CN106045848A - Method for preparing medicinal-level L-malic acid - Google Patents
Method for preparing medicinal-level L-malic acid Download PDFInfo
- Publication number
- CN106045848A CN106045848A CN201610354657.7A CN201610354657A CN106045848A CN 106045848 A CN106045848 A CN 106045848A CN 201610354657 A CN201610354657 A CN 201610354657A CN 106045848 A CN106045848 A CN 106045848A
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- China
- Prior art keywords
- malic acid
- preparation
- filtering
- pharmaceutical grade
- steps
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
-
- 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
- C07B2200/07—Optical isomers
Abstract
The invention discloses a method for preparing medicinal-level L-malic acid which is refined by adopting an ethyl acetate recrystallization method. The method comprises the steps of refining, crystallizing and spin-filtering, drying and crushing and mixing, wherein the refining process specifically comprises the steps of sequentially adding L-malic acid raw materials, medicinal charcoal and ethyl acetate into a refining tank according to a feeding weight ratio, and heating the refining tank until the added materials are boiled and dissolved; the crystallizing and spin-filtering process specifically includes the steps of subjecting a mixture solution in the refining tank to refluxing, then, carrying out cooling and filtering to a crystallizing tank, carrying out stirring, carrying out natural cooling, and then, carrying out spin-filtering; the drying process specifically includes the steps of loading an L-malic acid wet fine product, obtained after the mixture solution in the crystallizing tank is subjected to spin-filtering, to a baking tray of a vacuum dryer for drying treatment, so as to obtain L-malic acid; and the crushing and mixing process specifically includes the steps of crushing the dried L-malic acid, and then, feeding the crushed L-malic acid to a transfer station, and performing mixing and inner packing. As a whole, the method has the characteristics that the bioavailability is high, drugs are remarkable in effects, the stability is good, the yield is high, the purity is high, and the like.
Description
Technical field
The invention belongs to crude drug preparing technical field, relate to the preparation method of a kind of pharmaceutical grade L MALIC ACID.
Background technology
L MALIC ACID is distributed widely in plant, animal and microbial cell, produces energy matter ATP's at mitochondrion
Metabolic process plays an important role.And L MALIC ACID is also the important component part of malate aspartate shuttle, to born of the same parents
The transfer of the NADH between liquid and mitochondrion plays an important role, and L MALIC ACID has important metabolic significance in body.With
Time it can also effectively improve motor capacity, have resisting fatigue, promote liver ammonia metabolism, suppression γ-aminobutyric acid life
Become, the metabolism that to the protected effect of cardiac muscle of hypoxic-ischemic, promotes carboxylate, promote mitochondrial respiratory, improve memory ability, increasing
The activity of strong calcium, reducing physiological functions such as cancer therapy drug toxic and side effects etc., these effects are favourable to Exercise Mechanics undoubtedly
's.It addition, it is also one of addO-on therapy for the treatment of 20 kinds of amino acid transfusions of burn, amino acid whose absorption can be significantly improved
Rate, reduces amino acid whose metabolism loss and makes up hepatic dysfunction, can be used for treating uremia, hypertension and can alleviating anticarcinogen
Thing is to Normocellular toxic action.L MALIC ACID can be as the tranquilizer of calcium lactate injection, because it can promote medicine
Stability, improves the human body absorbability to medicine, and L MALIC ACID potassium, zinc and other salt can keep body water balance, mend
Congested potassium, prevent the accumulation of edema and hyperpiesia and fat.L MALIC ACID and its esters can also be made the growth of animal and promote
Agent.Therefore, L MALIC ACID has important metabolic significance in body, is a kind of safe and nontoxic, favourable to physical function merit
Can sex pill.The injection of L MALIC ACID is the most commercially sold.Research shows, under room temperature, the aqueous solution of L MALIC ACID exists
Under conditions of partial neutral (pH5-7) relatively stable.The stability of medicine it is critical that, especially protect within commercially available effect duration
Hold preferable stability, reduce medicine and produce impurity (having related substance) due to degraded, to ensureing curative effect of medication and safety
Property, the generation preventing adverse effect is significant.In order to improve the stability of L MALIC ACID medicine, pay the utmost attention to make
Use its crystal form.
Summary of the invention
It is an object of the invention to improve finished product stability and provide a kind of production technology simple, cost of manufacture is low, finished product
The preparation method of a kind of pharmaceutical grade L MALIC ACID that stability is strong.
The technical scheme is that and be achieved in that: the preparation method of a kind of pharmaceutical grade L MALIC ACID, including refined step
Suddenly, crystallization, rejection filter step, drying steps, pulverizing, blend step, described purification step is according to weight ratio in treatment tank
Example weighs and adds L MALIC ACID raw material, medicinal charcoal, ethyl acetate, and heating treatment tank carries out the remove impurity that refluxes；Described crystallization, get rid of
Filter step is to be stirred crystallization in heat filtering with pressure for the mixed solution in treatment tank to crystallizer, and Temperature fall cooling is laggard
Row rejection filter obtains the wet fine work of L MALIC ACID；Described drying steps is that wet for L MALIC ACID fine work is placed in drip pan loading vacuum
Process it is dried, it is thus achieved that L MALIC ACID in drying machine；Described pulverizing, blend step are will to enter through the L MALIC ACID being dried
Row is sent into batch mixer after pulverizing and is carried out mixing interior bag.
