阅读说明：本技术 一种复合引发剂在高性能医用聚维酮pvpk90制备中的应用 (Application of composite initiator in preparation of high-performance medical povidone PVPK90 ) 是由 应青 陈潜 朱明仕 朱南军 张明 于 2020-12-31 设计创作，主要内容包括：本发明公开了一种复合引发剂在高性能医用聚维酮PVPK90制备中的应用,及药剂辅料制备方法技术领域,方案具体为：反应体系中加入纯水,再加入氢氧化钠或氨水调节pH；加入NVP(N-乙烯基吡咯烷酮)单体,搅拌均匀；搅拌条件下加入复合引发剂,低温聚合；高温聚合；消除残留单体；复合引发剂包括水、NVP和两种以上偶氮引发剂。本发明采用一步加入复合引发剂引发聚合反应的做法,从整体上加快了反应启动和聚合速率,缩短了聚合反应的时间,避免了在低温聚合仅加入单一引发剂,后续再加入引发剂消除残单造成的问题,消残单效率高、效果好,最终得到了分子量分布窄且均匀,溶解度更高、残单含量更低的产品。(The invention discloses an application of a composite initiator in the preparation of high-performance medical povidone PVPK90 and the technical field of preparation methods of medicament auxiliary materials, and the scheme is as follows: adding pure water into the reaction system, and then adding sodium hydroxide or ammonia water to adjust the pH; adding NVP (N-vinyl pyrrolidone) monomer, and stirring uniformly; adding a composite initiator under the stirring condition, and polymerizing at low temperature; high-temperature polymerization; eliminating residual monomers; the composite initiator comprises water, NVP and more than two azo initiators. The method adopts the method of adding the composite initiator in one step to initiate the polymerization reaction, thereby integrally accelerating the reaction start and the polymerization rate, shortening the polymerization reaction time, avoiding the problem caused by adding only a single initiator in the low-temperature polymerization and subsequently adding the initiator to eliminate the residual monomers, having high residual monomer elimination efficiency and good effect, and finally obtaining the product with narrow and uniform molecular weight distribution, higher solubility and lower residual monomer content.)

1. The application of the composite initiator in the polymerization of povidone K90 is characterized in that: the method comprises the following steps:

(1) adding pure water into the reaction system, and then adding a sodium hydroxide solution or ammonia water to adjust the pH;

(2) adding NVP monomer, and stirring uniformly;

(3) adding a composite initiator under the stirring condition, and polymerizing at low temperature;

(4) high-temperature polymerization;

(5) eliminating residual monomers;

the composite initiator comprises water, NVP and more than two water-soluble azo initiators.

2. The use of the composite initiator according to claim 1 in the preparation of high performance medical povidone PVPK90, wherein: the water-soluble azo initiator is azobutyronitrile or azoamidine initiator.

3. The use of the composite initiator according to claim 2 in the preparation of high performance medical povidone PVPK90, wherein: the initiator is one or more than two of azoamidine initiators V-40, V-50, V-60 or V-65.

4. Use of the composite initiator according to claim 1 in povidone K90 polymerization, characterized in that: in the composite initiator, the mass ratio of water to NVP to the water-soluble azo initiator is (2-3) to (3-7).

5. The use of the composite initiator according to claim 1 in the preparation of high performance medical povidone PVPK90, wherein: and (2) adjusting the pH value in the step (1) to 8-11, wherein the concentration of the sodium hydroxide solution is 20-40% wt, and the concentration of the ammonia water is 15-20% wt.

6. Use of the composite initiator according to claim 1 in povidone K90 polymerization, characterized in that: the mass ratio of the water in the step (1) to the NVP monomer in the step (2) is (4-6): 1.

7. The use of the composite initiator according to claim 1 in the preparation of high performance medical povidone PVPK90, wherein: the mass ratio of the NVP monomer added in the step (2) to the composite initiator added in the step (3) is (250-800) to (3-10).

