CN110317144A - A kind of aspartic acid ornithine Crystal form of double salt compound and preparation method thereof - Google Patents
A kind of aspartic acid ornithine Crystal form of double salt compound and preparation method thereof Download PDFInfo
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- CN110317144A CN110317144A CN201810266263.5A CN201810266263A CN110317144A CN 110317144 A CN110317144 A CN 110317144A CN 201810266263 A CN201810266263 A CN 201810266263A CN 110317144 A CN110317144 A CN 110317144A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The present invention provides a kind of novel crystal forms of aspartic acid ornithine compound salt shown in formula (I) (chemical name: (S) -2,5- diaminovaleric acid-(S) -2- aminosuccinic acid salt).Formula (I):
Description
Technical field
The invention belongs to chemical medicine fields, specifically, are related to a kind of aspartic acid ornithine formula (I) double salt chemical combination
Object, chemical name: (S) -2,5- diaminovaleric acid-(S) -2- aminosuccinic acid salt novel crystal forms and preparation method thereof.
Background technique
Hepatic encephalopathy is the severe complication of cirrhosis, and the death rate is higher.Hepatic encephalopathy and blood ammonia increase, branched-chain amino acid
With ArAA is out of proportion and the factors such as false neurotransmitter are related, wherein ammonia poisoning theory is considered as the warp of morbidity
Allusion quotation theory.Hepatic encephalopathy reduces the treatment of blood ammonia mainly by the generation and absorption of the internal ammonia of reduction, promotes ammonia metabolism,
Restore the function of liver cell to complete.Aspartic acid ornithine can significantly reduce blood ammonia levels, improve liver function, alleviate liver property brain
The various neuropsychic symptoms of patient, are hepatic encephalopathies caused by the various hepatopathys for the treatment of, and treatment is hard because of acute and chronic hepatopathy such as liver
Hyperammonemia caused by change, fatty liver, hepatitis, especially suitable for the releasing because of central nervous system symptom caused by liver disease
And one of ideal medicament of rescue of hepatic coma.Aspartic acid ornithine is most used for clinic in Germany prior to the 1970s,
Record Deutscher Arzneibucs within 1991.U.S. FDA ratifies it and is used to treat hepatic encephalopathy, and is recommended as treating hepatic encephalopathy by FDA
Preferred medication obtains high clinical evaluation in international medical community.
Aspartic acid ornithine (L-Ornithine-L-Asparate) compound salt, chemical name: (S) -2,5- diamino
Base valeric acid-(S) -2- aminosuccinic acid salt is to be obtained by L-Orn and L-ASPARTIC ACID are reacted at salt, and structural formula is such as
Under:
The preparation method and therapeutical uses of aspartic acid ornithine have just had in earlier patents document DE4020980 retouches
It states.But the document about its substance existence (i.e. crystal form) report is seldom seen.Present inventor is existing in repetition
It is found during the preparation method of aspartic acid ornithine in technology, according to aspartic acid ornithine in the prior art
The aspartic acid ornithine product that preparation method obtains, stability is inadequate, discoloration is easy to happen during preservation, product holds
The problems such as easily expanding, brings very big difficulty to the storage of product.More inconvenient is L-aminobutanedioic acid bird in the prior art
The aspartic acid ornithine non-refractory that the preparation method of propylhomoserin obtains can not use the terminal overkill sterilization of the current international practice
Mode (i.e. sterility assurance level F0 value be greater than 12) provides Sterility Assurance, leads to that there are biggish drug safety hidden danger.And I
State is the district occurred frequently of virus hepatitis, currently, there are about 3,000,000 chronic hepatitis patients in China, that dies of hepatopathy every year has 500,000
People or so.Huge PATIENT POPULATION creates tempting hepatosis treating medicine market, also leads to drug safety potential problem more
Seriously.
Pharmacy value in view of aspartic acid ornithine compound salt and at present there is also above-mentioned technological deficiency, having must
New crystal form preparation method is researched and developed, to obtain the good aspartic acid ornithine of stability.
