CN104341339B - Crystal formation of the PEA dihydrochloride of N methyl 2 and preparation method thereof - Google Patents
Crystal formation of the PEA dihydrochloride of N methyl 2 and preparation method thereof Download PDFInfo
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- CN104341339B CN104341339B CN201310317336.6A CN201310317336A CN104341339B CN 104341339 B CN104341339 B CN 104341339B CN 201310317336 A CN201310317336 A CN 201310317336A CN 104341339 B CN104341339 B CN 104341339B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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Abstract
Crystal formation the invention discloses a kind of PEA dihydrochloride of N methyl 2 and preparation method thereof.Described crystal formation has characteristic absorption peak in using radiation source for the X-ray powder diffraction figure of Cu K α at θ=10.9 ° of the angle of diffraction 2,14.7 °, 15.0 °, 15.1 °, 15.5 °, 19.5 °, 23.7 °, 24.3 °, 25.9 °, 26.7 °, 29.6 °, 30.2 °, 30.3 °, 37.8 ° and 41.1 °.The invention also discloses the preparation method of the crystal formation, it comprises the steps：The PEA dihydrochloride heating for dissolving of N methyl 2 is mixed in solvent, then with anti-solvent, cooling crystallization, you can.The crystal formation can improve the stability of bulk drug, be conducive to the storage of bulk drug and the preparation of preparation.
Description
Technical field
The present invention relates to a kind of crystal formation of N- methyl -2- PEA dihydrochlorides and preparation method thereof.
Background technology
N- methyl -2- PEA dihydrochlorides are a kind of Histamine agents thing, general entitled Betahistine Hydrochloride, its structure
Formula is as follows：
Betahistine Hydrochloride is diamine oxidase inhibitor, is weak activator, the strong antagonism of H3 acceptors of histamine H1-receptor
Agent, has obvious dilating effect to the cerebrovascular, cardiovascular particularly Vertebro-basilar System, can improve blood circulation, increases cochlea
With vestibular CBF, so that eliminating auditory vertigo, tinnitus and ear closes sense, moreover it is possible to improve internal auditory artery blood supply, increase blood capillary
Pipe permeability, promotes the absorption of extracellular fluid, eliminates oedema in lymph.Betahistine Hydrochloride also has the contracting that can resist catecholamine
Blood vessel function and reduction angiosthenia effect, and have the suppression clotting of plasma and adenosine diphosphate (ADP)（ADP）The platelet aggregation of induction is made
With TFT can be extended.
Clinically, Betahistine Hydrochloride can be used to treat U.S. Neil formula syndrome, also can be used for treatment cerebral arteriovenous malformation,
ICVD and caused by hypertension positional vertigo, tinnitus etc..The easy moisture absorption of Betahistine Hydrochloride, it is easily molten in water
Solution, is slightly soluble in ethanol, is practically insoluble in acetone.The formulation for having listed mainly has tablet and injection, does not exist in injection
Crystal formation problem, but can there are different crystal forms in bulk drug and solid pharmaceutical preparation.The medicine is the old medicine of listing in 1970,
Limited by research and development condition at that time and the quality requirement of medicine, all of research work fails to make correlative study to its crystal formation.
The stability of existing Betahistine Hydrochloride bulk drug and solid pharmaceutical preparation is undesirable, and does not occur the crystalline substance on the compound so far
The document report of type.
The content of the invention
The technical problems to be solved by the invention be provide a kind of N- methyl -2- PEA dihydrochlorides crystal formation and
Its preparation method.The crystal formation of described N- methyl -2- PEA dihydrochlorides overcomes N- methyl -2- pyridines in the prior art
Amorphous state hygroscopicity is strong in ethylamine dihydrochloride bulk drug and preparation, the defect of less stable, is conducive to bulk drug
Storage and the preparation of preparation, are conducive to the raising of drug quality and stability.The preparation method for providing the crystal formation is simple, has
Extensive industrial prospect.
The invention provides a kind of crystal formation of N- methyl -2- PEA dihydrochlorides.The crystal formation is being using radiation source
In the X-ray powder diffraction figure of Cu-K α, θ=10.9 ° of the angle of diffraction 2,14.7 °, 15.0 °, 15.1 °, 15.5 °, 19.5 °,
There is characteristic absorption peak at 23.7 °, 24.3 °, 25.9 °, 26.7 °, 29.6 °, 30.2 °, 30.3 °, 37.8 ° and 41.1 °, the crystal formation is also
Have secondary at θ=18.0 ° of the angle of diffraction 2,21.6 °, 22.1 °, 22.6 °, 24.7 °, 35.7 °, 36.6 °, 39.6 °, 40.1 ° and 44.4 °
Absworption peak is wanted, 2 θ error ranges are ± 0.2 °.
