HK40090302A - Solid forms of pralsetinib - Google Patents

Description

solid form of pralatinib

Cross-references to related applications

This application claims the benefit and priority of U.S. Provisional Patent Application No. 63/032,121, filed May 29, 2020, and U.S. Provisional Patent Application No. 63/047,353, filed July 2, 2020, the disclosures of which are hereby incorporated by reference in their entirety for all purposes.

Technical Field

This disclosure relates to solid forms and salts of certain pralatinib that can be used to prepare pharmaceutical compositions and to selectively inhibit receptor tyrosine kinases that rearrange during transfection (RET).

Background Technology

Targeting oncogenic driver kinases with specially tailored inhibitors has transformed the management of various hematologic malignancies and solid tumors. Receptor tyrosine kinases that rearrange during transfection (RET) are oncogenic drivers activated in multiple cancers, including non-small cell lung cancer (NSCLC), medullary thyroid carcinoma (MTC), and papillary thyroid carcinoma (PTC). Oncogenic RET alterations promote ligand-independent constitutive RET kinase activation, thereby driving tumorigenesis (e.g., RET fusions are seen in 10%–20% of PTC, 1%–2% of NSCLC, and many other cancer subtypes).

Praltinib is a potent and selective RET inhibitor designed to overcome these limitations by efficiently and selectively targeting oncogenic RET alterations, including the most prevalent RET fusions and certain RET activating mutations. Praltinib is also known as (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexanecarboxamide and has the following chemical structure:

In early clinical trials, pralatinib attenuated RET signaling and produced durable clinical responses in patients with RET-altered NSCLC and MTC, without significant off-target toxicity, providing preliminary validation of the principle for highly selective RET targeting in RET-driven malignancies.

Chemical compounds can typically form one or more different salts and/or solid forms, including amorphous and polymorphic crystalline solid forms. The salts and solid forms of active pharmaceutical ingredients (APIs) can have different properties. It is necessary to discover and select appropriate salts and/or solid forms (e.g., crystalline salts of APIs) of API compounds suitable for developing pharmaceutically acceptable dosage forms to treat a variety of diseases.

Pralsetinib is disclosed as one of many RET inhibitor compounds in patent publication WO2017/079140. A clinical trial under NCT03037385, entitled "Phase 1/2 Study of the Highly-selective RET Inhibitor, Pralsetinib (BLU-667), in Patients With Thyroid Cancer, Non-Small Cell Lung Cancer, and Other Advanced Solid Tumors (ARROW)," was also mentioned. However, therapeutic compounds often exist in various solid forms with different properties. It remains necessary to identify solid forms of pralatinib that can be used to prepare therapeutic compositions, including oral dosage forms.

Summary of the Invention

In a first embodiment, the present invention relates to a solid form and a method for selectively producing a polymorph of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide (compound (I)) in the form of a free base solid.

The presence of compound (I) in solid form can be identified by one or more techniques, including DSC, TGA, DVS and XRPD.

Figure 1A is a schematic diagram showing the three crystalline solid forms of the free base of the identified and characterized compound (I): the anhydrous solid form is designated as solid form A, the hydrated solid form is designated as solid form C, and the dehydrated solid form of solid form C is designated as solid form B. After drying at 50°C, solid form C transforms into the dehydrated form, solid form B.

In some embodiments, the free base solid form may be a first anhydrous solid form of the free base of pralatinib. The first pralatinib free base solid form designated as solid form A can be identified by one or more of the following characteristics: (a) an X-ray powder diffraction (XRPD) pattern containing characteristic diffraction peaks at 2θ angles of approximately (±0.2 degrees) 5.0, 9.7, 12.7, 13.6, and 16.1; (b) a differential scanning calorimetry (DSC) thermogram showing an endothermic event observed at approximately 205 °C (±0.2 degrees); and/or (c) a reversible mass change of approximately 10% between 2% and 95% relative humidity based on dynamic vapor adsorption (DVS).

The solid form A of pralatinib can be the crystalline anhydrous solid form of the free base of pralatinib. The solid form A of the free base of compound (I) can exhibit an XRPD pattern with characteristic peaks expressed in 2θ degrees of approximately the following (±0.2): 5.0, 9.7, 12.7, 13.6, and 16.1, which correspond to lattice spacings (Å ±0.2) of 17.8, 9.1, 7.0, 6.5, and 5.5, respectively. A further feature of the solid form A of the free base of compound (I) is an XRPD with additional diffraction at angles (2θ ±0.2) of 6.8, 19.2, 19.5, and 23.1, which correspond to lattice spacings (Å ±0.2) of 13.0, 4.6, 4.5, and 3.8, respectively. Figures 3A, 20B, and 22A show the XRPD patterns obtained from samples of the solid form A of the free base of pralatinib. In some embodiments, the solid form of the free base of compound (I) is an XRPD pattern A comprising peaks at the same or substantially the same angles (2θ ± 0.2) as shown in Table 1A, and corresponding lattice spacings (Å ± 0.2) as follows:

Table 1A

2θ (degrees) Lattice spacing (angstroms) relative strength 4.95 17.82 62 9.74 9.07 29 12.71 6.96 48 13.62 6.50 100 16.06 5.52 39

In some embodiments, the solid form A of the free base of compound (I) is characterized by a differential scanning calorimetry (DSC) thermogram (±0.2 degrees) showing an endothermic event observed at approximately 205 °C; and/or a reversible mass change of approximately 10% between 2% and 95% relative humidity based on dynamic vapor adsorption (DVS). Figure 3B shows a DSC/TGA thermogram, and Figure 20A shows a DVS isotherm obtained from a sample of the solid form A of the free base of pralatinib. The solid form A of the free base of pralatinib is characterized by a DSC thermogram showing an endothermic event observed at approximately 205 °C (±0.2 degrees). The solid form A of the free base of pralatinib exhibits a reversible mass change of approximately 10% between 2% and 95% relative humidity based on DVS. The solid form A of the free base of compound (I) can be obtained by a method comprising steps selected from the group consisting of: (a) forming a slurry in an alcohol, acetone, or ACN; (b) evaporation crystallization and cooling crystallization in IPA and 1-propanol; and (c) recrystallization in acetone:water. The solid form A of pralatinib can also be obtained by heating a sample of the free base of pralatinib in solid form B to at least about 190°C under conditions suitable for forming solid form A (e.g., in an alcohol, slurry such as IPA); or heating a sample of the free base of pralatinib in solid form C to at least about 190°C under conditions suitable for forming solid form A (e.g., in an alcohol, acetone, or ACN).

In some embodiments, the free base solid form may be a second anhydrous solid form of the free base of pralatinib. The second pralatinib free base solid form designated as solid form B can be identified by one or more of the following characteristics: (a) an X-ray powder diffraction (XRPD) pattern containing characteristic diffraction peaks at 2θ angles of approximately (±0.2 degrees) 5.9, 8.8, 11.6, 14.7, and 19.5; and/or (b) a DSC thermogram including endothermic initiation at approximately 149 °C (±0.2 degrees), followed by exothermic initiation at 162 °C (±0.2 degrees), and melting initiation at approximately 205 °C (±0.2 degrees).

The solid form B of the free base of compound (I) exhibits an XRPD pattern with characteristic peaks expressed in 2θ degrees of approximately the following (±0.2): 5.9, 8.8, 11.6, 14.7, and 19.5, which correspond to lattice spacings (Å ±0.2) of 15.0, 10.0, 7.6, 6.0, and 4.6, respectively. A further feature of the solid form B of the free base of compound (I) is X-ray powder diffraction (XRPD) with additional diffraction at angles of 17.0, 17.6, and 22.2 (2θ ±0.2), which correspond to lattice spacings (Å ±0.2) of 5.2, 5.0, and 4.0, respectively. Figures 4A, 22B, and 23B show the XRPD patterns obtained from samples of the solid form B of the free base of pralatinib. In some embodiments, the solid form of the free base of compound (I) is an XRPD pattern B comprising peaks at the same or substantially the same angles (2θ ± 0.2) as those in Table 2A, and corresponding lattice spacings (A ± 0.2) as follows:

Table 2A

2θ (degrees) Lattice spacing (angstroms) relative strength 5.89 14.99 100 8.81 10.03 28 11.58 7.64 33 14.73 6.01 twenty three 19.45 4.56 13

The anhydrous solid form B of the free base of pralatinib is characterized by a DSC thermogram including an endothermic reaction starting at approximately 149 °C (±0.2 °C), followed by an exothermic reaction starting at 162 °C (±0.2 °C) and a melting reaction starting at approximately 205 °C (±0.2 °C). The solid form B of the free base of compound (I) can be a solid form obtained by a method comprising heating a sample of the free base of pralatinib in solid form C to approximately 150 °C. Figure 4B shows the DSC and TGA thermograms of the sample of the free base of pralatinib in solid form C, used to obtain the XRPD pattern shown in Figure 4A. Figure 23A shows the DVS isotherm obtained from the sample of the free base of pralatinib in solid form B.

In some embodiments, the free base solid form may be the hydrated solid form of the free base of pralatinib. The hydrated pralatinib free base solid form designated as solid form C can be identified by one or more of the following characteristics: (a) an X-ray powder diffraction (XRPD) pattern containing characteristic diffraction peaks at 2θ angles of approximately (±0.2 degrees) 5.8, 8.7, 11.0, 13.6, and 20.2; (b) a differential scanning calorimetry (DSC) thermogram initiating at 122° (±0.2 degrees), 127° (±0.2 degrees), and 206° (±0.2 degrees); and/or (c) a TGA with approximately 3 wt.% observed mass loss.

The solid form C of the free base of compound (I) can exhibit an XRPD pattern with characteristic peaks expressed in 2θ degrees of approximately the following (±0.2): 5.8, 8.7, 11.0, 13.6, and 20.2, which correspond to lattice spacings (Å ±0.2) of 15.2, 10.2, 8.1, 6.5, and 4.4, respectively. A further feature of the solid form C of the free base of compound (I) is X-ray powder diffraction (XRPD) with additional diffraction at angles (2θ ±0.2) of 11.6, 14.5, 22.2, and 23.2, which correspond to lattice spacings (Å ±0.2) of 7.6, 6.1, 4.0, and 3.8, respectively. The solid form C of compound (I) can have the XRPD pattern shown in Figure 5A. Figures 5A, 21B, and 22C show XRPD patterns obtained from the sample of solid form C of the free base of pralatinib. In some embodiments, the solid form of the free base of compound (I) is an XRPD pattern C showing XRPD peaks at the same or substantially the same angle (2θ ± 0.2) and corresponding lattice spacing (A ± 0.2) as shown in Table 3A:

Table 3A

2θ (degrees) Lattice spacing (angstroms) relative strength 5.81 15.21 100 8.69 10.17 32 10.96 8.06 60 13.56 6.52 48 20.19 4.39 29

The solid form of pralatinib can be described as a crystalline hydrated solid form of the free base of pralatinib, as described in solid form C, which has certain characteristics as determined by DSC and/or TGA analysis. In some embodiments, the solid form C of the free base of compound (I) is characterized by differential scanning calorimetry (DSC) thermograms initiating at 122°, 127°, and 206° (e.g., Figure 5B). The TGA of the solid form C of the free base of compound (I) may have an associated observed mass loss of approximately 3 wt.% (e.g., Figure 5B). The crystalline hydrated solid form of the free base of pralatinib is characterized by DSC thermograms showing multiple endothermic events observed at approximately 122 (±0.2°), 127 (±0.2°), and 206 (±0.2°). Figure 5B shows the DSC/TGA thermograms obtained from a sample of the solid form C of the free base of pralatinib. Figure 21A shows the DVS isotherm obtained from a sample of the free base of pralatinib in solid form C. The crystalline anhydrous solid form of the free base of pralatinib exhibits a reversible mass change of approximately 1.4% based on DVS between 2% and 95% relative humidity. The solid form C of the free base of pralatinib can be obtained by forming a slurry from a sample of the free base of pralatinib in anhydrous solid form and then recrystallizing it (e.g., forming a slurry of the free base of pralatinib in water and methanol, followed by recrystallization in acetone/IPA/methanol and water to obtain the hydrated crystalline solid form C of the free base of pralatinib).

The applicant has discovered numerous additional solid forms of the free base of pralatinib. Figure 1B is a schematic diagram illustrating the additional solid forms of the free base of compound (I) besides the solid form shown in Figure 1A, and the methods that can be used to prepare these solid forms. Figure 2 is a table summarizing the characteristics of the solid forms of the free base of pralatinib.

Solid forms D, F, and G are characterized by XRPD patterns D (Fig. 6), F (Fig. 7A), and G (Fig. 8A), respectively, and are obtained using a methanol:chloroform 1:1 slurry method. The free base of pralatinib in solid form D can be converted into solid form F (desolvent 1 of solid form D) or solid form G (desolvent 2 of solid form D) by drying in a vacuum and heating to 50°C. These solid forms can then be further converted into anhydrous solid form B (e.g., by heating to 140°C).

Solid forms I, O, and N are characterized by XRPD patterns I (Fig. 10A), O (Fig. 16), and N (Fig. 15), respectively, and are obtained using the THF method. The free pralatinib base in solid form I is characterized by XRPD pattern I and can be obtained by recrystallization of the free pralatinib base in THF/heptane as an antisolvent, followed by slow cooling in THF (producing a mixture with solid form O). Solid form O is characterized by XRPD pattern O and can be obtained by slow cooling in THF, resulting in a mixture with solid form I. Solid form N is characterized by XRPD pattern N and can be obtained by rapid cooling in THF.

Solid forms J, K, and M are characterized by XRPD patterns J (Fig. 11), K (Fig. 12A), and M (Fig. 14A), respectively, and are obtained using various antisolvent methods. The free base of pralatinib in solid form J is characterized by XRPD pattern J and can be obtained by recrystallization from an antisolvent in THF/cyclohexane. Solid form K is characterized by XRPD pattern K and can be obtained by recrystallization from an antisolvent in DMSO/water. Solid form M is characterized by XRPD pattern M and can be obtained by further drying the solid form K sample obtained by antisolvent crystallization from DMSO:water.

Solid forms L and P are characterized by XRPD patterns L (Fig. 13A) and P (Fig. 17), respectively, and are obtained using various antisolvent methods. The free base of pralatinib in solid form L is characterized by XRPD pattern L and can be obtained by recrystallization from an antisolvent in methanol/water. Solid form P is characterized by XRPD pattern P and can be obtained by rapid cooling in methanol to 0°C, followed by stagnant cooling to -20°C.

The solid form Q is characterized by an XRPD pattern Q (Fig. 18A) and can be obtained by cooling in 1,4-dioxane.

The free base of pralatinib can also form a solid form H, characterized by an XRPD pattern H (Figure 9A).

Solid form E can be obtained from solid form B (anhydrous) in slurry in MtBE.

Amorphous forms of the free base of pralatinib are also provided, including compositions providing the XRPD pattern of Figure 19A.

In a second embodiment, the invention also relates to salt forms of compounds (I) in anhydrous or aqueous form, and salt forms of compounds (I) in various polymorphic solid forms of these salts. Salts of compound (I) include certain salt forms formed using counterions selected from the group consisting of: benzenesulfonic acid (BSA) (e.g., in solid form characterized by XRPD pattern 18-A or 18-B as shown in FIG. 44), methanesulfonic acid (MSA) (e.g., in solid form of a pralatinib MSA salt composition, characterized by XRPD pattern 2-B in FIG. 43A, 2-A or 2-B in FIG. 43C, 2-C in FIG. 43E, or 2-D in FIG. 43D), hydrobromic acid (HBr) (e.g., in solid form characterized by XRPD pattern 19-A as shown in FIG. 45A, pattern 19-A or 19-B or 19-C as shown in FIG. 45C, or pattern 19-C as shown in FIG. 45D), or nitric acid (HNO3) (e.g., in solid form characterized by XRPD pattern 20-A as shown in FIG. 46A). FIG. 3-A provides an XRPD pattern obtained from the solid form 3-A of pralatinib citrate. Figures 40A and 40B provide XRPD patterns obtained from various solid forms of praltinib fumarate (i.e., XRPD patterns from samples of solid forms 4-A and 4-C in Figure 40A and XRPD patterns from samples of solid forms 4-B and 4-D of praltinib fumarate). Figure 41 shows an XRPD pattern obtained from a sample of saccharin salt of praltinib in solid form 6-A, designated herein. Figure 42 shows an XRPD pattern obtained from solid form 7-A of praltinib gentianate. Figure 32 shows an XRPD pattern obtained from solid form 8-A of praltinib maleate. Figure 33A shows an XRPD pattern obtained from solid form 9-A of praltinib oxalate. Figure 34A shows an XRPD pattern obtained from solid form 10-A of praltinib salicylate. Figures 29A and 30 show XRPD patterns obtained from solid forms 11-A and 11-B (respectively) of pralatinib glutarate. Figures 35A and 35G show XRPD patterns obtained from solid forms 12-A and 12-G (respectively) of pralatinib sulfate. Figure 36A shows an XRPD pattern obtained from solid form 13-A of pralatinib tartrate. Figure 36E shows XRPD patterns obtained from solid forms 13-A, 13-B, and 13-C of pralatinib tartrate. Figure 28A shows an XRPD pattern obtained from solid form 14-A of pralatinib phosphate. Figure 31A shows an XRPD pattern obtained from solid form 15-A of pralatinib succinate. Figure 37A shows an XRPD pattern obtained from solid form 16-A of pralatinib urea. Figure 47 shows the XRPD pattern obtained from the solid form 17-A of quercetin dihydrate (QD) salt of pralatinib.

In some embodiments, the hydrochloride salt of pralatinib may be in a crystalline solid form selected from HCl salts comprising solid form 5-A, solid form 5-B, and/or solid form 5-C (e.g., obtained by drying the solid form 5-B of the HCl salt of compound (I)). Pralatinib hydrochloride (HCl) salt may be prepared in a solid form characterized by XRPD pattern 5-A in Figure 27A, XRPD pattern 5-B in Figure 27C, and XRPD pattern 5-C in Figure 27E.

For example, the solid form of pralitinib HCl salt designated as solid form 5-A can be identified by X-ray powder diffraction (XRPD) patterns containing characteristic diffraction peaks at 2θ angles of approximately (±0.2 degrees) 5.0°, 6.1°, 9.1°, 9.9°, and 14.7°. The solid form 5-A of the HCl salt of compound (I) exhibits an XRPD pattern with characteristic peaks expressed in 20 degrees of approximately (±0.2 degrees): 5.0°, 6.1°, 9.1°, 9.9°, and 14.7°, corresponding to lattice spacings of 17.6, 14.5, 9.7, 9.0, and 6.0 Å (±0.2 Å), respectively. A further characteristic of the solid form 5-A of the HCl salt of compound (I) is X-ray powder diffraction (XRPD) with additional diffraction at angles (2θ ± 0.2) of 13.8, 15.3, 17.2, 18.1, 19.6, 20.3, 20.7, 21.8, 24.2, 25.6 and 26.3, respectively, corresponding to lattice spacings (Å ± 0.2) of 6.4, 5.8, 5.2, 4.9, 4.5, 4.4, 4.3, 4.1, 3.7, 3.5 and 3.4.

