CN110156810B - Purification method of moxidectin - Google Patents
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Abstract
The invention provides a purification method of moxidectin, which comprises the following steps: s1) mixing and fully dissolving the crude moxidectin product and a solvent to obtain a sample solution; s2) purifying the sample solution by column chromatography to obtain moxidectin; the chromatographic packing of the column chromatography takes polystyrene/divinylbenzene copolymer with high crosslinking degree as a matrix. Compared with the prior art, the method adopts a column chromatography purification mode, can increase the sample loading amount in the chromatography process, has simple process, small solvent amount, higher recovery rate and purity of moxidectin in the whole process, similar types of used fillers, solvent types and industrial amplification process routes of a large number of products, can be industrialized, and passes pilot plant test verification tests.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry purification, and particularly relates to a purification method of moxidectin.
Background
Moxidectin (moxidectin ) is an avermectin drug, and a macrolide antibiotic with a single structure, which is chemically modified or derived from nemadectin (nemadectin) generated by streptomyces fermentation, is a novel antiparasitic drug. Antiparasitic drugs are widely used in basic agriculture such as animal husbandry and breeding industry, and the demand of international antiparasitic drugs is continuously increasing. Compared with other avermectins, the moxidectin has the advantages of single component, higher anthelmintic activity, long-acting effect, safety and the like, and has wide market prospect.
Chinese patent publication No. CN101372492A provides a method for preparing high-purity moxidectin, but the process is complicated, multi-step chromatography is required, the amount of solvent used is large, and the operation is complicated. Chinese patent publication No. CN107216338A provides a method for separating and purifying moxidectin, which uses a supercritical fluid chromatography system, silica gel matrix filler as a stationary phase, supercritical carbon dioxide as a mobile phase, and methanol as an entrainer, and can separate and purify to obtain a pure product with a purity of more than 96%, but does not provide information such as yield, and requires special equipment. Chinese patent publication No. CN107686489A provides a separation and purification method of high-purity moxidectin, and the purity of the finally obtained pure product is about 98%, and the yield is 74% -83%, but the method provided by the patent requires further crystallization and purification after chromatography and purification, the operation process is still somewhat complicated, and the crystallization requires the use of a large amount of organic solvent, and is not suitable for industrial production.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a purification method of moxidectin with simple process and high yield and purity.
The invention provides a purification method of moxidectin, which comprises the following steps:
s1) mixing and fully dissolving the crude moxidectin product and a solvent to obtain a sample solution;
s2) purifying the sample solution by column chromatography to obtain moxidectin; the chromatographic packing of the column chromatography takes polystyrene/divinylbenzene copolymer with high crosslinking degree as a matrix.
Preferably, the solvent in step S1) is selected from a mixed solution of an organic solvent and water; the volume ratio of the organic solvent to the water is (50-90): (50-10); the organic solvent is selected from one or more of methanol, acetonitrile and ethanol.
Preferably, the solvent in step S1) further contains an organic acid; the volume of the organic acid is 0.05-0.5% of the volume of the solvent.
Preferably, after the chromatographic packing for column chromatography is balanced by a balancing solution, the sample loading solution is purified by column chromatography; the equilibrium liquid comprises a first mobile phase and a second mobile phase; the volume ratio of the first mobile phase to the second mobile phase is (50-10): (50-90); the first mobile phase is an aqueous solution comprising an organic acid; the second mobile phase is an organic solvent comprising an organic acid; the volume concentration of the organic acid in the first mobile phase and the second mobile phase is 0.05-0.5% respectively and independently.
Preferably, the high crosslinking degree polystyrene/divinylbenzene copolymer has a crosslinking degree of 70 to 90%.
Preferably, the high crosslinking degree polystyrene/divinylbenzene copolymer has a crosslinking degree of 80%.
Preferably, the column chromatography in the step S2) adopts isocratic elution; the eluent used for the column chromatography comprises a mobile phase A and a mobile phase B; the volume ratio of the mobile phase A to the mobile phase B is (50-10): (50-90); the mobile phase A is water; the mobile phase B is an organic solvent containing organic acid.
Preferably, the organic solvent is selected from one or more of methanol, acetonitrile and ethanol; the volume concentration of the organic acid in the mobile phase B is 0.05-0.5%.
Preferably, the organic acid is selected from one or more of formic acid, acetic acid and trifluoroacetic acid.
