CN114716655B - Process for preparing lactide-glycolide copolymer - Google Patents
Process for preparing lactide-glycolide copolymer Download PDFInfo
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- 229920001577 copolymer Polymers 0.000 title claims abstract description 29
- 238000004519 manufacturing process Methods 0.000 title claims description 18
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims abstract description 124
- 238000006243 chemical reaction Methods 0.000 claims abstract description 102
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 99
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims abstract description 54
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims abstract description 50
- 239000004310 lactic acid Substances 0.000 claims abstract description 49
- 235000014655 lactic acid Nutrition 0.000 claims abstract description 49
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 22
- 238000006068 polycondensation reaction Methods 0.000 claims abstract description 20
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- 230000018044 dehydration Effects 0.000 claims abstract description 18
- 238000010438 heat treatment Methods 0.000 claims abstract description 11
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 9
- 238000005303 weighing Methods 0.000 claims abstract description 7
- 238000005070 sampling Methods 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 57
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 51
- 239000008215 water for injection Substances 0.000 claims description 43
- 238000003756 stirring Methods 0.000 claims description 40
- 238000000034 method Methods 0.000 claims description 39
- 239000000126 substance Substances 0.000 claims description 30
- 238000001035 drying Methods 0.000 claims description 25
- 239000002244 precipitate Substances 0.000 claims description 23
- 239000003054 catalyst Substances 0.000 claims description 22
- 238000001816 cooling Methods 0.000 claims description 17
- 238000001556 precipitation Methods 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 13
- 230000035484 reaction time Effects 0.000 claims description 11
- 238000007670 refining Methods 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 5
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 238000009826 distribution Methods 0.000 abstract description 19
- 239000000463 material Substances 0.000 abstract description 10
- 238000013268 sustained release Methods 0.000 abstract description 6
- 239000012730 sustained-release form Substances 0.000 abstract description 6
- 229960000448 lactic acid Drugs 0.000 description 42
- 239000000047 product Substances 0.000 description 26
- 230000001276 controlling effect Effects 0.000 description 22
- 229920000642 polymer Polymers 0.000 description 21
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 13
- 208000005156 Dehydration Diseases 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 10
- 238000001125 extrusion Methods 0.000 description 9
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 9
- 239000003814 drug Substances 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000006116 polymerization reaction Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 238000003760 magnetic stirring Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- 229920000954 Polyglycolide Polymers 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000004633 polyglycolic acid Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 229920001519 homopolymer Polymers 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 108010000817 Leuprolide Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000003763 carbonization Methods 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 2
- 229960004338 leuprorelin Drugs 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 238000007151 ring opening polymerisation reaction Methods 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- 235000011150 stannous chloride Nutrition 0.000 description 2
- 239000001119 stannous chloride Substances 0.000 description 2
- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical compound [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 description 2
- 210000002268 wool Anatomy 0.000 description 2
- 238000004383 yellowing Methods 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- 208000034530 PLAA-associated neurodevelopmental disease Diseases 0.000 description 1
- CANRESZKMUPMAE-UHFFFAOYSA-L Zinc lactate Chemical compound [Zn+2].CC(O)C([O-])=O.CC(O)C([O-])=O CANRESZKMUPMAE-UHFFFAOYSA-L 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000011952 anionic catalyst Substances 0.000 description 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical class [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- VUZPPFZMUPKLLV-UHFFFAOYSA-N methane;hydrate Chemical compound C.O VUZPPFZMUPKLLV-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- -1 oligomers Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000010815 organic waste Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012885 slow-release drug carrier Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000012974 tin catalyst Substances 0.000 description 1
- MCULRUJILOGHCJ-UHFFFAOYSA-N triisobutylaluminium Chemical compound CC(C)C[Al](CC(C)C)CC(C)C MCULRUJILOGHCJ-UHFFFAOYSA-N 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 229940050168 zinc lactate Drugs 0.000 description 1
- 235000000193 zinc lactate Nutrition 0.000 description 1
- 239000011576 zinc lactate Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/78—Preparation processes
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
- C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
- C08G63/08—Lactones or lactides
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Polyesters Or Polycarbonates (AREA)
Abstract
The invention provides a preparation method of a lactide-glycolide copolymer, which comprises the following steps: (1) lactic acid dehydration: heating and dehydrating lactic acid to obtain dehydrated lactic acid with water content below 2wt%; (2) prepolymerization: adding the dehydrated lactic acid and the glycolic acid into a reactor with a condenser pipe according to the proportion of the comonomer in the lactide-glycolide copolymer for prepolymerization, wherein the temperature of the condenser pipe is controlled in two stages, the lactide steam, the lactic acid steam and the water steam are respectively condensed and respectively received for weighing, the reaction end point is determined according to the amount of the condensed water, and the lactic acid loss amount is calculated according to the total amount of the condensed lactide and lactic acid; (3) polycondensation reaction: adding lactide in an amount corresponding to the lactic acid loss amount to the reaction product of the step (2), and determining the reaction end point by sampling and measuring viscosity and molecular weight. The preparation method can stably produce the pharmaceutical grade sustained-release auxiliary material with components meeting design requirements, controllable molecular weight, narrow molecular weight distribution and high purity.
Description
Technical Field
The invention relates to a preparation method of a lactide-glycolide copolymer.
Background
Lactide-glycolide copolymer (PLGA) is a polymer material chemically synthesized by using Lactic Acid (LA) and Glycolic Acid (GA) as raw materials, and has the following characteristics: the product is nontoxic, non-irritating, has good biocompatibility in vivo, is bioabsorbable, and the degradation products are carbon dioxide and water. Different monomer ratios can produce different types of PLGA, for example: PLGA 75:25 means that the polymer consists of 75% lactic acid and 25% glycolic acid. The regulation and control of the degradation rate of the polymer can be realized to a certain extent by regulating the molecular weight of the copolymer and the content ratio of LA to GA in the copolymer. The preparation method has the advantages of good biocompatibility, adjustability of degradation rate and the like, and is widely applied to the medical fields of slow-release drug carriers and the like.
