Method for preparing non-toxic medical-grade polylactic acid by using toxic catalyst

Abstract

The invention provides a method for preparing non-toxic medical-grade polylactic acid by using a toxic catalyst. The method comprises the following steps: S1, preparing and purifying lactide; s2, preparing and purifying polylactic acid: S21, uniformly mixing and stirring lactide, a second catalyst and an initiator, vacuumizing, adding nitrogen for protection, vacuumizing again, reacting in an oil bath, cooling, adding dichloromethane for dissolving, precipitating with ethanol, washing, and drying to obtain polylactic acid; s22, taking polylactic acid and adding dichloromethane for dissolving; and adding inorganic acid or water-soluble organic acid, fully stirring, standing for layering, separating a dichloromethane layer, repeatedly extracting, adding a drying agent, drying, filtering, and evaporating the filtrate to dryness to obtain the nontoxic medical-grade polylactic acid. The invention also provides non-toxic medical-grade polylactic acid and application thereof. According to the method for preparing the nontoxic medical-grade polylactic acid by using the toxic catalyst, the problems of product purity, toxicity and molecular weight distribution are solved by adopting a stage temperature control method and a pickling method.

Description

Technical Field

[0001] The invention relates to the technical field of polymer materials, and in particular to a method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst. Background Art

[0002] Polylactic acid (PLA) is an important biodegradable biopolymer material. Due to its excellent biocompatibility and degradability, it is widely used in clinical orthopedics, drug sustained-release systems, medical surgical sutures, fracture fixation materials and tissue engineering materials. There are many methods for synthesizing polylactic acid. Among them, the preparation of PLA by ring-opening polymerization of lactide is one of the earlier studied and currently widely used polymerization methods. This method often uses organic tin compounds as catalysts, but these compounds have certain physiological toxicity. Whether the medical materials synthesized in this way are safe in the human body remains to be verified, and there are problems such as complex procedures, insufficient purity, and uneven molecular weight distribution.

[0003] Chinese patent CN202010662506.4 discloses a medical polylactic acid with controllable molecular weight and a preparation method thereof, comprising the following components and weight proportions: 150 parts of lactide; 0.1-1 parts of catalyst; 0.005-10 parts of lactic acid; the lactic acid is selected from at least one of racemic lactic acid and L-lactic acid, and the purity of the lactic acid is 50-90%. Although the medical polylactic acid with controllable molecular weight and the preparation method thereof of the invention avoid the toxicity problem of the initiator and ensure the stability and controllability of the molecular weight of the medical polylactic acid, the catalyst stannous octoate used is potentially toxic and there is a risk of medical toxicity.

[0004] Chinese patent CN202010409375.9 discloses a medical polylactic acid and a preparation method thereof, which comprises: preparing a lactide monomer, a catalyst and an initiator, and mixing them in a polymerization reaction vessel to obtain a mixture; heating the mixture so that the lactide monomer undergoes a polymerization reaction under the action of the catalyst and the initiator, and obtaining a polymer; and drying the crude polylactic acid product to obtain medical polylactic acid, the weight average molecular weight of the medical polylactic acid being greater than or equal to 400KDa, wherein, in the mixture, the molar ratio between the lactide monomer and the catalyst is 8000:1 to 60000:1, the molar ratio between the lactide monomer and the initiator is 4000:1 to 30000:1, and the purity of the lactide monomer is 95% to 100%. Although the disclosure can provide a medical polylactic acid and a preparation method thereof that can improve reaction efficiency and reduce costs, the catalyst uses a tin compound, which also has potential cytotoxicity and a high risk of long-term use.

[0005] Chinese patent CN202210419689.6 discloses a novel biomedical polylactic acid synthesis method, comprising the following steps: (1) dehydration under normal pressure without any catalyst; (2) adding catalyst-1 to the lactic acid after dehydration, first reacting under low vacuum, and then continuing pre-condensation under high vacuum, which is polymerization dehydration; (3) combining catalyst-2 with isocyanate, and using the lactic acid prepolymer obtained by the prepolymerization process to carry out melt vacuum polycondensation polymerization. Although this method has higher production efficiency, high polymerization activity, and reduced production costs, the obtained product has basically no metal residue and no biological toxicity. However, the catalyst used is complex and difficult to control, and isocyanate releases hydrogen cyanide at a certain temperature, which is a highly toxic substance and has potential safety hazards.

[0006] Therefore, the prior art needs to be solved urgently. Summary of the invention

[0007] The purpose of the present invention is to provide a method for preparing non-toxic medical grade polylactic acid using a toxic catalyst in view of the deficiencies in the prior art.

[0008] The technical solution of the present invention is achieved in this way: A method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst comprises the following steps: S1. Preparation and purification of lactide: adding lactic acid and the first catalyst, heating to a certain temperature under vacuum and maintaining for a certain period of time for dehydration, evaporating to dryness, filtering, recrystallizing, and drying to obtain refined lactide crystals; S2. Preparation and purification of non-toxic medical grade polylactic acid: S21. Take the lactide, the second catalyst and the initiator obtained in step S1, mix and stir evenly, place in a water bath, and rotate and mix under vacuum for 0.5 to 2 h, first evacuate and then add nitrogen protection, evacuate again and place in an oil bath at 120 to 150 ° C for reaction for 12 to 48 h, cool and add dichloromethane to dissolve, then precipitate and wash with ethanol, and dry at 20 to 40 ° C for 12 to 36 h to obtain polylactic acid; S22. Take polylactic acid and add dichloromethane to dissolve it, wash it with acid, add a desiccant to dry it, filter it, and evaporate the filtrate to dryness to obtain refined non-toxic medical grade polylactic acid.

[0009] In the method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst as described above, the first catalyst in step S1 is zinc acetate or zinc oxide. Under this condition, dehydration is more stable, and zinc is an essential trace element for the human body, which is safe and reliable.