8. The use of the composite initiator according to claim 1 in the preparation of high performance medical povidone PVPK90, wherein: and (3) carrying out low-temperature polymerization at the polymerization temperature of 45-70 ℃ for 1.0-3.0 h.

9. The use of the composite initiator according to claim 1 in the preparation of high performance medical povidone PVPK90, wherein: and (4) carrying out high-temperature polymerization at the polymerization temperature of 70-90 ℃ for 1.0-3.0 h.

10. Use of the composite initiator according to claim 1 in povidone K90 polymerization, characterized in that: the method for eliminating the residual monomers in the step (5) comprises the following steps: cooling the reaction system, adding glacial acetic acid, adjusting pH to below 4.0, stirring for 1.0-3.0h, cooling to 30-45 deg.C.

Technical Field

The invention relates to the technical field of preparation methods of medicament accessories, in particular to application of a composite initiator in preparation of high-performance medical povidone PVPK 90.

Background

The povidone PVPK90 belongs to a homopolymer, is water-soluble white powder, is polymerized from N-vinyl pyrrolidone (NVP) monomers, has a molecular weight of about 130 ten thousand, and has a relatively wide molecular weight distribution curve. Homopolymers are generally expressed in terms of K values for different molecular weights, the higher the K value the higher the molecular weight, the K value range of 81-99 for PVPK 90. Povidone PVPK90 is widely used as a pharmaceutical excipient, especially oral tablets and solutions. After oral administration, povidone is not absorbed by gastrointestinal tract and mucous membrane, and has no toxicity. In oral tablets, povidone solution acts as a binder in wet granulation. The powder of povidone PVPK90 can also be added into other powder directly in dry state, mixed, added with water, alcohol or water-alcohol solution and granulated. In oral or parenteral administration, povidone PVPK90 acts as a solubilizing agent to accelerate the dissolution of poorly soluble drugs from solid formulations. Povidone PVPK90 solution can also be used as coating material. In addition, povidone PVPK90 also acts as a suspending, stabilizing or viscosity-increasing agent in some topical and oral suspensions and solutions. Many poorly soluble drugs have increased solubility when mixed with povidone.

When the PVPK90 is used as a pore-forming agent, when the PVPK90 is used as a pore-forming agent and applied to a pure water ultrafiltration membrane and a kidney filtration membrane, the PVP is enriched on the surface of the membrane, when the surface of the membrane is contacted with water, PVP is dissolved in the water to form a channel for a non-solvent to enter the interior of the membrane, and the points form growth points of finger-shaped pores which grow to a membrane matrix in a subsequent process. Finally, the polymer dense phase forms a film, and the polymer dilute phase is eluted. The addition ratio of PVPK90 is generally about 10 wt%. The higher addition amount increases the porosity of the film, but decreases the strength and hydrophobicity of the film, which affects the usability of the film.

Good solubility properties and very low residual vinylpyrrolidone monomer are particularly required in the polymerization of PVPK90 for pharmaceutical and filtration applications. The present data show that a single initiator is used for polymerization, and then an initiator is added to eliminate the residual monomer. Such a process may result in a long reaction time that makes it difficult to satisfy the solubility of PVPK90 and low residue simultaneously.

Disclosure of Invention

In order to solve the problems, the invention provides a novel preparation method of povidone PVPK90, which adopts a composite initiator process, wherein an initiator is added at one time, and the elimination of residues is completed at one time by raising the temperature after the polymerization of PVPK90 is completed. This results in a low temperature polymerization and a high temperature elimination of the residual monomers simultaneously with the complex initiator. The molecular weight distribution of the produced PVPK90 is narrow and uniform, the solubility is good, and simultaneously, the residual monomer is low, and the specific scheme is as follows:

the application of the composite initiator in the preparation of the high-performance medical povidone PVPK90 comprises the following steps:

(1) adding pure water into the reaction system, and adding a sodium hydroxide solution or ammonia water to adjust the pH;

(2) adding NVP (N-vinyl pyrrolidone) monomer, and stirring uniformly;

(3) adding a composite initiator under the stirring condition, and polymerizing at low temperature;

(4) high-temperature polymerization;

(5) eliminating residual monomers;

the composite initiator comprises water, NVP and more than two water-soluble azo initiators.

