Exploring the pivotal role of hot melt extrusion technology in developing PLGA based novel drug delivery platforms for better therapeutic outcomes

Abstract

Among various biodegradable polymers, polylactic-co-glycolic acid (PLGA) is one of most widely studied synthetic polymer for controlled and targeted drug delivery. PLGA is a smart polymer as it has stimuli-responsive behaviour. PLGA is approved by the US FDA for multiple therapeutic applications due to its biodegradability, biocompatibility and sustained-release behaviour. PLGA is commercially available as different molecular weights and copolymer ratios, which allow for tuning polymer behaviour to suit numerous applications. Different methods have been used to process PLGA into diverse morphologies, structures and sizes. Traditional PLGA processing methods face many limitations related to scalability and residual solvents. This review was limited to the emerging hot melt extrusion (HME), a more specific, solvent-free and highly scalable technology for fabricating PLGA-based formulations. Key operational parameters such as glass transition temperature, melt viscosity, and degradation behaviour are discussed alongside with the drug-related stability, dispersion and final solid-state properties that need several factors to be fine-tuned to offer a performance with optimal efficiency. This tunability of characteristics makes PLGA driven by HME ideal for fabrication with advanced manufacturing technologies to deliver surprisingly novel drug delivery platforms that can boost therapeutic efficacy and patient compliance across a range of clinical fields.

Introduction

Over the past decades, non-absorbable polymers such as polypropylene, polyacrylates, polyether urethane, and polysiloxanes have been gradually replaced by both natural and synthetic absorbable or biodegradable biomaterials in biomedical and pharmaceutical fields (Oleksy et al. 2023). The advancement of biodegradable polymers has revolutionized the pharmaceutical field, offering innovative solutions for drug delivery (Veeman et al. 2021), tissue engineering (Iqbal et al. 2019), and regenerative medicine (Sharma et al. 2021; Veeman et al. 2021). These polymers degrade into non-toxic byproducts within the body, eliminating the need for surgical removal and minimizing long-term side effects (Kuperkar et al. 2024). Among the various biodegradable polymers explored, poly(lactic-co-glycolic) acid (PLGA) stands out due to its excellent biocompatibility, tunable degradation rates, and regulatory approval for clinical use (Lu et al. 2023; Makadia and Siegel 2011).

Synthetic biodegradable polyesters, notably polylactide (PLA) and polyglycolide (PGA), were utilized since the early 1970 s, primarily as absorbable sutures and monofilament materials (Benicewicz and Hopper 1991; Oleksy et al. 2023). In subsequent years, polylactic-co-glycolic acid (PLGA) was increasingly introduced into clinical applications, starting in 1989, mainly in the form of microsphere formulations, Lupron® Depot (Blasi 2019). Leuprolide was formulated within PLGA microspheres for a depot action for the treatment of prostate cancer (Alsaab et al. 2022). By that time, approximately 20 PLGA-based formulations had already received approval from regulatory authorities such as the U.S. Food and Drug Administration and European Medicines Agency, further establishing its significance as a versatile drug delivery carrier (Rocha et al. 2022). Some leading examples include Zoladex®, Bydureon™, Sandostatin® LAR Depot, Signifor® LAR™, Eligard®, and Ozurdex®, which act as long-acting drug delivery vehicles (Gonella et al. 2022; Tice 2023; Yadav et al. 2024). These regulatory approvals, combined with PLGA’s biocompatibility and biodegradability, have made it one of the most widely utilized synthetic polymers in biomedical applications (Martins et al. 2018).

PLGA is a synthetic, biodegradable copolymer synthesized from two aliphatic monomers, lactic acid and glycolic acid, and its properties can be precisely tailored by adjusting the monomer ratio (Makadia and Siegel, 2011b). The nomenclature reflects its structure: “poly” denotes its polymeric nature, “D, L” indicates the racemic form of lactic acid, and “co” highlights its copolymeric configuration with glycolic acid. The physicochemical properties of PLGA, including degradation rate and mechanical behavior, can be modulated by adjusting the molar ratio of its constituent monomers during synthesis (Singh and Singha 2021). Therefore, PLGA is commercially available with various molecular weights and copolymer ratios, enabling customization of its properties to suit specific pharmaceutical applications (Rocha et al. 2022). This versatility makes PLGA an ideal candidate for controlled drug release systems, where the polymer matrix gradually degrades to release therapeutic agents over a desired timeframe (Kapoor et al. 2015). Its applications span a wide range of pharmaceutical formulations, including nanoparticles (Lagreca et al. 2020), microparticles (Lagreca et al. 2020; Park et al. 2019), implants (Hu et al. 2023), injectable depots (Butreddy et al. 2021), and molecular imaging (Alsaab et al. 2022).

A thorough understanding of the physicochemical characteristics of polymeric materials is essential for ensuring their biological performance (Martins et al. 2018). In fact, PLGA’s unique properties have positioned it as one of the most promising options among biodegradable and biocompatible polymers (Martins et al. 2018). Today, PLGA is widely available from various manufacturers in multiple compositions. Concerning the lactic acid to glycolic acid ratio, the most commonly used formulation is 50:50, meaning equal proportions of lactic acid and glycolic acid within the copolymer structure (Martins et al. 2018). This ratio is critical for imparting specific attributes to PLGA, such as its melting temperature. For instance, Lan et al. reported that the melting temperature of PLGA decreases as the mole fraction of glycolic acid in the polymer increases (Martins et al. 2018). This variation in melting point is beneficial because it enables the fabrication of a wide range of formulation designs (Martins et al. 2018).

The solubility of PLGA also varies according to its lactic acid to glycolic acid ratio (Blasi 2019; Martins et al. 2018). Unlike its individual monomers, lactic acid and glycolic acid, PLGA exhibits solubility in a range of organic solvents, such as tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, hexafluoroisopropanol, acetone, and benzyl alcohol (Martins et al. 2018). However, this solubility tends to decrease as the glycolic acid content increases (Martins et al. 2018). Similarly, the glass transition temperature (Tg) of PLGA is influenced by its lactic acid: glycolic acid composition (Martins et al. 2018). Tg represents the temperature at which polymers shift from a glassy state (below Tg) to a rubbery state (above Tg). For PLGA, Tg is approximately 50 °C, which is higher than physiological temperature, giving the polymer notable mechanical strength and rigidity. Moreover, Tg rises with increasing molecular weight and higher lactic acid content (Blasi 2019; Park 1995).

