CN107011328B - A kind of crystal form and its crystallization preparation method of compound of Lansoprazole - Google Patents
A kind of crystal form and its crystallization preparation method of compound of Lansoprazole Download PDFInfo
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- CN107011328B CN107011328B CN201710312484.7A CN201710312484A CN107011328B CN 107011328 B CN107011328 B CN 107011328B CN 201710312484 A CN201710312484 A CN 201710312484A CN 107011328 B CN107011328 B CN 107011328B
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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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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention relates to a kind of Lansoprazole crystal compound crystal form and its crystallization preparation methods.Lansoprazole crystal form appearance is rodlike.TGA is analyzed the results show that having characteristic peak at 184 DEG C ± 2 DEG C.Under stirring at room temperature, lansoprazole solid is added in dehydrated alcohol or ethyl acetate, is made into the suspension of 0.015~0.03g/ml；It is placed in ultrasonic-microwave combined system while carrying out ultrasonic and microwave treatment and be completely dissolved solid, obtain clear solution；It is 9~12 that sodium bicarbonate is added into solution and adjusts pH value；Then dissolved agent is added dropwise into solution；It is cooled to 0~5 DEG C, 5~10h of growing the grain；With petroleum ether, and obtained suspension is filtered by vacuum, obtains wet product；Final Lansoprazole crystal form product is obtained after drying；Purity is higher than 99%, and yield is higher than 90%, and average grain diameter is conducive to subsequent preparation, storage and transport at 850~900 μm；There is very big advantage in pharmaceutical preparation.
Description
Technical field
The invention belongs to medicine separation technical field, in particular to the crystal form and its crystallization system of a kind of compound of Lansoprazole
Preparation Method.
Background technique
The chemical name of Lansoprazole (lansoprazole) is 2- [[[3- methyl -4- (2,2,2- trifluoro ethoxy) -2-
Pyridyl group] methyl]-sulfinyl] -1H- benzimidazole, molecular formula C16H14F3N3O2S, molecular weight 369.36, appearance are
White crystalline powder.Structural formula such as formula (I).
Lansoprazole (lansoprazole) is the proton pump inhibitor of Japanese Wu Tian company exploitation, acts on parietal cell
H+-K+ATP enzyme prevents the H of parietal cell+It transports in stomach, thus gastric acid secretion inhibiting.Clinically it is used for gastric ulcer, reflux
The treatment of esophagitis, duodenal ulcer, Zhuo-Chinese mugwort (Zollinger-Ellison) syndrome (gastrinoma), especially to pylorus
Helicobacter plays inhibiting effect.
There are many crystal forms for Lansoprazole.European Journal of Pharmaceutical Sciences, 4 (SI),
Page 1996,182 proposes Lansoprazole A, B crystal form, and wherein B crystal form is unstable, but without providing the X-ray powder of A, B crystal form
The data of last diffraction.Lansoprazole D, E, F crystal form is proposed in CN1681802A.Lansoprazole is proposed in CN102180866A
M, N crystal form.CN102234265A, CN102558154A etc. disclose the crystal form of numerous different Lansoprazoles.
Although the prior art develops the crystal form of numerous Lansoprazoles, granularity is generally lower, and it is low to still remain stability,
The problems such as heap density is small, and mobility is bad, and there are security risks.The properties such as the mobility and stability of drug are to the subsequent of drug
Processing, transport, storage, guarantee curative effect of medication and safety, adverse drug reaction are prevented to be of great significance.And crystal
The physical property of drug is to be determined by the form of molecule in the unit cell with orientation, therefore the Lansoprazole for also needing exploitation to optimize is new
Crystal form.
Summary of the invention
The present invention discloses a kind of Lansoprazole crystal compound crystal form and its crystallization preparation method.
The X-ray powder diffraction collection of compound of Lansoprazole crystal form of the present invention 2 θ=5.2 of the angle of diffraction ±
0.2,5.5 ± 0.2,10.5 ± 0.2,11.2 ± 0.2,15.8 ± 0.2,16.8 ± 0.2,17.8 ± 0.2,18.4 ± 0.2,21.1
There is characteristic peak at ± 0.2,22.7 ± 0.2,24.8 ± 0.2,25.4 ± 0.2,27.6 ± 0.2,28.3 ± 0.2 degree, such as Fig. 1 institute
Show.
The Lansoprazole crystal form, TGA analysis are decomposition temperature the results show that it has characteristic peak at 184 DEG C ± 2 DEG C,
As shown in Figure 2.