Preferably, the water-soluble azo initiator is an azoisobutyronitrile or azoamidine initiator.

Preferably, the azo amidine initiator is one or more of azo amidine initiators V-40, V-50, V-60 or V-65.

Preferably, in the composite initiator, the mass ratio of water to NVP to the water-soluble azo initiator is (2-3) to (3-7).

Preferably, the pH is adjusted to 8-11 in the step (1), the concentration of the sodium hydroxide solution is 20-40% wt, and the concentration of the ammonia water is 15-20% wt.

Preferably, after the pH is adjusted in the step (1), the water can be heated to 55-65 ℃, and then the vacuum-pumping deoxidation is carried out for 5-15 min.

Preferably, the mass ratio of the water in the step (1) to the NVP monomer in the step (2) is (4-6): 1.

Preferably, the NVP monomer added in the step (2) can be continuously vacuumized for 5-15min during stirring, and then the nitrogen is continuously introduced.

Preferably, the mass ratio of the NVP monomer added in the step (2) to the composite initiator added in the step (3) is (250- & lt 800) & gt to (3-10).

Preferably, the polymerization in step (3) is carried out at a low temperature of 45-70 ℃ for 1.0-3.0 h.

Preferably, the high-temperature polymerization in the step (4) is carried out at the polymerization temperature of 70-90 ℃ for 1.0-3.0 h.

Preferably, the method for eliminating residual monomers in the step (5) is as follows: cooling the reaction system, adding glacial acetic acid, adjusting the pH to be below 4.0, and stirring for 1.0-3.0 h. Cooling to 30-45 deg.C.

Preferably, in the method for eliminating residual monomers in the step (5), a single initiator can be added into the system before cooling, and then the mixture is stirred for 1.0 to 3.0 hours. The single initiator is one of the water-soluble azo initiators described above.

Preferably, after eliminating residual monomers in step (5), the solution can be further preserved after adjusting pH to 8-12 with sodium hydroxide solution.

Advantageous effects

The invention has the beneficial effects that:

the method adopts the method of adding the composite initiator in one step to initiate the polymerization reaction, thereby integrally accelerating the reaction start and the polymerization rate, shortening the polymerization reaction time, avoiding the problem caused by adding only a single initiator in the low-temperature polymerization and subsequently adding the initiator to eliminate the residual monomers, having high residual monomer elimination efficiency and good effect, and finally obtaining the product with narrow and uniform molecular weight distribution, higher solubility and lower residual monomer content.

Detailed Description

The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.

The following examples and comparative examples are parallel runs, with the same processing steps and parameters, unless otherwise indicated.

Example 1 povidone K90 was synthesized by initiating polymerization with the addition of a composite initiator:

(1) 1000g of process water was added to a 2000ml three-necked flask. Starting a stirrer (the stirrer is started, the speed is slowly regulated), adding 20 wt% of sodium hydroxide solution, and regulating the pH value to 9;

(2) adding 250g of NVP (N-vinyl pyrrolidone) monomer, and uniformly stirring;

(3) adding a composite initiator under the stirring condition, wherein the low-temperature polymerization temperature is 45-70 ℃, and the polymerization time is 2 hours;

(4) polymerizing at high temperature, wherein the polymerization temperature is 70-90 ℃, and the polymerization time is 2 h;

(5) elimination of residual monomers: cooling the reaction system, adding glacial acetic acid, adjusting the pH value to 4.0, and stirring for 2 h. And cooling to 40 ℃.

The composite initiator comprises 0.5g of azobisisobutyronitrile, 1.5g of azobisisobutyramidine hydrochloride, 1.5g of NVP and 1.5g of water.

