CN102827017A - Crystal form of double salt compound and preparation method thereof - Google Patents
Crystal form of double salt compound and preparation method thereof Download PDFInfo
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- CN102827017A CN102827017A CN2011101591378A CN201110159137A CN102827017A CN 102827017 A CN102827017 A CN 102827017A CN 2011101591378 A CN2011101591378 A CN 2011101591378A CN 201110159137 A CN201110159137 A CN 201110159137A CN 102827017 A CN102827017 A CN 102827017A
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Abstract
The invention provides a new crystal form of a double salt compound ((S)-2,5-diamino pentanoic acid-(S)-2-amino succinate) shown in formula (I). The crystal form is characterized by using an X-ray powder diffraction pattern. The invention further provides a preparation method of the new crystal form of the (S)-2,5-diamino pentanoic acid-(S)-2-amino succinate. The new crystal form of the (S)-2,5-diamino pentanoic acid-(S)-2-amino succinate has very obvious advantage in stability, wherein crystal form, appearance and color of the product are stable after the product is stored for 18 months, and the volume does not change obviously, and thus the product has wide application prospects in pharmaceutical industry.
Description
Technical field
The invention belongs to the chemicals field, specifically, relate to the compound salt (S)-2 of a kind of formula (I), new crystal of 5-Ornithine-(S)-2-amino-succinic acid salt and preparation method thereof.
Background technology
Compound salt (S)-2, the 5-Ornithine-(S)-and 2-amino-succinic acid salt, general ornithine Aspartic Acid by name (L-Ornithine-L-Asparate) is to be obtained through the reaction salify by L-ornithine and L-Aspartic Acid, its structural formula is following:
The ornithine Aspartic Acid is the most clinical prior to being used in Germany the seventies in 20th century, records Ph.G in 1991 years.It is used to treat hepatogenic encephalopathy drugs approved by FDA, and by the first-selected medication that FDA is recommended as the treatment hepatogenic encephalopathy, obtains high clinical evaluation at international medical community.China is the district occurred frequently of viral hepatitis, and at present, China has 3,000,000 chronic hepatitis patients approximately, and that dies from hepatopathy every year has about 500,000 people.Huge patient colony has brought up tempting liver disease medicine market.These article are medicines that first biochemical type tool protects liver, detoxifcation, the unification of energy triple effect, and clinical reflection effect is fine, is the drug of first choice of hepatic coma.
The ornithine Aspartic Acid can be supplied urea and Stimulina synthetic substrate in vivo.Stimulina is the detoxifcation product of ammonia, also is the storage and the types of transportation of ammonia simultaneously.Under physiology and pathological conditions, the synthetic meeting synthetic and Stimulina of urea receives the influence of ornithine, Aspartic Acid and other dicarboxylic compounds.Ornithine almost relates to the activation of ornithine cycle and the toxicide whole process of ammonia.In this process, form l-arginine, isolate urea then and form ornithine.Aspartic Acid is participated in the synthetic of the interior nucleic acid of liver cell, is beneficial to repair the liver cell that is damaged.In addition,, be beneficial to the hepatocellular reparation of damage, accelerate the recovery of liver function because Aspartic Acid, has promoted that the energy in the liver cell is synthetic to the indirect promoter action of tricarboxylic acid cycle metabolic process in the liver cell.Therefore, be applicable to that clinically acute and chronic hepatopathy comprises liver cirrhosis, fatty liver, various viral and toxic hepatitis and hyperammonemia, particularly because of the improvement of the caused cns symptom of hepatic diseases and the treatment of hepatogenic encephalopathy.
The preparation method of ornithine Aspartic Acid and therepic use patent documentation DE4020980 have in early days just had description.But the document about this product material existence report is seldom seen.We find that in repeating the process of this experiment problems such as variable color, the easy expansion of product take place the product according to document obtains easily, have brought very big difficulty for the storage of product in the process of preserving.
In view of the pharmacy value of ornithine Aspartic Acid compound, it is most important obtaining purity product state of matter good and that especially circulation ratio is fabulous.This form is in stripping and make things convenient for and demonstrate valuable characteristic aspect the configuration, allows its long-time storage and the characteristic of temperature, light, humidity or oxygen level is not had special demands.
Summary of the invention
The applicant has developed the method intact, reproducible crystal formation that obtains at present, and said crystal formation is in stripping and make things convenient for and demonstrate valuable characteristic aspect the preparation.This form of what is more important allows its optimum storage and does not have special protection along with the stability that has highly significant in the past of time, and this has constituted most important advantage in pharmaceutical industry.
More particularly, the present invention relates to the new crystal of formula (I) compound:
It characterizes through following X-ray powder diffraction pattern, uses that powder XRD X meter (Cu/K) is measured and with term spacing d, 2 θ angles, Prague and relative intensity I (to represent with respect to the percentage ratio of strong ray) expression:
A kind of new crystal formation of formula (I) compound, it is through the infrared spectrum characterization shown in the accompanying drawing 2.
