77. The XRPD data for tartrate type 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 for tartrate type B is shown in Figure 78. The XRPD data for tartrate type B gives a first peak at 8.9, 14.5, and 23.5; a second peak at 11.3, 16.9, and 24.2; and a third peak at 9.9, 13.4, and 15.4 (peak shifts are within ±0.2°).

[0256] The XRPD pattern for tartrate type C is shown in Figure 79. The XRPD data for tartrate type C gives a first peak at 7.2, 10.2, and 11.1; a second peak at 9.3, 13.8, and 18.9; and a third peak at 8.7, 20.4, and 23.5 (peak shifts are within ±0.2°).

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

[0258] Furthermore, the stoichiometric ratio is 1 ¹H NMR determined the acid / base ratio to be 1.02 for type A and 0.52 for types B and C.

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

[0260] The XRPD pattern for fumarate type B is shown in Figure 84. The XRPD data for fumarate type B gives a first peak at 10.0, 12.4, and 17.2; a second peak at 15.3, 19.1, and 20.3; and a third peak at 17.2, 22.6, and 24.9 (peak shifts are within ±0.2°).

[0261] The XRPD pattern for fumarate type C is shown in Figure 85. The XRPD data for fumarate type C gives a first peak at 6.7, 9.1, and 26.6; a second peak at 11.2, 15.4, and 20.1; and a third peak at 13.7, 19.4, and 21.1 (peak shifts are within ±0.2°).

[0262] For Type A, the TGA and DSC data show a weight loss of 0.8% 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 Type B, the TGA and DSC data show a weight loss of 4.2% 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 Type C, the TGA and DSC data show a weight loss of 0.4% 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] Furthermore, stoichiometry is,1 ¹H NMR determined the acid / base ratios for types A-C to be 0.81, 0.61, and 1.03, respectively.

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

[0265] The XRPD pattern for citrate type B is shown in Figure 90. The XRPD data for citrate type 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 are within ±0.2°).

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

[0267] Furthermore, the stoichiometric ratios are shown in Figures 108 and 109, respectively. 1 ¹H NMR determined the acid / base ratios to be 1.02 and 0.53 (acid / base) for types A and B, respectively.

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

[0269] The XRPD pattern for lactate type B is shown in Figure 94. The XRPD data for lactate type B gives a first peak at 5.8, 7.6, and 9.4; a second peak at 6.8, 11.6, and 14.0; and a third peak at 8.5, 18.8, and 25.6 (peak variations are within ±0.2°).

[0270] For type A, a weight loss of 0.4% was observed in TGA up to 100°C, and in Figure 95, the DSC results show endothermic peaks at 85.4°C, 159.5°C, and 169.4°C (peak temperature) before decomposition. For type B, the TGA and DSC results in Figure 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] Furthermore, the stoichiometric ratio is, 1 ¹H NMR determined the acid / base ratios for lactate types A and B to be 1.07 and 0.96, respectively.

[0272] 5.4.13 Succinate Two succinate crystalline forms were obtained through screening. Succinate type A (807919-07-C13) and type B (807919-07-E13) were produced at room temperature via reactive crystallization (1:1 molar ratio) in siRNA and MeOH / H2O. The XRPD pattern of succinate type A is shown in Figure 97. The XRPD data for succinate type 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 for succinate type B is shown in Figure 98. The XRPD data for succinate type B gives a first peak at 10.5, 17.5, and 23.9; a second peak at 8.7, 12.2, and 14.1; and a third peak at 16.6, 19.7, and 22.3 (peak shifts are within ±0.2°).

[0274] For type A, the TGA and DSC results in Figure 99 show a 2.0% weight loss up to 130°C and a sharp endothermic peak at 174.4°C (start temperature) before decomposition. For type B, the data (Figure 100) shows a 4.6% weight loss up to 100°C and three endothermic peaks at 103.5°C, 188.4°C, and 209.6°C (peak temperatures) before decomposition. The stoichiometric ratio is as follows: 1 The values ​​were determined to be 1.00 and 0.52 (acid / base) by 1H NMR.

