Various forms of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide

Abstract

To provide various forms of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide. [Solution] The present invention relates to various forms of the compound 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide and methods for producing such forms / compounds. The present invention further relates to its monoacid salt, methods for producing such monoacid salts, and pharmaceutical compositions comprising any of the aforementioned compounds. Furthermore, the present invention relates to the use of any of these compounds.

Description

[Technical Field]

[0001] The present invention relates to various forms of the compound 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide and methods for producing such forms / compounds. The present invention further relates to its monoacid salt, methods for producing such monoacid salts, and pharmaceutical compositions comprising any of the aforementioned compounds. Furthermore, the present invention relates to the use of these compounds. [Background technology]

[0002] Tuberculosis continues to claim millions of lives each year. The inappropriate use of chemotherapy is leading to an increase in drug-resistant cases. This situation could worsen with the emergence of strains highly resistant to all currently known drugs. Current chemotherapy consists of compounds that directly target Mycobacterium tuberculosis, either by neutralizing common signaling pathways and key processes such as RNA polymerization and protein synthesis inhibition, or by interfering with the synthesis of mycobacteria-specific cell envelopes. The most widely used dedicated anti-tuberculosis drugs, isoniazid, ethionamide, and pyrazinamide, are prodrugs that require initial activation. These are administered to patients over a course of several months. Patients infected with multidrug-resistant M. tuberculosis may require long-term combination therapy. International Publication No. 2011 / 113606 describes various anti-tuberculosis compounds, including the compound "Q203", which is chemically 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide, and their use in the treatment of bacterial infections. In a publication by Pethe et al. (Nature Medicine, 19, 1157-1160 (2013)), this compound is reported to be effective against tuberculosis by interfering with bacterial energy metabolism and inhibiting cytochrome bc1 activity, an essential component of the electron transport system required for ATP synthesis.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Non-Patent Documents

[0004]

Non-Patent Document 1

Summary of the Invention

Means for Solving the Problems

[0005] This compound is expected to be useful in the future treatment of tuberculosis and related infections, but there is still a continuing need for a form that is particularly suitable for administration as a pharmaceutical. In particular, there is a need to provide a form with improved solubility compared to the free base of this compound. Furthermore, there is a need in the art to provide a form with improved stability.

Modes for Carrying Out the Invention

[0006] In a first aspect, the present invention provides Structure

Chemical Formula

[0007] In one embodiment, the differential scanning calorimetry (DSC) thermogram of this compound shows a single endothermic peak starting at 235°C to 237°C.

[0008] In one embodiment, this compound is produced by a method comprising the following steps: - A step of providing 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide free base and p-toluenesulfonic acid in a 1:2 stoichiometric ratio, in any order; - The step of mixing and dissolving these in a suitable solvent or solvent mixture, for example, isopropyl alcohol (IPA), tetrahydrofuran (THF), acetone, or a mixture of THF and acetone; - A step of evaporating the solvent or solvent mixture.

[0009] In a further embodiment, the present invention relates to a method for producing a compound as defined above, the method comprising the following steps: - A step of providing 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide free base and p-toluenesulfonic acid in a 1:2 stoichiometric ratio, in any order; - The step of mixing and dissolving these in a suitable solvent or solvent mixture, for example, isopropyl alcohol (IPA), tetrahydrofuran (THF), acetone, or a mixture of THF and acetone; - A step of evaporating the solvent or solvent mixture.

[0010] In a further embodiment, the present invention relates to a monoacid addition salt of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide, which is 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monoacid addition salt. The compounds are drochloride, 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monophosphate, or 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monotosylate.

[0011] In one embodiment, this monoacid addition salt is Cu-K α Radiation (Cu-K α ) is 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monohydrochloride, which has at least one or more of the following peaks in the X-ray powder diffraction (XRPD) spectrum obtained by irradiation with ): 6.4°2θ, 8.1°2θ, 16.2°2θ, 17.2°2θ, 24.3°2θ, and 25.0°2θ, ±0.2°2θ.

[0012] In one embodiment, this monoacid addition salt is Cu-K α Radiation (Cu-K α 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monophosphate has at least one or more of the following peaks in the X-ray powder diffraction (XRPD) spectrum obtained by irradiation with ): 9.0°2θ, 10.7±0.2°2θ, 11.7°2θ, 14.8°2θ, 18.4°2θ, 19.3°2θ, and 21.8°2θ, 22.8°2θ, ±0.2°2θ.

[0013] In one embodiment, this monoacid addition salt is Cu-K α Radiation (Cu-K α ) is 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monotosylate, which has at least one or more of the following peaks in the X-ray powder diffraction (XRPD) spectrum obtained by irradiation with ): 4.0°2θ, 11.4°2θ, 12.2°2θ, 14.4°2θ, 17.7°2θ, 18.9°2θ, 19.7°2θ, 20.3°2θ, 23.2°2θ, and 26.7°2θ, ±0.2°2θ.

[0014] In one embodiment, the monoacid addition salt is a monohydrochloride salt, and the XRPD spectrum is as shown below. It holds. [ka]

[0015] In one embodiment, the monoacid addition salt is a monophosphate and has the following XRPD spectrum. [ka]

[0016] In one embodiment, the monoacid addition salt is a monotosylate and has the following XRPD spectrum. [ka]

[0017] In a further embodiment, the present invention relates to a method for preparing a monoacid addition salt as defined above, the method comprising the following steps: - A step of providing 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide free base and an acid selected from hydrochloric acid, phosphoric acid, and p-toluenesulfonic acid in a 1:1 stoichiometric ratio; - The step of mixing and dissolving these in a suitable solvent or solvent mixture, for example, isopropyl alcohol (IPA), methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), acetone, or a mixture of THF and acetone; - A step of evaporating the solvent or solvent mixture.

[0018] In a further embodiment, the present invention relates to a pharmaceutical composition comprising at least one compound of the present invention or a monoacid addition salt of the present invention together with at least one pharmaceutically acceptable carrier, excipient and / or diluent.

[0019] In one embodiment, the pharmaceutical composition further comprises at least one other pharmaceutically active agent.

[0020] In a further embodiment, the present invention relates to compounds or monoacid salts of the present invention as defined above, for use in the treatment of bacterial infections.

[0021] In one embodiment, the bacterial infection is tuberculosis or Buruli ulcer.

[0022] In a further aspect, the present invention relates to a method of treating a bacterial infection, particularly tuberculosis or Buruli ulcer, comprising administering to a patient in need thereof a suitable amount of a compound or monoacid addition salt according to the present invention, or a pharmaceutical composition according to the present invention.

[0023] The inventors have found that a particular polymorphic form of the ditosylate of this compound (which may also be referred to herein as "Pattern A" or "Form A") is particularly stable, and that other forms are converted to such stable polymorphic forms. Cu-K α In an X-ray powder diffraction (XRPD) spectrum obtained by irradiation with Cu-K radiation, such a form has at least one or several of the following peaks: 3.9° 2θ, 5.6° 2θ, 8.0° 2θ, 16.1° 2θ, 19.1° 2θ, and 22.4° 2θ, ±0.2° 2θ.

[0024] In one embodiment where the standard deviation of the 2θ value is ±0.2° 2θ, the compound has an XRPD spectrum as shown below. [Chemical formula]

[0025] [[ID=二十六]]Compared with other forms, this form is the most stable form, and thus it is considered that this form is particularly suitable for pharmaceutical preparations. In one embodiment, the differential scanning calorimetry (DSC) thermogram of the compound described in the present invention shows a single endothermic peak starting at about 235°C to 237°C.

[0026] In one embodiment, the differential scanning calorimetry (DSC) thermogram of the compound described in the present invention shows a single endothermic peak starting at 235°C to 237°C.

[0027] In one embodiment, the compound described in the present invention is produced by a method comprising the following steps: - A step of providing 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide free base and p-toluenesulfonic acid in a 1:2 stoichiometric ratio, in any order; - The step of mixing and dissolving these in a suitable solvent or solvent mixture, for example, isopropyl alcohol (IPA), tetrahydrofuran (THF), acetone, or a mixture of THF and acetone; - A step of evaporating the solvent or solvent mixture.

[0028] The present invention also relates to a method for producing compounds as defined above, the method comprising the following steps: - A step of providing 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide free base and p-toluenesulfonic acid in a 1:2 stoichiometric ratio, in any order; - Mix these with a suitable solvent or solvent mixture, for example, isopropyl alcohol (IPA), tetrahydrofuran (THF), acetone, or a mixture of THF and acetone. Dissolve step; - A step of evaporating the solvent or solvent mixture.

[0029] Furthermore, the inventors have also found that the compound of the present invention, namely 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate, is stable for up to 60 months under long-term storage conditions of 25°C and 60% relative humidity, and for at least 6 months under accelerated conditions of 40°C and 75% relative humidity.

[0030] In a further embodiment, the present invention also relates to a monoacid salt of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide, wherein the monoacid salt is one of a monohydrochloride, a monophosphate, or a monotosylate.

[0031] When the monoacid addition salt is a monohydrochloride salt, this compound is, in one embodiment, Cu-K α Radiation (Cu-K α The X-ray powder diffraction (XRPD) spectrum obtained by irradiation with ) has at least one or more of the following peaks: 6.4°2θ, 8.1°2θ, 16.2°2θ, 17.2°2θ, 24.3°2θ, and 25.0°2θ (the standard deviation of all 2θ values ​​is ±0.2°2θ).

[0032] When the monoacid addition salt is a monophosphate, this compound is, in one embodiment, Cu-K α Radiation (Cu-K α The X-ray powder diffraction (XRPD) spectrum obtained by irradiation with ) has at least one or more of the following peaks: 9.0°2θ, 10.7±0.2°2θ, 11.7°2θ, 14.8°2θ, 18.4°2θ, 19.3°2θ, and 21.8°2θ, 22.8°2θ, ±0.2°2θ.

[0033] When the monoacid addition salt is a monotosylate, in one embodiment this is Cu-K α Radiation (Cu-K α The X-ray powder diffraction (XRPD) spectrum obtained by irradiation with ) has at least one or more of the following peaks: 4.0°2θ, 11.4°2θ, 12.2°2θ, 14.4°2θ, 17.7°2θ, 18.9°2θ, 19.7°2θ, 20.3°2θ, 23.2°2θ, and 26.7°2θ (the standard deviation of all 2θ values ​​is ±0.2°2θ).

[0034] In one embodiment of the monoacid addition salt described above, each compound is Cu-K α Radiation (Cu-K α The X-ray powder diffraction (XRPD) spectrum obtained by irradiation with ) has all of the aforementioned peaks.

[0035] In one embodiment, the monoacid addition salt is a monohydrochloride salt and has the following XRPD spectrum. [ka]

[0036] In one embodiment, the monoacid addition salt is a monophosphate and has the following XRPD spectrum. [ka]

[0037] In another embodiment, it is a monotosylate and has the following XRPD spectrum. [ka]

[0038] In a further embodiment, the present invention relates to a method for preparing a monoacid addition salt as defined above, the method comprising the following steps: - A step of providing 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide free base and an acid selected from hydrochloric acid, phosphoric acid, and p-toluenesulfonic acid in a 1:1 stoichiometric ratio; - The step of mixing and dissolving these in a suitable solvent or solvent mixture, for example, isopropyl alcohol (IPA), methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), acetone, or a mixture of THF and acetone; - A step of evaporating the solvent or solvent mixture.

[0039] The inventors have surprisingly found that the three monoacid addition salts mentioned above exhibit greater solubility at low pH values, particularly around pH 1. This is important insofar as the drug is intended to be taken orally and must pass through the gastrointestinal tract. Higher solubility compared to free bases means higher bioavailability.

[0040] In this specification, when a situation is described as having “an XRPD spectrum as shown below,” this means a situation in which the compound has peaks and signals in the XRPD spectrum at the positions indicated in each of the XRPD spectra mentioned. The intensities of the individual peaks shown do not necessarily have to be identical, as long as there are peaks or signals at the indicated positions, within the typical range (one or more) of acceptable values ​​for such an XRPD spectrum.

[0041] Furthermore, at low pH levels, especially around pH 1, monohydrochloride and monophosphate salts exhibit better solubility compared to nitrosylates.

[0042] Furthermore, the present invention also relates to pharmaceutical compositions comprising a compound 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate as defined above, or a monoacid addition salt of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide as defined above, together with at least one pharmaceutically acceptable carrier, excipient and / or diluent.

[0043] In one embodiment, such a pharmaceutical composition further comprises at least one other pharmaceutically active agent.

[0044] In a further embodiment, the present invention relates to nitrosylates as defined above, or monoacid addition salts as defined above, for use in the treatment of bacterial infections.

[0045] In one embodiment, the bacterial infection is tuberculosis or Buruli's ulcer.

