Different forms of imidazopyridinecarboxamide compounds

Abstract

The present invention relates to different forms of the compound 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide and methods for preparing these forms / compounds. The present invention also relates to monoacid addition salts thereof and methods for making these monoacid addition salts and pharmaceutical compositions comprising any of the above compounds. In addition, 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-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide and methods for preparing these forms / compounds. The present invention also relates to monoacid addition salts thereof and methods for making these monoacid addition salts, as well as pharmaceutical compositions comprising any of the above compounds. Furthermore, the present invention relates to any use of these compounds. Background Art

[0002] Tuberculosis, as a disease, continues to kill millions of people every year. The inappropriate use of chemotherapy has led to an increasing number of drug-resistant cases. This situation is likely to worsen with the emergence of strains that are extremely resistant to all currently known drugs. Current chemotherapy consists of compounds that directly target Mycobacterium tuberculosis by neutralizing common signaling pathways and key processes such as RNA polymerization and protein synthesis inhibition, or by interfering with the synthesis of mycobacterium-specific cell envelopes. The most widely used dedicated anti-tuberculosis drugs, isoniazid, ethionamide, and pyrazinamide, are prodrugs that first need to be activated. They are administered to patients over a course of several months. Patients infected with multidrug-resistant strains of Mycobacterium tuberculosis may have to undergo combination therapy for a longer period of time.

[0003] WO 2011 / 113606 describes various anti-tuberculosis compounds and their use in treating bacterial infections, including the compound "Q203," whose chemical name is 6-chloro-2-ethyl-N-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide. Pethe et al. (Nature Medicine, 19, 1157-1160 (2013)) report that this compound exhibits anti-tuberculosis activity by interfering with bacterial energy metabolism and inhibiting the activity of cytochrome bc1, an essential component of the electron transport chain required for ATP synthesis.

[0004] Although the compounds show promise for future treatments of tuberculosis and related infections, there remains a need for forms particularly suitable for pharmaceutical administration. Specifically, there is a need for forms that exhibit improved solubility compared to the free base of the compounds. Furthermore, there is a need in the art for forms that exhibit improved stability. Summary of the Invention

[0005] In the first aspect, the present invention relates to a compound 6-chloro-2-ethyl-N-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditoluenesulfonate having the following structure

[0006]

[0007] And further using Cu-K α -Radiation (Cu-K α ) irradiated with an X-ray powder diffraction (XRPD) spectrum having at least one or more of the following peaks:

[0008] 3.9°2θ, 5.6°2θ, 8.0°2θ, 16.1°2θ, 19.1°2θ and 22.4°2θ, ±0.2°2θ.

[0009] In one embodiment, the compound has an XRPD spectrum as shown below:

[0010]

[0011] In one embodiment, the compound has a differential scanning calorimetry (DSC) thermogram showing a single endothermic peak with an onset temperature of 235°C-237°C.

[0012] In one embodiment, the compound is produced by a method comprising the steps of:

[0013] - providing 6-chloro-2-ethyl-N-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide free base and p-toluenesulfonic acid in a stoichiometric ratio of 1:2 in any order;

[0014] - mixing and dissolving them in a suitable solvent or solvent mixture such as isopropyl alcohol (IPA), tetrahydrofuran (THF), acetone or a mixture of THF and acetone;

[0015] - evaporating the solvent or solvent mixture.

[0016] In another aspect, the present invention relates to a method for producing a compound as defined above, said method comprising the steps of:

[0017] - providing 6-chloro-2-ethyl-N-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide free base and p-toluenesulfonic acid in a stoichiometric ratio of 1:2 in any order;

[0018] - mixing and dissolving them in a suitable solvent or solvent mixture such as isopropyl alcohol (IPA), tetrahydrofuran (THF), acetone or a mixture of THF and acetone;

[0019] - evaporating the solvent or solvent mixture.

[0020] In another aspect, the present invention relates to a monoacid addition salt of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide, which is 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monohydrochloride, 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monophosphate or 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monotoluenesulfonate.

[0021] In one embodiment, the monoacid addition salt is 6-chloro-2-ethyl-N-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monohydrochloride, which is reacted with Cu-K α -Radiation (Cu-K α ) irradiated with an X-ray powder diffraction (XRPD) spectrum having at least one or more of the following peaks:

[0022] 6.4°2θ, 8.1°2θ, 16.2°2θ, 17.2°2θ, 24.3°2θ and 25.0°2θ, ±0.2°2θ.

[0023] In one embodiment, the monoacid addition salt is 6-chloro-2-ethyl-N-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monophosphate, which is α -Radiation (Cu-K α ) irradiated with an X-ray powder diffraction (XRPD) spectrum having at least one or more of the following peaks:

[0024] 9.0°2θ, 10.7±0.2°2θ, 11.7°2θ, 14.8°2θ, 18.4°2θ, 19.3°2θ, 21.8°2θ and 22.8°2θ, ±0.2°2θ.

[0025] In one embodiment, the monoacid addition salt is 6-chloro-2-ethyl-N-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monotosylate, which is reacted with Cu-K α -Radiation (Cu-K α ) irradiated with an X-ray powder diffraction (XRPD) spectrum having at least one or more of the following peaks:

[0026] 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.

[0027] In one embodiment, the mono-acid addition salt is a mono-hydrochloride salt and has an XRPD spectrum as shown below:

[0028]

[0029] In one embodiment, the monoacid addition salt is a monophosphate salt and has an XRPD spectrum as shown below:

[0030]

[0031] In one embodiment, the mono-acid addition salt is a mono-methanesulfonate salt and has an XRPD spectrum as shown below:

[0032]

[0033] In another aspect, the present invention relates to a process for preparing a monoacid addition salt as defined above, said process comprising the steps of:

[0034] - providing 6-chloro-2-ethyl-N-(4-(4-(trifluoromethoxy)phenyl)piperidin-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 stoichiometric ratio of 1:1 in any order;

[0035] - mixing and dissolving them 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;

[0036] - evaporating the solvent or solvent mixture.

[0037] In another aspect, the present invention relates to a pharmaceutical composition comprising at least one compound according to the present invention or a monoacid addition salt according to the present invention and at least one pharmaceutically acceptable carrier, excipient and / or diluent.

[0038] In one embodiment, the pharmaceutical composition further comprises at least one other pharmaceutically active agent.

[0039] In another aspect, the invention relates to a compound or a monoacid addition salt according to the invention as defined above for use in the treatment of bacterial infections.

[0040] In one embodiment, the bacterial infection is tuberculosis or Buruli's ulcer.

[0041] In another aspect, the present invention relates to a method for treating bacterial infection, in particular tuberculosis or Buruli ulcer, which comprises 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.

[0042] The present inventors have discovered that one particular form of the xylenesulfonate salt of the compound, a polymorph sometimes referred to herein as "Form A" or "Form A," is particularly stable and that other forms convert to this stable polymorph. α - In the X-ray powder diffraction (XRPD) spectrum obtained by irradiation, this form has at least one or more of the following peaks:

[0043] 3.9°2θ, 5.6°2θ, 8.0°2θ, 16.1°2θ, 19.1°2θ and 22.4°2θ, ±0.2°2θ.

[0044] The 2Θ values have a standard deviation of ±0.2° 2Θ. In one embodiment, the compound has an XRPD spectrum as shown below.

[0045]

[0046] This form appears to be the most stable form compared to other forms, thus making it particularly suitable for pharmaceutical dosage forms. In one embodiment, the compound according to the present invention has a differential scanning calorimetry (DSC) thermogram showing a single endothermic peak with an onset temperature of about 235-237°C.

[0047] In one embodiment, the compound according to the present invention has a differential scanning calorimetry (DSC) thermogram showing a single endothermic peak with an onset temperature of 235°C-237°C.

[0048] In one embodiment, the compound according to the present invention is produced by a method comprising the following steps:

[0049] - providing 6-chloro-2-ethyl-N-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide free base and p-toluenesulfonic acid in a stoichiometric ratio of 1:2 in any order;

[0050] - mixing and dissolving them in a suitable solvent or solvent mixture such as isopropyl alcohol (IPA), tetrahydrofuran (THF), acetone or a mixture of THF and acetone;

[0051] - evaporating the solvent or solvent mixture.

[0052] The present invention also relates to a method for producing the compound as defined above, said method comprising the steps of:

[0053] - providing 6-chloro-2-ethyl-N-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide free base and p-toluenesulfonic acid in a stoichiometric ratio of 1:2 in any order;

[0054] - mixing and dissolving them in a suitable solvent or solvent mixture such as isopropyl alcohol (IPA), tetrahydrofuran (THF), acetone or a mixture of THF and acetone;

[0055] - evaporating the solvent or solvent mixture.

[0056] Furthermore, the present inventors have also found that the compound according to the present invention, 6-chloro-2-ethyl-N-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditosylate, is stable under long-term storage conditions of 25°C and 60% relative humidity for up to 60 months, and is stable under accelerated conditions of 40°C and 75% relative humidity for at least 6 months.

[0057] In another aspect, the present invention also relates to a monoacid addition salt of 6-chloro-2-ethyl-N-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide, which is a monohydrochloride, monophosphate or monotoluenesulfonate.

[0058] In one embodiment, when the monoacid addition salt is a monohydrochloride, the compound is reacted with Cu-K α -Radiation (Cu-K α ) irradiated with an X-ray powder diffraction (XRPD) spectrum having at least one or more of the following peaks:

[0059] 6.4°2θ, 8.1°2θ, 16.2°2θ, 17.2°2θ, 24.3°2θ, and 25.0°2θ, wherein all 2θ values have a standard deviation of ±0.2°2θ.

[0060] In one embodiment, when the monoacid addition salt is a monophosphate, the compound is α -Radiation (Cu-K α ) irradiated with an X-ray powder diffraction (XRPD) spectrum having at least one or more of the following peaks:

[0061] 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.

[0062] In one embodiment, when the monoacid addition salt is a monotosylate, the compound is reacted with Cu-K α -Radiation (Cu-K α ) irradiated with an X-ray powder diffraction (XRPD) spectrum having at least one or more of the following peaks:

[0063] 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, wherein all 2θ values have a standard deviation of ±0.2°2θ.

[0064] In one embodiment of the above-mentioned monoacid addition salt, the corresponding compound is reacted with Cu-K α -Radiation (Cu-K α ) irradiation obtained in the X-ray powder diffraction (XRPD) spectrum has all the above corresponding peaks.

[0065] In one embodiment, the mono-acid addition salt is a mono-hydrochloride salt and has an XRPD spectrum as shown below:

[0066]

[0067] In one embodiment, the monoacid addition salt is a monophosphate salt and has an XRPD spectrum as shown below:

[0068]

[0069] In another embodiment, it is a monotosylate salt and has an XRPD spectrum as shown below:

[0070]

[0071] In another aspect, the present invention also relates to a method for preparing a monoacid addition salt as defined above, said method comprising the steps of:

[0072] - providing 6-chloro-2-ethyl-N-(4-(4-(trifluoromethoxy)phenyl)piperidin-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 stoichiometric ratio of 1:1 in any order;

[0073] - mixing and dissolving them 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;

[0074] - evaporating the solvent or solvent mixture.

[0075] The present inventors have surprisingly found that the three monoacid addition salts described above have higher solubility at low pH values, particularly around pH 1. This is important because such drugs should be taken orally and therefore must pass through the gastrointestinal tract. The increased solubility compared to the free base means higher bioavailability.

[0076] When referring to a compound herein as having "the XRPD spectrum shown below," it is meant that the compound has peaks and signals in the XRPD spectrum at the positions shown in the referenced corresponding XRPD spectrum. The intensity of the individual peaks shown need not be the same, as long as the peak or signal is present at the indicated position and is within the typical tolerance range for such XRPD spectra.

[0077] Furthermore, at low pH, particularly around pH 1, the monohydrochloride and monophosphate salts have better solubility than the xylenesulfonate salt.

[0078] In addition, the present invention also relates to a pharmaceutical composition comprising the compound 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditoluenesulfonate as defined above or the monoacid addition salt of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide as defined above, and at least one pharmaceutically acceptable carrier, excipient and / or diluent.

[0079] In one embodiment, such pharmaceutical compositions further comprise at least one other pharmaceutically active agent.

[0080] In another aspect, the present invention relates to a ditosylate compound as defined above or a monoacid addition salt as defined above for use in the treatment of bacterial infections.

[0081] In one embodiment, the bacterial infection is tuberculosis or Buruli's ulcer.

