CN109490448A - A kind of preparation method of digoxin standard substance - Google Patents
A kind of preparation method of digoxin standard substance Download PDFInfo
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Abstract
The invention discloses a kind of preparation method of digoxin standard substance, include the following steps: digoxin crude product digoxin standard substance is finally prepared by active carbon decoloring, liquid-liquid extraction, solvent crystallization.Effective removing is carried out using the trace impurity that method of the invention can will affect digoxin product color, product colour is whiter；The impurity such as digoxin and digitalis and bigitalin can be efficiently separated, effectively improve product purity；The similar impurity of the structures such as double bigitalins is separated from digoxin product, product purity reaches 99.5% or more.The content of the digoxin crystal product obtained using method of the present invention is higher than 99.5% (HPLC method), can be used as standard substance for digoxin raw medicine quality-monitoring and therapeutic drug monitoring, preparation method is simple.
Description
Technical field
The present invention relates to the preparation methods of standard substance, more particularly to a kind of preparation method of digoxin standard substance.
Background technique
Digoxin also known as digoxin, be it is a kind of for treat various acute and chronic cardiac insufficiencies and
Supraventricular tachycardia, auricular fibrillation and the cardiac glycoside drug fluttered, chemical name are as follows: 3 β-O-2, O- dideoxy-β-D- cores-
Hexpyranosyl-(1 → 4)-O-2,6- dideoxy-β-D- core-hexpyranosyl-(1 → 4) -2,6- dideoxy-β-D- core-oneself
Pyranose oxo-12 β, 14-5 β of beta-dihydroxy-heart steroid-20 (22) alkene lactone.Molecular formula are as follows: C41H64O14；Molecular weight is
780.94.Digoxin sterling is white crystals or crystalline powder, and fusing point is 248 DEG C (decomposition), and digoxin is not soluble in water, second
Alcohol, ether, acetone are slightly soluble in chloroform, dilute alcohol, are dissolved in the organic solvents such as pyridine, chloroform-ethanol, methylene chloride-methanol.It is tied
Structure formula is shown in formula I:
A kind of cardiac glycoside drug of the digoxin as common heart disease has reliable effect, absorption and drains fast etc.
Advantage, but the disadvantage is that treatment safety range is small, general treatment amount is equivalent to the 60% of dosis toxica, leads to Yi Fasheng in therapeutic process
Toxic reaction.Therefore it needs to carry out digoxin plasma concentration detection in therapeutic process, it is ensured that digoxin concentration is in treatment safety model
It encloses, prevents from leading to unsatisfactory curative effect due to underdosage, while preventing excessive concentration from causing to be poisoned again.Therefore testing result is accurate
Property and reliability be to ensure that the key of therapeutic effect, it is domestic at present to lack the digoxin high quality standards substance that traced to the source, therefore
Purifying preparation digoxin standard substance is to ensure that the vital task of digoxin testing result and cardiac disease treatment effect.
Due to its complicated structure (Formulas I), digoxin is not yet artificial synthesized, is at present still to ferment from the leaf of digitalis
It extracts and obtains.Because Official pharmacopoeias provides the digoxin for using high-purity in pharmaceutical preparation, researcher is caused always
Power is in the exploitation of digoxin separation and method for preparing purified.The general journey of digoxin is extracted from the leaf of the digitalis of fermentation at present
Sequence includes several stages: A), with Diluted Alcohol extract total extracting substance；B), using chloroform or trichloro ethylene as extractant from dilute
Ethanol extract extracts secondary glycosides fraction；C), with ad hoc approach from secondary glucoside extract separating-purifying digoxin.Document at present
The method of the separating-purifying digoxin of report includes:
(1) it prepares chromatographic process: digoxin and impurity being isolated and purified using chromatographic technique is prepared, collection meets pure
Desired fraction is spent, but the unsuitable scale of this method prepares digoxin；
(2) it fractional solution method: using solvent to the difference of digoxin and impurity solvability, is dissolved by multiple fractionation
Process separates impurity from digoxin product, but this method is to four ocean ground of impurity diginatin and digoxin
The separating effect of pornography and drug saccharide is limited, causes digoxin product purity that standard substance purity requirement is not achieved；
(3) liquid-liquid extraction method: digoxin and impurity solvability difference are realized using immiscible dicyandiamide solution
The purpose of digoxin is purified, but since the dopant species in digoxin product are more, distinct, liquid-liquid extraction result will lead to production
The content decline of partial impurities, the content for accordingly having partial impurities will increase in product.Therefore this method can only be directed to specific miscellaneous
The separation of matter is effective, does not have universality.
