CN115448837A - Preparation method of medium-chain triglyceride - Google Patents
Preparation method of medium-chain triglyceride Download PDFInfo
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- CN115448837A CN115448837A CN202210256059.1A CN202210256059A CN115448837A CN 115448837 A CN115448837 A CN 115448837A CN 202210256059 A CN202210256059 A CN 202210256059A CN 115448837 A CN115448837 A CN 115448837A
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- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 80
- 238000006243 chemical reaction Methods 0.000 claims abstract description 57
- 238000000034 method Methods 0.000 claims abstract description 29
- 238000004321 preservation Methods 0.000 claims abstract description 27
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 15
- 239000000194 fatty acid Substances 0.000 claims abstract description 15
- 229930195729 fatty acid Natural products 0.000 claims abstract description 15
- 150000004667 medium chain fatty acids Chemical class 0.000 claims abstract description 15
- 238000012423 maintenance Methods 0.000 claims abstract description 8
- 238000002156 mixing Methods 0.000 claims abstract description 3
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 40
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 claims description 20
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 claims description 19
- 238000001914 filtration Methods 0.000 claims description 19
- 229960002446 octanoic acid Drugs 0.000 claims description 19
- 238000004821 distillation Methods 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 17
- 239000003513 alkali Substances 0.000 claims description 16
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 16
- 229940057917 medium chain triglycerides Drugs 0.000 claims description 14
- 239000012528 membrane Substances 0.000 claims description 14
- 238000005406 washing Methods 0.000 claims description 14
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 10
- 238000006386 neutralization reaction Methods 0.000 claims description 10
- 238000002347 injection Methods 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 7
- 239000008213 purified water Substances 0.000 claims description 7
- 239000005639 Lauric acid Substances 0.000 claims description 6
- 239000002960 lipid emulsion Substances 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- 239000004810 polytetrafluoroethylene Substances 0.000 claims description 4
- 229920001343 polytetrafluoroethylene Polymers 0.000 claims description 4
- 239000002033 PVDF binder Substances 0.000 claims description 3
- 239000004695 Polyether sulfone Substances 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 230000003472 neutralizing effect Effects 0.000 claims description 3
- 229920006393 polyether sulfone Polymers 0.000 claims description 3
- -1 polytetrafluoroethylene Polymers 0.000 claims description 3
- 239000011148 porous material Substances 0.000 claims description 3
- 239000004677 Nylon Substances 0.000 claims description 2
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 claims description 2
- 229920001778 nylon Polymers 0.000 claims description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 claims description 2
- 238000005292 vacuum distillation Methods 0.000 claims 1
- 235000011187 glycerol Nutrition 0.000 abstract description 26
- 239000000047 product Substances 0.000 abstract description 15
- 208000012839 conversion disease Diseases 0.000 abstract description 8
- 239000006227 byproduct Substances 0.000 abstract description 6
- 238000012805 post-processing Methods 0.000 abstract description 5
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 238000006116 polymerization reaction Methods 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 19
- 230000000052 comparative effect Effects 0.000 description 16
- 239000002253 acid Substances 0.000 description 13
- 238000010438 heat treatment Methods 0.000 description 10
- 238000003860 storage Methods 0.000 description 10
- 238000005886 esterification reaction Methods 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 5
- 230000032050 esterification Effects 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 238000005086 pumping Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 238000004891 communication Methods 0.000 description 3
- 238000005520 cutting process Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000005809 transesterification reaction Methods 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910001510 metal chloride Inorganic materials 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000000199 molecular distillation Methods 0.000 description 1
- 239000002417 nutraceutical Substances 0.000 description 1
- 235000021436 nutraceutical agent Nutrition 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
- C07C67/54—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation by distillation
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- C07—ORGANIC CHEMISTRY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
- C07C69/30—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with trihydroxylic compounds
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- C11C3/00—Fats, oils, or fatty acids by chemical modification of fats, oils, or fatty acids obtained therefrom
- C11C3/02—Fats, oils, or fatty acids by chemical modification of fats, oils, or fatty acids obtained therefrom by esterification of fatty acids with glycerol
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Abstract
The invention discloses a preparation method of medium-chain triglyceride, which comprises the following steps: s1, mixing medium-chain fatty acid and glycerol, and keeping the temperature and the pressure at 140-150 ℃ for 3-4 h and the vacuum degree at 0.07-0.09 Mpa in the first stage; in the second stage, the temperature is 160-170 ℃, the heat preservation and pressure maintaining are carried out for 3-4 h, and the vacuum degree is 0.07-0.09 Mpa; in the third stage, the temperature is 190-200 ℃, the heat preservation and the pressure maintenance are carried out for 8-16 h, and the vacuum degree is 0.06-0.08 Mpa; and S2, post-processing. According to the method, different reaction vacuum degrees, temperatures and time are controlled according to the reaction stage, so that the polymerization of glycerin caused by high temperature at the initial stage of the reaction is avoided, the loss of fatty acid in the reaction process is also avoided, the reaction conversion rate and yield are improved, the generation of reaction byproducts is reduced, the product purity is improved, the residue of the fatty acid is greatly reduced, and the real conversion rate is up to more than 98%; the reaction by-product is water, which is non-toxic and harmless.