[0082] In another aspect, the present invention also relates to a method for treating bacterial infection, in particular tuberculosis or Buruli ulcer, which comprises administering to a patient in need thereof a suitable amount of a compound as defined above, or a monoacid addition salt as defined above, or a pharmaceutical composition as defined above.

[0083] In another aspect, the present invention also relates to the use of the ditosylate compound as defined above, or the monoacid addition salt as defined above, or the pharmaceutical composition as defined above, for the manufacture of a medicament for treating bacterial infection, wherein preferably, the bacterial infection is tuberculosis or Buruli ulcer.

[0084] It should be noted that when used herein, the compound 6-chloro-2-ethyl-N-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide is sometimes also referred to herein as "Q203." BRIEF DESCRIPTION OF THE DRAWINGS

[0085] The present invention will now be further described with reference to the following drawings, in which

[0086] Figure 1 Shown is the XRPD spectrum of Form A (or "Form A") of the Q203 ditosylate salt.

[0087] Figure 2 a and Figure 2 Panel b shows the XRPD spectra of the mono-HCl form and the mono-phosphate form of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide, respectively.

[0088] Figure 3 Shown is the XRPD spectrum of the monotosylate salt form of 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide.

[0089] Figure 4 Shown is a DSC scan of Form A of the Q203 ditosylate salt.

[0090] Figure 5 Shown is a TGA scan of Form A of the Q203 ditosylate salt.

[0091] Figure 6 Shown are XRPD scans of the different forms obtained, which are described further below.

[0092] Figure 7 DSC scans of the resulting different forms described further below are shown.

[0093] Figure 8 A DVS scan of Form A is shown.

[0094] Figure 9 An XRPD scan of Form C is shown.

[0095] Figure 10 A DSC scan of Form C is shown.

[0096] Figure 11 A TGA scan of Form C is shown.

[0097] Figure 12 A DVS scan of Form C is shown.

[0098] Figure 13 Shown is an XRPD scan of Form G solid from a slurry experiment.

[0099] Figure 14 Shown is a DSC scan of Form G solid from a slurry experiment.

[0100] Figure 15 Shown is a TGA scan of Form G solid from a slurry experiment.

[0101] Figure 16 Shown is an XRPD scan of Form A solid from a 100% RH experiment.

[0102] Figure 17 Shown is an XRPD scan of Form A solid from a 100% RH experiment.

[0103] Figure 18 Shown is an XRPD scan of Form C solid from a 100% RH experiment.

[0104] Figure 19 Shown is a DSC scan of the Form A solid from a 100% RH experiment.

[0105] Figure 20 Shown is a DSC scan of the Form A solid from a 100% RH experiment.

[0106] Figure 21 Shown is a DSC scan of Form C solid from a 100% RH experiment.

[0107] Figure 22 Shown is the XRPD pattern of Q203 free base from batch C12032302-J16001.

[0108] Figure 23 Shown is the XRPD pattern of Q203 ditosylate salt Form A (ie, the correct "Q203" ditosylate salt) from batch C12032302-K16001M.

[0109] Figure 24 Shown are the XRPD patterns of Q203 free base (top trace), ditosylate salt (Form A, second trace from the top), ND-0006E-007-16 (third trace from the top), and pTSA (bottom trace).

[0110] Figure 25 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-003-01 (Pattern 2, bottom trace).

[0111] Figure 26 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-003-25 (Pattern 3, bottom trace).

[0112] Figure 27 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-003-04 (pattern 4, middle trace), and fumaric acid (bottom trace).

[0113] Figure 28 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-006-14 (pattern 5, middle trace), and urea (bottom trace).

[0114] Figure 29 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-006-15 (pattern 6, bottom trace), and benzenesulfonic acid.

[0115] Figure 30 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-003-16 (pattern 7, middle trace), and pTSA (bottom trace).

[0116] Figure 31 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-006-16 (pattern 8, middle trace), and pTSA (bottom trace).

[0117] Figure 32Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-003-22 (pattern 9, middle trace), and EDSA (bottom trace).

[0118] Figure 33 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-003-24 (pattern 10, middle trace), and NDSA (bottom trace).

[0119] Figure 34 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-006-24 (pattern 10, middle trace), and NDSA (bottom trace).

[0120] Figure 35 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-005-15 (pattern 12, middle trace), and BSA (bottom trace).

[0121] Figure 36 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-004-01 (pattern 13, middle trace), and 2-furoic acid (bottom trace).

[0122] Figure 37 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-004-03 (pattern 14, middle trace), and citric acid (bottom trace).

[0123] Figure 38 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-004-04 (pattern 14, middle trace), and fumaric acid (bottom trace).

[0124] Figure 39 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-004-06 (pattern 16, middle trace), and ketoglutarate (bottom trace).

[0125] Figure 40 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-004-24 (pattern 17, middle trace), and NDSA (bottom trace).

[0126] Figure 41 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-004-20 (pattern 18, middle trace), and maleic acid (bottom trace).

[0127] Figure 42Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-004-17 (pattern 19, middle trace), and gentisic acid (bottom trace).

[0128] Figure 43 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-004-16 (pattern 20, middle trace), and pTSA (bottom trace).

[0129] Figure 44 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-004-13 (pattern 21, middle trace), and tartaric acid (bottom trace).

[0130] Figure 45 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-004-12 (pattern 22, middle trace), and succinic acid (bottom trace).

[0131] Figure 46 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-004-12 (pattern 22, bottom trace), and mandelic acid (bottom trace).

[0132] Figure 47 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-004-07 (pattern 24, middle trace), and malic acid (bottom trace).

[0133] Figure 48 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-005-13 / 20 / 27 (pattern 25, second / third / bottom trace).

[0134] Figure 49 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-007-24 (pattern 26, middle trace), and NDSA (bottom trace).

[0135] Figure 50 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-006-17 (pattern 27, middle trace), and gentisic acid (bottom trace).

[0136] Figure 51 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-008-15 (pattern 28, bottom trace).

[0137] Figure 52Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-005-06 (pattern 29, middle trace), and ketoglutarate (bottom trace).

[0138] Figure 53 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-005-04 (type 30, middle trace), and fumaric acid (bottom trace).

[0139] Figure 54 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-007-28 (pattern 31, bottom trace).

[0140] Figure 55 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-007-06 (pattern 32, bottom trace).

[0141] Figure 56 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-007-15 (type 33, middle trace), and benzenesulfonic acid (BSA) (bottom trace).

[0142] Figure 57 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-007-22 (pattern 34, middle trace), and ethanedisulfonic acid (EDSA) (bottom trace).

[0143] Figure 58 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-007-18 (pattern 35, bottom trace).

[0144] Figure 59 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-004-18 (pattern 36, bottom trace).

[0145] Figure 60 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-008-13 (pattern 37, bottom trace).

[0146] Figure 61 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-009-07 (pattern 38, bottom trace).

[0147] Figure 62 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-009-06 (pattern 39, bottom trace).

[0148] Figure 63 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-008-10 (pattern 40, bottom trace).

[0149] Figure 64 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-008-09 (pattern 41, bottom trace).

[0150] Figure 65 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-008-08 (pattern 42, bottom trace).

[0151] Figure 66 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-008-02 (pattern 43, bottom trace).

[0152] Figure 67 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-008-01 (pattern 44, bottom trace).

[0153] Figure 68 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-010-04 (pattern 45, bottom trace).

[0154] Figure 69 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-010-05 (pattern 46, bottom trace).

[0155] Figure 70 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-010-13 (pattern 47, bottom trace).

[0156] Figure 71 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-003-34 (pattern 48, bottom trace).

[0157] Figure 72 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-005-30 (pattern 49, bottom trace).

[0158] Figure 73 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-004-33 (50 pattern, bottom trace).

[0159] Figure 74 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-005-33 (pattern 51, bottom trace).

[0160] Figure 75 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-004-34 (pattern 52, bottom trace).

[0161] Figure 76 Shown are the XRPD patterns of Q203 free base (top trace) and ND-0006E-005-34 (pattern 53, bottom trace).

[0162] Figure 77 Shown are the XRPD patterns of Q203 free base (top trace), ND-0006E-004-23 (type 54, purple trace).

[0163] Figure 78 Shown is the XRPD trace of the solid isolated after the pH solubility experiment. DETAILED DESCRIPTION

[0164] Additionally, reference is made to the following examples, which are provided to illustrate and not to limit the present invention.

[0165] Example

[0166] Example 1

[0167] Overview

[0168] Polymorph screening studies for Q203 were conducted using various crystallization techniques, including slurry and salt formation experiments. Due to the very low solubility of the solid in various solvents, cooling, evaporation, and antisolvent experiments were not performed. Eight XRPD patterns were identified: A, B, C, D, E, F, G, and H. Forms A and C were confirmed to be true crystalline forms of the ditosylate salt. Polymorph screening reslurry experiments were conducted starting with Form A. Form A was a pure form that maintained its crystalline form after exposure to 100% RH at room temperature for 6 days. Form C was also a pure form that was obtained by reslurrying Form A in methanol; it maintained its crystalline form after exposure to 100% RH at room temperature for 6 days. Form G was obtained from water; its 1H-NMR showed a base:acid ratio of 1:1.3. Form H also maintained its crystalline XRPD pattern after exposure to 100% RH at room temperature for 3 days. Form H was obtained from toluene, and its NMR showed a base:acid ratio of 3:3.46. Therefore, Forms G and H are not considered to be true polymorphs of the ditosylate salt. Forms A and C were stirred in six pure solvents at RT and 50° C. for 4 days. Based on XRPD scans, the residual solid obtained from stability experiments in most solvents (THF, EtOH, and IPA) was Form A, but methanol as a reslurry medium produced Form C. Based on these data, Form A is considered to be more stable than Form C.

[0169] XRPD

[0170] Details of the XRPD method used in the experiments are as follows:

[0171] -Rigaku D / MAX 2200 X-ray powder diffractometer

[0172] -X-ray generator: Cu, kα

[0173] -Tube voltage: 40kV, tube current: 40mA

[0174] -DivSlit: 1deg

[0175] - DivH.L.Slit: 10mm

[0176] -SctSlit: 1deg

[0177] -RecSlit: 0.15mm

[0178] -Monochromator: Fixed monochromator

[0179] -Scanning range: 3-36 degrees (2-θ)

[0180] -Scanning step: 5deg / min

[0181] DSC

[0182] Details of the DSC method used in the experiments are as follows:

[0183] -Mettler Toledo Q2000 MDSC

[0184] - Experimental heating from 40°C to 300°C at a rate of 10°C / min

[0185] Analysis of starting materials

[0186] XRPD, DSC and TGA scans of the starting ditosylate salt Form A showed Figure 1 、 4 and 5. According to XRPD, the solid (designated Form A) was crystalline; a DSC scan of the solid showed a melting onset temperature around 235°C; and TGA data showed a weight loss of 0.3% from 30°C to 200°C. The purity of the starting material was 99.46%.

[0187] Solubility test

[0188] Experiment 1: Solubility of Free Base

[0189] The purpose of measuring the solubility of the free base was to identify potential solvents for salt formation method development. The approximate solubility of the free base was determined gravimetrically. Excess solid was added to various solvents, including some Class III solvents (ICH guidelines), at room temperature and 50°C. Because solubility in these solvents was generally low, it was decided to mix water with these solvents. The suspension was slurried for one day; the clear solution from the top of the suspension was used to determine solubility gravimetrically. Solubility data are provided in Table 2-1. At 50°C, solubility in IPA or its mixtures with water was generally low (11-22 mg / ml), solubility in acetone and its mixtures with water ranged from 41-74 mg / ml, solubility in EA and its mixtures with water ranged from 55-98 mg / ml, and solubility in methyl acetate ranged from 94-105 mg / ml. The solubility in THF at 50°C was 279 mg / ml.

[0190] Table 2-1: Approximate solubility data of free bases in pure solvents at RT and 50°C*

[0191]

[0192]

[0193] *: The solubility figures stated are approximate and intended for method development only

[0194] Experiment 2: Solubility of the starting material (ditosylate salt form A)

[0195] The approximate solubility of the starting ditoluenesulfonate salt (Form A) was measured gravimetrically. 100 mg of the solid was suspended in 10 vol of various solvents and stirred at RT and 50°C for 3 days. The mother liquors were then used to measure solubility. The results are shown in Table 2-2. Based on the solubility data, the solid has low solubility in most solvents except MeOH. The solubility in MeOH at RT and 50°C was 126 mg / ml and 275 mg / ml, respectively.

