CN114315797B - Preparation method of high-crystal-form-purity esomeprazole magnesium dihydrate crystal - Google Patents
Preparation method of high-crystal-form-purity esomeprazole magnesium dihydrate crystal Download PDFInfo
- Publication number
- CN114315797B CN114315797B CN202210217821.5A CN202210217821A CN114315797B CN 114315797 B CN114315797 B CN 114315797B CN 202210217821 A CN202210217821 A CN 202210217821A CN 114315797 B CN114315797 B CN 114315797B
- Authority
- CN
- China
- Prior art keywords
- esomeprazole magnesium
- crystal
- crystal form
- drying
- controlling
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Abstract
The invention discloses a preparation method of a high-crystal-form-purity esomeprazole magnesium dihydrate crystal, belonging to the technical field of medical chemistry, and the preparation method comprises the steps of dropwise adding a dissolving-out agent, carrying out crystal transformation, drying and controlling the water content; the temperature of the esomeprazole magnesium intermediate is controlled to be 15-25 ℃, the desolvation agent is added under stirring, crystal transformation is carried out at the temperature of-5 ℃ to 20 ℃, the crystal transformation time is controlled to be 4-8h, and the esomeprazole magnesium hydrate with the transition crystal form is obtained after the crystal transformation is finished; the drying and water content control are carried out, and the esomeprazole magnesium hydrate in the transition state crystal form is dried; the esomeprazole magnesium dihydrate crystal prepared by the preparation method has high crystal form purity, narrow particle size distribution, good fluidity and low magnesium content.
Description
Technical Field
The invention relates to the technical field of medical chemistry, in particular to a preparation method of a high-crystalline-purity esomeprazole magnesium dihydrate crystal.
Background
The esomeprazole magnesium is an S-isomer of omeprazole, is weakly alkaline, is concentrated and converted into an active form in a high-acid environment of acid microtubules secreted by gastric parietal cells, inhibits H + -K + -ATP enzyme (proton pump) at the part, and further has an inhibition effect on gastric acid and gastric acid secretion caused by stimulation. It features small first pass effect of liver after taking orally, higher bioavailability and blood medicine concentration than omeprazole or R-type isomer, so its medicinal effect is higher and longer lasting than omeprazole.
For esomeprazole magnesium, the existing drug crystals are more in form, and the common esomeprazole magnesium anhydrate, the esomeprazole magnesium dihydrate crystal form A, the esomeprazole magnesium dihydrate crystal form B, the esomeprazole magnesium trihydrate and the like exist, wherein the drug effect of the esomeprazole magnesium dihydrate crystal form A is higher, but the existing technology for preparing the esomeprazole magnesium dihydrate crystal form A has limitations, and is difficult to prepare the esomeprazole magnesium dihydrate crystal form A solid drug with high crystal purity, and in addition, the existing preparation technology of the esomeprazole magnesium dihydrate crystal form A drug also has the technical problems of wide particle size distribution, poor flowability, high magnesium content and the like.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a preparation method of high-crystal-form-purity esomeprazole magnesium dihydrate crystal, and the prepared esomeprazole magnesium dihydrate crystal has the advantages of high crystal form purity, narrow particle size distribution, good fluidity and low magnesium content.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a preparation method of high-crystal-form-purity esomeprazole magnesium dihydrate crystal comprises the steps of dropwise adding a dissolving-out agent and crystal transformation, and drying and controlling the water content.
And dropwise adding a elutriation agent and crystal transformation, controlling the temperature of the esomeprazole magnesium intermediate to 15-25 ℃, adding the elutriation agent under stirring, carrying out crystal transformation at the temperature of-5 ℃ to 20 ℃, controlling the crystal transformation time to be 4-8h, and obtaining the esomeprazole magnesium hydrate in the transition state crystal form after the crystal transformation is finished.
