CN104447946A - Novel crystal form of N-glycyl tyrosine monohydrate and preparation method of novel crystal form - Google Patents
Novel crystal form of N-glycyl tyrosine monohydrate and preparation method of novel crystal form Download PDFInfo
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- CN104447946A CN104447946A CN201410615982.5A CN201410615982A CN104447946A CN 104447946 A CN104447946 A CN 104447946A CN 201410615982 A CN201410615982 A CN 201410615982A CN 104447946 A CN104447946 A CN 104447946A
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- XBGGUPMXALFZOT-VIFPVBQESA-N NCC(N[C@@H](Cc(cc1)ccc1O)C(O)=O)=O Chemical compound NCC(N[C@@H](Cc(cc1)ccc1O)C(O)=O)=O XBGGUPMXALFZOT-VIFPVBQESA-N 0.000 description 1
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Abstract
The invention relates to a crystal form of N-glycyl tyrosine, and particularly relates to a novel crystal form of an N-glycyl tyrosine monohydrate as well as a method for preparing the crystal form and an application in the medical field. The novel crystal form of the N-glycyl tyrosine monohydrate is characterized in that Cu-Ka radiation is used, and the X-ray powder diffraction indicated by adopting a 2-theta angle has characteristic peaks at 7.6+/-0.2, 9.9+/-0.2, 12.2+/-0.2, 15.2+/-0.2, 17.4+/-0.2, 23.0+/-0.2, 24.6+/-0.2, 30.1+/-0.2. The monohydrate crystal form is excellent in stability, lower in moisture absorption property and easier to store; the preparation method is simple in process, good in reproducibility and high in purity.
Description
Technical field
The present invention relates to medical compounds crystallization art, particularly a kind of new crystal and preparation method thereof of Glycyl-L-tyrosine monohydrate.
Background technology
Glycyl-L-tyrosine (N-glycyltyrosine); i.e. glycyl-L-Tyr; chemistry is by name: (2S)-2-(2-glycyl) amino-3-(4-hydroxy phenyl) propionic acid; being applied to can not be oral or through the outer supply nutrition of enteron aisle; and the patient that nutrition can not be satisfied the demand, be particularly in the patient of Metabolism.This compound has following structural formula:
The method of the sweet ammonia phthalein-TYR of current preparation, more employing is with the glycine of TYR ester and N-protected for starting raw material carries out being condensed into reactive polypeptide, and the condensing agent just adopted is different from the method for Deprotection and own.According to the document of retrieval, more feasible in production, roughly can be summarized as following three routes:
Route one biliographic data Paul; R.et al.; Journal Organic Chemistry Vo127:2094 ~ 99 (1962); with N; N '-carbonyl dimidazoles is that condensing agent is by carbobenzoxyglycine and tyrosine ethyl ester; be condensed into peptide, be then hydrolyzed protecting group and namely obtain glycyl-L-tyrosine.
Route two biliographic data S.Rajappa; K e1 al.; Tetrahedron Vo123:4805 ~ 9 (1967); (carbobenzoxy-(Cbz)) glycylglycine and new penta hydroxamic acid is adopted to be add tyrosine ethyl ester under active ester low temperature; first be condensed into peptide, be then hydrolyzed protecting group and namely obtain glycyl-L-tyrosine.
Route three referenced patent EP311057 (1988); take Dicyclohexylcarbodiimide as condensing agent; N-hydroxy-succinamide and carbobenzoxyglycine are made active ester, is then condensed into peptide with tyrosine ethyl ester, be then hydrolyzed protecting group and namely obtain glycyl-L-tyrosine.
Patent EP0950664 reports A and B two crystal formations of Glycyl-L-tyrosine dihydrate, does not report about the crystal formation of Glycyl-L-tyrosine monohydrate at present.
Summary of the invention
One aspect of the present invention there are provided Glycyl-L-tyrosine monohydrate crystal form, and described monohydrate crystal form has excellent stability, lower water absorbability, is beneficial to storage; Another aspect of the present invention there are provided its preparation method, and its technique is simple, and favorable reproducibility, purity is high.