Glycolide-lactide copolymer (25:75) of multiple enterprises in China can be co-examined with the preparation on a registration information display platform of raw medicines, pharmaceutical excipients and medicine package materials. The lactide-glycolide copolymer (75:25) (for injection) was carried in the first supplementary edition of the 2015 edition of the chinese pharmacopoeia and the 2020 edition of the chinese pharmacopoeia, together with the lactide-glycolide copolymer (85:15) (for injection) and the lactide-glycolide copolymer (50:50) (for injection). The FDA Inactive ingredient database in the United states has incorporated lactide-co-glycolide (75:25) and lactide-co-glycolide (50:50). PLGA has been approved by the FDA and European drug administration as a pharmaceutical excipient for formulations such as microspheres for injection, implants, gels, and the like. In 1989, the FDA approved the first long-acting formulation of leuprorelin with PLGA (75:25) as carrier. Up to 19 PLGA sustained-release injections approved by the FDA for sale by 2019 have been available.
There are more than 40 manufacturers of PLGA, abbot, takeda, GP, astellas, etc., among the major manufacturers abroad. The national food and drug administration approved the imitation varieties of the leuprorelin injection sustained-release microspheres by the stock company of the Beijing Boen Tex pharmaceutical industry and the Shanghai Lizhu pharmaceutical Co., respectively, until 7 and 8 months in 2009.
Among them, shanghai Lizhu pharmaceutical Co.Ltd mainly uses self-produced lactide-glycolide copolymer (75:25) (1 month dosage form). The imitated drug consistency evaluation guiding principle not only requires the same curative effect as the original drug for the imitated sustained release preparation in China, but also enables the in-vitro and in-vivo release curve to be basically consistent with the original drug. Besides higher requirements on the stability of the production process of the sustained-release preparation, higher requirements are also put on the quality (the size of molecular weight, the molecular weight distribution, the crystal form and the ratio of LA to GA in the copolymer) of key sustained-release auxiliary materials. The above quality factors have a direct effect on the in vivo release period and release profile of the drug, and it is imperative that the quality differences between batches be kept as consistent as possible. The stability and reliability of the PLGA production process is particularly important.
The current production technology for preparing PLGA slow-release materials has great progress under the continuous efforts of technological workers at home and abroad, and related documents and patents at home and abroad are numerous. The reaction system is largely classified into liquid phase polycondensation, melt polycondensation and solid phase polycondensation. From the classification of the starting materials, two main categories are as follows:
the method comprises the following steps: direct melt polycondensation (one-step process)
For example, references:
1. wangzeng, wang Rui, zhu Zhiguo, dong Zhenfeng chain extension reaction studies of L-lactic acid-glycolic acid copolymers, polyester industry, vol.23, 2 nd, 2010-03
2. Chen Dehui, wang Rui, zhu Zhiguo, zhang Cheng preparation of high molecular weight poly L-lactic acid-glycolic acid and its properties, textile journal, vol.32, 9 th, 2011, 9 th month
3. Wang Chaoyang, zhao Yaoming, principals, influence of lactic acid of different configurations on direct melt copolymerization products of lactic acid-glycolic acid, material science and engineering report, general 94 th, volume 23, apr.2005, vol.2.3 No.2
4. Wei Zhiyong, liu Lian, zhang Meng, etc., preparation of polylactic acid, lactic acid-glycolic acid copolymer and in vitro degradation thereof, journal of biomedical engineering, volume 25, 1 st 2008, 2 nd month
5. Lv Li, ding Xiaohui, lin Guoliang solid-phase polymerization studies of polylactic acid-glycolic acid, vol.52, 5 th 2013, 9 months of the university of Xiamen (Nature science edition)
6. Wang Ning Ind, reviewed in methods for preparing lactic acid-glycolic acid copolymers, wool spinning technology, vol.46, 9, 2018, 9
Related patent:
CN201110237778.0、CN200410065149.4、CN201310295018.4、CN201110355215.1、CN201910896204.0；
the second method is as follows: ring-opening polymerization method (two-step method)
For example, related patents:
CN200810032196.7、CN201710126988.X、CN201910244772.2、CN201910505426.5。
among them, the related literature and patent of the one-step method all use DL-lactic acid and glycollic acid as raw materials, and adopt direct melt polycondensation method to synthesize. The synthetic process flow is as follows: DL-lactic acid and glycolic acid are mixed, dehydrated, prepolymerized, polycondensed, refined, dried and finished product is obtained. The synthesis process has the advantages that: simple operation, low cost and high product purity. However, higher vacuum levels are required, especially in the later stages of increasing viscosity, stirring and water removal are difficult, resulting in difficulty in synthesizing higher molecular weight polymers (suitably less than 40000), and long reaction times.
The related patents of the two-step method are to take DL-lactide and glycolide as raw materials, to synthesize by a solid phase polycondensation method, or to synthesize PLA and PGA homopolymers with certain molecular weight by a direct melt polycondensation method, to purify the homopolymers, and then to carry out solid phase polycondensation. The synthetic process flow is as follows: DL-lactide, glycolide (or PLA, PGA), ring-opening polycondensation, refining, drying and obtaining the final product. The synthesis process has the advantages of being capable of synthesizing copolymer with higher molecular weight (the molecular weight can reach 4-10 ten thousand), short in reaction time and low in vacuum degree requirement. But the synthesis process is complex, low homopolymers or dimers are needed to be synthesized respectively, the production period is long, the material cost is high, and the yield is low.
The ring-opening homopolymerization reaction proposed in document 6 (Wang Ning, yi will, reviewed in the preparation methods of lactic acid-glycolic acid copolymers, wool spinning technology, volume 46, 9 th, 2018, 9 th) is not suitable for industrialization because the process of synthesizing the hexacyclic glycolide-lactide monomer is complicated and the cost is high. The other documents and patents provide production process technologies which are random copolymerization reactions, the produced polymers are random copolymers, the structure is irregular, the composition proportion of the final polymers is controlled only by adopting a feeding ratio mode, the composition ratio difference between the produced finished product batches is large, even the composition ratio is far from the designed composition ratio, and the degradation performance is unstable. The stable production of the sustained-release auxiliary material meeting the design requirements cannot be ensured.
Disclosure of Invention
Therefore, the invention aims to provide a preparation method of lactide-glycolide copolymers (for example, 80:20, 75:25, 50:50 and the like) with different compositions, which aims to ensure that pharmaceutical grade sustained release auxiliary materials with components meeting design requirements, controllable molecular weight, narrow molecular weight distribution and high purity are stably produced.
