CN104165965A - 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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- CN104165965A CN104165965A CN201410271714.6A CN201410271714A CN104165965A CN 104165965 A CN104165965 A CN 104165965A CN 201410271714 A CN201410271714 A CN 201410271714A CN 104165965 A CN104165965 A CN 104165965A
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- methyl propionate
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- perchloric acid
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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 analytical approach of nonaqueous titration determination Meldonium bulk drug intermediate 3-(2,2-dimethyl diazanyl) methyl propionate content, relates to Meldonium bulk drug the first Quality control of intermediates technical field.
Background technology
International generic name is Meldonium, and chemistry 3-(2,2,2-trimethyl hydrazine) propionate dihydrate by name is famous due to its cardioprotection.
Known have a multiple preparation 3-(2,2,2-trimethyl callosity) method of propionate dihydrate, generally include: 1,1-dimethylhydrazine reacts with methyl acrylate and forms 3-(2,2-dimethyl diazanyl) methyl propionate, further methylate, then to its be hydrolyzed and deionization after obtain Meldonium dihydrate inner salt.Obtain for the production of 3-(2,2,2-trimethyl hydrazine) the high-quality Meldonium bulk drug of propionate dihydrate, the first intermediate 3-(2,2-dimethyl diazanyl) its content of methyl propionate height will directly affect the quality of Meldonium bulk drug, therefore sets up a kind of easy quick test method of quality control extremely important.
Detect at present 3-(2,2-dimethyl diazanyl) method of methyl propionate content discloses a kind of 3-(2 except the patent WO2009144221A1 of Green Dyax Corp of Latvia, 2-dimethyl diazanyl) method of using gas-matter coupling (GC/MS) in methyl propionate preparation method detects outside this compounds content, has no the report of other method of testing at present both at home and abroad.3-(2,2-dimethyl diazanyl) methyl propionate is a kind of liquid hydrazine class compound, although its boiling point is between 188-200 DEG C but to poor heat stability, heat 100 DEG C of left and right and start degraded or oxidizable, more outstanding in the time using chromatography of gases (GC) method to detect especially, cause repeatability and the poor stability of each test result to be unsuitable for 3-(2,2-dimethyl diazanyl) methyl propionate assay.3-(2,2-dimethyl diazanyl) methyl propionate chemical structural formula is: (CH
3)
2nNHCH
2cH
2cOOCH
3, in its molecule, containing diazanyl structure, can react with perchloric acid, as long as get rid of the interference of contained other type dopant of this compound, available the method is surveyed its content.Reaction principle is
In general, this reaction is:
Summary of the invention
The object of this invention is to provide a kind of method of quick and accurate analysis bulk drug Meldonium the first intermediate content.For bulk drug Meldonium being carried out to quality control in actual production, we pass through the means of testing such as GC, GC/MS, PMR, TLC, are affirming on the basis of dopant type with the comparative analysis of impurity standard items for its contained impurity, set up the method that one is suitable for measuring 3-(2,2-dimethyl diazanyl) methyl propionate content.
Technical scheme of the present invention: a kind of nonaquepous tration is improved the analytical approach of measuring Meldonium bulk drug the first intermediate content, it is characterized in that in order to stop the interference of other related impurities to non-aquametry method, improve detection sensitivity, in the method, add a kind of degradation agent for known impurities and eliminate interference, realize non-aquametry operation.Analytic process is: taking glacial acetic acid and a small amount of acetic anhydride mixed liquor as solvent, quantitatively dissolve 3-(2,2-dimethyl diazanyl) methyl propionate, in potpourri, add after a kind of impurity degradation agent minimal amount of agitation a period of time, fixed with perchloric acid titration drop, adopt indicator titration method to carry out titration, and calculate 3-(2,2-dimethyl diazanyl) methyl propionate content.
Computing formula:
Wherein: the volume ml of the perchloric acid standard solution that V---consumes; V
0---the blank perchloric acid volume ml that consumes; C---perchloric acid titration liquid concentration mol/L; The heavy g of m---sample;
Note: every 1ml 0.1mol/L perchloric acid titration liquid is equivalent to 0.01462g 3-(2,2-dimethyl diazanyl) methyl propionate (C
6h
14n
2o
2).
In said method of the present invention, adopt indicator titration method, with phenol red or crystal violet be indicator directing terminal.