Digoxin plasma concentration carries out during being either monitored still Case treatment to the quality of digoxin raw medicine
Monitoring is using efficient liquid-phase chromatography method, and in order to ensure testing result is accurate and reliable, detection process must use digoxin
Standard substance.Meanwhile in order to ensure analysis test result has the traceability of science and the uncertainty of measurement, test machine is analyzed
Structure must confirm the analysis test method of use using digoxin standard substance.Furthermore digoxin standard substance is to implementation
The foundation of the quality management system in the comparison of laboratory monitoring magnitude and laboratory is also essential.
Standard substance usually requires that high-purity, forms uniform and chemical stabilization.In order to meet the detection of domestic drug quality and
To the requirement that patient is accurately administered, the demand to digoxin standard substance is increasingly urgent to.Research institution's energy not yet domestic at present
Digoxin standard substance is enough provided, and the digoxin standard substance of import foreign countries is there are somewhat expensive, the arrival period is long and detects
As a result the problems such as lacking traceability, therefore there is an urgent need to develop the purification preparation technologies of high-purity digoxin.
Summary of the invention
The purpose of the present invention is overcome the deficiencies of the prior art and provide the one kind that can be obtained purity and be up to 99.5% or more
The preparation method of digoxin standard substance.
Technical solution of the present invention is summarized as follows:
A kind of preparation method of digoxin standard substance, includes the following steps:
(1) in the ratio of 2g:100~400mL, digoxin crude product is dissolved in solvent one, active carbon, decoloration 30 is added
~120min, is obtained by filtration filtrate, and filtrate evaporates to obtain digoxin crystal crude product；The active carbon is digoxin crude product weight
3%~10%；
(2) step (1) is obtained digoxin crystal crude product to be dissolved into 100-250mL diluent, adds and dilutes
The immiscible extractant of agent stirs 5~30min in 800~2000rpm, pours out extraction phase after clarifying split-phase, retains extraction
The volume ratio of Yu Xiang, the diluent and extractant is (0.5~5): 1；
(3) extractant is added into raffinate phase, in 800~2000rpm, stirs 5~30min, will be extracted after clarifying split-phase
It takes and is mutually discharged, retain raffinate phase, the volume ratio for the raffinate phase that the extractant of this step and step (2) obtain is 1:(0.5~5)；
(4) step (3) are repeated 2-5 times；
(5) raffinate phase for obtaining step (4) evaporates, decrease temperature crystalline, and the production of digoxin crystal is obtained by filtration after being down to room temperature
Product, then washed 2-5 times with diluent, digoxin head product is obtained after vacuum drying；
(6) step (5) is obtained into digoxin head product ultrasonic dissolution in 100~400mL solvent two, 500~
Under the conditions of 1200rpm, deionized water is added dropwise and filters until crystal is precipitated completely, be dried to obtain digoxin standard substance.
The volume ratio of diluent and extractant is preferably (1~2) in step (2): 1.
Step (4) is preferred are as follows: repeats step (3) 4 times.
Step (6) is preferred are as follows: step (5) is obtained digoxin head product and is dissolved in solvent two, in 1000rpm condition
Under, deionized water 100-300mL is added dropwise, the time for adding of deionized water is 90~150min, until crystal is precipitated completely, filter,
It is dried to obtain digoxin standard substance.
Amount of deionized water additional amount is preferably 120mL, and the time for adding of deionized water is 100-120min.
