CN105738533B - method for separating and measuring 1, 2-propylene glycol enantiomer by gas chromatography - Google Patents
method for separating and measuring 1, 2-propylene glycol enantiomer by gas chromatography Download PDFInfo
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- CN105738533B CN105738533B CN201410738980.5A CN201410738980A CN105738533B CN 105738533 B CN105738533 B CN 105738533B CN 201410738980 A CN201410738980 A CN 201410738980A CN 105738533 B CN105738533 B CN 105738533B
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- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical class CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 title claims abstract description 54
- 238000000034 method Methods 0.000 title claims abstract description 34
- 238000004817 gas chromatography Methods 0.000 title claims abstract description 18
- 229960004063 propylene glycol Drugs 0.000 claims abstract description 22
- 238000001212 derivatisation Methods 0.000 claims abstract description 21
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 11
- -1 aldehyde ketone compound Chemical class 0.000 claims abstract description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 47
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 38
- 239000007789 gas Substances 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 229960003834 dapagliflozin Drugs 0.000 claims description 16
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 claims description 15
- 239000002808 molecular sieve Substances 0.000 claims description 13
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 claims description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 239000012085 test solution Substances 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 6
- 238000005259 measurement Methods 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- 230000005526 G1 to G0 transition Effects 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 235000013772 propylene glycol Nutrition 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000002516 radical scavenger Substances 0.000 claims description 4
- 229920000858 Cyclodextrin Polymers 0.000 claims description 3
- 239000001116 FEMA 4028 Substances 0.000 claims description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical group OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 3
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 3
- 229960004853 betadex Drugs 0.000 claims description 3
- 150000002500 ions Chemical class 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 3
- 239000001307 helium Substances 0.000 claims description 2
- 229910052734 helium Inorganic materials 0.000 claims description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000004445 quantitative analysis Methods 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 31
- 239000003814 drug Substances 0.000 abstract description 7
- 238000002360 preparation method Methods 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000003638 chemical reducing agent Substances 0.000 abstract 1
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 23
- 239000012488 sample solution Substances 0.000 description 22
- 239000000047 product Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 238000005303 weighing Methods 0.000 description 15
- 239000000523 sample Substances 0.000 description 13
- 238000001514 detection method Methods 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 9
- 238000007865 diluting Methods 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 238000007789 sealing Methods 0.000 description 7
- 238000003908 quality control method Methods 0.000 description 5
- 230000007547 defect Effects 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000012088 reference solution Substances 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 150000001299 aldehydes Chemical group 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000010812 external standard method Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 125000005372 silanol group Chemical group 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- BGXNGARHYXNGPK-UHFFFAOYSA-N 2-[1-[(4-methoxyphenyl)methylsulfanyl]cyclohexyl]acetic acid Chemical compound C1=CC(OC)=CC=C1CSC1(CC(O)=O)CCCCC1 BGXNGARHYXNGPK-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229960001713 canagliflozin Drugs 0.000 description 1
- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000002983 circular dichroism Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 150000002009 diols Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
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- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses methods for separating and measuring 1, 2-propylene glycol, 1, 2-propylene glycol-containing raw material medicines and 1, 2-propylene glycol enantiomer impurities in preparations thereof by adopting a pre-column derivatization gas chromatography, which uses an aldehyde ketone compound as a derivatization reagent, performs pre-column derivatization with the 1, 2-propylene glycol in the presence of a catalyst and a water reducing agent, and measures trace enantiomer impurities by using the gas chromatography.
Description
Technical Field
The invention belongs to the field of analytical chemistry, and particularly relates to a method for separating and measuring 1, 2-propylene glycol enantiomer by adopting a pre-column derivatization gas chromatography.
Background
Dapagliflozin (dapagliflozin) is sodium-glucose cotransporter 2 (SGLT 2) inhibitors, developed by Aslicon and Shi Guibao Co., Ltd., and having a molecular formula of C21H25ClO6The chemical name is as follows: (1S) -1, 5-anhydro-1-C- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl group]Phenyl radical]Because dapagliflozin exists in the form of the hydrate of (2 s) -1, 2-propanediol, another enantiomer of propanediol (2R) -1, 2-propanediol is introduced in the process of synthesizing the compound, and impurities of (2R) -1, 2-propanediol remain in the product, so that the content control and the sizing detection analysis of the impurities of (2R) -1, 2-propanediol in the dapagliflozin product are required, and the method has important practical significance in the quality control of bulk drugs and preparations of the dapagliflozin.
