CN108148209A - Based on shell pure solvent coaxial electrical spray for the method for polymer beads of the size less than 100nm - Google Patents

Abstract

The invention discloses a method for preparing polymer particles with a size less than 100nm by coaxial electrospraying based on a pure shell solvent. In the method, a volatile pure solvent is used as the shell solution, and a polymer solution with a certain concentration is used as the core solution. , using the coaxial EFI technology to produce charged droplets with a core-shell structure, the droplet shell is pure solvent, the core layer is a polymer, and the charged droplets fly from the nozzle to the collecting plate, the pure solvent in the shell is fast Volatilization will not solidify the surface of the droplet into a shell, and the pure solvent of the shell layer will volatilize the solvent of the core layer slowly, and the polymer chain segment will shrink with the volatilization of the solvent, and finally, the droplet of the core-shell structure will shrink to a size smaller than 100nm polymer particles. The method of the invention overcomes the defects of the prior art, the product size is small, and the method is reliable and stable.

Description

Preparation of Polymer Particles with a Size Less than 100nm Based on Coaxial Electrospraying of Shell Pure Solvents Methods

technical field

The invention belongs to the technical field of nanomaterial preparation, and relates to a method for preparing polymer particles by electrostatic spraying, in particular to a method for preparing polymer particles with a size less than 100 nm based on coaxial electrospraying of pure shell solvents.

Background technique

With the development of nanotechnology, electrostatic spray technology has attracted more and more attention of researchers. The basic principle of electrostatic spraying is that under the action of a high-voltage electric field, the repulsive force of the charge is greater than the surface tension of the liquid. The solution is injected from the nozzle and split into charged droplets in the air. The charged droplets are volatilized and solidified by the solvent to form small balls. The electrostatic spray device is mainly composed of four parts: syringe pump, nozzle, high voltage power supply, and receiving board. Coaxial electrostatic spraying can simply and efficiently prepare polymer microspheres with core-shell structure. Compared with traditional self-assembly methods for preparing drug carriers, electrostatic spraying has its unique advantages. For example, the electrostatic spray method can carry both hydrophilic and hydrophobic drugs, can effectively control the particle size of electrosprayed particles, has good repeatability, and is suitable for large-scale preparation of polymer particles and construction of core-shell structure carriers. Much simpler and does not require the synthesis of amphiphilic block polymers. However, the preparation of supports by traditional electrostatic spraying method also has limitations. For example, the size of polymer particles prepared by electrostatic spraying is generally in the micron or submicron range. However, only carrier particles with a size of about 100 nm can be enriched by the EPR effect in tumor tissue sites, and micron or submicron carrier particles will be quickly cleared by macrophages. In current reports, the size of PCL particles (polycaprolactone) prepared by electrostatic spraying method is 0.3-20um, and the size of PLA particles (polylactic acid) prepared is 3.7-19um. There are few reports on the one-step preparation of PCL and PLA with sizes smaller than 100nm by electrostatic spraying.

Polymer particles of different sizes can be prepared by changing the electrospray parameters. For example, by reducing the concentration of the solution, reducing the injection speed, increasing the voltage, etc., the particle size of the electrospray particles can be reduced. However, the above method can only reduce the particle size within a certain range, and it is difficult to make the particle size of the electrospray particles drop below 100nm. And if the injection speed is too low or the voltage is too high, the electrospray will be unstable. There are many semi-empirical formulas about the relationship between EFI droplet size and EFI parameters. Then calculate the size of the EFI particles by the following formula:

Where d _p refers to the particle size of the electrosprayed particles, ρ _s and ρ _p are the densities of the solvent and the polymer, respectively, w is the mass fraction of the polymer, and d is the original particle size of the droplet.

These studies focus on the formation and size of charged droplets, ignoring the process of solidification of charged droplets through solvent volatilization to form electrospray particles. The premise of the above formula is that the size of the charged droplet will decrease as the solvent evaporates. However, during the EFI process, the rapid volatilization of the solvent on the surface of the charged droplet will make the surface solidify rapidly, so its size cannot be further reduced with the volatilization of the solvent. Therefore, microspheres with loose or even hollow structures will be produced, which is an important reason why the size of EFI particles cannot be further reduced.

Contents of the invention

The purpose of the present invention is to address the deficiencies of the prior art and provide a method for preparing polymer particles with a size less than 100 nm based on coaxial electrospraying of pure shell solvents.

The technical scheme adopted in the present invention is as follows:

Weigh the polymer and dissolve it in a volatile solvent, stir until completely dissolved to obtain a core layer solution; use the pure above-mentioned volatile solvent as a shell layer solution; use a coaxial EFI device, pass through two independent injection pumps The shell solution and the core layer solution are injected into the nozzle, and the high-voltage power supply voltage is adjusted to form a stable Taylor cone at the bottom of the nozzle to prepare nanoparticles.

In the above technical solution, preferably, the polymer is a polyester polymer such as PCL, PLA or PLGA.

Preferably, the molecular weight of the polymer is 10000-20000.

Preferably, the volatile solvent is TFE (trifluoroethanol), DCM (dichloromethane) or chloroform, etc.