Polymers derived from L-lactic acid tend to exhibit semicrystalline structures, whereas those synthesized from D,L-lactic acid are typically amorphous (de França et al. 2022). While glycolic acid is generally associated with highly crystalline polymers; however, this characteristic is largely lost when glycolic acid is incorporated into PLGA, resulting in an amorphous material (Makadia and Siegel 2011). Although crystalline polymers possess superior mechanical strength compared to amorphous ones, the latter remain highly suitable for biomedical applications, particularly drug delivery, due to their ability to provide a more uniform distribution of active compounds within the polymer matrix (Martins et al. 2018).

The molecular weight of PLGA copolymers ranges from low (< 10000) to over 200,000 g/mol. The molecular weight of PLGA can have a significant impact on the mechanical characteristics, stability, drug loading capacity, and drug release kinetics (Abbasnezhad et al. 2021). The lactic acid to glycolic acid ratio in PLGA has a major effect on the polymer rate of degradation as well as polymer hydrophobicity (Makadia and Siegel 2011). While a higher glycolic acid level increases the polymer's hydrophilicity, resulting in faster hydrolysis and rapid drug release, a higher lactic acid content in PLGA increases its hydrophobicity, slowing down the breakdown process by lowering water absorption (Alexis 2005). In addition, the blockiness of PLGA governs its degradation rate and drug release profile and it significantly affects the efficiency of drug delivery systems (Xu et al. 2017). The more blocky PLGA is, the more structured and uniform the succession of these units and hence, the slower and more controlled the breakdown (Xu et al. 2017). Finally, the breakdown and drug release properties of PLGA polymers are greatly impacted by their ester or acid end-cap (Badawi 2017). The integration of several functional end groups into PLGA has been made possible by advancements in synthesis, expanding its uses in drug delivery systems (Martins et al. 2018).

Nowadays, PLGA has been processed using a wide range of technologies, indicating the polymer's versatility in drug delivery. Even though techniques like solvent evaporation and spray drying have been widely used to produce microparticles and nanoparticles, they usually run into problems with solvent residues and scale-up limitations (Deshmukh et al. 2016; Wan and Yang 2016). Better control over particle size and high drug loading are offered by emulsification and nanoprecipitation, but these processes may also result in subpar industrial repeatability (Liu et al. 2020; Real et al. 2022). Phase separation techniques have also been used, although their applicability is limited by their requirement for organic solvents (Liu et al. 2020). More complex methods like microfluidics enable precise control of particle shape and drug encapsulation, while electrospinning offers the ability to produce nanofibers for targeted delivery applications (Daniele et al. 2015). Other innovative strategies include supercritical fluid processing, which eliminates harmful solvents, lyophilization for enhanced stability of protein-loaded formulations, and 3D printing, which provides customizable dosage forms (Fonte et al. 2016; Jovanović et al. 2004). Collectively, these technologies highlight the diverse toolbox available for tailoring PLGA formulations, although each method carries its own limitations in terms of scalability, stability, or compatibility with thermosensitive drugs.

Hot-melt extrusion (HME), one of these methods, has gained popularity as a continuous, solvent-free, and industry-friendly method for processing PLGA (Cossé et al. 2017; Veeran et al. 2022). By subjecting the polymer and the active pharmaceutical ingredient (API) to carefully regulated mechanical and thermal forces, HME produces homogeneous solid dispersions with enhanced consistency and repeatability (Sarode et al. 2013). HME offers significant potential for scalable and continuous production while mitigating environmental risks and residual solvent concerns when compared to solvent-based methods (Matić et al. 2020; Sarode et al. 2013). The optimization of the critical processing parameters, such as feed rate, barrel temperature, screw speed, and screw design, HME serves as a highly effective approach for developing PLGA-based formulations, offering precision, scalability, and flexibility to address the evolving requirements of contemporary pharmaceutical manufacturing.

PLGA has been extensively investigated as a biodegradable and biocompatible polymer for controlled drug delivery, and its physicochemical properties—including molecular weight, monomer ratio, glass transition temperature, and degradation behavior—are well documented across numerous reviews and experimental studies. Similarly, hot‑melt extrusion (HME) is an established pharmaceutical manufacturing technology, widely reviewed in the context of amorphous solid dispersions, implants, and continuous processing. However, existing literature largely treats PLGA material science and HME technology as parallel topics rather than as interdependent components of an integrated formulation and manufacturing framework.

Notably, there remains a critical gap in systematically elucidating how PLGA physicochemical attributes directly govern HME process feasibility, robustness, optimization, and final product performance. Many published studies report successful PLGA extrusion conditions or drug‑delivery outcomes without clearly rationalizing how polymer characteristics—such as monomer composition–dependent melt behavior, molecular‑weight‑driven viscosity changes, glass transition temperature constraints, or degradation kinetics—dictate processing windows, screw design requirements, thermal stability limits, and reproducibility during extrusion. As a result, formulation development is often empirical, and knowledge transfer across PLGA grades, drug classes, and dosage forms remains limited.

The lack of an integrated, process‑oriented perspective is particularly relevant in the context of industrial scale‑up, regulatory acceptance, and clinical translation, where hot‑melt extrusion demands consistent material behavior, predictable thermal and rheological performance, and robust quality control. While PLGA‑based systems are widely used in solvent‑based particle fabrication, comparatively fewer reviews critically address why specific PLGA grades succeed or fail during HME processing, or how polymer selection can be strategically aligned with extrusion parameters to mitigate degradation, reduce burst release, and improve product uniformity.

Accordingly, the primary scope and novel contribution of this review is to bridge this gap by providing a mechanistically driven and process‑focused analysis of PLGA within the context of hot‑melt extrusion. This review explicitly links PLGA physicochemical properties to key HME processing parameters, formulation strategies, and performance outcomes, emphasizing the cause–effect relationships that underpin successful extrusion‑based drug‑delivery platforms. By integrating material science, process engineering, and application‑level evidence, this work aims to serve as a practical and translational guide for researchers and formulators seeking to rationally design PLGA‑based systems using HME for scalable and clinically viable pharmaceutical applications.