, because 1, 2-propylene glycol structure has no obvious conjugate group, no ultraviolet absorption, can not be used to determine by conventional liquid phase separation detection method, the prior art mainly adopts gas chromatography for determining enantiomer in 1, 2-propylene glycol, uses chemical bonding β -cyclodextrin as chiral gas chromatographic column of stationary phase to perform separation determination, the ortho hydroxyl group in 1, 2-propylene glycol structure is easy to form hydrogen bond with silanol group (-Si-OH) on the surface of the stationary phase carrier of chromatographic column, and the adsorption occurs, causing serious tailing of chromatographic peak, can not satisfy the requirement of trace impurity accurate quantification.
In another aspect , the prior art methods for determining enantiomeric impurities in vicinal diols based on derivatizationIn the operation, definite defects exist and cannot meet the requirements of the conventional medicine quality control method, the investigation result of Liujing et al (volume 30, No. 9, No. 1270-1278 in organic chemistry 2010) shows that the transition metal reagent M is usedO2(OAC)4The optical active complex is formed with an o-diol structural compound, and circular dichroism determination is carried out, so that the qualitative requirement of absolute configuration research can be met, and quantitative determination cannot be carried out; the results of the power L et al (Anal biochem. 1994 Sep;221(2): 323-8) showed that the gas chromatography-mass spectrometry technique was used with NaB2H4The sample is processed, and the content of the 1, 2-propylene glycol enantiomer is measured by adopting a common gas phase column, because the method is used for measuring the concentration of the sample, the content of trace impurities in the sample can not be measured, and the used instrument is expensive and is not suitable for the use requirement of daily medicine quality control.
Disclosure of Invention
The invention aims to provide methods for separating and measuring 1, 2-propylene glycol enantiomer by adopting pre-column derivatization gas chromatography, which overcome the defects of the prior art, namely the technical defects that 1, 2-propylene glycol has serious tailing of peaks in the separation process of a common chiral gas chromatography column and trace impurities cannot be accurately quantified.
To achieve the object of the present invention, the following embodiments are provided:
in embodiment, methods for separating and measuring 1, 2-propanediol enantiomers by gas chromatography according to the present invention comprise derivatizing 1, 2-propanediol and injecting the derivatized 1, 2-propanediol into a gas chromatography column for quantitative measurement, wherein the method comprises adding a derivatizing reagent, a water scavenger and a catalyst into a sample containing propanediol enantiomers, stirring the mixture for reaction, performing post-treatment to obtain a sample solution, and performing quantitative analysis by gas chromatography, wherein the derivatizing reagent is an aldehyde or ketone derivatizing reagent, and the catalyst is or more selected from acidic resins, inorganic acids, organic acids and lewis acids.
In the method of the present invention, preferably, the aldehyde or ketone derivatization reagent is acetone, butanone, formaldehyde or benzaldehyde, more preferably acetone, wherein the weight-to-volume ratio of the 1, 2-propanediol enantiomer to the derivatization reagent is 1-20:1mg/ml, preferably 1-10: 1, the 1, 2-propanediol enantiomer referred to herein is (S) -1, 2-propanediol or (R) -1, 2-propanediol or a mixture thereof.
In the above embodiments, the method of the present invention, preferably, the water scavenger is selected from anhydrous magnesium sulfate, 4A molecular sieve and anhydrous sodium sulfate, more preferably 4A molecular sieve, wherein the weight ratio of the water scavenger to the 1, 2-propanediol enantiomer is 10-20: 1.
In the above embodiment, the method of the present invention, preferably, the catalyst is sulfuric acid, phosphoric acid, Amberlyst-15, Amberlyst-16, methanesulfonic acid or p-toluenesulfonic acid, more preferably Amberlyst-15, wherein the weight ratio of the catalyst to 1, 2-propanediol is 0.2-1.0: 1.
the method of the invention, the sample containing the propylene glycol enantiomer, also contains dapagliflozin, preferably dapagliflozin (S) -1, 2-propanediol compound.
In the above embodiments, the method of the present invention, the derivatization time is 15 minutes to 5 hours, preferably 30 minutes to 2 hours.
In the above embodiment, the method of the present invention is characterized in that the measurement conditions of the sample by the gas chromatograph are:
chromatographic column with chemically bonded β -cyclodextrin as stationary phase;
a detector: a hydrogen flame ion detector;
column temperature: the initial temperature is 60 ℃, the temperature is maintained for 5-30 minutes, the temperature is raised to 150 ℃ at the rate of 40 ℃ per minute, and the temperature is maintained for 1-10 minutes;
sample inlet temperature: 180-300 ℃;
the split ratio is as follows: 1: 1-50: 1;
detector temperature: 200-320 ℃;
flow rate of nitrogen or helium: 0.1-2.0 ml per minute.