The solid form 5-A of the HCl salt of compound (I) may have the XRPD pattern shown in Figure 27A. In some embodiments, the solid form of the hydrochloride salt of compound (I) is an XRPD pattern 5-A having peaks at the same or substantially the same angle (2θ ± 0.2) as shown in Table 17A and corresponding lattice spacings (A ± 0.2) as follows:

Table 17A

In some embodiments, the DSC of the solid form of the HCl salt of compound (I) 5-A is characterized by a very broad endothermic effect, wherein the initial temperature is 70.9°C and the endothermic effect is rapid at 240.5°C.

For example, the solid form of praltinib HCl salt designated as solid form 5-B can be identified by X-ray powder diffraction (XRPD) patterns containing characteristic diffraction peaks at 2θ angles of approximately (±0.2 degrees) 6.1, 8.9, 9.5, 15.0, and 16.6. The solid form 5-B of the HCl salt of compound (I) exhibits an XRPD pattern with characteristic peaks expressed in 2θ degrees of approximately (±0.2) the following: 6.1, 8.9, 9.5, 15.0, and 16.6, corresponding to lattice spacings of 14.5, 9.9, 9.3, 5.9, and 5.3 Å (±0.2 Å), respectively. A further feature of the solid form 5-B of the HCl salt of compound (I) is X-ray powder diffraction (XRPD) with additional diffraction at angles of 17.2, 17.9, 18.4, 19.8, 25.8 and 28.3 (2θ ± 0.2), which correspond to lattice spacings of 5.2, 5.0, 4.8, 4.5, 3.5 and 3.3 (Å ± 0.2), respectively.

The solid form 5-B of the HCl salt of compound (I) may have the XRPD pattern shown in Figure 27C. In some embodiments, the solid form of the hydrochloride salt of compound (I) is an XRPD pattern 5-B with peaks at the same or substantially the same angle (2θ ± 0.2) as in Table 18A and corresponding lattice spacings (A ± 0.2) as follows:

Table 18A

2θ (degrees) Lattice spacing (angstroms) relative strength 6.10 14.47 56 8.90 9.93 100 9.54 9.26 twenty two 15.02 5.89 6 16.64 5.32 15 17.19 5.15 7 17.89 4.95 13 18.41 4.82 8 19.80 4.48 6 25.82 3.45 twenty one 26.83 3.32 36

In some embodiments, the TGA/DSC of the solid form of the HCl salt of compound (I) 5-B is characterized by an initial mass loss of about 3 wt.% (e.g., 3.4 wt.%), associated with extensive endothermicity, wherein the initial temperature is about 89 °C (e.g., 88.7 °C) and the melting initiation is about 244 °C (e.g., 244.2 °C).

For example, the solid form of praltinib HCl salt designated as solid form 5-C can be identified by X-ray powder diffraction (XRPD) patterns containing characteristic diffraction peaks at 2θ angles of approximately (±0.2 degrees) 6.4°, 8.5°, 8.9°, 9.6°, and 17.3°. The solid form 5-C of the HCl salt of compound (I) exhibits XRPD patterns with characteristic peaks expressed in 2θ degrees of approximately (±0.2) the following: 6.4°, 8.5°, 8.9°, 9.6°, and 17.3°, corresponding to lattice spacings of 13.9, 10.4, 9.9, 9.2, and 5.1 Å, respectively. A further feature of the solid form 5-C of the HCl salt of compound (I) is X-ray powder diffraction (XRPD) with additional diffraction at angles of 11.5, 16.7 and 19.2 (2θ ± 0.2), which correspond to lattice spacings of 7.7, 5.3 and 4.6 (Å ± 0.2), respectively.

The solid form 5-C of the HCl salt of compound (I) may have the XRPD pattern shown in Figure 27E. In some embodiments, the solid form of the hydrochloride salt of compound (I) is an XRPD pattern 5-C having peaks at the same or substantially the same angle (2θ ± 0.2) as in Table 18C and corresponding lattice spacings (A ± 0.2) as follows:

Table 18C

2θ (degrees) Lattice spacing (angstroms) relative strength 5.99 14.75 6 6.38 13.85 42 8.49 10.40 55 8.92 9.91 100 9.60 9.21 48 11.51 7.68 9 12.70 6.97 8 15.89 5.57 5 16.74 5.29 twenty one 17.34 5.11 28 19.19 4.60 9 21.00 4.23 7 26.88 3.31 7

In some embodiments, the TGA of the solid form 5-C of the HCl salt of compound (I) is characterized by an initial mass loss of 3.4 wt.% and a second mass loss event of 2 wt.%. In some embodiments, the DSC of the solid form 5-C of the HCl salt of compound (I) is characterized by starting temperatures of 86.8 °C, 224.1 °C, and 241.7 °C.

Attached Figure Description

Figure 1A is a schematic diagram of some anhydrous and hydrated solid forms of the free base of pralatinib.

Figure 1B is a schematic diagram showing the additional solid form of the free base of pralatinib.

Figure 2 is a table summarizing the characteristics of various solid forms of the free base of pralatinib.

Figure 3A shows the XPPD pattern designated as pattern A, which was obtained from the free base of praltinib designated as solid form A, 4-40°2θ.

Figure 3B shows the DSC and TGA thermograms of the substance tested in Figure 3A, obtained from a sample designated as solid form A of pralatinib free base.

Figure 4A shows the XPPD pattern designated as pattern B, which was obtained from the free base of praltinib designated as solid form B.

Figure 4B shows the DSC and TGA thermograms obtained from the free base of pralatinib in solid form, designated as solid form B.

Figure 5A shows the XPPD pattern designated as pattern C, which was obtained from the free base of praltinib designated as solid form C, 4-40°2θ.

Figure 5B shows the DSC and TGA thermograms of the substance tested in Figure 4A, obtained from the free base of praltinib designated as solid form C.

Figure 6 shows the XPPD pattern designated as pattern D, which was obtained from the free base of praltinib designated as solid form D.

Figure 7A shows the XPPD pattern designated as pattern F, which was obtained from the free base of praltinib designated as solid form F.

Figure 7B shows the DSC and TGA thermograms of the substance tested in Figure 7A, obtained from the free base of praltinib designated as solid form F.

Figure 8A shows the XPPD pattern designated as pattern G, which was obtained from the free base of praltinib designated as solid form G.

Figure 8B shows the DSC and TGA thermograms of the substance tested in Figure 8A, obtained from the free base of praltinib designated as solid form G.

Figure 9A shows the XPPD pattern designated as pattern H, which was obtained from praltinib HCl salt designated as solid form H.

Figure 9B shows the DSC and TGA thermograms of the substance tested in Figure 9A, obtained from praltinib HCl salt designated as solid form H.

Figure 10A shows the XPPD pattern designated as Pattern I, which was obtained from pralatinib HCl salt designated as Solid Form I.

Figure 10B shows the DSC and TGA thermograms of the substance tested in Figure 10A, obtained from praltinib HCl salt designated as solid form I.

Figure 11 shows the XPPD pattern designated as pattern J, which was obtained from the free base of praltinib designated as solid form J.

Figure 12A shows the XPPD pattern designated as pattern K, which was obtained from the free base of pralatinib designated as solid form K.

Figure 12B shows the DSC and TGA thermograms of the substance tested in Figure 12A, obtained from the free base of praltinib designated as solid form K.

Figure 13A shows the XPPD pattern designated as pattern L, which was obtained from the free base of praltinib designated as solid form L.

Figure 13B shows the DSC and TGA thermograms of the substance tested in Figure 13A, obtained from the free base of praltinib designated as solid form L.

Figure 13C shows an overlay of pattern C, designated as originating from solid form C, and pattern L, obtained from the free base of pralatinib, designated as solid form L, with XPPD pattern.

Figure 14A shows the XPPD pattern designated as pattern M, which was obtained from the free base of praltinib designated as solid form M.

Figure 14B shows the DSC and TGA thermograms of the substance tested in Figure 14A, obtained from the free base of praltinib designated as solid form M.

Figure 15 shows the XPPD pattern designated as pattern N, which was obtained from the free base of praltinib designated as solid form N.

Figure 16 shows the XPPD pattern designated as pattern O, which was obtained from the free base of praltinib designated as solid form O.

Figure 17 shows the XPPD pattern designated as pattern P, which was obtained from the free base of praltinib designated as solid form P.

Figure 18A shows the XPPD pattern designated as pattern Q, which was obtained from the free base of praltinib designated as solid form Q.

Figure 18B shows the DSC and TGA thermograms of the substance tested in Figure 18A, obtained from the free base of praltinib designated as solid form Q.

Figure 19A shows the XPPD pattern obtained from the amorphous pralatinib free base.

Figure 19B shows the DSC and TGA thermograms of the substance tested in Figure 19A, obtained from the free base of amorphous pralatinib.

Figure 20A shows the DVS isotherm of a sample of free pralatinib base in solid form A.

Figure 20B shows the XRPD patterns obtained from the sample of free pralatinib base before (1) and after (2) the DVS isotherm measurement shown in Figure 20A.

Figure 21A shows the DVS isotherm of a sample of free pralatinib base in solid form C.

Figure 21B shows the XRPD patterns obtained from the sample of free pralatinib base before (1) and after (2) the DVS isotherm measurement shown in Figure 21A.

Figure 22A shows the XRPD patterns obtained from a sample of free pralatinib base in solid form A before (1) and after (2) a week of humidity exposure (75% RH, at 40°C).

Figure 22B shows the XRPD patterns obtained from samples of free pralatinib base in solid form B before (1) and after (2) a week of humidity exposure (75% RH, at 40°C).

Figure 22C shows the XRPD patterns obtained from a sample of free pralatinib base in solid form C before (1) and after (2) a week of humidity exposure (75% RH, at 40°C).

Figure 23A shows the DVS isotherm obtained from the sample of free pralatinib base in solid form B.

Figure 23B shows the XRPD patterns obtained from the sample of free pralatinib base in solid form C before (top trace) and after (bottom trace) the DVS measurement shown in Figure 23A.

Figure 24 is a table summarizing some physical characteristics of the solid forms obtained from various pralatinib salts.

Figure 25 is a table summarizing some physical characteristics of the solid forms obtained from various pralatinib salts.

Figure 26A is a table summarizing some physical characteristics of the solid forms obtained from various pralatinib salts.

Figure 26B is a table summarizing some physical characteristics of the solid forms obtained from various pralatinib salts.

Figure 27A shows the XRPD pattern obtained from the hydrochloride of 5-A pralatinib in solid form.

Figure 27B shows the DSC of solid form 5-A.

Figure 27C shows the XRPD pattern obtained from the hydrochloride of 5-B in solid form.

Figure 27D shows the TGA/DSC in solid form 5-B.

Figure 27E shows the XRPD pattern obtained from the hydrochloride of 5-C praltinib in solid form.

Figure 27F shows the TGA/DSC in solid form 5-C.

Figure 28A shows the XRPD pattern obtained from phosphate of pralatinib in solid form 14-A.

Figure 28B shows the DSC and TGA thermograms of the substance tested in Figure 28A, obtained from the phosphate of pralatinib in solid form 14-A.

Figure 28C shows the DVS isotherm obtained from a sample of praptinib phosphate in solid form 14-A.

Figure 29A shows the XRPD pattern obtained from glutaric acid of praltinib in solid form 11-A.

Figure 29B shows the DSC and TGA thermograms of the substance tested in Figure 29A, obtained from the glutarate of praltinib in solid form 11-A.

Figure 29C shows the DVS isotherm obtained from a sample of glutaric acid pralatinib in solid form 11-A.

Figure 30 shows the XRPD pattern obtained from glutaric acid of praltinib in solid form 11-B.

Figure 31A shows the XRPD pattern obtained from the succinate of praltinib in solid form 15-A.

Figure 31B shows the DSC and TGA thermograms of the substance tested in Figure 31A, obtained from the succinate of praltinib in solid form 15-A.

Figure 31C shows the DVS isotherm obtained from a sample of succinate of pralitinib in solid form 15-A.

Figure 32 shows the XRPD pattern obtained from maleate of 8-A pralatinib in solid form.

Figure 33A shows the XRPD pattern obtained from the oxalate of praltinib in solid form 9-A.

Figure 33B shows the DSC and TGA thermograms of the substance tested in Figure 33A, obtained from the oxalate of praltinib in solid form 9-A.

Figure 34A shows the XRPD pattern obtained from salicylate of pralatinib in solid form 10-A.

Figure 34B shows the DSC thermogram of the substance tested in Figure 34A, obtained from the salicylate of pralatinib in solid form 10-A.

Figure 34C shows the DSC thermogram of the substance tested in Figure 34A, obtained from the salicylates of pralatinib in solid form 10-A and 10-B.

Figure 35A shows the XRPD pattern obtained from the sulfate of pralatinib in solid form 12-A.

Figure 35B shows the DSC thermogram obtained from the sulfate of pralatinib in solid form 12-A.

Figure 35C shows the DSC thermogram obtained from the sulfate of pralatinib in solid form 12-B.

Figure 35D shows the DSC thermogram obtained from the sulfate of pralatinib in solid form (12-C).

Figure 35E shows the DSC thermogram obtained from the sulfate of pralatinib in solid form 12-E.

Figure 35F shows the DSC thermogram obtained from the sulfate of pralatinib in solid form (12-H).

Figure 35G shows the XRPD pattern (1) obtained from the qualitative water-soluble residual solid from sulfate and the XRPD pattern 12-G (2) obtained from the sulfate of pralatinib in solid form 12-G.

Figure 36A shows the XRPD pattern obtained from the tartrate of praltinib in solid form 13-A.

Figure 36B shows the DSC thermogram obtained from the sulfate of pralatinib in solid form 13-A.

Figure 36C shows the DSC thermogram obtained from the sulfate of pralatinib in solid form 13-B.

Figure 36D shows the DSC thermogram obtained from the sulfate of pralatinib in solid form (13-C).

Figure 36E shows XRPD patterns obtained from pralatinib tartrate from qualitatively water-soluble residual solids (1) and solid forms 13-A (2), 13-B (3), and 13-C (4).

Figure 37A shows XRPD patterns obtained from the following: urea (1), free base pattern FB-A (2), free base pattern FB-C (3), and solids (in solid form 16-A of urea salt of urea) produced after co-evaporation of free base and urea in wet cake from MeOH (4), drying solids (5), and exposure to 97% RH (6).

Figure 37B shows the DSC thermogram obtained from the urea salt of pralatinib in solid form 16-A.

Figure 38A shows the XRPD pattern obtained from pyruvate of praltinib in solid form 1-A.

Figure 38B shows the XRPD pattern of pyruvate of pralatinib in solid form 1-B, obtained from a wet cake (1) of free base and pyruvate in EtOAc, a dried solid (2), and a solid produced after exposure to 97% RH (3).

Figure 39 shows the XRPD pattern of citrate of 3-A pralatinib in solid form, obtained from a solid produced by wet cake (1) and dry solid (2) of free base and citric acid in IPA:water (:1vol).

Figure 40A shows the XRPD pattern of fumarate of pralatinib in solid form 4-A and the XRPD pattern obtained from fumarate of pralatinib in solid form 4-C, which was obtained from a solid produced by wet cake (1), dry solid (2), and solid after exposure to 97% RH (3) of free base and fumaric acid in EtOH.

Figure 40B shows the XRPD patterns obtained from fumarate of pralatinib in solid form 4-B and fumarate of pralatinib in solid form 4-D, which were obtained from a wet cake (1), a dry solid (2), and a solid produced after exposure to 97% RH (3) by free base and fumaric acid in IPA:water (9:1 vol).

Figure 41 shows the XRPD pattern obtained from the saccharin salt of 6-A pralatinib in solid form, which was obtained from a wet cake (1) and a dry solid (2) produced by free base and saccharin in EtOAc and then exposed to 97% RH (3).

Figure 42 shows the XRPD pattern (5) obtained from the gentianate of 7-A pralatinib in solid form, showing the XRPD pattern obtained from gentianic acid (1), free base pattern FB-A (2), free base pattern FB-C (3), and free base and gentianic acid in wet cakes in MtBE (4), EtOAc (5), and IPAc (6).

Figure 43A shows the XRPD pattern obtained from the mesylate of pralatinib in solid form 2-B.

Figure 43B shows the TGA/DSC thermogram obtained from the mesylate of pralatinib in solid form 2-B.

Figure 43C shows the XRPD pattern of pralatinib mesylate in solid form 2-A and the XRPD pattern obtained from pralatinib mesylate in solid form 2-B, which was obtained by MSA screening under wet (1) and dry (2) conditions in EtOH.

Figure 43D shows the XRPD pattern of pralatinib mesylate in solid form 2-B in (1) and (2) and the XRPD pattern (3) obtained from pralatinib mesylate in solid form 2-D, which was obtained by MSA screening in EtOAc under wet (1), dry (2) and humid (3) conditions.

Figure 43E shows the XRPD pattern (1) of pralatinib mesylate in solid form 2-C, obtained by MSA sieving under wet (1) and dry (2) conditions in IPA:water (9:1 vol).

Figure 44 shows the XRPD pattern of the BSA salt of pralatinib in solid form (1) and (2) and the XRPD pattern (3) obtained from the mesylate of pralatinib in solid form (18-B), which was obtained by screening under the conditions of BSA wet cake (1), IPA:water (9:1 vol), dry solid (2) and humidity (3).

Figure 45A shows the XRPD pattern obtained from the HBr salt of pralatinib in solid form 19-A.

Figure 45B shows the TGA and DSC thermograms obtained from the HBr salt of pralatinib in solid form 19-A.

Figure 45C shows XRPD patterns obtained from the HBr salt of pralatinib in solid form 19-A (1), the HBr salt of pralatinib in solid form 19-B (2), and the XRPD pattern (3) obtained from the HBr salt of pralatinib in solid form 19-C, which was obtained from a wet solid obtained by sieving with HBr in (1) EtOH, (2) EtOAc and (3) IPA:water (9:1 vol).

Figure 45D shows the XRPD pattern obtained from the HBr salt of pralatinib in solid form at 19-C.

Figure 45E shows the TGA and DSC thermograms obtained from the HBr salt of pralatinib in solid form (19-C+D).

Figure 46A shows the XRPD pattern obtained from nitrate of pralatinib in solid form 20-A.

Figure 46B shows the TGA/DSC thermogram obtained from the HBr salt of pralatinib in solid form 20-A.

Figure 47 shows the XRPD pattern of the quercetin dihydrate (QD) salt of pralatinib in solid form 17-A, obtained from the solid produced by co-evaporation of free base and quercetin dihydrate from MeOH in wet cake form (4), drying solid (5), and exposure to 97% RH (6).

Figure 48 shows the TGA/DSC thermogram obtained from glutarate of pralatinib in solid form 11-A.