The Lansoprazole crystal form, appearance is as shown in figure 3, be rodlike.
The preparation method of Lansoprazole crystalline compounds of the present invention: steps are as follows:
(1) under room temperature, stirring action, lansoprazole solid is added in dehydrated alcohol or ethyl acetate, is configured to
The suspension of 0.015~0.03g/ml；
(2) suspension is placed in ultrasonic-microwave combined system at the same carry out ultrasound and microwave treatment solid is completely molten
Solution, obtains clear solution；
(3) it is 9~12 that sodium bicarbonate is added into the solution after ultrasound and adjusts pH value；
(4) dissolved agent is then added dropwise into solution, dissolved agent dosage is 0.4~1.0 times of ethanol solution；
(5) it is cooled to 0~5 DEG C, 5~10h of growing the grain；
(6) petroleum ether is used, and obtained suspension is filtered by vacuum, obtains wet product；
(7) final Lansoprazole crystal form product is obtained after drying.
The method step (2) the ultrasonic-microwave time is 3~10min, and ultrasonic temperature is 30~40 DEG C, and acting frequency is
20~60KHz, 100~300W of power of ultrasonic wave；Microwave frequency is 1500~2450MHz, and the power of microwave is 200W.
In the method step (4), dissolved agent is selected from distilled water, methylene chloride, n-hexane, neopentane, isohexane, hexamethylene
The mixture of one or more of alkane, petroleum ether.
In the method step (4), the drop rate of dissolved agent be it is per minute be added dropwise dissolved agent volume 0.2%~
2.5%.
In the method step (5), the rate of temperature fall of solution is 0.05~1 DEG C/min.
In the method step (7), drying condition is dried in vacuo for 24 hours at 60~90 DEG C.
In the method, crystallization mode is ultrasound-dissolved-cooling coupling crystallization.
The product crystalline substance is practised in rodlike, by Malvern laser particle size analyzer measurement average grain diameter 850~900 μm it
Between, even particle size distribution, heap density is higher, and mobility is more preferable, is conducive to subsequent preparation, storage and transport.In pharmaceutical preparation
In occupy very big advantage.
Long-term stable experiment is carried out to this product, is 40 DEG C in temperature, relative humidity is stored under the conditions of being 75 ± 5%
Significant change does not occur for color, form, purity in 60 days, and product stability is good, and the results are shown in Table 1 for investigation.
1 Lansoprazole product stability investigation table of table
| 10 |
20 |
30 |
40 days | 50 |
60 days | |
| Character | White crystal | White crystal | White crystal | White crystal | White crystal | White crystal |
| Purity | 99.3% | 99.2% | 99.2% | 99.2% | 99.1% | 99.1% |
Present invention applicant is by repeating in patent CN1681802A in Lansoprazole crystal form D and patent CN102180866A
Lansoprazole crystal form M compares it with product of the present invention, and comparative situation is as shown in table 2.
2 the application product of table and prior art products comparison
As can be seen from Table 2, product of the present invention is different from traditional flake crystal form, and crystalline substance is practised in rodlike；Experiment is repeated through Ma Er
Literary Particle Size Analyzer measures average grain diameter between 850~900 μm, is much larger than Lansoprazole crystal form D and crystal form M；The present invention produces
Product heap density is 0.49g/cm3, 25% is improved compared with document Lansoprazole crystal form D, improves 19% compared with document crystal form M；This product is stopped
Only angle is less than Lansoprazole crystal form D and crystal form M, it is seen that mobility is more preferable, is conducive to the packaging of drug；It measures and analyzes via TGA
This product decomposition temperature is 184 ± 2 DEG C, is higher than Lansoprazole crystal form D and crystal form M, thermal stability are higher.
In addition, being investigated by hygroscopicity of the dynamic vapor sorption instrument to three kinds of crystal forms, result such as 4 institute of attached drawing is investigated
Show.The hygroscopicity of Lansoprazole crystal form D is most strong it can be seen from attached drawing 4, is higher than 20%, followed by crystal form M, is in 10-20%
Between, product of the present invention hygroscopicity is most weak, is lower than 10%, so this product is more advantageous to the subsequent storage of drug and transport.
Lansoprazole crystal form of the invention is free of any crystallization water and recrystallisation solvent, easy to operate, and energy consumption is few, and economy is high,
Experimental period is short, and the yield of this product is up to 90% or more, and product purity reaches 99% or more, stable preparation process, reproducibility
Height is conducive to extensive industrialized implementation.
