CN107857756B - Ilaprazole magnesium crystal form and preparation method thereof - Google Patents
Ilaprazole magnesium crystal form and preparation method thereof Download PDFInfo
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Abstract
The invention provides a crystal form A of ilaprazole magnesium salt, which uses Cu-Kalpha radiation, and has characteristic absorption peaks at 4.795, 12.295, 12.710, 14.684 and 15.887 in an X-ray powder diffraction pattern expressed by a 2 theta angle. The ilaprazole magnesium salt crystal form A provided by the invention has the advantages of high purity, excellent fluidity and good stability, and the preparation method is simple and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to an ilaprazole magnesium salt crystal form and a preparation method thereof.
Background
Ilaprazole (Ilaprazole) belongs to the benzimidazole class in structure and is an irreversible proton pump inhibitor. After oral administration, ilaprazole selectively enters gastric parietal cells and is converted into a sulfenamide active metabolite and H + 、K + -thiol action on ATPase, covalent binding to form disulfide bonds, irreversible inhibition of H + 、K + -ATPase, which produces an effect of inhibiting gastric acid secretion.
The first generation of Proton Pump Inhibitors (PPIs) have limited clinical use because they can cause delayed gastric emptying, parietal cell swelling and significant rebound of gastric acid secretion after withdrawal. Ilaprazole, as one of the new-generation Proton Pump Inhibitors (PPI), has overcome some of the defects of the original similar products to different degrees, and can enhance the curative effects on dyskinetic functional dyspepsia (GERD) and other acid-related diseases. The main characteristics of ilaprazole include: the clinical acid inhibition effect is good; secondly, the acid inhibiting effect is quick; ③ the day and night can maintain higher acid-inhibiting level; fourthly, the curative effect is definite, and the individual difference is small; fifthly, no mutual influence exists between the medicine and other medicines; sixthly, the adverse reaction is little.
Patent CN102140092B reports ilaprazole magnesium hydrate and its preparation method, and ilaprazole magnesium hydrate prepared by the method of the patent is a mixture containing different numbers of crystal water, and has poor crystallinity, so there is no report of a single crystal form of ilaprazole magnesium salt at present.
The structure of the ilaprazole magnesium salt is shown as a formula (1):
disclosure of Invention
The invention aims to provide a crystal form A of the ilaprazole magnesium salt.
Another object of the present invention is to provide a process for preparing the above form a of the magnesium ilaprazole salt.
In one aspect, the invention provides a crystal of a compound represented by formula (1), wherein an X-ray powder diffraction pattern of a crystal form A of the magnesium ilaprazole salt expressed by an angle of 2 theta by using Cu-Kalpha radiation has characteristic absorption peaks at 4.795, 12.295, 12.710, 14.684 and 15.887.
Specifically, the X-ray powder diffraction pattern of the ilaprazole magnesium salt form A expressed by the angle of 2 theta has characteristic absorption peaks at 4.795, 12.295, 12.710, 14.684, 15.887, 16.480, 17.287, 19.342, 22.004 and 23.012 by using Cu-K alpha radiation.
Specifically, the X-ray powder diffraction pattern of the magnesium ilaprazole salt form A expressed by an angle of 2 theta by using Cu-Ka radiation has characteristic absorption peaks at 4.795, 12.295, 12.710, 14.684, 15.887, 16.480, 17.287, 19.342, 22.004, 23.012, 24.097, 25.302, 25.835, 27.690, 28.894, 29.820, 35.604 and 36.034.
More specifically, the peak of an X-ray powder diffraction pattern of the ilaprazole magnesium salt crystal form A expressed by an angle of 2 theta by using Cu-Kalpha radiation is shown as the attached figure 1, the TGA pattern is shown as the attached figure 2, and the DSC pattern is shown as the attached figure 3.
Specifically, the ilaprazole magnesium salt of the ilaprazole magnesium salt crystal form a is ilaprazole magnesium salt tetrahydrate.
In another aspect, the present invention provides a method for preparing the above ilaprazole magnesium salt form a, comprising the following steps:
1) dissolving ilaprazole sodium shown in formula (2) in a solvent;
2) filtering to remove insoluble substances, and dropwise adding a magnesium agent into the solution;
3) stirring and crystallizing;
4) filtering and drying to constant weight to obtain the ilaprazole magnesium crystal form A.
