CN113670680A - Preparation method of acarbose impurity reference substance - Google Patents
Preparation method of acarbose impurity reference substance Download PDFInfo
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- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 title claims abstract description 133
- 229960002632 acarbose Drugs 0.000 title claims abstract description 133
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 title claims abstract description 133
- 239000012535 impurity Substances 0.000 title claims abstract description 127
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 239000013558 reference substance Substances 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 21
- 238000001514 detection method Methods 0.000 claims abstract description 17
- 238000004108 freeze drying Methods 0.000 claims abstract description 12
- 239000000126 substance Substances 0.000 claims abstract description 5
- 239000000945 filler Substances 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 238000007710 freezing Methods 0.000 claims description 14
- 230000008014 freezing Effects 0.000 claims description 14
- 238000000746 purification Methods 0.000 claims description 14
- 238000000926 separation method Methods 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 9
- 238000004821 distillation Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000012528 membrane Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 239000000741 silica gel Substances 0.000 claims description 6
- 229910002027 silica gel Inorganic materials 0.000 claims description 6
- 238000011049 filling Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 2
- 229910000069 nitrogen hydride Inorganic materials 0.000 claims description 2
- 239000004952 Polyamide Substances 0.000 claims 2
- 239000013068 control sample Substances 0.000 claims 2
- 229920002647 polyamide Polymers 0.000 claims 2
- 239000000523 sample Substances 0.000 claims 2
- 238000012856 packing Methods 0.000 claims 1
- 238000005292 vacuum distillation Methods 0.000 claims 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 abstract description 13
- 238000004811 liquid chromatography Methods 0.000 abstract description 11
- 238000005516 engineering process Methods 0.000 abstract description 10
- 238000001196 time-of-flight mass spectrum Methods 0.000 abstract description 8
- 238000012790 confirmation Methods 0.000 abstract description 7
- 238000000862 absorption spectrum Methods 0.000 abstract description 4
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- 229940079593 drug Drugs 0.000 abstract description 3
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- 238000005220 pharmaceutical analysis Methods 0.000 abstract description 2
- 229910052799 carbon Inorganic materials 0.000 description 39
- 238000001228 spectrum Methods 0.000 description 35
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 33
- 229910052739 hydrogen Inorganic materials 0.000 description 22
- 239000001257 hydrogen Substances 0.000 description 18
- BXWLVQXAFBWKSR-UHFFFAOYSA-N 2-methoxy-5-methylsulfonylbenzoic acid Chemical compound COC1=CC=C(S(C)(=O)=O)C=C1C(O)=O BXWLVQXAFBWKSR-UHFFFAOYSA-N 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 5
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
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- 238000000605 extraction Methods 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
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- HCIFJKWFKHPOMC-IILQJVAWSA-N (1S,2S,3R,6S)-6-[[(2R,3S,4S,5R,6R)-6-[(2R,3S,4R,5R,6S)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(1R,4R,5S,6R)-4,5,6-trihydroxy-2-(hydroxymethyl)cyclohex-2-en-1-yl]oxyoxan-3-yl]oxy-4,5-dihydroxy-2-methyloxan-3-yl]amino]-4-(hydroxymethyl)cyclohex-4-ene-1,2,3-triol Chemical compound C[C@H]1O[C@H](O[C@@H]2[C@@H](CO)O[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](O)C=C3CO)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O)[C@@H]1N[C@H]1C=C(CO)[C@@H](O)[C@H](O)[C@H]1O HCIFJKWFKHPOMC-IILQJVAWSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- UMFZJPRJFORIIJ-BGDITRTQSA-N (2R,3R,4R,5R)-4-[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-en-1-yl]amino]oxan-2-yl]oxy-2,3,5,6-tetrahydroxyhexanal Chemical compound C[C@H]1O[C@H](O[C@H]([C@H](O)CO)[C@H](O)[C@@H](O)C=O)[C@H](O)[C@@H](O)[C@@H]1N[C@@H]1[C@H](O)[C@@H](O)[C@H](O)C(CO)=C1 UMFZJPRJFORIIJ-BGDITRTQSA-N 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- 108010073178 Glucan 1,4-alpha-Glucosidase Proteins 0.000 description 1
- 102100022624 Glucoamylase Human genes 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 102400000471 Isomaltase Human genes 0.000 description 1
- 108010026867 Oligo-1,6-Glucosidase Proteins 0.000 description 1
- 101710184309 Probable sucrose-6-phosphate hydrolase Proteins 0.000 description 1
- 102400000472 Sucrase Human genes 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 101710112652 Sucrose-6-phosphate hydrolase Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- 108010028144 alpha-Glucosidases Proteins 0.000 description 1
- 102000016679 alpha-Glucosidases Human genes 0.000 description 1
- 230000002902 bimodal effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 235000011073 invertase Nutrition 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- SNVLJLYUUXKWOJ-UHFFFAOYSA-N methylidenecarbene Chemical group C=[C] SNVLJLYUUXKWOJ-UHFFFAOYSA-N 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
- G01N2001/2893—Preparing calibration standards
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of an acarbose impurity reference substance, and belongs to the technical field of pharmaceutical analysis. The method adopts multiple technologies such as liquid chromatography, ultraviolet absorption spectrum, infrared absorption spectrum, time of flight mass spectrum (TOF-MS), nuclear magnetic resonance spectrum (NMR), freeze drier, quantitative nuclear magnetic detection and the like to separate and purify the four impurities including acarbose impurities I, II, III and IV, freeze drying, content detection, structure confirmation and standardization, and the four impurities can be used as impurity reference substances in the quality detection of acarbose bulk drugs and preparations. The invention provides a method for separating and purifying acarbose impurities, which is a universal method for separating acarbose impurity reference substances, can be used for purifying and preparing acarbose and other related substances, and solves the problem of lack of impurity reference substances in the existing acarbose quality control and impurity research.
