CN104341339A - Crystal form and preparation method of N-methyl-2-pyridine ethylamine dihydrochloride - Google Patents
Crystal form and preparation method of N-methyl-2-pyridine ethylamine dihydrochloride Download PDFInfo
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- CN104341339A CN104341339A CN201310317336.6A CN201310317336A CN104341339A CN 104341339 A CN104341339 A CN 104341339A CN 201310317336 A CN201310317336 A CN 201310317336A CN 104341339 A CN104341339 A CN 104341339A
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- 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
The present invention discloses a crystal form and a preparation method of N-methyl-2-pyridine ethylamine dihydrochloride, wherein the crystal form has the characteristic absorption peaks when the diffraction angle 2[theta] is 10.9 DEG, 14.7 DEG, 15.0 DEG, 15.1 DEG, 15.5 DEG, 19.5 DEG, 23.7 DEG, 24.3 DEG, 25.9 DEG, 26.7 DEG, 29.6 DEG, 30.2 DEG, 30.3 DEG, 37.8 DEG and 41.1 DEG in the X-ray powder diffraction spectrum adopting Cu-K[alpha] as a radiation source. The present invention further discloses the preparation method of the crystal form, wherein the preparation method comprises: heating and dissolving N-methyl-2-pyridine ethylamine dihydrochloride in a solvent, mixing with an anti-solvent, cooling, and crystallizing. With the crystal form, the stability of the bulk drug can be increased, and the bulk drug storage and the formulation preparation are easily achieved.
Description
Technical field
The present invention relates to crystal formation of a kind of N-methyl-2-PEA dihydrochloride and preparation method thereof.
Background technology
N-methyl-2-PEA dihydrochloride is a kind of Histamine agents thing, general Betahistine Hydrochloride by name, and its structural formula is as follows:
Betahistine Hydrochloride is diamine oxidase inhibitor, the weak agonist of histamine H1-receptor, the strong antagonist of H3 acceptor, obvious dilating effect is had to the cerebrovascular, cardiovascular particularly Vertebro-basilar System, can improve circulation of blood, increase cochlea and vestibular volume of blood flow, thus elimination auditory vertigo, tinnitus and ear close sense, internal auditory artery blood supply can also be improved, increase capillary permeability, promote the absorption of extracellular fluid, eliminate oedema in lymph.Betahistine Hydrochloride can resist the contracting blood vessel function of catecholamine in addition and reduce arterial pressure effect, and has the platelet aggregation effect suppressing the clotting of plasma and adenosine diphosphate (ADP) (ADP) to be induced, and can extend thrombus formation time.
Clinically, Betahistine Hydrochloride can be used for treating U.S. Neil formula syndromes, also can be used for treatment cerebral arteriosclerosis, ischemic cerebrovascular and caused by hypertension positional vertigo, tinnitus etc.The easy moisture absorption of Betahistine Hydrochloride, very easily dissolves, is slightly soluble in ethanol, be dissolved in acetone hardly in water.The formulation of having gone on the market mainly contains tablet and injection, in injection, there is not crystal formation problem, but can there is the problem of different crystal forms in bulk drug and solid preparation.This medicine is the old medicine of listing in 1970, and the specification of quality by research and development condition at that time and medicine limit, and all research work fail to do correlative study to its crystal formation.The stability of existing Betahistine Hydrochloride bulk drug and solid preparation is undesirable, and does not occur the bibliographical information of the crystal formation about this compound so far.
Summary of the invention
Technical problem to be solved by this invention is crystal formation providing a kind of N-methyl-2-PEA dihydrochloride and preparation method thereof.The crystal formation of described N-methyl-2-PEA dihydrochloride to overcome in prior art that metamict water absorbability in N-methyl-2-PEA dihydrochloride bulk drug and preparation is strong, the defect of less stable, be conducive to the storage of bulk drug and the preparation of preparation, be conducive to the raising of drug quality and stability.Provide the preparation method of this crystal formation simple, there is industrial prospect widely.
The invention provides a kind of crystal formation of N-methyl-2-PEA dihydrochloride.This crystal formation is using in the X-ray powder diffraction figure that source of radiation is Cu-K α, in diffraction angle 2 θ=10.9 °, there is charateristic avsorption band at 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 ° of places, this crystal formation also in diffraction angle 2 θ=18.0 °, there is secondary absorption peak at 21.6 °, 22.1 °, 22.6 °, 24.7 °, 35.7 °, 36.6 °, 39.6 °, 40.1 ° and 44.4 ° of places, 2 θ limit of error are ± 0.2 °.
Present invention also offers the preparation method of the crystal formation of described N-methyl-2-PEA dihydrochloride, it comprises the steps: by N-methyl-2-PEA dihydrochloride heating for dissolving in solvent, then mixes with anti-solvent, cooling crystallization; Described solvent is the aqueous solution of alcohol; Described anti-solvent is esters solvent.