The esomeprazole magnesium intermediate is one of an esomeprazole magnesium trihydrate mother liquor or an esomeprazole magnesium dihydrate crystal form B;
the preparation method of the esomeprazole magnesium trihydrate mother liquor comprises the following steps: dissolving esomeprazole magnesium trihydrate into methanol at 15-25 ℃, and filtering to obtain a methanol solution of esomeprazole magnesium; and then carrying out reduced pressure evaporation on the methanol solution of esomeprazole magnesium, and stopping evaporation when the residual amount of the solution is 5 times of the mass of the magnesium trihydrate of the esomeprazole magnesium to obtain the mother liquor of the magnesium trihydrate of the esomeprazole magnesium.
The temperature of reduced pressure evaporation in the preparation of the esomeprazole magnesium trihydrate mother liquor is 30-40 ℃, and the pressure of reduced pressure evaporation is-0.09 MPa to-0.06 MPa;
in the preparation of the esomeprazole magnesium trihydrate mother liquor, the mass-to-volume ratio of the esomeprazole magnesium trihydrate to the methanol is 10 g: 150 mL.
The stirring speed in the step of dripping the elution agent and transferring the crystal is 200-400 rpm;
the esomeprazole magnesium intermediate is an esomeprazole magnesium trihydrate mother liquor, the elution agent is added in a dropping mode, and the dropping speed of the elution agent is controlled to be 1-3 mL/min;
the esomeprazole magnesium intermediate is an esomeprazole magnesium trihydrate mother liquor, and the mass-volume ratio of the esomeprazole magnesium trihydrate mother liquor to the elution solvent is 50 g: 80-150 mL;
the esomeprazole magnesium intermediate is an esomeprazole magnesium dihydrate crystal form B, and the mass-volume ratio of the esomeprazole magnesium dihydrate crystal form B to the elution agent is 10 g: 80-150 mL;
the preparation method of the elution agent comprises the steps of uniformly mixing acetone and water, carrying out ultrasonic mixing for 10-15min, and filtering through a 0.45-micrometer filter membrane to obtain the elution agent.
Wherein the volume ratio of acetone to water is 80-120: 10.
and drying and controlling the water content, drying the transition-state crystal form esomeprazole magnesium hydrate, controlling the drying temperature to be 35-45 ℃ and the drying pressure to be-0.09 MPa to-0.06 MPa, measuring the solid water content once every 1 hour, and collecting when the solid water content is less than 5.5% to obtain the esomeprazole magnesium dihydrate crystal form A solid.
Compared with the prior art, the invention has the beneficial effects that:
(1) the preparation method of the high-crystal-form-purity esomeprazole magnesium dihydrate crystal has the advantages of being simple to operate, saving manpower and material resources and the like, and the product of the high-crystal-form-purity esomeprazole magnesium dihydrate crystal almost does not contain solid esomeprazole magnesium in other crystal forms according to XRD (X-ray diffraction) spectrum display;
(2) according to the preparation method of the high-crystal-purity esomeprazole magnesium dihydrate crystal, the solid yield of the prepared esomeprazole magnesium dihydrate crystal form A is 75% -94%, the total operation time is within 24h, and the operation time in the prior art is more than 48 h;
(3) the high-crystal-purity esomeprazole magnesium dihydrate crystal prepared by the invention has the advantages of high crystal purity, high particle size uniformity, short crystallization time, simple operation, qualified product water content and magnesium content and the like, wherein D10 is 48-64, D50 is 100-plus-117, D90 is 183-plus-214, D90-D10 is 132-plus-163, the purity is 99.6-99.9%, the angle of repose is 30-35%, and the magnesium content is 3.42-3.47%.
Drawings
Fig. 1 is an XRD pattern of esomeprazole magnesium prepared in example 1 and its hydrate crystal form;
figure 2 is a thermogravimetric plot of esomeprazole magnesium dihydrate crystal form a prepared in example 1 and a transition state crystal form of esomeprazole magnesium hydrate;
figure 3 is a microscope photograph of esomeprazole magnesium dihydrate form a prepared in example 1 and a transition state form of esomeprazole magnesium hydrate;
figure 4 is a graph of the particle size distribution of esomeprazole magnesium dihydrate form a prepared in example 1 and the transition state form of esomeprazole magnesium hydrate.
