CN113387929A - Preparation method of esomeprazole magnesium trihydrate - Google Patents
Preparation method of esomeprazole magnesium trihydrate Download PDFInfo
- Publication number
- CN113387929A CN113387929A CN202110742089.9A CN202110742089A CN113387929A CN 113387929 A CN113387929 A CN 113387929A CN 202110742089 A CN202110742089 A CN 202110742089A CN 113387929 A CN113387929 A CN 113387929A
- Authority
- CN
- China
- Prior art keywords
- esomeprazole
- magnesium trihydrate
- esomeprazole magnesium
- trihydrate
- preparation
- 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.)
- Pending
Links
- KWORUUGOSLYAGD-YPPDDXJESA-N esomeprazole magnesium Chemical compound [Mg+2].C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C.C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C KWORUUGOSLYAGD-YPPDDXJESA-N 0.000 title claims abstract description 97
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 238000003756 stirring Methods 0.000 claims abstract description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 238000001035 drying Methods 0.000 claims abstract description 29
- 159000000003 magnesium salts Chemical class 0.000 claims abstract description 15
- FOFFPEFVSRGLOZ-JIDHJSLPSA-N potassium;5-methoxy-2-[(s)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-1-ide Chemical compound [K+].C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C FOFFPEFVSRGLOZ-JIDHJSLPSA-N 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 238000001816 cooling Methods 0.000 claims abstract description 11
- 238000002425 crystallisation Methods 0.000 claims abstract description 6
- 230000008025 crystallization Effects 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 18
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical group [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 238000006073 displacement reaction Methods 0.000 claims description 4
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 4
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 3
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 3
- 238000011068 loading method Methods 0.000 claims description 2
- 230000007774 longterm Effects 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 239000008213 purified water Substances 0.000 description 16
- 239000002245 particle Substances 0.000 description 15
- 230000000052 comparative effect Effects 0.000 description 13
- 239000000243 solution Substances 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- FOFFPEFVSRGLOZ-UHFFFAOYSA-N potassium;5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-3-ide Chemical compound [K+].N=1C2=CC(OC)=CC=C2[N-]C=1[S+]([O-])CC1=NC=C(C)C(OC)=C1C FOFFPEFVSRGLOZ-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 229960004770 esomeprazole Drugs 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 6
- 229940050906 magnesium chloride hexahydrate Drugs 0.000 description 5
- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 description 5
- 238000009826 distribution Methods 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229960000197 esomeprazole magnesium Drugs 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 229960000496 esomeprazole sodium Drugs 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 229960002337 magnesium chloride Drugs 0.000 description 2
- 229940091250 magnesium supplement Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- WRUGWIBCXHJTDG-UHFFFAOYSA-L magnesium sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Mg+2].[O-]S([O-])(=O)=O WRUGWIBCXHJTDG-UHFFFAOYSA-L 0.000 description 1
- 229940061634 magnesium sulfate heptahydrate Drugs 0.000 description 1
- YYINWHOQKIUBNL-UHFFFAOYSA-N magnesium;trihydrate Chemical compound O.O.O.[Mg] YYINWHOQKIUBNL-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000006911 nucleation Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 210000001711 oxyntic cell Anatomy 0.000 description 1
- 229920000333 poly(propyleneimine) Polymers 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 238000004383 yellowing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a preparation method of esomeprazole magnesium trihydrate, which comprises the following steps: dissolving esomeprazole potassium in water, adding an inorganic magnesium salt for salt replacement at the temperature of 35-55 ℃ and the rotating speed of a stirring paddle of 10-45 r/min, cooling for crystallization, and centrifuging to obtain an esomeprazole magnesium trihydrate wet product; and drying the esomeprazole magnesium trihydrate wet product by adopting a pulse vacuum dryer or a fluidized bed to obtain an esomeprazole magnesium trihydrate dry product. The invention effectively improves the grain diameter of the esomeprazole magnesium trihydrate so as to reduce the moisture content, the moisture content of a wet product of the esomeprazole magnesium trihydrate is less than or equal to 50 percent, the drying efficiency is improved, the drying time is 7-24 hours, the purity is more than or equal to 99.9 percent, the manufacturing cost of the esomeprazole magnesium trihydrate is reduced, and the long-term stable product quality is ensured.