[0046] In a further embodiment, the present invention also relates to a method for treating bacterial infections, particularly tuberculosis or Buruli ulcer, comprising applying a suitable amount of a compound as defined above, or a monoacid salt as defined above, or a pharmaceutical composition as defined above, to a patient in need.

[0047] In a further embodiment, the present invention relates to the manufacture of a drug for treating bacterial infections, The use of ditosylate compounds as defined above, or monoacid addition salts as defined above, or pharmaceutical compositions as defined above, preferably the bacterial infection is tuberculosis or Buruli ulcer.

[0048] It should be noted that the compound 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide, as used herein, may also be referred to as "Q203".

[0049] The present invention will now be further explained with reference to the following diagrams. [Brief explanation of the drawing]

[0050] [Figure 1] Figure 1 shows the XRPD spectrum of form A (or "pattern A") of Q203 nitrosylate.

[0051] [Figure 2]Figures 2a and 2b show the XRPD spectra of the monohydrochloride and monophosphate forms of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide, respectively.

[0052] [Figure 3] Figure 3 shows the XRPD spectrum of the monotosylate form of -chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide.

[0053] [Figure 4] Figure 4 shows the DSC scan of Form A of Q203 nitrate.

[0054] [Figure 5] Figure 5 shows the TGA scan of Form A of Q203 nitrate.

[0055] [Figure 6] Figure 6 shows the various forms of XRPD scans obtained, which will be further explained below.

[0056] [Figure 7] Figure 7 shows the various forms of DSC scans obtained, which will be further explained below.

[0057] [Figure 8] Figure 8 shows the DVS scan of Form A.

[0058] [Figure 9] Figure 9 shows the XRPD scan of Form C.

[0059] [Figure 10] Figure 10 shows the DSC scan of Form C.

[0060] [Figure 11] Figure 11 shows the TGA scan of Form C.

[0061] [Figure 12] Figure 12 shows the DVS scan of Form C.

[0062] [Figure 13] Figure 13 shows the XRPD scan of the solid form G from the slurrying experiment.

[0063] [Figure 14] Figure 14 shows the DSC scan of the solid of pattern G from the slurrying experiment.

[0064] [Figure 15] Figure 15 shows the TGA scan of the solid of pattern G from the slurrying experiment.

[0065] [Figure 16] Figure 16 shows the XRPD scan of the solid form A from a 100% RH experiment.

[0066] [Figure 17] Figure 17 shows the XRPD scan of the solid form A from a 100% RH experiment.

[0067] [Figure 18] Figure 18 shows an XRPD scan of the solid form C from a 100% RH experiment.

[0068] [Figure 19] Figure 19 shows a DSC scan of the solid form A from a 100% RH experiment.

[0069] [Figure 20] Figure 20 shows a DSC scan of the solid form A from a 100% RH experiment.

[0070] [Figure 21] Figure 21 shows a DSC scan of a solid of morphology C from a 100% RH experiment.

[0071] [Figure 22] Figure 22 shows the XRPD patterns of Q203 free base, batch C12032302-J16001.

[0072] [Figure 23] Figure 23 shows the XRPD pattern of Q203 nitrate, batch C12032302-K16001M, form A (i.e., the appropriate "Q203" nitrate).

[0073] [Figure 24] Figure 24 shows the XRPD patterns of Q203 free base (top trace), nitrosylate (pattern A, second trace from the top), ND-0006E-007-16 (third trace from the top), and pTSA (bottom trace).

[0074] [Figure 25] Figure 25 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-003-01 (type 2, lower trace).

[0075] [Figure 26] Figure 26 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-003-25 (type 3, lower trace).

[0076] [Figure 27] Figure 27 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-003-04 (type 4, middle trace), and fumarate (bottom trace).

[0077] [Figure 28]Figure 28 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-006-14 (type 5, middle trace), and urea (bottom trace).

[0078] [Figure 29] Figure 29 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-006-15 (type 6, middle trace), and benzenesulfonic acid.

[0079] [Figure 30] Figure 30 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-003-16 (type 7, middle trace), and pTSA (bottom trace).

[0080] [Figure 31] Figure 31 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-006-16 (type 8, middle trace), and pTSA (bottom trace).

[0081] [Figure 32] Figure 32 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-003-22 (type 9, middle trace), and EDSA (bottom trace).

[0082] [Figure 33] Figure 33 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-003-24 (type 10, middle trace), and NDSA (bottom trace).

[0083] [Figure 34] Figure 34 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-006-24 (type 10, middle trace), and NDSA (bottom trace).

[0084] [Figure 35] Figure 35 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-005-15 (type 12, middle trace), and BSA (bottom trace).

[0085] [Figure 36] Figure 36 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-004-01 (type 13, middle trace), and 2-furoic acid (bottom trace).

[0086] [Figure 37] Figure 37 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-004-03 (type 14, middle trace), and citrate (bottom trace).

[0087] [Figure 38] Figure 38 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-004-04 (type 14, middle trace), and fumarate (bottom trace).

[0088] [Figure 39] Figure 39 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-004-06 (type 16, middle trace), and ketoglutaric acid (bottom trace).

[0089] [Figure 40] Figure 40 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-004-24 (type 17, middle trace), and NDSA (bottom trace).

[0090] [Figure 41] Figure 41 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-004-20 (type 18, middle trace), and maleic acid (bottom trace).

[0091] [Figure 42] Figure 42 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-004-17 (type 19, middle trace), and gentisic acid (bottom trace).

[0092] [Figure 43] Figure 43 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-004-16 (type 20, middle trace), and pTSA (bottom trace).

[0093] [Figure 44] Figure 44 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-004-13 (type 21, middle trace), and tartaric acid (bottom trace).

[0094] [Figure 45] Figure 45 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-004-12 (type 22, middle trace), and succinic acid (bottom trace).

[0095] [Figure 46] Figure 46 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-004-12 (type 22, middle trace), and mandelic acid (bottom trace).

[0096] [Figure 47] Figure 47 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-004-07 (type 24, middle trace), and malic acid (bottom trace).

[0097] [Figure 48] Figure 48 shows the XRPD patterns of Q203 free base (top trace) and ND-0006E-005-13 / 20 / 27 (type 25, second / third / bottom trace).

[0098] [Figure 49] Figure 49 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-007-24 (type 26, middle trace), and NDSA (bottom trace).

[0099] [Figure 50] Figure 50 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-006-17 (type 27, middle trace), and gentisic acid (bottom trace).

[0100] [Figure 51] Figure 51 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-008-15 (type 28, lower trace).

[0101] [Figure 52] Figure 52 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-005-06 (type 29, middle trace), and ketoglutaric acid (bottom trace).

[0102] [Figure 53] Figure 53 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-005-04 (type 30, middle trace), and fumarate (bottom trace).

[0103] [Figure 54] Figure 54 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-007-28 (type 31, lower trace).

[0104] [Figure 55] Figure 55 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-007-06 (type 32, lower trace).

[0105] [Figure 56] Figure 56 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-007-15 (type 33, middle trace), and benzenesulfonic acid (BSA) (bottom trace).

[0106] [Figure 57] Figure 57 shows the XRPD patterns of Q203 free base (top trace), ND-0006E-007-22 (type 34, middle trace), and ethane disulfonic acid (EDSA) (bottom trace).

[0107] [Figure 58] Figure 58 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-007-18 (type 35, lower trace).

[0108] [Figure 59] Figure 59 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-004-18 (type 36, lower trace).

[0109] [Figure 60] Figure 60 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-008-13 (type 37, lower trace).

[0110] [Figure 61] Figure 61 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-009-07 (type 38, lower trace).

[0111] [Figure 62] Figure 62 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-009-06 (type 39, lower trace).

[0112] [Figure 63]Figure 63 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-008-10 (type 40, lower trace).

[0113] [Figure 64] Figure 64 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-008-09 (type 41, lower trace).

[0114] [Figure 65] Figure 65 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-008-08 (type 42, lower trace).

[0115] [Figure 66] Figure 66 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-008-02 (type 43, lower trace).

[0116] [Figure 67] Figure 67 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-008-01 (type 44, lower trace).

[0117] [Figure 68] Figure 68 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-010-04 (type 45, lower trace).

[0118] [Figure 69] Figure 69 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-010-05 (type 46, lower trace).

[0119] [Figure 70] Figure 70 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-010-13 (type 47, lower trace).

[0120] [Figure 71] Figure 71 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-003-34 (type 48, lower trace).

[0121] [Figure 72] Figure 72 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-005-30 (type 49, lower trace).

[0122] [Figure 73] Figure 73 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-004-33 (type 50, lower trace).

[0123] [Figure 74] Figure 74 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-005-33 (type 51, lower trace).

[0124] [Figure 75] Figure 75 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-004-34 (type 52, lower trace).

[0125] [Figure 76] Figure 76 shows the XRPD patterns of Q203 free base (upper trace) and ND-0006E-005-34 (type 53, lower trace).

[0126] [Figure 77] Figure 77 shows the XRPD patterns of Q203 free base (top trace) and ND-0006E-004-23 (type 54, purple trace).

[0127] [Figure 78] Figure 78 shows the XRPD trace of the solid separated after the pH solubility experiment. [Examples]

[0128] Furthermore, refer to the following examples, which are given not to limit the present invention but to illustrate it.

[0129] Example 1 overview Polymorphic screening studies of Q203 were conducted using various crystallization techniques, including slurrying and salt formation experiments. Cooling, evaporation, and reverse solvent experiments were not performed due to the very low solubility of the solid in various solvents. Eight XRPD patterns, namely A, B, C, D, E, F, G, and H, were identified. Patterns A and C were proven to be the true crystalline forms of the nitrosylates. Reslurrying experiments for polymorphic screening were performed starting with form A. Form A is a neat form and retains its crystalline form after exposure to 100% RH at RT for 6 days. Form C is also a neat form and can be obtained by restluring form A with methanol and retains its crystalline form after exposure to 100% RH at RT for 6 days. Pattern G was obtained from water, and its 1H-NMR shows a base:acid ratio of 1:1.3. Pattern H also retains its crystalline XRPD pattern after exposure to 100% RH at RT for 3 days. Pattern H was obtained from toluene, and its NMR spectrum shows a base:acid ratio of 3:3.46. Therefore, patterns G and H are not considered true polymorphs of the nitrosylate. Forms A and C were stirred in six pure solvents at RT and 50°C for 4 days. According to XRPD scans, the residual solid in stability experiments from most solvents (THF, EtOH, and IPA) was form A, while methanol as a reslurry medium produced form C. Based on the data, form A appears to be more stable than form C.

[0130] XRPD The details of the XRPD method used in the test are as follows: - Rigaku D / MAX 2200 X-ray Powder Diffractometer -X-ray generator: Cu, kα, (λ=1.54056Å) - Tube voltage: 40kV, Tube current: 40mA -DivSlit:1 degree -DivH.L.Slit:10mm -SctSlit: 1 degree -RecSlit:0.15mm - Monochrome meter: Fixed monochrome meter - Scanning range: 3 to 36 degrees (2θ) - Scanning step: 5 degrees / minute DSC The details of the DSC method used in the test are as follows: - Mettler Toledo Q2000MDSC Heat from 40°C to 300°C at a rate of -10°C / min. experiment Analysis of starting materials

[0131] XRPD, DSC, and TGA scans of the starting ditosylate from A are shown in Figures 1, 4, and 5. According to the XRPD, this solid (referred to as form A) is crystalline. The DSC scan of this solid shows a melting onset temperature of around 235°C. The TGA data shows a weight loss of 0.3% from 30°C to 200°C. The purity of the starting material is 99.46%. Solubility experiment Experiment 1: Solubility of free bases

[0132] The purpose of measuring the solubility of free bases was to identify potential solvents for salt formation process development. The approximate solubility of free bases was measured by gravimetric analysis. Excess solids were added at RT and 50°C to various solvents, including several Class III solvents (ICH guidelines). Since solubility in these solvents is generally low, water was added to these solvents. This suspension was slurryed over a day, and the clear liquid at the top of the suspension was used for gravimetric solubility measurement. Solubility data are shown in Table 2-1. At 50°C, solubility in IPA or its water mixture was generally low (11–22 mg / ml), solubility in acetone or its water mixture was in the range of 41–74 mg / ml, solubility in EA or its water mixture was in the range of 55–98 mg / ml, and solubility in methyl acetate was in the range of 94–105 mg / ml. Solubility in THF was 279 mg / ml at 50°C. Table 2-1: Approximate solubility of free bases in pure solvents at RT and 50°C * data [Table 2-1] [Table 2-2] * The solubility figures are approximate and are for process development purposes only. Experiment 2: Solubility of starting material (nitrosylate, Form A)

[0133] The approximate solubility of the starting material, nitrosylate (Form A), was determined by gravimetric analysis. 100 mg of the solid was suspended in 10 vol of various solvents and stirred for 3 days at RT and 50°C. The solubility was then measured using the mother liquor. The results are shown in Table 2-2. According to the solubility data, this solid has low solubility in most solvents except MeOH. The solubility in MeOH was 126 mg / ml and 275 mg / ml at RT and 50°C, respectively. Table 2-2: Approximate solubility of starting materials in various pure solvents at RT and 50°C. * [Table 2-3] [Table 2-4] * The solubility figures are approximate and are for process development purposes only. Polymorphic screening experiment

[0134] Polymorphism screening experiments were conducted using two methods: slurrying and salt formation (reactive crystallization). Some experimental samples were analyzed both before and after drying (wet and dry). Reslurrying experiment Experiment 1: Reslurrying in various pure solvents at RT and 50°C for 7 days.