Detailed Description
In order to more clearly understand the technical features, objects, and effects of the present invention, specific embodiments of the present invention will now be described.
Example 1
A method for preparing high-crystalline-purity esomeprazole magnesium dihydrate crystals by using esomeprazole magnesium trihydrate as a raw material comprises the following specific steps:
1. dissolving and concentrating: firstly, dissolving 10g of esomeprazole magnesium trihydrate in 150mL of methanol at 25 ℃, and filtering after complete dissolution to obtain an esomeprazole magnesium methanol solution; and then carrying out reduced pressure evaporation on the methanol solution of esomeprazole magnesium, controlling the temperature of the reduced pressure evaporation to be 35 ℃, controlling the pressure of the reduced pressure evaporation to be-0.09 MPa, stopping evaporation when the residual amount of the solution is 50g to obtain mother liquor, and transferring the mother liquor to a 250mL jacket crystallizer.
2. Dripping a solventing-out agent and crystal transformation: uniformly mixing 100 mL of acetone and 10 mL of water, ultrasonically mixing for 10 min, and filtering through a 0.45-micrometer filter membrane to obtain a elution agent;
and then controlling the temperature of the mother liquor in a 250mL jacket crystallizer to be 25 ℃, stirring at the speed of 350rpm, dropwise adding a elutriation agent into the 250mL jacket crystallizer, controlling the dropwise adding speed of the elutriation agent to be 2mL/min, and obtaining the esomeprazole magnesium hydrate transition state crystal form crude product after the elutriation agent is dropwise added.
The temperature of a 250mL jacket crystallizer is set to be 15 ℃ for crystal transformation, and the crystal transformation time is controlled to be 6 h. And obtaining a primary product after crystal transformation is finished, filtering the primary product, leaching with acetone, and obtaining the transition state crystal form of the esomeprazole magnesium hydrate.
The water content of the esomeprazole magnesium hydrate in the transition state crystal form is 9%, as shown in fig. 1, the XRD characteristic peaks of the esomeprazole magnesium hydrate in the transition state crystal form are 5.23 °, 7.31 °, 8.62 °, 12.21 ° and 18.40 °, and the crystal form is a hexagonal crystal.
3. Drying and controlling the water content: placing the esomeprazole magnesium hydrate transition state crystal form in a dryer with the functions of stirring, heating and vacuumizing for drying, controlling the drying temperature to be 40 ℃, the drying pressure to be-0.09 MPa, measuring the solid water content every 1 hour in the period, receiving the solid water content when the solid water content is less than 5.5%, collecting the solid water content, and obtaining the esomeprazole magnesium dihydrate crystal form A solid after drying, wherein the content of the main component in the esomeprazole magnesium dihydrate crystal form A solid is 99.7%, the content of the magnesium is 3.45%, other pharmaceutical indexes meet pharmacopeia requirements, and XRD characteristic peaks are 5.63 °, 13.37 °, 14.27 °, 16.95 ° and 18.70 °.
The crystalline form a of esomeprazole magnesium dihydrate prepared in this example was characterized, as shown in fig. 2, the water loss of the crystalline form a of esomeprazole magnesium dihydrate before 180 ℃ was 5%, corresponding to 2 crystal waters; the water loss of the esomeprazole magnesium hydrate transition state crystal form is 8% before 180 ℃, and 3.5 crystal waters are correspondingly adopted; as shown in fig. 3, the esomeprazole magnesium dihydrate crystal form a is spherical particles, and the esomeprazole magnesium hydrate transition state crystal form is hexagonal particles; as shown in figure 4, the average particle size of esomeprazole magnesium dihydrate form a was 110 microns and the average particle size of the transition form of esomeprazole magnesium hydrate was 145 microns.
