A method for preparing a polyester having a controlled molecular weight and a controlled number of terminal carboxyl groups and a low monomer residue

Abstract

The application relates to the field of medical injection adjuvants, and discloses a preparation method of polyester with controllable molecular weight and terminal carboxyl quantity and low monomer residue, which comprises the following steps: (1) obtaining linear polyester crude product through ring-opening polymerization of a cyclic monomer; (2) dissolving the linear polyester crude product in a first solvent to form a polyester solution, dissolving an acidic reagent in a second solvent, adding the second solvent into the polyester solution, keeping the linear polyester in an intermediate state of flocculating and precipitating but not agglomerating, incubating until the molecular weight is 18000-22000 Da, quenching with water, and taking the polyester precipitate; (3) redissolving the polyester precipitate with a third solvent to obtain a polyester redissolution, granulating, washing, collecting the polyester, and drying to obtain the polyester. The polyester prepared by the method has high batch consistency, a narrow molecular weight fluctuation range, a stable terminal carboxyl quantity, and low monomer residue rate; in addition, the method has mild conditions, a short cycle, high safety, and can be mass-produced.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical injection adjuvant, in particular to a preparation method of polyester with controllable molecular weight and terminal carboxyl number and low monomer residue. BACKGROUND

[0002] Biodegradable polyesters have been widely used for controlled drug delivery. They have the advantage that they do not require surgical removal after completing the sustained release of drugs, and are directly enzymatically or chemically degraded into small molecules that can be excreted from the body. The polylactic acid (PLA) and poly(lactic-co-glycolic acid) (PLGA) families have shown desirable biocompatible properties, and are therefore widely accepted as pharmaceutical components and are particularly used in sustained release formulations.

[0003] Drugs encapsulated in polylactic acid microparticles are released by diffusion through the aqueous environment or by degradation of the polymer. The properties of the polyester product significantly affect the in vitro and in vivo release behavior of the microspheres made from the polyester. The molecular weight of the polyester, first and foremost, affects the biodegradation rate. Secondly, the residual catalyst, for the diffusion mechanism of active agent release, the polymer should remain intact until all the active agent is released from the microspheres, and then it degrades. For certain basic polypeptide long-acting formulations, in order to prolong the sustained release period, the binding force between the drug and the polyester needs to be increased, which has a certain requirement for the number of free carboxyl groups of the polyester.

[0004] The synthesis method of the polyester is well known in the art, which can be prepared by polycondensation of lactic acid, or lactic acid and glycolic acid, or by ring-opening polymerization of lactide, or lactide and glycolide. Among them, the ring-opening polymerization is the mainstream process for the synthesis of polyesters due to its many advantages. The ring-opening polymerization of the polyester is to convert the linear polyester by heating the cyclic monomer under the condition of catalyst, but the polyester prepared by this ring-opening polymerization method does not always have free carboxyl groups at the end of the generated polyester, or the number of free carboxyl groups is not enough to meet the encapsulation of a certain number of polypeptide compounds with basic amino acids into the formulation. For example, the polyester obtained by direct ring-opening polymerization, when the molecular weight of the polyester product is in the range of 15,000-25,000 Da, the number of free carboxyl groups is often less than 50 μmol / g. Although the catalyst can significantly improve the molecular weight of the polyester and the reaction rate, the obtained polyester often lacks polydispersity, i.e. the proportion of low molecular weight of the polyester is not enough.

[0005] It is also difficult to control the polyester molecular weight within a very narrow fluctuation range by the ring-opening polymerization method, thus it is impossible to ensure the consistency of the number of free carboxyl groups between batches, which is critical for the development of a polypeptide sustained-release preparation suitable for the sustained release of a physiologically active polypeptide for at least about 3 months or more. Small molecular weight distribution and differences in the number of free carboxyl groups can cause significant changes in the pharmacokinetics in vivo, including the burst effect (Cmax) and the area under the curve (AUC).

[0006] Korean Patent KR100142016B1 discloses a method for producing a polyester by ring-opening polymerization of a cyclic ester compound, the purpose of the invention is to provide a method for producing a polyester which can accurately control the molecular weight of the polyester within the desired range. It determines the amount of hydroxyl compound added to the reaction system based on the amount of free carboxylic acid contained in the cyclic ester compound and the quantitative value before the ring-opening polymerization of the cyclic ester compound to prepare the polyester. This method can stabilize the molecular weight of the polyester synthesis, but it cannot guarantee the content of the terminal carboxyl group within the required range.

[0007] Japanese Patent JP2000159865A discloses a method for preparing a bioabsorbable polyester by ring-opening polymerization of a cyclic ester compound, which includes charging the main raw materials containing the cyclic ester compound, the catalyst and the initiator into the reaction system and performing dehydration operation. Specifically, it includes controlling the water content in the reaction system to be within the range of 0.10-0.20% by weight relative to the total amount of the cyclic ester compound, and then starting the ring-opening polymerization. Similar to the principle of KR100142016B1, it can control the molecular weight of the polymer within a relatively narrow range (intrinsic viscosity r1±0.005), but it cannot guarantee the content of the terminal carboxyl group within the required range. With the same weight average molecular weight, the narrower the molecular weight distribution, the lower the content of the terminal carboxyl group.

[0008] In summary, each method in the prior art has its own shortcomings, therefore it is necessary to develop a polyester preparation method that is easy to control the molecular weight and has sufficient free carboxyl group content, especially when the polyester molecular weight is between 15,000-25,000 Da, the terminal carboxyl group content needs to reach 50-200 μmol / g. Moreover, the preparation steps are simple and easy to control, and do not involve extreme conditions, excessive flammable and explosive reagents, especially some dangerous reagents that need to be isolated from oxygen and water, such as ether reagents, zinc catalysts and some highly toxic reagents. The polyester obtained by this method has a batch size of at least 10 kg. SUMMARY

[0009] In order to solve the above technical problems, the application provides a preparation method of polyester with controllable molecular weight and terminal carboxyl quantity and low monomer residue.