Summary of the invention
The applicant, which developed, obtains intact, good, the reproducible crystal form of stability method, which is dissolving out
With facilitate prepare aspect show valuable characteristic.More importantly the crystal form has the stability of highly significant, allow
Its optimum is stored without special protection, this constitutes most important advantage in pharmaceuticals industry.
The first purpose of the invention is to provide a kind of aspartic acid ornithine Crystal form of double salt compound, to realize above-mentioned mesh
, the invention adopts the following technical scheme:
A kind of crystal form of aspartic acid ornithine compound salt shown in formula (I),
The crystal form of the aspartic acid ornithine compound salt is characterized by X-ray powder diffraction figure, is penetrated using powder
Line diffractometer (Cu/K) measurement, and with term interplanar distance d, 2 angle θ of Prague and relative intensity I (relative to most strong ray
Percentage indicate) be expressed as follows table:
According to the present invention, the crystal form of the aspartic acid ornithine compound salt passes through attached X-ray powder shown in FIG. 1
Last diffraction pattern characterization,
Further, the aspartic acid ornithine compound salt passes through attached drawing 2 to attached nuclear magnetic resonance shown in Fig. 4
HNMR, CNMR and H-HCOSY characterization.
Second object of the present invention is to provide the preparation method of above-mentioned aspartic acid ornithine Crystal form of double salt compound,
Include the following steps:
1), aspartic acid ornithine compound salt crude product is dissolved in deionized water, suitable active carbon, mistake is added
Filter, obtains filtrate A；
2), the filtrate A that step 1) obtains is added in the hydrophilic solvent by preheating, cooling, filtering, vacuum drying,
Up to aspartic acid ornithine compound salt.
By identification, step 2) prepares resulting aspartic acid ornithine compound salt with crystalline substance of the present invention
Type.
According to the present invention, after active carbon being added in the step 1), 48 ± 3 DEG C are warming up to, keep the temperature after 30 ± 5min after
Filter.
With this condition handle after refilter, can utmostly by reaction system impurity and intracellular toxin remove.
The filtration step can be filtered using film.
According to the present invention, in the step 2), the cooling step is specifically included: 12 are cooled to 2~6 DEG C per hour ±
3 DEG C, then keep the temperature crystallization 3~4 hours.
According to the present invention, the quality of the volume of the deionized water and the aspartic acid ornithine compound salt crude product
Than for 1~6:1.
Preferably, the volume of the deionized water and the mass ratio of the aspartic acid ornithine compound salt crude product are
2~5:1.
It is highly preferred that the mass ratio of the volume of the deionized water and the aspartic acid ornithine compound salt crude product
For 2~4:1.
According to the present invention, the mass ratio of the active carbon and the aspartic acid ornithine compound salt crude product is
0.001~0.10:1.
Preferably, the mass ratio of the active carbon and the aspartic acid ornithine compound salt crude product be 0.01~
0.08:1.
It is highly preferred that the mass ratio of the active carbon and the aspartic acid ornithine compound salt crude product be 0.02~
0.05:1.
According to the present invention, the hydrophilic solvent is one of methanol, ethyl alcohol or acetone or their mixture.
According to the present invention, the preheating temperature of the hydrophilic solvent is 30~75 DEG C.
Preferably, the preheating temperature of the hydrophilic solvent is 35~60 DEG C.
It is highly preferred that the preheating temperature of the hydrophilic solvent is 45~55 DEG C.
Compared with prior art, the present invention has following advantageous effects:
The novel crystal forms of aspartic acid ornithine compound salt of the invention, it is with good stability, even if storing
The appearance luster of crystal form is stablized after 24 months, and volume does not also find significant change, therefore allows long-time storage, to temperature, light,
Humidity or the characteristic of oxygen level do not specially require, thus non-having compared with crystal form in the prior art in terms of stability
Normal apparent advantage.
The excellent especially reproducibility of purity is fabulous simultaneously, and valuable characteristic is shown in terms of dissolving out and facilitating configuration,
Therefore it is with a wide range of applications in pharmaceuticals industry.
Detailed description of the invention
Fig. 1 is the powder x-ray diffraction figure for the aspartic acid ornithine crystal form that embodiment 1 obtains.