Example 2
A method for preparing high-crystal-form-purity esomeprazole magnesium dihydrate crystal by taking the esomeprazole magnesium dihydrate crystal form B as a raw material comprises the following steps:
1. suspension crystal transformation: uniformly mixing 100 mL of acetone and 10 mL of water, ultrasonically mixing for 10 min, and filtering through a 0.45-micrometer filter membrane to obtain a elution agent;
adding 10g of esomeprazole magnesium dihydrate crystal form B solid into a dissolving-out agent to obtain a suspension, adding the suspension into a 250mL jacket crystallizer, setting the temperature of the 250mL jacket crystallizer to 15 ℃, starting stirring to perform suspension crystal transformation, controlling the stirring speed to be 350rpm, controlling the suspension crystal transformation time to be 6h, filtering after suspension crystallization is finished, leaching with acetone to obtain an esomeprazole magnesium hydrate transition state crystal form, wherein the water content of the esomeprazole magnesium hydrate transition state crystal form is 12%.
2. Drying and controlling water content: the procedure was the same as in step 3 of example 1. And (3) obtaining the esomeprazole magnesium dihydrate crystal form A solid after drying, wherein the content of the main component in the esomeprazole magnesium dihydrate crystal form A solid is 99.6%, the content of magnesium is 3.44%, and other pharmaceutical indexes meet the requirements of pharmacopoeia.
Example 3
A method for preparing high-crystalline-purity esomeprazole magnesium dihydrate crystals by using esomeprazole magnesium trihydrate as a raw material comprises the following specific steps:
1. dissolving and concentrating: firstly, dissolving 10g of esomeprazole magnesium trihydrate in 150mL of methanol at 15 ℃, and filtering after complete dissolution to obtain an esomeprazole magnesium methanol solution; and then carrying out reduced pressure evaporation on the methanol solution of esomeprazole magnesium, controlling the temperature of the reduced pressure evaporation to be 35 ℃, controlling the pressure of the reduced pressure evaporation to be-0.06 MPa, stopping evaporation until the residual amount of the solution is 50g to obtain mother liquor, and transferring the mother liquor to a 250mL jacket crystallizer.
2. Dripping a dissolving agent and crystal transformation: uniformly mixing 100 mL of acetone and 10 mL of water, ultrasonically mixing for 10 min, and filtering through a 0.45-micrometer filter membrane to obtain a elution agent;
and then controlling the temperature of the mother liquor in a 250mL jacket crystallizer to be 15 ℃, stirring at the speed of 350rpm, dropwise adding a elutriation agent into the 250mL jacket crystallizer, controlling the dropwise adding speed of the elutriation agent to be 2mL/min, and obtaining the esomeprazole magnesium hydrate transition state crystal form crude product after the elutriation agent is dropwise added.
The temperature of a 250mL jacket crystallizer is set as 15 ℃ for crystal transformation, and the crystal transformation time is controlled to be 6 h. And obtaining a primary product after crystal transformation is finished, filtering the primary product, leaching with acetone, and obtaining the transition state crystal form of the esomeprazole magnesium hydrate. The water content of the esomeprazole magnesium hydrate transition state crystal form is 8.9%.
3. Drying and controlling water content: placing the esomeprazole magnesium hydrate transition state crystal form in a dryer with the functions of stirring, heating and vacuumizing for drying, controlling the drying temperature to be 40 ℃, the pressure of the drying process to be-0.09 MPa, measuring the solid water content every 1 hour in the period, receiving materials when the solid water content is less than 5.5%, wherein the total drying time is 16 hours, and obtaining the esomeprazole magnesium dihydrate crystal form A solid after drying, wherein the content of the main component in the esomeprazole magnesium dihydrate crystal form A solid is 99.6%, the content of magnesium is 3.42%, other pharmaceutical indexes meet pharmacopeia requirements, and XRD characteristic peaks are 5.63 degrees, 13.37 degrees, 14.27 degrees, 16.95 degrees and 18.70 degrees.