In step (1), it is (0.2~4) that the solvent one, which is selected from methanol, ethyl alcohol, methylene chloride, chloroform, volume ratio:
1 Methanol+Water, volume ratio are (0.2~4): 1 ethanol-water mixed solvent, volume ratio are (0.2~4): the two of 1
Chloromethanes-methanol mixed solvent, volume ratio are (0.2~4): 1 dichloromethane-ethanol mixed solvent, volume ratio be (0.2~
4): 1 chloroform-methanol mixed solvent or volume ratio is (0.2~4): 1 chloroform-alcohol mixed solvent.
Diluent is selected from least one of methylene chloride, chloroform, ethyl acetate.
It is the Water-Methanol Mixtures of (0.5~2:1), the water-that volume ratio is (0.5~2:1) that extractant, which is selected from volume ratio,
Alcohol mixed solvent, the boiling mixed solvent that volume ratio is (0.5~2:1) or water-DMSO that volume ratio is (0.5~2:1)
Mixed solvent.
It is (0.5~2) that solvent two, which is selected from volume ratio: 1 dichloro methane-methanol, volume ratio are (0.5~2): 1
Dichloromethane-ethanol mixed solvent, volume ratio are (0.5~2): 1 chloroform-methanol mixed solvent, volume ratio are (0.5
~2): 1 chloroform-alcohol mixed solvent, volume ratio are (2~5): 1 Methanol+Water or volume ratio be (2~
5): 1 ethanol-water mixed solvent.
Advantages of the present invention:
Effective removing, product have been carried out using the trace impurity that method of the invention can will affect digoxin product color
Color is whiter；The impurity such as digoxin and digitalis and bigitalin can be efficiently separated, keep product pure
Degree is effectively improved；The similar impurity of the structures such as double bigitalins is separated from digoxin product,
Product purity reaches 99.5% or more.The content of the digoxin crystal product obtained using method of the present invention is higher than
99.5% (HPLC method) can be used as standard substance for digoxin raw medicine quality-monitoring and therapeutic drug monitoring, preparation side
Method is simple.
Detailed description of the invention
The multi-stage ms figure of digoxin in the digoxin standard substance candidate that Fig. 1 prepares for embodiment 1；
Fig. 2 is the liquid chromatogram definite value spectrogram for the digoxin standard substance candidate that embodiment 1 is prepared.
Specific embodiment:
Digoxin crude product is prepared according to various methods known in the art or using commercially available digoxin original
Expect medicine.
The present invention is further illustrated combined with specific embodiments below.It should be pointed out that being to the present invention below
Claimed technical solution for example, not to any restrictions of these technical solutions.Protection scope of the present invention with
Subject to the content that claims are recorded.
Embodiment 1
A kind of preparation method of digoxin standard substance, comprising the following steps:
(1) it weighs the commercially available digoxin crude product (raw material) of 2g to be added in the round-bottomed flask of 250ml, 150mL trichlorine is added
Methane loads onto reflux condensing tube, dissolves solid all using electric heating cover ebuillition of heated, solution temperature is then dropped to 55
DEG C when, the active carbon of 0.1g is added, then at the boiling point reflux decoloration 45min, fall active carbon, gained with hot funnel heat filtering
Filter body rotary evaporation obtains digoxin white crystal crude product 1.9g；
By liquid chromatographic detection, digoxin content is 97.9%, and double bigitalin contents are 1.0%, ocean ground
Yellow content is 0.3%, and bigitalin content is 0.3%, and strange land Gaoxin content is 0.3%, and other impurities are unknown group
Point.