[0196] Table 2-2: Approximate solubility of starting materials in various pure solvents at RT and 50°C*

[0197]

[0198] *: The solubility figures stated are approximate and intended for method development only

[0199] Polymorph screening experiment

[0200] Polymorph screening experiments were performed using two methods: slurry and salt formation experiments (reactive crystallization). In some experiments, samples were analyzed both before and after drying (wet and dry).

[0201] Reslurry experiments Experiment 1: Reslurry in different pure solvents at RT and 50 °C for 7 days

[0202] Samples of the residual solids from the solubility experiments were used for XRPD analysis. The samples were analyzed in both wet and dry states to ensure that potential solvates / hydrates were captured. Table 3-1 shows the results of the analysis. As observed, the residual solids from re-slurrying in water showed form B. Re-slurrying in methanol produced form C. Ethanol, acetone (some experiments) and acetonitrile produced solids with form D. Some experiments using MEK and THF showed solids with form E or a mixture thereof with A. All other samples produced solids that did not change from their original XRPD pattern (form A).

[0203] Table 3-1: Results of format screening by reslurrying in different pure solvents at RT and 50°C for 7 days

[0204]

[0205] Experiment 2: Reslurry in binary solvent at RT for 5 days

[0206] To extend the slurry experiment, a solvent mixture was used as the slurry medium. The residual solid was then analyzed by XRPD and DSC machines. The experimental procedure is described below.

[0207] Add 30 mg of Form B to a 1.5 ml vial

[0208] Prepare a binary solvent with a ratio of 1:1 according to Table 4-1

[0209] Slurry the suspension at RT for 5 days

[0210] The sample was filtered and dried in a vacuum oven at 50°C for 15 minutes

[0211] Perform XRPD and DSC scans

[0212] The results are shown in Table 4-1. It is noted that methanol: water and IPA: water (0.5 ml: 0.5 ml) produce solids with Form B. It is suspected that Form B is associated with water, meaning that this form is produced in the presence of water. On the other hand, mixtures of most solvents with methanol produce Form C. Starting from Form A, methanol seems to be required as at least a portion of the solvent to produce Form C. In pure solvents, it has been shown that in methanol, Form A transforms into Form C. In further experiments, it will be seen that reactive crystallization using solvents other than methanol can produce Form C at the beginning, but over time, Form C transforms into Form A. New XRPD pattern (F) was observed in both cases. In addition to the above, it is noted that Form A remains unchanged in all other experiments.

[0213]

[0214] Salt formation experiment

[0215] In order to screen conditions other than the slurry experiment, salt formation (reactive crystallization) experiments were performed in 12 solvents. The experimental procedures are shown below.

[0216] Add 150 mg of free base to a 4 ml vial with a magnetic stir bar

[0217] Add 10 vol (1.5 ml) of solvent (the list of solvents is shown in Table 4)

[0218] Stir the solution at 50°C for 2 hours

[0219] · Add 2.2eq mol (113mg) of p-toluenesulfonic acid to the solution at 50°C

[0220] After a suspension containing sufficient solids for XRPD / DSC testing is formed, the sample is immediately filtered / dried and subjected to XRPD / DSC analysis.

[0221] Analyze solids with new XRPD patterns by NMR to determine acid / base ratios

[0222] Table 5-1 shows the observations during the salt formation experiment. Note that the free base was dissolved in the target solvent at 50°C before adding the counter ion. In all cases, the solid (potential salt) formed almost immediately after adding the counter ion. At this point (immediately after salt formation), the solid before and after drying was analyzed. Wet and dry XRPD analysis helps to identify the potential solvates / hydrates of the salt. Some deviations from Form C were observed in some wet solids, but in all other solvents except toluene, the dry solids all produced Form C. The main observation from the experiment was that Form C consistently appeared immediately after salt formation. It is known that Form C eventually transforms into Form A in solvents (except methanol).

[0223]

[0224] Attempts to generate solids with different XRPD patterns

[0225] Various slurry and reactive crystallization experiments produced different crystalline forms including A, B, C, D, E, F, G and H. Previous analysis (NMR) indicated that Form H was not a true crystalline form of the ditoluenesulfonate salt and should therefore be crossed out from the list. In order to evaluate and further analyze other solids with other XRPD forms (AG), attempts were made to reproduce the solids (previous experiments showing these solids were performed on a small scale and most of the solids had been consumed for XRPD / DSC analysis). Table 6-1 shows the experiments aimed at producing solids with XRPD forms B, C, D, E and F. The solid with Form A was the starting material and therefore it was obtained.

[0226] Table 6-1: Preparation results of Forms B, C, D, E and F

[0227]

[0228]

[0229] Various forms of analysis

[0230] Figure 6Shown is an overlay of scans of the various XRPD patterns observed in this study. Patterns A and C are true crystalline polymorphs of the ditosylate salt. Therefore, the inventors refer to these solids as Forms A and C. However, because other XRPD patterns have not yet been shown to be true polymorphs of the ditosylate salt, the inventors refer to them simply as "patterns." It should be noted that Patterns C and D are very similar and can be referred to as the same crystalline form.

[0231] Figure 7 Depicted are DSC overlays associated with various XRPD patterns of the solid. The onset temperatures for Forms A, C (and D), and Form E are identical and vary between 235°C and 240°C. Form B exhibits a double endotherm, one with an onset temperature around 139°C and the other with an onset temperature around 208°C.

[0232] Analysis of Form A

[0233] Form A is the true polymorph of the ditosylate salt; NMR shows an acid:base ratio of 6:3. Crystallinity is generally low, with a DSC scan showing a melting onset around 235°C; a TGA scan shows a weight loss of 0.3% (from 30°C to 200°C). Figure 4-5 ). It is the predominant form obtained in slurry experiments. Transitions from Form A to other XRPD patterns are primarily obtained from methanol (to Form C) or water (to Form B) in the slurry medium. However, as will be shown in other sections, Form C transforms to Form A upon re-slurrying in most other solvents (except methanol). The transformation of Form A to a Form B solid does not imply that the solid having Form B is a more stable form than Form A, as it is very likely that Form B is a partially (or completely) hydrolyzed species of the salt. Figure 8 The DVS of Form A is shown to have a water absorption of around 0.35% at 90% RH and RT.

[0234] Analysis of Form C

[0235] Figures 9 to 11 XRPD, DSC and TGA of a solid with Form C are shown. Form C is a true polymorph of the ditoluenesulfonate salt, as NMR shows an acid:base ratio of 2:1. The XRPD peaks of Form C are sharper than those of Form A. When methanol is used as the slurry medium, Form C is the predominant form. However, Form "C" is not a methanol solvate form of the ditoluenesulfonate salt. Many reactive crystallization experiments using different solvents produced Form C immediately after salification. Later experiments showed that overnight slurrying of the same suspension (reactive crystallization) converted Form C to A. Figure 12Shown is a DVS scan of Form C. The DVS scan showed that the solid absorbed only less than 0.3% water at 90% RH and RT.

[0236] Analysis of Form G

[0237] XRPD, DSC and TGA of a solid having Form G are shown in Figures 13 to 15 The solid was crystalline, exhibiting a DSC melting onset of 216° C. (lower than Forms A and C) and a 0.3% weight loss over the range of 30° C. to 200° C. HPLC data showed an acid-base ratio of 3.45:1, so it was not considered a ditosylate salt.

[0238] Other types

[0239] Efforts to reproduce the XRPD patterns did not yield these patterns, meaning these solids were only observed once or twice during the form screening. Pattern B is important because it may indicate a hydrated form. However, it is likely a hydrolyzed salt rather than a hydrated form of the ditosylate salt (a partial salt hydrate).

[0240] Stability test

[0241] The purpose of the work in this section was to observe possible transformations of these forms upon exposure to 100% RH and to identify the most stable polymorph observed in this study.

[0242] Experiment 1: Forms A and C were exposed to RT for 6 days in a 100% RH experiment

[0243] Forms A and C were exposed to a 100% RH environment at RT for 6 days; the solids were then analyzed using DSC and XRPD.

[0244] The results are shown in Figures 16 to 21 In. Figure 1 and 17 , depicted are XRPDs of samples of Form A (forms previously obtained in EA and IPA / MEK) before and after exposure to 100% RH for 6 days. Figure 19 and 20 Shown is a DSC scan of the same sample after exposure. Both graphs show no change in crystallinity, indicating that Form A is stable (from a polymorphic point of view) in a high RH environment. Figure 18 and 21 Shown are the results of the same treatment performed on Form C. The results show that there is no change in the crystal structure as a result of exposure to high RH.

[0245] Exp 2: Forms A and C were reslurried in 6 different pure solvents at RT for 5 days (aging experiment)

[0246] These experiments were performed to investigate potential conversion between Forms A and C. The experimental procedures are as follows.

[0247] Add 15 mg of Form A and 15 mg of Form C to a 1.5 ml vial with a magnetic stir bar

[0248] Add 20 vol (600 ul) of various solvents to the vials

[0249] The suspension was stirred at RT for 5 days

[0250] • The solid was then filtered and sent for XRPD (before and after drying in an oven) and DSC analysis

[0251] Experimental data are shown in Table 10-1. Water, methanol, IPA, acetone, and THF were used as slurry media. Data from the 5th day sample indicated that the ditoluenesulfonate salt partially hydrolyzed in water (producing Form G solid). Once again, methanol as the slurry medium produced Form C, which is consistent with previous re-slurry findings. These data indicate that Form A is more stable than Form C (except in methanol) and therefore appears to be the most stable form under most conditions.

[0252] Table 10-1: Results of Forms A and C reslurried in 6 different pure solvents at RT for 5 days

[0253]

[0254] Experiment 3: Forms A, C, and H were reslurried in 6 different pure solvents at RT and 50°C for 3 days

[0255] The procedures for these experiments are as follows.

[0256] Add 10 mg of Form A and 5 mg of Form C to a 1.5 ml vial with a magnetic stir bar

[0257] Add 20 vol (300 ul) of each solvent to the vial and ensure the solution is cloudy

[0258] Add a small amount of Form H as a seed

[0259] The suspension was stirred at RT for 3 days

[0260] The solid was then filtered and sent for XRPD (after drying in an oven) and DSC analysis

[0261] The results are shown in Table 11-1. Except for water (partial hydrate) and methanol (Form C), other treatments at both temperatures gave Form A (as expected).

[0262] Table 11-1: Results of stability tests of Forms A, C, and H

[0263]

[0264] Experiment 4: Stability of Form C obtained by seeding experiments

[0265] Salt screening (reactive crystallization experiment) produces Form C. In order 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 solvent) and stirred overnight at RT. The suspension was filtered and the solid (wet and dry samples) was analyzed using XRPD. The results are as follows. The data show that Form C transforms into Form A in all solids, confirming the previous results on the stability of Form A.

[0266] Table 12-1: Results of stability test

[0267]

[0268]

[0269] Example 2

[0270] The present inventors intended to perform a salt / co-crystal screen of the Q203 free base as shown below. To this end, a standard salt / co-crystal screen of Q203 was performed to identify salts with acceptable properties, and a physicochemical characterization of the Q203 free base was also performed. The starting materials used in this Example 2 were the Q203 free base from batch C12032302-J16001 and the ditoluenesulfonate salt of Q203 from batch C12032302-K16001M.

[0271]

[0272] Chemical formula: C 29 H 28 ClF3N4O2

[0273] Molecular weight: 557.01

[0274] Elemental analysis: C, 62.53; H, 5.07; Cl, 6.36; F, 10.23; N, 10.06; O, 5.74

[0275] Chemical structure of Q203 free base

[0276] The co-crystal formers listed in Table 1 below were used for the salts / co-crystals of Q203 free base:

[0277] Table 1: List of co-crystal formers used in this Example 2

[0278]

[0279]

[0280] 2. Experiment

[0281] 2.1 Solubility estimation

[0282] At ambient temperature, an aliquot of the test solvent was added to an accurately weighed sample (~25 mg) of Q203 of batch C12032302-J16001. The volume of the aliquot was typically 50-100 μL. Complete dissolution of the test material was determined by visual inspection. Solubility was estimated from these experiments based on the total solvent used to provide complete dissolution. It should be noted that the true solubility may be greater than the calculated solubility due to the use of too large aliquots of solvent or due to slow dissolution rates.

[0283] If dissolution did not occur after the addition of the last solvent aliquot (usually ~40 volumes of solvent), the sample was subjected to two rounds of the following temperature cycling protocol on the clarification crystallization workstation:

[0284] • Heat at a rate of 0.5°C / min from 20°C to within 3°C of the boiling point of the solvent (or 100°C, whichever is lower).

[0285] Cool to 20°C at a rate of 0.2°C / min.