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

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

[0277] For type A, the TGA and DSC results in Figure 103 show a 1.3% weight loss up to 130°C and a sharp endothermic peak at 201.5°C (start temperature) before decomposition. For type B, the data (Figure 104) shows a 5.3% weight loss up to 150°C and four endothermic peaks at 61.1°C, 185.4°C, 189.9°C, and 201.9°C (peak temperatures) before decomposition. Furthermore, the stoichiometric ratio is: 1 ¹H NMR determined the acid / base ratios for types A and B to be 0.89 and 0.92, respectively.

[0278] 5.4.15 Mesylates One crystalline form of mesylate was obtained through screening. Mesylate type A was produced at room temperature in acetone via reactive crystallization (1:1 molar ratio). The XRPD pattern is shown in Figure 105. The XRPD data for mesylate type 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, a 1.5% weight loss is observed up to 130°C, and a sharp endothermic peak is shown at 206.6°C (start temperature) before decomposition. Furthermore, the stoichiometric ratio is as follows: 1 The acid / base ratio was determined to be 0.93 by 1H NMR.

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

[0281] The XRPD pattern for oxalate type B is shown in Figure 108. The XRPD data for oxalate type 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 are within ±0.2°).

[0282] For type A, the TGA and DSC data (Figure 109) show a 0.7% weight loss up to 130°C and a sharp endothermic peak at 227.3°C (start temperature) before decomposition. For type B, the TGA and DSC results (Figure 110) show a 1.8% weight loss up to 130°C and two endothermic peaks at 190.5°C and 218.2°C (peak temperatures) before decomposition. The stoichiometric ratios were calculated by HPLC / IC as 0.92 and 1.02 (acid / base) for types A and B, respectively.

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

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

[0285] For type A, the TGA and DSC data (Figure 113) show a 4.9% weight loss up to 150°C, with an endothermic peak at 210.4°C (start temperature) and an exothermic peak at 145.5°C (peak temperature) before decomposition. For type B, the TGA and DSC results shown in Figure 114 show a 1.7% weight loss up to 150°C, with an endothermic peak at 208.2°C (start temperature) and an exothermic peak at 148.5°C (peak temperature) before decomposition. Furthermore, their stoichiometric ratios are: 1 ¹H NMR determined the acid / base ratios to be 0.99 and 1.00 for types A and B, respectively.

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

[0287] The XRPD pattern for benzoate type B is shown in Figure 116. The XRPD data for benzoate type B gives a first peak at 7.7, 12.5, and 18.8; a second peak at 13.5, 22.6, and 26.7; and a third peak at 19.8, 21.4, and 24.4 (peak shifts are within ±0.2°).

[0288] For type A, the TGA and DSC results (Figure 117) show a 0.6% weight loss up to 130°C and an endothermic peak at 199.0°C (start temperature) before decomposition. For type B, the TGA and DSC data shown in Figure 118 show a 4.0% weight loss up to 100°C and two endothermic peaks at 102.2°C and 199.8°C (start temperature) before decomposition. Furthermore, its stoichiometry is as follows: 1 Based on 1H NMR, the values ​​were calculated as 0.98 and 0.99 (acid / base) for types A and B, respectively.

[0289] 5.4.19 Nitrates Two crystalline morphologies of nitrates were obtained through screening. Nitrate type A (807919-07-D20) and type B (807919-07-B204) were produced at room temperature in THF and EtOH via solution crystallization (1:1 molar ratio). The XRPD pattern of nitrate type A is shown in Figure 119. The XRPD data for nitrate type 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 for nitrate type B is shown in Figure 120. The XRPD data for nitrate type B gives a first peak at 6.7, 9.1, and 25.5; a second peak at 9.7, 12.7, and 15.6; and a third peak at 14.4, 20.1, and 26.8 (peak shifts are within ±0.2°).

[0291] For type A, the TGA and DSC results in Figure 121 show a 1.6% weight loss up to 130°C and a sharp endothermic peak at 212.5°C (starting temperature) before decomposition. For type B, the TGA and DSC results (Figure 122) show a 0.6% weight loss up to 130°C and a sharp endothermic peak at 217.6°C (starting temperature) before decomposition. The stoichiometric ratio for both types A and B was determined to be 1.04 (acid / base) by HPLC / IC.

