CN100526289C - Non-toxic ion liquid its production and use - Google Patents
Non-toxic ion liquid its production and use Download PDFInfo
- Publication number
- CN100526289C CN100526289C CNB2006100712938A CN200610071293A CN100526289C CN 100526289 C CN100526289 C CN 100526289C CN B2006100712938 A CNB2006100712938 A CN B2006100712938A CN 200610071293 A CN200610071293 A CN 200610071293A CN 100526289 C CN100526289 C CN 100526289C
- Authority
- CN
- China
- Prior art keywords
- liquid
- acid
- ion
- ionic liquid
- medicine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A non-toxic ionic liquid, its production and use are disclosed. In the molecular formula, cation is quaternary cationics. R1, R2, R3 and R4 can be H, different or indifferent alkyl of C1-C8 or contain hydroxyl or carboxylic derivatives. It can make various medicine insoluble into solution or micro-emulsion with different concentration. It can be used fro solvent, fusing agent or surface active agent. It has better melting degree and biological utilization.
Description
Technical field
The invention belongs to new ion liquid synthetic reaching in chemical material and the manufacturing field as a kind of new solvent, solubility promoter or tensio-active agent application in medicine, agricultural chemicals.
Background technology
Ionic liquid (Ionic Liquids) is meant by organic alkyl imidazole, quaternary amine, positive ion such as alkyl pyridine and different negative ion as, chlorion, BF
4 -, PF
6 -, CF
3CO
2 -, N (CN)
- 2Deng the low melting point organic molten salt of forming, they have many is liquid under room temperature even low temperature, therefore is referred to as ionic liquid at room temperature again.They have and do not have vapour pressure, and are thermally-stabilised good, (reaching as high as 300-400 ℃), good electrical conductivity; To organic compound, mineral compound, organometallics, gas is as H
2, CO, O
2Solvability is widely arranged; Can be also and organic solvent, water is miscible, or insoluble formation two-phase or heterogeneous reaction system; The most attractive is its polarity, the length that hydrophilic, close ester can be by alkyl carbon chain with select different negative ions to regulate, programmable solvent therefore is otherwise known as.Ionic liquid, has been used widely in the research fields such as electrochemistry at organic synthesis, novel material as new green solvent, and it has mainly been used: 1, replace volatile organic solvent, reduce environmental pollution; 2, solid-carried catalyst reduces the consumption of catalyzer; 3, improve Activity of Chemical Reaction and selectivity; 4, as electrochemical material such as battery etc.Above-mentioned ionic liquid is as 1-methyl-3-butyl imidazole hexafluorophosphate, in water, can produce hydrolysis and generate volatile deleterious HF and POF3, (R.P.Swalowski, J.D.Holbery, andR.D.Rogers, Green Chem., 2003,5,361.) 1-methyl-its acute toxicity of 3-butyl imidazole a tetrafluoro borate LD
50=1.4g/kg (female rats), LD
50=1.37g/kg (male rat) (J.Pernak, et.al., Ind.Eng.Chem.Res.2001,40,2379.), so these ionic liquids commonly used all are to have necessarily toxicly, can not be used for medicine or use as foodstuff additive.To at present, also there is not relevant ionic liquid to be used to prepare medicine or pesticides new formulation or as the report of foodstuff additive as a kind of new solvent, solubility promoter or tensio-active agent.In pharmaceutical industry, there are many medicines to be insoluble in water, are difficult to be absorbed by the body and utilize.Therefore solve the solvability of insoluble medicine in water, the raising bioavailability of medicament remains difficult point and the hot issue in the pharmaceutical industry.The method of often taking now is that medicine is dissolved in the oil phase, adds then that tensio-active agent is made emulsion or microemulsion improves bioavailability of medicament.But need to add a large amount of oil phases, simultaneously, also need add tensio-active agent.Some has side effect to human body these additives.Owing to tensio-active agent, the solubility promoter kind is very limited simultaneously, complicated process of preparation, and cost is higher.And can not solve all insoluble medicines deliquescent problem in water.