This review begins with an overview of PLGA’s physicochemical properties that underpin its versatility in drug delivery systems. The article then details the setup and operational requirements of the HME process, emphasizing critical parameters and conditions that influence the feasibility and performance of PLGA formulations. Various preparation techniques are discussed, highlighting their integration with HME to produce innovative PLGA-based dosage forms. Furthermore, the review discusses the application of HME-based PLGA systems in controlled and targeted drug delivery, showcasing their potential to enhance therapeutic outcomes. Finally, future perspectives and challenges are addressed, focusing on scalability, regulatory considerations, and emerging trends that could shape next-generation pharmaceutical platforms.

PLGA characteristics (Fig. 1)

Fig. 1.

Structure and chemical characteristics of PLGA for designing the final product performance, and successful setup of the extrusion process

Molecular Weight (MW)

Transition of the ring-opening polymerization of lactide and glycolide is the most efficient route for preparing high-molecular-weight copolymers (Kapoor et al. 2015). Polymers with higher molecular weight generally degrade more slowly because their longer chains take more time to break down (Kapoor et al. 2015). Breakdown of molecular weight occurs through scission of the long polymer chains, which leads to increased hydrophilicity (Mir et al. 2017). Low‑molecular‑weight PLGA polymers exhibit reduced hydrophobicity because their accelerated hydrolytic degradation increases the availability of hydrophilic end groups. This may cause early burst release before the normal tailored release profile in low-molecular-weight PLGA polymers, resulting in fast degradation leading to an accelerated release of drugs. In addition, low‑molecular‑weight PLGA polymers typically exhibit reduced mechanical strength and stiffness, which can compromise their structural stability and lead to premature drug release under physiological conditions, ultimately decreasing therapeutic efficacy. Besides, the drug-loading capacity of these polymers may be limited due to limited space for encapsulation to some extent that impacts on whole efficiency in terms of drug delivery system (Yang et al. 2024a, b).

Monomer ratio

Table 1 presents the commercial manufacturers of different pharmaceutical-grade PLGA polymers and their available product specifications. PLGA is a biodegradable polymer composed of varying ratios of lactic acid (LA) and glycolic acid (GA) monomers. These monomers form ester bonds during polymerization to produce a polyester, which subsequently undergoes hydrolytic cleavage at the ester linkages in vivo. Upon degradation, the polymer releases its monomers, which are metabolized through the Krebs cycle into nontoxic byproducts, such as water (H₂O) and carbon dioxide (CO₂), ultimately eliminated from the body. This property contributes to PLGA’s excellent biocompatibility, making it highly suitable for a wide range of pharmaceutical and biomedical applications (Chatterjee and Chanda 2022). The ratio of lactic acid to glycolic acid in PLGA significantly impacts its degradation rate and other key properties, such as hydrophobicity, glass transition temperature (Tg), and mechanical strength (Liu and McEnnis 2022). Increasing the lactic acid content in PLGA raises its hydrophobicity, thereby reducing water uptake and slowing the overall degradation rate. However, increasing the glycolic acid content enhances the polymer’s hydrophilicity, resulting in faster hydrolytic degradation and consequently accelerating drug release (Chatterjee and Chanda 2022).

Table 1.

Commercial manufacturers of pharmaceutical-grade PLGA polymers and their available product specifications

