CN102584743A - Dimethylaminopyridine repaglinide eutectic - Google Patents
Dimethylaminopyridine repaglinide eutectic Download PDFInfo
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- CN102584743A CN102584743A CN2011104465220A CN201110446522A CN102584743A CN 102584743 A CN102584743 A CN 102584743A CN 2011104465220 A CN2011104465220 A CN 2011104465220A CN 201110446522 A CN201110446522 A CN 201110446522A CN 102584743 A CN102584743 A CN 102584743A
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- repaglinide
- eutectic
- dimethylamino pyridine
- dimethylaminopyridine
- dsc
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Abstract
The invention relates to a dimethylaminopyridine repaglinide eutectic formed through combining dimethylaminopyridine with repaglinide. Under the Cu-Ka radiation, an X-ray powder diffraction spectrum expressed by an bragg angle (2 Theta) has characteristic peaks at 7.630, 8.472, 8.676, 10.238, 11.182, 11.977, 13.006, 14.765, 16.120, 16.945, 17.896, 18.326, 18.999, 21.024, 22.551, 23.659, 24.586, 28.782 and 32.831, a KBr pellet is used for determining that the obtained infrared absorption spectrum has absorption peaks at 3239, 3054, 2932, 2794, 1672, 1643, 1561, 1446, 1382, 1244, 1217, 1175, 1053, 942, 816, 769, 728, 650, 535 and 426 cm<-1>, and DSC endothermic transition is mainly conducted at a temperature of 160.0 DEG C. The powder X-ray diffraction, the DSC, the infrared spectrum and the melting point of the dimethylaminopyridine repaglinide eutectic are different from those of the reported repaglinide eutectics in the prior art, therefore, the crystalline form of the dimethylaminopyridine repaglinide eutectic is completely different from that of repaglinide in the prior art. Compared with equivalent repaglinide, the dimethylaminopyridine repaglinide eutectic has the remarkably improved dissolution rate.
Description
Technical field
The invention belongs to medical technical field, be specifically related to Dimethylamino pyridine repaglinide eutectic and preparation method thereof.
Background technology
Repaglinide; I.e. (S)-2-oxyethyl group-4 [2-[[3-methyl isophthalic acid-[2-(piperidino) phenyl]-butyl] amino-2-oxygen ethyl] phenylformic acid (Repaglinide); It is a kind of new oral antidiabetic drug with non-sulfourea insulin secretion accelerating of amino acid structure; Can promote insulin secretion apace, reduce type ii diabetes patient's glycolated hemoglobin (HbA1c) and postprandial blood sugar (PBG).Its mechanism of action is through the ATP K+ passage on the inhibition B cell film, makes the cytolemma depolarize, and calcium ion flows in cell through voltage-dependent ca channel, to promote insulin secretion.
Repaglinide is almost insoluble in water, and the medicine dissolution in vitro is poor, causes its bioavailability low.Bibliographical information can improve its dissolution rate and bioavailability through the solid-state form that changes repaglinide, improves its dissolution rate as prepare the repaglinide amorphous substance through the rapid freezing method or the precipitator method; Neha S.Desai etc. prepares inclusion compound with hydroxypropyl-beta-cyclodextrin, makes the dissolution rate of repaglinide significantly improve; Sunil K.Jain etc. are that matrix prepares the repaglinide microballoon with the Calucium Silicate powder, and its bioavailability improves 3.17 times.
Summary of the invention
The purpose of this invention is to provide a kind of to Dimethylamino pyridine repaglinide eutectic.
Of the present invention to Dimethylamino pyridine repaglinide eutectic, have following characteristic:
1, powder x-ray diffraction:
Instrument: D8Advance X-ray diffractometer (German Bruker)
Target: Cu-K α radiation
Wavelength:
Pipe is pressed: 40kV
Pipe stream: 40mA
Step-length: 0.02 °
Sweep velocity: 4 °/min
2, dsc (DSC)
Instrument: NETZSCH DSC 204 differential scanning calorimeter appearance (Germany)
Scope: 30-300 ℃
Heat-up rate: 10 ℃/minute
Dimethylamino pyridine repaglinide eutectic there is strong absorption peak at 160.0 ℃.
3, fusing point
Instrument: YRT-3 fusing point appearance (Tianjin was sent out ltd in huge day)
Fusing point to Dimethylamino pyridine repaglinide eutectic is 160-162 ℃.
4, ir spectra instrument:
Nicolet Impact 410 type IRs (U.S. Nicolet company)
Ir spectra wave number (cm to Dimethylamino pyridine repaglinide eutectic (pressing potassium bromide troche)
-1) be:
3239,3054,2932,2794,1672,1643,1561,1446,1382,1244,1217,1175,1053,942,816,769,728,650,535 and 426cm
-1
Another object of the present invention provides this method to Dimethylamino pyridine repaglinide eutectic of preparation.