Summary of the invention
The purpose of this invention is to provide a kind of non-toxic ion liquid, it is used to prepare novel pharmaceutical formulation as new solvent, solubility promoter or tensio-active agent, can improve the solubleness of insoluble medicine in water, makes insoluble medicine
Design of the present invention is such.Because ionic liquid is programmable solvent, therefore by selecting different zwitterions good solvability to be arranged to insoluble medicine.Using as pharmaceutical auxiliary agent simultaneously need be nontoxic.It is used for preparation medicine or pesticides new formulation as new solvent, solubility promoter or tensio-active agent, can well improve the solubleness of a lot of insoluble medicines in water, insoluble medicine can be dissolved in water, thereby can better improve bioavailability of medicament.Particularly, non-toxic ion liquid of the present invention partly is made up of positively charged ion and negatively charged ion two, the raw material that its design philosophy is that to select at present be nontoxic or is used for medicine or foodstuff additive synthesizes ionic liquid, positively charged ion is made of the quaternary ammonium salts positively charged ion, negatively charged ion is made of carboxylic acid and derivative thereof, and structural formula is expressed as follows:
Carboxylic-acid negatively charged ion R=C in the formula
1-C
17Alkyl or its contain hydroxyl, carboxy derivatives as acetate, lactic acid, propionic acid, butyric acid, oxysuccinic acid, citric acid, tartrate, lauric acid, oleic acid, palmitinic acid, stearic acid etc.The many food or drug additive and life-time service of being used for of these organic carboxyl acids prove nontoxic.
Wherein, R in the quaternary ammonium salts positively charged ion
1, R
2, R
3, R
4Can be H, identical or different C
1-C
8Alkyl or its contain hydroxyl, carboxy derivatives.As: H ,-CH
3.-CH
2CH
3.-CH
2CH
2OH ,-CH
2CH
2COOH ,-(CH
2)
3CH
3Deng.Quaternary ammonium salts such as choline chloride 60 are the food or the drug additives of generally recognized as safe.
Above-mentioned non-toxic ion liquid can obtain by following two kinds of preparation methods:
The preparation method one:
Generate corresponding ionic liquid and water by quaternary amine alkali and organic carboxyl acid direct reaction, then water is prepared by the high vacuum underpressure distillation.Alkyl imidazole alkali exchanges by basic resin and prepares.Reaction formula is as follows:
The preparation method two:
In organic solvent, carry out ion-exchange, generate ionic liquid and inorganic salt by corresponding salt.Inorganic salt evaporate organic solvent and prepare ionic liquid by removing by filter, and reaction formula is as follows:
The security of above-mentioned non-toxic ion liquid is by to the small white mouse oral administration, measures its acute toxicity LD
50Estimate, concrete outcome is seen embodiment subordinate list 1.
Above-mentioned non-toxic ion liquid can well dissolve many in water the medicine of indissoluble, solution, microemulsion or submicron emulsion that simultaneously can insoluble medicine formation soluble in water is transparent or semitransparent.Its particle diameter is 50-300nm.Thereby can improve the bioavailability of insoluble medicine.Concrete implementation and operation is as follows:
Get one or more mixed liquid of ionic liquid, its ratio is by being added 0.1-100 times of medicines.Also can add some chaotropic agents such as ethanol, propylene glycol, glycerine, polyoxyethylene glycol etc., or tensio-active agent such as anionic surfactant such as sodium lauryl sulphate, sodium sulfonate, bile acide etc., amphoterics Yelkin TTS, nonionic surface active agent such as spans, Tweens and sucrose fatty ester mix use.Its add-on is add 0.1-100 times of medicine.
Insoluble medicine is dissolved in the above-mentioned solution, and insoluble medicine comprises, Western medicine class such as taxanes, camptothecine and derivative thereof, amphotericin B, rapamycin, encircle rhzomorph A, Chinese medicine class scutellarin, Chinese medicine miscellany and volatile oil such as Mountain Spicy Tree Fruit volatilization wet goods and all are insoluble in the medicine of water.Consumption is decided according to preparation type.
