CN115925573A - Purification method of D-calcium pantothenate - Google Patents
Purification method of D-calcium pantothenate Download PDFInfo
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- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 title claims abstract description 219
- 238000000034 method Methods 0.000 title claims abstract description 45
- 238000000746 purification Methods 0.000 title claims abstract description 24
- 239000012043 crude product Substances 0.000 claims abstract description 42
- 238000000926 separation method Methods 0.000 claims abstract description 37
- 239000007864 aqueous solution Substances 0.000 claims abstract description 36
- 239000011347 resin Substances 0.000 claims abstract description 27
- 229920005989 resin Polymers 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000002245 particle Substances 0.000 claims abstract description 15
- 238000001179 sorption measurement Methods 0.000 claims abstract description 14
- 229920001577 copolymer Polymers 0.000 claims abstract description 11
- 230000005526 G1 to G0 transition Effects 0.000 claims abstract description 5
- 125000000524 functional group Chemical group 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 96
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 229960002079 calcium pantothenate Drugs 0.000 claims description 12
- 238000007599 discharging Methods 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 8
- 238000000855 fermentation Methods 0.000 claims description 7
- 230000004151 fermentation Effects 0.000 claims description 7
- 230000000813 microbial effect Effects 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000012535 impurity Substances 0.000 abstract description 46
- 238000009776 industrial production Methods 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract 2
- GHOKWGTUZJEAQD-UHFFFAOYSA-N pantothenic acid Chemical compound OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 10
- OTOIIPJYVQJATP-BYPYZUCNSA-N (R)-pantoic acid Chemical compound OCC(C)(C)[C@@H](O)C(O)=O OTOIIPJYVQJATP-BYPYZUCNSA-N 0.000 description 9
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 9
- 235000004279 alanine Nutrition 0.000 description 9
- -1 pantoic acid lactone Chemical class 0.000 description 9
- 239000003463 adsorbent Substances 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000004364 calculation method Methods 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000003957 anion exchange resin Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 238000003892 spreading Methods 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P10/00—Technologies related to metal processing
- Y02P10/20—Recycling
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- Treatment Of Liquids With Adsorbents In General (AREA)
Abstract
The invention relates to a purification method of D-calcium pantothenate. The method comprises the steps of taking an aqueous solution of a crude product of the calcium D-pantothenate as a raw material, taking macroporous adsorption resin as a stationary phase and water as a mobile phase, and separating by adopting a sequential simulated moving bed, wherein the macroporous adsorption resin is a styrene-divinylbenzene copolymer without functional groups, the particle size of the macroporous adsorption resin is 250-400 mu m, the uniformity coefficient is less than 1.2, the uniformity coefficient is the ratio of D90 to D40, and the mass concentration of the aqueous solution of the crude product of the calcium D-pantothenate is 380-420 g/Kg. The purification method can effectively separate the D-calcium pantothenate from C8 homologous compounds and C10 homologous compound impurities, the purity of the purified D-calcium pantothenate is more than 99%, and the separation method has high automation degree and is suitable for industrial production.
Description
Technical Field
The invention particularly relates to a purification method of D-calcium pantothenate.
Background
The production of calcium D-pantothenate is usually carried out by chemical synthesis or microbial fermentation. Wherein C8 and C10 homologue impurities with the following structures are present in the crude product of the D-calcium pantothenate obtained by the microbial fermentation method,
The existing separation and purification of D-calcium pantothenate mainly adopts a methanol crystallization method, but the method has low efficiency, low yield after the purification of the D-calcium pantothenate, large consumption of methanol, and higher cost due to the need of a matched dissolution and stripping process. In addition, in the prior art, the separation of the two homologous impurities is neglected in the separation and purification of the D-calcium pantothenate.
For example, chinese granted patent CN1074791C discloses the purification of calcium D-pantothenate using activated carbon, contacting a solution of D-pantothenic acid with activated carbon, adsorbing it to the activated carbon, eluting the D-pantothenic acid with a hydrophilic organic solvent, neutralizing the eluate with an alkaline agent containing calcium, and precipitating the calcium D-pantothenate. However, this patent does not deal with the separation of calcium D-pantothenate from the aforementioned homologue impurities.