Description
Technical Field
The invention relates to a preparation method of medium-chain triglyceride.
Background
The medium-chain triglyceride is generally triglyceride formed by C6-C12 fatty acid, and can be used as a raw material drug in fat emulsion injection in the pharmaceutical field. The preparation of medium-chain triglycerides mainly comprises two methods, one is chemical synthesis, and the medium-chain triglycerides are prepared by directly esterifying medium-chain fatty acids and glycerol or by means of ester exchange; another class is the enzymatic processes, catalyzed esterification or transesterification by lipases. The enzyme-catalyzed method has an advantage of mild reaction conditions, but has a problem of enzyme residue. In the chemical synthesis method, the transesterification method has the defect of low product purity, so the injection-grade medium chain triglyceride serving as the raw material medicine of the fat emulsion injection is mainly prepared by the chemical synthesis method of directly esterifying medium chain fatty acid and glycerol.
The Chinese patent application (CN 109836328A) adopts methyl sulfonate as catalyst, the excessive proportion of glycerin is used for esterification, and the reaction is finished and washed by water for many times for refining. The method adopts excessive glycerol, which inevitably results in low content of medium chain triglyceride and high content of mono-and diester. In the patent (CN 108382722A), a strong-acid cation exchange resin is used as a catalyst, a material external circulation mode is adopted, the reaction conversion rate is improved, and the reaction purity is improved through molecular distillation. The patent (CN 104203896A) uses metal alumina or metal chloride as catalyst and provides a formulation using medium chain triglycerides as excipient.
The above patents all adopt a catalyst system, and have a problem of catalyst residue.
In the patent (CN 107129430A), a catalyst-free system is adopted, the esterification reaction is carried out by controlling the vacuum degree and the temperature in the reaction process, and the product is obtained by distilling acid after the reaction is finished. The method adopts a non-catalytic and non-solvent system, is safe and accords with the concept of green chemistry. However, in this patent, too high a temperature rise rate leads to the formation of by-products, and purification is too simple, which may cause a problem of fatty acid residue.
Disclosure of Invention
The invention provides a preparation method of medium chain triglyceride, aiming at overcoming the defects of low reaction conversion rate and yield of the medium chain triglyceride prepared in the prior art, improving the reaction conversion rate and yield, reducing the generation of reaction byproducts, improving the product purity, greatly reducing the residue of fatty acid, and the method has simple operation and low equipment requirement and can realize industrial production.
The invention solves the technical problems through the following technical scheme.
The invention provides a preparation method of medium-chain triglyceride, which comprises the following steps:
s1, mixing medium-chain fatty acid and glycerol, and reacting under vacuum;
the temperature, vacuum degree and time of the reaction are controlled as follows:
in the first stage, the temperature is 140-150 ℃, the heat preservation and the pressure maintenance are carried out for 3-4 h, and the vacuum degree is 0.07-0.09 Mpa;
in the second stage, the temperature is 160-170 ℃, the heat preservation and pressure maintaining are carried out for 3-4 h, and the vacuum degree is 0.07-0.09 Mpa;
in the third stage, the temperature is 190-200 ℃, the heat preservation and pressure maintaining are carried out for 8-16 h, and the vacuum degree is 0.06-0.08 Mpa;
and S2, post-treating to obtain the medium-chain triglyceride.
In step S1, the vacuum degree in the first stage is preferably 0.08Mpa.
In step S1, the vacuum degree of the second stage is preferably 0.08Mpa.
In step S1, the vacuum degree of the third stage is preferably 0.07Mpa.
The vacuum degree is preferably controlled by a pressure-building reaction, namely the reaction kettle is communicated with the storage tank, and continuous vacuum pumping is not needed.
In step S1, the temperature rise mode in the first stage may be continuous temperature rise or segmented temperature rise.
In step S1, the temperature increase mode in the second stage may be continuous temperature increase or segmented temperature increase.
In step S1, the temperature rise manner in the third stage may be continuous temperature rise or segmented temperature rise.
In step S1, the medium-chain fatty acid may be one or more of caprylic acid, capric acid, C6 fatty acid and C12 fatty acid. The C6 fatty acid is preferably hexanoic acid; the C12 fatty acid is preferably lauric acid. The medium-chain fatty acid is preferably caprylic acid and capric acid, and the mass ratio of the caprylic acid to the capric acid is preferably 0.1-10, more preferably 6-8. The medium-chain fatty acid is preferably caproic acid and caprylic acid, and the mass ratio of the caproic acid to the caprylic acid is preferably 0.1. The medium-chain fatty acid is preferably lauric acid and capric acid, and the mass ratio of the lauric acid to the capric acid is preferably 0.1.
