CN106699631A - Glimepiride gamma crystal form and preparation method thereof - Google Patents
Glimepiride gamma crystal form and preparation method thereof Download PDFInfo
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- CN106699631A CN106699631A CN201710068924.9A CN201710068924A CN106699631A CN 106699631 A CN106699631 A CN 106699631A CN 201710068924 A CN201710068924 A CN 201710068924A CN 106699631 A CN106699631 A CN 106699631A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/38—2-Pyrrolones
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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 relates to a glimepiride gamma crystal form. The preparation method comprises the following steps: dissolving a glimepiride crystal form in isopropanol at 60-75 DEG C; crystallizing at -80-0 DEG C for 12-48 hours; and filtering to obtain a solid which is the glimepiride gamma crystal form. The glimepiride gamma crystal form disclosed by the invention has different powder X-ray diffraction and differential scanning spectra from the glimepiride crystal forms in the existing documents, and therefore, the solid state is a crystal form state which is completely different from the existing glimepiride.
Description
[technical field]
The invention belongs to field of medicaments, and in particular to a kind of Glimepiride γ crystal formations and preparation method thereof.
[background technology]
In recent years, with the development and the raising of Living consumption of countries in the world social economy, the incidence of disease of diabetes
And illness rate is raised year by year, as the Social Events for threatening people's health.
According to the suggestion of the World Health Organization (WHO) and IDF (IDF) expert group, diabetes can be divided into 1
4 kinds of type, 2 types, other specific types and gestational diabetes mellitus.Glimepiride is used as a kind of new sulfonylurea hypoglycemic agent thing
In the treatment of diabetes B, its site of action is not quite similar with first and second generation sulfonylurea, mainly with pancreas islet gamma cells film on
The 65ku subunits of sulfonylurea receptor are combined and play a role.Foreign study finds that it has and makees the outer hypoglycemic of strong pancreas
With, including increase insulin sensitivity and simulation periphery insulin action, improve the indexing/go of glucose transporter (GLUT-4)
Phosphorylation, increases intake of the glucose in peripheral tissues.In all of sulfonylureas, the plasma insulin of Glimepiride
It is minimum to raise with blood sugar reduction ratio.
Its chemical entitled 1- [4- [2- (3- ethyl -4- methyl -2- oxo -3- pyrrolin -1- formamidos)-ethyl]-benzene
Sulphonyl] -3- (trans -4- methylcyclohexyls)-urea
Chemical constitution：
Molecular formula：C24H34N4O5S
Molecular weight：490.619
Glimepiride is tasteless, white or ivory buff crystalline powder, is dissolved in 1-METHYLPYRROLIDONE, dimethyl sulfoxide (DMSO),
Dichloromethane, tetrahydrofuran are slightly soluble in, EGME, Isosorbide-5-Nitrae-dioxane, 1,2- dichloroethanes is slightly soluble in, it is atomic to be dissolved in second
Alcohol, isopropanol, water insoluble, normal heptane, methyl tertiary butyl ether(MTBE) are the class medicines of BCS II, and its poor solubility and dissolution rate are low
It is the main cause for causing bioavilability low.
Glimepiride has unformed and crystal formation I, crystal formation II, and crystal formation I is relatively stable crystal formation, for treating glycosuria
Disease, in M.Iwata, H.Nagase, T.Endo, H.Ueda.Glimepiride [J] Acta Cryst. (1997) .1997,53
(3):Mistake disclosed in 329-331, the fusing point of crystal formation I is at 207 DEG C；Crystal formation II in T.Endo, M.Iwata, H.Nagase,
H.Ueda.Polymorphism of glimepiride:Crystallographic study,thermal transitions
behavior and dissolution study[J].S.T.P.Pharma Sci.,2003,13(4):Disclosed in 281-286
Cross, crystal formation II is changed into crystal formation I in heating process, differential scanning calorimetric curve (DSC) is shown as having exothermic peak at 104 DEG C.