Measuring 0.4 wt% of residual monomer and a K value of 90.6 after the step (3); and (4) measuring 0.2 wt% of the residual monomer and the K value of 90.0 after the step (4). The residual content of the final product is below 10 ppm.

Example 2 povidone K90 was synthesized by initiating polymerization with the addition of a composite initiator:

(1) 1000g of process water was added to a 2000ml three-necked flask. Starting a stirrer (the stirrer is started, the speed is slowly regulated), adding 20 wt% of sodium hydroxide solution, and regulating the pH value to 10;

(2) adding 250g of NVP (N-vinyl pyrrolidone) monomer, and uniformly stirring;

(3) adding a composite initiator under the stirring condition, wherein the low-temperature polymerization temperature is 45-70 ℃, and the polymerization time is 1.5 h;

(4) polymerizing at high temperature, wherein the polymerization temperature is 70-90 ℃, and the polymerization time is 1 h;

(5) elimination of residual monomers: cooling the reaction system, adding glacial acetic acid, adjusting the pH value to 4.0, and stirring for 1 h. And cooling to 35 ℃.

The composite initiator comprises 0.5g of azoisobutyronitrile, 2g of azoisobutyramidine, 1.5g of NVP and 1.5g of water.

Measuring 0.5 wt% of residual monomer and a K value of 90.5 after the step (3); and (4) measuring 0.2 wt% of the residual monomer and the K value of 90.1 after the step (4). The residual content of the final product is below 10 ppm.

Example 3 povidone K90 was synthesized by initiating polymerization with the addition of a composite initiator:

(1) 1000g of process water was added to a 2000ml three-necked flask. Starting a stirrer (the stirrer is started, the speed is slowly regulated), adding 20 wt% of sodium hydroxide solution, regulating the pH value to 9, heating water to 60 ℃, and vacuumizing and deoxidizing for 5 min;

(2) adding 250g of NVP (N-vinyl pyrrolidone) monomer, stirring uniformly, continuously vacuumizing for 5min, and then continuously introducing nitrogen for replacement;

(3) adding a composite initiator under the stirring condition, wherein the low-temperature polymerization temperature is 45-70 ℃, and the polymerization time is 2 hours;

(4) polymerizing at high temperature, wherein the polymerization temperature is 70-90 ℃, and the polymerization time is 2 h;

(5) elimination of residual monomers: adding 0.5g of azoisobutyramidine, and stirring for 1 h; cooling the reaction system, adding glacial acetic acid, adjusting the pH value to 4, and stirring for 2 h. And cooling to 40 ℃.

After the reaction is finished, the pH value is adjusted to 8-12 by using a sodium hydroxide solution, and then the mixture is stored.

The composite initiator comprises 0.5g of azobisisobutyronitrile, 1.5g of azobisisobutyramidine, 1.5g of NVP and 1.5g of water.

Measuring 0.4 wt% of residual monomer and a K value of 90.7 after the step (3); and (3) measuring 0.2 wt% of the residual monomer and the K value of 90.3 after the step (4), adding 0.5g of azodiisobutyamidine in the step (5), and measuring 0.1 wt% of the residual monomer and the K value of 90.0 after stirring for 1 h. The residual content of the final product is below 10 ppm.

Example 4 production of povidone K90 in reactor (the detailed steps and conditions not listed in this example refer to examples 1-3, the effect of ammonia is the same as that of sodium hydroxide solution in examples 1-3):

prescription: the feed ratio of each kettle is shown in the following table

In the table, the initiator a and the initiator B are different initiators and are selected from the water-soluble azo initiators described above, for example, the initiator a is selected as azo amidine initiator V60, and the initiator B is selected as azo amidine initiator V50.