Present invention also offers the preparation method of the crystal formation of described N- methyl -2- PEA dihydrochlorides, it includes
Following step：N- methyl -2- PEA dihydrochloride heating for dissolving is mixed in solvent, then with anti-solvent, cooling crystallization,
；Described solvent is the aqueous solution of alcohol；Described anti-solvent is esters solvent.
The moisture content of the aqueous solution of described alcohol is preferably 0.1%~3%, and percentage is percent by volume.Described alcohol
Preferably carbon number is the alcohol of 1-3, is more preferably methyl alcohol, one or more in ethanol and isopropanol, especially more preferably
It is ethanol.The consumption of described solvent can be selected according to this area conventional method, preferably 2~60ml/g, more preferably
It is 5~10ml/g, ml/g herein refers to every gram of volume of the solvent of N- methyl -2- PEAs dihydrochloride addition.
Described anti-solvent is preferably one or more in ethyl acetate, butyl acetate and isoamyl acetate, more preferably
Ground is butyl acetate.Described solvent is preferably 1 with the volume ratio of described anti-solvent:1~1:20, more preferably it is 1:5~
1:15。
Wherein, the temperature of described heating can be selected according to this area normal ranges, preferably 40~80 DEG C.Institute
The cooling stated is preferably standing cooling.The temperature of described crystallization is preferably -10~30 DEG C, is more preferably 0~25 DEG C.
On the basis of common sense in the field is met, above-mentioned each optimum condition can be combined, and obtain final product each preferable reality of the present invention
Example.
Agents useful for same of the present invention and raw material are commercially available.
Positive effect of the invention is：The present invention can be obtained relative to unbodied N- methyl -2- pyridine second
The more preferable crystal formation of stability of amine dihydrochloride, and preparation method of the invention is simple to operate, flexibility is strong, it is easy to control, institute
The crystal formation for obtaining bulk drug is easy to storage, is easy to the preparation of follow-up preparation, the need for being adapted to industrialized production.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction figure of the crystal formation of N- methyl -2- PEA dihydrochlorides in the present invention.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality
Apply among a scope.
In following embodiments：Percentage in embodiment 1~6 refers to percent by volume, in effect example 2~3 hundred
Ratio is divided to refer to mass percent.
Embodiment 1
N- methyl -2- PEA dihydrochloride 1g are heated to 60 DEG C in the ethanol 10ml containing 0.5% water, make its complete
Portion is dissolved, and drops in anti-solvent butyl acetate 100ml, is stood at 25 DEG C, and white solid 0.84g is dried to obtain in filtering, is institute
The crystal formation of the N- methyl -2- PEA dihydrochlorides stated.
Embodiment 2
N- methyl -2- PEA dihydrochloride 1g are heated to 78 DEG C in the ethanol 5ml containing 0.1% water, make its whole
Dissolving, is dropped in anti-solvent butyl acetate 25ml, is stood at 0 DEG C, and white solid 0.81g is dried to obtain in filtering, is described
The crystal formation of N- methyl -2- PEA dihydrochlorides.
Embodiment 3
N- methyl -2- PEA dihydrochloride 1g are heated to 60 DEG C in the methyl alcohol 2ml containing 0.5% water, make its whole
Dissolving, is dropped in anti-solvent ethyl acetate 40ml, is stood at 30 DEG C, and white solid 0.61g is dried to obtain in filtering, is described
N- methyl -2- PEA dihydrochlorides crystal formation.
Embodiment 4
N- methyl -2- PEA dihydrochloride 1g are heated to 78 DEG C in the ethanol 5ml containing 1% water, make it all molten
Solution, is dropped in anti-solvent butyl acetate 75ml, is stood at 5 DEG C, and white solid 0.78g is dried to obtain in filtering, is described N-
The crystal formation of methyl -2- PEA dihydrochlorides.
Embodiment 5
N- methyl -2- PEA dihydrochloride 1g are heated to 80 DEG C in the isopropanol 60ml containing 3% water, make its complete
Portion is dissolved, and drops in anti-solvent isoamyl acetate 60ml, is stood at -10 DEG C, and white solid 0.44g is dried to obtain in filtering, is
The crystal formation of the N- methyl -2- PEA dihydrochlorides.
Embodiment 6
N- methyl -2- PEA dihydrochloride 1g are heated to 40 DEG C in the methyl alcohol 5ml containing 0.2% water, make its whole
Dissolving, is dropped in anti-solvent ethyl acetate 20ml, is stood at -10 DEG C, and white solid 0.46g is dried to obtain in filtering, is described
N- methyl -2- PEA dihydrochlorides crystal formation.
