HK40090305A - Pralsetinib pharmaceutical compositions - Google Patents

Description

Pralatinib drug composition

Cross-reference to related applications

This application claims the benefit and priority of U.S. Provisional Patent Application No. 63/032,030, filed May 29, 2020, the disclosure of which is incorporated herein by reference in its entirety for all purposes.

Background Technology

Pralsetinib is disclosed as one of many RET inhibitor compounds in patent publication WO2017/079140. A clinical trial (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)" is ongoing. Pralsetinib is a potent and selective RET inhibitor available orally that selectively targets oncogenic RET alterations in certain cancer patients, including those with the most prevalent RET fusions and certain RET activating mutations. Praltinib can also be called: (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:

However, pralatinib has low water solubility, and therefore, there is still a need for pharmaceutical compositions that not only enhance its water solubility but also provide immediate release of pralatinib upon administration.

Summary of the Invention

The present invention is characterized by a pharmaceutical composition comprising 1) an amorphous solid dispersion comprising pralatinib or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable hydrophilic polymer; and 2) a foaming pair.

In one aspect, this document provides a pharmaceutical composition comprising 1) an amorphous solid dispersion comprising pralatinib or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable amphiphilic polymer; and 2) a foaming pair.

In one aspect, this document provides a pharmaceutical composition comprising 1) an amorphous solid dispersion comprising pralatinib or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable hydrophilic and amphiphilic polymer; and 2) a foaming pair.

In one embodiment, the invention is characterized by an oral dosage form comprising (a) an amorphous solid dispersion of pralatinib or a pharmaceutically acceptable salt thereof; and hydroxypropyl methylcellulose (HPMC); (b) a diluent; (c) sodium bicarbonate; (d) citric acid; (e) a dehumidifier; and (f) a lubricant.

In one embodiment, the invention is characterized by an oral dosage form comprising (a) an amorphous solid dispersion of pralatinib or a pharmaceutically acceptable salt thereof; and hydroxypropyl methylcellulose (HPMC); (b) a diluent; (c) sodium bicarbonate; (d) citric acid; and (e) a lubricant.

In one embodiment, the invention is characterized by an oral dosage form comprising (a) an amorphous solid dispersion of pralatinib or a pharmaceutically acceptable salt thereof; and hydroxypropyl methylcellulose acetate succinate (HPMCAS); (b) a diluent; (c) sodium bicarbonate; (d) citric acid; (e) a desiccant; and (f) a lubricant.

In one embodiment, the invention is characterized by an oral dosage form comprising (a) an amorphous solid dispersion of pralatinib or a pharmaceutically acceptable salt thereof; and hydroxypropyl methylcellulose (HPMC); (b) microcrystalline cellulose (MCC); (c) pregelatinized starch; (d) sodium bicarbonate; (e) citric acid; and (f) magnesium stearate.

In one embodiment, the invention is characterized by an oral dosage form comprising (a) an amorphous solid dispersion of pralatinib or a pharmaceutically acceptable salt thereof; and hydroxypropyl methylcellulose (HPMC); (b) microcrystalline cellulose (MCC); (c) sodium bicarbonate; (d) citric acid; and (e) magnesium stearate.

Another embodiment of the present invention is characterized by a method for preparing an amorphous solid dispersion as described herein, the method comprising: using a suitable manufacturing method, for example, dissolving pralatinib or a pharmaceutically acceptable salt thereof in a hydrophilic polymer at a 1:1 ratio to achieve an amorphous solid dispersion.

This document also provides a method for preparing an amorphous solid dispersion as described herein, the method comprising: using a suitable manufacturing method, for example, dissolving pralatinib or a pharmaceutically acceptable salt thereof in an amphiphilic polymer at a 1:1 ratio to achieve an amorphous solid dispersion.

Amorphous solid dispersions can be prepared by hot melt extrusion, freeze drying, spray drying, solvent casting, or melt quenching. One embodiment of the invention uses spray drying with a suitable solvent as a manufacturing method (e.g., adding a suitable solvent and removing the solvent by heating).

Another embodiment of the invention is characterized by a method for treating RET-altered cancer, the method comprising administering a therapeutically effective amount of the composition and oral dosage form disclosed herein to a patient in need.

Another embodiment of the invention features a method for treating a patient with transfection rearrangement (RET)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC), the method comprising administering to a patient in need a therapeutically effective amount of the composition and oral dosage form disclosed herein. In one particular aspect, the (RET)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) is detected by an FDA-approved test.

Another embodiment of the invention is characterized by a method of treating a patient with RET mutation-positive locally advanced or metastatic medullary thyroid carcinoma (MTC), the method comprising administering to a patient in need a therapeutically effective amount of the composition and oral dosage form disclosed herein. In one particular aspect, the patient is 12 years of age or older.

Another embodiment of the invention is characterized by a method for treating a patient with RET fusion-positive locally advanced or metastatic thyroid cancer who requires systemic therapy and has no satisfactory alternative treatment options, the method comprising administering to the patient in need a therapeutically effective amount of the compositions disclosed herein and oral dosage forms. In one particular aspect, the patient is 12 years of age or older.

Attached Figure Description

Figure 1A shows the X-ray powder diffraction (XRPD) pattern of praltinib form A.

Figure 1B shows the DSC and TGA thermograms of praltinib form A.

Figure 1C shows the DVS thermogram of praltinib form A.

Figure 2A shows the X-ray powder diffraction (XRPD) pattern of praltinib form B.

Figure 2B shows the DSC and TGA thermograms of praltinib form B.

Figure 2C shows the DVS thermogram of praltinib form B.

Figure 3A shows the X-ray powder diffraction (XRPD) pattern of pralatinib form C.

Figure 3B shows the DSC and TGA thermograms of praltinib form C.

Figure 3C shows the DVS thermogram of praltinib form C.

Figure 4A shows the X-ray powder diffraction (XRPD) pattern of pralatinib HCl salt form I.

Figure 4B shows the DSC thermogram of pralatinib HCl salt form I.

Figure 5A shows the X-ray powder diffraction (XRPD) pattern of pralatinib HCl salt form II.

Figure 5B shows the DSC and TGA thermograms of pralatinib HCl salt form II.

Figure 6A shows the X-ray powder diffraction (XRPD) pattern of pralatinib HCl salt form III.

Figure 6B shows the DSC and TGA thermograms of pralatinib HCl salt form III.

Figure 7A shows the X-ray powder diffraction (XRPD) pattern of the amorphous solid dispersion of pralatinib.

Figure 7B shows the DSC thermogram of the amorphous solid dispersion of pralatinib.

Detailed Implementation

Praltinib is an effective kinase inhibitor but has low water solubility. To enhance the bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs) such as pralatinib, APIs can be dispersed in molecular form into polymer matrix systems, creating solid dispersions. While dissolving the API in a polymer improves overall solubility, depending on the polymer matrix, the initiation of API dissolution can be delayed because the API needs to be released from the matrix. This delay poses a formulation challenge if the composition is intended for immediate release. Disintegrants promote disintegration via, for example, wicking, swelling, and/or strain recovery, and are typically added to solid oral dosage forms to promote the rupture of tablet, capsule, granule, or powder matrix, thereby increasing the API release rate. However, depending on the matrix contents, not all types of disintegrants cause the matrix to rupture sufficiently to support the immediate release of the API.

Praltinib is a potent kinase inhibitor but has low water solubility. To enhance its solubility, it is dispersed in a molecular form within a polymer matrix system. While encapsulation in the matrix system improves pralatinib's solubility, this also slows the release rate of pralatinib due to hydration, swelling, and/or gelation of the polymer matrix, thus inducing a diffusion-release mechanism. This slowed release rate presents a challenge for formulating immediate-release dosage forms. Conventional superdisintegrants used to rupture the matrix via swelling (e.g., crospovidone, crospovidone sodium carboxymethyl cellulose, and sodium glycolate starch) have failed to effectively rupture the pralatinib-polymer matrix. Surprisingly, the addition of foaming agents effectively ruptures the matrix, allowing pralatinib to be released at a rate suitable for immediate-release solid oral dosage forms.

Pharmaceutical Composition

The present invention is characterized by a pharmaceutical composition comprising 1) an amorphous solid dispersion comprising pralatinib or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable hydrophilic polymer; and 2) a foaming pair.

The present invention is characterized by a pharmaceutical composition comprising 1) an amorphous solid dispersion comprising pralatinib or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable amphiphilic polymer; and 2) a foaming pair.

The present invention is characterized by a pharmaceutical composition comprising 1) an amorphous solid dispersion comprising pralatinib or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable hydrophilic and amphiphilic polymer; and 2) a foaming pair.

Pralatinib, 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)cyclohexaneformamide (or "compound (I)"), can be prepared in the form of a free base in solid form or in various salt forms:

Praltinib, also known as CAS No. 2097132-94-8, is a highly effective and selective inhibitor of oncogenic RET fusions and activating mutations in clinical trials. In vivo, pralatinib effectively inhibits the growth of NSCLC and thyroid cancer xenografts driven by multiple RET mutations and fusions without inhibiting VEGFR2.

"Hydrophilic polymer" refers to a polymer that is soluble in water or swells in water. "Amphiphilic polymer" refers to a polymer containing both hydrophobic and hydrophilic components. Hydrophilic and/or amphiphilic polymers suitable for the amorphous solid dispersions of this invention include, but are not limited to, homopolymers or copolymers of N-vinyl lactams, such as homopolymers or copolymers of N-vinylpyrrolidone (e.g., polyvinylpyrrolidone (PVP), or copolymers of N-vinylpyrrolidone with vinyl acetate or vinyl propionate); cellulose esters or cellulose ethers, such as alkyl cellulose (e.g., methylcellulose or ethylcellulose), hydroxyalkyl cellulose (e.g., hydroxypropyl cellulose), hydroxyalkylalkyl cellulose (e.g., hydroxypropyl methylcellulose), and cellulose phthalates or succinates (e.g., cellulose acetate phthalate and hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate, or hydroxypropyl methylcellulose acetate succinate); and high molecular weight polyoxyethylene, such as polyethylene oxide. Polyolefins, polypropylene oxides, and copolymers of ethylene oxide and propylene oxide; polyacrylates or polymethacrylates, such as methacrylate/ethyl acrylate copolymers, methacrylate/methyl methacrylate copolymers, butyl methacrylate/dimethylaminoethyl 2-methacrylate copolymers, poly(hydroxyalkyl acrylates) and poly(hydroxyalkyl methacrylates); polyacrylamide; vinyl acetate polymers, such as copolymers of vinyl acetate and crotonic acid and partially hydrolyzed polyvinyl acetate (also known as partially saponified "polyvinyl alcohol"); polyvinyl alcohol; oligosaccharides or polysaccharides, such as carrageenan, galactomannan, and tragacanth; polyhydroxyalkyl acrylates; polyhydroxyalkyl-methacrylates; copolymers of methyl methacrylate and acrylic acid; polyethylene glycol (PEG), including polyvinyl graft copolymers; or any mixture thereof. In one aspect, the polymer is hydroxypropyl methylcellulose (or hydroxypropyl methylcellulose), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose E5 (HPMC-E5), hydroxypropyl methylcellulose E3 (HPMC-E3), vinylpyrrolidone-vinyl acetate copolymer (KOLLIDON VA64 or KOLLIDON K30), dimethylaminoethyl methacrylate copolymer (EUDRAGIT EPO), polyethylene oxide (POLYOX), or polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOLUPLUS). HPMC E3 refers to hydroxypropyl methylcellulose with a viscosity of about 2.4-3.6 mPa s (2% in water). HPMC E5 refers to hydroxypropyl methylcellulose with a viscosity of about 4 to 6 mPa s (2% in water). In one particular aspect, the hydrophilic polymer is hydroxypropyl methylcellulose. In one particular aspect, the hydrophilic polymer is hydroxypropyl methylcellulose E5 or hydroxypropyl methylcellulose E3.

Unless otherwise indicated, all numerical values of the amounts of ingredients, reaction conditions, data points (e.g., temperature, angle, etc.) used in this specification and claims should be understood to be modified by the term "about" in all cases. Therefore, unless indicated to the contrary, the numerical parameters set forth in this specification and appended claims are approximate values that may vary depending on the desired properties obtained by attempting to achieve them through this invention.

In one aspect, pralatinib or an equivalent amount of its pharmaceutically acceptable salt is in a weight percentage ratio of about 1:1 to the hydrophilic polymer. For example, the disclosed composition may contain about 100 mg of pralatinib and about 100 mg of the hydrophilic polymer as disclosed herein. In another aspect, pralatinib or an equivalent amount of its pharmaceutically acceptable salt is in a weight percentage ratio of about 1:1 to the amphiphilic polymer. For example, the disclosed composition may contain about 100 mg of pralatinib and about 100 mg of the polymer as disclosed herein. In yet another aspect, pralatinib or an equivalent amount of its pharmaceutically acceptable salt is in a weight percentage ratio of about 1:5 to about 5:1 to the hydrophilic polymer. In yet another aspect, pralatinib or an equivalent amount of its pharmaceutically acceptable salt is in a weight percentage ratio of about 1:5 to about 5:1 to the amphiphilic polymer.