For another example, chinese granted patent CN1946851B discloses a method for purifying D-pantothenic acid by eluting D-pantothenic acid from strongly basic anion exchange resin with a weak organic acid and neutralizing the eluate with a basic calcium salt, which method is separated by the difference in dissociation constants between D-pantothenic acid and other heteroacids and anion exchange resin, but which method also fails to separate the calcium D-pantothenate from the aforementioned homolog impurities, and the purity of the obtained calcium D-pantothenate is still not high enough.
Disclosure of Invention
The invention aims to provide a method for purifying D-calcium pantothenate, which can separate C8 and C10 homologue impurities to obtain high-purity D-calcium pantothenate.
In order to achieve the purpose, the invention adopts the technical scheme that:
a purification method of D-calcium pantothenate uses an aqueous solution of a crude product of D-calcium pantothenate as a raw material, the purification method uses macroporous adsorption resin as a stationary phase and water as a mobile phase, and adopts a sequential simulated moving bed to carry out separation, the macroporous adsorption resin is a styrene-divinylbenzene copolymer without functional groups, the particle size of the macroporous adsorption resin is 250-400 mu m, the uniformity coefficient is below 1.2, the uniformity coefficient is the ratio of D90 to D40, and the mass concentration of the aqueous solution of the crude product of D-calcium pantothenate is 380-420 g/Kg.
In the invention, the crude product of D-calcium pantothenate refers to a product obtained by recrystallizing and purifying a D-calcium pantothenate mother liquor when D-calcium pantothenate is prepared by a microbial fermentation method, and the product contains a certain amount of impurities. The D90 means a mesh diameter at which 90% by volume of the resin particles pass and 10% by volume of the resin particles remain, and the D40 means a mesh diameter at which 40% by volume of the resin particles pass and 60% by volume of the resin particles remain.
Further, the crude product of D-calcium pantothenate contains D-calcium pantothenate with the structural formula
Furthermore, the crude product of the D-calcium pantothenate contains 90-99% of calcium pantothenate, less than 8% of C8 homologues and less than 2% of C10 homologues in percentage by mass.
In some embodiments, the macroporous adsorbent resin is preferably a styrene-divinylbenzene copolymer macroporous adsorbent resin having the designation PAD600FM, PAD500, XAD1600N, LK-1600, or LX-1600.
In some embodiments, the mass concentration of the aqueous solution of the crude calcium D-pantothenate is 380 to 420g/Kg.
In some embodiments, the mobile phase has a pH of 6.0 to 7.0 and a conductivity of 0.1 to 20 μ S/cm.
In some embodiments, the sequential simulated moving bed is divided into 4 zones, respectively:
and (3) region I: a mobile phase inlet to a high-purity D-calcium pantothenate solution outlet;
and (2) zone II: the high-purity D-calcium pantothenate solution is exported to the water solution inlet of the crude product of D-calcium pantothenate;
zone III: the water solution of the crude product of the D-calcium pantothenate enters the outlet of the low-purity D-calcium pantothenate solution;
region IV: the outlet of the low-purity D-calcium pantothenate solution is connected to the inlet of the mobile phase;
the purity of the D-calcium pantothenate in the high-purity D-calcium pantothenate solution is 99.0-99.5%, and the purity of the D-calcium pantothenate in the low-purity D-calcium pantothenate solution is 60.0-80.0%;
the method comprises the following steps which are carried out in sequence:
1) The 4 areas are communicated through a valve; pushing the mobile phase in the IV area to circulate in the sequential simulated moving bed;
2) Isolating the IV zone; inputting a mobile phase between the IV area and the I area; discharging a low-purity D-calcium pantothenate solution between the zones III and IV;
3) Isolating the region II and the region IV; inputting a mobile phase between the IV area and the I area, and collecting a high-purity D-calcium pantothenate solution between the I area and the II area; simultaneously inputting the aqueous solution of the crude product of the calcium D-pantothenate between the zones II and III, and discharging a low-purity calcium D-pantothenate solution between the zones III and IV;
4) Switching valves on the chromatographic column along the flowing direction of the mobile phase, and changing the positions of the mobile phase inlet, the high-purity D-calcium pantothenate solution outlet, the aqueous solution of the crude product of the D-calcium pantothenate and the low-purity D-calcium pantothenate solution outlet, so that the 4 regions move the position of one chromatographic column towards the flowing direction of the mobile phase;
5) Repeating the steps 1) -4).
Further, the step 1) lasts for 20-30 min, the step 2) lasts for 3-5 min, the high-purity calcium D-pantothenate solution collected in the step 3) lasts for 10-15 min, and the low-purity calcium D-pantothenate solution discharged in the step 3) lasts for 1.5-2.5 min.