Detailed Implementation

The bioactive compound (I), also known as prallatinib, or (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexanecarboxamide as shown below, can be prepared in the form of a free base in solid form or in various salt forms.

Pralatinib may also be known as CAS No. 2097132-94-8, cis-N-{(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl}-1-methoxy-4-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}cyclohexane-1-carboxamide, or BLU-667, and may include a free base or a salt thereof. Human clinical trials of pralatinib included administration of pralatinib to patients diagnosed with unresectable or metastatic non-small cell lung cancer (NSCLC) or medullary thyroid carcinoma (MTC) (e.g., NCT04204928), patients diagnosed with RET fusion-positive metastatic NSCLC (e.g., NCT04222972), and patients diagnosed with medullary thyroid carcinoma, RET-altering NSCLC, and other RET-altering solid tumors (e.g., NCT03037385).

When used alone, the term "solid form A" refers to the crystalline polymorphic solid form A of pralatinib. The terms "solid form A," "form A," "form A of pralatinib," "form A of ((cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide," or "form A of compound (I)" are used interchangeably. Form A can be characterized, for example, by XRPD alone or in combination with any or more of DSC, DVS, and TGA. Form A is anhydrous.

When used alone, the term "solid form B" refers to the crystalline polymorphic solid form B of pralatinib. The terms "solid form B," "form B," "form B of pralatinib," "form B of ((cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide," or "form B of compound (I)" are used interchangeably. Form B can be characterized, for example, by XRPD alone or in combination with any or more of DSC, DVS, and TGA. Form B is a dehydrated product.

When used alone, the term "solid form C" refers to the crystalline polymorphic solid form C of pralatinib. The terms "solid form C," "form C," "form C of pralatinib," "form C of ((cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide," or "form C of compound (I)" are used interchangeably. Form C can be characterized, for example, by XRPD alone or in combination with any or more of DSC, DVS, and TGA. Form C is a hydrate.

As used in this article, “crystallization” refers to a solid with a crystalline structure in which individual molecules have a highly uniform, regularly locked chemical configuration.

As used herein, “anhydrous” means a crystalline form that contains essentially no water in its crystal lattice, for example, less than 1% by weight as determined by Karl Fisher (KF), or less than 1% by weight as determined by another quantitative analysis.

As used herein, the term "hydrate" refers to a crystalline solid form containing compound (I) within a crystal structure and incorporating stoichiometric or non-stoichiometric amounts of water. "Dehydrated form" refers to a crystalline solid form containing compound (I) in which stoichiometric or non-stoichiometric amounts of water incorporated into the crystal structure have been removed. Techniques known to those skilled in the art for determining the amount of water present include, for example, TGA and KF.

The solid-state ordering of solids can be determined using standard techniques known in the art, such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), or dynamic vapor adsorption (DVS). Amorphous solids can also be distinguished from crystalline solids, for example, by using birefringence in a polarized microscope. Amorphous solids consist of randomly arranged molecules and do not have a distinguishable crystal lattice.

Relative intensity is calculated as the ratio of the peak intensity of the target peak to the peak intensity of the largest peak. In some embodiments, the relative intensity of the peaks may vary due to the preferred orientation of the sample. The preferred orientation in the sample affects the intensity of various reflections, thus some reflections are stronger than expected from a completely random sample, while others are less intense. Typically, the morphology of many crystalline particles tends to cause the sample to exhibit a certain degree of preferred orientation in the sample holder. This is particularly evident for needle-like or plate-like crystals when the size is reduced, resulting in finer needle-like or plate-like crystals.

In some embodiments, the purity of form A is at least 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9%. The purity of form A is determined by dividing the weight of form A of compound (I) in the composition containing compound (I) by the total weight of compound (I) in the composition.

In some embodiments, the purity of form B is at least 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9%. The purity of form B is determined by dividing the weight of form B of compound (I) in the composition containing compound (I) by the total weight of compound (I) in the composition.

In some embodiments, the purity of form C is at least 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9%. The purity of form C is determined by dividing the weight of form C of compound (I) in the composition containing compound (I) by the total weight of compound (I) in the composition.

In some embodiments, the purity of form 5-A is at least 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9%. The purity of form 5-A is determined by dividing the weight of form 5-A of compound (I) in the composition containing compound (I) by the total weight of compound (I) in the composition.

In some embodiments, the purity of form 5-B is at least 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9%. The purity of form 5-B is determined by dividing the weight of form 5-B of compound (I) in the composition containing compound (I) by the total weight of compound (I) in the composition.

In some embodiments, the purity of form 5-CI is at least 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9%. The purity of form 5-C is determined by dividing the weight of form 5-C of compound (I) in the composition containing compound (I) by the total weight of compound (I) in the composition.

The crystalline forms disclosed in this application, such as form A, form B, form C, form 5-A, form 5-B, and form 5-C, have many advantages. In particular, the advantages of forms A, B, C, 5-A, 5-B, and 5-C include ease of separation, process reproducibility, and suitability for large-scale manufacturing processes.

pralatinib free base solid form

The free base form of compound (I) may exist as an amorphous solid or as a mixture of different solid forms, which may additionally include one or more equivalents of water (e.g., in anhydrous or hydrated form). As provided herein, the crystalline solid form of compound (I) can be identified by a unique XRPD peak not characterized in previous disclosures of compound (I). This document provides certain crystalline solid forms of the free base of compound (I) and related methods for preparing and using substances in these solid forms.

The first solid form of the free base of compound (I) can be identified by an X-ray powder diffraction (XRPD) pattern containing characteristic diffraction peaks at 2θ angles of approximately ±0.2°, 5.0°, 9.7°, 12.7°, 13.6°, and 16.1°. Solid form A is an anhydrous solid that can be produced by various methods. For example, solid form A is observed after forming a slurry in alcohol, acetone, and ACN. Solid form A is prepared by evaporation crystallization in various solvents and by cooling crystallization in IPA and 1-propanol. Solid form A can also be produced by recrystallization in acetone:water. Methods for producing the free base of pralatinib in solid form A of compound (I) are provided in the examples.

Figure 3A shows the XRPD pattern obtained from the free base solid form A of pralatinib; Tables 1A, 1B, 1C and 1D are lists of XRPD (2θ) peaks obtained from the sample of the free base solid form A of pralatinib.

Table 1A

2θ (degrees) Lattice spacing (angstroms) relative strength 4.95 17.82 62 9.74 9.07 29 12.71 6.96 48 13.62 6.56 100 16.06 5.52 39

Table 1B

2θ (degrees) Lattice spacing (angstroms) relative strength 4.95 17.82 62 6.80 12.98 16 9.74 9.07 29 12.71 6.96 48 13.62 6.50 100 16.06 5.52 39 19.22 4.62 20 19.52 4.54 35 23.51 3.78 16

Table 1C

2θ (degrees) Lattice spacing (angstroms) relative strength 4.95 17.82 62 6.80 12.98 16 9.74 9.07 29 12.71 6.96 48 13.62 6.50 100 14.82 5.97 9 16.06 5.52 39 17.18 5.16 5 17.83 4.97 8 19.22 4.62 20 19.52 4.54 35 20.50 4.33 5 21.56 4.12 6 23.09 3.85 14 23.51 3.78 16 24.77 3.59 5 25.59 3.48 10

2θ (degrees) Lattice spacing (angstroms) relative strength 25.97 3.43 9 27.86 3.20 7 29.41 3.03 7

Table 1D

The solid form A of compound (I) was characterized by differential scanning calorimetry (DSC) endothermic and thermogravimetric analysis (TGA) plots shown in Figure 3B. The solid form A of the free base of pralatinib (referred to herein as "solid form A") was found to be crystalline throughout the screening process, with the sample exhibiting a melting initiation at approximately 205 °C. Solid form A was observed when slurries were formed in alcohols, acetone, and acetonitrile. Solid form A was prepared by evaporation crystallization in various solvents and by cooling crystallization in isopropanol and 1-propanol. Solid form A can also be produced by recrystallization in acetone:water (e.g., as described in the examples). Solid form A was stable upon exposure to humidity by X-ray powder diffraction (75% RHU and 40 °C for one week, and increased to 95% RHU according to dynamic vapor adsorption cycles), but dynamic vapor adsorption measurements showed that the sample was hygroscopic, yielding 10% water mass at 25 °C and between 2% and 95% RHU. However, the water absorption rate was approximately 2% between 15% and 75% RHU.

Furthermore, dynamic vapor adsorption (DVS) experiments were performed on a sample of solid form A of the free base of pralatinib. This solid form A sample was prepared via IPA slurry, in which the solid was recovered from previous recrystallization. The total mass chance observed between 2% and 95% relative humidity was 10.2 wt.%, indicating that the sample is hygroscopic. Most of the mass change occurred at high humidity (70% of the mass change occurred above 80% relative humidity, and 80% of the mass change occurred above 70% relative humidity). The mass change was reversible. The DVS isotherm is shown in Figure 20A. The XRPD of the sample before and after DVS measurement is shown in Pattern A (Figure 20B).

The second solid form of pralatinib, designated as solid form B, can be identified by X-ray powder diffraction (XRPD) patterns containing characteristic diffraction peaks at 2θ angles of approximately (±0.2 degrees) 5.9°, 8.8°, 11.6°, 14.7°, and 19.5°. Figure 4A shows the XRPD pattern obtained from solid form B of the free base of pralatinib; Tables 2A, 2B, and 2C are lists of XRPD (2θ) peaks obtained from solid form B of the free base of compound (I).

Table 2A

2θ (degrees) Lattice spacing (angstroms) relative strength 5.89 14.99 100 8.81 10.03 28 11.58 7.64 33 14.73 6.01 twenty three 19.45 4.56 13

Table 2B

2θ (degrees) Lattice spacing (angstroms) relative strength 5.89 14.99 100 8.81 10.03 28 11.58 7.64 33 14.73 6.01 twenty three 17.01 5.21 11 17.63 5.03 8 19.45 4.56 13 22.21 4.00 5

Table 2C

The solid form B of compound (I) can be obtained by heating a sample of solid form B to 150 °C, endothermic by differential scanning calorimetry (DSC) and characterization by thermogravimetric analysis (TGA) to obtain the graph shown in Figure 4B.

The DVS isotherm of pattern B is shown in Figure 23A. The sample showed a total mass change of 1.4 wt.% between 2% and 95% relative humidity. A simple drying experiment was conducted by placing pattern C (filtered from the slurry sample) under vacuum at 50°C. The resulting solid was pattern B by XRD. During high humidity exposure, no conversion of the free base of pralitinib, characterized by XRPD pattern B (the dehydrated form of pattern C), back to the hydrated form of XRPD pattern C was observed.

The third free base solid form of pralatinib, designated as form C, can be identified by X-ray powder diffraction (XRPD) patterns containing characteristic diffraction peaks at 2θ angles of approximately (±0.2 degrees) 5.8°, 8.7°, 11.0°, 13.6°, and 20.2°. Figure 5A shows the XRPD pattern obtained from the free base solid form C of compound (I); Tables 3A, 3B, 3C, and 3D are each a list of XRPD (2θ) peaks obtained from the free base solid form C of compound (I).

Table 3A

2θ (degrees) Lattice spacing (angstroms) relative strength 5.81 15.21 100 8.69 10.17 32 10.96 8.06 60 13.56 6.52 48 20.19 4.39 29

Table 3B

2θ (degrees) Lattice spacing (angstroms) relative strength 5.81 15.21 100 8.69 10.17 32 10.96 8.06 60 11.59 7.63 twenty one 13.56 6.52 48 14.49 6.11 twenty one 20.19 4.39 29 22.18 4.00 20 23.20 3.83 10

Table 3C

Table 3D

Solid form C is a hydrated solid form that is retained when this solid form is slurried in various solvents. Solid form C also recrystallizes in various aqueous solvent systems (acetone:water, MeOH:water, IPA:water, DMAc:water, THF:water). The solid form C of the free base of compound (I) was characterized by differential scanning calorimetry (DSC) endothermic and thermogravimetric analysis (TGA) plots shown in Figure 5B. The DSC thermograms begin at 122°, 127°, and 206°. The TGA shows a mass loss of 3.09 wt.%.

DVS was performed on the free base sample of pralitinib in solid form C. The observed total mass change was 1.4 wt.%. The DVS isotherm is shown in Figure 21A. The XRPD of the sample was the same before and after the DVS measurement (Figure 22C).

The characteristic feature is that the solid form of pralatinib free base, characterized by XRPD pattern A, transforms into the pralatinib free base, characterized by XRPD pattern C, during a competitive slurry experiment in methanol:water at a high water:methanol ratio and a lower temperature. It was also found that the solid form C of pralatinib free base remained crystalline throughout the screening process. The solid form C of pralatinib free base was recrystallized in various aqueous solvent systems (acetone:water, methanol:water, isopropanol:water, dimethylacetamide:water, tetrahydrofuran:water). After prolonged exposure to humidity, the solid form A of pralatinib free base did not transform into the solid form C of pralatinib free base.

The solid form C of pralatinib free base was stably dried under vacuum at 50°C and transformed into pattern B (anhydrous) upon heating to 150°C. The solid form B of pralatinib then transformed into solid form A of pralatinib before melting. During humidity testing (75% relative humidity and 40°C for one week, reduced to 2% relative humidity according to dynamic vapor adsorption cycles), the solid form C of pralatinib free base remained stable by X-ray powder diffraction. During dynamic vapor adsorption measurements, the solid form C of pralatinib free base was not hygroscopic like the solid form A of pralatinib free base, yielding only 1.44% water. During competitive slurry experiments in acetone and isopropanol, the solid form C of pralatinib free base transformed into solid form A of pralatinib free base. A summary of the properties of patterns A and C is presented in Table 3E below.

Table 3E

The solid form of the free base of compound (I) characterized by XRPD patterns A, B (with small additional peaks) and C was exposed to 75% relative humidity at 40°C for one week. The solids were collected after one week for XRPD analysis. The XRPD patterns of patterns A, B, and C remained unchanged after one week. Figure 22A shows the XRPD patterns of the solid form of the free base of compound (I) A before (1) and after (2) exposure to moisture. Figure 22B shows the XRPD patterns of the solid form of the free base of compound (I) B before (1) and after (2) exposure to moisture. Figure 22C shows the XRPD patterns of the solid form of the free base of compound (I) C before (1) and after (2) exposure to moisture.

Figure 1B is a schematic diagram summarizing the additional solid forms of the free base of pralatinib. A total of 14 additional solid forms of the free base of pralatinib (designated as solid forms D, F, G, H, I, J, K, L, M, N, O, P, and Q, excluding amorphous forms) were also prepared and observed, and prepared as described in the examples. Many of these solid forms can be converted into solid forms A, B, or C of the free base of pralatinib.

Solid form D, initially a wet solid, was observed to subsequently transform into solid form B (e.g., by the XPRD pattern in Figure 4A and/or the TGA or DSC thermogram in Figure 4B), solid form F (e.g., characterized by the XPRD pattern in Figure 7A and/or the DSC/TGA thermogram in Figure 7B), or solid form G (e.g., characterized by the XPRD pattern in Figure 8A and/or the DSC/TGA thermogram in Figure 8B), depending on the drying method used. Upon exposure to atmosphere, solid form D also transforms into other solid forms. Figure 6 shows the XPRD pattern obtained from the free base solid form D of compound (I); Table 4 lists the XPRD (2θ) peaks obtained from the free base solid form D of compound (I).

Table 4

When the free alkali solid form B sample was slurried in MtBE, the solid form E of compound (I) was observed.

The free base of compound (I) in solid form D was observed to be in solid form F. Figure 7A shows the XRPD patterns obtained from two different samples of the free base solid form F of compound (I). The XRPD pattern of solid form F shown in Figure 7A was obtained after vacuum drying the sample in solid form D at 50 °C (XRPD pattern D in Figure 6 is provided). The solid form F substance was not directly recrystallized. Table 5 is a list of XRPD (2θ) peaks obtained from the free base solid form F of compound (I).

Table 5

The solid form F of the free base of compound (I) was obtained by vacuum drying of a sample in solid form D at 50 °C (characterized by the XRPD pattern in Figure 6), and characterized by endothermic differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) to obtain the figure shown in Figure 7B.

The solid form G of the free base of compound (I) was observed as a desolvated compound in solid form D (characterized by XRPD pattern D in Figure 6). Solid form G was obtained after air-drying the substance in solid form D. Solid form G was not directly recrystallized. Figure 8A shows two XRPD patterns: (a) the upper XRPD pattern of the free base of compound (I) in solid form G obtained by air-drying the sample of the free base solid form D of compound (I); and (b) the lower XRPD pattern from the free base of compound (I) in solid form G. The solid form G substance was not directly recrystallized. Table 6 is a list of XRPD (2θ) peaks obtained from the solid form G of the free base of compound (I), with the upper XRPD pattern shown in Figure 8A.

Table 6

The solid form G of the free base of compound (I) (characterized by the upper XRPD pattern in FIG8A) was characterized by differential scanning calorimetry (DSC) endothermic method and by thermogravimetric analysis (TGA) to obtain the figure shown in FIG8B.

After forming a slurry in chloroform, the solid form H of the free base of compound (I) was observed as a viscous solid. The solid form H of the free base of compound (I) was also observed after the solid obtained from chloroform evaporation was subjected to an amorphous slurry. The composition characterized by solid form H was first observed by filtering the slurry in chloroform for two days. The chloroform slurry phase was slightly oily, but a solid was obtained during filtration. The solid obtained by this method was viscous. The solid form H of the free base of pralatinib was also observed in the amorphous slurry experiment. Figure 9A shows the XRPD pattern obtained from the free base of compound (I) in solid form H. Table 7 is a list of XPRD (2θ) peaks obtained from the solid form H of the free base of compound (I), with the XRPD pattern shown in Figure 9A.

Table 7

The solid form H of the free base of compound (I) prepared by chloroform slurry (characterized by the XRPD pattern in Figure 9A) was characterized by endothermic differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) to obtain the graph shown in Figure 9B. The DSC thermogram of the solid form H sample shows a melting initiation of 235 °C, which is about 30 °C higher than the melting initiation of the anhydrous free base of compound (I) providing XRPD pattern A. The residual solvent is below the level detectable by proton NMR.

Solid form I of the free base of compound (I) was observed (as a mixture with solid form O) by recrystallization from the antisolvent in THF/heptane and slow cooling in THF. Based on the residual THF in DSC and proton NMR, solid form I is most likely a THF solvate. Figure 10A shows the XRPD pattern obtained from the sample of the free base of compound (I) in solid form I. Table 8 lists the XRPD (2θ) peaks obtained from solid form I of the free base of compound (I).

Table 8

The solid form I of the free base of compound (I) (characterized by the upper XRPD pattern in Figure 10A) was endothermic by differential scanning calorimetry (DSC) and further characterized by thermogravimetric analysis (TGA) to obtain the figure shown in Figure 10B.

