Release mechanisms of PLGA-based drug delivery systems: A review

Abstract

Poly(lactic-co-glycolic acid) (PLGA)-based microparticles and implants are of continuously increasing importance as parenteral controlled drug delivery systems. However, the underlying drug release mechanisms are often not understood, rendering product optimization difficult: The effects of formulation and processing parameters on drug release can be surprising. Also, upscaling and troubleshooting during production at industrial scale can be highly cumbersome. This can be attributed to the complexity of the physicochemical processes, which can be involved in the control of drug release. Generally, tri-phasic drug release patterns are observed: An initial burst release is followed by a zero order release phase and a final, again, rapid release phase. The relative importance of the different phases can strongly depend on the: (i) composition (e.g., type & amount of drug and polymer), geometry and dimensions of the system, (ii) manufacturing procedure, and (iii) conditions in the surrounding environment (e.g., bulk fluid versus human tissue). Water penetration into the system, drug dissolution, limited solubility effects, drug diffusion through an “intact polymeric matrix” (polymer phase) and/or through water filled pores, pore closure due to local PLGA swelling, osmotic effects, polymer degradation, local drops in micro-pH, autocatalytic effects, substantial swelling of the entire system as well as other phenomena can be of importance. This article aims at giving an overview on the current knowledge in this field. Please note that it is hypotheses-driven, thus, general conclusions should be seen with caution. Also, each drug delivery system should be considered on a case-by-case basis. This article also aims at raising awareness on two aspects, which are often neglected: (i) Substantial system swelling is likely the root cause for the onset of the third drug release phase in many systems. (ii) In the case of microparticles, only looking at drug release from ensembles (hundreds of thousands/millions) of particles can be misleading.

Introduction

Poly(lactic-co-glycolic acid) (PLGA)-based drug delivery systems are of steadily increasing practical importance, because they offer a variety of advantages, including the following: (i) The systems are completely biodegradable. Thus, the removal of empty remnants upon drug exhaust is avoided. (ii) PLGA is degraded into its monomers: lactic acid and glycolic acid. Hence, the biocompatibility of the systems is generally good. (iii) The resulting drug release kinetics can be controlled during flexible periods of time, ranging from a few hours up to several months (Mauduit et al., 1993; Jiang et al., 2002; Chen et al., 2017; Park et al., 2019). (iv) Various manufacturing technologies can be used to prepare PLGA-based drug delivery systems (Wischke and Schwendeman, 2008; Zhang et al., 2020), such as emulsification – solvent extraction/evaporation (O’Donnell and McGinity, 1997, Yang et al., 2000, Berkland et al., 2003, Fu et al., 2003, Kim and Park, 2004, Yeo and Park, 2004., Freitas et al., 2005, Katou et al., 2008, Park et al., 2021b, Zhang et al., 2021), spray-drying (Wan et al., 2013; Wan and Yang, 2016; Arrighi et al., 2019; Shi et al., 2020; Melnik et al., 2023; Zhang et al., 2025a), ink-jet injection (Sato et al., 2023), electrospraying/spinning (Bohr et al., 2012; Liu et al., 2018; Wang et al., 2019; Wang et al., 2025), compression (Maturavongsadit et al., 2021), hot melt extrusion (Gosau and Mueller, 2010, Cossé et al., 2017. Koshari et al., 2022, Lehner et al., 2024), injection molding (McConville et al., 2015), 3D printing (Serris et al., 2020), and casting (Lehner et al., 2021). Pre-formed and in-situ forming systems can be used (Giteau et al., 2008; Sun et al., 2017). Also, the geometries and dimensions of the devices are flexible, with spherical microparticles and cylindrical implants being most frequently used. Since decades a large variety of PLGA-based controlled drug delivery systems is available on the market and successfully applied in daily practice for the benefit of the patients (e.g., Nkanga et al., 2020).