Description
Technical Field
The invention belongs to the field of medical chemistry, and relates to a preparation method of esomeprazole magnesium trihydrate.
Background
Esomeprazole is the S-optical isomer of omeprazole, the first global isomer Proton Pump Inhibitor (PPI), which reduces gastric acid secretion by specifically inhibiting parietal cell proton pump. A large number of clinical experiments and pharmaceutical researches prove that: the esomeprazole can maintain the pH value in the stomach to be greater than 4 for a longer time, the acid inhibition efficiency is higher, the curative effect is superior to that of the PPI in the first two generations, and the individual difference is small. As a new generation of PPIs, esomeprazole has been widely used in clinical treatment of many polyacid-related diseases. Esomeprazole magnesium is marketed as trihydrate, having the chemical formula:
WO9854171A1, WO2004089935A1, CN1110477A and the like report preparation methods of esomeprazole magnesium trihydrate in sequence. Currently, there are two main methods for preparing esomeprazole magnesium trihydrate. The method comprises the following steps: firstly, preparing esomeprazole sodium from high-purity esomeprazole and sodium hydroxide, then performing replacement and drying on the obtained esomeprazole sodium and inorganic magnesium in water to obtain an esomeprazole magnesium trihydrate; the second method comprises the following steps: firstly, preparing esomeprazole into high-purity esomeprazole potassium, dissolving the esomeprazole potassium in a water system, and replacing the esomeprazole potassium with inorganic magnesium to obtain the esomeprazole magnesium trihydrate. Because the stability of the esomeprazole in the first method is poor and the purification is difficult, the second method is a main large-scale production process at present. However, both the first and second processes require the preparation of esomeprazole magnesium trihydrate in an aqueous or water-containing system, otherwise only other crystalline or anhydrous crystalline forms of esomeprazole magnesium can be obtained.
After the esomeprazole magnesium trihydrate is separated from water or a water-containing system, if the particles of the esomeprazole magnesium trihydrate are not controlled, the wet product has high viscosity, the moisture content of the wet product can reach 80 percent at most, and the esomeprazole magnesium trihydrate is unstable at high temperature, if a conventional flat oven is adopted, the drying period is as high as 5 to 8 days, the efficiency is low, the cost is high, the drying time is long, the appearance of the esomeprazole magnesium turns yellow, and the purity is reduced. The ebullated bed drying is adopted, although the drying time can be effectively shortened, the obtained dried esomeprazole magnesium trihydrate is darker in color, namely faint yellow or grey white, due to the fact that the steam temperature is too high in the ebullated bed drying process, and stability proves that the impurity growth speed is obviously higher than that of the esomeprazole magnesium trihydrate dried by a flat plate oven in long-term and accelerated tests.
Considering that the conventional flat oven drying time is long, the manufacturing cost of the esomeprazole magnesium trihydrate is high, the product quality is low or the product quality is difficult to control due to ebullated bed drying, the development of a preparation process of the high-efficiency and high-quality dried esomeprazole magnesium trihydrate is particularly important.
Disclosure of Invention
The invention aims to provide a preparation method of esomeprazole magnesium trihydrate, aiming at the problems that the conventional flat plate oven is long in drying time, so that the manufacturing cost of the esomeprazole magnesium trihydrate is high, the product quality is low, or the product quality is difficult to control due to fluidized bed drying in the prior art.
The purpose of the invention is realized by the following technical scheme:
a preparation method of esomeprazole magnesium trihydrate comprises the following steps: dissolving esomeprazole potassium in water, adding an inorganic magnesium salt to perform a salt replacement reaction at the temperature of 35-55 ℃ and the rotating speed of a stirring paddle of 10-45 revolutions per minute, cooling, crystallizing, and centrifuging to prepare an esomeprazole magnesium trihydrate wet product with large particle size; and drying the esomeprazole magnesium trihydrate wet product by adopting a pulse vacuum dryer or a fluidized bed to obtain an esomeprazole magnesium trihydrate dry product.