[0010] The method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst as described above, wherein in step S1, the temperature is raised to a certain temperature under vacuum and maintained for a certain time for dehydration and evaporation, and specifically comprises the following steps: (1) Raise the temperature to 30-40°C under vacuum and maintain for 0.2-0.6h; (2) Raise the temperature to 80-90°C under vacuum and maintain for 0.2-0.6h; (3) Raise the temperature to 90-110°C under vacuum and maintain for 0.2-0.6 h; (4) Raise the temperature to 110-130°C under vacuum and maintain for 1.0-2.5 hours; (5) Raise the temperature to 130-150°C under vacuum and maintain for 1.0-2.5 hours; (6) Raise the temperature to 210-230°C under vacuum until the solution is evaporated to dryness.

[0011] Preferably, in step S1, the temperature is raised to a certain temperature under vacuum and maintained for a certain time to perform dehydration and evaporation, which specifically includes the following steps: (1) Raise the temperature to 35°C under vacuum and maintain for 0.2 to 0.6 h; (2) Raise the temperature to 86°C under vacuum and maintain for 0.2 to 0.6 h; (3) Raise the temperature to 100°C under vacuum and maintain for 0.2 to 0.6 h; (4) Raise the temperature to 120°C under vacuum and maintain for 1.0 to 2.5 hours; (5) Raise the temperature to 140°C under vacuum and maintain for 1.0 to 2.5 hours; (6) Raise the temperature to 220°C under vacuum until the product is evaporated to dryness.

[0012] Under this condition, dehydration is more thorough, reducing residual water and providing high-purity raw materials for subsequent polymerization. Under a certain pressure, different mixture compositions have different corresponding boiling ranges. If the temperature rises too fast, more lactic acid will evaporate, reducing the yield. If the temperature rises too slowly, dehydration will be too slow and incomplete.

[0013] Most preferably, in step S1, the temperature is raised to a certain temperature under vacuum and maintained for a certain time to perform dehydration and evaporation, which specifically comprises the following steps: (1) Raise the temperature to 35°C under vacuum and maintain for 0.5 h; (2) Raise the temperature to 86°C under vacuum and maintain for 0.2 to 0.6 h; (3) Raise the temperature to 100°C under vacuum and maintain for 0.2 to 0.6 h; (4) Raise the temperature to 120°C under vacuum and maintain for 1.0 to 2.5 hours; (5) Raise the temperature to 140°C under vacuum and maintain for 1.0 to 2.5 hours; (6) Raise the temperature to 220°C under vacuum until the product is evaporated to dryness.

[0014] In the method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst as described above, the mass ratio of lactic acid to the first catalyst in step S1 is (30-50): 1. Under this condition, the best dehydration effect is achieved. If the mass ratio of lactic acid to the first catalyst in step S1 is lower than 30: 1, the dehydration is insufficient; if the mass ratio of lactic acid to the first catalyst in step S1 is higher than 50: 1, the raw material is wasted if it is too high, and the molecular weight of the oligolactic acid is too large, making the next step of depolymerization difficult and reducing the yield.

[0015] In the method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst as described above, the second catalyst in step S21 is any one of stannous octoate, aluminum alkoxide, and stannous chloride. Preferably, the second catalyst in step S21 is stannous octoate.

[0016] In the method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst as described above, the initiator in step S21 is dodecanol or p-toluenesulfonic acid. Preferably, the initiator in step S21 is dodecanol.

[0017] In the method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst as described above, the mass ratio of lactide to the second catalyst in step S21 is 20000: (1-5). Under this condition, the polymerization reaction occurs fully. If the mass ratio of lactide to the second catalyst in step S21 is higher than 20000: 1, the reaction time is slow, the consumption time is long, and energy is wasted; if the mass ratio of lactide to the second catalyst in step S21 is lower than 20000: 5, the metal ion residue is too high, the catalyst is wasted, and pressure is placed on the subsequent pickling process.

[0018] The method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst as described above, the specific steps of pickling in step S22 are: adding 0.1-0.2 mol / L inorganic acid or water-soluble organic acid, stirring at 2000-3000r / min for 20-40 min, standing and stratifying, taking the dichloromethane layer, and repeatedly extracting 3-5 times with the same volume and concentration of inorganic acid or water-soluble organic acid. Under this condition, the organotin is removed by acid-water extraction, that is, the polymer containing organotin is dissolved in a dichloromethane organic solvent that is completely immiscible with water, and then the solution is added to water containing an inorganic acid or a water-soluble organic acid for extraction, and the organic phase is separated. After the solvent is evaporated, the purified product is obtained by drying. Tin ions can be fully removed, reducing the cytotoxicity of the material. Optionally, the inorganic acid is hydrochloric acid. Optionally, the water-soluble organic acid is citric acid.

[0019] In the method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst as described above, the vacuuming condition of step S21 is to reach -0.1 MPa, and the entire experimental process is vacuumed.

[0020] Based on the same inventive concept, the present invention also provides a non-toxic medical-grade polylactic acid prepared by the method as described above.

[0021] Based on the same inventive concept, the present invention provides a method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst. The prepared non-toxic medical-grade polylactic acid or the non-toxic medical-grade polylactic acid as described above has a wide range of applications in the preparation of clinical orthopedic materials, drug sustained-release materials, medical surgical sutures, fracture fixation materials and tissue engineering materials.

[0022] The beneficial effects of the present invention are: 1. The method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst provided by the present invention adopts a stage temperature control method. Different temperature ranges help to evaporate the water of different mixtures at different stages, thereby achieving efficient dehydration. By gradually increasing the temperature, the rate of the dehydration reaction can be effectively controlled to avoid side reactions or product decomposition caused by a sudden increase in temperature, thereby ensuring the directionality of the reaction and the purity of the product lactide crystals. Staged temperature increase can protect the catalyst from high temperature damage, maintain its activity, and ensure catalytic efficiency and product quality. The vacuum environment combined with stage temperature increase helps to reduce the internal vapor pressure of lactide, making it easier for water to escape from lactide, while avoiding the destruction of the lactide structure that may be caused by a sudden increase in internal pressure. The purity of the above lactide crystals is the key to ensuring the purity of non-toxic medical-grade polylactic acid.