The free base J of compound (I) was observed in solid form as a solid by recrystallization from the antisolvent in THF/cyclohexane. Solid form J is unstable and rapidly transforms into an amorphous form upon drying in vacuum and at atmosphere. Figure 11 shows the XRPD pattern obtained from the sample of the free base J of compound (I). Table 9 lists the XRPD (2θ) peaks obtained from the solid form J of the free base of compound (I).

Table 9

The solid form K of the free base of compound (I) was observed by recrystallization from DMSO/water antisolvent. Solid form K is unstable upon drying and transforms into a substance characterized by the XRPD pattern M. Figure 12A shows the XRPD pattern obtained from the sample of the free base of compound (I) in solid form K. Table 10 lists the XRPD (2θ) peaks obtained from the solid form K of the free base of compound (I).

Table 10

The sample of the free base K of compound (I) prepared by antisolvent crystallization in DMSO/water was further characterized by differential scanning calorimetry (DSC) endothermic and thermogravimetric analysis (TGA) to obtain the figure shown in Figure 12B.

The solid form L of the free base of compound (I) was observed by recrystallization via MeOH/water antisolvent. Pattern L is stable upon drying. Figure 13A shows the XRPD pattern obtained from the sample of the free base of compound (I) in solid form L. Tables 11A, 11B, 11C, and 11D are lists of XRPD (2θ) peaks obtained from the sample of the free base of compound (I) in solid form L.

Table 11A

2θ (degrees) Lattice spacing (angstroms) relative strength 5.81 15.19 59 8.69 10.17 100 11.57 7.64 68 13.32 6.64 64 23.55 3.77 35

Table 11B

2θ (degrees) Lattice spacing (angstroms) relative strength 5.81 15.19 59 8.69 10.17 100 10.89 8.12 38 11.57 7.64 68 13.32 6.64 64 19.40 4.57 35 19.40 4.57 35 19.75 4.49 47 22.47 3.95 27 23.55 3.77 35

Table 11C

Table 11D

The sample of the free base solid form L of compound (I) prepared by antisolvent crystallization in DMSO/water was further characterized by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) to obtain the figure shown in Figure 13B.

The solid form M of the free base of compound (I) shares all peaks with the free base composition of compound (I) characterized by XRPD pattern B, but some additional peaks are observed in the XRPD (e.g., 2θ 13.84, 16.11, 19.09). The solid form M is prepared by drying and crystallizing from the antisolvent in DMSO:water to obtain the solid form of the free base of compound (I) characterized by XRPD pattern K. Figure 14A shows the XRPD pattern obtained from the sample of the free base of compound (I) in solid form M. Table 12 is a list of XRPD (2θ) peaks obtained from the solid form M of the free base of compound (I).

Table 12

The sample of the free base M of compound (I) was endothermic by differential scanning calorimetry (DSC) and characterized by thermogravimetric analysis (TGA) to obtain the thermogram shown in Figure 14B.

Upon rapid cooling in THF, the solid form N of the free base of compound (I) was observed. Very little solid was obtained for analysis. The solid form N may be a THF solvate. Figure 15 shows the XRPD pattern obtained from the wet sample of the free base of compound (I) in solid form N. Table 13 lists the XRPD (2θ) peaks obtained from the solid form N of the free base of compound (I).

Table 13

The solid form O of the free base of compound (I) is characterized by XRPD pattern I. A mixture of compositions of the free base of compound (I) is obtained by slow cooling in THF. Solid form O may be a THF solvate. Figure 16 shows the XRPD pattern obtained from a wet sample of the free base of compound (I) in solid form O. Table 14 lists the XRPD (2θ) peaks obtained from the solid form O of the free base of compound (I).

Table 14

The solid form P of the free base of compound (I) was obtained by rapid cooling to 0°C in MeOH followed by stagnant cooling to -20°C. The solid form P is unstable upon drying and transforms upon drying into a mixture of substances characterized by XRPD patterns P and L, along with additional peaks. Figure 17 shows the XRPD patterns obtained from the wet sample of the free base of compound (I) in solid form P. Table 15 lists the XRPD (2θ) peaks obtained from the solid form P of the free base of compound (I).

Table 15

Upon cooling in 1,4-dioxane, the solid form Q of the free base of compound (I) was observed. Solid form Q lost its crystallinity upon drying and is likely a 1,4-dioxane solvate. Figure 18A shows the XRPD pattern obtained from the wet sample of the free base of compound (I) in solid form Q. Table 16 lists the XRPD (2θ) peaks obtained from the solid form Q of the free base of compound (I).

Table 16

The solid form Q of the free base of compound (I) obtained by cooling crystallization from 1,4-dioxane was characterized by endothermic differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) to obtain the thermogram shown in Figure 18B.

An amorphous solid of compound (I) was produced by evaporation from a chloroform solution. The evaporated solid was a hard gel that could break into more flowable powders. It was later determined that the amorphous solid contained trace amounts of free alkali of compound (I) characteristic of the XRPD pattern H, a solid obtained from many amorphous slurries. Significant chloroform was observed in proton NMR, consistent with the mass loss observed in TGA at low temperatures. Figure 19A shows the XRPD pattern obtained by XRPD of the amorphous solid produced by evaporation from a DCM solution. Figure 19B shows the DSC and TGA thermograms of the amorphous solid of compound (I) obtained by evaporation from a chloroform solution.

pralatinib salt form

Various salts of pralatinib were formed using various counterions and solvents (e.g., as described in Example 3). The preparation and characterization of at least twenty different pralatinib salts are described herein. For example, Figures 24 and 25 are tables summarizing the characteristics of five pralatinib salt forms (formed using BSA, MSA, HCl, HBr, and HNO3 counterions). Figures 26A and 26B are tables summarizing the characteristics of thirteen pralatinib salt forms (formed using pyruvate, citric acid, fumaric acid, HCl, saccharin, maleic acid, oxalic acid, salicylic acid, glutaric acid, sulfuric acid, succinic acid, tartaric acid, and phosphoric acid).

Crystalline patterns of pralitinib salts were obtained using many, but not all, of the counterions tested in the examples. Fumarate and sulfate salts changed upon drying. As described in the examples, some citrate, hydrochloride, and gentianate salts were deliquescent upon exposure to >95% relative humidity. Pyruvate, saccharin salt, and sulfate salts derived from 1.1 equivalent experiments all changed upon exposure to >95% relative humidity. X-ray powder diffraction patterns of many salts were stable to both drying and moisture exposure (e.g., maleate 8-A, oxalate 9-A, glutarate 11-A, succinate 15-A, and phosphate 14-A). Low-crystallinity patterns were obtained by screening with pyruvate, sulfuric acid, citrate, fumarate, and saccharin, while medium to high-crystallinity patterns were obtained from hydrochloric acid, maleic acid, oxalic acid, salicylic acid, glutaric acid, sulfuric acid, succinic acid, tartaric acid, and phosphoric acid. The viability of crystalline salts is characterized and evaluated based on melting point, crystallinity, stability under dry conditions and exposure to moisture, water solubility, polymorphism, and acceptability of counterions.

Turning to the specific pralatinib salt provided herein, compound (I) is prepared into a variety of different solid hydrochloride (HCl) forms, including various crystalline solid HCl forms of compound (I).

In one aspect, this disclosure provides crystalline pralatinib HCl salt form 5-A. In one aspect, crystalline pralatinib HCl salt form 5-A is characterized by an X-ray powder diffraction pattern. The X-ray powder diffraction pattern can be obtained using the Rigaku MiniFlex 600 described herein. In one embodiment, crystalline pralatinib HCl salt form 5-A is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at a 2θ angle (±0.2 degrees) selected from 5.0°, 6.1°, 9.1°, 9.9°, and 14.7°.

Alternatively, the crystalline prantinib HCl salt form 5-A is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten X-ray powder diffraction peaks at 2θ angles (±0.2 degrees) of 5.0°, 6.1°, 9.1°, 9.9°, 13.8°, 14.7°, 15.3°, 17.2°, 18.1°, 19.6°, 20.3°, 20.7°, 21.8°, 24.2°, 25.6°, and 26.3°. Alternatively, crystalline pralatinib HCl salt form 5-A is characterized by X-ray powder diffraction peaks at 2θ angles (±0.2 degrees) of 5.0°, 6.1°, 9.1°, 9.9°, 13.8°, 14.7°, 15.3°, 17.2°, 18.1°, 19.6°, 20.3°, 20.7°, 21.8°, 24.2°, 25.6°, and 26.3°. In some embodiments, the peaks described above for crystalline pralatinib HCl salt form 5-A have a relative intensity of at least 10%, at least 15%, at least 20%, or at least 25%.

In another aspect, the crystalline pralatinib HCl salt form 5-A has an XRPD pattern that is substantially the same as the XRPD pattern shown in Figure 27A.

In the other case, the crystalline prantinib HCl salt form 5-A has an XRPD pattern that substantially includes the peaks in Tables 17A-B.

In one aspect, the crystalline pralatinib HCl salt form 5-A has a DSC pattern substantially identical to the DSC pattern shown in Figure 27B. In particular, pralatinib HCl salt form 5-A was observed to have a very broad endothermic range, with an initial temperature of 70.9 °C (±0.2 °C) and a sharp endothermic reaction at 240.5 °C (±0.2 °C).

In one aspect, the crystalline pralatinib HCl salt form 5-A is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at 2θ angles (±0.2 degrees) of 5.0°, 6.1°, 9.1°, 9.9°, and 14.7°; optionally in conjunction with the TGA and DSC parameters described above for pralatinib HCl salt form 5-A. Alternatively, the crystalline pralatinib HCl salt form 5-A is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten X-ray powder diffraction peaks at a 2θ angle (±0.2 degrees) selected from 5.0°, 6.1°, 9.1°, 9.9°, 13.8°, 14.7°, 15.3°, 17.2°, 18.1°, 19.6°, 20.3°, 20.7°, 21.8°, 24.2°, 25.6°, and 26.3°, optionally in conjunction with the DSC parameters described above for pralatinib HCl salt form 5-A.

In one aspect, the crystalline pralatinib HCl salt form 5-A is characterized by one or more of the following features: (a) an X-ray powder diffraction (XRPD) pattern containing characteristic diffraction peaks at 2θ angles of approximately (±0.2 degrees) 5.0°, 6.1°, 9.1°, 9.9°, and 14.7°; and/or (b) a differential scanning calorimetry (DSC) thermogram with very broad endothermic activity, wherein the onset temperature is 70.9 °C (±0.2 degrees) and the endothermic activity is rapid at 240.5 °C (±0.2 degrees).

Pralatinib HCl salt 5-A can be obtained by methods including separating the solid from a slurry of HCl salt in EtOH or IPA:water (9:1 Vol).

In one aspect, this disclosure provides crystalline pralatinib HCl salt form 5-B. In one aspect, crystalline pralatinib HCl salt form 5-B is characterized by an X-ray powder diffraction pattern. The X-ray powder diffraction pattern can be obtained using the Bruker D8 described herein. In one embodiment, crystalline pralatinib HCl salt form 5-B is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at a 2θ angle (±0.2 degrees) selected from 6.1°, 8.9°, 9.5°, 15.0°, and 16.6°.

Alternatively, the crystalline pralatinib HCl salt form 5-B is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten X-ray powder diffraction peaks at 2θ angles (±0.2 degrees) of 6.1°, 8.9°, 9.5°, 15.0°, 16.6°, 17.2°, 17.9°, 18.4°, 19.8°, 25.8°, and 26.8°. Alternatively, the crystalline pralatinib HCl salt form 5-B is characterized by X-ray powder diffraction peaks at 2θ angles (±0.2 degrees) of 6.1°, 8.9°, 9.5°, 15.0°, 16.6°, 17.2°, 17.9°, 18.4°, 19.8°, 25.8°, and 26.8°. In some embodiments, the peak described above for crystalline pralatinib HCl salt form 5-B has a relative intensity of at least 10%, at least 15%, at least 20%, or at least 25%.

In another aspect, the crystalline pralatinib HCl salt form 5-B has an XRPD pattern that is substantially the same as the XRPD pattern shown in Figure 27C.

In another aspect, the crystalline prantinib HCl salt form 5-B has an XRPD pattern that substantially includes the peaks in Tables 18A-B.

In one aspect, the crystalline pralatinib HCl salt form 5-B has a DSC pattern substantially identical to the DSC pattern shown in Figure 27D. In particular, pralatinib HCl salt form 5-B is observed to have extensive endothermic activity, with an onset temperature of 88.7 °C (±0.2 °C) and a melting onset temperature of 244.2 °C (±0.2 °C).

In one aspect, the crystalline pralatinib HCl salt form 5-B exhibits a TGA pattern substantially identical to that shown in Figure 27D. Specifically, the initial mass loss of 3.4 wt.% is associated with extensive endothermic reaction, starting at 88.7 °C (±0.2 °C), and a second mass loss event of 6.7 wt.% is observed from the end of the first extensive endothermic reaction to the end of melting at 244.2 °C (±0.2 °C). This was observed in the TGA thermogram of the pralatinib HCl salt form 5-B.

In one aspect, crystalline pralatinib HCl salt form 5-B is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at a 2θ angle (±0.2 degrees) selected from 6.1°, 8.9°, 9.5°, 15.0°, and 16.6°; optionally in conjunction with one or more TGA and DSC parameters described above for pralatinib HCl salt form 5-B. Alternatively, crystalline pralatinib HCl salt form 5-B is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine X-ray powder diffraction peaks at a 2θ angle (±0.2 degrees) selected from 6.1°, 8.9°, 9.5°, 15.0°, 16.6°, 17.2°, 17.9°, 18.4°, 19.8°, 25.8°, and 26.8°, optionally in conjunction with the TGA and DSC parameters described above for pralatinib HCl salt form 5-B.

In one aspect, the crystalline pralatinib HCl salt form 5-B is characterized by one or more of the following features: (a) an X-ray powder diffraction (XRPD) pattern containing characteristic diffraction peaks at 2θ angles of approximately (±0.2 degrees) 6.1°, 8.9°, 9.5°, 15.0°, and 16.6°; (b) a DSC thermogram with extensive endothermicity, wherein the onset is 88.7 °C (±0.2 degrees) and the melting onset is 244.2 °C (±0.2 degrees); and/or (c) an initial mass loss of 3.4 wt.%, associated with extensive endothermicity, wherein the onset is 88.7 °C and a second mass loss event of 6.7 wt.% is observed from the end of the first extensive endothermic event to the end of the melting event at 244.2 °C (±0.2 degrees).

Pralatinib HCl salt 5-B can be obtained by a method that includes separating the solid from EtOAc and IPA:water (9:1 Vol).

In one aspect, this disclosure provides crystalline pralatinib HCl salt form 5-C. In another aspect, crystalline pralatinib HCl salt form 5-C is characterized by an X-ray powder diffraction pattern. The X-ray powder diffraction pattern can be obtained using a Bruker D8 Advance as described herein. In one embodiment, crystalline pralatinib HCl salt form 5-C is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at a 2θ angle (±0.2 degrees) selected from 6.4°, 8.5°, 8.9°, 9.6°, and 17.3°.

Alternatively, the crystalline pralatinib HCl salt form 5-C is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine X-ray powder diffraction peaks at 2θ angles (±0.2 degrees) of 6.4°, 8.5°, 8.9°, 9.6°, 11.5°, 16.7°, 17.3°, and 19.2°. Alternatively, the crystalline pralatinib HCl salt form 5-C is characterized by X-ray powder diffraction peaks at 2θ angles (±0.2 degrees) of 6.4°, 8.5°, 8.9°, 9.6°, 11.5°, 16.7°, 17.3°, and 19.2°. Alternatively, the crystalline pralatinib HCl salt form 5-C is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten X-ray powder diffraction peaks at a 2θ angle (±0.2 degrees) selected from 6.0°, 6.4°, 8.5°, 8.9°, 9.6°, 11.5°, 12.7°, 15.9°, 16.7°, 17.3°, 19.2°, 21.0°, and 26.9°. In another alternative, the crystalline pralatinib HCl salt form 5-C is characterized by X-ray powder diffraction peaks at a 2θ angle (±0.2 degrees) of 6.0°, 6.4°, 8.5°, 8.9°, 9.6°, 11.5°, 12.7°, 15.9°, 16.7°, 17.3°, 19.2°, 21.0°, and 26.9°. In some embodiments, the peaks described above for crystalline pralatinib HCl salt form 5-C have a relative intensity of at least 10%, at least 15%, at least 20%, or at least 25%.

In the other case, the crystalline pralatinib HCl salt form 5-C has an XRPD pattern that is substantially the same as the XRPD pattern shown in Figure 27E.

In the other case, the crystalline pralatinib HCl salt form II has an XRPD pattern that substantially includes the peaks in Table 18C-E.

In one aspect, the crystalline pralatinib HCl salt form 5-C has a DSC pattern substantially identical to that shown in Figure 27F. Specifically, pralatinib HCl salt form 5-C was observed to have DSCs starting at 86.8 °C (±0.2 °C), 224.1 °C (±0.2 °C), and 241.7 °C (±0.2 °C).

In one aspect, the crystalline pralatinib HCl salt form 5-C has a TGA pattern substantially identical to that shown in Figure 27F. Specifically, an initial mass loss of 3.4 wt.% and a second mass loss event of 2 wt.% were observed in the TGA thermogram of pralatinib HCl salt form 5-C.

In one aspect, crystalline pralatinib HCl salt form 5-C is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at a 2θ angle (±0.2 degrees) selected from 6.4°, 8.5°, 8.9°, 9.6°, and 17.3°; optionally in conjunction with one or more TGA and DSC parameters described above for pralatinib HCl salt form 5-C. Alternatively, crystalline pralatinib HCl salt form 5-C is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine X-ray powder diffraction peaks at a 2θ angle (±0.2 degrees) selected from 6.4°, 8.5°, 8.9°, 9.6°, 11.5°, 16.7°, 17.3°, and 19.2°, optionally in conjunction with the TGA, DSC, and DVS parameters described above for pralatinib HCl salt form 5-C. Alternatively, the crystalline pralatinib HCl salt form 5-C is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten X-ray powder diffraction peaks at a 2θ angle (±0.2 degrees) selected from 6.0°, 6.4°, 8.5°, 8.9°, 9.6°, 11.5°, 12.7°, 15.9°, 16.7°, 17.3°, 19.2°, 21.0°, and 26.9°, optionally together with one or both of the TGA and DSC parameters described above for pralatinib HCl salt form 5-C.

In one aspect, the crystalline pralatinib HCl salt form 5-C is characterized by one or more of the following features: (a) an X-ray powder diffraction (XRPD) pattern containing characteristic diffraction peaks at 2θ angles of approximately (±0.2 degrees) 6.4°, 8.5°, 8.9°, 9.6°, and 17.3°; and (b) observation of DSCs starting at 86.8°C (±0.2 degrees), 224.1°C (±0.2 degrees), and 241.7°C (±0.2 degrees); and/or (c) observation of an initial mass loss of 3.4 wt.% and a second mass loss event of 2 wt.% in the TGA thermogram of the pralatinib HCl salt form 5-C.

