CN112625078A

CN112625078A - Novel crystal form of ursodeoxycholic acid and preparation method thereof

Info

Publication number: CN112625078A
Application number: CN202011381603.2A
Authority: CN
Inventors: 吴虎成; 刘志宏; 李龙; 戴立明; 王进; 黄华子; 姜冬冬; 陈勇
Original assignee: Zhejiang Warrant Pharmaceutical Co ltd
Current assignee: Zhejiang Warrant Pharmaceutical Co ltd
Priority date: 2020-12-01
Filing date: 2020-12-01
Publication date: 2021-04-09

Abstract

The invention discloses a novel crystal form of ursodeoxycholic acid and a preparation method thereof, wherein the structure of the ursodeoxycholic acid is as follows:

in an X-ray powder diffraction pattern of the crystal form, diffraction peaks exist at 2 theta positions of 9.5 +/-0.2, 13.4 +/-0.2, 13.9 +/-0.2, 14.5 +/-0.2, 15.2 +/-0.2, 15.9 +/-0.2, 16.4 +/-0.2, 16.6 +/-0.2, 20.1 +/-0.2 and 24.9 +/-0.2 degrees, wherein the diffraction peak intensity between 14.9 and 16.2 degrees is higher than 50 percent. The method comprises the following steps: (1) adding ursodeoxycholic acid into a dissolving agent for dissolving; (2) dripping the mixture into a poor solvent for crystallization; (3) and (5) drying. The dissolving agent is acetone, ethanol, methanol and a mixed solvent composed of acetone, ethanol, methanol and water. The poor solvent is water. The crystal form of ursodeoxycholic acid is a 'basically pure' crystal form, is stable and non-hygroscopic, and is suitable for industrial production.

Description

Novel crystal form of ursodeoxycholic acid and preparation method thereof

Technical Field

The invention relates to the technical field of medicines, in particular to a novel crystal form of ursodeoxycholic acid and a preparation method thereof.

Background

Ursodeoxycholic acid (UDCA), chinese name: ursodeoxycholic Acid, the english name Ursoxyolic Acid. Chemical name: 3 alpha, 7 beta-dihydroxy-5 beta-cholestane-24-acid. The structure is as follows:

ursodeoxycholic acid is used for increasing bile acid secretion, changing bile components, reducing cholesterol and cholesterol ester in bile, and facilitating the gradual dissolution of cholesterol in gallstone.

In the existing literature, the literature of the UDCA crystal form developed by the invention is not searched.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides a novel crystal form of ursodeoxycholic acid and a preparation method thereof, wherein the crystal compound has multiple peaks with the peak intensity higher than 50 percent in the range of 14-16 degrees at 2 theta through X-ray powder diffraction; the melting point was measured by DSC at 205-207 ℃.

In some embodiments, the substantially pure crystalline form has an X-ray powder diffraction 2 Θ having one or more peaks at approximately 9.5, 13.4, 13.8, 14.9, 15.2, 15.6, 15.9, 16.3, 24.9 degrees.

In some embodiments, the substantially pure crystalline form has an X-ray powder diffraction 2 Θ having one or more peaks at approximately 9.5, 13.4, 13.9, 14.5, 15.0, 15.3, 15.6, 16.0, 20.5, 24.9 degrees.

In some embodiments, a Differential Scanning Calorimetry (DSC) of the substantially pure crystalline form has an endothermic peak at 205 to 207 ℃.

In another aspect of the invention, a method for preparing the crystalline form is provided.

In some embodiments, the prepared substantially pure UDCA is added with a solvent and water, heated to dissolve, then added with water to crystallize, cooled to crystallize, filtered, and the filter cake is dried under reduced pressure to obtain the target crystal form product.

The solvent is acetone, methanol, ethanol and a mixed solvent thereof, the ratio of UDCA to solvent to water is 1:5:1 to 1:5:10, the crystallization conditions are that the temperature is-5 to 30 ℃, the drying temperature is 40 to 100 ℃, and the drying time is 12 to 24 hours.

In order to achieve the purpose, the technical scheme of the invention is as follows:

a novel crystal form of ursodeoxycholic acid, which has the following structure:

in an X-ray powder diffraction pattern of the crystal form, diffraction peaks exist at 2 theta positions of 9.5 +/-0.2, 13.4 +/-0.2, 13.9 +/-0.2, 14.5 +/-0.2, 15.2 +/-0.2, 15.9 +/-0.2, 16.4 +/-0.2, 16.6 +/-0.2, 20.1 +/-0.2 and 24.9 +/-0.2 degrees, wherein the intensity of the diffraction peaks between 14.9 and 16.2 degrees is higher than 50 percent; and the map is shown in the attached figures 1 and 2 of the specification.

The DSC analysis chart of the crystal form is an exothermic single peak, the melting point is 205-207 ℃, and the chart is shown in figure 2.

As a further scheme of the invention, the method comprises the following steps: (1) adding ursodeoxycholic acid into a dissolving agent for dissolving; (2) dropwise adding the mixture into a poor solvent for crystallization; (3) and (5) drying.

As a further scheme of the invention, the dissolving agent is acetone, ethanol, methanol and a mixed solvent composed of acetone, ethanol, methanol and water.

As a further embodiment of the present invention, the poor solvent is water.

The invention has the beneficial effects that: the crystal form of ursodeoxycholic acid is a 'basically pure' crystal form, is stable and non-hygroscopic, and is suitable for industrial production.

Drawings

FIG. 1 is an X-ray powder diffraction pattern XRD-1 of the product of example 1;

FIG. 2 is a differential scanning calorimetry thermogram DSC-1 of the product of example 1;

FIG. 3 is an X-ray powder diffraction pattern XRD-2 of the product of example 4;

FIG. 4 is a DSC-2 of the product of example 4.