[0135] Residual solid samples obtained from solubility experiments were used for XRPD analysis. Samples were analyzed in both wet and dry conditions to ensure the capture of potential solvates / hydrates. Table 3-1 shows the analytical results. As observed, residual solids from reslurrying with water show pattern B. Reslurrying with methanol produced form C. Ethanol, acetone (in some experiments), and acetonitrile produced solids of pattern D. Some experiments using MEK and THF showed solids of pattern E or mixtures with A. All other samples produced solids with no change from the original XRPD pattern (form A). Table 3-1: Results of morphological screening by RT and reslurrying at 50°C for 7 days in various pure solvents. [Table 3-1] Experiment 2: Reslurry formation in a two-component solvent at RT for 5 days.

[0136] To extend the slurrying experiment, a mixture of solvents was used as the slurry medium. The residual solid was then analyzed using XRPD and DSC machines. The experimental procedure is described below. • 30 mg of Form B was added to a 1.5 ml vial. A two-component solvent in a 1:1 ratio was prepared according to Table 4-1. • The suspension was slurryed in RT for 5 days. • Filter the sample and vacuum dry it in a 50°C oven for 15 minutes. • Performed XRPD scan and DSC scan.

[0137] The results are shown in Table 4-1. It was found that methanol:water and IPA:water (0.5 ml:0.5 ml) produced solids of pattern B. Pattern B appears to be related to water; that is, this pattern is produced when water is present. On the other hand, most solvents mixed with methanol produced pattern C. Starting from pattern A, it appears that methanol is required as at least a portion of the solvent to produce pattern C. In a pure solvent... It was shown that pattern A is converted to pattern C in methanol. Further experiments showed that reactive crystallization using solvents other than methanol initially produces pattern C, but over time, pattern C is converted to pattern A. In two examples, a new XRPD pattern (F) was observed. Apart from the above, pattern A remained unchanged in all other experiments. [Table 4-1] Salt formation experiment

[0138] To screen conditions other than those used in slurry formation experiments, salt formation (reactive crystallization) experiments were performed in 12 different solvents. The experimental procedure is described below. 150 mg of free base was added to a 4 ml vial equipped with a magnetic stirrer. . Add 10 vol (1.5 ml) of solvent (see Table 4 for a list of solvents). The solution was stirred at 50°C for 2 hours. 2.2 equivalent moles (113 mg) of p-toluenesulfonic acid were added to a solution at 50°C. As soon as a suspension containing a sufficient amount of solid (for XRPD / DSC testing) is formed, the sample is filtered / dried and subjected to XRPD / DSC analysis. • Solids with novel XRPD patterns were analyzed by NMR for acid / base ratio.

[0139] Table 5-1 shows the observations during the salt formation experiment. It can be seen that the free base dissolved in the target solvent at 50°C before the addition of the counterion. In all cases, the solid (potential salt) was formed almost immediately after the addition of the counterion. The solid at this point (immediately after salt formation) was analyzed before and after drying. XRPD analysis of the wet and dry samples helps to identify the potential solvate / hydrate of the salt. In some wet solids, deviations from pattern C were observed, but the dry solids produced pattern C in all solvents except toluene. The main finding from the experiment is the consistent appearance of pattern C immediately after salt formation. Pattern C is known to eventually change to pattern A in the solvent (except methanol). [Table 5-1] Attempts to manufacture solids with various XRPD patterns

[0140] Various slurrying and reactive crystallization experiments generated a variety of crystal patterns, including A, B, C, D, E, F, G, and H. Previous analysis (NMR) showed that pattern H is not the true crystalline form of the nitrosylate and therefore should be excluded from the list. Attempts were made to reproduce the solids to evaluate and further analyze other solids with other XRPD patterns (A-G) (previous experiments demonstrating these solids were performed on a small scale, and most of the solids were consumed for XRPD / DSC analysis). Table 6-1 shows the results of attempts to generate solids with XRPD patterns B, C, D, E, and F. The experiment demonstrates this. The solid with pattern A was the starting material and was therefore already available. Table 6-1: Preparation results for forms B, C, D, E, and F [Table 6-1] Analysis of various forms

[0141] Figure 6 shows an overlay of scans of various XRPD patterns observed in this study. Patterns A and C are true crystalline polymorphs of the nitrosylate. Therefore, we refer to these solids as Form A and Form C. However, since the other XRPD patterns have not been shown to be true polymorphs of the nitrosylate, we refer to them simply as “patterns.” Patterns C and D are very similar and could be called the same crystalline form.

[0142] Figure 7 shows DSC overlays associated with various XRPD patterns of a solid. Forms A, C (and D), and pattern E have the same onset temperature, varying between 235°C and 240°C. Pattern B shows two endothermic peaks, one with an onset temperature around 139°C and the other around 208°C. Analysis of Form A

[0143] Form A is the true polymorph of the nitrosylate, and NMR indicates an acid:base ratio of 6:3. Crystallinity is generally low, with DSC scans showing melting initiation around 235°C and TGA scans showing a 0.3% weight loss from 30°C to 200°C (Figures 4-5). This is the main form obtained in slurry experiments. Conversion from Form A to other XRPD patterns was mainly obtained from methanol (to Form C) or water (to Pattern B) in the slurry medium. However, as shown in subsequent sections, Form C is converted back to Form A when reslurried with most other solvents (other than methanol). Since Pattern B is likely a partially (or completely) hydrolyzed species of the salt, the conversion from Form A to the solid of Pattern B does not mean that the solid with Pattern B is a more stable form than Form A. Figure 8 shows the DVS of Form A, with a water absorption of approximately 0.35% at 90% RH, RT. Analysis of Form C

[0144] Figures 9-11 show the XRPD, DSC, and TGA of solids with form C. Form C is the true polymorph of the nitrosylate, as shown by NMR to have an acid:base ratio of 2:1. The XRPD peak of form C is sharper than that of form A. When methanol is used as the slurry medium, form C is the dominant form. However, form "C" is not the methanol solvate form of the nitrosylate. In many reactive crystallization experiments using various solvents, form C was produced immediately after salt formation. Subsequent experiments showed that overnight slurring (reactive crystallization) of the same suspension converted form C to A. Figure 12 shows a DVS scan of form C. The DVS scan shows that the solid absorbs less than 0.3% water at 90% RH, RT. Analysis of Form G

[0145] The XRPD, DSC, and TGA of the solid exhibiting pattern G are shown in Figures 13–15. This solid is crystalline, with DSC melting initiation at 216°C (lower than forms A and C), and a weight loss of 0.3% in the range of 30°C–200°C. HPLC data indicate an acid-to-base ratio of 3.45:1, therefore this is not considered a nitrosylate. Other patterns

[0146] Attempts were made to reproduce other XRPD patterns, but these patterns were not generated. This means that these solids were observed only once or twice during the form screening. Among these, pattern B is important because it may indicate a hydrate form. However, it is likely a hydrated form of a hydrolyzed salt, not a nitrosylate (a partial salt hydrate). Stability experiment

[0147] The objective of this section is to observe the potential transformations of these forms when exposed to 100% RH, and to identify the most stable polymorphs observed in this study. Experiment 1: Exposure of Forms A and C to 100% RH at RT for 6 days.

[0148] Forms A and C were exposed to a 100% RH environment at RT for 6 days; subsequently, the solids were analyzed using DSC and XRPD.

[0149] The results are shown in Figures 16-21. Figures 1 and 17 depict the XRPDs of Form A (previously obtained Form EA and IPA / MEK) samples before and after 6 days of exposure to 100% RH. Figures 19 and 20 show DSC scans of the same samples after exposure. Both figures show no change in crystal structure, indicating that Form A is stable (in terms of polymorphism) in a high RH environment. Figures 18 and 21 show the results of the same treatment of Form C. These results indicate that the crystal structure does not change as a result of exposure to high RH. Experiment 2: Reslurrying of Forms A and C in six different pure solvents for 5 days at RT (aging experiment)

[0150] These experiments were conducted to investigate the potential conversion between form A and form C. The experimental procedure is as follows: Form A (15 mg) and Form C (15 mg) were added to a 1.5 ml vial equipped with a magnetic stirrer. • 20 vol (600 μl) of various solvents were added to the vial. The suspension was stirred in RT for 5 days. • Afterwards, the solid was filtered and sent to XRPD (before and after drying in the oven) and DSC.

[0151] The experimental data are shown in Table 10-1. Water, methanol, IPA, acetone, and THF were used as slurry media. The data for the samples on day 5 showed that nitrosylates were partially dissolved in water. Hydrolysis was observed (producing a solid of pattern G). When methanol was used again as the slurry medium, form C was produced. This is consistent with previous findings from reslurrying. These data suggest that form A is more stable than form C (except in methanol) and therefore appears to be the most stable form under most conditions. Table 10-1: Results of restrush of Forms A and C at RT for 5 days in six different pure solvents [Table 10-1]

[0152] Experiment 3: Reslurrying of Forms A, C, and H in six different pure solvents at RT and 50°C for 3 days.

[0153] The procedures for these experiments are shown below. Form A (10 mg) and Form C (5 mg) were added to a 1.5 ml vial equipped with a magnetic stirrer. • 20 vol (300 μl) of various solvents were added to the vial, and it was confirmed that the solution was cloudy. • Add a small amount of Form H as a seed. The suspension was stirred in RT for 3 days. • Afterwards, the solid was filtered and sent to XRPD (after drying in an oven) and DSC.

[0154] Except for water (partially hydrated) and methanol (Form (From) C), the results are shown in Table 11-1. Performing other treatments at both temperatures yields Form A (as expected). Table 11-1: Results of stability experiments for forms A, C, and H [Table 11-1] [Table 11-2]

[0155] Experiment 4: Stability of Form C by Seeding Experiment

[0156] Form C was generated by salt formation screening (reactive crystallization experiment). To evaluate the polymorphic stability of Form C, a small amount of Form A was added to a suspension of Form C (in the following solvents) and stirred overnight at RT. The suspension was filtered, and the solid was analyzed using XRPD (wet and dry samples ). The results are shown below. The data indicate that Form C is converted to Form A in all solids, corroborating previous results regarding the stability of Form A. Table 12-1: Results of the Stability Experiment

Table 12-1

[0157] Example 2

[0158] The inventors wanted to conduct the salt / cocrystal screening of the Q203 free base as shown below. For this purpose, a standard salt / cocrystal screening of Q203 was performed to identify salts with acceptable properties, and the physicochemical properties of the Q203 free base were also evaluated. The starting materials used in this Example 2 were the Q203 free base, batch C12032302-J16001, and the ditosylate of Q203, batch C12032302-K16001M.

Chemical formula

Table 1

[0159] If dissolution did not occur after adding the last aliquot of solvent (usually about 40 times the amount of solvent), the sample was subjected to the next temperature cycle regime for two cycles in the Clarity crystallisation station. Heat from 20°C to within 3°C of the solvent's boiling point (or 100°C, whichever is lower) at a rate of 0.5°C / min. Cool to 20°C at a rate of 0.2°C / min. • Stirrer speed: 800 rpm.