Effect example 1
The crystal formation of the N- methyl -2- PEA dihydrochlorides obtained to above-described embodiment carries out powder x-ray diffraction, spoke
Source is penetrated for Cu-K α, spectrogram is shown in Fig. 1, specific diffraction peak is shown in Table 1, and error range is ± 0.2 °.
X-ray powder diffraction detecting instrument：The D8ADVANCE type X-ray diffractometers of German Brooker instrument company；
Test condition：With the continuous scanning from 3 ° to 45 ° of 0.02 ° of step-length, 8.0 °/min of sweep speed, pipe pressure 40KV, Guan Liu
40mA；
Detection foundation：2 annex IX F of Chinese Pharmacopoeia 2010 edition；
Detection environmental condition：Room temperature.
The XRPD diffraction maximums of the crystal formation of table 1N- methyl -2- PEA dihydrochlorides
| Numbering | 2 θ angles（°） | Relative intensity | Numbering | 2 θ angles（°） | Relative intensity |
| 1 | 10.9 | 5.12 | 14 | 25.9 | 100.00 |
| 2 | 14.7 | 10.69 | 15 | 26.7 | 12.92 |
| 3 | 15.0 | 42.00 | 16 | 29.6 | 12.06 |
| 4 | 15.1 | 43.44 | 17 | 30.2 | 14.92 |
| 5 | 15.5 | 4.43 | 18 | 30.3 | 7.96 |
| 6 | 18.0 | 1.61 | 19 | 35.7 | 1.54 |
| 7 | 19.5 | 11.13 | 20 | 36.6 | 0.45 |
| 8 | 21.6 | 3.82 | 21 | 37.8 | 9.58 |
| 9 | 22.1 | 1.26 | 22 | 39.6 | 1.64 |
| 10 | 22.6 | 1.33 | 23 | 40.1 | 0.88 |
| 11 | 23.7 | 4.12 | 24 | 41.1 | 5.16 |
| 12 | 24.3 | 4.71 | 25 | 44.4 | 1.98 |
| 13 | 24.7 | 2.92 |
Effect example 2
Press《Medicine draws moist test guideline》（2 annex of Chinese Pharmacopoeia 2010 edition）To the crystalline substance obtained by above-described embodiment
Type carries out draws moist test with amorphous samples, as a result as shown in table 2：
The draws moist test result of table 2
| Sample | Draw wet weightening within 1 hour |
| Crystal formation of the present invention | 3.7% |
| It is amorphous | 9.3% |
Knowable to above-mentioned result of the test, crystal formation of the invention, substantially than amorphous more advantage, is conducive in hygroscopicity
The preservation of bulk drug and the preparation of preparation.
Effect example 3
To crystal formation of the present invention and amorphous samples（It is purity>99.5%, single impurity content<0.1% sample）, in 40 DEG C of bars
Accelerated stability test, experiment 10 days, liquid phase analysis sample purity and relevant material are carried out under part, as a result as shown in table 3：
The stability test result of table 3
| Sample | Purity and relevant material |
| Crystal formation of the present invention | Purity>99.0%, total impurities content<1.0% |
| It is amorphous | Purity>98.1%, total impurities content<1.9% |
It can be seen that, crystal formation involved in the present invention can significantly improve the steady of N- methyl -2- PEA dihydrochloride bulk drugs
It is qualitative, be conducive to the preservation of bulk drug and the preparation of preparation.
Claims (6)
1. a kind of crystal formation of N- methyl -2- PEA dihydrochlorides, it is characterised in that described crystal formation is being using radiation source
In the X-ray powder diffraction figure of Cu-K α, θ=10.9 ° of the angle of diffraction 2,14.7 °, 15.0 °, 15.1 °, 15.5 °, 19.5 °,
There is characteristic absorption peak at 23.7 °, 24.3 °, 25.9 °, 26.7 °, 29.6 °, 30.2 °, 30.3 °, 37.8 ° and 41.1 °, in the angle of diffraction
There is secondary absorption at 2 θ=18.0 °, 21.6 °, 22.1 °, 22.6 °, 24.7 °, 35.7 °, 36.6 °, 39.6 °, 40.1 ° and 44.4 °
Peak, 2 θ error ranges are ± 0.2 °.