Praltinib HCl salt 5-C can be obtained by a method including drying the isolated pralatinib HCl salt form 5-B.

Table 17A. List of XRPD peaks for 5-A form of praltinib HCl salt

Table 17B. List of selected XRPD peaks for 5-A form of praltinib HCl salt

Table 18A. List of XRPD peaks in 5-B form of praltinib HCl salt

Table 18B. List of selected XRPD peaks for 5-B form of praltinib HCl salt

2θ (degrees) Lattice spacing (angstroms) relative strength 6.10 14.47 56 8.90 9.93 100 9.54 9.26 twenty two 15.02 5.89 6 16.64 5.32 15

Table 18. List of XRPD peaks at 5-C of praltinib HCl salt.

2θ (degrees) Lattice spacing (angstroms) relative strength 5.99 14.75 6 6.38 13.85 42 8.49 10.40 55 8.92 9.91 100 9.60 9.21 48 11.51 7.68 9 12.70 6.97 8 15.89 5.57 5 16.74 5.29 twenty one 17.34 5.11 28 19.19 4.60 9 21.00 4.23 7 26.88 3.31 7

Table 18. List of selected XRPD peaks in 5-C form of pralatinib HCl salt.

Table 18E. Further selection of XRPD peaks for 5-C of pralatinib HCl salt form.

2θ (degrees) Lattice spacing (angstroms) relative strength 6.38 13.85 42 8.49 10.40 55 8.92 9.91 100 9.60 9.21 48 17.34 5.11 28

Compound (I) can be prepared in solid phosphate form. The pralatinib phosphate salt form, in solid form 14A (e.g., characterized by the XRPD pattern 14A in Figure 28A), was the only pattern isolated from all three solvent systems and exhibited high crystallinity and stability to both drying and humidification. Pralatinib phosphate solid form 14-A was also the only pattern observed during screening for this counterion and was found to be stable to both drying and humidification. Tables 19A, 19B, 19C, and 19D are each a list of XPRD (2θ) peaks obtained from samples of pralatinib phosphate in solid form 14-A.

Table 19A

2θ (degrees) Lattice spacing (angstroms) relative strength 10.05 8.80 85 12.99 6.81 88 15.16 5.84 50 19.51 4.55 49 21.23 4.18 100

Table 19B

2θ (degrees) Lattice spacing (angstroms) relative strength 5.88 15.01 39 8.8O 10.04 48 9.62 9.18 41 10.05 8.80 85 12.99 6.81 88 15.16 5.84 50 17.55 5.05 43 19.51 4.55 49 21.23 4.18 100 22.54 3.94 47

Table 19C

Table 19D

2θ (degrees) Lattice spacing (angstroms) relative strength 5.88 15.01 53 8.80 10.04 57 9.62 9.19 43 10.05 8.80 100 11.23 7.88 30 12.99 6.81 86 14.66 6.04 6 15.15 5.84 58 16.39 5.40 7 16.69 5.31 9 17.57 5.04 51 18.95 4.68 twenty three 19.49 4.55 60 20.17 4.40 39 21.21 4.19 89 21.87 4.06 5 2250 3.05 67 23.55 3.77 13 24.29 3.66 29 25.43 3.50 13 26.09 3.41 20 26.53 3.36 twenty three 27.40 3.25 8 28.48 3.13 twenty four 29.07 3.07 8 30.71 2.91 9 32.95 2.72 6 35.27 2.54 6

The prantinib phosphate salt in solid form 14-A has low residual solvent (0.06 wt.% in EtOH). Thermochromatography shows high-temperature melting, starting at 198.4 °C. TGA/DSC of the prantinib phosphate salt in solid form 14-A in Figure 28B shows an initial mass loss of 1.3 wt.%, associated with a small, extensive endothermic event starting at 105.8 °C. A second mass loss of 1.6 wt.% was observed from the end of the initial endothermic event to the end of the melting event starting at 241.9 °C, followed by decomposition. A water content of 1.1 wt.% was found by KF analysis, and 1H-NMR showed 0.32 wt.% residual EtOH in the dry solid.

Samples of pralatinib phosphate in solid form 14-A exhibited high purity (99.88% by HPLC). Pralatinib phosphate in solid form 14-A was stable for 7 days in slurries formed in EtOH, EtOAc, and EtOH:water (95:5 vol) by XRPD and HPLC, although the amount of material separated from EtOAc decreased by 0.07%. Pralatinib phosphate was also stable after exposure to 75% RH at 40°C for 7 days. Furthermore, pralatinib phosphate in solid form 14-A exhibited high solubility in water and several simulated fluids. The solubility in simulated intestinal fluid under fasting conditions was 0.20 mg/mL, and the residual solid was identified as pralatinib free base solid form A. The solubility in simulated intestinal fluid under fed conditions was 0.49 mg/mL, and the residual solid was amorphous. The solubility in simulated gastric fluid under fasting conditions was 1.76 mg/mL, and the resulting solid was amorphous. The solubility in water is 1.70 mg/mL, and the residual solids are characterized by XRPD pattern 14-A (Fig. 28A). Praltinib phosphate in solid form 14-A showed a mass change of 0.94 wt.% between 2% and 90% relative humidity. Between 15% and 75% relative humidity, the mass change was 0.86 wt.%. Minimal hysteresis was observed in the figure, and this water loss appears to be reversible. The DVS isotherm for praltinib phosphate in solid form 14-A is shown in Fig. 28C.

Compound (I) can be prepared as a solid glutarate. For example, pralatinib glutarate in solid form 11-A (Fig. 29A) is isolated from various solvent systems as a highly crystalline substance and is stable to drying and humidification. It exhibits moderate water solubility at room temperature (0.24 mg/mL) with low residual solvent (e.g., 0.09 wt.% EtOH in one sample) and a thermogram (Fig. 29B) showing a single, rapid endothermic reaction starting at 177.8 °C. XRPD patterns (Fig. 29A) and peak lists (Tables 20A, 20B, 20C, and 20D) of pralatinib glutarate in solid form 11-A are provided below.

Table 20A

20 (degrees) Lattice spacing (angstroms) relative strength 5.89 14.99 68 8.20 10.78 31 8.82 10.02 100 10.15 8.71 96 11.76 7.52 45

Table 20B

2θ (degrees) Lattice spacing (angstroms) relative strength 5.89 14.99 68 8.20 10.78 31 8.82 10.02 100 10.15 8.71 96 11.76 7.52 45 16.75 5.29 twenty one 17.46 5.07 18 20.63 4.30 twenty one 21.42 4.15 16 23.70 3.75 17

Table 20C

2θ (degrees) Lattice spacing (angstroms) relative strength 5.89 14.99 68 8.20 10.78 31 8.82 10.02 100 10.15 8.71 96 11.76 7.52 45 14.26 6.21 15 14.36 6.16 11 16.45 5.38 6 16.75 5.29 twenty one 16.91 5.24 15 17.46 5.07 18 18.53 4.78 10 18.78 4.72 13 19.64 4.52 6 20.63 4.30 twenty one 20.93 4.24 9 21.42 4.15 16 23.70 3.75 17 24.35 3.65 9 24.74 3.60 12 26.69 3.34 9

Table 20D

2θ (degrees) Lattice spacing (angstroms) relative strength 4.36 20.25 41 5.90 14.97 75 8.25 10.71 28 8.85 9.98 100 10.15 8.71 95 11.76 7.52 51 14.34 6.17 18 16.81 5.27 32 17.48 5.07 14 18.80 4.72 15 20.62 4.30 14 20.96 4.24 6 21.43 4.14 14 23.74 3.75 27 24.70 3.60 25 26.68 3.34 10

During the initial screening experiments, the solid form of pralatinib glutarate 11-A, which counterionizes this ion, was initially observed and found to be stable under both drying and humidification. TGA/DSC (Figure 29B) of pralatinib glutarate in solid form 11-A showed a gradual mass loss of 0.8 wt.% from 40 °C to the end of the melting event, which began at 187.9 °C. The water content, as determined by KF, was found to be below the detection limit for a sample size of 14.4 mg, and 1H-NMR showed 0.11 wt.% residual EtOH in the dried solid. The stoichiometry by NMR was higher than expected, with a ratio of 1.16:1 (CI:API). However, it should be noted that the peak corresponding to glutarate overlaps with one of the API peaks, which may increase calculation error. Pralatinib glutarate solid form 11-A exhibited high purity (99.85% by HPLC). The DVS isotherm of pralatinib glutarate solid form 11-A is shown in Figure 29C. The solid form 11-A of pralitinib glutarate showed a small mass change of 0.48 wt.% between 2% and 90% relative humidity. Between 15% and 75% relative humidity, the mass change was 0.27 wt.%. Minimal hysteresis was observed in the figure, and this water loss appears to be reversible.

During a week-long slurry experiment, pralitinib glutarate in solid form 11-A was converted in EtOH and EtOAc into a solid form designated as solid form 11-B, which is a mixture of pattern 11-B and another form. XRPD pattern 11-B (Fig. 30) of this solid form of compound (I) glutarate is provided with a list of XRPD peaks (e.g., Tables 21A, 21B, 21C, and 21D).

Table 21A

2θ (degrees) Lattice spacing (angstroms) relative strength 9.65 9.15 63 10.08 8.77 100 13.02 6.79 59 21.25 4.18 93 22.55 3.94 54

Table 21B

2θ (degrees) Lattice spacing (angstroms) relative strength 9.65 9.15 63 10.08 8.77 100 11.26 7.85 25 13.02 6.79 59 17.57 5.04 13 20.15 4.40 31 21.25 4.18 93 22.55 3.94 54 24.30 3.66 19 29.13 3.06 twenty one

Table 21C

2θ (degrees) Lattice spacing (angstroms) relative strength 8.82 10.01 6 9.65 9.15 63 10.08 8.77 100 11.26 7.85 25 13.02 6.79 59 17.57 5.04 13 19.54 4.54 5 20.15 4.40 31 21.25 4.18 93 22.55 3.94 54 24.30 3.66 19 29.13 3.06 twenty one

Table 21D

2θ (degrees) Lattice spacing (angstroms) relative strength 5.93 14.90 6 8.83 10.01 5 9.66 9.15 59 10.09 8.76 100 11.27 7.84 29 13.03 6.79 58 15.17 5.84 twenty four 17.56 5.05 11 19.53 4.54 10 20.16 4.40 twenty three 21.25 4.18 79 22.51 3.95 43 24.28 3.66 19 26.48 3.36 7 28.41 3.14 6 29.08 3.07 twenty four 29.68 3.01 7

Compound (I) can be prepared as a solid succinate. Praltinib succinate is prepared as a solid form 15-A, characterized by the XRPD pattern 15-A in Figure 31A, the DSC/TGA thermogram in Figure 31B, and/or the DVS isotherm pattern in Figure 31C. While pralatinib succinate solid 15-A separates from EtOH as a stable and highly crystalline solid, it exhibits higher residual solvent levels than other candidates and displays a wide range of low enthalpy events as observed by TGA/DSC, whereas other candidates exhibit a single rapid melting event. For example, pralatinib succinate solid form 15-A can be identified by an XRPD pattern containing a peak at the 2θ angle specified in Table 22.

Table 22

2θ (degrees) Lattice spacing (angstroms) relative strength 4.33 20.38 100 5.70 15.48 20 6.85 12.89 18 7.47 11.83 95 8.63 10.24 94 11.42 7.74 30 11.85 7.46 5 15.00 5.90 27 17.20 5.15 20 17.53 5.05 7 19.51 4.55 9 19.90 4.46 17 21.26 4.18 5 21.89 4.06 5 23.61. 3.77 14 25.95 3.43 19 28.63 3.12 5

The solid form of praltinib succinate, which provides XRPD pattern 15-A, is the only pattern of this counterion observed during the initial screening experiments and was found to be stable under both drying and humidification conditions.

From 45 °C to the end of the second endothermic reaction starting at 151.9 °C, TGA/DSC (Figure 31B) of the solid form 15-A of praltinib succinate showed a gradual mass loss of 1.7 wt.%. The first endothermic reaction began at 140.1 °C. Water content, as determined by KF, was found to be below the detection limit for the 8.2 mg sample size, and 1H-NMR showed 0.74 wt.% residual EtOH and 0.38 wt.% residual MeOH in the dry solid. The stoichiometry by NMR was higher than expected, with a ratio of 1.10:1 (CI:API).

The 15-A form of pralatinib succinate exhibits high purity (99.85% by HPLC). The solid form 15-A of pralatinib succinate is stable in a slurry formed in EtOH and EtOAc for 7 days, but transforms into pattern 15-C by XRPD in EtOH:water (95:5 vol). This pralatinib succinate is stable by HPLC, but its purity decreases by 0.13% in an EtOH:water (95:5 vol) slurry. The succinate transforms into pattern 15-A+B after exposure to 75% RH at 40°C for 7 days.

Praltinib succinate in solid form 15-A exhibits high solubility in simulated gastric fluid under fasting conditions. The solubility in simulated intestinal fluid under fasting conditions is 0.02 mg/mL. The solubility in simulated intestinal fluid under fed conditions is 0.84 mg/mL, and the residual solid is identified as amorphous. The solubility in simulated gastric fluid under fasting conditions is 1.12 mg/mL, and the resulting solid is designated as solid form 15-D. The solubility in water is 0.45 mg/mL.

The DVS isotherm of pralatinib succinate in solid form 15-A is shown in Figure 31C. Pralatinib succinate in solid form 15-A shows a mass change of 3.4 wt.% between 2% and 90% relative humidity. Between 15% and 75% relative humidity, the mass change is 1.9 wt.%. Minimal hysteresis is observed in the figure, and this water loss appears to be reversible. However, upon exposure to moisture in the DVS, a new peak appears in the XRPD plot that does not correspond to the free base or counterion, and the pattern is designated as pattern/solid form 15A+B.

Compound (I) can be prepared as a solid maleate. Maleate 8-A is only moderately crystalline, less so than the other candidates. However, it does have a melting initiation point, a clean thermogram, and NMR shows low residual solvent. Salicylate 10-A has low solubility in water and is isolated only from EtOAc, while IPA:water (9:1 vol) appears to give a mixed pattern, and the substance isolated from EtOH is amorphous. Despite the high crystallinity of salicylate 10-A and a single, sharp endothermic reaction at 167.3 °C, the low solubility of this substance rules out the possibility of its scale-up.

Compound (I) can be prepared in the form of a solid maleate, characterized by an XRPD pattern 8-A (Figure 32) having the XRPD 2θ degree and lattice spacing peaks shown in Table 23 below.

Table 23

2θ (degrees) Lattice spacing (angstroms) relative strength 6.69 13.21 100 7.55 11.69 75 8.26 10.70 35 12.78 6.92 17 13.28 6.66 30 14.02 6.31 26 15.03 5.89 11 15.74 5.63 13 16.42 5.39 38 18.99 4.67 12 20.59 4.31 10 25.18 3.53 6 26.20 3.40 9

Compound (I) can be prepared as a solid oxalate, characterized by an XRPD pattern 9-A (Figure 33A) having the XRPD 2θ degree and lattice spacing peaks shown in Table 24 below. Figure 33B provides a coupled TGA/DSC thermogram of the solid form 9-A of praltinib oxalate.

Table 24

2θ (degrees) Lattice spacing (angstroms) relative strength 6.69 13.19 100 7.89 11.19 30 8.34 10.60 36 9.12 9.69 twenty two 9.99 3.34 5 11.28 7.84 11 13:30 6.65 10 16.60 5.33 14 17.05 5.19 14 19.81 4.48 10 24.74 3.60 twenty two

Compound (I) can be prepared as a solid salicylate form 10-A, characterized by the XRPD pattern 10-A in Figure 34A and/or the DSC thermogram in Figure 34B. The solid form 10-A of pralatinib salicylate is characterized by the XRPD spectrum of the 20° and lattice spacing peaks shown in Table 25 below. The solid form 10-A of pralatinib salicylate was found to have 0.12 wt.% residual EtOAc in the sample by 1H-NMR, a stoichiometry of 1:1 (CI:API), and a single, rapidly endothermic onset at 167.3 °C.

Table 25

2θ (degrees) Lattice spacing (angstroms) relative strength 4.90 18.01 100 6.91 12.77 twenty four 8.90 9.93 twenty two 11.64 7.60 13 12.09 7.31 6 12.59 7.03 5 14.12 6.27 twenty one 15.88 5.57 27 16.38 5.41 13 17.82 4.97 10 18.24 4.86 14 20.28 4.37 5 21.19 4.19 13 21.79 4.08 15 22.64 3.92 6 24.47 3.64 5 25.32 3.51 10 26.08 3.41 8 30.19 2.96 9

Figure 34C is a DSC thermogram of pralatinib salicylate in solid form, designated as solid form 10-A+B. It exhibits the same endothermic event at 167.0 °C, as well as two low-temperature endothermic events starting at 87.03 °C and 127.0 °C. The endothermic event immediately following 127.0 °C is followed by an exothermic event starting at 137.1 °C.

Figure 48 shows the coupled DSC and TGA thermograms of pralatinib glutarate. The pralatinib glutarate salt in solid form 11-A exhibits a single endothermic TGA/DSC with an initial temperature of 177.8 °C and a low mass loss of 0.3 wt% from the start of the experiment to the end of melting. The zero mass loss after the melting event may be related to decomposition. ¹H-NMR revealed that the pralatinib glutarate salt in solid form 11-A has 0.09 wt.% residual EtOH and a stoichiometry of 1:1 (CI:API) in the sample.

Compound (I) can be prepared from solid sulfate form, such as pralatinib sulfate solid form 12-A, characterized by the XRPD pattern in Figure 35A and/or the DSC thermogram in Figure 34B. Pralatinib sulfate solid form 12-A (0.55 equivalents of sulfuric acid) is characterized by low broad-spectrum endothermic activity and low qualitative water solubility observed in DSC. Pralatinib sulfate solid form 12-A, obtained from 0.55 equivalents of sulfuric acid, exhibits broad endothermic activity associated with the hydrate, with an initial temperature of 81.7 °C, and two smaller endothermic periods, with initial temperatures of 159.7 °C and 207.6 °C, with evidence of decomposition above 280 °C.

Table 26

2θ (degrees) Lattice spacing (angstroms) relative strength 5.99 14.75 100 8.93 9.90 47 9.86 8.96 12 10.32 8.57 62 11.37 7.78 58 13.07 6.77 95 16.66 5.32 15 17.15 5.17 19 18.04 4.91 twenty one 18.73 4.73 5 20.22 4.39 49 21.85 4.06 35 23.02 3.86 7 25.28 3.52 54 26.92 3.31 14 29.57 3.02 13

Alternatively, compound (I) can be prepared in other solid sulfate forms having the XRPD pattern shown in Figure 35G, including solid forms of pralatinib sulfate characterized by XRPD patterns 12-B, 12-C, 12-D, 12-E, 12-F, 12-G, or 12-H (see Figures 35G, 35H, and 35I).