Specifically, in the step 1), the volume/weight ratio (mL/g) of the solvent to the ilaprazole sodium is 6-20: 1, preferably 7-15: 1.
Preferably, in step 1), the solvent is a pure organic solvent or an aqueous organic solvent, wherein the pure organic solvent is selected from one or more of tetrahydrofuran, isopropanol, n-butanol, methanol, ethanol, acetone, and acetonitrile.
Preferably, the solvent is an aqueous organic solvent, wherein the aqueous organic solvent is selected from one or more of tetrahydrofuran/water, isopropanol/water, n-butanol/water, methanol/water, ketone/water, acetonitrile/water, preferably isopropanol/water; more preferably, in the water-containing organic solvent, the volume ratio of water to the organic solvent is 1: 1-4, preferably 1: 2-3.
Preferably, in the step 1), the temperature during dissolving is 10-30 ℃, and preferably 15-25 ℃.
In step 2), the magnesium agent may be one or more of magnesium chloride, magnesium acetate, magnesium formate, magnesium sulfate, magnesium nitrate, preferably magnesium chloride or magnesium acetate.
Preferably, in the step 2), the molar ratio of the magnesium agent to the ilaprazole sodium is 0.5-0.6: 1, preferably 0.5-0.52: 1.
Preferably, in step 2), the magnesium agent is added in the form of an aqueous solution thereof at a concentration of 5 to 30 wt%, preferably 5 to 15 wt%.
Preferably, in the step 2), the magnesium agent is added slowly, preferably dropwise; the dropping time is 10-50min, preferably 20-40 min.
Preferably, in the step 3), the temperature for stirring and crystallizing is 5-30 ℃, and preferably 10-25 ℃.
Preferably, in the step 3), the stirring and crystallization time is 2-6 h, preferably 2-4 h.
Preferably, in step 4), the drying conditions are vacuum drying at a temperature not exceeding 35 ℃, preferably at a temperature of 20-30 ℃.
The ilaprazole sodium in the step 1) can be prepared by a method of formula (3) with reference to patents CN106045978A and CN 103204842A:
in addition, the invention also provides application of the ilaprazole magnesium salt crystal form A in preparation of a medicine for treating duodenal ulcer.
The advantages are that: the ilaprazole magnesium salt crystal form A provided by the invention has the advantages of high purity, excellent fluidity and good stability, and in addition, the preparation method is simple and is suitable for industrial production.
Drawings
Figure 1 is an X-ray powder diffraction pattern of form a of the magnesium ilaprazole salt prepared according to example 4.
Figure 2 is a TGA profile of magnesium ilaprazole form a prepared according to example 4.
Figure 3 is a DSC profile of form a of the magnesium ilaprazole salt prepared according to example 4.
Detailed Description
The invention is illustrated below with reference to specific examples. It will be understood by those skilled in the art that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention in any way.
Example 1
Preparation of ilaprazole sodium salt
The preparation method is prepared by referring to Chinese patent CN106045978A in example 6, and comprises the following steps:
100g (272.9mmol) of ilaprazole is added into 500ml of methanol, the temperature is raised to 50 ℃, 49.2g (273.2mmol) of methanol solution containing 30% (weight) of sodium methoxide is added, the mixture is stirred for 2 hours, the mixture is cooled to 0 ℃, the mixture is filtered, and the solid is dried under reduced pressure at 60 ℃ overnight to obtain 89.3g of white crystalline ilaprazole sodium with the mass yield of 89.3%.
Example 2
Preparation of ilaprazole sodium salt
The preparation method is prepared by referring to Chinese patent CN103204842A in example 6, and comprises the following steps:
100g (272.9mmol) of ilaprazole, 30g (300.0mmol) of 40% sodium hydroxide solution and a proper amount of isopropanol are added into a reaction bottle to prepare a saturated solution, the saturated solution is stirred and dissolved, the solution is filtered, the filtrate is crystallized at the low temperature of 4 ℃ for 12 hours, and the white powdery solid is obtained after filtering, wherein the mass yield is 97.5%.