[0023] 2. The present invention provides a method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst. The stage heating of lactide crystal preparation is not only for effective dehydration, but also indirectly affects the control of molecular weight distribution in subsequent polylactic acid synthesis. On the one hand, stage heating helps to more thoroughly remove moisture and other volatile impurities in lactide. Since the presence of these impurities may become chain transfer agents in the subsequent ring-opening polymerization reaction, leading to premature termination of the polymer chain, affecting the growth of molecular weight, and then affecting the width of the molecular weight distribution, therefore, a higher purity lactide raw material is conducive to obtaining a polylactic acid product with a narrower molecular weight distribution. On the other hand, the fine control of temperature during the stage heating process helps to optimize the crystal morphology and melting characteristics of lactide, which is crucial to the selection of ring-opening polymerization reaction conditions. The appropriate crystal morphology helps to form a more uniform reaction environment during the polymerization process, thereby ensuring the uniformity of the molecular weight.

[0024] 3. The present invention provides a method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst. The acid washing method can completely remove tin ions, thereby ensuring the biocompatibility and biosafety of the final polylactic acid material, which is crucial for applications such as clinical orthopedic materials, drug sustained-release materials, medical surgical sutures, fracture fixation materials, and tissue engineering materials that need to be implanted in the human body. It further improves the purity of polylactic acid and solves the problem of potential toxicity of products in the prior art. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 A schematic diagram of experimental instrument connections for a method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst provided by the present invention (part of distilling out lactide); Figure 2 HPLC chart of the non-toxic medical grade polylactic acid prepared by the present invention. DETAILED DESCRIPTION

[0026] The following will combine the contents in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0027] Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used in this specification includes any and all combinations of one or more of the related listed items.

[0028] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0029] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0030] The instruments and equipment used in the embodiments and comparative examples of the present invention are as follows: Waters gpc1525 gel permeation chromatograph; U3000 high performance liquid chromatograph; SXJB-2000 digital display constant temperature magnetic stirring electric heating jacket; SHZ-D (III) circulating water multi-purpose vacuum pump; 2XZ-4 rotary vane vacuum pump; JJ-I (A) 300W precision power-enhancing electric stirrer; Buchner funnel; Yamai 1000 mL sand core filter; Lichen brand C20 glass instrument air flow dryer; RE-52AA rotary evaporator; C-DFY-5 / 20 low temperature constant temperature reaction bath; 101-3 electric heating blast drying oven; TopPetter type manual adjustable & fixed pipette; FA224C electronic analytical balance; 2000 mL three-necked flask; 500 mL sealed reaction bottle; 500 mL three-necked reactor. A method for preparing non-toxic medical grade polylactic acid with toxic catalysts. Figure 1 shown.

[0031] The materials and reagents used in the examples and comparative examples of the present invention are as follows: Polymer grade lactic acid (mass fraction Wt 80-98%) was purchased from Jingliang Longjiang Bioengineering Co., Ltd.; zinc acetate (AR) was purchased from Tianjin Damao Chemical Reagent Factory; ethanol (AR) was purchased from Yantai Shuangshuang Chemical Co., Ltd.; ethyl acetate (AR) was purchased from Tianjin Yongda Chemical Reagent Co., Ltd.; stannous octoate (AR) was purchased from Sinopharm Chemical Reagent Co., Ltd.; dodecanol (AR) was purchased from Sinopharm Chemical Reagent Co., Ltd.; dichloromethane (AR) was purchased from Tianjin Fuyu Fine Chemical Co., Ltd.

[0032] Embodiment 1: This embodiment provides a method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst, comprising the following steps: (1) Preparation and purification of lactide: In a 2000 mL three-necked flask, add 900 g of polymer grade lactic acid (mass fraction Wt 80%) and 20 g of analytical pure zinc acetate, heat to a certain temperature under vacuum and keep it for a certain time for dehydration. Specifically, heat to 35 ° C under vacuum and maintain for 0.2 h, then heat to 86 ° C under vacuum and maintain for 0.2 h, then heat to 100 ° C under vacuum and maintain for 0.2 h, then heat to 120 ° C under vacuum and maintain for 1 h, then heat to 140 ° C under vacuum and maintain for 1 h. The material ratio, temperature control and holding time are shown in Table 1. Finally, a light yellow liquid was obtained in the three-necked flask. A new clean and dry reactor was replaced as the receiving flask. The temperature was quickly raised to 220°C under vacuum to evaporate the material in the three-necked flask to dryness. Crude lactide was obtained in the receiving flask, crushed and transferred to a beaker, and filtered with a Buchner funnel. The filter cake was recrystallized twice from ethanol and twice from ethyl acetate, and then dried in an oven at 40°C for 48 h to obtain dry refined lactide crystals.

[0033] (2) Preparation and purification of non-toxic medical grade polylactic acid: Take 130 g of refined lactide, grind it with a mortar, transfer it to a single-necked flask, place it in a 40 ℃ water bath, and rotary evaporate it under vacuum for 2 h. Take out 10 g of lactide from the single-necked flask and put it in a beaker, add 0.05% stannous octoate and 0.3% dodecanol according to the mass ratio, stir evenly and transfer it back to the single-necked flask. Remove the water bath, rotate and mix under vacuum for 1 h, then transfer it to a 500 mL sealed reaction bottle, first evacuate to -0.1MPa and then add nitrogen protection for 5 min, repeat once, and nitrogen protection for the third time for 1 h. After evacuating again, place it in an oil bath at 130 ℃ for reaction for 24 h, and obtain crude polylactic acid after cooling. Add dichloromethane according to the mass ratio of crude polylactic acid to dichloromethane of 1:2 to dissolve, then precipitate with ethanol, wash, and dry at 30 ℃ for 24 h to obtain polylactic acid.

[0034] Take 20 g of polylactic acid and dissolve it in 2 L of dichloromethane; then add 2 L of 0.1 mol / L hydrochloric acid, stir thoroughly at 2000 r / min for 30 min, and then stand to separate the layers. Take the dichloromethane layer and extract it three times with the same volume of 0.1 mol / L hydrochloric acid. Add 10 g of anhydrous sodium sulfate, dry it, filter it, and evaporate the filtrate to obtain refined non-toxic medical grade polylactic acid.