Preparation work before production: and checking the clearing state and the state mark of the post, and checking whether various weighing apparatus and instruments meet the requirements. And confirming the name, the batch number, the specification and the quantity of the acquired required raw and auxiliary materials and the name, the batch number, the quantity and the specification of the product to be produced according to the batch production instruction of the production department. Checking the states of production equipment and instruments: whether a bottom valve and a steam valve of the polymerization kettle are closed or not, whether valves of all metering tanks are in a closed state or not, and whether valves of machine seal cooling water are opened or not. Checking whether a thermometer and a pressure gauge on the reaction kettle are normal or not; checking whether the display of the weight sensor can normally display data or not. And (3) checking whether the pressure of a pressure gauge of a raw cooling water pipe on the reaction kettle is normal (at least 0.2MPa), and immediately checking the reason if the pressure is not normal.

And sequentially feeding materials according to the proportion of the fed materials.

The metering of the process water is carried out by a metering tank, and a liquid level scale meter is arranged on the metering tank. And (3) starting a process water valve to process water into the metering tank, closing the water inlet valve when the liquid level reaches a calibration scale, starting a vacuum pump to vacuumize the reaction kettle, starting a purified water metering tank to the valve of the reaction kettle, and pumping 2400 +/-50 Kg of the metered process water into the reaction kettle. Starting a reaction kettle stirrer (the stirrer needs to be slowly regulated when being started), opening a drain valve and a steam valve of a polymerization kettle, heating water in the reaction kettle to 60 +/-2 ℃, vacuumizing until purified water in the kettle is boiled, and deoxidizing for 5 minutes.

Adding NVP and replacing nitrogen

And (3) after the deoxidation in the reaction kettle is finished, immediately pumping the prepared NVP into the reaction kettle, continuing to vacuumize for 5 minutes, stopping vacuumization, opening a nitrogen valve on the kettle, and injecting nitrogen to relieve the vacuum until the pressure is 0.05 MPa. And the nitrogen replacement is finished after the operation is performed again.

Adding an initiator

Ammonia water 500. + -.10 ml is added and the pH value is measured. When the temperature is controlled to 60 +/-2 ℃, the composite initiator dissolved by water is quickly added into the reaction kettle through a funnel when the reaction kettle is in the last vacuum state, the valve is quickly closed, the nitrogen valve is opened until the pressure in the kettle is 0.05MPa, and the nitrogen valve is closed.

Constant temperature, constant pressure polymerization

The temperature in the reaction kettle is controlled at 60 +/-2 ℃, the pressure is controlled at 0.05MPa under the condition of nitrogen sealing, the temperature is monitored at any time, cooling water is adjusted or a steam valve is opened, and the temperature is kept at 60 +/-2 ℃ for reaction for 2 hours.

Eliminating the remnant bill

After reacting for 2 hours, heating the reaction kettle to 80 +/-2 ℃, monitoring the temperature at any time under the condition that the nitrogen sealing pressure is 0.05MPa, adjusting cooling water or opening a steam valve, and preserving the temperature at 80 +/-2 ℃ for reacting for 2 hours.

Starting to add an initiator for residue elimination:

first residue removal: dissolving an initiator B1000g in 2KG water, pumping the solution into a reaction kettle, and reacting at the temperature of 80 +/-2 ℃ and under the pressure of 0.05MPa, the pH value: 8-9 for 2 hours

Eliminate incomplete list bundle sampling test PH value, K value and incomplete list content, the control index is: k value is 81.0-110, and the residual list is controlled according to the indexes of different grades of products.

And after the residue elimination is finished, closing the steam valve, opening a cooling water valve of a circulating water inlet and outlet, cooling to below 45 ℃, and discharging.

Example 5 production of povidone K90 in reactor (the detailed steps and conditions not listed in this example refer to examples 1-3, the effect of ammonia is the same as that of sodium hydroxide solution in examples 1-3):

prescription: the feed ratio of each kettle is shown in the following table

In the table, the initiator a and the initiator B are different initiators and are selected from the water-soluble azo initiators described above, for example, the initiator a is the initiator AIBN, and the initiator B is the initiator AIBA.

