CN106749182A - A kind of Dexlansoprazole crystal-form compound and preparation method thereof - Google Patents
A kind of Dexlansoprazole crystal-form compound and preparation method thereof Download PDFInfo
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- CN106749182A CN106749182A CN201610981744.5A CN201610981744A CN106749182A CN 106749182 A CN106749182 A CN 106749182A CN 201610981744 A CN201610981744 A CN 201610981744A CN 106749182 A CN106749182 A CN 106749182A
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- dexlansoprazole
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
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Abstract
The invention belongs to pharmaceutical technology field.Specifically, the present invention relates to Dexlansoprazole crystal-form compound.The structural formula of described Dexlansoprazole compound is as follows：Described Dexlansoprazole crystal-form compound is as shown in Figure 1 using the X ray powder diffractograms that Cu Ka radionetric surveys are obtained.The Dexlansoprazole that the present invention is provided is a kind of crystal compound different from prior art, and the crystal compound is more stablized compared with prior art, and with more preferable solubility.
Description
Technical field
The invention belongs to pharmaceutical technology field, specifically, it is related to a kind of Dexlansoprazole crystalline compounds and its system
Preparation Method.
Background technology
Lansoprazole (lansoprazole) is that second proton pump inhibitor in the world developed by Wu Tian companies is anti-bursts
Ulcer medicine.Put on market within 1992, in June, 2004 is approved listing in the U.S..Lansoprazole is by suppressing gastric mucosa parietal cell proton
Pump, and suppress H+, K+-ATP enzyme activity, prevent the H+ of parietal cell from being transported in stomach, thus constantly gastric acid inhibitory and
The secretion of pepsin.Lansoprazole has trifluoro ethoxy to replace base because importing fluorine in 4 side chains of pyridine ring, gives birth to it
Thing availability improves more than 30% compared with Omeprazole, and lipophilicity is also better than Omeprazole, therefore the product in acid condition can be fast
Fast ground is changed into sulfenic acids and sulfenic acids derivative and plays drug effect through parietal cell film, and the bacteriostatic activity to HP is improved to Aomei
Draw azoles 4 times.
Dexlansoprazole is the enantiomer of proton pump inhibitor Lansoprazole, Lan Suola of its activity apparently higher than racemization
Azoles, Lansoprazole of the toxic and side effect less than racemization.List abroad at present.Existing result shows：Dexlansoprazole
Drug effect be better than the Lansoprazole of laevo-configuration, the drug effect of raceme is essentially from Dexlansoprazole.Dexlansoprazole sodium
Chemical constitution it is as follows：
R-lansoprazole has various crystal formations, various crystal formations of Dexlansoprazole is also disclosed that in the prior art, such as
WO2000/78745 (patent families CN1150186C) discloses a kind of anhydrous crystal forms and a kind of contains 1.5 hydrates of the crystallization water
Crystal formation, CN102234265A discloses two hypocrystalline crystal types of Dexlansoprazole, and CN102875531A discloses one kind
(R)-Lansoprazole anhydrous crystal forms and preparation method thereof, CN104086532A discloses Dexlansoprazole crystal form α, crystal formation β and crystalline substance
Type γ.
The discovery of patent CN102875531B researchs, (R)-Lansoprazole is placed easily inhale in atmosphere to moisture-sensitive
Receive moisture.Crystal formation hydrate stability is poor in the prior art, easily degraded, and the anhydrous crystal forms for seeking to prepare Dexlansoprazole are
It is highly desirable to.
Patent CN1150186C (anhydrous crystal forms are referred to as A) and CN102875531B (anhydrous crystal forms are referred to as B), it is wondrous
Ground, it is found that prepared by the present invention and the third anhydrous crystal forms be obtained, referred to as crystal formation C, and it thermodynamically more stablizes than crystal formation A, and
With than the more preferable solubility of crystal formation B.
So the present invention provides new Dexlansoprazole crystal formation, it is higher than unexpectedly crystal formation B expection solubility, and with
Polymorphic A is compared and is improve thermodynamic stability.Crystal formation of the invention has improved pharmacology compared with known crystal formation A and B
Property.