[0292] 5.5 Experiments for screening sulfate polymorphisms 5.5.1 Addition of reverse solvent A total of 18 additional experiments with reverse solvents were conducted. Approximately 15 mg of the starting sulfate (807919-21-A) was dissolved in 0.1–2.5 mL of solvent to obtain a clear solution, which was then stirred with a magnetic stirrer. Subsequently, 0.2 mL of reverse solvent was added in stages until a precipitate formed or the total volume of reverse 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] ※ The solid was observed after stirring the clear solution for 2 days at 5°C following the addition of the reverse solvent. ※※ The solid could not be obtained by stirring the clear solution at 5°C; evaporation was employed.

[0294] 5.5.2 Solid vapor diffusion Solid vapor diffusion experiments were conducted using 13 different solvents. Approximately 10 mg of the starting sulfate (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 tested by XRPD, and the results summarized in Table 5-24 show that sulfate types A and B were produced.

[0295] [Table 5-24]

[0296] 5.5.3 Liquid vapor diffusion Vapor diffusion experiments were performed on 10 liquids. Approximately 15 mg of the starting sulfate (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 with 3 mL of volatile solvent. The 20 mL glass vial was sealed with a cap and stored at room temperature for a sufficient amount of time for organic vapors to interact with the solution. The precipitate was isolated for XRPD analysis. After 7 days, the solid was isolated for XRPD analysis. The results summarized in Table 5-25 show that only sulfate type A was obtained.

[0297] [Table 5-25]

[0298] 5.5.4 Slow evaporation Slow evaporation experiments were conducted under eight conditions. Briefly, approximately 15 mg of the starting sulfate (807919-21-A) was dissolved in 0.1–2.5 mL of solvent in a 3 mL glass vial. If it did not dissolve completely, 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 evaporated at the desired temperature with the vial sealed with PARAFILM®. The solid was isolated for XRPD analysis, and the results summarized in Table 5-26 show that a mixture of sulfate type A and hemisulfate type A was produced.

[0299] [Table 5-26]

[0300] 5.5.5 Polymer-induced crystallization Polymer-induced crystallization experiments were performed in two sets of polymer mixtures in three solvents. Approximately 15 mg of the starting sulfate (807919-21-A) was dissolved in a suitable solvent in a 3-mL vial to obtain a clear solution. 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 solid was isolated for XRPD analysis. The results summarized in Table 5-27 show that only sulfate type 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) (mass ratio of 1:1:1:1:1) Polymer mixture B: Polycaprolactone (PCL), polyethylene glycol (PEG), poly(methyl methacrylate) (PMMA), sodium alginate (SA), and hydroxyethylcellulose (HEC) (mass ratio of 1:1:1:1:1)

[0302] 5.5.6 Suspension at room temperature Conversion experiments of the suspension were performed at room temperature in different solvent systems. Approximately 15 mg of the 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 with a magnetic stirrer at room temperature for 5 days, the remaining solid was isolated for XRPD analysis. The results summarized in Table 5-28 show that hemisulfate type A was produced alongside sulfate type A.

[0303] [Table 5-28]

[0304] 5.5.7 Suspension at 50°C Suspension conversion experiments were performed at 50°C in different solvent systems. Approximately 15 mg of the starting sulfate (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 show that only sulfate type A was produced.

[0305] [Table 5-29]

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

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

[0308] (Example 2) 1. Summary Polymorphism screening of resikimod free bases was performed, and crystalline polymorphism was evaluated to confirm appropriate crystalline forms for further drug development.

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

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

[0311] Type A was selected as the primary form, and its hygroscopicity and solid-state stability were further evaluated. Hygroscopicity was assessed using water vapor adsorption spectroscopy (DVS) at 25°C, and the results indicated that Type A is non-hygroscopic. Physicochemical stability was examined under conditions of 25°C / 60%RH and 40°C / 75%RH for one week, and under conditions of 80°C for 24 hours. No changes in crystal morphology or decrease in HPLC purity were observed, indicating good physical and chemical stability of Type A under the tested conditions.

[0312] 2. Characterization of crystal morphology Polymorphic screening was performed under 100 experimental conditions, yielding eight crystalline forms, including one anhydrous form (type A), two metastable forms (types C / F), four solvates (types B / D / E / G), and one acetate / acetic acid cocrystal (sample H). Interconversion relationships between these forms were investigated through storage and heating experiments, and the results are shown in Figure 144.

[0313] [Table 2-1] N / A: Data was not collected due to format conversion to type A. N / A: The data was not used.