Detailed description of the invention
Fig. 1: the X-ray powder diffraction figure of Lansoprazole crystal form；
Fig. 2: the TGA analysis chart of Lansoprazole crystal form；
Fig. 3: the microscope photo of Lansoprazole crystal form；
Fig. 4: Lansoprazole crystal form D, crystal form M and this product hygroscopicity investigate figure.
Specific embodiment
Embodiment 1:
(1) under room temperature, stirring action, 1.05g lansoprazole solid is added in 70ml dehydrated alcohol and forms suspension；
(2) suspension is placed in ultrasonic-microwave composite reaction system while carries out ultrasound and dissolve solid with microwave 5min, obtained
Clear solution, ultrasonic temperature are 30 DEG C, frequency 50KHz, power 150W；Solution microwave frequency 2000MHz, the power of microwave are
200W；(3) it is 10 that sodium bicarbonate is added into the solution after ultrasound and adjusts pH value；(4) with the rate of 0.3ml/min into solution
30ml distilled water is added dropwise；(5) suspension is cooled to 0 DEG C with the cooling rate of 0.1 DEG C/min, growing the grain 5h；(6) it is washed with petroleum ether
It washs, and obtained suspension is filtered by vacuum, obtain wet product；(7) products therefrom is dried for 24 hours extremely under 60 DEG C, vacuum condition
Constant weight obtains Lansoprazole crystal form product.
The X-ray powder diffraction figure of product is in 2 θ=5.18 of the angle of diffraction, and 5.50,10.49,11.16,15.77,16.74,
Have characteristic peak at 17.85,18.49,21.17,22.63,24.79,25.35,27.65,28.38 degree, TGA analysis chart without weightlessness,
It is solved in 184.3 DEG C of punishment, higher than the fusing point of traditional crystal form, there is better thermal stability.Product appearance be it is rodlike, through Malvern
Laser particle size analyzer measures D50It is 850 μm, product purity 99.2%, process yield 92.6%.
Embodiment 2:
(1) under room temperature, stirring action, 1.41g lansoprazole solid is added in 50ml dehydrated alcohol and forms suspension；
(2) suspension is placed in ultrasonic-microwave composite reaction system while carries out ultrasound and dissolve solid with microwave 5min, obtained
Clear solution, ultrasonic temperature are 40 DEG C, frequency 20KHz, power 100W；Solution microwave frequency 2450MHz, the power of microwave are
200W；(3) it is 12 that sodium bicarbonate is added into the solution after ultrasound and adjusts pH value；(4) with the rate of 0.1ml/min into solution
20ml hexamethylene is added dropwise；(5) suspension is cooled to 3 DEG C with the cooling rate of 0.05 DEG C/min, growing the grain 8h；(6) petroleum ether is used
Washing, and obtained suspension is filtered by vacuum, obtain wet product；(7) products therefrom is dried for 24 hours under 70 DEG C, vacuum condition
To constant weight, Lansoprazole crystal form product is obtained.
The X-ray powder diffraction figure of product is in 2 θ=5.17 of the angle of diffraction, and 5.50,10.47,11.15,15.77,16.72,
Have characteristic peak at 17.85,18.48,21.17,22.62,24.78,25.35,27.62,28.34 degree, TGA analysis chart without weightlessness,
It is solved in 185.1 DEG C of punishment, higher than the fusing point of traditional crystal form, there is better thermal stability.Product appearance be it is rodlike, through Malvern
Laser particle size analyzer measures D50It is 897 μm, product purity 99.1%, process yield 94.1%.
Embodiment 3:
(1) under room temperature, stirring action, 1.49g lansoprazole solid is added in 50ml ethyl acetate and forms suspension；
(2) suspension is placed in ultrasonic-microwave composite reaction system while carries out ultrasound and dissolve solid with microwave 3min, obtained
Clear solution, ultrasonic temperature are 35 DEG C, frequency 60KHz, power 300W；Solution microwave frequency 1800MHz, the power of microwave are
200W；(3) it is 9 that sodium bicarbonate is added into the solution after ultrasound and adjusts pH value；(4) with the rate of 0.1ml/min into solution
50ml dichloroethanes is added dropwise；(5) suspension is cooled to 5 DEG C with the cooling rate of 0.07 DEG C/min, growing the grain 5h；(6) petroleum is used
Ether washing, and obtained suspension is filtered by vacuum, obtain wet product；(7) products therefrom is dry under 80 DEG C, vacuum condition
For 24 hours to constant weight, Lansoprazole crystal form product is obtained.