[0286] • The stirrer speed was 800 rpm.

[0287] Based on the infrared (IR) transmission data of the sample bottle, dissolution and precipitation events were recorded as the point of complete IR transmission and the point at which IR turbidity appeared, respectively. The solubility values of Q203 were expressed as a range and rounded to the nearest integer.

[0288] 2.2 Screening method

[0289] Experiments were performed on a -25 mg scale using 1:1 and 2:1 stoichiometry (salt / co-crystal former: Q203 free base).

[0290] 2.2.1 Slow evaporation

[0291] A stock solution of the co-crystal former (1 eq.) in the selected solvent was added to a stock solution of Q203 free base (batch C12032302-J16001, 1 or 2 eq.). In the case where a stock solution of the co-crystal former was not prepared, the co-crystal former 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 isolated solid was dried under nitrogen and then analyzed by XRPD.

[0292] 2.2.2 Slurrying experiment

[0293] Q203 free base (batch C12032302-J16001, 1 eq.) and co-crystal former (1 or 2 eq.) were added to a given solvent until undissolved solids remained at the desired temperature (20 or 40° C.). The vial was sealed and the slurry was maintained at the selected temperature and agitated by magnetic stirring for 5-7 days. The solid was isolated by centrifugation and liquid decantation and dried under nitrogen before analysis by XRPD.

[0294] 2.2.3 Ultrasonic treatment

[0295] The selected neat or mixed solvent system was added to Q203 free base (batch C12032302-J16001, 1 eq) and a co-crystal former (1 eq) to form a paste. The paste was sonicated at 70% intensity using a Cole-Parmer 130W ultrasonic processor using a pulse program. All solids recovered from these experiments were dried under nitrogen and then analyzed by XRPD.

[0296] 2.2.4 Liquid-Assisted Grinding (LAG)

[0297] Q203 free base (~50 mg, 1 eq.) was added to a stainless steel grinding chamber containing the selected co-crystal former (1 eq.). Milling beads and solvent (25 μl) were added to the grinding chamber and the mixture was milled at 25 Hz for 3 x 2 minutes, scraping the grinding chamber walls between each run. The ground solid was analyzed by XRPD.

[0298] 2.2.5 Eutectic (Kofler Melting)

[0299] Q203 free base (~50 mg, 1 eq.) was added to an HPLC vial containing the selected co-crystal former (1 eq.). 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. The molten material was allowed to cool to ambient temperature and then subsequently analyzed by XRPD.

[0300] 2.2.6 Humidity stress caused by salt production

[0301] Approximately 25 mg of the resulting Q203 salt was added to a vial and placed unsealed in a 75% relative humidity chamber (a sealed cabinet with relative humidity conditions controlled by supersaturated salt solution) at ambient temperature for 7 days before analysis by XRPD.

[0302] 2.3 Experimental techniques

[0303] 2.3.1 X-ray powder diffraction (XRPD)

[0304] XRPD analysis was performed using a Panalytical Xpert Pro diffractometer equipped with a Cu X-ray tube and a Pixcel detection system. Isothermal samples were analyzed in transmission mode and held between low-density polyethylene films. Two XRPD programs were used (range 3-40° 2θ, step size 0.013°, counting time 99 seconds, ~22 minutes run time; and range 3-40° 2θ, step size 0.013°, counting time 46 seconds, ~11 minutes run time). XRPD patterns were classified and interpreted using HighScore Plus 2.2c software.

[0305] 2.3.2 Differential Scanning Calorimetry (DSC)

[0306] DSC analyses were performed on a Perkin Elmer 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 to a maximum of 300°C. Indium metal was used as a calibration standard. The temperature at the onset of the phase transition is reported to the nearest 0.01 degree. Note that the DSC traces reported in this report may contain automatic peak integration, which calculates the ΔH of melting. These ΔH values are prone to significant error when multiple thermal events are observed at similar temperatures.

[0307] 2.3.3 Thermogravimetric and differential thermal analysis (TG / DTA)

[0308] Thermogravimetric analysis was performed on a Mettler Toledo TGA / DSC1 STARe. Calibration standards were indium and tin. The sample was placed in an aluminum sample pan, inserted into the TG furnace, and accurately weighed. The heat flow signal was allowed to stabilize at 25°C for 1 minute, then heated to 300°C at a rate of 10°C / min under a nitrogen flow.

[0309] 2.3.4 1 H / 13 C nuclear magnetic resonance spectroscopy (NMR)

[0310] NMR analyses were performed on a Bruker 500 MHz instrument in MeOD-d4 or DMSO-d6. The instrument parameters are listed above the relevant spectra.

[0311] 2.3.5 Optical microscopy

[0312] Microscopic analysis was performed using an Olympus BX51 stereo microscope with crossed polarized light and a first-order red compensator plate. Optical microscopic images were captured using a ColorView IIIu digital camera and SynchronizIR basic V5.0 imaging software at a magnification of x10 objective lens.

[0313] 2.3.6 HPLC

[0314] HPLC is used to determine equilibrium solubility in various solvents. A sample in a water-immiscible solvent is evaporated to dryness and redissolved in the sample diluent.

[0315] 2.3.7 Solubility determination

[0316] In order to determine the solubility of the suspension of Q203 salts (p-TSA salt, phosphate salt and HCl salt) under selected pH conditions (1, 4.5, 6.8 and 7.5), two replicate experiments were set up. The salt was weighed into a vial (~25 mg) and an aliquot (1 mL) of the selected buffer was added. 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 the pH was adjusted to maintain within + / - 0.5 pH units of the parent buffer solution. At the end of the experiment, an aliquot was extracted and filtered through a syringe-type PTFE filter (0.45 μm), the pH was checked, and the solution was injected into the HPLC system without dilution. If the result shows that the sample is too concentrated, the sample is diluted and rerun. The recovered solid is analyzed and checked for form changes by XRPD.

[0317] The solutions used in this study were prepared as follows:

[0318] 2.3.8 Components for Preparation of Standard Buffer Solutions (According to USP 27)

[0319] 2.3.8.1 0.2 M potassium chloride

[0320] Potassium chloride (1.5 g) was weighed in a 100 mL volumetric flask and water was added to the mark.

[0321] 8.2.1.2 0.2M potassium dihydrogen phosphate

[0322] Potassium dihydrogen phosphate (2.8 g) was weighed in a 100 mL volumetric flask and water was added to the mark.

[0323] 2.3.8.2 0.2 M sodium hydroxide

[0324] A 100 mL volumetric flask was charged with a NaOH standard solution (2.0 M, 10 mL) and filled to the mark with water.

[0325] 2.3.8.3 0.2M potassium hydrogen phthalate

[0326] Potassium hydrogen phthalate (4.1 g) was added to a 100 mL volumetric flask and water was added to the mark.

[0327] 8.2.1.4 0.2 M hydrochloric acid

[0328] A 100 mL volumetric flask was charged with HCl standard solution (1.0 M, 20 mL) and filled to the mark with water.

[0329] 2.3.8.4 USP buffer at pH 1

[0330] To a 200 mL volumetric flask was added 0.2 M potassium chloride solution (50 mL) + 0.2 M HCl solution (85 mL), and water was added to the mark.

[0331] 2.3.8.5 USP buffer at pH 4.5

[0332] To a 200 mL volumetric flask, 0.2 M potassium hydrogen phthalate solution (50 mL) + 0.2 M NaOH solution (6.6 mL) were added, and water was added to the mark.

[0333] 2.3.8.6 USP Buffer, pH 6.8

[0334] To a 200 mL volumetric flask, 0.2 M potassium dihydrogen phosphate solution (50 mL) + 0.2 M NaOH solution (22.4 mL) were added, and water was added to the mark.

[0335] 2.3.8.7 USP Buffer, pH 7.5

[0336] To a 200 mL volumetric flask, 0.2 M potassium dihydrogen phosphate solution (50 mL) + 0.2 M NaOH solution (39.1 mL) were added, and water was added to the mark.

[0337] If necessary, adjust the buffer with 1.0 M HCl and 2.0 M NaOH to achieve the correct pH.

[0338] 2.3.9 pKa analysis

[0339] The pKa values of the samples were determined using a spectroscopic (UV) technique. The samples were titrated in triplicate UV titrations from pH 2.0 to 12.0 at concentrations of 31–23 μM in a methanol-water cosolvent (methanol ratios ranging from 63.9 to 46.7% w / w).

[0340] 3. Characterization of Q203 and Solvent Screening

[0341] 3.1 pKa determination

[0342] For pKa determination, no precipitation of the sample from solution was observed and from the collected spectral data, two pKa aqueous values of 3.70 ± 0.06 and 4.97 ± 0.01 were determined by Yasuda-Shedlovsky extrapolation of the respective results obtained (see Table 2).

[0343] It should be noted that additional potentiometric measurements were performed to confirm the pKa and that no other pKa was associated with the sample within the measurable pH range (2.0-12.0).

[0344] Table 2: pKa results of Q203 free base

[0345] pKa T / ℃ Ionic environment method 3.70±0.06 25.0-25.1 0.15M KCl UV measurement 4.97±0.01 25.0-25.1 0.15M KCl UV measurement

[0346] 3.2 Characterization of Q203 Free Base

[0347] The XRPD pattern obtained for Q203 free base of batch C12032302-J16001 is shown at Figure 22 The XRPD pattern indicated a highly crystalline material. Proton NMR analysis of the Q203 free base showed the material to be consistent with a molecular structure with the possible presence of residual solvent (possibly acetone -80 ppm) (data not shown).

[0348] 3.3 Characterization of Q203 Ditoluenesulfonate

[0349] The XRPD pattern obtained for the Q203 ditosylate salt of batch C12032302-K16001M is shown at Figure 23 The XRPD pattern indicated crystalline material, with a slight rise in the baseline and broadening of the peaks suggesting possible amorphous inclusions. Proton NMR analysis of the Q203 ditosylate salt showed that the material was consistent with a molecular structure having an acid / API stoichiometric ratio of 2:1 (data not shown).

[0350] 3.4 Estimated Solubility of Q203 Free Base

[0351] The solubility of Q203 free base in 10 solvent systems was estimated using the aliquot addition method. Temperature cycling experiments were also performed using a clarification crystallization workstation to assess the compound's solubility upon heating. The solubility data are detailed in Table 3. The observations recorded for each experiment are described in Table 3. Q203 free base was present at ~25 mg / mL in four solvents at room temperature and in another four solvents upon heating. No dissolution with temperature was observed in acetone and MTBE.

[0352] Table 3: Estimated solubility of Q203 free base at 20°C

[0353]

[0354]

[0355] * = Shows partial dissolution on heating, however solids remain after two clear heating / cooling cycles

[0356] 3.5 Conclusions from Characterization of Q203 Free Base and Solvent Screening

[0357] - XRPD analysis showed that Q203 free base ("free base" is also sometimes abbreviated herein as "FB") of batch C12032302-J16001 was indicative of a highly crystalline material.

[0358] • Proton NMR analysis of the Q203 free base (data not shown) showed the material to be consistent with a molecular structure with the possible presence of residual solvent (probably acetone ~80 ppm).

[0359] TG / DTA data showed a ~0.4% weight loss from ~40°C to 235°C, indicating very low moisture or solvent content, indicating that the Q203 free base of batch C12032302-J16001 is an anhydrous material with some residual moisture / solvent. The second weight loss at temperatures above 235°C corresponds to the onset of material decomposition. A melting endotherm was observed at an onset temperature of 166.8°C.

[0360] • DSC analysis confirmed the TG / DTA results, showing an endothermic event with an onset temperature of -167°C.

[0361] • Polarized light microscopy of Q203 free base showed the presence of individual and aggregated particles, indicating a polydisperse PSD.

[0362] • pKA analysis showed two aqueous pKA values of 3.70 ± 0.06 and 4.97 ± 0.01.

[0363] 4. Salt / Co-crystal Screening

[0364] An extended salt / cocrystal screening of Q203 was conducted using 37 cocrystal formers with the goal of discovering alternative salts with more desirable properties (e.g., reduced hygroscopicity, chemical stability, dissolution rate, crystallinity, physical stability, etc.).

[0365] The method is designed to generate solids under a wide range of nucleation conditions, designed to mimic the process conditions and solvents used during development and formulation. Customized manual / semi-automated surveys performed by experienced experts are widely considered the preferred method and have been found to perform as well or better than high-throughput screening, while using fewer experiments. 1 .

