CN103554218B - N (2)-Ala-Gln crystal formation and preparation method thereof - Google Patents
N (2)-Ala-Gln crystal formation and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to medical art, be specifically related to N (2)-Ala-Gln IV, V crystal formation and preparation method thereof.V crystal formation, compared with N (2)-Ala-Gln I crystal formation, II crystal formation, III crystal formation, IV crystal formation, has more outstanding physico-chemical property, is mainly manifested in the clarity of product, residual solvent, weight loss on drying are more easy to control.N (2) obtained by the present invention-Ala-Gln V crystal formation is more conducive to suitability for industrialized production, and can better ensure quality product homogeneity, controllability, clinical application is safer.
Description
Technical field
The invention belongs to medical art, be specifically related to N (2)-Ala-Gln new crystal and preparation method.
Background technology
N (2)-Ala-Gln (molecular formula: C
8h
15n
3o
4) be the material that a kind of desirable vein supplements glutamine, can glutamine be converted into rapidly and be utilized in vivo.The characteristic that N (2)-Ala-Gln can be decomposed into glutamine and L-Ala in vivo makes to supplement glutamine via parenteral nutrition transfusion becomes possibility, two peptide decompose the amino acid that discharges as nutritive substance be stored in separately health corresponding site and with body need carry out metabolism.
In prior art, certain references disclose the synthesis of N (2)-Ala-Gln itself.In crystallization, disclose N (2)-Ala-Gln aseptic powdery preparation and preparation method thereof in ZL200510009619.X, crystallizing system is water/ethanol, finally obtains white crystalline powder (I crystal formation); Disclose the preparation method of N (2)-Ala-Gln in ZL201210371136.4, wherein selected water/methyl alcohol to be crystallizing system, final refining obtains white crystals (II crystal formation); And ZL201210579815.0 is described in detail N (2)-Ala-Gln III crystal formation especially, its solvent Wei diox selected and dimethyl formamide, its solvent is not all suitable for the production of bulk drug.But all do not do detailed research to the physico-chemical property of various crystal formation in each patent, especially in product drying process, various crystal formation has what impact not research to the clarity of product, organic residual solvent, weight loss on drying.Because each producer's quality product domestic as clarity, organic residual solvent, weight loss on drying exceeds standard often has generation, product homogeneity, poor controllability, thus govern the output of N (2)-whole industry of Ala-Gln, product price remains high.
The present inventor is in production practice, and through concentrated research, found the new crystal of the N being different from prior art (2)-Ala-Gln, it has good physical and chemical performance.
Summary of the invention
The present inventor has found two kinds of new crystalline form IV crystal formations and V crystal formation of N (2)-Ala-Gln, particularly V crystal formation is compared with other crystal formation, there is more outstanding physico-chemical property, be mainly manifested in the clarity of product, residual solvent, weight loss on drying are more easy to control; N (2) obtained by the present invention-Ala-Gln V crystal formation is more conducive to suitability for industrialized production, and can better ensure quality product homogeneity, controllability, clinical application is safer.
The invention provides IV crystal formation of N (2)-Ala-Gln, use Cu-Ka radiation, with 2
θthe X-ray powder diffraction that angle represents 10.678,13.700,18.381,
18.560,18.679,19.081,19.297,19.560,20.639,21.400,22.183,22.259,22.439,22.859,23.742,23.819,23.923,24.300,24.375,26.003,27.559,27.640,27.756,32.400,32.656,32.920,33.023,34.423,34.781,36.037,36.181,36.578,42.236,42.843(± 0.1 degree) there is characteristic peak, it has powder x-ray diffraction figure as shown in Figure 1.
The invention provides V crystal formation of N (2)-Ala-Gln, use Cu-Ka radiation, with 2
θthe X-ray powder diffraction that angle represents 13.699,20.619,
23.220,34.760,36.459(± 0.1 degree) there is characteristic peak, it has powder x-ray diffraction figure as shown in Figure 2.
The invention provides the preparation method of IV crystal formation of N (2)-Ala-Gln, comprising:
) at the temperature of 10 ~ 20 DEG C, N (2)-Ala-Gln powder is dissolved in purified water;
) control stirring velocity 250 ~ 300r/min, slowly drip solvent;
) time for adding controls at 1 hour ~ 5 hours, drips and finishes, and continues stirring 30 minutes ~ 3 hours;
) suction filtration, collect IV crystal formation of separating out.Wherein said solvent is Virahol.
The invention provides the preparation method of V crystal formation of N (2)-Ala-Gln, comprising:
) at the temperature of 20 ~ 30 DEG C, N (2)-Ala-Gln powder is dissolved in purified water;
) control stirring velocity 100 ~ 300r/min, slowly drip solvent;
) time for adding controls at 30 minutes ~ 5 hours, drips and finishes, and continues stirring 30 minutes ~ 3 hours;
) suction filtration, collect V crystal formation of separating out, wherein said solvent is Virahol.If need the crystal seed that can add V crystal formation to carry out induced crystallization.