In one aspect, the composition or oral dosage form as described herein comprises an amorphous solid dispersion comprising about 25% to about 75% by weight of the total weight of the composition or oral dosage form. In another aspect, the composition or oral dosage form as described herein comprises an amorphous solid dispersion comprising about 25% to about 65% by weight of the total weight of the composition or oral dosage form. In yet another aspect, the composition or oral dosage form as described herein comprises an amorphous solid dispersion comprising about 25% to about 35% by weight of the total weight of the composition or oral dosage form. In yet another aspect, the composition or oral dosage form as described herein comprises an amorphous solid dispersion comprising about 35% to about 45% by weight of the total weight of the composition or oral dosage form. In yet another aspect, the composition or oral dosage form as described herein comprises an amorphous solid dispersion comprising about 45% to about 55% by weight of the total weight of the composition or oral dosage form. In another aspect, the composition or oral dosage form as described herein comprises an amorphous solid dispersion comprising about 55% to about 65% by weight of the total weight of the composition or oral dosage form. In another aspect, the composition or oral dosage form as described herein comprises an amorphous solid dispersion comprising about 65% to about 75% by weight of the total weight of the composition or oral dosage form. In another aspect, the composition or oral dosage form as described herein comprises an amorphous solid dispersion comprising about 20% to about 30% by weight of the total weight of the composition or oral dosage form. In another aspect, the composition or oral dosage form as described herein comprises an amorphous solid dispersion comprising about 30% to about 40% by weight of the total weight of the composition or oral dosage form. In another aspect, the composition or oral dosage form as described herein comprises an amorphous solid dispersion comprising about 40% to about 50% by weight of the total weight of the composition or oral dosage form. In another aspect, the composition or oral dosage form as described herein comprises about 50% to about 60% by weight of an amorphous solid dispersion based on the total weight of the composition or oral dosage form. In another aspect, the composition or oral dosage form as described herein comprises about 60% to about 70% by weight of an amorphous solid dispersion based on the total weight of the composition or oral dosage form. In another aspect, the composition or oral dosage form as described herein comprises about 70% to about 75% by weight of an amorphous solid dispersion based on the total weight of the composition or oral dosage form. In another aspect, the composition or oral dosage form as described herein comprises about 25% by weight, about 35% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 60% by weight, about 65% by weight, about 70% by weight, or 75% by weight of an amorphous solid dispersion based on the total weight of the composition or oral dosage form.

In one aspect, amorphous solid dispersions are prepared by hot melt extrusion, freeze drying, spray drying, solvent casting, or melt quenching.

In one aspect, the foaming pair comprises a water-soluble acid and a water-soluble base. In another aspect, the foaming pair comprises a water-soluble base. In one aspect, the water-soluble acid includes, but is not limited to, citric acid, tartaric acid, fumaric acid, adipic acid, succinic acid, malonic acid, benzoic acid, oxalic acid, malic acid, and glutaric acid. In one aspect, the water-soluble base includes, but is not limited to, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, and magnesium carbonate. In a particular aspect, the water-soluble acid is citric acid and the water-soluble base is sodium bicarbonate. In a particular aspect, the water-soluble acid is anhydrous citric acid and the water-soluble base is sodium bicarbonate.

In one aspect, the composition or oral dosage form as described herein comprises a water-soluble acid comprising from 0% to 20% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a water-soluble acid comprising from about 1% to about 20% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a water-soluble acid comprising from about 1% to about 5% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a water-soluble acid comprising from about 5% to about 10% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a water-soluble acid comprising from about 10% to about 15% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises about 15% to about 20% by weight of a water-soluble acid based on the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises about 3% to about 10% by weight of a water-soluble acid based on the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises about 10% to about 20% by weight of a water-soluble acid based on the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises about 5% to about 15% by weight of a water-soluble acid based on the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, or about 20% by weight of a water-soluble acid based on the total weight of the composition or oral dosage form.

In one aspect, the composition or oral dosage form as described herein comprises a water-soluble base comprising from about 1% to about 35% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a water-soluble base comprising from about 1% to about 10% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a water-soluble base comprising from about 10% to about 20% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a water-soluble base comprising from about 20% to about 30% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a water-soluble base comprising from about 30% to about 35% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises about 10% to about 25% by weight of a water-soluble base based on the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises about 12% to about 35% by weight of a water-soluble base based on the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises about 20% to about 35% by weight of a water-soluble base based on the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises, based on the total weight of the composition or oral dosage form, about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, etc. Water-soluble alkali in the following amounts: approximately 19 wt%, approximately 20 wt%, approximately 21 wt%, approximately 22 wt%, approximately 23 wt%, approximately 24 wt%, approximately 25 wt%, approximately 26 wt%, approximately 27 wt%, approximately 28 wt%, approximately 29 wt%, approximately 30 wt%, approximately 31 wt%, approximately 32 wt%, approximately 33 wt%, approximately 34 wt%, approximately 35 wt%, approximately 36 wt%, approximately 37 wt%, approximately 38 wt%, approximately 39 wt%, or approximately 40 wt%.

In one particular aspect, the composition or oral dosage form as described herein comprises a water-soluble acid comprising about 5% to about 15% by weight of the total weight of the composition or oral dosage form, and a water-soluble base comprising about 12% to about 35% by weight of the total weight of the composition or oral dosage form.

In one aspect, the composition further comprises a desiccant. Non-limiting examples of suitable moisture include cellulose, cellulose derivatives, silica, and silica derivatives. Specific examples are cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, or silica, including calcined silica. In particular, the microcrystalline cellulose may be Avicel ^™ and/or the calcined silica may be Cabosil ^™ . In one aspect, the desiccant is starch. In a specific aspect, the starch is pregelatinized starch.

In one aspect, the composition or oral dosage form as described herein comprises a dehumidifier comprising from 0% to 30% by weight of the total weight of the composition or oral dosage form. In another aspect, the composition or oral dosage form as described herein comprises a dehumidifier comprising from about 0.5% to 30% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a dehumidifier comprising from about 0.5% to 5% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a dehumidifier comprising from about 5% to 10% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a dehumidifier comprising from about 10% to 15% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a dehumidifier comprising about 15% to about 20% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a dehumidifier comprising about 20% to about 25% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a dehumidifier comprising about 25% to about 30% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a dehumidifier comprising about 5% to about 15% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a dehumidifier comprising about 2% to about 4% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a desiccant in an amount of about 0.5% by weight, about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, or about 30% by weight of the composition or oral dosage form based on the total weight of the composition or oral dosage form. In an alternative aspect, the composition does not contain a desiccant.

In one aspect, the composition further comprises a diluent (also referred to as a filler). Non-limiting examples of suitable diluents include starches (e.g., cellulose, potato, or corn starch), salts (e.g., dicalcium phosphate, magnesium oxide), sugars such as lactose (e.g., lactose monohydrate), silicates (e.g., silicon dioxide), talc, isomaltitol, or polyvinyl alcohol. In one aspect, the diluent is cellulose. In a particular aspect, the diluent is microcrystalline cellulose (e.g., Avicel or, in particular, Avicel PH-102).

In one aspect, the composition or oral dosage form as described herein comprises a diluent comprising about 5% to about 70% by weight of the total weight of the composition or oral dosage form. In another aspect, the composition or oral dosage form as described herein comprises a diluent comprising about 5% to about 60% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a diluent comprising about 5% to about 10% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a diluent comprising about 10% to about 15% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a diluent comprising about 15% to about 20% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a diluent comprising about 20% to about 25% by weight of the composition or oral dosage form based on its total weight. In one aspect, the composition or oral dosage form as described herein comprises a diluent comprising about 25% to about 30% by weight of the composition or oral dosage form based on its total weight. In one aspect, the composition or oral dosage form as described herein comprises a diluent comprising about 30% to about 35% by weight of the composition or oral dosage form based on its total weight. In one aspect, the composition or oral dosage form as described herein comprises a diluent comprising about 35% to about 40% by weight of the composition or oral dosage form based on its total weight. In one aspect, the composition or oral dosage form as described herein comprises a diluent comprising about 40% to about 45% by weight of the composition or oral dosage form based on its total weight. In one aspect, the composition or oral dosage form as described herein comprises a diluent comprising about 45% to about 50% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a diluent comprising about 50% to about 55% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a diluent comprising about 55% to about 60% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a diluent comprising about 60% to about 65% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a diluent comprising about 65% to about 70% by weight of the total weight of the composition or oral dosage form. In one aspect, the composition or oral dosage form as described herein comprises a diluent comprising, based on the total weight of the composition or oral dosage form, about 5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 60% by weight, or about 65% by weight, or about 70% by weight.

In one aspect, the composition further comprises a lubricant. Non-limiting examples of suitable lubricants include talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, sodium stearate fumarate, and mixtures thereof. In a particular aspect, the lubricant is magnesium stearate.

In one aspect, the composition or oral dosage form as described herein comprises a lubricant comprising from about 0.1% to about 5% by weight of the composition or oral dosage form based on its total weight. In one aspect, the composition or oral dosage form as described herein comprises a lubricant comprising from about 0.1% to about 1% by weight of the composition or oral dosage form based on its total weight. In one aspect, the composition or oral dosage form as described herein comprises a lubricant comprising from about 1% to about 2% by weight of the composition or oral dosage form based on its total weight. In one aspect, the composition or oral dosage form as described herein comprises a lubricant comprising from about 2% to about 3% by weight of the composition or oral dosage form based on its total weight. In one aspect, the composition or oral dosage form as described herein comprises a lubricant comprising from about 3% to about 4% by weight of the composition or oral dosage form based on its total weight. In one aspect, the composition or oral dosage form as described herein comprises a lubricant comprising from about 4% to about 5% by weight of the composition or oral dosage form based on its total weight. In one aspect, the composition or oral dosage form as described herein comprises a lubricant in an amount of about 0.1% by weight, about 0.5% by weight, about 1% by weight, about 1.5% by weight, about 2% by weight, about 2.5% by weight, about 3% by weight, about 3.5% by weight, about 4% by weight, about 4.5% by weight, or about 5% by weight, based on the total weight of the composition or oral dosage form.

In one embodiment, the invention is characterized by an oral dosage form comprising (a) an amorphous solid dispersion of pralatinib or a pharmaceutically acceptable salt thereof; and hydroxypropyl methylcellulose (HPMC); (b) microcrystalline cellulose (MCC); (c) pregelatinized starch; (d) sodium bicarbonate; (e) citric acid; and (f) magnesium stearate. In one aspect, the amount of the amorphous solid dispersion is as described above. In one aspect, the amount of microcrystalline cellulose (MCC) is as described above for diluents. In one aspect, the amount of pregelatinized starch is as described above for desiccant. In one aspect, the amount of sodium bicarbonate is as described above for water-soluble bases. In one aspect, the amount of citric acid is as described above for water-soluble acids. In one aspect, the amount of magnesium stearate is as described above for lubricants.

In one aspect, the composition is prepared as an oral dosage form. The oral dosage form can be prepared as any suitable dosage form, such as capsules, lozenges, granules, powders, or tablets. In one particular aspect, the oral dosage form is a capsule. In one particular aspect, the oral dosage form is a tablet. In one particular aspect, the oral dosage form is intended for immediate release. Whether a composition or oral dosage form is an immediate-release formulation can be determined based on methods known to those skilled in the art, such as USP standards.

As used herein, “total weight of oral dosage form” means the substance within the oral dosage form (e.g., within capsules) or the oral dosage form without any coating (e.g., without tablet coating).

Oral dosage forms can be formulated in any suitable form, such as capsules, lozenges, granules, powders, or tablets. In one particular aspect, the oral dosage form is a capsule. In one embodiment, the capsule size is from size 4 to size 0. In another embodiment, the capsule size is from size 4 to size 0. In some embodiments, the capsule size is from size 3 to size 0. In some embodiments, the capsule size is 0. In other embodiments, the capsule size is 0. In some embodiments, the capsule size is 1. In some embodiments, the capsule size is 2. In other embodiments, the capsule size is 3. In some embodiments, the capsule size is 4.

In one aspect, the oral dosage form or composition described herein comprises about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or about 200 mg of pralatinib or an equivalent amount of its pharmaceutically acceptable salt. In some embodiments, the oral dosage form (e.g., tablets) comprises about 50 mg of pralatinib or an equivalent amount of its pharmaceutically acceptable salt.

In one aspect, the oral dosage form or composition described herein comprises about 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 200 mg, 300 mg, or 400 mg of pralatinib or an equivalent amount of its pharmaceutically acceptable salt. In some embodiments, the oral dosage form (e.g., tablets) comprises about 200 mg of pralatinib or an equivalent amount of its pharmaceutically acceptable salt.

In one aspect, this disclosure provides an immediate-release oral dosage form comprising:

a) An amorphous solid dispersion comprising: pralatinib or a pharmaceutically acceptable salt thereof, and hydroxypropyl methylcellulose E3, wherein pralatinib or an equivalent amount of its pharmaceutically acceptable salt is in a weight ratio of about 1:1 to hydroxypropyl methylcellulose E3.

b) A foaming pair comprising about 3 to about 13 w/w% citric acid and about 7 to about 30 w/w% sodium bicarbonate; wherein w/w% is based on the total weight of the oral dosage form;

c) Diluent; and optionally

d) Dehumidifiers and/or lubricants.

In some embodiments, the amorphous solid dispersion comprises about 30 mg, about 50 mg, about 60 mg, about 100 mg of pralatinib, or an equivalent amount of its pharmaceutically acceptable salt.

