CN104447502A - Gliclazide and carvedilol common amorphous substance - Google Patents
Gliclazide and carvedilol common amorphous substance Download PDFInfo
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- CN104447502A CN104447502A CN201510011519.4A CN201510011519A CN104447502A CN 104447502 A CN104447502 A CN 104447502A CN 201510011519 A CN201510011519 A CN 201510011519A CN 104447502 A CN104447502 A CN 104447502A
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- Prior art keywords
- gliclazide
- carvedilol
- amorphous substance
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- altogether
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a gliclazide and carvedilol common amorphous substance which has the obviously-improved solubility and dissolution rate in various buffer solutions. The common amorphous substance is in an amorphous state completely different from gliclazide and carvedilol crystals, and is different from the gliclazide and carvedilol crystals in melting point, powder X-ray diffraction spectrum, DSC spectrum and infrared spectroscopy. Cu-Kalpha radiation is adopted, and the X-ray powder diffraction spectrum shown through the degree of 2theta has no sharp diffraction peak, and only has a large diffraction ring. The glass-transition temperature is about 69.2 DEG C.
Description
Technical field
The invention belongs to medical art, be specifically related to gliclazide and be combined gliclazide carvedilol altogether amorphous substance and preparation method thereof of being formed at 1: 1 in molar ratio with carvedilol.
Background technology
Gliclazide (GL) is one of medicine of commonly using of diabetic subject, and belong to s-generation sulfonylurea oral hypoglycemic, its chemical name is 1-(3-azabicyclo [3,3,0] octyl group)-3-tolylsulfonylurea.Compared to the first-generation such as tolbutamide, P-607 sulfonylurea hypoglycemic agent, gliclazide can reduce fasting plasma glucose and postprandial blood sugar, and blood sugar reducing function is strong, and hypoglycemic effect affects by other drug and disturbs few, and side effect is lighter, less.Its hypoglycemic mechanism is mainly by promoting the Ca on pancreatic islet B cell film
2+the transhipment of passage, stimulates the secretion of Regular Insulin; Meanwhile, also by increasing hepatic vein insulin level, suppressing hepatic glycogenolytic and glyconeogenesis, causing liver to generate and exporting glucose and reducing, thus reducing blood sugar; And this product has the effect reducing platelet aggregation and adhesive power, contributes to the control of diabetic microvascular complication.But gliclazide is BCS II class medicine, in water, solvability is very poor, water-soluble hardly, medicine enters after in body, its stripping is the rate-limiting step that drug absorption plays curative effect, if when ensureing drug safety, its solubleness and stripping improved, just greatly can improve absorption and the bioavailability of gliclazide.
Carvedilol (CVD), chemical name is 1-carbazole-4-oxygen base-3-[2-(2-methoxyphenoxy) ethylamino-]-2-propyl alcohol, belongs to novel medicament for expanding vascellum.Be used for the treatment of essential hypertension, cardiac insufficiency.But CVD also belongs to BCS II class medicine, and oral administration biaavailability is extremely low, make it absorb to be improved largely by improving its solvability.We are by large quantity research, and gliclazide and carvedilol two kinds of medicines can be made a kind of amorphous substance altogether by discovery, and in this common amorphous substance, the solubleness of gliclazide and carvedilol and dissolution rate are all significantly improved.
Summary of the invention
The object of this invention is to provide a kind of gliclazide carvedilol amorphous substance altogether.
Gliclazide carvedilol of the present invention is amorphous substance altogether, has following feature:
1, powder x-ray diffraction
Instrument: XTRA/3KW X-ray diffractometer (Arl Inc. of Switzerland)
Target: Cu-K α radiation
Wavelength: 1.5406 A
Pipe pressure: 40KV
Guan Liu: 40mA
Step-length: 0.02 °
Sweep velocity: 10 °/min
Result shows: the spectrogram of gliclazide carvedilol altogether amorphous substance only has a larger diffraction ring, does not have sharp-pointed diffraction peak.
2, dsc (DSC)
Instrument: Pyris 1 DSC differential scanning calorimeter instrument (PerKinElmer, USA)
Scope :-5-300 DEG C
Heat-up rate: 10 DEG C/min
The endothermic transition of gliclazide is at 170.4 DEG C.
The endothermic transition of carvedilol is at 120.0 DEG C.
Gliclazide carvedilol is total to the glass transition of amorphous substance at 69.2 DEG C, turns crystalline substance and appears at 117.6 DEG C.
3, infrared spectra
Instrument: TENSOR 27 type infrared spectrometer (Bruker, Germany)
Gliclazide carvedilol is total to the infrared spectra wave number (cm of amorphous substance (pressing potassium bromide troche)
-1) be: 3289.9,3059.4,2945.8,2863.2,1709.8,1505.7,1454.9,1347.7,1254.9,1222.3,1127.1,1092.4,1021.0,921.4,875.6,814.7,752.9,725.2,670.5,605.5,553.6cm
-1.