[0160] Dissolution and precipitation events were recorded from infrared (IR) transmission data of the sample vials, as the point of complete IR transmission and the point of onset of IR-induced turbidity, respectively. The solubility values ​​of Q203 were expressed as a range and rounded to the nearest integer. 2.2 Screening Methods

[0161] The experiment was performed on a scale of approximately 25 mg using 1:1 and 2:1 stoichiometric concentrations (salt / cocrystal-forming agent: Q203 free base). 2.2.1 Slow evaporation

[0162] A stock solution of the co-forming agent in the selected solvent (1 equivalent) was added to a stock solution of Q203 free base (batch C12032302-J16001, 1 or 2 equivalents). If a stock solution of the co-forming agent could not be prepared, the co-forming agent was added as a solid / liquid. The resulting solution was evaporated in a fume hood at ambient temperature in a vial covered with perforated aluminum foil. The separated solid was dried under nitrogen and analyzed by XRPD. 2.2.2 Slurry Formation Experiment

[0163] Q203 free base (batch C12032302-J16001, 1 equivalent) and co-forming agent (1 or 2 equivalents) were added to the specified solvent at the desired temperature (20 or 40°C) until undissolved solids remained. The vial was sealed, the slurry was maintained at the selected temperature, and stirred with a magnetic stirrer for 5–7 days. Prior to XRPD analysis, the solids were separated by centrifugation and liquid decantation and dried under nitrogen. 2.2.3 Ultrasonic Treatment

[0164] A selected neat or mixed solvent system was added to Q203 free base (batch C12032302-J16001, 1 equivalent) and co-forming agent (1 equivalent) to form a paste. This paste was sonicated using a Cole-Parmer 130W ultrasonic processor with a pulse program at 70% intensity. All solids recovered from these experiments were dried under nitrogen before analysis by XRPD. 2.2.4 Liquid-assisted grinding (LAG)

[0165] Free Q203 base (approximately 50 mg, 1 equivalent) was added to a stainless steel milling chamber along with a selected co-forming agent (1 equivalent). A milling ball and solvent (25 μl) were added to the chamber and milled at 25 Hz for 3 × 2 minutes, scraping the chamber walls between each run. The ground solid was analyzed by XRPD. 2.2.5 Euclide (Kofler fusion)

[0166] Free Q203 base (approximately 50 mg, 1 equivalent) was added to an HPLC vial along with a selected co-forming agent (1 equivalent). The vial was pre-purged with nitrogen, and the temperature of the hot plate was increased until one solid melted and diffused into the other. After the molten material cooled to ambient temperature, it was analyzed by XRPD. 2.2.6 Humidity stress of generated salts

[0167] Approximately 25 mg of the generated Q203 salt was added to a vial and left unsealed at ambient temperature for 7 days in a chamber with 75% relative humidity (a sealed cabinet where relative humidity conditions were controlled by a supersaturated salt solution) before analysis by XRPD. 2.3 Experimental Techniques 2.3.1 X-ray Powder Diffraction (XRPD)

[0168] XRPD analysis was performed using a Panalytical Xpert Pro diffractometer equipped with a Cu X-ray tube and a Pixcel detector system. Isothermal samples were analyzed in transmission mode and sandwiched between low-density polyethylene films. Two XRPD programs were used (analysis range 3–40°²θ, step size 0.013°, measurement time 99 seconds, run time approximately 22 minutes, and analysis range 3–40°²θ, step size 0.013°, measurement time 46 seconds, run time approximately 11 minutes). XRPD patterns were sorted and manipulated using HighScore Plus 2.2c software. 2.3.2 Differential Scanning Calorimetry (DSC)

[0169] DSC analysis was performed using a PerkinElmer Jade differential scanning calorimeter. Accurately weighed samples were placed in crimped aluminum pans. Each sample was heated under nitrogen at a rate of 10°C / min up to a maximum of 300°C. Indium metal was used as the calibration standard. Temperatures were reported in 0.01°C increments at the start of the transition. Note that the DSC traces in this report may include automated peak integrals for calculating the fusion ΔH. These ΔH values ​​are prone to significant errors when multiple thermal events are observed at similar temperatures. 2.3.3 Thermogravimetric Differential Thermal Analysis (TG / DTA)

[0170] Thermogravimetric analysis was performed using a METTLER TOLEDO TGA / DSC1 STARe. The calibration standards were indium and tin. The sample was placed in an aluminum sample pan, inserted into the TG furnace, and accurately weighed. After stabilizing the heat flow signal at 25 °C for 1 minute, it was heated to 300 °C at a rate of 10 °C / min in a nitrogen flow. 2.3.4 1 H / 13 H /

[0171] NMR analysis was performed using a Bruker 500 MHz instrument in MeOD-d4 or DMSO-d6. The instrument parameters are described in the relevant spectral plots. 2.3.5 Optical Microscopy

[0172] Microscopic analysis was performed using an Olympus BX51 stereomicroscope equipped with crossed polarizers and a first-order red compensator plate. Microscopic photographs were taken at an objective lens magnification of 10 times using a ColorView IIIu digital camera and SynchronizIR Basic V5.0 imaging software. 2.3.6 HPLC

[0173] HPLC was used to determine the equilibrium solubility in various solvents. The sample in a water-immiscible solvent was evaporated to dryness and redissolved in a sample diluent. 2.3.7 Determination of Solubility

[0174] To determine the solubility suspension of Q203 salts (p-TSA, phosphate, and HCl) at selected pH conditions (1, 4.5, 6.8, and 7.5), the experiment was set up in duplicate. The salt was weighed into a vial (approximately 25 mg), and an aliquot of the selected buffer was added (1 mL). The suspension was placed on a plate and stirred at room temperature for 22–72 hours. The pH of the sample was monitored during stirring and adjusted to maintain the pH within + / - 0.5 pH units of the parent buffer. At the end of the experiment, the aliquot was removed, filtered through a syringe PTFE filter (0.45 μm), the pH was checked, and the solution was injected into the HPLC system without dilution. If the results indicated that the sample concentration was too high, the sample was diluted and the experiment was repeated. The recovered solid was analyzed by XRPD to check for morphological changes. The method for preparing the solutions used in this study is shown below. 2.3.8 Components for preparing standard buffer solutions (according to USP27) 2.3.8.1 Potassium chloride 0.2M

[0175] Measure 1.5g of potassium chloride into a 100mL flask and fill it with water up to the marked line. 8.2.1.2 Potassium dihydrogen phosphate 0.2M

[0176] 2.8g of potassium dihydrogen phosphate was weighed into a 100mL flask and filled with water up to the marked line. 2.3.8.2 Sodium hydroxide 0.2M

[0177] A standard solution of NaOH (2.0 M, 10 mL) was added to a 100 mL flask, and the flask was filled with water up to the marked line. 2.3.8.3 Potassium biphthalate 0.2M

[0178] Add 4.1 g of potassium biphthalate to a 100 mL flask and fill with water up to the marked line. 8.2.1.4 Hydrochloric acid 0.2M

[0179] Add HCl standard solution (1.0 M, 20 mL) to a 100 mL flask and fill with water up to the mark. did. 2.3.8.4 USP Buffer pH1

[0180] 0.2M potassium chloride solution (50 mL) + 0.2M HCl solution (85 mL) were added to a 200 mL flask, and the flask was filled with water up to the marked line. 2.3.8.5 USP buffer pH4.5 50 mL of 0.2 M potassium biphthalate solution and 6.6 mL of 0.2 M NaOH solution were added to a 200 mL flask, and the flask was filled with water up to the marked line. 2.3.8.6 USP buffer pH6.8

[0181] 50 mL of 0.2 M potassium dihydrogen phosphate solution and 22.4 mL of 0.2 M NaOH solution were added to a 200 mL flask, and the flask was filled with water up to the marked line. 2.3.8.7 USP buffer pH7.5

[0182] 50 mL of 0.2 M potassium dihydrogen phosphate solution and 39.1 mL of 0.2 M NaOH solution were added to a 200 mL flask, and the flask was filled with water up to the marked line.

[0183] If necessary, the buffer was adjusted with 1.0 M HCl and 2.0 M NaOH to achieve the correct pH. 2.3.9 pKa analysis

[0184] The pKa of the samples was determined using spectroscopic analysis (UV measurement). The samples were titrated under methanol-water cosolvent conditions (methanol mixing ratio varied from 63.9% to 46.7% w / w) at concentrations of 31–23 μM from pH 2.0 to 12.0 by UV triple titration. 3. Characterization and Solvent Screening of Q203 3.1 Determining pKa

[0185] In determining the pKa, no precipitation of the sample from the solution was observed, and two pKa values ​​of 3.70±0.06 and 4.97±0.01 in aqueous solution were determined from spectroscopic analysis data collected by Yasuda-Shedlovsky extrapolation of the individual results obtained (see Table 2).

[0186] Note that an additional potentiometric assay was performed to confirm the pKa, and no further pKas associated with the sample were found within the measurable pH range (2.0–12.0). Table 2: pKa results of Q203 free base [Table 2-5]

[0187] 3.2 Characterization of Q203 Free Bases

[0188] Figure 22 shows the XRPD patterns obtained for the Q203 free base batch C12032302-J16001. The XRPD patterns indicate that the material is highly crystalline. Proton NMR analysis of the Q203 free bases showed that the material fits the molecular structure and that there is a high probability of residual solvent (potentially about 80 ppm of acetone) being present (data not shown). 3.3 Characterization of Q203 ditoyslate salt

[0189] XRP obtained for Q203 nitrosylate batch C12032302-K16001M The D pattern is shown in Figure 23 (Form A or "Pattern A"). The XRPD pattern indicates a crystalline material, with a slightly elevated baseline and broadened peaks suggesting the possibility of amorphous content. Proton NMR analysis of the Q203 nitrosylate showed that the material fits the molecular structure with a 2:1 acid / API stoichiometry (data not shown). 3.4 Estimated solubility of Q203 free base

[0190] The solubility of Q203 free base was estimated in 10 solvent systems using the aliquot addition method. Temperature cycling experiments were also performed using a Clarity crystallization station to evaluate the solubility of the compound upon heating. Solubility data are detailed in Table 3. Observations recorded in each experiment are also listed in Table 3. Q203 free base was found at approximately 25 mg / mL in four solvents at room temperature, and was found in four additional solvents upon heating. No temperature-dependent solubility was observed in acetone and MTBE. Table 3: Estimated solubility of Q203 free base at 20°C [Table 3-2] [Table 3-3] * =While it showed partial solubility upon heating, a solid remained even after two Clarity heating / cooling cycles.

[0191] 3.5 Conclusions from Characterization and Solvent Screening Q203 Free Base XRPD analysis showed that batch C12032302-J16001 of Q203 free base (hereinafter, "free base" may be abbreviated as "FB") exhibits high crystalline properties. Proton NMR analysis of the free base of Q203 (data not shown) indicated that the material was compatible with the molecular structure and that a residual solvent (potentially about 80 ppm of acetone) was likely present. • TG / DTA data showed a weight loss of approximately 0.4% between 40°C and 235°C. This suggests minimal water or solvent content, and Q203 The presence of free bases indicates that batch C12032302-J16001 is an anhydrous material containing some residual moisture / solvent. The second weight loss at temperatures above 235°C corresponds to the initiation of material decomposition. Endothermic melting was observed at the initiation temperature of 166.8°C. DSC analysis confirmed that the TG / DTA results indicate an endothermic event at an initiation temperature of approximately 167°C. Polarized light microscopy of the Q203 free base revealed the presence of individual aggregated particles suggestive of polydisperse PSD. pKA analysis revealed aqueous values ​​of two pKAs, 3.70±0.06 and 4.97±0.01. 4. Salt / cocrystal screening

[0192] Extended salt / cocrystal screening was performed on Q203 using 37 co-forming agents. The objective was to find alternative salts with more desirable properties (e.g., reduced hygroscopicity, reduced chemical stability, reduced dissolution rate, reduced crystallinity, reduced physical stability, etc.).

[0193] This approach involved generating solids under a wide variety of nucleation conditions designed to mimic the process conditions and solvents used during development and formulation. Purpose-specific manual / semi-automated investigations conducted by experienced experts are widely considered the preferred approach and have been shown to perform comparably to or better than high-throughput screening with fewer experiments. 1

[0194] All solids obtained from the crystallization experiments were analyzed by XRPD, and the resulting patterns were compared to those of the starting materials. Novel XRPD patterns were assigned alphabetical descriptors in the order of detection (e.g., Type 2, Type 3). Where sufficient material was available, further analysis (e.g., NMR or TGA) was performed on solids with novel XRPD patterns to allow for the temporary assignment of the novel patterns as polymorphs, solvates, hydrates, decomposition products, or mixtures thereof. A summary of all experiments performed is further provided in Table 25 of Appendix 1 below. 4.1 Solvent-based screening techniques

[0195] Solvent-based experiments were conducted on a scale of approximately 25–40 mg in glass vials or thin-walled glass capillaries. The methods used are described in detail in Section 2.2. Evaporation, slow cooling, impact cooling, impact precipitation, and prolonged slurries (at ambient and high temperatures) mimic conditions that may be encountered during process development and manufacturing. By varying the nucleation conditions in this way, the possibility of discovering new morphologies is maximized, as is the frequency with which these morphologies occur under general processing conditions. 1 AJAlvarez, A. Singh, AS Myerson, ``Polymorph Screening: Comparing a Semi-Automated Approach with a High Throughput Method'', Crystal Growth and Design, 2009, 9, 4181-4188 4.1.1 Slow evaporation

[0196] Slow evaporation experiments were performed as described in Section 2.2.1. The results are shown in Table 4. XRPD analysis of the obtained solids revealed 14 novel types (pure or mixed) from the co-forming agents, including fumaric acid (type 4), urea (type 5), BSA (type 6), pTSA (types 7 and 8), EDSA (type 9), NDSA (types 10 and 11), saccharin (types 25+3), gentisic acid (type 27), and salicylic acid (type 48). As shown, types 2 and 3 were observed in both pure and mixed states from multiple co-forming agents. These types will be discussed in more detail in Section 5. Table 4: Screening results of slow evaporation experiments containing Q203 free base [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] 4.1.2 RT Slurry Formation

