CN103204842A - Crystalline Ilaprazole sodium hydrate and preparation method thereof - Google Patents
Crystalline Ilaprazole sodium hydrate and preparation method thereof Download PDFInfo
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Abstract
The invention provides a crystalline Ilaprazole sodium hydrate and a preparation method thereof. An X ray powder diffraction spectrum of the crystalline Ilaprazole sodium hydrate provided by the invention includes diffraction peaks represented by the following 2 theta angles: 5.9 degrees +/- 0.1 degree, 25.4 degrees +/- 0.1 degree and 10.7 degrees +/- 0.1degree. The crystalline Ilaprazole sodium hydrate provided in the invention has high crystal purity. In addition, the method provided in the invention for preparation of the crystalline Ilaprazole sodium hydrate has the advantages of simple operation, mild reaction conditions, easy control, low production cost, definite obtaining of a target product crystal with good repeatability, less introduction of impurities, and significantly improves drug bioavailability.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of crystal type lY 81149 sodium hydrate and preparation method thereof.
Background technology
LY 81149 (Ilaprazole) structure belongs to the benzimidazole class, is the proton pump inhibitor of irreversible type.Optionally enter parietal cell after the lY 81149 oral administration, be converted into the sulphenamide active metabolite, with the sulfydryl effect on H+, the K+-ATP enzyme, form the covalent attachment of disulfide linkage, irreversible inhibition H+, K+-ATP enzyme produce the effect that gastric acid inhibitory is secreted.
First-generation PPI is because gastric acid secretion rebounds after can causing delayed gastric emptying, parietal cell swelling and tangible drug withdrawal, so clinical application has limitation.LY 81149 is overcoming some defective of original like product in varying degrees as one of proton pump inhibitor (PPI) of a new generation, can strengthen the curative effect to dyskinesis sample functional dyspepsia (GERD) and other acid-related diseases simultaneously.But the principal feature of lY 81149 comprises: 1. clinical sour effective; 2. it is rapid-action to press down the acid effect; 3. all can keep the higher sour water that presses down round the clock puts down; 4. determined curative effect, individual difference is little; 5. do not have and between the other drug and influence each other; 6. untoward reaction is few.
What adopt in the lY 81149 medicine that preparation is used at present is the sodium-salt form of lY 81149, and its chemical formula is suc as formula shown in (I):
But this stability of drug and bioavailability etc. are still waiting further raising.
Summary of the invention
Therefore, the purpose of this invention is to provide a kind of crystal type lY 81149 sodium hydrate.
Another object of the present invention provides the method for the above-mentioned crystal type lY 81149 sodium hydrate of preparation.
The objective of the invention is to be achieved through the following technical solutions.
On the one hand, the invention provides a kind of crystal type lY 81149 sodium hydrate, use Cu-K α radiation, comprise the following diffraction peak of representing with 2 θ angles in the X-ray powder diffraction collection of illustrative plates of described crystal: 5.9 ° ± 0.1 °, 25.4 ° ± 0.1 ° and 10.7 ° ± 0.1 °.
Preferably, also comprise the following diffraction peak of representing with 2 θ angles in the X-ray powder diffraction collection of illustrative plates of described crystal type lY 81149 sodium hydrate: 23.7 ° ± 0.1 °, 16.7 ° ± 0.1 °, 24.9 ° ± 0.1 ° and 15.0 ° ± 0.1 °.
Preferably, also comprise the following diffraction peak of representing with 2 θ angles in the X-ray powder diffraction collection of illustrative plates of described crystal type lY 81149 sodium hydrate: 12.1 ° ± 0.1 °, 22.9 ° ± 0.1 °, 9.8 ° ± 0.1 °, 27.1 ° ± 0.1 °, 20.0 ° ± 0.1 °, 19.0 ° ± 0.1 ° and 30.9 ° ± 0.1 °.
Preferably, the X-ray powder diffraction collection of illustrative plates of described crystal type lY 81149 sodium hydrate basically as shown in Figure 1.