The content of the invention
It is an object of the invention to provide a kind of Dexlansoprazole crystal-form compound, the stability of crystal form is high, water-soluble
To being effectively improved.
Another object of the present invention also resides in the preparation method for disclosing Dexlansoprazole crystal-form compound.
To realize the purpose of the present invention, the present invention is adopted the following technical scheme that：
A kind of Dexlansoprazole crystal-form compound shown in formula (I), wherein,
The X-ray powder diffraction spectrogram that described Dexlansoprazole crystal-form compound is obtained using Cu-K alpha ray measurements
As shown in Figure 1.
The present invention furthermore provides the preparation method of described Dexlansoprazole crystal-form compound, and the method is included such as
Lower step：
1) alcohols solvent is added to be stirred dissolving in room temperature with halogenated hydrocarbon mixed solvent Dexlansoprazole crude product；
2) after step 1) in it is molten it is clear after filtering, be cooled to -10 DEG C~10 DEG C, growing the grain 2~12 hours is obtained dextrorotation Lan Suola
Azoles crystal formation.
As preferred, step 1) described in alcohols solvent be methyl alcohol, ethanol or isopropanol.
As preferred, step 2) described in halogenated hydrocarbon solvent be dichloromethane or chloroform.
Used as preferred, the alcohols solvent is 1: 1~6 with the volume ratio of halogenated hydrocarbon solvent.
The present inventor changes method for crystallising by substantial amounts of repetition test, constantly and crystallizes bar including solvent, temperature etc.
Part, finally gives a kind of novel crystal forms of Dexlansoprazole, and the Dexlansoprazole of the novel crystal forms has preferable stability, and
Solubility in water is improved compared to the Dexlansoprazole crystal formation of prior art.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction figure of the Dexlansoprazole crystal-form compound prepared by the embodiment of the present invention 1；
Fig. 2 is the thermogravimetric analysis collection of illustrative plates of the Dexlansoprazole crystal-form compound prepared by the embodiment of the present invention 1.
Specific embodiment
The present invention can be conducted further description by the following examples, however, invention of the invention is not limited
In the following examples, these embodiments limit the scope of the present invention never in any form.Those skilled in the art is in right
It is required that in the range of done some change and adjustment also is regarded as belonging to the scope of the present invention.
The preparation of the Dexlansoprazole crystal-form compound of embodiment 1
In the 100ml four-hole boiling flasks of clean dried, input Dexlansoprazole crude product 10g, methyl alcohol 10ml, dichloromethane
10ml, is stirred at room temperature molten clear rear filtering, and filtrate is cooled to -10~-5 DEG C, has a small amount of crystal to separate out, and growing the grain 2h, filtering, wet product is put
Enter 45 DEG C of vacuum drying and obtain finished product Dexlansoprazole crystal-form compound.
Obtained Dexlansoprazole is determined with powder x-ray diffraction determination method, obtains X-ray powder diffraction collection
As shown in Figure 1.
Using Perkin-Elmer companies of U.S. PE Pyris Diamond TG thermogravimetric analyzers, thermogravimetric analysis collection of illustrative plates is such as
Shown in Fig. 2, crystal formation fusing point is 145-151 DEG C, Dexlansoprazole crystal formation zero gravity loss before degrading, using cassette moisture
Measure water content is 0.12wt%, may infer that to be Dexlansoprazole without hydrate.
The preparation of the Dexlansoprazole crystal-form compound of embodiment 2
In the 100ml four-hole boiling flasks of clean dried, input Dexlansoprazole crude product 10g, methyl alcohol 10ml, chloroform
30ml, is stirred at room temperature molten clear rear filtering, and filtrate is cooled to -10~-5 DEG C, has a small amount of crystal to separate out, growing the grain 12h, filtering, wet product
It is put into 45 DEG C of vacuum drying and obtains finished product Dexlansoprazole crystal-form compound.