According to the method, a special derivatization reagent is adopted, a catalyst and a water removal agent are used in the derivatization process, and the 1, 2-propylene glycol is subjected to pre-column derivatization under specific conditions, so that the hydroxyl in the 1, 2-propylene glycol structure can be sealed, the hydroxyl is prevented from forming hydrogen bonds with silanol groups (-Si-OH) existing on the surface of a chromatographic column stationary phase carrier, adsorption is avoided, and the phenomenon of tailing of chromatographic peaks is improved; and the derivatization efficiency can be improved, so that the 1, 2-propylene glycol in the sample is completely converted into a derivatization product, and the accuracy of the detection method is ensured. The method has the advantages of mild reaction conditions, high reaction speed, no interference of excessive derivatization reagent in determination, stable derivatization product, high analysis sensitivity and capability of accurately determining 0.05 percent of enantiomer in a test sample. The method overcomes the defects that the peak of the 1, 2-propylene glycol is seriously trailing in the separation process of the common chiral gas chromatographic column and trace impurities cannot be accurately quantified, and achieves the aim of accurately measuring the trace 1, 2-propylene glycol enantiomer impurities, thereby ensuring the quality control of the 1, 2-propylene glycol, the 1, 2-propylene glycol-containing raw material medicine and the preparation thereof, and particularly ensuring the quality control of the 1, 2-propylene glycol enantiomer-containing canagliflozin and the preparation.
Drawings
FIG. 1 gas chromatogram of reagent blank
FIG. 2 gas chromatogram of (R) -1, 2-propanediol
FIG. 3 gas chromatogram of (S) -1, 2-propanediol
FIG. 41 gas chromatogram of 2-propanediol racemate derivative product (R and S configuration)
FIG. 5 gas chromatogram of (R) -1, 2-propanediol impurity detection test solution in (S) -1, 2-propanediol
FIG. 6 gas chromatogram of (S) -1, 2-propanediol impurity detection test solution in (R) -1, 2-propanediol
FIG. 7 gas chromatogram of (R) -1, 2-propanediol impurity detection test solution in dapagliflozin raw material
FIG. 8 gas chromatogram of (R) -1, 2-propylene glycol impurity detection reference solution in dapagliflozin raw material
FIG. 9 gas chromatogram of (R) -1, 2-propanediol impurity detection test solution in dapagliflozin preparation
FIG. 10 gas chromatogram of (R) -1, 2-propanediol impurity detection control solution in dapagliflozin preparation
Detailed Description
The following provides a further explanation of the invention
Example 1
Apparatus and conditions
Shimadzu gas chromatograph (GC-2010) and Lab Solutions workstation; automatic sample introduction; CD-Chirasil-DEX CB (0.25 μm, 25m × 0.25 μm) is used as an analytical column; the detector is a hydrogen flame ion detector; the initial temperature is 60 ℃, the temperature is maintained for 10 minutes, the temperature is raised to 150 ℃ at the rate of 40 ℃ per minute, and the temperature is maintained for 5 minutes; the temperature of a sample inlet is 250 ℃, and the split ratio is 50: 1; the temperature of the detector is 250 ℃; the carrier gas is nitrogen, the flow rate is 1.0ml per minute, and the sample injection volume is 1 ml.
Experimental procedure
Precisely measuring 5ml of acetone, placing in a micro-reactor, adding 0.5g of water removing agent (4A molecular sieve) and 10mg of catalyst (Amberlyst-15), sealing, stirring at room temperature for 1h, filtering the reaction solution with a thickness of 0.45 μm, and collecting the filtrate as a test solution. The test solution was subjected to gas chromatography under the above conditions, and the results are shown in FIG. 1.
Taking a proper amount of (R) -1, 2-propylene glycol, dissolving with acetone, diluting to obtain a solution containing about 100 μ g per 1ml, and performing gas chromatography under the above conditions to obtain a result shown in FIG. 2; the results of the same measurement of (S) -1, 2-propanediol are shown in FIG. 3.