[0035] Embodiment 2: This embodiment provides a method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst, comprising the following steps: (1) Preparation and purification of lactide: 900 g of polymer grade lactic acid (mass fraction Wt 88%) and 20 g of analytical pure zinc acetate were added to a 2000 mL three-necked flask, and the temperature was raised to a certain temperature under vacuum and maintained for a certain time for dehydration. Specifically, the temperature was raised to 35°C under vacuum and maintained for 0.3 h, then raised to 86°C under vacuum and maintained for 0.3 h, then raised to 100°C under vacuum and maintained for 0.3 h, then raised to 120°C under vacuum and maintained for 1.5 h, then raised to 140°C under vacuum and maintained for 1.5 h. The material ratio, temperature control and maintenance time are shown in Table 1. Finally, a light yellow liquid was obtained in the three-necked flask. Replace a new clean and dry reactor as the receiving bottle, and quickly heat up to 220°C under vacuum to evaporate the material in the three-necked flask to dryness. Crude lactide is obtained in the receiving bottle, crushed and transferred to a beaker, filtered with a Buchner funnel, and the filter cake is recrystallized twice from ethanol and twice from ethyl acetate, and then dried in an oven at 40°C for 48 h to obtain dry refined lactide crystals.

[0036] (2) Preparation and purification of non-toxic medical grade polylactic acid: Take 130 g of refined lactide, grind it with a mortar, transfer it to a single-necked flask, place it in a 40 ℃ water bath, and rotary evaporate it under vacuum for 2 h. Take out 10 g of lactide from the single-necked flask and put it in a beaker, add 0.05% stannous octoate and a certain amount of 0.2% dodecanol according to the mass ratio, stir evenly and transfer it back to the single-necked flask. Remove the water bath, rotate and mix under vacuum for 1 h, then transfer it to a 500 mL sealed reaction bottle, first evacuate to -0.1MPa and then add nitrogen protection for 5 min, repeat once, and nitrogen protection for the third time for 1 h. After evacuating again, place it in an oil bath at 130 ℃ for reaction for 24 h. After cooling, crude polylactic acid is obtained. Dichloromethane is added to dissolve it according to the mass ratio of crude polylactic acid and dichloromethane of 1:2, and then precipitated and washed with ethanol. Polylactic acid is obtained after drying at 30 ℃ for 24 h.

[0037] Take 20 g of polylactic acid and dissolve it in 2 L of dichloromethane; then add 2 L of 0.1 mol / L hydrochloric acid, stir thoroughly at 2000 r / min for 30 min, and then stand to separate the layers. Take the dichloromethane layer and extract it three times with the same volume of 0.1 mol / L hydrochloric acid. Add 10 g of anhydrous sodium sulfate, dry it, filter it, and evaporate the filtrate to obtain refined non-toxic medical grade polylactic acid.

[0038] Embodiment 3: This embodiment provides a method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst, comprising the following steps: (1) Preparation and purification of lactide: 900 g of polymer grade lactic acid (mass fraction Wt 98%) and 20 g of analytical pure zinc acetate were added to a 2000 mL three-necked flask, and the temperature was raised to a certain temperature under vacuum and maintained for a certain time for dehydration. Specifically, the temperature was raised to 35°C under vacuum and maintained for 0.5 h, then raised to 86°C under vacuum and maintained for 0.5 h, then raised to 100°C under vacuum and maintained for 0.5 h, then raised to 120°C under vacuum and maintained for 2.0 h, then raised to 140°C under vacuum and maintained for 2.0 h. The material ratio, temperature control and maintenance time are shown in Table 1. Finally, a light yellow liquid was obtained in the three-necked flask. Replace a new clean and dry reactor as the receiving bottle, and quickly heat up to 220°C under vacuum to evaporate the material in the three-necked flask to dryness. Crude lactide is obtained in the receiving bottle, crushed and transferred to a beaker, filtered with a Buchner funnel, and the filter cake is recrystallized twice from ethanol and twice from ethyl acetate, and then dried in an oven at 40°C for 48 h to obtain dry refined lactide crystals.

[0039] (2) Preparation and purification of non-toxic medical grade polylactic acid: Take 130 g of refined lactide, grind it with a mortar, transfer it to a single-necked flask, place it in a 40 ℃ water bath, and rotary evaporate it under vacuum for 2 h. Take out 10 g of lactide from the single-necked flask and put it in a beaker, add 0.05% stannous octoate and 0.1% dodecanol according to the mass ratio, stir evenly and transfer it back to the single-necked flask. Remove the water bath, rotate and mix under vacuum for 1 h, then transfer it to a 500 mL sealed reaction bottle, first evacuate to -0.1MPa and then add nitrogen protection for 5 min, repeat once, and nitrogen protection for the third time for 1 h. After evacuating again, place it in an oil bath at 130 ℃ for reaction for 24 h. After cooling, crude polylactic acid is obtained. Dichloromethane is added to dissolve it according to the mass ratio of crude polylactic acid and dichloromethane of 1:2, and then precipitated and washed with ethanol. Polylactic acid is obtained after drying at 30 ℃ for 24 h.

[0040] Take 20 g of polylactic acid and dissolve it in 2 L of dichloromethane; then add 2 L of 0.1 mol / L hydrochloric acid, stir thoroughly at 2000 r / min for 30 min, and then stand to separate the layers. Take the dichloromethane layer and extract it three times with the same volume of 0.1 mol / L hydrochloric acid. Add 10 g of anhydrous sodium sulfate, dry it, filter it, and evaporate the filtrate to obtain refined non-toxic medical grade polylactic acid.

