CN102807550B - Method for preparing medical high-purity lactide - Google Patents
Method for preparing medical high-purity lactide Download PDFInfo
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- CN102807550B CN102807550B CN201210297933.2A CN201210297933A CN102807550B CN 102807550 B CN102807550 B CN 102807550B CN 201210297933 A CN201210297933 A CN 201210297933A CN 102807550 B CN102807550 B CN 102807550B
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Abstract
The invention relates to a method for preparing medical high-purity lactide. The method includes steps of fusion of crude lactide, primary molecular distillation and secondary molecular distillation. The method provided can realize continuous operation, is free of solvent, simple and environment-friendly in the whole purification process and can be used for preparation of medical high-purity lactide.
Description
Technical field
The present invention relates to field of fine chemical, particularly, relate to a kind of preparation method of high-purity medical rac-Lactide.
Background technology
Poly(lactic acid) is ferment the lactic acid that obtains as raw material taking starch base farm crop through modern biotechnology, then through the macromolecule resin of special polyreaction generation.Poly(lactic acid) has good biocompatibility and degradation property, can be degradable by the microorganism of occurring in nature after use, and can be by the slow Absorption And Metabolism of human body after implant into body.
Poly(lactic acid), because possessing good biocompatibility, biological degradability and non-toxic nature, medically can be used as medical surgical sewing thread of exempting to take out stitches, bone renovating material, drug controlled release material, artificial bone, artificial skin, ophthalmology embedded material etc.At present, developed country's part poly-lactic acid products such as the U.S., European Union, Japan has passed through clinical and has started mass-producing application.
The synthesis material of poly(lactic acid) is rac-Lactide, mainly comprises: L-rac-Lactide, D-rac-Lactide, D, L-rac-Lactide and meso-rac-Lactide.At present, for the purifying of different purposes rac-Lactides, prepare highly purified rac-Lactide and mainly contain two kinds of methods, medical rac-Lactide mainly carrys out purifying by solvent recrystallization technique, and general rac-Lactide is mainly realized purifying by the technique such as rectifying tower and fusion-crystallization.
Chinese patent application 01815139.6(publication number is CN 1452618A) introduce the method for a kind of purifying rac-Lactide (or glycollide), method comprises: crystallization control, extractive crystallization crude lactide in water medium, the crystal suspension that separation obtains is dried and obtains wet lotion, and then the dry rac-Lactide for preparing purifying of recrystallize in melting media.
Chinese patent application 91103421.8(publication number is CN 1056689A) relate to the evaporation method of air aided of purifying lactide, this method makes lactide separate with impurity phase as the steam component in air-flow, then obtains highly purified lactide by solvent wash.
Chinese patent application 200710135532.6(publication number is CN101157680A) a kind of method of utilizing ethanol and two kinds of solvent recrystallization purifying rac-Lactides of ethyl acetate is provided.
Chinese patent application 94112795.8(publication number is CN1112559A) introduce a kind of method of separate lactide and Study of Meso-Lactide, thus by being contacted with water, rac-Lactide make Study of Meso-Lactide hydrolysis occur and removal soluble in water.
Chinese patent application 200710302479.4(publication number is CN101468978) introduce a kind of method of purification of rac-Lactide, comprise that the pure and mild solvent elution of water elution is pure and dry, the water washing process that washing is purified is that crude lactide is inserted in water, mixes, slough again water, obtain washing rac-Lactide; The pure solvent process of washing of solvent elution is that washing rac-Lactide is put in solvent, mixes, then sloughs solvent, obtains smart rac-Lactide, obtains after drying dry smart rac-Lactide.
Chinese patent application 200910234132.X(publication number is CN101696204A) on the basis of Chinese patent application 200710302479.4, further simplify the purification step of rac-Lactide, through repeatedly washing the rac-Lactide that directly obtains certain quality, yield reaches more than 80%, optical purity is more than 98%, and the poly(lactic acid) viscosity-average molecular weight obtaining for polymerization is more than 80,000.