The invention provides a preparation method of a lactide-glycolide copolymer, which comprises the following steps:
(1) Lactic acid dehydration: heating lactic acid to 110-130 ℃, and dehydrating under the vacuum degree of minus 0.06-minus 0.1MPa to obtain dehydrated lactic acid with the water content of below 2 wt%;
(2) Prepolymerization reaction: adding the dehydrated lactic acid and the glycolic acid into a reactor with a condensing tube according to the proportion of the comonomer in the lactide-glycolide copolymer, adding a molecular weight regulator, heating to 130-150 ℃, and performing prepolymerization under the vacuum degree of minus 0.08-minus 0.1MPa, wherein the temperature of the condensing tube is controlled in two stages, so that lactide steam, lactic acid steam and water steam are respectively condensed and respectively received and weighed, the reaction end point is determined according to the amount of condensed water, and the lactic acid loss amount is calculated according to the total amount of the condensed lactide and lactic acid;
(3) Polycondensation reaction: adding lactide with the amount corresponding to the lactic acid loss amount into the reaction product of the step (2), adding a catalyst, reacting at 150-170 ℃ and a vacuum degree of minus 0.08-minus 0.1MPa, and determining the reaction end point by sampling and measuring the viscosity and the molecular weight.
The steps of the production method of the present invention will be described in detail below.
Lactic acid dehydration
According to the preparation method provided by the invention, the water content of the lactic acid can be 10-15 wt%. In a preferred embodiment of the present invention, the step (1) further comprises collecting condensed water obtained by dehydration and weighing to determine the degree of dehydration. Preferably, the dehydration time of the step (1) is 1 to 2 hours.
In the existing preparation method of the lactide-glycolide copolymer, lactic acid and glycolic acid with different proportions are placed in a reaction bottle with magnetic stirring for mixing, and then a catalyst is added for reaction for 3-4 hours. In the process, not only the free water in the lactic acid is removed, but also the intramolecular or intermolecular dehydration reaction is carried out. After the reaction is finished, the products in the system include lactic acid, glycolic acid, glycolide, lactide, oligomers, water and the like. The dewatering effect is difficult to evaluate and control. If the dehydration is insufficient, an excessive amount of free water participates in the next condensation reaction, resulting in difficulty in proceeding the forward reaction. Meanwhile, the components of the system are complex, so that the later polycondensation reaction is complex, the sequence of the produced finished product is complex, the crystal form is complex, and the quality of the finished product is difficult to control and repeat. In the method of the present invention, only lactic acid is dehydrated first, in order to remove 10 to 15% of water in lactic acid as much as possible. Because the dehydration is carried out at a low temperature of 110-130 ℃, no catalyst is added, and the intramolecular or intermolecular dehydration reaction is hardly carried out in the dehydration process.
In addition, in a preferred embodiment of the present invention, the dehydration treatment is performed using a rotary evaporator. The dehydration efficiency of the rotary evaporator is higher than that of magnetic stirring, and the reaction time is short, so that the product in the system basically only contains lactic acid and a small amount of oligomers after the dehydration treatment is finished, the later polycondensation reaction is facilitated, the sequence of the finished product is more regular than that of the prior art, and the crystal form is single.
Prepolymerization reaction
According to the preparation method provided by the invention, the temperature of the condensation pipe in the step (2) can be-5 ℃. Preferably, the temperature of the condensing tube is controlled to be 4-5 ℃ and-5-0 ℃ in sequence in two stages from one end close to the reactor.
In a preferred embodiment of the present invention, the theoretical water yield in step (2) when the amount of condensed water is equal to the molecular weight of the oligomers of 7000 to 8000 produced by polymerization of lactic acid and glycolic acid is the reaction endpoint. Preferably, the time for the pre-polymerization in step (2) is 1 to 3 hours.
According to the preparation method provided by the invention, the molecular weight regulator in the step (2) can be a phosphoric acid and/or lactic acid solution with the weight of 5-20wt%.
According to the preparation method provided by the invention, the glycolic acid and the molecular weight distribution regulator are added in the step (2), and the temperature is slightly increased compared with the step (1). Due to the low viscosity, mixing can be performed using a rotary evaporator. The lactic acid is subjected to the early dehydration treatment, so that the free water is extremely low, the lactic acid concentration is high, and the forward reaction can be promoted to be rapidly carried out. The temperature of the condensing tube is controlled to be-5 ℃ in the reaction process, and the condensing temperature is controlled in a sectional way, so that the lactide steam is separated from the lactic acid steam and the water steam when the lactide steam is removed. In addition, as the interference of free water in the lactic acid is avoided, the weight of condensed water in the receiving bottle can be calculated by weighing in the reaction process, and the polymerization degree can be estimated by calculating. The weight of the lactic acid and lactide condensed on the condensation sleeve is calculated, and the loss of the lactic acid is estimated through calculation, so that data is provided for the next step of supplementing raw materials. The pretreatment of a large amount of free water (10-15%) in the raw material lactic acid eliminates the biggest adverse factor of forming the oligomer, the oligomer is rapidly generated, and the intrinsic viscosity can reach about 10ml/g after 3-4 hours of reaction, and the molecular weight is about 7000.
Polycondensation reaction
According to the preparation method provided by the invention, the catalyst in the step (3) can be selected from high-activity tin catalyst systems (stannous chloride, stannous octoate, stannous iso-octoate and the like); proton acid catalysts (sulfuric acid, phosphoric acid, etc.); organic acid catalyst: p-toluenesulfonic acid and the like; composite catalyst: zinc lactate and p-toluenesulfonic acid, stannous chloride and p-toluenesulfonic acid, etc.; a halide: zinc chloride, and the like; anionic catalyst: triisobutylaluminum, and the like.
In a preferred embodiment of the present invention, the step (3) further comprises using a reactor having a condenser, a drying column and a vapor receiving device, and controlling the temperature of the condenser to be less than or equal to-20 ℃.
In a preferred embodiment of the present invention, the step (3) may further include: after 3 hours of reaction, sampling and measuring viscosity and molecular weight at intervals, and stopping the reaction after the reaction is determined to be required. Preferably, the reaction time in step (3) is 3 to 6 hours.