Example 3
Preparation of ilaprazole magnesium salt
Raw materials: ilaprazole sodium obtained in example 1
20g (47.6mmol) of ilaprazole sodium are dissolved in 150ml of purified water and 150ml of methanol, and then 5.8g (28.5mmol) of MgCl are added dropwise 2 ·6H 2 And (3) after finishing dripping for about 15min, controlling the temperature to be 10-20 ℃ in a solution of O/109.2mL of water, stirring and crystallizing for 3h, filtering, and drying the obtained solid in vacuum at 30 ℃ for 24h to obtain 19.8g of a white crystal target product, wherein the mass yield is 99.0% and the chemical purity is 99.89%.
Example 4
Preparation of ilaprazole magnesium salt
Raw materials: EXAMPLE 2 ilaprazole sodium obtained
20g (47.1mmol) of ilaprazole sodium are dissolved in 50ml of purified water and 150ml of isopropanol, insoluble matter is filtered off, and then 5.8g (28.5mmol) of MgCl are added dropwise 2 ·6H 2 Dripping solution of O/109mL of water for about 20min, controlling the temperature to be 10-20 ℃, stirring for crystallization for 3h, filtering, vacuum-drying the obtained solid for 24h at 30 ℃,18.7g of white crystal target product is obtained, the mass yield is 93.5%, and the chemical purity is 99.92%.
Example 5
Preparation of ilaprazole magnesium salt
Raw materials: EXAMPLE 2 ilaprazole sodium obtained
Sodium ilaprazole 5g (11.8mmol) was dissolved in 20ml of purified water and 40ml of tetrahydrofuran, and then 1.4g (6.9mmol) of MgCl was added dropwise 2 ·6H 2 And (3) after finishing dripping for about 15min, controlling the temperature to be 10-20 ℃ in an O/27.5mL water solution, stirring and crystallizing for 3h, filtering, and drying the obtained solid at 30 ℃ in vacuum for 24h to obtain 4.9g of a white crystal target product, wherein the mass yield is 98.0%, and the chemical purity is 99.90%.
Example 6
Preparation of ilaprazole magnesium salt
Raw materials: EXAMPLE 2 ilaprazole sodium obtained
Sodium ilaprazole 5g (11.8mmol) was dissolved in purified water 20ml and acetone 50ml, insoluble matter was filtered off, and then 1.3g (6.1mmol) of C was added dropwise 4 H 6 O 4 Mg· 4 H 2 And (3) after finishing dripping for about 15min, controlling the temperature to be 10-20 ℃, stirring and crystallizing for 4h, filtering, and drying the obtained solid at 30 ℃ for 24h in vacuum to obtain 4.8g of a white crystal target product, wherein the mass yield is 96.0% and the chemical purity is 99.91%.
Example 7
Preparation of ilaprazole magnesium salt
Raw materials: EXAMPLE 2 ilaprazole sodium obtained
2.5g (5.9mmol) of ilaprazole sodium is dissolved in 25ml of isopropanol, insoluble matter is filtered off, and then 0.6g (3.0mmol) of MgCl is added dropwise 2 ·6H 2 And (3) after finishing dripping for about 15min, controlling the temperature to be 10-20 ℃, stirring and crystallizing for 3h, filtering, washing, and drying the obtained solid in vacuum for 24h at room temperature to obtain 2.2g of a white crystal target product, wherein the mass yield is 88.0%, and the chemical purity is 99.85%.
Example 8
Detection of ilaprazole magnesium crystal form A
The invention has the following condition parameters:
(1) the X-ray powder diffraction test conditions in the present invention are as follows:
the instrument model is as follows: bruker D8 Advance; a light source Cu-Ka 40kV and 40 mA; 2 θ range: 3-40 degrees, step length of 0.02 degrees and residence time of 0.5s in each step.
The X-ray diffraction peak of the ilaprazole magnesium salt form A is shown in the attached figure 1 of the specification and is expressed by the percentage of interplanar spacing d, Bragg angle (2 Theta, 2-Theta) and relative intensity, and is shown in the following table 1.
TABLE 1 interplanar spacing d, Bragg angle (2. theta.)) and relative strength of crystalline form A of the magnesium salt of ilaprazole
(2) The TGA conditions in the present invention are as follows:
the instrument model is as follows: NETZSCH TG 209;
detection conditions are as follows: atmosphere: air, 20 ml/min; and (3) scanning procedure: room temperature-350 ℃, heating rate: 10 ℃/min.