The water ratio of the aqueous solution of described alcohol is preferably 0.1% ~ 3%, and per-cent is volume percent.Described alcohol is preferably the alcohol of 1-3 for carbonatoms, and being more preferably one or more in methyl alcohol, ethanol and Virahol, is especially more preferably ethanol.The consumption of described solvent can be selected according to this area ordinary method, is preferably 2 ~ 60ml/g, is more preferably 5 ~ 10ml/g, and ml/g herein refers to the volume of the solvent that every gram of N-methyl-2-PEA dihydrochloride adds.
Described anti-solvent is preferably one or more in ethyl acetate, butylacetate and Isoamyl Acetate FCC, is more preferably butylacetate.The volume ratio of described solvent and described anti-solvent is preferably 1:1 ~ 1:20, is more preferably 1:5 ~ 1:15.
Wherein, the temperature of described heating can be selected according to this area normal ranges, is preferably 40 ~ 80 DEG C.Described cooling is preferably for leaving standstill cooling.The temperature of described crystallization is preferably-10 ~ 30 DEG C, is more preferably 0 ~ 25 DEG C.
On the basis meeting this area general knowledge, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material are all commercially.
Positive progressive effect of the present invention is: the present invention can obtain the better crystal formation of stability relative to unbodied N-methyl-2-PEA dihydrochloride, and preparation method of the present invention is simple to operate, handiness is strong, be easy to control, the crystal formation of gained bulk drug is easy to store, be convenient to the preparation of follow-up preparation, be applicable to the needs of suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction pattern of the crystal formation of N-methyl-2-PEA dihydrochloride in the present invention.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.
In following embodiment: the per-cent in embodiment 1 ~ 6 refers to volume percent, the per-cent in effect example 2 ~ 3 refers to mass percent.
Embodiment 1
N-methyl-2-PEA dihydrochloride 1g is heated to 60 DEG C in containing the ethanol 10ml of 0.5% water, it is made all to dissolve, drop in anti-solvent butylacetate 100ml, leave standstill at 25 DEG C, filter, drying to obtain white solid 0.84g, is the crystal formation of described N-methyl-2-PEA dihydrochloride.
Embodiment 2
N-methyl-2-PEA dihydrochloride 1g is heated to 78 DEG C in containing the ethanol 5ml of 0.1% water, makes it all dissolve, drop in anti-solvent butylacetate 25ml, leave standstill at 0 DEG C, filter, drying to obtain white solid 0.81g, is the crystal formation of described N-methyl-2-PEA dihydrochloride.
Embodiment 3
N-methyl-2-PEA dihydrochloride 1g is heated to 60 DEG C in containing the methyl alcohol 2ml of 0.5% water, it is made all to dissolve, drop in anti-solvent ethyl acetate 40ml, leave standstill at 30 DEG C, filter, drying to obtain white solid 0.61g, is the crystal formation of described N-methyl-2-PEA dihydrochloride.
Embodiment 4
N-methyl-2-PEA dihydrochloride 1g is heated to 78 DEG C in containing the ethanol 5ml of 1% water, makes it all dissolve, drop in anti-solvent butylacetate 75ml, leave standstill at 5 DEG C, filter, drying to obtain white solid 0.78g, is the crystal formation of described N-methyl-2-PEA dihydrochloride.
Embodiment 5
N-methyl-2-PEA dihydrochloride 1g is heated to 80 DEG C in containing the Virahol 60ml of 3% water, it is made all to dissolve, drop in anti-solvent Isoamyl Acetate FCC 60ml, leave standstill at-10 DEG C, filter, drying to obtain white solid 0.44g, is the crystal formation of described N-methyl-2-PEA dihydrochloride.
Embodiment 6
N-methyl-2-PEA dihydrochloride 1g is heated to 40 DEG C in containing the methyl alcohol 5ml of 0.2% water, it is made all to dissolve, drop in anti-solvent ethyl acetate 20ml, leave standstill at-10 DEG C, filter, drying to obtain white solid 0.46g, is the crystal formation of described N-methyl-2-PEA dihydrochloride.
Effect example 1
Carry out powder x-ray diffraction to the crystal formation of the N-methyl-2-PEA dihydrochloride that above-described embodiment obtains, source of radiation is Cu-K α, and spectrogram is shown in Fig. 1, and concrete diffraction peak is in table 1, and limit of error is ± 0.2 °.