[0010] The specific technical scheme of the application is as follows: a preparation method of polyester with controllable molecular weight and terminal carboxyl quantity and low monomer residue, comprising the following steps:

[0011] (1) heating a cyclic monomer in the presence of a catalyst and an initiator to obtain a linear polyester with a molecular weight of 30000-60000 Da through ring-opening polymerization, and then heating the linear polyester to obtain a linear polyester crude product.

[0012] (2) cooling and crushing the linear polyester crude product, dissolving the linear polyester in a first solvent to form a polyester solution in a sealed reactor, dissolving an acidic reagent in a second solvent, adding the acidic reagent to the polyester solution to keep the linear polyester in a flocculent state without agglomeration, incubating until the molecular weight of the linear polyester is 18000-22000 Da, then adding water to quench the reaction, and collecting the polyester precipitate.

[0013] The first solvent is a good solvent for the polyester; the acidic reagent is one or more degradation products of the linear polyester; and the second solvent is a hydrophilic reagent that is miscible with the first solvent.

[0014] (3) redissolving the polyester precipitate in a third solvent to obtain a polyester redissolution, granulating the polyester redissolution in an aqueous solution, washing, collecting the polyester, and drying to obtain a polyester product. The polyester product has a molecular weight range of 18,000-22,000 Da, a polydispersity of 1.3-1.7, a polyester terminal carboxyl content of 50-200 μmol / g, and is a linear polyester with only one carboxyl unit at each end of each polyester chain.

[0015] In the above step (1), taking GA and L-LA as examples of the cyclic monomer, the cyclic monomer undergoes ring-opening polymerization under the action of the catalyst to generate PLGA with a molecular weight of 30000-60000 Da, and the reaction principle is as follows:

[0016]

[0017] In the above step (2), the acid reagent is gradually added to the polyester solution in a closed reaction kettle, the mixed solution is initially clear, as the proportion of acid reagent increases, the mixed solution begins to flocculate and precipitate but does not agglomerate, that is, the flocculation precipitates in a dispersed state, before forming larger agglomerates, the addition of acid reagent is stopped, and incubation is carried out until the molecular weight reaches 18000-22000 Da. Among them, the reaction principle of ester bond acidolysis of polyester under acidic conditions is as follows:

[0018]

[0019] The present application finds that the change rate of polyester molecular weight is strongly related to the incubation temperature and the acid reagent system. Regardless of the acid reagent system, temperature can accelerate the degradation rate of polyester in acidic solution, but temperature can accelerate the volatilization of some volatile reagents and exacerbate the uniformity of the late reaction of some systems.

[0020] Further, the present application finds that when the polyester in the mixed solution is in a flocculation and precipitation but not agglomeration intermediate state, rather than a completely clear and transparent or partially agglomerated or completely agglomerated polyester precipitation state, it is beneficial to obtain a polyester product with controllable molecular weight and number of terminal carboxyl groups. Through the above method of the present application, the flocculation and precipitation but not agglomeration intermediate state of the polyester in the mixed solution is controllable, the intermediate state refers to the flocculation and precipitation of the polyester in the mixed solution, and the intermediate state before forming agglomerates, that is, the initial period of flocculation and precipitation to the mature period of flocculation and precipitation; further, the intermediate state of the flocculation and precipitation of the polyester in the mixed solution is in the mature period. With the continuous addition of acid reagent solution in step (2), partial agglomeration and precipitation occurs, until complete agglomeration and precipitation.

[0021] Even if the incubation temperature is raised above the glass transition temperature of the polyester, the polyester should exist in an intermediate state of flocculation but not agglomeration. If it exists in a completely clear and transparent state, the hydrolysis rate is slow, it takes 48-72 h to reduce the molecular weight from the range of 30,000-60,000 Da to the range of 18,000-22,000 Da, and the molecular weight distribution is wide, and the content of terminal carboxyl groups of the polyester is uncontrollable; if it exists in an entirely agglomerated state, the agglomerates form a dough with a certain fluidity when the solution is stirred, the hydrolysis process mainly occurs on the surface, and there is a difference in the hydrolysis rate between the surface and the interior, the small molecules formed by the surface degradation can be quickly transferred to the solution, and the small molecules formed by the interior degradation need a certain process and time to be transferred to the solution, and at least 24 h or more is needed for the polyester to reduce the molecular weight from the range of 30,000-60,000 Da to the range of 18,000-22,000 Da, and similarly, the molecular weight distribution is wide, and the content of terminal carboxyl groups of the polyester is uncontrollable. Surprisingly, the pre-polyester of the application remains in the above-mentioned intermediate state in an acidic system, and the hydrolysis time of the polyester to reduce the molecular weight from the range of 30,000-60,000 Da to the range of 18,000-22,000 Da is only within 12 h, and the molecular weight distribution of the polyester is narrower, and the content of terminal carboxyl groups of the polyester is controllable.

[0022] As a preference, in step (1), the cyclic monomer is selected from glycolide and / or lactide; and the linear polyester is selected from linear lactide-glycolide copolymer, linear polyglycolide, linear polylactide.

[0023] As a preference, in step (1), the initiator is selected from lactic acid and glycolic acid (since lactic acid is unstable and prone to form lactic anhydride, it is actually a 90% lactic acid aqueous solution).

[0024] As a preference, in step (1), the catalyst is selected from organic tin catalysts; and can be selected from alkyl tin, such as stannous octoate, tin dichloride, tin tetrachloride, stannous fluoride, stannous acetate, stannous stearate; among them, stannous octoate has been approved by FDA for use, and therefore stannous octoate is the most preferred.

