The University of New South Wales - Sydney, Australia

Towards Biocompatible microspheres - “Synthesis and Characterisation of poly ( Ethylene Glycol Dimethacrylate co-vinyl acetate) microspheres”

Jingya Tan
Supervisors: Thomas P. Davis, Christopher Barner-Kowollik, Martina H. Stenzel and Leonie Barner

Centre for Advanced Macromolecular Design
School of Chemical Engineering and Industrial Chemistry
The University of New South Wales
Sydney, NSW 2052, Australia
camd@unsw.edu.au

1. Introduction

In recent times, the applications of polymeric microspheres in biomedical field such as drug delivery systems, immunoassays and other diagnostic purposes have caused an interest in formulating structures that are biodegradable and harmless to the human body. Vinyl acetate (VAc) has been employed as the monomer for creating such structures. The hydrophilic nature of the monomer makes it an excellent choice as a biocompatible chemical.

Method

The monomer is crosslinked with Ethylene Glycol Dimethacrylate (EGDMA) via a single step precipitation polymerisation process using 2,2’-azobis(isobutyronitrile), AIBN as the thermal initiator. Methods of characterising the microspheres include scanning electron microscope, and particle size distribution analysis. Thermal gravimetric analysis was also carried out to determine chemical composition of the microspheres.

Figure 1 – Schematic of microspheres formation via precipitation polymerisation

Precipitation polymerisation

Precipitation polymerisation is a relatively simple, one step process used for creating surfactant free microspheres. The products are usually sized between 1 – 7µm. The reaction proceeds by dissolving the reactants in a solvent; as the reaction progresses, the products formed are insoluble in the solvent and hence precipitates out of the reaction mixture, giving microspheres. The key to successful microspheres formation is a near theta state reaction medium – i.e. a theta solvent. There is no unique theta solvent for a particular monomer. On the contrary, there are many solvents that can be employed as theta solvents. The main criteria is that it has to be at its theta temperature. Hence the most important criteria in making a solvent a theta solvent lies in its temperature.

The following parameters were explored:

1. Cosolvent variation:
   To create that near theta reaction medium for the monomer - VAc, the amount of acetone used as a cosolvent was varied. The amount of acetone added ranged from 5% to 50% (relative to the total reaction volume).
2. Comonomer variation:
   With the optimum reaction medium, comonomer ratios were varied. Amount of monomer - Vac was steadily increased in a series of experiments. VAc was increased from 50% to 90% (relative to the total monomer added to the system).

OUTLOOK

We are extending the study by polymerising vinyl acetate with other crosslinkers, in particular a acid cleavable crosslinker. The acid degradable copolymer thus formed could possibly be used for drug delivery. We will also be investigating the possibility of initiating the polymerisation process via radiation. This would enable heat sensitive drugs and proteins to be loaded directly into the microspheres during polymerisation process; reducing complexities and cost of manufacture. As vinyl alcohol is a widely used biomaterial, our microspheres could possibly be hydrolysed thereby enhancing its versatility as an applicant for biomaterial

Results & Discussions

1. Cosolvent variation (At 15:85 - vol:vol comonomer ratio):

A decrease in average particle size is observed with an increase in use of acetone as a cosolvent. Similarly, particle size distribution is narrow for high acetone content system (50vol% acetone) and broad for low acetone content system (5vol% acetone). No significant differences were observed for systems ranging between 20vol% and 40vol% of acetone. Thermal gravimetric analysis results show no significant changes in the chemical composition of the microspheres; with around 40 mol% of vinyl acetate content for all.

Fig. 2 - SEM image of microspheres with 5 vol% acetone

Fig. 3 - SEM image of microspheres with 20 vol% acetone

Fig. 4 - SEM image of microspheres with 25 vol% acetone

Fig. 5 - SEM image of microspheres with 30 vol% acetone

Fig. 6 - SEM image of microspheres with 40 vol% acetone

Fig. 7 - SEM image of microspheres with 50 vol% acetone

Fig. 8a and 8b – TGA results for cosolvent variations tests

Fig. 9 – Effects of cosolvent variation on particle size distribution

Fig. 10 –Effects of cosolvent variation on CV and average particle size of microspheres

2. Comonomer variation (At 25vol% acetone; 53°C):

In the optimum reaction medium of 25 volume % acetone and 53°C, microspheres formation were observed as amount of monomer – VAc is increased. Clean, stable microspheres were formed with comonomer ratio greater than or equal to 15:85 (vol:vol). Consequently, results from particle size distribution analysis also showed narrower distribution with comonomer ratio greater than or equal to 15:85. It is however interesting to note that when comonomer ratio increases to a value of 10:90, two distinct sized populations were observed. Furthermore, we observe a trend of average particle size decreasing when monomer content in the comonomer feed was increased. Results from thermal gravimetric analyses showed an increase in the amount of vinyl acetate content as comonomer ratio increases.

Fig. 11 – SEM image of microspheres at comonomer ratio of 50:50

Fig. 12 – SEM image of microspheres at comonomer ratio of 20:80

Fig. 13 – SEM image of microspheres at comonomer ratio of 15:85

Fig. 14 – SEM image of microspheres at comonomer ratio of 10:90

Fig. 14a & b – Effects of comonomer variation on particle size distribution

Fig. 15 – Effects of comonomer variation on CV and average particle size of microspheres

Fig. 16a & b – TGA results for comonomer variation tests

Conclusions

• Moderate reaction temperature of 53°C was employed for effective thermal initiation for all experiments carried out in this project.
• A decrease in particle sizes and particle size distributions were observed with increasing amounts of cosolvent (acetone) added.
• Stable microspheres with a relatively uniform particle size distribution can be obtained with 25 volume% acetone added as cosolvent.
• A high monomer content in comonomer feed was essential in creating stable microspheres
• Best comonomer ratio to work with is 15:85 (vol:vol)
• Thermal gravimetric analysis provided evidence that vinyl acetate has been successfully incorporated into the microspheres.
• Precipitation polymerisation can be employed as a simple, one step process to create microspheres when a near theta solvent is used.

Selected References

1. K. Li, H. D. H. Stover, “Synthesis Of Monodispersed Poly(Divinylbenzene) Microspheres”, Journal Of Polymer Science, Part A: Polymer Chemistry, 1993, 31, 3257-3263
2. Sang Eun Shim, Shunhye Yang, Hyang Hee Choi, Soonja Choe, “Fully Crosslinked Poly(Styrene-Co-Divinylbenzene) Microspheres By Precipitation Polymerisation And Their Superior Thermal Properties”, Journal Of Polymer Science, Part A: Polymer Chemistry, 2004, 42, 835-845
3. Haruma Kawaguchi, “Functional Polymer Microspheres”, Journal Of Progress In Polymer Science, 25 (2000) 1171 - 1210
4. Hans – G. Elias, Polymer Handbook, “VII/291 - Theta Solvents”, Michigan Molecular Institute, 1910 West St, Andrews Rd, Midland, Mi 48640, USA

Acknowledgements

The authors acknowledge financial support from the Australian Research Council and Faculty of Engineering at UNSW. We would also like to thank the Electron Microscope Unit (UNSW) especially Sigrid Fraser for her assistance with S900 and John Starling (Centre for Particle and Catalyst Technology) for his assistance with the particle size distribution measurements.

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