CN104165965B - Analysis method for determining content of mildronate bulk drug intermediate of 3-(2,2-dimethyl hydrazino)methyl propionate by non-aqueous titration - Google Patents
Analysis method for determining content of mildronate bulk drug intermediate of 3-(2,2-dimethyl hydrazino)methyl propionate by non-aqueous titration Download PDFInfo
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- CN104165965B CN104165965B CN201410271714.6A CN201410271714A CN104165965B CN 104165965 B CN104165965 B CN 104165965B CN 201410271714 A CN201410271714 A CN 201410271714A CN 104165965 B CN104165965 B CN 104165965B
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- methyl propionate
- perchloric acid
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- dimethyl diazanyl
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Abstract
The invention relates to an analysis method for determining content of a mildronate bulk drug intermediate of 3-(2,2-dimethyl hydrazino)methyl propionate by non-aqueous titration, and provides an analysis method for determining the content of a first mildronate bulk drug intermediate. The method is characterized by inhibiting interferences of other related impurities to a non-aqueous determination method and increasing detection sensitivity. The method eliminates the interferences by adding a degrading agent for known impurities to realize non-aqueous determination. An analysis process comprises the steps of quantitatively dissolving a to-be-detected sample by using a mixed solution of acetate acid gracial and a small amount of acetic anhydride as a solvent; adding a trace amount of an impurity-degrading agent in a mixture; stirring for a certain time; titrating with perchloric acid; and determining a titration end point by an indicator method. The detection results obtained by the method are substantially identical to that of HPLC. The method is simple and rapid. The determination results are precise and highly accurate. The method can be used for routine analysis and quality control of the first mildronate bulk drug intermediate (C6H14N2O2).
Description
Technical field
A kind of nonaqueous titration determination Meldonium crude drug intermediate 3- (2,2- dimethyl diazanyl) methyl propionate content point
Analysis method, is related to Meldonium crude drug the first Quality control of intermediates technical field.
Background technology
International Non-Proprietary Name is Meldonium, and chemical entitled 3- (2,2,2- trimethyl hydrazine) propionate dihydrate is due to it
Cardioprotection and famous.
The known method having multiple preparation 3- (2,2,2_ trimethyl callosity) propionate dihydrate, generally includes：1,1- bis-
Methyl hydrazine and acrylic acid methyl ester. react formation 3- (2,2- dimethyl diazanyl) methyl propionate, methylate further in prepared Meldonium
Mesosome 3- (2,2,2- trimethyl hydrazine) methyl propionate halogen, then it is hydrolyzed and deionization after obtain Meldonium two water
Compound inner salt.Obtain the high-quality Meldonium crude drug for producing 3- (2,2,2- trimethyl hydrazine) propionate dihydrate, the
One intermediate 3- (2,2- dimethyl diazanyl) its content height of methyl propionate will directly affect Meldonium intermediate and Meldonium is former
The quality of material medicine product, hence sets up a kind of simplicity fast mass and controls detection method extremely important.
The method of detection 3- (2,2- dimethyl diazanyl) methyl propionate content is except Latvia Green Dai Kesi public affairs at present
Department's patent WO2009144221A1 discloses uses gas-matter connection in a kind of 3- (2,2- dimethyl diazanyl) methyl propionate preparation method
Detect the report having no other method of testings outside this compounds content at present both at home and abroad with the method for (GC/MS).3- (2,2- bis-
Methyl diazanyl) methyl propionate is a kind of liquid hydrazine class compound although its boiling point is between 188-200 DEG C but steady to heat
Qualitative difference, 100 DEG C about of heating starts degraded or oxidizable, especially more prominent when being detected using chromatography of gases (GC) method,
The repeatability of each test result and stability difference is led to be unsuitable for 3- (2,2- dimethyl diazanyl) methyl propionate assay.
3- (2,2- dimethyl diazanyl) methyl propionate chemical structural formula is：(CH3)2NNHCH2CH2COOCH3, contain diazanyl in its molecule and tie
Structure, can be reacted with perchloric acid, as long as excluding the interference of other type dopant contained by this compound, you can survey it with the method and contain
Amount.Reaction principle is
In general, this reaction is：
Content of the invention
It is an object of the invention to provide a kind of fast side of analysis crude drug Meldonium first intermediates content of precision
Method.In order to carry out quality control to crude drug Meldonium in actual production, we are directed to its contained impurity through GC, GC/
The comparative analysiss of the means of testing such as MS, PMR, TLC and contamination levels product, on the basis of having affirmed dopant type, establish one
Plant the method being suitable for measuring 3- (2,2- dimethyl diazanyl) methyl propionate content.
