# US 10,246,401 B2 · Crystalline form of chlorogenic acid and preparation method thereof

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- Number: US 10,246,401 B2
- Document ID: US10246401B2
- Status: Granted
- Kind: B2
- Application number: 15/308,034
- Filed: 2014-05-16
- Published: 2017-02-23
- Granted: 2019-04-02
- Earliest claimed: 2014-05-09
- Assignees: Sichuan Jiuzhang Biological Science and Technology Co., Ltd.
- Applicants: Sichuan Jiuzhang Biological Science and Technology Co., Ltd.
- Inventors: Jie Zhang; Liang Zhang; Wang Huang
- Web page: https://patentgrep.com/patent/US10246401B2

## CPC

- C07C 69/618: having unsaturation outside the six-membered aromatic ring
- C07C 67/52: by change in the physical state, e.g. crystallisation
- C07C 69/732: of unsaturated hydroxy carboxylic acids
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07C 2601/14: The ring being saturated
- 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

Provided is a crystalline form of chlorogenic acid. The crystalline form is an orthorhombic crystal system, the space group is P212121, the cell parameters are a=7.7291 (2) Å, b=10.9808 (2) Å, and c=3.5334 (7) Å, α=β=γ=90.00°, Z=8, and the cell volume is 3100.65 (11) Å3. Also provided is a preparation method for the crystalline form. The present crystalline form has good stability and does not significantly change during storage for 48 months in a cool, dark place, and the various indices all meet the relevant requirements for active pharmaceutical ingredients. The crystallization process provided by the present invention can not only use raw materials having different purities to prepare the same crystalline form of chlorogenic acid, but can also significantly reduce solvent residue in the raw materials, thereby improving product safety.

## Claims

### Claim 1

A crystalline form of chlorogenic acid having an orthorhombic crystalline structure of space group P212121.

### Claim 2 (depends on 1)

The crystalline form according to claim 1, having an X-ray powder diffraction pattern as shown in FIG. 1 or FIG. 2.

### Claim 3 (depends on 1)

A process for preparing a crystalline form of chlorogenic acid of claim 1, comprising:
dissolving a crude chlorogenic acid with a purity of more than 90% and less than or equal to 98% in water to obtain a first solution;
filtering the first solution with a filter to obtain a first filtrate;
freezing the first filtrate to 5° C. to obtain a second solution;
filtering the second solution to get a filter residue; and
freeze-drying the filter residue to obtain the claimed crystal form of chlorogenic acid.

### Claim 4 (depends on 3)

The process according to claim 3, wherein the crude chlorogenic acid is dissolved in water at 5° C. to 70° C.

### Claim 5 (depends on 3)

The process according to claim 3, wherein a concentration of chlorogenic acid in the first solution is 20 mg/ml to 2 g/ml.

### Claim 6 (depends on 5)

The process according to claim 5, wherein an aperture size of the filter used for filtration of the first solution, the second solution, or both is 0.22 μm to 200 μm.

### Claim 7 (depends on 3)

The process according to claim 3, wherein the filter used for filtration of the first solution, the second solution, or both has a filter membrane or a filter element.

### Claim 8 (depends on 3)

The process according to claim 3, wherein the filtering of the first solution is at 5° C. to 70° C. and the filtering of the second solution is at 0° C. to 25° C.

### Claim 9 (depends on 3)

The process according to claim 3, wherein the freeze-drying of the filter residue comprises a pre-freezing step at a temperature of −10° C. to −30° C. for 1 h-5 h; a drying step that raises a temperature from a range between −10° C. and −30° C. to 30° C. in 8 h-48 h; and a further drying step at 30° C. for 1 h-12 h, wherein a pressure is 5 Pa to 40 Pa during freeze-drying.

### Claim 10

A purification method of chlorogenic acid, comprising:
dissolving a crude chlorogenic acid with a purity of more than 90% and less than 98% in water to obtain a solution, filtering the solution to obtain a filtrate, freezing the filtrate to 5° C. to −20° C. to obtain a second solution, filtering the second solution to obtain a filter residue, freeze-drying the filter residue to obtain a chlorogenic acid with a purity of more than 98%.

### Claim 11 (depends on 1)

The crystalline form according to claim 1 having unit cell parameters: a=7.7291(2) Å, b=10.9808(2) Å, c=36.5334(7) Å, α=β=γ=90°, Z=8, and a unit cell volume of 3100.65(11) Å3.

### Claim 12 (depends on 1)

A process for preparing a crystalline form of chlorogenic acid of claim 1, comprising: dissolving a crude chlorogenic acid having a purity of more than 98% in water to obtain a solution;
filtering the solution to obtain a filtrate; and
freeze-drying the filtrate.

### Claim 13 (depends on 12)

The process according to claim 12, wherein a concentration of chlorogenic acid in the first solution is 10 mg/ml to 2 g/ml.

### Claim 14 (depends on 12)

The process according to claim 12, wherein the filtering of the solution is at 5° C. to 70° C.

### Claim 15 (depends on 12)

The process according to claim 12, wherein the freeze-drying of the filtrate comprises a pre-freezing step at a temperature of −20° C. to −50° C. for 1 hr to 8 hr; a warming step that raises a temperature from a range between −20° C. and −50° C. to 30° C. in 8 hr to 48 hr; and a drying step at 30° C. for 1 hr to 12 hr, wherein a pressure is 5 Pa to 40 Pa during freeze-drying.

### Claim 16 (depends on 12)

The process according to claim 12, wherein an aperture size of the filter used for filtration of the solution is 0.22 μm-200 μm.