(2) the 1.9g digoxin crystal crude product that step (1) obtains is dissolved into 150ml diluent, diluent is body
The dichloromethane-ethyl acetate mixed solvent than being 1:1 is accumulated, is transferred in 500ml three neck round bottom flask, loads onto after ultrasonic dissolution
Motor stirring, 150ml extractant is added into flask, extractant is the Methanol+Water that volume ratio is 1:1；It carries out
Liquid-liquid extraction, control speed of agitator are 1500rpm, stir 5min, extraction phase is discharged after clarifying split-phase, retain raffinate phase；
(3) extractant identical with the raffinate phase volume is added in the raffinate phase obtained to step (2), extractant is
Volume ratio is the Methanol+Water of 1:1；In 1500rpm, 5min is stirred, extraction phase is discharged after clarifying split-phase, retains extraction
Yu Xiang；
(4) it repeats step (3) 4 times；
(5) raffinate phase that step (4) obtains is evaporated to the 1/3 of original volume, decrease temperature crystalline, after temperature is down to room temperature
Continuing to keep 30min, digoxin crystal product is obtained by filtration, then washed 3 times with diluent, each diluent dosage is 10ml,
Diluent is the dichloromethane-ethyl acetate mixed solvent that volume ratio is 1:1, and digoxin head product is obtained after vacuum drying
1.1g；
By liquid chromatographic detection, digoxin content is 99.1%, and double bigitalin contents are 0.6%, ocean ground
Pornography and drug glycosides content is 0.05%, and bigitalin content is 0.1%, and strange land Gaoxin content is 0.1%, and other impurities are not
Bright component；
(6) step (5) is obtained digoxin head product 1.1g to be put into 200mL solvent two, solvent two is volume ratio 1:1 bis-
Deionized water 120mL, time for adding is added dropwise under the conditions of 1000rpm in chloromethanes-alcohol mixed solvent, ultrasonic dissolution 10min
For 100min, until crystal is precipitated completely, filter, filter cake with methylene chloride wash 3 times (each volumetric usage is 10ml), it is dry
To digoxin standard substance 0.9g.
By liquid chromatographic detection, digoxin content is 99.52%, and double bigitalin contents are 0.35%, ocean
Glutinous rehmannia content is 0.03%, and bigitalin content is 0.05%, and unknown composition impurity content is 0.05%, digoxigenin
Glycosides and strange land Gaoxin content are not detected.
The resulting digoxin product of embodiment 1 is used into LCMS-IT-TOF mass spectrograph and the efficient liquid of Agilent 1200 respectively
Chromatography carries out Structural Identification and definite value analysis (see Fig. 1 and Fig. 2).It can be seen from the figure that pure using preparing for embodiment 1
Change method obtains high-purity digoxin.
Comparative example 1
(not passing through activated carbon adsorption decolorization process)
A kind of preparation method of drinox standard substance, comprising the following steps:
A. it liquid-liquid extraction: weighs the commercially available digoxin crude product (raw material) of 2g and is added to 150mL diluent methylene chloride-acetic acid
It is transferred in ethyl ester (volume ratio 1:1), after ultrasonic dissolution in 500ml three neck round bottom flask, motor stirring is loaded onto, into flask
It adding 150ml extractant methanol-water solution (volume ratio 1:1) and carries out liquid-liquid extraction, control speed of agitator is 1500rpm,
Split-phase is clarified after stirring 5min.Extraction phase is poured out after split-phase, the fresh extractant methanol-water solution of 150ml is added, and (volume ratio is
1:1) continue Liquid-liquid Extraction Processes.The above process is repeated 4 times.By gained diluent phase rotary evaporation to the 1/3 of original volume, drop
Temperature crystallization precipitates crystal, and continues to keep 30min after temperature is down to room temperature, suction filtration obtains crystal crude product, product dichloromethane
Alkane-ethyl acetate (volume ratio 1:1) mixed solvent washs 3 times (each volumetric usage is 10ml), is dried to obtain digoxin crystalline substance
Body product obtains product 1.15g.By liquid chromatographic detection, digoxin content is 98.9%, double bigitalin contents
It is 0.8%, digitalis content is 0.05%, and bigitalin content is 0.05%, and other impurities are unknown component, product
For light gray obfuscation crystal.
B. the resulting 1.15g digoxin crude product of step a dilution crystallization: is added to 100ml dichloromethane-ethanol solution
In (volume ratio 1:1), ultrasonic dissolution 10min.It is transferred in 500ml beaker after digoxin all dissolution, loads onto motor stirring,
Control speed of agitator is 1000rpm, and the total 120ml of deionized water, time for adding 100min are added dropwise into solution, will be high containing ground
Pungent Crystal suspensions filtering, filter cake are washed 3 times (each volumetric usage is 10ml) with methylene chloride, and gained crystal is carried out vacuum
It is dry, obtain light gray obfuscation crystal product 0.96g.By liquid chromatographic detection, digoxin content is 99.38%, double hydroxyl oceans
Granules glycosides content is 0.35%, and digitalis content is 0.04%, and bigitalin content is 0.04%, and other impurities are
Unknown component.