Research purpose of the invention is started with from the research of Glimepiride crystal formation, biological living by crystal formation triage techniques, crystal formation
Property assessment technique, in identical active principle different crystal forms state aspect find, find, exploitation Glimepiride advantage crystal formation thing
Matter state, to apply for that country or the intellectual property invention patent protection of the world provide science from the basis of Glimepiride crystal-form substances
Data.
The present invention is successfully prepared a kind of Glimepiride γ crystal formations, it is found that the crystal formation has the Glimepiride than document report
The relatively stable more preferable solubility characteristics of crystal formation I, the characteristic is suitable to medical research and development, and its preparation method is simple to operation.
[content of the invention]
The purpose of the present invention is to prepare a kind of Glimepiride γ crystal formations, Glimepiride of its solubility compared with document report
Compared with stable crystal form I, it is significantly improved.
Glimepiride γ crystal formations have following characteristics：
1st, powder x-ray diffraction
Instrument：Sharp shadow X-ray diffractometer (Dutch PANalytical)
Target：Cu-K α are radiated
Wavelength：
X-ray light tube voltage：45kV
X-ray light pipe fulgurite stream：40mA
Step-length：0.01313°
Sweep speed：0.041683°/s
Sweep limits：5°-40°
Result shows：9.7294 °, 10.0331 °, 10.6670 °, 12.9949 °, 13.4081 °, 17.8538 °,
There is characteristic peak at 19.5368 °.
2nd, differential scanning calorimetry (DSC)
Instrument：DSC Q2000 differential scanning calorimeters (U.S., TA instruments)
Temperature range：25℃-225℃
Programming rate：10℃/min
Result shows：Glimepiride γ crystal formations are respectively in 57.52 DEG C, 61.53 DEG C, 201.05 DEG C of (onset
Temperature) there is endothermic peak.
3rd, thermogravimetry (TGA)
Instrument：TGA Q500 thermogravimetric analyzers (U.S., TA instruments)
Temperature range：30℃-400℃
Programming rate：10℃/min
Result shows：Glimepiride γ crystal formations are weightless 12.51% in the range of 30-80 DEG C.
It is a further object of the present invention to provide a kind of method for preparing Glimepiride γ crystal formations.
Glimepiride crystal formation I is dissolved in isopropanol at a temperature of 60 DEG C -75 DEG C；
Crystallized at -80 DEG C -0 DEG C, crystallization time is 12-48 hours；
It is filtrated to get solid, as Glimepiride γ crystal formations.
Wherein crystallization temperature is preferably -80 DEG C -- and 24 DEG C.
The powder x-ray diffraction of Glimepiride γ crystal formations disclosed in the present invention and the Glimepiride crystal formation having been reported,
DSC is different, therefore the solid forms are a kind of crystal formation forms of the Glimepiride for being totally different from prior art.Simultaneously should
The solubility of new γ crystal formations is higher than the more stable crystal formation I of known Glimepiride, can improve Glimepiride dissolubility.
[brief description of the drawings]
Fig. 1 is the XRPD diffracting spectrums of Glimepiride γ crystal formations of the present invention；
Fig. 2 is the DSC figures of Glimepiride γ crystal formations of the present invention；
Fig. 3 is the TGA figures of Glimepiride γ crystal formations of the present invention.
[specific embodiment]
Detection method
1st, powder x-ray diffraction
Instrument：Sharp shadow X-ray diffractometer (Dutch PANalytical)
Target：Cu-K α are radiated
Wavelength：
X-ray light tube voltage：45kV
X-ray light pipe fulgurite stream：40mA
Step-length：0.01313°
Sweep speed：0.041683°/s
Sweep limits：5°-40°
Result shows：9.7294 °, 10.0331 °, 10.6670 °, 12.9949 °, 13.4081 °, 17.8538 °,
There is characteristic peak at 19.5368 °；As shown in Figure 1.
