(T1230-05-27) Impact of Polymer Residual Content on the Quality Characteristics of Risperidone PLGA Microspheres

Purpose: Poly (lactic-co-glycolic acid) (PLGA) microspheres are a sustained-release drug delivery system. This study aims to explore the impact of polymer residual content on the quality characteristics of risperidone microspheres (such as drug loading, particle size, in vitro release, and particle morphology). Several commercial products use PLGA microsphere technology for the treatment of a variety of diseases. It has been shown that both the in vitro drug release characteristics and the in vivo performance of microspheres are very sensitive to minor manufacturing process changes, and minor differences in polymer characteristics^1,2. However, the impact of polymer residual content has yet to be explored.

Methods: Extensive characterization of PLGA residual content was performed. PLGA weight loss was calculated using thermogravimetric analysis (TGA). PLGA with different residual content were obtained using vacuum drying and purification of raw PLGA polymer. Purification was achieved via reprecipitation. Briefly, the polymer was dissolved in chloroform and reprecipitated using excess ethanol followed by vacuum drying (72 h). Risperidone microspheres were prepared via solvent evaporation with raw (high residue) PLGA (FA), reprecipitated (low residue) PLGA (FB) as well as medium residue PLGA (FC). Particle size was determined using an AccuSizer. Moreover, scanning electron microscopy (SEM) images of the microspheres were obtained to analyze their morphological features. Drug loading was determined via HPLC, and in vitro release characteristics were studied using USP apparatus IV with HEPES buffer media.

Results: Thermal degradation analysis demonstrated a weight loss of approximately 15% w/w and 6% w/w for PLGA with high and medium residual content, respectively, prior to reaching 150°C. This reduction in weight can be attributed to residual components of the polymer, such as organic solvents, monomers, and oligomers. Notably, a mere 0.7% w/w weight loss was observed in the reprecipitated PLGA. Microspheres formulated with high residual content PLGA exhibited smaller average particle sizes, approximately 10 μm smaller, and lower drug loading compared to those prepared with low residue PLGA. Scanning electron microscopy (SEM) images revealed the presence of pores on the surface of microspheres containing high and medium residual content PLGA. Additionally, microspheres incorporating high residual content PLGA displayed a higher burst release rate (12.4% in 24 h) compared to those utilizing low residue PLGA (1.7%). This elevated burst release may be linked to the pores and irregular surface features present on microspheres formulated with high residual content PLGA

Conclusion: These results underscore the importance of controlling residual content in PLGA-based drug delivery systems to ensure performance and efficacy. The findings highlight the significant impact of residual content, which includes organic solvents, monomers, and oligomers, on microsphere performance. Residual components, potentially originating from the manufacturing process, can interact with the polymer and active pharmaceutical ingredient (API) during processing, leading to alterations in the polymer matrix (such as size, drug loading, morphology and microstructure), which in turn affect the kinetics of drug release. Reprecipitation was effective in reducing residual content, resulting in improved drug loading and reduced burst release. Overall, these findings emphasize the necessity of carefully managing residual content in PLGA-based drug delivery systems to maintain desired performance and safety

References: 1. Wan, B., Bao, Q., Zou, Y., Wang, Y., & Burgess, D. J. (2021). Effect of polymer source variation on the properties and performance of risperidone microspheres. International Journal of Pharmaceutics, 610, 121265.
2. Andhariya, J. V., Shen, J., Wang, Y., Choi, S., & Burgess, D. J. (2019). Effect of minor manufacturing changes on stability of compositionally equivalent PLGA microspheres. International journal of pharmaceutics, 566, 532-540.

Acknowledgements: Funding for this project was made possible by Pfizer Distinguished Chair in Pharmaceutical Technology fund.


Fig: 1 A. Thermal degradation profile (derivative weight loss against temperature) for PLGA (Low, medium and high residues). B. Percentage drug loading for the prepared microspheres FA (microspheres prepared with high residual content PLGA) and FB (microspheres prepared with low residual content PLGA).


Fig: 2 A. Amount of risperidone released within first 24 hours of release testing for formulation FA (High residue PLGA) and FB (low residue PLGA). B. SEM images reveal the highly porous structure and irregularities present on microspheres prepared with high residual content (FA) and relatively smoother surface for microspheres prepared using medium (FC) and low (FB) residual content.