# US 10,370,334 B2 · Inositol nicotinate crystalline form A and preparation method therefor

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- Number: US 10,370,334 B2
- Document ID: US10370334B2
- Status: Granted
- Kind: B2
- Application number: 15/762,849
- Filed: 2016-09-21
- Published: 2018-09-27
- Granted: 2019-08-06
- Earliest claimed: 2015-09-23
- Assignees: Weifang Shengyu Pharma Co., Ltd.
- Applicants: Weifang Shengyu Pharma Co., Ltd.
- Inventors: Liwei Zhu; Xuefeng Mei; Jianrong Wang
- Web page: https://patentgrep.com/patent/US10370334B2

## CPC

- C07D 213/80: in position 3
- A61P 9/08: Vasodilators for multiple indications
- B01D 9/0031: {by heating (B01D9/0022, B01D9/0027 take precedence)}
- B01D 9/0054: {Use of anti-solvent}
- B01D 9/0063: {Control or regulation (control per se G05)}
- C07D 213/803: Processes of preparation
- A61K 31/455: Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- B01D: SEPARATION (separating solids from solids by wet methods B03B, B03D; by pneumatic jigs or tables B03B; by other dry methods B07; magnetic or electrostatic separation of solid materials from solid materials or fluids, separation by high-voltage electric fields B03C; centrifuges, vortex apparatus B04; presses per se for squeezing-out liquid from liquid-containing material B30B9/02; treatment of water C02F, e.g. softening by ion-exchange C02F1/42; {arrangements of air intake cleaners in gas turbine plants F02C7/05} ; arrangements or mounting of filters in air-conditioning, air-humidification or ventilation F24F13/28)
- 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)

## Abstract

Provided are an inositol nicotinate crystalline form A and a preparation method therefor. The X-ray powder diffraction analysis, obtained by using Cu-Kα ray measurement, of the inositol nicotinate crystalline form A has obvious characteristic diffraction peaks at least at 2θ values, expressed in degrees, of 7.05, 7.41, 9.74, 17.80, 19.86, 23.57, 25.48 and 26.20 with an error range of +/−0.2°. The preparation method is one of or a mixed crystallization method of two or more of an evaporation crystallization method, a cooling crystallization method or an anti-solvent crystallization method. The process thereof is simple and easy to operate, and has more selectivity; the inositol nicotinate crystalline form A can be prepared by various methods, and the prepared product has a good crystallization degree and high chemical stability; and the inositol nicotinate crystalline form A prepared by the present method does not have the problem that a residual solvent is out-of-limit.

## Claims

### Claim 1

A crystal form A of inositol nicotinate, wherein X-ray powder diffraction analysis of the crystal form A obtained using Cu-Kα ray measurement, with an error range of ±0.2°, has characteristic diffraction peaks at 7.05, 7.41, 9.74, 17.80, 19.86, 23.57, 25.48 and 26.20 of 2θ value expressed as degrees, with an error range of ±0.2°.

### Claim 2 (depends on 1)

The crystal form A of inositol nicotinate of claim 1, wherein the X-ray powder diffraction of crystal form A expressed as 20 value degrees has characteristic diffraction peaks at diffraction angles of 7.05, 7.41, 9.74, 10.16, 11.26, 12.75, 17.80, 19.86, 20.97, 23.57, 25.48 and 26.20, 26.58, with an error range of ±0.2°.

### Claim 3 (depends on 1)

The crystal form A of inositol nicotinate of claim 1, wherein the interplanar spacing d expressed as Å and the relative intensity of the diffraction peak expressed as percentage have the following characteristics:
2θ
d
relative intensity %
7.05
12.53
23.4
7.41
11.92
46.1
9.74
9.08
23.3
10.16
8.70
4.3
11.26
7.85
8.7
12.75
7.04
3.6
13.66
6.48
9.2
17.04
5.20
12.9
17.80
4.98
100
18.36
4.83
17.3
19.28
4.60
16.2
19.86
4.47
24.3
20.62
4.30
5.0
20.97
4.23
14.9
21.29
4.17
8.6
21.58
4.11
15.5
22.03
4.03
9.0
22.23
3.99
16.8
22.45
3.95
12.5
23.57
3.77
20.4
23.93
3.71
11.0
25.2
3.53
11.9
25.48
3.49
33.9
26.20
3.40
26.1
26.58
3.35
9.0.

### Claim 4 (depends on 1)

The crystal form A of inositol nicotinate of claim 1, wherein the X-ray powder diffraction pattern of the crystal form A is essentially as shown in FIG. 1.

### Claim 5 (depends on 1)

The crystal form A of inositol nicotinate of claim 1, wherein the crystal form A has one or more characteristics selected from the group consisting of:
(1) the crystal form A belongs to a monoclinic system, of which the spatial point group is P21/c;
(2) the unit cell parameters of the crystal form A is: a=12.0470(2) Å, b=17.4688(3) Å, c=18.3057(3) Å; α=γ=90.00°, β=94.5170(10°);
(3) the unit cell volume of the crystal form A is 3840.41 Å3; and/or
(4) the crystal density of the crystal form A is 1.4022 g/cm3.