A kind of method for preparing said to Dimethylamino pyridine repaglinide eutectic; It comprises repaglinide is dissolved in the ETHYLE ACETATE, adds the Dimethylamino pyridine dissolving, stirs 5-60 minute at 0-40 ℃; Obtain containing the suspension of white precipitate; Obtain white solid through suction filtration, under 10-45 ℃, volatilize ETHYLE ACETATE, obtain Dimethylamino pyridine repaglinide eutectic.
Stirring reaction carries out at 0-40 ℃ usually, and preferred temperature is 5-30 ℃.
Consumption to Dimethylamino pyridine is a 0.8-2.5 times of molar equivalent of repaglinide, preferred 1.0-2.0 times of molar equivalent.
The consumption of ETHYLE ACETATE (volume) is 50-200 a times of repaglinide consumption (weight), is preferably 50-90 doubly.
Disclosed all different with powder x-ray diffraction, DSC, ir spectra, the fusing point of each crystal formation of repaglinide of existing patent report to Dimethylamino pyridine repaglinide eutectic among the present invention, therefore said crystal habit is a kind of crystal habit that is different from the repaglinide of prior art fully.
Description of drawings
Fig. 1 is the x-ray diffractogram of powder to Dimethylamino pyridine.
Fig. 2 is the x-ray diffractogram of powder of repaglinide.
Fig. 3 is the x-ray diffractogram of powder of embodiment 1 gained to Dimethylamino pyridine repaglinide eutectic.
Fig. 4 is the DSC figure to Dimethylamino pyridine.
Fig. 5 is the DSC figure of repaglinide.
Fig. 6 is the DSC figure of embodiment 1 gained to Dimethylamino pyridine repaglinide eutectic.
Fig. 7 is the infrared spectrogram to Dimethylamino pyridine.
Fig. 8 is the infrared spectrogram of repaglinide.
Fig. 9 is the infrared spectrogram of embodiment 1 gained to Dimethylamino pyridine repaglinide eutectic.
Embodiment
Embodiment
1. dissolution determination
According to Chinese Pharmacopoeia version in 2010 two appendix XC dissolution method appendix second method (oar method); Measure repaglinide and said respectively to the dissulution of Dimethylamino pyridine repaglinide eutectic in 900ml water, phosphate buffered saline buffer (pH6.8) and 0.01mol/L hydrochloric acid; The digestion instrument rotating speed is 50 rev/mins, and temperature is 37 ℃; Respectively at sampling in 5,10,15,20,30,45,60 minutes, filter the back and use HPLC mensuration absorbancy, and relatively calculate dissulution with the repaglinide standardized solution.The result sees table 1, table 2 and table 3.
The dissulution of table 1 in water relatively
| Time (minute) | The dissulution of repaglinide (%) | To Dimethylamino pyridine repaglinide eutectic dissulution (%) |
| 5 | 0 | 88.97 |
| 10 | 0 | 93.99 |
| 15 | 0 | 95.21 |
| 20 | 0 | 95.59 |
| 30 | 0 | 96.14 |
| 45 | 0 | 96.61 |
| 60 | 0 | 98.78 |
The dissulution of table 2 in phosphate buffered saline buffer (pH6.8) relatively
| Time (minute) | The dissulution of repaglinide (%) | To Dimethylamino pyridine repaglinide eutectic dissulution (%) |
| 5 | 1.28 | 53.76 |
| 10 | 2.46 | 82.16 |
| 15 | 2.73 | 97.32 |
| 20 | 3.77 | 96.32 |
| 30 | 4.56 | 98.30 |
| 45 | 6.93 | 101.73 |
| 60 | 9.61 | 99.19 |
The dissulution of table 3 in 0.01mol/L hydrochloric acid relatively
| Time (minute) | The dissulution of repaglinide (%) | To Dimethylamino pyridine repaglinide eutectic dissulution (%) |
| 5 | 1.13 | 69.74 |
| 10 | 2.07 | 85.79 |
| 15 | 4.37 | 93.79 |
| 20 | 6.49 | 96.50 |
| 30 | 12.39 | 98.29 |
| 45 | 19.58 | 98.91 |
| 60 | 25.31 | 98.95 |
This shows, to Dimethylamino pyridine repaglinide eutectic in water, phosphate buffered saline buffer (pH6.8) and 0.01mol/L hydrochloric acid dissulution all apparently higher than the repaglinide of equivalent.
2. powder x-ray diffraction device:
D8Advance X-ray diffractometer (German Bruker)
Target: Cu-K α radiation
Wavelength:
Pipe is pressed: 40kV
Pipe stream: 40mA
Step-length: 0.02 °
Sweep velocity: 4 °/min
The result is following to the powder x-ray diffraction characteristic of Dimethylamino pyridine repaglinide eutectic:
3. dsc (DSC):
Instrument: NETZSCH DSC 204 differential scanning calorimeter appearance
Scope: 30-300 ℃
Heat-up rate: 10 ℃/minute
Dimethylamino pyridine repaglinide eutectic there is strong endotherm(ic)peak at 160.0 ℃.
4. fusing point:
Instrument: YRT-3 fusing point appearance
Fusing point to Dimethylamino pyridine repaglinide eutectic is about 160-162 ℃.