[0041] Embodiment 4: This embodiment provides a method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst, comprising the following steps: (1) Preparation and purification of lactide: 900 g of polymer grade lactic acid (mass fraction Wt 98%) and 20 g of analytical pure zinc acetate were added to a 2000 mL three-necked flask, and the temperature was raised to a certain temperature under vacuum and maintained for a certain time for dehydration. Specifically, the temperature was raised to 35°C under vacuum and maintained for 0.6 h, then raised to 86°C under vacuum and maintained for 0.6 h, then raised to 100°C under vacuum and maintained for 0.6 h, then raised to 120°C under vacuum and maintained for 2.5 h, then raised to 140°C under vacuum and maintained for 2.5 h. The material ratio, temperature control and maintenance time are shown in Table 1. Finally, a light yellow liquid was obtained in the three-necked flask. Replace a new clean and dry reactor as the receiving bottle, and quickly heat up to 220°C under vacuum to evaporate the material in the three-necked flask to dryness. Crude lactide is obtained in the receiving bottle, crushed and transferred to a beaker, filtered with a Buchner funnel, and the filter cake is recrystallized twice from ethanol and twice from ethyl acetate, and then dried in an oven at 40°C for 48 h to obtain dry refined lactide crystals.

[0042] (2) Preparation and purification of non-toxic medical grade polylactic acid: Take 130 g of refined lactide, grind it with a mortar, transfer it to a single-necked flask, place it in a 40 ℃ water bath, and rotary evaporate it under vacuum for 2 h. Take out 10 g of lactide from the single-necked flask and put it in a beaker, add 0.05% stannous octoate and 0.05% dodecanol according to the mass ratio, stir evenly and transfer it back to the single-necked flask. Remove the water bath, rotate and mix under vacuum for 1 h, then transfer it to a 500 mL sealed reaction bottle, first evacuate to -0.1MPa and then add nitrogen protection for 5 min, repeat once, and nitrogen protection for the third time for 1 h. After evacuating again, place it in an oil bath at 130 ℃ for reaction for 24 h, and obtain crude polylactic acid after cooling. Add dichloromethane according to the mass ratio of crude polylactic acid to dichloromethane of 1:2 to dissolve, then precipitate with ethanol, wash, and dry at 30 ℃ for 24 h to obtain polylactic acid.

[0043] Take 20 g of polylactic acid and dissolve it in 2 L of dichloromethane; then add 2 L of 0.1 mol / L hydrochloric acid, stir thoroughly at 2000 r / min for 30 min, and then stand to separate the layers. Take the dichloromethane layer and extract it three times with the same volume of 0.1 mol / L hydrochloric acid. Add 10 g of anhydrous sodium sulfate, dry it, filter it, and evaporate the filtrate to obtain refined non-toxic medical grade polylactic acid.

[0044] Comparative Example 1: This comparative example provides a method for preparing polylactic acid, comprising the following steps: (1) Preparation and purification of lactide: Add 900 g of polymer grade lactic acid (mass fraction Wt 80%) and 20 g of analytically pure stannous octoate to a 2000 mL three-necked flask, heat to a certain temperature under vacuum and maintain for a certain time for dehydration. Specifically, heat to 140°C under vacuum and maintain for 2.6 h, then heat to 220°C under vacuum until evaporated to dryness. The material ratio, temperature control and maintenance time are shown in Table 1. Finally, a light yellow liquid is obtained in the three-necked flask. Replace a new clean and dry reactor as a receiving bottle, and quickly heat to 220°C under vacuum to evaporate the material in the three-necked flask to dryness. Crude lactide is obtained in the receiving bottle, crushed and transferred to a beaker, and filtered with a Buchner funnel. The filter cake is recrystallized twice with ethanol and twice with ethyl acetate, and then dried in an oven at 40°C for 48 h to obtain dry refined lactide crystals.

[0045] (2) Preparation and purification of polylactic acid: Take 130 g of refined lactide, grind it with a mortar, transfer it to a single-necked flask, place it in a 40 ℃ water bath, and rotary evaporate it under vacuum for 2 h. Take out 10 g of lactide from the single-necked flask and put it in a beaker, add 0.5% stannous octoate and 0.3% dodecanol according to the mass ratio, stir evenly and transfer it back to the single-necked flask. Remove the water bath, rotate and mix under vacuum for 1 h, then transfer it to a 500 mL sealed reaction bottle, first evacuate to -0.1MPa and then add nitrogen protection for 5 min, repeat once, and nitrogen protection for the third time for 1 h. After evacuating again, place it in an oil bath at 130 ℃ for reaction for 24 h, and obtain crude polylactic acid after cooling. Add dichloromethane according to the mass ratio of crude polylactic acid and dichloromethane of 1:2 to dissolve, then precipitate with ethanol, wash, and dry at 30 ℃ for 24 h to obtain polylactic acid.

[0046] Comparative Example 2: This comparative example provides a method for preparing polylactic acid, comprising the following steps: (1) Preparation and purification of lactide: Add 900 g of polymer grade lactic acid (mass fraction Wt 88%) and 20 g of analytically pure stannous octoate to a 2000 mL three-necked flask, heat to a certain temperature under vacuum and maintain for a certain time for dehydration. Specifically, heat to 140°C under vacuum and maintain for 4 hours. The material ratio, temperature control and maintenance time are shown in Table 1. Finally, a light yellow liquid is obtained in the three-necked flask. Replace a new clean and dry reactor as a receiving bottle, and quickly heat to 220°C under vacuum to evaporate the material in the three-necked flask to dryness. Crude lactide is obtained in the receiving bottle, crushed and transferred to a beaker, and filtered with a Buchner funnel. The filter cake is recrystallized twice with ethanol and twice with ethyl acetate, and then dried in an oven at 40°C for 48 hours to obtain dry refined lactide crystals.

[0047] (2) Preparation and purification of polylactic acid: Take 130 g of refined lactide, grind it with a mortar, transfer it to a single-necked flask, place it in a 40 ℃ water bath, and rotary evaporate it under vacuum for 2 h. Take out 10 g of lactide from the single-necked flask and put it in a beaker, add 0.5% stannous octoate and 0.2% dodecanol according to the mass ratio, stir evenly and transfer it back to the single-necked flask. Remove the water bath, rotate and mix under vacuum for 1 h, then transfer it to a 500 mL sealed reaction bottle, first evacuate to -0.1MPa and then add nitrogen protection for 5 min, repeat once, and nitrogen protection for the third time for 1 h. After evacuating again, place it in an oil bath at 130 ℃ for reaction for 24 h, and obtain crude polylactic acid after cooling. Add dichloromethane according to the mass ratio of crude polylactic acid to dichloromethane of 1:2 to dissolve, then precipitate with ethanol, wash, and dry at 30 ℃ for 24 h to obtain polylactic acid.