Comparative example 2
(not passing through liquid-liquid extraction step)
The resulting 2g digoxin crude product of 1 step (a) of embodiment is added to 200ml dichloromethane-ethanol solution (volume
Than 1:1) in, ultrasonic dissolution 10min.It is transferred in 500ml beaker after digoxin all dissolution, loads onto motor stirring, control
Speed of agitator is 1000rpm, and the total 240ml of deionized water, time for adding 100min are added dropwise into solution, will be brilliant containing digoxin
Liquid suspension filtering, filter cake are washed 3 times (each volumetric usage is 20ml) with methylene chloride, gained crystal progress vacuum are done
It is dry, obtain white crystal product 1.8g.By liquid chromatographic detection, digoxin content is 99.2%, double bigitalins
Content is 0.35%, and digitalis content is 0.15%, and bigitalin content is 0.22%, and other impurities are unknown group
Point.
Embodiment 2-6
Starting material is the commercially available digoxin crude product of 2g, and preparation step is same as Example 1, and design parameter is shown in Table 1.
Table 1
It is demonstrated experimentally that the methanol-that the Methanol+Water for being 0.2:1 with methylene chloride, volume ratio, volume ratio are 4:1
Ethanol-water mixed solvent that ethanol-water mixed solvent that water mixed solvent, volume ratio are 0.2:1, volume ratio are 4:1, volume ratio
For the methylene chloride-methanol mixed solvent of 0.2:1, volume ratio be 4:1 methylene chloride-methanol mixed solvent, volume ratio be
Dichloromethane-ethanol mixed solvent that the dichloromethane-ethanol mixed solvent of 0.2:1, volume ratio are 4:1, volume ratio 0.2:1
Chloroform-methanol mixed solvent, volume ratio be 4:1 chloroform-methanol mixed solvent, volume ratio be 0.2:1 three
Chloroform-alcohol mixed solvent alternate embodiment 1 chloroform that chloromethanes-alcohol mixed solvent or volume ratio are 4:1,
The purity of the other the same as in Example 1, the high-purity digoxin prepared is close with embodiment 1.
It is demonstrated experimentally that with the Water-Methanol Mixtures of 0.5:1, volume ratio be 2:1 water-ethanol mixed solvent, volume ratio
For the water-ethanol mixed solvent of 0.5:1, volume ratio be 0.5:1 boiling mixed solvent, volume ratio be 0.5:1 water-
The methanol-water that the water-DMSO mixed solvent substitution that DMSO mixed solvent or volume ratio are 2:1 is 1:1 for the volume ratio of embodiment 1
The purity of mixed solvent, the other the same as in Example 1, the high-purity digoxin prepared is close with embodiment 1.
It is demonstrated experimentally that the dichloro methane-methanol for being 0.5:1 with volume ratio, the methylene chloride-for being 2:1 with volume ratio
The dichloromethane-ethanol mixing that dichloromethane-ethanol mixed solvent that methanol solution, volume ratio are 0.5:1, volume ratio are 2:1
Chloroform-methanol mixed solvent that chloroform-methanol mixed solvent that solvent, volume ratio are 0.5:1, volume ratio are 2:1,
Chloroform-alcohol mixed solvent that chloroform-alcohol mixed solvent that volume ratio is 0.5:1, volume ratio are 2:1, volume
Than the Methanol+Water for 2:1, volume ratio be 5:1 Methanol+Water, volume ratio be 2:1 alcohol-water it is mixed
The volume ratio 1:1 dichloromethane-ethanol mixing for the ethanol-water mixed solvent alternate embodiment 1 that bonding solvent or volume ratio are 5:1 is molten
The purity of agent, the other the same as in Example 1, the high-purity digoxin prepared is close with embodiment 1.
Gained digoxin sterling uses 1200 efficient liquid phase of LCMS-IT-TOF mass spectrograph and Agilent in embodiment 2-6
Chromatograph carries out Structural Identification and definite value analysis, shows to obtain high-purity digoxin using the purification process for preparing of embodiment 2-6.