In described purification step, L MALIC ACID raw material, medicinal charcoal, ethyl acetate are according to 1kg:10-12g:2.0-3.5L's
Rate of charge weighs, and after being sequentially added into L MALIC ACID raw material, medicinal charcoal, ethyl acetate in treatment tank, heat temperature raising is carried out
Reflux 0.7-1.5 hour, be cooled to 50-60 DEG C of filter pressing in the crystallizer of clean area.
Described crystallization, rejection filter step are the stirring of mixed solution slow cooling to be crystallized, after being cooled to less than 15 DEG C
It is centrifuged rejection filter, it is thus achieved that the wet fine work of L MALIC ACID.
Described drying steps is wet for L MALIC ACID fine work to be put into drip pan load vacuum drier, and evacuation also keeps
Vacuum≤-0.08MPa, rises high-temperature to being dried after 60-70 DEG C 2-5 hour until moisture≤2.0%.
Described pulverizing, blend step are to pulverize in dried L MALIC ACID feeding pulverizer, use 80-
150 mesh sieves screen, and be sufficiently mixed, test in the L MALIC ACID filtered out is put into mixer, and it is qualified to check
After pack.
Described crystallization, get rid of worry, be dried, pulverize, blend step is all to complete in D level purifying area.
Generally, the present invention uses crystallization process in ethyl acetate to refine L MALIC ACID, has bioavailability high, and medicine shows
Writing, good stability, yield is high, purity high.
Accompanying drawing explanation
Fig. 1 is L MALIC ACID process chart of the present invention.
Specific embodiment
Below in conjunction with the accompanying drawings to embodiments of the present invention further instruction.
Embodiment
As it is shown in figure 1, the preparation method of a kind of pharmaceutical grade L MALIC ACID, including purification step, crystallization, rejection filter step, do
Dry step, pulverizing, blend step:
Purification step is to be sequentially added into L MALIC ACID raw material, medicinal charcoal, ethyl acetate according to charged material weight ratio in treatment tank,
Heating treatment tank temperature is to dissolving of seething with excitement；
Crystallization, rejection filter step are to crystallizer and to be stirred by the cold filtration after backflow of the mixed solution in treatment tank,
Rejection filter is carried out after natural cooling；
Mixed solution in drying steps crystallizer obtains the wet fine work of L MALIC ACID after rejection filter, is filled by wet for L MALIC ACID fine work
The drip pan entering vacuum drier is dried process, it is thus achieved that L MALIC ACID；
Pulverize, blend step is to mix after sending into terminal after dry L MALIC ACID is pulverized, interior bag.
In purification step, L MALIC ACID raw material, medicinal charcoal, the rate of charge of ethyl acetate be: 1kg:10g:2.5L, refined
Be sequentially added into L MALIC ACID raw material in tank, medicinal charcoal, ethyl acetate heating-up temperature are 70 DEG C, and backflow 1 hour, is cooled to 50 afterwards
DEG C filter in the crystallizer of clean area.
Refined rate of charge such as following table:
| Name of material | Rank | Rate of charge | Molecular formula | Molecular weight |
| L MALIC ACID raw material | Pharmaceutic adjuvant | 1kg | C4H6O5 | 134.09 |
| Medicinal charcoal | Pharmaceutic adjuvant | 10g | C | 12.01 |
| Ethyl acetate | Self-control | 2.5L | C4H8O2 | 88.11 |
Crystallization, rejection filter step crystallize and is carrying out rejection filter when reaching below 15 DEG C, it is thus achieved that the wet fine work of L MALIC ACID.
Being to deliver in vacuum drier by drip pan at drying steps, vacuum ensures at≤-0.08MPa, baking temperature control
System is dried 3 hours after 70 DEG C.
Drying control requires:
| Project name | Quality index |
| Character | White crystals or crystalline powder；Odorless, tasteless |
| Moisture | ≤2.0% |
| Assay | Must not be less than 99.0% containing C4H6O5 |
Dry yield:
Yield calculation: [(being dried intermediate products amount+sampling amount+visible losing quantity that post is submitted)/Crystallization Procedure is submitted
Intermediate products amount] × 100%
L MALIC ACID through being dried is sent in pulverizer, crosses 80 mesh sieves and carries out pulverization process；L MALIC ACID after pulverizing
In input mixer, even if mixing 30 minutes, testing afterwards, packing after the assay was approved.
Pulverizing yield:
Yield calculation: [(pulverizing intermediate products amount+sampling amount+visible losing quantity that post is submitted)/drying process is submitted
Intermediate products amount] × 100%.
Generally, it is high that the present invention has bioavailability, and medicine is notable, good stability, and yield is high, purity high.