Description
Technical Field
The invention belongs to the field of pharmaceutical analysis, and particularly relates to a preparation method of an acarbose impurity reference substance.
Background
Acarbose (Acarbose) is O-4, 6-dideoxy-4- [1S, 4R, 5S, 6S ] -4, 5, 6-trihydroxy-3- (hydroxymethyl) -2-cyclohexene-1-amino ] -alpha-D-glucopyranosyl- (1 → 4) -O-alpha-D-glucopyranosyl- (1 → 4) -alpha-D-glucopyranosyl, is an alpha-glucosidase inhibitor, competitively inhibits the glucoside hydrolase (maltase, isomaltase, glucoamylase and sucrase) in the intestinal tract, reduces the decomposition of polysaccharide and sucrose into glucose, correspondingly slows the absorption of sugar, has the function of reducing the blood sugar after meals, thereby relieving the postprandial hyperglycemia, can be used for reducing blood sugar.
Acarbose is a raw material for oral preparations, and impurities contained in acarbose affect the safety of product use, so that the impurities in samples are thoroughly researched and strictly limited. The existing method and literature do not carry out detailed impurity preparation, and cannot provide an impurity reference substance preparation method which is necessary for acarbose quality control and impurity research.
Disclosure of Invention
Aiming at the existing problems, the invention provides a method for separating and purifying acarbose impurities, which is used for obtaining high-purity acarbose impurities I, II, III and IV through separation and purification, freeze drying, structure confirmation and standardization by preparing liquid chromatography, and is used for quality detection and research of acarbose bulk drugs and preparations.
The invention is realized by the following technical scheme:
the preparation method of the acarbose impurity reference substance comprises the following steps:
1) taking the acarbose impurity enriched solution, adjusting the pH value to 3.0-6.0 by using dilute hydrochloric acid, and carrying out reduced pressure distillation and concentration until each milliliter of concentrated solution contains 10-40mg of acarbose impurities;
2) adjusting the pH value of the concentrated solution in the step 1) to 7.0-10.0 by using dilute ammonia water, and then filtering by using a 0.45-micron filter membrane to obtain an impurity concentrated solution;
3) two times in succession with C18Eluting the impurity concentrated solution under the condition of filler separation and purification, and collecting fractions containing acarbose impurities;
4) then NH2Purifying the fraction collected in the step 3) under the condition of filler separation and purification, and collecting the fraction with the purity of more than 95%;
5) mixing the fractions with the purity of more than 95% collected in the step 4), distilling under reduced pressure to remove methanol, adding water for dissolution, adjusting the pH value to 3.0-6.0 with dilute hydrochloric acid, and pre-freezing in a refrigerator;
6) freeze-drying the fraction subjected to the pre-freezing treatment in the step 5) in a freeze dryer to obtain white crystalline powder, namely acarbose impurity; and finally, detecting the purity of the obtained acarbose impurity and carrying out structure confirmation and standardization.
The preparation method of the acarbose impurity reference substance is characterized in that the acarbose impurities in the step 1) are respectively impurity I, impurity II, impurity III and impurity IV in acarbose in the second part of the pharmacopoeia of the people's republic of China 2020 edition, and the structural formulas are respectively as follows:
the preparation method of the acarbose impurity reference substance is characterized in that the acarbose impurity reference substance is subjected to reduced pressure distillation and concentration in the step 1) until each milliliter of concentrated solution contains 20-30mg of acarbose impurity.
The preparation method of the acarbose impurity reference substance is characterized in thatIn step 3) C18The conditions for separating and purifying the filler are as follows: a chromatographic column: welch Xtimate C18200-400g of 10-micron filler filling; mobile phase: methanol-water solution 8-92 (V/V); flow rate: 40-70 mL/min; sample introduction volume: 10 mL; detection wavelength: 210nm, wherein the methanol-water solution contains 0.1% NH3。
The preparation method of the acarbose impurity reference substance is characterized in that NH in the step 4)2And (3) separating and purifying conditions of the filler: a chromatographic column: welch Ultimate XB-NH2150-350g of 10-micron filler filling; mobile phase: methanol; flow rate: 40-70 mL/min; sample introduction volume: 10 mL; detection wavelength: 210 nm.