Preferably, the unit cell parameters of described crystal type lY 81149 sodium hydrate is: a=16.3406 (5)
α=90 °, b=7.7394 (2)
β=115.523 (4) °, c=18.1425 (6)
γ=90 °, spacer is P2 (1)/c.
On the other hand, the invention provides a kind of method for preparing above-mentioned crystal type lY 81149 sodium hydrate, said method comprising the steps of: under the room temperature, lY 81149 is dissolved in alkaline Virahol (pH=11) makes saturated solution, carry out the diffusion of liquid liquid with 33% aqueous sodium hydroxide solution with 1: 1 volume ratio, obtain faint yellow needle-like crystal.
The invention provides the method for the above-mentioned crystal type lY 81149 sodium hydrate of another kind of preparation, said method comprising the steps of: lY 81149 sodium is dissolved in makes saturated solution in the Virahol, 20～30 ℃ are carried out liquid liquid diffusion with isopropyl ether with 1: 1 volume ratio, obtain faint yellow needle-like crystal.
The present invention also provides a kind of method for preparing above-mentioned crystal type lY 81149 sodium hydrate, said method comprising the steps of: lY 81149 sodium is dissolved in Virahol or the acetonitrile makes saturated solution, 20～30 ℃ are carried out gas-liquid diffusion with isopropyl ether, obtain faint yellow needle-like crystal.
The present invention also provides the method for the above-mentioned crystal type lY 81149 sodium hydrate of another kind of preparation, said method comprising the steps of: lY 81149 sodium is dissolved in the alkaline Virahol makes saturated solution, be heated to 40 ℃, slowly be cooled to 4 ℃ again, obtain faint yellow needle-like crystal.
The present invention also provides another to prepare the method for above-mentioned crystal type lY 81149 sodium hydrate, said method comprising the steps of: lY 81149 is joined in acetone or the Virahol make saturated solution, add 50% aqueous sodium hydroxide solution again and stir, in 4 ℃ of following crystallizations, obtain white powder.
In addition, the present invention also provides above-mentioned crystal type lY 81149 sodium hydrate for the preparation of the application in the medicine for the treatment of stomach ulcer, reflux esophagitis, duodenal ulcer.
As oral therapy, crystal type lY 81149 sodium hydrate can be prepared into enteric coated tablet or enteric coated capsule.Crystal type lY 81149 sodium hydrate can also be prepared into injection powder injection, can be used as the alternative medicine when oral therapy is inapplicable.
Crystal type lY 81149 sodium hydrate provided by the invention is a kind of more stable morphology, and crystal formation purity height has a higher bioavailability than amorphous, has better package stability.Proof by experiment, the crystal formation purity height of crystal type lY 81149 sodium hydrate provided by the invention, stable and bioavailability in animal body is higher.In addition, the method for preparing crystal type lY 81149 sodium hydrate provided by the invention is simple to operate, the reaction conditions gentleness, and control easily, low production cost, and can acquisition target product crystal formation very definite, favorable reproducibility, it is few to introduce impurity.
Description of drawings
Below, describe embodiment of the present invention by reference to the accompanying drawings in detail, wherein:
Fig. 1 is the actual measurement powder diagram of embodiment 1 prepared crystal type lY 81149 sodium hydrate.
Fig. 2 is that embodiment 1 prepared crystal type lY 81149 sodium hydrate is from the powder diagram of single crystal structure digital simulation.
Fig. 3 is the single crystal structure figure of embodiment 1 prepared crystal type lY 81149 sodium hydrate.
Fig. 4 is the structure cell accumulation graph of embodiment 1 prepared crystal type lY 81149 sodium hydrate.
Fig. 5 is differential scanning calorimeter (DSC) figure of embodiment 1 prepared crystal type lY 81149 sodium hydrate.
Fig. 6 is the infrared spectrogram of embodiment 1 prepared crystal type lY 81149 sodium hydrate.