Claims (6)
1. a preparation method for pharmaceutical grade L MALIC ACID, including purification step, crystallization, rejection filter step, drying steps, pulverize,
Blend step, it is characterised in that: described purification step is to weigh according to part by weight in treatment tank and add L MALIC ACID
Raw material, medicinal charcoal, ethyl acetate, heating treatment tank carries out the remove impurity that refluxes；Described crystallization, rejection filter step are by treatment tank
Mixed solution heat filtering with pressure is stirred crystallization to crystallizer, carries out rejection filter acquisition L MALIC ACID wet after Temperature fall cooling
Fine work；Described drying steps be wet for L MALIC ACID fine work is placed in drip pan loading vacuum drier in be dried place
Reason, it is thus achieved that L MALIC ACID；Described pulverizing, blend step are will to send into batch mixer after dry L MALIC ACID is pulverized
Carry out mixing interior bag.
The preparation method of a kind of pharmaceutical grade L MALIC ACID the most according to claim 1, it is characterised in that: described refined step
In rapid, L MALIC ACID raw material, medicinal charcoal, ethyl acetate weigh according to the rate of charge of 1kg:10-12g:2.0-3.5L, in essence
After being sequentially added into L MALIC ACID raw material, medicinal charcoal, ethyl acetate in tank processed, heat temperature raising carries out backflow 0.7-1.5 hour, cooling
In to 50-60 DEG C of filter pressing to the crystallizer of clean area.
The preparation method of a kind of pharmaceutical grade L MALIC ACID the most according to claim 1, it is characterised in that: described crystallization,
Rejection filter step is the stirring of mixed solution slow cooling to be crystallized, and carries out centrifugal drying filter, it is thus achieved that L-after being cooled to less than 15 DEG C
The wet fine work of malic acid.
The preparation method of a kind of pharmaceutical grade L MALIC ACID the most according to claim 1, it is characterised in that: described dry step
Suddenly being wet for L MALIC ACID fine work to be put into drip pan load vacuum drier, evacuation also keeps vacuum≤-0.08MPa, rises
High-temperature is to being dried after 60-70 DEG C 2-5 hour until moisture≤2.0%.
The preparation method of a kind of pharmaceutical grade L MALIC ACID the most according to claim 1, it is characterised in that: described pulverizing,
Blend step is to pulverize in dried L MALIC ACID feeding pulverizer, uses 80-150 mesh sieve to screen, will sieve
The L MALIC ACID selected is sufficiently mixed in putting into mixer, tests, packs after the assay was approved.
The preparation method of a kind of pharmaceutical grade L MALIC ACID the most according to claim 1, it is characterised in that: described crystallization,
Get rid of worry, be dried, pulverize, blend step be all to complete in D level purifying area.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610354657.7A CN106045848A (en) | 2016-05-26 | 2016-05-26 | Method for preparing medicinal-level L-malic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610354657.7A CN106045848A (en) | 2016-05-26 | 2016-05-26 | Method for preparing medicinal-level L-malic acid |
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| Publication Number | Publication Date |
|---|---|
| CN106045848A true CN106045848A (en) | 2016-10-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610354657.7A Pending CN106045848A (en) | 2016-05-26 | 2016-05-26 | Method for preparing medicinal-level L-malic acid |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110878017A (en) * | 2018-09-05 | 2020-03-13 | 北京哈三联科技有限责任公司 | Refining and purifying method of L-malic acid for injection |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0940603A (en) * | 1995-08-01 | 1997-02-10 | Nippon Shokubai Co Ltd | Purification of optically active organic polybasic acid |
| CN103642853A (en) * | 2013-12-02 | 2014-03-19 | 山东阜丰发酵有限公司 | Novel process for extracting L-malic acid |
| CN103910621A (en) * | 2013-12-30 | 2014-07-09 | 西安万隆制药股份有限公司 | L-malic acid compound |
-
2016
- 2016-05-26 CN CN201610354657.7A patent/CN106045848A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0940603A (en) * | 1995-08-01 | 1997-02-10 | Nippon Shokubai Co Ltd | Purification of optically active organic polybasic acid |
| CN103642853A (en) * | 2013-12-02 | 2014-03-19 | 山东阜丰发酵有限公司 | Novel process for extracting L-malic acid |
| CN103910621A (en) * | 2013-12-30 | 2014-07-09 | 西安万隆制药股份有限公司 | L-malic acid compound |
Non-Patent Citations (2)
| Title |
|---|
| MOURGUES JEAN等: "Extraction and purification of D,L-malic acid, produced by chemical synthesis, L-malic acid produced by microbiological synthesis or susceptible to be recovered during the manufacturing of food products", 《INDUSTRIES ALIMENTAIRES ET AGRICOLES》 * |
| 刘建军等: "L-苹果酸的应用及研究进展", 《中国食品添加剂》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110878017A (en) * | 2018-09-05 | 2020-03-13 | 北京哈三联科技有限责任公司 | Refining and purifying method of L-malic acid for injection |
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Application publication date: 20161026 |
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