The weight ratio of the esomeprazole potassium to the water is 1: 3-10.
The molar ratio of the inorganic magnesium salt to the esomeprazole potassium is more than or equal to 1:1, and preferably 1: 1-1.5: 1.
The inorganic magnesium salt is magnesium chloride or hydrate thereof, magnesium sulfate or hydrate thereof.
Preferably, the inorganic magnesium salt is added to the aqueous esomeprazole potassium solution in the form of an aqueous solution. The inorganic magnesium salt aqueous solution is prepared from inorganic magnesium salt and water according to the weight ratio of 1.5-2: 1.
Considering that the magnesium salt is easy to deteriorate and the purity of the product is influenced when the temperature is higher during the salt replacement reaction; and the lower temperature can cause the product to be separated out more quickly, the particles to be fine and the moisture content to be high, and can also influence the product yield. Therefore, the salt displacement reaction is carried out at the temperature of 35-55 ℃. Preferably, the temperature of the salt displacement reaction is 40 ℃.
The rotating speed of the stirring paddle is slow, so that large nucleation particles are facilitated; if the stirring paddle rotates at a high speed, the friction of the system is increased, the crystallization is fast, a large amount of foam is generated during the rapid stirring, and the material cannot be discharged. Therefore, the salt replacement reaction is carried out at the rotating speed of the stirring paddle of 10-45 revolutions per minute. Preferably, the stirring paddle speed is 10-15 rpm during the salt replacement reaction.
The crystallization temperature is 5-25 ℃.
The moisture content of the esomeprazole magnesium trihydrate wet product is less than or equal to 50 percent.
The temperature of the drying treatment is 40-60 ℃.
Preferably, drying the esomeprazole magnesium trihydrate wet product by adopting a pulsating vacuum dryer; the loading capacity (weight of the esomeprazole magnesium trihydrate wet product loaded by the pulse vacuum dryer per cubic meter) is 30-120 kg/m3。
Specifically, the preparation method of the esomeprazole magnesium trihydrate comprises the following steps: dissolving esomeprazole potassium in water according to the weight ratio of the esomeprazole potassium to the water of 1: 3-10, and stirring until the esomeprazole potassium is dissolved clearly; adding an inorganic magnesium salt aqueous solution at the temperature of 35-55 ℃ and the rotating speed of a stirring paddle of 10-45 revolutions per minute, carrying out a salt displacement reaction, cooling to 5-25 ℃, stirring for crystallization, and centrifuging to obtain an esomeprazole magnesium trihydrate wet product; and drying the esomeprazole magnesium trihydrate wet product by adopting a pulsating vacuum dryer to obtain an esomeprazole magnesium trihydrate dry product.
The purity of the esomeprazole magnesium trihydrate dry product is more than or equal to 99.9 percent.
Compared with the prior art, the preparation method of the esomeprazole magnesium trihydrate has the following advantages:
1. the reaction temperature, the stirring paddle speed, the solvent amount and the crystallization temperature of salt replacement are controlled, the crystal grain size of the esomeprazole magnesium trihydrate can be effectively increased, and through detection, the D90 can be increased from 3-8 microns to 60-120 microns, so that the moisture content of the esomeprazole magnesium trihydrate wet product is reduced to be less than or equal to 50% from the original 80%.
2. The pulse vacuum dryer is adopted to replace a conventional flat oven to dry the wet esomeprazole magnesium trihydrate product, so that the drying efficiency can be improved, and the product quality can be ensured. The impurities generated by the degradation of the product due to the instability of the esomeprazole magnesium trihydrate at high temperature and high humidity for a long time are reduced, the purity of the esomeprazole magnesium trihydrate is more than or equal to 99.9 percent, and the molar yield is more than or equal to 96.0 percent.