Fig. 2 is the HNMR map for the aspartic acid ornithine crystal form that embodiment 1 obtains.
Fig. 3 is the CNMR map for the aspartic acid ornithine crystal form that embodiment 1 obtains.
Fig. 4 is the H-H COSY map for the aspartic acid ornithine crystal form that embodiment 1 obtains.
Fig. 5 is the HMBC map for the aspartic acid ornithine crystal form that embodiment 1 obtains.
Fig. 6 is the HSQC map for the aspartic acid ornithine crystal form that embodiment 1 obtains.
Fig. 7 is the DEPT map for the aspartic acid ornithine crystal form that embodiment 1 obtains.
Fig. 8 is the infrared absorption spectrum for the aspartic acid ornithine crystal form that embodiment 1 obtains.
Fig. 9 is powder x-ray diffraction figure of the aspartic acid ornithine crystal form of the acquisition of embodiment 1 after placing 6 months.
Figure 10 is powder x-ray diffraction of the aspartic acid ornithine crystal form of the acquisition of embodiment 1 after placing 12 months
Figure.
Figure 11 is powder x-ray diffraction of the aspartic acid ornithine crystal form of the acquisition of embodiment 1 after placing 24 months
Figure.
Figure 12 indicate aspartic acid ornithine novel crystal forms of the invention place 6 months, 12 months, 24 months powder X-rays penetrate
The comparison diagram of ray diffraction diagram spectrum.
Specific embodiment
Below in conjunction with specific embodiment, the invention will be further described.It should be understood that following embodiment is merely to illustrate this
Invention is not for limiting the scope of the invention.
The method that aspartic acid ornithine crude product used in following embodiment can be reported according to the prior art, such as patent
Method described in GB965637 and GB1067742 prepares, also commercially available.
Embodiment 1, aspartic acid ornithine novel crystal forms preparation
1), by shown in table 1, aspartic acid ornithine crude product 13.2g is taken, the deionized water of 40ml, stirring to door winter is added
All after dissolution, active carbon 0.4g is added in propylhomoserin ornithine crude product, and stirring is warming up to 48 ± 3 DEG C, keeps the temperature mistake after 30 ± 5min
Filter, obtains the filtrate A of clear；
2), the filtrate A that step 1) obtains is added dropwise to 160 ± 5ml in the hydrophilic solvent for being preheated to 50 DEG C；It was added dropwise
Journey is kept stirring, and drop finishes, and after maintaining the temperature to stir half an hour, is cooled to 12 ± 3 DEG C with 4 DEG C per hour, is then kept the temperature crystallization
3.5 hours, filtering, obtained filter cake was washed 2 times with hydrophilic solvent, and 50 ± 2 DEG C of vacuum drying obtain aspartic acid ornithine
White solid.
Embodiment 2, aspartic acid ornithine novel crystal forms preparation
1), by shown in table 1, aspartic acid ornithine crude product 13.2g is taken, the deionized water of 13.2ml, stirring to door is added
All after dissolution, active carbon 0.0132g is added in aspartic acid ornithine crude product, and stirring is warming up to 48 ± 3 DEG C, keeps the temperature 30 ± 5min
After filter, obtain the filtrate A of clear；
2), the filtrate A that step 1) obtains is added dropwise to 160 ± 5ml in the hydrophilic solvent for being preheated to 30 DEG C；It was added dropwise
Journey is kept stirring, and drop finishes, and after maintaining the temperature to stir half an hour, is cooled to 12 ± 3 DEG C with 6 DEG C per hour, then keeps the temperature crystallization 3
Hour, filtering, obtained filter cake is washed 2 times with hydrophilic solvent, and 50 ± 2 DEG C of vacuum drying obtain aspartic acid ornithine white
Solid.