The preparation method of the acarbose impurity reference substance is characterized in that the flow rate is 50-60 mL/min.
The preparation method of the acarbose impurity reference substance is characterized in that the amount of the acarbose enrichment liquid collected in each time in the step 1) is 200-500ml, and the volume dissolved by water in the step 5) is 20-50 ml.
The preparation method of the acarbose impurity reference substance is characterized in that the conditions of the freeze dryer in the step 6) are as follows: the freezing temperature is-70 ℃ to-80 ℃ under the pressure condition of 0.01-0.03 Mpa.
The preparation method of the acarbose impurity reference substance is characterized in that the freezing pressure is 0.02Mpa, and the freezing temperature is-76. C
The method adopts various technologies such as liquid chromatography, ultraviolet absorption spectrum, infrared absorption spectrum, time-of-flight mass spectrum (TOF-MS), nuclear magnetic resonance spectrum (NMR), freeze dryer and the like to separate and purify the acarbose impurities I, II, III and IV, freeze-dry, detect the content, confirm the structure and standardize the impurities, and the four impurities can be used as impurity reference substances in the quality detection of acarbose bulk drugs and preparations. The invention provides a method for separating and purifying acarbose impurities, which is a universal method for separating acarbose impurities, can be used for purifying and preparing other related substances of acarbose, and solves the problem of the lack of impurity reference substances in the existing acarbose quality control and impurity research. The method can be used for rapidly preparing a large amount of high-purity acarbose impurities, provides powerful technical support for determining the quality safety of acarbose products and guaranteeing the health of consumers and the like, and has important practical significance.
Drawings
FIG. 1 is an HPLC chromatogram of acarbose impurity I from example 1;
FIG. 2 is a time-of-flight mass spectrum of acarbose impurity I of example 1;
FIG. 3 is a nuclear magnetic resonance spectrum (H spectrum) of acarbose impurity I in example 1;
FIG. 4 is a nuclear magnetic resonance spectrum (C spectrum) of acarbose impurity I in example 1;
FIG. 5 is an HPLC chromatogram of acarbose impurity II from example 2;
FIG. 6 is a time-of-flight mass spectrum of acarbose impurity II of example 2;
FIG. 7 is a nuclear magnetic resonance spectrum (H spectrum) of acarbose impurity II in example 2;
FIG. 8 is a nuclear magnetic resonance spectrum (C spectrum) of acarbose impurity II in example 2;
FIG. 9 is an HPLC chromatogram of acarbose impurity III from example 3;
FIG. 10 is a time-of-flight mass spectrum of acarbose impurity III of example 3;
FIG. 11 is a nuclear magnetic resonance spectrum (H spectrum) of acarbose impurity III in example 3;
FIG. 12 is a nuclear magnetic resonance spectrum (C spectrum) of acarbose impurity III in example 3;
FIG. 13 is an HPLC chromatogram of acarbose impurity IV from example 4;
FIG. 14 is a time-of-flight mass spectrum of acarbose impurity IV of example 4;
FIG. 15 is a nuclear magnetic resonance spectrum (H spectrum) of acarbose impurity IV in example 4;
FIG. 16 shows the NMR spectrum (C spectrum) of acarbose impurity IV in example 4.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention will be described in further detail below with reference to the accompanying drawings, and specific examples will be given.
Example 1
Extraction of acarbose impurity I
(1) And (3) enriching the acarbose impurity I from the acarbose sample by using an LC silica gel pre-column with the particle size of 20-45 mu m. Taking 300mL of acarbose impurity I enriched solution, adjusting the pH value to 3.0-6.0 by using dilute hydrochloric acid, carrying out reduced pressure distillation and concentration to 30mg/mL, adjusting the pH value to 7.0-10.0 by using diluted ammonia water, and finally filtering by using a 0.45-micrometer filter membrane to obtain an I impurity concentrated solution.
(2) Two times in succession with C18And (3) eluting the impurity concentrated solution I under the condition of filler separation and purification. C18The conditions for separating and purifying the filler are as follows: the instrument comprises the following steps: DAC50 preparation of liquid chromatography system (Beijing Innovation technology, Inc.); a chromatographic column: welch Xtimate C18300g of 10-micron filler is filled; mobile phase: methanol-Water (containing 0.1% NH)3) Solution 8-92 (V/V); flow rate: 50 mL/min; sample introduction volume: 10 mL; detection wavelength: 210 nm.
(3) Collecting the fraction containing acarbose impurity I, adding NH2And purifying the fraction under the condition of filler separation and purification, and collecting the fraction with the purity of more than 95%. NH (NH)2The conditions for separating and purifying the filler are as follows: the instrument comprises the following steps: DAC50 preparation of liquid chromatography system (Beijing Innovation technology, Inc.); a chromatographic column: welch Ultimate XB-NH2250g of 10-micron filler is filled; mobile phase: methanol; flow rate: 50 mL/min; sample introduction volume: 10 mL; detection wavelength: 210 nm.