In step S1, the molar ratio of the medium-chain fatty acid to the glycerin is preferably greater than 3.
In step S1, the temperature of the first stage is preferably 143-147 deg.C, such as 145 deg.C, 146 deg.C.
In step S1, the time for the first stage of heat preservation and pressure maintaining is preferably 3.5h.
In step S1, the temperature of the second stage is preferably 163 to 167 ℃, for example 164 ℃ and 165 ℃.
In step S1, the time for the second stage of heat preservation and pressure maintaining is preferably 3.5h.
In step S1, the temperature of the third stage is preferably 193 to 197 ℃, for example 195 ℃ and 197 ℃.
In step S1, the time for maintaining the temperature and pressure in the third stage is preferably 10 to 12 hours.
In certain preferred embodiments of the present invention, in step S1,
the temperature, vacuum degree and time of the reaction are controlled as follows:
in the first stage, the temperature is 143-147 ℃, the heat preservation and pressure maintaining are carried out for 3-4 h, and the vacuum degree is 0.07-0.09 Mpa;
in the second stage, the temperature is 163-167 ℃, the heat preservation and pressure maintaining are carried out for 3-4 h, and the vacuum degree is 0.07-0.09 Mpa;
in the third stage, 193-197 deg.c, heat preservation and pressure maintaining are carried out for 8-16 hr, and the vacuum degree is 0.06-0.08 MPa.
In one embodiment of the present invention, in step S1,
the temperature, vacuum degree and time of the reaction are controlled as follows:
in the first stage, the temperature is 146 ℃, the heat preservation and the pressure maintenance are carried out for 4 hours, and the vacuum degree is 0.09Mpa;
in the second stage, the temperature and the pressure are kept at 164 ℃ for 4 hours, and the vacuum degree is 0.08Mpa;
in the third stage, the temperature and the pressure are kept at 180 ℃ for 12h, and the vacuum degree is 0.07Mpa.
In one embodiment of the present invention, in step S1,
the temperature, vacuum degree and time of the reaction are controlled as follows:
in the first stage, the temperature and the pressure are kept at 140 ℃ for 3h, and the vacuum degree is 0.07Mpa;
at the second stage, the temperature and the pressure are kept at 170 ℃ for 3h, and the vacuum degree is 0.07Mpa;
in the third stage, the temperature and the pressure are kept at 200 ℃ for 8h, and the vacuum degree is 0.06Mpa.
In one embodiment of the present invention, in step S1,
the temperature, vacuum degree and time of the reaction are controlled as follows:
in the first stage, the temperature is 150 ℃, the heat preservation and the pressure maintenance are carried out for 4 hours, and the vacuum degree is 0.07Mpa;
in the second stage, the temperature and the pressure are kept at 160 ℃ for 4h, and the vacuum degree is 0.07Mpa;
at the third stage, the temperature and the pressure are kept at 190 ℃ for 16h, and the vacuum degree is 0.09Mpa.
In one embodiment of the present invention, in step S1,
the temperature, vacuum degree and time of the reaction are controlled as follows:
in the first stage, the temperature is 145 ℃, the pressure is maintained for 3 hours, and the vacuum degree is 0.08Mpa;
at the second stage, the temperature and the pressure are kept at 170 ℃ for 3h, and the vacuum degree is 0.07Mpa;
and in the third stage, the temperature is kept at 200 ℃, the pressure is kept for 10 hours, and the vacuum degree is 0.06Mpa.
In one embodiment of the present invention, in step S1,
the temperature, vacuum degree and time of the reaction are controlled as follows:
in the first stage, the temperature and the pressure are kept at 140 ℃ for 3.5h, and the vacuum degree is 0.09Mpa;
at the second stage, the temperature and the pressure are kept at 165 ℃ for 3.5 hours, and the vacuum degree is 0.08Mpa;
in the third stage, the temperature and pressure are kept for 12h at 195 ℃, and the vacuum degree is 0.07Mpa.
In the present invention, in the step S2, the post-treatment can be performed by a method conventional in the art, and generally includes:
and S21, distilling.
In step S21, the distillation may be a reduced pressure distillation.
In step S21, the distillation temperature may be 160 to 180 ℃, preferably 165 to 175 ℃.
In the step S21, the vacuum degree of the distillation can be less than or equal to-0.09 Mpa; wherein, the vacuum degree control can be continuous vacuum pumping.
In step S21, the distillation time may be 2 to 6 hours, preferably 3 to 5 hours.
In step S21, the distillation removes fatty acids.
Preferably, the post-processing further comprises:
s22, neutralizing and washing;
and S23, concentrating and filtering.