Technical scheme：A kind of nonaquepous tration improves the analysis measuring Meldonium crude drug first intermediates content
Method, it is characterised in that in order to stop the interference to non-aqueous assay method for other related impuritieses compared with existing non-aqueous titration,
Improve detection sensitivity, add one kind on this method for known in this intermediate 3- (2,2- dimethyl diazanyl) methyl propionate
The degradation agent of impurity, to eliminate interference, realizes non-aquametry operation.Analysis process is：With glacial acetic acid and a small amount of acetic anhydride mixed liquor
For solvent, quantitative dissolving 3- (2,2- dimethyl diazanyl) methyl propionate, add a kind of micro impurity degradation agent in mixture
After stirring a period of time, fixed with perchloric acid titration drop, titrated using indicator titration method, and calculated 3- (2,2- diformazans
Base diazanyl) methyl propionate content.
Computing formula：
Wherein：Volume ml of the perchloric acid standard solution that V--- consumes；V0--- blank consumption perchloric acid volume ml；C---
Perchloric acid titration liquid concentration mol/L；M--- sample weight g；
Note：Every 1ml 0.1mol/L perchloric acid titration liquid is equivalent to 0.01462g 3- (2,2- dimethyl diazanyl) propanoic acid first
Ester (C6H14N2O2).
In the said method of the present invention, using indicator titration method, it is indicator directing terminal with phenol red or crystal violet.
Said method 3- (2, the 2- dimethyl diazanyl) methyl propionate (C of the present invention6H14N2O2) measure as 0.1～0.3g, addition
The amount of glacial acetic acid is C6H14N2O250～200 times of quality, impurity degradation agent is：Amide-type, anhydrides or aldoketoneses therein
Kind or two kinds of mixing, addition is C6H14N2O2The 5%-60% of quality, glacial acetic acid and acetic anhydride mixed proportion are 35: 1～10
Addition is 25ml.Indicator is phenol red or the addition of crystal violet is 0.05ml～0.10ml.
In the nonaquepous tration content assaying method of the present invention, described for titrating C6H14N2O2Perchloric acid titration liquid dense
Spend for 0.01～0.1mol/L, the present invention selects 0.1mol/L.
Additionally, after being titrated using indicator titration method in above-mentioned analysis method, also including entering its titration results
Line blank corrects.
The analysis method of 3- (2,2- dimethyl diazanyl) the methyl propionate assay that the present invention provides, it is nonaquepous tration
Method, the method and high performance liquid chromatography (HPLC) compare, and high performance liquid chromatography separating power is high, and specificity is strong,
Consume sample size few；This non-hyperbolic curve method has the advantages of simple to operate, quick, measurement result is accurate, and accuracy is high, can
For Meldonium crude drug the first intermediate C6H14N2O2Conventional analyses and quality control.
Specific embodiment
Following examples will be helpful to the understanding to the present invention, but these embodiments are only for being illustrated to the present invention,
The present invention is not limited to these contents.
Embodiment 1
1st, the preparation of 0.1mol/L perchloric acid titration liquid：Anhydrous glacial acetic acid is taken (to calculate by water content, every 1g water adds acetic anhydride
5.22ml) 750ml, adds perchloric acid (70%～72%) 8.5ml, shakes up, at room temperature slowly Deca acetic anhydride 13ml, Bian Jia
While shaking, shaking again after adding uniformly, letting cool, plus anhydrous glacial acetic acid makes into 1000ml, shakes up, place 24 hours.
2nd, the demarcation of 0.1mol/L perchloric acid titration liquid：It is taken at 105 DEG C of dryings to the benchmark Potassium Hydrogen Phthalate of constant weight
About 0.16g, accurately weighed, plus anhydrous glacial acetic acid 20ml makes dissolving, plus crystal violet indicator solution 1, slowly it is titrated to indigo plant with this liquid
Color, and the result blank assay of titration is corrected.Every 1ml perchloric acid titration liquid (0.1mol/L) is equivalent to the neighbour of 20.42mg
Potassium hydrogen phthalate, according to the amount of taking of this liquid consumption and Potassium Hydrogen Phthalate, calculates the concentration of this liquid, obtains final product.