In some embodiments, using USP<711>, with a Type 2 device, a medium containing 900 mL of 0.1 M HCl, and a paddle speed of 100 rpm, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of pralatinib are released within 45 minutes. In some embodiments, using USP<711>, with a Type 2 device, a medium containing 900 mL of 0.1 M HCl, and a paddle speed of 100 rpm, at least 80% of pralatinib are released within 45 minutes. In some embodiments, using USP<711>, with a Type 2 device, a medium containing 900 mL of 0.1 M HCl, and a paddle speed of 100 rpm, at least 85% of pralatinib are released within 45 minutes. In some embodiments, using USP<711>, with a Type 2 device, a medium containing 900 mL of 0.1 M HCl, and a stirring speed of 100 rpm, at least 90% of pralatinib is released within 45 minutes. In some embodiments, using USP<711>, with a Type 2 device, a medium containing 900 mL of 0.1 M HCl, and a stirring speed of 100 rpm, at least 95% of pralatinib is released within 45 minutes.

In some embodiments, the dosage form is a capsule, wherein USP<701> is used, utilizing a basket A and a disc maintained at 37°C ± 2°C, and the capsule disintegrates within approximately 5 to 15 minutes (e.g., approximately 7 to 15 minutes, approximately 6 minutes, approximately 7 minutes, approximately 10 minutes, approximately 15 minutes). In other embodiments, the dosage form is a capsule, wherein USP<701> is used, such as a basket A and a disc maintained at 37°C ± 2°C, and the capsule disintegrates within less than 15 minutes (e.g., less than 10 minutes, less than 5 minutes).

In some embodiments, the dosage form is a capsule, wherein USP<701> is used, the capsule disintegrates in about 5 to about 15 minutes (e.g., about 7 to 15 minutes, e.g., about 6 minutes, about 7 minutes, about 10 minutes, about 15 minutes), wherein the capsule is placed together with a disc in each of the 6 tubes in a basket (basket type A), and analytical grade water is added, and the temperature is maintained at 37°C ± 2°C.

In some embodiments, the dosage form is a capsule, wherein at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of pralatinib are released in about 120 minutes or alternatively in 45 minutes using a USP II device and a medium containing 900 mL of pH 6.8 sodium phosphate buffer with 0.5% CTAB and a stirring speed of 75 rpm ± 2 rpm.

In some embodiments, the dosage form is capsules, wherein at least 80% of pralatinib is released within approximately 45 minutes using a USP II device and a medium containing 900 mL of pH 6.8 sodium phosphate buffer with 0.5% CTAB and a stirring speed of 75 rpm ± 2 rpm. In some embodiments, the dosage form is capsules, wherein at least 85% of pralatinib is released within approximately 45 minutes using a USP II device and a medium containing 900 mL of pH 6.8 sodium phosphate buffer with 0.5% CTAB and a stirring speed of 75 rpm ± 2 rpm. In some embodiments, the dosage form is capsules, wherein at least 90% of pralatinib is released within approximately 45 minutes using a USP II device and a medium containing 900 mL of pH 6.8 sodium phosphate buffer with 0.5% CTAB and a stirring speed of 75 rpm ± 2 rpm. In some embodiments, the dosage form is a capsule, wherein a USP II device and a medium containing 900 mL of pH 6.8 sodium phosphate buffer with 0.5% CTAB and a stirring speed of 75 rpm ± 2 rpm are used, and at least 95% of pralatinib is released within about 45 minutes.

Another embodiment of the invention is characterized by a method for preparing the amorphous solid dispersion described herein, the method comprising: mixing pralatinib or a pharmaceutically acceptable salt thereof with a hydrophilic polymer in a ratio of about 1:1; adding a solvent; and removing the solvent by heating.

Another embodiment of the invention is characterized by a method for preparing the amorphous solid dispersion described herein, the method comprising: mixing pralatinib or a pharmaceutically acceptable salt thereof with an amphiphilic polymer in a ratio of about 1:1; adding a solvent; and removing the solvent by heating.

solid form

Compound (I) may be in an amorphous solid form or in various solid forms, or may additionally contain a mixture of solid forms (e.g., anhydrous or hydrated forms) containing one or more equivalents of water. As provided herein, pralatinib is in an amorphous solid 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 forms of compound (I) and related methods for preparing and using these solid forms. As provided herein, these crystalline forms of compound (I) can be used to prepare amorphous solid dispersions containing pralatinib and a hydrophilic polymer. As provided herein, these crystalline forms of compound (I) can be used to prepare amorphous solid dispersions containing pralatinib and an amphiphilic polymer.

When used alone, the term "Form A" refers to Form A of the crystalline polymorph of pralatinib. The terms "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 "Form B" refers to Form B of the crystalline polymorph of pralatinib. The terms "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 "Form C" refers to Form C of the crystalline polymorph of pralatinib. The terms "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.

When used alone, the term "Form I" or "Platinib HCl salt Form I" refers to Form I of the crystalline polymorph of prlatinib hydrochloride. The terms "Form I," "Form I of prlatinib hydrochloride," "Form I of the hydrochloride 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 I of the hydrochloride of compound (I)" are used interchangeably. Form I can be characterized, for example, by XRPD alone or in combination with any or more of DSC, DVS, and TGA.

When used alone, the term "Form II" or "Platinib HCl salt Form II" refers to Form I, the crystalline polymorph of prlatinib hydrochloride. The terms "Form II," "Form II of prlatinib hydrochloride," "Form II 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," or "Form II of the hydrochloride of compound (I)" are used interchangeably. Form II can be characterized, for example, by XRPD alone or in combination with any or more of DSC, DVS, and TGA.

When used alone, the term "Form III" or "Platinib HCl salt Form IIII" refers to Form III of the crystalline polymorph of pralatinib hydrochloride. The terms "Form III," "Form III of pralatinib hydrochloride," "Form III of the hydrochloride 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 III of the hydrochloride of compound (I)" are used interchangeably. Form III can be characterized, for example, by XRPD alone or in combination with any or more of DSC, DVS, and TGA.

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), dynamic vapor adsorption (DVS), or vibrational spectroscopy. 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 I is at least 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9%. The purity of form I is determined by dividing the weight of form I 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 II is at least 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9%. The purity of form II is determined by dividing the weight of form II 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 III is at least 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9%. The purity of form III is determined by dividing the weight of form III 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 forms A, B, C, I, II, and III, have many advantages. In particular, the advantages of forms A, B, C, I, II, and III include ease of separation, process reproducibility, and suitability for large-scale manufacturing processes.

In one aspect, this disclosure provides crystalline form A of pralatinib.

In one aspect, crystalline form A of pralatinib 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 form A is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at a 2θ angle selected from 5.0 ± 0.2°, 9.7 ± 0.2°, 12.7 ± 0.2°, 13.6 ± 0.2°, and 16.1 ± 0.2°.

Alternatively, crystalline form A 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 selected from 5.0±0.2°, 6.8±0.2°, 9.7±0.2°, 12.7±0.2°, 13.6±0.2°, 16.1±0.2°, 19.2±0.2°, 19.5±0.2°, and 23.5±0.2°. Alternatively, crystalline form A is characterized by X-ray powder diffraction peaks at a 2θ angle of 5.0±0.2°, 6.8±0.2°, 9.7±0.2°, 12.7±0.2°, 13.6±0.2°, 16.1±0.2°, 19.2±0.2°, 19.5±0.2°, and 23.5±0.2°.

Alternatively, crystalline form A is characterized by having 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 selected from 5.0±0.2°, 6.8±0.2°, 9.7±0.2°, 12.7±0.2°, 13.6±0.2°, 14.8±0.2°, 16.1±0.2°, 17.2±0.2°, 17.8±0.2°, 19.2±0.2°, 19.5±0.2°, 20.5±0.2°, 21.6±0.2°, 23.1±0.2°, 23.5±0.2°, 24.8±0.2°, 25.6±0.2°, 26.0±0.2°, 27.9±0.2°, and 29.4±0.2°. In another alternative, crystalline form A is characterized by X-ray powder diffraction peaks at 2θ angles of 5.0±0.2°, 6.8±0.2°, 9.7±0.2°, 12.7±0.2°, 13.6±0.2°, 14.8±0.2°, 16.1±0.2°, 17.2±0.2°, 17.8±0.2°, 19.2±0.2°, 19.5±0.2°, 20.5±0.2°, 21.6±0.2°, 23.1±0.2°, 23.5±0.2°, 24.8±0.2°, 25.6±0.2°, 26.0±0.2°, 27.9±0.2°, and 29.4±0.2°. In some embodiments, the peak described above for crystalline form A has a relative intensity of at least 10%, at least 15%, at least 20%, or at least 25%.

In the other case, crystalline form A of pralatinib has an XRPD pattern that is substantially the same as the XRPD pattern shown in Figure 1A.

In the other case, crystalline form A of pralatinib has an XRPD pattern that substantially includes the peaks in Table 1A.

In one aspect, crystalline form A of pralatinib has a DSC pattern substantially identical to that shown in Figure 1B. In particular, an endothermic event was observed in the thermogram of crystalline form A (DSC) at approximately 205 °C ± 2 °C.

In one aspect, crystalline form A of pralatinib has a TGA pattern that is substantially the same as the TGA pattern shown in Figure 1B.

In one aspect, crystalline form A of pralatinib has a DVS pattern substantially identical to that shown in Figure 1C. In particular, form A of pralatinib is characterized by a reversible mass change of approximately 10% according to DVS between 2% and 95% relative humidity.

In one aspect, crystalline form A of pralatinib is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at a 2θ angle selected from 5.0±0.2°, 9.7±0.2°, 12.7±0.2°, 13.6±0.2°, and 16.1±0.2°, optionally together with one, two, or three of the TGA, DSC, and DVS parameters described above for form A. Alternatively, crystalline form A 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 selected from 5.0±0.2°, 6.8±0.2°, 9.7±0.2°, 12.7±0.2°, 13.6±0.2°, 16.1±0.2°, 19.2±0.2°, 19.5±0.2°, and 23.5±0.2°, optionally together with one, two, or three of the TGA, DSC, and DVS parameters described above for form A. Alternatively, crystalline form A is characterized by a crystallization angle selected from 5.0±0.2°, 6.8±0.2°, 9.7±0.2°, 12.7±0.2°, 13.6±0.2°, 14.8±0.2°, 16.1±0.2°, 17.2±0.2°, 17.8±0.2°, 19.2±0.2°, 19.5±0.2°, 20.5±0.2°, 21.6±0.2°, and 23.1±0.2°. 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 of 23.5±0.2°, 24.8±0.2°, 25.6±0.2°, 26.0±0.2°, 27.9±0.2°, and 29.4±0.2°, optionally together with one, two, or three of the TGA, DSC, and DVS parameters described above for form A.

In one aspect, crystalline form A of pralatinib 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±0.2°, 9.7±0.2°, 12.7±0.2°, 13.6±0.2°, and 16.1±0.2°; (b) an endothermic event observed at approximately 205 °C±2 °C in a differential scanning calorimetry (DSC) thermogram; and/or (c) a reversible mass change of approximately 10% between 2% and 95% relative humidity based on dynamic vapor adsorption (DVS).

Form A may be a solid form obtained by a method comprising steps selected from the group consisting of: (a) forming a slurry in an alcohol, acetone, or ACN; (b) evaporating and cooling crystallizing in IPA and 1-propanol; and (c) recrystallizing in acetone:water. Form A may also be obtained by heating a sample of form B to at least about 190°C under conditions suitable for producing form A (e.g., in an alcohol, a slurry such as IPA); or heating a sample of pralitinib form C to at least about 190°C under conditions suitable for producing form A (e.g., in an alcohol, acetone, or ACN).

In one aspect, this disclosure provides crystalline form B of pralatinib.

In one aspect, crystalline form B of pralatinib 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 form B is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at a 2θ angle selected from 5.9 ± 0.2°, 8.8 ± 0.2°, 11.6 ± 0.2°, 14.7 ± 0.2°, and 19.5 ± 0.2°.

Alternatively, crystalline form B is characterized by at least three, at least four, at least five, at least six, at least seven, or at least eight X-ray powder diffraction peaks at a 2θ angle selected from 5.9±0.2°, 8.8±0.2°, 11.6±0.2°, 14.7±0.2°, 17.0±0.2°, 17.6±0.2°, 19.5±0.2°, and 22.2±0.2°. Alternatively, crystalline form B is characterized by X-ray powder diffraction peaks at a 2θ angle of 5.9±0.2°, 8.8±0.2°, 11.6±0.2°, 14.7±0.2°, 17.0±0.2°, 17.6±0.2°, 19.5±0.2°, and 22.2±0.2°. In some embodiments, the peak crystals described above for form B have a relative intensity of at least 10%, at least 15%, at least 20%, or at least 25%.

In the other case, crystalline form B of pralatinib has an XRPD pattern that is substantially the same as the XRPD pattern shown in Figure 2A.

In the other case, crystalline form B of pralatinib has an XRPD pattern that substantially includes the peaks in Table 2A.

In one aspect, crystalline form B of pralatinib has a DSC pattern that is substantially the same as the DSC pattern shown in Figure 2B. In particular, three characteristics were observed when crystalline form B was characterized by DSC: endothermic reaction starting at 149 °C ± 2 °C, exothermic reaction starting at 162 °C ± 2 °C, and melting starting at 205 °C ± 2 °C.