2. a kind of preparation method of the crystal formation of N- methyl -2- PEA dihydrochlorides as claimed in claim 1, its feature exists
In it comprises the steps：N- methyl -2- PEA dihydrochloride heating for dissolving is mixed in solvent, then with anti-solvent,
Cooling crystallization, you can；Described solvent is the aqueous solution of alcohol；The moisture content of the aqueous solution of described alcohol is 0.1%~3%, hundred
Divide than being percent by volume；Described alcohol is one or more in methyl alcohol, ethanol and isopropanol；Described anti-solvent is acetic acid
One or more in ethyl ester, butyl acetate and isoamyl acetate；Described solvent is 1 with the volume ratio of described anti-solvent:1
~1:20；The consumption of described solvent is 2~60ml/g；The temperature of described heating is 40~80 DEG C；The temperature of described crystallization
Spend is -10~30 DEG C.
3. the preparation method of the crystal formation of N- methyl -2- PEA dihydrochlorides as claimed in claim 2, it is characterised in that
The consumption of described solvent is 5~10ml/g.
4. the preparation method of the crystal formation of N- methyl -2- PEA dihydrochlorides as claimed in claim 2, it is characterised in that
Described solvent is 1 with the volume ratio of described anti-solvent:5~1:15.
5. the preparation method of the crystal formation of N- methyl -2- PEA dihydrochlorides as claimed in claim 2, it is characterised in that
Described is cooled to standing cooling.
6. the preparation method of the crystal formation of N- methyl -2- PEA dihydrochlorides as claimed in claim 2, it is characterised in that
The temperature of described crystallization is 0~25 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310317336.6A CN104341339B (en) | 2013-07-25 | 2013-07-25 | Crystal formation of the PEA dihydrochloride of N methyl 2 and preparation method thereof |
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| CN201310317336.6A CN104341339B (en) | 2013-07-25 | 2013-07-25 | Crystal formation of the PEA dihydrochloride of N methyl 2 and preparation method thereof |
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| CN104341339B true CN104341339B (en) | 2017-06-06 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3410861A (en) * | 1965-08-17 | 1968-11-12 | Unimed Inc | Production of beta-(2-or 4-pyridyl alkyl)-amines |
| EP0416393A1 (en) * | 1989-09-05 | 1991-03-13 | Abbott Laboratories | Peptidyl difluorodiol renin inhibitors |
| RU2340603C1 (en) * | 2007-07-18 | 2008-12-10 | Федеральное государственное унитарное предприятие "Государственный научный центр "Научно-исследовательский институт органических полупродуктов и красителей" (ФГУП "ГНЦ "НИОПИК") | Method of obtaining 2-(2-methylaminoethyl)pyridine salts |
-
2013
- 2013-07-25 CN CN201310317336.6A patent/CN104341339B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3410861A (en) * | 1965-08-17 | 1968-11-12 | Unimed Inc | Production of beta-(2-or 4-pyridyl alkyl)-amines |
| EP0416393A1 (en) * | 1989-09-05 | 1991-03-13 | Abbott Laboratories | Peptidyl difluorodiol renin inhibitors |
| RU2340603C1 (en) * | 2007-07-18 | 2008-12-10 | Федеральное государственное унитарное предприятие "Государственный научный центр "Научно-исследовательский институт органических полупродуктов и красителей" (ФГУП "ГНЦ "НИОПИК") | Method of obtaining 2-(2-methylaminoethyl)pyridine salts |
Non-Patent Citations (4)
| Title |
|---|
| N-甲基-2-吡啶乙胺二盐酸盐的合成;叶瑾亮等;《广东化工》;20081231;第35卷(第8期);第23页第1.2.2节 * |
| N-甲基-2-吡啶乙胺二盐酸盐的合成;魏宏阳等;《辽宁化工》;20050831;第34卷(第8期);第336页左栏 * |
| β-(2-and 4-pyridylalkyl)-amines;L.A.Walter等;《J. Am. Chem. Soc.》;19411031;第63卷(第10期);第2771-2773页 * |
| 正交优化盐酸倍他司汀的合成工艺;蒋敏等;《安徽化工》;20121231;第38卷(第6期);第20页第1.3.4节 * |
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Address after: 232000 No.16 Chaoyang East Road, Huainan Economic and Technological Development Zone, Anhui Province Patentee after: CHINA NATIONAL MEDICINES GUORUI PHARMACEUTICAL Co.,Ltd. Patentee after: SHANGHAI INSTITUTE OF PHARMACEUTICAL INDUSTRY Address before: 232001 No.28, Guoqing West Road, Huainan City, Anhui Province Patentee before: CHINA NATIONAL MEDICINES GUORUI PHARMACEUTICAL Co.,Ltd. Patentee before: SHANGHAI INSTITUTE OF PHARMACEUTICAL INDUSTRY |