The TGA spectrum of the ilaprazole magnesium salt crystal form A is shown in the attached figure 2 of the specification, and the TGA spectrum shows that the weight loss is 3.54 percent between room temperature and 85 ℃; slight weight loss between 85 ℃ and 150 ℃, about 1.09%; the weight loss is 4.34 percent between 150 ℃ and 196 ℃; the total weight loss between room temperature and 196 ℃ was 8.97%.
TGA shows that the crystal moisture of the crystal form A of the ilaprazole magnesium salt is lost in two stages, and the first stage is between 50 and 85 ℃, which shows that part of crystal water is easy to leave; the second stage is 150-195 deg.c, and the partial crystal water is stable at 85-150 deg.c, showing that the partial crystal water is stable.
(3) In the present invention, the DSC conditions are as follows:
the instrument model is as follows: METTLER TOLEDO DSC 1;
detection conditions are as follows: atmosphere: nitrogen gas; and (3) scanning procedure: 25-250 ℃, heating rate: 15 k/min.
The DSC pattern of the ilaprazole magnesium salt crystal form A is shown in the attached figure 3 of the specification, and the DSC pattern shows that the ilaprazole magnesium salt crystal form A has endotherm at about 79 ℃ and 171 ℃ and melts at 218 ℃.
Example 9
Experiment of influence factors of ilaprazole magnesium crystal form A
The HPLC conditions in the invention are as follows:
column: Gemini-NX 5U C18110A (150X 4.6mm)
Column temperature: 25 deg.C
Mobile phase: a, acetonitrile: buffer B (10mM dipotassium hydrogen phosphate, pH7.5) (36: 64)
Wavelength: 237 nm.
The experimental method comprises the following steps: the method is carried out according to the method in the guidance principle of 9001 raw material medicaments and pharmaceutical preparation stability tests of the general rules of the four departments of the 2015 edition of pharmacopoeia of the people's republic of China.
The test samples are spread in a watch glass, respectively placed under the conditions of high temperature (40 ℃, 60 ℃) and strong light irradiation (4500Lux) high humidity (RH 75%, RH 92.5%), and respectively sampled for 0 day, 5 days, 10 days and 30 days to detect the purity and the properties of the samples so as to examine the stability of the samples.
Table 2: experimental result of influence factors of ilaprazole magnesium crystal form A
And (4) conclusion: the experimental result shows that except for illumination, the related substances and properties of the ilaprazole magnesium salt crystal form A have no obvious change, which shows that the ilaprazole magnesium salt crystal form A has better stability.
Example 10
Product quality contrast experiment
This example examines the quality of the crystalline form a of the magnesium ilaprazole salt of the invention and the magnesium ilaprazole hydrate obtained in the prior art.
Sample numbers are as follows:
sample 1: the crystal form A of the ilaprazole magnesium salt prepared in patent example 4 of the invention;
sample 2: ilaprazole magnesium hydrate prepared according to patent CN102140092B example 9;
sample 3: ilaprazole magnesium hydrate obtained according to patent CN102140092B example 10.
Table 3: experimental results of product quality comparison
And (4) conclusion: experimental results show that the crystal form A of the ilaprazole magnesium salt is superior to ilaprazole magnesium hydrate obtained by the existing method in the aspects of properties, crystallinity, fluidity, related substances and the like. In addition, the preparation process of the ilaprazole magnesium salt crystal form A has strong operability and is suitable for large-scale production.
Claims (15)
1. The form A of the magnesium ilaprazole salt is characterized in that an X-ray powder diffraction pattern expressed by 2 theta angles by using Cu-Kalpha radiation has characteristic absorption peaks at 4.795, 12.295, 12.710, 14.684, 15.887, 16.480, 17.287, 19.342, 22.004, 23.012, 24.097, 25.302, 25.835, 27.690, 28.894, 29.820, 35.604 and 36.034;
the preparation method of the ilaprazole magnesium salt crystal form A comprises the following steps:
1) dissolving ilaprazole sodium shown in formula (2) in a solvent; the solvent is a water-containing organic solvent, wherein the water-containing organic solvent is selected from one or more of tetrahydrofuran/water, isopropanol/water, methanol/water and acetone/water, and the volume ratio of water to the organic solvent in the water-containing organic solvent is 1: 2-3;
2) filtering to remove insoluble substances, and then dropwise adding a magnesium agent into the filtrate, wherein the magnesium agent is magnesium chloride or magnesium acetate;
3) stirring and crystallizing;
wherein the stirring crystallization temperature is 10-25 ℃, and the stirring crystallization time is 2-4 h;
4) filtering and drying to constant weight to obtain an ilaprazole magnesium crystal form A;
wherein the drying condition is vacuum drying at 20-30 deg.C.