3. The pulsating vacuum dryer is adopted to replace a fluidized bed drying or double (single) cone drying oven to dry the wet product of the esomeprazole magnesium trihydrate, so that the quality problems of yellowing of the appearance of the product, fast degradation in long-term and accelerated stability tests and the like caused by overhigh steam temperature on the outer surface of the product or uneven heating due to the drying of the fluidized bed or the double (single) cone drying oven can be avoided.
4. According to the invention, by reducing the moisture content of the esomeprazole magnesium trihydrate wet product and effectively controlling the drying mode and conditions, the drying time can be reduced from 5-8 days to 7-24 hours, the manufacturing cost is greatly reduced, the working efficiency is improved, and the industrialization of the product and the market competitiveness are facilitated.
Drawings
FIG. 1 is an HPLC (related substances) spectrum of a dried esomeprazole magnesium trihydrate prepared in example 1.
FIG. 2 shows esomeprazole prepared in example 1Process for preparation of magnesium trihydrate1H NMR (hydrogen spectrum).
FIG. 3 is MS (Mass Spectrometry) of esomeprazole magnesium trihydrate prepared in example 1.
Figure 4 is an XRD (X-powder diffraction pattern) of esomeprazole magnesium trihydrate prepared in example 1.
Fig. 5 is a graph showing a distribution of particle sizes of a dried esomeprazole magnesium trihydrate prepared in example 1.
FIG. 6 is an HPLC (related substances) profile of a dried esomeprazole magnesium trihydrate prepared in example 2.
Fig. 7 is a graph showing a distribution of particle sizes of a dried esomeprazole magnesium trihydrate obtained in example 2.
FIG. 8 is an HPLC (related substances) profile of a dried esomeprazole magnesium trihydrate prepared in example 3.
FIG. 9 is an HPLC (related substances) profile of a dried esomeprazole magnesium trihydrate prepared in example 4.
FIG. 10 is an HPLC (related substances) chromatogram of a dried esomeprazole magnesium trihydrate prepared in example 5.
FIG. 11 is an HPLC (related substances) spectrum of a dried esomeprazole magnesium trihydrate prepared in comparative example 1.
FIG. 12 is an HPLC (related substances) spectrum of a dried esomeprazole magnesium trihydrate prepared in comparative example 2.
Fig. 13 is a distribution diagram of the particle size of a dried esomeprazole magnesium trihydrate prepared in comparative example 3.
FIG. 14 is an HPLC (related substances) spectrum of a dried esomeprazole magnesium trihydrate prepared in comparative example 4.
FIG. 15 is an HPLC (related substances) spectrum of a dried esomeprazole magnesium trihydrate prepared in comparative example 5.
Fig. 16 is a distribution diagram of the particle size of a dried esomeprazole magnesium trihydrate prepared in comparative example 5.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments.
Example 1
Adding 20kg of esomeprazole potassium salt and 60kg of purified water into a 200L reaction kettle, and stirring until the mixture is clear; and (3) heating the reaction system to 55 ℃, controlling the speed of a stirring paddle to be 10 r/min, dropwise adding a solution prepared from 11.6kg of magnesium chloride hexahydrate and 23.2kg of purified water, continuing stirring for 1h after dropwise adding, cooling to 25 ℃, preserving heat, stirring for 4h, and centrifuging to obtain 32.8kg of wet esomeprazole magnesium trihydrate (moisture content: 39%).
Taking 15.0kg of wet product, and adopting the volume of 0.5m3The obtained esomeprazole magnesium trihydrate is dried for 20 hours at 50 ℃ to obtain 7.6kg of a dry esomeprazole magnesium trihydrate product, a white solid is obtained, the molar yield is 98.0%, and the purity is 99.98% by HPLC (see figure 1).