According to XPRD data, gained crystal formation is consistent with crystal formation in embodiment 1.Using Perkin-Elmer companies of U.S. PE
The thermogravimetric analysis collection of illustrative plates that Pyris Diamond TG thermogravimetric analyzers are obtained is consistent with embodiment 1.
The preparation of the Dexlansoprazole crystal-form compound of embodiment 3
In the 100ml four-hole boiling flasks of clean dried, input Dexlansoprazole crude product 10g, ethanol 10ml, dichloromethane
60ml, is stirred at room temperature molten clear rear filtering, and filtrate is cooled to -5~0 DEG C, has a small amount of crystal to separate out, and growing the grain 7h, filtering, wet product is put into
45 DEG C of vacuum drying obtain finished product Dexlansoprazole crystal-form compound.
According to XPRD data, gained crystal formation is consistent with crystal formation in embodiment 1.Using Perkin-Elmer companies of U.S. PE
The thermogravimetric analysis collection of illustrative plates that Pyris Diamond TG thermogravimetric analyzers are obtained is consistent with embodiment 1.
The preparation of the Dexlansoprazole crystal-form compound of embodiment 4
In the 100ml four-hole boiling flasks of clean dried, input Dexlansoprazole crude product 10g, isopropanol 10ml, dichloromethane
Alkane 60ml, is stirred at room temperature molten clear rear filtering, and filtrate is cooled to -10~-5 DEG C, has a small amount of crystal to separate out, growing the grain 2h, filtering, wet product
It is put into 45 DEG C of vacuum drying and obtains finished product Dexlansoprazole crystal-form compound.
According to XPRD data, gained crystal formation is consistent with crystal formation in embodiment 1.Using Perkin-Elmer companies of U.S. PE
The thermogravimetric analysis collection of illustrative plates that Pyris Diamond TG thermogravimetric analyzers are obtained is consistent with embodiment 1.
Test example 1
1st, Accelerated stability test of the Dexlansoprazole crystal formation crystal formation under high temperature, high humidity, intense light conditions.
1.1 high temperature influence factors are tested：1g Dexlansoprazoles A, B, C crystal form are taken respectively, are placed in clean container, in temperature
60 DEG C of degree, places 10 days under conditions of relative humidity 75%, is sampled at 0,5,10 days respectively, observes its outward appearance, color measuring miscellaneous
Matter content, the results detailed in Table 1.
Table 1：Dexlansoprazole crystal formation high temperature influence factor experimental result
Crystal formation A：According to Dexlansoprazole crystal formation prepared by patent CN1150186C embodiments 2.
Crystal formation B：According to Dexlansoprazole crystal formation prepared by patent CN102875531B embodiments 1.
Crystal formation C：According to Dexlansoprazole crystal formation prepared by the embodiment of the present invention 1.
Result shows, after Dexlansoprazole places 10 days under the high temperature conditions, from proterties, sees dextrorotation Lan Suola in appearance
Azoles crystal formation A, B darken, Dexlansoprazole crystal formation C essentially unchangedization, from table 1, Dexlansoprazole C crystal form and its
Its Dexlansoprazole crystal formation is compared, Dexlansoprazole C crystal form place under the high temperature conditions 10 days after its impurity content it is bright
It is aobvious to be less than other Dexlansoprazole crystal formations.
1.2 high humidity influence factors are tested
1g Dexlansoprazoles A, B, C crystal form are taken respectively, and in the drier containing saturation potassium nitrate solution (25 DEG C, relatively
Humidity 92.5%) place 10 days, sampled at the 0th, 5,10 days respectively, impurity content is determined, the results are shown in Table 2.
Table 2：Dexlansoprazole crystal formation high humidity influence factor experimental result
Result shows, from table 2, Dexlansoprazole C crystal form is compared with other Dexlansoprazole crystal formations, and dextrorotation is blue
Rope draw azoles X crystal formations place under conditions of high humidity 10 days after its impurity content be significantly lower than other Dexlansoprazole crystalline forms.