US Patent No. 5521278 has been mentioned a kind of method of purifying rac-Lactide, and mainly, by fusion-crystallization purifying lactide, the rac-Lactide acid number obtaining is in 6meq/kg.
US Patent No. 6326458 has been introduced a kind of purification process of industrialization rac-Lactide, mainly realizes serialization rac-Lactide purifying by rectification process.
Existing patented technology is prepared highly purified rac-Lactide, mainly has the following disadvantages:
1) in the technological process of Chinese patent application 91103421.8,200710135532.6 and 200710302479.4 purifying rac-Lactides, all use solvent, had environmental protection and safety problem;
2) Chinese patent application 01815139.6,94112795.8,200710302479.4 and 200910234132.X have adopted the method for water extraction or washing to carry out purifying rac-Lactide, rac-Lactide is to water more responsive (especially under certain temperature condition), easily there is dimer or the lactic acid impurity of hydrolysis generation lactic acid, therefore water is also hydrolyzed rac-Lactide in separated and dissolved lactic acid or lactic acid oligomer, causes rac-Lactide product yield to decline and cannot separate totally with impurity;
3) US Patent No. 5521278 and US6326458 have mentioned fusion-crystallization and rectification process purifying rac-Lactide, the rac-Lactide acid number obtaining can reach in 10meq/kg, the poly(lactic acid) number-average molecular weight that polymerization obtains is between 5 ~ 100,000, can reach the requirement of general poly(lactic acid), but the purity at medical field rac-Lactide does not still reach requirement, for example in fracture, the number-average molecular weight general requirement of fixed network poly(lactic acid) is more than 100,000, and corresponding rac-Lactide acid number is in 1meq/kg.
Therefore, need to provide a kind of new method of preparing high-purity medical rac-Lactide, solve prior art deficiency in actual applications.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of high-purity medical rac-Lactide.
The preparation method of high-purity medical rac-Lactide provided by the invention, comprising: crude lactide melting, one-level molecular distillation and secondary molecular distillation.
The preparation method of high-purity medical rac-Lactide of the present invention, particularly, comprises the following steps:
1) crude lactide melting: crude lactide is placed in to melting plant, is furnished with nitrogen system, temperature remains on 100 ~ 150 DEG C and carries out melting;
2) one-level molecular distillation: the crude lactide through step 1) melting is injected to one-level molecular distillation apparatus, and distillation is carried out under 20 ~ 500Pa and 50 ~ 150 DEG C of conditions, separates residual light constituent in crude lactide;
3) secondary molecular distillation: will be through step 2) crude lactide of one-level molecular distillation injects secondary molecular distillation apparatus, and distillation is carried out under 10 ~ 500Pa and 60 ~ 180 DEG C of conditions, separates residual heavy constituent in crude lactide, collects the rac-Lactide of purifying.
In aforesaid method:
In step 1), described crude lactide refers to need the crude lactide raw material of purifying, and main component has L-rac-Lactide, D-rac-Lactide, meso-rac-Lactide, lactic acid, moisture and lactic acid oligomer.
In step 1), the nitrogen gas purity in nitrogen system is greater than 99.99%.
In step 1), the nitrogen system of melting plant preparation, ensures that material (described crude lactide) is in constant voltage 0.11 ~ 0.20MPa nitrogen protection state.Pressure is 0.12 ~ 0.18MPa preferably, more preferably 0.18MPa.
In step 1), melt temperature is preferred: 105 ~ 130 DEG C.
Step 2) in, described light constituent is mainly the impurity composition of boiling point lower than rac-Lactide, as water, lactic acid etc.
Step 2) in, distillation is preferably carried out under 20 ~ 300Pa and 50 ~ 130 DEG C of conditions.Or preferably under 30 ~ 80Pa and 90 ~ 110 DEG C of conditions, carry out.More preferably under 30 ~ 60Pa and 100 ~ 110 DEG C of conditions, carry out.
In step 3), distillation is preferably carried out under 10 ~ 200Pa and 80 ~ 170 DEG C of conditions.Or preferably under 10 ~ 20Pa and 128 ~ 150 DEG C of conditions, carry out.More preferably under 10 ~ 20Pa and 135 ~ 150 DEG C of conditions, carry out.