Fig. 7 is the mass spectrum of embodiment 1 prepared crystal type lY 81149 sodium hydrate.
Fig. 8 is the Raman spectrogram of embodiment 1 prepared crystal type lY 81149 sodium hydrate.
Fig. 9 is thermogravimetric (TG) figure of embodiment 1 prepared crystal type lY 81149 sodium hydrate.
Embodiment
Followingly with reference to specific embodiment the present invention is described.It will be appreciated by those skilled in the art that these embodiment only are used for explanation the present invention, the scope that it does not limit the present invention in any way.
Following examples 1-6 provides the preparation method of crystal type lY 81149 sodium hydrate provided by the invention.
Embodiment 1
Earlier be that 33% aqueous sodium hydroxide solution places test tube lower floor with concentration, the 100mg lY 81149 is dissolved in Virahol is prepared into saturated solution, again this solution is carefully dropped to test tube upper strata (v/v 1: 1), room temperature leaves standstill carries out liquid liquid and spreads about a week, obtain faint yellow needle-like crystal 80mg, productive rate 80%.
100mg lY 81149 sodium is dissolved in 40 ℃, makes saturated solution in the alkaline Virahol of pH 11, filter, slowly be cooled to 4 ℃, obtain faint yellow needle-like crystal 86mg, productive rate 86% after 12 hours.
Embodiment 3
Under the room temperature, 100mg lY 81149 sodium is dissolved in makes saturated solution in the Virahol, place the isopropyl ether atmosphere to carry out the gas-liquid diffusion this solution under the room temperature, obtain faint yellow needle-like crystal 85mg, productive rate 85% after 24 hours.
Embodiment 4
Under the room temperature, 100mg lY 81149 sodium is dissolved in makes saturated solution in the acetonitrile, place the isopropyl ether atmosphere to carry out the gas-liquid diffusion this solution under the room temperature, obtain faint yellow needle-like crystal 84mg, productive rate 84% after 24 hours.
Under the room temperature, 100mg lY 81149 sodium is dissolved in makes saturated solution in the Virahol, this solution is placed test tube lower floor, isopropyl ether is carefully dropped to test tube upper strata (v/v, 1: 1), room temperature leaves standstill carries out liquid liquid and spreads about a week again, obtain faint yellow needle-like crystal 81mg, productive rate 81%.
Embodiment 6
Add lY 81149 10g in reaction flask, concentration is 40% sodium hydroxide solution 3g, after an amount of Virahol is prepared into the saturated solution stirring and dissolving, filters, and filtrate is filtered in 4 ℃ of low temperature crystallizatioies 12 hours, obtains white powdery solid 10.7g, productive rate 92.5%.
Embodiment 7
Present embodiment is measured and characterized embodiment 1 prepared crystal type lY 81149 sodium hydrate, and is specific as follows.
Adopt Bruker D8Advance diffractometer to measure the X-ray powder diffraction figure of crystal type lY 81149 sodium hydrate, condition determination is as follows: Cu K α, 40kV, 40mV is light source, 0.018 ° of step-length, sweep velocity 4o/min, 5～35 ° of sweep limits, room temperature, in X-ray powder diffraction figure, there is diffraction peak at 2 θ angle of diffraction places below it: 5.986,9.815,10.784,12.181,15.077,16.524,16.725,19.002,20.042,22.829,22.95,23.591,23.739,23.764,24.942,25.432,27.108,30.904 powder diagram as shown in Figure 1.Per-cent I with spacing d, Bragg angle (2 θ) and relative intensity expresses, and is as follows:
In addition, use the Oxford Gemini S Ultra single crystal diffractometer that has graphite monochromator under 150 (2) K, to measure the crystalline structure of crystal type lY 81149 sodium hydrate.With Cu K alpha-ray (1.54178
), collect data with ω/2 θ scan modes.The reduction of data and absorption correction use Rigaku RAPID AUTO (Rigaku, 1998, Ver2.30) routine package.Spacer is definite according to the delustring rule of system, and by the refine result verification.All crystalline structure all use the SHELXS-97 program, are solved by direct method, and with complete matrix least-squares refinement structure, the hydrogen atom coordinate is added by Theoretical Calculation with the SHELXL-97 program.Its crystallographic parameter is as shown in the table:
*R
1＝∑||F
o|-|F
c||/∑|F
o|，wR
2＝[∑w(F
o 2-F
c 2)
2/∑w(F
o 2)
2]
1/2，w＝[σ
2(F
o)
2+(0.1(max(0，F
o 2)+2F
c 2)/3)
2]
-1
According to the powder diagram of single crystal structure digital simulation crystal type lY 81149 sodium hydrate as shown in Figure 2, overlap with the peak of the powder diagram (see figure 1) of surveying prepared crystal type lY 81149 sodium hydrate, prove that the crystal type lY 81149 sodium hydrate of preparation is pure single crystal form.