Preferably, the moxidectin is obtained by purifying in the step S2), detecting by high performance liquid chromatography, concentrating and freeze-drying.
The invention provides a purification method of moxidectin, which comprises the following steps: s1) mixing and fully dissolving the crude moxidectin product and a solvent to obtain a sample solution; s2) purifying the sample solution by column chromatography to obtain moxidectin; the chromatographic packing of the column chromatography takes polystyrene/divinylbenzene copolymer with high crosslinking degree as a matrix. Compared with the prior art, the method adopts a column chromatography purification mode, can increase the sample loading amount in the chromatography process, has simple process, small solvent amount, higher recovery rate and purity of moxidectin in the whole process, similar types of used fillers, solvent types and industrial amplification process routes of a large number of products, can be industrialized, and passes pilot plant test verification tests.
Experiments show that the purification method provided by the invention has the advantages that the recovery rate of the moxidectin reaches 50-70%, and the purity is over 99%.
Drawings
FIG. 1 is a preparative liquid chromatogram of moxidectin obtained in example 1 of the present invention;
FIG. 2 is a preparative liquid chromatogram of moxidectin obtained in comparative example 1 of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides a purification method of moxidectin, which comprises the following steps: s1) mixing and fully dissolving the crude moxidectin product and a solvent to obtain a sample solution; s2) purifying the sample solution by column chromatography to obtain moxidectin; the chromatographic packing of the column chromatography takes polystyrene/divinylbenzene copolymer with high crosslinking degree as a matrix.
The present invention is not particularly limited in terms of the source of all raw materials, and may be commercially available.
Wherein, the purity of the crude moxidectin is preferably more than or equal to 75%, more preferably more than or equal to 80%, and still more preferably 80-95%.
Mixing and fully dissolving a crude moxidectin product and a solvent to obtain a sample solution; the solvent is preferably a mixed solution of an organic solvent and water; the volume ratio of the organic solvent to water is preferably (50-90): (50-10), more preferably (60-90): (40-10), and more preferably (70-80): (30-20); in some embodiments provided herein, the volume ratio of the organic solvent to water is preferably 75: 25; in some embodiments provided herein, the volume ratio of the organic solvent to water is preferably 70: 30; in other embodiments provided herein, the volume ratio of the organic solvent to water is preferably 80: 20. The solvent preferably further comprises an organic acid; the volume of the organic acid is preferably 0.05% to 0.5%, more preferably 0.05% to 0.3%, still more preferably 0.1% to 0.2%, most preferably 0.1% of the volume of the solvent; the organic acid is preferably one or more of acid, acetic acid and trifluoroacetic acid; the concentration of the crude moxidectin in the sample loading liquid is preferably 5-20%, more preferably 10-20%, and still more preferably 10-17.75%.
In the invention, the chromatographic packing of column chromatography is preferably balanced by a balancing solution; the chromatographic packing takes a polystyrene/divinylbenzene copolymer with high crosslinking degree as a matrix; the degree of crosslinking of the high-crosslinking-degree polystyrene/divinylbenzene copolymer is preferably 70 to 90%, more preferably 75 to 85%, and still more preferably 80%; the matrix contains phenyl functional groups, and the skeleton of the matrix also has strong hydrophobic property, and the matrix can be directly used as reversed phase separation filler, and compared with the conventional silica gel filler, the silica gel filler has the advantages of uniform particle size distribution, controllable particle size, wide pH tolerance range and the like; the equilibrium liquid comprises a first mobile phase and a second mobile phase; the volume ratio of the first mobile phase to the second mobile phase is preferably (50-10): (50-90), more preferably (40-10): (60-90), preferably (30-20): (70-80); in some embodiments provided herein, the volume ratio of the first mobile phase to the second mobile phase is preferably 25: 75; in some embodiments provided herein, the volume ratio of the first mobile phase to the second mobile phase is preferably 30: 70; in other embodiments provided herein, the volume ratio of the first mobile phase to the second mobile phase is preferably 20: 80; the first mobile phase is preferably an aqueous solution comprising an organic acid; the volume concentration of the organic acid in the first mobile phase is preferably 0.05% to 0.5%, more preferably 0.05% to 0.3%, still more preferably 0.1% to 0.2%, most preferably 0.1%; the second mobile phase is preferably an organic solvent comprising an organic acid; the volume concentration of the organic acid in the second mobile phase is preferably 0.05% to 0.5%, more preferably 0.05% to 0.3%, even more preferably 0.1% to 0.2%, most preferably 0.1%; the organic acid is preferably one or more of formic acid, acetic acid and trifluoroacetic acid; the organic solvent is preferably one or more of methanol, acetonitrile and acetic acid; the flow rate of the balancing liquid during the balancing treatment is preferably 200-800 ml/min, more preferably 300-700 ml/min, still more preferably 300-500 ml/min, and most preferably 4000 ml/min; the time for the equilibration treatment is preferably 10-30 min, more preferably 10-20 min, and still more preferably 15 min.