[0366] All solids from the crystallization experiments were analyzed by XRPD, and the resulting patterns were compared with those exhibited by the starting materials. The new XRPD patterns were assigned alphabetical descriptors (2-type, 3-type, etc.) in the order in which they were found. Where sufficient material was available, the solids with the new XRPD patterns were further analyzed (e.g., NMR or TGA) to allow the new patterns to be provisionally designated as polymorphs, solvates, hydrates, degradants, or mixtures thereof. An overview of all experiments performed is provided in Appendix 1, Table 25, described further below.

[0367] 4.1 Solvent-based screening techniques

[0368] Solvent-based experiments are conducted in glass vials or thin-walled glass capillaries on a scale of approximately 25–40 mg. The methods employed are described in detail in Section 2.2. Evaporation, slow cooling, rapid cooling, rapid precipitation, and prolonged slurrying (at both ambient and elevated temperatures) simulate conditions likely to be encountered during process development and manufacturing. Varying nucleation conditions in this way maximizes the chances of discovering new forms and their frequency under typical processing conditions.

[0369] 4.1.1 Slow evaporation

[0370] Slow evaporation experiments were performed as described in Section 2.2.1, and the results are shown in Table 4. XRPD analysis of the resulting solids revealed 14 new forms (pure or in mixture) from cocrystal formers including fumaric acid (Form 4), urea (Form 5), BSA (Form 6), pTSA (Forms 7 and 8), EDSA (Form 9), NDSA (Forms 10 and 11), saccharin (Forms 25+3), gentisic acid (Form 27), and salicylic acid (Form 48). Forms 2 and 3 were also observed, both pure and in mixture, from various cocrystal formers. These forms are discussed further in Section 5.

[0371] Table 4: Screening results from slow evaporation experiments involving Q203 free base

[0372]

[0373]

[0374]

[0375] 4.1.2RT pulping

[0376] RT (ambient) temperature slurry experiments were performed as described in Section 2.2.2 using solids generated from slow evaporation experiments involving Q203 free base and cocrystal formers (1:1 eq.). The results are shown in Table 5. New forms were observed from XRPD analysis of solids involving urea (5 forms), EDSA (9 forms), 2-furoic acid (13 forms), citric acid (14 forms), fumaric acid (15 forms), ketoglutaric acid (16 forms), NDSA (17 forms), maleic acid (18 forms), gentisic acid (19 forms), pTSA (20 forms), tartaric acid (21 forms), succinic acid (22 forms), mandelic acid (23 forms), malic acid (24 forms), HCl (36 forms), pamoic acid (50 forms), salicylic acid (52 forms), and MSA (54 forms). Form 3 was also observed from various cocrystal formers, both pure and in mixtures. These forms are further discussed in Section 5.

[0377] Table 5: Screening results from RT slurry experiments

[0378]

[0379]

[0380]

[0381] 4.1.3HT pulping (40℃)

[0382] High temperature slurry experiments were performed as described in Section 2.2.2 using solids generated from slow evaporation experiments involving Q203 free base and cocrystal formers (both 1:1 and 2:1 eq.). The results are shown in Table 6. New patterns were observed from XRPD analysis of solids involving urea (5 forms), 2-furancarboxylic acid (13 forms), fumaric acid (15 forms), tartaric acid (21 forms), mandelic acid (23 forms), NDSA (26 forms), sulfuric acid (31 forms), BSA (33 forms), EDSA (34 forms), and HCl (35 forms). Solids of forms 32, 40, and 41 (pure and in mixtures) were observed from a variety of cocrystal formers. These patterns are discussed in more detail in Section 5.

[0383] Table 6: Screening results from slow evaporation experiments involving Q203 free base

[0384]

[0385]

[0386]

[0387] 4.1.4 Ultrasonic treatment

[0388] The selected pure or mixed solvent system is added to a sufficient amount of Q203 free alkali (batch C12032302-J16001M) to form a paste. The paste is sonicated using a Cole-Parmer 130W ultrasonic processor at 70% intensity using a pulse program. All solids recovered from these experiments are dried under nitrogen and then analyzed by XRPD. The results of these experiments are shown in Table 7. The XRPD analysis of the solid obtained shows novel formulas from experiments involving pTSA (7 types), NDSA (10 types), mandelic acid (23 types), malic acid (24 types), ketoglutaric acid (29 types), nitric acid (49 types), pamoic acid (51 types) and salicylic acid (53 types). Solids (pure and in mixtures) of types 3 and 25 are observed from a variety of eutectic formers. These types are discussed in more detail in sections 5. Each type is further described in detail in sections 5.

[0389] Table 7: Screening results from ultrasonic treatment experiments

[0390]

[0391]

[0392] 4.2 Solid-state screening technology

[0393] Non-solvent-based (solid-state) screening methods include ball milling, sublimation, melting, and compression (Section 2.2). These techniques simulate conditions that may be encountered in large-scale processing, such as on hot reactor walls or during drying and tableting operations. Varying the nucleation conditions in this way maximizes the chance of discovering new forms and the frequency with which these forms appear under typical processing conditions.

[0394] 4.2.1 Eutectic (Kofler Melting)

[0395] Eutectic (Kofler melting) experiments were performed as described in Section 2.2.5 using Q203 free base and a eutectic former (1:1 eq.). The results are detailed in Table 8. These experiments generally produced amorphous or very disordered solids. XRPD analysis of the solids produced by melting Q203 free base with gluconic acid showed a new form designated as Form 38. A new form (Form 39) was also observed from melting experiments involving a variety of eutectic formers. These two forms are discussed in more detail in Section 5.

[0396] Table 8: Results from eutectic experiments

[0397]

[0398]

[0399] 4.2.2 Liquid-assisted grinding (LAG)

[0400] Eutectic (Kofler melt) experiments were performed as described in Section 2.2.5 using Q203 free base and eutectic formers (1:1 eq.). The results are detailed in Table 9. XRPD analysis of the solids obtained from LAG experiments involving phosphoric acid (Form 37) and ascorbic acid (Form 43) showed new forms. Forms 28, 40, and 41 were observed from various eutectic formers. These forms are detailed in Section 5.

[0401] Table 9: Results from LAG experiments

[0402]

[0403]

[0404] 4.3 Conclusions from Salt / Cocrystal Screening

[0405] Approximately 200 experiments were performed using both solvent-based and non-solvent-based techniques. Including the received raw material, 55 crystalline XRPD patterns were observed during this study. This demonstrates the high propensity of Q203 to generate novel forms from a variety of co-crystal formers and techniques. Polymorphism of Q203 was observed, but the majority of novel forms can likely be attributed to salts of the Q203 free base and / or potential co-crystals.

[0406] Table 10: Summary of observed Q203 solids (classified by eutectic former)

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416] 5. Preparation and Characterization of New Types

[0417] 5.1 Form A (p-toluenesulfonic acid)

[0418] Form A material (ditosylate salt "Form A") was isolated from slow evaporation followed by HT slurry experiments using pTSA and Q203 free base (1:1 acid / API) in IPA. XRPD analysis of Form A (ND-0006E-003-16) showed that the material was crystalline (see also Figure 24 +30).

[0419] 5.2 Type 2

[0420] Form 2 material was generated from slow evaporation experiments involving various acids and Q203 free base (both 1:1 and 2:1 acid / API) in THF / MeOH. The experimental conditions that produced pure Form 2 and Form 2 mixtures (with co-crystal former or Form 3) are highlighted in Table 11. XRPD analysis of the Form 2 solid (ND-0006E-003-01) showed that the material was crystalline with some disorder ( Figure 25 ). Type 2 material 1 H NMR analysis showed no salt formation (data not shown). Since this type was obtained from a different co-crystal former, it is likely a polymorph of the free base of Q203.

[0421] Table 11: Experimental conditions for producing Type 2 solids (pure and mixtures)

[0422]

[0423]

[0424] 5.3 Type 3

[0425] Form 3 material was generated from multiple experiments involving selected acids and Q203 free base (1:1 and 2:1 acid / API) in neat and mixed solvent systems. The experimental conditions that produced pure Form 3 and Form 3 mixtures (with co-crystal former, Form 2, Form 6, or unknown) are highlighted in Table 12. XRPD analysis of Form 3 solid (ND-0006E-003-25) showed that the material was crystalline ( Figure 26 ). Type 3 material 1 H NMR analysis showed no salt formation (data not shown). Since this species was obtained from different co-crystal formers and solvent systems, it is likely a polymorph of the free base of Q203.

[0426] Table 12: Experimental conditions for producing Type 3 solids (pure and mixtures)

[0427]

[0428]

[0429]

[0430] 5.4 Type 4 (fumaric acid)

[0431] Type 4 material was produced from slow evaporation experiments involving fumaric acid and Q203 free base (both 1:1 and 2:1 acid / API) 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 H NMR analysis showed no salt formation and residual MeOH (-0.5 molar equivalents) (data not shown). This suggests that Form 4 may be a co-crystal or polymorph of Q203 free base, possibly a hemisolvate with MeOH.

[0432] 5.5 Type 5 (urea)

[0433] Type 5 material was obtained from experiments involving urea and Q203 free base (both 1:1 and 2:1 acid / API) in a mixture of THF / MeOH, MTBE, and IPA. The experimental conditions that produced the Type 5 solid are highlighted in Table 13. XRPD analysis of the Type 5 solid (ND-0006E-006-14) showed that the material was crystalline ( Figure 28 ). Type 5 material 1 H NMR analysis showed no peak shift, indicating that the salt had not formed (data not shown), and no residual solvent. DSC was performed to determine whether a Q203:urea co-crystal had formed, however, the thermogram corresponded to melting of the free base and urea. Further investigation is required to determine whether Form 5 is a co-crystal.

[0434] Table 13: Experimental conditions for producing Type 5 solids

[0435]

[0436] 5.6 Type 6 (benzenesulfonic acid)

[0437] Form 6 material was isolated from slow evaporation experiments using benzenesulfonic acid and Q203 free base (2:1 acid / API) in a THF / acetone mixture. Form 6 was also observed as a mixture with Form 3. XRPD analysis of Form 6 solid (ND-0006E-006-15) showed that the material was disordered and crystalline ( Figure 29 ),and 1 H NMR analysis (data not shown) showed a peak shift indicating salt formation, likely with a 1:1 or 2:1 stoichiometry (to be confirmed), with -0.25 molar equivalents of THF.

[0438] 5.7 Type 7 (p-toluenesulfonic acid)

[0439] Form 7 material was isolated from 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 Form 7 solid (ND-0006E-003-16) showed that the material was crystalline ( Figure 30 ),and 1 H NMR analysis showed a peak shift indicative of salt formation and no residual solvent, likely with a 1:1 (acid:API) stoichiometry (data not shown). The presence of other peaks should be noted.

[0440] 5.8 Type 8 (p-toluenesulfonic acid)

[0441] Form 8 solids were generated from slow evaporation experiments using pTSA and Q203 free base (2:1 acid / API) in a THF / acetone mixture. XRPD analysis of Form 8 solids (ND-0006E-006-16) showed that the material was crystalline ( Figure 31 ),and 1 H NMR analysis showed a peak shift with -0.15 molar equivalents of THF, indicating salt formation, likely with a 2:1 stoichiometry (data not shown).

[0442] 5.9 Type 9 (ethane-1,2-disulfonic acid)

[0443] Type 9 material was generated from experiments involving EDSA and Q203 free base (1:1 acid / API). The experimental conditions that produced Type 9 solid are highlighted in Table 14. XRPD analysis of Type 9 solid (ND-0006E-006-14) showed that the material was crystalline ( Figure 32 ). 1 H NMR analysis showed a peak shift with -0.07 molar equivalents of MTBE, indicating salt formation, likely with a 1:1 stoichiometry (data not shown).

[0444] Table 14: Experimental conditions for producing Type 9 solids

[0445] Sample number (ND-0006E-) solvent antisolvent Screening methods result 003-22 THF acetone Slow evaporation solid 004-22 MTBE none Slurry (20℃) solid 005-22 THF none Ultrasonic treatment solid

[0446] 5.10 Type 10 (1,5-naphthalene disulfonic acid)

[0447] Form 10 material was isolated from both slow evaporation experiments using NDSA and Q203 free base (1:1 acid / API) in a THF / acetone mixture and sonication experiments using THF. XRPD analysis of the Form 10 solid (ND-0006E-003-24) showed that the material was crystalline ( Figure 33 ),and 1 H NMR analysis showed a peak shift indicative of salt formation, possibly with a 2:1 (acid:API) stoichiometric ratio (data not shown). Residual THF (~0.5 molar equivalents) also indicated a possible THF hemisolvate of the Q203 salt.