The X-ray powder diffraction figure of product is in 2 θ=5.15 of the angle of diffraction, and 5.50,10.49,11.16,15.77,16.74,
Have characteristic peak at 17.85,18.49,21.17,22.63,24.79,25.35,27.65,28.38 degree, TGA analysis chart without weightlessness,
It is solved in 184.8 DEG C of punishment, higher than the fusing point of traditional crystal form, there is better thermal stability.Product appearance be it is rodlike, through Malvern
Laser particle size analyzer measures D50It is 854 μm, product purity 99.4%, process yield 91.6%.
Embodiment 4:
(1) under room temperature, stirring action, 1.80g lansoprazole solid is added in 60ml dehydrated alcohol and forms suspension；
(2) suspension is placed in ultrasonic-microwave composite reaction system while carries out ultrasound and dissolve solid with microwave 8min, obtained
Clear solution, ultrasonic temperature are 30 DEG C, frequency 40KHz, power 150W；Solution microwave frequency 1500MHz, the power of microwave are
200W；(3) it is 11 that sodium bicarbonate is added into the solution after ultrasound and adjusts pH value；(4) with the rate of 0.75ml/min to solution
Middle dropwise addition 30ml isohexane；(5) suspension is cooled to 0 DEG C with the cooling rate of 0.5 DEG C/min, growing the grain 10h；(6) petroleum is used
Ether washing, and obtained suspension is filtered by vacuum, obtain wet product；(7) products therefrom is dry under 70 DEG C, vacuum condition
For 24 hours to constant weight, Lansoprazole crystal form product is obtained.
The X-ray powder diffraction figure of product is in 2 θ=5.18 of the angle of diffraction, and 5.52,10.49,11.16,15.79,16.74,
Have characteristic peak at 17.85,18.49,21.18,22.65,24.79,25.36,27.66,28.39 degree, TGA analysis chart without weightlessness,
It is solved in 184 DEG C of punishment, higher than the fusing point of traditional crystal form, there is better thermal stability.Product appearance be it is rodlike, through Malvern swash
Light particle size analyzer D50It is 900 μm, product purity 99.2%, process yield 94.0%.
Embodiment 5:
(1) under room temperature, stirring action, 1.62g lansoprazole solid is added in 50ml dehydrated alcohol and forms suspension；
(2) suspension is placed in ultrasonic-microwave composite reaction system while carries out ultrasound and dissolve solid with microwave 10min, obtained
Clear solution, ultrasonic temperature are 35 DEG C, frequency 50KHz, power 150W；Solution microwave frequency 2200MHz, the power of microwave are
200W；(3) it is 10 that sodium bicarbonate is added into the solution after ultrasound and adjusts pH value；(4) with the rate of 0.05ml/min to solution
The middle mixed liquor that 10ml distilled water and 10ml petroleum ether is added dropwise；(5) suspension is cooled to 5 with the cooling rate of 1.0 DEG C/min
DEG C, growing the grain 10h；(6) petroleum ether is used, and obtained suspension is filtered by vacuum, obtains wet product；(7) products therefrom is existed
90 DEG C, dry for 24 hours to constant weight under vacuum condition, obtain Lansoprazole crystal form product.
The X-ray powder diffraction figure of product is in 2 θ=5.15 of the angle of diffraction, and 5.50,10.49,11.16,15.77,16.74,
Have characteristic peak at 17.85,18.49,21.17,22.63,24.79,25.35,27.65,28.38 degree, TGA analysis chart without weightlessness,
It is solved in 185.2 DEG C of punishment, higher than the fusing point of traditional crystal form, there is better thermal stability.Product appearance be it is rodlike, through Malvern
Laser particle size analyzer measures D50It is 851 μm, product purity 99.1%, process yield 92.6%.
The crystal form of compound of Lansoprazole and preparation method thereof that the present invention is disclosed and proposed, those skilled in the art can lead to
Reference present disclosure is crossed, the links such as appropriate feed change, technological parameter are realized.Method and product of the invention passes through preferable reality
Example is applied to be described, related technical personnel obviously can not depart from the content of present invention, in spirit and scope to described herein
Method and product is modified or appropriate changes and combinations, Lai Shixian the technology of the present invention.In particular, it should be pointed out that Suo Youxiang
Similar replacement and change is apparent to those skilled in the art, they are considered as being included in essence of the invention
In mind, range and content.