Product	Molar ratio	Inherent viscosity	End group	Product grade
Ashland (Viatel)
PLGA	50:50	0.1–0.3	Acid \ ester	Viatel™ DLG 5002 A/E
PLGA	50:50	0.2–0.4	Acid \ ester	Viatel™ DLG 5003 A/E
PLGA	50:50	0.4–0.6	Acid \ ester	Viatel™ DLG 5005 A/E
PLGA	50:50	0.6–0.8	Acid \ ester	Viatel™ DLG 5007 A/E
PLGA	50:50	0.8–1.0	Acid \ ester	Viatel™ DLG 5009 A/E
PLGA	50:50	1.0–1.2	Acid \ ester	Viatel™ DLG 5011 A/E
PLGA	50:50	1.2–1.4	Acid \ ester	Viatel™ DLG 5013 A/E
PLGA	55:45	0.2–0.4	Acid \ ester	Viatel™ DLG 5503 A/E
PLGA	55:45	0.4–0.6	Acid \ ester	Viatel™ DLG 5505 A/E
PLGA	65:35	0.2–0.4	Acid \ ester	Viatel™ DLG 6503 A/E
PLGA	75:25	0.1–0.3	Acid \ ester	Viatel™ DLG 7502 A/E
PLGA	75:25	0.2–0.4	Acid \ ester	Viatel™ DLG 7503 A/E
PLGA	75:25	0.4–0.6	Acid \ ester	Viatel™ DLG 7505 A/E
PLGA	75:25	0.6–0.8	Acid \ ester	Viatel™ DLG 7507 A/E
PLGA	75:25	0.8–1.0	Acid \ ester	Viatel™ DLG 7509 A/E
PLGA	75:25	1.0–1.2	Acid \ ester	Viatel™ DLG 7511 A/E
PLGA	75:25	1.2–1.4	Acid \ ester	Viatel™ DLG 7513 A/E
PLGA	85:15	0.1–0.3	Acid \ ester	Viatel™ DLG 8502 A/E
PLGA	85:15	0.2–0.4	Acid \ ester	Viatel™ DLG 8503 A/E
PLGA	85:15	0.4–0.6	Acid \ ester	Viatel™ DLG 8505 A/E
PLGA	85:15	0.6–0.8	Acid \ ester	Viatel™ DLG 8507 A/E
PLGA	85:15	0.8–1.0	Acid \ ester	Viatel™ DLG 8509 A/E
PLGA	85:15	1.0–1.2	Acid \ ester	Viatel™ DLG 8511 A/E
PLGA	85:15	1.2–1.4	Acid \ ester	Viatel™ DLG 8513 A/E
Evonik (RESOMER)
PLGA	82:18	1.7–2.6	Acid \ ester	RESOMER LG 824 S
PLGA	85:15	2.5 −3.5	Acid \ ester	RESOMER LG 855 S
PLGA	85:15	5.0–7.0	Acid \ ester	RESOMER LG 857 S
PLGA	50:50	0.16–0.24	Acid \ ester	RESOMER RG 502
PLGA	50:50	0.16–0.24	Acid \ ester	RESOMER RG 502H
PLGA	50:50	0.32–0.44	Acid \ ester	RESOMER RG 503
PLGA	50:50	0.32–0.44	Acid \ ester	RESOMER RG 503 H
PLGA	50:50	0.45- 0.60	Acid \ ester	RESOMER RG 504
PLGA	50:50	0.45- 0.60	Acid \ ester	RESOMER RG 504 H
PLGA	50:50	0.61 −0.74	Acid \ ester	RESOMER RG 505
PLGA	65:35	0.32–0.44	Acid \ ester	RESOMER RG 653 H
PLGA	75:25	0.14–0.22	Acid \ ester	RESOMER RG 752 H
PLGA	75:25	0.16–0.24	Acid \ ester	RESOMER RG 752 S
PLGA	75:25	0.32–0.44	Acid \ ester	RESOMER RG 753 H
PLGA	75:25	0.32–0.44	Acid \ ester	RESOMER RG 753 S
PLGA	75:25	0.50–0.70	Acid \ ester	RESOMER RG 755 S
PLGA	75:25	0.7–1.0	Acid \ ester	RESOMER RG 756 S
PLGA	75:25	0.8–1.2	Acid \ ester	RESOMER RG 750 S
PLGA	85:15	1.3–1.7	Acid \ ester	RESOMER RG 858 S
Polyscience
PLGA	50:50	0.32–0.48	Acid/ester	26297
PLGA	50:50	0.32–0.48	Acid	26270
PLGA	50:50	0.32–0.44	Acid	50328
PLGA	50:50	0.32–0.44	Ester	50329
PLGA	50:50	0.45–0.60	Acid	50330
PLGA	50:50	0.45–0.60	Ester	50331
PLGA	50:50	0.50–0.75	Acid/ester	23986
PLGA	50:50	0.60–0.75	Acid	50332
PLGA	50:50	0.60–0.75	Ester	50333
PLGA	50:50	0.8–1.2	Acid/ester	23987
PLGA	55:45	0.45–0.60	Glucose	50334
PLGA	65:35	0.32–0.44	Acid	50335
PLGA	70:30	0.12–0.30	Acid/ester	19247
PLGA	75:25	0.15–0.25	Acid/ester	26268
PLGA	75:25	0.14–0.22	Acid	50336
PLGA	75:25	0.16–0.24	Ester	50337
PLGA	75:25	0.32–0.44	Acid	50338
PLGA	75:25	0.32–0.44	Ester	50339
PLGA	75:25	0.50–0.70	Ester	50340
PLGA	75:25	0.55–0.85	Acid/ester	25107
PLGA	75:25	0.70–1.00	Ester	50341
PLGA	75:25	0.90–1.30	Acid	50342
PLGA	75:25	0.90–1.30	Ester	50343
PLGA	85:15	0.16–0.24	Acid	50344
PLGA	85:15	0.16–0.24	Ester	50345
PLGA	85:15	0.70–1.00	Ester	50346
PLGA	85:15	0.75–0.85	Acid/ester	23989
PLGA	85:15	1.30–1.70	Ester	50347
PLGA	90:10	0.15–0.30	Acid/ester	19076
Nomisma healthcare
PLGA	50:50	0.32–0.44	Acid	DLLG 3A
PLGA	50:50	0.32–0.44	Ester	DLLG 3E
PLGA	50:50	0.45–0.60	Ester	DLLG 3E
PLGA	50:50	0.61–0.74	Acid	DLLG 5A
PLGA	50:50	0.61–0.74	Ester	DLLG 5E
PLGA	50:50	0.2	Acid	DLG502A
PLGA	50:50	0.2	Ester	DLG502E
PLGA	50:50	0.45–0.60	Acid	DLG504A
PLGA	55:45	0.45–0.60		DLG554Glu
PLGA	65:35	0.32–0.44	Acid	DLG653A
PLGA	75:25	0.90–1.30	Ester	DLLG 10A
PLGA	75:25	0.90–1.30	Ester	DLLG 10E
PLGA	75:25	0.32–0.44	Acid	DLLG 3A
PLGA	75:25	0.32–0.44	Ester	DLLG 3E
PLGA	75:25	0.50–0.70	Ester	DLLG 5E
PLGA	75:25	0.70–1.00	Ester	DLLG 7E
PLGA	75:25	0.90–1.30	Ester	DLLG 9E
PLGA	75:25	0.14–0.22	Ester	DLLAGA 2E
PLGA	75:25	0.14–0.22	Acid	DLLAGA 2A
PLGA	85:15	1.30–1.70	Ester	DLG8512E
PLGA	85:15	0.16–0.24	Acid	DLG852A
PLGA	85:15	0.16–0.24	Ester	DLG852E
PLGA	85:15	0.71–1.00	Ester	DLG857E

In biomedical applications, the choice of monomer ratio is crucial for tailoring the performance of PLGA in drug delivery systems. Commonly used ratios include 50:50, 75:25, and 85:15 (Huang and Ali 2023; Surya and Bhattacharyya 2021). A 50:50 lactide‑to‑glycolide ratio is commonly used when rapid polymer degradation and fast drug release are desired, whereas higher lactide ratios such as 75:25 or 85:15 are more suitable for sustained release formulations and provide improved mechanical strength. By carefully selecting the monomer ratio, researchers can tailor PLGA formulations to meet diverse therapeutic and biomedical needs, ensuring their efficacy and safety (J. Yang et al. 2024a, b).

