CN104356114B - Preparation method of esomeprazole magnesium trihydrate - Google Patents
Preparation method of esomeprazole magnesium trihydrate Download PDFInfo
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- CN104356114B CN104356114B CN201410655014.7A CN201410655014A CN104356114B CN 104356114 B CN104356114 B CN 104356114B CN 201410655014 A CN201410655014 A CN 201410655014A CN 104356114 B CN104356114 B CN 104356114B
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- 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
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Abstract
The invention discloses a preparation method of large-granularity esomeprazole magnesium trihydrate. The preparation method comprises the following steps: dissolving esomeprazole potassium in water, adding a right amount of benign solvent, heating the solution to 35-40 DEG C, slowly adding an inorganic magnesium salt water solution for salification, heating the salification solution to 45-50 DEG C to grow the grain, slowly cooling to 5-25 DEG C to crystallize, and filtering to obtain the large-granularity esomeprazole magnesium trihydrate. The method effectively solve the problems of difficulty in filtration, long centrifuging time, difficulty in drying, long drying time, high energy consumption and the like after the esomeprazole magnesium trihydrate is salified. The esomeprazole magnesium trihydrate obtained by the method has the advantages of high crystallinity, high crystal separation speed, short drying time, low energy consumption and the like, and can easily implement industrialization.
Description
Technical field
The present invention relates to a kind of Task-size Controlling technology of crystal, and in particular to a kind of bulky grain three is hydrated esomeprazole magnesium
Preparation method.
Background technology
Three hydrations esomeprazole magnesium (Esomeprazole Magnesium), the entitled double [5- methoxyl group -2- of chemistry
((S)-((4- methoxyl group -3,5- dimethyl -2- pyridine radicals) methyl) sulfinyl) -1H- benzimidazoles] magnesium trihydrate.
Esomeprazole is to research and develop proton pump inhibitor of new generation by AstraZeneca, is global first isomer proton pump suppression
Preparation (PPI), suppresses parietal cell proton pump to reduce gastric acid secretion by specificity.Three hydration esomeprazole magnesiums are that Esso is beautiful
Draw a kind of hydrate of azoles magnesium salt.Calendar year 2001 becomes the chiral proton pump inhibitor of global first listing, and common name Esso is beautiful to be drawn
Azoles (Esomeprazole), trade name Nexium (Nexium).In recent years prostatitis of the medicine always situated in global best-selling drugs, with wide
Market prospect.Esomeprazole magnesium salt trihydrate is the pharmaceutical composition of listing, and its structural formula is as shown below：
WO94/27988 discloses sodium, magnesium, lithium, potassium, calcium and quaternary ammonium salt of esomeprazole and preparation method thereof.The patent
Crystal formation problem is not specialized in.The shortcoming of this patent under objective description.
WO04/046134 describes to crystallize Esomeprazole magnesium salt trihydrate forms II, and wherein term trihydrate is used
The crystalline material in lattice is strapped in define hydrone.WO04/089935 provide crystallization esomeprazole magnesium trihydrate,
Semihydrate and the new polymorphic of monohydrate.WO07/031845 discloses the new many of esomeprazole magnesium trihydrate
Crystal formation (G1 and G2) and preparation method thereof.The preparation method of the trihydrate described in above-mentioned patent is used in water directly
Into salt, it is poor to there is degree of crystallinity in the three water magnesium salts for obtaining, filtration difficulty, and the problems such as drying time is long, some products will even be adopted
The methods such as microwave drying could be dried.The shortcoming of above three patent under objective description.
WO98/54171 makes public for the first time the crystal formation of Esomeprazole magnesium salt, describes highly crystalline and stable Esso is beautiful
Azoles magnesium salt trihydrate is drawn, is the stable crystal form in known crystal formation.It further discloses many of Esomeprazole magnesium salt dihydrate
Crystal formation (A and B) and the method that they are prepared using esomeprazole potassium salt as intermediate.
WO2006/003163, WO2004/089935, WO2004/046134 also disclose that Esomeprazole magnesium salt and its water
Multiple crystal formations of compound.
WO04/102145 discloses II crystal formations of esomeprazole magnesium trihydrate and preparation method thereof.