1H NMR：δ8.19(1H，S)，δ7.57(1H，d)，δ7.14(1H，d)，δ6.94(1H，q)，δ5.39(2H，S)，δ4.75(2H，m)，3.82(3H，S)，3.69(3H，S)，δ2.18(3H，S)，δ2.18(3H，S)。
MS(m/z)：344.1[M-H]-，MS(m/z):346[M+H]+。
TABLE 1X-ray powder diffraction data for esomeprazole magnesium trihydrate
| 2θ | d value | Relative intensity/%) |
| 5.244 | 16.837 | 100.0 |
| 12.523 | 7.063 | 8.7 |
| 13.089 | 6.758 | 37.8 |
| 15.779 | 5.612 | 11.4 |
| 21.238 | 4.180 | 6.3 |
| 22.307 | 3.982 | 24.9 |
| 25.118 | 3.543 | 19.4 |
The particle size of the dry esomeprazole magnesium trihydrate (see figure 5) was measured using a marvensapaceae laser particle sizer Mastersizer 3000 with a D90 of 115 μm.
Example 2
Adding 40kg of esomeprazole potassium salt and 240kg of purified water into a 500L reaction kettle, and stirring until the mixture is dissolved; and (3) heating the reaction system to 35 ℃, controlling the speed of a stirring paddle to be 20 r/min, dropwise adding a solution prepared from 18.8kg of magnesium sulfate and 37.6kg of purified water, continuously stirring for 1h after dropwise adding, cooling to 10 ℃, preserving heat, stirring for 2h, and centrifuging to obtain 71.6kg of wet esomeprazole magnesium trihydrate (moisture content: 45%).
Taking 60.0kg of wet product, and adopting the volume of 0.5m3The obtained product was dried at 60 ℃ for 18 hours in a pulsed vacuum drier to obtain 32.4kg of a dried esomeprazole magnesium trihydrate, a white solid, a molar yield of 96.7%, and a purity of 99.96% by HPLC (see FIG. 6).
The particle size of the dry esomeprazole magnesium trihydrate was measured using a malverpa laser sizer 3000 (see figure 7) and D90 was 90.5 μm.
Example 3
Adding 40kg of esomeprazole potassium salt and 160kg of purified water into a 500L reaction kettle, and stirring until the mixture is clear; and (3) heating the reaction system to 35 ℃, controlling the speed of a stirring paddle to be 45 r/min, dropwise adding a solution prepared from 30.8kg of magnesium sulfate heptahydrate and 61.6kg of purified water, continuing stirring for 1h after dropwise adding, cooling to 5 ℃, preserving heat, stirring for 2h, and centrifuging to obtain 77.5kg of wet esomeprazole magnesium trihydrate (moisture content: 49%).
Taking 60.0kg of wet product, and adopting the volume of 0.5m3The obtained product was dried at 60 ℃ for 20 hours in a pulsed vacuum drier to obtain 30.08kg of a dry esomeprazole magnesium trihydrate product as a white solid with a molar yield of 97.1% and a purity of 99.90% by HPLC (see FIG. 8).
Example 4
Adding 40kg of esomeprazole potassium salt and 320kg of purified water into a 500L reaction kettle, and stirring until the mixture is clear; and (3) heating the reaction system to 40 ℃, controlling the speed of a stirring paddle to be 15 r/min, dropwise adding a solution prepared from 23.2kg of magnesium chloride hexahydrate and 46.4kg of purified water, continuing stirring for 1h after dropwise adding, cooling to 20 ℃, preserving heat, stirring for 2h, and centrifuging to obtain 67.0kg (moisture content: 41%) of an esomeprazole magnesium trihydrate wet product.
Taking 60.0kg of wet product, and adopting the volume of 0.5m3The obtained product was dried at 40 ℃ for 18 hours in a pulsed vacuum dryer to obtain 34.87kg of a dried esomeprazole magnesium trihydrate product as a white solid with a molar yield of 97.3% and a purity of 99.91% by HPLC (see FIG. 9).