(4) Mixing the fractions I with the acarbose impurity with the purity of more than 95 percent, distilling under reduced pressure to remove methanol, adding 20mL of water for dissolving, adjusting the pH value to 5.0-6.0 by using dilute hydrochloric acid, and placing the mixture into a refrigerator for pre-freezing.
(5) And then freeze-drying in a freeze-drying machine at the temperature of minus 76 ℃ and under the pressure of 0.02Mpa to obtain white crystalline powder, namely the target product acarbose impurity I, and storing the product under the drying condition of 2-8 ℃.
Confirmation of structure of acarbose impurity I
(1) The high resolution mass spectrum is shown in FIG. 2, and the analysis and conclusion are as follows:
sample molecular formula: c25H43NO18Absolute molecular weight M: 645.2480
[M+H]+Experimental values: 646.2573 [ M + H]+Theoretical value: 646.2553
According to the high-resolution mass spectrogram of the acarbose impurity I, the molecular formula of the sample is [ M + H ] in the positive ion mode]+Experimental values and molecular formula C25H43NO18Corresponding [ M + H]+The relative error of the theoretical value is 3.09ppm, thereby confirming that the molecular formula of the acarbose impurity I is C25H43NO18。
(2) Nuclear magnetic resonance spectroscopy, nuclear magnetic resonance hydrogen spectrum of a sample: (1H-NMR), carbon spectrum (13C-NMR) is shown in FIGS. 3 and 4.
1The proton signals appeared in the H-NMR spectrum (figure 3) can be divided into 15 groups, and the result of hydrogen signal peak area integration shows that the sample at least contains 29 hydrogen atoms (no active hydrogen), including hydrogen signals (delta) on 1 double bondH5.741-5.734, d, J ═ 4.0Hz,1H), 2 sugar end hydrogen signals (δH5.172-5.151,d,J＝3.5Hz,1H；δH5.083-5.053, d, J ═ 3.8Hz,1H), 1 triplet methine signal (δH2.326-2.295, t, J ═ 9.5Hz,1H), 1 bimodal methyl signal (δH1.186-1.176, d, J ═ 6.3Hz,3H) and other methine and methylene signals.
13C-NMR (FIG. 4) showed that the sample contained 34 sets of signals for 25 pairs of carbons in total, including 1 double-bonded carbon (. delta.)C140.820；δC125.628), 1 quaternary carbon (. delta.)C103.794/100.138), 2 sugar end methine groups (. delta.))C102.189/99.998；δC101.711), 15 other methines (. delta.)C83.240/80.027；δC81.828/71.022；δC79.056；δC77.090/68.749；δC75.223/75.046；δC74.814；δC74.787；δC74.568；δC73.436；δC73.015；δC72.862/72.724；δC72.638；δC71.446；δC66.791；δC57.836), 4 methylene groups (. delta.),C65.635/64.239；δC65.251/64.549；δC63.464；δC62.452) and 1 methyl group (. delta.))C19.184)。
Nuclear magnetic resonance hydrogen spectrum of acarbose impurity I (f: (b))1H-NMR), carbon spectrum (13C-NMR) confirmed C, H assignment to correspond to the sample molecular structure formula:
three, acarbose impurity I standardization
The HPLC purity of acarbose impurity I was 96.4%, as shown in FIG. 1. The content of acarbose impurity I detected by a quantitative nuclear magnetic method is 90.5 percent and is used as an impurity reference substance.
Example 2
Extraction of acarbose impurity II
(1) And (3) enriching the acarbose impurity II from the acarbose sample by using an LC silica gel pre-column with the particle size of 20-45 mu m. Taking 300mL of acarbose impurity II enriched solution, adjusting the pH value to 3.0-6.0 by using dilute hydrochloric acid, carrying out reduced pressure distillation and concentration to 30mg/mL, adjusting the pH value to 7.0-10.0 by using diluted ammonia water, and finally filtering by using a 0.45-micrometer filter membrane to obtain a concentrated solution.
(2) Two times in succession with C18And (3) eluting the II impurity concentrated solution under the conditions of filler separation and purification, and collecting the fraction containing the acarbose impurity II. C18And (3) separating and purifying conditions of the filler: the instrument comprises the following steps: DAC50 preparation of liquid chromatography system (Jiangsu Hanbang science and technology, Inc.); a chromatographic column: welch Xtimate C18300g of 10-micron filler is filled; mobile phase: methanol-Water (containing 0.1% NH)3) Solution 8-92 (V/V); flow rate: 50 mL/min; sample introduction volume: 10 mL; detection wavelength: 210 nm.