In the existing preparation method, after the dehydration reaction is finished, a catalyst is added, the temperature is raised to a higher temperature, the vacuum degree is controlled, and the polycondensation reaction is directly carried out until the reaction is finished. The reaction temperature is above 160 ℃, the early stage mainly comprises the generation of polyglycolic acid (PGA), the reaction is faster, the stirring capability of magnetic stirring is challenged along with the continuous increase of the viscosity, the stirring is insufficient, the participation probability of the oligomer in the reaction is reduced, and the conversion rate is lower. The residual free water of lactic acid and water molecules generated by the reaction need to be removed in time, the vacuum degree is also very high, the vacuum degree is not reached, the reaction time is greatly prolonged and even the reaction is stopped, the high polymer is degraded at high temperature, and the low polymer is darkened by carbonization. It becomes very difficult to maintain a sufficient stirring ability and an extremely high vacuum degree throughout the reaction production, particularly in the latter stages of the reaction. At higher temperatures, the long reaction times (more than 16 hours), the formation of steam and water vapor together with the oligomeric lactide at low vacuum is eliminated, a process which is difficult to control. If too much lactide is lost, this directly results in a final polymer with a proportion of components that do not meet the design requirements.
The polycondensation reaction in step (3) of the present invention is carried out on the basis of a prepolymerization reaction. After the prepolymerization reaction is finished, the total loss amount of lactic acid and lactide is obtained, and the lactide added with a proper amount (the loss amount in the polymerization reaction process can be considered at the same time) is calculated. The high-purity lactide is fed before the polymerization reaction starts, so that the loss of lactic acid in the reaction process is compensated, and the defect that the components of the finished product do not meet the design requirements due to insufficient lactide can be effectively avoided. And (3) heating to 150-170 ℃ again in a small range, so that the risk that the high polymer is degraded at high temperature and the color of the low polymer is darkened by carbonization is avoided.
In a preferred embodiment of the invention, a drying tower and a steam receiving device are arranged, the temperature of a condensing pipe is controlled to be less than or equal to minus 20 ℃, and the vacuum degree is controlled to be less than or equal to minus 0.1MPa for reaction. The low vacuum ensures that trace moisture generated by the condensation reaction is timely extracted. And a condensing pipe, a steam receiving device and a drying tower are also arranged in sequence, so that the pumped water is ensured to be cooled and received in time. The drying tower will not be thoroughly absorbed by the cooled and received water vapor. The combined device can effectively capture and absorb the water vapor, and effectively avoid the water backflow caused by factors such as vacuum fluctuation, sampling and the like of the extracted water vapor. Ensures that the polymerization reaction always proceeds in the forward direction.
In a preferred embodiment of the invention, after about 2 hours of reaction in step (3), samples are taken to measure viscosity and molecular weight. Stopping the reaction after the molecular weight reaches the requirement. And the judgment of the reaction end point is based on the measured molecular weight, so that the molecular weight of the final finished product is accurately controlled, and the large difference caused by controlling the reaction end point by only adopting the intrinsic viscosity is avoided.
The preparation method provided by the invention can further comprise the step of (4) refining: cooling the reactant, dissolving the reactant with acetone, pouring the dissolved substance into water for injection at 60-80 ℃, stirring and separating out, extruding the precipitate, dissolving the precipitate with acetone, pouring the dissolved substance into 90-99% medicinal ethanol for precipitation, extruding the precipitate, repeatedly washing and extruding the precipitate with ethanol for 2-5 times, and drying.
In the existing preparation method, after the reaction is finished, organic solvents such as acetone, chloroform and the like are adopted for dissolution, or the mixture is cooled and crushed, and then the mixture is added into deionized water, diethyl ether or ethanol for precipitation extraction, so that impurities such as lactic acid, glycollic acid, catalyst and the like are removed. The process requires more organic solvent and generates more organic waste liquid; the finished product impurities are out of standard because the impurities wrapped in the particles are difficult to wash out by adding the cooled and crushed powder into deionized water or ethanol for washing.
The preparation method of the invention adopts a small amount of acetone to dissolve the reactant after cooling. Slowly pouring the dissolved substances into water for injection at 60-80 ℃, stirring and separating out, removing impurities such as small molecules, polar substances and the like, and simultaneously removing inorganic substances such as heavy metal arsenic salt and the like. Extruding the precipitate, dissolving with small amount of acetone, precipitating the solution with 95% medicinal ethanol to remove lactide and glycolide as macromolecular impurities, extruding the precipitate, repeatedly washing with ethanol, extruding for 2-5 times, and vacuum drying at 35-45deg.C to obtain the final product. The refining process of the invention adopts a small amount of acetone for dissolution, and a large amount of injection water is used for precipitation, so that the use amount of organic solvents is reduced and polar impurities are fully removed.
The finished product prepared by the invention meets the quality standard of Chinese pharmacopoeia, and specific indexes can comprise one or more of molecular weight distribution, molar ratio, viscosity, properties, microorganisms, endotoxin, lactide residue, glycolide residue, ethanol residue, acetone residue and infrared identification product. The lactide-glycolide copolymer prepared by the method has good and controllable molecular weight, molecular weight distribution, polymer component ratio, residue and other indexes, and the process is reliable.
Detailed Description
The following detailed description of the invention is provided in connection with the accompanying drawings that are presented to illustrate the invention and not to limit the scope thereof.
In the following examples, 0.25 liter of DL-lactic acid (85%) and 75 g of glycolic acid (content. Gtoreq.98%) were used as raw materials, and it was calculated that the water content of lactic acid was reduced to 2% or less in step (1), and that it was necessary to obtain 39ml or more of condensed water. Taking a lactide-glycolide copolymer with the ratio of 75:25 as an example, the intrinsic viscosity after the reaction in the step (2) needs to reach about 10ml/g, and the condensate water needs to be more than or equal to 70ml; the reaction intrinsic viscosity of the step (3) needs to reach about 16ml/g, and the molecular weight reaches 12500-13000.
The molecular weight regulator used in the following examples and comparative examples was a 10wt% phosphoric acid solution and the catalyst was a 0.1wt% stannous octoate solution.
Example 1
(1) The DL-lactic acid (0.25L) is placed in a reaction bottle of a rotary evaporator, heated to 120 ℃ in an oil bath, and reacted for 2 hours under the vacuum degree of-0.07 MPa to obtain 39ml of condensed water, and the reaction is ended.
(2) 75 g of glycolic acid was added to the reaction flask with stirring, and the molecular weight regulator was added and the temperature was controlled to 130 ℃. A cooling jacket (controlling the temperature of the condenser tube 1 at 5 ℃ and the temperature of the condenser tube 2 at 0 ℃) is arranged, and the vacuum degree is controlled to rotate for 3 hours under-0.08 MPa. The intrinsic viscosity reached about 7.1ml/g, 63ml of condensed water was obtained, and the weight of the condensate on the condenser jacket was about 10 g, to terminate the reaction.