[0025] As a preference, in step (1), the molar ratio of the initiator to the cyclic monomer is 1:150-1:300, and the molar ratio of the catalyst to the cyclic monomer is 1:1000-1:2500. The temperature of the ring-opening polymerization reaction is 130-200℃, and the time is 2-8 h.

[0026] The amount of catalyst and the reaction temperature mainly determine the reaction time of the system, and the amount of initiator mainly determines the average molecular weight range of the linear polyester crude product.

[0027] As preferred, in step (2), the particle size of the linear polyester crude product has no particular limitation, and the particle size only affects the dissolution time, but does not affect the final state of the polyester solution. In order to meet the requirement of fully dissolving the polyester block within 0.5-2 hours, the particle size of the coarse block can be less than 1 cm.

[0028] As preferred, in step (2), the first solvent is selected from chlorinated hydrocarbons, acetone, methyl acetate, ethyl acetate and other good solvents for polyester. The acidic agent is selected from lactic acid and glycolic acid. When the acidic agent is selected from lactic acid, since lactic acid itself is unstable and easy to produce lactic anhydride, the acidic agent can be a 90% lactic acid aqueous solution. The second solvent is selected from ethyl acetate, acetone, dimethyl sulfoxide and water.

[0029] As preferred, in step (2), the first solvent is selected from chlorinated hydrocarbons and acetone, and the second solvent is selected from dimethyl sulfoxide and water, and more preferably water.

[0030] It is found by experimental exploration that when the first solvent is selected from dichloromethane and the second solvent is selected from an acidic aqueous solution, the linear polyester crude product is insoluble in the mixed system, presents a white precipitated state (dough-like), i.e. a state of agglomeration and precipitation. After heating the system and stirring for a period of time, the white polymer is still in the form of dough and has a certain flowability, and moves with the movement of the solution system. Therefore, the surface degradation of the hydrolysis process of the system is faster, and the polyester inside cannot be fully contacted with the acidic agent. When the system is heated, the flowability of the polyester increases, which can increase the penetration of the acidic agent, but the heating also accelerates the volatilization of dichloromethane, and only polyester, acid and aqueous solution are left in the system. The polyester is insoluble in the acidic aqueous solution, which aggravates its precipitation state (the volume of the dough increases). Using this system for polyester hydrolysis, the number of carboxyl groups meets the requirements as the hydrolysis time is prolonged, but the polydispersity of the polyester product is more significant, which increases its non-uniformity.

[0031] When the first solvent is selected from chlorinated hydrocarbons and acetone, and the second solvent is selected from dimethyl sulfoxide and water, both can form such a flocculent precipitated intermediate state when mixed. When the second solvent is selected from water, the polyester remains in this intermediate state within a relatively wide window even at different acetone-water ratios. Among them, the first solvent is preferably acetone, and the second solvent is dimethyl sulfoxide and water; the first solvent is preferably acetone, and the second solvent is water. It should be noted that the acetone-water mixture has a high boiling point, low toxicity and is easy to remove.

[0032] As preferred, in step (2), the content of the linear polyester crude product in the first solvent is 5-50 wt%, the content of the acidic agent in the second solvent is 20-80 wt%, and the weight ratio of the acidic agent to the linear polyester crude product is 1:1-10:1.

[0033] As preferred, in step (2), the temperature of the incubation is 20-80℃, the stirring speed is 100-500 rpm, and the time is 6-16 h; further preferably 8-12 h.

[0034] As preferred, in step (2), the temperature of the quenching water is 0-10℃, and the amount is 1-10 times the volume of the first solvent.

[0035] As preferred, in step (3), the third solvent is selected from ethyl acetate and acetone, preferably acetone; and the weight ratio of the polyester precipitate to the third solvent is 1:10-1:20.

[0036] The third solvent is a redissolving agent. When the viscosity of the polyester solution is large, the polyester system can be diluted to a suitable viscosity range by adjusting the amount of the third solvent, facilitating further spray treatment. The polyester precipitate is redissolved in the third solvent, and the amount of the third solvent can be determined according to the viscosity of the polyester.

[0037] As preferred, in step (3), the aqueous solution is water; and the volume ratio of the aqueous solution to the polyester redissolution solution is 25:1-100:1.

[0038] As preferred, in step (3), the granulation, washing, collection of the polyester, and drying are performed as follows: the polyester redissolution solution is sprayed into the aqueous solution under the liquid surface, forming extremely fine polyester particles during the spraying process; the polyester particles are stirred and washed in the aqueous solution to remove catalysts, solvents, acidic reagents, and other impurities; the polyester particles are collected by filtration or centrifugation, and dried by vacuum drying, air flow drying, or freeze drying to remove residual low-boiling solvents and residual water.

[0039] Compared with the prior art, the present application has the following beneficial effects:

[0040] (1) The polyester prepared according to the method of the present application has high batch consistency, a narrow molecular weight fluctuation range (18,000-22,000 Da, with a polydispersity of 1.3-1.7), a stable number of terminal carboxyl groups (50-200 μmol / g), and low monomer residual rate, meeting the quality requirements for injection grade (<0.5%).

[0041] (2) The preparation method of the present application has mild and safe conditions, and does not involve a large amount of flammable and explosive reagents, especially some dangerous reagents that need to be isolated from oxygen and water, catalysts such as ether reagents and zinc catalysts, and some highly toxic reagents. It does not involve extreme condition control such as ultralow temperature, and saves costs.

[0042] (3) The preparation method of the present application has fewer process steps, a short route, and a short cycle, with a production cycle of 1.5 days.