In some embodiments, the step 5) is repeated 24 to 30 times, and the separation process of the sequential simulated moving bed reaches a steady state.
In some embodiments, the high purity calcium D-pantothenate solution has a mass concentration of 60 to 75g/Kg.
In some embodiments, the sequential simulated moving bed is formed by connecting 4-24 identical chromatography columns in series, and the I zone is formed by 0.17N General assembly ～0.25*N General assembly The same chromatographic columns are connected in series to form the II region consisting of 0.3 × N General assembly ～0.45*N General assembly The same chromatographic columns are connected in series to form the III region consisting of 0.23 × N General assembly ～0.35*N General assembly The same chromatographic columns are connected in series to form the IV region consisting of 0.1 × N General assembly ～0.15*N General assembly Formed by connecting chromatographic columns with the same roots in series, wherein N General (1) The total number of chromatographic columns of the sequential simulated moving bed.
In some embodiments, the separation is performed at an operating temperature of 20 to 40 ℃, preferably 25 to 30 ℃.
In some embodiments, the aqueous solution of crude calcium D-pantothenate comprises methanol, and the purification process further comprises a step of stripping the aqueous solution of crude calcium D-pantothenate before separation using a sequential simulated moving bed. The aqueous solution of crude D-calcium pantothenate can be further freed from methanol by steam stripping.
In some embodiments, the purification process results in calcium D-pantothenate having a purity of 99% or greater.
The invention also provides a method for producing the D-calcium pantothenate, which comprises the steps of obtaining a crude product of the D-calcium pantothenate by a microbial fermentation method, dissolving the crude product of the D-calcium pantothenate in water to obtain an aqueous solution of the crude product of the D-calcium pantothenate, and purifying the D-calcium pantothenate.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
1) By adopting macroporous adsorption resin with a specific particle size range as a stationary phase of a sequential simulated moving bed separation technology, C8 homologue and C10 homologue impurities in the crude product of the calcium D-pantothenate can be effectively separated, and the purity of the pure product of the calcium D-pantothenate in the crude product of the calcium D-pantothenate produced by a microbial fermentation method is obviously improved.
2) The sequential simulated moving bed is a continuous operation process, so the separation method has high automation degree and is suitable for industrial production.
3) By adopting the purification method, the purity of the D-calcium pantothenate can be more than 99%, and the yield of the separation method can reach more than 90%.
Drawings
FIG. 1 is a schematic diagram of a sequential simulated moving bed separation process of the present invention, wherein I, II, III, IV represent zones I, II, III, IV, respectively, D represents a mobile phase, F represents an aqueous feed of a crude product of D-calcium pantothenate, E represents D-calcium pantothenate, and R represents a C8 homolog and a C10 homolog;
FIG. 2 is a liquid chromatogram of an aqueous solution of the crude calcium D-pantothenate of example 1;
FIG. 3 is a liquid chromatogram of the high purity calcium D-pantothenate solution of example 1;
FIG. 4 is a liquid chromatogram of the low-purity calcium D-pantothenate solution in example 1.
FIG. 5 is a mass spectrum of the C8 homolog impurity of example 1;
FIG. 6 is a mass spectrum of the C10 homolog impurity of example 1;
Detailed Description
The prior art generally adopts methanol recrystallization to purify the D-calcium pantothenate mother liquor obtained by microbial fermentation, but the purity is not high enough, and although various substances can be separated by a sequential simulated moving bed separation method, the prior art does not disclose the separation of crude D-calcium pantothenate, and the prior art does not recognize the need to separate crude D-calcium pantothenate from C8 homolog and C10 homolog impurities. The innovation of the invention is that a sequential simulated moving bed separation method is adopted to separate the aqueous solution of the crude product of the calcium D-pantothenate, and the discovery is that when the macroporous adsorption resin of the styrene-divinylbenzene copolymer which has specific particle diameter and uniformity coefficient and does not contain functional groups is used as a stationary phase and the specific mass concentration of the aqueous solution of the crude product is controlled, the impurities of the calcium D-pantothenate and C8 homologues and C10 homologues thereof can be well separated, so that the purity of the crude product of the calcium D-pantothenate is obviously improved, and the yield can also be improved.
