Crystalline form of N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide

Abstract

The present invention provides a pharmaceutical composition containing a crystalline form of aciminib hydrochloride, a tablet formulation containing aciminib hydrochloride, and a process for manufacturing the tablet formulation. [Solution] A pharmaceutical composition comprising a crystalline form A of aciminib hydrochloride and a pharmaceutically acceptable carrier, wherein the crystalline form A of aciminib hydrochloride is Cu-K alpha having a wavelength of 0.1541 Å. 1,2 A pharmaceutical composition is provided, characterized in that, when measured using radiation at a temperature in the range of 20 to 25°C, it has an X-ray powder diffraction pattern that includes reflections at 2-theta angles of 12.6±0.2°, 18.9±0.2°, and 20.9±0.2°.

Description

[Technical Field]

[0001] This invention relates to N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3 -Hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine- The crystalline form (crystal shape) of 3-carboxamide, its manufacturing method, a pharmaceutical composition containing it, and This concerns the treatment methods for which it is used. [Background technology]

[0002] Polymorphism indicates the existence of two or more crystalline forms of a substance. Polymorphs (or crystalline transformations) are identical. Although they have the same chemical structure, they often possess completely different physicochemical properties. Polymorphs are... Includes non-nantiotropic polymorphs and monotropic polymorphs. A chemical substance has two or more crystalline forms. This ability to crystallize in its natural state affects the drug's storage life, solubility, formulation properties, and processing properties. It can have a significant impact. In addition, the effects of drugs are influenced by the polymorphism of drug molecules. It can be affected. Different polymorphs have different uptake rates in the body, and may be lower than desired or It can result in high biological activity. In extreme cases, unwanted polymorphs may even exhibit toxicity. The emergence of unknown crystalline forms during manufacturing can have a significant impact.

[0003] Understanding and controlling polymorphism offers a clear advantage when bringing new drugs to market. To give. First and foremost, using the search for all possible polymorphs for drug products, The possibility of contamination by other polymorphic forms during the manufacture or storage of drugs can be reduced. Failure to capture it can, in some cases, have life-threatening consequences. The failure of polymorphs to crystallize would mean a manufacturing shutdown of several weeks or even months. 、Meanwhile, scientists find the cause of the new crystalline form and correct it, or conduct another series of tests to obtain approval for the new crystalline form.

[0004] Second, by understanding which crystalline forms of a drug are possible in specific cases, researchers can maximize the desired properties of the compound, such as solubility, formulation characteristics, processing characteristics, and storage period. Understanding these factors early in the development of a new drug can mean a more active drug, a more stable drug, or a drug manufactured at a lower cost.

[0005] Formula

Chemical Formula

[0006] International Publication No. 2013 / 171639A1 pamphlet describes Abelson protein (ABL1), Abelson-related protein (ABL2) and related chimeric proteins In particular, to treat diseases that respond to inhibition of BCR-ABL1 tyrosine kinase enzyme activity. We provide a compound of formula (I) which is useful for [the purpose]. International Publication No. 2013 / 171639A Pamphlet No. 1 is N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3 R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl) A pharmaceutical composition containing an amorphous dispersion of lysine-3-carboxamide is described, but N-[4- (chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine] -1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide No crystalline form of the substance or a pharmaceutical preparation containing it is specifically disclosed. [Overview of the project]

[0007] N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydrox Cypirrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carb Crystalline forms of xamide have been discovered, and these are being utilized to obtain new pharmacological properties. It can be used, and N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R )-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyri This demonstrates novel physical properties that can be utilized in the development of drug products containing din-3-carboxamide. vinegar.

[0008] This invention relates to N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3 -Hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine- This paper concerns the crystalline morphology of free 3-carboxamide base.

[0009] Furthermore, the present invention relates to N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R) -3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyrid This also relates to the crystalline form of n-3-carboxamide hydrochloride.

[0010] Furthermore, the present invention provides (a) a therapeutically effective amount of the present invention's N-[4-(chlorodifluoromethyl) Toxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-( 1H-pyrazole-5-yl)pyridine-3-carboxamide free base or its hydrochloride The pharmaceutical composition also includes a crystalline form and (b) at least one pharmaceutically acceptable carrier. To provide.

[0011] Furthermore, the present invention is a method for treating ABL1 / BCR-ABL1 mediated disorders. , to subjects requiring such treatment, a therapeutically effective amount of the present invention's N-[4-( Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine- 1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide free salt The present invention also relates to a method comprising the step of administering a crystalline form of the base or its hydrochloride salt. [Brief explanation of the drawing]

[0012] [Figure 1] The X-ray powder diffraction (XRPD) pattern of crystalline form A of the free base N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide according to the present invention is shown. [Figure 2]The differential scanning calorimetry curve of crystalline form A of N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide free base according to the present invention is shown. [Figure 3] The thermogravimetric plot of crystalline form A of the free base N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide according to the present invention is shown. [Figure 4] The XRPD pattern of the morphology SA of the free base of N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide according to the present invention is shown. [Figure 5] The XRPD pattern of the free base SB of N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide according to the present invention is shown. [Figure 6] The XRPD pattern of the morphology SC of the free base of N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide according to the present invention is shown. [Figure 7] The XRPD pattern of the morphological SD of the free base of N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide according to the present invention is shown. [Figure 8] The XRPD pattern of crystalline form A of the hydrochloride salt of N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide according to the present invention is shown. [Figure 9]The differential scanning calorimetry curve for crystalline form A of the hydrochloride salt of N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide according to the present invention is shown. [Figure 10] The thermogravimetric plot of crystalline form A of the hydrochloride salt of N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide according to the present invention is shown. [Figure 11] The XRPD pattern of crystalline form B of the hydrochloride salt of N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide according to the present invention is shown. [Figure 12] The XRPD patterns of forms A and B of the hydrochloride salt of N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide according to the present invention are shown. [Figure 13] The XRPD pattern of morphological HA of the hydrochloride salt of N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide according to the present invention is shown. [Figure 14] This diagram shows the manufacturing process used to produce tablets containing crystalline form A of N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide hydrochloride. [Modes for carrying out the invention]

[0013] In relation to the present invention, unless otherwise explicitly stated, the following definitions have the meanings indicated. It has.

[0014] As used herein, the terms "room temperature" or "RT" refer to the range of 20 to 30°C. This refers to the temperature.

[0015] As used herein, the term "reflection" in relation to X-ray powder diffraction (XRPD) refers to X-ray This refers to the peak in the diffractogram, which is caused by scattering of atoms in parallel planes within the solid material. This phenomenon occurs at a specific diffraction angle (Bragg angle) due to constructive interference from X-rays, and over a long period of time. The positional order is distributed into a regular, repeating pattern. Such solid materials are crystalline materials. Although classified as a material, amorphous materials lack long-term order and only possess short-term order. It is defined as a solid material that exhibits and therefore causes broad scattering. According to the literature, over a long period of time... The order extends, for example, across approximately 100 to 1000 atoms, but the order is short-term. It is limited to just a few atoms ("Fundamentals of Powder r Diffraction and Structural Characteriz ation of Materials”by Vitalij K.Pecharsk y and Peter Y. Zavalij, Kluwer Academic Pu (See Blishers, 2003, page 3).

[0016] The crystalline form of the present invention is, in this specification, represented by the graphic data "shown in the drawings", for example. It may be mentioned that it features XRPD. Those skilled in the art will be able to see the changes in the type of equipment, the response, and Factors such as sample orientation, sample concentration, and changes in sample purity are shown in graph form. When this happens, small changes in such data, for example, regarding the exact peak position and intensity, It is understood that this may bring about changes. However, the graphics of the drawings in this specification The data is compared with graphic data created for another or unknown solid form. Confirming that two sets of graphic data relate to the same crystal morphology is well known to those skilled in the art. It is within the realm of knowledge.

[0017] As used herein, the terms “solid form” or “solid state form” refer to any compound. This term interchangeably refers to the crystalline and / or amorphous phases of a substance.

[0018] As used herein, the term "amorphous" refers to the solid form of a compound that is not crystalline. This refers to amorphous compounds that lack long-term order and exhibit clear XRPD patterns due to reflection. I won't.

[0019] As used herein, the term "polymorph" refers to a crystalline polymorph having the same chemical composition. This refers to a crystalline form having different spatial arrangements of molecules, atoms, and / or ions that form it. .

[0020] As used herein, the term “hydrate” refers to a crystalline structure in which water cooperates or Contained by the crystal structure, for example, being part of the crystal structure or trapped within the crystal This refers to a crystalline solid that contains water. As a result, water is present in stoichiometric or non-stoichiometric quantities. It can exist. When water exists in stoichiometric quantities, the hydrate is a Greek numeral prefix. It can be mentioned by adding a suffix. For example, hydrates depend on the stoichiometry of water / compound. Therefore, it can be called a hemihydrate or monohydrate. The water content is, for example, Karl Fischer It can be measured by coulometry.

[0021] As used herein, the term "dehydrating" or "dehydration" refers to the crystallization of a host molecule. This explains how to remove water from a structure, at least partially.

[0022] As used herein, the term “solvate” refers to a compound in which one or more organic solvents are used in a crystalline structure. They cooperate within or are housed by the crystal structure, for example, they are part of the crystal structure. or refers to a crystalline solid that contains trapped (water-containing) material within a crystal. Thus, one or more The organic solvent can exist in stoichiometric or non-stoichiometric amounts. When the solvent is present in stoichiometric quantities, the solvate is given a Greek numeral prefix. This can be mentioned by: For example, solvates are half-solvated depending on the stoichiometry of the solvent / compound. It can be called a substance or a monosolvate. The solvent content can be determined, for example, by GC, NMR, or SXRD. It can be measured by and / or TGA / MS.