Add distilled water then while stirring, or add behind the ionic liquid solution contain medicine by the equal breast of excusing from death ripple or equal newborn machine, water consumption is 1-5000 times of medicine.Can form transparent or semitransparent solution, microemulsion or submicron emulsion.Its particle diameter is 50-300nm.
The aqueous solution of prepared insoluble medicine can be used as oral liquid, injection liquid, infusion solutions, sprays, the administering mode that eye drop etc. are different.Embodiment is seen in concrete operations.
The technique effect that the present invention obtains is:
(1) ionic liquid of mentioning in the present invention and the background technology compare have its general ion liquid physicochemical property such as liquid range wide, thermally-stabilised good, to organic, mineral compound has good solvability, and nontoxic;
(2) non-toxic ion liquid of the present invention can be used as solvent, solubility promoter, or tensio-active agent is used for the solvability that field of medicaments increases the medicine that is insoluble in water.
(3) non-toxic ion liquid of the present invention is as solvent, solubility promoter, or tensio-active agent is used for field of medicaments, increases when being insoluble in the solvability of water medicine, has good solubilising and hydrotropy effect.Compare with other tensio-active agent or solubilizing agent, better effects if, preparation technology is simple, and cost is low.Be easy to realize industrialization.
Embodiment
The following example has further disclosed technical scheme of the present invention.Embodiment has only illustrated conception of the present invention, does not limit the present invention.Can carry out many changes according to thought of the present invention and scope.
Embodiment 1
The ion liquid preparation of L-lactoylcholine
Synthesize by ion liquid synthetic method one: in the methanol solution of 32ml bursine 45%, drip the 9.6ml90%L-lactic acid solution.Stir after 0.5 hour, purified after, 45 ℃ of high vacuum evaporated under reduced pressure solvents get the colourless L-lactoylcholine of 22.0g. ionic liquid.
Embodiment 2
The ion liquid preparation of DL-lactoylcholine
Synthesize by ion liquid synthetic method one: in the methanol solution of 32ml bursine 45%, drip 11.0ml80% DL-lactic acid solution.Stir after 0.5 hour, purified after, 45 ℃ of high vacuum evaporated under reduced pressure solvents get the colourless DL-lactoylcholine of 22.3g. ionic liquid.
Embodiment 3
The preparation of isopropylformic acid cholinium ion liquid
Synthesize by ion liquid synthetic method one: in the methanol solution of 20ml bursine 45%, drip the 6.14g isopropylformic acid.Stir after 0.5 hour, purified after, 45 ℃ of high vacuum evaporated under reduced pressure solvents get the colourless isopropylformic acid cholinium ion of 15.4g liquid.
Embodiment 4
The preparation of n-caproic acid cholinium ion liquid
Synthesize by ion liquid synthetic method one: in the methanol solution of 18.6 bursines 45%, drip the 9.04g n-caproic acid.Stir after 0.5 hour, purified after, 45 ℃ of high vacuum evaporated under reduced pressure solvents get the colourless n-caproic acid cholinium ion of 18.4g. liquid.
Embodiment 5
The preparation of lauric acid cholinium ion liquid
Synthesize by ion liquid synthetic method one: in the methanol solution of 10ml bursine 45%, add 6.95g lauric acid solid.After the stirring and dissolving, purified, 45 ℃ of high vacuum evaporated under reduced pressure solvents get the colourless lauric acid cholinium ion of 12.1g. liquid.Become waxy solid after the cooling.
Embodiment 6
The ion liquid preparation of choline stearate
Synthesize by ion liquid synthetic method one: in the methanol solution of 10ml bursine 45%, add the hard ester acid of 9.9g solid.After the stirring and dissolving, purified, 45 ℃ of high vacuum evaporated under reduced pressure solvents get 13.2g.The hard ester acid of colourless waxy solid cholinium ion liquid.