The present invention realizes by the following technical solutions:
A kind of new crystal of Glycyl-L-tyrosine monohydrate, it is characterized in that, use Cu-Ka radiation, the X-ray powder diffraction represented with 2 θ angles has characteristic peak at 7.6 ± 0.2,9.9 ± 0.2,12.2 ± 0.2,15.2 ± 0.2,17.4 ± 0.2,23.0 ± 0.2,24.6 ± 0.2,30.1 ± 0.2 places.Glycyl-L-tyrosine monohydrate has following structural formula:
Preferably, the new crystal of described Glycyl-L-tyrosine monohydrate, it is characterized in that, use Cu-Ka radiation, the X-ray powder diffraction represented with 2 θ angles has characteristic peak at 7.6 ± 0.2,9.9 ± 0.2,11.4 ± 0.2,12.2 ± 0.2,14.3 ± 0.2,15.2 ± 0.2,17.4 ± 0.2,18.3 ± 0.2,18.8 ± 0.2,23.0 ± 0.2,23.7 ± 0.2,24.6 ± 0.2,28.9 ± 0.2,29.5 ± 0.2,30.1 ± 0.2,31.0 ± 0.2 places.
Preferred, the new crystal of described Glycyl-L-tyrosine monohydrate has the X-ray powder diffractogram represented by accompanying drawing 1.
The present invention also comprises the preparation method of Glycyl-L-tyrosine monohydrate, the preparation method of described Glycyl-L-tyrosine monohydrate, it is characterized in that: be warming up to 50 DEG C of stirring and dissolving by water-soluble for Glycyl-L-tyrosine with in the mixed solvent of organic solvent, molten clear rear slow cooling is to-10 DEG C, temperature-fall period controls at 1 hour,-10 DEG C are stirred 4 hours, filter, washing, 40-45 DEG C, vacuum tightness >=0.095Mpa obtain Glycyl-L-tyrosine hydrate crystallization in dry 8 hours; Described organic solvent is acetone, acetonitrile or its mixed solvent, and in the mixed solvent of described water and organic solvent, the volume fraction of organic solvent is 20% ~ 50%.
Further, described Glycyl-L-tyrosine monohydrate crystal form or according to the purposes of described preparation method for the preparation of parenteral nutrition pharmaceutical composition, is preferably injection parenteral nutrition preparation.
Accompanying drawing explanation
Below in conjunction with accompanying drawing, this invention is further described;
Accompanying drawing 1 is X-ray powder diffraction (XPRD) collection of illustrative plates of the Glycyl-L-tyrosine hydrate crystallization that the embodiment of the present invention 2 obtains.
Accompanying drawing 2 is thermogravimetric (TG) curve of the Glycyl-L-tyrosine hydrate crystallization that the embodiment of the present invention 2 obtains.
Accompanying drawing 3 is differential scanning calorimetric analysis (DSC) curve of the Glycyl-L-tyrosine hydrate crystallization that the embodiment of the present invention 2 obtains.
embodiment:
Following examples are only for illustration of the specific embodiment of the present invention, but not any limitation of the present invention.
embodiment 1: the preparation of Glycyl-L-tyrosine hydrate crystallization
Install WA-30 resin column in advance, and be washed till with deionized water neutral stand-by; Glycyl-L-tyrosine crude product 30g is dissolved in 450ml pure water, is heated to 50 DEG C of stirring and dissolving, then crosses resin column, and cross post time controling at 2 hours, elutriant 50 DEG C of evaporated under reduced pressure, obtain white powder 23.5g Glycyl-L-tyrosine highly finished product.
The Glycyl-L-tyrosine highly finished product that 10g aforesaid method obtains are added the mixed solvent of 50ml water and 50ml acetone, be warming up to 50 DEG C of stirring and dissolving, molten clear rear slow cooling is to-10 DEG C, temperature-fall period controls at 1 hour,-10 DEG C are stirred 4 hours, filter, washing with acetone, 40-45 DEG C, vacuum tightness >=0.095Mpa obtain Glycyl-L-tyrosine hydrate crystallization 6.8g in dry 8 hours.(HPLC purity 99.98%) moisture content 7.1%.