[0043]

[0044] (4) The preparation method of the present application involves very few types of solvents or reagents, and the residual solvents are all below the minimum requirement. BRIEF DESCRIPTION OF DRAWINGS

[0045] Figure 1 Figure 2 is a photograph of the polyester in the initial stage of flocculation but not agglomeration in Example 2 of the present application;

[0046] Figure 2 Figure 3 is a photograph of the polyester in the mature stage of flocculation but not agglomeration in Example 2 of the present application, i.e. before the formation of agglomerates after the increase in flocculation;

[0047] Figure 3 Figure 4 is a photograph of the polyester in the precipitation state in Comparative Example 1 of the present application;

[0048] Figure 4 Figure 5 is a photograph of the polyester in the dissolution state in Comparative Example 2 of the present application. DETAILED DESCRIPTION

[0049] The present application will be further described below in conjunction with examples.

[0050] General Examples

[0051] A method for preparing a polyester with controllable molecular weight and number of terminal carboxyl groups and low monomer residue, comprising the following steps:

[0052] (1) heating a cyclic monomer in the presence of a catalyst and an initiator to obtain a linear polyester with a molecular weight of 30,000-60,000 Da through ring-opening polymerization, and then hot discharging to obtain a crude linear polyester.

[0053] As a preferred embodiment, the cyclic monomer is selected from glycolide and / or lactide; the linear polyester is selected from linear lactide-glycolide copolymer, linear polyglycolide and linear polylactide; the initiator is selected from d, 1-lactic acid and glycolic acid; the catalyst is selected from organotin catalysts; and the organotin catalysts can be selected from alkyl tin, such as stannous octoate, tin dichloride, tin tetrachloride, stannous fluoride, stannous acetate and stannous stearate; and the most preferred catalyst is stannous octoate. The molar ratio of the initiator to the cyclic monomer is 1:150-1:300, and the molar ratio of the catalyst to the cyclic monomer is 1:1000-1:2500. The temperature of the ring-opening polymerization is 130-200°C, and the time is 2-8 h.

[0054] (2) The linear polyester crude product is cooled and broken into pieces, dissolved in a first solvent in a closed reactor to form a polyester solution, an acidic reagent is dissolved in a second solvent and gradually added to the polyester solution, so that the linear polyester in the resulting mixed solution is kept in an intermediate state of flocculation but not agglomeration, incubated, and after the molecular weight of the linear polyester reaches 18000-22000 Da, water is added to quench, and the polyester precipitate is collected.

[0055] As a preference, the particle size of the linear polyester crude product is below 1 cm. The first solvent is selected from chlorinated hydrocarbons, acetone, methyl acetate, ethyl acetate and other good solvents for polyester. The acidic reagent is a degradation product of linear polyester and is selected from lactic acid and glycolic acid; when the acidic reagent is selected from lactic acid, it can be a 90% lactic acid aqueous solution. The second solvent is a hydrophilic reagent that is miscible with the first solvent and is selected from ethyl acetate, acetone, dimethyl sulfoxide and water. The first solvent is selected from chlorinated hydrocarbons and acetone; the second solvent is selected from dimethyl sulfoxide and water; more preferably, water. The content of the linear polyester crude product in the first solvent is 5-50 wt%; the content of the acidic reagent in the second solvent is 20-80 wt%; the weight ratio of the acidic reagent to the linear polyester crude product is 1:1-10:1. The temperature for incubation is 20-80°C, the stirring speed is 100-500 rpm, and the time is 6-16 h; further preferably, 8-12 h. The temperature of the quenching water is 0-10°C, and the amount is 1-10 times the volume of the first solvent.

[0056] (3) The polyester precipitate is redissolved in a third solvent to obtain a polyester redissolution, which is sprayed into an aqueous solution under the liquid surface, and during the spraying process, extremely fine polyester particles are formed, which are stirred and washed in the aqueous solution to remove catalysts, solvents and acidic reagents and other impurities; the polyester particles are collected by filtration or centrifugation, and dried by vacuum drying, air flow drying or freeze drying to remove residual low-boiling solvents and residual water, thereby obtaining a polyester with a molecular weight of 18000-22000 Da, a PDI of 1.3-1.7 and a terminal carboxyl content of 50-100 μmol / g.

[0057] As a preference, the third solvent is selected from ethyl acetate and acetone, preferably acetone; the weight ratio of the polyester precipitate to the third solvent is 1:10-1:20. The aqueous solution is water; the volume ratio of the aqueous solution to the polyester redissolution is 25:1-100:1.

[0058] Example 1:

[0059] (1) Synthesis of high molecular weight PLA from DL-lactide

[0060] Into a reaction vessel 1 under nitrogen protection, 10 mol of lactide and 0.05 mol of lactic acid were added, and the temperature of the system was raised to 150°C to melt the substrate and initiator. 0.01 mol of stannous octoate was dissolved in 200 uL of xylene, and then added to the above reaction system under nitrogen protection, followed by polymerization at 180°C for 4 h. The reaction vessel was opened, and the obtained linear polyester crude product was directly subjected to hot discharge. The molecular weight of the linear polyester crude product was Mw=52113 Da.

[0061] (2) Hydrolysis of high molecular weight PLA into low molecular weight PLA

[0062] 50 g of the obtained linear polyester crude product was added into 250 g of acetone and stirred to dissolve. 111.1 g of 90 wt% lactic acid aqueous solution was dissolved in 111.1 g of water, and then gradually added into the obtained linear polyester crude product solution. After stirring, the solution was kept in a flocculent intermediate state without agglomeration, the temperature of the reaction system was controlled at 65°C, and the stirring speed was 200 rpm. Samples were taken at 4 h, 8 h, and 16 h of acidolysis, respectively, and then vacuum dried to detect the polyester molecular weight and terminal carboxyl content.