[0448] 5.11 Type 11 (1,5-naphthalenedisulfonic acid)

[0449] Type 11 material was produced from 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 the material was crystalline and that the form was similar to Type 10 with minor differences ( Figure 34 ). 1 H NMR analysis showed a peak shift, indicating salt formation (data not shown). Residual THF (-0.7 molar equivalents) also indicated a possible THF solvate. Due to the presence of free acid, the stoichiometry of the salt has not been determined.

[0450] 5.12 Type 12 (benzenesulfonic acid)

[0451] The Type 12 material was isolated from 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 the material was crystalline ( Figure 35Proton NMR analysis showed a peak shift with -0.03 molar equivalents of THF, indicating salt formation with a 1:1 stoichiometric ratio (data not shown).

[0452] 5.13 Type 13 (furancarboxylic acid)

[0453] Type 13 material was generated from experiments involving furanoic acid and Q203 free base (1:1 and 2:1 acid / API). The experimental conditions that produced the Type 13 solid are highlighted in Table 15. XRPD analysis of the Type 13 solid (ND-0006E-004-01) showed that the material was crystalline ( Figure 36 ). In DMSO-d6 1 H NMR analysis showed no peak shift or residual solvent, suggesting possible polymorphs of the free base, Q203:furancarboxylic acid cocrystals, or degradants (data not shown).

[0454] Table 15: Experimental conditions for producing Type 13 solids

[0455]

[0456] 5.14 Type 14 (citric acid)

[0457] Type 14 material was produced from a 7-day ambient temperature slurry experiment using citric acid and Q203 free base (1:1 acid / API) in MTBE. XRPD analysis of the Type 14 solid (ND-0006E-004-03) showed that the material was crystalline ( Figure 37 ),and 1 H NMR analysis showed no peak shift or residual solvent, suggesting possible polymorphs of the free base or Q203:citric acid cocrystals (data not shown).

[0458] 5.15 Type 15 (fumaric acid)

[0459] The Type 15 material was isolated from slurry 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 the material was crystalline ( Figure 38 ),and 1 H NMR analysis showed no peak shift or residual solvent, suggesting possible polymorphs of the free base or Q203:fumaric acid cocrystals (-0.7 molar equivalents of fumaric acid) (data not shown).

[0460] 5.16 Type 16 (Ketoglutaric acid)

[0461] Type 16 material was produced 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 the material was crystalline ( Figure 39 Proton NMR analysis showed a possible peak shift at 2.9 ppm, ~0.02 molar equivalents of MTBE. Further analysis was required to determine the nature of this species (data not shown).

[0462] 5.17 Type 17 (1,5-naphthalene disulfonic acid)

[0463] Type 17 material was produced from a 7-day ambient temperature slurry 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 the material was crystalline and the form was similar to Type 11 with additional and missing peaks ( Figure 40 ). 1 H NMR analysis showed peak shift and -0.08 molar equivalents of MTBE, indicating salt formation and a possible 2:1 acid / API stoichiometry (data not shown).

[0464] 5.18 Type 18 (maleic acid)

[0465] Form 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 Form 18 solid (ND-0006E-004-20) showed that the material was crystalline and the form was similar to Form 19 with the presence of additional peaks in the diffraction pattern ( Figure 41 ). 1 H NMR analysis showed a peak shift, indicating salt formation with a possible 1:1 (acid:API) stoichiometry and residual MTBE (-0.2 eq) (data not shown).

[0466] 5.19 Type 19 (gentisic acid)

[0467] Type 19 material was generated 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 19 solid (ND-0006E-004-17) showed that the material was crystalline and that the form showed some similarity to Type 3 ( Figure 42 ). 1 H NMR analysis showed no peak shift and some residual MTBE (0.1 molar equivalent) and free acid (0.2 molar equivalent), indicating possible polymorphs of the free base or Q203:gentisic acid cocrystals (data not shown).

[0468] 5.20 20 type (p-toluenesulfonic acid)

[0469] 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. Type 20 solid (ND-0006E-004-16, Figure 43 ) showed that the material was crystalline, and 1 HNMR analysis showed peak shift with trace amounts of residual MTBE (0.01 molar equivalents), indicating salt formation and a 1:1 acid / API stoichiometry (data not shown).

[0470] 5.21 Type 21 (Tartaric acid)

[0471] Type 21 material was isolated from slurry 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 the material was crystalline ( Figure 44 ), and solid (ND-0006E-007-13) 1 H NMR analysis (data not shown) showed no peak shift or residual solvent, with ~0.6 molar equivalents of tartaric acid and an unknown peak at 8.1 ppm. TG / DTA analysis showed a weight loss of ~0.4% before melting was observed at an onset temperature of 168° C. These results suggest a possible cocrystal or polymorph of Q203 free base.

[0472] 5.22 Type 22 (succinic acid)

[0473] 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. Type 20 solid (ND-0006E-004-12, Figure 45 ) showed that the material was crystalline, and 1 H NMR analysis showed no peak shift and trace amounts of residual MTBE (0.003 molar equivalents) and 1 molar equivalent of succinic acid, suggesting possible cocrystals or polymorphs of Q203 free base (data not shown).

[0474] 5.23 Type 23 (mandelic acid)

[0475] Type 23 material was generated from experiments involving mandelic acid and Q203 free base (1:1 and 2:1 acid / API). The experimental conditions that produced the Type 23 solid are highlighted in Table 16. XRPD analysis of the Type 23 solid (ND-0006E-004-01) showed that the material was crystalline ( Figure 46 ), and other peaks were observed in sample ND-0006E-007-09. 1 H NMR analysis showed no peak shift, trace amounts of residual solvent (0.01 molar equivalents), and 0.8 molar equivalents of mandelic acid, possibly indicating a polymorph of Q203 free base or a mandelic acid cocrystal (data not shown).

[0476] Table 16: Experimental conditions for producing Type 23 solid

[0477]

[0478] 5.24 Type 24 (Malic Acid)

[0479] Type 24 material was isolated from ambient temperature slurry experiments using malic acid and Q203 free base (1:1 acid / API) in MTBE and sonication experiments using THF. XRPD analysis of the Type 24 solid (ND-0006E-004-07) showed that the material was disordered and crystalline ( Figure 47 ), and solid (ND-0006E-005-07) 1 H NMR analysis showed no peak shift or residual solvent, with 1 molar equivalent of malic acid, which could indicate a polymorph of Q203 free base or a malic acid cocrystal (data not shown).

[0480] 5.25 Type 25

[0481] Form 25 material was generated from sonication experiments involving various acids and Q203 free base (1:1 acid / API) in THF. The experimental conditions that produced pure Form 25 and mixtures of Form 25 (with Form 3) are highlighted in Table 17. XRPD analysis of pure Form 5 solids (ND-0006E-005-13, 20, 27) showed that the material was crystalline ( Figure 48 Since this form was obtained from a different co-crystal former using THF, Form 25 is likely a polymorph of the Q203 free base and may be solvated (THF).

[0482] It should be noted that proton NMR analysis of type 25 material (ND-0006E-005-20) showed a peak shift indicating salt formation (1:1 acid / API) with ~0.5 molar equivalents of THF, which could indicate a possible hemisolvate of the Q203 maleate salt (data not shown). This could be explained by in situ salt formation during sample preparation in deuterated methanol for NMR spectroscopy analysis.

[0483] Table 17: Experimental conditions for producing Type 25 solids (pure and mixtures)

[0484]

[0485] 5.26 Type 26 (1,5-naphthalene disulfonic acid)

[0486] Type 26 material was produced from slow evaporation followed by a 7 day high temperature slurry experiment (40°C) using NDSA and Q203 free base in IPA (2:1 acid / API). Type 26 solid (ND-0006E-007-24, Figure 49 ) showed that the material was crystalline, and proton NMR spectroscopy showed a peak shift indicating salt formation (data not shown) with -0.04 molar equivalents of IPA. The stoichiometric ratio needed to be confirmed.

[0487] 5.27 Type 27 (gentisic acid)

[0488] Solid Type 27 was generated from a slow evaporation experiment using gentisic acid and Q203 free base (2:1 acid / API) in a THF / methanol mixture. XRPD analysis of solid Type 27 (ND-0006E-006-17) showed that the material was disordered, crystalline ( Figure 50 ),and 1 H NMR analysis showed no peak shift and contained 0.5 molar equivalents of THF and 2 molar equivalents of the co-crystal former, suggesting a possible THF hemisolvate of gentisic acid cocrystal or polymorph of Q203 free base (data not shown).

[0489] 5.28 Type 28 (galactaric acid)

[0490] Type 28 material was isolated from two LAG experiments using galactaric acid and gluconic acid with Q203 free base (1:1 acid:API) in an IPA / water mixture and acetone, respectively. XPRD analysis of Type 28 (ND-0006E-008-15) showed that the material was disordered, crystalline ( Figure 51). Proton NMR analysis (data not shown) showed no peak shift with ~0.07 molar equivalents of IPA. TG / DTA results showed multiple endothermic events. Form 28 is likely a polymorph of the free base obtained from different co-crystal formers.

[0491] 5.29 Type 29 (Ketoglutaric acid)

[0492] Type 29 material was obtained from sonication experiments using ketoglutaric acid and Q203 free base (1:1 acid / API) in THF. Type 29 solid (ND-0006E-005-06, Figure 52 ) showed that the material was disordered, crystalline, and additional peaks were observed similar to Form 25. Proton NMR analysis showed no peak shift, contained 0.16 molar equivalents of THF and 0.9 molar equivalents of ketoglutaric acid, indicating a possible cocrystal or polymorph of Q203 free base (data not shown).

[0493] 5.30 Type 30 (fumaric acid)

[0494] Type 30 material was isolated from sonication experiments using ketoglutaric acid and Q203 free base (1:1 acid / API) in THF. Type 30 solid (ND-0006E-005-04, Figure 53 ) showed that the material was crystalline, and 1 HNMR analysis (data not shown) showed no peak shift or residual solvent and contained -0.85 molar equivalents of fumaric acid, indicating a possible polymorph of Q203 free base or a fumaric acid cocrystal.

[0495] 5.31 Type 31 (sulfuric acid)

[0496] Type 31 material was produced from slow evaporation followed by a 7-day high temperature slurry experiment (40°C) in IPA using sulfuric acid and Q203 free base (2:1 acid / API). Type 31 solid (ND-0006E-007-28, Figure 54 ) showed that the material was crystalline, and proton NMR spectroscopy showed significant peak shifts and no residual solvent, indicating salt formation (data not shown). It should be noted that other peaks are present, which may be explained by degradation. The stoichiometric ratio was not determined.

[0497] 5.32 Type 32

[0498] The Type 32 material was produced from high temperature slurry experiments (40°C) involving various acids and Q203 free base (2:1 acid / API) in IPA. The experimental conditions that produced pure Type 32 and mixtures of Type 32 (with co-crystal acid) are highlighted in Table 18. XRPD analysis of the Type 32 solid (ND-0006E-007-06) showed that the material was crystalline ( Figure 55 ). 32 type material 1 HNMR analysis showed no peak shift (data not shown) and residual solvent, and contained 0.2 molar equivalents of co-crystal former. Since this type was obtained from different co-crystal formers, it is likely a polymorph of Q203 free base.

[0499] Table 18: Experimental conditions for producing Type 32 solids (pure and mixtures)

[0500]

[0501]

[0502] 5.33 Type 33 (benzenesulfonic acid)

[0503] Type 33 material was generated from a 7-day high temperature slurry experiment (40°C) in IPA using BSA and Q203 free base (2:1 acid / API). Type 33 solid (ND-0006E-007-15, Figure 56 ) showed that the material was crystalline, and proton NMR spectroscopy (data not shown) indicated possible salt formation, no residual solvent, and a possible acid / API stoichiometry of 2: 1. Similarity to the observed Form 6 should be noted.

[0504] 5.34 Type 34 (ethane-1,2-disulfonic acid)

[0505] Type 34 material was produced from a 7-day high temperature slurry experiment (40°C) in IPA using EDSA and Q203 free base (2:1 acid / API). Type 34 solid (ND-0006E-007-22, Figure 57 ) showed that the material was crystalline and disordered, and proton NMR spectroscopy (data not shown) showed peak shifts and no residual solvent, indicating salt formation, probably with a 2:1 acid / API stoichiometry.

[0506] 5.35 Type 35 (HCl)

[0507] Type 35 material was produced from slow evaporation followed by a 7 day high temperature slurry experiment (40°C) in IPA using HCl and Q203 free base (2:1 acid / API). Type 35 solid (ND-0006E-007-18, Figure 58 ) showed that the material was disordered and crystalline, and proton NMR spectroscopy (data not shown) showed peak shifts, indicating salt formation. No residual solvent or degradation was observed from the NMR spectrum. The stoichiometric ratio has not yet been determined.