Viscosity

Poly(lactic‑co‑glycolic acid) (PLGA) solutions typically remain free‑flowing at lower temperatures, but it forms a gel with higher viscosity at body temperature 37 °C (Kolter et al. 2012). The viscosity of PLGA is directly proportional to its molecular weight (Huang and Ali 2023). therefore, PLGA is produced in a range of viscosity grades, each corresponding to a specific molecular‑weight class (Surya and Bhattacharyya 2021). Polymers with high intrinsic viscosity—indicative of a higher molecular weight—tend to generate larger particles and exhibit slower drug‑release rates. This also enhances the mechanical strength and rigidity of the polymer, which helps maintain the structural integrity of the drug delivery system (DDS), improving its stability over time and extending its shelf life. A higher intrinsic viscosity decreases the diffusion of protein molecules through the polymer matrix, thereby enhancing the encapsulation efficiency of proteins and peptides (J. Yang et al. 2024a, b).

Blockiness

The effectiveness of drug delivery systems is greatly impacted by the blockiness of PLGA, which is crucial in defining its rate of degradation and drug release profile. This characteristic describes how the units of lactic and glycolic acids are arranged inside the polymer structure. A slower and more regulated degradation process results from a more organized, structured succession of these units, which is indicated by higher blockiness. This feature is very helpful in sustained-release medication administration, when the objective is to give the medicine continuously and steadily over a long period of time. Various studies indicate that PLGA block copolymers composed of distinct lactic‑acid and glycolic‑acid segments exhibit enhanced hydrolytic stability, resulting in slower degradation in aqueous environments and reducing the likelihood of burst release. This results in a more consistent and prolonged therapeutic effect (J. Yang et al. 2024a, b). In addition, the controlled degradation profile of PLGA with higher blockiness allows for more predictable molecular‑weight reduction over time, which supports a consistent drug‑release rate. This predictability is particularly important for long‑term therapeutic applications—such as chronic disease management—where sustained and reliable drug delivery is essential. In particular, PLGA microspheres with a high degree of blockiness degrade at a more controlled pace, providing a stable drug release profile and preventing fluctuations in drug concentration (Walker et al. 2023). Moreover, the polymer’s mechanical properties, such as elasticity and strength, can be finely tuned by adjusting the molecular weight and the ratio of lactic to glycolic acid, further enhancing its suitability for various biomedical applications (J. Yang et al. 2024a, b).

End cap group

PLGA polymers can be synthesized with either ester end groups or free carboxylic (acid) end groups, and this end‑capping significantly influences their degradation behavior and drug‑release profile. Ester‑end‑capped PLGA is more resistant to hydrolytic degradation than acid‑end‑capped PLGA because it contains fewer reactive carboxyl end groups at the outset, resulting in a slower initiation of chain cleavage (Huang n.d.). This slower degradation is further influenced by the chemical composition of chain ends, with stannous octoate initiators introducing hydrophobic residues that modify chain ends and impact degradation behavior (Avgoustakis 2005). Long alkyl chain initiators, such as decanol or dodecanol, used in ester end-capped PLGA synthesis led to slower degradation compared to acid end-capped PLGA synthesized with lactic acid as the initiator (Makadia and Siegel, 2011c). Acid‑end‑capped PLGA undergoes faster degradation and drug release because the free carboxyl end groups promote autocatalytic chain scission and increase water uptake (Kapoor et al. 2015; Makadia and Siegel, 2011c). The presence of acid end caps accelerates hydrolysis, leading to swelling of the polymer matrix and enhanced release of hydrophobic drugs. Recent advances in PLGA synthesis have made it possible to introduce a wide range of functional end groups, thereby expanding its versatility and applications in drug delivery systems (J. Yang et al. 2024a, b).

HME process setup and requirements (Fig. 2)

Fig. 2.

Hot melt extrusion process setup and requirements

Barrel temperature

Table 2 shows the HME process setup and requirements for different PLGA and APIs. Barrel temperature is a critical parameter in HME, as it governs the thermal and mechanical conditions under which the material is processed. It directly affects the melt viscosity, shear rate, and the thermal stability of APIs. Insufficient heating increases melt viscosity and shear stress, which can promote localized thermal accumulation. In contrast, excessively high temperatures may induce degradation of thermolabile constituents. For optimal process control, the extruder barrel is commonly segmented into several heating zones, each regulated independently to achieve precise thermal management along the extrusion pathway. Accurate adjustment and real-time monitoring of these different zones are essential to ensure efficient melting, uniform mixing, and preservation of the API’s integrity, ultimately contributing to consistent product quality (Kolter et al. 2012).

Table 2.

The commonly utilized PLGA, active pharmaceutical ingredients, and the relevant processing parameters and conditions for the hot melt extrusion process

PLA:GA ratio	APIs	Screw Type	Temperature (°C)	Screw Speed (RPM)	Ref
50:50	-	-	45–105	-	(Ghalanbor et al. 2012a)
50:50	Dexamethasone	Twin Screws	100	20–60	(Kelley et al. 2020)
50:50	Ibuprofen	-	105	-	(Bassand et al. 2022)
50:50	Dexamethasone, Carbamazepine, Metformin Hydrochloride	Single Screw	70—120	50–125	(F. Yang et al. 2024a, b)
75:25/50:50	Progesterone	Twin Screws	40–80	20	(Guo et al. 2017)
50:50	Sildenafil citrate	Twin Screws	80–130	20–50	(Almutairi et al. 2024)
75:25/50:50	Lysozyme	Twin Screws	60–105	25	(Farinha et al. 2020)
50:50	Disulfiram	Twin Screws	80–90	-	(McConville et al. 2015)
50:50	Goserelin	Single screw	80	10–20	(Ren et al. 2022)
75:25	-	Twin Screws	65–75	50	(Veeran et al. 2022)
50:50	Prednisolone Acetate, Propranolol HCI	-	150	-	(Kamel and Abbas 2018)
50:50	-	-	105	-	(Ghalanbor et al. 2013)
50:50	Lysosome	Twin Screws	90–105	20	(Ghalanbor et al. 2010)
50:50, 75:25, 100:0	Dexamethasone	-	95	-	(Bode et al. 2019)