(3) An appropriate amount (12 g) of lactide was weighed, added to a reaction flask with stirring, catalyst was added, and the temperature was raised to 170 ℃. And (3) installing a condensing pipe, a drying tower and a steam receiving device, controlling the temperature of the condensing pipe to be minus 25 ℃, and stirring and reacting for 6 hours under the vacuum degree of minus 0.1MPa. The intrinsic viscosity was found to be about 16.8ml/g, the molecular weight was 12800, and the reaction was terminated.
Examples2
(1) The DL-lactic acid (0.25L) is placed in a reaction bottle of a rotary evaporator, heated to 120 ℃ in an oil bath, and reacted for 1.5 hours under the vacuum degree of-0.08 MPa to obtain 40ml of condensed water, and the reaction is ended.
(2) 75 g of glycolic acid was added to the reaction flask with stirring, and the molecular weight regulator was added and the temperature was controlled to 145 ℃. A cooling jacket (controlling the temperature of the condenser tube 1 at 5 ℃ and the temperature of the condenser tube 2 at 0 ℃) is arranged, and the vacuum degree is controlled to rotate for 3 hours under-0.09 MPa. The intrinsic viscosity reached about 9.7ml/g, 73ml of condensate was obtained, the condensate weight on the condenser jacket was about 12 g, and the reaction was terminated.
(3) An appropriate amount (12 g) of lactide was weighed, added to a reaction flask with stirring, catalyst was added, and the temperature was raised to 160 ℃. And (3) installing a condensing pipe, a drying tower and a steam receiving device, controlling the temperature of the condensing pipe to be minus 20 ℃, and stirring and reacting for 6 hours under the vacuum degree of minus 0.1MPa. The reaction was terminated by measuring about 26ml/g of intrinsic viscosity and 30000 of molecular weight.
(4) After cooling the reaction product, it was dissolved in 300ml of acetone. Taking 75ml of the dissolved substance, slowly pouring the dissolved substance into water for injection at 60-80 ℃, and stirring and separating out the dissolved substance. When the water for injection is turbid, the water for injection is replaced until all water for injection is separated out, 75ml of acetone is used for redissolving after extrusion, 750ml of 95% medicinal ethanol is used for precipitation, after the precipitate is extruded, ethanol is used for repeatedly washing and extruding for 3 times, and finally, 41 g of finished product is obtained after vacuum drying at 35-45 ℃. The molar ratio, molecular weight distribution, viscosity of lactide to glycolide in the polymer were determined.
Example 3
(1) The DL-lactic acid (0.25L) is placed in a reaction bottle of a rotary evaporator, heated to 130 ℃ in an oil bath, and reacted for 1 hour under the vacuum degree of minus 0.1MPa to obtain 42ml of condensed water, and the reaction is ended.
(2) 75 g of glycolic acid was added to the reaction flask with stirring, and the molecular weight regulator was added and the temperature was controlled to 155 ℃. A cooling jacket (controlling the temperature of the condenser tube 1 at 5 ℃ and the temperature of the condenser tube 2 at 0 ℃) is arranged, and the vacuum degree is controlled to rotate for 3 hours under-0.1 MPa. The intrinsic viscosity reached about 10.2ml/g, 75ml of condensed water was obtained, the weight of the condensate on the condensation jacket was about 15 g, and the reaction was terminated.
(3) An appropriate amount (15 g) of lactide was weighed, added to a reaction flask with stirring, catalyst was added, and the temperature was raised to 160 ℃. And (3) installing a condensing pipe, a drying tower and a steam receiving device, controlling the temperature of the condensing pipe to be minus 20 ℃, and stirring and reacting for 6 hours under the vacuum degree of minus 0.1MPa. The intrinsic viscosity was measured to be about 17.1ml/g, and the molecular weight was 13000, whereby the reaction was terminated.
Example 4
(1) And (3) placing 0.25L of DL-lactic acid into a reaction bottle of a rotary evaporator, heating an oil bath to 120 ℃, adding a catalyst, controlling the vacuum degree to be-0.08 MPa, reacting for 1.5 hours, obtaining 60ml of condensed water, and ending the reaction.
(2) 75 g of glycolic acid was added to the reaction flask with stirring, and the molecular weight regulator was added and the temperature was controlled to 155 ℃. A cooling jacket (controlling the temperature of the condenser tube 1 at 5 ℃ and the temperature of the condenser tube 2 at 0 ℃) is arranged, and the vacuum degree is controlled to rotate for 3 hours under-0.1 MPa. The intrinsic viscosity reached about 10.2ml/g, 61ml of condensate was obtained, the condensate weight on the condenser jacket was about 14 g, and the reaction was terminated.
(3) An appropriate amount (14 g) of lactide was weighed, added to a reaction flask with stirring, catalyst was added, and the temperature was raised to 160 ℃. And (3) installing a condensing pipe, a drying tower and a steam receiving device, controlling the temperature of the condensing pipe to be minus 20 ℃, and stirring and reacting for 6 hours under the vacuum degree of minus 0.1MPa. The reaction was terminated by measuring about 16.1ml/g of intrinsic viscosity and 12050 of molecular weight.
Example 5
(1) The DL-lactic acid (0.25L) is placed in a reaction bottle of a rotary evaporator, heated to 120 ℃ in an oil bath, and reacted for 1.5 hours under the vacuum degree of-0.08 MPa to obtain 40ml of condensed water, and the reaction is ended.
(2) 75 g of glycolic acid was added to the reaction flask with stirring, and the molecular weight regulator was added and the temperature was controlled to 145 ℃. A cooling jacket (controlling the temperature of the condenser tube 1 at 5 ℃ and the temperature of the condenser tube 2 at 0 ℃) is arranged, and the vacuum degree is controlled to rotate for 3 hours under-0.09 MPa. The intrinsic viscosity reached about 9.8ml/g, 74ml of condensate was obtained, the condensate weight on the condenser jacket was about 12 g, and the reaction was terminated.
(3) An appropriate amount (12 g) of lactide was weighed, added to a reaction flask with stirring, catalyst was added, and the temperature was raised to 160 ℃. And (3) installing a condensing pipe, a drying tower and a steam receiving device, controlling the temperature of the condensing pipe to be minus 20 ℃, and stirring and reacting for 3 hours under the vacuum degree of minus 0.1MPa. The intrinsic viscosity was found to be about 16.3ml/g, the molecular weight was found to be 12300, and the reaction was terminated.
