CN104045547B - A kind of Sodium.alpha.-ketopropionate recrystallization preparation method - Google Patents
A kind of Sodium.alpha.-ketopropionate recrystallization preparation method Download PDFInfo
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- CN104045547B CN104045547B CN201410315976.8A CN201410315976A CN104045547B CN 104045547 B CN104045547 B CN 104045547B CN 201410315976 A CN201410315976 A CN 201410315976A CN 104045547 B CN104045547 B CN 104045547B
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Abstract
The invention provides a kind of Sodium.alpha.-ketopropionate recrystallization preparation method, comprise the following steps: (1) prepares the Sodium.alpha.-ketopropionate aqueous solution: Sodium.alpha.-ketopropionate crude product is dissolved in purified water, cross and filter inorganic impurity; (2) Sodium.alpha.-ketopropionate wet product is prepared: dropped to by the Sodium.alpha.-ketopropionate aqueous solution in ice bath anhydrous alcohol for medical use, Sodium.alpha.-ketopropionate crystallization, filter to obtain wet product; (3) Sodium.alpha.-ketopropionate finished product is prepared: wet product is through drying under reduced pressure, and pulverizing of sieving, inspection and finished product packing, obtain lily Sodium.alpha.-ketopropionate solid.The recyclable recycling of solvent environmental protection of the present invention; Simple process is controlled, and operability is high, and yield is more than 85%, is applicable to suitability for industrialized production; Under D level clean environment, this technique can obtain the highly purified Sodium.alpha.-ketopropionate of high-quality, and microbial limit meets the requirement of respiratory tract administration preparation.
Description
Technical field
The present invention relates to medical art, refer in particular to a kind of Sodium.alpha.-ketopropionate recrystallization preparation method.
Background technology
Sodium.alpha.-ketopropionate, chemical name Acetylformic acid sodium salt, structural formula is such as formula one:
Sodium.alpha.-ketopropionate is the sodium salt of pyruvic acid, and the simplest alpha-ketoacid of pyruvic acid, plays important role in the metabolism of biology, is important metabolic intermediate, has again excellent oxidation-resistance.Sodium.alpha.-ketopropionate is the stable existence form of pyruvic acid, has purposes widely at present in pharmacy and scientific research, simultaneously also as fitness and weight losing dietary supplements, in food, makeup.But Sodium.alpha.-ketopropionate liquid preparation is is still researched and developed in the most promising application of Sodium.alpha.-ketopropionate, for clinical economics aspect.
Current industrial production Sodium.alpha.-ketopropionate mainly first adopts chemical synthesis and fermentation method to obtain high purity pyruvic acid, and the then obtained Pyruvic acid sodium salt with caustic soda or sodium bicarbonate etc., namely a small amount of ethanolic soln drip washing obtain finished product.This type of not purified product, often can not be directly used in pharmacy and scientific research.China does not have bulk drug rank Sodium.alpha.-ketopropionate to sell at present, and the report about Sodium.alpha.-ketopropionate recrystallization method is also few.
Summary of the invention
The invention reside in and prepare Problems existing for current Sodium.alpha.-ketopropionate, and a kind of Sodium.alpha.-ketopropionate recrystallization preparation method that proposition overcomes the above problems.
To achieve these objectives, the present invention adopts following technical scheme:
A kind of Sodium.alpha.-ketopropionate recrystallization preparation method, comprises the following steps:
(1) prepare the Sodium.alpha.-ketopropionate aqueous solution: Sodium.alpha.-ketopropionate crude product is dissolved in purified water, cross and filter inorganic impurity;
(2) Sodium.alpha.-ketopropionate wet product is prepared: dropped to by the Sodium.alpha.-ketopropionate aqueous solution in ice bath anhydrous alcohol for medical use, Sodium.alpha.-ketopropionate crystallization, filter to obtain wet product;
(3) Sodium.alpha.-ketopropionate finished product is prepared: wet product is through drying under reduced pressure, and pulverizing of sieving, inspection and finished product packing, obtain lily Sodium.alpha.-ketopropionate solid.
Wherein,
In described step (1), the weightmeasurement ratio (W/V) of Sodium.alpha.-ketopropionate and water is 1:2.1.