In step S22, the neutralization may be performed by adding an alkali solution. The alkali liquor can be potassium hydroxide solution or sodium hydroxide solution. The addition amount of the alkali liquor is calculated according to the acid value of the medium-chain triglyceride obtained after the distillation. The acid number is defined as the number of milligrams of base (calculated as KOH) required to neutralize all the acidic components in 1g of medium chain triglyceride, expressed as mgKOH/g.
Preferably, the addition amount of the alkali liquor is 1.2 to 2.0 times, preferably 1.2 to 1.5 times of the theoretical alkali amount for neutralizing the medium-chain triglyceride based on the mass of the alkali in the alkali liquor. The addition amount of the alkali liquor is specifically calculated as follows: if the obtained crude product of the medium-chain triglyceride is M kg, detecting that the acid value is a mgKOH/g, and when the used neutralization alkaline liquor is KOH, the addition amount of the alkaline liquor is (1.2-2.0) M a g by the mass of the KOH; when the neutralized alkali liquor is NaOH, the addition amount of the alkali liquor is (1.2-2.0) M a 40/56g based on the mass of the NaOH.
Preferably, the volume of the alkali liquor is 0.5-3 times of the volume of the medium-chain triglyceride.
In step S22, the temperature for neutralization may be 50 to 80 ℃, preferably 60 to 70 ℃.
In step S22, the neutralization time may be 15 to 60min, preferably 20 to 50min, for example 25min.
In step S22, purified water may be added for washing. The single volume amount of the purified water is preferably 0.5 to 3 times the volume of the medium chain triglyceride to be washed, and the number of washing times is preferably 2 to 4.
In step S22, the washing temperature may be 50 to 80 ℃, preferably 60 to 70 ℃, for example, 60 ℃.
In step S22, the washing time may be 15 to 60min, preferably 20 to 50min, for example 25min.
In step S22, the neutralization removes residual fatty acids, and the washing removes excess neutralization solution.
In step S23, the concentration may be concentration under reduced pressure.
In step S23, the temperature of the concentration may be 70 to 100 ℃, preferably 75 to 90 ℃, for example 80 ℃.
In step S23, the vacuum degree of the concentration can be less than or equal to-0.07 Mpa.
In step S23, a filter element filter may be used for the filtration; wherein, the aperture of the filter element filter can be 0.2-50 μm. The filter membrane of the filter element filter can be an organic filter membrane, and the material of the organic filter membrane can be nylon, polyvinylidene fluoride, polytetrafluoroethylene or polyether sulfone; the organic filter membrane is preferably a microporous organic filter membrane.
In step S23, the filtering is preferably a secondary filtering; wherein, the aperture of the filter element of the first stage filtration can be 0.2-50 μm; the pore size of the filter element of the second stage filtration may be in the range of 0.2 to 0.45 μm, for example 0.2 μm or 0.45. Mu.m.
In step S23, the concentration may remove water; the filtration can sterilize and filter microorganisms, so that indexes such as microorganisms, endotoxin and the like can meet the requirements of injection products.
The invention also provides medium-chain triglyceride, which is prepared by the preparation method.
The invention provides a fat emulsion injection which comprises medium-chain triglyceride prepared by the preparation method. In the fat emulsion injection, the medium chain triglycerides are used as nutraceuticals for parenteral nutritional supplementation.
The invention provides an oil-soluble solvent, which comprises medium-chain triglyceride prepared by the preparation method. The oil-soluble solvent is used as a pharmaceutic adjuvant.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
the preparation method disclosed by the invention has the advantages that different reaction vacuum degrees, temperatures and time are controlled according to the reaction stages, the polymerization of glycerol caused by high temperature in the initial stage of reaction is avoided, the loss of fatty acid in the reaction process is also avoided, the reaction conversion rate and yield are improved, the generation of reaction byproducts is reduced, the product purity is improved, the residue of fatty acid is greatly reduced, and the real conversion rate is up to more than 98%; the reaction by-product is water, which is non-toxic and harmless. The method has simple process operation and low equipment requirement, and can realize industrial production.
The excessive fatty acid in the preparation process of the method can be recycled, and the method conforms to the concept of green chemistry. Furthermore, a microporous organic filter membrane is adopted for sterilization and filtration, so that indexes such as microorganisms, endotoxin and the like in the medium-chain triglyceride meet the requirement of injection products.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
S1, adding 1800g of caprylic acid, 1200g of capric acid and 550g of glycerol into an esterification kettle, vacuumizing to be below-0.09 Mpa, cutting off the connection between a storage tank and a vacuum pump, and keeping the communication between the reaction kettle and the storage tank.
Continuously heating to 146 ℃, regulating the vacuum degree to 0.09Mpa by nitrogen, and carrying out heat preservation and pressure maintaining reaction for 4 hours.
Continuously heating to 164 deg.C, maintaining the vacuum degree at 0.08Mpa, and reacting for 4 hr.