Said method 3-of the present invention (2,2-dimethyl diazanyl) methyl propionate (C
6h
14n
2o
2) amount be 0.1～0.3g, the amount that adds glacial acetic acid is C
6h
14n
2o
250～200 times of quality, preferably C
6h
14n
2o
2amount is for 0.16g, and impurity degradation agent is: one or both the mixing wherein of amide-type, acetate type, anhydrides or aldoketones, addition is C
6h
14n
2o
2the 5%-60% of quality, glacial acetic acid and acetic anhydride blending ratio are (35: 1～10, V/V), addition is 25ml.Indicator addition phenol red or crystal violet is 0.05ml～0.10ml (1～2).
In nonaquepous tration content assaying method of the present invention, described for titration C
6h
14n
2o
2perchloric acid titration liquid concentration be 0.01～0.1mol/L, the present invention selects 0.1mol/L.
In addition, in above-mentioned analytical approach, adopt indicator titration method to carry out, after titration, also comprising its titration results being carried out to blank correction.
The analytical approach of 3-provided by the invention (2,2-dimethyl diazanyl) methyl propionate assay, it is non-aqueous titration, the method and high performance liquid chromatography (HPLC) compare, high performance liquid chromatography separating power is high, and specificity is strong, and consumption sample size is few; That this non-water potential titrimetry has is simple to operate, quick, measurement result is accurate, accuracy advantages of higher, can be used for Meldonium bulk drug the first intermediate C
6h
14n
2o
2conventional analysis and quality control.
Embodiment
Following examples will contribute to understanding of the present invention, but these embodiment are only for the present invention is illustrated, and the present invention is not limited to these contents.
Embodiment 1
1, the preparation of 0.1mol/L perchloric acid titration liquid: get anhydrous glacial acetic acid and (calculate by water cut, every 1g water adds acetic anhydride 5.22ml) 750ml, add perchloric acid (70%～72%) 8.5ml, shake up, at room temperature slowly drip acetic anhydride 13ml, limit edged shakes, after adding, jolting is even again, lets cool, and adds anhydrous glacial acetic acid and makes into 1000ml, shake up, place 24 hours.
2, the demarcation of 0.1mol/L perchloric acid titration liquid: be taken at 105 DEG C of about 0.16g of benchmark Potassium Hydrogen Phthalate that are dried to constant weight, accurately weighed add anhydrous glacial acetic acid 20ml make dissolve, add 1 of crystal violet indicator solution, be slowly titrated to blueness with this liquid, and the result of titration is proofreaied and correct with blank test.Every 1ml perchloric acid titration liquid (0.1mol/L) is equivalent to the Potassium Hydrogen Phthalate of 20.42mg, according to the amount of taking of this liquid consumption and Potassium Hydrogen Phthalate, calculates the concentration of this liquid, to obtain final product.
Perchloric acid titration liquid concentration:
Wherein C is perchloric acid titration liquid concentration, mol/L; M is the amount of taking of benchmark Potassium Hydrogen Phthalate, mg; V is the consumption of this vs in demarcating, ml; V
0for the consumption of this vs in blank test, ml.
3, replica test: precision takes C
6h
14n
2o
2intermediate sample, according to potentiometric titration METHOD FOR CONTINUOUS DETERMINATION 6 times, perchloric acid titration liquid actual concentrations in the time of 25 DEG C is 0.1092mol/L, blank consumption perchloric acid solution is 0.020ml, and measurement result is 98.62%, and relative standard deviation is 0.19%, test findings shows, this method is reproducible, meets the quality control requirement of assay completely, C
6h
14n
2o
2assay Precision Experiment the results are shown in Table 1.
Table 1 C
6h
14n
2o
2intermediate sample size is measured Precision test result
Embodiment 2
Precision takes C
6h
14n
2o
2the about 0.15g of intermediate sample, add respectively glacial acetic acid and aceticanhydride (35: 5) 25ml and 7ml acetone and dimethyl formamide (2: 1, V/V) mixed liquor make its dissolving by electromagnetic agitation, at the temperature of 30 DEG C, continue to stir 10min left and right, add 3 of crystal violet indicator, becoming blueness with perchloric acid titration liquid (0.1092mol/L) titration from purple is terminal, and titration results is proofreaied and correct with blank test.The perchloric acid titration liquid (0.10mol/L) of every 1ml is equivalent to the C of 14.62mg
6h
14n
2o
2.Non-aqueous titration of the present invention and high performance liquid chromatography C
6h
14n
2o
2measurement result is in table 2.
Table 2 sample determination data
High performance liquid chromatography: chromatographic column be Krom asilC18 (250mm × 4.6mm, 5 μ m); Mobile phase is methanol-water-acetic anhydride (36: 60: 1.0, v/v/v), flow velocity 1.0mL/min, and detection wavelength is 254nm; 30 DEG C of column temperatures.C
6h
14n
2o
2, r=0.9999; Method precision RSD is 0.45% (n=5); Average recovery rate is 98.7% (n=7).