Embodiment 3, aspartic acid ornithine novel crystal forms preparation
1), by shown in table 1, aspartic acid ornithine crude product 13.2g is taken, the deionized water of 79.2ml, stirring to door is added
All after dissolution, active carbon 1.32g is added in aspartic acid ornithine crude product, and stirring is warming up to 48 ± 3 DEG C, after keeping the temperature 30 ± 5min
Filtering, obtains the filtrate A of clear；
2), the filtrate A that step 1) obtains is added dropwise to 160 ± 5ml in the hydrophilic solvent for being preheated to 75 DEG C；It was added dropwise
Journey is kept stirring, and drop finishes, and after maintaining the temperature to stir half an hour, is cooled to 12 ± 3 DEG C with 3 DEG C per hour, then keeps the temperature crystallization 4
Hour, filtering, obtained filter cake is washed 2 times with hydrophilic solvent, and 50 ± 2 DEG C of vacuum drying obtain aspartic acid ornithine white
Solid.
Embodiment 4, aspartic acid ornithine novel crystal forms preparation
1), by shown in table 1, aspartic acid ornithine crude product 13.2g is taken, the deionized water of 26.4ml, stirring to door is added
All after dissolution, active carbon 0.264g is added in aspartic acid ornithine crude product, and stirring is warming up to 48 ± 3 DEG C, after keeping the temperature 30 ± 5min
Filtering, obtains the filtrate A of clear；
2), the filtrate A that step 1) obtains is added dropwise to 160 ± 5ml in the hydrophilic solvent for being preheated to 55 DEG C；It was added dropwise
Journey is kept stirring, and drop finishes, and after maintaining the temperature to stir half an hour, is cooled to 12 ± 3 DEG C with 5 DEG C per hour, then keeps the temperature crystallization 4
Hour, filtering, obtained filter cake is washed 2 times with hydrophilic solvent, and 50 ± 2 DEG C of vacuum drying obtain aspartic acid ornithine white
Solid.
Embodiment 5, aspartic acid ornithine novel crystal forms preparation
1), by shown in table 1, aspartic acid ornithine crude product 13.2g is taken, the deionized water of 66ml, stirring to door winter is added
All after dissolution, active carbon 1.056g is added in propylhomoserin ornithine crude product, and stirring is warming up to 48 ± 3 DEG C, keeps the temperature mistake after 30 ± 5min
Filter, obtains the filtrate A of clear；
2), the filtrate A that step 1) obtains is added dropwise to 160 ± 5ml in the hydrophilic solvent for being preheated to 35 DEG C；It was added dropwise
Journey is kept stirring, and drop finishes, and after maintaining the temperature to stir half an hour, is cooled to 12 ± 3 DEG C with 6 DEG C per hour, then keeps the temperature crystallization 3
Hour, filtering, obtained filter cake is washed 2 times with hydrophilic solvent, and 50 ± 2 DEG C of vacuum drying obtain aspartic acid ornithine white
Solid.
Embodiment 6, aspartic acid ornithine novel crystal forms preparation
1), by shown in table 1, aspartic acid ornithine crude product 13.2g is taken, the deionized water of 52.8ml, stirring to door is added
All after dissolution, active carbon 0.66g is added in aspartic acid ornithine crude product, and stirring is warming up to 48 ± 3 DEG C, after keeping the temperature 30 ± 5min
Filtering, obtains the filtrate A of clear；
2) the filtrate A that step 1) obtains, is added dropwise to 160 ± 5ml to be preheated in 45 DEG C of hydrophilic solvent；Dropwise addition process
It is kept stirring, drop finishes, and after maintaining the temperature to stir half an hour, is cooled to 12 ± 3 DEG C with 5 DEG C per hour, and it is small then to keep the temperature crystallization 4
When, filtering, obtained filter cake is washed 2 times with hydrophilic solvent, and it is solid that 50 ± 2 DEG C of vacuum drying obtain aspartic acid ornithine white
Body.