5. ir spectra:
Instrument: Nicolet Impact 410 type IRs (U.S. Nicolet company)
Ir spectra wave number to Dimethylamino pyridine repaglinide eutectic is about: 3239,3054,2932,2794,1672,1643,1561,1446,1382,1244,1217,1175,1053,942,816,769,728,650,535 and 426cm
-1
Embodiment 1: to the preparation of Dimethylamino pyridine repaglinide eutectic
The 1.000g repaglinide is added in the 52ml ETHYLE ACETATE, stir clear solution.To be added in the above-mentioned repaglinide solution Dimethylamino pyridine 0.2699g, room temperature (20 ± 5 ℃) stirring generated white precipitate in about 2 minutes again, continued to stir to make deposition fully in 20-40 minute again.With gained white suspension liquid suction filtration, the gained white solid puts in the stink cupboard that (25 ± 5 ℃) volatilize solvent about 12 hours, obtains white crystal 1.0378g.
Claims (2)
1. one kind to Dimethylamino pyridine repaglinide eutectic, it is characterized in that, be by repaglinide with Dimethylamino pyridine is combined to form, use Cu-K α radiation, following to spend the X-ray powder diffraction spectral signature that 2 θ represent:
Measure the infrared absorption spectrum obtain about 3239,3054 with the KBr compressing tablet, 2932,2794,1672,1643,1561,1446,1382,1244,1217,1175,1053,942,816,769,728,650,535 and 426cm
-1There is absorption peak at the place;
Its DSC endothermic transition is mainly about 160.0 ℃.
2. as claimed in claim 1ly Dimethylamino pyridine repaglinide eutectic is characterized in that its preparation method is that repaglinide is dissolved in the ETHYLE ACETATE; Adding is dissolved Dimethylamino pyridine; Stirred 5-60 minute at 0-40 ℃, obtain containing the suspension of white precipitate, obtain white solid through suction filtration; Under 10-45 ℃, volatilize ETHYLE ACETATE, obtain Dimethylamino pyridine repaglinide eutectic.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011104465220A CN102584743A (en) | 2011-12-28 | 2011-12-28 | Dimethylaminopyridine repaglinide eutectic |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103497178A (en) * | 2013-09-27 | 2014-01-08 | 中国药科大学 | Irbesartan and repaglinide co-amorphous substance |
| CN114315716A (en) * | 2021-11-10 | 2022-04-12 | 华南理工大学 | Hydroxychloroquine novel eutectic crystal, preparation method, content determination method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1068820A (en) * | 1991-06-21 | 1993-02-10 | 卡尔·托马有限公司 | (S) (+)-2-oxyethyl group-4-[N-[1-(2-piperidino-phenyl)-3-methyl isophthalic acid-butyl] amino carbonyl methyl] phenylformic acid, contain pharmaceutical composition of this compound and preparation method thereof |
| US5312924A (en) * | 1983-12-30 | 1994-05-17 | Dr. Karl Thomae Gmbh | Phenylacetic acid benzylamides |
| US20040102477A1 (en) * | 2002-08-23 | 2004-05-27 | Dr. Reddy's Laboratories Limited | Polymorphic forms of (S)-Repaglinide and the processes for preparation thereof |
| CN102267959A (en) * | 2011-07-06 | 2011-12-07 | 海南锦瑞制药股份有限公司 | Repaglinide crystal, preparation method thereof, and solid oral preparation containing same |
-
2011
- 2011-12-28 CN CN2011104465220A patent/CN102584743A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5312924A (en) * | 1983-12-30 | 1994-05-17 | Dr. Karl Thomae Gmbh | Phenylacetic acid benzylamides |
| CN1068820A (en) * | 1991-06-21 | 1993-02-10 | 卡尔·托马有限公司 | (S) (+)-2-oxyethyl group-4-[N-[1-(2-piperidino-phenyl)-3-methyl isophthalic acid-butyl] amino carbonyl methyl] phenylformic acid, contain pharmaceutical composition of this compound and preparation method thereof |
| US20040102477A1 (en) * | 2002-08-23 | 2004-05-27 | Dr. Reddy's Laboratories Limited | Polymorphic forms of (S)-Repaglinide and the processes for preparation thereof |
| CN102267959A (en) * | 2011-07-06 | 2011-12-07 | 海南锦瑞制药股份有限公司 | Repaglinide crystal, preparation method thereof, and solid oral preparation containing same |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103497178A (en) * | 2013-09-27 | 2014-01-08 | 中国药科大学 | Irbesartan and repaglinide co-amorphous substance |
| CN103497178B (en) * | 2013-09-27 | 2015-04-08 | 中国药科大学 | Irbesartan and repaglinide co-amorphous substance |
| CN114315716A (en) * | 2021-11-10 | 2022-04-12 | 华南理工大学 | Hydroxychloroquine novel eutectic crystal, preparation method, content determination method and application thereof |
| CN114315716B (en) * | 2021-11-10 | 2024-02-23 | 华南理工大学 | Hydroxychloroquine eutectic, preparation method thereof, content determination method and application |
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Application publication date: 20120718 |