The mean particle size of the esomeprazole magnesium dihydrate crystal form a obtained in this example was 100 microns and the mean particle size of the transition state crystal form of the esomeprazole magnesium hydrate was 130 microns.
Example 4
A method for preparing high-crystal-form-purity esomeprazole magnesium dihydrate crystal by taking the esomeprazole magnesium dihydrate crystal form B as a raw material comprises the following steps:
1. suspension crystal transformation: uniformly mixing 100 mL of acetone and 10 mL of water, ultrasonically mixing for 15min, and filtering through a 0.45-micrometer filter membrane to obtain a elution agent;
adding 15g of esomeprazole magnesium dihydrate crystal form B solid into a dissolving-out agent to obtain a suspension, adding the suspension into a 250mL jacket crystallizer, setting the temperature of the 250mL jacket crystallizer to be 25 ℃, starting stirring to perform suspension crystal transformation, controlling the stirring speed to be 350rpm, controlling the suspension crystal transformation time to be 5h, filtering after suspension crystallization is finished, leaching with acetone to obtain an esomeprazole magnesium hydrate transition state crystal form, wherein the water content of the esomeprazole magnesium hydrate transition state crystal form is 11.7%.
2. Drying and controlling water content: the procedure was the same as in step 3 of example 1. And (3) obtaining the esomeprazole magnesium dihydrate crystal form A solid after drying, wherein the content of the main component in the esomeprazole magnesium dihydrate crystal form A solid is 99.8%, the content of magnesium is 3.47%, and other pharmaceutical indexes meet the requirements of pharmacopoeia.
Example 5
The same as in example 1, except that the temperature at the time of distillation under reduced pressure in the dissolution and concentration steps in the 1 st step was 30 ℃.
Example 6
The same as in example 1, except that the temperature at the time of distillation under reduced pressure in the dissolution and concentration steps in the 1 st step was 40 ℃.
Example 7
The same as in example 1, except that the pressure at the time of distillation under reduced pressure in the dissolution and concentration steps in the 1 st step was-0.06 MPa.
Example 8
The same as in example 1, except that the temperature at the time of dropping the precipitating agent in the 2 nd step and the time of the crystallization in the crystallization step was-5 ℃.
Example 9
The same as in example 1, except that the temperature of the dropping of the solventing-out agent in the step 2 and the crystallization in the step of the crystal transformation were 20 ℃.
Example 10
The same as example 1, except that the time for dropping the precipitating agent in the 2 nd step and for the crystallization in the crystal transformation step was 4 hours.
Example 11
The same as example 1, except that the time for dropping the precipitating agent in the 2 nd step and for the crystallization in the crystal transformation step was 8 hours.
Example 12
The same as in example 1, except that the stirring speed in the step 2 of dropping the elutant and the step of crystal transformation was 200 rpm.
Example 13
The same as in example 1, except that the stirring speed in the step 2 of dropping the elutant and the step of crystal transformation was 400 rpm.
Example 14
The same as example 1, except that the dropping speed of the eluting agent in the step 2 and the dropping speed of the eluting agent in the crystal transferring step were controlled to be 1 mL/min.
Example 15
The same as example 1, except that the dropping speed of the eluting agent in the step 2 and the dropping speed of the eluting agent in the crystal transferring step were controlled to be 3 mL/min.
Example 16
The method is the same as the example 1, and is characterized in that the mass-to-volume ratio of the liquating agent added dropwise in the step 2 to the mother solution to the liquating agent in the crystal transferring step is 50 g: 80 mL.
Example 17
The method is the same as example 1, except that the mass volume ratio of the liquating agent added dropwise in the step 2 to the mother liquor and the liquating agent in the crystal transformation step is 50 g: 150 mL.
Example 18
The method is the same as the example 2, and is characterized in that the mass-to-volume ratio of the esomeprazole magnesium dihydrate crystal form B to the elution reagent in the suspension crystal transformation step in the step 1 is 10 g: 80 mL.