X-ray powder diffraction detecting instrument: the D8ADVANCE type X-ray diffractometer of German Brooker instrument company;
Test condition: with the continuous sweep from 3 ° to 45 ° of 0.02 ° of step-length, sweep velocity 8.0 °/min, pipe pressure 40KV, pipe stream 40mA;
Detect foundation: Chinese Pharmacopoeia 2010 editions 2 annex IX F;
Sense environmental conditions: room temperature.
The XRPD diffraction peak of the crystal formation of table 1N-methyl-2-PEA dihydrochloride
| 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
Draw moist test by " medicine draws moist test direction principle " (Chinese Pharmacopoeia 2010 editions 2 annex) to the crystal formation of above-described embodiment gained and amorphous samples, result is as shown in table 2:
Table 2 draws moist test-results
| Sample | Within 1 hour, draw wet weightening finish |
| Crystal formation of the present invention | 3.7% |
| Amorphous | 9.3% |
From above-mentioned test-results, crystal formation of the present invention obviously has more advantage than amorphous in water absorbability, is conducive to the preservation of bulk drug and the preparation of preparation.
Effect example 3
(purity >99.5% is to crystal formation of the present invention and amorphous samples, single foreign matter content <0.1% sample), under 40 DEG C of conditions, carry out Accelerated stability test, test 10 days, liquid phase analysis sample purity and related substance, result is as shown in table 3:
Table 3 stability test result
| Sample | Purity and related substance |
| Crystal formation of the present invention | Purity>99.0%, total impurities content<1.0% |
| Amorphous | Purity>98.1%, total impurities content<1.9% |
Visible, crystal formation involved in the present invention can significantly improve the stability of N-methyl-2-PEA dihydrochloride bulk drug, is conducive to the preservation of bulk drug and the preparation of preparation.
Claims (10)
1. the crystal formation of a N-methyl-2-PEA dihydrochloride, it is characterized in that, described crystal formation is using in the X-ray powder diffraction figure that source of radiation is Cu-K α, in diffraction angle 2 θ=10.9 °, there is charateristic avsorption band at 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 ° of places, and 2 θ limit of error are ± 0.2 °.
2. the preparation method of the crystal formation of a N-methyl-2-PEA dihydrochloride as claimed in claim 1, it is characterized in that, it comprises the steps: by N-methyl-2-PEA dihydrochloride heating for dissolving in solvent, then mixes with anti-solvent, cooling crystallization; Described solvent is the aqueous solution of alcohol; Described anti-solvent is esters solvent.
3. the preparation method of the crystal formation of N-methyl-2-PEA dihydrochloride as claimed in claim 2, it is characterized in that, the water ratio of the aqueous solution of described alcohol is 0.1% ~ 3%, and per-cent is volume percent.
4. the preparation method of the crystal formation of N-methyl-2-PEA dihydrochloride as claimed in claim 3, is characterized in that, the alcohol of described alcohol to be carbonatoms be 1-3, is preferably one or more in methyl alcohol, ethanol and Virahol.
5. the preparation method of the crystal formation of N-methyl-2-PEA dihydrochloride as claimed in claim 4, it is characterized in that, described alcohol is ethanol.
6. the preparation method of the crystal formation of N-methyl-2-PEA dihydrochloride as claimed in claim 2, is characterized in that, described anti-solvent is one or more in ethyl acetate, butylacetate and Isoamyl Acetate FCC.
7. the preparation method of the crystal formation of N-methyl-2-PEA dihydrochloride as claimed in claim 6, it is characterized in that, described anti-solvent is butylacetate.
8. the preparation method of the crystal formation of the N-methyl-2-PEA dihydrochloride as described in any one of claim 2-5, it is characterized in that, the consumption of described solvent is 2 ~ 60ml/g, is preferably 5 ~ 10ml/g.
9. the preparation method of the crystal formation of the N-methyl-2-PEA dihydrochloride as described in any one of claim 2-7, it is characterized in that, the volume ratio of described solvent and described anti-solvent is 1:1 ~ 1:20, is preferably 1:5 ~ 1:15.
10. the preparation method of the crystal formation of the N-methyl-2-PEA dihydrochloride as described in any one of claim 2-7, it is characterized in that, the temperature of described heating is 40 ~ 80 DEG C; Described being cooled to leaves standstill cooling; The temperature of described crystallization is-10 ~ 30 DEG C, is preferably 0 ~ 25 DEG C.
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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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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 |
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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 |
|---|
| L.A.WALTER等: "β-(2-and 4-pyridylalkyl)-amines", 《J. AM. CHEM. SOC.》 * |
| 叶瑾亮等: "N-甲基-2-吡啶乙胺二盐酸盐的合成", 《广东化工》 * |
| 蒋敏等: "正交优化盐酸倍他司汀的合成工艺", 《安徽化工》 * |
| 魏宏阳等: "N-甲基-2-吡啶乙胺二盐酸盐的合成", 《辽宁化工》 * |
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