[0048] Comparative Example 3: This comparative example provides a method for preparing polylactic acid, comprising the following steps: (1) Preparation and purification of lactide: Add 900 g of polymer grade lactic acid (mass fraction Wt 98%) and 20 g of analytically pure stannous octoate to a 2000 mL three-necked flask, heat to a certain temperature under vacuum and maintain for a certain time for dehydration. Specifically, heat to 140°C under vacuum and maintain for 5 hours. The material ratio, temperature control and maintenance time are shown in Table 1. Finally, a light yellow liquid is obtained in the three-necked flask. Replace a new clean and dry reactor as a receiving bottle, and quickly heat to 220°C under vacuum to evaporate the material in the three-necked flask to dryness. Crude lactide is obtained in the receiving bottle, crushed and transferred to a beaker, and filtered with a Buchner funnel. After the filter cake is recrystallized twice with ethanol and twice with ethyl acetate, it is dried in an oven at 40°C for 48 hours to obtain dry refined lactide crystals.

[0049] (2) Preparation and purification of polylactic acid: Take 130 g of refined lactide, grind it with a mortar, transfer it to a single-necked flask, place it in a 40 ℃ water bath, and rotary evaporate it under vacuum for 2 h. Take out 10 g of lactide from the single-necked flask and put it in a beaker, add 0.5% stannous octoate and 0.1% dodecanol according to the mass ratio, stir evenly and transfer it back to the single-necked flask. Remove the water bath, rotate and mix under vacuum for 1 h, then transfer it to a 500 mL sealed reaction bottle, first evacuate to -0.1MPa and then add nitrogen protection for 5 min, repeat once, and nitrogen protection for the third time for 1 h. After evacuating again, place it in an oil bath at 130 ℃ for reaction for 24 h, and obtain crude polylactic acid after cooling. Add dichloromethane according to the mass ratio of crude polylactic acid to dichloromethane of 1:2 to dissolve, then precipitate with ethanol, wash, and dry at 30 ℃ for 24 h to obtain polylactic acid.

[0050] Comparative Example 4: This comparative example provides a method for preparing polylactic acid, comprising the following steps: (1) Preparation and purification of lactide: Add 900 g of polymer grade lactic acid (mass fraction Wt 98%) and 20 g of analytical pure zinc acetate to a 2000 mL three-necked flask, heat to a certain temperature under vacuum and maintain for a certain time for dehydration. Specifically, heat to 140°C under vacuum and maintain for 6 hours, then heat to 220°C under vacuum until evaporated to dryness. The material ratio, temperature control and maintenance time are shown in Table 1. Finally, a light yellow liquid is obtained in the three-necked flask. Replace a new clean and dry reactor as a receiving bottle, and quickly heat to 220°C under vacuum to evaporate the material in the three-necked flask to dryness. Crude lactide is obtained in the receiving bottle, crushed and transferred to a beaker, and filtered with a Buchner funnel. The filter cake is recrystallized twice with ethanol and twice with ethyl acetate, and then dried in an oven at 40°C for 48 hours to obtain dry refined lactide crystals.

[0051] (2) Preparation and purification of polylactic acid: Take 130 g of refined lactide, grind it with a mortar, transfer it to a single-necked flask, place it in a 40 ℃ water bath, and rotary evaporate it under vacuum for 2 h. Take out 10 g of lactide from the single-necked flask and put it in a beaker, add 0.5% stannous octoate and 0.05% dodecanol according to the mass ratio, stir evenly and transfer it back to the single-necked flask. Remove the water bath, rotate and mix under vacuum for 1 h, then transfer it to a 500 mL sealed reaction bottle, first evacuate to -0.1MPa and then add nitrogen protection for 5 min, repeat once, and nitrogen protection for the third time for 1 h. After evacuating again, place it in an oil bath at 130 ℃ for reaction for 24 h, and obtain crude polylactic acid after cooling. Add dichloromethane according to the mass ratio of crude polylactic acid to dichloromethane of 1:2 to dissolve, then precipitate with ethanol, wash, and dry at 30 ℃ for 24 h to obtain polylactic acid.

[0052] The material compositions of Examples 1-4 and Comparative Examples 1-4 and the time of maintaining at different dehydration temperatures are shown in Table 1.

[0053] Table 1 Material composition of Examples 1-4 and Comparative Examples 1-4 and the time of holding at different dehydration temperatures

[0054] The test results are as follows: 1. Lactide testing experiment 1. Experimental methods: (1) Yield calculation Calculate according to the formula: yield = actual output / theoretical output.

[0055] (2) Purity test The lactide prepared in Examples 1-4 and Comparative Examples 1-4 was subjected to a purity test using gas chromatography. The test conditions were as follows: Instrument: Gas chromatograph GC-2014C (Shimadzu, Japan); Conditions: Inlet: 270°C; FID detector: 280°C; split injection (50:1); carrier gas: high-purity ammonia; carrier gas flow rate: 1mL / min; injection volume: 0.4uL; chromatographic column: 40mm threaded glass column.

[0056] 2. Experimental results: The steps of “(1) Preparation and purification of lactide” in Example 1 and Comparative Example 1 were repeated 5 times, and the yield and purity of the prepared lactide were measured. The results are shown in Table 2.

[0057] Table 2 Results of the lactide yield and purity, molecular weight and distribution of polylactic acid in Example 1 and Comparative Example 1 repeated 5 times

[0058] As can be seen from Table 2, the average yield of lactide in Example 1 is 34.9%, the average purity is 88.6%, the maximum deviation of the yield after 5 repetitions is 1.7%, and the average deviation is 0.04%; although the purity after 5 repetitions is not high, the maximum deviation is 0.6%, the average deviation is 0.01%, the molecular weight distribution average is 1.82, the distribution is narrow, and the data dispersion is small.