In described step (2), the volume ratio (V/V) of the Sodium.alpha.-ketopropionate aqueous solution and ethanol is 1:(4-12).
In described step (2), the rate of addition of the Sodium.alpha.-ketopropionate aqueous solution controls at 2-5 drop/sec.
In described step (3), drying under reduced pressure temperature is 50 DEG C-80 DEG C.
Sodium.alpha.-ketopropionate recrystallization preparation method of the present invention, tool has the following advantages:
1 the present invention adopts Sodium.alpha.-ketopropionate first to dissolve completely in water, after filtering, filtrate adds to the technique of crystallization in pharmaceutical grade anhydrous ethanol, compared to the mode only adopting the crystallization of washing with alcohol Sodium.alpha.-ketopropionate of traditional technology, can effectively control mechanical impurity and particulate matter;
2 the present invention adopt Sodium.alpha.-ketopropionate first first to dissolve completely in water, after filtration, filtrate is added to the technique of crystallization in pharmaceutical grade anhydrous ethanol, the mode of >=90% washing with alcohol purifying acetone acid sodium is adopted compared to traditional technology, not only effectively can filter out inorganic impurity, yield is also more than 85%;
Separating out Sodium.alpha.-ketopropionate in 3 ethanol is an exothermic process.The present invention adopts ice bath crystallization, and controlling the rate of addition of filtrate is 2-5 drop/sec, effectively temperature of reaction is controlled below 5 DEG C, not only can the solubleness of Sodium.alpha.-ketopropionate in reduction system, improves crystallization yield; Can also avoid, because temperature of reaction height produces other organic impurity, improve the quality of product simultaneously;
4 the present invention are at the sample of D level clean area recrystallization, and its microbial limit meets the requirement of respiratory tract administration preparation;
4 the present invention use the recyclable recycling of solvent environmental protection;
5 present invention process are easy to be controlled, and product is stablized, and are applicable to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is production process route block diagram of the present invention;
Fig. 2 is the HPLC collection of illustrative plates that the related substance of Sodium.alpha.-ketopropionate finished product prepared by method of the present invention detects;
Fig. 3 is the IR collection of illustrative plates of Sodium.alpha.-ketopropionate finished product prepared by method of the present invention;
Fig. 4 is the XRD figure spectrum of Sodium.alpha.-ketopropionate finished product prepared by method of the present invention.
Embodiment
The present invention is further illustrated below by embodiment.Method in embodiment in the present invention is only provide for illustration of the present invention, instead of limitation of the present invention.
Embodiment 1
Take 100.01g Sodium.alpha.-ketopropionate in 250ml beaker, add 100ml purified water, stir, ultrasonic dissolution.Increase progressively with 10ml successively and slowly add purified water, dissolve completely, add 210ml altogether to Sodium.alpha.-ketopropionate, recording solution temperature is 30.4 DEG C.With the water system membrane filtration of 0.22 μm, obtain the 264ml Sodium.alpha.-ketopropionate aqueous solution;
Measure the 50ml Sodium.alpha.-ketopropionate aqueous solution, be added in 125ml separating funnel, slowly drop in the 200ml ethanol (ice-water bath) under whipped state, dropwise, stir 30 minutes at 0-5 DEG C, filter immediately, obtain Sodium.alpha.-ketopropionate wet product;
By the vacuum drying oven drying under reduced pressure about 2 hour of above-mentioned wet product at 50 DEG C, weigh, detect related substance.Result is as shown in table 1.
Embodiment 2
The preparation of the Sodium.alpha.-ketopropionate aqueous solution is with embodiment 1;
Measure the 50ml Sodium.alpha.-ketopropionate aqueous solution, be added in 125ml separating funnel, slowly drop in the 400ml ethanol (ice-water bath) under whipped state, dropwise, stir 30 minutes at 0-5 DEG C, filter immediately, obtain Sodium.alpha.-ketopropionate wet product;
By the vacuum drying oven drying under reduced pressure about 2 hour of above-mentioned wet product at 50 DEG C, weigh, detect related substance.Result is as shown in table 1.