[0197] Slurrying experiments at RT (ambient) temperature were performed using solids produced from slow evaporation experiments containing Q203 free base and co-forming agent (1:1 equivalent), as described in Section 2.2.2. The results are shown in Table 5. XRPD analysis of the solids revealed novel patterns including urea (type 5), EDSA (type 9), 2-furoic acid (type 13), citric acid (type 14), fumaric acid (type 15), ketoglutaric acid (type 16), NDSA (type 17), maleic acid (type 18), gentisic acid (type 19), pTSA (type 20), tartaric acid (type 21), succinic acid (type 22), mandelic acid (type 23), malic acid (type 24), HCl (type 36), pamoic acid (type 50), salicylic acid (type 52), and MSA (type 54). Type 3 was observed in both pure and mixed states from multiple co-forming agents. These types will be discussed in more detail in Section 5. Table 5: Screening results of RT slurrying experiments [Table 5-2] [Table 5-3] 4.1.3 HT slurry formation (40°C)

[0198] Slurrying experiments at high temperatures were performed using solids produced from slow evaporation experiments containing Q203 free base and co-forming agents (both 1:1 and 2:1 equivalents), as described in Section 2.2.2. The results are shown in Table 6. XRPD analysis of the solids revealed novel patterns including urea (type 5), 2-furoic acid (type 13), fumaric acid (type 15), tartaric acid (type 21), mandelic acid (type 23), NDSA (type 26), sulfuric acid (type 31), BSA (type 33), EDSA (type 34), and HCl (type 35). Solids of types 32, 40, and 41 (in both pure and mixed states) were observed from multiple co-forming agents. These types are discussed in more detail in Section 5. Table 6: Screening results of slow evaporation experiments containing Q203 free base [Table 6-2] [Table 6-3] [Table 6-4] 4.1.4 Ultrasonic Treatment

[0199] A selected neat or mixed solvent system was added to a sufficient amount of Q203 free base (batch C12032302-J16001M) to form a paste. This paste was sonicated using a Cole-Parmer 130W ultrasonic processor with a pulse program at 70% intensity. All solids recovered from these experiments were dried under nitrogen before XRPD analysis. The results of these experiments are shown in Table 7. XRPD analysis of the resulting solids revealed novel patterns obtained from the experiments, including pTSA (type 7), NDSA (type 10), mandelic acid (type 23), malic acid (type 24), ketoglutaric acid (type 29), nitric acid (type 49), pamoic acid (type 51), and salicylic acid (type 53). Solids of types 3 and 25 (in pure and mixed states) were observed from multiple co-forming agents. These types are discussed in more detail in Section 5. Each type is described in further detail in Section 5. Table 7: Screening results of ultrasonic treatment experiments [Table 7] 4.2 Screening Techniques for Solid States

[0200] Non-solvent-based (solid state) screening methods include ball milling, sublimation, melting, and compression (Section 2.2). These techniques mimic conditions that may be encountered in large-scale processing, such as on the walls of a high-temperature reactor or during drying and formulation operations. By varying the nucleation conditions in this way, the likelihood of discovering new morphologies is maximized, as is the frequency with which these morphologies occur under common processing conditions. 4.2.1 Eutelescence (Kofler fusion)

[0201] Co-melting (Koeffler melting) experiments were performed using Q203 free base and co-forming agent (1:1 equivalent) as described in Section 2.2.5. The results are detailed in Table 8. These experiments generally produced amorphous or highly disordered solids. XRPD analysis of the solid produced by melting Q203 free base with gluconic acid showed a novel pattern assigned as type 38. A novel pattern (type 39) was also observed from melting experiments involving multiple co-forming agents. These two types are discussed in more detail in Section 5. Table 8: Results of the eufusion experiment [Table 8] 4.2.2 Liquid-assisted grinding (LAG)

[0202] Co-melting (Koeffler melting) experiments were performed using Q203 free base and co-forming agent (1:1 equivalent) as described in Section 2.2.5. The results are detailed in Table 9. XRPD analysis of the obtained solids revealed a new pattern from the LAG experiments, including phosphoric acid (type 37) and ascorbic acid (type 43). Types 28, 40, and 41 were observed from multiple co-forming agents. These types are described in Section 5. Table 9: Results of the LAG experiment [Table 9] 4.3 Conclusions from Salt / Cocrystal Screening

[0203] Approximately 200 experiments were conducted using solvent- and non-solvent-based techniques. Including the material received as is, 55 crystalline XRPD patterns were observed. This indicates a high tendency for Q203 to generate novel patterns from various co-forming agents and techniques. Although polymorphism of Q203 was observed, most of the novel patterns may be attributable to salts of the Q203 free base and / or potential co-crystals. Table 10: Summary of observed Q203 solids (classified by co-forming agent) [Table 10-2] [Table 10-3] [Table 10-4] [Table 10-5] [Table 10-6] 5. Preparation and Characterization of Novel Types 5.1 Pattern A (p-toluenesulfonic acid)

[0204] The material of pattern A (nitrosylate "form A") was separated by slow evaporation, and then an HT slurry experiment was performed using pTSA and Q203 free base (1:1 acid / API) in IPA. XRPD analysis of pattern A (ND-0006E-003-16) showed that this material is crystalline (see also Figures 24 and 30). 5.2 Type 2

[0205] Type 2 material was generated from slow evaporation experiments involving various acids and Q203 free bases (both 1:1 and 2:1 acids / APIs) in THF / MeOH. Table 11 lists the experimental conditions that yielded pure Type 2 and mixtures of Type 2 (with co-forming agents or Type 3). XRPD analysis of the solid Type 2 (ND-0006E-003-01) showed that this material is crystalline and contains some disorder (Figure 25). 1 ¹H NMR analysis showed no salt formation (data not shown). Since this type was obtained from different co-forming agents, it may be a polymorph of the Q203 free base. Table 11: Experimental conditions yielding Type 2 solids (pure and mixed) [Table 11-3] 5.3 Type 3

[0206] Type 3 material was generated from a series of experiments involving selected acids and Q203 free bases (both 1:1 and 2:1 acids / APIs) in neat and mixed solvent systems. Table 12 lists the experimental conditions that yielded pure Type 3 and mixtures of Type 3 (with co-forming agents, Type 2, Type 6, or unknown). XRPD analysis of the solid Type 3 (ND-0006E-003-25) demonstrated that this material is crystalline (Figure 26). 1 ¹H NMR analysis showed no salt formation (data not shown). Since this type was obtained from different co-forming agents and solvent systems, it may be a polymorph of the Q203 free base. Table 12: Experimental conditions yielding Type 3 solids (pure and mixed) [Table 12-2] [Table 12-3] [Table 12-4] 5.4 Type 4 (Fumaric Acid)

[0207] Type 4 material was generated from slow evaporation experiments involving fumaric acid and Q203 free base (both 1:1 and 2:1 acids / APIs) in THF / MeOH. XRPD analysis of the Type 4 solid (ND-0006E-003-04) showed that the material was crystalline (Figure 27) and in acetone-d6 1 ¹H NMR analysis did not show salt formation by residual MeOH (approximately 0.5 molar equivalents) (data not shown). This suggests that type 4 may be a potential cocrystal or polymorph of the Q203 free base, which may have been half-solvated with MeOH. 5.5 Type 5 (Urea)

[0208] Type 5 material was generated from experiments involving urea and Q2O3 free base (both 1:1 and 2:1 acid / API) in a mixture of THF / MeOH, MTBE, and IPA. The experimental conditions yielding Type 5 solids are listed in Table 13. XRPD analysis of the Type 5 solid (ND-0006E-006-14) demonstrated that this material is crystalline (Figure 28). 1 1H NMR analysis showed no peak shift, suggesting no salt formation and no residual solvent (data not shown). Q203: DSC was performed to investigate whether a urea cocrystal was formed, but the thermogram corresponded to free base and urea molten material. Further investigation is needed to determine whether type 5 is a cocrystal. Table 13: Experimental conditions that yield Type 5 solids [Table 13] 5.6 Type 6 (Benzenesulfonic acid)

[0209] Type 6 material was isolated by slow evaporation experiments using benzenesulfonic acid and Q203 free base (2:1 acid / API) in a THF / acetone mixture. Type 6 was also observed as a mixture with Type 3. XRPD analysis of the solid Type 6 (ND-0006E-006-15) showed that this material is disordered crystalline (Figure 29). 1 ¹H NMR analysis (data not shown) revealed a peak shift suggestive of salt formation at approximately 0.25 molar equivalents of THF, likely in a 1:1 or 2:1 stoichiometric ratio (under verification). 5.7 Type 7 (p-toluenesulfonic acid)

[0210] Type 7 material was isolated by both slow evaporation experiments using pTSA and Q203 free base (1:1 acid / API) in a THF / acetone mixture and sonication experiments using THF. XRPD analysis of the Type 7 solid (ND-0006E-003-16) showed that this material is crystalline (Figure 30). 11H NMR analysis revealed a peak shift suggesting salt formation with no residual solvent, likely at a 1:1 (acid:API) stoichiometric ratio (data not shown). The presence of additional peaks should be noted. 5.8 Type 8 (p-toluenesulfonic acid)

[0211] Type 8 was produced in slow evaporation experiments using pTSA and Q203 free base (2:1 acid / API) in a THF / acetone mixture. XRPD analysis of the solid type 8 (ND-0006E-006-16) showed that this material is crystalline (Figure 31). 1 ¹H NMR analysis revealed a peak shift and approximately 0.15 molar equivalents of THF, suggesting possible 2:1 stoichiometric salt formation (data not shown). 5.9 Type 9 (Ethane-1,2-disulfonic acid)

[0212] Type 9 material was generated from experiments involving EDSA and Q203 free base (1:1 acid / API). The experimental conditions yielding Type 9 solids are listed in Table 14. XRPD analysis of the Type 9 solid (ND-0006E-006-14) demonstrated that this material is crystalline (Figure 32). 1 ¹H NMR analysis revealed a peak shift and an MTBE of approximately 0.07 molar equivalents, suggesting possible 1:1 stoichiometric salt formation (data not shown). Table 14: Experimental conditions that yield Type 9 solids [Table 14] 5.10 Type 10 (1,5-Naphthalenedisulfonic acid)

[0213] Type 10 material was isolated by slow evaporation experiments using NDSA and Q203 free base (1:1 acid / API) in a THF / acetone mixture, and by sonication experiments using THF. XRPD analysis of the type 10 solid (ND-0006E-003-24) showed that this material is crystalline (Figure 33).1 ¹H NMR analysis showed a peak shift suggesting salt formation, likely with a 2:1 (acid:API) stoichiometric ratio (data not shown). The presence of residual THF (approximately 0.5 molar equivalents) also suggests the possibility of a THF half-solvate of the Q2O3 salt. 5.11 Type 11 (1,5-Naphthalenedisulfonic acid)

[0214] Type 11 material was generated in slow evaporation experiments using NDSA and Q203 free base (2:1 acid / API) in a THF / acetone mixture. XRPD analysis of the type 11 solid (ND-0006E-006-24) showed that this material is crystalline and its pattern is similar to type 10, albeit with slight differences (Figure 34). 1 1H NMR analysis showed a peak shift suggestive of salt formation (data not shown). Residual THF (approximately 0.7 molar equivalents) also suggests the possibility of a THF solvate. The stoichiometry of this salt has not been determined due to the presence of free acid. 5.12 Type 12 (Benzenesulfonic acid)

[0215] Type 12 material was isolated by sonication experiments using BSA and Q203 free base (1:1 acid / API) in THF. XRPD analysis of the type 12 solid (ND-0006E-005-15) showed that this material is crystalline (Figure 35). Proton NMR analysis showed a peak shift, approximately 0.03 molar equivalents of THF, suggesting salt formation at a 1:1 stoichiometric ratio (data not shown). 5.13 Type 13 (Frolic Acid)

[0216] Type 13 material was generated from experiments involving furoic acid and Q203 free base (1:1 and 2:1 acid / API). The experimental conditions yielding Type 13 solids are listed in Table 15. XRPD analysis of the Type 13 solid (ND-0006E-004-01) demonstrated the crystalline nature of this material (Figure 36). In DMSO-d6... 1¹H NMR analysis showed no peak shift or residual solvent, suggesting the possibility of polymorphism of the free base, or cocrystals or degradation products of Q203:fluroic acid (data not shown). Table 15: Experimental conditions yielding type 13 solids [Table 15] 5.14 Type 14 (Citric Acid)