Technique effect:
Technique effect of the present invention is the measurement result there was no significant difference statistically of high performance liquid chromatography and non-water potential titrimetry.High performance liquid chromatography separating power is high, and specificity is strong, and consumption sample size is few; Non-water potential titrimetry of the present invention is simple, quick, measurement result precision, and accuracy is high, can be used for Meldonium bulk drug the first intermediate C
6h
14n
2o
2conventional analysis and quality control.
Claims (2)
1. a nonaqueous titration determination Meldonium bulk drug intermediate 3-(2,2-dimethyl diazanyl) analytical approach of methyl propionate content, it is characterized in that in order to stop the interference of other related impurities to non-aquametry method, improve detection sensitivity, add a kind of degradation agent for known impurities and eliminate to disturb and realize the operation of non-aquametry.Analytic process is: taking glacial acetic acid and a small amount of acetic anhydride mixed liquor as solvent, quantitatively dissolve 3-(2,2-dimethyl diazanyl) methyl propionate, in potpourri, add after a kind of impurity degradation agent minimal amount of agitation a period of time, fixed with perchloric acid titration drop, adopt titrimetry to carry out titration, and calculate 3-(2,2-dimethyl diazanyl) methyl propionate content.
Computing formula:
Wherein:
The volume ml of the perchloric acid standard solution that V---consumes;
V
0---the blank perchloric acid volume ml that consumes;
C---perchloric acid titration liquid concentration mol/L;
The heavy g of m---sample;
Note: every 1ml 0.1mol/L perchloric acid titration liquid is equivalent to 0.01462g 3-(2,2-dimethyl diazanyl) methyl propionate (C
6h
14n
2o
2).
2. analytical approach according to claim 1 is characterized in that: 3-(2,2-dimethyl diazanyl) methyl propionate (C
6h
14n
2o
2) amount be 0.1～0.3g, the amount that adds glacial acetic acid is C
6h
14n
2o
250～200 times of quality, preferably C
6h
14n
2o
2amount is for 0.16g, and impurity degradation agent is: amide-type, acetate type, anhydrides or aldoketones one or both mixed solution wherein, addition is C
6h
14n
2o
2the 5%-60% of quality, glacial acetic acid and acetic anhydride blending ratio are (35: 1～10, V/V), addition is 25ml.Indicator addition phenol red or crystal violet is 0.05ml～0.10ml (1～2).
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| CN105372383A (en) * | 2015-11-11 | 2016-03-02 | 福建科宏生物工程有限公司 | Method for determination of monomenthyl succinate content |
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| EP2128126A1 (en) * | 2008-05-26 | 2009-12-02 | Grindeks, a joint stock company | New process for the preparation of 3-(2,2,2-Trimethylhydrazinium) propionate dihydrate |
| CN101952245A (en) * | 2008-02-19 | 2011-01-19 | 格林代克斯联合股份公司 | Carbonic and sulphuric acid salts of 3-(2,2,2-trimethylhydrazinium)propionate esters and their use for 3-(2,2,2-trimethylhydrazinium)propionate dihydrate preparation |
| CN102036949A (en) * | 2008-05-26 | 2011-04-27 | 格林代克斯联合股份公司 | Process for preparing 3-(2,2-dimethylhydrazino) methylpropionate |
| CN101320014B (en) * | 2008-07-01 | 2012-11-21 | 江苏省原子医学研究所 | Analytical method for measuring raw medicine content of thiohydroxylamine tropine by non-aqueous titrimetry |
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| CN101952245A (en) * | 2008-02-19 | 2011-01-19 | 格林代克斯联合股份公司 | Carbonic and sulphuric acid salts of 3-(2,2,2-trimethylhydrazinium)propionate esters and their use for 3-(2,2,2-trimethylhydrazinium)propionate dihydrate preparation |
| EP2128126A1 (en) * | 2008-05-26 | 2009-12-02 | Grindeks, a joint stock company | New process for the preparation of 3-(2,2,2-Trimethylhydrazinium) propionate dihydrate |
| CN102036949A (en) * | 2008-05-26 | 2011-04-27 | 格林代克斯联合股份公司 | Process for preparing 3-(2,2-dimethylhydrazino) methylpropionate |
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| CN105372383A (en) * | 2015-11-11 | 2016-03-02 | 福建科宏生物工程有限公司 | Method for determination of monomenthyl succinate content |
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