Definition of terms

The term "crystal form" is used to describe the state of existence of a solid compound, describing the collection of various parameters of ionic, atomic or molecular composition, symmetry properties and periodic arrangement regularity within a crystal.

The term "substantially pure" means that a sample consists essentially of one predominant crystalline form, is substantially free of another or additional other crystalline forms or amorphous forms, and has a predominant crystalline form purity of at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%.

The term "substantially as shown in the figures" means that a substantially pure form of a "crystalline form" has at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in its X-ray powder diffraction pattern that appear in the X-ray powder diffraction pattern given. When the content of a certain crystal form in a sample is gradually reduced, diffraction peaks in an X-ray powder diffraction pattern of the sample, which are assigned to the crystal form, may be reduced due to the detection sensitivity of an instrument.

Detailed Description

The technical solution of the present patent will be described in further detail with reference to the following embodiments.

In order that those skilled in the art may better understand the present invention, the following embodiments further illustrate the present invention. It should be understood that the following examples are given for better illustration of the present invention and are not intended to limit the present invention.

The Differential Scanning Calorimetry (DSC) of the crystal form has experimental errors, the positions and peak values of endothermic peaks may slightly differ between one machine and another machine and between one sample and another sample, and the numerical value of the experimental errors or differences may be 10 ℃ or less, 5 ℃ or less, 4 ℃ or less, 3 ℃ or less, 2 ℃ or less, 1 ℃ or less, so that the peak positions or peak values of the DSC endothermic peaks cannot be regarded as absolute.

The solvents (reagents) used in the present invention are all technical grade, in the present invention g represents g, mL represents mL, min represents min, h represents h.

Example 1:

adding 100g of prepared substantially pure UDCA into a reactor, adding 500g of acetone and 100g of purified water, heating to 60 ℃, stirring until the mixture is dissolved, dropwise adding 500g of purified water, stirring for 1h until the temperature is 25-30 ℃ after the dropwise adding is finished, continuously cooling to 0 ℃, stirring for 2h, filtering, adding a filter cake into a drying oven, controlling the temperature to be 60 ℃, and drying under reduced pressure for 12h to obtain 96g of a target crystal form product. See the attached figures XRD-1 and DSC-1.

Example 2: stability study

According to the pharmacopoeia regulation, experiments are designed, and the stability of the UDCA crystal form in the patent under various extreme environments is inspected.

Table 1: stability experiment investigation design scheme

Table 2: stability test investigation result at 40 DEG C

Table 3: stability test investigation result at 60 DEG C

Table 4: RH 75%, stability test result at 25 deg.C

Table 5: RH 92.5%, stability test investigation result under 25 deg.C condition

As can be seen from tables 1-5, the stability of the crystal form is relatively stable under the conditions of high temperature, high humidity and strong illumination. Stability experiments at 40 ℃, 60 ℃ and under strong illumination conditions for 6 months show that the impurity level, the content and the dry loss are not obviously changed, the melting point is also in a specified range, and the crystal form is stable and has no degradation and crystal transformation phenomena; the high humidity test shows that the drying weight loss slightly rises for 6 months, but all the drying weight loss are within the qualified range.

Example 3: study of hygroscopicity

Table 6: results of moisture absorption test

Table 6 above shows that the results of moisture absorption test on the two samples are less than 0.2%, indicating that the crystal form has almost no moisture absorption.

Example 4: crystal form XRD stability data

Stability sample 6 month XRD pattern: figure 3.

Stability sample 6 month DSC profile: figure 4.

FIG. 3 shows that, in XRD (X-ray diffraction) of 6-month stability data, diffraction peaks exist at 2 theta positions of 9.5 +/-0.2, 13.4 +/-0.2, 13.9 +/-0.2, 14.5 +/-0.2, 15.2 +/-0.2, 15.9 +/-0.2, 16.4 +/-0.2, 16.6 +/-0.2, 20.1 +/-0.2 and 24.9 +/-0.2 degrees, wherein the intensity of the diffraction peak between 14.9 and 16.2 degrees is higher than 50 percent; the crystal form is consistent with the XRD pattern of 0 month, which shows that the crystal form is stable within 6 months.

Figure 4 shows that the 6-month stability data DSC shows an exothermic single peak with a melting point of 206.9 ℃ consistent with 0 months, also indicating that the crystalline form is stable within 6 months.

In conclusion, the crystal form is stable within 6 months of stability test.

Claims

1. A novel crystal form of ursodeoxycholic acid, which has the following structure:

the method is characterized in that: in an X-ray powder diffraction pattern of the crystal form, diffraction peaks exist at 2 theta positions of 9.5 +/-0.2, 13.4 +/-0.2, 13.9 +/-0.2, 14.5 +/-0.2, 15.2 +/-0.2, 15.9 +/-0.2, 16.4 +/-0.2, 16.6 +/-0.2, 20.1 +/-0.2 and 24.9 +/-0.2 degrees, wherein the intensity of the diffraction peaks between 14.9 and 16.2 degrees is higher than 50 percent; the map is shown in the attached figures 1 and 2 in the specification;

2. The preparation method of the novel crystal form of ursodeoxycholic acid according to claim 1, characterized by comprising the following steps: (1) adding ursodeoxycholic acid into a dissolving agent for dissolving; (2) dripping the mixture into a poor solvent for crystallization; (3) and (5) drying.

3. The method for preparing the novel crystal form of ursodeoxycholic acid according to claim 2, characterized in that: the dissolving agent is acetone, ethanol, methanol and a mixed solvent composed of acetone, ethanol, methanol and water.

4. The method for preparing the novel crystal form of ursodeoxycholic acid according to claim 2, characterized in that: the poor solvent is water.