Example 19
The method is the same as the example 2, and is characterized in that the mass-to-volume ratio of the esomeprazole magnesium dihydrate crystal form B to the elution reagent in the suspension crystal transformation step in the step 1 is 10 g: 150 mL.
Example 20
The same as example 2, except that the volume ratio of acetone to water in the preparation of the eluent in the suspension crystallization step of step 1 was 80: 10.
example 21
The same as example 2, except that the volume ratio of acetone to water in the preparation of the eluent in the suspension crystallization step of step 1 was 120: 10.
example 22
The same as in example 2, except that the temperature at the time of drying in the 2 nd step and drying in the water content controlling step was 35 ℃.
Example 23
The same as in example 2, except that the temperature at the time of drying in the 2 nd step and drying in the water content controlling step was 45 ℃.
Example 24
The same as in example 2, except that the pressure at the time of drying in the 2 nd step and the water content controlling step was-0.06 mPa.
The crystalline form a of esomeprazole magnesium dihydrate prepared by the prior art and the crystalline forms a of esomeprazole magnesium dihydrate prepared in examples 1-4 were tested for D10, D50, and D90, purity, angle of repose, and magnesium content, and the test results were as follows:
the prior art comprises the following steps: uniformly mixing 100 mL of acetone and 10 mL of water, ultrasonically mixing for 10 min, and filtering through a 0.45-micrometer filter membrane to obtain a solventing-out agent;
adding 10g of esomeprazole magnesium dihydrate crystal form B solid into a dissolving agent to obtain a suspension, adding the suspension into a 500mL jacket crystallizer, setting the temperature of the 500mL jacket crystallizer to be-5 ℃, starting stirring to perform suspension crystal transformation, controlling the stirring speed to be 500rpm, controlling the suspension crystal transformation time to be more than 24h, washing the product with acetone, and performing vacuum drying at the temperature of 40 ℃ and the pressure of-0.09 MPa for 20h to obtain a final product. The final product is not pure esomeprazole magnesium dihydrate crystal form a, and is often a mixed crystal of esomeprazole magnesium dihydrate crystal form a and form B.
In the above table, the difference between D10 and D90 can be used to characterize the width of the particle size distribution, and the flowability is expressed as the angle of repose, with the smaller the angle of repose, the better the flowability.
The calculation method of the solid yield is as follows: the ratio of the mass of the finally prepared esomeprazole magnesium dihydrate crystal form a to the mass of the dosed solid (esomeprazole magnesium trihydrate or esomeprazole magnesium dihydrate crystal form B).
All percentages used in the present invention are mass percentages unless otherwise indicated.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (2)
1. A preparation method of high-crystal-form-purity esomeprazole magnesium dihydrate crystal is characterized by comprising the steps of dissolving and concentrating, dripping a dissolving-out agent and crystal transformation, drying and controlling the water content;
the dissolving and concentrating process comprises the steps of firstly dissolving 10g of esomeprazole magnesium trihydrate into 150mL of methanol at 25 ℃, and filtering after complete dissolving to obtain a methanol solution of esomeprazole magnesium; then, carrying out reduced pressure evaporation on the methanol solution of esomeprazole magnesium, controlling the temperature of the reduced pressure evaporation to be 35 ℃, controlling the pressure of the reduced pressure evaporation to be-0.09 MPa, stopping evaporation until the residual amount of the solution is 50g to obtain mother liquor, and transferring the mother liquor to a 250mL jacket crystallizer;
the elution agent is dropwise added and crystal is transferred, 100 mL of acetone and 10 mL of water are uniformly mixed and then ultrasonically mixed for 10 min, and the elution agent is obtained after passing through a 0.45-micron filter membrane;