[0508] 5.36 Type 36 (HCl)

[0509] Type 36 material was isolated from a 7 day ambient temperature slurry experiment using HCl and Q203 free base (1:1 acid / API) in MTBE. Type 36 solid (ND-0006E-004-18, Figure 59 XRPD analysis of the material (Figure 2) showed that the material was crystalline, with a diffraction pattern similar to Form 3 plus other peaks. Proton NMR analysis (data not shown) showed peak shifts with trace amounts of residual MTBE (0.007 molar equivalents) and suggested the presence of the HCl salt of Q203. The stoichiometric ratio has not been determined.

[0510] 5.37 Type 37 (phosphoric acid)

[0511] Type 37 material was produced from high temperature slurry experiments (40°C) and LAG techniques using acetone and Q203 free base (1:1 acid / API). Type 37 solid (ND-0006E-008-13, Figure 60 XRPD analysis of the material indicated that it was crystalline. A slight baseline shift indicated the presence of amorphous inclusions. Proton NMR analysis indicated peak shifts, containing approximately 0.09 molar equivalents of residual acetone Q2O3 phosphate (data not shown). The stoichiometric ratio has not been determined.

[0512] 5.38 Type 38 (gluconic acid)

[0513] Type 38 material was isolated from a eutectic experiment using gluconic acid and Q203 free base (1:1 acid / API). Type 38 solid (ND-0006E-009-07, Figure 61 ) showed that the material was crystalline. Baseline drift indicated the presence of amorphous inclusions. Proton NMR analysis (data not shown) showed no peak shift, no evidence of residual solvent, and no co-crystal former, as expected. TG / DTA results (data not shown) showed a melting onset of 164°C and another endothermic peak associated with weight loss starting at 218°C. These results suggest that Form 38 is likely a polymorph of the free base.

[0514] 5.39 Type 39 (multiple eutectic formers)

[0515] Type 39 material was isolated from eutectic experiments using various eutectic formers (malonic acid, pyruvic acid, saccharin) and Q203 free base (1:1 acid / API). Type 39 solid (ND-0006E-009-06, Figure 62 XRPD analysis of the material (Figure 2A) indicated that the material was crystalline. Baseline drift indicated the presence of amorphous inclusions. Proton NMR analysis (data not shown) showed no peak shift, approximately 0.9 molar equivalents of co-crystal former, and suggested that it may be a co-crystal or a polymorph of the free base.

[0516] Table 19: Experimental conditions for producing Type 39 solids (pure and mixtures)

[0517]

[0518]

[0519] 5.40 Type 40 (multiple eutectic formers)

[0520] Type 40 material was isolated from HT slurries and LAG experiments using various eutectic formers (malonic acid, pyruvic acid, pyroglutamic acid, etc.) and Q203 free base (1:1 acid / API). A Type 40 solid (ND-0006E-008-10, Figure 63 XRPD analysis of the material indicated that it was crystalline. A slight baseline shift indicated the presence of amorphous inclusions. Proton NMR analysis showed no peak shift, approximately 0.3 molar equivalents of residual acetone, and no evidence of a co-crystal former, suggesting a possible polymorph of the free base (data not shown).

[0521] Table 20: Experimental conditions for producing Type 40 solids (pure and mixtures)

[0522]

[0523]

[0524] 5.41 Type 41 (multiple eutectic formers)

[0525] Type 41 material was isolated from HT slurries and LAG experiments using various eutectic formers (lactobionic acid, ascorbic acid, 2-furancarboxylic acid, galactaric acid) and Q203 free base (1:1 acid / API). A Type 41 solid (ND-0006E-008-09, Figure 64 XRPD analysis of Form 41 indicated that the material was crystalline. A slight baseline shift indicated the presence of amorphous inclusions. Proton NMR analysis showed no peak shift, approximately 0.3 molar equivalents of residual acetone, and no evidence of a co-crystal former, suggesting that Form 41 is likely a polymorph of the free base (data not shown).

[0526] Table 21: Experimental conditions for producing Type 41 solids (pure and mixtures)

[0527]

[0528] 5.42 Type 42 (gentisic acid)

[0529] Type 42 material was isolated from a LAG experiment using gentisic acid and Q203 free base (1:1 acid / API) in acetone. Type 42 solid (ND-0006E-008-08, Figure 65 ) showed that the material was crystalline. A slight baseline drift indicated the presence of amorphous inclusions. Proton NMR analysis showed no peak shift, ~0.14 molar equivalents of acetone (~1.12% w / w), and ~0.67 molar equivalents of co-crystal former (data not shown). TG / DTA showed a weight loss from 25 to 113°C (possibly water), and an endotherm was observed starting around 121°C. These results suggest a polymorph of Q203 free base or a potential co-crystal. Further analysis is required to confirm either of these hypotheses.

[0530] 5.43 Type 43 (ascorbic acid)

[0531] Type 43 material was isolated from a LAG experiment using ascorbic acid and Q203 free base (1:1 acid / API) in an IPA / water mixture. Type 43 solid (ND-0006E-008-02, Figure 66 ) showed that the material was crystalline. A slight baseline drift indicated the presence of amorphous inclusions. Proton NMR analysis (data not shown) showed no peak shift as expected, no residual IPA, and ~0.8 molar equivalents of co-crystal former. TG / DTA showed a ~0.9% weight loss from 25 to ~131 °C, likely due to moisture. Two endothermic events were observed starting at 136 and 158 °C, with a constant weight loss of ~11% from 130 to 300 °C. These results suggest that Form 43 may be a mixture of polymorphs of Q203 (free base and co-crystal former) or a potential co-crystal. Further analysis is needed to better understand the nature of this form.

[0532] 5.44 Type 44 (saccharin)

[0533] Type 44 material was isolated from a LAG experiment using saccharin and Q203 free base (1:1 acid / API) in an IPA / water mixture. Type 44 solid (ND-0006E-008-14, Figure 67XRPD analysis of the material (Figure 2) showed that the material was disordered and crystalline. A slight baseline shift indicated the presence of amorphous inclusions. Proton NMR analysis (data not shown) showed a peak shift containing ~0.5 molar equivalents of IPA, indicating an IPA hemisolvate of the saccharinate salt of Q203. Further experiments may yield the unsolvated saccharinate salt of Q203.

[0534] 5.45 45 type (oxalic acid)

[0535] Type 45 material was isolated from a 5 day HT slurry experiment (40°C) in acetone using oxalic acid and Q203 free base (1:1 acid / API). Type 45 solid (ND-0006E-010-04, Figure 68 ) showed that the material was crystalline. A slight baseline drift indicated the presence of amorphous inclusions. Proton NMR analysis showed peak shift and ~0.06 molar equivalents of acetone, indicating the formation of the Q203 oxalate salt (data not shown).

[0536] 5.46 46 type (oxalic acid)

[0537] 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. Type 46 solid (ND-0006E-010-05, Figure 69 ) showed that the material was crystalline. A slight baseline drift indicated the presence of amorphous inclusions. Proton NMR analysis (data not shown) showed no peak shift, indicating polymorphic forms of the free base.

[0538] 5.47 Type 47 (saccharin)

[0539] 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. Type 47 solid (ND-0006E-010-13, Figure 70 XRPD analysis of the material (Figure 2) showed that the material was crystalline. A slight baseline shift indicated the presence of amorphous inclusions. Proton NMR analysis (data not shown) showed a peak shift containing trace amounts of IPA, ~0.7 molar equivalents of co-crystal former, indicating salification of the Q203 saccharin salt.

[0540] 5.48 Type 48 (salicylic acid)

[0541] Type 48 material was isolated from a slow evaporation experiment using salicylic acid and Q203 free base (1:1 acid / API) in a THF / acetone mixture. Type 47 solid (ND-0006E-003-34, Figure 71) showed that the material was crystalline. Proton NMR analysis showed no peak shift, contained 0.9 molar equivalents of co-crystal former, 0.1 molar equivalents of THF and no residual acetone, indicating a possible co-crystal or polymorph of the free base (data not shown).

[0542] 5.49 Type 49 (nitric acid)

[0543] Type 49 material was isolated from sonication experiments using nitric acid and Q203 free base (1:1 acid / API) in THF. Type 49 solid (ND-0006E-005-30, Figure 72 ) showed that the material was crystalline, very similar to Form 3 with additional peaks. Proton NMR analysis (data not shown) showed a peak shift containing -0.25 molar equivalents of THF, indicating that Form 49 was likely the nitrate salt of Q203.

[0544] 5.50 Type 50 (Pamoic acid)

[0545] 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. Type 50 solid (ND-0006E-004-33, Figure 73 ) showed that the material was crystalline, very similar to Form 3 with additional peaks. Proton NMR analysis (data not shown) showed no peak shift, contained 0.07 molar equivalents of MTBE and 0.65 molar equivalents of co-crystal former, indicating a possible polymorph or co-crystal of Q203 free base.

[0546] 5.51 Type 51 (Pamoic acid)

[0547] Type 51 material was isolated from sonication experiments using Pamoic acid and Q203 free base (1:1 acid / API) in THF. Type 51 solid (ND-0006E-005-33, Figure 74 ) showed that the material was crystalline. Proton NMR analysis (data not shown) showed no peak shift, contained 0.02 molar equivalents of THF and 0.9 molar equivalents of co-crystal former, indicating that it may be a polymorph or co-crystal of Q203 free base.

[0548] 5.52 Type 52 (salicylic acid)

[0549] 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. Type 52 solid (ND-0006E-005-33, Figure 75) showed that the material was crystalline and exhibited similarity to Form 3. Proton NMR analysis (data not shown) showed no peak shift and contained -0.36 molar equivalents of co-crystal former, -0.40 molar equivalents of MTBE, indicating a possible polymorph of Q203 free base.

[0550] 5.53 Type 53 (salicylic acid)

[0551] Type 53 material was isolated from sonication experiments using salicylic acid and Q203 free base (1:1 acid / API) in THF. Type 53 solid (ND-0006E-005-34, Figure 76 ) showed that the material was crystalline. Proton NMR analysis (data not shown) showed no peak shift, containing ~1 molar equivalent of co-crystal former, ~0.04 molar equivalent of THF (~0.4% w / w). TG / DTA analysis (data not shown) showed a ~0.9% weight loss from 25°C to ~125°C, likely due to moisture, followed by an endotherm at ~132°C, with a possible ~20% weight loss at 300°C, likely due to loss of salicylic acid. These results suggest a possible co-crystal of Q203FB, but further analysis is needed to confirm.

[0552] 5.54 Type 54 (methanesulfonic acid)

[0553] 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 and crystalline and very similar to Type 3 ( Figure 77 Proton NMR analysis (data not shown) showed a peak shift containing -0.18 molar equivalents of MTBE, indicating a 1:1 stoichiometric salt formation.

[0554] 6. Evaluation of Q203 Candidates (Salts / Co-crystals)

[0555] All data generated from this study were collected in the table below and used to select candidates of particular interest.

[0556] Table 22: Evaluation of Q203 Salt / Co-crystal Solids (Classified by Co-crystal Former)

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563] 1. Pharmaceutical class, class 1 = minimal toxicity and not restricted for use as a salt-forming agent, class 2 = low toxicity and well tolerated but not naturally occurring, class 3 = potentially interesting in specific circumstances

[0564] 2.√√√=Good crystallinity, =Low crystallinity

[0565] 3. Deliquescence test: the sample was stressed at 75% RH for several days.

[0566] 4. Approximate values are listed, based on measurements obtained by adding aliquots in unbuffered water. PS: peak shift; stoi.: stoichiometric ratio of acid / API; mol.eq.: molar equivalent; RT and HT: room temperature and high temperature

[0567] From the above preliminary results, the selection was made on the basis of various criteria such as polymorphism, crystallinity, class, nature of each type (salt or potential co-crystal), specific toxicity, thermal behavior, etc.

[0568] Three candidates that have been identified by the inventors as particularly useful are the first three entries in the table below (see Table 23).

[0569] Table 23: Selection of Q203 salt / co-crystal solids (3 candidates are shown in bold as the first three entries)

[0570]

[0571]

[0572]

[0573]

[0574]

[0575] 1. Pharmaceutical class, class 1 = minimal toxicity and not restricted for use as a salt-forming agent, class 2 = low toxicity and well tolerated but not naturally occurring, class 3 = potentially interesting in specific circumstances

[0576] 2.√√√=Good crystallinity, =Low crystallinity

[0577] 3. Deliquescence test: the sample was stressed at 75% RH for several days.

