# US 10,246,437 B2 · Crystal form of neratinib maleate and preparation method therefor

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- Number: US 10,246,437 B2
- Document ID: US10246437B2
- Status: Granted
- Kind: B2
- Application number: 15/542,597
- Filed: 2016-01-08
- Published: 2018-09-20
- Granted: 2019-04-02
- Earliest claimed: 2015-01-09
- Assignees: Crystal Pharmatech Co., Ltd.
- Applicants: Crystal Pharmatech Co., Ltd
- Inventors: Minhua Chen; Yanfeng Zhang; Xiaojuan Diao; Xiaoyu Zhang
- Web page: https://patentgrep.com/patent/US10246437B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61P 35/00: Antineoplastic agents
- C07C 51/412: {by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part}
- C07C 51/43: by change of the physical state, e.g. crystallisation
- C07C 57/145: Maleic acid
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention relates to novel crystalline forms of Neratinib maleate and the preparation method thereof. The novel crystalline forms of Neratinib maleate in the present invention have high solubility, good stability, good processability, easy post-treatment process and other favorable properties. The preparation method is simple, low cost, and has an important value for future optimization and development of the drug.

## Claims

### Claim 1

A maleate crystalline Form C of the compound of Formula (I), wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 10.9±0.2°, 15.2°±0.2° and 23.5°±0.2°

### Claim 2 (depends on 1)

The maleate crystalline Form C of the compound of Formula (I) according to claim 1, wherein the X-ray powder diffraction pattern further shows one or more of the characteristic peaks at 2theta values of 14.2±0.2°, 21.4°±0.2°, 24.5°±0.2°, 23.0°±0.2°, 18.2°±0.2° and 20.3°±0.2°.

### Claim 3 (depends on 1)

The maleate crystalline Form C of the compound of Formula (I) according to claim 1, wherein the X-ray powder diffraction pattern is substantially as depicted in FIG. 7.

### Claim 4 (depends on 1)

A process of preparing maleate crystalline Form C according to claim 1, wherein the process comprises: adding the compound of Formula (I) and maleic acid into one or more nitro-hydrocarbon solvents, then stirring to get crystals; or stirring the amorphous maleate salt of Formula (I) in one or more halogenated hydrocarbon solvents, then stirring to get crystals.

### Claim 5 (depends on 4)

The process of preparing maleate crystalline Form C according to claim 4, wherein the halogenated hydrocarbon solvents is dichloromethane and the nitro-hydrocarbon solvent is nitromethane.

### Claim 6 (depends on 4)

The process of preparing maleate crystalline Form C according to claim 4, wherein the molar ratio of the compound of Formula (I) and maleic acid is from 1:1 to 1:1.5.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising maleate crystalline Form C according to claim 1 and pharmaceutically acceptable excipients.

### Claim 8 (depends on 1)

A method of treating, or inhibiting cancer, comprising administering the maleate crystalline Form C according to claim 1.

### Claim 9

A tri-maleate crystalline Form A of compound of Formula (I), wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 5.1°±0.2°, 6.9°±0.2°, 11.4°±0.2°, and 13.9°±0.2°

### Claim 10 (depends on 9)

The tri-maleate crystalline Form A of compound of Formula (I) according to claim 9, wherein the X-ray powder diffraction pattern further shows one or more of the characteristic peaks at 2theta values of 18.3°±0.2°, 13.2°±0.2°, 15.2°±0.2°, 21.6°±0.2° and 22.5°±0.2°.

### Claim 11 (depends on 9)

The tri-maleate crystalline Form A of compound of Formula (I) according to claim 9, wherein the X-ray powder diffraction pattern is substantially as shown in FIG. 1.

### Claim 12 (depends on 9)

The tri-maleate crystalline Form A of compound of Formula (I) according to claim 9, wherein crystalline Form A is an anhydrate.

### Claim 13 (depends on 9)

A process of preparing tri-maleate crystalline Form A according to claim 9, wherein the process comprises: adding the compound of Formula (I) and maleic acid into one or more organic solvents selected from ketone solvents, alcohol solvents and halogenated hydrocarbon solvents, then stirring to get crystals.

### Claim 14 (depends on 13)

The process of preparing tri-maleate crystalline Form A according to claim 13, wherein the organic solvent is selected from acetone, isopropanol and dichloromethane.

### Claim 15 (depends on 13)

The process of preparing tri-maleate crystalline Form A according to claim 13, wherein the molar ratio of the compound of Formula (I) and maleic acid is between 1:2 to 1:5.

### Claim 16 (depends on 9)

A pharmaceutical composition, comprising an effective amount of tri-maleate crystalline Form A according to claim 9 and pharmaceutically acceptable excipients.

### Claim 17 (depends on 9)

A method of treating, or inhibiting cancer, comprising administering the tri-maleate crystalline Form A according to claim 9.

### Claim 18

A tri-maleate crystalline Form B of the compound of Formula (I), wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 5.4°±0.2°, 13.5°±0.2° and 19.6°±0.2°

### Claim 19 (depends on 18)

The tri-maleate crystalline Form B of the compound of Formula (I) according to claim 18, wherein the X-ray powder diffraction pattern further shows one or more of the characteristic peaks at 2theta values of 10.7±0.2, 12.1°±0.2°, 23.8°±0.2°, 9.9°±0.2°, 22.2°±0.2° and 17.6°±0.2°.

### Claim 20 (depends on 18)

The tri-maleate crystalline Form B of the compound of Formula (I) according to claim 18, wherein the X-ray powder diffraction pattern is substantially as shown in FIG. 4.

### Claim 21 (depends on 16)

The tri-maleate crystalline Form B of the compound of Formula (I) according to claim 16, wherein the crystalline Form B is a hydrate.

### Claim 22 (depends on 18)

A process of preparing tri-maleate crystalline Form B of the compound of Formula (I) according to claim 18, wherein the process comprises: stirring tri-maleate crystalline Form A in water or placing tri-maleate crystalline Form A at 60% or above humidity conditions.

### Claim 23 (depends on 18)

A pharmaceutical composition, comprising tri-maleate crystalline Form B according to claim 18 and pharmaceutically acceptable excipients.

### Claim 24 (depends on 18)

A method of treating, or inhibiting cancer, comprising administering the tri-maleate crystalline Form B according to claim 18.

### Claim 25 (depends on 1, 9, 18)

A pharmaceutical composition comprising effective amount of tri-maleate crystalline Form A of the compound of Formula (I) according to claim 9, tri-maleate crystalline Form B of the compound of Formula (I) according to claim 18, maleate crystalline Form C of the compound of Formula (I) according to claim 1, or a combination thereof and pharmaceutically acceptable excipients.