(3) Then NH2And purifying the fraction under the condition of filler separation and purification, and collecting the fraction with the purity of more than 95%. NH (NH)2And (3) separating and purifying conditions of the filler: the instrument comprises the following steps: DAC50 preparation of liquid chromatography system (Jiangsu Hanbang science and technology, Inc.); a chromatographic column: daisogel SP-120-APS-P, 10 μm filler pack300g of the mixture is filled; mobile phase: methanol; flow rate: 50 mL/min; sample introduction volume: 10 mL; detection wavelength: 210 nm.
(4) Mixing the acarbose impurity II fractions with the purity of more than 95%, distilling under reduced pressure to remove methanol, adding 20mL of water for dissolving, adjusting the pH value to 5.0-6.0 by using dilute hydrochloric acid, and placing the mixture into a refrigerator for pre-freezing.
(5) And (3) freeze-drying in a freeze-drying machine at the temperature of minus 76 ℃ and under the pressure of 0.02Mpa to obtain white crystalline powder, namely a target product, namely acarbose impurity II, and storing the product under the drying condition of 2-8 ℃.
Confirmation of structure of acarbose impurity II
(1) The high resolution mass spectrum is shown in FIG. 6, and the analysis and conclusion are as follows:
sample molecular formula: c26H43NO17Absolute molecular weight M: 641.2531
[M+H]+Experimental values: 642.2614 [ M + H]+Theoretical value: 642.2604
According to the high-resolution mass spectrogram of the acarbose impurity B, the molecular formula of the sample is [ M + H ] in the positive ion mode]+Experimental values and molecular formula C26H43NO17Corresponding [ M + H]+The relative error of the theoretical value is 1.55ppm, thereby confirming that the molecular formula of the acarbose impurity B is C26H43NO17。
(2) Nuclear magnetic resonance spectroscopy, nuclear magnetic resonance hydrogen spectrum of a sample: (1H-NMR), carbon spectrum (13C-NMR) is shown in FIGS. 7 and 8.
1The proton signals of 17 groups of samples appearing in the H-NMR spectrum (FIG. 7) were found to contain at least 29 hydrogen atoms (containing no active hydrogen) from their integrated areas.1The proton signal (. delta.) at the group 2 double bonds occurs in the low field region of the H-NMR spectrumH5.920,d,J＝3.7Hz,1H；δH5.758, s,1H) and group 2 end group proton signals (. delta.)H5.471,d,J＝3.9Hz,1H；δH5.383,d,J＝3.7Hz,1H)；1In the high-field region of H-NMR spectrum, 13 groups of hydrogen proton signals appear, including 4 groups of overlapped proton signals (delta)H4.268-4.192,overlap,4H；δH3.964-3.932,overlap,2H；δH3.901-3.863,overlap,5H；δH3.684-3.623, overlap,3H), proton signal (. delta.) for group 5 methinesH 4.477,d,J＝7.5Hz,1H；δH 4.116,d,J＝6.8Hz,1H；δH4.046,br,1H；δH3.811,m,1H；δH3.481,dd,J＝9.9,8.7Hz,1H；δH2.941 br,1H), proton signal (. delta.) of a methylene group of group 2 coupled to carbonH4.151,d,J＝13.5Hz,1H；δH3.791, m,1H), proton signal (. delta.) for group 1 methyl groupsH1.406,d,J＝6.1Hz,3H)。
13C-NMR (FIG. 8) showed that the sample contained 24 carbon signals, with 2 carbon signals appearing low-field in the carbon spectrum, being quaternary (delta) on 1 double bondC136.321) and tertiary carbon signal (delta)C127.518); the midfield part presents 22 carbon signals, including 2 terminal tertiary carbon signals (delta)C99.681；δC98.206), 16 tertiary carbon signals (. delta.) attached to heteroatomsC78.640；δC77.220；δC75.371；δC75.214；δC73.303；δC72.456；δC72.176；δC71.303；δC71.020；δC70.747；δC70.718；δC70.007；δC 68.406；δC66.715；δC63.341；δC56.271), secondary carbon signal (δ) of 3 hydroxymethyl groupsC61.341；δC61.322；δC60.548) and 1 methyl carbon signal (. delta.))C17.351)。
Nuclear magnetic resonance hydrogen spectrum of acarbose impurity II (1H-NMR), carbon spectrum (13C-NMR) confirmed C, H assignment to correspond to the sample molecular structure formula:
third, acarbose impurity II standardization
The HPLC purity of acarbose impurity II was 94.0%, see FIG. 5. The content of acarbose impurity II detected by a quantitative nuclear magnetic method is 86.7 percent and is used as an impurity reference substance.
Example 3
Extraction of acarbose impurity III
(1) And (3) enriching the acarbose impurity III from the acarbose sample by using an LC silica gel pre-column with the particle size of 20-45 mu m. Taking 300mL of acarbose impurity III enriched solution, adjusting the pH value to 3.0-6.0 by using dilute hydrochloric acid, carrying out reduced pressure distillation and concentration to 30mg/mL, adjusting the pH value to 7.0-10.0 by using diluted ammonia water, and finally filtering by using a 0.45-micrometer filter membrane to obtain a concentrated solution.