Continuously heating to 197 deg.C, regulating vacuum degree to 0.07Mpa, and reacting for 12 hr.
S2, post-processing:
s21, opening the connection between the storage tank and the vacuum pump, starting vacuum-pumping and reduced-pressure distillation, and distilling for 2 hours at 180 ℃; vacuum degree of reduced pressure distillation is 0.09Mpa, temperature is reduced to 60 ℃, and 2960g of crude medium-chain triglyceride is obtained.
S22, sampling to determine that the acid value of the crude product is 9mgKOH/g. Adding 1500g of alkali solution (wherein the amount of sodium hydroxide is 1.5 times of the calculated value), stirring at 60 deg.C for 25min, standing for liquid separation, and discarding the lower water phase. Washing the oil phase with 1500g purified water twice, stirring at 60 deg.C for 25min, and separating.
S23, vacuum concentrating at 80 ℃ to remove water, wherein the vacuum degree is-0.08 Mpa. After the concentration is finished, the temperature is reduced to be below 40 ℃, and the medium chain triglyceride 2731g is obtained by filtering through two stages of polyethersulfone organic filter membranes of 50 microns and 0.2 microns, the reaction conversion rate is 99 percent, and the real yield is 91.3 percent. The hydroxyl value is 3, the acid value is 0.05mgKOH/g, and the unsaponifiable matter is 0.06 percent through detection. Here, "50 μm +0.2 μm" means that the pore size of the filter element of the first stage filtration is 50 μm; the aperture of the filter element of the second stage of filtration is 0.2 μm.
The purity data of the finally prepared medium-chain triglycerides are 99.3% of medium-chain triglycerides, 0.5% of medium-chain diglycerides and 0.06% of medium-chain monoglycerides.
Comparative example 1
S1, adding 1800g of caprylic acid, 1200g of capric acid and 550g of glycerol into an esterification kettle, vacuumizing to be below-0.05 Mpa, cutting off the connection between a storage tank and a vacuum pump, and keeping the communication between the reaction kettle and the storage tank.
Continuously heating to 145 ℃, regulating the vacuum degree to 0.05Mpa by nitrogen, and carrying out heat preservation and pressure maintaining reaction for 4 hours.
Continuously heating to 165 ℃, keeping the vacuum degree at 0.05Mpa, and carrying out heat preservation and pressure maintaining reaction for 4 hours.
Continuously heating to 195 ℃, adjusting the vacuum degree to 0.04Mpa, and carrying out heat preservation and pressure maintaining reaction for 13h.
S2, post-processing:
s21, opening the connection between the storage tank and the vacuum pump, starting vacuum-pumping and reduced-pressure distillation, and distilling for 3 hours at 170 ℃; the vacuum degree of the reduced pressure distillation is 0.09Mpa, the temperature is reduced to 50 ℃, and 2976g of the crude product of the medium-chain triglyceride is obtained.
S22, sampling to determine that the acid value of the crude product is 9mgKOH/g. Adding 1200g of alkali liquor (wherein the amount of sodium hydroxide is 1.2 times of the calculated value), stirring at 50 deg.C for 30min, standing for liquid separation, and discarding the lower water phase. Washing the oil phase with purified water twice, using 6000g each time, keeping the volume of the oil phase at 3000ml, stirring at 55 deg.C for 25min, and separating the liquid.
S23, concentrating under reduced pressure at 85 ℃ to remove water, wherein the vacuum degree is-0.08 Mpa. Concentrating under reduced pressure for 3h, cooling to below 40 deg.C after concentration, and filtering with PTFE (polytetrafluoroethylene) filter membrane to obtain 2632g of medium chain triglyceride, with reaction conversion rate of 92% and real yield of 88%. The detection shows that the hydroxyl value is 18, the acid value is 0.06mgKOH/g, and the unsaponifiable matter is 0.2 percent.
Comparative example 2
S1, adding 2100g of caprylic acid, 900g of capric acid and 550g of glycerol into an esterification kettle, vacuumizing to be below-0.09 Mpa, cutting off the connection between a storage tank and a vacuum pump, and keeping the communication between the reaction kettle and the storage tank.
Continuously heating to 160 ℃, regulating the vacuum degree to 0.09Mpa by nitrogen, and carrying out heat preservation and pressure maintaining reaction for 4 hours.
Continuously heating to 190 deg.C, maintaining the vacuum degree at 0.08Mpa, and reacting for 12h under heat and pressure.
S2, post-processing:
s21, opening the connection between the storage tank and the vacuum pump, starting vacuum-pumping and reduced-pressure distillation, and distilling for 3 hours at 165 ℃; vacuum degree of reduced pressure distillation is 0.09Mpa, temperature is reduced to 50 ℃, and 2890g of medium chain triglyceride crude product is obtained.