After the equilibrium treatment, purifying the sample solution by column chromatography; the mass of the crude moxidectin in the sample loading liquid is preferably 2-15% of that of column chromatography packing, more preferably 3-10%, still more preferably 5-10%, and most preferably 5.6-10%; the sample loading speed of the sample loading liquid during column chromatography is preferably 100-500 ml/min, and more preferably 200-400 ml/min; after the sample loading of the sample loading liquid is finished, preferably adopting a solvent for washing; the speed of the solvent during washing is preferably 100-500 ml/min, and more preferably 200-400 ml/min; the flushing time is preferably 0.5-1 min; after washing, eluting; isocratic elution is preferably adopted in the invention; the eluent used for the column chromatography comprises a mobile phase A and a mobile phase B; the volume ratio of the mobile phase A to the mobile phase B is preferably (50-10): (50-90), more preferably (40-10): (60-90), preferably (30-20): (70-80); in some embodiments provided herein, the volume ratio of mobile phase a to mobile phase B is preferably 25: 75; in some embodiments provided herein, the volume ratio of mobile phase a to mobile phase B is preferably 30: 70; in other embodiments provided herein, the volume ratio of mobile phase a to mobile phase B is preferably 20: 80; the mobile phase A is water; the mobile phase B is an organic solvent containing organic acid; the volume concentration of the organic acid in the mobile phase B is preferably 0.05 to 0.5%, more preferably 0.05 to 0.3%, still more preferably 0.1 to 0.2%, and most preferably 0.1%; the organic acid is preferably one or more of formic acid, acetic acid and trifluoroacetic acid; the organic solvent is preferably one or more of methanol, acetonitrile and acetic acid; the flow rate of the eluent is preferably 200-600 ml/min, more preferably 300-500 ml/min, and still more preferably 400 ml/min.
After purification, the moxidectin is obtained by preferably detecting through high performance liquid chromatography, concentrating and freeze-drying.
The method adopts a column chromatography purification mode, can increase the sample loading amount in the chromatography process, has simple process, uses less solvent, has higher recovery rate and purity of moxidectin in the whole process, uses the filler types and the solvent types which are similar to the industrial amplification process route of a large amount of products, can carry out industrialization, and passes a pilot test verification test.
In order to further illustrate the present invention, the following examples are provided to describe the purification method of moxidectin provided in the present invention in detail.
The reagents used in the following examples are all commercially available; the filler used in the examples was a filler manufactured by Seiko technologies Inc. under the batch number 263010-1030.
Example 1
Column chromatography Moxidectin preparation column (100 mm. times.250 mm) (the packing used was polystyrene/divinylbenzene (PS/DVB) with a degree of crosslinking of 80% as a matrix with phenyl functional groups)
Mobile phase:
a first mobile phase: 0.1% aqueous formic acid; second mobile phase (mobile phase B): methanol (containing 0.1% formic acid)
Flow rate of 400ml/min sample introduction amount of 400ml column temperature of room temperature
Sample preparation: pressure of 100mg/ml 1.2MPa
The instrument comprises the following steps: sepax preparative chromatograph
Detection wavelength of UV @242nm
Isocratic elution: 75% of B
The specific method comprises the following steps:
1. weighing a sample: weighing 40g of crude moxidectin on an analytical balance;
2. preparing a solvent: 400ml of 75% aqueous methanol solution containing 0.1% formic acid was prepared: the methanol amount was taken to be 300ml, the purified water amount was taken to be 100ml, and the pipette tip was taken to be 400. mu.l of formic acid, mixed together, and stirred uniformly. Preparing two parts for later use;
3. sample dissolution: adding one part of the prepared solvent in the step (2) into the crude moxidectin product in the step (1)40g, sealing the opening by using a preservative film, adding a stirrer, and keeping the stirring state on a magnetic stirrer to fully dissolve the solvent to obtain a sample solution;
4. and (3) chromatographic column balancing: on an LC6000 instrument, a channel A is 0.1% formic acid aqueous solution, a channel B is methanol (containing 0.1% formic acid), under the condition of switching on a moxidectin preparation column, the flow rate is 400ml/min for flushing, the column is balanced by 25% A (100ml/min) and 75% B (300ml/min), and the balance is 15 min;
5. sample loading: stopping all pumps after the balance is finished, inserting the pipeline A into the other part of the prepared solvent (2), flushing the pipeline A at the speed of 400ml/min, stopping the pumps after 0.5min, changing the pipeline A into the prepared sample loading liquid, stopping the pumps after 1min of sample loading at the speed of 400ml/min, and stopping the pumps after flushing the rest of the solvent in the previous step (2) at the speed of 400ml/min for 0.5 min;
6. sample elution: after (5) the pump A was replaced in pure water while the on-line signal recording of the preparation station was started and the column was rinsed with 75% B (300ml/min) at 400 ml/min;
7. collecting samples: sample collection started when the target peak was seen, 3 min/tube, and a total of 14 tubes were received. As shown in figure 1, collecting the components with retention time of 36-78 min.