Preferably, the concentration of the nuclear layer solution ranges from 2% to 0.5% (W/V).

Preferably, the parameters during coaxial electrospraying are: the distance between the nozzle and the receiving plate is 15-25cm, and the voltage is 16-25kV; the injection speed of the shell solution is 0.8-1.2mL/h; The injection speed of the above nuclear layer solution is 0.1-0.5mL/h.

The idea based on the method of the present invention is as follows: the droplet size produced in the electrospray process will decrease rapidly with the volatilization of the solvent, and the use of a pure solvent shell can avoid the rapid solidification of the droplet surface, and at the same time select a low-concentration polymer core In the layer solution, the solvent in the droplets produced by the low-concentration polymer solution accounts for most of the volume. After the solvent is completely volatilized, the size of the droplets has the potential to change from micron to nanometer.

The invention adopts the strategy of coaxial electrospraying of the shell layer pure solvent to prepare polymer particles with a size less than 100nm: the shell layer solution is a volatile pure solvent, and the core layer is a polymer solution. Coaxial EFI produces charged droplets with a core-shell structure where the shell is a pure solvent and the core is a polymer. During the process of charged droplets flying from the nozzle to the collecting plate, the rapid volatilization of the pure solvent in the shell layer will not solidify the surface of the droplet into a shell, and the pure solvent in the shell layer will cause the solvent in the core layer to volatilize slowly, and the polymer chain segments will The solvent evaporates and shrinks. Eventually, the droplets of the core-shell structure shrink into polymer particles with a size smaller than 100 nm.

Description of drawings

Figure 1 is a schematic diagram of coaxial electrospraying of pure solvent in the shell layer;

Fig. 2 is the PCL particle electron micrograph that embodiment 1 obtains;

Fig. 3 is the electron micrograph of the different magnifications of the PLA particle that embodiment 2 obtains;

Fig. 4 is the PCL particle electron micrograph that comparative example 1 obtains;

Fig. 5 is the electron micrograph of PLA particles obtained in Comparative Example 2, and the scale is 50um;

FIG. 6 is an electron micrograph of particles obtained in Comparative Example 3.

Detailed ways

Example 1: Preparation of PCL particles with a size of less than 100 nm by coaxial electrospraying of pure solvent in the shell layer

A certain amount of PCL (Mn=10000) was weighed, dissolved in TFE solvent, and a solution with a concentration of 1% (W/V) was prepared. The solution was stirred until it was completely dissolved to obtain a core layer solution; the pure solvent TFE was used as a shell layer solution; a coaxial electrospray device was selected to prepare nanoparticles. The distance between the nozzle and the receiving plate was set to 20 cm, and the shell and core layer TFE and PCL solutions were injected into the nozzle through two independent syringe pumps. The injection rate of the shell layer was 1.0 mL/h, and that of the core layer was 0.3 mL/h. Adjust the high-voltage power supply voltage to about 20kV, and at this time, a stable Taylor cone is formed at the bottom of the nozzle. Collect the EFI particles onto tinfoil.

As shown in Figure 2, PCL particles with uniform size, regular shape and size less than 100 nm can be efficiently prepared by electrospraying strategy with pure solvent in the shell.

Example 2: Preparation of PLA particles with a size less than 100nm by coaxial electrospraying of pure solvent in the shell layer

A certain amount of PLA (Mn=17000) was weighed, dissolved in TFE solvent, and a solution with a concentration of 0.8% (W/V) was prepared. The solution was stirred until it was completely dissolved to obtain a core layer solution; the pure solvent TFE was used as a shell layer solution; a coaxial electrospray device was selected to prepare nanoparticles. The distance between the nozzle and the receiving plate was set to 20 cm, and the shell and core layer TFE and PCL solutions were injected into the nozzle through two independent syringe pumps. The injection rate of the shell layer was 1.0 mL/h, and that of the core layer was 0.1 mL/h. Adjust the high-voltage power supply voltage to about 20kV, and at this time, a stable Taylor cone is formed at the bottom of the nozzle. Collect the EFI particles onto tinfoil.

As shown in Figure 3, PLA particles with uniform size, regular shape, and a size of about 100 nm can be efficiently prepared by using the electrospray strategy of pure solvent in the shell.

Example 3: Preparation of PLGA particles with a size less than 100nm by coaxial electrospraying of pure solvent in the shell layer

A certain amount of PLGA (Mn=15000) was weighed, dissolved in DCM solvent, and a solution with a concentration of 1% (W/V) was prepared. The solution was stirred until completely dissolved to obtain a core layer solution; the pure solvent DCM was used as a shell layer solution; a coaxial electrospray device was selected to prepare nanoparticles. The distance between the nozzle and the receiving plate was set to 20 cm, and the shell and core layer DCM and PLGA solutions were injected into the nozzle through two independent syringe pumps. The injection rate of the shell layer was 1.0 mL/h, and that of the core layer was 0.1 mL/h. Adjust the high-voltage power supply voltage to about 20kV, and at this time, a stable Taylor cone is formed at the bottom of the nozzle. Collect the EFI particles onto tinfoil.