WO09/099933 and WO11/012957 are individually disclosed and are prepared Esso by Esomeprazole magnesium salt trihydrate
The beautiful method for drawing azoles magnesium dihydrate B crystal form.
CN103509001A, CN103788069 disclose an a kind of Esomeprazole Sodium and dissociate through persulfuric acid for raw material,
Again with inorganic magnesium salt into salt method, but from DSC, TGA of product and XRD analysis understand the method to magnesium salts crystalise
Degree is very low, and stability is also relatively poor.
Above-mentioned patent is not furtherd investigate for the granularity problem of magnesium salt, into salt from water or in other poor solvents
The magnesium salt form for obtaining is poor, not only filters extremely difficult, and is difficult to dry, and product easily lumps when drying, the moisture of residual
And organic solvent has large effect to the quality of product.For the problem, patent CN103044400, CN102993181 is public
The method for having opened three water Esomeprazole magnesium salt recrystallization, although relatively good crystal can be obtained, but be to increase recrystallization
Step can undoubtedly increase the production cost of product, simultaneously because esomeprazole molecule easily forms the spy of hydrogen bond with polar solvent
, also there is the risk for obtaining other solvates of esomeprazole in point.
A kind of different solid forms of active constituents of medicine can have different characteristics, and can provide some advantages,
For example in terms of stability, dissolubility or bioavailability.The storage for being found to be crude drug of new solid form improves work
Property composition pharmaceutical dosage form characteristic provide may.In addition, in new solid forms crystal structure integrity, by direct shadow
Ring quality stability and the drug safety of medicine.
Content of the invention
The invention provides a kind of preparation method of three hydrations esomeprazole magnesium, the method can obtain degree of crystallinity high,
Three big hydration esomeprazole magnesiums of granularity, product are easily filtered, are easily dried, and stability is high.
A kind of preparation method of three hydrations esomeprazole magnesium, its step include：Esomeprazole potassium salt is dissolved in water
Afterwards, good solvent is added, solution is warming up to 35～40 DEG C and the aqueous solution of inorganic magnesium salt is added into salt, into the solution after salt,
45～55 DEG C are warming up to, then are cooled to 5～25 DEG C of crystallizations, be filtrated to get three hydration Esomeprazole magnesium salts of bulky grain degree；Institute
The good solvent that states is methanol, ethanol, N,N-dimethylformamide, dimethyl sulfoxide.
Described good solvent is 0.5～5 with the mass ratio of water：1.
Described inorganic magnesium salt is magnesium chloride, magnesium sulfate, Magnesium dichloride hexahydrate.
The time of the aqueous solution of Deca inorganic magnesium salt was at 1～5 hour, or Deca is conducted batch-wise, total time at 1～5 hour,
The temperature control of Deca inorganic magnesium salt aqueous solution is at 35～40 DEG C.
Rearing crystal time was controlled at 30～120 minutes.
The cooling rate of slow cooling be per 5 minutes drop 1 DEG C～per 30 minutes drop 1 DEG C.
Implement the preferred embodiments of the invention to be usually：5-20 times of esomeprazole potassium (ml/g) water that synthesis is obtained
After dissolving, appropriate good solvent is added, solution is warming up to 35～40 DEG C and the aqueous solution of inorganic magnesium salt is slow added into into salt,
Addition is finished, and is warming up to 50 ± 5 DEG C of insulation growing the grains, then slow cooling is crystallized to 5～15 DEG C, is filtered, and vacuum drying obtains big
Three hydration Esomeprazole magnesium salts of granularity.
We are had found by research, the product particle why three hydration esomeprazole magnesiums are directly obtained into salt in water
Degree is little, and solution easily bubbles, and is the reason for cause filtration difficulty, three dissolubility poles of the hydration esomeprazole magnesium in water
Low, the process into salt belongs to the outburst nucleation of crystal, and crystal does not have any growing space and time, and the crystal habit for obtaining is poor,
As can be seen that the D of product from the particle size distribution figure (Fig. 1) of final products50Only 1.51um, D75Only 2.35um, the granule of product
Very little, easily forms blocking when filtering to filter cloth or filter paper, causes to filter not thoroughly, and the moisture remained in filter cake is too high, dries
Dry difficulty, and three hydration esomeprazole magnesiums require that to drying condition strictly, hot environment can cause the degraded of product, and when long
Between expose can equally there is a possibility that in atmosphere oxidized, can only be by temperature control in relatively low scope during drying.So as to
Cause product drying time long, perishable equivalent risk.As the detached time is long, also cause the product in commercial scale
Production capacity is extremely limited.