[0023] As used herein, the term “pharmaceutically acceptable excipient” means a significant amount at a given dose. This refers to a substance that does not exhibit pharmacological activity and is added to a pharmaceutical composition in addition to the active ingredient of the drug. The agents are, in particular, media, diluents, release agents, disintegrants, solvent modifiers, absorption enhancers, stabilizers, or manufacturing agents. Excipients can function as additives. Excipients include fillers (diluents), binders, disintegrants, lubricants, and fluids. May contain chemical agents.

[0024] As used herein, the terms “filler” or “diluent” refer to the drug’s active ingredients before delivery. This refers to a substance used to dilute an ingredient. Diluents and fillers function as stabilizers. It can also accomplish that.

[0025] As used herein, the term “binder” refers to a pharmaceutically active ingredient and a pharmaceutically permitted This refers to a substance that binds together excipients to hold together separate, tightly adhering parts.

[0026] As used herein, the terms “disintegrant” or “disintegrating agent” refer to a solid pharmaceutical composition. When added, it promotes the breakdown or disintegration of the active pharmaceutical ingredient after administration, making it as efficient as possible. This refers to a substance that is released onto a target, enabling its rapid dissolution.

[0027] As used herein, the term “lubricant” refers to an additive to a powder blend that has been compressed. This refers to a substance that prevents powder clumps from sticking to the equipment during the tableting or encapsulation process. The lubricant can help eject the tablets from the die and improve the flow of the powder.

[0028] As used herein, the term “flow agent” refers to an agent used to improve the flow properties during tablet compression. This refers to a substance used in tablet and capsule formulations to prevent solidification and to provide an anti-caking effect.

[0029] One aspect of the present invention is the compound N-[4-(chlorodifluoromethoxy)phenyl]- 6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5 Provides distinct crystalline forms of the free base and hydrochloride of -yl)pyridine-3-carboxamide. These "crystalline forms" (or "crystalline form" or "crystalline transformation" or "polymorphic form") (These terms may be used interchangeably in this specification.) are thermodynamically stable, They differ in terms of physical parameters, X-ray structure, and preparation method. The polymorphs are enantiomers. It exists in two main categories: enantiotropy or monotropy. — The polymorph changes depending on the temperature at a given pressure or depending on the pressure at a given temperature (transition temperature or It is something that can be interconverted (called pressure). Relative thermodynamic stability is It reverses above or below the transition temperature or pressure. If one polymorph is more stable regardless of temperature, That is "monotropy." Polymorphism classically refers to two or more distinct types of crystals (identical). The ability of a compound to crystallize (having the same chemical structure but with completely different physicochemical properties). While it refers to this, the term pseudopolymorphism is usually applied to solvates and hydrates in crystalline form. However, for the purposes of the present invention, true polymorphs as well as pseudopolymorphs, i.e., hydrates and solvents, are used. The crystalline form is also included within the range of "crystalline form." Furthermore, "amorphous" refers to a disordered solid state. This refers to a state. Samples with different specific crystalline morphologies can be analyzed using the same primary X-ray powder diffraction (XRPD) method. They will share either a "peak" or "reflection," but for smaller peaks, the powder pattern will be used. It should be noted that there may be fluctuations. In addition, regarding the XRPD peak value (degrees) The term "approximately" generally means within 0.3°, more preferably within 0.2°, of a given value. It also preferably means within 0.1°. Or, the term "approximately" (this and all (Regarding) means within the range of standard errors that would be permissible if considered by those skilled in the art. When used in a specification, the term "substantially pure" refers to crystalline N-[4-(chlorodi Fluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl ]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide or its hydrochloride More than 50% of them exist in one of the forms described herein, and preferably less 70%, more preferably at least 80%, and most preferably at least 90% of the original material This means that one of the crystalline forms described in the detailed document exists.

[0030] In one embodiment, the crystalline form of the free base is called A, and N-[4-(chlorodifluoro Methoxyphenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5- The crystalline form of (1H-pyrazole-5-yl)pyridine-3-carboxamide is provided. Free base form A is non-hygroscopic (less than 0.1% at 25°C in relative humidity up to 92%). (This indicates water absorption), and it has very low solubility above pH 3. The intrinsic dissolution rate of morphology A when measured using a 100 photometer in a VanKel instrument. It was determined that the following conditions apply in HCl media at pH 4.5, pH 6.8, and 0.1N: Ta:

[0031] [Table 1]

[0032] In one embodiment, the present invention relates to a Cu-K alpha 1,2 emission having a wavelength of 0.1541 Å. When measured using radiation at temperatures in the range of 20-25°C, 12.7±0.2°, 18.9±0.2°, and 20.8±0.2°; or 12.7±0.2°, 15.3±0.2°, 18.9±0.2°, 20.8±0.2° and 25.0±0.2°; or 5.8°±0.2°, 11.3°±0.2°, 11.6°±0.2°, 12.2°±0. 2°, 12.7°±0.2°, 13.2°±0.2°, 14.7°±0.2°, 15.3 °±0.2°, 17.0°±0.2°, 17.4°±0.2°, 18.6°±0.2°, 18.9°±0.2°, 19.4°±0.2°, 19.8°±0.2°, 20.8°±0 0.2°, 21.8°±0.2°, 22.2°±0.2°, 22.7°±0.2°, 23. 4°±0.2°, 24.0°±0.2°, 24.5°±0.2°, 25.0°±0.2° , 25.5°±0.2°, 26.7°±0.2°, 27.1°±0.2°, 27.7°± 0.2°, 28.7°±0.2°, 29.3°±0.2°, 29.6°±0.2°, 30 0.2°±0.2°, 31.2°±0.2°, 32.0°±0.2°, 32.3°±0.2° °, 32.8°±0.2°, 33.7°±0.2°, 34.5°±0.2°, 35.3° ±0.2°, 37.0°±0.2°, 38.4°±0.2°, and 38.6°±0.2° It is characterized by having an XRPD pattern that includes reflections at the 2-theta angle (2-theta value). N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydro [Xypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-cal Regarding crystalline form A of boxamide.

[0033] In another embodiment, N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3 R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl) The crystalline form A of lysine-3-carboxamide is Cu-K with a wavelength of 0.1541 Å. When measured using alpha-1,2 radiation at temperatures in the range of 20-25°C, the reading was 5.8°. 11.3°, 11.6°, 12.2°, 12.7°, 13.2°, 14.7°, 15.3 °, 17.0°, 17.4°, 18.6°, 18.9°, 19.4°, 19.8°, 20 0.8°, 21.8°, 22.2°, 22.7°, 23.4°, 24.0°, 24.5°, 25.0°, 25.5°, 26.7°, 27.1°, 27.7°, 28.7°, 29.3° °, 29.6°, 30.2°, 31.2°, 32.0°, 32.3°, 32.8°, 33 0.7°, 34.5°, 35.3°, 37.0°, 38.4°, and 38.6° (2θ degrees ± At least three, or at least four, or fewer than, selected from the group consisting of 0.2°. It is characterized by having an XRPD pattern that includes five or all of the 2-theta values.

[0034] In another embodiment of the present invention, N-[4-(chlorodifluoromethoxy)phenyl]-6 -[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5- Crystalline form A of the free base of yl(pyridine-3-carboxamide) is shown in the XRPD pattern in Figure 1. It is characterized by [something].

[0035] N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydrox Cypirrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carb The thermal properties of crystalline form A of xamide were determined by differential scanning calorimetry at a scanning speed of 5°C / min. Analysis was performed by DSC (Figure 2) and thermogravimetric analysis (TGA) (Figure 3).

[0036] Furthermore, N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3- Hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3 -During the equilibration, crystallization, and precipitation studies of crystalline form A of carboxamide, several solvents A compound was discovered. During equilibration and crystallization studies using each solvent, methanol solvent Japanese form S A , 1-propanol solvate form S B , and ethanol solvate form SC is isolated. In precipitation studies using acetone and water, acetone solvate form S D is isolated and solvate form S A 、S B 、S C 、and S D are characterized by the XRPD patterns shown in FIGS. 4-7, respectively. respectively.

[0037] In another embodiment, the present invention relates to crystalline forms A and B and the trihydrate modification H A so-called, N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy pyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carbox amide hydrochloride crystalline forms. Forms A and B are enantiotropically related . Form A has greater physical stability at temperatures lower than the enantiotropic transition temperature range of 65° C. to 90° C., and form B has greater physical stability at temperatures higher than this range . Form B spontaneously converts to form A under ambient conditions. Form A can be converted to modification H or form H when equilibrated in water at pH 1. A or form H A .

[0038] Form A of the hydrochloride is non-hygroscopic (showing less than 0.4% water uptake at 25° C. at relative humidities up to 95%) and has a fairly low solubility above pH 3. When measured in a VanKel apparatus using a Cary 10 0 spectrophotometer, the intrinsic dissolution rate of form A was determined to be as follows in pH 3.5, pH 4.5 and 0.1 N HCl media: 0 spectrophotometer, the intrinsic dissolution rate of form A was determined to be as follows in pH 3.5, pH 4.5 and 0.1 N HCl media: pH 3.5, pH 4.5 and 0.1 N HCl media as follows:

[0039]

Table 2

[0040] In another embodiment, the present invention relates to Cu-K alpha 1,2 having a wavelength of 0.1541 Å. When measured using radiation at temperatures in the range of 20-25°C, 12.6±0.2°, 18.9±0.2° and 20.9±0.2°; or 12.6±0.2°, 17.0±0.2°, 18.9±0.2°, 20.9±0.2° and 32.5±0.2°; or 8.5°±0.2°, 9.5°±0.2°, 11.8°±0.2°, 12.3°±0.2 °, 12.6°±0.2°, 13.9°±0.2°, 14.8°±0.2°, 15.9° ±0.2°, 16.5°±0.2°, 17.0°±0.2°, 17.6°±0.2°, 1 8.9°±0.2°, 19.1°±0.2°, 19.8°±0.2°, 20.4°±0. 2°, 20.9°±0.2°, 21.2°±0.2°, 22.4°±0.2°, 22.7 °±0.2°, 23.9°±0.2°, 24.3°±0.2°, 24.8°±0.2°, 25.0°±0.2°, 25.9°±0.2°, 26.8°±0.2°, 27.0°±0 0.2°, 28.3°±0.2°, 28.6°±0.2°, 28.9°±0.2°, 29. 8°±0.2°, 30.5°±0.2°, 31.3°±0.2°, 31.5°±0.2° , 31.8°±0.2°, 32.1°±0.2°, 32.5°±0.2°, 32.9°± 0.2°, 33.6°±0.2°, 34.0°±0.2°, 34.6°±0.2°, 35 0°±0.2°, 35.6°±0.2°, 36.3°±0.2°, and 38.8°±0. 2° It is characterized by having an XRPD pattern that includes reflections at the 2-theta angle (2-theta value). N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydro [Xypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-cal This concerns crystalline form A of boxamide hydrochloride.