In one aspect, crystalline form B of pralatinib has a TGA pattern substantially identical to the TGA pattern shown in Figure 2B. Specifically, as characterized by TGA, the mass loss is 0.5%.

In one aspect, crystalline form B of pralatinib has a DVS pattern substantially the same as that shown in Figure 2C. Specifically, crystalline form B shows a total mass variation of 1.4 wt.% between 2% and 95% relative humidity.

In one aspect, crystalline form B of pralatinib is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at a 2θ angle selected from 5.9±0.2°, 8.8±0.2°, 11.6±0.2°, 14.7±0.2°, and 19.5±0.2°; optionally together with one, two, or three of the TGA, DSC, and DVS parameters described above for form B. Alternatively, crystalline form B is characterized by at least three, at least four, at least five, at least six, at least seven, or at least eight X-ray powder diffraction peaks at a 2θ angle selected from 5.9±0.2°, 8.8±0.2°, 11.6±0.2°, 14.7±0.2°, 17.0±0.2°, 17.6±0.2°, 19.5±0.2°, and 22.2±0.2°, optionally together with one, two, or three of the TGA, DSC, and DVS parameters described above for form B.

In one aspect, crystalline form B of pralatinib 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) 5.9±0.2°, 8.8±0.2°, 11.6±0.2°, 14.7±0.2°, and 19.5±0.2°; (b) three features observed when crystalline form B is characterized by DSC: endothermic onset at 149℃±2℃, exothermic onset at 162℃±2℃, and melting onset at 205℃±2℃; (c) a mass loss of 0.5% as characterized by TGA; and/or (c) a total mass change of 1.4 wt.% between 2% and 95% relative humidity by DVS.

Form B can be obtained by a method including the following steps: heating the sample of form C to about 150°C.

In one aspect, this disclosure provides crystalline form C of pralatinib.

In one aspect, the crystalline form C of pralatinib 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, the crystalline form C is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at a 2θ angle selected from 5.8 ± 0.2°, 8.7 ± 0.2°, 11.0 ± 0.2°, 13.6 ± 0.2°, and 20.2 ± 0.2°.

Alternatively, crystalline form 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 selected from 5.8±0.2°, 8.7±0.2°, 11.0±0.2°, 11.6±0.2°, 13.6±0.2°, 14.5±0.2°, 20.2±0.2°, 22.2±0.2°, and 23.2±0.2°. Alternatively, crystalline form C is characterized by X-ray powder diffraction peaks at a 2θ angle of 5.8±0.2°, 8.7±0.2°, 11.0±0.2°, 11.6±0.2°, 13.6±0.2°, 14.5±0.2°, 20.2±0.2°, 22.2±0.2°, and 23.2±0.2°.

Alternatively, crystalline form C is characterized by a crystallinity selected from 5.8±0.2°, 8.7±0.2°, 11.0±0.2°, 11.6±0.2°, 12.0±0.2°, 13.6±0.2°, 14.5±0.2°, 17.1±0.2°, 18.2±0.2°, 19.5±0.2°, 20.2±0.2°, 20.6±0.2°, and 21.3°. 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 of ±0.2°, 22.2±0.2°, 22.6±0.2°, 23.2±0.2°, 24.2±0.2°, 24.5±0.2°, 26.0±0.2°, 26.8±0.2°, and 28.1±0.2°. In another alternative, crystalline form C is characterized by X-ray powder diffraction peaks at 2θ angles of 5.8±0.2°, 8.7±0.2°, 11.0±0.2°, 11.6±0.2°, 12.0±0.2°, 13.6±0.2°, 14.5±0.2°, 17.1±0.2°, 18.2±0.2°, 19.5±0.2°, 20.2±0.2°, 20.6±0.2°, 21.3±0.2°, 22.2±0.2°, 22.6±0.2°, 23.2±0.2°, 24.2±0.2°, 24.5±0.2°, 26.0±0.2°, 26.8±0.2°, and 28.1±0.2°. In some embodiments, the peak described above for crystalline form C has a relative intensity of at least 10%, at least 15%, at least 20%, or at least 25%.

In the other case, the crystalline form C of pralatinib has an XRPD pattern that is substantially the same as the XRPD pattern shown in Figure 3A.

In the other case, the crystalline form C of pralatinib has an XRPD pattern that substantially includes the peaks in Table 3A.

In one aspect, crystalline form C of pralatinib has a DSC pattern substantially the same as that shown in Figure 3B. In particular, crystalline form C has DSCs starting at 122°, 127°, and 206°.

In one aspect, crystalline form C of pralatinib has a TGA pattern substantially identical to the TGA pattern shown in Figure 3B. In particular, a mass loss of approximately 3 wt.% was observed in the TGA thermogram of form C.

In one aspect, crystalline form C of pralatinib has a DVS pattern substantially the same as that shown in Figure 3C. Specifically, crystalline form C shows a total mass variation of 1.4 wt.% between 2% and 95% relative humidity.

In one aspect, crystalline form C of pralatinib is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at a 2θ angle selected from 5.8±0.2°, 8.7±0.2°, 11.0±0.2°, 13.6±0.2°, and 20.2±0.2°; optionally together with one, two, or three of the TGA, DSC, and DVS parameters described above for form C. Alternatively, crystalline form 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 selected from 5.8±0.2°, 8.7±0.2°, 11.0±0.2°, 11.6±0.2°, 13.6±0.2°, 14.5±0.2°, 20.2±0.2°, 22.2±0.2°, and 23.2±0.2°, optionally together with one, two, or three of the TGA, DSC, and DVS parameters described above for form C. Alternatively, crystalline form C is characterized by a crystallinity selected from 5.8±0.2°, 8.7±0.2°, 11.0±0.2°, 11.6±0.2°, 12.0±0.2°, 13.6±0.2°, 14.5±0.2°, 17.1±0.2°, 18.2±0.2°, 19.5±0.2°, 20.2±0.2°, 20.6±0.2°, 21.3±0.2°, 22.2±0.2°, and 22.6. 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 of ±0.2°, 23.2±0.2°, 24.2±0.2°, 24.5±0.2°, 26.0±0.2°, 26.8±0.2°, and 28.1±0.2°, optionally together with one, two, or three of the TGA, DSC, and DVS parameters described above for form C.

In one aspect, the crystalline form C of pralatinib 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) 5.8±0.2°, 8.7±0.2°, 11.0±0.2°, 13.6±0.2°, and 20.2±0.2°; (b) differential scanning calorimetry (DSC) thermograms starting at 122°, 127°, and 206°; (c) a mass loss of approximately 3 wt.% observed in the TGA thermogram; and/or (d) a total mass change of 1.4 wt.% between 2% and 95% relative humidity via DVS.

Form C can be a solid form obtained by a method comprising steps selected from the group consisting of: a) recrystallization in a variety of aqueous solvent systems (acetone:water, methanol (MeOH):water, isopropanol (IPA):water, dimethylacetamide (DMAc):water, tetrahydrofuran (THF):water); b) conversion from form A in methanol:water at a high water to methanol ratio and a lower temperature during a competitive slurry experiment. Solid form C of the free pralatinib base can be obtained by: forming a slurry from a sample of the free pralatinib base in an anhydrous solid form and then recrystallizing it (e.g., forming a slurry of the free pralatinib base solid form A in water and methanol, followed by recrystallization in acetone/IPA/methanol and water to obtain the hydrated crystalline solid form C of the free pralatinib base).

In one aspect, this disclosure provides crystalline pralatinib HCl salt form I. In one aspect, crystalline pralatinib HCl salt form I 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 I is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at a 2θ angle selected from 5.0 ± 0.2°, 6.1 ± 0.2°, 9.1 ± 0.2°, 9.9 ± 0.2°, and 14.7 ± 0.2°.

Alternatively, the crystalline prantinib HCl salt form I 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 selected from 5.0±0.2°, 6.1±0.2°, 9.1±0.2°, 9.9±0.2°, 13.8±0.2°, 14.7±0.2°, 15.3±0.2°, 17.2±0.2°, 18.1±0.2°, 19.6±0.2°, 20.3±0.2°, 20.7±0.2°, 21.8±0.2°, 24.2±0.2°, 25.6±0.2°, and 26.3±0.2°. Alternatively, crystalline pralatinib HCl salt form I is characterized by X-ray powder diffraction peaks at 2θ angles of 5.0±0.2°, 6.1±0.2°, 9.1±0.2°, 9.9±0.2°, 13.8±0.2°, 14.7±0.2°, 15.3±0.2°, 17.2±0.2°, 18.1±0.2°, 19.6±0.2°, 20.3±0.2°, 20.7±0.2°, 21.8±0.2°, 24.2±0.2°, 25.6±0.2°, and 26.3±0.2°. In some embodiments, the peaks described above for crystalline pralatinib HCl salt form I have a relative intensity of at least 10%, at least 15%, at least 20%, or at least 25%.

In the other case, crystalline pralatinib HCl salt form I has an XRPD pattern that is substantially the same as the XRPD pattern shown in Figure 4A.

In the other case, the crystalline pralatinib HCl salt form I has an XRPD pattern that substantially includes the peaks in Table 4A.

In one aspect, the crystalline pralatinib HCl salt form I has a DSC pattern substantially identical to that shown in Figure 4B. In particular, pralatinib HCl salt form I was observed to exhibit a very broad endothermic effect, with an initial temperature of 70.9 °C ± 2 °C and a sharp endothermic effect at 240.5 ± 2 °C.

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

In one aspect, the crystalline pralatinib HCl salt form I 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 very broad endothermic spectrum in a differential scanning calorimetry (DSC) thermogram, wherein the initial temperature is 70.9 °C ± 2 °C and there is a sharp endothermic reaction at 240.5 °C ± 2 °C.

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

Alternatively, the crystalline prantinib HCl salt form II 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 selected from 6.1±0.2°, 8.9±0.2°, 9.5±0.2°, 15.0±0.2°, 16.6±0.2°, 17.2±0.2°, 17.9±0.2°, 18.4±0.2°, 19.8±0.2°, 25.8±0.2°, and 26.8±0.2°. Alternatively, crystalline pralatinib HCl salt form II is characterized by X-ray powder diffraction peaks at 2θ angles of 6.1±0.2°, 8.9±0.2°, 9.5±0.2°, 15.0±0.2°, 16.6±0.2°, 17.2±0.2°, 17.9±0.2°, 18.4±0.2°, 19.8±0.2°, 25.8±0.2°, and 26.8±0.2°. In some embodiments, the peaks described above for crystalline pralatinib HCl salt form II have a relative intensity of at least 10%, at least 15%, at least 20%, or at least 25%.

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

In the other case, the crystalline pralatinib HCl salt form II has an XRPD pattern that substantially includes the peaks in Table 5A.

In one aspect, the crystalline pralatinib HCl salt form II has a DSC pattern substantially identical to that shown in Figure 5B. In particular, pralatinib HCl salt form II was observed to have a broad endothermic onset of 88.7 °C ± 2 °C and a melting onset of 244.2 °C ± 2 °C.

In one aspect, the crystalline pralatinib HCl salt form II has a TGA pattern substantially identical to that shown in Figure 5B. Specifically, an initial mass loss of 3.4 wt.% was observed in the TGA thermogram of pralatinib HCl salt form II, associated with a broad endothermic start at 94.4 °C ± 2 °C, and a second mass loss event of 6.7 wt.% was observed from the end of the first broad endothermic start to the end of melting at 244.2 °C ± 2 °C.

In one aspect, the crystalline pralatinib HCl salt form II is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at a 2θ angle selected from 6.1±0.2°, 8.9±0.2°, 9.5±0.2°, 15.0±0.2°, and 16.6±0.2°; optionally in conjunction with one or both of the TGA and DSC parameters described above for pralatinib HCl salt form II. Alternatively, the crystalline pralatinib HCl salt form II 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 selected from 6.1±0.2°, 8.9±0.2°, 9.5±0.2°, 15.0±0.2°, 16.6±0.2°, 17.2±0.2°, 17.9±0.2°, 18.4±0.2°, 19.8±0.2°, 25.8±0.2°, and 26.8±0.2°, optionally together with one, two, or three of the TGA and DSC parameters described above for pralatinib HCl salt form II.

In one aspect, the crystalline pralatinib HCl salt form II 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 broad endothermic start at 88.7 °C ± 2 °C and a melting start at 244.2 °C ± 2 °C in the DSC thermogram; and/or (c) an initial mass loss of 3.4 wt.% associated with the broad endothermic start at 88.7 °C, and a second mass loss event of 6.7 wt.% observed from the end of the first broad endothermic start to the end of the melting start at 244.2 °C ± 2 °C.

The HCl salt form II of pralatinib can be obtained by a method including the separation of solids from EtOAc and IPA:water (9:1 Vol).

In one aspect, this disclosure provides crystalline pralatinib HCl salt form III. In one aspect, crystalline pralatinib HCl salt form III 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 III is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at a 2θ angle selected from 6.4 ± 0.2°, 8.5 ± 0.2°, 8.9 ± 0.2°, 9.6 ± 0.2°, and 17.3 ± 0.2°.