(2) With C18And (3) eluting the concentrated solution under the condition of filler separation and purification, and collecting the fraction containing the acarbose impurity III. C18And (3) separating and purifying conditions of the filler: the instrument comprises the following steps: DAC50 preparation of liquid chromatography system (Jiangsu Hanbang science and technology, Inc.); a chromatographic column: welch Xtimate C18300g of 10-micron filler is filled; mobile phase: methanol-Water (containing 0.1% NH)3) Solution 8-92 (V/V); flow rate: 50 mL/min; sample introduction volume: 10 mL; detection wavelength: 210 nm.
(3) Then NH2And purifying the fraction under the condition of filler separation and purification, and collecting the fraction with the purity of more than 95%. NH (NH)2And (3) separating and purifying conditions of the filler: the instrument comprises the following steps: DAC50 preparation of liquid chromatography system (Jiangsu Hanbang science and technology, Inc.); a chromatographic column: daisogel SP-120-APS-P, and filling 300g of 10-micron filler; mobile phase: methanol; flow rate: 50 mL/min; sample introduction volume: 10 mL; detection wavelength: 210 nm.
(4) Mixing the fraction III with the purity of more than 95 percent of acarbose impurity, then distilling under reduced pressure to remove methanol, adding 20mL of water for dissolving, adjusting the pH value to 5.0-6.0 by using dilute hydrochloric acid, and placing the mixture into a refrigerator for pre-freezing.
(5) And (3) freeze-drying in a freeze-drying machine at the temperature of minus 76 ℃ and under the pressure of 0.02Mpa to obtain white crystalline powder, namely a target product, namely acarbose impurity III, and storing the product under the drying condition of 2-8 ℃.
Confirmation of II, III acarbose impurity structure
(1) The high resolution mass spectrum is shown in FIG. 10, and the analysis and conclusion are as follows:
sample molecular formula: c25H43NO18Absolute molecular weight M: 645.2480
[M+H]+Experimental values: 646.2573 [ M + H]+Theoretical value: 646.2553
According to the high-resolution mass spectrogram of the acarbose impurity III, the molecular formula of the sample is [ M + H ] in the positive ion mode]+Experimental values and molecular formula C25H43NO18Corresponding [ M + H]+The relative error of the theoretical value is 3.05ppm, thereby confirming that the molecular formula of the acarbose impurity III is C25H43NO18。
(2) Nuclear magnetic resonance spectroscopy, nuclear magnetic resonance hydrogen spectrum of a sample: (1H-NMR), carbon spectrum (13C-NMR) is shown in FIGS. 11 and 12.
1The proton signals of 13 groups of samples appearing in H-NMR spectrum (figure 11) show that the sample structure at least contains 13 groups of hydrogen nuclear spin systems with different chemical environments, and the integral area of the proton signals shows that the sample at least contains 29 hydrogen atoms (methyl signals delta without active hydrogen and residual additive acetic acid)H1.962,s,3H)。1The proton signal (. delta.) at group 1 double bonds appears in the low field region of the H-NMR spectrumH5.909,m,1H)；1In the high-field region of H-NMR spectrum, 12 groups of hydrogen proton signals appear, including 4 groups of overlapped proton signals (delta)H5.190,overlap,2H；δH4.096,overlap,2H；δH3.880-3.748,overlap,10H；δH3.697-3.632, overlap,4H), proton signal (. delta.) for group 5 methinesH5.387,d,J＝3.9Hz,1H；δH4.017,dq,J＝12.5,6.2Hz,1H；δH3.942,m,1H；δH3.450,t,J＝9.5Hz,1H；δH2.897, t, J ═ 10.1Hz,1H), proton signals (δ) of 2 groups of methylene groups coupled to carbonH4.235,d,J＝14.6Hz,1H；δH4.205, d, J ═ 14.6Hz,1H), proton signal (δ) of group 1 methyl groupsH1.395,d,J＝6.2Hz,3H)。
13C-NMR (FIG. 12) showed that the sample contained 24 groups with 25 carbon signals (no residual additive acetic acid: (C) (C))CH3 COOH：δC22.500，δC180.195) of the sample). The carbon spectrum presents 2 carbon signals in low field, including 1 double-bond quaternary carbon signal (delta)C143.025), 1 double bond tertiaryCarbon signal (delta)C118.923); the midfield part presents 23 carbon signals, including 19 tertiary carbon signals (delta) connected with hetero atomsC99.650；δC93.408；δC93.174；δC77.421；δC72.938；δC72.525；δC72.428；δC72.214；δC72.170；δC71.023；δC70.786；δC70.731；δC70.622；δC70.446；δC69.649；δC68.558；δC66.876；δC63.826；δC56.171) and 3 secondary carbon signals (. delta.) attached to the heteroatomC61.326；δC60.490 × 2) and 1 primary carbon signal (δ)C17.314)。
NMR spectrum of acarbose impurity III: (1H-NMR), carbon spectrum (13C-NMR) confirmed C, H assignment to correspond to the sample molecular structure formula:
III-standardization of acarbose impurity
The HPLC purity of acarbose impurity III was 98.5%, see FIG. 9. The content of acarbose impurity III detected by a quantitative nuclear magnetic method is 89.4 percent and is used as an impurity reference substance.
