# US 2021/0276973 A1 · Crystal habit of quinoline derivative and preparation method for crystalline powder thereof

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- Number: US 2021/0276973 A1
- Document ID: US20210276973A1
- Status: Published application
- Kind: A1
- Application number: 17/255,476
- Filed: 2019-06-24
- Published: 2021-09-09
- Earliest claimed: 2018-06-25
- Assignees: Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
- Applicants: Chia Tai Tianqing Pharmaceutical Group Co., Ltd
- Inventors: Ping DONG; Xiongxiong HE; Lei LIU; Rui ZHAO
- Web page: https://patentgrep.com/patent/US20210276973A1

## CPC

- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61P 35/00: Antineoplastic agents
- A61K 9/4866: {Organic macromolecular compounds}
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present application relates to the field of pharmaceutical technology, specifically to the crystal habit and crystalline powder preparation of quinoline derivatives, and more specifically, to the crystal habit and crystalline powder preparation of anlotinib dihydrochloride. The compound of formula II disclosed herein is a crystalline powder with a flaky crystal habit having a specific surface area ≥10 m2/g and a particle-size distribution of X50≤50 μm and/or X90≤500 μm, such that a large specific surface area is provided without reducing the particle size of the drug by a physical method under the condition of a broad particle-size distribution, and the drug can rapidly dissolving. In addition to excellent dissolution property, the crystalline powder is also beneficial to industrial manufacturing, featuring simplified process and cost-efficiency.

## Claims

### Claim 1

A crystalline powder of compound of formula II, having a crystal habit comprising a specific surface area ≥10 m2/g and a particle-size distribution of X50≤50 μm and/or X90≤500 μm,

### Claim 2 (depends on 1)

The crystalline powder according to claim 1, wherein the crystal habit comprises a specific surface area of 10 to 50 m2/g.

### Claim 3 (depends on 1)

The crystalline powder according to claim 1, wherein, in the X-ray diffraction (XRD) pattern using Cu-Kα radiation, the crystal has diffraction peaks at the following 2θ of about 7.83, 8.83, 10.29, 14.63, 24.60 and 27.37.

### Claim 4 (depends on 1)

The crystalline powder according to claim 1, wherein, the particle-size distribution of the crystal habit is 20 μm≤X50≤50 μm and/or 300 μm≤X90≤500 μm.

### Claim 5 (depends on 1)

The crystalline powder according to claim 1, wherein the method for preparing the crystals comprising:
(1) stirring, mixing and separating the compound of formula II and one or more slightly or hardly soluble organic solvents until no liquid flows out to give a mixture;
(2) heating and drying under reduced pressure to give the crystalline powder; and
(3) optionally, pulverizing and mixing to give the crystalline powder.

### Claim 6 (depends on 1)

A crystalline powder composition, comprising the crystalline powder according to claim 1 accounts for 50 wt % or more by weight of the crystalline powder composition.

### Claim 7 (depends on 1)

A pharmaceutical composition, comprising the crystalline powder according to claim 1, and one or more pharmaceutically acceptable carriers.

### Claim 8 (depends on 7)

A method for treating non-small cell lung cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition according to claim 7.

### Claim 9 (depends on 1)

A method for preparing the crystalline powder according to claim 1, comprising:
(1) stirring, mixing and separating the compound of formula II and one or more slightly or hardly soluble organic solvents until no liquid flows out to give a mixture;
(2) heating and drying under reduced pressure to give the crystalline powder; and
(3) optionally, pulverizing and mixing to give the crystalline powder.

### Claim 10 (depends on 9)

The method for preparation according to claim 9, wherein the slightly or hardly soluble organic solvent includes one or any mixture of ethanol, ethyl acetate, methanol, and acetone.

### Claim 11 (depends on 2)

The crystalline powder according to claim 2, wherein the crystal habit comprises a specific surface area of 10 to 25 m2/g.

### Claim 12 (depends on 2)

The crystalline powder according to claim 2, wherein the crystal habit comprises a specific surface area of 10 to 15 m2/g.

### Claim 13 (depends on 3)

The crystalline powder according to claim 3, wherein, in the X-ray diffraction (XRD) pattern using Cu-Kα, radiation, the crystal has diffraction peaks at the following 2θ of about 7.83, 8.83, 9.56, 10.29, 13.90, 14.63, 19.40, 20.19, 22.35, 22.91, 24.60 and 27.37.

### Claim 14 (depends on 3)

The crystalline powder according to claim 3, wherein, in the X-ray diffraction (XRD) pattern using Cu-Kα radiation, the crystal has diffraction peaks at the following 2θ of about 7.83, 8.83, 9.56, 10.29, 13.90, 14.63, 15.34, 15.93, 17.32, 18.70, 19.40, 20.19, 22.35, 22.91, 24.60, 25.64, 27.37, 28.17 and 29.94.

### Claim 15 (depends on 3)

The crystalline powder according to claim 3, wherein, in the X-ray diffraction (XRD) pattern using Cu-Kα, radiation, the crystal has an XRD pattern essentially identical to FIG. 1.

### Claim 16 (depends on 1)

The crystalline powder according to claim 1, wherein, the particle-size distribution of the crystal habit is X50≤20 μm and/or 150 μm≤X90≤300 μm.

### Claim 17 (depends on 1)

The crystalline powder according to claim 1, wherein, the particle-size distribution of the crystal habit is X50≤10 μm and/or 70 μm≤X90≤150 μm.

### Claim 18 (depends on 1)

A crystalline powder composition, comprising the crystalline powder according to claim 1 accounts for 70 wt % or more by weight of the crystalline powder composition.

### Claim 19 (depends on 6)

A pharmaceutical composition, comprising the crystalline powder composition according to claim 6, and one or more pharmaceutically acceptable carriers.

### Claim 20 (depends on 9)

The method for preparation according to claim 9, wherein the slightly or hardly soluble organic solvent is selected from ethanol, ethyl acetate, and a mixture of ethanol and ethyl acetate.