The invention has another innovation that the arrangement of each area of the sequential simulated moving bed and the specific separation steps is realized, and the D-calcium pantothenate can be effectively separated from C8 homologues and C10 homologues by arranging the specific areas I, II, III and IV and repeatedly carrying out the steps 1) -4), so that the loss of the D-calcium pantothenate is ensured to be small, and the product yield can reach more than 90%.
The technical solutions of the present invention are described in detail below with reference to specific examples so that those skilled in the art can better understand and implement the technical solutions of the present invention, but the present invention is not limited to the scope of the examples.
A schematic diagram of the sequential simulated moving bed separation process of the present invention is shown in figure 1.
Example 1
A12-piece 60mm x 1000mm chromatographic column was packed with a dow XAD1600N macroporous adsorbent resin (styrene-divinylbenzene copolymer, particle size 400 μm, uniformity coefficient D90/D40 1.15) to construct a sequential simulated moving bed in four zones with the number of columns of 2,5,4, 1:
and (3) region I: a mobile phase inlet to a high-purity D-calcium pantothenate solution outlet;
and (2) zone II: the high-purity D-calcium pantothenate solution is discharged to the water solution inlet of the crude D-calcium pantothenate product;
zone III: the water solution of the crude product of the D-calcium pantothenate enters the outlet of the low-purity D-calcium pantothenate solution;
and IV, region: and (3) discharging the low-purity D-calcium pantothenate solution to a mobile phase inlet.
The separation method comprises the following specific steps:
feeding: an aqueous solution of a crude calcium D-pantothenate having a mass concentration of 408g/Kg (in the solute of the solution, calcium pantothenate is 94.87%, C8 homologue impurities are 4.67%, C10 homologue impurities are 0.37%, and other impurities such as pantoic acid, pantoic acid lactone, alanine and the like account for 0.09% in total by mass%) was pumped into a simulated moving bed separation system from a feed port at a flow rate of 6.0L/min, and mobile phase water (pH 7, conductivity 20. Mu.S/cm) was flowed into the simulated moving bed separation system from a mobile phase inlet at a flow rate of 6.0L/min. The following steps were carried out at 30 ℃:
1) 4 areas are communicated through valves; pushing the regenerated mobile phase in the IV area to circulate in the chromatogram by using an intercolumn centrifugal pump, and spreading a material spectral band; the step time is 28.7min;
2) Isolating the IV area; inputting a mobile phase between the IV area and the I area; discharging the low-purity D-calcium pantothenate solution between the zones III and IV; the step time is 4.5min;
3) Then isolating the area II and the area IV; inputting a mobile phase between the IV area and the I area, and collecting a high-purity D-calcium pantothenate solution between the I area and the II area; the step time is 11.1min; meanwhile, inputting the aqueous solution of the crude product of the D-calcium pantothenate between the areas II and III, and discharging the low-purity solution of the D-calcium pantothenate between the areas III and IV; the step time is 2min;
4) Switching valves on the chromatographic column along the flowing direction of the mobile phase, and changing the positions of a mobile phase inlet, a high-purity D-calcium pantothenate solution outlet, a D-calcium pantothenate crude aqueous solution and a low-purity D-calcium pantothenate solution outlet so that the 4 regions move the position of one chromatographic column along the flowing direction of the mobile phase;
5) Repeating the steps 1) -4) for 30 times, balancing the system materials, and stably producing the D-calcium pantothenate product.
Performing liquid chromatography detection on the aqueous solution of the crude product of the D-calcium pantothenate, the obtained high-purity D-calcium pantothenate solution and the obtained low-purity D-calcium pantothenate solution under the conditions of flow rate: 1.2mL/min, column temperature: 35 ℃, sample introduction amount of 10 μ L, running time of 20min, detection wavelength of 200nm, mobile phase: 1.36g/L potassium dihydrogen phosphate aqueous solution, column: ZORBAX SB-Aq 460 × 150mm,5 μm. The results showed a relative retention time of 0.55 for the C8 homologue impurity relative to calcium D-pantothenate and 2.17 for the C10 homologue impurity relative to calcium D-pantothenate. Liquid chromatogram charts of the aqueous solution of the crude calcium D-pantothenate, the obtained high-purity calcium D-pantothenate solution, and the obtained low-purity calcium D-pantothenate solution are shown in FIGS. 2 to 4, respectively, and it can be seen that the purity of calcium D-pantothenate in the high-purity calcium D-pantothenate solution obtained by the above-described purification method is significantly improved. FIG. 5 is a mass spectrum of the C8 homolog impurity. FIG. 6 is a mass spectrum of the C10 homolog impurity.