Example 5
Adding 160kg of esomeprazole potassium salt and 1600kg of purified water into a 2000L reaction kettle, and stirring until the mixture is dissolved clearly; heating the reaction system to 40 ℃, controlling the speed of a stirring paddle to be 15 r/min, dropwise adding a solution prepared from 39.7kg of magnesium chloride and 79.4kg of purified water, after the dropwise adding is finished, continuously stirring for 1h, cooling to 25 ℃, preserving the temperature, stirring for 2h, and centrifuging to obtain 259.8kg of wet esomeprazole magnesium trihydrate (moisture content: 40%).
Taking 60.0kg of wet product, and adopting the volume of 0.5m3The pulse vacuum drier is dried for 18 hours at the temperature of 40 ℃ to obtain 35.61kg of a dried esomeprazole magnesium trihydrate product, a white solid, a molar yield: 96.3%, and the purity was 99.95% by HPLC (see FIG. 10).
Comparative example 1
60kg of the wet esomeprazole magnesium trihydrate product prepared in example 5 was dried in a flat oven having a volume equivalent to that of a pulse oven at 60 ℃ under reduced pressure (pressure of-0.1 Mpa) for 6 days to obtain 60.02kg of a light yellow dry esomeprazole magnesium trihydrate product having a purity of 97.97% by HPLC (see FIG. 11).
Comparative example 2
100kg of the esomeprazole magnesium trihydrate wet product prepared in example 5 was taken, and dried at 50 ℃ for 7h by using a 300kg boiling bed to obtain 51.5kg of the esomeprazole magnesium trihydrate dry product, the molar yield was 83.6%, the product was an off-white solid, and the purity was 99.11% by HPLC (see FIG. 12).
Comparative example 3
Adding 40kg of esomeprazole potassium salt and 120g of purified water into a 500L reaction kettle, and stirring until the mixture is clear; controlling the temperature of the system to be 40 ℃, controlling the speed of a stirring paddle to be 100 r/min, dropwise adding a solution prepared from 23.2kg of magnesium chloride hexahydrate and 46.4kg of purified water, keeping the temperature and stirring for 2h after dropwise adding, and observing that a large amount of foam is generated in the reaction kettle in the stirring process, and the kettle cannot discharge and centrifuge due to the fact that solids are too much and are difficult to stir. The feed liquid was flushed out with a large amount of water to give 210.5kg of a viscous wet product, which was dried at 50 ℃ for 10h using a 300kg bubbling bed to give 34.6kg of an off-white solid with a molar yield of 85.4% and a mother liquor quantitative loss of 13.7%.
Particle size detection was carried out using a Marknparaceae laser particle sizer Mastersizer 3000 (see FIG. 13) with a D90 of 3.51 μm.
Comparative example 4
Adding 20kg of esomeprazole potassium salt and 60kg of purified water into a 200L reaction kettle, and stirring until the mixture is clear; heating a reaction system to 60 ℃, controlling the speed of a stirring paddle to be 10 r/min, dropwise adding a solution prepared from 11.6kg of magnesium chloride hexahydrate and 23.2kg of purified water, after dropwise adding, continuously stirring for 1h, cooling to 25 ℃, keeping the temperature and stirring for 4h, and centrifuging to obtain 33.9kg (moisture content: 41%) of a purple esomeprazole magnesium trihydrate wet product, drying the wet product for 22h at 50 ℃ by adopting a pulse vacuum dryer, and drying to obtain 19.46kg of a dry product, wherein the molar yield is as follows: 97.3% and a purity of 98.10% by HPLC analysis (see FIG. 14).
Comparative example 5
Adding 20kg of esomeprazole potassium salt and 60kg of purified water into a 200L reaction kettle, and stirring until the mixture is clear; controlling the temperature of a reaction system at 20 ℃, controlling the speed of a stirring paddle at 10 r/min, dropwise adding a solution prepared from 11.6kg of magnesium chloride hexahydrate and 23.2kg of purified water, continuously stirring for 1h after dropwise adding, cooling to 25 ℃, preserving heat, stirring for 4h, and centrifuging to obtain 90.9kg (moisture content: 78%) of an esomeprazole magnesium trihydrate wet product; a flat oven with the volume equivalent to that of a pulse oven is adopted, and drying is carried out for 8 days at the temperature of 60 ℃ under reduced pressure (the pressure is-0.1 Mpa), so as to obtain 17.42kg of light yellow esomeprazole magnesium trihydrate dry product with the molar yield of 87.1%. HPLC assay showed the purity to be 98.24% (see fig. 15). Particle size detection was carried out using a Marknparaceae laser particle sizer Mastersizer 3000 (see FIG. 16) with a D90 of 64.4 μm.