The present invention carries out into salt using the compositionss of good solvent and poor solvent to esomeprazole, the product three for obtaining
Hydration esomeprazole degree of crystallinity is high, granularity is big, separating rate is fast, easily dry, and industrial operation low cost is suitable for industry
Scale is implemented.
Shown in the three hydration solubility curve Fig. 6 of esomeprazole magnesium in water.
By solubility curve it can be found that three hydration dissolubility of the esomeprazole magnesium in water are relatively low, essentially slightly soluble
State, if be not controlled into the process of salt to esomeprazole, then crystal does not have enough growth times when being formed
Product can be caused to separate out at a terrific speed, the Small granular product of precipitation becomes the crystal seed of the product generated in subsequent solution again,
Whole salification process is the process that a kind of crystal breaks out nucleation, and all nucleus almost do not experience nucleus growth in forming process
Process, the product for ultimately resulting in precipitation is all the crystal that there is significant drawback, and degree of crystallinity is low, and stability is poor, or even obtains two
Mixed crystal of hydrate etc..Product particle degree in solution is little, and crystal habit is poor, causes follow-up separation, drying all extremely difficult.
Three hydration solubility curves of the esomeprazole magnesium in methanol/water are as shown in Figure 7.
Three solubility curves of the hydration esomeprazole magnesium in water and methanol, ethanol, DMF or DMSO mixed solvents are as schemed
Shown in 8.
By solubility curve it can be found that by the ratio of increase good solvent in water, can effectively improve three water
Esomeprazole magnesium dissolubility in the solution is closed, by rational control device, can make product that there is dissolving in the solution
The process of crystallize, it is to avoid crystal breaks out the danger of nucleation.Product can effectively be improved using the control method in this technique
Size, obtain the more perfect product of crystal habit, from the particle size distribution figure (Fig. 2) of final products it can be seen that from
D50Never the 1.51um using control method is promoted to 19.42um, D7529.636um, product cut size are promoted to from 2.35um
Clearly, while efficiency increases when product is filtered, drying time shortens for increase.
Beneficial effect
It is an advantage of the current invention that using good solvent and poor solvent compositionss as product into salt solvent, energy
Enough allow the crystal of three hydration esomeprazole magnesiums have certain growth time when into salt, three hydrations angstrom for finally giving
Suo Meila azoles magnesium will occur with a kind of bulky grain form.
The degree of crystallinity of product is high, granularity is big, separating rate is fast, easily dry, and industrial operation low cost is suitable for industry
Scale is implemented.
Description of the drawings
The common salifying methods of Fig. 1, the particle size distribution that the three hydration esomeprazole magnesiums that Task-size Controlling technology is obtained are not used
Collection of illustrative plates (PSD).
The particle size distribution collection of illustrative plates (PSD) of the three hydration esomeprazole magnesiums that Fig. 2 is obtained according to the present invention.
The X-ray powder diffraction collection (XRPD) of the three hydration esomeprazole magnesiums that Fig. 3 is obtained according to the present invention；
The means of differential scanning calorimetry figure (DSC) of the three hydration esomeprazole magnesiums that Fig. 4 is obtained according to the present invention；
The thermogravimetric analysiss (TGA) of the three hydration esomeprazole magnesiums that Fig. 5 is obtained according to the present invention；
Fig. 6 tri- is hydrated solubility curve of the esomeprazole magnesium in water
Fig. 7 tri- is hydrated solubility curve of the esomeprazole magnesium in methanol/water
Fig. 8 tri- is hydrated solubility curve of the esomeprazole magnesium in water and methanol, ethanol, DMF or DMSO mixed solvents
Specific embodiment
The present invention is further elaborated with reference to embodiment, but these examples do not constitute any limit to the present invention
System.