The solid form 12-B of pralatinib sulfate is characterized by the corresponding XRPD pattern 12-B (Fig. 35G) and/or the DSC thermogram of Fig. 35C obtained from 1.1 equivalents of sulfuric acid, which is a single endothermic, with an initial temperature of 184.9 °C and evidence of decomposition above 260 °C.

The solid form of pralatinib sulfate, 12-C, is characterized by the corresponding XRPD pattern 12-C (Fig. 35G) and/or the DSC thermogram of Fig. 35D obtained from 1.1 equivalents of sulfuric acid, which exhibits a broad endothermic event at 126.5 °C and 1H-NMR shows the presence of water, possibly indicating that this substance is a hydrate. This event is followed by two additional endothermic events at 154.7 °C and 186.4 °C prior to decomposition.

The solid form of pralatinib sulfate, 12-D, is characterized by the corresponding XRPD pattern 12-D (Fig. 35G).

The solid form of pralatinib sulfate, 12-E, is characterized by the corresponding XRPD pattern 12-E (Fig. 35H), and/or the DSC thermogram of Fig. 35E is observed to have two endothermic phases, the first of which begins at 119.0 °C as water precipitates from the hydrate, and the second of which begins at 169.6 °C.

The solid form of pralatinib sulfate, 12-F, is characterized by the corresponding XRPD pattern 12-F (Fig. 35H).

The solid form of pralatinib sulfate 12-G is characterized by the corresponding XRPD pattern 12-G (Figure 35G).

The solid form 12-H of pralatinib sulfate is characterized by the corresponding XRPD pattern 12-H (Fig. 35I). The solid form 12-H was also analyzed by DSC (Fig. 35F) and found to be endothermic, starting at 60.2 °C with a corresponding mass loss of 2.4 wt.%. Another gradual mass loss of 0.8 wt.% was observed until the endothermic melting at an initial temperature of 186.9 °C.

Although the stoichiometry of sulfate could not be determined by 1H-NMR, the residual solvent in solid form 12-A was 0.10 wt.% IPA, solid form 12-B was 3.10 wt.% EtOH, solid form 12-C was 5.86 wt.% EtOAc, and solid form 12-E was 3.20 wt.% IPA.

Compound (I) was prepared in several different solid tartrate forms. The first solid form 13-A of pralitinib tartrate is characterized by the XRPD pattern 13-A (Fig. 36A). Furthermore, although the DSC thermogram of pralitinib tartrate in solid form 13-A (Fig. 36B) shows a single endothermic event at 150.1 °C, the thermogram does exhibit a large, broad characteristic at lower temperatures and becomes disordered above 180 °C. Solid form 13-B of pralitinib tartrate has the DSC thermogram shown in Fig. 36C, exhibiting a broad endothermic event starting at 99.3 °C, followed by a more abrupt endothermic event starting at 127.6 °C. A third broad endothermic event was observed, starting at 169.3 °C. Another solid form of pralitinib tartrate, 13-C, exhibits the DSC thermogram shown in Figure 36D, revealing a large, broad characteristic, starting at 77.3 °C and followed by a sharp endothermic reaction at 132.4 °C. All three solid tartrate forms showed the presence of water in the samples. ¹H-NMR yielded the following stoichiometry for the tartrate samples: solid form 13-A was 0.79:1 (CI:API) with a residual solvent of 0.03 wt.% EtOH; solid form 13-B was 1.03:1 (CI:API) with a residual solvent of 0.34 wt.% EtOAc; and solid form 13-C was 1.03:1 (CI:API) with a residual solvent of 1.36 wt.% IPA.

The solid form of compound (I) can be prepared from urea and compound (I), characterized by XRPD pattern 16-A (Fig. 37A) and/or DSC thermograms of Fig. 37B. The solid produced by urea and free base in solid form FB-C, pattern 16-A (Fig. 37A), was found to exhibit a wide range of endothermic characteristics from low temperature to decomposition. The first endothermic event begins at 78.3 °C, followed by an endothermic event beginning at 131.1 °C, corresponding to the melting temperature of urea. This endothermic event has a shoulder peak at 136.7 °C, followed by a series of very wide endothermic events beginning at 170.8 °C, 179.6 °C, and 167.01 °C, respectively.

Compound (I) can be prepared as a salt of pralatinib and pyruvate. For example, the pyruvate of pralatinib can be in solid form 1-A characterized by XRPD pattern 1-A as shown in FIG. 38A, or in solid form 1-B characterized by XRPD pattern 1-B as shown in FIG. 38B.

Compound (I) can be prepared as a salt of pralatinib and citrate. For example, the citrate of pralatinib can be in solid form 3-A, characterized by the XRPD pattern 3-A shown in Figure 39.

Compound (I) can be prepared in the form of a solid fumarate. For example, the fumarate of pralatinib can be in solid form 4-A characterized by XRPD pattern 4-A as shown in Figure 40A, solid form 4-B characterized by XRPD pattern 4-B as shown in Figure 40B, solid form 4-C characterized by XRPD pattern 4-C as shown in Figure 40A, or solid form 4-D characterized by XRPD pattern 4-D as shown in Figure 40B.

Compound (I) can be prepared as a salt of pralatinib and saccharin. For example, the saccharin salt of pralatinib can be in solid form 6-A, characterized by the XRPD pattern 6-A shown in Figure 41.

Compound (I) can be prepared as a salt of pralatinib and gentic acid. For example, the gentic acid salt of pralatinib can be in solid form 7-A, characterized by the XRPD pattern 7-A shown in Figure 42.

Compound (I) can be prepared as a salt of pralatinib and its mesylate. For example, the mesylate of pralatinib can be in solid form 2-A, characterized by the XRPD pattern 2-A shown in Figure 43A and/or the TGA/DSC thermogram shown in Figure 43B. In other examples, the mesylate of pralatinib can be in solid form 2-A+2B, characterized by the XRPD pattern 2-A+2B shown in Figure 43C, and/or in solid form 2-B or 2-D, characterized by the XRPD pattern 2B or 2D shown in Figure 43D. In some examples, the salt of pralatinib and its mesylate can be in solid form 2-C, having the XRPD pattern 2-C shown in Figure 43E.

Compound (I) can be prepared as a salt of pralatinib and benzenesulfonic acid (BSA). For example, the BSA salt of pralatinib can be in solid form 18-A, characterized by the XRPD pattern 18-A shown in Figure 44.

Compound (I) can be prepared as a salt of pralatinib and hydrobromic acid (HBr). For example, the HBr salt of pralatinib can be in solid form 19-A, characterized by XRPD pattern 19-A as shown in Figure 45A and/or the TGA/DSC thermogram shown in Figure 45B. In other examples, the HBr salt of pralatinib can be in solid form 19-B or 19-C, characterized by XRPD pattern 19-B or 19-C as shown in Figure 45C, and/or in solid form 19-C, characterized by XRPD pattern 19-C as shown in Figure 45D. In some examples, the salt of pralatinib and HBr can be in solid form 19-C+D, having the TGA/DSC thermogram 19C+D shown in Figure 45E.

Compound (I) can be prepared as a salt of pralatinib and nitrate. For example, the nitrate of pralatinib can be in solid form 20-A, characterized by the XRPD pattern 20-A shown in Figure 46A or the TGA/DSC thermogram shown in Figure 46B.

Compound (I) can be prepared as a salt of pralatinib and quercetin dihydrate (QD). For example, the QD salt of pralatinib can be in solid form 17-A, characterized by the XRPD pattern 17-A shown in Figure 47.

Pharmaceutical Composition

The salt and solid forms of compound (I) can be used to manufacture and prepare pharmaceutical compositions. The pharmaceutical composition may comprise an active pharmaceutical ingredient (API) that contains, is substantially composed of, or is composed of compound (I) prepared according to applicable Good Manufacturing Practices (GMP). For example, the pharmaceutical composition may be a batch composition comprising compound (I) which may be converted from one or more suitable salt forms or free base solid forms, or between, during API manufacturing or preparation. For example, examples provide methods for manufacturing compound (I) in multiple salt and solid forms, and techniques for converting between multiple free base solid forms and salts of compound (I) in multiple solid forms. The salt and/or solid forms of compound (I) may be selected at different steps in the manufacture of the active pharmaceutical ingredient to provide desired physical properties, such as storage stability. APIs can be combined with one or more excipients to form drug substances in batch compositions conforming to Good Manufacturing Practices (GMP) (e.g., ICH Harmonized Tripartite Guideline, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients Q7, current version Phase 4 as of November 10, 2010). The FDA (Food and Drug Administration) provides applicable guidance on Good Manufacturing Practices (GMP) for the manufacture of active pharmaceutical ingredients (APIs) under an appropriate quality management system. For the manufacture of APIs under GMP, "manufacturing" is defined as all operations and related controls including material receiving, production, packaging, repackaging, labeling, relabeling, quality control, release, storage, and dispensing of the API. "API starting material" refers to raw materials, intermediates, or APIs used in the production of the API and incorporated as important structural fragments into the API structure. API starting materials typically have well-defined chemical properties and structures.

In some embodiments, the oral dosage form may comprise compound (I) and one or more pharmaceutically acceptable excipients, such as tablets or capsules. In some embodiments, the oral dosage form is prepared by converting the crystalline solid form of compound (I) into an amorphous form and then combining it with one or more excipients. In some embodiments, the oral dosage form of compound (I) is a capsule comprising compound (I) disclosed herein in a solid form. In some embodiments, the oral dosage form comprises fillers, lubricants, flow aids, anti-adhesives, and/or antistatic agents.

Example

instrument

Unless otherwise stated herein, the following instruments were used in the analysis of the free alkali solids in Examples 1-3 and to obtain the data shown in the corresponding figures.

As used herein, the term “pattern”* (where “*” represents any letter or number-letter combination (e.g., A, or 1-A or the like)) refers to the corresponding solid form of pralatinib in the form of a free base or salt characterized by the corresponding XRPD pattern (e.g., pattern A refers to the solid form of pralatinib in the form of a free base having XRPD pattern A; pattern 5-A refers to pralatinib hydrochloride having XRPD pattern 5-A).

Differential scanning calorimetry (DSC)

Differential scanning calorimetry (DSC) was performed using a Mettler Toledo DSC3+. The required sample amount was weighed directly into a sealed aluminum pan with a pinhole. Typical sample masses were 3–5 mg. The typical temperature range was 30 °C to 300 °C, with a heating rate of 10 °C per minute (total time 27 minutes). Typical DSC parameters are listed below.

Table 27

Dynamic vapor adsorption (DVS)

Dynamic vapor adsorption (DVS) was performed using a DVS Intrinsic 1. The sample was loaded into a sample pan and suspended from a microbalance. A typical sample mass for DVS measurements was 25 mg. Nitrogen gas bubbled through distilled water provided the required relative humidity. A typical measurement included the following steps:

1- Equilibrium at 50% RH

2-50% to 2% (50%, 40%, 30%, 20%, 10% and 2%)

a. Maintain at various humidity levels for a minimum of 5 minutes and a maximum of 60 minutes. The standard is a change of less than 0.002%.

3-2% to 95% (2%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%)

a. Maintain at various humidity levels for a minimum of 5 minutes and a maximum of 60 minutes. The standard is a change of less than 0.002%.

4-95% to 2% (95%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 2%)

a. Maintain at various humidity levels for a minimum of 5 minutes and a maximum of 60 minutes. The standard is a change of less than 0.002%.

5-2% to 50% (2%, 10%, 20%, 30%, 40%, 50%)

a. Maintain at various humidity levels for a minimum of 5 minutes and a maximum of 60 minutes. The standard is a change of less than 0.002%.

High-performance liquid chromatography (HPLC)

High-performance liquid chromatography (HPLC) was performed using an Agilent 1220 Infinity LC. The flow rate range was 0.2–5.0 mL/min, the operating pressure range was 0–600 bar, the temperature range was 5°C to 60°C above ambient temperature, and the wavelength range was 190–600 nm.

Table 28

Thermogravimetric analysis and differential scanning calorimetry (TGA and DSC)

Thermogravimetric analysis and differential scanning calorimetry (DSC) were performed using a Mettler Toledo TGA/DSC3+. The required sample volume was weighed directly into a sealed aluminum pan with a pinhole. Typical sample masses for measurement were 5–10 mg. The typical temperature range was 30 °C to 300 °C, with a heating rate of 10 °C per minute (total time 27 minutes). Nitrogen was used as the protective and purging gas (20–30 mL/min and 50–100 mL/min, respectively). Typical parameters for the DSC/TGA are listed below.

Table 29

X-ray powder diffraction (XRPD)

Use a Rigaku MiniFlex 600 or Bruker D8 Advance instead of Rigaku for powder X-ray diffraction.

Samples were fabricated on Si zero-gauge wafers. Typical scans were 2θ scans from 4 to 30 degrees, with 0.05-degree steps over five minutes at 40 kV and 15 mA. High-resolution scans were 2θ scans from 4 to 40 degrees, with 0.05-degree steps over thirty minutes at 40 kV and 15 mA. Typical XRPD parameters are listed below.

Table 30

For Bruker:

X-ray powder diffraction was performed using a Bruker D8 Advance equipped with a Lynxeye detector (i.e., Bragg-Brentanogeometry). Samples were prepared on Si zero-base wafers. The XRPD parameters are shown in Table A-1 below:

Table A-1

Unless otherwise stated herein, the following instruments were used in the analysis of salt solids in Examples 4-7 and to obtain the data shown in the corresponding figures.

Differential scanning calorimetry (DSC)

Differential scanning calorimetry was performed using Mettler Toledo DSC3+. Samples (3-5 mg) were weighed directly into a 40 μL sealed aluminum dish with a pinhole, and analyzed according to the following parameters:

Table 31

Dynamic vapor adsorption (DVS)

Dynamic vapor adsorption (DVS) was performed using DVS Intrinsic 1. Samples (12–31 mg) were placed in a sample pan, suspended from a microbalance, and exposed to a humidified nitrogen flow. Samples were held at each level for at least 5 minutes, moving to the next humidity level only when the weight change between measurements was less than 0.002% (time interval: 60 seconds) or when 240 minutes had elapsed. The following procedure was used:

1- Equilibrium at 50% RH

2-50% to 2% (50%, 40%, 30%, 20%, 10% and 2%)

3-2% to 95% (2%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%)

4-95% to 2% (95%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 2%)

5-2% to 50% (2%, 10%, 20%, 30%, 40%, 50%)

High-performance liquid chromatography (HPLC)

Agilent 1220 Infinity LC: High-performance liquid chromatography (HPLC) was performed using the Agilent 1220 Infinity LC. Flow rate range: 0.2–5.0 mL/min; operating pressure range: 0–600 bar; temperature range: 5°C to 60°C above ambient temperature; wavelength range: 190–600 nm.

Agilent 1220 Infinity 2LC: High-performance liquid chromatography (HPLC) was performed using the Agilent 1220 Infinity 2LC equipped with a diode array detector (DAD). Flow rates ranged from 0.2 to 5.0 mL/min, operating pressures from 0 to 600 bar, temperatures from 5°C above ambient to 60°C, and wavelengths from 190 to 600 nm.

The HPLC methods used in this study are as follows:

Table 32

Karl Fischer titration

Karl Fischer titration for water determination was performed using a Mettler Toledo C20S coulometric KF titrator equipped with a diaphragm-equipped current generator cell and double platinum needle electrodes. The instrument's detection range is from 1 ppm to 5% water. Aquastar ^™ CombiCoulomat glassless reagent was used in both the anolyte and cathode chambers. Approximately 0.03–0.10 g of sample was dissolved in the anolyte chamber and titrated until the solution potential dropped below 100 mV. A 1 wt.% water standard was used for validation prior to sample analysis.

Simultaneous thermogravimetric analysis and differential scanning calorimetry (TGA and DSC)

Thermogravimetric analysis and differential scanning calorimetry (DSC) were performed simultaneously on the same sample using a Mettler Toledo TGA/DSC3+. The protective gas and purge gas were nitrogen at flow rates of 20-30 mL/min and 50-100 mL/min, respectively. The required sample volume (5-10 mg) was weighed directly into a sealed aluminum dish with a pinhole, and the analysis was performed according to the following parameters:

Table 33

Common abbreviations

Unless otherwise stated, the following abbreviations shall be used throughout the instruction manual.

Table 34A

Table 34B

Table 36C

Example 1: Compound Synthesis

1A. Synthesis of compound (I)

For each form of compound (I) (i.e., pralatinib) described in Example 1B of this document and for each HCl salt of compound (I) described in Example 4 of this document, compound (I) may be prepared as described with respect to compound 130 disclosed in publication WO2017/079140.

1B: Synthesis of compound (I) in solid form

a) Crystallize solid form A (anhydrous) in a methanol/water system. Add 2-3 g of compound (I) to a container, followed by 6.5 vol of MeOH. Stir the mixture at 350 rpm (approximately 0.25 W/kg) using a backward-curved impeller throughout the process. Heat the mixture to 60-65°C over a 35-minute period, observing dissolution at 63-64°C. Then cool the solution to 44-45°C, adding 1 volume of water over a 20-minute period. Inoculate the solution as is with 0.5 wt.% solid form A in a saturated methanol:water (1:1 vol). Over 6 hours, add 4.5 vol of water to obtain a final composition of methanol:water (54:46 vol). Hold the solution at 45°C for 6-10 hours, then cool to 25°C (-10°C/h) over 2 hours, and then hold at 25°C for 1-2 hours. The mixture was then filtered and washed with 2×2 volumes of methanol:water (1:1 vol), and dried under vacuum at 50°C overnight to give an anhydrous solid form A of 85%-88% w/w.

Upon prolonged exposure to moisture, solid form A did not transform into solid form C. In a competitive slurry experiment with methanol:water, solid form A transformed into solid form C at a high water-to-methanol ratio and lower temperature. Solid form A exhibited low solubility in simulated intestinal fluid and water, but high solubility in simulated gastric fluid (possibly due to transformation into an HCl salt).

b) Crystallization of solid form C (hydrate) in an acetone/water system. Compound (I) was added to 10 volumes of acetone/water in an 87:13 v/v solution and the mixture was heated to 50-55°C to dissolve. The temperature was adjusted to 40°C, and 3 volumes of water were added over a 30-minute period (at a rate of 15 mL/h, 2.5 g scale) to obtain an acetone/water solvent system of 67:33 v/v. The solution was seeded with 0.5 wt.% solid form C, wherein the seed crystals were added as a slurry of water treated by acoustic wave. The slurry was maintained for 6 hours, and then 7 volumes of water were added over an 8-hour period (at a rate of 2.2 mL/h, 2.5 g scale) to form an acetone/water solvent system of 43:57 v/v. The mixture was cooled to 23°C and filtered, with a yield of 85%-90%.

c) After drying at 50°C, solid form C (hydrate) is transformed into dehydrated solid form B. Example 2: Screening of polymorphs of solid form C

Polymorph screening was performed starting with a sample of solid form C, the free base form of compound (I), including (a) short-term slurry, (b) evaporative crystallization, (c) cooling crystallization, (d) antisolvent crystallization, (e) grinding, (f) amorphous slurry, and (g) heat treatment, as described in the polymorph screening of Example 2 below.