[0578] 4. Approximate values are listed, based on measurements obtained by adding aliquots in unbuffered water. PS: peak shift; stoi.: stoichiometric ratio of acid / API; mol.eq.: molar equivalent; RT and HT: room temperature and high temperature

[0579] 7 Scale-up of selected salts

[0580] 7.1P-TSA(ND-6E-012-01)

[0581] API (1 g) was added to a scintillation vial containing THF (18 ml). Seeds of Form 20 solid (ND-0007E-004-16) were added to the solution, which did not dissolve. To the API solution was added pTSA (342 mg, 18 ml) dissolved in acetone. Precipitation was observed upon stirring. Proton NMR analysis after T=1 d indicated that the pTSA salt had formed (1.3 molar equivalents with an additional peak at 8.6 ppm). The solid was isolated and slurried in MTBE for 3 days. XRPD analysis of the resulting solid confirmed Form 20.

[0582] 7.2 Phosphate (ND-6E-012-02)

[0583] Concentrated H2PO4 (122.8ul) was added to a scintillation vial containing acetone (7.5ml). Seeds of Form 37 solid (ND-0007E-008-13) were added to the solution, which did not dissolve. API (1g) was added to the vial with stirring, resulting in a solid mass. This was vortexed until a thick slurry was obtained. After ~10mins at 40°C, the slurry (which did not mix well) became better mixed. A sample was taken for proton NMR analysis at T=1 day, which showed ~0.43 molar equivalents of acetone. The slurry was continued until T=5 days, after which the solid was isolated by filtration. XRPD analysis showed Form 37.

[0584] 7.3HCl(ND-6E-012-03)

[0585] Concentrated HCl (147.3 ul) was added to a scintillation vial containing THF (18 ml). Seeds of type 36 solid (ND-0007E-004-18) were added to the solution, which dissolved. The HCl / THF solution was added to the API (1 g), producing a solution. The solution was seeded again with T36 solid, which dissolved. The solution was evaporated under nitrogen for ~5 mins until the solution became cloudy. Seeds of T36 were added to give a suspension. The solution was evaporated under nitrogen with stirring. XRPD showed new type 55. Proton NMR analysis showed migration, confirming the formation of the salt.

[0586] 8. pH analysis

[0587] The pH profile of three salt candidates of Q203 (monotosylate, phosphate and HCl salts) was evaluated. The HPLC method is detailed in Section 2.3.6.

[0588] 8.1 HPLC method check

[0589] The suitability of the HPLC method was first checked, and the working range for Q203 was determined to be 0.0625 mg / mL to 0.5 mg / mL. (Note that the diluent was changed to methanol, as the material was insoluble in the diluents listed in the provided methods). Samples from the solubility experiments were diluted as needed to bring the API concentration within the working concentration range. A linearity of R² = 0.999 was observed, indicating a very good fit (data not shown).

[0590] 8.2 pH Solubility Analysis

[0591] As described in Sections 2.3.6 and 2.3.7, the solubility of the salt at pH 1, 4.5, 6.8, and 7.5 was determined. pTSA remained in the same form after slurrying in pH 1 buffer and exhibited an average solubility of ˜0.33 mg / mL. However, at pH 4.5 and above, the pTSA salt transformed into Form 28, which was found to be the polymorph of the free base from XRPD and proton NMR analysis and exhibited very limited solubility (<0.00037 mg / ml), see Table 25.

[0592] The same was true for the phosphate salt at pH 4.5 and higher, but upon slurrying in pH 1 buffer, it transformed into the new HCl salt Form 56. Form 56 was also observed in all solids isolated from the HCl solubility experiments. The maximum solubility was observed for the HCl salt Form 56 at pH 1 at -5.58 mg / mL (sample LMCG-0007E-004-09_1 was not included because this number was significantly lower than the other three values and there may have been dilution errors). Selected results (XRPD traces of solids isolated after pH solubility experiments) are also shown in Figure 78 middle.

[0593] Table 24. Results of pH Solubility Analysis

[0594]

[0595]

[0596]

[0597] 1 Possible dilution errors

[0598] 8.3 Conclusion of pH situation analysis

[0599] The pTSA salt remained stable in pH 1 buffer with a solubility of ˜0.33 mg / mL, but converted to the free base (form 28) with lower solubility at pH 4.5 and above. The phosphate salt was unstable in any pH buffer, converting to form HCl 56 at pH 1 and to the free base at pH 4.5 and above. The form HCl salt 36 converted to the novel form HCl salt 56 in all buffers tested.

[0600] The three candidates were found to have improved solubility compared to the free base and the current candidate (xylene sulfonate).It should be noted that below pH 4.5 the phosphate and pTSA showed a shift towards the free base, indicating some degree of instability.

[0601] On the other hand, the HCl salt showed higher solubility and no conversion to the free base was observed under the conditions tested. This can be explained by lower wettability and kinetic factors (time, stirring effects).

[0602] 9 Conclusion

[0603] Using 37 salt-forming agents, Q203 was screened in various solvent systems. More than 50 new types were observed, showing that Q203 has a very high tendency to produce new types (polymorphs of the free base, but mainly salts and potential co-crystals).

[0604] These novel formulas have been analyzed by different analytical techniques (eg XRPD, proton NMR, aqueous solubility where sufficient material is available).

[0605] The selection of three salt candidates for further pH situation analysis is made on the basis of multiple criteria, such as polymorphic situation, crystallinity, classification, the nature of each type (salt or potential co-crystal), specific toxicity, thermal behavior, etc. All potential co-crystals are not considered, because further characterization is required to confirm the nature of these solids (whether they are co-crystals). The pharmaceutical category of the counter ion has also been taken into account (HCl and phosphoric acid are considered to be Class 1, which are defined as having minimal toxicity and are not restricted to be used as salt-forming agents). Monotoluenesulfonate has also been selected, although it is considered to be Class 2 (low toxicity and good tolerance, but not naturally occurring). By comparison between monotoluenesulfonate and ditoluenesulfonate, monotoluenesulfonate shows lower toxicity because, in contrast to ditoluenesulfonate, there is only one molecule of counter ion for each API molecule.

[0606] It should be noted that other candidates may be of interest for further development but require further investigation and comparison with these three candidates.

[0607] The three candidates were found to have improved solubility compared to the free base and the xylene sulfonate salt. It should be noted that below pH 4.5 the phosphate salt and pTSA showed a shift towards the free base, indicating some instability.

[0608] On the other hand, the HCl salt showed a higher solubility and no conversion to the free base was observed under the conditions tested. This can be explained by low wettability, especially above pH 4, and kinetic factors (time, stirring effects).

[0609] Appendix 1:

[0610] Table 25: Summary of observed Q203 solids (classified by eutectic former)

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619] Example 3

[0620] Stability testing was performed on 6-chloro-2-ethyl-N-(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide (Q203)-ditoluenesulfonate Form A. More specifically, samples of Q203-ditoluenesulfonate Form A were exposed to an environment at 60% RH (relative humidity) and 25°C for a period of time between 6 months and 60 months. In addition, additional stability testing was performed using some samples of Q203-ditoluenesulfonate Form A under accelerated conditions (40°C-75% relative humidity (RH)). These experiments under accelerated conditions were performed for a period of up to 6 months. Subsequently, the samples were analyzed by HPLC and checked for impurities. It was confirmed that under 25°C and 60% RH, Q203-ditoluenesulfonate Form A remained stable and did not decompose or otherwise deteriorate, with only minor impurities being identified in the corresponding HPLC chromatogram (chromatogram trace not shown). The results are summarized in the following table:

[0621] Table 26: Stability results of Form A of Q203-ditosylate at 25°C / 60% RH

[0622]

[0623] As can be seen, the purity remained >98% and did not show any signs of decomposition or deterioration.

[0624] Furthermore, in experiments under accelerated conditions, there was no decomposition over a period of up to 6 months, during which time the samples still showed a purity of >98% (data not shown).

[0625] From these data, it can be concluded that Q203-ditosylate Form A is stable under long-term storage conditions of 25°C and 60% RH for up to 60 months and under accelerated conditions of 40°C and 75% RH for up to 6 months.

Claims

1. The compound 6-chloro-2-ethyl-N-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide ditoluenesulfonate, which has the following structure: And further using Cu-K α -Radiation (Cu-K α The X-ray powder diffraction (XRPD) spectrum obtained by irradiation has 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.

2. The compound according to claim 1, which has an XRPD spectrum as shown below: 。 3. The compound according to claim 1 or 2, wherein the differential scanning calorimetry (DSC) thermogram thereof shows a single endothermic peak with an onset temperature of 235°C to 237°C.

4. A compound according to claim 1 or 2, produced by a method comprising the steps of: - Provides 6-chloro-2-ethyl- in a stoichiometric ratio of 1:2 in any order N -(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide free base and p-toluenesulfonic acid; - mixing and dissolving them in a suitable solvent or solvent mixture; - evaporating the solvent or solvent mixture. 5 . The compound according to claim 4 , wherein the suitable solvent or solvent mixture is isopropyl alcohol (IPA), tetrahydrofuran (THF), acetone or a mixture of THF and acetone.

6. A method for producing the compound according to any one of claims 1 to 5, comprising the steps of: - Provides 6-chloro-2-ethyl- in a stoichiometric ratio of 1:2 in any order N -(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide free base and p-toluenesulfonic acid; - mixing and dissolving them in a suitable solvent or solvent mixture; - evaporating the solvent or solvent mixture.

7. The method according to claim 6, wherein the suitable solvent or solvent mixture is isopropyl alcohol (IPA), tetrahydrofuran (THF), acetone or a mixture of THF and acetone.

8. 6-Chloro-2-ethyl- N -(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monoacid addition salt, which is 6-chloro-2-ethyl- N -(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monohydrochloride, 6-chloro-2-ethyl- N -(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monophosphate or 6-chloro-2-ethyl- N -(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monotoluenesulfonate, wherein The monoacid addition salt is 6-chloro-2-ethyl- N -(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monohydrochloride, which is used in the treatment of Cu-K α -Radiation (Cu-K α The X-ray powder diffraction (XRPD) spectrum obtained by irradiation has the following peaks: 6.4° 2θ, 8.1° 2θ, 16.2° 2θ, 17.2° 2θ, 24.3° 2θ, and 25.0° 2θ, ± 0.2° 2θ; or The monoacid addition salt is 6-chloro-2-ethyl- N -(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monophosphate, which is used in the treatment of Cu-K α -Radiation (Cu-K α The X-ray powder diffraction (XRPD) spectrum obtained by irradiation has the following peaks: Or The monoacid addition salt is 6-chloro-2-ethyl- N -(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monotoluenesulfonate, which is used in the treatment of Cu-K α -Radiation (Cu-K α The X-ray powder diffraction (XRPD) spectrum obtained by irradiation has 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, ± 0.2° 2θ.

9. The monoacid addition salt according to claim 8, wherein the monoacid addition salt is 6-chloro-2-ethyl- N -(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monohydrochloride, which has the XRPD spectrum shown below: 。 10. The monoacid addition salt according to claim 8, wherein the monoacid addition salt is 6-chloro-2-ethyl- N -(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monophosphate, which has the XRPD spectrum shown below: 。 11. The mono-acid addition salt according to claim 8, wherein the mono-acid addition salt is 6-chloro-2-ethyl-N-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)benzyl)imidazo[1,2-a]pyridine-3-carboxamide monotosylate, which has an XRPD spectrum as shown below: 。 12. A method for preparing the monoacid addition salt according to any one of claims 8 to 11, comprising the steps of: - Provides a 1:1 stoichiometric ratio of 6-chloro-2-ethyl- N -(4-(4-(4-(trifluoromethoxy)phenyl)piperidin-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; - mixing and dissolving them in a suitable solvent or solvent mixture; - evaporating the solvent or solvent mixture.

13. The process according to claim 12, wherein the suitable solvent or solvent mixture is isopropyl alcohol (IPA), methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), acetone or a mixture of THF and acetone.

14. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 5 or a monoacid addition salt according to any one of claims 8 to 11, and at least one pharmaceutically acceptable carrier, excipient and / or diluent.

15. The composition of claim 14, further comprising at least one other pharmaceutically active agent.

16. Use of a compound according to any one of claims 1 to 5 or a monoacid addition salt according to any one of claims 8 to 11 in the preparation of a medicament for treating bacterial infection.

17. The use according to claim 16, wherein the bacterial infection is tuberculosis or Buruli ulcer.

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