S22, sampling to determine that the acid value of the crude product is 9mgKOH/g. Adding 1200g of alkali liquor (wherein the amount of sodium hydroxide is 1.2 times of the calculated value), stirring at 50 deg.C for 45min, standing for liquid separation, and discarding the lower water phase. Washing the oil phase with purified water for three times, wherein the dosage is 4500g each time, the volume of the oil phase is 3000ml, stirring at 50 deg.C for 30min, and separating.
S23, vacuum concentration at 90 ℃ for dewatering, wherein the vacuum degree is-0.09 Mpa. Concentrating under reduced pressure for 2h, cooling to below 40 deg.C, filtering with PVDF (polyvinylidene fluoride) filter membrane to obtain 2620g of medium chain triglyceride, with a reaction conversion rate of 95% and a real yield of 89.0%. The detection shows that the hydroxyl value is 11, the acid value is 0.08mgKOH/g, and the unsaponifiable matter is 0.7 percent.
Comparative example 4
The technical scheme is implemented by adopting a patent (CN 107129430A), and 2000g of caprylic acid, 1000g of capric acid and 500g of glycerol are adopted; vacuum-conditioning to-0.09 Mpa, slowly heating to 180 deg.C, and keeping the temperature for 3h; the vacuum is gradually adjusted to-0.06 Mpa along with the temperature rise. Vacuum of-0.09 Mpa, and removing for 0.5h. See table 1 for details.
Comparative example 5
2000g of caprylic acid, 1000g of capric acid and 500g of glycerol are adopted; the operation steps of heating and distillation adopt the technical scheme of a patent (CN 107129430A), and the post-treatment mode is the same as the implementation of the post-treatment process of the application. See table 1 for details.
Examples 2 to 5 and comparative example 3
Examples 2 to 5 and comparative example 3 were prepared by the method of example 1, with the operating conditions being as shown in Table 1 except that the difference from example 1 was that the other conditions were the same as example 1 (including: starting materials, the sum of the mass of caprylic acid and capric acid was 3000g, and glycerin was 550 g).
TABLE 1 operating condition tables for examples 1-5 and comparative examples 1-3
Effect embodiment:
the measured purity data, real yield, conversion, hydroxyl value, unsaponifiable matter and acid value data for the medium chain triglycerides of examples 1-5 and comparative examples 1-5 are shown in table 2.
The real yield should be the ratio of the actual to the theoretical yield. The fatty acid is in excess in this example and comparative example and should therefore be calculated as the amount of glycerol when calculating the theoretical yield and conversion. Theoretical charge = (mass of glycerol/molecular weight of glycerol) × (average molecular weight of glycerol) product, average molecular weight of product can be calculated approximately from the fatty acid ratio charged, using example 1 as an example, 1800g caprylic acid charge, 1200 capric acid charge and 550g glycerol charge. Assuming that the proportion of caprylic acid and capric acid in the product is kept unchanged after the reaction is finished, the molar ratio of caprylic acid to capric acid in the product is 64.2%, the capric acid is 35.8%, the average molecular weight of the product is 501, the theoretical yield is 2991g, and the real yield is 91.3%.
The consumption quality of glycerol cannot be directly obtained and can be calculated by the hydroxyl value of the product. The glycerol has 3 hydroxyl groups, and the molar number of the hydroxyl groups before reaction can be calculated by dividing the mass of the glycerol by the molecular weight of the glycerol; the hydroxyl mole number after reaction can be calculated by the hydroxyl value of the product; conversion = (number of moles of hydroxyl groups before reaction-number of moles of hydroxyl groups after reaction)/number of moles of hydroxyl groups before reaction.
In addition, purity data for medium chain diglycerides and medium chain monoglycerides were also determined. As can be seen from table 2, when comparative example 1 employs three-stage temperature rise, but the operating conditions are not within the scope of its own protection, the purity, conversion and true yield of the medium-chain triglyceride produced are not as high as those of examples 1-5; when comparative example 2 employs a two-stage temperature increase, it produces medium-chain triglycerides with less high conversion and purity than examples 1-5; when comparative example 3 employs a one-step temperature increase, it produces a true yield, conversion and purity of medium chain triglycerides that are not as high as examples 1-5. When comparative example 4 was carried out using the technique of the patent (CN 107129430A), the actual yield, conversion and purity of medium chain triglycerides were not as high as those obtained in examples 1-5. When the technical scheme of the patent (CN 107129430A) is adopted in the comparative example 5 and the post-treatment process is added, the post-treatment mode is the same as the post-treatment mode of the application, and the real yield, the conversion rate and the purity of the prepared medium-chain triglyceride are not as high as those of the examples 1-5.