The single crystal structure figure of crystal type lY 81149 sodium hydrate as shown in Figure 3.The structure cell accumulation graph of crystal type lY 81149 sodium hydrate is seen Fig. 4.
The differential scanning calorimeter figure (DSC) of crystal type lY 81149 sodium hydrate as shown in Figure 5.The infrared spectrogram of crystal type lY 81149 sodium hydrate is that 3454,3136,3098,3057,3018,2972,2942,2841,1905,1649,1613,1584,1497,1408,1437,1384,1331,1296,1277,1255,1218,1157,1133,1099,1075,1017,981,958,896,858,815,777,721,696,628,613,531,476,441 places have absorption peak in wave number as shown in Figure 6.
The mass spectrum of crystal type lY 81149 sodium hydrate as shown in Figure 7, m/z=389 is molecular ion peak.The Raman spectrogram of crystal type lY 81149 sodium hydrate as shown in Figure 8.
Crystal type lY 81149 sodium hydrate thermogravimetric (TG) figure as shown in Figure 9, thermal multigraph weightlessness between room temperature to 120 ℃ is 8.5%, and is consistent with the calculating that loses two water moleculess weightless 8.4%, shows and contain two water moleculess in the crystal type lY 81149 sodium hydrate.Thermal multigraph does not have weightlessness at 120 ℃ to about 210 ℃, show that the crystal type lY 81149 sodium after the dehydration can be stabilized to more than 200 ℃.
In addition, after testing, the crystalline structure of embodiment 2～5 preparation crystal type lY 81149 sodium hydrates is identical with the crystalline structure of embodiment 1 preparation crystal type lY 81149 sodium hydrate, and the x ray powder diffraction of embodiment 6 preparation crystal type lY 81149 sodium hydrates is consistent with the x ray powder diffraction of embodiment 1.As seen, the inventive method repeated fine can obtain stable crystal type lY 81149 sodium hydrate.
Embodiment 8
Present embodiment has been investigated the bioavailability of crystal type lY 81149 sodium ethylate by pharmacokinetic.
Trial drug: lY 81149, crystal type lY 81149 sodium hydrate are made enteric coated capsule respectively.
Experimental animal: Beagle dog.
Dosage and mode: dosage is respectively 10mg, after the animal fasting morning oral administration, clean a week back at every turn and intersect administration.
Sample collecting: get blood by the dog forelimb respectively at different time (0.5,0.75,1,1.33,1.67,2,2.5,3,4,6,8,12,24h) before the animals administer and after the administration, get the about 2ml of blood at every turn, add and use in advance in the centrifuge tube of anticoagulant heparin, be put at once after the blood specimen collection in the insulating foam box that is built-in with ice bag and left standstill 20 minutes, the 3000rpm low-temperature centrifugation is separated plasma after 10 minutes,-40 ℃ of preservations, to be checked.