In step 3), described heavy constituent is mainly the impurity composition of boiling point higher than rac-Lactide, as lactic acid oligomer etc.
Preparation method's tool of high purity rac-Lactide of the present invention has the following advantages:
1, different from prior art preparation method: prior art is mainly by Methods For Purification rac-Lactides such as solvent recrystallization, washing, rectifying or fusion-crystallizations; The present invention adopts the technique of short-range molecular distillation to carry out the purifying of rac-Lactide, does not use solvent.
2, the present invention adopts physical method purifying lactide, does not use other medium such as solvent and water, and the high purity rac-Lactide acid number obtaining can be controlled in 0.5meq/kg, be suitable for medical, the simple environmental protection of method.
3, purifying process of the present invention can be realized serialization production, and the purity of the rac-Lactide obtaining can reach medical grade requirement; Although the rectificating method in existing patent also can be produced in serialization, the purity of the rac-Lactide that rectificating method obtains does not reach medical grade requirement.
Embodiment
Following examples are used for illustrating the present invention, but are not used for limiting the scope of the invention.
Nitrogen gas purity in embodiment of the present invention nitrogen system is all greater than 99.99%.
Firsts and seconds molecular distillation apparatus of the present invention is the KD50 of POPE company of the U.S..Other operational conditions that relate in preparation process are the routine of this area and select.
Embodiment 1
1, raw material is thick L-rac-Lactide, purity 92.50%wt, and other composition comprises: lactic acid 5.74%wt, meso-rac-Lactide 0.84%wt, D-rac-Lactide 0.2%wt, moisture 0.15%wt, lactic acid oligomer 0.57%wt.
2, the preparation technology of high purity rac-Lactide is:
1) crude lactide raw materials melt: the thick L-rac-Lactide raw material of 500kg is placed in to storage tank, and storage tank is furnished with nitrogen system, ensures that material is in constant voltage 0.15MPa nitrogen protection state; Tank temperature remains on the 105 DEG C of thick L-rac-Lactide of melting raw materials.
2) one-level molecular distillation: the thick L-rac-Lactide raw material of melting injects one-level molecular distillation apparatus continuously by pump, distillation is carried out under 80Pa and 90 DEG C of conditions, separates light constituent residual in thick L-rac-Lactide raw material (comprising lactic acid, meso-rac-Lactide and moisture).
3) secondary molecular distillation: the thick L-rac-Lactide raw material of one-level molecular distillation is injected to secondary molecular distillation apparatus continuously by pump, distillation is carried out under 20Pa and 128 DEG C of conditions, separate residual heavy constituent in thick L-rac-Lactide raw material and (comprise lactic acid oligomer and D, L-rac-Lactide [D, L-rac-Lactide refers in particular to the blend of 50%D-rac-Lactide and 50%L-rac-Lactide]), the L-rac-Lactide of collection purifying.
3, the refining L-rac-Lactide index preparing is: L-rac-Lactide 99.90%wt, lactic acid 0.04%wt, meso-rac-Lactide 0.03%wt, moisture 0.01%wt, lactic acid oligomer 0.02%wt; Content of carboxyl end group (acid number of high purity rac-Lactide) is 0.32meq/kg.
Embodiment 2
1, raw material is with embodiment 1.
2, the preparation technology of high purity rac-Lactide is:
1) crude lactide raw materials melt: the thick L-rac-Lactide raw material of 500kg is placed in to storage tank, and storage tank is furnished with nitrogen system, ensures that material is in constant voltage 0.12MPa nitrogen protection state; Tank temperature remains on the 105 DEG C of thick L-rac-Lactide of melting raw materials.
2) one-level molecular distillation: the thick L-rac-Lactide raw material of melting injects one-level molecular distillation apparatus continuously by pump, distillation is carried out under 60Pa and 90 DEG C of conditions, separates light constituent residual in thick L-rac-Lactide raw material (comprising lactic acid, meso-rac-Lactide and moisture).