[0063] (I) Polyester molecular weight detection method:

[0064] Reference solution: about 10 mg of polystyrene reference material with molecular weight of 3, 13, 30, 50, 100, and 200 kDa, respectively, was added into a 10 mL volumetric flask to dissolve in tetrahydrofuran;

[0065] Test solution: 50 mg of sample was added into a 10 mL volumetric flask to dissolve in tetrahydrofuran;

[0066] Chromatographic column: HR 4 THF, HR 3 THF, HR 4 THF in series;

[0067] Mobile phase: tetrahydrofuran;

[0068] Column temperature: 40°C;

[0069] Injection volume: 100 uL.

[0070] (II) Polyester terminal carboxyl content detection method: 0.02 mol / L tetrabutylammonium hydroxide standard solution: 100 mL of 0.1N tetrabutylammonium hydroxide standard solution was added into a 500 mL volumetric flask to dissolve in methanol;

[0071] Background solution: 100 mg of L-lactic acid was dissolved in a mixture of methanol: 1, -dioxane (1:1) to make up to 1000 mL;

[0072] Blank solution: Take tetrahydrofuran solution 80 mL, add background solution 40 mL, mix well and then titrate;

[0073] Test sample solution: Take sample 1.5 g, add tetrahydrofuran solution 80 mL to dissolve, add background solution 40 mL, mix well and then titrate;

[0074] Instrument: potentiometric titrator.

[0075] Table 1: Polyester molecular weight and terminal carboxyl group results of Example 1

[0076]

[0077] As can be seen from Table 1, as the hydrolysis time is prolonged, the polyester molecular weight gradually decreases, and the number of terminal carboxyl groups of the polyester gradually increases. When the molecular weight reaches the range of 18,000-22,000 Da, the content of terminal acidic groups is between 50-100 μmol / g.

[0078] As can be seen from Table 1, the hydrolysis rate has a linear relationship with time, y = -2192.8x + 51702, R 2 = 0.9958. Under fixed hydrolysis conditions, the polyester molecular weight can be controlled by the hydrolysis time.

[0079] Example 2:

[0080] (1) Synthesis of high molecular weight PLA from DL-lactide

[0081] 10 mol of lactide and 0.05 mol of lactic acid were added to a reaction kettle 1 under nitrogen protection, and the temperature of the system was raised to 150°C to melt the substrate and initiator. 0.01 mol of stannous octoate was dissolved in 200 uL of xylene, and then added to the above reaction system under nitrogen protection, followed by polymerization at 180°C for 4 h. The reaction kettle 1 was disassembled, and the obtained linear polyester crude product was directly subjected to hot discharge. The molecular weight of the linear polyester crude product was Mw = 52113 Da (same as Example 1).

[0082] (2) Hydrolysis of high molecular weight PLA into low molecular weight PLA

[0083] The obtained 135 g of linear polyester crude product was cooled to room temperature and then crushed to below 0.5 cm, and then put into a reaction vessel 2, and 270 g of acetone was added and stirred to dissolve. 30 g of 90 wt% lactic acid aqueous solution was dissolved in 15 g of water, and then gradually added to the obtained linear polyester crude product solution, and after stirring, the solution was kept in a flocculation state but not in an intermediate state of agglomeration (the state when the lactic acid aqueous solution was just added is shown in Figure 1 , at this time the polyester was in the initial intermediate state of flocculation but not agglomeration, and the state when the lactic acid aqueous solution was added was as shown in Figure 2At this time, the polyester was in the intermediate state of the mature stage of flocculation but not agglomeration, i.e., after the flocculation increased, the agglomeration was formed, and the temperature in the reaction container 2 was controlled to 70°C, and the stirring was maintained at 250 rpm for 8 h. Then, 540 g of 5°C water was added for quenching and precipitation.

[0084] (3) Extraction, collection, and drying of low molecular weight PLA

[0085] In the reaction kettle 3, 10 L of water was filled, and the precipitated polyester after the incubation was dissolved in acetone (10%, w / w) at a rate of 50 mL / min, and the polyester solution was sprayed into the reaction kettle 3. The pressure of the nozzle was 4-6 bar, and the polyester solution was sprayed into the water in the reaction kettle 3, and the stirring was started at the same time. The spraying and washing were performed at the same time, and after the removal of the residual reagents such as acetone, lactic acid, stannous octoate, and xylene, the polyester product was collected by centrifugation and vacuum dried. The molecular weight of the polyester product was 18790 Da, and the content of the carboxyl group at the end of the polyester was 64 μmol / g.

[0086] Example 3:

[0087] (1) Synthesis of high molecular weight PLA from DL-lactide

[0088] 9 mol of lactide and 0.05 mol of lactic acid were added to the reaction kettle 1 under nitrogen protection, and the temperature of the system was increased to 150°C to melt the substrate and the initiator. 0.0045 mol of stannous octoate was dissolved in 100 uL of xylene, and then added to the above reaction system under nitrogen protection, followed by polymerization at 175°C for 6 h. The reaction kettle was opened, and the obtained linear polyester crude product was directly subjected to hot discharge. The molecular weight of the linear polyester crude product was 40057 Da.

[0089] (2) Hydrolysis of high molecular weight PLA into low molecular weight PLA

[0090] The obtained 121 g of linear polyester crude product was cooled to room temperature and crushed to below 0.5 cm, and then added to the reaction container 2. 60.5 g of acetone was added and stirred to dissolve. 67.2 g of 90 wt% lactic acid aqueous solution was dissolved in 28.8 g of dimethyl sulfoxide, and then gradually added to the obtained linear polyester crude product solution. After stirring, the solution was initially clear, and then the intermediate state of flocculation but not agglomeration was formed. The temperature in the reaction container 2 was controlled to 60°C, and the stirring was maintained at 250 rpm for 12 h. Then, 1000 g of 2°C water was added for quenching and precipitation.