Another object of the present invention is to provide prepares the method that gliclazide carvedilol is total to amorphous substance.
A kind of described gliclazide carvedilol is total to the preparation method of amorphous substance, it comprises and is dissolved in the mixed solvent of ethanol, methyl alcohol or methyl alcohol and ethanol by gliclazide and carvedilol, obtain clarified liq, reduce pressure rotary evaporation of solvent at 40-60 DEG C, vacuum-drying.
Described organic solvent preferably uses methyl alcohol.
The consumption of gliclazide lattice is 1 times of molar equivalent of carvedilol.
The temperature 40 ~ 60 DEG C of decompression rotary evaporation of solvent, preferable temperature is for being 55 DEG C.
Altogether amorphous substance is from the gliclazide crystal of existing patent report with the x-ray diffractogram of powder of carvedilol is composed, DSC collection of illustrative plates, infrared spectra are all different for the carvedilol of gliclazide disclosed in the present invention, and therefore described solid form is a kind ofly different from the gliclazide of prior art and the form of carvedilol completely.
Accompanying drawing explanation
Fig. 1 is the x-ray diffractogram of powder of gliclazide.
Fig. 2 is the x-ray diffractogram of powder of carvedilol.
Fig. 3 is the x-ray diffractogram of powder of gliclazide carvedilol crystallophy mixture.
Fig. 4 is the x-ray diffractogram of powder that gliclazide carvedilol is total to amorphous substance.
Fig. 5 is the DSC figure of gliclazide.
Fig. 6 is the DSC figure of carvedilol.
Fig. 7 is the DSC figure of gliclazide carvedilol crystallophy mixture.
Fig. 8 is the DSC figure that gliclazide carvedilol is total to amorphous substance.
Fig. 9 is the infrared spectrogram of gliclazide.
Figure 10 is the infrared spectrogram of carvedilol.
Figure 11 is the infrared spectrogram of gliclazide carvedilol crystallophy mixture.
Figure 12 is the infrared spectrogram that gliclazide carvedilol is total to amorphous substance.
Embodiment
Embodiment
1, powder x-ray diffraction
Instrument: XTRA/3KW X-ray diffractometer (Arl Inc. of Switzerland)
Target: Cu-K α radiation
Wavelength: 1.5406A
Pipe pressure: 40KV
Guan Liu: 40mA
Step-length: 0.02 °
Sweep velocity: 10 °/min
Result shows: the spectrogram of gliclazide carvedilol altogether amorphous substance only has a larger diffraction ring, does not have sharp-pointed diffraction peak.
2, dsc (DSC)
Instrument: Pyris 1 DSC differential scanning calorimeter instrument (PerKinElmer, USA)
Scope :-5-300 DEG C
Heat-up rate: 10 DEG C/min
Gliclazide carvedilol is total to the glass transition of amorphous substance at 69.2 DEG C, turns crystalline substance and appears at 117.6 DEG C.
3, infrared spectra
Instrument: TENSOR 27 type infrared spectrometer (Bruker, Germany)
The infrared spectra wave number (cm-1) of gliclazide carvedilol altogether amorphous substance (pressing potassium bromide troche) is: 3436.7,2936.9,2873.8,1734.1,1693.0,1494.2,1424.3,1330.5,1177.0,1026.4,896.9,742.4,591.9 and 521.3cm
-1.
Embodiment 1: gliclazide carvedilol is total to the preparation of amorphous substance
0.323g gliclazide and 0.406g carvedilol are added in 50ml dehydrated alcohol, room temperature (20 ± 5 DEG C) stirs to obtain settled solution, reduce pressure this settled solution at 55 DEG C rotary evaporation of solvent, and 25 DEG C of vacuum-drying 24h, obtain white powder 0.601g.
Embodiment 2: gliclazide carvedilol is total to the preparation of amorphous substance
Add in 50ml methyl alcohol by 0.323g gliclazide and 0.406g carvedilol, room temperature (20 ± 5 DEG C) stirs to obtain settled solution, and reduce pressure this settled solution at 55 DEG C rotary evaporation of solvent, and 25 DEG C of vacuum-drying 24h, obtain white powder 0.646g.
Solubility test
Measure the solubleness that gliclazide, carvedilol crystal and gliclazide carvedilol are total to amorphous substance gliclazide and carvedilol in water and various pH damping fluid respectively.Measure the medium (phosphate buffered saline buffer of water, 0.01mol/L HCl solution, pH 4.5 and pH 6.8) of 20ml respectively in cillin bottle, after adding overdose of medicine thing, cillin bottle sealing is placed in 37 DEG C of constant temperature oscillators.After jolting 24h reaches balance, get solution and cross 0.22um filter membrane, get subsequent filtrate sample introduction after appropriate dilution and record solubleness in HPLC.