(4) After cooling the reaction product, it was dissolved in 300ml of acetone. Taking 75ml of the dissolved substance, slowly pouring the dissolved substance into water for injection at 60-80 ℃, and stirring and separating out the dissolved substance. When the water for injection is turbid, the water for injection is replaced until all the water for injection is separated out, 75ml of acetone is used for redissolving after extrusion, then the water for injection is slowly poured into the water for injection at 60-80 ℃ and stirred for separation out. And (3) repeatedly washing and extruding the precipitate for 3 times by using water for injection, and finally drying the precipitate in vacuum at 35-45 ℃ to obtain 45 g of finished product. The molar ratio of lactide to glycolide, the molecular weight distribution, and the lactide+glycolide residue in the polymer were determined. The relevant parameters and results are listed in tables 1 and 2.
Example 6
75ml of the acetone solution obtained in the step (4) of example 5 was slowly poured into water for injection at 60 to 80℃and stirred to precipitate. When the water for injection is turbid, the water for injection is replaced until all water for injection is separated out, 75ml of acetone is used for redissolving after extrusion, the dissolved substance is poured into 750ml of 95% medicinal ethanol for precipitation, the precipitate is extruded, the ethanol is used for repeatedly washing and extruding for 3 times, and finally, 40 g of finished product is obtained after vacuum drying at 35-45 ℃. The molar ratio of lactide to glycolide, the molecular weight distribution, and the lactide+glycolide residue in the polymer were determined. The relevant parameters and results are listed in tables 1 and 2.
Example 7
75ml of the acetone solution obtained in the step (4) of example 5 was slowly poured into water for injection at 2 to 8℃and stirred to precipitate. When the water for injection is turbid, the water for injection is replaced until all water for injection is separated out, 75ml of acetone is used for redissolving after extrusion, the dissolved substance is poured into 750ml of 95% medicinal ethanol for precipitation, the precipitate is extruded, the ethanol is used for repeatedly washing and extruding for 3 times, and finally 43 g of finished product is obtained after vacuum drying at 35-45 ℃. The molar ratio of lactide to glycolide, the molecular weight distribution, and the lactide+glycolide residue in the polymer were determined. The relevant parameters and results are listed in tables 1 and 2.
Example 8
75ml of the acetone solution obtained in the step (4) of example 5 was slowly poured into 750ml of 95% medicinal ethanol to precipitate, and the precipitate was stirred to precipitate. When turbidity appears, the ethanol is replaced until all the ethanol is separated out. And (3) re-dissolving the mixture by 75ml of acetone after extrusion, pouring the dissolved substance into 750ml of 95% medicinal ethanol for precipitation, repeatedly washing and extruding the precipitate by ethanol for 3 times after extrusion, and finally, drying the precipitate in vacuum at 35-45 ℃ to obtain 30 g of finished product. The molar ratio of lactide to glycolide, the molecular weight distribution, and the lactide+glycolide residue in the polymer were determined. The relevant parameters and results are listed in tables 1 and 2.
Example 9
Synthesis of lactide-glycolide copolymer (8020)
Taking DL-lactic acid (85%) 0.25L, placing into a reaction bottle of a rotary evaporator, heating to 120 ℃ in an oil bath, controlling the vacuum degree at-0.08 MPa, and reacting for 1.5 hours. 42ml of condensed water is obtained to meet the requirement. Weighing 54 g of glycolic acid (the content is more than or equal to 98 percent), adding the glycolic acid into a reaction bottle under stirring, mixing, adding a molecular weight regulator, and controlling the temperature to 145 ℃. A cooling jacket (temperature 5 ℃ C. Of the condenser tube 1, temperature 0 ℃ C. Of the condenser tube 2) was installed, and the vacuum was controlled to rotate at-0.09 for 4 hours. The intrinsic viscosity reaches about 9.0ml/g, and 68ml of condensed water is obtained. The condensate on the condenser jacket weighed about 13 grams. Weighing a proper amount of lactide, adding the lactide into a reaction bottle under stirring, adding a catalyst, and heating to 160 ℃. And (3) installing a drying tower and a steam receiving device, controlling the temperature of a condensing tube to be minus 20 ℃, and stirring and reacting for 6 hours under the vacuum degree of minus 0.1MPa. After the reaction, the mixture was purified by the procedure of example 1, and dried to obtain 170 g of a final product. The intrinsic viscosity was about 16.0ml/g and the molecular weight was 12000.
Example 10
Synthesis of lactide-glycolide copolymer (5050)
Taking DL-lactic acid (85%) 0.25L, placing into a reaction bottle of a rotary evaporator, heating to 120 ℃ in an oil bath, controlling the vacuum degree at-0.08 MPa, and reacting for 1.5 hours. 39ml of condensed water is obtained to meet the requirement. 216 g of glycolic acid (content not less than 98%) are weighed, added into a reaction bottle under stirring, mixed, added with a molecular weight regulator and controlled to 145 ℃. A cooling jacket (temperature 5 ℃ C. Of the condenser tube 1, temperature 0 ℃ C. Of the condenser tube 2) was installed, and the vacuum was controlled to rotate at-0.09 for 4 hours. The intrinsic viscosity reaches about 13.0ml/g, and 74ml of condensed water is obtained. The condensate on the condenser jacket weighed about 15 grams. Weighing a proper amount of lactide, adding the lactide into a reaction bottle under stirring, adding a catalyst, and heating to 160 ℃. And (3) installing a drying tower and a steam receiving device, controlling the temperature of a condensing tube to be minus 20 ℃, and stirring and reacting for 2 hours under the vacuum degree of minus 0.1MPa. After the reaction, refining according to the test 21 step, and drying to obtain 286 g of finished product. The intrinsic viscosity was about 16.5ml/g, molecular weight 12300.
Comparative example 1
(1) 0.25 liter of lactic acid (85%) and 75 g of glycollic acid are taken, placed in a reaction bottle with magnetic stirring for mixing, then catalyst is added, the vacuum degree is controlled at-0.06 MPa, and dehydration reaction is carried out for 4 hours, thus obtaining 65ml of condensed water.