[0314] The procedure for preparing the following crystal forms is described 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 type A reference (807919-05-A). The XRPD pattern is shown in Figure 141, giving a first peak at 8.9, 12.4, and 17.7; a second peak at 19.7, 21.5, and 23.4; and a third peak at 16.5, 20.1, and 26.7 (peak shifts within ±0.2°).

[0318] Regarding the crystalline morphology of anhydrous type A, TGA and DSC data showed a 2.5% weight loss up to 100°C, with a sharp endothermic peak at 193.0°C (starting temperature) before decomposition (Figure 125). Furthermore, a purity in the 99.4% range was detected by HPLC (Table 2-2). Considering all the results, type A was considered anhydrous.

[0319] [Table 2-2]

[0320] 2.2 Metastable form 2.2.1 Type C Type C was produced in a 1,4-dioxane system. A sample of Type C (807920-11-A11) was obtained via solid vapor diffusion in 1,4-dioxane. As shown in the XRPD pattern in Figure 126, Type C converted to Type A after being dried overnight under ambient conditions, and the metastable form of Type C is shown under ambient conditions. The XRPD pattern gives a 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 type F (807929-09-A4) was obtained via slow cooling in MEK, and the XRPD pattern, as shown in Figure 127, 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°).

[0322] After storage at ambient temperature for two days, type F converted to type A, demonstrating that type F is metastable at ambient temperature.

[0323] 2.3 Solvates 2.3.1 type B Isomorphism occurred in type B, which was prepared in several solvent systems including IBA / toluene, siRNA, and THF / H2O. The XRPD pattern of type B is shown in Figure 128. The XRPD pattern gives a first peak at 6.2, 16.3, and 21.4; a second peak at 12.3, 22.3, and 24.7; and a third peak at 20.4, 27.0, and 28.4 (peak shifts are within ±0.2°).

[0324] Three batches of isomorphic type B crystal morphology were produced. Batch 1: TGA and DSC data (Figure 129) showed a 10.8% weight loss up to 165°C and two endothermic peaks at 158.4°C and 192.9°C (peak temperature) before decomposition. Batch 2: TGA and DSC data (Figure 130) showed a 9.3% weight loss up to 150°C and two endothermic peaks at 146.7°C and 191.9°C (peak temperature) before decomposition. Batch 3: TGA and DSC data (Figure 131) showed a 6.5% weight loss up to 160°C and two endothermic peaks at 143.7°C and 194.4°C (peak temperature) before decomposition.

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

[0326] [Table 2-3]

[0327] 2.3.2 Type D A sample of type D (807920-12-A9) was prepared via solution vapor diffusion in DMAc / MTBE. The XRPD pattern is shown in Figure 157. The XRPD pattern gives a first peak at 8.7, 17.6, and 23.9; a second peak at 11.2, 21.2, and 22.8; and a third peak at 9.1, 15.5, and 16.9 (peak shifts within ±0.2°). 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 (start temperature) before decomposition. 1 1H NMR confirmed the presence of 18.3% DMAc in the type D sample, indicating the presence of a DMC solvate for type D.

[0328] 2.3.3 Type E Type E was produced in an NMP / MTBE system. Samples of Type E were 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 first peak at 8.7, 17.9, and 23.9; a second peak at 16.9, 21.3, and 22.9; and a third peak at 9.2, 11.2, and 12.5 (peak shifts within ±0.2°). TGA and DSC data (Figure 135) show a 25.5% weight loss up to 120°C and two endothermic peaks at 134.0°C and 187.4°C (peak temperatures) before decomposition. 1 ¹H NMR detected a 22.9% NMP content, which is consistent with the weight loss due to TGA, indicating that type E is an NMP solvate.

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

[0330] 2.4 Salt / co-crystal (Sample H) Sample H (807920-22-A1) was obtained by the addition of a reverse solvent in ethyl lactate / n-heptane with added acetic acid (molar ratio 0.4:1, acid / base), and a mixture of type A and sample H was produced by the addition of a reverse solvent in ethyl lactate / n-heptane (acetic acid content 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; and a third peak at 12.4, 20.6 and 23.4 (peak shift 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 (start temperature) before decomposition. Furthermore, the acetic acid content is 0.47:1 (molar ratio, acid / base). 1 The determination was made by 1H NMR. The combination of characterization data suggested that sample H was an acetate / acetic acid cocrystal.