Accompanying drawing explanation
Accompanying drawing 1 is N of the present invention (2)-Ala-Gln IV crystal formation, powder x-ray diffraction figure.N (2)-Ala-Gln IV crystal formation powder x-ray diffraction figure;
Accompanying drawing 2 is N of the present invention (2)-Ala-Gln V crystal formations, powder x-ray diffraction figure.N (2)-Ala-Gln crystal formation powder x-ray diffraction figure.
Embodiment
The embodiment of form by the following examples, foregoing of the present invention is described in further detail, but this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following examples, all technology realized based on foregoing of the present invention all belong to scope of the present invention.
the preparation of embodiment 1. N (2)-Ala-Gln IV crystal formation
N (2)-Ala-Gln crude product 70g, deionized water 210g, activated carbon 3.5g is added in 500ml there-necked flask, stirring at normal temperature is decoloured 1 hour, with organic membrane filtration removing activated carbon, a small amount of purified water washing leaching cake, drains to obtain filtrate; Filtrate is transferred in 1000ml there-necked flask, mechanical stirring rotating speed is controlled at 250 ~ 300r/min, control temperature 15 ~ 20 DEG C slowly drips Virahol 560 ml in filtrate, altogether drip Virahol time controling at 2.5 ~ 3 hours, drip Bi Jixu and stir 30 minutes, suction filtration, reduces pressure lower 55 DEG C and dries obtained N (2)-Ala-Gln IV crystal formation 62g.
the preparation of embodiment 2. N (2)-Ala-Gln V crystal formation
N (2)-Ala-Gln crude product 70g, deionized water 210g, activated carbon 3.5g is added in 500ml there-necked flask, stirring at normal temperature is decoloured 1 hour, with organic membrane filtration removing activated carbon, a small amount of purified water washing leaching cake, drains to obtain filtrate; Filtrate is transferred in 1000ml there-necked flask, mechanical stirring rotating speed is controlled at 200 ~ 250r/min, control temperature 25 ~ 30 DEG C slowly drips Virahol 560 ml in filtrate, 0.5g V Form seeds is added when solution becomes muddy, altogether drip Virahol time controling at 1.0 ~ 2.0 hours, drip Bi Jixu and stir 30 minutes, suction filtration, reduce pressure lower 55 DEG C and dry obtained N (2)-Ala-Gln V crystal formation 60g.
The N (2) prepared the embodiment of the present invention-Ala-Gln IV type is brilliant, V type is brilliant and I crystal formation, II crystal formation, III crystal formation have carried out comparison test, the results are shown in following table:
From upper table data, N (2)-Ala-Gln V type is brilliant compared with other crystal formation, and various index is all better than other crystal formation.
Claims (2)
1.N (2)-Ala-Gln V crystal formation, is characterized in that, uses Cu-Ka radiation, with 2
θx-ray powder diffraction V crystal formation that angle represents is in 13.699,20.619,23.220,34.760,36.459(± 0.1 degree) there is characteristic peak.
2. prepare the crystallization method of N according to claim 1 (2)-Ala-Gln V crystal formation, comprising:
) at the temperature of 20 ~ 30 DEG C, N (2)-Ala-Gln powder is dissolved in purified water;
) control stirring velocity 100 ~ 300r/min, slowly drip solvent Virahol;
) time for adding controls at 30 minutes ~ 5 hours, drips and finishes, and continues stirring 30 minutes ~ 3 hours;
) suction filtration, collect V crystal formation of separating out, be characterised in that,
) slowly drip in step and need to add V Form seeds in solvent Virahol process and carry out induction crystallization.
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| CN107805275B (en) * | 2016-09-08 | 2023-07-21 | 重庆莱美隆宇药业有限公司 | Novel N (2) -L-alanyl-L-glutamine crystal form and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1786019A (en) * | 2005-10-14 | 2006-06-14 | 邢将军 | Process for producing alanyl-glutamine dipeptide |
| CN101062938A (en) * | 2006-04-25 | 2007-10-31 | 福建三爱药业有限公司 | Process for producing N (2) -L-alanyl-L-glutamine |
| CN103073617A (en) * | 2012-12-27 | 2013-05-01 | 西安万隆制药股份有限公司 | N-(2)-L-alanyl-L-glutamine compound |
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| JPWO2007119503A1 (en) * | 2006-03-23 | 2009-08-27 | 協和発酵バイオ株式会社 | Wake-up agent |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1786019A (en) * | 2005-10-14 | 2006-06-14 | 邢将军 | Process for producing alanyl-glutamine dipeptide |
| CN101062938A (en) * | 2006-04-25 | 2007-10-31 | 福建三爱药业有限公司 | Process for producing N (2) -L-alanyl-L-glutamine |
| CN103073617A (en) * | 2012-12-27 | 2013-05-01 | 西安万隆制药股份有限公司 | N-(2)-L-alanyl-L-glutamine compound |
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Address after: Jiulongpo Branch Park Science Park four street 400039 six Chongqing City No. 70 standard factory building 4 floor IJ Patentee after: CONSCIENECE PHARMACEUTICALS LTD. Address before: Jiulongpo Branch Park Science Park four street 400039 six Chongqing City No. 70 standard factory building 4 floor IJ Patentee before: Conscienece Pharmaceuticals Ltd. |
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