Embodiment 7
The preparation of palmitinic acid cholinium ion liquid
Synthesize by ion liquid synthetic method one: in the methanol solution of 10ml bursine 45%, add 8.9g palmitinic acid solid.After the stirring and dissolving, purified, 45 ℃ of high vacuum evaporated under reduced pressure solvents get the colourless waxy solid palmitinic acid of 12.3g. cholinium ion liquid.
Embodiment 8
Choline stearate preparation method of ionic liquid 2
Synthesize by ion liquid synthetic method two: in the 14.00g choline chloride 60, add acetone and the 22.2g sodium stearate solid of 100ml.Stir after 24 hours, remove sodium-chlor after filtration, behind the purifying, 45 ℃ of high vacuum evaporated under reduced pressure solvents get the hard ester acid of the colourless waxy solid of 29.5g. cholinium ion liquid.
Embodiment 9
The choline acetate preparation method of ionic liquid
Synthesize by ion liquid synthetic method two: in the 14.00g choline chloride 60, add acetone and the 8.2g sodium-acetate solid of 100ml.Stir after 24 hours, remove sodium-chlor after filtration, behind the purifying, 45 ℃ of high vacuum evaporated under reduced pressure solvents get the colourless choline acetate ionic liquid of 16.0g..
Above-mentioned ionic liquid is through its acute toxicity of the oral mensuration of small white mouse LD
50The results are shown in table 1:
Subordinate list 1. ion liquid acute toxicity LD
50Measurement result
| Ionic liquid | LD 50(g/kg) |
| 1.L-lactoylcholine 2.DL-lactoylcholine 3. isopropylformic acid choline 4. n-caproic acid choline 5. lauric acid choline 6. choline stearates 7. palmitinic acid choline 8. choline acetates | (5.3 female), 6.4 (heros) 5.5 5.3 5.4 5.6 6.4 6.2 6.5 |
Following examples are used for illustrating the application of above-mentioned non-toxic ion liquid in the preparation novel pharmaceutical formulation.
Embodiment 10
The aqueous solution combination formula 1 of cyclosporin A:
Composition weight (mg)
Cyclosporin A 61.6
L-lactoylcholine 780
Choline stearate 200
Water 2000
This component is a solution, is diluted with water to 100ml, can form microemulsion, and particle diameter is 249.9 nanometers.
Embodiment 11
The aqueous solution combination formula 2 of cyclosporin A (also can add other tensio-active agent preparation in the prescription):
Composition weight (mg)
Cyclosporin A 71.8
L-lactoylcholine 600
Sodium laurylsulfonate 200
Water 2000
This component is a solution, is diluted with water to 100ml, can form microemulsion, and particle diameter is 260 nanometers.
Embodiment 12
The aqueous solution combination formula 1 of amphotericin B:
Composition weight (mg)
Amphotericin B 100
DL-lactoylcholine 1000
Palmitinic acid choline 200
Water 1000
This component is a solution, is diluted with water to 100ml, can form microemulsion, and particle diameter is 193.4 nanometers.
Embodiment 13
The aqueous solution combination formula 2 of amphotericin B (also can add other solubility promoter in the prescription):
Composition weight (mg)
Amphotericin B 47
Isopropylformic acid choline 500
PEG400 200
Water 500
This component is a solution, is diluted with water to 50ml, can form microemulsion, and particle diameter is 230 nanometers.
Embodiment 14
The aqueous solution combination formula 2 of scutellarin (also can add other solubility promoter in the prescription):
Composition weight (mg)
Scutellarin 200
Choline acetate 500
Sucrose fatty ester 20
Water 500
This component is a solution, is diluted with water to 50ml, can form microemulsion, and particle diameter is 270 nanometers.
Claims (6)
1, a kind of non-toxic ion liquid of forming by positively charged ion and negatively charged ion, it is characterized in that: positively charged ion is made of the quaternary ammonium salts of short carbon chain, and negatively charged ion is made of carboxylate radical, and its structural formula is expressed as:
In the formula, R=C
1-C
17Alkyl;
R
1, R
2, R
3, R
4Be identical or different C
1-C
2Alkyl or-CH
2CH
2OH.