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

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

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

[0334] [Table 3-1] ※ The data was collected in the salt screening section.

[0335] 4. Conclusion Using free base form A of compound 001 as the starting material, a total of 100 polymorphic screening experiments were prepared, revealing that eight crystalline forms were obtained by solid-state XRPD analysis. The results of morphological identification showed the presence of one anhydrous form (form A), two metastable forms (forms C / F), four solvated compounds (forms B / D / E / G), and one acetate / acetic acid cocrystal (sample H). Interconversion results showed that all forms B-G were converted to form A after heating or storage, indicating the good physical stability of form A. Furthermore, form A was evaluated for hygroscopicity and solid-state stability. The results showed that form A is non-hygroscopic and possesses 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 drug development.

[0336] 5. Others 5.1 Sample Information The received starting material was used directly for polymorphism screening and evaluation experiments, and detailed information is shown in Table 5-1.

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

[0338] 5.2 Abbreviations for solvents used Abbreviations for solvents are listed in Table 5-2.

[0339] [Table 5-2]

[0340] 5.3 Apparatus and Methods 5.3.1 XRPD A PANalytical Empyrean X-ray powder diffractometer was used for XRPD analysis. 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 TA Instruments' TAQ500 / Q5000TGA. DSC was performed using TA Instruments' TAQ200 / Q2000DSC. The detailed parameters used are listed in Table 5-4.

[0343] [Table 5-4]

[0344] 5.3.3 HPLC The Aglient 1100 HPLC was used for purity analysis, and the detailed procedure is shown 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 dissolution points of LiCl, Mg(NO3)2, and KCl. Actual parameters for the DVS test are listed in Table 5-6.

[0347] [Table 5-6]

[0348] 5.3.5 NMR of solutions The NMR spectrum of the solution was collected on a Bruker 400M NMR Spectrometer using DMSO-d6.

[0349] 5.4 Polymorphic Screening The solubility of the starting material (807920-05-A) was evaluated at room temperature. Approximately 2 mg of the solid was added to a 3 mL glass vial. Then, solvent was added in steps (100 μL per step) until the solid dissolved or the total volume reached 1 mL. The results summarized in Table 5-7 were used as a guide for solvent selection in polymorphism screening.

[0350] Polymorphic screening experiments were conducted using different crystallization or solid-state transformation methods. The crystalline forms identified using these methods are summarized in Table 5-8.

[0351] [Table 5-7]

[0352] [Table 5-8]

[0353] 5.4.1 Addition of reverse solvent A total of 20 additional experiments with reverse solvents were conducted. Approximately 15 mg of the starting material (807920-05-A) was dissolved in 0.1–2.3 mL of solvent to obtain a clear solution, which was then stirred with a magnetic stirrer. Subsequently, 0.2 mL of reverse solvent was added in stages until a precipitate formed or the total volume of reverse solvent reached 15.0 mL. The resulting precipitate was isolated for XRPD analysis. The results in Table 5-9 show that types B, G, and sample H were produced alongside type A.

[0354] [Table 5-9] ※ The solid was observed after stirring the clear solution at 5°C for 2 days, followed by the addition of the reverse solvent. ※※ The solid could not be obtained by stirring the transparent solution at 5°C, so evaporation was performed.

[0355] 5.4.2 Slow evaporation Slow evaporation experiments were performed under 10 conditions. Briefly, approximately 15 mg of the starting material (807920-05-A) was dissolved in 1.0–2.0 mL of solvent in a 3 mL glass vial. If it did not dissolve completely, 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 subjected to evaporation at room temperature with the vial sealed with PARAFILM®. The solid was isolated for XRPD analysis, and the results summarized in Table 5-10 show that types A and B were obtained.

[0356] [Table 5-10]

[0357] 5.4.3 Slow Cooling Slow cooling experiments were performed in 10 solvent systems. Approximately 15 mg of the 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, allowed to equilibrate for 2 hours, 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 isolation for XRPD analysis. Clear solutions were transferred to -20°C and, if still clear, were exposed to evaporation at room temperature. The results summarized in Table 5-11 show that types B, F, and G were produced alongside type A.