[0059] The average yield of lactide in comparative example 1 is 31.0%, the average purity is 84.5%, the maximum deviation of the yield after 5 repetitions is 3.2%, the average deviation is 0.16%; the maximum deviation of the purity after 5 repetitions is 2.2%, the average deviation is 0.04%, and the average molecular weight distribution is 2.28. Whether it is yield or purity, Example 1 is higher than Comparative Example 1. These two sets of data show that as a dehydration catalyst, under stage heating conditions, the performance of the first catalyst zinc acetate is better than that of the traditional stannous octoate.

[0060] The steps of “(1) Preparation and purification of lactide” in Example 2 and Comparative Example 2 were repeated 5 times, and the yield and purity of the prepared lactide were measured. The results are shown in Table 3.

[0061] Table 3 Results of the lactide yield and purity, molecular weight and distribution of polylactic acid in Example 2 and Comparative Example 2 repeated 5 times

[0062] As can be seen from Table 3, the average yield of lactide in Example 2 is 38.3%, the average purity is 92.4%, the maximum deviation of the yield after 5 repetitions is 0.9%, and the average deviation is 0.04%; the purity after 5 repetitions is improved, with a maximum deviation of 0.5% and an average deviation of 0.02%. The average molecular weight distribution is 1.73, the distribution is narrow, and the data dispersion is small.

[0063] The average yield of lactide in Comparative Example 2 is 37.2%, the average purity is 91.3%, the maximum deviation of the yield after 5 repetitions is 1.2%, and the average deviation is 0.22%; the maximum deviation of the purity after 5 repetitions is 1%, the average deviation is 0.16%, and the average molecular weight distribution is 2.24. Whether it is the yield or the purity, Example 2 is higher than Comparative Example 2. These two sets of data show that as a dehydration catalyst, zinc acetate performs better than traditional stannous octoate. The data are significantly improved relative to Example 1 and Comparative Example 1, indicating that the extension of each time period is beneficial to the synthesis of lactide.

[0064] The steps of “(1) Preparation and purification of lactide” in Example 3 and Comparative Example 3 were repeated 5 times, and the yield and purity of the prepared lactide were measured. The results are shown in Table 4.

[0065] Table 4 Results of the lactide yield and purity, molecular weight and distribution of polylactic acid in Example 3 and Comparative Example 3 repeated 5 times

[0066] As can be seen from Table 4, the average yield of lactide in Example 3 is 46.3%, the average purity is 98.8%, and the maximum deviation of the yield after 5 repetitions is 0.24%, and the average deviation is 0.01%; the purity after 5 repetitions is improved, with a maximum deviation of 1.12% and an average deviation of 0.01%. The average molecular weight distribution is 1.43, the distribution is narrow, and the data dispersion is small.

[0067] The average yield of lactide in Comparative Example 3 is 41.0%, the average purity is 95.3%, the maximum deviation of the yield after 5 repetitions is 1.46%, the average deviation is 0.01%; the maximum deviation of the purity after 5 repetitions is 1.12%, the average deviation is 0.01%, and the average molecular weight distribution is 3.00. Both the yield and the purity of Example 3 are higher than those of Comparative Example 3. These two sets of data show that as a dehydration catalyst, zinc acetate performs better than traditional stannous octoate. The data are also significantly improved relative to Example 1, Example 2, Comparative Example 1, and Comparative Example 2, indicating that the temperature and time control under this condition is better.

[0068] The steps of “(1) Preparation and purification of lactide” in Example 4 and Comparative Example 4 were repeated 5 times, and the yield and purity of the prepared lactide were measured. The results are shown in Table 5.

[0069] Table 5 Results of the lactide yield and purity, molecular weight and distribution of polylactic acid in Example 4 and Comparative Example 4 repeated 5 times

[0070] As can be seen from Table 5, the average yield of lactide in Example 4 is 43.9%, the average purity is 97.4%, the maximum deviation of the yield after 5 repetitions is 3.16%, and the average deviation is 9.6%; the purity after 5 repetitions is improved, with a maximum deviation of 0.52% and an average deviation of 0.01%, a narrow molecular weight distribution, and a small degree of data dispersion.

[0071] The average yield of lactide in Comparative Example 4 is 38.2%, the average purity is 93.5%, the maximum deviation of the yield after 5 repetitions is 0.26%, the average deviation is 0.01%; the maximum deviation of the purity after 5 repetitions is 0.44%, the average deviation is 0.01%, and the average molecular weight distribution is 2.40. Whether it is yield or purity, Example 4 is higher than Comparative Example 4. These two sets of data show that as a dehydration catalyst, zinc acetate performs better than traditional stannous octoate. The data are significantly lower than Example 3 and Comparative Example 3, indicating that the temperature and time control under this condition are not as good as Example 3 and Comparative Example 3.

[0072] Based on the above, it can be seen that Example 3 is the best process condition for “(1) Preparation and purification of lactide”.

[0073] 2. Testing experiment of polylactic acid: 1. Experimental methods: (1) Cytotoxicity test Cytotoxicity test is a cytotoxicity risk assessment using in vitro cell culture methods. This test was conducted in accordance with the MTT cytotoxicity test method of the National Standard for Biological Evaluation of Medical Devices Part 5: In Vitro Cytotoxicity Test GB / T 16886.5-2017 / ISO10993-5:2009.

[0074] The medium control group consisted of a cell culture medium without test samples, namely MEM containing 10% fetal bovine serum (Gibco).

[0075] Test group: Based on the ratio of 0.2 g / mL, 1.9272 g of the test sample was added to 9.6 mL + 0.0 mL (adsorption amount) of cell culture medium, and the sample was shaken and extracted at 60 r / min for (24 ± 2) h at (37 ± 1) °C to prepare the test solution; then the test solution was prepared with the cell culture medium to prepare test groups with volume fractions of 12.5%, 25%, 50%, and 100%; Positive control group: latex gloves, based on 6cm 2 / mL ratio, take 90cm 2The test sample was extracted in 15.0 mL of cell culture medium at (37±1)°C and 60 r / min for (24±2) h.