Alternatively, the crystalline pralatinib HCl salt form III 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 selected from 6.4±0.2°, 8.5±0.2°, 8.9±0.2°, 9.6±0.2°, 11.5±0.2°, 16.7±0.2°, 17.3±0.2°, and 19.2±0.2°. Alternatively, the crystalline pralatinib HCl salt form III is characterized by X-ray powder diffraction peaks at a 2θ angle of 6.4±0.2°, 8.5±0.2°, 8.9±0.2°, 9.6±0.2°, 11.5±0.2°, 16.7±0.2°, 17.3±0.2°, and 19.2±0.2°.

Alternatively, the crystalline prantinib HCl salt form III 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 selected from 6.0±0.2°, 6.4±0.2°, 8.5±0.2°, 8.9±0.2°, 9.6±0.2°, 11.5±0.2°, 12.7±0.2°, 15.9±0.2°, 16.7±0.2°, 17.3±0.2°, 19.2±0.2°, 21.0±0.2°, and 26.9±0.2°. In another alternative, the crystalline pralatinib HCl salt form III is characterized by X-ray powder diffraction peaks at a 2θ angle selected from 6.0±0.2°, 6.4±0.2°, 8.5±0.2°, 8.9±0.2°, 9.6±0.2°, 11.5±0.2°, 12.7±0.2°, 15.9±0.2°, 16.7±0.2°, 17.3±0.2°, 19.2±0.2°, 21.0±0.2°, and 26.9±0.2°. In some embodiments, the peaks described above for the crystalline pralatinib HCl salt form III have a relative intensity of at least 10%, at least 15%, at least 20%, or at least 25%.

In the other case, crystalline pralatinib HCl salt form III has an XRPD pattern that is substantially the same as the XRPD pattern shown in Figure 6A.

In the other case, the crystalline prantinib HCl salt form II has an XRPD pattern that substantially includes the peaks in Table 6A.

In one aspect, the crystalline pralatinib HCl salt form III has a DSC pattern substantially identical to that shown in Figure 5C. In particular, pralatinib HCl salt form III was observed to have DSCs starting at 86.8℃±2℃, 224.1℃±2℃, and 241.7℃±2℃.

In one aspect, the crystalline pralatinib HCl salt form III has a TGA pattern substantially identical to that shown in Figure 5C. 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 III.

In one aspect, the crystalline pralatinib HCl salt form III is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at a 2θ angle selected from 6.4±0.2°, 8.5±0.2°, 8.9±0.2°, 9.6±0.2°, and 17.3±0.2°, optionally in conjunction with one or both of the TGA and DSC parameters described above for pralatinib HCl salt form III. Alternatively, the crystalline pralatinib HCl salt form III 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 selected from 6.4±0.2°, 8.5±0.2°, 8.9±0.2°, 9.6±0.2°, 11.5±0.2°, 16.7±0.2°, 17.3±0.2°, and 19.2±0.2°, optionally together with one, two, or three of the TGA, DSC, and DVS parameters described above for pralatinib HCl salt form III.

Alternatively, the crystalline pralatinib HCl salt form III 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 selected from 6.0±0.2°, 6.4±0.2°, 8.5±0.2°, 8.9±0.2°, 9.6±0.2°, 11.5±0.2°, 12.7±0.2°, 15.9±0.2°, 16.7±0.2°, 17.3±0.2°, 19.2±0.2°, 21.0±0.2°, and 26.9±0.2°, optionally together with one or both of the TGA and DSC parameters described above for pralatinib HCl salt form III.

In one aspect, crystalline pralatinib HCl salt form III 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±0.2°, 8.5±0.2°, 8.9±0.2°, 9.6±0.2°, and 17.3±0.2°; and (b) observation of DSCs starting at 86.8℃±2℃, 224.1℃±2℃, and 241.7℃±2℃; 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 pralatinib HCl salt form III.

Pralatinib HCl salt form III can be obtained by a method including drying the separated pralatinib HCl salt form II.

It should be understood that the 2θ values of the X-ray powder diffraction patterns for crystalline forms A, B, C, I, II, and III can vary slightly between instruments and depend on variations in sample preparation and batch-to-batch changes. Therefore, the XRPD peak positions for crystalline forms A, B, C, I, II, and III in Tables 1A, 1B, 1C, 2A, 2B, 3A, 3B, 3C, 4A, 4B, 5A, 5B, 6A, 6B, and 6C should not be considered absolute and can vary by ±0.2 degrees.

As intended herein, the phrases "substantially the same as the XRPD pattern shown in Figure 1A," "substantially the same as the XRPD pattern shown in Figure 2A," "substantially the same as the XRPD pattern shown in Figure 3A," "substantially the same as the XRPD pattern shown in Figure 4A," "substantially the same as the XRPD pattern shown in Figure 5A," and "substantially the same as the XRPD pattern shown in Figure 6A" indicate, for comparative purposes, the presence of at least 90% of the peaks shown in Figures 1A, 2A, 3A, 4A, 5A, and 6A. Furthermore, for comparative purposes, some variation in peak position relative to the positions shown in Figures 1A, 2A, 3A, 4A, 5A, and 6A is permitted, such as +0.2 degrees.

In one aspect, this disclosure provides a method for preparing crystalline forms A, B, or C. In a particular aspect, form A can be obtained by forming a slurry in an alcohol, acetone, and acetonitrile, or by evaporation crystallization in a variety of solvents and cooling crystallization in isopropanol and 1-propanol. Form A can also be produced by recrystallization in acetone:water. Form C can be obtained by recrystallizing compound (I) in a variety of aqueous solvent systems (acetone:water, methanol:water, isopropanol:water, dimethylacetamide:water, tetrahydrofuran:water). Form C is stable when vacuum dried at 50°C and transforms into form B (anhydrous) upon heating to 150°C. Form B then transforms into form A before melting. Form C remains stable by X-ray powder diffraction during humidity testing (75% relative humidity and 40°C for one week, and cyclically down to 2% relative humidity via dynamic vapor adsorption). During dynamic vapor adsorption measurements, form C is less hygroscopic than form A, yielding only 1.44% water. Form C exhibits lower solubility in simulated intestinal fluid and water than form A, but higher solubility in simulated gastric fluid (possibly due to conversion to an HCl salt). Form C converts to form A in acetone and isopropanol during competitive slurry experiments.

Treatment

Another embodiment of the invention is characterized by a method for treating RET-altered cancer, the method comprising administering a therapeutically effective amount of the composition and oral dosage form disclosed herein to a patient in need.

Another embodiment of the invention is characterized by a method of treating a patient with transfection rearrangement (RET)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC), the method comprising administering to a patient in need a therapeutically effective amount of the composition and oral dosage form disclosed herein. In one particular aspect, (RET)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) is detected by an FDA-approved test.

Another embodiment of the invention is characterized by a method of treating a patient with RET mutation-positive locally advanced or metastatic medullary thyroid carcinoma (MTC), the method comprising administering to a patient in need a therapeutically effective amount of the composition and oral dosage form disclosed herein. In one particular aspect, the patient is 12 years of age or older.

Another embodiment of the invention is characterized by a method for treating a patient with RET fusion-positive locally advanced or metastatic thyroid cancer who requires systemic therapy and has no satisfactory alternative treatment options, the method comprising administering to the patient in need a therapeutically effective amount of the compositions disclosed herein and oral dosage forms. In one particular aspect, the patient is 12 years of age or older.

As used herein, the terms “subject” or “patient” refer to an organism to be treated by the methods of this disclosure. Such organisms include, but are not limited to, mammals (e.g., rodents, apes, horses, cattle, swine, canines, felines, etc.) and, in some embodiments, humans. In one particular aspect, the patient or subject suffers from or is suspected of suffering from a disease or condition associated with abnormal RET expression (i.e., increased RET activity resulting from RET signaling) or biological activity. In particular, said disease or condition is cancer. Many cancers have been associated with abnormal RET expression (Kato et al., Clin. Cancer Res. 23(8):1988-97(2017)). As used herein, non-limiting examples of “cancer” include lung cancer, head and neck cancer, gastrointestinal cancer, breast cancer, skin cancer, genitourinary cancer, gynecological cancer, hematologic cancer, central nervous system (CNS) cancer, peripheral nervous system cancer, endometrial cancer, colorectal cancer, bone cancer, sarcoma, spitzoid neoplasm, adenosquamous carcinoma, pheochromocytoma (PCC), hepatocellular carcinoma, multiple endocrine tumors (MEN2A and MEN2B), and inflammatory myofibroblastic tumor. For other examples, see Nature Reviews Cancer 14:173-86 (2014).

"Treatment" in this context refers to improving at least one symptom of the disease or condition. When used in conjunction with conditions such as cancer, these terms refer to one or more of the following: stopping cancer growth, causing cancer to shrink in weight or volume, prolonging the patient's expected survival time, inhibiting tumor growth, reducing tumor size, reducing the size or number of metastatic lesions, inhibiting the development of new metastatic lesions, prolonging survival, prolonging progression-free survival, prolonging progression time and/or improving quality of life.

The term "therapeutic effect" refers to a beneficial local or systemic effect resulting from the administration of the compounds or compositions of the present invention to animals, particularly mammals and more particularly humans. The phrase "therapeutic effective amount" means the amount at which the compounds or compositions of the present invention are effective in treating a disease or ailment caused by RET overexpression or abnormal RET biological activity, given a reasonable benefit/risk ratio. Therapeutic effective amounts of such substances will vary depending on the subject being treated and the disease or ailment, the subject's weight and age, the severity of the disease or ailment, the method of administration, etc., and will be readily determined by those skilled in the art.

Example

Example 1: Synthesis of compound (I)

For each form of compound (I) (i.e., pralatinib) described in Example 2 of this document and for each HCl salt of compound (I) described in Example 3 of this document, compound (I) may be prepared as described with respect to compound 130 disclosed in publication WO2017/079140.

Example 2: Synthesis of compound (I) in solid form

Form A (anhydrous) was crystallized in a methanol/water system. Compound (I) (2-3 g) was added to a container, followed by 6.5 vol of MeOH. The mixture was stirred at 350 rpm (approximately 0.25 W/kg) using a backward-curved impeller throughout the process. The mixture was heated to 60-65°C over a 35-minute period, and dissolution was observed at 63-64°C. The solution was then cooled to 44-45°C, and 1 volume of water was added over a 20-minute period. The solution was inoculated as is with 0.5 wt.% Form A in a saturated methanol:water (1:1 vol). Over 6 hours, 4.5 vol of water was added to obtain a final composition of methanol:water (54:46 vol). The solution was held at 45°C for 6-10 hours, then cooled to 25°C (-10°C/h) over 2 hours, and then held 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 form A of 85%-88% w/w.

Prolonged exposure to moisture did not convert form A to form C. In a methanol:water competitive slurry experiment, form A converted to form C at a high water to methanol ratio and lower temperature. Form A exhibited low solubility in simulated intestinal fluid and water, but high solubility in simulated gastric fluid (possibly due to conversion to an HCl salt).

a) Crystallization of form C (hydrate) in an acetone/water system. Compound (I) was added to 10 volumes of acetone/water 87:13 v/v 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 67:33 v/v solvent system. The solution was seeded with 0.5 wt.% 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 43:57 v/v solvent system. The mixture was cooled to 23°C and filtered, with a yield of 85%-90%.

b) After drying at 50°C, form C (hydrate) transforms into dehydrated form B.

Example 3: Synthesis of the solid form of HCl salt of compound (I)

a) Pralatinib HCl salt form I

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 (Figure 4A). This form was identified as form I, an HCl salt. Form I is stable to drying but deliquescent at high humidity.

b) Praltinib HCl salt form II and raltinib HCl salt form III

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 II, an HCl salt. This substance was then vacuum dried at 50 °C for 3 hours to remove any residual solvent. After drying, form II transformed into form III, which is stable to humidification and stability.

Example 4: Preparation of amorphous solid dispersion of pralatinib

Methanol is added to the feed vessel. Praltinib free base (e.g., in any crystalline form described herein (e.g., forms A, B, and C) or in amorphous form) and HPMC-E3 are added to this feed vessel at a 1:1 w/w ratio, and the mixture is stirred to provide a solution.

Example 5: Immediately Released Composition

A foaming disintegration mechanism using a combination of a water-soluble acid (e.g., citric acid) and a water-soluble base (e.g., sodium bicarbonate or sodium carbonate) was employed to overcome the rapid formation of the HPMC gel network in the pralitinib/HPMC amorphous solid dispersion (ASD) formulation obtained in Example 4 after exposure to an aqueous environment. For the experiments described in Example 5, capsule prototyping was performed using HPMC-E3 placebo ASD to preserve a limited amount of API. Static disintegration tests were performed in which the capsules were exposed to 0.1 M HCl. The time taken for the capsules to disintegrate was recorded.

5a. Sodium bicarbonate/anhydrous citric acid foaming agent

The following formulations are used to implement the foaming system of sodium bicarbonate and citric acid:

Components Composition (% w/w) Batch composition (g) ASD(HPMC-E3) 50.0 5.0 Sodium bicarbonate 33.3 3.3 Citric acid 16.7 1.7 total 100.0 10.0

The ingredients were blended and dry granulated using a slugging method to achieve a bulk density of approximately 0.6 g/mL. This excludes components outside the granules. The granules were manually filled into gelatin capsules, and the aforementioned static disintegration test was performed. The capsules began to disintegrate after three minutes, with obvious signs of foaming.