[0358] [Table 5-11] The solid was not obtained by slow cooling, and all samples were transferred to -20°C. ※ A small amount of solid was obtained, and the system was evaporated at room temperature.

[0359] 5.4.4 Polymer-induced crystallization Polymer-induced crystallization experiments were performed in two sets of polymer mixtures in seven solvents. Approximately 15 mg of the starting material (807920-05-A) was dissolved in a suitable solvent in a 3-mL vial to obtain a clear solution. Approximately 2 mg of the polymer mixture was added to a 3-mL glass vial. All samples were exposed to evaporation at room temperature to induce precipitation. The solid was isolated for XRPD analysis. The results summarized in Table 5-12 show that types 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) (mass ratio of 1:1:1:1:1) Polymer mixture B: polycaprolactone (PCL), polyethylene glycol (PEG), poly(methyl methacrylate) (PMMA) sodium alginate (SA), and hydroxyethylcellulose (HEC) (mass ratio of 1:1:1:1:1).

[0361] 5.4.5 Solid vapor diffusion Solid vapor diffusion experiments were conducted using 13 different solvents. Approximately 10 mg of the 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 solid was tested by XRPD, and the results summarized in Table 5-13 show that types A and C were produced.

[0362] [Table 5-13]

[0363] 5.4.6 Liquid vapor diffusion Vapor diffusion experiments were performed on 10 liquids. Approximately 15 mg of the starting material (807920-05-A) was dissolved in a suitable solvent in a 3 mL glass vial to obtain a clear solution. This solution was then placed in a 20 mL glass vial with 3 mL of volatile solvent. The 20 mL glass vial was sealed with a cap and stored at room temperature for a sufficient amount of time for the organic vapor to interact with the solution. The precipitate was isolated for XRPD analysis. After 6 days, the solid was isolated for XRPD analysis. The results summarized in Table 5-14 show that types B, D, and E were produced alongside type A.

[0364] [Table 5-14]

[0365] 5.4.7 Suspension at room temperature Suspension conversion experiments were performed at room temperature in different solvent systems. Approximately 15 mg of the 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 with a magnetic stirrer at room temperature for 3 days, the remaining solid was isolated for XRPD analysis. The results summarized in Table 5-15 show that only type A was obtained.

[0366] [Table 5-15]

[0367] 5.4.8 Suspension at 50°C Suspension conversion experiments were performed at 50°C in different solvent systems. Approximately 15 mg of the 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 Table 5-16 show that types A and C were obtained.

[0368] [Table 5-16]

[0369] The above disclosures are specific examples. It should be recognized by those skilled in the art that the technologies disclosed herein describe representative technologies that play a role in carrying out the disclosures herein. However, in light of the disclosures herein, those skilled in the art will be able to make many modifications to the specific embodiments disclosed without departing from the spirit and scope of the invention, and obtain similar or comparable results.

[0370] Unless otherwise specified, all numbers used in the specification and claims to represent properties such as component amounts and molecular weights, and reaction conditions, are understood to be modified in all instances by the word "approximately." Accordingly, unless otherwise stated, the numerical parameters described in the specification and appended claims are approximations that may be modified depending on the desired properties to be obtained by the present invention. Without attempting to limit the scope of the claims to the theory of synonyms in the specification, each numerical parameter should be interpreted at least in light of the number of significant figures described and by applying common rounding techniques. Although the numerical ranges and parameters describing the broad scope of the invention are approximations, the numbers are reported and described as accurately as possible in specific examples. However, some numbers inherently contain certain differences resulting from the standard deviation found in each test measurement.

[0371] In the context describing the present invention (particularly in the context of the following claims), “a,” “an,” “the,” and similar references are to be interpreted as encompassing both one and multiple values, unless otherwise indicated in the application or clearly contradicted in the context. The ranges of values ​​described in the application are merely abbreviated notation indicating that each value within that range is individually separated. Unless otherwise specified, each individual value is incorporated into the specification as if it were described in the specification. Unless otherwise specified or clearly contradicted in the context, all methods described in the application may be performed in several appropriate orders. The use of some or all examples, or representative language described in the application (e.g., “such as”), is merely to better illustrate the invention and not to limit the scope of the invention as described in the claims. Language in the specification should not be interpreted to indicate that elements not described in the claims are essential to the implementation of the invention.