Above-described embodiment is only some examples in the present invention, but is not intended as to the restriction in the present invention.
Claims (9)
1. a kind of preparation method of digoxin standard substance, it is characterized in that including the following steps:
(1) in the ratio of 2g:100~400mL, digoxin crude product is dissolved in solvent one, addition active carbon, decoloration 30~
120min, is obtained by filtration filtrate, and filtrate evaporates to obtain digoxin crystal crude product；The active carbon is digoxin crude product weight
3%~10%；
(2) step (1) is obtained digoxin crystal crude product to be dissolved into 100-250mL diluent, is added mutual with diluent
Immiscible extractant stirs 5~30min in 800~2000rpm, pours out extraction phase after clarifying split-phase, retains raffinate phase,
The volume ratio of the diluent and extractant is (0.5~5): 1；
(3) extractant is added into raffinate phase, in 800~2000rpm, stirs 5~30min, is clarified extraction phase after split-phase
Discharge, retains raffinate phase, and the volume ratio for the raffinate phase that the extractant of this step and step (2) obtain is 1:(0.5~5)；
(4) step (3) are repeated 2-5 times；
(5) raffinate phase for obtaining step (4) evaporates, and digoxin crystal product is obtained by filtration after being down to room temperature in decrease temperature crystalline, then
It is washed 2-5 times with diluent, digoxin head product is obtained after vacuum drying；
(6) step (5) is obtained into digoxin head product ultrasonic dissolution in 100~400mL solvent two, in 500~1200rpm item
Under part, deionized water is added dropwise and filters until crystal is precipitated completely, be dried to obtain digoxin standard substance.
2. according to the method described in claim 1, it is characterized in that the volume ratio of diluent and extractant is in the step (2)
(1~2): 1.
3. according to the method described in claim 1, it is characterized in that the step (4) are as follows: repeat step (3) 4 times.
4. according to the method described in claim 1, it is characterized in that the step (6) are as follows: step (5) is obtained digoxin primiparity
Product are dissolved in solvent two, under the conditions of 1000rpm, deionized water 100-300mL are added dropwise, the time for adding of deionized water is 90
~150min is filtered until crystal is precipitated completely, is dried to obtain digoxin standard substance.
5. according to the method described in claim 4, it is characterized in that the amount of deionized water additional amount is 120mL, deionized water
Time for adding be 100-120min.
6. according to the method described in claim 1, it is characterized in that the solvent one is selected from methanol, ethyl alcohol, two in step (1)
Chloromethanes, chloroform, volume ratio are (0.2~4): 1 Methanol+Water, volume ratio are (0.2~4): 1 ethyl alcohol-
Water mixed solvent, volume ratio are (0.2~4): 1 methylene chloride-methanol mixed solvent, volume ratio are (0.2~4): 1 dichloro
Methane-alcohol mixed solvent, volume ratio are (0.2~4): 1 chloroform-methanol mixed solvent or volume ratio be (0.2~
4): 1 chloroform-alcohol mixed solvent.
7. method according to claim 1 or 2, it is characterised in that the diluent is selected from methylene chloride, chloroform, second
At least one of acetoacetic ester.
8. method according to claim 1 or 2, it is characterised in that it is (0.5~2:1) that the extractant, which is selected from volume ratio,
Water-Methanol Mixtures, volume ratio are the water-ethanol mixed solvent of (0.5~2:1), the water-the third that volume ratio is (0.5~2:1)
Ketone mixed solvent or volume ratio are the water-DMSO mixed solvent of (0.5~2:1).
9. according to claim 1, method described in 4 or 5, it is characterised in that it is (0.5~2) that the solvent two, which is selected from volume ratio: 1
Dichloro methane-methanol, volume ratio be (0.5~2): 1 dichloromethane-ethanol mixed solvent, volume ratio be (0.5~
2): 1 chloroform-methanol mixed solvent, volume ratio are (0.5~2): 1 chloroform-alcohol mixed solvent, volume ratio
It is (2~5): 1 ethanol-water mixed solvent for (2~5): 1 Methanol+Water or volume ratio.
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