5b. Addition of diluents and lubricants

To illustrate the manufacturing process, diluent and lubricant are added:

The same dry granulation process as described in 5a was used. Magnesium stearate was incorporated into the granules for two minutes. A final blend volumetric density equivalent to that of Example 5a was achieved. The composition was manually filled into gelatin capsules, and the static disintegration test was performed. With reduced amounts of sodium bicarbonate and anhydrous citric acid, the disintegration time of the capsules was slightly longer than that of the capsules manufactured during 5a, but still within the ideal timeframe.

5c. Sodium carbonate/anhydrous citric acid foaming agent

Sodium bicarbonate is replaced with sodium carbonate, which is known to have slightly lower hygroscopicity than sodium bicarbonate, thus reducing the possibility of formulation instability. The composition is as follows:

Using the same manufacturing process as described in 5b, a final blend volumetric density equivalent to that of Example 5b was achieved. The composition was manually filled into gelatin capsules and the static disintegration test was performed. Equivalent disintegration behavior as in 5b and 5c was observed.

5d. Effer-/Anhydrous Citric Acid Foaming Agent

Effer is primarily sodium bicarbonate with a modified surface containing 8% or 12% sodium carbonate. This surface modification prevents accidental contact of moisture with sodium bicarbonate, which could cause formulation instability. The composition of Effer is as follows:

Using the same manufacturing process as described in 5b, a final blend volumetric density equivalent to that of Example 5b was achieved. The composition was manually filled into gelatin capsules and the static disintegration test was performed. Equivalent disintegration behavior was observed for 5b, 5c, and 5d.

5e and 5f reduce the amount of sodium carbonate (5e) and Effer- (5f).

To minimize the content of hygroscopic excipients in the composition, lower contents of sodium carbonate and Effer- were investigated. The resulting compositions for 5e and 5f are shown respectively:

Using the same manufacturing process as described in 5b, a final blend volumetric density equivalent to that of Example 5b was achieved. The final blend was passed through a 1 mm sieve and manually filled into gelatin capsules, and the static disintegration test was performed. Immediate bubbling was observed after the capsule shell ruptured, and complete disintegration and dissolution were achieved within 45 minutes.

Composition 5f followed the same manufacturing process as detailed for 5e, again achieving a bulk density of approximately 0.6 g/mL. The final blend was passed through a 1 mm sieve and manually filled into gelatin capsules for the aforementioned static disintegration test. Immediate foaming was observed upon capsule shell rupture, and complete disintegration and dissolution were achieved within 45 minutes. Equivalent disintegration behavior was observed for 5e and 5f. Reduced foaming content had no significant effect on the static disintegration of the composition in 0.1 M HCl.

5g of dehumidifier added.

Due to the hygroscopic nature of foaming agents, pregelatinized starch is introduced into the composition as a desiccant to promote long-term stability. The following compositions are prepared:

Using the same manufacturing process as described in 5b, a final blend volumetric density equivalent to that of Example 5b was achieved. The final blend was passed through a 1 mm sieve and manually filled into gelatin capsules, and the static disintegration test was performed. The capsules and contents disintegrated and dissolved within 40 minutes.

5 hours. Reduce the amount of desiccant.

The following compositions were prepared to determine the appropriate level of pregelatinized starch required to produce a final blend with ideal material properties, such as bulk density and flow rate:

Using the same manufacturing process as described in 5b, a final blend volumetric density equivalent to that of Example 5b was achieved. The final blend was passed through a 1 mm sieve. The blend was manually filled into size 1 HPMC capsule shells (e.g., Plus), instead of the size 0 gelatin capsules used in 5a-5f. The HPMC capsules (Plus) were filled to their maximum capacity to investigate whether the tightly packed capsules still disintegrated adequately. The resulting capsules underwent the aforementioned static disintegration test. Although the size 1 Plus capsules were filled to their maximum capacity, disintegration comparable to that of the size 0 gelatin capsules containing starch Effer- and citric acid was observed.

5i. Compositions 1, 2 and 3: Additional Compositions

Compositions 1, 2 and 3 were also prepared, comprising the pralatinib amorphous solid dispersion described in Example 4.

Composition 1

*Adjusting composition 2 based on intraparticle yield

*Adjusting composition 3 based on intragranular yield

*Adjusted based on intragranular yield

The manufacturing process of compositions 1-3 is as follows:

1) Using a Turbula mixer, mix the intraparticle components in an appropriately sized container at 23 rpm for 3 minutes.

2) The admixtures within the particles are dry-granulated by using a Riva minipress with a 22×9mm capsule processing tool for densification.

3) The material obtained by grinding using a Comil 193 mill equipped with a 991μm sieve.

4) Measure the bulk density of the granules. If it is not within the range of 0.55-0.6 g/mL, repeat densification and grinding until the desired bulk density is achieved.

5) In a Turbula mixer, mix the extra-granular components with the granules at 23 rpm for 2 minutes.

6) Manually fill the final blend into size 0 HPMC capsules (Plus).

7) Squeeze the capsules into 60mL HDPE bottles using a 4g desiccant cap, counting 30 capsules per bottle.

8) The compressed product was subjected to accelerated stabilization at 40℃/75%RH for 4 weeks.

All compositions exhibited physical and chemical stability within the studied storage conditions and time frames. X-ray powder diffraction (XRPD) showed that pralatinib remained an amorphous solid dispersion for 4 weeks at 40°C/75% RH. Composition 3 showed a faster drug release than compositions 1 and 2, releasing more than 85% within 45 minutes (United States Pharmacopeia (USP) <711> using a type 2 setting with 900 mL of 0.1 M HCl medium and a stirring speed of 100 rpm).

5j. Composition 4

Composition 4 was also prepared, comprising the pralatinib amorphous solid dispersion described in Example 4.

Material Formula (wt%) Formula (mg/capsule) ASD (Example 4) 55.0 200.00 MCC (Avicel PH102) 9.0 32.73 Sodium bicarbonate 22.0 80.00 Citric acid 9.0 32.73 magnesium stearate 0.5 1.82 Total particles 95.5 347.28 Starch 1500 4.0 14.55 magnesium stearate 0.5 1.82 Total particles outside 4.5 16.37 total 100 363.65

The admixtures within the granules were dry-granulated using a roller mill, and the strips were ground through a sieve of approximately 1 mm. The granules were then blended with the ex-granule materials, and the final blend was filled into size 0 HPMC capsules using Profill.

Disintegration time. The disintegration time of the capsules described as composition 4 was determined using the USP <701> disintegration assay, specifically using the procedure for uncoated or conventionally coated tablets. Specifically, individual capsules were placed together with a disc into each of six tubes in a basket (basket type A). Analytical grade water was added, and the temperature was maintained at 37°C ± 2°C. The disintegration time of the capsules of composition 4 was measured to be 6 minutes and 14 seconds.

Dissolution time. The dissolution time of the capsules of composition 4 was determined using the following dissolution protocol:

result:

time average value Minimum value Maximum value 0 0 0 0 15 60.9 47.4 70.1 30 89.9 84.5 94.2 45 96.6 93.6 99.6 60 98.4 95.8 101.4 75 98.8 96.2 101.8 90 98.8 96.1 102.0 120 98.9 96.3 101.9

5k. Tablet formulation

Tablet formulations (effervescent tablets) were prepared at two dosage intensities according to the composition described in the table below [50 mg (tablet size: 8.5 mm round) and 200 mg (tablet size: 22 × 9 mm capsules)].

ASD was blended with the excipients shown in the table above. All excipients were dispensed and passed through a 1 mm sieve and mixed at 30 RPM for 15 minutes. The in-particle blend was then dry-granulated and ground through a 1 mm sieve.

The resulting granules were blended with excipients. Tablets were produced from the final blend, with a target hardness of 15 ± 3 kp for a 200 mg dose strength and 12 ± 3 kp for a 50 mg dose strength, and were coated with a film. Over 80% drug release was achieved at 30 minutes using a USP paddle device at 75 rpm in a pH 6.8 buffer containing 0.5% CTAB.

Example 6: Comparative formulations with no foaming

Comparative formulations with non-foaming pairs were prepared. Disintegrants were used to break down the polymer matrix instead of foaming pairs. The disintegrants tested included crospovidone, crospovidone sodium carboxymethyl cellulose, and sodium glycolate starch.

Rapid gelation due to HPMC gel matrix formation was observed during disintegration tests of the prototype capsule formulation containing crospovidone and crospovidone sodium in water. The formulation containing the disintegrants crospovidone and crospovidone sodium did not disintegrate during dissolution tests in 0.1M HCl, but instead showed "plugging" formation within a 45-minute test period. Disintegration within a 15-minute timeframe indicated immediate release.

Examples 6a and 6b: Comparative formulations with disintegrants

Compared to compositions containing foaming pairs as described in Example 5, compositions using disintegrants croscarmellose sodium and croscarmellose instead of foaming pairs form "plugs".

6a. Cross-linked sodium carboxymethyl cellulose (Ac-di-) composition:

6b. Cross-linked polyvinylpyrrolidone (Polyplasdone XL) composition:

The formulation manufacturing method involved initially blending ASD with 200 to attempt to coat the ASD particles to improve flow properties. The mixture was blended for 1 minute using a mixer set at 23 rpm. The remaining intraparticle components were then blended in the mixer at 23 rpm for 3 minutes. Dry granulation was then simulated using a Riva Minipress via a "pounding" method with a 22×9 mm capsule-shaped processing tool and maximum compression setting. The final pound was broken ("ground") into particles using a mortar and pestle, and then blended with the extraparticle components in the mixer for 3 minutes. The bulk density of the final blend was measured to be approximately 0.6 g/mL before capsule fabrication. The resulting blend was then manually filled into size 0 gelatin capsules, and three (3) capsules were subjected to the following dissolution studies:

parameter set up Dissolving medium pH 1.2 buffer solution Bath temperature 37℃ Medium volume 900mL Sampling points 45 minutes Sample volume 10mL Dissolution operation time 45 minutes Dissolving equipment USP<711> Equipment II, with linear settling device Stirring speed 75rpm

Based on the relatively high solubility of prallatinib's free base at acidic pH, a pH 1.2 medium was chosen. Other typical method parameters for the USP solubility test in solid dosage form were also selected.

Although dissolution studies were initiated, sampling was abandoned at 45 minutes because it was visually observed that the capsules being tested had not yet disintegrated and had formed plugs. This observation led to the decision that the formulations outlined in experiments 6a and 6b were not feasible.

Example 7: X-ray Powder Diffraction (XRPD)

X-ray powder diffraction of forms A, B, and C, and HCl salt forms II and III, was performed using a Bruker D8 Advance equipped with a Lynxeye detector (i.e., Bragg-Brentano geometry). Samples were prepared on Si zero-gravity wafers. The XRPD parameters are shown in Table A-1 below:

Table A-1

X-ray powder diffraction of HCl salt form I was performed using Rigaku MiniFlex 600 (i.e., Bragg-Brentano geometry) in reflection mode. Samples were prepared on Si zero-valued wafers. The parameters of the XRPD method are listed in Table A-2 below:

Table A-2

The XRPD pattern of pralatinib form A is shown in 1A. The XRPD pattern of pralatinib form B is shown in 2A. The XRPD pattern of pralatinib form C is shown in 3A. The XRPD pattern of pralatinib HCl salt form I is shown in 4A. The XRPD pattern of pralatinib HCl salt form II is shown in 5A. The XRPD pattern of pralatinib HCl salt form III is shown in 6A.

Table 1A. List of XRPD peaks for prallatinib form A

Table 1B. List of selected XRPD peaks for praltinib form A

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. Further selection of XRPD peaks for praltinib form A

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

Table 2A. List of XRPD peaks for prallatinib form B

Table 2B. List of selected XRPD peaks for praltinib form B

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 3A. List of XRPD peaks for pralatinib form C

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 11.96 7.40 14 13.56 6.52 48 14.49 6.11 twenty one 17.09 5.19 12 18.19 4.87 6 19.51 4.55 11 20.19 4.39 29 20.58 4.31 12 21.27 4.17 8 22.18 4.00 20 22.63 3.93 7 23.20 3.83 10 24.18 3.68 6 24.48 3.63 9 26.00 3.42 10 26.75 3.33 7 28.08 3.18 5

Table 3B. List of selected XRPD peaks for praltinib form C

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. Further selection of XRPD peaks for praltinib form C

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 4A. List of XRPD peaks for pralatinib HCl salt form II

Table 5B. List of selected XRPD peaks for prallatinib HCl salt form I

Table 5A. List of XRPD peaks for pralatinib HCl salt form II

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

Table 5B. List of selected XRPD peaks for prallatinib HCl salt form II

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 6A. List of XRPD peaks for pralatinib HCl salt form III

Table 6B. List of selected XRPD peaks for prallatinib HCl salt form III

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 11.51 7.68 9 16.74 5.29 twenty one 17.34 5.11 28 19.19 4.60 9

Table 6C. Further selection of XRPD peaks for praltinib HCl salt form III

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

Example 8: 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 in Table B below.

Table B

Example 9: 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 (or 350 °C), with a heating rate of 10 °C per minute (total time 27 minutes). The protective and purging gases were nitrogen (20–30 mL/min and 50–100 mL/min, respectively). Typical parameters for the DSC/TGA are listed in Table C below.

Table C

Figure 1B shows the ADSC thermogram of the endothermic event observed at approximately 205 °C ± 2 °C.