Granularity：Shimadzu laser particle analyzer (paraffin oil dispersed)
XRPD：PANalytical X-ray diffractometer
DSC：Differential scanning calorimeter (prunus mume (sieb.) sieb.et zucc. Teller-support benefit)
TGA：Thermogravimetric analyzer (prunus mume (sieb.) sieb.et zucc. Teller-support benefit)
Embodiment 1
20g (0.052mol) esomeprazole potassium, 100ml water are put in reaction bulb successively, and stirring is molten clear, then to reaction
60ml methanol is added in liquid, is stirred, and reactant liquor is warming up to 35 DEG C.6.3g (0.052mol) magnesium sulfate is dissolved in
In 20g water, slowly to Deca in reactant liquor, time for adding was controlled at 2 hours, and reactant liquor is warming up to 50 DEG C by completion of dropping, was protected
Temperature stirring 1 hour, stirring is finished, and reactant liquor, has been lowered the temperature to 15 DEG C according to per 5 minutes -1 DEG C of cooling rate slow coolings
Finish, insulated and stirred 2 hours, filter, filter cake is vacuum dried to obtain three hydration esomeprazole magnesium finished product 15.2g, yield 76.4%.Grain
Degree measurement result is shown in that Fig. 1, XRPD results are shown in that Fig. 2, DSC results are shown in that Fig. 3, TGA results are shown in Fig. 4.
Embodiment 2
20g (0.052mol) esomeprazole potassium, 100ml water are put in reaction bulb successively, and stirring is molten clear, then to reaction
100ml methanol is added in liquid, is stirred, and reactant liquor is warming up to 35 DEG C.6.3g (0.052mol) magnesium sulfate is dissolved in
In 25g water, slowly to Deca in reactant liquor, time for adding was controlled at 2 hours, and reactant liquor is warming up to 45 DEG C by completion of dropping, was protected
Temperature stirring 1 hour, stirring is finished, and reactant liquor, has been lowered the temperature to 15 DEG C according to per 10 minutes -1 DEG C of cooling rate slow coolings
Finish, insulated and stirred 2 hours, filter, filter cake is vacuum dried to obtain three hydration esomeprazole magnesium finished product 16.1g, yield 80.7%.
Embodiment 3
20g (0.052mol) esomeprazole potassium, 200ml water are put in reaction bulb successively, and stirring is molten clear, then to reaction
50mlDMF is added in liquid, is stirred, and reactant liquor is warming up to 35 DEG C.Will be molten for 10.7g (0.052mol) Magnesium dichloride hexahydrate
Solution in 30g water, in being slowly added dropwise to reactant liquor in three times, each completion of dropping, insulated and stirred 30 minutes.Completion of dropping, will
Reactant liquor is warming up to 50 DEG C, insulated and stirred 1 hour, and stirring is finished, by reactant liquor according to slow per 5 minutes -1 DEG C of cooling rates
20 DEG C are cooled to, cooling is finished, insulated and stirred 2 hours is filtered, filter cake is vacuum dried to obtain three hydration esomeprazole magnesium finished products
15.7g, yield 78.7%.
Embodiment 4
20g (0.052mol) esomeprazole potassium, 300ml water are put in reaction bulb successively, and stirring is molten clear, then to reaction
120mlDMSO is added in liquid, is stirred, and reactant liquor is warming up to 40 DEG C.By 10.7g (0.052mol) Magnesium dichloride hexahydrate
It is dissolved in 30g water, in being slowly added dropwise to reactant liquor in three times, each completion of dropping, insulated and stirred 30 minutes.Completion of dropping,
Reactant liquor is warming up to 50 DEG C, insulated and stirred 120 minutes, stirring is finished, by reactant liquor according to per 5 minutes -1 DEG C of cooling rates
To 20 DEG C, cooling is finished slow cooling, insulated and stirred 2 hours, filter, filter cake be vacuum dried three hydration esomeprazole magnesiums into
Product 17.1g, yield 85.7%.