2nd, differential scanning calorimetry (DSC)
Instrument：DSC Q2000 differential scanning calorimeters (U.S., TA instruments)
Temperature range：25℃-225℃
Programming rate：10℃/min
Result shows：Glimepiride γ crystal formations are respectively in 57.52 DEG C, 61.53 DEG C, 201.05 DEG C of (onset
Temperature) there is endothermic peak, as shown in Figure 2.
3rd, thermogravimetry (TGA)
Instrument：TGA Q500 thermogravimetric analyzers (U.S., TA instruments)
Temperature range：30℃-400℃
Programming rate：10℃/min
Result shows：Glimepiride γ crystal formations weightlessness 12.51% in the range of 30-80 DEG C, as shown in Figure 3.
It is a further object of the present invention to provide a kind of method for preparing Glimepiride γ crystal formations.
Glimepiride crystal formation I is dissolved in isopropanol at 60 DEG C -75 DEG C；Wherein, Glimepiride crystal formation I is fragrant by Guangzhou card
Bio tech ltd produces, and No. CAS is 93479-97-1, by the sign of X-RPD, DSC, and is contrasted with document, identification
Go out the Glimepiride crystal formation I that it is document report；
Crystallized under -80 DEG C -0 DEG C (preferably -80 DEG C -24 DEG C), crystallization time is 12-48 hours；
It is filtrated to get solid, as Glimepiride γ crystal formations.
Embodiment 1：Glimepiride γ crystal formation preparation methods
By 43mg Glimepirides crystal formation I, 8.5ml isopropanols are added, stirred at 75 DEG C to being completely dissolved, be placed at -24 DEG C
Crystallization 24 hours, is separated by filtration, and obtains Glimepiride γ crystal formations.
Embodiment 2：Glimepiride γ crystal formation preparation methods
By 43mg Glimepirides crystal formation I, 8.5ml isopropanols are added, 75 DEG C of stirrings are tied to being completely dissolved at being placed in -40 DEG C
It is brilliant 16 hours, it is separated by filtration, obtain Glimepiride γ crystal formations.
Embodiment 3：Glimepiride γ crystal formation preparation methods
By 43mg Glimepirides crystal formation I, 15ml isopropanols are added, stirred at 60 DEG C to being completely dissolved, tied at being placed in -80 DEG C
It is brilliant 12 hours, it is separated by filtration, obtain Glimepiride γ crystal formations.
Embodiment 4：Glimepiride γ crystal formation preparation methods
85mg Glimepirides crystal formation I is weighed, 16ml isopropanols are added, stirred at 70 DEG C to being completely dissolved, be placed at -24 DEG C
Crystallization 20 hours, is separated by filtration, and obtains Glimepiride γ crystal formations.
Embodiment 5：Glimepiride γ crystal formation preparation methods
85mg Glimepirides crystal formation I is weighed, 30ml isopropanols are added, 60 DEG C of stirrings are tied to being completely dissolved at being placed in -24 DEG C
It is brilliant 48 hours, it is separated by filtration, obtain Glimepiride γ crystal formations.
Glimepiride crystal formation I in above-mentioned preparation method is produced by Guangzhou Ka Fen bio tech ltd, No. CAS
It is 93479-97-1, by the sign of X-RPD, DSC, and is contrasted with document, identifies the Glimepiride that it is document report brilliant
Type I.
Solubility test：
Ultraviolet-visible spectrophotometry condition
Instrument：UV756CRT ultraviolet-uisible spectrophotometers (Shanghai You Ke instrument and meters Co., Ltd)
Organic solvent：Ethanol
Detection wavelength：229nm
Glimepiride is determined respectively compared with stable crystal form I and Glimepiride γ crystal formations different time points Glimepiride in ethanol
Solubility.The ethanol of certain volume is measured respectively in sample bottle, add be placed in sample bottle sealing after equivalent sample it is same
On magnetic stirring apparatus.Stirring 30 seconds, 1 minute, 2 minutes, after 5 minutes, take solution and cross 0.22 μm of filter membrane, take subsequent filtrate through appropriate dilute
Rear sample introduction ultraviolet specrophotometer is released, scanning wavelength 100-1000nm, Glimepiride has maximum absorption band at 229nm.Selection
229nm measures solubility as quantitative determination wavelength.