Fusing point: 285 ~ 290 DEG C (decomposition)
Water content (Karl_Fischer method): 7.12%(calculates with monohydrate: 7.03%)
IR(KBr，cm
-1)：3358，1672，1543，1464，1428，1395，1242，1150，1121。
The X-ray powder diffraction analysis result display of Glycyl-L-tyrosine monohydrate, Glycyl-L-tyrosine monohydrate is the crystal of the obvious characteristic diffractogram had as shown in Figure 1, lists the I/I with at least 3% in table 1
0the main peak of value.
Result shows, and it is that 7.6,9.9,11.4,12.2,14.3,15.2,17.4,18.3,18.8,23.0,23.7,24.6,28.9,29.5,30.1,31.0 places have I/I that its X-ray Powder Diffraction pattern is presented at 2 θ ± 0.2
0value is at least the peak of 3%.
In addition, composition graphs 2 and Fig. 3 visible, there is exothermic peak at differential scanning calorimetric analysis (DSC) curve display 92.3 DEG C of places of Glycyl-L-tyrosine monohydrate prepared by the present invention, its Quality Down 7.11%, its crystal water all loses, as can be seen from TG curve, sample is weightless few before 40 DEG C, loses crystal water fast at 50-90 DEG C.
embodiment 2: the preparation of Glycyl-L-tyrosine hydrate crystallization
10g is added the mixed solvent of 80ml water and 20ml acetonitrile with the Glycyl-L-tyrosine highly finished product that embodiment 1 method obtains, be warming up to 50 DEG C of stirring and dissolving, molten clear rear slow cooling is to-10 DEG C, temperature-fall period controls at 1 hour,-10 DEG C are stirred 4 hours, filter, acetonitrile wash, 40-45 DEG C, vacuum tightness >=0.095Mpa obtain Glycyl-L-tyrosine II type crystallization 6.4g in dry 8 hours.(HPLC purity 99.99%) moisture content 6.7%.
Fusing point: 285 ~ 290 DEG C (decomposition)
Water content (Karl_Fischer method): 7.09%(calculates with monohydrate: 7.03%)
Through the display of X-ray powder diffraction analysis result, embodiment 2 and embodiment 1 are all the crystal of the obvious characteristic diffractogram had as shown in Figure 1.
embodiment 3: stability test
Given the test agent is originated: obtain according to the method for the embodiment of the present invention 1.
Experimental technique: carry out according to the method in Pharmacopoeia of the People's Republic of China version in 2010 two annex XIX C bulk drugs and pharmaceutical preparation stability test governing principle.
Given the test agent is laid in watch-glass, places under high temperature (40 DEG C) and strong illumination (4500Lux) condition respectively, sampled respectively respectively at 0 day, 5 days, 10 days and detect sample purity, to investigate its stability.
High temperature (40 DEG C) the test-results table of table 2 Glycyl-L-tyrosine hydrate crystallization
| Test conditions | Examination item | 0 day | 5 days | 10 days |
| High temperature | Content (%) | 100.0 | 99.8 | 99.7 |
The exposure experiments to light of table 3 Glycyl-L-tyrosine hydrate crystallization
| Test conditions | Examination item | 0 day | 5 days | 10 days |
| Illumination | Content (%) | 100.0 | 99.9 | 99.8 |
As table 2 and 3 results prove, Glycyl-L-tyrosine monohydrate of the present invention has higher stability, places 10 days intensive amounts substantially unchanged under high temperature (40 DEG C) or strong illumination (4500Lux) condition.
embodiment 4: wettability test
Glycyl-L-tyrosine monohydrate sample the present invention prepared is laid in watch-glass, places under 25 DEG C to 35 DEG C relative humidity 40%-75% conditions, respectively at 0 day, 5 days, 10 days respectively sampling detect water-content in sample, to investigate its stability to water.
The wettability test test-results table of table 4 Glycyl-L-tyrosine hydrate crystallization
As shown in table 4, under high humidity conditions, Glycyl-L-tyrosine monohydrate of the present invention has less water absorbability, and keeps its initial water content under low humidity conditions.
Except as otherwise noted, in the present invention, moisture content adopts plum Teller DL31 Ka Shi Moisture Meter to measure.
Except as otherwise noted, the X-ray powder diffraction test condition in the present invention is as follows:
INSTRUMENT MODEL: Bruker D8ADVANCE; Light source Cu-Ka 40kV 40mA; Graphite monochromator; Divergent slit (DS): 1 °; LynxEye detector array, scan mode: θ/θ, continuous sweep; Sweep limit: 0 ° ~ 50 °.