[0041] In another embodiment, N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3 R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl) The XRPD pattern of crystalline morphology A of lysine-3-carboxamide hydrochloride is 0.1541. Measurements were taken using Cu-K alpha 1,2 radiation with wavelengths of Å at temperatures in the range of 20-25°C. When fixed, the angles are 8.5°, 9.5°, 11.8°, 12.3°, 12.6°, and 13.9°. 14.8°, 15.9°, 16.5°, 17.0°, 17.6°, 18.9°, 19. 1°, 19.8°, 20.4°, 20.9°, 21.2°, 22.4°, 22.7°, 2 3.9°, 24.3°, 24.8°, 25.0°, 25.9°, 26.8°, 27.0° 28.3°, 28.6°, 28.9°, 29.8°, 30.5°, 31.3°, 31. 5°, 31.8°, 32.1°, 32.5°, 32.9°, 33.6°, 34.0°, 3 From 4.6°, 35.0°, 35.6°, 36.3°, 38.8° (2θ degrees ± 0.2°) At least three, or at least four, or at least five, selected from the group, It features all 2-theta values.

[0042] In another embodiment of the present invention, N-[4-(chlorodifluoromethoxy)phenyl]-6 -[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5- Crystalline form A of yl(pyridine-3-carboxamide hydrochloride) is shown in Figures 8 and / or 12. It is characterized by an RPD pattern.

[0043] N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydrox Cypirrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carb The thermal properties of crystalline form A of xamide hydrochloride are determined by differential scanning heat at a scanning rate of 2°C / min. Analysis was performed by measurement (DSC) (Figure 9) and thermogravimetric analysis (TGA) (Figure 10).

[0044] N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydrox Cypirrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carb The XRPD pattern of crystalline form B of xamide hydrochloride has a wavelength of 0.1541 Å. When measured using uK-alpha 1,2 radiation at temperatures in the range of 100-125°C, 8.5°, 8.6°, 9.2°, 10.8°, 11.8°, 12.7°, 13.8°, 1 4.7°, 15.6°, 14.8°, 15.9°, 16.1°, 16.9°, 18.0° 18.4°, 18.9°, 19.2°, 19.5°, 19.8°, 20.2°, 20. 4°, 20.8°, 20.9°, 21.1°, 21.6°, 21.9°, 22.3°, 2 2.6°, 23.1°, 23.4°, 23.7°, 24.0°, 24.1°, 24.3° 24.6°, 24.7°, 25.2°, 25.5°, 25.9°, 26.5°, 27. 0°, 27.6°, 28.4°, 28.5°, 28.9°, 29.5°, and 29.8° At least three, or at least four, selected from the group consisting of (2θ degrees ± 0.2°), Or it features at least five, or all, two-theta values.

[0045] In another embodiment of the present invention, N-[4-(chlorodifluoromethoxy)phenyl]-6 -[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5- Crystalline form B of yl(pyridine-3-carboxamide hydrochloride) is shown in Figures 11 and / or 12. It features the XRPD pattern.

[0046] In another embodiment, the present invention relates to Cu-K alpha 1,2 having a wavelength of 0.1541 Å. When measured using radiation at temperatures in the range of 20-25°C, 10.4±0.2°, 21.8±0.2°, and 30.6±0.2°; or 10.4±0.2°, 12.0±0.2°, 16.8±0.2°, 21.8±0.2° and 30.6±0.2°; or 7.9°±0.2°, 10.4°±0.2°, 12.0°±0.2°, 13.0°±0. 2°, 13.3°±0.2°, 13.8°±0.2°, 15.5°±0.2°, 15.9 °±0.2°, 16.4°±0.2°, 16.8°±0.2°, 17.5°±0.2°, 19.7°±0.2°, 20.1°±0.2°, 20.5°±0.2°, 20.8°±0 0.2°, 21.1°±0.2°, 21.8°±0.2°, 22.2°±0.2°, 22. 7°±0.2°, 23.0°±0.2°, 23.5°±0.2°, 23.9°±0.2° , 24.2°±0.2°, 24.6°±0.2°, 25.0°±0.2°, 26.0°± 0.2°, 26.3°±0.2°, 26.5°±0.2°, 26.8°±0.2°, 27 0.8°±0.2°, 28.2°±0.2°, 28.5°±0.2°, 28.8°±0.2 °, 29.5°±0.2°, 30.0°±0.2°, 30.6°±0.2°, 31.0° ±0.2°, 31.3°±0.2°, 31.7°±0.2°, 32.0°±0.2°, 3 3.2°±0.2°, 34.0°±0.2°, 34.2°±0.2°, 35.3°±0. 2°, 35.9°±0.2°, 36.7°±0.2°, 37.0°±0.2°, 37.4 °±0.2°, 37.7°±0.2°, 38.2°±0.2°, 28.9°±0.2° and 39.6°±0.2° It is characterized by having an XRPD pattern that includes reflections at the 2-theta angle (2-theta value). N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydro [Xypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-cal Boxamide hydrochloride crystalline trihydrate form H A Regarding.

[0047] In another embodiment, N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3 R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl) Lysine-3-carboxamide hydrochloride crystalline trihydrate form H A The XRPD pattern is 0 Using Cu-K alpha 1,2 radiation with a wavelength of 0.1541 Å in the range of 20-25°C. When measured at these temperatures, the readings were 7.9°, 10.4°, 12.0°, 13.0°, and 13.3°. 13.8°, 15.5°, 15.9°, 16.4°, 16.8°, 17.5°, 19. 7°, 20.1°, 20.5°, 20.8°, 21.1°, 21.8°, 22.2°, 2 2.7°, 23.0°, 23.5°, 23.9°, 24.2°, 24.6°, 25.0° , 26.0°, 26.3°, 26.5°, 26.8°, 27.8°, 28.2°, 28. 5°, 28.8°, 29.5°, 30.0°, 30.6°, 31.0°, 31.3°, 3 1.7°, 32.0°, 33.2°, 34.0°, 34.2°, 35.3°, 35.9° , 36.7°, 37.0°, 37.4°, 37.7°, 38.2°, 38.9°, and 3 At least three, or at least, selected from the group consisting of 9.6° (2θ degrees ± 0.2°) It also features four, or at least five, or all of the 2-theta values.

[0048] In another embodiment of the present invention, N-[4-(chlorodifluoromethoxy)phenyl]-6 -[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5- Crystalline trihydrate of yl(pyridine-3-carboxamide) hydrochloride, form H A This is the XR in Figure 13. It is characterized by a PD pattern.

[0049] Using various methods, N-[4-(chlorodifluoromethoxy)phenyl]-6-[( 3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl) Crystalline form of free base of pyridine-3-carboxamide (Morphology A, S) A S B S C , and biS D ) and the crystalline form of the hydrochloride (forms A, B, and H A ) can be achieved. The method described above is as described in the examples presented below. As described above, equilibration with a solvent, crystallization at room temperature, crystallization from a hot saturated solution, and sol This includes precipitation due to the addition of a medium.

[0050] Another embodiment of the present invention is, (a) A therapeutically effective amount of N-[4-(chlorodi) according to one of the earlier embodiments of the present invention. Fluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl ]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide free base or The crystalline form of the hydrochloride salt, At least one pharmaceutically acceptable carrier, diluent, medium or excipient This relates to a pharmaceutical composition containing [a specific ingredient / component].

[0051] In a preferred embodiment, the crystalline form is N-[4-(chlorodifluoromethoxy)phen [Nyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrzo This is form A of the hydrochloride salt of yl-5-yl)pyridine-3-carboxamide. Preferably, More than 50%, more preferably at least 70%, of the crystalline form present in the composition Preferably at least 80%, most preferably at least 90%, of the selected form It's one of ours.

[0052] As described in detail below, the pharmaceutical compositions of the present invention include those suitable for the following: , may be specially formulated for administration in solid or liquid form: (1) Oral administration, e.g., water Drugs (aqueous or non-aqueous solutions or suspensions), tablets, for example, buccal, sublingual, and systemic absorption Tablets, boluses, powders, granules, and pastes for tongue application that target the target; (2) For example , sterile solution or suspension, or sustained-release formulation, for example, subcutaneous, intramuscular, intravenous or (3) For example, creams, ointments, or creams applied to the skin. (4) Topical application as a controlled-release patch or spray; e.g., pessary, cream (5) Intravaginal or rectal administration as a sm or form; (6) Sublingual administration; (7) Intraocular administration; (8) Transdermal administration; (9) Nasal administration; (10) Lung administration; or (10) Intrathecal administration.

[0053] The general terms used above and below, unless otherwise specified, are in the context of this disclosure. In this context, the following meanings are preferred, and the more general terms used here are: Even if they are replaced by more specific definitions that are independent of each other, or remain as they are This may also be done, and therefore more detailed embodiments of the present invention can be defined:

[0054] The term "disintegrant" refers to an agent that causes tablets to swell and dissolve when wet, allowing them to move through the digestive tract. It refers to a substance that breaks down a tablet into small pieces, releasing the active ingredient for absorption. Disintegrants are substances that break down tablets into small pieces and release the active ingredient. It ensures rapid decomposition and accelerated dissolution upon contact. The disintegrant is cross-linked polymer. Vinylpyrrolidone (crospovidone), cross-linked carboxymethylcellulose sodium, e.g. For example, croscarmellose sodium and sodium starch glycolate, preferably The group is selected from the group consisting of croscarmellose sodium.