Precisely weighing about 100mg of 1, 2-propylene glycol, placing the weighed 1, 2-propylene glycol into a 10ml measuring flask, adding acetone for dissolving and diluting to scale, shaking up, precisely weighing 5ml, placing the weighed 1, 2-propylene glycol into a micro-reactor, adding 0.5g of a water removal agent (4A molecular sieve) and 10mg of a catalyst (Amberlyst-15), sealing, stirring for 1h at room temperature, filtering a reaction solution by using 0.45 mu m, and taking a filtrate as a sample solution. The test solution was subjected to gas chromatography under the above conditions, and the results are shown in FIG. 4.
As can be seen from fig. 1, the chromatographic peak before 2.4 minutes and the chromatographic peak after 10.1 minutes are negative blank solvent peaks; as can be seen from FIGS. 2 and 3, both (R) -1, 2-propanediol and (S) -1, 2-propanediol peaked at 12.8 minutes; from FIG. 4, it can be seen that the chromatographic peaks at retention times of 5.8 minutes and 6.4 minutes are the (R) -1, 2-propanediol derivative product and the (S) -1, 2-propanediol derivative product, respectively. The results show that the 1, 2-propylene glycol derivative products with two configurations have good peak shapes, can achieve baseline separation, do not interfere detection with negative blank solvents, and have high derivatization reaction efficiency, and the (R) -1, 2-propylene glycol and the (S) -1, 2-propylene glycol are not detected.
Example 2
Taking about 100mg of (R) -1, 2-propylene glycol, precisely weighing, placing in a 10ml measuring flask, adding acetone for dissolving and diluting to scale, shaking uniformly, precisely weighing 5ml, placing in a micro-reactor, adding 0.5g of a water removal agent (4A molecular sieve) and 10mg of a catalyst (Amberlyst-15), sealing, stirring at room temperature for 1h, taking a reaction solution, filtering with 0.45 mu m, and taking a filtrate as a test solution. Subjecting the sample solution to gas chromatograph analysis under the above conditions, and obtaining the result shown in FIG. 5; the results of the same measurement of (S) -1, 2-propanediol are shown in FIG. 6.
The chromatographic peaks at retention times of 6.0 minutes and 7.0 minutes in fig. 5 were (R) -1, 2-propanediol derived product and its enantiomeric impurity (S) -1, 2-propanediol derived product, respectively (impurity content 0.96%), and the chromatographic peaks at 6.6 minutes and 6.4 minutes in fig. 6 were (S) -1, 2-propanediol derived product and its enantiomeric impurity (R) -1, 2-propanediol derived product, respectively (impurity content 0.45%). The result shows that the method can accurately determine the content of the enantiomer impurities in the 1, 2-propylene glycol.
Example 3
Taking about 0.5g of dapagliflozin bulk drug (about equivalent to 90mg of (S) -1, 2-propylene glycol), precisely weighing, placing in a 10ml measuring flask, adding acetone for dissolving, diluting to scale, shaking up, precisely weighing 5ml, placing in a micro reactor, adding 0.5g of water removal agent (4A molecular sieve) and 20mg of catalyst (Amberlyst-15), sealing, stirring at room temperature for 1h, taking reaction liquid, filtering with 0.45 mu m, and taking filtrate as sample solution; taking about 10mg of (R) -1, 2-propylene glycol as a reference substance, precisely weighing, placing in a 10ml measuring flask, adding acetone for dissolving and diluting to a scale, shaking up, precisely weighing 5ml, placing in a micro-reactor, adding 0.5g of a water removing agent (4A molecular sieve) and 20mg of a catalyst (Amberlyst-15), sealing, stirring for 1h at room temperature, filtering a reaction solution by using 0.45 mu m, precisely weighing 1ml of a subsequent filtrate, placing in a 100ml measuring flask, diluting to a scale by using acetone, and shaking up to obtain a reference substance solution. The reference solution and the sample solution were analyzed by gas chromatography under the above conditions, and the results are shown in fig. 7 and 8, and the impurity content was calculated by external standard method using the peak area of the (R) -1, 2-propanediol derivative product.
The chromatographic peaks at retention times of 6.4 minutes and 6.1 minutes in FIG. 7 are the (S) -1, 2-propanediol derivative product and its enantiomeric impurity (R) -1, 2-propanediol derivative product, respectively (impurity content 0.02%). The result shows that the method can accurately determine the content of optical isomer impurities in the 1, 2-propylene glycol in the dapagliflozin bulk drug.