then controlling the temperature of mother liquor in a 250mL jacket crystallizer to be 25 ℃, the stirring speed to be 350rpm, dropwise adding a elutriation agent into the 250mL jacket crystallizer, controlling the dropwise adding speed of the elutriation agent to be 2mL/min, and obtaining a transition state crystal form crude product of the esomeprazole magnesium hydrate after the elutriation agent is dropwise added;
setting the temperature of a 250mL jacket crystallizer to be 15 ℃ for crystal transformation, and controlling the crystal transformation time to be 6 h;
obtaining a primary product after crystal transformation is finished, filtering the primary product, leaching with acetone to obtain an esomeprazole magnesium hydrate transition state crystal form;
the water content of the esomeprazole magnesium hydrate transition state crystal form is 9%; the XRD characteristic peaks of the esomeprazole magnesium hydrate in the transition state crystal form are 5.23 degrees, 7.31 degrees, 8.62 degrees, 12.21 degrees and 18.40 degrees, and the esomeprazole magnesium hydrate is a hexagonal crystal;
the drying and water content control are carried out, the esomeprazole magnesium hydrate transition state crystal form is placed in a dryer with the functions of stirring, heating and vacuumizing for drying, the drying temperature is controlled to be 40 ℃, the drying pressure is-0.09 MPa, the solid water content is measured every 1 hour in the period, the solid water content is collected when the solid water content is less than 5.5%, the total drying time is 16 hours, and the esomeprazole magnesium dihydrate crystal form A solid is obtained after the drying is finished, wherein the content of the main component in the esomeprazole magnesium dihydrate crystal form A solid is 99.7%, the content of magnesium is 3.45%, and XRD characteristic peaks are 5.63 degrees, 13.37 degrees, 14.27 degrees, 16.95 degrees and 18.70 degrees;
the water loss of the esomeprazole magnesium dihydrate crystal form A before 180 ℃ is 5%, and the water loss of the esomeprazole magnesium hydrate transition state crystal form A before 180 ℃ is 8%;
the esomeprazole magnesium dihydrate crystal form A is spherical particles, and the transition state crystal form of the esomeprazole magnesium hydrate is hexagonal particles;
the average particle size of the esomeprazole magnesium dihydrate crystal form a is 110 microns, and the average particle size of the transition state crystal form of the esomeprazole magnesium hydrate is 145 microns.
2. A preparation method of high-crystal-form-purity esomeprazole magnesium dihydrate crystal is characterized by comprising the steps of suspending crystal transformation, drying and water content control;
the suspension crystal transformation is to mix 100 mL of acetone and 10 mL of water uniformly, then mix the mixture for 10 min by ultrasonic wave, and obtain a dissolution agent after passing through a 0.45 micron filter membrane;
adding 10g of esomeprazole magnesium dihydrate crystal form B solid into a dissolving-out agent to obtain a suspension, adding the suspension into a 250mL jacket crystallizer, setting the temperature of the 250mL jacket crystallizer to be 15 ℃, starting stirring to perform suspension crystal transformation, controlling the stirring speed to be 350rpm, controlling the suspension crystal transformation time to be 6h, filtering after the suspension crystallization is finished, leaching with acetone to obtain an esomeprazole magnesium hydrate transition state crystal form, wherein the water content of the esomeprazole magnesium hydrate transition state crystal form is 12%;
and drying and controlling the water content, namely placing the transition state crystal form of the esomeprazole magnesium hydrate in a dryer with the functions of stirring, heating and vacuumizing, controlling the drying temperature to be 40 ℃, the drying pressure to be-0.09 MPa, measuring the water content of the solid once every 1 hour in the period, receiving the solid when the water content of the solid is less than 5.5 percent, controlling the total drying time to be 16 hours, and obtaining the solid of the esomeprazole magnesium dihydrate crystal form A after the drying is finished, wherein the content of the main component in the solid of the esomeprazole magnesium dihydrate crystal form A is 99.6 percent, and the content of the magnesium is 3.44 percent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210217821.5A CN114315797B (en) | 2022-03-08 | 2022-03-08 | Preparation method of high-crystal-form-purity esomeprazole magnesium dihydrate crystal |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210217821.5A CN114315797B (en) | 2022-03-08 | 2022-03-08 | Preparation method of high-crystal-form-purity esomeprazole magnesium dihydrate crystal |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114315797A CN114315797A (en) | 2022-04-12 |