[0055] The term "filler," also known as a "diluent," is used when the amount of active drug is too small to be convenient. Because it cannot be handled (manufacturing and handling are difficult), in order to increase the contents of the dosage form This refers to inert ingredients commonly used in tablets and capsules. Examples of fillers / diluents are provided. For example, starch, dextrin, sucrose, sorbitol, sodium saccharin, Acesulfame potassium, xylitol, aspartame, mannitol, starch, P VP (polyvinylpyrrolidone), low molecular weight HPC (hydroxypropyl cellulose), fine Crystalline cellulose (MCC), low molecular weight HPMC (hydroxypropyl methylcellulose) Low molecular weight carboxymethylcellulose, ethylcellulose, dicalcium phosphate, ke Microcrystalline cellulose, alginate, gelatin, polyethylene oxide, acacia, Quitrin, sucrose, magnesium aluminum silicate, polymethacrylate, lac Chitol, lactose, appropriate inorganic calcium salts, sucrose, glucose, mannitol Examples of fillers include, but are not limited to, silicic acid and combinations thereof. Based on the total weight of the tablet formulation, the granular content makes up approximately 60% to 80% of the total weight. It is an ingredient.

[0056] The term "fluidizer" is used to improve the "flowability" of powders, i.e., their fluidity. This refers to substances added to powders. Examples include magnesium stearate and fumaric acid. Sodium stearyl, talc, magnesium carbonate, fumed silica (silicon dioxide) , silica, aerosol (colloidal anhydrous / colloidal silicon dioxide) and starch, or Any combination of these is possible, but not limited to them.

[0057] The term "lubricant" refers to the insertion of an intermediate layer between the tablet component and the die wall during compression and discharge. This refers to a compound that acts to reduce friction. An example of a lubricant is... Therate, sodium stearyl fumarate, magnesium salt, and magnesium stearate Cium is one example, but it is not limited to these.

[0058] "A therapeutically effective dose" is defined as the amount administered to the person who needs it, according to Abels. on protein (ABL1), Abelson-associated protein (ABL2), and related proteins This can be mitigated by inhibiting the tyrosine kinase enzyme activity of melanin proteins, particularly BCR-ABL1. This means an amount of inventive crystalline form sufficient to treat the diseased condition. The amount of a given compound of the present invention that may be therapeutically effective depends on the condition and its severity. This will vary depending on factors such as the identity of the object that needs it, and this amount will be This can be routinely determined by those skilled in the art.

[0059] The phrase "pharmaceutically acceptable" in this specification means within the scope of sound medical judgment. Therefore, in line with a reasonable benefit / risk ratio, excessive toxicity, irritation, and allergic reactions are avoided. To use in contact with human and animal tissues without causing any problems or complications. It is used to refer to compounds, materials, compositions, and / or dosage forms that are suitable for doing so.

[0060] As used herein, the term “pharmaceutically acceptable carrier” refers to a single organ or body. Liquids or solids involved in the transport or delivery of this compound from one part to another organ or part of the body. Body fillers, diluents, excipients, manufacturing aids (e.g., lubricants, talc magnesium, stear) Calcium phosphate or zinc, or stearic acid, or This refers to pharmaceutically acceptable materials, compositions, or media, such as solvent encapsulation materials. "Acceptable" means that it is compatible with other components of the formulation and is not harmful to the patient. It must be possible to use materials that can function as pharmaceutically acceptable carriers. Examples include (1) sugars, such as lactose, glucose and sucrose; (2) (3) Cellulose and its Derivatives, for example, sodium carboxymethylcellulose, ethylcellulose, and ethylcellulose acetate. (4) Lurose; (5) Tragacanth powder; (6) Malt; (7) Gelatin; (8) Talc; (9) Formulating agents, for example, cocoa butter and suppository wax; (9) Oils, for example, peanut oil and cottonseed oil Oils, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) Glycols, e.g. For example, propylene glycol; (11) polyols, e.g., glycerin, sorbitol , mannitol and polyethylene glycol; (12) esters, for example, oleic acid (13) Cylyl and ethyl laurate; (14) Agar; (15) Buffering agent, e.g., magnesium hydroxide (1) Aluminum hydroxide; (15) Alginate; (16) Pyrogen-free water; (1 7) Isotonic saline; (18) Ringer's solution; (19) Ethyl alcohol; (20) pH Buffer solution; (21) polyester, polycarbonate and / or polyanhydrous; and (2 2) Other non-toxic, suitable substances used in pharmaceutical formulations.

[0061] Wetting agents, emulsifiers and lubricants, for example, sodium lauryl sulfate and magnesium stearate. Cium, as well as colorants, release agents, coating agents, sweeteners, flavorings and fragrances, preservatives and Antioxidants can also be present in the composition.

[0062] Examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants, e.g., as Corbic acid, cysteine ​​hydrochloride, sodium bicarbonate, sodium metabisulfite, sodium sulfite (2) Thorium, etc.; (2) Oil-soluble antioxidants, e.g., ascorbyl palmitate, butylated Hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, Propyl gallate, alpha-tocopherol, etc.; and (3) metal chelating agents, for example , citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc. These are some examples.

[0063] The formulations of the present invention can be administered orally, nasally, topically (including buccal and sublingual), rectally, vaginally, and / or non-oral. It includes formulations suitable for oral administration. The preparations are sometimes conveniently provided in single dosage forms, and pharmacology It can be prepared by any method known in the field. Carrier material for producing a single dosage form The amount of active ingredient that can be combined with the agent depends on the host being treated and the specific method of administration. It may vary depending on the circumstances. Active can be combined with carrier material to produce a single dosage form. The amount of the active ingredient generally corresponds to the amount of the compound that produces the therapeutic effect. Generally, 100 percent Of the total, this amount is approximately 0.1 percent to approximately 99 percent, preferably approximately 5 percent. Approximately 70 percent, most preferably about 10 percent to 30 percent of the active ingredient This falls within the range of [the specified range].

[0064] In certain embodiments, the formulation of the present invention comprises cyclodextrin, cellulose, and liposomes. , micellar-forming agents, such as bile acids, and polymer carriers, such as polyesters and polyhydrous anhydrides. The present invention comprises an excipient selected from the group consisting of substances and a crystalline form of the present invention. In certain embodiments The above-mentioned formulation makes the inventive crystalline form of the present invention orally bioavailable.

[0065] The method for preparing these formulations or compositions involves the inventive crystalline form of the present invention, and a carrier and The process includes a step of selectively associating one or more auxiliary components. Generally, The agent comprises the inventive crystalline form of the present invention and a liquid carrier or a micronized solid carrier or both. The mixture is then made uniform and closely related, and if necessary, the product is prepared by shaping it. ru.

[0066] Formulations of the invention suitable for oral administration include capsules, cachets, pills, tablets, and lozenges (flavored). A base material (usually sucrose and acacia or tragacanth), powder, granules. In form, or as a solution, suspension, or solid dispersion in an aqueous or non-aqueous liquid, It is used as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup. or inhalant base (for example, gelatin and glycerin, or sucrose and glycerin) It may be in the form of cassia (using cassia) and / or mouthwash, etc. Each contains a predetermined amount of the inventive crystalline form of the present invention as an active ingredient. The inventive crystalline form may be administered as a bolus, lick, or paste.

[0067] Furthermore, the present invention relates to N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R) -3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyrid Tablet formulations containing the crystalline form of n-3-carboxamide free base or hydrochloride, and their use This also relates to the method of use.

[0068] In one embodiment, the tablet formulations provided herein can be formulated in unit dosage forms, each The dosage form is approximately 5 to 500 mg of N-[4-(chlorodifluoromethoxy)phenyl]-6 -[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5- It contains the crystalline form of yl)pyridine-3-carboxamide free base or hydrochloride.

[0069] In further embodiments, the unit dosage form is 10 mg to 200 mg of N-[4-(chlorodiphtholol). [(3R)-3-hydroxypyrrolidine-1-yl] -5-(1H-pyrazole-5-yl)pyridine-3-carboxamide free base or hydrochloride It contains the crystalline form of salt.

[0070] In further embodiments, the unit dosage form is 25 mg to 150 mg (comprehensive) of N-[4-( Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine- 1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide free salt It contains a crystalline form of the group or hydrochloride salt.

[0071] In further embodiments, the unit dosage form is 20 mg, 40 mg, or 60 mg of N-[4- (chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine] [-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide release It contains a crystalline form of a base or hydrochloride salt.

[0072] In another embodiment, the tablet formulation of the present invention contains 10-30% N-[4] by weight percentage. -(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidi [1H-pyrazole-5-yl]pyridine-3-carboxamide Crystalline form of the exobase or hydrochloride, 60-80% of one or more fillers, 2-10% of one It contains one or more disintegrants and one or more fluidizing agents in an amount of 0.2-3%.

[0073] In further embodiments, the filler is lactose, anhydrous lactose, spray-dried lactose. - Direct compressible starch, hydrolyzed starch, MCC (cellulose MK GR, Avi cel PH 101), other cellulose derivatives (sodium-CMC XL), dibase Calcium phosphate dihydrate, sorbitol, sucrose, dehydrated calcium sulfate and dextrin One or more selected from the Strauss family.

[0074] In further embodiments, the disintegrant is cross-linked polyvinylpyrrolidone (crospovidone), Promellose (low-substituted hydroxypropyl cellulose), cross-linked carboxymethyl cellulose Sodium (croscarmellose sodium) and sodium starch glycolate It is one or more that are selected.

[0075] In further embodiments, the fluidizing agent is magnesium stearate, stearyl fumarate. Sodium, magnesium carbonate, fumed silica, silica, aerosol (colloidal) Selected from water / colloidal silicon dioxide (Aerosil 200PH) and starch. It is one or more.

[0076] In another embodiment, the tablet formulation of the present invention comprises an inner granular phase, an outer granular phase, and a film coating. include.