The hydroxyl value refers to the weight (mg) of potassium hydroxide required for acylation of hydroxyl group contained in 1g of the test sample according to 0713 fat and fatty oil determination method in general rules of the four parts of Chinese pharmacopoeia. The hydroxyl number represents the amount of free hydroxyl groups in the product, which reflects the extent of reaction of glycerol, which is one of the starting materials, the lower the hydroxyl number, the more complete the esterification reaction of glycerol. Acid number refers to the number of milligrams of base (calculated as KOH) required to neutralize all of the acidic components in 1g of medium chain triglyceride, expressed as mgKOH/g.
The unsaponifiable matter here represents a level of non-glyceride, non-fatty acid impurities. The hydroxyl numbers of comparative examples 1-5 were all above 10 and the hydroxyl numbers of examples 1-5 were between 2-5, indicating that the esterification reactions of examples 1-5 were more complete.
TABLE 2 Effect data Table for examples 1-5 and comparative examples 1-5
Claims (10)
1. A process for the preparation of medium chain triglycerides comprising the steps of:
s1, mixing medium-chain fatty acid and glycerol, and reacting under vacuum;
the temperature, vacuum degree and time of the reaction are controlled as follows:
in the first stage, the temperature is 140-150 ℃, the heat preservation and pressure maintaining are carried out for 3-4 h, and the vacuum degree is 0.07-0.09 Mpa;
in the second stage, the temperature is 160-170 ℃, the heat preservation and pressure maintaining are carried out for 3-4 h, and the vacuum degree is 0.07-0.09 Mpa;
in the third stage, the temperature is 190-200 ℃, the heat preservation and the pressure maintenance are carried out for 8-16 h, and the vacuum degree is 0.06-0.08 Mpa;
and S2, post-treating to obtain the medium-chain triglyceride.
2. The method of claim 1, wherein in step S1, the first stage vacuum is 0.08Mpa;
and/or in the step S1, the vacuum degree of the second stage is 0.08Mpa;
and/or in the step S1, the vacuum degree of the third stage is 0.07Mpa.
3. The method according to claim 1, wherein the first stage temperature is a continuous or stepwise temperature increase in step S1;
and/or in the step S1, the temperature of the first stage is continuously increased or gradually increased;
and/or in step S1, the temperature of the first stage is continuously increased or increased in sections.
4. The method of claim 1, wherein in step S1, the medium-chain fatty acid is one or more of caprylic acid, capric acid, C6 fatty acid and C12 fatty acid; the C6 fatty acid is preferably hexanoic acid; the C12 fatty acid is preferably lauric acid;
preferably, the medium-chain fatty acid is caprylic acid and capric acid, and the mass ratio of the caprylic acid to the capric acid is preferably 0.1 to 10, more preferably 6 to 8;
preferably, the medium-chain fatty acid is caproic acid and caprylic acid, and the mass ratio of the caproic acid to the caprylic acid is preferably 0.1;
preferably, the medium-chain fatty acid is lauric acid and capric acid, and the mass ratio of the lauric acid to the capric acid is 0.1.
5. The method for preparing medium chain triglycerides according to claim 1, wherein in step S1, the molar ratio of medium chain fatty acids to glycerol is greater than 3;
and/or, in step S1, the temperature of the first stage is 143 to 147 ℃, e.g. 145 ℃, 146 ℃;
and/or in the step S1, the heat preservation and pressure maintaining time of the first stage is 3.5 hours;
and/or, in step S1, the temperature in the second stage is 163 to 167 ℃, for example 164 ℃,165 ℃;
and/or in the step S1, the heat preservation and pressure maintaining time of the second stage is 3.5 hours;
and/or, in step S1, the temperature of the third stage is 193 to 197 ℃, for example 195 ℃ and 197 ℃;
and/or in the step S1, the heat preservation and pressure maintaining time of the third stage is 10-12 h.