Example 4
Extraction of acarbose impurity IV
(1) And (3) enriching the acarbose impurity IV from the acarbose sample by using an LC silica gel pre-column with the particle size of 20-45 mu m. Taking 300mL of acarbose impurity IV enriched solution, adjusting the pH value to 3.0-6.0 by using dilute hydrochloric acid, carrying out reduced pressure distillation and concentration to 30mg/mL, adjusting the pH value to 7.0-10.0 by using diluted ammonia water, and finally filtering by using a 0.45-micrometer filter membrane to obtain a concentrated solution.
(2) Two times in succession with C18And eluting the concentrated solution under the condition of filler separation and purification, and collecting the fraction containing the acarbose impurity IV. C18And (3) separating and purifying conditions of the filler: the instrument comprises the following steps: DAC50 preparation of liquid chromatography system (Jiangsu Hanbang science and technology, Inc.);a chromatographic column: welch Xtimate C18300g of 10-micron filler is filled; mobile phase: methanol-Water (containing 0.1% NH)3) Solution 8-92 (V/V); flow rate: 50 mL/min; sample introduction volume: 10 mL; detection wavelength: 210 nm.
(3) For passing through C18And (3) desalting qualified fractions obtained by separating and purifying the filler according to the following conditions, and collecting fractions containing acarbose impurities IV and having the purity of more than 95%. Chromatographic conditions are as follows: the instrument comprises the following steps: DAC50 preparation of liquid chromatography system (Jiangsu Hanbang science and technology, Inc.); a chromatographic column: welch Xtimate C18300g of 10-micron filler is filled; mobile phase: methanol-water solution 25-75 (V/V); flow rate: 50 mL/min; sample introduction volume: 10 mL; detection wavelength: 210 nm.
(4) And mixing the fraction IV of the acarbose impurity with the purity of more than 95%, distilling under reduced pressure to remove the acarbose impurity and concentrate the acarbose impurity to 20mL, adjusting the pH value to 5.0-6.0 by using dilute hydrochloric acid, and placing the mixture into a refrigerator for pre-freezing.
(5) And then freeze-drying in a freeze-drying machine at the temperature of minus 76 ℃ and under the pressure of 0.02Mpa to obtain white crystalline powder, namely a target product, namely acarbose impurity IV, and storing the product under the drying condition of 2-8 ℃.
II, IV, confirmation of acarbose impurity structure
(1) The high resolution mass spectrum is shown in fig. 14, and the analysis and conclusion are as follows:
sample molecular formula: c19H33NO13Absolute molecular weight M: 483.1952
[M+H]+Experimental values: 484.2015 [ M + H]+Theoretical value: 484.2025
According to the high-resolution mass spectrogram of the acarbose impurity D, the molecular formula of the sample is [ M + H ] in the positive ion mode]+Experimental values and molecular formula C19H33NO13Corresponding [ M + H]+The relative error of the theoretical value is-2.07 ppm, thereby confirming that the molecular formula of the acarbose impurity IV is C19H33NO13。
(2) Nuclear magnetic resonance spectroscopy, nuclear magnetic resonance hydrogen spectrum of a sample: (1H-NMR), carbon spectrum (13C-NMR) is shown in FIGS. 15 and 16.