3) secondary molecular distillation: the thick L-rac-Lactide raw material of one-level molecular distillation is injected to secondary molecular distillation apparatus continuously by pump, distillation is carried out under 10Pa and 128 DEG C of conditions, separate residual heavy constituent in thick L-rac-Lactide raw material and (comprise lactic acid oligomer and D, L-rac-Lactide [D, L-rac-Lactide refers in particular to the blend of 50%D-rac-Lactide and 50%L-rac-Lactide]), the L-rac-Lactide of collection purifying.
3, the refining L-rac-Lactide index preparing is: L-rac-Lactide 99.95%wt, lactic acid 0.02%wt, meso-rac-Lactide 0.01%wt, moisture 0.01%wt, lactic acid oligomer 0.01%wt; Content of carboxyl end group 0.25meq/kg.
Embodiment 3
1, raw material is with embodiment 1.
2, the preparation technology of high purity rac-Lactide is:
1) crude lactide raw materials melt: the thick L-rac-Lactide raw material of 500kg is placed in to storage tank, and storage tank is furnished with nitrogen system, ensures that material is in constant voltage 0.18MPa nitrogen protection state; Tank temperature remains on the 105 DEG C of thick L-rac-Lactide of melting raw materials.
2) one-level molecular distillation: the thick L-rac-Lactide raw material of melting injects one-level molecular distillation apparatus continuously by pump, distillation is carried out under 60Pa and 100 DEG C of conditions, separates light constituent residual in thick L-rac-Lactide raw material (comprising lactic acid, meso-rac-Lactide and moisture).
3) secondary molecular distillation: the thick L-rac-Lactide raw material of one-level molecular distillation is injected to secondary molecular distillation apparatus continuously by pump, distillation is carried out under 10Pa and 135 DEG C of conditions, separate residual heavy constituent in thick L-rac-Lactide raw material and (comprise lactic acid oligomer and D, L-rac-Lactide [D, L-rac-Lactide refers in particular to the blend of 50%D-rac-Lactide and 50%L-rac-Lactide]), the L-rac-Lactide of collection purifying.
3, the refining L-rac-Lactide index preparing is: L-rac-Lactide 99.97%wt, and lactic acid 0.01%wt, meso-rac-Lactide 0.01%wt, lactic acid oligomer 0.01%wt, moisture is 0; Content of carboxyl end group 0.13meq/kg.
Embodiment 4
1, raw material is thick D, L-rac-Lactide, and purity 93.00%wt, other composition comprises: lactic acid 4.50%wt, meso-rac-Lactide 1.60%wt, moisture 0.20%wt, lactic acid oligomer 0.70%wt.
2, the preparation technology of high purity rac-Lactide is:
1) crude lactide raw materials melt: by the thick D of 500kg, L-rac-Lactide raw material is placed in storage tank, and storage tank is furnished with nitrogen system, ensures that material is in constant voltage 0.18MPa nitrogen protection state; Tank temperature remains on 130 DEG C of thick D of melting, L-rac-Lactide raw material.
2) one-level molecular distillation: the thick D of melting, L-rac-Lactide raw material injects one-level molecular distillation apparatus continuously by pump, distillation is carried out under 50Pa and 110 DEG C of conditions, separates thick D, residual light constituent (comprising lactic acid, meso-rac-Lactide and moisture) in L-rac-Lactide raw material.
3) secondary molecular distillation: by the thick D of one-level molecular distillation, L-rac-Lactide raw material injects secondary molecular distillation apparatus continuously by pump, distillation is carried out under 20Pa and 140 DEG C of conditions, separate thick D, residual heavy constituent (lactic acid oligomer) in L-rac-Lactide raw material, collect the D of purifying, L-rac-Lactide.
3, the refining D preparing, L-rac-Lactide index is: D, L-rac-Lactide 99.93%wt, lactic acid 0.02%wt, meso-rac-Lactide 0.02%wt, moisture 0.01%wt, lactic acid oligomer 0.02%wt; Content of carboxyl end group 0.27meq/kg.
Embodiment 5
1, raw material is with embodiment 4.