Figure 2B shows a Form B DSC thermogram with three characteristics: endothermic onset at 149℃±2℃, exothermic onset at 162℃±2℃, and melting onset at 205℃±2℃.

Figure 3B shows the initial CDSC thermograms at 122°±2℃, 127°±2℃, and 206°±2℃.

Figure 4B shows a Form I DSC thermogram with very broad endothermic activity at an initial temperature of 70.9℃±2℃ and a sharp endothermic activity at 240.5℃±2℃.

Figure 5B shows the Form II DSC thermogram with extensive endothermic onset at 88.7℃±2℃ and melting onset at 244.2℃±2℃.

Figure 6B shows Form III DSC with initial temperatures of 86.8℃±2℃, 224.1℃±2℃, and 241.7℃±2℃.

Figure 1B shows the TGA pattern of form A, in which a mass loss of 0.8 is observed.

Figure 2B shows the TGA pattern of form B, in which a mass loss of 0.5% is observed.

Figure 3B shows the TGA pattern of form C, in which a mass loss of approximately 3 wt.% is observed.

Figure 5B shows the TGA pattern of form II, in which a first mass loss of approximately 3.4 wt.% and a second mass loss event of 6.7 wt.% were observed.

Figure 5C shows the TGA pattern of form III, in which an initial mass loss of 3.4 wt.% and a second mass loss event of 2 wt.% were observed.

Example 10: 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- Equilibrate 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%.

Figure 1C shows the DVS thermogram of form A, where a reversible mass change of about 10% is visible between 2% and 95% relative humidity according to DVS.

Figure 2C shows the DVS thermogram of form B, where there is a total mass change of 1.4 wt.% between 2% and 95% relative humidity.

Figure 3C shows the DVS thermogram of form C, where a total mass change of 1.4 wt.% is visible between 2% and 95% relative humidity.

Many embodiments of the invention have been described. However, it should be understood that various modifications can be made without departing from the scope of the invention. Therefore, other embodiments will be recognized by those skilled in the art as being within the scope of the following claims.

Claims (132)