8. Collecting samples for analysis: samples were collected for analysis on analytical column C18-5 um.
9. Analyzing and combining samples: sampling, collecting all qualified components after HPLC detection, combining, freezing in vacuum and freeze-drying to obtain the moxidectin.
10. The data during the purification are shown in table 1.
TABLE 1 purification results
Note: the quality and purity of the purified sample refer to the result of sampling and detection after freeze-drying.
Example 2
Taking 40g of crude moxidectin with the purity of 80.09% (m/m), adding 400ml of 80% ethanol (V/V) containing 0.1% trifluoroacetic acid, and stirring to fully dissolve; loading to a chromatographic column (100mm multiplied by 250mm, and the mass of the filler is about 0.71kg) balanced by 80% ethanol containing 0.1% trifluoroacetic acid, wherein the flow rate of the sample loading is 200ml/min, eluting with 80% mobile phase B (the mobile phase A is water, and the mobile phase B is ethanol containing 0.1% trifluoroacetic acid) as an eluent at the flow rate of 400ml/min for 100min, collecting moxidectin component solution by HPLC detection, merging qualified components, freeze-drying to obtain 29.87g of a moxidectin pure product, and the purity is 99.02% by HPLC detection, and the recovery rate is 74.68%.
Example 3
Taking 71g of crude moxidectin (10% of the weight of column packing) with the purity of 94.86% (m/m), adding 400ml of 70% acetonitrile (V/V) of 0.1% trifluoroacetic acid, and stirring to fully dissolve; loading to a chromatographic column (100mm multiplied by 250mm, containing about 0.71kg of filler mass) balanced by 70% acetonitrile of 0.1% trifluoroacetic acid, wherein the flow rate of loading is 200ml/min, after loading, using 70% acetonitrile mobile phase B (mobile phase A is water, mobile phase B is acetonitrile containing 0.1% trifluoroacetic acid) as eluent to elute at the flow rate of 400ml/min, eluting for 100min, detecting and collecting moxidectin component solution by HPLC, merging qualified components, freeze-drying to obtain 55.51g of moxidectin pure product, wherein the purity of HPLC is 99.09%, and the recovery rate is 78.18%.
Comparative example 1
The CN107686489A patent provides a method for separating and purifying moxidectin with high purity, and a chromatographic purification method in the purification method is taken as a comparative example. The same crude moxidectin as in example 3 was loaded under the conditions of column chromatography purification in column chromatography purification of high purity moxidectin as provided in CN 107686489A. The specific method comprises the following steps: taking 40g of crude moxidectin with the purity of 94.86 percent (m/m), adding 400ml of 90 percent ethanol (V/V), and stirring to fully dissolve; loading to a chromatographic column (100mm × 250mm, ODS-C18 as column filler, and filler mass about 1.08kg) equilibrated with 90% ethanol at a flow rate of 200ml/min, eluting with 90% ethanol at a flow rate of 400ml/min for 100min, and preparing a chromatogram as shown in FIG. 2. And (3) detecting and collecting the moxidectin component solution by HPLC, combining more than 99 percent of components, and freeze-drying to obtain 6.19g of a moxidectin pure product, wherein the recovery rate is 15.48 percent.