1The proton signals appeared in the H-NMR spectrum (FIG. 15) can be divided into 14 groups, and the sample can be known to contain at least 22 hydrogen atoms (no active hydrogen) by integrating the area of the hydrogen signal peak.1The hydrogen signal (. delta.) at group 1 double bonds is visible in the low field part of the H-NMR spectrumH5.941-5.932, d, J ═ 5.0Hz,1H) and 2 groups of sugar end methine hydrogen signals (5.359-5.350, d, J ═ 3.4Hz, 1H; 5.266-5.260, d, J ═ 3.8Hz, 1H); the middle-high field part has 11 groups of proton signal peaks, wherein 3 groups of overlapped proton signals (delta)H 4.010-3.946,overlap,0.8H；δH3.811-3.754,overlap,3.6H；δH3.654-3.565, overlap,4H), 4 sets of methine signals (. delta.) (S.))H 4.083-4.072,d,J＝7.0Hz,1H；δH3.716-3.692,dd,J＝9.8,4.6Hz,1H；δH 3.581-3.565,d,J＝6.7Hz,1H；δH2.526-2.495, t, J ═ 9.5Hz,1H), 3 sets of methylene signals coupled to carbons (4.275-4.252, d, J ═ 13.8Hz, 1H; deltaH 4.164-4.141,d,J＝13.8Hz,1H；δH3.925-3.854, m,1H) and group 1 methyl signals (. delta.)H1.384-1.373,d,J＝6.3Hz,3H)。
13C-NMR (FIG. 16) showed that the sample contained 19 carbon signals, and that the low field of the carbon spectrum gave 4 carbon signals, including the carbon signal at 2 double bonds (. delta.) (C141.618,s；δC126.338, d), tertiary carbon signal at 2 sugar end groups (. delta.)C102.492/102.373,d；δC94.510, d). The middle-high field part shows 15 carbon signals, including 11 tertiary carbon signals (delta) on six-membered cyclic sugarC79.945,d；δC 75.881,d；δC 75.542,d；δC75.358/75.254,d；δC73.882,d；δC 73.769,d；δC73.374,d；δC 72.625,d；δC 72.154,d；δC 67.568/67.540,d；δC58.595, d), 2 methylene carbon signals (. delta.))C64.213,t；δC63.370/63.252, t) and 1 methyl carbon signal (. delta.)C19.932,q)。
Nuclear magnetic resonance hydrogen spectrum of acarbose impurity IV: (1H-NMR), carbon spectrum (13C-NMR) confirmed C, H assignment to correspond to the sample molecular structure formula:
III, acarbose impurity IV standardization
The HPLC purity of acarbose impurity IV was 96.0%, see FIG. 13. The content of the acarbose impurity IV detected by a quantitative nuclear magnetic method is 92.0 percent and is used as an impurity reference substance.
The invention separates and prepares impurities to obtain impurity monomers, provides theoretical basis for safe use of the medicine, can provide effective data support for improving the quality standard of the acarbose, and provides effective guarantee for clinical safe use of the acarbose.
The technical solutions of the present invention or similar technical solutions designed by those skilled in the art based on the teachings of the technical solutions of the present invention are all within the scope of the present invention.
Claims (9)
1. The preparation method of the acarbose impurity reference substance is characterized by comprising the following steps:
1) taking the acarbose impurity enriched solution, adjusting the pH value to acidity, and concentrating the acarbose impurity enriched solution by reduced pressure distillation;
2) adjusting the pH of the concentrated solution in the step 1) to be alkaline, and then filtering with a filter membrane to obtain an impurity concentrated solution;
3) eluting the impurity concentrated solution twice continuously under the conditions of reversed-phase silica gel filler separation and purification, and collecting fractions containing acarbose impurities;
4) purifying the fraction collected in the step 3) by using polyamide filler separation and purification conditions, and collecting high-purity fraction;
5) mixing the high-purity fractions collected in the step 4), distilling under reduced pressure to remove methanol, adding water for dissolution, adjusting the pH value to acidity, and placing in a refrigerator for pre-freezing;
6) and then, freeze-drying the fraction subjected to the pre-freezing treatment in the step 5) in a freeze dryer to obtain white crystalline powder, namely acarbose impurity.
2. The method for preparing acarbose impurity reference substance according to claim 1, wherein the concentration in step 1) is performed by vacuum distillation until each milliliter of the concentrated solution contains 10-40mg of acarbose impurity, the pH value in step 1) and step 5) is adjusted to 3.0-6.0 by using dilute hydrochloric acid, and the pH value in step 2) is adjusted to 7.0-10.0 by using dilute ammonia water.
3. The method for preparing acarbose impurity control substance as claimed in claim 1, wherein the reverse silica gel filler in step 3) is C18The filler has the separation and purification conditions that: a chromatographic column: welch Xtimate C18200-400g of 10-micron filler filling; mobile phase: methanol-water solution 8-92 (V/V); flow rate: 40-70 mL/min; sample introduction volume: 10 mL; detection wavelength: 210nm, wherein the methanol-water solution contains 0.1% NH3。
4. The method of claim 1, wherein the polyamide filler in step 4) is NH2Packing, and separation and purification conditions thereof: a chromatographic column: welch Ultimate XB-NH2150-350g of 10-micron filler filling; mobile phase: methanol; flow rate: 40-70 mL/min; sample introduction volume: 10 mL; detection wavelength: 210 nm.
5. The method of preparing a control of acarbose impurity according to claim 3 or 4, wherein the flow rate is 50-60 mL/min.
6. The method for preparing the acarbose impurity control substance as claimed in claim 1, wherein the amount of the acarbose enriched liquid collected in step 1) is 200-500ml each time, and the volume of the acarbose enriched liquid dissolved in the water added in step 5) is 20-50 ml.
7. The method of preparing a control sample of acarbose impurity according to claim 1, wherein the conditions of the freeze dryer in step 6) are: the freezing temperature is-70 ℃ to-80 ℃ under the pressure condition of 0.01-0.03 Mpa.
8. The method of claim 7, wherein the freezing pressure is 0.02Mpa and the freezing temperature is-76 ℃.
9. The method of preparing a control sample of acarbose impurity according to claim 1, wherein the high purity in step 4) and step 5) is a fraction having a purity of greater than 95%.
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