Embodiment 7, aspartic acid ornithine novel crystal forms preparation
1), by shown in table 1, aspartic acid ornithine crude product 13.2g is taken, the deionized water of 50ml, stirring to door winter is added
All after dissolution, active carbon 0.792g is added in propylhomoserin ornithine crude product, and stirring is warming up to 48 ± 3 DEG C, keeps the temperature mistake after 30 ± 5min
Filter, obtains the filtrate A of clear；
2) the filtrate A that step 1) obtains, is added dropwise to 160 ± 5ml to be preheated in 60 DEG C of hydrophilic solvent；Dropwise addition process
It is kept stirring, drop finishes, and after maintaining the temperature to stir half an hour, is cooled to 12 ± 3 DEG C with 2 DEG C per hour, and it is small then to keep the temperature crystallization 4
When, filtering, obtained filter cake is washed 2 times with hydrophilic solvent, and it is solid that 50 ± 2 DEG C of vacuum drying obtain aspartic acid ornithine white
Body.
The preparation technology parameter of table 1, aspartic acid ornithine Crystal form of double salt compound
Embodiment 8, aspartic acid ornithine Crystal form of double salt compound identification
The aspartic acid ornithine white solid that Example 1 obtains, measures its interplanar with x-ray powder diffraction
It is as a result as shown in Figure 1, corresponding away from d, 2 angle θ of Prague and relative intensity I (being indicated with the percentage relative to most strong ray)
X-ray powder diffraction data are as shown in table 2:
The X-ray powder diffraction data for the aspartic acid ornithine white solid that table 2, embodiment 1 obtain
The sample one that the crystal form data and embodiment 1 for the aspartic acid ornithine white solid that embodiment 2~7 obtains obtain
It causes.
Fig. 2-8 show the resulting aspartic acid ornithine white solid of embodiment 1 nuclear magnetic resonance map and infrared suction
Receive spectrum.The sample that the nuclear magnetic resonance map and embodiment 1 for the aspartic acid ornithine white solid that embodiment 2~7 obtains obtain
Product are consistent.
Consolidate by the ornithine L-aminobutanedioic acid white that compared with existing aspartic acid ornithine crystal form, the present invention is obtained
The crystal form of body is a kind of new crystal form, is not reported in the prior art.
Embodiment 9, stability experiment
By investigating the aspartic acid ornithine white solid sample of the acquisition of embodiment 1 after placing 6,12,24 months
Appearance color variation, volume change and x-ray diffractogram of powder spectrum, the stability of sample is investigated with this.Test result such as table 3
Shown, the investigation result of the sample of embodiment 2-7 preparation is consistent with sample prepared by embodiment 1.
The stability test result of table 3, aspartic acid ornithine novel crystal forms
Even if by the test result of table 3 as it can be seen that aspartic acid ornithine novel crystal forms of the invention store 24 months after crystal form
Appearance luster stablize, volume also do not find significant change.Figure 12 indicates that aspartic acid ornithine novel crystal forms of the invention place 6
A month, 12 months, the comparison diagram of 24 months x-ray diffractogram of powder spectrum.
The x-ray diffractogram of powder as shown in Fig. 9 to Figure 12 is composed it is found that aspartic acid ornithine novel crystal forms of the invention are put
It is consistent to set front and back crystal form, even if crystal form is constant after storage 24 months, therefore, aspartic acid ornithine novel crystal forms of the invention have
Good stability, therefore there is obviously advantage in terms of stability, before being had a wide range of applications in pharmaceuticals industry
Scape.
Specific embodiments of the present invention are described in detail above, but it is only used as example, the present invention is not intended to limit
In particular embodiments described above.To those skilled in the art, it any equivalent modifications to the practical progress and replaces
In generation, is also all among scope of the invention.Therefore, without departing from the spirit and scope of the invention made by equal transformation and repair
Change, all should be contained within the scope of the invention.
Claims (10)
1. a kind of crystal form of aspartic acid ornithine compound salt shown in formula (I), it is characterised in that:
The crystal form of the aspartic acid ornithine compound salt is characterized by X-ray powder diffraction figure, is spread out using powder ray
Meter (Cu/K) measurement is penetrated, and with term interplanar distance d, 2 angle θ of Prague and relative intensity I (with hundred relative to most strong ray
Fraction representation) it is expressed as follows table:
2. the crystal form of compound salt according to claim 1, which is characterized in that the aspartic acid ornithine rechlorination
The crystal form for closing object is characterized by attached X-ray powder diffraction figure shown in FIG. 1.