High performance liquid chromatography chromatographic condition is as follows:
Instrument: Shimadzu LC-2010 AHT high performance liquid chromatograph
Chromatographic column: Inertsil ODS-SP chromatographic column (150 × 4.6mm, 5 μm)
Moving phase: acetonitrile: 0.02mol/LKH
2pO
4solution (phosphoric acid adjusts pH 4.5)=50: 50 (V/V)
Flow velocity: 1.0ml/min
Determined wavelength: 222nm
The preparation of reference substance solution: precision takes gliclazide reference substance 50mg, put in 50ml measuring bottle, and be diluted to scale with dissolve with methanol, shake up, precision measures 1ml and puts in 10ml measuring bottle, adds methanol dilution to scale, to obtain final product; Precision takes carvedilol reference substance 10mg, put in 100ml measuring bottle, and be diluted to scale with dissolve with methanol, shake up, precision measures 1ml and puts in 10ml measuring bottle, adds methanol dilution to scale, must the results are shown in Table 1.
The solubleness (μ g/ml) of table 1 sample gliclazide and carvedilol in various medium
As can be seen here, altogether the solubleness of amorphous middle gliclazide and carvedilol in various damping fluid all higher than gliclazide and carvedilol crystal, and obvious lower to the susceptibility of pH.
Dissolution determination
Gliclazide, carvedilol crystal, gliclazide carvedilol are total to amorphous substance powder and cross 100 mesh sieves respectively, take gliclazide and each 40mg of carvedilol crystal respectively, take gliclazide carvedilol amorphous substance (being equivalent to gliclazide 40mg amount) powder altogether, according to " Chinese Pharmacopoeia " version in 2010 two annex XC second method (paddle method) devices, dissolution medium is respectively the phosphate buffer soln of 900ml water, 0.01mol/ml HCL solution, pH 4.5 and pH 6.8, rotating speed 100rpm, temperature 37 DEG C.Respectively at 5,10,15,30,45,60min samples 3ml, and fluid infusion 3ml in time, 0.22 μm of filter membrane crossed by sample, carries out HPLC analysis, calculates accumulation dissolution rate.The results are shown in Table 2.
The gliclazide of table 2 sample powder 1h in various medium and the accumulation dissolution rate (%) of carvedilol
As can be seen here, in different dissolution mediums, gliclazide carvedilol is total to the accumulation dissolution rate of gliclazide and carvedilol in amorphous substance all far above gliclazide and carvedilol crystal, shows that the dissolution rate of gliclazide and carvedilol after becoming to be total to amorphous substance by gliclazide and carvedilol two kinds of crystal preparation all obtains significant raising.
Claims (3)
1. gliclazide carvedilol amorphous substance altogether, it is characterized in that, be in molar ratio by gliclazide and carvedilol be combined formed at 1: 1, use Cu-K α radiation, the X-ray powder diffraction spectrum represented to spend 2 θ only has a larger diffraction ring, does not have sharp-pointed crystalline diffraction peak; Measure with KBr compressing tablet the infrared absorption spectrum that obtains 3289.9,3059.4,2945.8,2863.2,1709.8,1505.7,1454.9,1347.7,1254.9,1222.3,1127.1,1092.4,1021.0,921.4,875.6,814.7,752.9,725.2,670.5,605.5,553.6cm
-1there is absorption peak at place; Its DSC second-order transition temperature is 69.2 DEG C.
2. gliclazide carvedilol according to claim 1 is total to the preparation method of amorphous substance, it is characterized in that, that gliclazide and carvedilol are dissolved in organic solvent according to mol ratio 1: 1, reduce pressure rotary evaporation of solvent at 40-60 DEG C, vacuum-drying, obtains gliclazide carvedilol amorphous substance altogether.
3. gliclazide carvedilol as claimed in claim 2 is total to the preparation method of amorphous substance, and it is characterized in that, described organic solvent is ethanol and methyl alcohol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510011519.4A CN104447502A (en) | 2015-01-06 | 2015-01-06 | Gliclazide and carvedilol common amorphous substance |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510011519.4A CN104447502A (en) | 2015-01-06 | 2015-01-06 | Gliclazide and carvedilol common amorphous substance |
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| Publication Number | Publication Date |
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| CN104447502A true CN104447502A (en) | 2015-03-25 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510011519.4A Pending CN104447502A (en) | 2015-01-06 | 2015-01-06 | Gliclazide and carvedilol common amorphous substance |
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| Country | Link |
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| CN (1) | CN104447502A (en) |
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2015
- 2015-01-06 CN CN201510011519.4A patent/CN104447502A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 郭慧慧等: "共无定形药物-新型单相无定形二元体系", 《化学进展》 * |
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Application publication date: 20150325 |