[0217] Type 14 material was produced from a 7-day ambient temperature slurry experiment using citrate and Q203 free base (1:1 acid / API) in MTBE. XRPD analysis of the type 14 solid (ND-0006E-004-03) showed that this material is crystalline (Figure 37). 1 ¹H NMR analysis showed no peak shift or residual solvent, suggesting the possibility of polymorphism of the free base or cocrystallization of Q203:citric acid (data not shown). 5.15 Type 15 (Fumaric Acid)

[0218] The Type 15 material was isolated by slurrying experiments using fumaric acid and Q203 free base (1:1 acid / API) in MTBE (20°C) and IPA (40°C). XRPD analysis of the Type 15 solid (ND-0006E-004-04) showed that this material is crystalline (Figure 38). 1 ¹H NMR analysis showed no peak shift or residual solvent, suggesting the possibility of polymorphism of the free base or the presence of a cocrystal of Q203: fumaric acid (approximately 0.7 molar equivalents of fumaric acid) (data not shown). 5.16 Type 16 (Ketoglutaric Acid)

[0219] Type 16 material was generated from a 7-day ambient temperature slurry experiment using ketoglutaric acid and Q203 free base (1:1 acid / API) in MTBE. XRPD analysis of the type 16 solid (ND-0006E-004-06) showed that this material is crystalline (Figure 39). Proton NMR analysis indicated a possible peak shift of 2.9 ppm, approximately 0.02 molar equivalents of MTBE. Further analysis is needed to determine the properties of this type (data not shown). 5.17 Type 17 (1,5-Naphthalenedisulfonic acid)

[0220] Type 17 material was generated from a 7-day ambient temperature slurrying experiment using NDSA and Q203 free base (1:1 acid / API) in MTBE. XRPD analysis of the type 17 solid (ND-0006E-004-24) showed that this material was crystalline and its pattern was similar to type 11, but with some additional and missing peaks (Figure 40). 1 ¹H NMR analysis revealed a peak shift and an MTBE of approximately 0.08 molar equivalents, suggesting salt formation, possibly with a 2:1 acid / API stoichiometry (data not shown). 5.18 Type 18 (maleic acid)

[0221] Type 18 material was isolated from a 7-day ambient temperature slurry experiment using maleic acid and Q203 free base (1:1 acid / API) in MTBE. XRPD analysis of the type 18 solid (ND-0006E-004-20) showed that this material is crystalline, its pattern is similar to type 19, and it has an additional peak in the diffractogram (Figure 41). 1 1H NMR analysis revealed a peak shift suggesting salt formation, likely in a 1:1 (acid / API) stoichiometric ratio, and residual MTBE (approximately 0.2 equivalents) (data not shown). 5.19 Type 19 (Gentidic Acid)

[0222] Type 19 material was generated from a 7-day ambient temperature slurrying experiment using maleic acid and Q203 free base (1:1 acid / API) in MTBE. XRPD analysis of the type 19 solid (ND-0006E-004-17) showed that this material was crystalline and its pattern showed some similarity to type 3 (Figure 42). 1 ¹H NMR analysis showed no peak shift, some residual MTBE (0.1 molar equivalent) and free acid (0.2 molar equivalent), suggesting the possibility of polymorphism of the free base or cocrystallization of Q203:gentisic acid (data not shown). 5.20 Type 20 (p-toluenesulfonic acid)

[0223] Type 20 material was isolated from a 7-day ambient temperature slurry experiment using pTSA and Q203 free base (1:1 acid / API) in MTBE. XRPD analysis of the solid type 20 (ND-0006E-004-16, Figure 43) showed that this material is crystalline. 1 ¹H NMR analysis revealed peak shifts and trace amounts of residual MTBE (0.01 molar equivalent), suggesting stoichiometric salt formation of a 1:1 acid / API (data not shown). 5.21 Type 21 (Tartaric acid)

[0224] The Type 21 material was isolated by slurrying experiments using tartaric acid and Q203 free base (1:1 and 2:1 acid / API) in MTBE and IPA (20°C and 40°C, respectively). XRPD analysis of the Type 21 solid (ND-0006E-004-13) showed that this material is crystalline (Figure 44), and the solid (ND-0006E-007-13) 1 ¹H NMR analysis (data not shown) revealed no peak shift or residual solvent, and showed approximately 0.6 molar equivalents of tartaric acid and an unknown peak at 8.1 ppm. TG / DTA analysis showed a weight loss of approximately 0.4% from before melting, observed at a starting temperature of 168°C. These results suggest the possibility of a cocrystal or polymorphism of the Q203 free base. 5.22 Type 22 (Succinic Acid)

[0225] Type 22 material was isolated from a 7-day ambient temperature slurry experiment using succinic acid and Q203 free base (1:1 acid / API) in MTBE. XRPD analysis of the type 20 solid (ND-0006E-004-12, Figure 45) showed that this material is crystalline. 1 ¹H NMR analysis revealed no peak shift, trace amounts of residual MTBE (0.003 molar equivalents), and approximately 1 molar equivalent of succinic acid, suggesting the possibility of a cocrystal or polymorphism of the Q203 free base (data not shown). 5.23 Type 23 (mandelic acid)

[0226] Type 23 material was generated from experiments involving mandelic acid and Q203 free base (1:1 and 2:1 acid / API). The experimental conditions yielding type 23 solids are listed in Table 16. XRPD analysis of the type 23 solid (ND-0006E-004-01) showed that this material is crystalline (Figure 46), and additional peaks were observed in sample ND-0006E-007-09. 1 ¹H NMR analysis revealed no peak shift, trace amounts of residual solvent (0.01 molar equivalents), and approximately 0.8 molar equivalents of mandelic acid, suggesting the possibility of polymorphism of the Q203 free base or mandelic acid cocrystals (data not shown). Table 16: Experimental conditions yielding type 23 solids [Table 16] 5.24 Type 24 (Malic Acid)

[0227] Type 24 material was isolated by ambient temperature slurrying experiments using malic acid and Q203 free base (1:1 acid / API) in MTBE and sonication experiments using THF. XRPD analysis of the solid type 24 (ND-0006E-004-07) showed that this material is disordered crystalline (Figure 47), and the solid (ND-0006E-005-07)1 ¹H NMR analysis revealed no peak shift or residual solvent, and showed 1 molar equivalent of malic acid, suggesting the possibility of a polymorph of the Q203 free base or a malic acid cocrystal (data not shown). 5.25 Type 25

[0228] Type 25 material is a mixture of various acids in THF and Q203 free base (1:1 acid / AP). It was produced from sonication experiments including (I). Table 17 lists the experimental conditions that yielded pure type 25 and mixtures of type 25 (with type 3). XRPD analysis of solid pure type 25 (ND-0006E-005-13, 20, 27) showed that this material is crystalline (Figure 48). Since this type was obtained from various co-forming agents using THF, type 25 is likely a polymorph of the Q203 free base and may be solvated (THF).

[0229] It should be noted that proton NMR analysis of the type 25 material (ND-0006E-005-20) showed a peak shift and approximately 0.5 molar equivalents of THF suggesting salt formation (1:1 acid / API), which may indicate the possibility of a semisolvate of Q203 maleate (data not shown). This can be explained by the situ salt formation during sample preparation in deuterated methanol for NMR spectroscopy. Table 17: Experimental conditions yielding Type 25 solids (pure and mixed). [Table 17] 5.26 Type 26 (1,5-Naphthalenedisulfonic acid)

[0230] The type 26 material was produced from a 7-day high-temperature slurry experiment (40°C) using slow evaporation followed by NDSA and Q203 free base in IPA (2:1 acid / API). XRPD analysis of the type 26 solid (ND-0006E-007-24, Figure 49) showed that this material is crystalline, and proton NMR spectroscopy showed a peak shift (data not shown) suggesting salt formation, indicating approximately 0.04 molar equivalents of IPA. Stoichiometry needs to be confirmed. 5.27 Type 27 (Gentidic Acid)

[0231] Type 27 was produced in slow evaporation experiments using gentisic acid and Q203 free base (2:1 acid / API) in a THF / methanol mixture. XRPD analysis of the solid type 27 (ND-0006E-006-17) showed that this material is disordered crystalline (Figure 50). 1 ¹H NMR analysis revealed no peak shift, approximately 0.5 molar equivalents of THF, and approximately 2 molar equivalents of co-forming agent, suggesting the possibility of a half-solvate of THF in a gentisic acid cocrystal or a polymorph of the Q203 free base (data not shown). 5.28 Type 28 (Galactaric Acid)

[0232] Type 28 material was isolated from two LAG experiments using galactaric acid, gluconic acid, and Q203 free base (1:1 acid:API) in IPA / water and acetone mixtures, respectively. XPRD analysis of type 28 (ND-0006E-008-15) showed the material to be disordered crystalline (Figure 51). Proton NMR analysis (data not shown) showed no peak shift and approximately 0.07 molar equivalents of IPA. TG / DTA results showed multiple endothermic events. Type 28 may be a polymorph of free bases obtained from various co-forming agents. 5.29 Type 29 (Ketoglutaric Acid)

[0233] The type 29 material was isolated by sonication experiments using ketoglutaric acid and Q203 free base (1:1 acid / API) in THF. XRPD analysis of the type 29 solid (ND-0006E-005-06, Figure 52) showed that this material was disordered crystalline, similar to type 25, with additional peaks observed. Proton NMR analysis showed no peak shift, approximately 0.16 molar equivalents of THF and approximately 0.9 molar equivalents of ketoglutaric acid, suggesting the possibility of cocrystals or polymorphisms of the Q203 free base (data not shown). 5.30 Type 30 (Fumaric Acid)

[0234] The Type 30 material was isolated by sonication experiments using ketoglutaric acid and Q203 free base (1:1 acid / API) in THF. XRPD analysis of the Type 30 solid (ND-0006E-005-04, Figure 53) showed that this material is crystalline. 1 ¹H NMR analysis (data not shown) revealed no peak shift or residual solvent, and approximately 0.85 molar equivalents of fumaric acid were observed, suggesting the possibility of a polymorph of the Q203 free base or a fumaric acid cocrystal. 5.31 Type 31 (Sulfuric Acid)

[0235] The type 31 material was generated from a 7-day high-temperature slurry experiment (40°C) using slow evaporation followed by sulfuric acid in IPA and Q203 free base (2:1 acid / API). XRPD analysis of the type 31 solid (ND-0006E-007-28, Figure 54) indicated that the material is crystalline, and proton NMR spectroscopy showed a significant peak shift with no residual solvent, suggesting salt formation (data not shown). It should be noted the presence of additional peaks that may be explained by decomposition. Stoichiometry was not determined. 5.32 Type 32

[0236] Type 32 material was produced from high-temperature slurry experiments (40°C) involving various acids and Q203 free base (2:1 acid / API) in THF. Table 18 lists the experimental conditions yielding pure Type 32 and mixtures of Type 32 (with co-acids). XRPD analysis of solid Type 32 (ND-0006E-007-06) demonstrated the crystalline nature of this material (Figure 55). 1 ¹H NMR analysis showed no peak shift (data not shown) and revealed residual solvent and approximately 0.2 molar equivalents of co-forming agent. Since this type was obtained from different co-forming agents, it may be a polymorphism of the Q203 free base. Table 18: Experimental conditions yielding Type 32 solids (pure and mixed). [Table 18] 5.33 Type 33 (Benzenesulfonic acid)

[0237] Type 33 material was generated from a 7-day high-temperature slurry experiment (40°C) using BSA and Q203 free base (2:1 acid / API) in IPA. XRPD analysis of the solid type 33 (ND-0006E-007-15, Figure 56) showed that this material is crystalline, and proton NMR spectroscopy (data not shown) suggested the absence of residual solvent and the possibility of salt formation at the stoichiometric rate of the 2:1 acid / API. It should be noted the similarities observed with type 6. 5.34 Type 34 (Ethane-1,2-disulfonic acid)

[0238] The type 34 material was generated from a 7-day high-temperature slurry experiment (40°C) using EDSA and Q203 free base (2:1 acid / API) in IPA. XRPD analysis of the type 34 solid (ND-0006E-007-22, Figure 57) showed that this material was disordered crystalline, and proton NMR spectroscopy (data not shown) showed peak shifts but no residual solvent was indicated, suggesting salt formation, possibly at a 2:1 acid / API stoichiometry. 5.35 Type 35 (HCl)

[0239] Type 35 material was generated from a 7-day high-temperature slurry experiment (40°C) using slow evaporation followed by HCl and Q203 free base in IPA (2:1 acid / API). XRPD analysis of the solid type 35 (ND-0006E-007-18, Figure 58) indicated that the material is disordered crystalline, and proton NMR spectroscopy (data not shown) showed peak shifts, suggesting salt formation. No residual solvent or decomposition was observed from the NMR spectrum. Stoichiometry has not been determined. 5.36 Type 36 (HCl)

[0240] Type 36 material was isolated from a 7-day ambient temperature slurry experiment using HCl and Q2O3 free base (1:1 acid / API) in MTBE. XRPD analysis of the solid type 36 (ND-0006E-004-18, Figure 59) showed that this material is disordered crystalline and similar to the diffraction pattern of type 3+ additional peaks. Proton NMR analysis (data not shown) showed peak shift and trace amounts of residual MTBE (0.007 molar equivalent), suggesting the presence of an HCl salt of Q2O3. Stoichiometry was not determined. do not have. 5.37 Type 37 (Phosphate)

[0241] Type 37 material was produced from high-temperature slurry experiments (40°C) using acetone and Q203 free base (1:1 acid / API) and LAG techniques. XRPD analysis of the type 37 solid (ND-0006E-008-13, Figure 60) showed that this material is crystalline. A slight baseline drift suggests the presence of amorphous inclusions.