[0091] (3) Extraction, collection, and drying of low molecular weight PLA

[0092] In the reactor 3 filled with 10 L water, the polyester was redissolved in acetone (10%, w / w), and fed into the single-fluid nozzle at a rate of 50 mL / min, with the nozzle air pressure of 4-6 bar. The polyester redissolved solution was sprayed into the water in the reactor 3, while the stirring in the reactor 3 was started. The spraying and washing were performed simultaneously. After removing the residual reagents such as dichloromethane, dimethyl sulfoxide, lactic acid, stannous octoate, dimethylbenzene, etc., the polyester product was collected by centrifugation and vacuum dried. The molecular weight of the finished product was Mw=20547 Da, and the content of the terminal carboxyl group of the polyester was 47 μmol / g.

[0093] Example 4:

[0094] (1) Synthesis of high molecular weight PLA from DL-lactide

[0095] 5 mol of lactide and 0.045 mol of lactic acid were added to the reactor 1 under nitrogen protection, and the temperature of the system was raised to 155°C to melt the substrate and initiator. 0.005 mol of stannous octoate was dissolved in 100 μL of dimethylbenzene, and then added to the above reaction system under nitrogen protection. Subsequently, the polymerization was performed at 175°C for 4 h. The reactor was disassembled, and the obtained linear polyester crude product was directly subjected to hot discharge. The molecular weight of the linear polyester crude product was Mw=38593 Da.

[0096] (2) Hydrolysis of high molecular weight PLA into low molecular weight PLA

[0097] The obtained 650 g of linear polyester crude product was cooled to room temperature and then crushed to below 0.5 cm, and then put into the reactor 2. 1.3 kg of acetone was added to dissolve and stir. 1.5 kg of 90 wt% lactic acid aqueous solution was dissolved in 4.5 kg of water, and then gradually added to the obtained linear polyester crude product solution. After stirring, the solution was kept in an intermediate state of flocculation but not agglomeration. The temperature in the reactor 2 was controlled to 55°C, and the stirring was maintained at 250 rpm for 6 h. Subsequently, 4 kg of 2°C water was added for quenching and precipitation.

[0098] (3) Extraction, collection, and drying of low molecular weight PLA

[0099] In the reactor 3 filled with 400 L water, the polyester was redissolved in acetone (8%, w / w), and fed into the single-fluid nozzle at a rate of 500 mL / min, with the nozzle air pressure of 4-6 bar. The polyester redissolved solution was sprayed into the water in the reactor 3, while the stirring in the reactor 3 was started. The spraying and washing were performed simultaneously. After removing the residual reagents such as dichloromethane, acetone, lactic acid, stannous octoate, dimethylbenzene, etc., the polyester product was collected by centrifugation and vacuum dried. The molecular weight of the finished product was Mw=21420 Da, and the content of the terminal carboxyl group of the polyester was 35 μmol / g.

[0100] Example 5:

[0101] (1) Synthesis of high molecular weight PLA from DL-lactide

[0102] Into a reaction vessel 1 under nitrogen protection, 10 mol of lactide and 0.05 mol of lactic acid were added, and the system was raised to 150°C to melt the substrate and initiator. 0.01 mol of stannous octoate was dissolved in 200 uL of xylene and added to the above reaction system under nitrogen protection, followed by polymerization at 180°C for 4 h. The reaction vessel was disassembled, and the obtained linear polyester crude product was directly subjected to hot discharge. The molecular weight of the linear polyester crude product was Mw=50541 Da.

[0103] (2) Hydrolysis of high molecular weight PLA into low molecular weight PLA

[0104] The obtained 1.40 kg of linear polyester crude product was cooled to room temperature and crushed to below 0.5 cm, and then was put into a reaction vessel 2, and 14.0 kg of acetone was added and stirred to dissolve. 5 kg of 90 wt% lactic acid aqueous solution was dissolved in 15 kg of water, and was gradually added to the obtained linear polyester crude product solution, and after stirring, the solution was kept in a flocculated but not agglomerated intermediate state, the temperature in the reaction vessel 2 was controlled to 55°C, and stirring was maintained at 250 rpm for 8 h. Subsequently, 20 kg of 5°C water was added for quenching and precipitation.

[0105] (3) Extraction, collection, and drying of low molecular weight PLA

[0106] In a reaction vessel 3, 420 L of water was filled, and the polyester was precipitated in acetone at 10% (w / w) and was supplied into a single-fluid nozzle at a rate of 500 mL / min, and the pressure of the nozzle gas port was 4-6 bar. The polyester solution was sprayed into the water in the reaction vessel 3, and at the same time, the stirring of the reaction vessel 3 was started, and the spraying and washing were simultaneously performed. After removing the residual reagents such as acetone, lactic acid, stannous octoate, and xylene, the polyester product was collected by centrifugation, and was vacuum dried. The molecular weight of the obtained polyester product was Mw=19240 Da, and the carboxyl end group content of the polyester was 57 pmol / g.

[0107] Example 6:

[0108] (1) Synthesis of high molecular weight PLA from DL-lactide, glycolide

[0109] Into a reaction vessel 1 under nitrogen protection, 2.5 mol of lactide, 2.5 mol of glycolide, and 0.025 mol of lactic acid were added, and the system was raised to 150°C to melt the substrate and initiator. 0.005 mol of stannous octoate was dissolved in 100 uL of xylene and added to the above reaction system under nitrogen protection, followed by polymerization at 180°C for 6 h. The reaction vessel was disassembled, and the obtained linear polyester crude product was directly subjected to hot discharge. The molecular weight of the linear polyester crude product was Mw=45204 Da.