Claims (6)
1. a kind of crystal of compound of Lansoprazole, it is characterised in that the crystal is rhabdolith, and X-ray powder diffraction figure exists
2 θ=5.2 ± 0.2,5.5 ± 0.2,10.5 ± 0.2,11.2 ± 0.2,15.8 ± 0.2,16.8 ± 0.2,17.8 of the angle of diffraction ±
At 0.2,18.4 ± 0.2,21.1 ± 0.2,22.7 ± 0.2,24.8 ± 0.2,25.4 ± 0.2,27.6 ± 0.2,28.3 ± 0.2 degree
There is characteristic peak.
2. the crystal of Lansoprazole as described in claim 1, it is characterized in that TGA analysis chart is shown in 184 DEG C of ± 2 DEG C of punishment
Solution.
3. the preparation method of the crystal of compound of Lansoprazole as claimed in claim 1 or 2, it is characterized in that steps are as follows:
(1) under room temperature, stirring action, lansoprazole solid is added in dehydrated alcohol or ethyl acetate, it is configured to 0.015~
The suspension of 0.03g/ml；
(2) suspension is placed in ultrasonic-microwave combined system while carries out ultrasonic and microwave and dissolve solid, clarified
Solution；
(3) it is 9~12 that sodium bicarbonate is added into the solution after ultrasound and adjusts pH value；
(4) dissolved agent is then added dropwise into solution, dissolved agent dosage is 0.4~1.0 times of ethanol solution；
(5) it is cooled to 0~5 DEG C, 5~10h of growing the grain；
(6) petroleum ether is used, and obtained suspension is filtered by vacuum, obtains wet product；
(7) final Lansoprazole crystal form product is obtained after drying；
Dissolved agent is selected from distilled water, methylene chloride, n-hexane, neopentane, isohexane, hexamethylene, petroleum ether in the step (4)
One or more of mixture；The drop rate of dissolved agent is dropwise addition dissolved agent volume per minute in the step (4)
0.2%~2.5%.
4. preparation method as claimed in claim 3, it is characterized in that in the step (2) the ultrasonic-microwave time be 3~10min,
Ultrasonic temperature is 30~40 DEG C, and acting frequency is 20~60KHz, 100~300W of power of ultrasonic wave；Microwave frequency is 1500
~2450MHz, the power of microwave are 200W.
5. preparation method as claimed in claim 3, it is characterized in that rate of temperature fall is 0.05~1 DEG C/min in the step (5).
6. preparation method as claimed in claim 3, it is characterized in that it is 60~90 that drying condition, which is temperature, in the step (7)
DEG C, carry out for 24 hours under vacuum condition.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1681802A (en) * | 2002-03-27 | 2005-10-12 | 特瓦制药工业有限公司 | Lansoprazole polymorphs and processes for preparation thereof |
| WO2007078154A1 (en) * | 2006-01-05 | 2007-07-12 | Daewoong Pharmaceutical Co., Ltd. | Process for preparing crystalline form a of lansoprazole |
| WO2008068767A2 (en) * | 2006-12-07 | 2008-06-12 | Hetero Drugs Limited | A novel crystalline form of lansoprazole |
| CN103012369A (en) * | 2011-05-23 | 2013-04-03 | 中山大学 | Lansoprazole N crystal form and preparation method and application thereof |
| CN103772359A (en) * | 2014-01-27 | 2014-05-07 | 马魁 | Lansoprazole compound |
| WO2020078729A1 (en) * | 2018-10-18 | 2020-04-23 | Asml Netherlands B.V. | System and method for facilitating chemical mechanical polishing |
-
2017
- 2017-05-05 CN CN201710312484.7A patent/CN107011328B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1681802A (en) * | 2002-03-27 | 2005-10-12 | 特瓦制药工业有限公司 | Lansoprazole polymorphs and processes for preparation thereof |
| WO2007078154A1 (en) * | 2006-01-05 | 2007-07-12 | Daewoong Pharmaceutical Co., Ltd. | Process for preparing crystalline form a of lansoprazole |
| WO2008068767A2 (en) * | 2006-12-07 | 2008-06-12 | Hetero Drugs Limited | A novel crystalline form of lansoprazole |
| CN103012369A (en) * | 2011-05-23 | 2013-04-03 | 中山大学 | Lansoprazole N crystal form and preparation method and application thereof |
| CN103772359A (en) * | 2014-01-27 | 2014-05-07 | 马魁 | Lansoprazole compound |
| WO2020078729A1 (en) * | 2018-10-18 | 2020-04-23 | Asml Netherlands B.V. | System and method for facilitating chemical mechanical polishing |
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