[0077] In further embodiments, the granular phase is N-[4-(chlorodifluoromethoxy)phenyl ]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole -5-yl)pyridine-3-carboxamide free base or crystalline form of its hydrochloride salt, lacto S, Avicel PH101, HP-Cellulose low subst_4 0UM, sodium-CMC XL, Aerosil 200PH, and stearic acid Contains magnesium.

[0078] In further embodiments, the extragranular phase is lactose, cellulose MK GR, sodium- Contains CMC XL, Aerosil 200PH, and magnesium stearate.

[0079] In further embodiments, the tablet formulation of the present invention can be film-coated.

[0080] In further embodiments, the film coating comprises one or more film-forming materials. It can also contain substances such as plasticizers, lubricants, colorants and / or pigments. Cut.

[0081] In further embodiments, the film coating is made of purified water and selected from white, yellow, red, and black. It comprises a mixture of one or more selected coating premixes.

[0082] In another embodiment, the granular phase consists of 22% by weight of N-[4-(chlorodiflu Olomethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]- Crystalline form of 5-(1H-pyrazole-5-yl)pyridine-3-carboxamide hydrochloride A, 33% lactose, 17% Avicel PH101, 5% HP-Cell ulose low substance 40UM, 2% sodium-CMC XL, 0.2 Contains 5% Aerosil 200PH and 0.50% magnesium stearate. do.

[0083] In a further embodiment, the outer granule phase consists of 10% lactose and 6% sediment by weight percentage. Lurose MK GR, 3% sodium - CMC XL, 0.25% Aerosil It contains 200 pH and 1% magnesium stearate.

[0084] In further embodiments, the film coating comprises 4.83% by weight. Coating premix white, 0.16% Coating premix yellow, 0.008% Contains Coating Premix Red and 85% purified water.

[0085] In a further embodiment, the film coating comprises 7.96% by weight. Coating premix white, 0.019% Coating premix red, 0.024% It contains a black coating premix and 85% purified water.

[0086] In further embodiments, the tablet formulation comprises an inner granular phase, an outer granular phase, and a film coating. Here, the granular phase is N-[4-(chlorodifluoromethoxy)phenyl]-6-[ (3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl) ) Pyridine-3-carboxamide hydrochloride crystalline form A, lactose, Avicel P H101, HP-Cellulose low substance 40UM, sodium- Contains CMC XL, Aerosil 200PH, and magnesium stearate, The outer phase of the granules consists of lactose, cellulose MK GR, sodium-CMC XL, and Aero The film coating contains sil 200PH and magnesium stearate. The lubricant may contain one or more film-forming materials, and further may contain plasticizers, intestinal lubricants, etc. It may contain substances such as colorants and / or pigments.

[0087] In further embodiments, the tablet formulation comprises an inner granular phase, an outer granular phase, and a film coating. Here, the granular phase consists of approximately 22% by weight of N-[4-(chlorodifluoro Methoxyphenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5- Crystalline form A of (1H-pyrazole-5-yl)pyridine-3-carboxamide hydrochloride. Approximately 33% lactose, approximately 17% Avicel PH 101, and approximately 5% HP-Cel Illulose low substance 40UM, approximately 2% sodium-CMC XL, Approximately 0.25% Aerosil 200PH and approximately 0.50% magnesium stearate Contains um.

[0088] In a further embodiment, the outer granule phase consists of approximately 10% lactose and approximately 6% by weight. Cellulose MK GR, approximately 3% sodium-CMC XL, approximately 0.25% Aero It contains sil 200PH and approximately 1% magnesium stearate, and also has a film coating. The coating consists of approximately 4.83% white coating premix by weight, and approximately 0.16% white coating. % coating premix yellow, approximately 0.008% coating premix red and approximately It contains 85% purified water.

[0089] In another embodiment, the outer granule phase consists of approximately 10% lactose and approximately 6% sediment by weight percentage. Lurose MK GR, approximately 3% sodium - CMC XL, approximately 0.25% Aerosi l 200PH, contains approximately 1% magnesium stearate, and film coating The coating premix is ​​approximately 7.96% white by weight, and approximately 0.019% Coating premix red, approximately 0.024% coating premix black and approximately 8 It contains 5% purified water.

[0090] Furthermore, the present invention relates to N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R) -3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyrid A method for manufacturing tablets containing the crystalline form of n-3-carboxamide free base or hydrochloride. Regarding the process, here, this process is (a) Intragranular phase component: N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3 R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl) Crystalline form A of lysine-3-carboxamide hydrochloride, Avicel PH101, HP- Cellulose low subst_40UM, sodium-CMC XL, A The steps include blending erosil 200PH and magnesium stearate, (b) Sift the blended ingredients from step (a), blend them, and roll The steps of compression and milling, (c) Exoplastic components: Lactose, Cellulose MK GR, Sodium-CMC XL, The steps include blending Aerosil 200PH and magnesium stearate, (d) A step of sieving the components from step (c), (e) A step of blending the components from step (b) and step (d), (f) A step of compressing the components of step (e) into a tablet and removing dust from the tablet, (g) Purified water and one or more coatings selected from white, yellow, red, and black The steps include forming a suspension of film coatings containing a mixture of materials, (h) Step (f) is a step of film coating the dust-free tablets and Includes.

[0091] Another aspect of the present invention is a method for treating ABL1 / BCR-ABL1 mediated disorders. , to subjects requiring such treatment, a therapeutically effective amount, according to the prior embodiment of the present invention N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3] follows one of the following -Hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine- A method comprising the step of administering a crystalline form of 3-carboxamide free base or its hydrochloride salt. Regarding the following: In a preferred embodiment, the crystalline form is N-[4-(chlorodifluoromethoxymethyl chlorodifluoro [(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H This is form A of the hydrochloride salt of -pyrazole-5-yl)pyridine-3-carboxamide. Or, more than 50%, more preferably at least 70%, of the administered crystalline form. Preferably at least 80%, most preferably at least 90%, of the inventive form. It is one of the methods. As mentioned above, examples of administration methods include oral, nasal, parenteral, and topical administration. This includes transdermal and rectal administration. Administration of the crystalline form is by administration of the pharmaceutical composition of the present invention. Alternatively, it may be achieved through any other effective means.

[0092] Specific embodiments of the present invention are demonstrated herein by reference to the following examples. These examples are disclosed solely to illustrate the present invention and do not necessarily represent the present invention. It should be understood that this should not be interpreted as limiting the scope. [Examples]

[0093] General test conditions The following procedure was used under each test condition.

[0094] Equilibrium with solvent at 25°C For equilibration at 25°C, use an Eppendorf shaker at 25°C ± 0.5°C. - About 50 mg of the drug substance was equilibrated with 1 mL of solvent for at least 1 week and about 4 weeks within. . The solution was filtered and dried in air for 10 minutes. The solid portion was examined by XRPD (X-ray powder diffraction). If the information from XRPD was insufficient to evaluate the changes, additional investigations by TG and NMR were carried out.

[0095] Equilibration with solvent at 50 °C For equilibration with solvent at 50 °C, about 50 mg of the drug substance was equilibrated with 1 mL of solvent for 2 days at 50 °C ± 0.1 in an Eppendorf shaker. The filtrate was examined as described above.

[0096] Crystallization at 25 °C When the solubility was determined by gravimetry in combination with equilibration, the residue was examined for its polymorphic form.

[0097] Crystallization from a hot saturated solution For crystallization from a hot saturated solution, about 300 mg of the drug substance was dissolved in the minimum amount of solvent at 60 °C and filtered while hot. No residual crystals were visible. The solution was placed in an ice bath and stirred. The precipitate was collected on a filter, dried and examined as described in the equilibration examples.

[0098] Precipitation by addition of solvent For precipitation by addition of solvent, the drug substance was dissolved in a solvent with high solubility and a solvent in which the substance was very poorly soluble was added. The precipitate was treated as described in the equilibration examples.

[0099] X-ray diffraction The X-ray powder diffraction (XRPD) patterns described herein were recorded on a Bruker D8 Advance diffractometer using CuKα radiation. 2° - 40° (2-theta) ​ The XRPD pattern was recorded during (T).

[0100] Those skilled in the art will know that the XRPD pattern is obtained along with the measurement error which depends on the measurement conditions under which it is used. You will realize that you will obtain this. In particular, the intensity of the XRPD pattern depends on the measurement conditions used. It is generally known that this can vary depending on the experimental conditions. Furthermore, relative intensity is also used in the experimental conditions. It should be understood that this may vary depending on the wavelength of the X-ray radiation. The agreement of the 2-theta diffraction angle between and is within 0.2° for the same crystal morphology, The degree of such measurement error should be considered in conjunction with the diffraction angle mentioned above. As such, the crystalline form of the present invention is the XRPD pattern described in the accompanying drawings disclosed herein. It is understood that the crystal morphology is not limited to providing an X-ray diffraction pattern that is completely identical to that of the original. It should be done. An XRPD pattern that is substantially identical to that disclosed in the attached drawings All crystal forms provided are within the scope of the present invention. Substantial same XRPD pattern The ability to verify identity falls within the scope of those skilled in the art.

[0101] thermogravimetry The TGA instrument used to test the crystalline morphology was the TA Q5000. 10 Add a sample of approximately 20 milligrams at a temperature range of 30°C to approximately 300°C at a rate of 20°C / min. The analysis was performed using thermal velocity.

[0102] Differential Scanning Calorimetry (DSC) The DSC instrument used to test the crystalline morphology was either a Mettler DSC1 or P It was an Erkin Elmer Diamond under a nitrogen stream of 30 mL / min at 30°C. The device was programmed to heat at a rate of 10°C / min within a temperature range of ~300°C.

[0103] Example 1 N-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy pyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carbox Preparation of Morph A of the Free Base of N-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy The starting material N-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3 -hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine- 3-carboxamide is prepared according to Example 9 of WO 2013 / 171639 A1. The starting material is suspended in methanol and heated to 30 °C to obtain a solution. Water is added to crystallize the free base. The suspension is cooled to 10 °C and the crystalline form A of the free base is isolated by filtration and drying.