Except as otherwise noted, in the present invention, HPLC condition is as follows:
Chromatographic column: Dikma PlatisilTM ODS, 150 × 4.6mm, 5 μm of column temperatures: 25 DEG C
Moving phase: A acetonitrile; B damping fluid (10mM SODIUM PHOSPHATE, MONOBASIC, pH 7.6) (40:60)
Determined wavelength: 280mm.
Although invention has been described with reference to embodiment, will be appreciated that the various amendment the present invention carried out by those skilled in the art and change also as claims within the scope of the present invention that defines.
Claims (5)
1. the new crystal of a Glycyl-L-tyrosine monohydrate, it is characterized in that, use Cu-Ka radiation, the X-ray powder diffraction represented with 2 θ angles has characteristic peak at 7.6 ± 0.2,9.9 ± 0.2,12.2 ± 0.2,15.2 ± 0.2,17.4 ± 0.2,23.0 ± 0.2,24.6 ± 0.2,30.1 ± 0.2 places.
2. the new crystal of Glycyl-L-tyrosine monohydrate according to claim 1, it is characterized in that, use Cu-Ka radiation, the X-ray powder diffraction represented with 2 θ angles has characteristic peak at 7.6 ± 0.2,9.9 ± 0.2,11.4 ± 0.2,12.2 ± 0.2,14.3 ± 0.2,15.2 ± 0.2,17.4 ± 0.2,18.3 ± 0.2,18.8 ± 0.2,23.0 ± 0.2,23.7 ± 0.2,24.6 ± 0.2,28.9 ± 0.2,29.5 ± 0.2,30.1 ± 0.2,31.0 ± 0.2 places.
3. the preparation method of the Glycyl-L-tyrosine monohydrate according to any one of claim 1-2, it is characterized in that: by water-soluble for Glycyl-L-tyrosine with in the mixed solvent of organic solvent, be warming up to 50 DEG C of stirring and dissolving, molten clear rear slow cooling is to-10 DEG C, and temperature-fall period controls at 1 hour, and-10 DEG C are stirred 4 hours, filter, washing, 40-45 DEG C, vacuum tightness >=0.095Mpa obtain Glycyl-L-tyrosine hydrate crystallization in dry 8 hours.
4. the preparation method of Glycyl-L-tyrosine monohydrate according to claim 3, is characterized in that: described organic solvent is acetone, acetonitrile or its mixed solvent, and in the mixed solvent of described water and organic solvent, the volume fraction of organic solvent is 20% ~ 50%.
5. the Glycyl-L-tyrosine monohydrate crystal form described in any one of claim 1-2 or according to the purposes of preparation method described in any one of claim 3-4 for the preparation of parenteral nutrition pharmaceutical composition, is preferably injection parenteral nutrition preparation.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0950664A1 (en) * | 1998-04-14 | 1999-10-20 | Kyowa Hakko Kogyo Co., Ltd. | Process for producing n-glycyltyrosine |
| CN101429227A (en) * | 2008-12-05 | 2009-05-13 | 北京博时安泰科技发展有限公司 | Refining method for Glycyl-L-tyrosine |
| CN102993270A (en) * | 2011-09-15 | 2013-03-27 | 山东齐都药业有限公司 | Preparation process of glycyl-L-tyrosine |
-
2014
- 2014-11-05 CN CN201410615982.5A patent/CN104447946B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0950664A1 (en) * | 1998-04-14 | 1999-10-20 | Kyowa Hakko Kogyo Co., Ltd. | Process for producing n-glycyltyrosine |
| CN101429227A (en) * | 2008-12-05 | 2009-05-13 | 北京博时安泰科技发展有限公司 | Refining method for Glycyl-L-tyrosine |
| CN102993270A (en) * | 2011-09-15 | 2013-03-27 | 山东齐都药业有限公司 | Preparation process of glycyl-L-tyrosine |
Non-Patent Citations (1)
| Title |
|---|
| R. A. PASTERNAK, ET AL.: "The crystal structure of glycyl-L-tryptophan dihydrate", 《ACTA CRYSTALLOGRAPHICA》 * |
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