2, by the described non-toxic ion liquid of claim 1, it is characterized in that: the anionic carboxylic acid root is an acetate, lactic acid, propionic acid, butyric acid, lauric acid, palmitinic acid, stearic acid group.
3, the preparation method of non-toxic ion liquid as claimed in claim 1 or 2 is characterized in that: comprise the steps:
(1) quaternary amine alkali and organic carboxyl acid direct reaction generate corresponding ionic liquid and water;
(2) water is promptly got ionic liquid by the high vacuum underpressure distillation.
4, the preparation method of non-toxic ion liquid as claimed in claim 1 or 2 is characterized in that: comprise the steps:
(1) in organic solvent, carries out ion-exchange, generate ionic liquid and inorganic salt by corresponding salt;
(2) inorganic salt evaporate organic solvent and make ionic liquid by removing by filter.
5, non-toxic ion liquid is characterized in that as the application method of drug solvent, solubility promoter or tensio-active agent as claimed in claim 1 or 2:
Get one or more mixed liquid of ionic liquid, its ratio is add 0.1-100 times of medicine, amphotericin B, cyclosporin A or scutellarin are dissolved in the above-mentioned solution, the solution of the ionic liquid medicine of making directly adds a large amount of water, water consumption is 1-5000 times of medicine, form transparent or semitransparent solution, microemulsion or submicron emulsion, its particle diameter is 50-300nm.
6, by the application method of the described non-toxic ion liquid of claim 5, it is characterized in that as drug solvent, solubility promoter or tensio-active agent:
Add chaotropic agent: ethanol, polyoxyethylene glycol; Or interpolation tensio-active agent: anionic surfactant's sodium lauryl sulphate, sodium sulfonate, bile acide or nonionic surface active agent sucrose fatty ester are mixed to be used;
Chaotropic agent or tensio-active agent add-on are add 0.1-100 times of medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100712938A CN100526289C (en) | 2004-12-06 | 2004-12-06 | Non-toxic ion liquid its production and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100712938A CN100526289C (en) | 2004-12-06 | 2004-12-06 | Non-toxic ion liquid its production and use |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100645830A Division CN100490898C (en) | 2004-12-06 | 2004-12-06 | Non-toxic ionic liquid, preparation method and its application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1854120A CN1854120A (en) | 2006-11-01 |
| CN100526289C true CN100526289C (en) | 2009-08-12 |
Family
ID=37194619
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006100712938A Expired - Fee Related CN100526289C (en) | 2004-12-06 | 2004-12-06 | Non-toxic ion liquid its production and use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100526289C (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL2017545B1 (en) | 2016-09-28 | 2018-04-06 | Eucaryo Beheer B V | Composition comprising a bioactive molecule |
| CN107827926B (en) * | 2017-10-31 | 2020-05-22 | 中国科学院兰州化学物理研究所 | Micromolecule functionalized surfactant and preparation method and application thereof |
| CN111012742A (en) * | 2020-01-07 | 2020-04-17 | 中国医学科学院生物医学工程研究所 | Method for realizing dispersion of insoluble drug in water |
| CN113101371A (en) * | 2021-04-07 | 2021-07-13 | 中国科学院大学温州研究院(温州生物材料与工程研究所) | Solubilization method of hydrophobic drug based on cation-pi effect |
| CN115232048B (en) * | 2021-04-22 | 2024-02-27 | 南京毓浠医药技术有限公司 | Ionic liquid and preparation method and application thereof |
| CN115572236A (en) * | 2022-11-10 | 2023-01-06 | 辽宁大学 | Choline lactic acid ionic liquid, preparation method thereof and application thereof in iodine extraction |
-
2004