6. The method of claim 1, wherein in step S1,
the temperature, vacuum degree and time of the reaction are controlled as follows:
in the first stage, the temperature is 146 ℃, the heat preservation and pressure maintaining are carried out for 4 hours, and the vacuum degree is 0.09Mpa;
in the second stage, the temperature and the pressure are kept at 164 ℃ for 4 hours, and the vacuum degree is 0.08Mpa;
in the third stage, the temperature and the pressure are kept at 180 ℃ for 12 hours, and the vacuum degree is 0.07Mpa;
alternatively, in step S1, the first step,
the temperature, vacuum degree and time of the reaction are controlled as follows:
in the first stage, the temperature is 140 ℃, the heat preservation and the pressure maintenance are carried out for 3 hours, and the vacuum degree is 0.07Mpa;
at the second stage, the temperature and the pressure are kept at 170 ℃ for 3h, and the vacuum degree is 0.07Mpa;
in the third stage, the temperature and the pressure are kept at 200 ℃ for 8h, and the vacuum degree is 0.06Mpa;
alternatively, in step S1, the first step,
the temperature, vacuum degree and time of the reaction are controlled as follows:
in the first stage, the temperature and the pressure are kept at 150 ℃ for 4h, and the vacuum degree is 0.07Mpa;
at the second stage, the temperature is 160 ℃, the heat preservation and the pressure maintenance are carried out for 4 hours, and the vacuum degree is 0.07Mpa;
at the third stage, the temperature and the pressure are kept at 190 ℃ for 16h, and the vacuum degree is 0.09Mp;
alternatively, in the step S1, the step of,
the temperature, vacuum degree and time of the reaction are controlled as follows:
in the first stage, the temperature is 145 ℃, the pressure is maintained for 3 hours, and the vacuum degree is 0.08Mpa;
at the second stage, the temperature and the pressure are kept at 170 ℃ for 3h, and the vacuum degree is 0.07Mpa;
in the third stage, the temperature and the pressure are kept at 200 ℃ for 10h, and the vacuum degree is 0.06Mpa;
alternatively, in the step S1, the step of,
the temperature, vacuum degree and time of the reaction are controlled as follows:
in the first stage, the temperature is 140 ℃, the heat preservation and the pressure maintenance are carried out for 3.5 hours, and the vacuum degree is 0.09Mpa;
at the second stage, the temperature and the pressure are kept at 165 ℃ for 3.5 hours, and the vacuum degree is 0.08Mpa;
in the third stage, the temperature and pressure are kept for 12h at 195 ℃, and the vacuum degree is 0.07Mpa.
7. The method of claim 1, wherein the post-treatment in step S2 comprises: s21, distilling;
wherein, the distillation is preferably vacuum distillation;
the temperature of the distillation is preferably 160 to 180 ℃, more preferably 165 to 175 ℃;
the vacuum degree of the distillation is preferably less than or equal to-0.09 MPa;
the distillation time is preferably 2 to 6 hours, more preferably 3 to 5 hours.
8. The method of claim 7, wherein the post-treatment further comprises:
s22, neutralizing and washing;
s23, concentrating and filtering;
preferably, in step S22, the neutralization is neutralization by adding alkali liquor; the alkali liquor is potassium hydroxide solution or sodium hydroxide solution;
preferably, in step S22, the temperature for neutralization is 50 to 80 ℃, preferably 60 to 70 ℃;
preferably, in step S22, the neutralization time is 15-60 min, preferably 20-50 min, for example 25min;
preferably, in step S22, the washing is performed by adding purified water, the volume of each time of the purified water is 0.5 to 3 times of the volume of the medium-chain triglyceride to be washed, and the number of times of washing is 2 to 4;
preferably, in step S22, the washing temperature is 50 to 80 ℃, preferably 60 to 70 ℃, for example 60 ℃;
preferably, in step S22, the washing time is 15 to 60min, preferably 20 to 50min, for example 25min.
9. The method according to claim 8, wherein the concentration is a concentration under reduced pressure in step S23;
and/or, in step S23, the temperature of the concentration is 70 to 100 ℃, preferably 75 to 90 ℃, for example 80 ℃;
and/or in step S23, the vacuum degree of the concentration is less than or equal to-0.07 Mpa;
and/or, in step S23, a filter element filter is used for the filtration; wherein, the aperture of the filter element filter is preferably 0.2-50 μm; the filter membrane of the filter element filter is preferably an organic filter membrane, and the material of the organic filter membrane is preferably nylon, polyvinylidene fluoride, polytetrafluoroethylene or polyether sulfone; the organic filter membrane is preferably a microporous organic filter membrane;
and/or, in the step S23, the filtration is secondary filtration; wherein, the aperture of the filter element of the first stage filtration is preferably 0.2-50 μm; the pore size of the filter element of the second stage filtration is preferably 0.2 to 0.45. Mu.m, for example 0.2 μm or 0.45. Mu.m.
10. A fat emulsion injection comprising medium chain triglycerides produced by the process for the preparation of medium chain triglycerides of any of claims 1-9.
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| CN102030634A (en) * | 2009-10-08 | 2011-04-27 | 奥克塞有限公司 | Method for manufacturing polyol esters |
| CN107129430A (en) * | 2017-05-09 | 2017-09-05 | 新兴（铁岭）药业股份有限公司 | A kind of bulk drug median chain triglyceride oil synthetic method |
| CN109836328A (en) * | 2019-03-16 | 2019-06-04 | 广州隽沐生物科技股份有限公司 | The synthetic method of median chain triglyceride oil |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102030634A (en) * | 2009-10-08 | 2011-04-27 | 奥克塞有限公司 | Method for manufacturing polyol esters |
| CN107129430A (en) * | 2017-05-09 | 2017-09-05 | 新兴（铁岭）药业股份有限公司 | A kind of bulk drug median chain triglyceride oil synthetic method |
| CN109836328A (en) * | 2019-03-16 | 2019-06-04 | 广州隽沐生物科技股份有限公司 | The synthetic method of median chain triglyceride oil |
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