The pretreatment: thaw under the plasma sample room temperature, the blood plasma of getting 0.2ml joins in the 1.5ml centrifuge tube, add 100 μ L 50mM ammonium formate solution again, mark liquid in the omeprazole of 50mL 280ng/ml, vortex mixed 30s adds the t-butyl methyl ether of 0.6ml again, vortex concussion 2 minutes, behind centrifugal (13,000 rev/mins) 10min, get 30 ℃ of heating in water bath N of supernatant liquor
2Volatilize, residue dissolves with 200 μ l moving phases, gets 10 μ l and carries out the LC/MS/MS analysis, the record color atlas.
Pharmacokinetics the results are shown in Table 1 and table 2.By table 1 and table 2 as seen, the Plasma Concentration of crystal type lY 81149 sodium hydrate is significantly higher than the Plasma Concentration of the lY 81149 of contrast non-crystalline type, shows that crystal type lY 81149 sodium hydrate makes effective constituent bioavailability in vivo be significantly improved.
Claims (10)
1. crystal type lY 81149 sodium hydrate, it is characterized in that, use Cu-K α radiation, comprise the following diffraction peak of representing with 2 θ angles in the X-ray powder diffraction collection of illustrative plates of described crystal type lY 81149 sodium hydrate: 5.9 ° ± 0.1 °, 25.4 ° ± 0.1 ° and 10.7 ° ± 0.1 °.
2. crystal type lY 81149 sodium hydrate according to claim 1, it is characterized in that, also comprise the following diffraction peak of representing with 2 θ angles in the X-ray powder diffraction collection of illustrative plates of described crystal type lY 81149 sodium hydrate: 23.7 ° ± 0.1 °, 16.7 ° ± 0.1 °, 24.9 ° ± 0.1 ° and 15.0 ° ± 0.1 °; Preferably, also comprise the following diffraction peak of representing with 2 θ angles in the X-ray powder diffraction collection of illustrative plates of described crystal type lY 81149 sodium hydrate: 12.1 ° ± 0.1 °, 22.9 ° ± 0.1 °, 9.8 ° ± 0.1 °, 27.1 ° ± 0.1 °, 20.0 ° ± 0.1 °, 19.0 ° ± 0.1 ° and 30.9 ° ± 0.1 °.
3. crystal type lY 81149 sodium hydrate according to claim 1 and 2 is characterized in that, the X-ray powder diffraction collection of illustrative plates of described crystal type lY 81149 sodium hydrate basically as shown in Figure 1.
4. according to each described crystal type lY 81149 sodium hydrate in the claim 1 to 3, it is characterized in that the unit cell parameters of described crystal type lY 81149 sodium hydrate is: a=16.3406 (5)
α=90 °, b=7.7394 (2)
β=115.523 (4) °, c=18.1425 (6)
γ=90 °, spacer is P2 (1)/c.
5. a method for preparing each described crystal type lY 81149 sodium hydrate in the claim 1 to 4 is characterized in that, said method comprising the steps of:
LY 81149 is dissolved in the alkaline Virahol makes saturated solution, carry out the diffusion of liquid liquid with 33% aqueous sodium hydroxide solution with 1: 1 volume ratio, obtain faint yellow needle-like crystal.
6. a method for preparing each described crystal type lY 81149 sodium hydrate in the claim 1 to 4 is characterized in that, said method comprising the steps of:
LY 81149 sodium is dissolved in makes saturated solution in the Virahol, carry out the diffusion of liquid liquid with isopropyl ether with 1: 1 volume ratio under the normal temperature, obtain faint yellow needle-like crystal.
7. a method for preparing each described crystal type lY 81149 sodium hydrate in the claim 1 to 4 is characterized in that, said method comprising the steps of:
LY 81149 sodium is dissolved in Virahol or the acetonitrile makes saturated solution, carry out the gas-liquid diffusion with isopropyl ether under 20～30 ℃, obtain faint yellow needle-like crystal.