Embodiment 5
20g (0.052mol) esomeprazole potassium, 500ml water are put in reaction bulb successively, and stirring is molten clear, then to reaction
300ml methanol is added in liquid, is stirred, and reactant liquor is warming up to 40 DEG C.By 10.7g (0.052mol) Magnesium dichloride hexahydrate
It is dissolved in 30g water, in being slowly added dropwise to reactant liquor, time for adding was controlled at 1 hour, and reactant liquor is warming up to by completion of dropping
50 DEG C, insulated and stirred 60 minutes, stirring is finished, by reactant liquor according to per 5 minutes -1 DEG C of cooling rate slow coolings to 20 DEG C,
Cooling is finished, insulated and stirred 2 hours, is filtered, and filter cake is vacuum dried to obtain three hydration esomeprazole magnesium finished product 14.1g, yield
70.7%.
Claims (2)
1. a kind of three preparation method of esomeprazole magnesium is hydrated, its step includes：After esomeprazole potassium salt is dissolved in water,
Good solvent is added, and solution is warming up to 35～40 DEG C and the aqueous solution of inorganic magnesium salt is added into salt, into the solution after salt, heated up
To 45～55 DEG C, then 5～25 DEG C of crystallizations are cooled to, are filtrated to get three hydration Esomeprazole magnesium salts of bulky grain degree；Described
Good solvent is methanol, ethanol, DMF, dimethyl sulfoxide；Described good solvent with the mass ratio of water is
0.5～5: 1；The time of the aqueous solution of Deca inorganic magnesium salt was at 1～5 hour, or Deca is conducted batch-wise, and total time is little 1～5
When, the temperature control of Deca inorganic magnesium salt aqueous solution is at 35～40 DEG C；Rearing crystal time was controlled at 30～120 minutes；Slow cooling
Cooling rate be per 5 minutes drop 1 DEG C～per 30 minutes drop 1 DEG C.
2. preparation method according to claim 1, it is characterised in that：Described inorganic magnesium salt be magnesium chloride, magnesium sulfate, six
Hydrated magnesium chloride.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105936632A (en) * | 2016-05-23 | 2016-09-14 | 江苏中邦制药有限公司 | Purifying method of crude esomeprazole magnesium trihydrate |
| CN106397402B (en) * | 2016-08-30 | 2019-05-03 | 山东罗欣药业集团股份有限公司 | A kind of esomeprazole magnesium crystal-form compound and preparation method thereof |
| CN106928193B (en) * | 2017-03-09 | 2018-12-11 | 上海华源医药科技发展有限公司 | Preparation meets the method for the esomeprazole magnesium trihydrate of standards of pharmacopoeia |
| CN113387929A (en) * | 2021-06-30 | 2021-09-14 | 江苏中邦制药有限公司 | Preparation method of esomeprazole magnesium trihydrate |
| CN113278008B (en) * | 2021-07-26 | 2021-11-26 | 寿光富康制药有限公司 | Preparation method of large-particle esomeprazole magnesium trihydrate |
| CN116102538B (en) * | 2023-01-29 | 2024-10-18 | 山东省分析测试中心 | Method for preparing magnesium esomeprazole trihydrate by crystal transformation |
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| WO2004089935A1 (en) * | 2003-04-10 | 2004-10-21 | Hetero Drugs Limitd | Novel crystalline forms of s-omeprazole magnesium |
| CN103509001B (en) * | 2012-06-15 | 2016-12-21 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of esomeprazole magnesium trihydrate and preparation method thereof |
| CN102993181B (en) * | 2012-12-26 | 2014-07-23 | 山东大学 | Preparation method of esomeprazole and preparation method of esomeprazole salt |
| CN102993184A (en) * | 2013-01-08 | 2013-03-27 | 湖南方盛制药股份有限公司 | Esomeprazole and preparation method of magnesium trihydrate of esomeprazole |
| CN103664888B (en) * | 2013-12-18 | 2015-07-08 | 成都医路康医学技术服务有限公司 | Preparation method of esomeprazole trihydrate |
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Application publication date: 20150218 Assignee: Nanjing Red Sun Pharmaceutical Research Institute Co.,Ltd. Assignor: Jiangsu Zhongbang Pharmaceutical Co.,Ltd. Contract record no.: X2022980010825 Denomination of invention: A preparation method of esomeprazole magnesium trihydrate Granted publication date: 20170222 License type: Common License Record date: 20220721 |