Glass Transition Temperature of PLGA Particles and the Influence on Drug Delivery Applications

Abstract

Over recent decades, poly(lactic-co-glycolic acid) (PLGA) based nano- and micro- drug delivery vehicles have been rapidly developed since PLGA was approved by the Food and Drug Administration (FDA). Common factors that influence PLGA particle properties have been extensively studied by researchers, such as particle size, polydispersity index (PDI), surface morphology, zeta potential, and drug loading efficiency. These properties have all been found to be key factors for determining the drug release kinetics of the drug delivery particles. For drug delivery applications the drug release behavior is a critical property, and PLGA drug delivery systems are still plagued with the issue of burst release when a large portion of the drug is suddenly released from the particle rather than the controlled release the particles are designed for. Other properties of the particles can play a role in the drug release behavior, such as the glass transition temperature (T_g). The T_g, however, is an underreported property of current PLGA based drug delivery systems. This review summarizes the basic knowledge of the glass transition temperature in PLGA particles, the factors that influence the T_g, the effect of T_g on drug release behavior, and presents the recent awareness of the influence of T_g on drug delivery applications.

Keywords: PLGA copolymers; drug delivery; glass transition temperature; nanoparticles.

Figure 1

Flow chart of steps of manufacturing PLGA particles and their influence on particle properties [37]. Reprinted from Journal of Controlled Release, 329, Park, K.; Otte, A.; Sharifi, F.; Garner, J.; Skidmore, S.; Park, H.; Jhon, Y.K.; Qin, B.; Wang, Y., Formulation composition, manufacturing process, and characterization of poly(lactide-co-glycolide) microparticles, 1150–1161, Copyright (2021), with permission from Elsevier.

Figure 2

Link between the related parameters and the rate of drug release from PLGA carriers [46]. Reproduced with permission from Xu, Y. et al. Journal of Biomedical Materials Research Part B: Applied Biomaterials, published by John Wiley and Sons, Copyright 2017.

Figure 3

Copolymerization of PLGA by ring-opening method [52]. Reproduced from Butreddy, A. et al., International Journal of Molecular Sciences, 22, 2021, under Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/ (accessed on 24 February 2022)).

Figure 4

T_g of PS thin films under different measuring environment [68]. Reprinted by permission from Springer Nature Customer Service Centre GmbH: Springer, The European Physical Journal E, Effect of atmosphere on reductions in the glass transition of thin polystyrene films, Raegen, A.N.; Massa, M.V.; Forrest, J.A.; Dalnoki-Veress, K., 2008.

Figure 5

PS nanoparticles suspended in various liquids [70]. Reproduced with permission from Christie, D. et al. Journal of Polymer Science Part B: Polymer Physics, published by John Wiley and Sons, Copyright 2016.

Figure 6

Processes of loading hydrophobic drug (single emulsion) and hydrophilic drug (double emulsion). Created in Biorender.com (accessed on 24 February 2022).

Figure 7

Plasticizing effects of drug types and drug loading efficiency [84]. Reprinted from Journal of Controlled Release, 115, Siepmann, F.; Le Brun, V.; Siepmann, J., Drugs acting as plasticizers in polymeric systems: A quantitative treatment, 298–306, Copyright (2006), with permission from Elsevier.

Figure 8

T_g of PLGA under different post-treatment [93]. Reproduced from D’Souza, S. et al., Advances in Biomaterials 2014, 2014, under Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/ (accessed on 13 February 2022)).

Figure 9

Effect of T_g on drug release profiles [35]. Reprinted from Colloids and Surfaces A: Physicochemical and Engineering Aspects, 520, Takeuchi, I.; Tomoda, K.; Hamano, A.; Makino, K., Effects of physicochemical properties of poly(lactide-co-glycolide) on drug release behavior of hydrophobic drug-loaded nanoparticles, 771–778, Copyright (2017), with permission from Elsevier.

Figure 10

Release behaviors of drug loaded PLGA nanoparticles at different release temperatures [34]. Reprinted from International Journal of Pharmaceutics, 517, Lappe, S.; Mulac, D.; Langer, K., Polymeric nanoparticles—Influence of the glass transition temperature on drug release, 338–347, Copyright (2017), with permission from Elsevier.

Figure 11

Explanation of structure relaxation in terms of free volume [104]. Reproduced from Motta Dias, M.H. et al., Mechanics of Time-Dependent Materials, 20, 2016, under Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/ (accessed on 13 February 2022)).

Figure 12

Appearance of micro spaces during polymer ageing process [102]. Reproduced with permission from Yoshioka, T. et al. Macromolecular Materials and Engineering, published by John Wiley and Sons, Copyright 2011.

Figure 13

T_g is an inherent property of PLGA nanoparticles that can predict the drug release profiles. Created with Biorender.com.