The samples of example 5, comparative example 1 and comparative example 2 were subjected to an accelerated test (6 months) and a long-term stability test (6 months), with the following stability results:
TABLE 2 accelerated test results
TABLE 3 Long term stability test results
Claims (10)
1. A preparation method of esomeprazole magnesium trihydrate is characterized in that: the method comprises the following steps: dissolving esomeprazole potassium in water, adding an inorganic magnesium salt to perform a salt replacement reaction at the temperature of 35-55 ℃ and the rotating speed of a stirring paddle of 10-45 revolutions per minute, cooling, crystallizing, and centrifuging to obtain an esomeprazole magnesium trihydrate wet product; and drying the esomeprazole magnesium trihydrate wet product by adopting a pulse vacuum dryer or a fluidized bed to obtain an esomeprazole magnesium trihydrate dry product.
2. The process for the preparation of esomeprazole magnesium trihydrate according to claim 1, characterized in that: the weight ratio of the esomeprazole potassium to the water is 1: 3-10.
3. The process for the preparation of esomeprazole magnesium trihydrate according to claim 1, characterized in that: the molar ratio of the inorganic magnesium salt to the esomeprazole potassium is more than or equal to 1:1, and preferably 1: 1-1.5: 1.
4. A process for the preparation of esomeprazole magnesium trihydrate as claimed in claim 1 or 3, characterized in that: the inorganic magnesium salt is magnesium chloride or hydrate thereof, magnesium sulfate or hydrate thereof.
5. The process for the preparation of esomeprazole magnesium trihydrate according to claim 1, characterized in that: adding inorganic magnesium salt into the esomeprazole potassium aqueous solution in the form of aqueous solution; the inorganic magnesium salt aqueous solution is prepared from inorganic magnesium salt and water according to the weight ratio of 1.5-2: 1.
6. The process for the preparation of esomeprazole magnesium trihydrate according to claim 1, characterized in that: the temperature of the salt displacement reaction was 40 ℃.
7. The process for the preparation of esomeprazole magnesium trihydrate according to claim 1, characterized in that: and during the salt replacement reaction, the speed of the stirring paddle is 10-15 revolutions per minute.
8. The process for the preparation of esomeprazole magnesium trihydrate according to claim 1, characterized in that: the crystallization temperature is 5-25 ℃.
9. The process for the preparation of esomeprazole magnesium trihydrate according to claim 1, characterized in that: the temperature of the drying treatment is 40-60 ℃.