Example 4
Taking 20 dapagliflozin tablets, grinding, weighing a proper amount of powder (about equal to 90mg of (S) -1, 2-propylene glycol), precisely weighing, putting into a 50ml measuring flask, adding 80ml of acetone, carrying out ultrasonic treatment for 10 minutes, taking out, cooling, diluting with acetone to a scale, precisely weighing 10ml, putting into a micro-reactor, volatilizing by nitrogen, precisely adding 2ml of acetone, carrying out vortex oscillation for redissolution, adding 0.2g of a water removal agent (4A molecular sieve) and 10mg of a catalyst (Amberlyst-15), sealing, stirring at room temperature for 1h, taking a reaction solution, filtering by 0.45 mu m, and taking a filtrate as a sample solution; taking about 10mg of (R) -1, 2-propylene glycol as a reference substance, precisely weighing, placing in a 10ml measuring flask, adding acetone for dissolving and diluting to a scale, shaking up, precisely weighing 2ml, placing in a micro-reactor, adding 0.2g of a water removing agent (4A molecular sieve) and 10mg of a catalyst (Amberlyst-15), sealing, stirring for 1h at room temperature, filtering a reaction solution by using 0.45 mu m, precisely weighing 1ml of a subsequent filtrate, placing in a 100ml measuring flask, diluting to a scale by using acetone, and shaking up to obtain a reference substance solution. The reference solution and the sample solution were analyzed by gas chromatography under the above conditions, and the results are shown in fig. 9 and fig. 10, and the impurity content was calculated by external standard method using the peak area of the (R) -1, 2-propanediol derivative product.
The chromatographic peaks at retention times of 6.4 minutes and 6.1 minutes in FIG. 9 are the (S) -1, 2-propanediol derivative product and its enantiomeric impurity (R) -1, 2-propanediol derivative product, respectively (impurity content 0.02%). The result shows that the method can accurately determine the content of the optical isomer impurity in the 1, 2-propylene glycol in the dapagliflozin tablet.
Example 5
Referring to example 1, about 250mg of (S) -1, 2-propanediol was weighed precisely, placed in a 25ml measuring flask, dissolved in acetone and diluted to the scale, shaken well, and 5ml of the solution was weighed precisely and placed in a microreactor, and 4 parts of the solution were prepared in parallel, and 0.5g of anhydrous sodium sulfate, anhydrous magnesium sulfate, and anhydrous sodium sulfate were added without adding a dehydrator, and the solution was prepared as a sample solution from # 1 to # 4 according to example 1. And (3) taking the sample solution to be tested for gas chromatograph analysis under the conditions. The results showed that the conversion efficiencies were 89.9%, 98.4%, and 96.3%, respectively.
Example 6
Referring to example 1, about 250mg of (S) -1, 2-propanediol was weighed precisely, placed in a 25ml measuring flask, dissolved in acetone and diluted to the scale, shaken well, and 5ml of the solution was weighed precisely and placed in a microreactor, and 4 parts of 4A molecular sieves, 0.05g, 0.5g, 1.0g, and 2.5 g, were added in parallel, and the solution was prepared as sample solutions No. 1 to No. 4 according to example 1. And (3) taking the sample solution to be tested for gas chromatograph analysis under the conditions. The results showed conversion efficiencies of 98.7%, 100.0%, respectively. Wherein, the No. 4 sample solution is difficult to obtain the continuous filtrate after being filtered.
Example 7
Referring to example 1, about 250mg of (S) -1, 2-propanediol was weighed out precisely, placed in a 25ml measuring flask, dissolved in acetone and diluted to the scale, shaken well, 5ml of the solution was weighed out precisely, placed in a microreactor, and 5 parts of 4A molecular sieves 0.5g and sulfuric acid, phosphoric acid, Amberlyst-16, methanesulfonic acid or p-toluenesulfonic acid 10mg were added in parallel, and the resulting mixture was sealed as sample solutions No. 1 to No. 5 as in example 1. And (3) taking the sample solution to be tested for gas chromatograph analysis under the conditions. The results showed that all conversions were complete.
Example 8
Referring to example 1, about 250mg of (S) -1, 2-propanediol was weighed out precisely, placed in a 25ml measuring flask, dissolved in acetone and diluted to the scale, shaken well, 5ml of the solution was weighed out precisely, placed in a microreactor, and 4 parts of 4A molecular sieves, 0.5g, Amberlyst-150.5 mg, 10mg, 20mg and 40 mg, were added in parallel, sealed, and prepared as sample solutions No. 1 to No. 4 as in example 1. And (3) taking the sample solution to be tested for gas chromatograph analysis under the conditions. The results showed conversion efficiencies of 98.1%, 100.0%, respectively.