Example 2A: Short-term slurry

During the initial screening, short-term slurries were formed in 15 solvents at two temperatures. The starting solid was pattern C. Most solids remained pattern C after slurry formation. At both temperatures, the solids transformed into pattern A in EtOH, IPA, acetone, and acetonitrile.

In EtOAc, the solid remains in solid form C at room temperature, but transforms into solid form A at 50°C. In IPAc, the solid remains in solid form C at room temperature, and a partial transformation into solid form A is observed at 50°C. A slurry forms in chloroform at room temperature, producing a thin slurry that forms a two-phase system upon centrifugation. The upper phase is viscous and produces a small amount of solid form characteristic of the XRPD pattern H upon filtration.

Table 37

Example 2B: Evaporation Crystallization

Some of the supernatant from the slurry was recovered for evaporative crystallization. The solution was evaporated to dryness at 50°C under atmospheric pressure, and then placed under vacuum at 50°C for 1.5 hours. Most of the resulting solids were in solid form A; however, evaporation from DCM and chloroform produced amorphous solids via XRPD. These solids may be solvates whose structures collapse into amorphous solids upon drying. The results are summarized in Table 38. The evaporation concentrations differed where the two experiment numbers were indicated.

Table 38

*Awaiting confirmation from other analytical methods.

Example 2C: Cooling Crystallization

Cooling crystallization was performed in a series of solvent systems. Two cooling schemes were used: cooling from 50°C at 5°C per hour, and rapid cooling from 50°C to 0°C. In all experiments, the solid completely dissolved before cooling. If the solid did not precipitate from the solution at room temperature or 0°C for slow or rapid cooling, the solution was further cooled to -20°C. In most cases, the solid did not precipitate at -20°C. Cooling in IPA yielded solid form A. Cooling in acetone at -20°C yielded a very dilute slurry, but the solid dissolved rapidly after being transferred to room temperature and filtered. Cooling in THF yielded two low-crystallinity solids, solid form N (rapid cooling) and solid form I (slow cooling). Pattern I lost its crystallinity upon drying. Rapid cooling in MeOH:chloroform yielded solid form D, which transformed into solid form B upon drying. This suggests that solid form B may not necessarily be a dehydrated form of solid form C, but rather an anhydrous solid. The results are summarized in Table 39.

Table 39

Example 2D: Antisolvent crystallization

Antisolvent crystallization was carried out in various solvent systems. First, approximately 30 mg of the solid free base (solid form C) of compound (I) characterized by XRPD pattern C was dissolved in a solvent. Antisolvent crystallization was then performed using either direct or reverse addition. For direct addition, the antisolvent was added dropwise to the solution until a slurry was formed. For reverse addition, the solution was added to the antisolvent in a single addition. The volume of antisolvent used was four times the volume of solvent required to dissolve the solid. For example, if 0.15 mL of solvent was needed to dissolve the solid, the solution was immediately added to 0.30 mL of antisolvent. Once a solid was formed, the slurry was filtered and the solid was recovered for XRPD analysis. The XRPD results of the reverse antisolvent experiments are summarized in Table 40A.

Table 40A

The XRPD results of the direct antisolvent experiments are summarized in Table 40B.

Table 40B

Pattern O shares peaks with pattern B, but differences are observed at high angles in the XRPD pattern, and pattern O has additional peaks compared to pattern B.

Pattern J was observed in the THF/cyclohexane system and it lost its crystallinity or became amorphous upon drying (i.e., the crystal structure began to collapse as THF evaporated).

Example 2E: Grinding

Solvent milling was performed using a small ball mill with 1/4” stainless steel balls as the milling medium. Approximately 50 mg of solid free base of compound (I) characterized by XRPD pattern C was weighed into a container and one volume of solvent was added. Milling was performed in increments of 3 × 30 seconds, scraping the solid off the container wall to minimize clumping between millings. Dry milling produced a lower crystalline solid form characterized by XRPD pattern C. A conversion to solid form A was observed after milling with MeOH and EtOH, consistent with observations in the slurry experiments (solid form C converted to solid form A in EtOH). Some conversion to solid form A was observed after milling with THF, and the solid also lost its crystallinity. The solid remained in solid form C, with trace amounts of solid converting to solid form A, but losing crystallinity upon milling with EtOAc. The results are summarized in Table 41.

Table 41

solvent XRPD pattern (initial) XRPD pattern none C C (Low crystallinity) MeOH C A EtOH C A÷Trace C THF C C ÷ some A (low crystallinity) EOAc C C ÷ some A (low crystallinity)

Example 2F: Amorphous Slurry

Amorphous solids were prepared by forming a very dilute slurry in chloroform and then evaporating the slurry. The resulting solid was amorphous by XRPD. The amorphous solid from the experiment (evaporated from the chloroform slurry) was slurried in 250 μL of solvent for 1 hour, filtered, and then subjected to XRPD. Gel formation was observed in the case of IPA, so the mixture was centrifuged and the gel was subjected to XRPD. When slurries were formed in MtBE, IPAc, ACN, acetone, and IPA, low-crystallinity substances with XRPD pattern H were observed. The amorphous solid remained in cyclohexane, and the solid remained in an IPAc solution. The results are summarized in Table 42.

Table 42

Solids (mg) solvent pattern 8.8 MIBE H 8.3 IPAc No solid 10.5 ACN H 9.5 acetone H 11.4 Cyclohexane Amorphous 11.1 IPA H

Example 2G: Heat Treatment

The selected solids were used for heat treatment in DSC. The solids were heated to a specified temperature and then cooled to room temperature for analysis by XRPD. The results are summarized in Table 30. Solid form C transformed into solid form B upon heating to 150 °C. Solid form A did not transform into the substance with XRPD pattern H after being held at its melting point. Solid form B transformed into solid form A upon heating to 190 °C. Solid form F transformed into solid form B upon heating to 140 °C.

Table 43

Starting pattern Heating solution The resulting pattern C(1-1) Heat to 150°C, then cool. B A(23) Maintain at 205°C for 10 minutes, then cool. A B(17-2) Up to 190°C, then cooled A F(17-4) Up to 146°C, then cooled B

Example 3: Salt Screening

Compound (I) was salt-screened using 15 counterions and three solvents, while eutectic screening employed 5 potential co-formations. Most counterions formed crystalline patterns. Fumarate and sulfate changed upon drying. Citrate, hydrochloride (5-A), and gentianate were deliquescent upon exposure to >95% relative humidity. Pyruvate, saccharin salt, and sulfate derived from 1.1 equivalent experiments all changed upon exposure to >95% relative humidity. X-ray powder diffraction patterns for many salts were stable to both drying and moisture exposure (maleate 8-A, oxalate 9-A, glutarate 11-A, succinate 15-A, and phosphate 14-A). Low-crystallinity patterns were obtained with pyruvate, sulfuric acid, citric acid, fumaric acid, and saccharin, while medium to high-crystallinity patterns were obtained from hydrochloric acid, maleic acid, oxalic acid, salicylic acid, glutaric acid, sulfuric acid, succinic acid, tartaric acid, and phosphoric acid. All salts showed improved solubility compared to free bases, and the selection results are summarized in Table 44.

Table 44

Five counterions (I) listed in Table 32 were used for evaluation during salt screening. EtOH, EtOAc, and IPA:water (9:1 vol) were selected solvents for salt screening and will also be used in this project. Data generated during this project are summarized in Tables 45 and 46. Additional counterions (I) listed in Table 45 were also evaluated.

Table 45

Table 46

Table 47

Table 48

ID Counterions pKa (lowest) Equivalent number used for filtering Solvent of the stock solution 1 Pyruvic acid 2.39 1.1 EtOH 2 benzoic acid 4.19 1.1 EtOH 3 Citric acid 3.13 1.1 EtOH 4 fumaric acid 3.03 1.1 EtOH 5 hydrochloric acid -6 2.2 EtOH 6 saccharin 1.31 1.1 EtOH 7 Gentian acid 2.93 1.1 EtOH 8 Maleic acid 1.92 1.1 EtOH 9 oxalic acid 1.27 1.1 EtOAc 10 salicylic acid 2.97 1.1 EtOH 11 glutaric acid 2.93 1.1 EtOH 12 sulfuric acid -3.0 0.55, 1.1 MeOH 13 tartaric acid 3.02 1.1 EtOH 14 Phosphoric acid 1.96 1.1 EtOH 15 Succinic acid 4.21 1.1 EtOH

Example 3A: Salt Screening

Prepare a stock solution of the free base (60.09 mg/mL) in MeOH. Depending on the solubility, prepare stock solutions of the counterions in EtOH, MeOH, or EtOAc. Salt formation is carried out at room temperature in 2 mL vials. Add 30 mg of compound (I) (499.3 μL stock solution) and 1.1 equivalents of the counterion to each vial, except for HCl (2.2 equivalents) and sulfuric acid (0.55 and 1.1 equivalents respectively). Allow the solvents to evaporate at room temperature over the weekend, then place under vacuum at 50°C for 3 hours to remove any residual solvent.

Approximately 25 volumes (0.6 mL) of solvent were added to each vial for screening. The three solvents selected were EtOH, EtOAc, and IPA:water (9:1 vol). After adding the solvent, the mixture (or solution) was stirred at 45°C for 1.5 hours, then cooled to room temperature and stirred overnight, and any solids produced were collected.

XRPD analysis was performed in three stages. All samples underwent wet cake XRPD. The unique solid was then left on the XRPD pan and vacuum dried at 50°C. XRPD of the unique dry solid was then performed. The solid was then exposed to 97% relative humidity for at least one day, and XRPD was performed on the resulting solid. The humid environment was created by placing a beaker containing a saturated potassium sulfate aqueous solution in a sealed container. All XRPD patterns were compared with counterion XRPD patterns and known free base patterns.

Unique XRPD patterns for salts are identified by their ID numbers, and then additional patterns are specified alphabetically. For example, the third unique XRPD pattern for citrate would be designated as 3-C.

If the amount of solids is insufficient for separation, evaporate the solvent at room temperature, actively vacuum dry the substance at 50°C for 3 hours, then heat it to 45°C for 30 minutes, and then reform the slurry overnight at room temperature in MtBE or IPAc.

During the screening phase of this project, pattern FB-A (anhydrous) (i.e., solid form A of the free base of pralatinib) was separated from a slurry containing the free base of compound (I) in EtOH, while pattern FB-C (hydrated) (i.e., solid form C of the free base of pralatinib) was collected from a slurry utilizing EtOAc. A mixture of pattern FB-A and FB-C was collected from an IPA:water (9:1 vol) slurry.

Pyruvate is poorly crystalline and stable for drying, but upon humidification, solid form 1-B with XRPD pattern 1-B transforms into pattern 1-C, and a peak shift is observed in solid form 1-A with XRPD pattern 1-A. Upon exposure to moisture, the almost amorphous pattern acquires a peak at 26.54. The solid formed with pyruvate is soluble in IPA:water (9:1 vol) and is alternatively separated from MtBE. Pyruvate, pattern 1-B, exhibits a single endothermic reaction, starting at 95.43 °C with a corresponding mass loss of 3.2 wt.%, followed by a 9.9 wt.% mass loss until operation ends at 300 °C.

No salt formation was found between benzoic acid and compound (I), and only peaks associated with the free base pattern FB-C were observed. Solids were separated from MtBE and IPAc.

Citrate is stable to dryness, with a low crystalline form collected from EtOH and IPA:water (9:1 vol), and higher crystallinity observed from the EtOH system. Amorphous substances were isolated from EtOAc. All solids were found to deliquesce upon exposure to moisture. Low crystalline citrate, pattern 3-A, was observed with three extensive endothermic reactions, starting at 124.4 °C, 153.7 °C, and 195.9 °C, with corresponding mass losses of 3.8 wt.%, 9.8 wt.%, and 4.6 wt.%, respectively.

Fumarates, patterns 4-A and 4-B, transform into patterns 4-C and 4-D, respectively, upon drying and are stable upon humidification. Pattern 4-D was analyzed using TGA/DSC and revealed three extensive endothermic events, starting at 111.8 °C, 167.9 °C, and 203.2 °C. The first endothermic event resulted in a mass loss of 3.5 wt.%, while the second endothermic event showed a much smaller mass loss of 0.3 wt.%. The final observed endothermic event had a mass loss of 6.2 wt.%. The lower-crystalline pattern, pattern 4-C, was also analyzed by TGA/DSC and was found to also exhibit three extensive endothermic events. A first extensive endothermic event was observed starting at 101.0 °C with a associated mass loss of 2.3 wt.%. The second endothermic event started at 181.7 °C and continued until 205 °C, with a associated mass loss of 8.5 wt.%. Both Pattern 4-D and Pattern 4-C show evidence of hydrate formation in DSC/TGA and 1H-NMR spectra.

The stoichiometry of patterns 4-D and 4-C was determined to be 0.96:1 and 0.6:1 (CI:API) by 1H-NMR, respectively. 0.26 wt.% IPA was present in the 1H-NMR of pattern 4-D, while EtOH was BDL in the 1H-NMR of pattern 4-C.

The HCl salt (2.2 equivalents) formed a viscous slurry in all three solvent systems. The substance collected from EtOAc and IPA:water (9:1 vol) was identified as pattern 5-B and dried to pattern 5-C, and was stable upon humidification. Pattern 5-A was separated from the slurry of the HCl salt in EtOH and was stable upon drying, but deliquescent upon increased humidity.

The salts formed with saccharin are low-crystalline or amorphous and stable to dryness, but the low-crystalline pattern, pattern 6-A, transforms into an amorphous form with a single peak upon exposure to increased humidity. The amorphous form deliquesces upon exposure to increased humidity. The solids formed with saccharin are soluble in EtOH and IPA:water (9:1 vol) and can be separated from MtBE and IPAc.

Gentian acid forms amorphous or low-crystallinity salts. In both cases, the substance deliquesces upon exposure to elevated humidity, and the amorphous form with a broad peak is observed to deliquesce under laboratory storage conditions (relative humidity approximately 56%). The amorphous form acquires a low-crystallinity, high-angle peak upon exposure to moisture. The solid formed from gentian acid is soluble in EtOH and IPA:water (9:1 vol) and can be separated from MtBE and IPAc.

Maleic acid and oxalic acid formed crystalline substances with the free base of BLU-667 in all three solvents, designated as patterns 8-A and 9-A, respectively. Both patterns were stable to drying and humidification, forming white slurries in EtOH and EtOAc. However, in IPA:water (9:1 vol), both slurries froze after stirring overnight.

Maleic acid forms a pattern, pattern 8-A, which exhibits a gradual mass loss of 1.1 wt.% until the first endothermic event begins at 188.5 °C, with a associated mass loss of 2.3 wt.%. A further mass loss of 6.5 wt.% is observed in the third endothermic event, which begins at 196.1 °C.

1H-NMR showed that the stoichiometry of pattern 8-A was 0.91:1 (CI:API), and 0.13 wt.% EtOH was the residual solvent.

The salt formed with salicylic acid is amorphous when it forms a slurry in EtOH and moderately crystalline in EtOAc, pattern 10-A. The substance separated from IPA:water (9:1 vol) was identified as pattern 9-A, which has additional peaks not corresponding to the free form of API or salicylic acid, and was designated as pattern 10-A+B. The amorphous form transforms into pattern 10-C upon humidification, and patterns 10-A+B and 10-A are stable for both drying and humidification. The solid formed with salicylic acid is soluble in EtOH and IPA:water (9:1 vol) and is alternatively separated from MtBE and IPAc. In MtBE, the solid forms a gel-like substance, while in EtOAc and IPAc, the solid freezes after stirring overnight.

Glutaric acid forms a highly crystalline salt, known as pattern 11-A, which is stable to both drying and humidification. The solid formed with glutaric acid dissolves in IPA:water (9:1 vol) and is instead separated from MtBE. All solids were observed to be a thick slurry prior to filtration.

The solid produced by 0.55 equivalents of sulfuric acid from EtOH and EtOAc is a very low-crystallinity solid, confirmed as pattern 12-A, which separates as a highly crystalline solid from IPA:water (9:1 vol). 1.1 equivalents of sulfuric acid and free base form a highly crystalline substance, but it is extremely polymorphic. Only pattern 12-A is stable to both drying and humidification, while patterns 12-B and 12-C are stable to drying. Pattern 12-C is very similar to pattern 12-E, which is produced by drying pattern 12-D. All crystalline solids formed with 1.1 equivalents of sulfuric acid become low-crystallinity patterns upon humidification, i.e., pattern 12-F. The solid formed with 0.55 equivalents of sulfuric acid is soluble in EtOH and separates from MtBE. The consistency of the slurry varied from white and flowable (0.55 equivalent sulfuric acid in MtBE) to thick (0.55 equivalent sulfuric acid in EtOAc and IPA:water (9:1 vol) and 1.1 equivalent in EtOAc) to frozen (1.1 equivalent in EtOH) or thick and gel-like (1.1 equivalent in IPA:water (9:1 vol)).

To characterize patterns 12-A and 12-B, an additional solid was produced by directly weighing 30 mg of free base into a 2 mL vial and forming a slurry in 1.0 mL of solvent. Ethanol was used to produce pattern 12-B, and IPA:water (9:1 vol) was used for pattern 12-A. Sulfuric acid was added dropwise to a solution in a suitable solvent system. Salt formation was incomplete after stirring overnight at room temperature; therefore, the slurry was heated to 50 °C for half an hour before cooling and then stirred at room temperature for another 4 hours. The solid was collected and actively vacuum dried at 50 °C for at least 6 hours. An additional 12-A was successfully produced; however, a new sulfate (1.1 equivalent sulfuric acid) pattern was produced, with some peaks resembling those of pattern 12-B. This new pattern was designated as pattern 12-G+2 peaks. This pattern transformed into pattern 12-H upon drying and reverted to pattern 12-G upon humidification.

Tartaric acid reacts with the free base of pralatinib to form a highly crystalline solid, with each solvent producing a different polymorph. The solid is stable to both drying and humidification. The slurry in IPA:water (9:1 vol) becomes viscous and gel-like after initial dissolution, and the solid in EtOH is also very viscous, while the slurry in EtOAc is more fluid.

Phosphoric acid and the free base of compound (I) produce a highly crystalline pattern, pattern 14-A, which is stable to both drying and humidification. The slurries in all three solvents are viscous.

The solids formed with succinic acid were all designated as pattern 15-A, but only the wet cake from EtOH exhibited high crystallinity. Drying reduced crystallinity, and the amount of solids collected from EtOAc and IPA:water (9:1 vol) was insufficient to produce a crystalline XRPD pattern. The solids were a white slurry in EtOH and EtOAc, and thinner in IPA:water (9:1 vol).