The invention still further relates to the preparation method of the compound new crystal shown in the formula (I), comprise the ornithine Aspartic Acid soluble in waterly, the aqueous solution that obtains joins in the hydrophilic solvent of preheating, cooling, filtration, vacuum-drying.
According to the present invention, the volume of water is 1～6: 1 with the ratio of ornithine Aspartic Acid quality, preferred 2～5: 1, more preferably 2～4: 1.
According to the present invention, said hydrophilic solvent is selected from: methyl alcohol, ethanol, propyl alcohol, Virahol or acetone a kind of or their mixture.
According to the present invention, the preheating temperature of said hydrophilic solvent is 30～80 ℃, preferred 35～60 ℃, and more preferably 45～55 ℃.
The appearance luster of ornithine Aspartic Acid new crystal of the present invention crystal formation after storing 18 months is stable, and volume is not found considerable change yet.
Description of drawings
Fig. 1 is the powder x-ray diffraction figure of the ornithine Aspartic Acid crystal formation of embodiment 1 acquisition.
Fig. 2 is the infrared absorption spectrum of the ornithine Aspartic Acid crystal formation of embodiment 1 acquisition.
Fig. 3 is the powder x-ray diffraction figure of ornithine Aspartic Acid crystal formation after placing 18 months that embodiment 1 obtains.
Embodiment
Below in conjunction with specific embodiment, the present invention is described further.Should be understood that following examples only are used to the present invention is described but not are used to limit scope of the present invention.
Employed ornithine Aspartic Acid bullion can prepare like patent GB965637 and the described method of GB1067742 according to the prior art reported method in following examples, also has commercially available.
Embodiment 1-4, ornithine Aspartic Acid new crystal preparation
Press shown in the table 1, get ornithine Aspartic Acid bullion 13.2g, add the deionized water of 40ml, be stirred to solid and all dissolve after-filtration, get the clear solution A;
This solution A is added dropwise to is preheated to 50 ℃ hydrophilic solvent to 160ml; Drip to finish, after keeping this temperature and stirring half a hour, with per hour 10 ℃ be cooled to 0 ℃, insulation crystallization 3～4 hours filters; Filter cake is with hydrophilic solvent washing 2 times, and 50 ℃ of vacuum-dryings obtain white solid 12.1g, yield 91.7%.
Table 1, ornithine Aspartic Acid new crystal preparation technology's solvent and hydrophilic solvent
| Embodiment | Solvent | |
|
| 1 | | Methyl alcohol | |
| 2 | Water | Ethanol | |
| 3 | Water | Virahol | |
| 4 | Water | Acetone |
Embodiment 5, ornithine Aspartic Acid new crystal evaluation
Get the ornithine Aspartic Acid white solid that embodiment 1 obtains; Measure its spacing d, 2 θ angles, Prague and relative intensity I (to represent) with x-ray powder diffraction with respect to the percentage ratio of strong ray; The result is as shown in Figure 1, and corresponding data are shown in following table 2:
Table 2, X-ray powder diffraction data
Fig. 2 has shown the ir spectra of the ornithine Aspartic Acid white solid that embodiment 1 obtains.
The crystal formation data of the ornithine Aspartic Acid white solid that embodiment 2～4 obtains are consistent with the sample that embodiment 1 obtains.
Process and the comparison that has known ornithine Aspartic Acid crystal formation now, the ornithine Aspartic Acid white solid that the present invention obtains is a kind of new crystal formation, does not report in the prior art.
Embodiment 6, stability experiment
Get the ornithine Aspartic Acid white solid that embodiment 1～4 obtains; Through the investigation of the product defects project of bibliographical information being observed the stability of this product; Wherein the mensuration result of the sample of embodiment 1 is shown in following table 3, and the result of all the other samples is consistent with the sample of embodiment 1.
Table 3, stability are relatively
Result by table 3 is visible; Ornithine Aspartic Acid new crystal of the present invention has very remarkable advantages aspect stable; The appearance luster that stores crystal formation after 18 months is stable, and volume is not found considerable change yet, thereby in pharmaceutical industry, is with a wide range of applications.
Claims (10)
1. the crystal formation of the compound salt shown in the formula (I) is characterized in that:
The crystal formation of said compound salt characterizes through following X-ray powder diffraction pattern, uses that powder XRD X meter (Cu/K) is measured and with term spacing d, 2 θ angles, Prague and relative intensity I (to represent with respect to the percentage ratio of strong ray) expression:
2. the crystal formation of compound salt according to claim 1 is characterized in that, said compound salt is through the infrared spectrum characterization shown in the accompanying drawing 2.
3. the preparation method of the crystal formation of compound salt according to claim 1 and 2 is characterized in that:
With compound salt (S)-2, the 5-Ornithine-(S)-and 2-amino-succinic acid salt bullion is soluble in water, and the aqueous solution that obtains joins in the hydrophilic solvent of preheating, cooling, filtration, vacuum-drying.
4. method according to claim 3 is characterized in that: the volume of said water is 1～6: 1 with the ratio of the quality of compound salt.