2. The form a of the magnesium ilaprazole salt of claim 1, wherein the X-ray powder diffraction pattern of the form a of the magnesium ilaprazole salt using Cu-ka radiation expressed in degrees 2 Θ is shown in figure 1.
3. The form a of magnesium ilaprazole of claim 1 or 2, wherein the TGA profile of the form a of magnesium ilaprazole is shown in figure 2 and the DSC profile is shown in figure 3.
4. The crystalline form a of ilaprazole magnesium salt of any of claims 1 to 3, wherein the crystalline form a of ilaprazole magnesium salt is a tetrahydrate crystalline form of ilaprazole magnesium salt.
5. A process for preparing the crystalline form A of the magnesium ilaprazole salt of any of claims 1 to 4, comprising the steps of:
1) dissolving ilaprazole sodium shown in formula (2) in a solvent; the solvent is a water-containing organic solvent, wherein the water-containing organic solvent is selected from one or more of tetrahydrofuran/water, isopropanol/water, methanol/water and acetone/water, and the volume ratio of water to the organic solvent in the water-containing organic solvent is 1: 2-3;
2) filtering to remove insoluble substances, and then dropwise adding a magnesium agent into the filtrate, wherein the magnesium agent is magnesium chloride or magnesium acetate;
3) stirring and crystallizing;
wherein the stirring crystallization temperature is 10-25 ℃, and the stirring crystallization time is 2-4 h;
4) filtering and drying to constant weight to obtain an ilaprazole magnesium crystal form A;
wherein the drying condition is vacuum drying at 20-30 ℃.
6. The method of claim 5, wherein in step 1), the volume/weight ratio of the solvent to the sodium ilaprazole is 6-20: 1 in mL/g.
7. The method of claim 5, wherein in step 1), the volume/weight ratio of the solvent to the sodium ilaprazole is 7-15: 1 in mL/g.
8. The method of claim 5, wherein in step 1), the solvent is isopropanol/water.
9. The method of claim 5, wherein the dissolution temperature in step 1) is 10-30 ℃.
10. The process of claim 5, wherein the dissolution temperature in step 1) is 15-25 ℃.
11. The method according to claim 5, wherein in step 2), the molar ratio of the magnesium agent to the ilaprazole sodium is 0.5 to 0.6: 1.
12. The method of claim 6, wherein in step 2), the molar ratio of magnesium agent to sodium ilaprazole is 0.5 to 0.52: 1.
13. The method of claim 5, wherein in step 2), the magnesium agent is added in the form of an aqueous solution having a concentration of 5 to 30 wt%.
14. The method of claim 13, wherein the aqueous solution has a concentration of 5 to 15 wt%.
15. Use of crystalline form a of ilaprazole magnesium salt according to any of claims 1-4 in the preparation of a medicament for the treatment of a duodenal ulcer.
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| CN202210967056.9A CN115403560A (en) | 2017-11-06 | 2017-11-06 | Ilaprazole magnesium crystal form and preparation method thereof |
| CN201711075793.3A CN107857756B (en) | 2017-11-06 | 2017-11-06 | Ilaprazole magnesium crystal form and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR101144600B1 (en) * | 2009-12-08 | 2012-05-16 | 일양약품주식회사 | Process for Preparing and Conversion of Ilaprazole Crystalline Form A, B |
| CN102140092B (en) * | 2010-02-03 | 2013-05-29 | 丽珠医药集团股份有限公司 | Hydrate of ilaprazole salt, preparation method thereof and application thereof |
| CN103204842B (en) * | 2012-01-13 | 2014-10-15 | 丽珠医药集团股份有限公司 | Crystalline Ilaprazole sodium hydrate and preparation method thereof |
| CN106045978A (en) * | 2016-06-17 | 2016-10-26 | 丽珠医药集团股份有限公司 | Synthesizing method of llaprazole sodium |
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