1. A pharmaceutical composition comprising 1) an amorphous solid dispersion comprising pralatinib or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable hydrophilic polymer; and 2) a foaming pair. 2. A pharmaceutical composition comprising 1) an amorphous solid dispersion comprising pralatinib or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable amphiphilic polymer; and 2) a foaming pair. 3. The composition of claim 1 or 2, wherein the polymer is selected from the group consisting of: hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), vinylpyrrolidone-vinyl acetate copolymer (KOLLIDON VA64 or KOLLIDON K30), dimethylaminoethyl methacrylate copolymer (EUDRAGIT EPO), polyethylene oxide (POLYOX), and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOLUPLUS). 4. The composition according to any one of claims 1-3, wherein the polymer is hydroxypropyl methylcellulose. 5. The composition according to any one of claims 1-4, wherein the polymer is hydroxypropyl methylcellulose E3 (HPMC-E3) or hydroxypropyl methylcellulose E5 (HPMC-E5). 6. The composition of any one of claims 1, 3 and 4, wherein the pralatinib or an equivalent amount of its pharmaceutically acceptable salt is in a weight percentage ratio of about 1:1 to the hydrophilic polymer. 7. The composition of any one of claims 2-4, wherein the pralatinib or an equivalent amount of its pharmaceutically acceptable salt is in a weight percentage ratio of about 1:1 to the amphiphilic polymer. 8. The composition of any one of claims 1, 3 and 4, wherein the pralatinib or an equivalent amount of its pharmaceutically acceptable salt is in a weight percentage ratio of about 1:5 to about 5:1 to the hydrophilic polymer. 9. The composition of any one of claims 2-4, wherein the pralatinib or an equivalent amount of its pharmaceutically acceptable salt is in a weight percentage ratio of about 1:5 to about 5:1 to the amphiphilic polymer. 10. The composition of any one of claims 1 to 9, wherein the composition comprises the amorphous solid dispersion comprising about 25% to about 65% by weight of the total weight of the composition. 11. The composition of any one of claims 1 to 10, wherein the composition comprises the amorphous solid dispersion comprising about 50% to about 60% by weight of the total weight of the composition. 12. The composition of any one of claims 1 to 11, wherein the amorphous solid dispersion is prepared by hot melt extrusion, freeze drying, spray drying, solvent casting, or melt quenching. 13. The composition of any one of claims 1 to 12, wherein the foaming pair comprises a water-soluble acid and a water-soluble base. 14. The composition of any one of claims 1 to 12, wherein the foaming agent comprises a water-soluble alkali. 15. The composition of claim 13, wherein the water-soluble acid is selected from the group consisting of: citric acid, tartaric acid, fumaric acid, adipic acid, succinic acid, malonic acid, benzoic acid, oxalic acid, malic acid, and glutaric acid. 16. The composition of any one of claims 13 to 15, wherein the water-soluble alkali is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, and magnesium carbonate. 17. The composition of claim 13, wherein the water-soluble acid is citric acid and the water-soluble base is sodium bicarbonate. 18. The composition of any one of claims 13 and 15-17, wherein the composition comprises about 1% to about 20% by weight of the water-soluble acid based on the total weight of the composition. 19. The composition of any one of claims 13-18, wherein the composition comprises about 1% to about 35% by weight of the water-soluble base based on the total weight of the composition. 20. The composition of any one of claims 1 to 19, wherein the composition further comprises a dehumidifier. 21. The composition of claim 20, wherein the dehumidifier is starch. 22. The composition of claim 21, wherein the starch is pregelatinized starch. 23. The composition of any one of claims 20 to 22, wherein the composition comprises a desiccant comprising about 0.5% by weight to about 30% by weight of the total weight of the composition. 24. The composition of any one of claims 1 to 23, wherein the composition further comprises a diluent. 25. The composition of claim 24, wherein the diluent is cellulose. 26. The composition of claim 25, wherein the cellulose is microcrystalline cellulose. 27. The composition of any one of claims 24 to 26, wherein the composition comprises the diluent in an amount of about 5% to about 60% by weight of the total weight of the composition. 28. The composition of any one of claims 1 to 27, wherein the composition further comprises a lubricant. 29. The composition of claim 28, wherein the lubricant is magnesium stearate. 30. The composition of any one of claims 28 or 29, wherein the composition comprises the lubricant in an amount of about 0.1% to about 5% by weight of the total weight of the composition. 31. The composition according to any one of claims 1 to 30, wherein the composition is prepared into an oral dosage form. 32. The composition of claim 31, wherein the oral dosage form is a capsule. 33. The composition of claim 31, wherein the oral dosage form is a tablet. 34. The composition of any one of claims 1 to 33, wherein the composition is an immediate-release composition. 35. The composition of any one of claims 1 to 34, wherein the composition comprises about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, or about 200 mg of pralatinib or an equivalent amount of its pharmaceutically acceptable salt. 36. An oral dosage form comprising a) an amorphous solid dispersion comprising pralatinib or a pharmaceutically acceptable salt thereof and hydroxypropyl methylcellulose (HPMC); b) microcrystalline cellulose (MCC); c) pregelatinized starch; d) sodium bicarbonate; e) citric acid; and f) magnesium stearate. 37. The oral dosage form of claim 36, wherein the oral dosage form comprises the amorphous solid dispersion comprising about 25% to about 65% by weight of the total weight of the oral dosage form. 38. The oral dosage form of claim 36 or 37, wherein the oral dosage form comprises about 5% to about 60% by weight of the microcrystalline cellulose (MCC) based on the total weight of the oral dosage form. 39. The oral dosage form of any one of claims 36 to 38, wherein the oral dosage form comprises about 0.5% by weight to about 30% by weight of the pregelatinized starch based on the total weight of the oral dosage form. 40. The oral dosage form of any one of claims 36 to 39, wherein the oral dosage form comprises sodium bicarbonate in an amount of about 1% to about 35% by weight of the total weight of the oral dosage form. 41. The oral dosage form of any one of claims 36 to 40, wherein the oral dosage form comprises about 1% to about 20% by weight of the citric acid based on the total weight of the oral dosage form. 42. The oral dosage form of any one of claims 36 to 41, wherein the oral dosage form comprises about 0.1% to about 5% by weight of the magnesium stearate based on the total weight of the oral dosage form. 43. The oral dosage form of any one of claims 36 to 42, wherein the pralatinib or an equivalent amount of its pharmaceutically acceptable salt is in a weight percentage ratio of about 1:1 to the hydrophilic polymer. 44. The oral dosage form according to any one of claims 36 to 43, wherein the amorphous solid dispersion is prepared by hot melt extrusion, freeze drying, spray drying, solvent casting, or melt quenching. 45. The oral dosage form according to any one of claims 36 to 44, wherein the oral dosage form is a capsule. 46. The oral dosage form as claimed in claim 32 or 45, wherein the size of the capsule is 0. 47. The oral dosage form according to any one of claims 36-44, wherein the oral dosage form is a tablet. 48. The oral dosage form of any one of claims 36 to 47, wherein the oral dosage form comprises about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg, or about 200 mg of pralatinib, or an equivalent amount of its pharmaceutically acceptable salt. 49. The oral dosage form according to any one of claims 36 to 48, wherein the oral dosage form is an immediate-release oral dosage form. 50. An immediate-release oral dosage form, said immediate-release oral dosage form comprising: a) An amorphous solid dispersion comprising: pralatinib or a pharmaceutically acceptable salt thereof and hydroxypropyl methylcellulose E3, wherein the pralatinib or an equivalent amount of its pharmaceutically acceptable salt is in a weight ratio of about 1:1 to the hydroxypropyl methylcellulose E3. b) A foaming pair comprising about 3 to about 13 w/w% citric acid and about 7 to about 30 w/w% sodium bicarbonate; wherein w/w% is based on the total weight of the oral dosage form; c) Diluent; and optionally d) Dehumidifiers and/or lubricants. 51. The oral dosage form of claim 50, wherein the amorphous solid dispersion comprises about 30 mg, about 50 mg, about 60 mg, or about 100 mg of pralatinib or an equivalent amount of its pharmaceutically acceptable salt. 52. The composition or oral dosage form of any one of claims 1-51, wherein, using USP<711>, at least 80% of said pralatinib is released within 45 minutes using a type 2 device, a medium containing 900 mL of 0.1 M HCl and a stirring speed of 100 rpm. 53. The composition or oral dosage form of any one of claims 1-51, wherein the dosage form is a capsule, wherein USP<701> is used, utilizing a basket A type and a disc maintaining a temperature of 37°C ± 2°C, and the capsule disintegrates within about 7 to 15 minutes. 54. The composition or oral dosage form of any one of claims 1-51, wherein the dosage form is a capsule, wherein at least 80% of the pralatinib is released within about 120 minutes using a USPII device and a medium containing 900 mL of pH 6.8 sodium phosphate buffer with 0.5% CTAB and a stirring speed of 75 rpm ± 2 rpm. 55. A method for preparing an amorphous solid dispersion according to any one of claims 1 to 54, the method comprising: mixing the pralatinib or a pharmaceutically acceptable salt thereof with the hydrophilic polymer in a ratio of about 1:1; adding a solvent; and removing the solvent by heating. 56. A method of treating cancer with RET alterations, the method comprising administering to a patient in need a therapeutically effective amount of the composition according to any one of claims 1 to 35 or an oral dosage form according to any one of claims 36 to 54. 57. A method of treating a patient with transfection rearrangement (RET)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC), the method comprising administering to the patient in need a therapeutically effective amount of the composition according to any one of claims 1 to 35 or an oral dosage form according to any one of claims 36 to 54. 58. The method of claim 57, wherein the (RET)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) is detected by an FDA-approved test. 59. A method of treating a patient with RET mutation-positive locally advanced or metastatic medullary thyroid carcinoma (MTC), the method comprising administering to the patient in need a therapeutically effective amount of the composition according to any one of claims 1 to 35 or an oral dosage form according to any one of claims 36 to 54. 60. A method for treating a patient with RET fusion-positive locally advanced or metastatic thyroid cancer who requires systemic therapy and has no satisfactory alternative treatment options, the method comprising administering to the patient in need a therapeutically effective amount of the composition according to any one of claims 1 to 35 or an oral dosage form according to any one of claims 36 to 54. 61. A crystalline form A of pralatinib. 62. The crystalline form A as claimed in claim 61, wherein the crystalline form is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at a 2θ angle selected from 5.0±0.2°, 9.7±0.2°, 12.7±0.2°, 13.6±0.2°, and 16.1±0.2°. 63. The crystalline form A as claimed in claim 61, wherein the crystalline form 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 selected from 5.0±0.2°, 6.8±0.2°, 9.7±0.2°, 12.7±0.2°, 13.6±0.2°, 16.1±0.2°, 19.2±0.2°, 19.5±0.2°, and 23.5±0.2°. 64. The crystalline form A as claimed in claim 61, wherein the crystalline form is characterized by a crystallinity selected from 5.0±0.2°, 6.8±0.2°, 9.7±0.2°, 12.7±0.2°, 13.6±0.2°, 14.8±0.2°, 16.1±0.2°, 17.2±0.2°, 17.8±0.2°, 19.2±0.2°, 19.5±0.2°, 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 of 20.5±0.2°, 21.6±0.2°, 23.1±0.2°, 23.5±0.2°, 24.8±0.2°, 25.6±0.2°, 26.0±0.2°, 27.9±0.2°, and 29.4±0.2°. 65. Crystalline form A as claimed in any one of claims 61 to 64, wherein the peak has a relative intensity of at least 10%, at least 15%, at least 20%, or at least 25%. 66. The crystalline form A as claimed in claim 61, wherein the crystalline form has an XRPD pattern substantially identical to the XRPD pattern shown in FIG. 1A. 67. The crystalline form A of claim 61, wherein the crystalline form has an XRPD pattern substantially comprising the peaks in Table 1A. 68. Crystalline form A as claimed in any one of claims 61 to 67, wherein the crystalline form has a DSC pattern substantially the same as the DSC pattern shown in FIG. 1B. 69. Crystalline form A as claimed in any one of claims 61 to 68, wherein an endothermic event at about 205°C ± 2°C is observed in the DSC thermogram. 70. Crystalline form A as claimed in any one of claims 61 to 69, wherein the crystalline form has a TGA pattern substantially the same as the TGA pattern shown in FIG. 1B. 71. Crystalline form A as claimed in any one of claims 61 to 70, wherein the crystalline form has a DVS pattern substantially the same as the DVS pattern shown in FIG. 1C. 72. Crystalline form A as claimed in any one of claims 61 to 71, wherein the crystalline form is characterized by a reversible mass change of about 10% between 2% and 95% relative humidity according to DVS. 73. A method for preparing crystalline form A as described in any one of claims 61 to 72, wherein the method comprises the steps selected from the group consisting of: (a) forming a slurry in an alcohol, acetone, or ACN; (b) evaporating and cooling crystallizing in IPA and 1-propanol; (c) recrystallizing in acetone:water; (d) heating a sample of form B to at least about 190°C; or (e) heating a sample of praltinib form C to at least about 190°C under conditions suitable for producing form A. 74. A crystalline form B of pralatinib. 75. The crystalline form B as claimed in claim 74, wherein the crystalline form is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at a 2θ angle selected from 5.9±0.2°, 8.8±0.2°, 11.6±0.2°, 14.7±0.2°, and 19.5±0.2°. 76. The crystalline form B as claimed in claim 74, wherein the crystalline form is characterized by at least three, at least four, at least five, at least six, at least seven, or at least eight X-ray powder diffraction peaks at a 2θ angle selected from 5.9±0.2°, 8.8±0.2°, 11.6±0.2°, 14.7±0.2°, 17.0±0.2°, 17.6±0.2°, 19.5±0.2°, and 22.2±0.2°. 77. Crystalline form B as claimed in any one of claims 74 to 76, wherein the peak has a relative intensity of at least 10%, at least 15%, at least 20%, or at least 25%. 78. The crystalline form B as claimed in claim 74, wherein the crystalline form has an XRPD pattern substantially the same as the XRPD pattern shown in FIG. 1A. 79. The crystalline form B as claimed in claim 74, wherein the crystalline form has an XRPD pattern substantially comprising the peaks in Table 2A. 80. Crystalline form B as claimed in any one of claims 74 to 79, wherein the crystalline form has a DSC pattern substantially the same as the DSC pattern shown in FIG. 2B. 81. Crystalline form B as claimed in any one of claims 74 to 80, wherein crystalline form B is characterized by DSC: endothermic initiation at 149°C ± 2°C, exothermic initiation at 162°C ± 2°C, and melting initiation at 205°C ± 2°C. 82. Crystalline form B as claimed in any one of claims 74 to 81, wherein the crystalline form has a TGA pattern substantially the same as the TGA pattern shown in FIG. 2B. 83. Crystalline form B as claimed in any one of claims 74 to 82, wherein the crystalline form has a TGA pattern displaying a mass loss of 0.5%. 84. Crystalline form B as claimed in any one of claims 74 to 83, wherein the crystalline form has a DVS pattern substantially the same as the DVS pattern shown in FIG. 2C. 85. Crystalline form B as claimed in any one of claims 74 to 84, wherein the crystalline form exhibits a total mass change of 1.4 wt.% between 2% and 95% relative humidity. 86. A method for preparing crystalline form B as described in any one of claims 74 to 85, wherein the method comprises the step of heating a sample of form C to about 150°C. 87. A crystalline form of pralatinib, C. 88. The crystalline form C as claimed in claim 87, wherein the crystalline form is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at a 2θ angle selected from 5.8±0.2°, 8.7±0.2°, 11.0±0.2°, 13.6±0.2°, and 20.2±0.2°. 89. The crystalline form C as claimed in claim 87, wherein the crystalline form 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 selected from 5.8±0.2°, 8.7±0.2°, 11.0±0.2°, 11.6±0.2°, 13.6±0.2°, 14.5±0.2°, 20.2±0.2°, 22.2±0.2°, and 23.2±0.2°. 90. The crystalline form C as claimed in claim 87, wherein the crystalline form is characterized by a crystallinity selected from 5.8±0.2°, 8.7±0.2°, 11.0±0.2°, 11.6±0.2°, 12.0±0.2°, 13.6±0.2°, 14.5±0.2°, 17.1±0.2°, 18.2±0.2°, 19.5±0.2°, 20.2±0.2°, 20.6± 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 of 0.2°, 21.3±0.2°, 22.2±0.2°, 22.6±0.2°, 23.2±0.2°, 24.2±0.2°, 24.5±0.2°, 26.0±0.2°, 26.8±0.2°, and 28.1±0.2°. 91. The crystalline form C as claimed in claim 87, wherein the peak has a relative intensity of at least 10%, at least 15%, at least 20%, or at least 25%. 92. The crystalline form C as claimed in claim 87, wherein the crystalline form has an XRPD pattern substantially the same as the XRPD pattern shown in FIG. 3A. 93. The crystalline form C of claim 87, wherein the crystalline form has an XRPD pattern substantially comprising the peaks in Table 3A. 94. The crystalline form C according to any one of claims 87 to 93, wherein the crystalline form has a DSC pattern substantially the same as the DSC pattern shown in FIG. 1B. 95. The crystalline form C according to any one of claims 87 to 94, wherein initiation at 122°±2°C, 127°±2°C and 206°±2°C is observed in the DSC thermogram. 96. The crystalline form C according to any one of claims 87 to 95, wherein the crystalline form has a TGA pattern substantially the same as the TGA pattern shown in FIG. 3B. 97. Crystalline form C as claimed in any one of claims 87 to 96, wherein a mass loss of about 3 wt.% is observed in the TGA thermogram of form C. 98. The crystalline form C according to any one of claims 87 to 97, wherein the crystalline form has a DVS pattern substantially the same as the DVS pattern shown in FIG. 3C. 99. The crystalline form C as claimed in any one of claims 87 to 98, wherein the DVS of the crystalline form shows a total mass change of 1.4 wt.% between 2% and 95% relative humidity. 100. A method for preparing crystalline form C as claimed in any one of claims 87 to 99, wherein the method comprises the steps selected from the group consisting of: a) recrystallization in a variety of aqueous solvent systems (acetone:water, MeOH:water, IPA:water, DMAc:water, THF:water); b) conversion from form A in methanol:water at a high water to methanol ratio and at a low temperature during a competitive slurry experiment. 101. A crystalline form of pralatinib in HCl salt form I. 102. The crystalline form I as claimed in claim 101, wherein the crystalline form is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at a 2θ angle selected from 0±0.2°, 6.1±0.2°, 9.1±0.2°, 9.9±0.2°, and 14.7±0.2°. 103. The crystalline form I as claimed in claim 101, wherein the crystalline form is characterized by having 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 selected from 5.0°±0.2, 6.1°±0.2, 9.1°±0.2, 9.9°±0.2, 13.8°±0.2, 14.7±0.2°, 15.3±0.2°, 17.2±0.2°, 18.1±0.2°, 19.6±0.2°, 20.3±0.2°, 20.7±0.2°, 21.8±0.2°, 24.2±0.2°, 25.6±0.2°, and 26.3±0.2°. 104. Crystalline form I as claimed in any one of claims 101 to 103, wherein the peak has a relative intensity of at least 10%, at least 15%, at least 20%, or at least 25%. 105. The crystalline form I as claimed in claim 101, wherein the crystalline form has an XRPD pattern substantially the same as the XRPD pattern shown in FIG. 4A. 106. The crystalline form I as claimed in claim 101, wherein the crystalline form has an XRPD pattern substantially comprising the peaks in Table 4A. 107. Crystalline form I as claimed in any one of claims 101 to 106, wherein the crystalline form has a DSC pattern substantially the same as the DSC pattern shown in FIG. 4B. 108. A method for preparing crystalline form I as described in any one of claims 101 to 107, wherein the method comprises the step of separating the solid from a slurry of the HCl salt in EtOH or IPA:water (9:1 Vol). 109. A crystalline form of pralatinib in HCl form II. 110. The crystalline form II as claimed in claim 109, wherein the crystalline form is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at a 2θ angle selected from 6.1±0.2°, 8.9±0.2°, 9.5±0.2°, 15.0±0.2°, and 16.6±0.2°. 111. The crystalline form II as claimed in claim 109, wherein the crystalline form 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 selected from 6.1±0.2°, 8.9±0.2°, 9.5±0.2°, 15.0±0.2°, 16.6±0.2°, 17.2±0.2°, 17.9±0.2°, 18.4±0.2°, 19.8±0.2°, 25.8±0.2°, and 26.8±0.2°. 112. Crystalline form II as claimed in any one of claims 109 to 111, wherein the peak has a relative intensity of at least 10%, at least 15%, at least 20%, or at least 25%. 113. The crystalline form II as claimed in claim 109, wherein the crystalline form has an XRPD pattern substantially the same as the XRPD pattern shown in FIG. 5A. 114. The crystalline form II as claimed in claim 109, wherein the crystalline form has an XRPD pattern substantially comprising the peaks in Table 5A. 115. Crystalline form II as claimed in any one of claims 109 to 114, wherein the crystalline form has a DSC pattern substantially the same as the DSC pattern shown in FIG. 5B. 116. Crystalline form II as claimed in any one of claims 109 to 115, wherein the crystalline form is observed to have a broad endothermic starting temperature of 88.7°C ± 2°C and a melting starting temperature of 244.2°C ± 2°C in the DSC thermogram. 117. Crystallization form II as claimed in any one of claims 109 to 116, wherein the crystallization form has a TGA pattern substantially the same as the TGA pattern shown in FIG. 5B. 118. Crystalline form II as claimed in any one of claims 109 to 117, wherein an initial mass loss of 3.4 wt.% is observed in the TGA thermogram in relation to a broad endothermic reaction starting at 94.4 °C ± 2 °C, and a second mass loss event of 6.7 wt.% is observed from the end of the first broad endothermic reaction to the end of melting starting at 244.2 °C ± 2 °C. 119. A method for preparing crystalline form II as described in any one of claims 109 to 118, wherein the method comprises the step of separating the solid from EtOAc and IPA:water (9:1 vol). 120. A crystalline form of prantinib HCl salt III. 121. The crystalline form III as claimed in claim 120, wherein the crystalline form is characterized by at least three, at least four, or at least five X-ray powder diffraction peaks at a 2θ angle selected from 6.4±0.2°, 8.5±0.2°, 8.9±0.2°, 9.6±0.2°, and 17.3±0.2°. 122. The crystalline form III as claimed in claim 120, wherein the crystalline form 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 selected from 6.4±0.2°, 8.5±0.2°, 8.9±0.2°, 9.6±0.2°, 11.5±0.2°, 16.7±0.2°, 17.3±0.2°, and 19.2±0.2°. 123. The crystalline form III as claimed in claim 120, wherein the crystalline form 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 selected from 6.0±0.2°, 6.4±0.2°, 8.5±0.2°, 8.9±0.2°, 9.6±0.2°, 11.5±0.2°, 12.7±0.2°, 15.9±0.2°, 16.7±0.2°, 17.3±0.2°, 19.2±0.2°, 21.0±0.2°, and 26.9±0.2°. 124. Crystalline form III as claimed in any one of claims 120 to 123, wherein the peak has a relative intensity of at least 10%, at least 15%, at least 20%, or at least 25%. 125. The crystalline form III as claimed in claim 120, wherein the crystalline form has an XRPD pattern substantially the same as the XRPD pattern shown in FIG. 6A. 126. The crystalline form III of claim 120, wherein the crystalline form has an XRPD pattern substantially comprising the peaks in Table 6A. 127. Crystalline form III as claimed in any one of claims 120 to 126, wherein the crystalline form has a DSC pattern substantially the same as the DSC pattern shown in FIG. 6B. 128. Crystalline form III as claimed in any one of claims 120 to 127, wherein the crystalline form is observed to have DSCs starting at 86.8°C ± 2°C, 224.1°C ± 2°C, and 241.7°C ± 2°C. 129. Crystalline form III as claimed in any one of claims 120 to 128, wherein the crystalline form has a TGA pattern substantially the same as the TGA pattern shown in FIG. 6B. 130. Crystalline form III as claimed in any one of claims 120 to 129, wherein an initial mass loss of 3.4 wt.% and a second mass loss event of 2 wt.% are observed in the TGA thermogram. 131. A method for preparing crystalline form III as described in any one of claims 120 to 130, wherein the method comprises the step of drying the separated pralatinib HCl salt form II. 132. A pharmaceutically acceptable hydrochloride salt of compound (I):