The final mass concentration of the obtained high-purity D-calcium pantothenate solution was 73g/Kg, and the calculation revealed that the yield of D-calcium pantothenate was 91.61%, and in the solute of the high-purity D-calcium pantothenate solution, in terms of mass%, calcium pantothenate was 99.42%, C8 homologue impurities was 0.24%, C10 homologue impurities was 0.22%, and the remaining 0.12% was other impurities such as pantoic acid, pantoic acid lactone, alanine, etc.
Example 2
Using a BYZ scientific LX-1600N macroporous adsorbent resin (styrene-divinylbenzene copolymer, 400 μm in particle size, 1.1 in uniformity coefficient D90/D40), 8 columns of 48mm × 2000mm were packed, and the following four-zone arrangement was constructed with a number of columns of 1,3, 1 for each zone:
and (3) region I: a mobile phase inlet to a high-purity D-calcium pantothenate solution outlet;
and (2) zone II: the high-purity D-calcium pantothenate solution is exported to the water solution inlet of the crude product of D-calcium pantothenate;
zone III: the water solution of the crude product of the D-calcium pantothenate enters the outlet of the low-purity D-calcium pantothenate solution;
and IV, region: and (3) discharging the low-purity D-calcium pantothenate solution to a mobile phase inlet.
The separation method comprises the following specific steps:
feeding: an aqueous solution of a crude calcium D-pantothenate having a mass concentration of 403g/Kg (in the solute of the solution, in terms of mass%, calcium pantothenate is 95.49%, C8 homologue impurities are 4.05%, C10 homologue impurities are 0.27%, and other impurities such as pantoic acid, pantoic acid lactone, alanine, etc., are 0.19% in total) was pumped into the simulated moving bed separation system from the feed port at a flow rate of 7.0L/min, and mobile phase water (pH 6.5, conductivity 10. Mu.S/cm) was fed into the simulated moving bed separation system from the mobile phase inlet at a flow rate of 7.0L/min. The following steps were carried out at 30 ℃:
1) 4 areas are communicated through valves; pushing the regenerated mobile phase in the IV area to circulate in the chromatogram by using an intercolumn centrifugal pump, and spreading a material spectral band; the step time is 24.5min;
2) Isolating the IV area; inputting a mobile phase between the IV area and the I area; discharging the low-purity D-calcium pantothenate solution between the zones III and IV; the time of the step is 4.1min;
3) Isolating the area II and the area IV; inputting a mobile phase between the IV area and the I area, and collecting a high-purity D-calcium pantothenate solution between the I area and the II area, wherein the time of the step is 12.0min; simultaneously inputting aqueous solution of crude D-calcium pantothenate between zones II and III, and discharging low-purity D-calcium pantothenate solution between zones III and IV for 2min;
4) Switching valves on the chromatographic column along the flowing direction of the mobile phase, and changing the positions of a mobile phase inlet, a high-purity D-calcium pantothenate solution outlet, a D-calcium pantothenate crude aqueous solution and a low-purity D-calcium pantothenate solution outlet so that the 4 regions move the position of one chromatographic column along the flowing direction of the mobile phase;
5) Repeating the steps 1) -4) for 24 times, balancing the system materials and stably producing the D-calcium pantothenate product.
Performing liquid chromatography detection on the aqueous solution of the crude product of the D-calcium pantothenate, the obtained high-purity D-calcium pantothenate solution and the obtained low-purity D-calcium pantothenate solution under the conditions of flow rate: 1.2mL/min, column temperature: 35 ℃, sample introduction amount of 10 μ L, running time of 20min, detection wavelength of 200nm, mobile phase: 1.36g/L potassium dihydrogen phosphate aqueous solution, column: ZORBAX SB-Aq 460 x 150mm,5 μm.
After separation, a high-purity D-calcium pantothenate solution with a mass concentration of 69g/Kg is finally obtained, and the yield of D-calcium pantothenate is 92.88%, the solute of the high-purity D-calcium pantothenate solution contains 99.45% by mass of calcium pantothenate, 0.17% by mass of C8 homologue impurities, 0.20% by mass of C10 homologue impurities, and the remaining 0.18% by mass of other impurities such as pantoic acid, pantoic acid lactone, alanine, and the like.