Screw speed

Screw speed is a critical parameter in HME, directly affecting shear forces, residence time, and material temperature. Increasing the screw speed intensifies shear forces, which improves mixing efficiency but also generates more frictional heat that can damage heat‑sensitive APIs. In contrast, while higher screw speeds shorten residence time and help limit thermal degradation, they may also lead to insufficient mixing and reduced material uniformity (Patil et al. 2016). In pharmaceutical manufacturing, co‑rotating intermeshing twin‑screw extruders are widely used because they offer excellent mixing and conveying performance, enabling versatile and easily adjustable processing conditions (Alshetaili et al. 2020). Changes in screw speed influence melt viscosity and pressure, affecting mechanical energy input and thermal distribution within the extruder. Maintaining the right balance between these parameters is essential, as improper adjustments can lead to undesirable material behavior. For example, lowering the screw speed can increase melt viscosity, which elevates shear stress and may cause localized overheating. On the other hand, excessively high screw speeds can generate too much heat through friction, resulting in thermal degradation of the material. These factors highlight the need for precise control of the extrusion process to ensure optimal product quality (Kolter et al. 2012).

Configuration

Most extruders are constructed with a modular design, enabling adaptability in screw configuration to meet various processing requirements. The number and arrangement of conveying and kneading elements in the screw design can be tailored to achieve the targeted process performance. Because the screw configuration governs how material moves through the extruder, it directly influences flow behavior, mixing efficiency, and the distribution of heat throughout the extrusion process. By altering the screw configuration, it is possible to control shear intensity, residence time, and the level of material homogenization, which are essential for achieving consistent product quality (Kolter et al. 2012).

Feeding rate

The HME process consists of several essential components, including the feeder system, the barrel, and the screws, which were continuously mixing and conveying the materials. A control system was integrated into the extrusion process to regulate and optimize key operating parameters. Among these, the feeding rate played a critical role, as it directly influenced the final product’s dimensions and was essential for maintaining consistent product uniformity (Tan et al. 2020; F. Yang et al. 2024a, b). For instance, the feeding rate had a strong impact on particle size as well as granule density and strength. Higher feeding rates promoted the formation of larger, denser granules because of the increased compressive forces within the system. In contrast, lower feeding rates tended to produce a greater amount of fines due to insufficient consolidation during processing. Maintaining a consistent and uniform feeding rate (while ensuring a stable fill volume) was considered crucial for achieving reproducibility in the granulation process (Patil et al. 2016; Zupan et al. 2024). However, different processing conditions were being applied depending on the composition of the polymeric matrix in which the API was being embedded (Zupan et al. 2024).

HME parameters and conditions affecting the feasibility of PLGA-based applications (Fig. 3)

Fig. 3.

Effect of physicochemical properties of the PLGA and incorporated materials on the success of the HME process, and on producing the final formulation

Glass transition

The glass transition temperature (Tg) is one of the most important issues to estimate the thermal processing conditions and ultimately the properties of PLGA films produced by HME. PLGA typically has a Tg of about 45–50 °C, which allows it to be processed at relatively low temperatures. This is advantageous because it helps minimize the risk of thermal degradation, particularly for heat‑sensitive drugs such as proteins. For polymers with a defined glass transition temperature (Tg), such as PLGA, it is essential to precisely control the processing temperature during extrusion. The temperature must be kept above the polymer’s Tg to allow adequate flow yet remain below its degradation threshold. Maintaining this balance is crucial to preserving the stability and functionality of both the polymer and any incorporated APIs (Farinha et al. 2020). Studies have also demonstrated that factors such as molecular weight and plasticizer content affect the Tg of PLGA. For instance, increasing molecular weight typically leads to a higher Tg, as the polymer chains become more rigid and less mobile (Yang et al. 2024a, b).Thus, maintaining proper control of the polymer’s Tg during the HME process is essential for producing high‑quality PLGA films with consistent and desirable properties. The process parameters, such as extrusion temperature and monomer content, must be carefully adjusted to maintain optimal Tg and ensure that the final product possesses the required characteristics, such as appropriate drug release profiles and mechanical integrity (Kelley et al. 2020).

Processing temperature

Temperature plays a critical role in the hot‑melt extrusion (HME) process. One of the primary challenges is ensuring that all formulation components remain stable at the chosen processing temperature. This requires careful polymer selection so that extrusion can occur at lower temperatures—especially important when incorporating thermally sensitive drugs, such as proteins, which can degrade when exposed to higher temperatures (Farinha et al. 2020).

Degradation temperature

When processing PLGA‑based polymers via hot‑melt extrusion (HME), it is crucial to consider the polymer’s degradation temperature, which represents the upper thermal limit beyond which breakdown can occur. Exceeding this limit can lead to a reduction in molecular weight, changes in drug‑release behaviour, and the formation of acidic degradation by‑products. Therefore, the processing temperature should be set above the polymer’s Tg—where adequate melt flow is achieved—but still safely below its degradation temperature. Operating within this temperature window ensures proper polymer flow while preventing thermally induced degradation (Farinha et al. 2020). Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) are essential analytical tools for assessing the thermal stability of PLGA and its excipients, providing critical guidance for selecting safe and appropriate processing conditions. TGA data ensure that PLGA and physical mixtures of PLGA remain stable in the range of temperature utilized for HME (20–150) °C. DSC analysis completes the thermal behaviour, and the Tg of PLGA is 45.63 °C, which is an intrinsic vital parameter in order to have sufficient processing temperature achievable without thermal strain and beyond the breakdown of polymer chains. Nevertheless, some excipients such as sodium bicarbonate and other excipients show a broad degradation peak from 55 °C to 80 °C of which the decomposition turns into CO₂, Na2CO3 and H2O could have an impact on formulation stability (Almutairi et al. 2024).