3. the crystal form of compound salt according to claim 2, which is characterized in that the aspartic acid ornithine rechlorination
Object is closed to characterize by attached drawing 2 to attached nuclear magnetic resonance HNMR, CNMR and H-HCOSY shown in Fig. 4.
4. the preparation method of the crystal form of compound salt according to any one of claim 1-3, which is characterized in that including
Following steps:
1), aspartic acid ornithine compound salt crude product is dissolved in deionized water, suitable active carbon is added, filters, obtains
To filtrate A；
2), the filtrate A that step 1) obtains is added in the hydrophilic solvent by preheating, cooling, filtering, be dried in vacuo to get
Aspartic acid ornithine compound salt.
5. the preparation method of the crystal form of compound salt according to claim 4, it is characterised in that: add in the step 1)
After entering active carbon, 48 ± 3 DEG C are warming up to, is refiltered after keeping the temperature 30 ± 5min.
6. the preparation method of the crystal form of compound salt according to claim 4, it is characterised in that: in the step 2),
The cooling step specifically includes: being cooled to 12 ± 3 DEG C with 2~6 DEG C per hour, then keeps the temperature crystallization 3~4 hours.
7. the preparation method of the crystal form of compound salt according to claim 4, it is characterised in that: the deionized water
The mass ratio of volume and the aspartic acid ornithine compound salt crude product is 1~6:1.
8. the preparation method of the crystal form of compound salt according to claim 7, it is characterised in that: the deionized water
The mass ratio of volume and the aspartic acid ornithine compound salt crude product is 2~5:1.
9. the preparation method of the crystal form of compound salt according to claim 4, it is characterised in that: the hydrophilic solvent
For one of methanol, ethyl alcohol or acetone or their mixture.
10. the preparation method of the crystal form of compound salt according to claim 4, it is characterised in that: the hydrophily is molten
The preheating temperature of agent is 30~75 DEG C.
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| CN102827017A (en) * | 2011-06-14 | 2012-12-19 | 上海励睿化学科技有限公司 | Crystal form of double salt compound and preparation method thereof |
| CN102924311A (en) * | 2011-08-12 | 2013-02-13 | 北京四环制药有限公司 | L-ornithine-L-aspartate preparation method |
| CN102964261A (en) * | 2012-04-17 | 2013-03-13 | 肖文辉 | Preparation method of ornithine aspartate |
| CN102942498A (en) * | 2012-11-29 | 2013-02-27 | 康普药业股份有限公司 | Ornithine aspartate compound and preparation method thereof |
| CN103936611A (en) * | 2013-01-23 | 2014-07-23 | 大同长兴制药有限责任公司 | Preparation method for ornithine aspartate |
| CN104058981A (en) * | 2013-03-18 | 2014-09-24 | 辽宁科泰生物基因制药股份有限公司 | Preparation method of ornithine aspartate |
| CN104649920A (en) * | 2013-11-18 | 2015-05-27 | 北京众和民健医药科技有限公司 | Method for preparing ornithine aspartate |
| CN103864634A (en) * | 2014-03-27 | 2014-06-18 | 常州兰陵制药有限公司 | Method for preparing ornithine aspartate |
| CN104774158A (en) * | 2015-02-12 | 2015-07-15 | 肖文辉 | Novel preparation method for ornithine aspartate |
| CN106699586A (en) * | 2016-12-08 | 2017-05-24 | 陕西天宇制药有限公司 | Preparation method of ornithine aspartate |
| CN106977413A (en) * | 2017-04-13 | 2017-07-25 | 蚌埠丰原涂山制药有限公司 | A kind of preparation method of DL L-aminobutanedioic acids DL ornithines |
| CN107441038A (en) * | 2017-08-31 | 2017-12-08 | 济南康和医药科技有限公司 | A kind of ornithine aspartate injection and preparation method thereof |
| CN107522629A (en) * | 2017-10-12 | 2017-12-29 | 福建金山生物制药股份有限公司 | A kind of preparation method of aspartic acid ornithine |
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