Example 3
Using a bleached PAD500 macroporous adsorbent resin (styrene-divinylbenzene copolymer, particle size 400 μm, uniformity coefficient D90/D40 of 1.2), 8 48mm by 2000mm chromatographic columns were packed, and a sequential simulated moving bed was constructed in the following four zones with the number of columns of 1,3, 1:
and (3) region I: a mobile phase inlet to a high-purity D-calcium pantothenate solution outlet;
and (2) zone II: the high-purity D-calcium pantothenate solution is exported to the water solution inlet of the crude product of D-calcium pantothenate;
zone III: the water solution of the crude product of the D-calcium pantothenate enters the outlet of the low-purity D-calcium pantothenate solution;
region IV: and (3) discharging the low-purity D-calcium pantothenate solution to a mobile phase inlet.
The specific separation procedure was the same as in example 2. After separation, a high-purity D-calcium pantothenate solution with a mass concentration of 66g/Kg is finally obtained, and the yield of D-calcium pantothenate is 90.27%, the solute of the high-purity D-calcium pantothenate solution contains 99.07% by mass of calcium pantothenate, 0.48% by mass of C8 homologue impurities, 0.25% by mass of C10 homologue impurities, and the remaining 0.20% by mass of other impurities such as pantoic acid, pantoic acid lactone, alanine, and the like.
Example 4
Using a Delaut PAD600FM macroporous adsorbent resin (styrene-divinylbenzene copolymer, particle size 250 μm, uniformity coefficient D90/D40 of 1.2), 8-column 48mm. Times.2000 mm chromatography was packed to construct a sequential simulated moving bed having four zones of 1,3, 1 column numbers:
and (3) region I: a mobile phase inlet to a high-purity D-calcium pantothenate solution outlet;
and (2) zone II: the high-purity D-calcium pantothenate solution is exported to the water solution inlet of the crude product of D-calcium pantothenate;
zone III: the water solution of the crude product of the D-calcium pantothenate enters the outlet of the low-purity D-calcium pantothenate solution;
and IV, region: and (3) discharging the low-purity D-calcium pantothenate solution to a mobile phase inlet.
The specific separation procedure was the same as in example 2. After separation, a high-purity D-calcium pantothenate solution with a mass concentration of 70g/Kg is finally obtained, and the yield of D-calcium pantothenate is 93.65%, the solute of the high-purity D-calcium pantothenate solution contains 99.48% by mass of calcium pantothenate, 0.14% by mass of C8 homologue impurities, 0.18% by mass of C10 homologue impurities, and the remaining 0.20% by mass of other impurities such as pantoic acid, pantoic acid lactone, alanine, and the like.
Example 5
This example provides a process for the purification of calcium D-pantothenate which essentially differs from example 1 only in the following steps: steps 1) to 5) were carried out at 40 ℃. The final high purity D-calcium pantothenate solution was obtained at a mass concentration of 68g/Kg, and the yield of D-calcium pantothenate was found to be 85.33% by calculation, and the solute of the obtained high purity D-calcium pantothenate solution contained 98.84% by mass of calcium pantothenate, 0.37% by mass of C8 homologue impurities, 0.30% by mass of C10 homologue impurities, and the remaining 0.49% by mass of other impurities such as pantoic acid, pantoic acid lactone, alanine, etc.
Comparative example 1
This comparative example provides a process for the purification of calcium D-pantothenate which essentially comprises the following steps as in example 1, except that: the mass concentration of the aqueous solution of the fed crude calcium D-pantothenate was 500g/Kg. The final high purity D-calcium pantothenate solution with a mass concentration of 76g/Kg was obtained, and the yield of D-calcium pantothenate was found to be 76.3% by calculation, and the solute of the obtained high purity D-calcium pantothenate solution contained 99.04% by mass of calcium pantothenate, 0.49% by mass of C8 homologue impurities, 0.23% by mass of C10 homologue impurities, and the remaining 0.24% by mass of other impurities, such as pantoic acid, pantoic acid lactone, alanine, etc.
Comparative example 2
This comparative example also provides a process for the purification of calcium D-pantothenate which essentially comprises the following steps as in example 1, except that: the dow XAD18 macroporous adsorption resin (styrene-divinylbenzene copolymer with particle size of 400 μm and uniformity coefficient D90/D40 of 1.7) is used to replace the dow XAD1600N macroporous adsorption resin. After separation, a high-purity D-calcium pantothenate solution with a mass concentration of 63g/Kg is finally obtained, and the yield of D-calcium pantothenate is 78.0%, the solute of the high-purity D-calcium pantothenate solution contains 98.89% by mass of calcium pantothenate, 0.51% by mass of C8 homologue impurities, 0.32% by mass of C10 homologue impurities, and the remaining 0.28% by mass of other impurities, such as pantoic acid, pantoic acid lactone, alanine, and the like.