[0110] (2) High molecular weight PLGA is hydrolyzed into low molecular weight PLGA

[0111] The obtained 450 g linear polyester crude product was cooled to room temperature and then crushed to below 0.5 cm, and was put into the reaction kettle 2, 3.6 kg of acetone was added and stirred to dissolve. 1 kg of 90 wt% lactic acid aqueous solution was dissolved in 1.8 kg of water, and was gradually added to the obtained linear polyester crude product liquid, and after stirring, the solution was kept in a flocculation state but not in an agglomeration state, the temperature in the reaction kettle 2 was controlled to 50°C, and stirring was maintained at 250 rpm for 10 h. Then 15 kg of 5°C water was added for quenching and precipitation.

[0112] (3) Extraction, collection and drying of low molecular weight PLGA

[0113] In the reaction kettle 3, 200 L of water was filled, and the polyester was precipitated in acetone at a concentration of 10% (w / w), and was supplied into the single-fluid nozzle at a rate of 500 mL / min, the pressure of the nozzle gas port was 4-6 bar, and the polyester resolvent was sprayed into the water in the reaction kettle 3, and at the same time the stirring of the reaction kettle 3 was started, and the spraying and washing were carried out at the same time, after removing the residual reagents such as acetone, lactic acid, stannous octoate and dimethylbenzene, the polyester product was collected by centrifugation, and was vacuum dried. The molecular weight of the polyester finished product was Mw=17340 Da, and the content of the terminal carboxyl group of the polyester was 89 μmol / g.

[0114] Table 2 Example 6 polyester molecular weight, terminal carboxyl group, LA / GA results

[0115]

[0116] Comparative Example 1:

[0117] (1) High molecular weight PLA is synthesized from DL-lactide

[0118] 9 mol of lactide and 0.05 mol of lactic acid were added to the reaction kettle 1 under nitrogen protection, and the temperature of the system was raised to 150°C to melt the substrate and initiator. 0.0045 mol of stannous octoate was dissolved in 100 uL of dimethylbenzene, and was added to the above reaction system under nitrogen protection, and then was polymerized at 175°C for 6 h. The reaction kettle was disassembled, and the obtained linear polyester crude product was directly discharged by heating. The molecular weight of the linear polyester crude product was Mw=40057 Da (the same as Example 3).

[0119] (2) High molecular weight PLA is hydrolyzed into low molecular weight PLA

[0120] 50 g of the obtained linear polyester crude product was added to 100 g of dichloromethane and stirred to dissolve, and 200 g of 45 wt% lactic acid aqueous solution was added to the above system, and during stirring, the linear polyester was partially agglomerated and precipitated (as shown in Figure 3The reaction temperature was raised to 65°C, and the polyester precipitated and the number of lumps increased. The semi-solid polyester crude product was removed at 10 h, 20 h, and 30 h, respectively, and dried under vacuum. The molecular weight and terminal carboxyl content of the polyester were determined.

[0121] Comparative Example 2

[0122] (1) Synthesis of high molecular weight PLA from DL-lactide

[0123] 9 moles of lactide and 0.05 moles of lactic acid were added to reaction kettle 1 under nitrogen protection, and the temperature of the system was raised to 150°C to melt the substrate and initiator. 0.0045 moles of stannous octoate was dissolved in 100 uL of xylene, and added to the above reaction system under nitrogen protection, followed by polymerization at 175°C for 6 h. The reaction kettle was disassembled, and the obtained linear polyester crude product was directly subjected to hot discharge. The molecular weight of the linear polyester crude product was Mw= 40057 Da (the same as Example 3).

[0124] (2) Hydrolysis of high molecular weight PLA to low molecular weight PLA

[0125] 50 g of the obtained polyester crude product was added to 500 g of acetone and stirred to dissolve, and 100 g of 90% lactic acid aqueous solution was added to the above system. The polyester was in a dissolved state (as shown in Figure 3 the solution appeared white), and the reaction temperature was raised to 65°C. The polyester solution was periodically removed, and the organic solvent was removed by vacuum evaporation. The molecular weight and terminal carboxyl content of the polyester were determined.

[0126] Comparative Example 3

[0127] (1) Synthesis of target molecular weight PLA from DL-lactide

[0128] 9 moles of lactide and 0.1 moles of lactic acid were added to reaction kettle 1 under nitrogen protection, and the temperature of the system was raised to 150°C to melt the substrate and initiator. 0.0045 moles of stannous octoate was dissolved in 100 uL of xylene, and added to the above reaction system under nitrogen protection, followed by polymerization at 175°C for 6 h. The reaction kettle was disassembled, and the obtained linear polyester crude product was directly subjected to hot discharge. The molecular weight of the linear polyester crude product was Mw= 21038 Da, Mn= 14712 Da, and PDI 1.43.

[0129] Table 3: Results of polyester molecular weight and terminal carboxyl content of Examples 2-5 and Comparative Examples 1-3

[0130]

[0131]

[0132] From the above table, it can be seen that:

[0133] The hydrolysis rate of Comparative Example 1 is significantly slower than that of Example 1, and when the molecular weight reaches the range of 18,000-22,000 Da, the content of terminal acidic groups exceeds 100 μmol / g, which is caused by the non-uniform hydrolysis rate of the surface and internal part of the molecule, the surface hydrolysis rate is faster, more low molecular weight polyesters are formed, and the number of terminal acidic groups is significantly increased, but the main part degrades slowly.

[0134] The hydrolysis rate of Comparative Example 2 is slower than that of Comparative Example 1, which may be due to the fact that when there is no water in the system, the hydrolysis rate is greatly slowed down, even if the system is in a homogeneous solution state, even if the molecular motion free energy is high, and is disordered.

[0135] As can be seen from Comparative Example 3, when the target molecular weight PLA is synthesized from DL-lactide by adjusting the amount of initiator, the number of terminal acidic groups is low, less than 50 μmol / g, which is not conducive to the encapsulation of polypeptide drugs because the interaction between such PLA and polypeptide drugs is weak. Moreover, it is difficult to accurately control the molecular weight by direct synthesis method.