Melting temperature

The melting temperature of the API is a crucial factor in PLGA-based HME, as it directly affects the drug’s stability, dispersion, and final solid-state properties. The API can be processed either above or below its melting temperature, but for extended-release formulations of thermolabile APIs, the extrusion temperature should be carefully controlled—above the polymer’s Tg yet as low as possible—to prevent degradation of biological activity. In such cases, micronization of the API before extrusion can improve its dispersion within the polymer matrix and reduce the required processing temperature (Farinha et al. 2020). The extent of API dispersion within PLGA depends not only on temperature but also on shear and mixing inside the extrusion system. If shear forces are insufficient, even an API processed above its melting temperature may partially revert to a crystalline state upon cooling, rather than remaining amorphous. This suggests that melting alone does not guarantee complete amorphization, and proper formulation strategies are necessary to ensure homogeneous drug-polymer distribution (McConville et al. 2015). The extrusion temperature is typically set much lower than the melting temperature of the API to prevent thermal degradation, which is particularly critical for heat-sensitive drugs. This careful balance between processing temperature, polymer properties, and drug stability ensures optimal drug incorporation, controlled release, and long-term efficacy in PLGA-based HME formulations (F. Yang et al. 2024a, b).

Melt viscosity

In PLGA‑based formulations, particularly during HME, viscosity plays a central role in determining how the material behaves during processing and ultimately influences the quality and performance of the final product. Viscosity variations can have a major impact on the mechanical characteristics, pore structure, and roughness of extrudates. A more irregular, porous structure with bigger, less defined cells is specifically the result of decreased viscosity, as is the case with increasing the ester-terminated PLGA ratio. This may have an effect on the rate of drug release, possibly speeding it up because of the larger surface area and quicker degradation (Almutairi et al. 2024). Melt viscosity is also influenced by temperature. Increasing the extrusion temperature lowers the viscosity of the PLGA melt, making extrusion easier. However, operating at higher temperatures can weaken the mechanical integrity of the final product and increase the risk of thermal degradation. In contrast, using lower temperatures increases the melt’s viscosity, which demands higher torque and may reduce the efficiency of mixing. This can negatively impact material uniformity and overall product quality (Farinha et al. 2020). Furthermore, viscosity can be further altered by adding plasticizers like PEG and benzyl benzoate, which improve drug release by expanding the free volume of the polymer and causing pores to form. This emphasizes how crucial it is to optimize viscosity parameters in PLGA formulations in order to avoid unintended degradation or instability during processing, achieve controlled drug release, and preserve mechanical integrity (Ghalanbor et al. 2013).

Overall, the mechanistic analysis presented in this section underscores that the feasibility and robustness of hot‑melt extrusion of PLGA‑based systems are governed by a tightly coupled interplay between polymer physicochemical properties and extrusion process parameters. Molecular weight and monomer ratio dictate melt viscosity, chain mobility, and torque requirements, thereby defining extrusion stability and residence‑time constraints, while the glass transition temperature establishes the lower thermal boundary for polymer flow and the upper limit for avoiding degradation. Degradation behavior and end‑group chemistry further modulate molecular‑weight loss, autocatalytic effects, and long‑term release performance as a function of thermal and shear exposure during processing. Collectively, these relationships demonstrate that successful PLGA‑HME formulation is not empirical but requires rational alignment of material selection with extrusion temperature, shear, and screw design, providing a predictive framework for optimizing processability, product uniformity, and therapeutic performance.

PLGA- based techniques (Fig. 4)

Fig. 4.

Different pharmaceutical technology approaches utilizing PLGA in different platforms

Several techniques—including solvent evaporation, spray drying, nanoprecipitation, microfluidics, electrospinning, and supercritical fluid processing—have been widely employed to fabricate PLGA‑based drug‑delivery systems, each offering distinct advantages and limitations when compared with hot‑melt extrusion (HME).

Spray drying

Table 3 summarizes some PLGA-based drug delivery techniques, polymer compositions, and associated pharmaceutical applications. Spray drying is one of the most widely used in pharmaceutical technology for producing drug delivery systems dry powders (Arpagaus 2019). Large-scale production has been achieved and deployed to some marketed particle products of PLGA. The continuous process can be applied to different kinds of feeds, including solutions, suspensions and emulsions. In the beginning spray drying was developed for pharmaceutical phase in order to produce dried materials by evaporation of solvent out of starting materials (Wan and Yang 2016). Several factors make spray drying an advantageous technique for pharmaceutical encapsulation. It allows precise control over particle size, shape, and morphology—including amorphous or crystalline structure and porosity—while offering straightforward operation and excellent scalability. Additionally, spray drying enables tailored particle design to achieve specific drug‑release profiles (Arpagaus 2019) and the milling of drugs––peptides or proteins––without a substantial reduction in biological activity (Kapoor et al. 2015). However, challenges still remain—for example, scale‑up can lead to unexpectedly high operational costs, which may limit the economic feasibility of large‑scale spray‑drying processes (Wan and Yang 2016). Storing PLGA nanoparticles is challenging because the polymer is susceptible to degradation through hydrolysis as well as exposure to light, air, heat, and moisture. These environmental factors accelerate polymer breakdown and can compromise nanoparticle stability. This particle morphological degradation to lactic and glycolic acid can change particle morphology, lower the potency of the drug and increase toxicity (Kapoor et al. 2015).

Table 3.

Overview of PLGA-based drug delivery techniques, polymer compositions, and associated pharmaceutical applications