- 2004-12-06 CN CNB2006100712938A patent/CN100526289C/en not_active Expired - Fee Related
Non-Patent Citations (6)
| Title |
|---|
| Deep Eutectic Solvents Formed between Choline ChlorideandCarboxylic Acids: Versatile Alternatives to Ionic Liquids. Abbott, Andrew P., Boothby, David, Capper, Glen.American Chemical Society,Vol.126 No.29. 2004 |
| Deep Eutectic Solvents Formed between Choline ChlorideandCarboxylic Acids: Versatile Alternatives to Ionic Liquids. Abbott, Andrew P., Boothby, David,Capper, Glen.American Chemical Society,Vol.126 No.29. 2004 * |
| 利用酒石制取天然右旋酒石酸铵工艺的研究. 郝立勇，朱晓慧.精细化工，第19卷第3期. 2002 |
| 利用酒石制取天然右旋酒石酸铵工艺的研究. 郝立勇，朱晓慧.精细化工，第19卷第3期. 2002 * |
| 化工辞典. 王箴，第444页左栏第2-6行、第1074页左栏第39-43行、第685页右栏第15-19行、第1098页右栏第31-39行，化学工业出版社. 2003 |
| 石蜡乳液的制备及影响因素探讨. 应向东，张声光.建筑人造板，第4期. 1996 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1854120A (en) | 2006-11-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100490898C (en) | Non-toxic ionic liquid, preparation method and its application | |
| CN100526289C (en) | Non-toxic ion liquid its production and use | |
| CN103450304B (en) | For obtaining the 17 α-monoesters of cortexolone and/or its 9, the enzyme process of 11-dehydro derivatives | |
| CH615668A5 (en) | ||
| CN100506208C (en) | Chansu-loaded nanoliposome and preparation method thereof | |
| EP1535916B1 (en) | Inclusion complexes of butylphthalide with cyclodextrin derivatives and processes for their preparation | |
| US9006215B2 (en) | Pharmaceutical preparation comprising propofol salt and cyclodextrin | |
| CN104273522A (en) | Curcumin nanor compound and preparation method thereof | |
| EP1132395B1 (en) | Process for the preparation of a pharmacologically active peptide | |
| CN111296729B (en) | Water-soluble astaxanthin product and preparation method thereof | |
| CN112574146A (en) | Preparation method of butenolide compound composite nanocrystal | |
| KR950006218B1 (en) | Freeze-dried pharmaceutical compositions of phenyl quinoline crboxylic acids | |
| CN107936080B (en) | Method for extracting ursolic acid in cynomorium songaricum by using eutectic solvent/salt aqueous two-phase system | |
| CN106176769B (en) | Long-acting veterinary Ursocycline injection and preparation method thereof | |
| CN102964377A (en) | Method for preparing natural L-alpha-glycerol phosphatidylcholine | |
| EP0004522B1 (en) | New compounds related to dilignols, compounds related to dilignols for use in the treatment of liver deseases and pharmaceutical compositions containing them | |
| EP0112451A2 (en) | Prostaglandin and hydroxylated fatty acid ester formulations | |
| EP1140197B1 (en) | Soluble compositions of toremifene | |
| JP6265550B2 (en) | Ascorbic acid derivative composition and method for producing the same, ascorbic acid derivative solution, and external preparation for skin | |
| CN102861532B (en) | Octadecanol glucose gemini surfactant and preparation method thereof | |
| EP2782666B1 (en) | Derivatives of tris(2-hydroxyphenyl)methanes, the production thereof and use thereof for oil production | |
| CN107028890A (en) | A kind of characteristics of indomethacin solid dispersion | |
| CN112791072B (en) | Asarin nanocrystallization method | |
| WO2011104631A1 (en) | Sn-38 compositions | |
| CN114010595A (en) | Butylphthalide emulsion and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Assignee: Shijiazhuang Baiqi Chemical Co., Ltd. Assignor: Hebei Normal University Contract record no.: 2010130000090 Denomination of invention: Non-toxic ionic liquid, preparation method and its application Granted publication date: 20090812 License type: Exclusive License Open date: 20061101 Record date: 20100830 |
|
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090812 Termination date: 20121206 |