[0104] The XRPD pattern of the crystalline form A of the free base is shown in Figure 1. The differential scanning calorimetry curve of the form A of the free base shows an onset of melting at about 194 °C and a peak at about 198 °C as shown in Figure 2. Figure 3 shows the thermogravimetric plot of the crystalline form A of the free base. The single crystal data of the crystalline form A of the free base at 100 K are as follows: Molecular formula: C 20 H 18 ClF2N5O3 Molecular weight: 449.84 Space symmetry Monoclinic Space group C2 Cell volume (Å 3 ) 2001.0(8) Crystal density (g / cm 3 ) 1.493 a (Å) 14.422(3) b (Å) 9.368(2) c (Å) 14.989(4) ​​​​​Beta (°) 98.853 (12) z 4

[0105] Example 2 N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy Pyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboc S morphology of samide free base A Preparation Equilibration of crystalline form A of free base in methanol at 50°C, and in methanol at 60°C Crystallization of free base from a hot saturated solution of crystalline form A, and free base in methanol solvent Japanese form S A The crystal form of the free base S was obtained. A The XRPD pattern is shown in Figure 4.

[0106] Example 3 N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy Pyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboc S morphology of samide free base B Preparation Crystal morphology of free base A in 1-propanol at 25°C (1 and 4 weeks) and 50°C Equilibration and crystallization at 25°C and in a hot saturated solution of 1-propanol at 60°C. Therefore, the free base is in the form of 1-propanol solvate S. B The crystal form of the free base S was obtained. B of The XRPD pattern is shown in Figure 5.

[0107] Example 4 N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy Pyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboc Samide free base morphology S C Preparation Equilibration of crystalline form A of free base in ethanol at 50°C, and in ethanol at 60°C Crystallization from a hot saturated solution yields the ethanol solvate form of the free base S. C I got it. Crystal morphology of the exobase S C The XRPD pattern is shown in Figure 6.

[0108] Example 5 N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy Pyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboc Samide free base morphology S D Preparation Precipitation of the free base in acetone and water by the addition of solvent A results in the free base Acetone solvate form S D The crystal form of the free base S was obtained. D The XRPD pattern is shown in Figure 7. It is shown here.

[0109] Example 6 N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy Pyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboc Preparation of form A of samide hydrochloride N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydrox Cypirrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carb The crystalline form A of the free xamide base is suspended in methanol, and hydrochloric acid is added. Heat to obtain a solution. Add tert-butyl methyl ether (TBME) to obtain the hydrochloride salt. It forms crystalline form A. The suspension is cooled and crystalline form A of the hydrochloride salt is isolated by filtration. Dry it.

[0110] Alternatively, crystalline form A of the hydrochloride salt can also be isolated under the following conditions: N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy Pyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboc Dissolve samide (1 wt) in methanol (8 wt) at 35°C. Add hydrochloric acid (1. Add 15 eq) to form crystalline form A of the hydrochloride salt. Heat the solution to 50°C. Add rt-butyl methyl ether (TBME) (5 wt) over 35 minutes. Seed of the hydrochloride crystalline form A (0.0009 wt) in a slurry of (0.01 vol) Add the seed to the solution using the provided solution. Age the suspension for 135 minutes. TBME(9.25wt Add the following over 1.5 hours. Cool the slurry to IT=0°C over 3 hours. Hold. Then filter the slurry and the cake is methanol:TBME1:9 w / w(2 Wash with V), then wash with TBME (2V). Leave the wet cake at 50°C for 24 hours. Dry under vacuum.

[0111] The XRPD pattern of crystalline morphology A of the hydrochloride is shown in Figure 8. Differential tracing of morphology A of hydrochloride. The calorific value measurement curve shows an endothermic event at approximately 90°C, as shown in Figure 9. Figure 10 is The thermogravimetric plot of crystalline form A of the hydrochloride salt is shown. The single crystal data is as follows: Spatial symmetry triclinic system space group P1 Cell volume (Å) 3 ) 1053.6(6) Crystal density (g / cm 3 ) 1.533 a(Å) 8.203(3) b(Å) 11.116(3) c(Å) 12.627(4) Beta (°) 97.711 (12) Z 2

[0112] The single-crystal data for crystalline form A of the hydrochloride salt at 298K is as follows: Spatial symmetry triclinic system space group P1 Cell volume (Å) 3 ) 1082.9(6) Crystal density (g / cm 3 ) 1.491 a(Å) 8.245(3) b(Å) 11.352(4) c(Å) 12.697(4) Beta (°) 97.289 (18) Z 2

[0113] Example 7 N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy Pyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboc Preparation of seed crystals of samide hydrochloride form A N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydrox Cypirrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carb The crystalline form A of the free xamide base and hydrochloric acid were dissolved in isopropanol, and the solid was completely dissolved. Heat until dissolved. Equilibrium the clear solution in RT and observe spontaneous crystallization. The solid material is isolated, dried, and analyzed by XRPD, NMR, and HPLC.

[0114] Example 8 N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy Pyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboc Preparation of form B of thamide hydrochloride Crystal forms A and B of the hydrochloride salt are enantiotropically related. When heated, N- [4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyro Lysine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxami Crystal form A of the hydrochloride salt spontaneously transforms into form B. If decomposition does not occur (decomposition occurs in 24 The phenomenon is completely reversible (observed above 0°C). Form B transforms spontaneously under ambient conditions. Then it returns to form A. The transition temperature could not be precisely determined, but it is in the range of 65°C to 90°C. The boundary is defined. Crystal morphology A of the hydrochloride salt is thermodynamically stable at temperatures lower than this transition temperature. This is one form, and crystal form B is preferred at higher temperatures.

[0115] The XRPD pattern of crystalline form B of the hydrochloride salt is shown in Figure 11. The superposition of the XRPD patterns of B is shown in Figure 12. The single crystal data for crystal morphology B is as follows: Spatial symmetry triclinic system space group P1 Cell volume (Å) 3 ) 1114.6(15) Crystal density (g / cm 3 ) 1.449 a(Å) 9.957(8) b(Å) 10.461(8) c(Å) 11.146(8) Beta (°) 75.71 (5) Z 2

[0116] Example 9 N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy Pyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboc Thermodynamic stability of thamide hydrochloride forms A and B During thermal studies, it was found that morphology B decomposes before melting when heated to 300°C. Therefore, the melting points of crystalline forms A and B of the hydrochloride salt could not be determined.

[0117] The effect of heating rate on the transition temperature is significant from -20°C to 200°C, and then back to -20°C. Heating and cooling cycles at various rates of 40, 20, 10, 5, 1, and 0.5°C / min until the temperature rises. The measurements were evaluated using a sealed, closed gold crucible. .

[0118] A new sample was prepared for each experiment (different heating rates). The observed transition temperature... This is listed in Table 3.

[0119] [Table 3]

[0120] Morphologies A and B are identified by their corresponding XRPD patterns and thermal parameters. Confirmed.

[0121] Example 10 N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy Pyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboc Form H of samide hydrochloride A Preparation When equilibrated in water, the crystalline form A of the hydrochloride salt tends to become unbalanced depending on the pH. (pH > 3.5), recrystallize as free base crystalline form A to maintain stability, or as a trihydrate. H A It is converted to (pH 1). Crystal form of free base H A The XRPD pattern is shown in Figure 13. It is shown here.

[0122] Example 11 N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy Pyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboc Tablet formulation containing crystalline form A of thamide hydrochloride Reasonable dose strength along with immediate release characteristics and acceptable size, and a favorable dissolution profile. N-[4-(chlorodifluoromethoxy), which enables an economical manufacturing process. )phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H- In order to develop a suitable formulation of pyrazole-5-yl)pyridine-3-carboxamide, We made several attempts. N-[4-(chlorodifluoromethoxy)phenyl]-6-[ (3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl) Film-coated tablets of pyridine-3-carboxamide hydrochloride in crystalline form A are used in drug development. It was discovered that it exhibits advantageous pharmacological properties for this purpose.

[0123] [Table 4]

[0124] Example 12 N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy Pyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboc Manufacturing process for film-coated tablets containing thamide hydrochloride crystalline form A The processes described below are designed to compensate for different batch sizes and / or equipment characteristics. While maintaining the same basic manufacturing steps, and / or can be reasonably adjusted based on experience. ru.

[0125] The manufacturing of core tablets involves standard mixing steps, sieving steps, and drying granulation steps. The process consists of a tableting step and a film coating step. The procedure is as follows:

[0126] Step 1: Mix all the components of the internal phase into a suitable container in the following order: lactose, Compound 1, sodium-CMC XL, Aerosil 200PH, HP-Cell ulose low substance 40UM and Avicel PH101. Expand the mixture. Blended in a blender.

[0127] Step 2: A screen with a 0.800mm hand sieve attached. The blends from Step 1 were screened using a pounding mill or vibratory mill. The mixture was further blended with magnesium stearate in a diffusion mixer.

[0128] Step 3: Compress the blend from Step 2 using a roller compressor to 0.8 mm. The flour is milled using a screening mill equipped with a screen.

[0129] Step 4: Screening mill or vibratory mill fitted with a 0.800 mm hand sieve. After screening using the following method, the external phase excipients are blended in an appropriate blending container (ble Ingredients in the bin: lactose, sodium CMC XL, Aerosi l 200PH and cellulose MK GR. Mix this mixture in a diffusion mixer in step 3 or It was blended with other blends.

[0130] Step 5: In a diffusion mixer, further stir the mixture from the blend in Step 4. Blended with magnesium alloyate.

[0131] Step 6: The mixture from Step 5 was compressed into tablets using a rotary tablet press. The core tablets were dedusted and inspected for metals.

[0132] Step 7: Mix the coating premix and purified water in the perforated pan coater. In addition, the coating used to film coat the dust-free tablets from step 6. A suspension was formed.

[0133] This process is explained in Figure 14.