However, unfortunately, the optimization of PLGA-based controlled drug delivery systems is often highly cumbersome, because the underlying drug release mechanisms are often not well understood. Frequently, unexpected tendencies can be observed when varying formulation or processing parameters, or when going from in vitro to in vivo studies. Consequently, time-consuming and cost-intensive series of trial-and-error experiments are required. This is particularly true when long release periods are targeted. Also, upscaling and troubleshooting during industrial production can be highly challenging, if the systems are treated like “black boxes”. The limited understanding of how PLGA-based delivery systems control drug release, can generally be attributed to the complexity of the involved physico-chemical and biological processes (Siepmann and Goepferich, 2001; Raman et al., 2005; Fredenberg, 2011; Fredenberg et al., 2011a; Fredenberg et al., 2011b). To give just some examples, the following phenomena might play a role: wetting of the dosage form, desorption of drug from the system’s surface, penetration of water into the device (via pores/channels and/or through an “intact polymer network”/dense polymer phase), drug dissolution (Siepmann and Siepmann, 2013), diffusion of dissolved drug molecules/ions through water-filled pores/channels and/or a dense polymer phase (Fick, 1855; Crank, 1975; Fan and Singh, 1989; Cussler, 1984), ester hydrolysis (Wang et al., 1990; Vert et al., 1994; Batycky et al., 1997; Li, 1999), polymer swelling (e.g., Gasmi et al., 2015; Bode et al., 2019; Rapier et al., 2021), pore closure (Kang and Schwendeman, 2007), local drops in micro-pH resulting in autocatalytic effects (ester hydrolysis being catalyzed by hydronium ions) (Fu et al., 2000, Liu et al., 2012, Versypt et al., 2013, Schaedlich et al., 2014. Hong et al., 2022), accelerated PLGA degradation due to base-catalyzed hydrolysis (Quan et al., 2023), osmotic effects due to the presence of water soluble drugs and/or water-soluble PLGA degradation products (Brunner et al., 1999), plasticizing effects of water on PLGA (Blasi et al., 2005), fusion of highly swollen microparticles into larger lumps (Klose et al., 2010), drug-polymer interactions (e.g., plasticizing effects, electrostatic attraction/repulsion, van der Waals forces) (Crotts et al., 1997; Cleland et al., 2001; Blasi et al., 2007), and phase separation and glassy-to-rubbery state transitions (Park et al., 2021a). Depending on the type of drug delivery system (e.g., its qualitative and quantitative composition, manufacturing procedure, geometry, dimensions, inner & outer morphology/structure) the relative importance of these phenomena can fundamentally vary. Often, one or just a few of these processes are “release rate controlling” or “dominant”: This means that a multitude of processes takes place, but most of them are not “decisive” for the control of the drug release rate. For example, if several processes occur in a sequence during drug transport and one of them is much slower than the other processes, only this slow process is determining the overall transport rate. In these cases, modifying the slow process allows adjusting desired drug release rates, whereas modifying a rapid process does not. Or, from a different perspective: The resulting release rate is highly sensitive to changes affecting the dominant process, while the system is robust (“forgiving”) with respect to changes affecting a rapid process.

A very important aspect, which should never be forgotten, is the fact that the key properties of PLGA-based drug delivery systems fundamentally change over time, e.g., the polymer molecular weight decreases and its hydrophilicity increases. These changes often alter the relative importance of the involved phenomena and different “phases of drug release” can be observed. For this reason, even a thorough characterization of the drug delivery system, which is limited to measurements conducted only before exposure to the release medium, is generally insufficient to elucidate the underlying drug release mechanisms: The dynamic changes of the system’s key properties occurring during drug release should also be monitored.

In most cases, tri-phasic drug release patterns are observed from PLGA-based dosage forms (e.g., Luan and Bodmeier, 2006; Arrighi et al., 2019; Sharifi et al., 2020). However, the relative importance of the three phases can substantially differ. In certain systems, one or two phases might be negligible. In these cases, drug release appears to be only mono-phasic or bi-phasic. Fig. 1 exemplarily shows the tri-phasic release kinetics of ketoprofen from PLGA-based microparticles, prepared by an oil-in-water (O/W) emulsification – solvent extraction/evaporation technique. During day 1, the release rate is high: This is the first release phase, the so-called “burst release”. During the second release phase (which lasts for about 5 d in this example), the release rate is about constant: In other words, zero order release kinetics are provided. In the third release phase, drug release is again rapid and leads to complete exhaust (100 % release).

Download the full article as PDF here: Release mechanisms of PLGA-based drug delivery systems

or continue reading here

J. Siepmann, F. Siepmann, Release mechanisms of PLGA-based drug delivery systems: A review, International Journal of Pharmaceutics: X, Volume 10, 2025, 100440, ISSN 2590-1567, https://doi.org/10.1016/j.ijpx.2025.100440.

Visit our Excipient Landscape 2025 here:

Get more information on different excipients and their manufacturers