Comparative example 1: Preparation of PCL particles by uniaxial EFI

A certain amount of polymer is weighed, and the polymer is PCL (Mn=10000), which is dissolved in TFE solvent, and solutions with concentrations of 10%, 6%, and 1% (W/V) are prepared respectively. PCL particles were prepared with a uniaxial electrospray device. The distance between the nozzle and the receiving plate was 20 cm, and the PCL solution was injected into the nozzle through a syringe pump, and the injection speed was 0.1, 0.5, and 1.0 mL/h. Adjust the high-voltage power supply voltage to about 20kV, and at this time, a stable Taylor cone is formed at the bottom of the nozzle.

As shown in Figure 4, when the concentration of PCL is reduced from 10% to 1%, the particle size of PCL microspheres tends to decrease, but the sizes are all at the micron level. As the concentration of PCL decreased, the morphology of PCL particles prepared by EFI also changed, from basically spherical to irregular in shape and even spread out into a piece. When the injection speed was reduced from 1.0mL/h to 0.1mL/h, the size of PCL microspheres also showed a tendency to decrease, but did not decrease to the nanometer level. And when the injection rate is 0.1mL/h, a stable Taylor cone cannot be formed, and the spray cannot be carried out continuously and stably.

Comparative example 2: Preparation of PLA particles by uniaxial EFI

Weigh a certain amount of polymer, said polymer is PLA (Mn=17000), dissolve it in TFE solvent, and prepare solutions with concentrations of 10%, 5%, and 0.8% (W/V) respectively. PLA particles were prepared by uniaxial electrospray. The distance between the nozzle and the receiving plate was 20 cm, and the PLA solution was injected into the nozzle through a syringe pump, and the injection speed was 0.1, 0.5, and 1.0 mL/h. Adjust the high-voltage power supply voltage to about 20kV, and at this time, a stable Taylor cone is formed at the bottom of the nozzle.

As shown in Figure 5, the size of the PLA microspheres could not be reduced below 100nm by reducing the solution concentration, reducing the injection speed, and increasing the voltage. The size of the obtained microspheres is basically still in the order of micrometers.

Comparative example 3: Preparation of core-shell structure PEG/PCL microspheres by coaxial EFI

A certain amount of PCL (Mn=10000) was weighed, dissolved in TFE solvent, and a solution with a concentration of 1% (W/V) was prepared. The solution was stirred until completely dissolved to obtain a core layer solution. A certain amount of polyethylene glycol PEG (Mn=20000) was weighed, dissolved in TFE solvent, and a solution with a concentration of 10% (W/V) was prepared. The solution was stirred until complete dissolution to obtain a shell solution. A coaxial EFI device was used to prepare core-shell microspheres. The distance between the nozzle and the receiving plate was set to 20 cm, and the shell layer and the core layer solution were injected into the nozzle through two independent syringe pumps. The injection rate of the shell layer was 1.0 mL/h, and that of the core layer was 0.1 mL/h. Adjust the high-voltage power supply voltage to about 20kV, and at this time, a stable Taylor cone is formed at the bottom of the nozzle. Collect the EFI particles onto tinfoil. As shown in Figure 6, if the pure TFE solution is replaced by PEG solution for the shell layer, the size of the microspheres prepared by coaxial electrospray is micron, and nano-sized particles cannot be obtained.

Claims (6)

1. based on shell pure solvent coaxial electrical spray for the method for polymer beads of the size less than 100nm, which is characterized in that packet Include following steps：

It weighs polymer to be dissolved in volatile solvents, stirs to being completely dissolved, obtain stratum nucleare solution；It will be pure above-mentioned Volatile solvents are as shell solution；Using coaxial electric injection device, by two independent syringe pumps by shell solution and core For layer solution sample introduction to nozzle, adjusting high-voltage power voltage makes head of the nozzle form stable taylor cone, prepares nano particle.

2. the polymer beads according to claim 1 for being less than 100nm for size based on shell pure solvent coaxial electrical spray Method, which is characterized in that the polymer is polyester polymer, selected from PCL (polycaprolactone), PLA (polylactic acid) or PLGA (polylactic acid-glycolic base lactic acid).

3. the polymer beads according to claim 1 for being less than 100nm for size based on shell pure solvent coaxial electrical spray Method, which is characterized in that the volatile solvents be TFE (trifluoroethanol), DCM (dichloromethane) or chloroform.

4. the polymer beads according to claim 1 for being less than 100nm for size based on shell pure solvent coaxial electrical spray Method, which is characterized in that the molecular weight of the polymer be 10000~20000.

5. the polymer beads according to claim 1 for being less than 100nm for size based on shell pure solvent coaxial electrical spray Method, which is characterized in that the concentration range of the stratum nucleare solution be 2%~0.5% (W/V).

6. the polymer beads according to claim 1 for being less than 100nm for size based on shell pure solvent coaxial electrical spray Method, which is characterized in that parameter during coaxial EFI is：The distance between nozzle and receiver board are 15-25cm, and voltage is 16-25kV；The sample introduction speed of the shell solution is 0.8~1.2mL/h, the sample introduction speed of stratum nucleare solution for 0.1~ 0.5mL/h。