(2) Taking a molecular weight regulator, adding the molecular weight regulator into a reaction bottle under stirring, mixing, and controlling the temperature to 145 ℃. And a cooling pipe is arranged, the temperature of the condensing pipe is 5 ℃, and the vacuum degree is controlled to be-0.08 MPa for rotary reaction for 3 hours. The intrinsic viscosity reached about 6.6ml/g, and 35ml of condensate was obtained, the condensate weight on the condenser jacket being about 10 g.
(3) The catalyst was taken and added to the reaction flask with stirring and the temperature was raised to 160 ℃. And (3) installing a drying tower, and stirring and reacting for 16 hours under the vacuum degree of-0.1 MPa. The intrinsic viscosity is about 10ml/g, and the molecular weight is 8000. After the reaction was continued for 12 hours, the intrinsic viscosity was about 16.2ml/g, the molecular weight was 12000, and the color was yellowing.
(4) After cooling the reaction product, it was dissolved in 300ml of acetone. Taking 75ml of the dissolved substance, slowly pouring the dissolved substance into water for injection at 60-80 ℃, and stirring and separating out the dissolved substance. When the water for injection is turbid, the water for injection is replaced until all the water for injection is precipitated. After extrusion, re-dissolving with 150ml of acetone, pouring the dissolved substance into 750ml of 95% medicinal ethanol for precipitation, extruding the precipitate, repeatedly washing and extruding with ethanol for 3 times, and finally drying in vacuum at 35-45 ℃ to obtain 35 g of finished product. The molar ratio of lactide to glycolide, the molecular weight distribution, and the lactide+glycolide residue in the polymer were determined. The relevant parameters and results are listed in tables 1 and 2.
Comparative example 2
0.25 liter of lactic acid (85%) and 75 g of glycollic acid are taken, placed in a reaction bottle with magnetic stirring, mixed, added with a catalyst, and dehydrated for 4 hours under the vacuum degree of-0.06 MPa. Taking a molecular weight regulator, adding the molecular weight regulator into a reaction bottle under stirring, mixing, and controlling the temperature to 145 ℃. And a cooling pipe is arranged, the temperature of the condensing pipe is 5 ℃, and the vacuum degree is controlled to be-0.08, and the rotary reaction is carried out for 3 hours. The catalyst was taken and added to the reaction flask with stirring and the temperature was raised to 160 ℃. And (3) installing a drying tower, and stirring and reacting for 16 hours under the vacuum degree of-0.1 MPa. The intrinsic viscosity is about 14ml/g, and the molecular weight is 11000. After the reaction was continued for 6 hours, the intrinsic viscosity was about 16.1ml/g, the molecular weight was 11800, and the color was yellowing.
After cooling the reaction product, it was dissolved in 300ml of acetone. Taking 75ml of the dissolved substance, slowly pouring the dissolved substance into water for injection at 60-80 ℃, and stirring and separating out the dissolved substance. When the water for injection is turbid, the water for injection is replaced until all the water for injection is precipitated. After extrusion, re-dissolving with 150ml of acetone, pouring the dissolved substance into 750ml of 95% medicinal ethanol for precipitation, extruding the precipitate, repeatedly washing and extruding with ethanol for 3 times, and finally drying in vacuum at 35-45 ℃ to obtain 36 g of finished product. The molar ratio of lactide to glycolide, the molecular weight distribution, and the lactide+glycolide residue in the polymer were determined. The relevant parameters and results are listed in tables 1 and 2.
Comparative example 3
380g DL-lactide, 100g glycolide were weighed into a formulation tank from a feed inlet and the material was heated to 190.+ -. 2 ℃. Adding a molecular weight distribution regulator and a catalyst, and reacting for 4 hours. After the reaction is finished, vacuumizing for 1 hour, and controlling the vacuum degree to be-0.095 MPa to-0.1 MPa. The materials are put into water for injection to obtain solid matters, crushed, washed by the water for injection, put into a vacuum drying oven and dried for 36 hours at 38+/-1 ℃. The intrinsic viscosity is about 16.5ml/g, and the molecular weight is 12300.
After cooling the reaction product, it was dissolved in 300ml of acetone. Taking 75ml of the dissolved substance, slowly pouring the dissolved substance into water for injection at 60-80 ℃, and stirring and separating out the dissolved substance. When the water for injection is turbid, the water for injection is replaced until all the water for injection is precipitated. After extrusion, re-dissolving with 150ml of acetone, pouring the dissolved substance into 750ml of 95% medicinal ethanol for precipitation, extruding the precipitate, repeatedly washing and extruding with ethanol for 3 times, and finally drying in vacuum at 35-45 ℃ to obtain 33 g of finished product. The molar ratio of lactide to glycolide, the molecular weight distribution, and the lactide+glycolide residue in the polymer were determined. The relevant parameters and results are listed in tables 1 and 2.
TABLE 1 comparison of polycondensation process parameters and results in examples 1-5 and comparative examples 1-3
Analysis of results
1. In example 2, a drying tower and a steam receiving device were installed, the temperature of a condenser was controlled to-20℃and the reaction was stirred at-0.1 MPa for 6 hours. The intrinsic viscosity reaches 26ml/g, the molecular weight is 30000, and the reaction is rapid.
2. In example 5 (similar to example 2) the intrinsic viscosity had reached 16.3ml/g after 3 hours of polycondensation, molecular weight 12200. The polymerization reaction is fastest, the time used is shortest, and the molecular weight reproducibility is good. The molecular weight can be accurately controlled by the reaction time.
3. Comparative examples 1 and 2 had a slow reaction rate, a long reaction time, charring occurred, and poor process stability.
4. Comparative example 3 directly adopts lactide and glycolide for ring-opening polymerization, and the cost of reaction materials is high, resulting in high production cost.
Table 2 comparison of the refining process parameters and results in example 2, examples 5-10 and comparative examples 1-3
Wherein: the molecular weight distribution should be less than or equal to 2.0, and the lactide and glycolide residue should be less than or equal to 2.7%.
TABLE 3 other quality indicators of the dried end product in examples 5, 7, 2, 9 and 10
Analysis of results
1. Examples 5-8 were all refined from the product of step (3) of example 5, first acetone-dissolved, first precipitate: slowly pouring the dissolved substances into water for injection at 60-80 ℃ and stirring to separate out the dissolved substances. When the water for injection is turbid, the water for injection is replaced until all the water for injection is precipitated. Extruded and redissolved in 75ml acetone. First precipitation: pouring into 750ml of 95% medicinal ethanol for precipitation, extruding the precipitate, repeatedly washing and extruding for 3 times by using ethanol, and finally drying in vacuum at 35-45 ℃ to obtain the finished product. By adopting a two-step method of feeding and feeding lactide before polycondensation, the molar ratio of lactide to glycolide in the polymer is highly consistent with the design requirement, and even if the molecular weight reaches 30000, the molecular weight distribution is narrower.