1.3 high light influence factors are tested：1g Dexlansoprazoles A, B, C crystal form are taken respectively, are (4500 ± 500) in illumination
Placed in the lighting box of the fluorescent lamp of 1x 10 days, sampled at the 0th, 5,10 days respectively, the results are shown in Table 3.
Table 3：Dexlansoprazole crystal formation high light influence factor result of the test
Result shows that as shown in Table 3, Dexlansoprazole C crystal form is compared with other Dexlansoprazole crystal formations, and dextrorotation is blue
The content of its impurity is significantly lower than other Dexlansoprazole crystal formations after rope draws azoles C crystal form to place 10 days under the intense light conditions.
2nd, Dexlansoprazole stability of crystal form experiment
1g Dexlansoprazoles A, B, C crystal form are taken respectively, is placed in clean container, in 40 DEG C of temperature, relative humidity 75%
Under conditions of place 6 months, sample within the 6th month, investigate the index such as Dexlansoprazole crystal formation impurity and content, experimental result is shown in
Table 4.
Table 4：Dexlansoprazole accelerates 6 months
Note：" clear colorless is that qualified, visible foreign matters≤4 are qualified, the particulate matter of >=25um to clarity with color
≤ 600 is qualified).
Result shows：From table 4, after Dexlansoprazole A, B, 6 months Acceleration studies of C crystal form, Dexlansoprazole C
Crystal formation compared with other Dexlansoprazole crystal formations, Dexlansoprazole C crystal form proterties essentially unchangedization, clarity and color,
Visible foreign matters, particulate matter are qualified, and other Dexlansoprazole crystal formations are unqualified；Dexlansoprazole C crystal form is relevant
Material is significantly less than other Dexlansoprazole crystal formations, and content is apparently higher than other Dexlansoprazole crystal formations.
2nd, solubility test
The test example has investigated the Dexlansoprazole of Dexlansoprazole crystal-form compound of the invention and prior art
Dissolubility in water.
Solubility test method：
The solubility test of following several solvents has been done according to the Chinese Pharmacopoeia method of version two " note on the use " regulation in 2010.
Method：Weigh be ground into fine powder each sample it is appropriate (being accurate to ± 2.0%), the water of a certain amount of volume is added, 25
± 2 DEG C shook 30 seconds every 5 minutes at room temperature, and observation dissolves situation in 30 minutes, the results are shown in Table 1.
Table 5：Solubility test result
| Crystal formation species | 25 DEG C of solubility (mg/ml) |
| Dexlansoprazole crystal formation A | 1.91 |
| Dexlansoprazole crystal formation B | 2.57 |
| Dexlansoprazole crystal formation C | 28.5 |
As can be seen from the test results, the present invention compared with prior art, the obtained Dexlansoprazole crystal formation of the present invention
Dissolubility of the compound in water is higher than prior art Dexlansoprazole anhydrous crystal forms.
Claims (5)
1. a kind of Dexlansoprazole crystal-form compound, it is characterised in that the knot of described Dexlansoprazole crystal-form compound
Structure formula is as follows：
X-ray powder diffraction spectrogram such as figure that described Dexlansoprazole crystalline compounds are obtained using Cu-K alpha ray measurements
Shown in 1.
2. a kind of preparation method of the Dexlansoprazole crystal-form compound described in claim 1, it is characterised in that described system
Preparation Method comprises the following steps：
1) alcohols solvent is added to be stirred dissolving in room temperature with halogenated hydrocarbon mixed solvent Dexlansoprazole crude product；
2) after step 1) in it is molten it is clear after filtering, be cooled to -10~10 DEG C, growing the grain 2~12 hours is obtained Dexlansoprazole brilliant
Type.
3. preparation method according to claim 2, it is characterised in that step 1) described in alcohols solvent be methyl alcohol, ethanol
Or isopropanol.
4. preparation method according to claim 2, it is characterised in that step 2) described in halogenated hydrocarbon solvent be dichloromethane
Alkane or chloroform.