[0134] Example 13 Pharmacokinetic studies To demonstrate the prediction of phagocytic effects in humans, N-[4-(chlorodifluoromethoxy)f [enyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrrolidine-1-yl] A capsule formulation of a solid amorphous dispersion of zole-5-yl)pyridine-3-carboxamide. and N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydro [Xypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-cal A study was conducted on dogs using a capsule formulation of crystalline form A of boxamide. The mean ± SD of pharmacokinetic parameters for the drug and crystalline formulations were determined by fasting overnight before administration and feeding. To observe the effect on absorption, the 150 mg dose was administered to subjects who were fasted for 2 hours and then fed. Evaluation was performed in the plasma of a canine model for each group following oral administration of the prescribed dose (n=3). Before administration, Each animal was then administered 0.25, 0.5, 1, 2, 4, 8, 24, 30, and 48 hours after administration. Several blood samples were taken from them.

[0135] [Table 5]

[0136] The efficacy of the food depends on the formulation. The following observations were made: 1. For crystalline preparations, the post-administration dose is 13 when administered with food compared to when administered without food. There was a 3% increase in exposure (AUCinf, 26100 vs. 11200 ng·h / mL). Positive effects of food). 2. For solid dispersion formulations, the post-administration results differ between cases with and without food. A 22.5% reduction in exposure (AUCinf, 41400 vs. 32100 ng·h / mL) was observed. Yes, there was (negative food effect). 3. Under fasting conditions, the solid dispersion formulation performed 3.7 times better than the crystalline formulation. Exposure (AUCinf, 41400 vs. 11200 ng·h / mL) occurred.

[0137] Example 14 Pharmacokinetic studies To demonstrate the prediction of phagocytic effects in humans, N-[4-(chlorodifluoromethoxy)f [enyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrrolidine-1-yl] Using a formulation of crystalline form A of zole-5-yl)pyridine-3-carboxamide hydrochloride A study was conducted on dogs. The mean ± SD of the pharmacokinetic parameters of the formulation was obtained after fasting for approximately 18 hours. To observe the effect of feeding on absorption, 150 mg was administered orally to a patient 2 hours after administration. Evaluation was performed in the plasma of a canine model that followed the administration (n=3). Pre-administration and 0.2% post-administration values ​​were evaluated. After 5, 0.5, 1, 2, 4, 8, 24, 30, and 48 hours, several blood samples were taken from each animal. A liquid sample was collected.

[0138] [Table 6]

[0139] The following observations were made: 1. Compared to solid dispersion formulations taken without food, hydrochloride formulations have a 1.6 times higher exposure rate. Dew (AUCinf, 51800 vs. 32000 ng·h / mL) was present. 2. Hydrochloride preparations and solid dispersion preparations provide equivalent bioavailability in humans. This is expected.

Claims

1. N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxyl Cypirrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carb Crystalline form A of xamide hydrochloride.

2. Cu-K alpha with a wavelength of 0.1541 Å １，２ Using radiation to create a temperature of 20-25°C When measured at temperatures within the specified range, the X-ray powder diffraction pattern was 12.6 ± 0.2°, 18.9°. The reflection according to claim 1, including reflections at 2-theta angles of ±0.2° and 20.9±0.2°. Crystalline form.

3. Cu-K alpha with a wavelength of 0.1541 Å １，２ Using radiation to create a temperature of 20-25°C When measured at temperatures within the specified range, the X-ray powder diffraction pattern was 12.6 ± 0.2°, 17.0°. ±0.2°, 18.9±0.2°, 20.9±0.2°, and 32.5±0.2° (2-C) The crystalline form according to claim 1 or 2, including reflection at the - angle.

4. Cu-K alpha with a wavelength of 0.1541 Å １，２ Using radiation to create a temperature of 20-25°C When measured at temperatures within the specified range, the X-ray powder diffraction pattern was 8.5°±0.2°, 9.5°. ±０．２°、１１．８°±０．２°、１２．３°±０．２°、１２．６°±０．２°、１ ３．９°±０．２°、１４．８°±０．２°、１５．９°±０．２°、１６．５°±０． ２°、１７．０°±０．２°、１７．６°±０．２°、１８．９°±０．２°、１９．１ °±０．２°、１９．８°±０．２°、２０．４°±０．２°、２０．９°±０．２°、 ２１．２°±０．２°、２２．４°±０．２°、２２．７°±０．２°、２３．９°±０ ．２°、２４．３°±０．２°、２４．８°±０．２°、２５．０°±０．２°、２５． ９°±０．２°、２６．８°±０．２°、２７．０°±０．２°、２８．３°±０．２° 、２８．６°±０．２°、２８．９°±０．２°、２９．８°±０．２°、３０．５°± ０．２°、３１．３°±０．２°、３１．５°±０．２°、３１．８°±０．２°、３２ ．１°±０．２°、３２．５°±０．２°、３２．９°±０．２°、３３．６°±０．２ °、３４．０°±０．２°、３４．６°±０．２°、３５．０°±０．２°、３５．６° Selected from the group consisting of ±0.2°, 36.3°±0.2°, and 38.8°±0.2°. N-[4-(chlorodifluorometh) containing three, four, five or more 2-theta values [Xy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1 Crystalline form A of H-pyrazole-5-yl)pyridine-3-carboxamide hydrochloride.

5. The X-ray powder diffraction pattern shown in Figure 8 is characterized by N-[4-(chlorodifluoromethyl Toxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-( Crystalline form A of 1H-pyrazole-5-yl)pyridine-3-carboxamide hydrochloride.

6. When measured at a heating rate of 2°C / min, the indicator shows an endothermic peak with an initial temperature of 90°C. The conclusion according to any one of claims 1 to 5, characterized in that it has a differential scanning calorimetry curve. Crystalline form.

7. When heated from 30°C to 300°C at a rate of 20°C / min, the weight of the crystalline form is used as the basis. It is characterized by having a thermogravimetric analysis curve showing a mass loss of 3.3% by weight or less. The crystalline form described in any one of the requirements 1 to 5.

8. N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxyl Cypirrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carb Crystalline form B of xamide hydrochloride.

9. The X-ray powder diffraction pattern shown in Figure 11 is characterized by N-[4-(chlorodifluoro Methoxyphenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5- Crystalline form B of (1H-pyrazole-5-yl)pyridine-3-carboxamide hydrochloride.

10. N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxyl Cypirrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carb Crystalline form of xamide hydrochloride H Ａ .

11. Cu-K alpha with a wavelength of 0.1541 Å １，２ Using radiation to create a temperature of 20-25°C When measured at temperatures within the specified range, the X-ray powder diffraction pattern was 10.4 ± 0.2°, 21.8°. The method according to claim 10, including reflections at 2-theta angles of ±0.2° and 30.6±0.2°. Crystalline form.

12. Cu-K alpha with a wavelength of 0.1541 Å １，２ Using radiation to create a temperature of 20-25°C When measured at temperatures within the specified range, the X-ray powder diffraction pattern was 10.4 ± 0.2°, 12.0°. The 2-Cs were ±0.2°, 16.8±0.2°, 21.8±0.2°, and 30.6±0.2°. The crystalline form according to claim 10, including reflection at the t-angle.

13. Cu-K alpha with a wavelength of 0.1541 Å １，２ Using radiation to create a temperature of 20-25°C When measured at temperatures within the specified range, the X-ray powder diffraction pattern was 7.9°±0.2°, 10.4°. °±０．２°、１２．０°±０．２°、１３．０°±０．２°、１３．３°±０．２°、 １３．８°±０．２°、１５．５°±０．２°、１５．９°±０．２°、１６．４°±０ ．２°、１６．８°±０．２°、１７．５°±０．２°、１９．７°±０．２°、２０． １°±０．２°、２０．５°±０．２°、２０．８°±０．２°、２１．１°±０．２° 、２１．８°±０．２°、２２．２°±０．２°、２２．７°±０．２°、２３．０°± ０．２°、２３．５°±０．２°、２３．９°±０．２°、２４．２°±０．２°、２４ ．６°±０．２°、２５．０°±０．２°、２６．０°±０．２°、２６．３°±０．２ °、２６．５°±０．２°、２６．８°±０．２°、２７．８°±０．２°、２８．２° ±０．２°、２８．５°±０．２°、２８．８°±０．２°、２９．５°±０．２°、３ ０．０°±０．２°、３０．６°±０．２°、３１．０°±０．２°、３１．３°±０． ２°、３１．７°±０．２°、３２．０°±０．２°、３３．２°±０．２°、３４．０ °±０．２°、３４．２°±０．２°、３５．３°±０．２°、３５．９°±０．２°、 ３６．７°±０．２°、３７．０°±０．２°、３７．４°±０．２°、３７．７°±０ From 2°, 38.2°±0.2°, 28.9°±0.2°, and 39.6°±0.2° N-[4-( [(3R)-3-hydroxypyrrolidine-1] (rolodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1] -yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide hydrochloride Crystalline form H Ａ .

14. The X-ray powder diffraction pattern shown in Figure 13 is characterized by N-[4-(chlorodifluoro Methoxyphenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5- Crystalline Form H of (1H-Pyrazol-5-yl)pyridine-3-carboxamide Hydrochloride Ａ 。

15. N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxyl Cypirrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carb Crystalline form A of xamide.

16. Cu-K alpha with a wavelength of 0.1541 Å １，２ Using radiation to create a temperature of 20-25°C When measured at temperatures within the specified range, the X-ray powder diffraction pattern was 12.7 ± 0.2°, 18.9°. The method according to claim 15, including reflections at 2-theta angles of ±0.2° and 20.8±0.2°. Crystalline form.

17. Cu-K alpha with a wavelength of 0.1541 Å １，２ Using radiation to create a temperature of 20-25°C When measured at temperatures within the specified range, the X-ray powder diffraction pattern was 12.7 ± 0.2°, 15.3°. ±0.2°, 18.9±0.2°, 20.8±0.2°, and 25.0±0.2° (2-C) The crystalline form according to claim 15 or 16, including reflection at a negative angle.