Comparative example 2
The CN107686489A patent provides a method for separating and purifying moxidectin with high purity, and a chromatographic purification method in the purification method is taken as a comparative example. The same crude moxidectin as in example 2 was loaded under the conditions of column chromatography purification in column chromatography purification of high purity moxidectin as provided in CN 107686489A. The specific method comprises the following steps: taking 40g of crude moxidectin with the purity of 80.09% (m/m), adding 400ml of 90% ethanol (V/V), and stirring to fully dissolve the moxidectin; loading to a chromatographic column (100mm × 250mm, ODS-C18 as column filler and about 1.08kg of filler mass) balanced by 90% ethanol, loading at a flow rate of 200ml/min, eluting with 90% ethanol at a flow rate of 400ml/min for 100min, collecting a moxidectin component solution by HPLC detection, mixing more than 99% of components, and freeze-drying to obtain a pure moxidectin 4.86g with a recovery rate of 12.15%.
Compared with the separation and purification method of high-purity moxidectin disclosed in patent CN107686489A, the purification method provided by the invention has the advantages that the technological process is obviously optimized, the operation steps are reduced, but the purity and the yield of the obtained pure product are still better than those of the comparative example, and the purification method has certain superiority compared with the purification method of high-purity moxidectin disclosed in patent CN 107686489A.
Claims (5)
1. A method for purifying moxidectin, comprising:
s1) mixing and fully dissolving the crude moxidectin product and a solvent to obtain a sample solution; the purity of the crude moxidectin product is more than or equal to 75 percent;
s2) purifying the sample solution by column chromatography to obtain moxidectin; the chromatographic packing for column chromatography takes high-crosslinking-degree polystyrene/divinylbenzene copolymer as a matrix;
the crosslinking degree of the high crosslinking degree polystyrene/divinylbenzene copolymer is 70 to 90 percent;
the solvent in the step S1) is selected from a mixed solution of an organic solvent and water; the volume ratio of the organic solvent to the water is (50-90): (50-10); the organic solvent is selected from one or more of methanol, acetonitrile and ethanol;
the solvent in the step S1) also contains organic acid; the volume of the organic acid is 0.05-0.5% of the volume of the solvent;
column chromatography in the step S2) adopts isocratic elution; the eluent used for the column chromatography comprises a mobile phase A and a mobile phase B; the volume ratio of the mobile phase A to the mobile phase B is (50-10): (50-90); the mobile phase A is water; the mobile phase B is an organic solvent containing organic acid;
the organic solvent is selected from one or more of methanol, acetonitrile and ethanol; the volume concentration of the organic acid in the mobile phase B is 0.05-0.5%.
2. The purification method according to claim 1, characterized in that, after the chromatographic packing of the column chromatography is balanced by a balancing solution, the sample loading solution is purified by the column chromatography; the equilibrium liquid comprises a first mobile phase and a second mobile phase; the volume ratio of the first mobile phase to the second mobile phase is (50-10): (50-90); the first mobile phase is an aqueous solution comprising an organic acid; the second mobile phase is an organic solvent comprising an organic acid; the volume concentration of the organic acid in the first mobile phase and the second mobile phase is 0.05-0.5% respectively and independently.
3. The purification process according to claim 1, wherein the high crosslinking degree polystyrene/divinylbenzene copolymer has a crosslinking degree of 80%.
4. The purification process according to claim 3, wherein the organic acid is selected from one or more of formic acid, acetic acid and trifluoroacetic acid.
5. The purification method of claim 1, wherein the moxidectin is obtained by purification in step S2), detection by high performance liquid chromatography, concentration and freeze-drying.
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| CN101372492B (en) * | 2007-06-29 | 2010-08-25 | 浙江海正药业股份有限公司 | Method for preparing high-purity moxidectin |
| CN104277050B (en) * | 2013-07-04 | 2016-05-04 | 北大方正集团有限公司 | A kind of method of preparing moxidectin |
| CN105418631B (en) * | 2015-12-07 | 2017-12-26 | 苏州纳微科技有限公司 | A kind of high performance liquid chromatography separation purify how the method for horse rhzomorph |
| CN107383053B (en) * | 2017-07-25 | 2019-11-05 | 宁夏泰瑞制药股份有限公司 | A kind of purification process of moxidectin crude product |
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