[0372] The group of alternative elements or embodiments of the invention disclosed herein shall not be construed as limiting. Parts of each group may be described and referred to in the claims individually or in combination with parts or elements of other groups described herein. One or more parts of a group may be included in or removed from a group for convenience and / or patentability. When such inclusion or removal occurs, the claim shall be deemed to have been modified to satisfy the description of all Markush groups used in the added claim.

[0373] The particular embodiments of the invention described herein include the best mode known to the inventor for carrying out the invention. Of course, variations of these described embodiments will be obvious to those skilled in the art who have read the foregoing description. The inventor expects those skilled in the art to make such appropriate variations and intends to modify the matters specifically described herein. Accordingly, the present invention includes all variations, and equivalents of the subject matter enumerated in the claims are added herein to the extent permitted by applicable law. Furthermore, in all possible modifications thereof, some combination of the elements described above are included herein unless otherwise specified or unless there is an obvious contradiction in the context.

[0374] Furthermore, numerous references have been made throughout this specification in patents and printed publications. Each of the references and printed publications mentioned above is individually incorporated into this application by reference throughout.

[0375] Furthermore, certain embodiments disclosed in this application may be limited in the claims using the phrases "consising of" or "consisting essentially of." When used in a submitted or amended claim, the transitional term "consising of" excludes certain elements, steps, or components not explicitly stated in the claim. The transitional term "consising essentially of" limits the scope of the claim to certain materials or steps that do not substantially affect the basic and novel properties. Embodiments of the invention as described in the claims in this manner are essentially or explicitly described and enabled in this application.

[0376] In conclusion, the embodiments of the invention disclosed herein are examples of the principles of the invention. Therefore, alternative configurations of the invention may be used in accordance with the disclosure, for example, but are not limited thereto. Accordingly, the invention is not limited to the exact content described and shown herein.

[0377] (Note) (Note 1) A composition comprising a reximod in the form of a sulfate of crystalline form A.

[0378] (Note 2) The sulfate is a monosulfate. The composition described in Appendix 1.

[0379] (Note 3) The sulfate is an anhydrous form. The composition described in Appendix 1.

[0380] (Note 4) Crystal morphology A is characterized by an X-ray powder diffraction spectrum containing peaks at 2θ from approximately 7° to approximately 8°, 2θ from approximately 13.5° to approximately 14.5°, 2θ from approximately 19° to approximately 20°, and 2θ from approximately 19.5° to approximately 20.5°. The composition described in Appendix 1.

[0381] (Note 5) The aforementioned crystal form A is stable at room temperature for at least about 2 days. The composition described in Appendix 1.

[0382] (Note 6) The aforementioned crystal form A remains stable at room temperature for at least about one week. The composition described in Appendix 1.

[0383] (Note 7) A dosage form comprising the composition described in Appendix 1.

[0384] (Note 8) Equation I [ka] (In the formula, R 1 hydrogen; substituted or unsubstituted C1-C 10 A linear or branched alkyl group, wherein the substituent is a C3-C6 cycloalkyl group or a C3-C6 cycloalkyl group substituted with a linear or branched C1-C4 alkyl group; a linear or branched C2-C 10 alkenyls; substituted linear or branched C2-C 10Alkenyls, wherein the substituent is a C3-C6 cycloalkyl or a C3-C6 cycloalkyl substituted with a linear or branched C1-C4 alkyl; C1-C6 hydroxyalkyl; alkoxyalkyl, wherein the alkoxy portion contains 1 to about 4 carbon atoms and the alkyl portion contains 1 to about 6 carbon atoms; acyloxyalkyl, wherein the acyloxy portion is an alkanoyloxy or benzoyloxy of 2 to about 4 carbon atoms and the alkyl portion contains 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 1 or 2 parts independently selected from C1-C4 alkyl, C1-C4 alkoxy, or halogen, provided that if the benzene ring is substituted in 2 parts, the 2 parts together contain 6 or fewer carbon atoms; R 2 and R 3 The substituent is independently selected from hydrogen, a C1-C4 alkyl, a phenyl, or a substituted phenyl, wherein the substituent is a C1-C4 alkyl, a C1-C4 alkoxy, or a halogen; X is an alkoxy, alkoxyalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, alkylamide, C1-C4 alkyl containing 1 to about 4 carbon atoms, an alkylamide, amino, substituted amino, amino whose substituent is C1-C4 alkyl or C1-C4 hydroxyalkyl; and, R is hydrogen, a linear or branched C1-C4 alkoxy, a halogen, or a linear or branched C1-C4 alkyl. It includes the crystalline form of the compound, The crystalline form is a hydrochloride, sulfate, phosphate, maleate, malate, adipine, glycolate, hippurate, tartrate, fumarate, citrate, lactate, succinate, tosylate, mesylate, oxalate, gentisinate, benzoate, or nitrate of crystalline form A, B, C, D, E, F, or G. composition.