[0136] Table 4: Detection results of monomer and catalyst residues in polyesters of Examples 1-6 and Comparative Example 3

[0137] Test group Lactide / % Lactic acid / % Glycolide / % Glycolic acid / % Stannous isooctoate / ppm Example 2 0.03 Not detected / / / Example 3 0.03 Not detected / / / Example 4 0.03 Not detected / / / Example 1 0.05 Not detected / / 80 Example 5 0.04 Not detected / / / Example 6 0.04 Not detected 0.02 Not detected / Comparative Example 3 1.99 0.05 / / /

[0138] As can be seen from the above table, the residual amount of each monomer in Examples 1-6 is extremely low, and the controllability of the quality of the polyester product is excellent. Comparative Example 3 barely meets the requirement of the limit of 2.0% for the residual lactide of the copolymer of the microspheres specified in the monograph of the 2020 edition of the Chinese Pharmacopoeia. The ideal control of the quality of the polyester product cannot be achieved, and the residual monomer can easily cause the degradation of the polyester product, and the quality of the polyester product is unstable with the storage period. The reason for the above difference is that Comparative Example 3 is directly synthesized to the target molecular weight of the polyester, and the monomer residue is high, while Examples 1-6 are first synthesized to a high molecular weight polyester, and then hydrolyzed to a low molecular weight range. The monomers (synthesis substrates: lactide, glycolide, synthesis by-products: lactic acid, glycolic acid) remaining in the crude polyester can be removed to a very low level during the hydrolysis, granulation and cleaning processes, and these oligomers have good solubility in aqueous solvents. The catalyst can be reduced to below 100 ppm, as shown in Example 1.

[0139] The raw materials and equipment used in the present application are conventional raw materials and equipment in the art unless otherwise specified; the methods used in the present application are conventional methods in the art unless otherwise specified.

[0140] The above description is only a preferred embodiment of the present application, and does not limit the present application in any way. Any simple modification, change and equivalent transformation of the above embodiment based on the technical essence of the present application still falls within the protection scope of the technical solution of the present application.

Claims

1. A method for producing a polyester having a controlled molecular weight and a controlled number of terminal carboxyl groups and a low monomer residue, characterized by The method comprises the following steps: (1) heating the cyclic monomer in the presence of a catalyst and an initiator to obtain linear polyester with a molecular weight of 30000-60000 Da through ring-opening polymerization, and then discharging the product to obtain crude linear polyester; (2) crushing the crude linear polyester after cooling, dissolving it in a first solvent to form a polyester solution, dissolving an acidic reagent in a second solvent, adding the acidic reagent to the polyester solution to keep the linear polyester in a flocculent state without agglomeration, incubating until the molecular weight of the linear polyester is 18000-22000 Da, then quenching with water, and collecting the polyester precipitate; the first solvent is a good solvent for polyester; the acidic reagent is one or more degradation products of the linear polyester; and the second solvent is a hydrophilic reagent that is miscible with the first solvent; (3) redissolving the polyester precipitate in a third solvent to obtain a polyester redissolution, granulating the polyester redissolution in an aqueous solution, washing, collecting the polyester, and drying to obtain polyester with a molecular weight of 18000-22000 Da, a PDI of 1.3-1.7, and a terminal carboxyl group content of 50-100 μmol / g.

2. The preparation method according to claim 1, wherein: In step (1), the cyclic monomer is selected from glycolide and / or lactide; the initiator is selected from lactic acid and glycolic acid; the catalyst is selected from organic tin catalysts; the linear polyester is selected from linear copoly(lactide-co-glycolide), linear poly(glycolide), and linear poly(lactide).

3. The production method according to claim 1 or 2, characterized by: In step (1), the molar ratio of the initiator to the cyclic monomer is 1:150-1:300; the molar ratio of the catalyst to the cyclic monomer is 1:1000-1:2500; the ring-opening polymerization is carried out at a temperature of 130-200°C for 2-8 h.

4. The production method according to claim 1 or 2, characterized by: In step (2), the first solvent is selected from chlorinated hydrocarbons, acetone, methyl acetate, and ethyl acetate; the acidic reagent is selected from lactic acid and glycolic acid; the second solvent is selected from ethyl acetate, acetone, dimethyl sulfoxide, and water.

5. The production method according to claim 4, characterized by: In step (2), the first solvent is selected from chlorinated hydrocarbons and acetone; the second solvent is selected from dimethyl sulfoxide and water.

6. The production method according to claim 4, characterized by: In step (2), the content of the crude linear polyester in the first solvent is 5-50 wt%; the content of the acidic reagent in the second solvent is 20-80 wt%; the weight ratio of the acidic reagent to the crude linear polyester is 1:1-10:

1.

7. The production method according to claim 4, wherein: In step (2), the incubation is carried out at a temperature of 20-80°C, a stirring speed of 100-500 rpm, and for 6-16 h; the quenching is carried out with water at a temperature of 0-10°C and in an amount of 1-10 times the volume of the first solvent.

8. The production method according to claim 1 or 2, characterized by: In step (3), the third solvent is selected from ethyl acetate and acetone; the weight ratio of the polyester precipitate to the third solvent is 1:10-1:

20.

9. The production method according to claim 1 or 2, wherein: In step (3), the aqueous solution is water; the volume ratio of the aqueous solution to the polyester redissolution is 25:1-100:

1.

10. The production method according to claim 1 or 2, characterized by: In step (3), the granulation, washing, collection and drying of the polyester are performed by spraying the polyester re-dissolved solution into the aqueous solution under the liquid surface, forming polyester particles in the spraying process, stirring and washing the polyester particles in the aqueous solution, collecting the polyester particles by filtration or centrifugation, and drying the polyester particles by vacuum drying, air flow drying or freeze drying.

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