| CN114315797B true CN114315797B (en) | 2022-07-05 |
Family
ID=81030956
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210217821.5A Active CN114315797B (en) | 2022-03-08 | 2022-03-08 | Preparation method of high-crystal-form-purity esomeprazole magnesium dihydrate crystal |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114315797B (en) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2147918A1 (en) * | 2008-07-21 | 2010-01-27 | LEK Pharmaceuticals D.D. | Process for the preparation of S-omeprazole magnesium in a stable form |
| US20100267959A1 (en) * | 2009-04-15 | 2010-10-21 | Glenmark Generics Limited | Process for the preparation of esomeprazole magnesium dihydrate |
| CN103214458B (en) * | 2012-01-19 | 2015-04-22 | 上海汇伦生命科技有限公司 | Esomeprazole magnesium dihydrate preparation method |
| CN104250243B (en) * | 2013-06-27 | 2016-12-28 | 四川国为制药有限公司 | A kind of preparation method of Esomeprazole magnesium dihydrate A crystal formation |
| CN103539782A (en) * | 2013-10-16 | 2014-01-29 | 江南大学 | Disesquihydrate of esomeprazole magnesium salt and preparation method of disesquihydrate |
-
2022
- 2022-03-08 CN CN202210217821.5A patent/CN114315797B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN114315797A (en) | 2022-04-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103012430B (en) | Mezlocillin sodium compound and medicine composition thereof | |
| CN105753904B (en) | A kind of process for purification of Tedizolid Phosphate | |
| CN111517980B (en) | N- [8- (2-hydroxybenzoyl) amino ] caprylic acid monopotassium crystal type compound, preparation method and application | |
| CN105111189B (en) | A kind of compound of pantoprazole sodium monohydrate sphaerocrystal and preparation method thereof | |
| CN114315797B (en) | Preparation method of high-crystal-form-purity esomeprazole magnesium dihydrate crystal | |
| CN107739396A (en) | It is a kind of to improve heap density, mobility and prepare the method for crystallising for not coalescing azithromycin | |
| CN103509001B (en) | A kind of esomeprazole magnesium trihydrate and preparation method thereof | |
| CN104856970A (en) | Vildagliptin tablet for treating type 2 diabetes mellitus | |
| WO2022222680A1 (en) | Method for preparing high-bulk-density ibuprofen spherical crystal and product thereof | |
| CN108727387A (en) | According to Shandong for Buddhist nun's isopropyl acetate solvent compound and preparation method thereof | |
| CN110101668B (en) | Preparation method of gefitinib composite particles | |
| CN108570045A (en) | The crystal form of Anisodamine, preparation method, pharmaceutical composition | |
| CN105106139A (en) | Medicine of tadalafil composition particles for treating urinary surgery diseases | |
| CN112898215B (en) | Preparation method of leflunomide crystal form I | |
| CN112500283B (en) | Crystallization process of dexibuprofen | |
| CN110903379B (en) | Iron protein succinate and method for industrially preparing iron protein succinate | |
| CN104311447B (en) | Acetaminophen novel crystal forms, its preparation method and compound paracetamol and amantadine hydrochloride preparations | |
| CN113429311B (en) | Method for removing impurities in asparagine bulk drug | |
| CN108727448A (en) | Spiramvcin class antibiotic spheroidal crystal and preparation method thereof | |
| CN117466864A (en) | Crystal preparation method of trelagliptin succinate | |
| CN102827147A (en) | Omeprazole sodium crystal compound and medicine composition containing omeprazole sodium crystal compound | |
| WO2023115523A1 (en) | Method for preparing amorphous anidulafungin | |
| CN104814942A (en) | Medicinal pantoprazole sodium composition capsule for treating digestive system disease | |
| CN117209473A (en) | Method for preparing micro-powder type fumaric acid voronoi | |
| CN105055411A (en) | Pantoprazole sodium composition for treating gastric ulcer |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |