Continuous Flow Process for Production of Biodegradable Nanospheres

By AZoNano

Table of Contents

Innovative Technique to Produce PLGA Nanospheres
Experimental Results
About Hielscher


Microspheres and nanospheres, which are biodegradable and made of poly(lactide-coglycolide) (PLGA) or other materials, are powerful drug and antigen delivery systems and offer innate possibility for drug and antigen targeting. However, current techniques used to develop PLGA nanospheres experience a number of complications when upscaling under sterile conditions.

Innovative Technique to Produce PLGA Nanospheres

This technical note discusses a new technique to develop PLGA nanospheres in a continuous, contamination-free and contact-free process, which can be instantly run under sterile conditions. All through the production process, only Teflon tubes and sterile glass come into direct with the product. In order to prevent environmental contamination, the process can be run in a closed system.

A modified solvent extraction/evaporation process is used to produce LGA50:50 nanoparticles (Resomer RG503H). Then, PLGA dissolved in dichloromethane is mixed in aqueous 0.5% (w/w) PVA-solution by using a new experimental set-up that involves a contact-free flow-through ultrasonication cell. First, with the help of a magnetic stirrer the coarse O/W-dispersion was premixed and then homogenized in the ultrasonic flow-through cell.

The PLGA-solvent nanodroplets that formed initially slowly solidified during the passage in the tubes to become PLGA nanoparticles. At last, particle hardening was attained in a larger volume of 0.5% PVA solution.

Figure 1. Experimental set-up for the production of PLGA nanospheres.

Figure 2. Design of ultrasonic flow-through cell

Experimental Results

Nanoparticles having 485 nm mean diameter were instantly prepared from a 2% PLGA solution in DCM at 32 W sonication power. The size of the nanoparticle ranged from 175 to 755 nm in accordance to the 10% and 90% percentiles. Repeatability of the manufacturing procedure was reliably good, with just a slight difference in the mean particle diameter.

Moreover, reducing the emulsion’s residence time in the sonic field from 14 to 7 had just a small impact on the size of the nanoparticle. But, when the sonication power was reduced from 32 to 25 W, the mean particle size increased from 485 to 700 nm, which was caused by a prominent tailing of the size distribution curve as shown in the figure given below.

Figure 3. Size distribution of particles prepared at polymer concentration/ sonication power of 2%/ 32W, 5%/ 32W, and 2%/ 25W%; residence time = 14 s.

Conversely, while using 5% instead of the normal 2% PLGA solution, a less prominent increase in the mean particle size between 485 and 600 nm was observed. Ultimately, the more hydrophilic PLGA was swapped for the more hydrophobic and lower molecular weight PLA without perceptible modifications in mean size and size distribution of particles.

In fact, no variations were found in the morphology of different batches of particles made from 2% polymer solutions. All the particles had smooth surfaces and perfect spherical shapes as shown in figure 4. However, the particles produced from the 5% PLGA solution had less spherical shapes and exhibited minor wrinkly surfaces with a mix of two or more particles, displayed in figure 5.

Figure 4. SEM pictures of particles prepared from 2% and 5% polymer solutions, respectively.

Table 1. Mean diameter of PLGA50:50 nanospheres prepared under different conditions. Mean of two batches ± absolute deviation.

Polymer conc.
(w/w, %)
Sonication power
Residence time
Mean particle diameter
D[4,3] (nm)
2 32 14 485 ± 15
2 32 7 500 ± 20
2 25 14 70U ±20
5 32 14 600 ± 10


The ultrasonic flow-through cell was found to be ideal for producing biodegradable polymeric nanospheres through solvent extraction/evaporation process. Future research will focus on upscaling the process and boosting the power input to manufacture even finer emulsions. Additionally, the suitability of the ultrasonic flow-through cell for preparing water-in-oil emulsions will be examined.

About Hielscher

Hielscher Ultrasonics is a family business, located in Teltow near Berlin (Germany). The main emphasis of its activities is the conception, development and production of ultrasonic devices for the use in laboratory and industrial applications. Technological innovations together with the realization of new ultrasound based processes substantiated the company growth and its market acceptance.

Today, ultrasonic devices made by Hielscher Ultrasonics are being used in laboratories and production plants on all continents across the world. More than 70% of the total sales is based on export. Almost every second device is supplied to customers outside Europe. Hielscher Ultrasonics integrates the ultrasonic devices into complex ultrasonic systems, such as wire cleaning systems, too. The systems are produced to meet the customers requirements in terms of power, extended range of accessories and steady state proof equipment.

Hielscher USA, Inc. is the representative for Hielscher ultrasonic equipment in the North American market. It is located in Ringwood, NJ.

This information has been sourced, reviewed and adapted from materials provided by Hielscher.

For more information on this source, please visit Hielscher.

Date Added: Mar 4, 2013 | Updated: Jun 11, 2013
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