### Claim 6 (depends on 1)

The crystal form A of inositol nicotinate of claim 1, wherein the differential scanning calorimetry analysis of crystal form A starts melting at 260° C., and has a maximum endothermic melting peak at 261.14° C.

### Claim 7 (depends on 1)

The crystal form A of inositol nicotinate of claim 1, wherein the differential scanning calorimetry pattern of the crystal form A is as essentially shown in FIG. 2.

### Claim 8 (depends on 1)

The crystal form A of inositol nicotinate of claim 1, wherein the thermogravimetic analysis pattern of the crystal form A is as essentially shown in FIG. 3.

### Claim 9 (depends on 1)

The crystal form A of inositol nicotinate of claim 1, wherein for the thermogravimetic analysis, the crystal form A has a decomposition temperature of 300±1° C., and there is no weight loss peak of crystal water or a binding solvent before the decomposition temperature.

### Claim 10 (depends on 1)

The crystal form A of inositol nicotinate of claim 1, wherein the Raman spectrum of the crystal form A has characteristic peaks at 622 cm−1, 827 cm−1, 903 cm−1, 1033 cm−1, 1194 cm−1, 1276 cm−1, 1302 cm−1, 1387 cm−1, 1592 cm−1, 1720 cm−1, 1741 cm−1, 2971 cm−1, and 3067 cm−1, with an error range of ±2 cm−1.

### Claim 11 (depends on 1)

The crystal form A of inositol nicotinate of claim 1, wherein the Raman spectrum of the crystal form A is as essentially shown in FIG. 4.

### Claim 12 (depends on 1)

A preparation method of the crystal form A of inositol nicotinate of claim 1, wherein the method is the evaporative crystallization method, the cooling crystallization method or the anti-solvent crystallization method, or a mixed crystallization method comprising at least two of the evaporative crystallization method, the cooling crystallization method and the anti-solvent crystallization method.

### Claim 13 (depends on 12)

The method of claim 12, comprising the steps:
(1) providing a mixture of inositol nicotinate and solvent S, the solvent S is selected from the group consisting of: haloalkane, alcohol, water, and the combinations thereof, and the solid-liquid ratio of the inositol nicotinate and the solvent S is 1 g: 5 mL to 1 g: 15 mL;
(2) Performing crystallization to obtain the crystal form A of inositol nicotinate.

### Claim 14 (depends on 13)

The method of claim 13, wherein
(a) before the step (2), the method further comprises: heating the mixture to 60-100° C., and optionally, cooling to 0-30° C.; or
(b) before the step (2), the method further comprises: adding an anti-solvent to the mixture described in step (1) at room temperature; or
(c) before the step (2), the method further comprises: adding an anti-solvent dropwise to the mixture described in step (1), heating the mixture to 25-70° C. for the evaporation; and/or
(d) the step (2) further comprises filtering, washing and drying step.

### Claim 15 (depends on 12)

The method of claim 12, wherein
the evaporative crystallization method comprises the following steps: dissolving inositol nicotinate in a mixed solvent of alkyl halide and alcohol, or a mixed solvent of alkyl halide with alcohol in water, and placing at room temperature or heating to volatilize or evaporate the alkyl halide in the system until solid crystals are precipitated, then the solid crystals are filtered, washed and dried; and/or
the cooling crystallization method comprises the following steps: dissolving inositol nicotinate in a mixed solvent of alkyl halide and alcohol, or a mixed solvent of alkyl halide with alcohol in water, heating to dissolve, and then cooling until solid crystals are precipitated, then the solid crystals are filtered, washed and dried; and/or
the anti-solvent crystallization method comprises the following steps: dissolving inositol nicotinate in a mixed solvent of alkyl halide with alcohol, or a mixed solvent of alkyl halide with alcohol in water, adding alcohol solvent dropwise at room temperature until solid crystals are precipitated, then the solid crystals are filtered, washed and dried; and/or
the mixed crystallization method comprises the following steps: dissolving inositol nicotinate in a mixed solvent of alkyl halide and alcohol, or a mixed solvent of alkyl halide with alcohol in water, and evaporating alkyl halide by heating, meanwhile, adding alcohol solvent to the reaction liquid solid until crystals are precipitated, then the solid crystals are filtered, washed and dried.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the alkyl halide is one or two or more of chloroform, dichloromethane, or dichloroethane; the alcohol is one or two or more of methanol, ethanol or isopropanol; and/or the alcohol in water is a mixed solvent of one or two or more of methanol, ethanol or isopropanol in water; and/or, in the mixed solvent of alkyl halide and alcohol, the volume ratio of the alkyl halide to the alcohol is 10:1 to 1:10; and/or, the anti-solvent is an alcohol or alcohol water solvent.

### Claim 17 (depends on 1)

The crystal form A of inositol nicotinate according to claim 1, prepared according to a method, for use in a medicament and feed, wherein the method is the evaporative crystallization method, the cooling crystallization method or the anti-solvent crystallization method, or a mixed crystallization method comprising at least two of the evaporative crystallization method, the cooling crystallization method and the anti-solvent crystallization method.