Comparative example 3
This comparative example also provides a process for the purification of calcium D-pantothenate which essentially comprises the following steps as in example 1, except that: the Dow MONOSPHRE 99Ca/310 calcium type strong acid resin (styrene-divinylbenzene copolymer with the grain diameter of 310 μm and bonded with sulfonate) is adopted to replace the Dow XAD1600N macroporous absorption resin. After separation, a high-purity D-calcium pantothenate solution with the mass concentration of 65g/Kg is finally obtained, the yield of the D-calcium pantothenate is 80.9%, the solute of the high-purity D-calcium pantothenate solution contains 96.51% of calcium pantothenate, 3.12% of C8 homologue impurities, 0.27% of C10 homologue impurities and the balance of other impurities according to mass percentage, and the separation task is not finished.
As can be seen from the separation results of the above examples and comparative examples, the present invention can improve the purity and yield of D-calcium pantothenate after separation and purification by controlling the particle size, uniformity coefficient and presence or absence of functional groups of the macroporous adsorbent resin, and by using a crude aqueous solution having a specific mass concentration.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (12)
1. A purification method of D-calcium pantothenate takes an aqueous solution of a crude product of D-calcium pantothenate as a raw material, and is characterized in that: the purification method comprises the steps of taking macroporous adsorption resin as a stationary phase, taking water as a mobile phase, and separating by adopting a sequential simulated moving bed, wherein the macroporous adsorption resin is a styrene-divinylbenzene copolymer without functional groups, the particle size of the macroporous adsorption resin is 250-400 mu m, the uniformity coefficient is less than 1.2, the uniformity coefficient is the ratio of D90 to D40, and the mass concentration of the aqueous solution of the crude product of the D-calcium pantothenate is 380-420 g/Kg.
2. The method for purifying calcium D-pantothenate according to claim 1, wherein: the crude product of the D-calcium pantothenate contains D-calcium pantothenate with the structural formula
C8 homologs and structural formula->
C10 homologues of (a).
3. The method for purifying calcium D-pantothenate according to claim 2, wherein: the crude product of the D-calcium pantothenate contains 90-99% of calcium pantothenate, less than 8% of C8 homologues and less than 2% of C10 homologues in percentage by mass.
4. The method for purifying calcium D-pantothenate according to claim 1, wherein: the macroporous adsorption resin is selected from PAD600FM, PAD500, XAD1600N, LK-1600N or LX-1600N.
5. The method for purifying calcium D-pantothenate according to claim 1, wherein: the mass concentration of the aqueous solution of the crude product of the D-calcium pantothenate is 380-420 g/Kg; and/or the pH value of the mobile phase is 6.0-7.0, and the conductivity is 0.1-20 mu S/cm.
6. The method for purifying calcium D-pantothenate according to claim 1, characterized in that: the operating temperature of the separation is 20-40 ℃, preferably 25-30 ℃.
7. The method for purifying calcium D-pantothenate according to claim 1, characterized in that: the sequential simulated moving bed is divided into 4 areas which are respectively as follows:
and (3) region I: a mobile phase inlet to a high-purity D-calcium pantothenate solution outlet;
and (II) zone: the high-purity D-calcium pantothenate solution is discharged to the water solution inlet of the crude D-calcium pantothenate product;
zone III: the water solution of the crude product of the D-calcium pantothenate enters the outlet of the low-purity D-calcium pantothenate solution;
region IV: the outlet of the low-purity D-calcium pantothenate solution is connected to the inlet of the mobile phase;
the purity of the D-calcium pantothenate in the high-purity D-calcium pantothenate solution is 99.0-99.5%, and the purity of the D-calcium pantothenate in the low-purity D-calcium pantothenate solution is 50.0-80.0%;
the method comprises the following steps which are carried out in sequence:
1) The 4 areas are communicated through a valve; pushing the mobile phase in the IV area to circulate in the sequential simulated moving bed;
2) Isolating the IV zone; inputting a mobile phase between the IV area and the I area; discharging a low-purity D-calcium pantothenate solution between the zones III and IV;
3) Isolating the region II and the region IV; inputting a mobile phase between the IV area and the I area, and collecting a high-purity D-calcium pantothenate solution between the I area and the II area; simultaneously inputting the aqueous solution of the crude product of the calcium D-pantothenate between the zones II and III, and discharging a low-purity calcium D-pantothenate solution between the zones III and IV;
4) Switching valves on the chromatographic column along the flowing direction of the mobile phase, and changing the positions of an inlet of the mobile phase, an outlet of a high-purity D-calcium pantothenate solution, an aqueous solution of a crude product of D-calcium pantothenate and an outlet of a low-purity D-calcium pantothenate solution, so that the 4 regions move the position of one chromatographic column towards the flowing direction of the mobile phase;
5) Repeating the steps 1) to 4).