Embodiment 3
The preparation of the Sodium.alpha.-ketopropionate aqueous solution is with embodiment 1;
Measure the 50ml Sodium.alpha.-ketopropionate aqueous solution, be added in 125ml separating funnel, slowly drop in the 500ml ethanol (ice-water bath) under whipped state, dropwise, stir 30 minutes at 0-5 DEG C, filter immediately, obtain Sodium.alpha.-ketopropionate wet product;
By the vacuum drying oven drying under reduced pressure about 2 hour of above-mentioned wet product at 50 DEG C, weigh, detect related substance.Result is as shown in table 1.
Embodiment 4
The preparation of the Sodium.alpha.-ketopropionate aqueous solution is with embodiment 1;
Measure the 50ml Sodium.alpha.-ketopropionate aqueous solution, be added in 125ml separating funnel, slowly drop in the 600ml ethanol (ice-water bath) under whipped state, dropwise, stir 30 minutes at 0-5 DEG C, filter immediately, obtain Sodium.alpha.-ketopropionate wet product;
By the vacuum drying oven drying under reduced pressure about 2 hour of above-mentioned wet product at 50 DEG C, weigh, detect related substance.Result is as shown in table 1.
The Sodium.alpha.-ketopropionate that table 1 embodiment 1-4 obtains adopts HPLC to carry out defects inspecting.
| Test item | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 |
| Single maximum contaminant content | 0.06％ | 0.07％ | 0.07％ | 0.06％ |
| Total impurities content | 0.17％ | 0.21％ | 0.20％ | 0.19％ |
Embodiment 5
The preparation of the Sodium.alpha.-ketopropionate aqueous solution is with embodiment 1;
Measure the 50ml Sodium.alpha.-ketopropionate aqueous solution, be added in 125ml separating funnel, slowly drop in the 400ml ethanol (ice-water bath) under whipped state, dropwise, stir 30 minutes at 0-5 DEG C, filter immediately, obtain Sodium.alpha.-ketopropionate wet product;
By the vacuum drying oven drying under reduced pressure about 2 hour of above-mentioned wet product at 80 DEG C, weigh, detect related substance.
The Sodium.alpha.-ketopropionate that table 2 embodiment 2 and 5 obtains adopts HPLC to carry out defects inspecting.
Embodiment 6
Experiment is carried out under D level clean environment.
At ambient temperature, the Sodium.alpha.-ketopropionate (crude product) of 300g is joined in the beaker of the 1000-ml of suitable magnetic stir bar, adds about 600ml purified water, open magnetic stirring apparatus, after dissolving is uniformly dispersed, continues to add 30ml purified water and make it dissolve completely, close magnetic stirring apparatus;
Use the aqueous phase millipore filtration of 0.22 μm to build filtration unit 1 (core filtration), open pump, filtered by the solution in above-mentioned beaker, filtrate is transferred to another 1L graduated cylinder.Filtration terminates rear closedown pump.Liquid in graduated cylinder is the Sodium.alpha.-ketopropionate aqueous solution, stand-by;
Appropriate (be 8:1 with the volume ratio of the Sodium.alpha.-ketopropionate aqueous solution) ethanol is added in 10L beaker, put into suitable agitation, put into suitable ice bath device (liquid level of ethanol is lower than the liquid level of frozen water), be placed on magnetic stirring apparatus, open magnetic stirring apparatus, the temperature of ethanol is made to control at 0 ~ 5 DEG C, stand-by;
Progressively be added in 500-ml pear shape separatory funnel by the Sodium.alpha.-ketopropionate aqueous solution, be fixed on iron stand, what drop to whipped state fills in the 10L beaker of 0 ~ 5 DEG C of dehydrated alcohol, controls rate of addition (2-5 drop/sec), and white solid is separated out.After being added dropwise to complete, continue stirring 10 minutes.Close magnetic stirring apparatus.Guarantee there is ice cube in ice bath device in whole process always;
Use fast qualitative filter paper to build filtration unit 2 (Büchner funnel), open pump, the crystallization solution in 10L beaker in upper step is filtered immediately, obtains Sodium.alpha.-ketopropionate wet product;
Sample is laid on clean pallet and carries out vacuum-drying, control temperature 50 DEG C; Control weight loss on drying≤0.5%, dry 2 hours of rear continuation up to standard, this is Sodium.alpha.-ketopropionate dry product;
Sodium.alpha.-ketopropionate dry product is pulverized grinding by No. 3 sieves; This is Sodium.alpha.-ketopropionate finished product; By Sodium.alpha.-ketopropionate finished product according to carrying out weighing bottling.Finished product sampling detects.This technique repeats 3 batches, and 3 batches of yields are respectively 87%, 87% and 88%, and 3 batch weight crystal product detected results are as shown in table 3:
Table 3 recrystallization finished product detection result
3 batches of finished appearance, white is to off-white color crystalline powder; Weight loss on drying < 0.5%; Vitriol < 100ppm; Muriate < 100ppm; Iron < 10ppm; Arsenic < 1ppm; Heavy metal < 10ppm; Free acid 0.01%, residual solvent (ethanol) does not detect; Content (in dry product) 100%; Related substance, maximum single impurity < 0.1%, total impurities 0.1%, meets ICHQ3A (R2) new raw material medicine impurity research governing principle; The requirement of microbial limit meets " Chinese Pharmacopoeia " version respiratory tract administration preparation in 2010.Fig. 2 is shown in by the HPLC collection of illustrative plates that I1000020 batch of corresponding related substance detects, and IR spectrogram is shown in Fig. 3, and XRD spectra is shown in Fig. 4.