8. a method for preparing each described crystal type lY 81149 sodium hydrate in the claim 1 to 4 is characterized in that, said method comprising the steps of:
LY 81149 sodium is dissolved in the alkaline Virahol makes saturated solution, be heated to 40 ℃, slowly be cooled to 4 ℃ again, obtain faint yellow needle-like crystal.
9. a method for preparing each described crystal type lY 81149 sodium hydrate in the claim 1 to 4 is characterized in that, said method comprising the steps of:
LY 81149 is joined in acetone or the Virahol, add aqueous sodium hydroxide solution again and stir, in 4 ℃ of following crystallizations, obtain white powder.
In the claim 1 to 4 each described crystal type lY 81149 sodium hydrate for the preparation of the application in the medicine for the treatment of stomach ulcer, reflux esophagitis, duodenal ulcer.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105055342A (en) * | 2015-08-13 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Sodium ilaprazole medicine composition freeze-dried powder injection for treating peptic ulcer |
| CN105055343A (en) * | 2015-08-31 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Ilaprazole sodium composition freeze-dried powder injection serving as medicine for treating stomach diseases |
| CN105461692A (en) * | 2014-09-04 | 2016-04-06 | 江苏奥赛康药业股份有限公司 | Ilaprazole sodium compound and pharmaceutical composition thereof |
| CN107857756A (en) * | 2017-11-06 | 2018-03-30 | 丽珠医药集团股份有限公司 | A kind of Magnesium 2-((4-methoxy-3-methylpyridin-2-yl)methylsulfinyl)-5-(1H-pyrrol-1-yl)benzo[d crystal formation and preparation method thereof |
| CN109305958A (en) * | 2017-07-28 | 2019-02-05 | 扬子江药业集团有限公司 | A kind of preparation method of high-purity Ilaprazole Sodium dihydrate |
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| CN101687849A (en) * | 2006-12-29 | 2010-03-31 | 一洋药品株式会社 | The crystalline form of solvated ilaprazole |
| WO2011071314A2 (en) * | 2009-12-08 | 2011-06-16 | Il-Yang Pharm. Co., Ltd. | Processes for preparing crystalline forms a and b of ilaprazole and process for converting the crystalline forms |
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2012
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101687849A (en) * | 2006-12-29 | 2010-03-31 | 一洋药品株式会社 | The crystalline form of solvated ilaprazole |
| WO2011071314A2 (en) * | 2009-12-08 | 2011-06-16 | Il-Yang Pharm. Co., Ltd. | Processes for preparing crystalline forms a and b of ilaprazole and process for converting the crystalline forms |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105461692A (en) * | 2014-09-04 | 2016-04-06 | 江苏奥赛康药业股份有限公司 | Ilaprazole sodium compound and pharmaceutical composition thereof |
| CN105055342A (en) * | 2015-08-13 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Sodium ilaprazole medicine composition freeze-dried powder injection for treating peptic ulcer |
| CN105055343A (en) * | 2015-08-31 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Ilaprazole sodium composition freeze-dried powder injection serving as medicine for treating stomach diseases |
| CN109305958A (en) * | 2017-07-28 | 2019-02-05 | 扬子江药业集团有限公司 | A kind of preparation method of high-purity Ilaprazole Sodium dihydrate |
| CN109305958B (en) * | 2017-07-28 | 2021-11-09 | 扬子江药业集团有限公司 | Preparation method of high-purity ilaprazole sodium dihydrate |
| CN107857756A (en) * | 2017-11-06 | 2018-03-30 | 丽珠医药集团股份有限公司 | A kind of Magnesium 2-((4-methoxy-3-methylpyridin-2-yl)methylsulfinyl)-5-(1H-pyrrol-1-yl)benzo[d crystal formation and preparation method thereof |
| CN115403560A (en) * | 2017-11-06 | 2022-11-29 | 丽珠医药集团股份有限公司 | Ilaprazole magnesium crystal form and preparation method thereof |
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