Example 9
Referring to example 1, about 50mg of (S) -1, 2-propanediol was weighed precisely and placed in a microreactor, 4 parts in parallel, 5ml of acetone, methyl ethyl ketone, formaldehyde and benzaldehyde were weighed precisely and placed in a microreactor, and prepared as sample solutions No. 1 to No. 4 in accordance with example 1. And (3) taking the sample solution to be tested for gas chromatograph analysis under the conditions. The results showed conversion efficiencies of 100.0%, 98.4%, 100.0%, respectively.
Example 10
Referring to example 1, 2.5mg, 5mg, 50mg, 100mg and 250mg of (S) -1, 2-propanediol were precisely weighed and placed in a microreactor, 5ml of acetone was precisely weighed and placed in an microreactor, and prepared as sample solutions 1# to 5# according to example 1, and the sample solutions were analyzed by a gas chromatograph under the above conditions, and the results showed that the conversion efficiencies 1# to 3# were 100.0%, 100% and 100.0%, and the conversion efficiencies 4# to 5# were 99.4% and 98.7%, respectively.
Example 11
Referring to example 1, about 100mg of (S) -1, 2-propanediol was weighed precisely, and placed in 10ml measuring flasks in parallel at 10 portions, wherein # 1 to # 3 were diluted to the scale with (R) -1, 2-propanediol stock solution (concentration about 0.01 mg/ml), # 4 to # 6 were diluted to the scale with (R) -1, 2-propanediol stock solution (concentration about 0.05 mg/ml), # 7 to # 9 were diluted to the scale with (R) -1, 2-propanediol stock solution (concentration about 0.06 mg/ml), and # 10 was diluted to the scale with acetone and shaken. Each sample was measured precisely at 5ml, and placed in a microreactor to prepare sample solutions 1# to 10# as in example 1. And (3) taking the sample solution to be tested for gas chromatograph analysis under the conditions. The recovery was calculated as the peak area of (R) -1, 2-propanediol and the results are shown in the following table:
the recovery rate test result shows that the recovery rate of the (R) -1, 2-propylene glycol impurity residue measured by the method is within the range of 98.0-101.6%, the recovery rate of the method is good, and the requirement of accurately measuring trace impurities is met.
The foregoing is only a preferred embodiment of the present invention, and it will be apparent to those skilled in the art that various modifications and improvements can be made without departing from the principle of the invention, and such modifications and improvements should be considered as the protection scope of the invention.
Claims (7)
1, method for separating and measuring 1, 2-propylene glycol enantiomer by gas chromatography, comprising the steps of injecting 1, 2-propylene glycol into a gas chromatographic column for quantitative measurement after derivatization, adding a derivatization reagent, a water removing agent and a catalyst into a sample containing the 1, 2-propylene glycol enantiomer, stirring for reaction, performing post-treatment to obtain a test solution, performing quantitative analysis according to the gas chromatography,
wherein,
the derivatization reagent is selected from or more of acetone, butanone, formaldehyde and benzaldehyde;
the catalyst is or more selected from sulfuric acid, phosphoric acid, Amberlyst-15, Amberlyst-16, methane sulfonic acid and p-toluenesulfonic acid;
the water removing agent is selected from or more of anhydrous magnesium sulfate, 4A molecular sieve and anhydrous sodium sulfate;
the measurement conditions of the gas chromatograph on the sample are as follows:
the chromatographic column takes β -cyclodextrin bonded chemically as a stationary phase, and the detector is a hydrogen flame ion detector;
the initial temperature of the column temperature is 60 ℃, the column temperature is maintained for 5-30 minutes, the temperature is raised to 150 ℃ at the rate of 40 ℃ per minute, and the column temperature is maintained for 1-10 minutes; the temperature of a sample inlet is 180-300 ℃; the split ratio is 1: 1-50: 1; the temperature of the detector is 200-320 ℃; the flow rate of nitrogen or helium is 0.1-2.0 ml per minute.
2. The method of claim 1, wherein the weight to volume ratio of 1, 2-propanediol to derivatizing agent is 1-20:1 mg/ml.
3. The method of claim 1, wherein the weight ratio of water scavenger to 1, 2-propanediol is 10-20: 1.
4. The method according to claim 1, wherein the catalyst is added in an amount of 0.2-1.0 by weight: 1.
5. the method of claim 1, wherein the sample containing the 1, 2-propanediol enantiomer further contains dapagliflozin.
6. The method of claim 1, wherein the derivatization time is 15 minutes to 5 hours.
7. The method according to claim 6, wherein the derivatization time is preferably 30 minutes to 2 hours.
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