8. The method for purifying calcium D-pantothenate according to claim 7, wherein: the step 1) lasts for 20-30 min, the step 2) lasts for 3-5 min, the high-purity D-calcium pantothenate solution collected in the step 3) lasts for 10-15 min, and the low-purity D-calcium pantothenate solution discharged in the step 3) lasts for 1.5-2.5 min; and/or, the repeated times in the step 5) are 24-30 times, and the separation process of the sequential simulated moving bed reaches a steady state; and/or the mass concentration of the high-purity D-calcium pantothenate solution is 60-75 g/Kg.
9. The method for purifying calcium D-pantothenate according to claim 7, wherein: the sequential simulated moving bed is formed by connecting 4-24 identical chromatographic columns in series, and the I area is formed by 0.17 × N General assembly ～0.25*N General assembly The same chromatographic columns are connected in series to form the II region consisting of 0.3N General assembly ～0.45*N General assembly The same chromatographic columns are connected in series to form the III region consisting of 0.23 × N General assembly ～0.35*N General (1) The same chromatographic columns are connected in series to form the IV region consisting of 0.1 × N General assembly ～0.15*N General (1) Formed by connecting chromatographic columns with the same roots in series, wherein N General assembly The total number of chromatographic columns of the sequential simulated moving bed.
10. The method for purifying calcium D-pantothenate according to claim 1, wherein: the aqueous solution of crude calcium D-pantothenate comprises methanol, and the purification method further comprises a step of stripping the aqueous solution of crude calcium D-pantothenate before separation by a sequential simulated moving bed.
11. The method for purifying calcium D-pantothenate according to claim 1, wherein: the purity of the calcium D-pantothenate obtained by the purification method is more than 99%.
12. A method for producing D-calcium pantothenate, which comprises the steps of obtaining a crude product of D-calcium pantothenate by a microbial fermentation method, and dissolving the crude product of D-calcium pantothenate in water to obtain an aqueous solution of the crude product of D-calcium pantothenate, wherein the aqueous solution comprises: the method for producing calcium D-pantothenate comprises a method for purifying calcium D-pantothenate according to any one of claims 1 to 11.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB892083A (en) * | 1959-11-12 | 1962-03-21 | Pfizer & Co C | Resin absorbate and use for purification |
| CN1946851A (en) * | 2004-04-26 | 2007-04-11 | 帝斯曼知识产权资产管理有限公司 | Process for the preparation of calcium-d-pantothenate |
| CN108129345A (en) * | 2018-01-10 | 2018-06-08 | 精晶药业股份有限公司 | A kind of preparation method of D-VB5 calcium |
| CN214361091U (en) * | 2020-12-14 | 2021-10-08 | 广安摩珈生物科技有限公司 | Calcium pantothenate production system |
| CN114456082A (en) * | 2021-12-29 | 2022-05-10 | 安徽泰格生物科技有限公司 | Preparation method of D-calcium pantothenate |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB892083A (en) * | 1959-11-12 | 1962-03-21 | Pfizer & Co C | Resin absorbate and use for purification |
| CN1946851A (en) * | 2004-04-26 | 2007-04-11 | 帝斯曼知识产权资产管理有限公司 | Process for the preparation of calcium-d-pantothenate |
| CN108129345A (en) * | 2018-01-10 | 2018-06-08 | 精晶药业股份有限公司 | A kind of preparation method of D-VB5 calcium |
| CN214361091U (en) * | 2020-12-14 | 2021-10-08 | 广安摩珈生物科技有限公司 | Calcium pantothenate production system |
| CN114456082A (en) * | 2021-12-29 | 2022-05-10 | 安徽泰格生物科技有限公司 | Preparation method of D-calcium pantothenate |
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