5. preparation method according to claim 2, it is characterised in that the volume of the alcohols solvent and halogenated hydrocarbon solvent
Than being 1:1~6.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866631A (en) * | 2017-04-06 | 2017-06-20 | 山东裕欣药业有限公司 | A kind of Dexlansoprazole crystal formation and preparation method |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1478086A (en) * | 2000-12-01 | 2004-02-25 | ����ҩƷ��ҵ��ʽ���� | Process for crystallization of(R)-or(S)-lansoprazole |
| WO2010056059A2 (en) * | 2008-11-14 | 2010-05-20 | Hanmi Pharm. Co., Ltd. | Novel crystalline dexlansoprazole and pharmaceutical composition comprising same |
| CN102399212A (en) * | 2010-08-23 | 2012-04-04 | 江苏豪森医药集团有限公司 | Dexlansoprazole crystal form and preparation method thereof |
| CN104086532A (en) * | 2014-07-21 | 2014-10-08 | 上海右手医药科技开发有限公司 | Dexlansoprazole polycrystalline type generated by alkylamine inducing as well as preparation method and pharmaceutical composition thereof |
| CN102875531B (en) * | 2011-07-15 | 2015-08-19 | 上海睿智化学研究有限公司 | A kind of (R)-lansoprazole anhydrous crystal forms and preparation method thereof |
| CN105017216A (en) * | 2014-04-16 | 2015-11-04 | 天津药物研究院 | Dexlansoprazole crystal form III and preparation method and application thereof |
| CN105017218A (en) * | 2015-07-01 | 2015-11-04 | 合肥安德生制药有限公司 | R-lansoprazole crystal form and preparation method therefor |
| CN105037327A (en) * | 2015-03-06 | 2015-11-11 | 海南海力制药有限公司 | Purifying method of dextral lansoprazole anhydrous substance |
| CN106866631A (en) * | 2017-04-06 | 2017-06-20 | 山东裕欣药业有限公司 | A kind of Dexlansoprazole crystal formation and preparation method |
-
2016
- 2016-11-08 CN CN201610981744.5A patent/CN106749182A/en active Pending
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1478086A (en) * | 2000-12-01 | 2004-02-25 | ����ҩƷ��ҵ��ʽ���� | Process for crystallization of(R)-or(S)-lansoprazole |
| WO2010056059A2 (en) * | 2008-11-14 | 2010-05-20 | Hanmi Pharm. Co., Ltd. | Novel crystalline dexlansoprazole and pharmaceutical composition comprising same |
| CN102399212A (en) * | 2010-08-23 | 2012-04-04 | 江苏豪森医药集团有限公司 | Dexlansoprazole crystal form and preparation method thereof |
| CN102875531B (en) * | 2011-07-15 | 2015-08-19 | 上海睿智化学研究有限公司 | A kind of (R)-lansoprazole anhydrous crystal forms and preparation method thereof |
| CN105017216A (en) * | 2014-04-16 | 2015-11-04 | 天津药物研究院 | Dexlansoprazole crystal form III and preparation method and application thereof |
| CN104086532A (en) * | 2014-07-21 | 2014-10-08 | 上海右手医药科技开发有限公司 | Dexlansoprazole polycrystalline type generated by alkylamine inducing as well as preparation method and pharmaceutical composition thereof |
| CN105037327A (en) * | 2015-03-06 | 2015-11-11 | 海南海力制药有限公司 | Purifying method of dextral lansoprazole anhydrous substance |
| CN105017218A (en) * | 2015-07-01 | 2015-11-04 | 合肥安德生制药有限公司 | R-lansoprazole crystal form and preparation method therefor |
| CN106866631A (en) * | 2017-04-06 | 2017-06-20 | 山东裕欣药业有限公司 | A kind of Dexlansoprazole crystal formation and preparation method |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866631A (en) * | 2017-04-06 | 2017-06-20 | 山东裕欣药业有限公司 | A kind of Dexlansoprazole crystal formation and preparation method |
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Application publication date: 20170531 |