[0242] Proton NMR analysis suggests a peak shift and the presence of residual acetone Q2O3 phosphate at approximately 0.09 molar equivalents (data not shown). Stoichiometry has not been determined. 5.38 Type 38 (Gluconate)

[0243] The type 38 material was isolated by eutectic experiment using gluconic acid and Q203 free base (1:1 acid / API). XRPD analysis of the type 38 solid (ND-0006E-009-07, Figure 61) showed that the material was crystalline. Baseline drift suggested the presence of amorphous contents. Proton NMR analysis (data not shown) showed, as expected, no peak shift, no trace amounts of residual solvent, and no co-forming agent. TG / DTA results (data not shown) showed melting at an onset temperature of 164°C and another endothermic reaction starting at 218°C, associated with weight loss. These results suggest that type 38 is likely a polymorph of the free base. 5.39 Type 39 (Multiple Co-forming Agents)

[0244] The type 39 material was isolated by eutectic experiments using multiple co-forming agents (malonic acid, pyruvate, saccharin) and a Q203 free base (1:1 acid / API). XRPD analysis of the type 39 solid (ND-0006E-009-06, Figure 62) showed that the material is crystalline. Baseline drift suggests the presence of amorphous contents. Proton NMR analysis (data not shown) showed a peak shift and a co-forming agent around 0.9 molar equivalents, suggesting a potential cocrystal or polymorphism of the free base. Table 19: Experimental conditions yielding Type 39 solids (pure and mixed). [Table 19] 5.40 Type 40 (Multiple Co-forming Agents)

[0245] Type 40 material was isolated by HT slurrying and LAG experiments using multiple co-forming agents (malonic acid, pyruvate, pyroglutamic acid, etc.) and Q203 free base (1:1 acid / API). XRPD analysis of one solid of type 40 (ND-0006E-008-10, Figure 63) indicated that this material is crystalline. A slight baseline drift suggests the presence of amorphous contents. Proton NMR analysis showed no peak shift, approximately 0.3 molar equivalents of residual acetone, and no trace of co-forming agents, suggesting the possibility of polymorphism of the free base (data not shown). Table 20: Experimental conditions yielding Type 40 solids (pure and mixed). [Table 20] 5.41 Type 41 (Multiple Co-forming Agents)

[0246] The type 41 material was isolated by HT slurrying and LAG experiments using multiple co-forming agents (lactobionic acid, ascorbic acid, 2-furoic acid, galactaric acid) and Q203 free base (1:1 acid / API). XRPD analysis of one solid of type 41 (ND-0006E-008-09, Figure 64) indicated that this material is crystalline. A slight baseline drift suggests the presence of amorphous contents. Proton NMR analysis showed no peak shift, approximately 0.3 molar equivalents of residual acetone, and no trace of co-forming agents, suggesting the possibility of type 41 as a polymorph of the free base (data not shown). Table 21: Experimental conditions yielding Type 41 solids (pure and mixed). [Table 21] 5.42 Type 42 (Gentidic Acid)

[0247] The type 42 material was isolated from LAG experiments using gentisic acid and Q203 free base (1:1 acid / API) in acetone. XRPD analysis of the type 42 solid (ND-0006E-008-08, Figure 65) showed that the material was crystalline. A slight baseline drift suggests the presence of amorphous contents. Proton NMR analysis showed no peak shift, approximately 0.14 molar equivalents of acetone (approximately 1.12% w / w) and approximately 0.67 molar equivalents of co-forming agent (data not shown). TG / DTA showed a weight loss (possibly due to water) from 25 to 113°C, with endothermic activity observed starting around 121°C. These results suggest polymorphism or potential cocrystallization of the Q203 free base. Further analysis is needed to confirm one of these assumptions. 5.43 Type 43 (Ascorbic Acid)

[0248] The type 43 material was isolated from LAG experiments using ascorbic acid and Q203 free base (1:1 acid / API) in an IPA / water mixture. XRPD analysis of the type 43 solid (ND-0006E-008-02, Figure 66) showed that the material was crystalline. A slight baseline drift suggested the presence of amorphous contents. Proton NMR analysis (data not shown) showed no peak shift as expected, no residual IPA, and approximately 0.8 molar equivalents of co-forming agent. TG / DTA showed a weight loss of approximately 0.9% from 25 to approximately 131°C, which is likely due to moisture. Two endothermic events were observed at the start of 136 and 158°C, associated with a constant weight loss of approximately 11% from 130 to 300°C. These results suggest that type 43 may be a polymorphic mixture of Q203 (free base and co-forming agent) or a potential cocrystal. Further analysis is needed to better understand the properties of this type. 5.44 Type 44 (Saccharin)

[0249] The type 44 material was isolated from LAG experiments using saccharin and Q203 free base (1:1 acid / API) in an IPA / water mixture. XRPD analysis of the type 44 solid (ND-0006E-008-14, Figure 67) showed that this material is disordered crystalline. A slight baseline drift suggests the presence of amorphous contents. Proton NMR analysis (data not shown) showed a peak shift and approximately 0.5 molar equivalents of IPA, suggesting an IPA hesolvate of the Q203 saccharin salt. Further experiments may yield a nonsolvated saccharin salt of Q203. 5.45 Type 45 (Oxalic Acid)

[0250] The type 45 material was isolated from a 5-day HT slurry experiment (40°C) using oxalic acid and Q203 free base (1:1 acid / API) in acetone. XRPD analysis of the type 45 solid (ND-0006E-010-04, Figure 68) showed that this material is crystalline. A slight baseline drift suggests the presence of amorphous contents. Proton NMR analysis showed a peak shift and approximately 0.06 molar equivalents of acetone, suggesting salt formation of Q203 oxalate (data not shown). 5.46 Type 46 (Oxalic Acid)

[0251] The type 46 material was isolated from a 5-day HT slurry experiment (40°C) using oxalic acid and Q203 free base (1:1 acid / API) in methanol. XRPD analysis of the type 46 solid (ND-0006E-010-05, Figure 69) showed that the material was crystalline. A slight baseline drift suggests the presence of amorphous contents. Proton NMR analysis (data not shown) showed no peak shift, suggesting polymorphism of the free base. 5.47 Type 47 (Saccharin)

[0252] The type 47 material was isolated from a 5-day HT slurry experiment (40°C) using saccharin and Q203 free base (1:1 acid / API) in an IPA / water mixture. XRPD analysis of the type 47 solid (ND-0006E-010-13, Figure 70) showed that this material is crystalline. A slight baseline drift suggests the presence of amorphous contents. Proton NMR analysis (data not shown) showed peak shifts and trace amounts of IPA, approximately 0.7 molar equivalents of co-forming agents, suggesting salt formation of the Q203 saccharin salt. 5.48 Type 48 (Salicylic Acid)

[0253] The Type 48 material is salicylic acid and Q2O3 free salt in a THF / acetone mixture. It was isolated by slow evaporation experiments using a group (1:1 acid / API). XRPD analysis of type 47 solid (ND-0006E-003-34, Figure 71) showed that this material is crystalline. Proton NMR analysis showed no peak shift, approximately 0.9 molar equivalents of co-forming agent, approximately 0.1 molar equivalents of THF, and no residual acetone, suggesting a potential cocrystal or polymorphism of the free base. 5.49 Type 49 (Nitric Acid)

[0254] The type 49 material was isolated by sonication experiments using nitric acid and Q203 free base (1:1 acid / API) in THF. XRPD analysis of the solid type 49 (ND-0006E-005-30, Figure 72) showed that this material is crystalline, very similar to type 3, and has an additional peak. Proton NMR analysis (data not shown) showed a peak shift and approximately 0.25 molar equivalents of THF, suggesting that type 49 may be the nitrate of Q203. 5.50 Type 50 (Pamoic Acid)

[0255] The Type 50 material was isolated from a 5-day RT slurry experiment using pamoic acid and Q203 free base (1:1 acid / API) in MTBE. XRPD analysis of the Type 50 solid (ND-0006E-004-33, Figure 73) showed that this material is crystalline, very similar to Type 3, and has an additional peak. Proton NMR analysis (data not shown) showed no peak shift, approximately 0.07 molar equivalents of MTBE and approximately 0.65 molar equivalents of co-forming agent, suggesting the possibility of polymorphism or cocrystallization of the Q203 free base. 5.51 Type 51 (Pamoic Acid)

[0256] The type 51 material was isolated by sonication experiments using pamoic acid and Q203 free base (1:1 acid / API) in THF. XRPD analysis of the type 51 solid (ND-0006E-005-33, Figure 74) showed that this material is crystalline. Proton NMR analysis (data not shown) showed no peak shift, approximately 0.02 molar equivalents of THF and approximately 0.9 molar equivalents of co-forming agent, suggesting the possibility of polymorphism or cocrystallization of the Q203 free base. 5.52 Type 52 (Salicylic Acid)

[0257] The type 52 material was isolated from a 5-day RT slurry experiment using salicylic acid and Q203 free base (1:1 acid / API) in MTBE. XRPD analysis of the type 52 solid (ND-0006E-005-33, Figure 75) showed that this material is crystalline and similar to type 3. Proton NMR analysis (data not shown) showed no peak shift, approximately 0.36 molar equivalents of co-forming agent and approximately 0.40 molar equivalents of MTBE, suggesting the possibility of polymorphism of the Q203 free base. 5.53 Type 53 (Salicylic Acid)

[0258] The type 53 material was isolated by sonication experiments using salicylic acid and Q203 free base (1:1 acid / API) in THF. XRPD analysis of the type 53 solid (ND-0006E-005-34, Figure 76) showed that this material is crystalline. Proton NMR analysis (data not shown) showed no peak shift, approximately 1 molar equivalent of co-forming agent, and approximately 0.04 molar equivalents of THF (approximately 0.4% w / w). TG / DTA analysis (data not shown) showed a weight loss of approximately 0.9% from 25°C to approximately 125°C, presumably due to water. Subsequently, an endothermic reaction associated with a weight loss of approximately 20% up to 300°C, possibly due to the reduction of salicylic acid, was observed at approximately 132°C. These results suggest the potential co-crystallization of Q203FB, but further analysis is needed to confirm this. 5.54 Type 54 (Methanesulfonic Acid)

[0259] The Type 54 material was isolated from a 5-day ambient temperature slurry experiment using methanesulfonic acid and Q203 free base (1:1 acid / API) in MTBE. XPRD analysis of Type 54 (ND-0006E-004-23) showed that the material was disordered crystalline and very similar to Type 3 (Figure 77). Proton NMR analysis (data not shown) showed a peak shift, approximately 0.18 molar equivalents of MTBE, suggesting salt formation at a 1:1 stoichiometric ratio. 6. Evaluation of Q203 candidate (salt / cocrystal)

[0260] All the data generated from this survey was compiled into the table below to select candidates of particular interest. Table 22: Evaluation of Q203 salt / cocrystal solids (classified by co-forming agent) [Table 22-1] [Table 22-2] [Table 22-3] [Table 22-4] [Table 22-5] [Table 22-6] 1. Pharmaceutical class: Class 1 = Lowest toxicity, not regulated for use as a salt-forming agent; Class 2 = Low toxicity, well-tolerated, but not naturally occurring; Class 3 = May be of interest under specific circumstances. 2. [ka] 3. Deliquescence test: The sample was subjected to stress at 75% RH for several days. 4. Approximate values ​​described based on measurements taken by adding aliquots to unbuffered water. PS: Peak shift; stoi.: Stoichiometric acid / API; mol.eq.: Molar equivalent; RT and HT: Room temperature and high temperature

[0261] Selection was made based on the above-mentioned previous results, using multiple criteria such as polymorphism status, degree of crystallinity, class, properties of each type (salt or potential cocrystal), specific toxicity, and thermal behavior.