Result see the table below shown in 1：
The solubility (mg/mL) of the sample of table 1 Glimepiride in ethanol
From upper table 1, Glimepiride γ crystal formations have solubility higher compared to relatively stable Glimepiride crystal formation I.
Claims (3)
1. a kind of Glimepiride γ crystal formations, it is characterised in that：Radiated using Cu-K α, to spend the X-ray powder diffraction light that 2 θ are represented
Spectrum has characteristic peak at 9.7294 °, 10.0331 °, 10.6670 °, 12.9949 °, 13.4081 °, 17.8538 °, 19.5368 °；
When being analyzed using differential scanning calorimetry, Glimepiride γ crystal formations are respectively at 57.52 DEG C, 61.53 DEG C, 201.05 DEG C
(onset temperature) has endothermic peak；
When being analyzed using thermogravimetry, weightless 12.51% in the range of 30-80 DEG C.
2. the preparation method of Glimepiride γ crystal formations according to claim 1, it is characterised in that：
Glimepiride crystal formation I is dissolved in isopropanol at a temperature of 60 DEG C -75 DEG C；
Crystallized at -80 DEG C -0 DEG C, crystallization time is 12-48 hours；
It is filtrated to get solid, as Glimepiride γ crystal formations.
3. the preparation method of Glimepiride γ crystal formations according to claim 2, it is characterised in that：
The crystallization temperature is preferably -80 DEG C -- and 24 DEG C.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110218171A (en) * | 2019-06-28 | 2019-09-10 | 威海迪素制药有限公司 | A method of preparing Glimepiride crystal form I |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004073585A2 (en) * | 2003-02-21 | 2004-09-02 | Zentiva, A. S. | Methode of manufacturing glimepiride and the respective intermediate |
| WO2005049532A2 (en) * | 2003-09-30 | 2005-06-02 | Sun Pharmaceutical Industries Limited | A process for purification |
| CN103420891A (en) * | 2013-06-09 | 2013-12-04 | 南通市华峰化工有限责任公司 | Triphosgene method for synthesizing benzene sulphanilamide, intermediate of glimepiride, drug for Type ii Diabetes Mellitus |
| CN103601661A (en) * | 2013-09-22 | 2014-02-26 | 江苏德峰药业有限公司 | Synthetic method for II-type diabetes medicine glimepiride by using triphosgene |
-
2017
- 2017-02-08 CN CN201710068924.9A patent/CN106699631A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004073585A2 (en) * | 2003-02-21 | 2004-09-02 | Zentiva, A. S. | Methode of manufacturing glimepiride and the respective intermediate |
| WO2005049532A2 (en) * | 2003-09-30 | 2005-06-02 | Sun Pharmaceutical Industries Limited | A process for purification |
| CN103420891A (en) * | 2013-06-09 | 2013-12-04 | 南通市华峰化工有限责任公司 | Triphosgene method for synthesizing benzene sulphanilamide, intermediate of glimepiride, drug for Type ii Diabetes Mellitus |
| CN103601661A (en) * | 2013-09-22 | 2014-02-26 | 江苏德峰药业有限公司 | Synthetic method for II-type diabetes medicine glimepiride by using triphosgene |
Non-Patent Citations (3)
| Title |
|---|
| MARIKO IWATA，等: "Glimepiride", 《ACTA CRYST.》 * |
| 刘胜高: "格列美脲的制备工艺研究", 《山东化工》 * |
| 邓勇，等: "降血糖新药——格列美脲合成工艺研究", 《中国药物化学杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110218171A (en) * | 2019-06-28 | 2019-09-10 | 威海迪素制药有限公司 | A method of preparing Glimepiride crystal form I |
| CN110218171B (en) * | 2019-06-28 | 2022-03-18 | 迪嘉药业集团有限公司 | Method for preparing glimepiride crystal form I |
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Application publication date: 20170524 |