2. The lactide+glycolide residues in examples 5 and 7 are higher, as related to the second use of water for injection and water temperature. Pure water for injection and low temperature are unfavorable for removing the oligomer, and the residue exceeds the standard. In examples 6 and 2, the water for injection is used in the first step and the water temperature is controlled to be 60-80 ℃, and the 95% ethanol is used in the second step, so that relevant impurities are finally and effectively removed, and the use amount of the organic solvent is reduced.
3. The results of comparative examples 1-3 show that the molar ratio of lactide to glycolide is greatly different from the design requirements, the batch-to-batch variation is also great, the molecular weight distribution is also wide, and the repeatability is poor. Comparative example 3 has low yield.
4. It can be seen from examples 2, 9 and 10 that the lactide-glycolide copolymer prepared by the method of the invention has good and controllable repeatability of indexes such as molecular weight, molecular weight distribution, polymer composition ratio, residue and the like, and reliable process. The higher molecular weight of the product obtained in step (3) of example 2 was due to the longer reaction time of 6 hours, which demonstrates that the control of the molecular weight can be achieved by controlling the reaction time, and the high efficiency of the process of the present invention is demonstrated by the molecular weight reaching 30000 after 6 hours of reaction.
Claims (12)
1. A method for preparing a lactide-glycolide copolymer, the method comprising the steps of:
(1) Lactic acid dehydration: heating lactic acid to 110-130 ℃, and dehydrating under the vacuum degree of minus 0.06-minus 0.1MPa to obtain dehydrated lactic acid with the water content of below 2 wt%;
(2) Prepolymerization reaction: adding the dehydrated lactic acid and the glycolic acid into a reactor with a condensing tube according to the proportion of the comonomer in the lactide-glycolide copolymer, adding a molecular weight regulator, heating to 130-150 ℃, and performing prepolymerization under the vacuum degree of minus 0.08-minus 0.1MPa, wherein the temperature of the condensing tube is controlled in two stages, so that lactide steam, lactic acid steam and water steam are respectively condensed and respectively received and weighed, the reaction end point is determined according to the amount of condensed water, and the lactic acid loss amount is calculated according to the total amount of the condensed lactide and lactic acid;
(3) Polycondensation reaction: adding lactide with the amount corresponding to the lactic acid loss amount into the reaction product in the step (2), adding a catalyst, reacting at 150-170 ℃ and a vacuum degree of minus 0.08-minus 0.1MPa, and determining a reaction end point by sampling and measuring viscosity and molecular weight;
(4) Refining: cooling the reactant, dissolving the reactant with acetone, pouring the dissolved substance into water for injection at 60-80 ℃, stirring and separating out, extruding the precipitate, dissolving the precipitate with acetone, pouring the dissolved substance into 90-99% medicinal ethanol for precipitation, extruding the precipitate, repeatedly washing and extruding the precipitate with ethanol for 2-5 times, and drying.
2. The production method according to claim 1, wherein the lactic acid has a water content of 5 to 15wt%.
3. The production method according to claim 1, wherein dehydration is performed in step (1) using a rotary evaporator.
4. The preparation method according to claim 1, wherein the step (1) further comprises collecting condensed water obtained by dehydration and weighing to determine the degree of dehydration.
5. The production method according to claim 1, wherein the dehydration time in the step (1) is 1 to 2 hours.
6. The process according to claim 1, wherein the temperature of the condensation tube in the step (2) is-5 to 5 ℃.
7. The production method according to claim 1, wherein the temperature of the condenser tube is controlled to be 4 to 5 ℃ and-5 to 0 ℃ in order in two stages from the end near the reactor.
8. The process according to claim 1, wherein the amount of condensed water in the step (2) is equal to the theoretical water yield at which lactic acid and glycolic acid are polymerized to form an oligomer having a molecular weight of 7000 to 8000, which is the reaction end point.
9. The process according to claim 1, wherein the time for the prepolymerization in the step (2) is 1 to 3 hours.
10. The production method according to claim 1, wherein the step (3) further comprises using a reactor having a condenser tube, a drying column and a vapor receiving device, and controlling the temperature of the condenser tube to be at most-20 ℃.
11. The method of manufacturing according to claim 1, wherein the step (3) further comprises: after 3 hours of reaction, sampling and measuring viscosity and molecular weight at intervals, and stopping the reaction after the reaction is determined to be required.
12. The production process according to claim 1, wherein the reaction time in the step (3) is 3 to 6 hours.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1385452A (en) * | 2002-05-23 | 2002-12-18 | 东华大学 | Process for preparing copolymer of L-lactic acid and glycollic acid by direct polycondensation |
| CN1706883A (en) * | 2004-06-09 | 2005-12-14 | 华东理工大学 | Completely biodegradable hydrophobic material and its prepn |
| CN102952258A (en) * | 2011-08-18 | 2013-03-06 | 上海丽珠制药有限公司 | Preparation method of polylactic acid-glycolic acid copolymer |
| CA2986456A1 (en) * | 2015-07-09 | 2017-01-12 | Evonik Rohm Gmbh | Process for preparing poly(glycolide-co-lactide) copolymer microparticles |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1385452A (en) * | 2002-05-23 | 2002-12-18 | 东华大学 | Process for preparing copolymer of L-lactic acid and glycollic acid by direct polycondensation |
| CN1706883A (en) * | 2004-06-09 | 2005-12-14 | 华东理工大学 | Completely biodegradable hydrophobic material and its prepn |
| CN102952258A (en) * | 2011-08-18 | 2013-03-06 | 上海丽珠制药有限公司 | Preparation method of polylactic acid-glycolic acid copolymer |
| CA2986456A1 (en) * | 2015-07-09 | 2017-01-12 | Evonik Rohm Gmbh | Process for preparing poly(glycolide-co-lactide) copolymer microparticles |
Non-Patent Citations (1)
| Title |
|---|
| 丙交酯连续化生产流程设计研究;魏顺安等;化学工程;第35卷(第01期);第72-74页 * |
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