18. Cu-K alpha with a wavelength of 0.1541 Å １，２ Using radiation to create a temperature of 20-25°C When measured at temperatures within the specified range, the X-ray powder diffraction pattern was 5.8°±0.2°, 11.3°. °±０．２°、１１．６°±０．２°、１２．２°±０．２°、１２．７°±０．２°、 １３．２°±０．２°、１４．７°±０．２°、１５．３°±０．２°、１７．０°±０ ．２°、１７．４°±０．２°、１８．６°±０．２°、１８．９°±０．２°、１９． ４°±０．２°、１９．８°±０．２°、２０．８°±０．２°、２１．８°±０．２° 、２２．２°±０．２°、２２．７°±０．２°、２３．４°±０．２°、２４．０°± ０．２°、２４．５°±０．２°、２５．０°±０．２°、２５．５°±０．２°、２６ ．７°±０．２°、２７．１°±０．２°、２７．７°±０．２°、２８．７°±０．２ °、２９．３°±０．２°、２９．６°±０．２°、３０．２°±０．２°、３１．２° ±０．２°、３２．０°±０．２°、３２．３°±０．２°、３２．８°±０．２°、３ ３．７°±０．２°、３４．５°±０．２°、３５．３°±０．２°、３７．０°±０． Three values ​​selected from the group consisting of 2°, 38.4°±0.2°, and 38.6°±0.2°. , containing four, five or more 2-theta values, N-[4-(chlorodifluoromethoxy )phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H- Crystalline form A of pyrazole-5-yl)pyridine-3-carboxamide.

19. The X-ray powder diffraction pattern shown in Figure 1 is characterized by N-[4-(chlorodifluoromethyl Toxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-( Crystalline form A of 1H-pyrazole-5-yl)pyridine-3-carboxamide.

20. When measured at a heating rate of 5°C / min, it includes an endothermic peak with an initial temperature of 194°C. The method described in any one of claims 15 to 19, characterized by having a differential scanning calorimetry curve. Crystalline form of the material.

21. When heated from 30°C to 300°C at a rate of 20°C / min, the weight of the crystalline form is used as the basis. It is characterized by having a thermogravimetric analysis curve showing a mass loss of 0.3% by weight or less. The crystalline form described in any one of the requirements 15 to 19.

22. The X-ray powder diffraction pattern shown in Figure 4 is characterized by N-[4-(chlorodifluoromethyl Toxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-( Crystalline form of 1H-pyrazole-5-yl)pyridine-3-carboxamide S Ａ .

23. The X-ray powder diffraction pattern shown in Figure 5 is characterized by N-[4-(chlorodifluoromethyl Toxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-( Crystalline form of 1H-pyrazole-5-yl)pyridine-3-carboxamide S Ｂ .

24. The X-ray powder diffraction pattern shown in Figure 6 is characterized by N-[4-(chlorodifluoromethyl Toxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-( Crystalline form of 1H-pyrazole-5-yl)pyridine-3-carboxamide S Ｃ .

25. The X-ray powder diffraction pattern shown in Figure 7 is characterized by N-[4-(chlorodifluoromethyl Toxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-( Crystalline form of 1H-pyrazole-5-yl)pyridine-3-carboxamide S Ｄ .

26. A pharmaceutical composition comprising the crystalline form described in claims 1 to 25 and a pharmaceutically acceptable carrier.

27. N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxyl Cypirrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carb A process for preparing crystalline form A of xamide hydrochloride, (a) In a mixture of hydrochloric acid and a suitable alcohol solvent, N-[4-(chlorodifluoromethyl Toxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-( Dissolving 1H-pyrazole-5-yl)pyridine-3-carboxamide, (b) Adding tert-butyl methyl ether to the mixture and optionally (c) N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-H] [Droxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3- To isolate crystalline form A of carboxamide hydrochloride and A process that includes this.

28. (a) A therapeutically effective amount of N-[4-(chloromethyl [(3R)-3-hydroxypyrrolidine-1- [yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide free base or This is the crystalline form of the hydrochloride salt, (b) at least one pharmaceutically acceptable carrier, diluent, medium or excipient A pharmaceutical composition containing the following:

29. The crystalline form is N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3 R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl) The pharmaceutical composition according to claim 28, wherein the form is lysine-3-carboxamide hydrochloride in form A.

30. The crystalline form is N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3 R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl) The pharmaceutical composition according to claim 28, which is form B of lysine-3-carboxamide hydrochloride.

31. The crystalline form is N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3 R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl) Lysine-3-carboxamide hydrochloride form H Ａ The pharmaceutical composition according to claim 28.

32. The crystalline form is N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3 R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl) The pharmaceutical composition according to claim 28, wherein lysine-3-carboxamide is form A.

33. The crystalline form is N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3 R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl) Lysine-3-carboxamide morphology S Ａ The pharmaceutical composition according to claim 28.

34. The crystalline form is N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3 R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl) Lysine-3-carboxamide morphology S Ｂ The pharmaceutical composition according to claim 28.

35. The crystalline form is N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3 R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl) Lysine-3-carboxamide morphology S Ｃ The pharmaceutical composition according to claim 28.

36. The crystalline form is N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3 R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl) Lysine-3-carboxamide morphology S Ｄ The pharmaceutical composition according to claim 28.

37. N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxyl Cypirrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carb A tablet formulation containing crystalline form A of xamide hydrochloride.

38. The aforementioned tablets can be formulated in unit dosage forms, with each dosage form containing approximately 5 to 500 mg of the active ingredient. A tablet formulation according to claim 37, comprising the above.

39. The aforementioned unit dosage form is 10 mg to 200 mg (comprehensive) of N-[4-(chlorodifluoromethyl Toxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-( Contains crystalline form A of 1H-pyrazole-5-yl)pyridine-3-carboxamide hydrochloride A tablet according to claim 38, having the properties of the tablet.

40. The aforementioned unit dosage form is 25 mg to 150 mg (comprehensive) of N-[4-(chlorodifluoromethyl Toxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-( Contains crystalline form A of 1H-pyrazole-5-yl)pyridine-3-carboxamide hydrochloride A tablet according to claim 38, having the properties of the tablet.

41. The unit dosage form is 20 mg, 40 mg, or 60 mg of N-[4-(chlorodifluoro Methoxyphenyl]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5- Crystalline form A of (1H-pyrazole-5-yl)pyridine-3-carboxamide hydrochloride A tablet containing the contents of claim 38.

42. By weight percentage, 10-30% N-[4-(chlorodifluoromethoxy)phenyl ]-6-[(3R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole Crystalline form A of -5-yl)pyridine-3-carboxamide hydrochloride, and 60-80% One or more fillers, 2-10% of one or more disintegrants, and 0.2-3% of one or The tablet formulation according to claim 37, further comprising a plurality of fluidizing agents.

43. The granular inner phase further comprises a granular outer phase and a film coating, wherein the granular inner phase is N-[4-( Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine- 1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide hydrochloride Crystalline form A, lactose, Avicel PH101, HP-Cellulose low subst_40UM, sodium-CMC XL, Aerosil 200 The granular outer phase comprises PH and magnesium stearate, and the granular outer phase is lactose, cellulose M K GR, sodium-CMC XL, Aerosil 200PH, and stearic acid A film containing magnesium, wherein the film coating is one or more film-forming materials It may contain substances such as plasticizers, intestinal lubricants, colorants and / or pigments. A tablet formulation according to claim 37, which can be taken.

44. The material further comprises an inner granular phase, an outer granular phase, and a film coating, wherein the inner granular phase is present in a weight percentage of From there, approximately 22% N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R) -3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl)pyrid n-3-carboxamide hydrochloride crystalline form A, approximately 33% lactose, approximately 18% Av icel PH101, approximately 5% HP-Cellulose low subst_4 0UM, approximately 2% sodium-CMC XL, approximately 0.25% Aerosil 200P A tablet formulation according to claim 37, comprising H and about 0.5% magnesium stearate.

45. The aforementioned outer granular phase consists of approximately 10% lactose and approximately 5.6% cellulose M by weight percentage. K GR, approximately 3% sodium-CMC XL, approximately 0.25% Aerosil 200 It contains pH and approximately 1% magnesium stearate, and the film coating The mixture consists of approximately 4.8% white coating premix and approximately 0.16% white coating by weight percentage. Contains yellow coating premix and approximately 0.008% red coating premix. The tablet formulation according to claim 44.

46. The aforementioned outer granular phase consists of approximately 10% lactose and approximately 5.6% cellulose M by weight percentage. K GR, approximately 3% sodium-CMC XL, approximately 0.25% Aerosil 200 It contains pH and approximately 1% magnesium stearate, and the film coating The mixture consists of approximately 8% white coating premix and approximately 0.02% white coating by weight percentage. Contains red coating premix and approximately 0.02% black coating premix. The tablet formulation described in item 44.

47. A process for manufacturing a tablet formulation according to claim 37, (a) Intragranular phase component: N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3 R)-3-hydroxypyrrolidine-1-yl]-5-(1H-pyrazole-5-yl) Crystalline form A of lysine-3-carboxamide hydrochloride, Avicel PH101, HP- Cellulose low subst_40UM, sodium-CMC XL, A The steps include blending erosil 200PH and magnesium stearate, (b) Sift the blended ingredients from step (a) above, blend them, and The steps include: pressing and milling, (c) Extragranular components: lactose, cellulose MK GR, sodium-CMC XL, The steps include blending Aerosil 200PH and magnesium stearate, (d) A step of sieving the components from step (c), (e) A step of blending the components from step (b) and step (d), (f) A step of compressing the components of step (e) into a tablet and removing dust from the tablet, (g) Purified water and one or more coating materials selected from white, yellow, red, and black The steps include forming a suspension of film coatings containing a mixture of materials, (h) The step of film coating the dust-free tablets from step (f) A process that includes this.

48. A method for treating ABL1 / BCR-ABL1 mediated disorders, and such treatment For patients requiring treatment, an effective amount of N-[4- [(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidine] [-1-yl]-5-(1H-pyrazole-5-yl)pyridine-3-carboxamide release A method comprising administering a crystalline form of a base or hydrochloride salt.

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