Figures 26A-26C summarize the XRPD results from the screening. In the summary tables of XRPD results from the screening (wet, dry, and after exposure to moisture), solvent in parentheses indicates that the original solution has been evaporated to dryness and new solvent has been added to the slurry. Hyphens indicate that the analysis was not completed.

Example 3B: Co-grinding

Approximately 30 mg of compound (I) free base and 1.05 equivalents of co-formed material were directly weighed into a grinding bag and manually mixed, followed by the addition of 1 volume of solvent (MtBE, MeOAc, or EtOH). Each system was ground once for 30 seconds before collecting the solids. The wet material was sampled for XRPD of the ‘wet’ material and then dried at 50°C for 2 hours under active vacuum. The unique pattern was further exposed to 97% R.H. for 24 hours.

From the co-grinding experiment, only urea and free base produced crystalline solids, which were identified as containing a new pattern, pattern 16-B. However, this substance also contained the free base pattern FB-C. Other potential co-formations either produce substances with a powder pattern containing crystalline FB-C, or produce combinations of crystalline FB-C and co-formations.

The solid containing 16-B and FB-C was dried to produce a substance containing crystalline urea. The urea-related peaks disappeared upon humidification.

Table 49 is a summary of the eutectic XRPD results from the co-grinding screening.

Table 49

Example 3C: Eutectic

Approximately 30 mg of pralatinib free base and 1.05 equivalents of the co-formed product were weighed directly into a 2 mL vial and thoroughly mixed until a visually homogeneous mixture was obtained. The resulting powder was loaded into a 100 μL DSC pan and heated at a rate of 10 °C/min to a temperature 10 °C higher than the melting temperature of the lowest melting component. The experiment was held isothermally for 5 minutes, then cooled to room temperature at a rate of 10 °C/min. Samples were then taken for XRPD.

Only the eutectic of urea and free base produces crystalline substances, and it is determined to have a pattern FB+A with urea.

Table 50 summarizes the eutectic XRPD results from the eutectic screening.

Table 50

The coupling of TGA/DSC or DSC to the crystalline solids produced during salt screening depends on the sample. TGA/DSC is the preferred characterization method when sufficient material is produced; however, many experiments result in low quantities of recovered solids. In these cases, independent DSC is used for characterization. The data are summarized in the tables of Figures 26A and 26B.

The crystalline solid, which is an permitted substance, was subjected to solution 1H-NMR in DMSO-d6 and characterized to determine the stoichiometry of counterions or co-formations and the quantitative presence of residual solvent.

Example 4: Compound (I) HCl salt in solid form

a) Pralatinib HCl salt form 5-A

A solution of compound (I) (60 mg/mL) was prepared in MeOH. 2.2 equivalents of HCl were added to 0.6 mL of EtOH. 0.5 mL of the MeOH/compound (I) solution was added to the EtOH/HCl solution. The mixture was stirred at 45 °C for 1.5 hours, then cooled to room temperature and stirred overnight. The mixture was then filtered, and XRPD was removed from the wet solid (Fig. 27A). This form was identified as form 5-A, an HCl salt. Form 5-A is stable to dry conditions but deliquescent at high humidity.

b) 5-B and 5-C of pralatinib HCl salt

A solution of compound (I) (60 mg/mL) was prepared in MeOH. 2.2 equivalents of HCl were added to 0.6 mL (25 volumes) of IPA/water (9:1). 0.5 mL of the MeOH/compound (I) solution was added to the IPA/HCl solution. The mixture was stirred at 45 °C for 1.5 hours, then cooled to room temperature and stirred overnight. The mixture was then filtered, and XRPD was removed from the wet solid. This wet form was identified as form 5-B, an HCl salt. This substance was then vacuum dried at 50 °C for 3 hours to remove any residual solvent. After drying, form 5-B was converted to form 5-C, which is stable for humidification and stability.

The HCl salt exhibits high purity (99.89% by HPLC). Pattern 5-B is stable for 7 days in slurries formed in EtOH, EtOAc, and EtOH:water (95:5 volume) by XRPD and HPLC. The HCl salt is also stable after 7 days of exposure to 75% RH at 40°C.

Example 5: Compound (I) in solid phosphate form

A slurry was formed at 35°C by dissolving 0.5255 g of the free base of compound (I) in 7.5 vol EtOH. Phosphoric acid, in a solution of 1.1 equivalents at 0.033 g/mL in EtOH, was added dropwise over 1 hour in 15-minute increments. After the initial addition of acid solution, a scraper tip of solid 14-A was added as a seed crystal. The initial API slurry was thin and turbid, but began to thicken after the first addition of phosphoric acid and seed crystals. After the second addition of phosphoric acid solution, the slurry was very viscous, but became more flowable with each subsequent addition of acid. The slurry was heated to 50°C and stirred for 1 hour while remaining flowable. The slurry was cooled to room temperature and stirred overnight.

XRPD analysis of the wet cake confirmed that the solid crystals were in solid form 14-A before drying. Microscopic examination revealed a fine granular morphology.

Filter the solid and dry the wet cake overnight under static vacuum at 50°C.

Example 6: Compound (I) glutarate in solid form

0.5092 g of the free base of compound (I) was prepared into a slurry in 7.5 vol EtOH at 35 °C. Glutaric acid, in a solution of 1.1 equivalents at 0.083 g/mL in EtOH, was added dropwise over 1 hour in 15-minute increments. After the initial addition of the acid solution, a scraper tip of solid form 11-A was added as a seed crystal. The initial API slurry was thin and turbid, but began to thicken after the first addition of glutaric acid and the seed crystal. After the second addition of the glutaric acid solution, the slurry was very viscous and almost motionless. Adding 5 vol EtOH made the slurry flowable. The slurry continued to thicken during subsequent additions of glutaric acid. The slurry was heated to 50 °C and stirred for 1 hour until it became flowable. The slurry was then cooled to room temperature and stirred overnight, resulting in a flowable slurry with large particles. XRPD showed only partial salt formation.

An additional 0.25 equivalents of glutaric acid were added to the slurry, and the solvent was evaporated to dryness. The solid was then dissolved in a minimal amount of MeOH at 50°C. The solution was removed from the heat source and inoculated with solid form 11-A. A thin slurry was formed, and the MeOH was evaporated at room temperature under a gentle nitrogen flow to condense into a solvent until a thick slurry was formed.

XRPD confirmed the solid to be in solid form 11-A glutarate, and the solid was filtered and dried under static vacuum at 50°C. The amount of solid collected was low, therefore additional scale-up was performed to produce sufficient material for analysis. Slurry samples used for microscopic examination showed the solid to be needle-like in morphology.

Example 7: Compound (I) succinate solid form

0.5020 g of the free base of compound (I) was dissolved in 10 vol MeOH at 50 °C. Succinic acid, in a solution of 1.1 equivalents at 0.028 g/mL in EtOH, was added dropwise over 1 hour in 15-minute increments. After the initial addition of acid solution, a scraper tip in solid form 15-A was added as a seed crystal, and this process was repeated after the second addition of acid. The solution became turbid after the addition of the seed crystal and began to thicken slightly during the acid addition, but remained thin after the final addition of glutaric acid. The MeOH was evaporated at 35 °C with a gentle nitrogen stream, and the solid was dried under active vacuum at 50 °C. The solid was then slurried in EtOH at 45 °C for 20 minutes. The slurry was then cooled to room temperature, and 2.5 vol of additional EtOH was added to loosen the very thick, stationary slurry so that it could be filtered. The solid was collected by vacuum filtration and dried overnight under a combination of static and active vacuum. Microscopic examination of the slurry revealed that it was morphologically fine needle-like and tended to form almond-shaped aggregates. XRPD analysis confirmed that it was in solid form 15-A.

Additional implementation plan

It should be understood that although the invention has been described in conjunction with its detailed description, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the claims. Those skilled in the art will recognize or be able to determine many equivalents of the particular embodiments of the invention described herein using only conventional experimentation. Such equivalents are intended to be covered by the following claims. All references and publications cited above are incorporated herein by reference.

Claims (59)

1. A compound (I) or a pharmaceutically acceptable salt thereof in crystalline solid form, 2. The solid form as claimed in claim 1, comprising a free base of compound (I). 3. A pharmaceutically acceptable salt of compound (I), 4. The solid form as claimed in claim 3, comprising compound (I) and a salt of an antiion selected from the group consisting of benzenesulfonic acid, methanesulfonic acid, hydrochloric acid, hydrobromic acid, and nitric acid. 5. The solid form of claim 3, comprising compound (I) and a salt of an antiion selected from the group consisting of: pyruvic acid, citric acid, fumaric acid, hydrochloric acid, saccharin, gentian acid, maleic acid, oxalic acid, salicylic acid, glutaric acid, sulfuric acid, tartaric acid, phosphoric acid, and succinic acid. 6. The solid form as claimed in any one of claims 1 or 3-5, comprising the hydrochloride salt of compound (I). 7. The anhydrous crystalline solid form of a free base of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide. 8. A crystalline solid form A of a free base of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide. 9. A solid form of a free base of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in 2θ degrees of approximately the following (±0.2): 5.0°, 9.7°, 12.7°, 13.6°, and 16.1°. 10. The solid form according to any one of claims 7-9, further characterized in that it has diffractive XRPD patterns at angles (2θ ± 0.2) of 5.0°, 9.7°, 12.7°, 13.6° and 16.1°, said angles corresponding to lattice spacings (Å ± 0.2) of 17.8, 9.1, 7.0, 6.5 and 5.5, respectively. 11. The solid form as claimed in any one of claims 7-10, characterized by X-ray powder diffraction (XRPD) with additional diffraction at angles (2θ ± 0.2) of 6.8, 19.2, 19.5 and 23.5. 12. The solid form as claimed in claim 11, characterized in that it has diffractive XRPD patterns at angles (2θ ± 0.2) of 6.8, 19.2, 19.5 and 23.5, said angles corresponding to lattice spacings (Å ± 0.2) of 13.0, 4.6, 4.5 and 3.8, respectively. 13. The solid form as claimed in any one of claims 7-12, characterized by X-ray powder diffraction (XRPD) showing peaks at the same or substantially the same angle (20 ± 0.2) and corresponding lattice spacings (A ± 0.2) as follows: . 14. The solid form as claimed in any one of claims 7-13, further characterized by one or more of the following: a. Differential scanning calorimetry (DSC) thermograms showing an endothermic event observed at approximately 205 °C; and b. Based on the reversible mass change of approximately 10% between 2% and 95% relative humidity for DVS. 15. The solid form of any one of claims 9-14, wherein it is the solid form A of the free base of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide. 16. The solid form as claimed in any one of claims 7-15, characterized in that the XRPD pattern A. 17. The solid form as claimed in any one of claims 7-16, obtained by a method comprising steps selected from the group consisting of: a. Formation of a slurry in alcohol, acetone, or ACN; b. Evaporation crystallization and cooling crystallization in IPA and 1-propanol; and c. Recrystallization in acetone:water. 18. A crystalline solid form B of a free base of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide. 19. A solid form of a free base of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide exhibiting an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in 2θ degrees of approximately the following (±0.2): 5.9°, 8.8°, 11.6°, 14.7°, and 19.5°. 20. The solid form according to any one of claims 18-19, further characterized in that it has diffractive XRPD patterns at angles (2θ ± 0.2) of 5.9°, 8.8°, 11.6°, 14.7° and 19.5°, said angles corresponding to lattice spacings (Å ± 0.2) of 15.0, 10.0, 7.6, 6.0 and 4.6, respectively. 21. The solid form as claimed in any one of claims 18-20, characterized by X-ray powder diffraction (XRPD) with additional diffraction at angles (2θ ± 0.2) of 17.0, 17.6, and 22.2. 22. The solid form as claimed in claim 11, characterized in that it has diffractive XRPD patterns at angles of 17.0, 17.6 and 22.2 (2θ ± 0.2), the angles corresponding to lattice spacings of 5.2, 5.0 and 4.0 (Å ± 0.2), respectively. 23. The solid form as claimed in any one of claims 18-22, characterized by X-ray powder diffraction (XRPD) showing peaks at the same or substantially the same angle (20 ± 0.2) and corresponding lattice spacings (A ± 0.2) as follows: . 24. The solid form as claimed in any one of claims 18-23, further characterized by one or more of the following: a. Differential scanning calorimetry (DSC) thermograms showing an endothermic event observed at approximately 205 °C; and b. Based on the reversible mass change of approximately 10% between 2% and 95% relative humidity for DVS. 25. The solid form as claimed in any one of claims 18-24, characterized in that the XRPD pattern A. 26. The solid form as claimed in any one of claims 18-24, obtained by a method comprising steps selected from the group consisting of: a. Formation of a slurry in alcohol, acetone, or ACN; b. Evaporation crystallization and cooling crystallization in IPA and 1-propanol; and c. Recrystallization in acetone:water. 27. A hydrated crystalline solid form of a free base of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide. 28. A crystalline solid form of a free base of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide. 29. A pyruvate solid form of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized by one or more of the following: a. XRPD pattern 1-A or XRPD pattern 1-B; and b. Single endothermic reaction measured by TGA/DSC, with an initial temperature of 95.43°C and a corresponding mass loss of 3.2 wt.%, followed by a mass loss of 9.9 wt.%, until operation ended at 300°C. 30. A solid form of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide in MSA salt form, characterized by XRPD pattern 2-A, XRPD pattern 2-B, XRPD pattern 2-C or XRPD pattern 2-D. 31. A solid citrate form of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized by one or more of the following: a. XRPD pattern 3-A; and b. Three extensive endothermic measurements by TGA/DSC, with onset temperatures of 124.4 °C, 153.7 °C, and 195.9 °C and associated mass losses of 3.8 wt.%, 9.8 wt.%, and 4.6 wt.%, respectively. 32. A fumarate solid form of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized by one or more of the following: a. XRPD pattern 4-A or XRPD pattern 4-B or XRPD pattern 4-C or XRPD pattern 4-D; and b. Three extensive endothermic events measured by TGA/DSC, with starting temperatures of 111.8 °C, 167.9 °C, and 203.2 °C, with the first endothermic event having a mass loss of approximately 3.5 wt.%, the second endothermic event having a mass loss of approximately 0.3 wt.%, and the third endothermic event having a mass loss of approximately 6.2 wt.%. 33. A solid form of crystalline pralatinib hydrochloride, 5-A. 34. A solid form of crystalline pralatinib hydrochloride, 5-B. 35. A solid hydrochloride form of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized by one or more of the following: a. XRPD patterns containing characteristic diffraction peaks at 2θ angles of approximately (±0.2 degrees) 6.1°, 8.9°, 9.5°, 15.0°, and 16.6°; and b. Characterized by the following TGA/DSC thermograms: an initial mass loss of 3.4 wt.% associated with extensive endothermic reaction starting at 88.7 °C (±0.2 °C), and a second mass loss event of 6.7 wt.% observed from the end of the first extensive endothermic reaction to the end of melting starting at 244.2 °C (±0.2 °C). 36. A solid form of 5-C crystalline hydrochloride of praltinib. 37. A solid form of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide hydrochloride, characterized by an XRPD pattern 5-C. 38. A saccharin salt solid form of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized by XRPD pattern 6-A. 39. A solid salt of gentic acid and (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized by XRPD pattern 7-A. 40. A maleate solid form of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized by one or more of the following: a. XRPD pattern 8-A; and b. Endothermic heat measured by TGA/DSC, with an initial temperature of 188.5 °C and a related mass loss of 2.3 wt.%, and a temperature of 196.1 °C and a related mass loss of 6.5 wt.%. 41. An oxalate solid form of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized by one or more of the following: a. XRPD pattern 9-A; and b. Gradual mass loss of 2.4 wt.% as measured by TGA/DSC until the melting event begins at approximately 231.8 °C. 42. A salt of salicylic acid and (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, which is in a solid form characterized by XRPD pattern 10-A, or in an amorphous solid form. 43. A solid form of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized by one or more of the following: a. XRPD pattern 11-A or XRPD pattern 11-B; and b. Characterized by the following TGA/DSC: single endothermic, with an initial temperature of approximately 177.8 °C and a mass loss of approximately 0.3 wt.% from the start of the experiment to the end of melting. 44. A sulfate of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized in that one or more of the following: an XRPD pattern comprising XRPD pattern 12-A, XRPD pattern 12-B, XRPD pattern 12-C, XRPD pattern 12-D, XRPD pattern 12-E, XRPD pattern 12-F, XRPD pattern 12-G or XRPD pattern 12-H. 45. A sulfate of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized by one or more of the following: a. XRPD pattern 12-A; and b. Characterized by the following TGA/DSC: initial endothermic temperatures of 81.7°C, 159.7°C, and 207.6°C. 46. A sulfate of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized by one or more of the following: a. XRPD pattern 12-B; and b. Characterized by the following TGA/DSC: single endothermic, with an initial temperature of 184.9°C, and evidence suggests decomposition above 260°C. 47. A sulfate of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized by one or more of the following: a. XRPD pattern 12-C; and b. Characterized by the following TGA/DSC: endothermic at 126.5°C, 154.7°C and 186.4°C. 48. A sulfate of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized by one or more of the following: a. XRPD pattern 12-E; and b. Characterized by the following TGA/DSC: endothermic at about 119.0°C and about 169.6°C. 49. A tartrate of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized in that one or more of the following are XRPD patterns comprising XRPD pattern 13-A, XRPD pattern 13-B and XRPD pattern 13-C. 50. A tartrate salt of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized by one or more of the following: a. XRPD pattern 13-A; and b. Characterized by the following TGA/DSC: single endothermic temperature at approximately 150.1°C. 51. A tartrate of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized by one or more of the following: a. XRPD pattern 13-B; and b. Characterized by the following TGA/DSC: endothermic at approximately 99.3°C, 127.6°C and 169.3°C. 52. A tartrate of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized by one or more of the following: a. XRPD pattern 13-C; and b. Characterized by the following TGA/DSC: endothermic at approximately 77.3°C and 132.4°C. 53. A phosphate of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized by one or more of the following: a. XRPD pattern 14-A; and b. Characterized by the following TGA/DSC: endothermic heat at about 113.3 °C and related mass loss of about 1.1 wt.%, and two endothermic heat losses with combined mass loss of about 1.6 wt.% at about 198.4 and 237.5 °C. 54. A succinate of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized by one or more of the following: a. XRPD pattern 15-A; and b. Characterized by the following TGA/DSC: endothermic at approximately 126.8°C and approximately 150.9°C. 55. A urea salt of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized by XRPD pattern 16-A. 56. A quercetin dihydrate salt of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized by XRPD pattern 17-A. 57. A benzenesulfonate of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized in that XRPD pattern 18-A or XRPD pattern 18-B. 58. A hydrobromide of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized in that it is XRPD pattern 19-A, XRPD pattern 19-B or XRPD pattern 19-C. 59. A nitrate of (cis)-N-((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)cyclohexaneformamide, characterized by XRPD pattern 20-A.