[0262] The three candidates identified by the inventors as particularly useful are the first three items in the following table (see Table 23). Table 23: Selection of Q203 salt / cocrystalline solid (the three candidates are shown in bold as the first three items) [Table 23-1] [Table 23-2] [Table 23-3] [Table 23-4] 1. Pharmaceutical class: Class 1 = Lowest toxicity, not regulated for use as a salt-forming agent; Class 2 = Low toxicity, well-tolerated, but not naturally occurring; Class 3 = May be of interest under specific circumstances. 2. [ka] 3. Deliquescence test: The sample was subjected to stress at 75% RH for several days. 4. Approximate values ​​described based on measurements taken by adding aliquots to unbuffered water. PS: Peak shift; stoi.: Stoichiometric acid / API; mol.eq.: Molar equivalent; RT and HT: Room temperature and high temperature 7. Scale up the selected salt 7.1 P-TSA (ND-6E-012-01)

[0263] API (1 g) was added to a scintillation vial containing THF (18 ml). A seed of type 20 solid (ND-0007E-004-16) was added to the solution but did not dissolve. pTSA dissolved in acetone (342 mg, 18 ml) was added to this API solution. Precipitation was observed while stirring. Proton NMR analysis after T=1d suggested the formation of a pTSA salt (an additional peak at 1.3 molar equivalents and 8.6 ppm). The solid was separated and slurryed in MTBE for 3 days. Type 20 was confirmed by XRPD analysis of the obtained solid. 7.2 Phosphate (ND-6E-012-02)

[0264] Concentrated H2PO4 (122.8 μl) was added to a scintillation vial containing acetone (7.5 ml). A seed of type 37 solid (ND-0007E-008-13) was added to this solution but did not dissolve. API (1 g) was added to the vial with stirring, and a block of solid was obtained. This was vortexed until a concentrated slurry was obtained. This slurry (which was not very mixable) became more mixable after about 10 minutes at 40°C. A pull was performed for proton NMR analysis at T=1 day, and approximately 0.43 molar equivalents of acetone were shown. After letting this slurry stand for T=5 days, the solid was separated by filtration. XRPD analysis showed type 37. 7.3 HCl (ND-6E-012-03)

[0265] Concentrated HCl (147.3 µl) is used in a scintillation biopsy containing THF (18 ml). It was added to Al. Seeds of type 36 solid (ND-0007E-004-18) were added to this solution and dissolved. An HCl / THF solution was added to API (1 g) to make a solution. Seeds of T36 solid were again added to this solution and dissolved. This solution was evaporated under nitrogen for about 5 minutes until the solution became hazy. Seeds of T36 were added to make a suspension. This solution was evaporated under nitrogen with stirring. A novel type 55 was revealed by XRPD. Proton NMR analysis showed a peak shift supporting salt formation. 8. pH Profile Analysis

[0266] The pH profiles of three candidate salts of Q203 (monosylate, phosphate, and HCl) were evaluated. The HPLC method is detailed in Section 2.3.6. 8.1 Checking the HPLC method

[0267] The suitability of the PLC method was checked first, and a measurement range of 0.0625 mg / mL to 0.5 mg / mL was set for Q203. (Note that the diluent was changed to methanol because the material did not dissolve in the diluent described in the supplied method.) The samples for the solubility experiment were diluted as needed so that the API concentration was within the measurement range. A linearity of R² = 0.999, indicating excellent suitability, was found (data not shown). 8.2 pH solubility profiling

[0268] The solubility of the salts at pH 1, 4.5, 6.8, and 7.5 was determined as described in sections 2.3.6 and 2.3.7. pTSA maintained the same pattern after slurring in pH 1 buffer, exhibiting an average solubility of approximately 0.33 mg / mL. However, the pTSA salts converted to type 28 at pH 4.5 and above. This was found to be a polymorphism of the free base by XRPD and proton NMR analysis, exhibiting very limited solubility (<0.00037 mg / mL). See Table 25.

[0269] This also applied to phosphates with pH 4.5 or higher, but after slurrying with pH 1 buffer, they were converted to a new HCl salt, type 56. Type 56 was also observed in all solids isolated from the HCl solubility experiment. The highest solubility was approximately 5.58 mg / mL observed for the HCl salt type 56 at pH 1 (sample LMcG-0007E-004-09_1 was not considered because this value was significantly lower than the other three values ​​and may have been due to dilution error). The selected results (XRPD traces of solids isolated after the pH solubility experiment) are shown in Figure 78. Table 24: Results of pH solubility profiling [Table 24-1] [Table 24-2] 1. Dilution error is possible. 8.3 Conclusions of pH Profile Analysis

[0270] The pTSA salt remained stable even in a pH 1 buffer with a solubility of approximately 0.33 mg / mL, but was converted to a less soluble free base (type 28) at pH 4.5 and above. The phosphate was unstable in all pH buffers, being converted to HCl type 56 at pH 1 and to a free base at pH 4.5 and above. The type 36 HCl salt was converted to a new type of HCl salt, type 56, in all buffers tested.

[0271] Improved solubility was observed in three candidates compared to the free base and the current candidate (nitrosylate). It should be noted that below pH 4.5, the phosphate and pTSA showed conversion to the free base, suggesting some degree of instability.

[0272] On the other hand, the HCl salt showed higher solubility, and no conversion to free base was observed under the test conditions. This may be explained by low wettability and kinetic factors (time, stirring effect). 9 Conclusion

[0273] Salt screening was performed using Q203 with 37 salt-forming agents in various solvent systems. More than 50 new types were observed, indicating a very high tendency for Q203 to generate new patterns (polymorphs of free bases, but mainly with salts and potential cocrystals).

[0274] These new patterns were analyzed using various analytical techniques (e.g., XRPD, proton NMR, and water solubility when sufficient material was available).

[0275] The selection of three salt candidates for further pH profile analysis was based on multiple criteria, including polymorphism, degree of crystallinity, class, properties of each type (salt or potential cocrystal), specific toxicity, and thermal behavior. Not all potential cocrystals were considered, as further characterization would be needed to confirm the properties of these solids (whether cocrystal or not). The pharmaceutical class of the counterions was also considered (HCl and phosphoric acid are considered Class 1, defined as having the lowest toxicity and not regulated for use as salt-forming agents). A monotosylate was selected, which is considered Class 2 (low toxicity, well tolerable, but not found in nature). Comparing monotosylates and nitosylates, monotosylates exhibit lower toxicity because, in contrast to nitosylates, there is only one counterion per API molecule.

[0276] Other candidates may be of interest for further development, but they require further investigation and should be kept in mind that they will be compared to these three candidates.

[0277] Improved solubility was observed in three candidates compared to free bases and nitrosylates. It should be noted that below pH 4.5, phosphates and pTSA showed conversion to free bases, suggesting some instability.

[0278] On the other hand, the HCl salt showed higher solubility, and no conversion to free base was observed under the test conditions. This may be explained by low wetting properties and kinetic factors (time, stirring effect), especially above pH 4. Addendum 1: Table 25: Summary of observed Q203 solids (classified by co-forming agent) [Table 25-1] [Table 25-2] [Table 25-3] [Table 25-4] [Table 25-5]

[0279] Example 3

[0280] Stability tests were conducted on form A of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide (Q203)-ditosylate. More specifically, samples of Q203-ditosylate form A were exposed to an environment of 60% RH (relative humidity) and 25°C for a period of 6 to 60 months. Furthermore, some samples of Q203-ditosylate form A were subjected to further stability tests under accelerated conditions (40°C - 75% relative humidity (RH)). These experiments under accelerated conditions were conducted for up to 6 months. Subsequently, the samples were analyzed by HPLC to check for impurities. Under conditions of 25°C and 60% RH, Q203-ditosylate form A remained stable, showing no degradation or deterioration, and contained only minimal impurities identifiable by the corresponding HPLC-chromatogram (chromatogram trace not shown). The results are summarized in the table below. Table 27: Stability results of Form A of Q203-Ditosylate at 25°C / 60%RH [Table 27]

[0281] The purity remains above 98%, and no signs of decomposition or degradation are observed.

[0282] Furthermore, in experiments under accelerated conditions, no decomposition occurred for up to 6 months, and the samples still showed a purity of over 98% (data not shown).

[0283] From this data, we can conclude that Q203-ditosylate form A is stable for up to 60 months under long-term storage conditions of 25°C and 60%RH, and stable for up to 6 months under accelerated conditions of 40°C and 75%RH. The present invention provides, for example, the following items: (Item 1) structure [ka] It has, Furthermore, Cu-K α Radiation (Cu-K α In the X-ray powder diffraction (XRPD) spectrum obtained by irradiation with ), the following peaks were observed: 3.9°2θ, 5.6°2θ, 8.0°2θ, 16.1°2θ, 19.1°2θ, and 22.4°2θ, ±0.2°2θ Having at least one or more of the following: Compound 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate. (Item 2) The compound described in item 1 having the XRPD spectrum shown below. [ka] (Item 3) A compound described in any one of the preceding items, whose differential scanning calorimetry (DSC) thermogram shows a single endothermic peak beginning at 235°C to 237°C. (Item 4) The following steps: - A step of providing 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide free base and p-toluenesulfonic acid in a 1:2 stoichiometric ratio, in any order; - The step of mixing and dissolving these in a suitable solvent or solvent mixture, for example, isopropyl alcohol (IPA), tetrahydrofuran (THF), acetone, or a mixture of THF and acetone; - The step of evaporating the solvent or solvent mixture. A compound described in any one of the preceding items, manufactured by a method comprising the above. (Item 5) A method for producing a compound described in any one of items 1 to 4, wherein the method comprises the following steps: - A step of providing 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide free base and p-toluenesulfonic acid in a 1:2 stoichiometric ratio, in any order; - The step of mixing and dissolving these in a suitable solvent or solvent mixture, for example, isopropyl alcohol (IPA), tetrahydrofuran (THF), acetone, or a mixture of THF and acetone; - The step of evaporating the solvent or solvent mixture. A method that includes this. (Item 6) A monoacid addition salt of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide, which is 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monohydrochloride, 6-chloro-2-ethyl-N-(4 The monoacid addition salt is -(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monophosphate, or 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monotosylate. (Item 7) The aforementioned monoacid addition salt is Cu-K α Radiation (Cu-K α In the X-ray powder diffraction (XRPD) spectrum obtained by irradiation with ), the following peaks were observed: 6.4°2θ, 8.1°2θ, 16.2°2θ, 17.2°2θ, 24.3°2θ, and 25.0°2θ, ±0.2°2θ The monoacid addition salt of item 6, which is 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monohydrochloride having at least one or several of the following: (Item 8) The aforementioned monoacid addition salt is Cu-K α Radiation (Cu-K α In the X-ray powder diffraction (XRPD) spectrum obtained by irradiation with ), the following peaks were observed: 9.0°2θ, 10.7±0.2°2θ, 11.7°2θ, 14.8°2θ, 18.4°2θ, 19.3°2θ, and 21.8°2θ, 22.8°2θ, ±0.2°2θ The monoacid addition salt of item 6, which is 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monophosphate, having at least one or several of the following: (Item 9) The aforementioned monoacid addition salt exhibits the following peaks in the X-ray powder diffraction (XRPD) spectrum obtained by irradiation with Cu-Kα radiation (Cu-Kα): 4.0°2θ, 11.4°2θ, 12.2°2θ, 14.4°2θ, 17.7°2θ, 18.9°2θ, 19.7°2θ, 20.3°2θ, 23.2°2θ, and 26.7°2θ, ±0.2°2θ The monoacid addition salt of item 6, which is 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monotosylate, having at least one or several of the following: (Item 10) The monohydrochloride salt described in item 7, having the XRPD spectrum shown below. [ka] (Item 11) A monophosphate as described in item 8, having the XRPD spectrum shown below. [ka] (Item 12) A monotosylate described in item 9 having the following XRPD spectrum. [ka] (Item 13) A method for preparing a monoacid addition salt as described in any one of items 6 to 12, wherein the method comprises the following steps: - A step of providing 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide free base and an acid selected from hydrochloric acid, phosphoric acid, and p-toluenesulfonic acid in a 1:1 stoichiometric ratio; - The step of mixing and dissolving these in a suitable solvent or solvent mixture, such as isopropyl alcohol (IPA), methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), acetone, or a mixture of THF and acetone; - The step of evaporating the solvent or solvent mixture. A method that includes this. (Item 14) A pharmaceutical composition comprising at least one compound described in any one of items 1 to 4 or a monoacid addition salt described in any one of items 6 to 12, together with at least one pharmaceutically acceptable carrier, excipient and / or diluent. (Item 15) The composition according to item 14, further comprising at least one other pharmaceutically active agent. (Item 16) A compound described in any one of items 1-4 or a monoacid addition salt described in any one of items 6-12, for use in the treatment of bacterial infections. (Item 17) The compound or monoacid addition salt for use described in item 16, for the bacterial infection described above being tuberculosis or Buruli ulcer. (Item 18) A method for treating a bacterial infection, particularly tuberculosis or Buruli ulcer, comprising applying a suitable amount of any one of items 1 to 4, or any one of items 6 to 12, or any one of items 14 to 15, to a patient in need.

Claims

【Request Item 1】 Bacterial infection.

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