Preparation work before production: and checking the clearing state and the state mark of the post, and checking whether various weighing apparatus and instruments meet the requirements. And confirming the name, the batch number, the specification and the quantity of the acquired required raw and auxiliary materials and the name, the batch number, the quantity and the specification of the product to be produced according to the batch production instruction of the production department. Checking the states of production equipment and instruments: whether a bottom valve and a steam valve of the polymerization kettle are closed or not, whether valves of all metering tanks are in a closed state or not, and whether valves of machine seal cooling water are opened or not. Checking whether a thermometer and a pressure gauge on the reaction kettle are normal or not; checking whether the display of the weight sensor can normally display data or not. And (3) checking whether the pressure of a pressure gauge of a raw cooling water pipe on the reaction kettle is normal (at least 0.2MPa), and immediately checking the reason if the pressure is not normal.

And sequentially feeding materials according to the proportion of the fed materials.

The metering of the process water is carried out by a metering tank, and a liquid level scale meter is arranged on the metering tank. And (3) starting a process water valve to process water into the metering tank, closing the water inlet valve when the liquid level reaches a calibration scale, starting a vacuum pump to vacuumize the reaction kettle, starting a purified water metering tank to the valve of the reaction kettle, and pumping 2400 +/-50 Kg of the metered process water into the reaction kettle. Starting a reaction kettle stirrer (the stirrer needs to be slowly regulated when being started), opening a drain valve and a steam valve of a polymerization kettle, heating water in the reaction kettle to 60 +/-2 ℃, vacuumizing until purified water in the kettle is boiled, and deoxidizing for 5 minutes.

Adding NVP and replacing nitrogen

And (3) after the deoxidation in the reaction kettle is finished, immediately pumping the prepared NVP into the reaction kettle, continuing to vacuumize for 5 minutes, stopping vacuumization, opening a nitrogen valve on the kettle, and injecting nitrogen to relieve the vacuum until the pressure is 0.05 MPa. And the nitrogen replacement is finished after the operation is performed again.

Adding an initiator

Ammonia water 500. + -.10 ml is added and the pH value is measured. When the temperature is controlled to 60 +/-2 ℃, the composite initiator dissolved by water is quickly added into the reaction kettle through a funnel when the reaction kettle is in the last vacuum state, the valve is quickly closed, the nitrogen valve is opened until the pressure in the kettle is 0.05MPa, and the nitrogen valve is closed.

Constant temperature, constant pressure polymerization

The temperature in the reaction kettle is controlled at 60 +/-2 ℃, the pressure is controlled at 0.05MPa under the condition of nitrogen sealing, the temperature is monitored at any time, cooling water is adjusted or a steam valve is opened, and the temperature is kept at 60 +/-2 ℃ for reaction for 2 hours.

Eliminating the remnant bill

After reacting for 2 hours, heating the reaction kettle to 80 +/-2 ℃, monitoring the temperature at any time under the condition that the nitrogen sealing pressure is 0.05MPa, adjusting cooling water or opening a steam valve, and preserving the temperature at 80 +/-2 ℃ for reacting for 2 hours.

Starting to add an initiator for residue elimination:

first residue removal: dissolving initiator V50,1000g in 2kg of water, pumping into a reaction kettle, and reacting at the temperature of 80 +/-2 ℃, the pressure of 0.05MPa, the pH: 8-9 for 2 hours

Eliminate incomplete list bundle sampling test PH value, K value and incomplete list content, the control index is: k value is 81.0-110, and the residual list is controlled according to the indexes of different grades of products.

Cooling: and after the residue elimination is finished, closing the steam valve, opening a cooling water valve of a circulating water inlet and outlet, cooling to below 45 ℃, and discharging.

While the preferred embodiments and examples of the present invention have been described in detail, the present invention is not limited to the embodiments and examples, and various changes can be made without departing from the spirit of the present invention within the knowledge of those skilled in the art.