10. The process for the preparation of esomeprazole magnesium trihydrate according to claim 1, characterized in that: drying the esomeprazole magnesium trihydrate wet product by adopting a pulsating vacuum dryer; the loading capacity is 30-120 kg/m3。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110742089.9A CN113387929A (en) | 2021-06-30 | 2021-06-30 | Preparation method of esomeprazole magnesium trihydrate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110742089.9A CN113387929A (en) | 2021-06-30 | 2021-06-30 | Preparation method of esomeprazole magnesium trihydrate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113387929A true CN113387929A (en) | 2021-09-14 |
Family
ID=77624827
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110742089.9A Pending CN113387929A (en) | 2021-06-30 | 2021-06-30 | Preparation method of esomeprazole magnesium trihydrate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113387929A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1728997A (en) * | 2002-10-22 | 2006-02-01 | 兰贝克赛实验室有限公司 | Amorphous form of esomeprazole salts |
| CN1777598A (en) * | 2003-02-28 | 2006-05-24 | 兰贝克赛实验室有限公司 | Polymorphs of s-omeprazole. |
| CN104356114A (en) * | 2014-11-17 | 2015-02-18 | 江苏中邦制药有限公司 | Preparation method of esomeprazole magnesium trihydrate |
| CN104447699A (en) * | 2014-12-10 | 2015-03-25 | 哈药集团技术中心 | Preparation method of esomeprazole magnesium trihydrate |
| CN105418589A (en) * | 2016-01-17 | 2016-03-23 | 青岛辰达生物科技有限公司 | Preparation method of esomeprazole magnesium trihydrate for treating digestive system diseases |
-
2021
- 2021-06-30 CN CN202110742089.9A patent/CN113387929A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1728997A (en) * | 2002-10-22 | 2006-02-01 | 兰贝克赛实验室有限公司 | Amorphous form of esomeprazole salts |
| CN1777598A (en) * | 2003-02-28 | 2006-05-24 | 兰贝克赛实验室有限公司 | Polymorphs of s-omeprazole. |
| CN104356114A (en) * | 2014-11-17 | 2015-02-18 | 江苏中邦制药有限公司 | Preparation method of esomeprazole magnesium trihydrate |
| CN104447699A (en) * | 2014-12-10 | 2015-03-25 | 哈药集团技术中心 | Preparation method of esomeprazole magnesium trihydrate |
| CN105418589A (en) * | 2016-01-17 | 2016-03-23 | 青岛辰达生物科技有限公司 | Preparation method of esomeprazole magnesium trihydrate for treating digestive system diseases |
Non-Patent Citations (1)
| Title |
|---|
| 谢龙: "枸杞真空脉动干燥特性及干燥品质的研究", 《CNKI》, pages 7 - 13 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3445742B1 (en) | Crystalline tapentadol phosphate | |
| CN105384735B (en) | A kind of preparation method of thiamine mononitrate bulk crystals product | |
| JPH0643400B2 (en) | A process for the stable transformation of torasemide. | |
| JP5552422B2 (en) | Process for producing stable, amorphous calcium salt of (6S) -N (5) -methyl-5,6,7,8-tetrahydrofolic acid | |
| WO2021012722A1 (en) | Sodium 3-hydroxybutyrate product and preparation method therefor | |
| WO2016107289A1 (en) | Method for preparing sofosbuvir crystal form-6 | |
| CN104743581A (en) | Preparation technique of high-purity potassium chloride | |
| CN104356114B (en) | Preparation method of esomeprazole magnesium trihydrate | |
| CN103664881A (en) | Dabigatran etexilate of crystallized variant form B as well as preparation method thereof and application | |
| CN108611378B (en) | Continuous cooling and rapid crystallization method of calcium gluconate | |
| US8779188B2 (en) | Process for the production of L-carnitine tartrate | |
| CN113387929A (en) | Preparation method of esomeprazole magnesium trihydrate | |
| CN106565716B (en) | Idelalisib crystal form A and preparation method thereof | |
| CN104355990B (en) | Method for recycling and mechanically using L- (+) -tartaric acid in D-ethyl ester production | |
| CN110527854A (en) | Method for preparing particle size controllable ultra-pure ammonium rhenate crystal | |
| CN110559265A (en) | preparation method of acetyl L-carnitine arginine dihydrochloride moisture-proof particles | |
| CN104817557B (en) | A kind of stable crystal form of moxifloxacin hydrochloride and preparation method thereof | |
| CN112552188B (en) | Preparation method of sertraline hydrochloride crystal form I | |
| EP3272734A1 (en) | Ahu377 crystal form, preparation method and use thereof | |
| CN113861164B (en) | Crystallization preparation method of nicotine | |
| CN107698563B (en) | Method for preparing neratinib maleate crystal form | |
| CN112939876A (en) | Crystal form I of Mavacamten and preparation method thereof | |
| CN110143973A (en) | A kind of preparation process of Flomoxef Sodium | |
| CN103819487A (en) | Novel rifampin crystal form and preparing method thereof | |
| CN107337708A (en) | Pidotimod novel crystal forms and preparation method thereof |
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 |