2, the preparation technology of high purity rac-Lactide is:
1) crude lactide raw materials melt: by the thick D of 500kg, L-rac-Lactide raw material is placed in storage tank, and storage tank is furnished with nitrogen system, ensures that material is in constant voltage 0.18MPa nitrogen protection state; Tank temperature remains on 130 DEG C of thick D of melting, L-rac-Lactide raw material.
2) one-level molecular distillation: the thick D of melting, L-rac-Lactide raw material injects one-level molecular distillation apparatus continuously by pump, distillation is carried out under 30Pa and 110 DEG C of conditions, separates thick D, residual light constituent (comprising lactic acid, meso-rac-Lactide and moisture) in L-rac-Lactide raw material.
3) secondary molecular distillation: by the thick D of one-level molecular distillation, L-rac-Lactide raw material injects secondary molecular distillation apparatus continuously by pump, distillation is carried out under 20Pa and 150 DEG C of conditions, separate thick D, residual heavy constituent (lactic acid oligomer) in L-rac-Lactide raw material, collect the D of purifying, L-rac-Lactide.
3, the refining D preparing, L-rac-Lactide index is: D, L-rac-Lactide 99.97%wt, lactic acid 0.01%wt, meso-rac-Lactide 0.01%wt, lactic acid oligomer 0.01%wt, moisture is 0; Content of carboxyl end group 0.15meq/kg.
Claims (7)
1. a preparation method for high-purity medical rac-Lactide, is characterized in that, comprises the following steps:
1) crude lactide melting: under the condition of nitrogen protection, temperature remains on 100～150 DEG C and carries out melting by crude lactide;
2) one-level molecular distillation: the crude lactide through step 1) melting is injected to one-level molecular distillation apparatus, and distillation is carried out under 20～500Pa and 50～150 DEG C of conditions, separates residual light constituent in crude lactide;
3) secondary molecular distillation: will be through step 2) crude lactide of one-level molecular distillation injects secondary molecular distillation apparatus, and distillation is carried out under 10～500Pa and 60～180 DEG C of conditions, separates residual heavy constituent in crude lactide, collects the rac-Lactide of purifying;
In step 1), the purity of described nitrogen is greater than 99.99%, and the pressure of nitrogen protection condition is 0.11～0.20MPa.
2. method according to claim 1, is characterized in that, in step 1), the pressure of nitrogen protection condition is 0.12～0.18MPa.
3. method according to claim 1 and 2, is characterized in that, in step 1), melt temperature is: 105～130 DEG C.
4. method according to claim 1 and 2, is characterized in that step 2) in, distillation is carried out under 20～300Pa and 50～130 DEG C of conditions.
5. method according to claim 4, is characterized in that step 2) in, distillation is carried out under 30～80Pa and 90～110 DEG C of conditions.
6. according to the method described in claim 1,2 or 5, it is characterized in that, in step 3), distillation is carried out under 10～200Pa and 80～170 DEG C of conditions.
7. method according to claim 6, is characterized in that, in step 3), distillation is carried out under 10～20Pa and 128～150 DEG C of conditions.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4075085B2 (en) * | 1996-10-25 | 2008-04-16 | トヨタ自動車株式会社 | Method for producing lactide |
| CN101696203A (en) * | 2009-10-26 | 2010-04-21 | 江苏科技大学 | Method for continuously refining L-lactide from crude L-lactide |
| CN102020628A (en) * | 2011-01-06 | 2011-04-20 | 云南富集生物材料科技有限公司 | Improved method of preparation process of polylactic acid midbody lactide |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4075085B2 (en) * | 1996-10-25 | 2008-04-16 | トヨタ自動車株式会社 | Method for producing lactide |
| CN101696203A (en) * | 2009-10-26 | 2010-04-21 | 江苏科技大学 | Method for continuously refining L-lactide from crude L-lactide |
| CN102020628A (en) * | 2011-01-06 | 2011-04-20 | 云南富集生物材料科技有限公司 | Improved method of preparation process of polylactic acid midbody lactide |
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