[0385] (Note 9) R1 is 2-methylpropyl or benzyl. The composition described in Appendix 8.

[0386] (Note 10) X is azide, hydroxy, ethoxy, methoxy, 1-morpholino, or methylthio. The composition described in Appendix 8.

[0387] (Note 11) R is hydrogen. The composition described in Appendix 8.

[0388] (Note 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]-quinoline-4-amine, or 4-amino-1-phenylmethyl-1H-imidazo-[4,5-c]-quinoline-2-methanol. The composition described in Appendix 8.

[0389] (Note 13) The aforementioned compound is a reximod. The composition described in Appendix 8.

[0390] (Note 14) The aforementioned crystal form is form A. The composition described in Appendix 8.

[0391] (Note 15) The aforementioned crystalline form is a sulfate. The composition described in Appendix 8.

[0392] (Note 16) The sulfate is a monosulfate. The composition described in Appendix 15.

[0393] (Note 17) The sulfate is an anhydrous form. The pharmaceutical composition described in Appendix 15.

[0394] (Note 18) A method for treating cancer in a subject requiring cancer treatment, comprising administering a composition containing a crystalline form of a compound of the formula described in Appendix 8 to the subject requiring cancer treatment.

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

[0396] (Note 20) The aforementioned tumor is a carcinoma, sarcoma, or blastoma. The method described in Appendix 18.

Claims

1. A crystalline form of reximod in sulfate form, The sulfates mentioned above are monosulfates and anhydrous forms. The crystalline form has an X-ray powder diffraction spectrum that includes peaks at 2θ of 7.6±0.2°, 2θ of 11.7±0.2°, and 2θ of 18.2±0.2°. Crystal form.

2. Thermodynamically stable at room temperature for at least about two days. The crystal form described in claim 1.

3. Thermodynamically stable at room temperature for at least about one week. The crystal form described in claim 1.

4. A differential scanning calorimetry thermogram including an endothermic peak at approximately 217.1°C, or A differential scanning calorimetry thermogram including endothermic peaks at approximately 105.3°C, approximately 219.2°C, or both. Having, The crystal form described in claim 1.

5. Furthermore, having an X-ray powder diffraction spectrum that includes peaks at 2θ of 15.5 ± 0.2°, 2θ of 17.6 ± 0.2°, and 2θ of 24.4 ± 0.2°, The crystal form described in claim 1.

6. Furthermore, having an X-ray powder diffraction spectrum that includes peaks at 2θ of 9.6 ± 0.2°, 2θ of 13.4 ± 0.2°, and 2θ of 23.5 ± 0.2°, The crystal form described in claim 5.

7. A composition comprising the crystalline form described in any one of Claims 1 to 6.

8. The composition is a pharmaceutical composition, further comprising a pharmaceutically acceptable carrier, The composition according to claim 7.

9. The crystal form according to any one of claims 1 to 6, A composition comprising the composition according to claim 7 or 8, A solid form of administration.

10. A combination of the crystalline form described in any one of claims 1 to 6 and a pharmaceutically acceptable carrier or excipient, Method for preparing a composition.

11. A method used to treat cancer in a subject who is in need of cancer treatment, including administering to the subject who is in need of cancer treatment. The crystalline form according to any one of claims 1 to 6, the composition according to claim 7 or 8, or the solid dosage form according to claim 9.

12. A method used to treat a tumor in a subject who is in need of treatment for a tumor, comprising administering the method to the subject who is in need of treatment for a tumor. The crystalline form according to any one of claims 1 to 6, the composition according to claim 7 or 8, or the solid dosage form according to claim 9.

13. The tumor is a carcinoma, sarcoma, or blastoma. The crystalline form, composition, or solid dosage form according to claim 12.

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