Claims (3)
1. a Sodium.alpha.-ketopropionate recrystallization preparation method, is characterized in that, comprises the following steps:
(1) prepare the Sodium.alpha.-ketopropionate aqueous solution: Sodium.alpha.-ketopropionate crude product is dissolved in purified water, cross and filter inorganic impurity;
(2) Sodium.alpha.-ketopropionate wet product is prepared: dropped to by the Sodium.alpha.-ketopropionate aqueous solution in ice bath anhydrous alcohol for medical use, Sodium.alpha.-ketopropionate crystallization, filter to obtain wet product;
(3) Sodium.alpha.-ketopropionate finished product is prepared: wet product is through drying under reduced pressure, and pulverizing of sieving, checks and finished product packing, obtain lily Sodium.alpha.-ketopropionate solid;
In described step (1), the weightmeasurement ratio (W/V) of Sodium.alpha.-ketopropionate and water is 1:2.1;
In described step (2), the volume ratio (V/V) of the Sodium.alpha.-ketopropionate aqueous solution and ethanol is 1:(4-12);
In described step (2), the rate of addition of the Sodium.alpha.-ketopropionate aqueous solution controls at 2-5 drop/sec.
2. Sodium.alpha.-ketopropionate recrystallization preparation method according to claim 1, is characterized in that, in described step (3), drying under reduced pressure temperature is 50 DEG C-80 DEG C.
3. Sodium.alpha.-ketopropionate recrystallization preparation method according to claim 1, is characterized in that, described preparation process is carried out under D level clean environment.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1103331C (en) * | 2000-01-21 | 2003-03-19 | 无锡轻工大学 | Process for extracting pyruvic acid from fermented liquid of pyruvic acid and preparing sodium pyrouvate |
| CN101205181A (en) * | 2007-11-12 | 2008-06-25 | 南昌大学 | Method for extracting and separating sodium ketopropionate from acetonic acid fermentation liquid by double membrane two-step process |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1103331C (en) * | 2000-01-21 | 2003-03-19 | 无锡轻工大学 | Process for extracting pyruvic acid from fermented liquid of pyruvic acid and preparing sodium pyrouvate |
| CN101205181A (en) * | 2007-11-12 | 2008-06-25 | 南昌大学 | Method for extracting and separating sodium ketopropionate from acetonic acid fermentation liquid by double membrane two-step process |
Non-Patent Citations (1)
| Title |
|---|
| 发酵法生产丙酮酸钠提取工艺的研究;赵南等;《江西农业学报》;20101231;第22卷(第3期);第161-162页 * |
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Address after: 225300 No.1, South Batang Road, China medicine city, Taizhou City, Jiangsu Province Patentee after: Jiangsu Changtai Pharmaceutical Co.,Ltd. Address before: Building G22, Phase III, Tai Road and Yuannan Road, China Pharmaceutical City, Taizhou City, Jiangsu Province, 225300 Patentee before: JIANG SU PHARMAMAXCORP Co.,Ltd. |
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