Perchloric acid titration liquid concentration C (mol/L)=mX0.1X 1000/ (V-V0)X 20.42
Wherein C is perchloric acid titration liquid concentration, mol/L；The amount of weighing of Potassium Hydrogen Phthalate on the basis of m, mg；V is mark
The consumption of this volumetric solution, ml in fixed；V0For the consumption of this volumetric solution in blank assay, ml.
3rd, replica test：Precision weighs C6H14N2O2Intermediate sample, according to potentiometric titration METHOD FOR CONTINUOUS DETERMINATION 6 times, high chlorine
Acidometric titration liquid actual concentrations when 25 DEG C are 0.1092mol/L, and the blank perchloric acid solution that consumes is 0.020ml, and measurement result is
98.62%, relative standard deviation is 0.19%, and result of the test shows, this method is reproducible, complies fully with the matter of assay
Amount controls requirement, C6H14N2O2Assay Precision Experiment the results are shown in Table 1.
Table 1 C6H14N2O2Intermediate sample size measures Precision test result
Embodiment 2
Precision weighs C6H14N2O2Intermediate sample about 0.15g, is separately added into glacial acetic acid and acetic anhydride (35: 5) 25ml and 7ml
Acetone and dimethylformamide (2: 1, V/V) mixed liquor simultaneously make it dissolve with electromagnetic agitation, continue stirring at a temperature of 30 DEG C
10min about, plus crystal violet indicator 2, being changed into blue with perchloric acid titration liquid (0.1092mol/L) titration from purple is eventually
Point, and titration results are corrected with blank assay.The perchloric acid titration liquid (0.10mol/L) of every 1ml is equivalent to 14.62mg's
C6H14N2O2.The non-aqueous titration of the present invention and high performance liquid chromatography C6H14N2O2Measurement result is shown in Table 2.
Table 2 sample determination data
High performance liquid chromatography：Chromatographic column is Krom asilC18 (250mm x 4.6mm, 5 μm)；Mobile phase be methanol-
Water-acetic anhydride (36: 60: 1.0, v/v/v), flow velocity 1.0mL/min；Detection wavelength is 254nm；30 DEG C of column temperature.C6H14N2O2, r=
0.9999；Method precision RSD is 0.45% (n=5)；Average recovery rate is 98.7% (n=7).
Technique effect：
The solution have the advantages that the measurement result of high performance liquid chromatography and non-hyperbolic curve method statistically
There was no significant difference.High performance liquid chromatography separating power is high, and specificity is strong, consumes sample size few；The non-water potential of the present invention
Titrimetry is simple, quick, and measurement result is accurate, and accuracy is high, can be used for Meldonium crude drug the first intermediate C6H14N2O2Normal
Rule analysis and quality control.
Claims (1)
1. a kind of analysis of nonaqueous titration determination Meldonium crude drug intermediate 3- (2,2- dimethyl diazanyl) methyl propionate content
Method, it is characterised in that in order to stop the interference to non-aqueous assay method for other related impuritieses, improving detection sensitivity, is added
A kind of degradation agent for known impurities in this intermediate 3- (2,2- dimethyl diazanyl) methyl propionate come to eliminate interference realize non-
Aquametry operates, and analysis process is：With glacial acetic acid and a small amount of acetic anhydride mixed liquor as solvent, quantitative dissolving 3- (2,2- dimethyl
Diazanyl) methyl propionate, after adding a kind of micro impurity degradation agent stirring a period of time in mixture, use perchloric acid titration liquid
Titrated, and calculated 3- (2,2- dimethyl diazanyl) methyl propionate content,
Computing formula：
Wherein：
Volume ml of the perchloric acid standard solution that V--- consumes；
V0--- blank consumption perchloric acid volume ml；
C--- perchloric acid titration liquid concentration mol/L；
M--- sample weight g；
0.01462--- every 1ml0.1mol/L perchloric acid titration liquid is equivalent to 0.01462g 3- (2,2- dimethyl diazanyl) propanoic acid
Methyl ester；
3- (2,2- dimethyl diazanyl) methyl propionate amount is 0.1～0.3g, and the amount adding glacial acetic acid is 3- (2,2- dimethylhydrazines
Base) 50～200 times of methyl propionate quality, impurity degradation agent is：Amide-type, acetate type, anhydrides or aldoketoneses therein
Kind or two kinds of mixed solution, addition is the 5%-60% of 3- (2,2- dimethyl diazanyl) methyl propionate quality, glacial acetic acid and
Acetic anhydride mixed volume ratio is 35: 1～10, and addition is 25ml, and indicator is phenol red or the addition of crystal violet is 0.05ml
～0.10ml.
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