[0076] Negative control group: high-density polyethylene resin, based on a ratio of 0.2 g / mL, take 1.6603 g of the test sample in 8.3 mL of cell culture medium, at (37±1)°C, 60 r / min shaking extraction for (24±2) h.

[0077] The non-toxic medical grade polylactic acid obtained in Example 3 was used to perform cytotoxicity MTT assay, and the results are shown in Table 6.

[0078] (2) Hemolysis rate test This test was conducted in accordance with the "Guidelines for Hemolysis Tests in the National Standard for Biological Evaluation of Medical Devices Part 4: Selection of Tests for Interaction with Blood GB / T 16886.4-2022 / ISO 10993-4:2017". The test sample was in direct contact with blood, and the amount of hemoglobin released by rupture and dissolution of red blood cells was measured to evaluate the in vitro hemolysis of the test sample. In this test, the test sample, sodium chloride injection, and purified water were mixed with fresh diluted anticoagulated rabbit blood in a water bath, incubated for 60 minutes, and then centrifuged. The supernatant was aspirated to determine its absorbance, and its hemolysis rate was calculated.

[0079] Among them, the test sample group (A) was prepared according to the ratio of 5g sample to 10mL sodium chloride injection. The actual sample added to each tube was: 5.02g, 5.03g, 5.03g, and then 10mL of sodium chloride injection was added respectively.

[0080] Negative control group (B): Add 10 mL of sodium chloride injection to each tube and prepare 3 tubes in parallel.

[0081] Positive control group (C): Add 10 mL of purified water to each tube and prepare 3 tubes in parallel.

[0082] The hemolysis rate test results of medical grade polylactic acid are shown in Table 7.

[0083] (3) Molecular weight and distribution The molecular weight and molecular weight distribution of the polymers were tested using a Waters GPC1525 gel permeation chromatograph.

[0084] 2. Experimental results: Table 6 MTT assay results of cytotoxicity of medical grade polylactic acid

[0085] As can be seen from Table 6, the survival rate of the 100% test group was greater than 70%, and no cytotoxicity was found.

[0086] Table 7 Hemolysis rate test results of medical grade polylactic acid

[0087] It can be seen from Table 7 that the hemolysis rate of the medical-grade polylactic acid material synthesized by the present invention is less than 5%, which meets the standards for medical materials.

[0088] The HPLC chart of the non-toxic medical grade polylactic acid prepared by the present invention is as follows: Figure 2 As shown, through integral calculation, the material purity reaches more than 99%.

[0089] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing non-toxic medical grade polylactic acid using a toxic catalyst, characterized in that: The following steps are involved: S1. Preparation and purification of lactide: adding lactic acid and the first catalyst, heating to a certain temperature under vacuum and maintaining for a certain period of time for dehydration, evaporating to dryness, filtering, recrystallizing, and drying to obtain refined lactide crystals; S2. Preparation and purification of non-toxic medical grade polylactic acid: S21. Take the lactide, the second catalyst and the initiator obtained in step S1, mix and stir evenly, place in a water bath, and rotate and mix under vacuum for 0.5 to 2 h, first evacuate and then add nitrogen protection, evacuate again and place in an oil bath at 120 to 150 ° C for reaction for 12 to 48 h, cool and add dichloromethane to dissolve, then precipitate and wash with ethanol, and dry at 20 to 40 ° C for 12 to 36 h to obtain polylactic acid; S22. Take polylactic acid and add dichloromethane to dissolve it, wash it with acid, add a desiccant to dry it, filter it, and evaporate the filtrate to dryness to obtain refined non-toxic medical grade polylactic acid.

2. The method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst according to claim 1, characterized in that: The first catalyst in step S1 is zinc acetate or zinc oxide.

3. The method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst according to claim 1, characterized in that: In step S1, the temperature is raised to a certain temperature under vacuum and maintained for a certain time to dehydrate and evaporate to dryness, which specifically includes the following steps: (1) Raise the temperature to 30-40°C under vacuum and maintain for 0.2-0.6h; (2) Heat to 80-90°C under vacuum and maintain for 0.2-0.6h; (3) Heat to 90-110°C under vacuum and maintain for 0.2-0.6h; (4) Raise the temperature to 110-130°C under vacuum and maintain for 1.0-2.5 hours; (5) Raise the temperature to 130-150°C under vacuum and maintain for 1.0-2.5 hours; (6) Then raise the temperature to 210-230°C under vacuum until the product is evaporated to dryness.

4. The method for preparing non-toxic medical grade polylactic acid using a toxic catalyst according to claim 2, characterized in that: In step S1, the mass ratio of lactic acid to the first catalyst is (30-50):

1.

5. The method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst according to claim 2, characterized in that: The second catalyst in step S21 is any one of stannous octoate, aluminum alkoxide, and stannous chloride.

6. The method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst according to claim 5, characterized in that: The initiator in step S21 is dodecanol or p-toluenesulfonic acid.

7. The method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst according to claim 6, characterized in that: In step S21, the mass ratio of lactide to the second catalyst is 20000:(1-5).

8. The method for preparing non-toxic medical grade polylactic acid using a toxic catalyst according to claim 1, characterized in that: The specific steps of the acid washing in step S22 are: adding 0.1-0.2 mol / L inorganic acid or water-soluble organic acid, stirring at 2000-3000 r / min for 20-40 min, standing for stratification, taking the dichloromethane layer, and repeatedly extracting 3-5 times with the same volume and concentration of inorganic acid or water-soluble organic acid.

9. A non-toxic medical grade polylactic acid, characterized in that: It is prepared by the method according to any one of claims 1 to 8.

10. Use of the non-toxic medical-grade polylactic acid prepared by the method for preparing non-toxic medical-grade polylactic acid using a toxic catalyst according to claims 1 to 8 or the non-toxic medical-grade polylactic acid according to claim 9 in the preparation of clinical orthopedic materials, drug sustained-release materials, medical surgical sutures, fracture fixation materials and tissue engineering materials.

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