5. method according to claim 4 is characterized in that: the volume of said water is 2～5: 1 with the ratio of the quality of compound salt.
6. method according to claim 5 is characterized in that: the ratio of the volume of said water and the quality of compound salt is more preferably 2～4: 1.
7. method according to claim 3 is characterized in that: said hydrophilic solvent is a kind of in methyl alcohol, ethanol, propyl alcohol, Virahol or the acetone or their mixture.
8. method according to claim 3 is characterized in that: the preheating temperature of said hydrophilic solvent is 30～80 ℃.
9. method according to claim 3 is characterized in that: the preheating temperature of said hydrophilic solvent is 35～60 ℃.
10. method according to claim 3 is characterized in that: the preheating temperature of said hydrophilic solvent is 45～55 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110159137.8A CN102827017B (en) | 2011-06-14 | 2011-06-14 | Crystal form of double salt compound and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110159137.8A CN102827017B (en) | 2011-06-14 | 2011-06-14 | Crystal form of double salt compound and preparation method thereof |
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| Publication Number | Publication Date |
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| CN102827017A true CN102827017A (en) | 2012-12-19 |
| CN102827017B CN102827017B (en) | 2014-07-02 |
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| CN201110159137.8A Expired - Fee Related CN102827017B (en) | 2011-06-14 | 2011-06-14 | Crystal form of double salt compound and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105985252A (en) * | 2015-02-11 | 2016-10-05 | 上海美悦生物科技发展有限公司 | Aspartic acid-ornithine crystal IV and preparation method thereof |
| CN108440324A (en) * | 2018-04-19 | 2018-08-24 | 成都倍特药业有限公司 | A kind of aspartic acid ornithine and its method for crystallising |
| CN110317144A (en) * | 2018-03-28 | 2019-10-11 | 上海贵之言医药科技有限公司 | A kind of aspartic acid ornithine Crystal form of double salt compound and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1034358A (en) * | 1963-05-01 | 1966-06-29 | Chugai Pharmaceutical Co Ltd | Body-protein-biosynthesis promoting composition |
| GB1067742A (en) * | 1963-09-16 | 1967-05-03 | Kyowa Hakko Kogyo Kk | Process for the preparation of l-ornithine l-aspartate |
| US5227007A (en) * | 1990-09-28 | 1993-07-13 | Kyowa Hakko Kogyo Co., Ltd. | Process for producing crystals of salt of acidic amino acid and basic amino acid |
-
2011
- 2011-06-14 CN CN201110159137.8A patent/CN102827017B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1034358A (en) * | 1963-05-01 | 1966-06-29 | Chugai Pharmaceutical Co Ltd | Body-protein-biosynthesis promoting composition |
| GB1067742A (en) * | 1963-09-16 | 1967-05-03 | Kyowa Hakko Kogyo Kk | Process for the preparation of l-ornithine l-aspartate |
| US5227007A (en) * | 1990-09-28 | 1993-07-13 | Kyowa Hakko Kogyo Co., Ltd. | Process for producing crystals of salt of acidic amino acid and basic amino acid |
Non-Patent Citations (5)
| Title |
|---|
| D.M.SALUNKE等: "X-ray studies on crystalline complexes involving amino acids and peptides IX. Crystal structure of L-ornithine L-aspartate hemihydrate", 《INTERNATIONAL JOURNAL OF PEPTIDE & PROTEIN RESEARCH》 * |
| SANG-MOK CHANG等: "Agglomeration Control of L-Ornithine Aspartate Crystals by Operating Variables", 《INDUSTRIAL & ENGINEERING CHEMISTRY RESEARCH》 * |
| WOOCHAN HYUNG等: "Agglomeration behavior of anhydrous L-ornithine-L-aspatate crystals during semi-batch drowning-out crystallization", 《KOREAN J. CHEM. ENG.》 * |
| YEHOON KIM等: "Parameters Determining the Agglomeration Behavior of Anhydrous L-ornithine-L-aspartate (LOLA) Crystals Prepared by Drowning Out Crystallization", 《KOREAN J. CHEM. ENG.》 * |
| 郑岚等: "药用氨基酸复合盐的合成研究", 《化学试剂》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105985252A (en) * | 2015-02-11 | 2016-10-05 | 上海美悦生物科技发展有限公司 | Aspartic acid-ornithine crystal IV and preparation method thereof |
| CN110317144A (en) * | 2018-03-28 | 2019-10-11 | 上海贵之言医药科技有限公司 | A kind of aspartic acid ornithine Crystal form of double salt compound and preparation method thereof |
| CN108440324A (en) * | 2018-04-19 | 2018-08-24 | 成都倍特药业有限公司 | A kind of aspartic acid ornithine and its method for crystallising |
| CN108440324B (en) * | 2018-04-19 | 2021-04-20 | 成都倍特药业股份有限公司 | Ornithine aspartate and crystallization method thereof |
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|---|---|
| CN102827017B (en) | 2014-07-02 |
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Granted publication date: 20140702 Termination date: 20190614 |