Techniques	Drug	PLA: GA ratio	Formulation	Application	Ref
Double emulsion W/0/W	Alendronate	50:50	I.V. injection	Inhibition of raw 264 macrophage. Inhibition of restenosis in rat model. Depletion of rabbit circulating monocyte	(Cohen-Sela et al. 2009)
	Losartan	50:50	Microspheres	Sustain release of water-soluble drug	(Huang n.d.)
	Goserelin	50:50	Microspheres	Sustain the release of the hydrophilic peptide	(Huang n.d.)
	Insulin	50:50	Microspheres	As a growth factor for cartilage tissue engineering	(Kapoor et al. 2015)
	Calcium phosphate cements	50:50	Microspheres	Used as a bone substitute material	(Kapoor et al. 2015)
	Cucurbitacin	50:50	N\A	Encapsulation of hydrophilic drugs	(Alshamsan 2014)
	Liraglutide	50:50	Microspheres	Treatment of Diabetes	(Lee and Pokorski 2018)
	Lupron Depot	50:50	Microspheres	Treatment of prostate cancer	(Lee and Pokorski 2018)
	Nutropin Depot	50:50	Microspheres	Treatment of growth hormone deficiency	(Lee and Pokorski 2018)
	Sandostatin LAR depot	50:50	Microspheres	Treatment of acromegaly	(Lee and Pokorski 2018)
	Bovin serum albumin	50:50	Microspheres	Sustain release drug delivery systems	(Park 2024)
Oil in water single emulsion	Paclitaxel	50:50	I.V. injection	Cancer therapy	(Kapoor et al. 2015)
	Cucurbitacin	50:50	N\A	Encapsulation of hydrophilic drugs	(Alshamsan 2014)
	Progesterone	50:50	N\A	Preparation of porous PLGA microspheres with spongelike morphology	(Lee and Sah 2022)
Spray drying	Rifampicin	75:25	N\A	Respiratory disease of tuberculosis	(Arpagaus 2019)
	Etanidazole	65:35	Radiotherapy	Cancer treatment	(Arpagaus 2019)
	siRNA	75:25	Pulmonary delivery	Treatment of severe lung disease	(Kapoor et al. 2015)
Freeze drying	Cyclosporine	50:50	Oral\topical rout	Immunosuppressant	(Jain et al. 2010)
	(MSE)	50:50	Injection	Treatment of inflammatory acne	(Srihaphon et al. 2021)
Ring-Opening polymerization	Dexamethasone	75:25	Implant	Treatment of diabetic muscular edema	(Tabatabaei Mirakabad et al. 2014)
	Alpha- Tocopherol	65:75	N\A	Treat some chronic, age-related disease	(Varga et al. 2019)
Microwave functionalization	Dexamethasone	50:50	N\A	Enhancement of drug release	(Islam and Mitra, 2023c)
Electrospinning	Drug-free scaffold	75:25	Composite nanofibrous membrane	Guided Tissue Regeneration. Guided Bone Regeneration	(Kalluri et al. 2021)
Electro spraying	Metronidazole	90:10	microparticles	Sustained release of drug suitable for periodontal regeneration	(Prabhakaran et al. 2015)
Supercritical fluid technology	Ketoprofen	50:50	Microspheres	Orthopedic applications specifically for implant	(Kravanja et al. 2024)
	Rutin	75:25	Foam	Controlled release of rutin for medical treatment	(Valor et al. 2021)
Phase separation	Minocycline HCL	50:50	Parenteral	Local antibiotic treatment	(Huang n.d.)
3D printing	Aspirin	N\A	Microspheres	Bone implant (osseointegration)	(You et al. 2022)
Nanoprecipitation	Indomethacin	50:50	Nanoparticle	Targeted drug delivery and improving bioavailability	(Serhan et al. 2019)
	Sorafenib	50:50	Nanoparticle	Targeted drug delivery and improving bioavailability	(Serhan et al. 2019)
	Clofazimine	50:50	Nanoparticle	Targeted drug delivery and improving bioavailability	(Serhan et al. 2019)
	Carbamazepine	50:50	Nanoparticle	Improve drug administration	(Kandilli et al. 2020)
	Levetiracetam	50:50	Nanoparticle	Improve drug administration	(Kandilli et al. 2020)

Microwave-assisted method

Microwave‑assisted methods have been explored as an alternative or complementary approach for modifying PLGA properties through rapid, volumetric heating, which promotes molecular‑level interactions via dipole rotation and ionic conduction. In the context of PLGA, microwave irradiation has primarily been investigated for polymer blending, functionalization, and surface modification, resulting in changes to molecular weight, oxidation state, and functional group density that can influence degradation behaviour and drug–polymer interactions (Sridhar et al. 2024). Studies have shown that microwave treatment can induce partial chain scission and increased carboxylation or hydroxylation of PLGA, thereby enhancing hydrophilicity and potentially accelerating drug release or improving compatibility with hydrophobic drugs (Islam and Mitra 2023a; Martins et al. 2018).

Microwave irradiation was employed for blending PLLA and PGA at various concentration ratios to obtain compatible blends. Blending was performed using a Panasonic domestic microwave oven (2450 MHz, 1300 W) with variable power levels from ∼130 W to 1300 W. The IR spectra of both pure polymers before and after microwave treatment showed characteristic bands, indicating the presence of methylene and carboxylic > C = O bond. The acid oxidation of PLGA was conducted in a CEM microwave reactor. PLGA was mixed with a 3:1 H₂SO₄ and HNO3 mixture and reacted at 800 W (maximum 1600 W) and 60 °C. After filtering and drying, the functionalized PLGA particles were sonicated to produce nanoparticles. Microwave functionalization significantly altered PLGA properties. SEM–EDS analysis revealed an increase in oxygen content from 24.76% to 53.07%, indicating extensive oxidation. Some ester linkages were broken, resulting in increased carboxylation and hydroxylation in the synthesized product (Islam and Mitra 2023b). However, microwave‑assisted processing is typically conducted as a batch‑based or post‑synthetic modification technique, with limited control over shear, residence time, and large‑scale reproducibility, which restricts its direct applicability for industrial drug‑delivery manufacturing.

Double emulsion

The encapsulation of hydrophilic molecules in nanoparticles (NP) is challenging due to rapid drug diffusion. A double emulsion system with ethyl acetate improves encapsulation and reduces NP size. The DES-D method enhances formulation by reducing size, narrowing distribution, increasing efficiency, and using biocompatible components. It minimizes drug leakage and integrates DES-E and ESD advantages. NPs with Pluronic F-68 or Tween 80 were ~ 20 nm smaller than those with Polyvinyl Alcohol (PVA) (Cohen-Sela et al. 2009). The W/O/W solvent evaporation technique encapsulates hydrophilic drugs into PLGA microparticles. The double-emulsion method precipitates polymer around droplets, forming solid particles. Particle size depends on the first emulsification step, while the second affects morphology. Stabilizers like PVA and poloxamers prevent droplet coalescence (Ortega-Oller et al. 2015). This method is widely used for drug delivery and depends on PLGA and PVA concentrations (Hernández-Giottonini et al. 2020). Emulsion diffusion, solvent displacement, and double emulsions aid drug embedding (Parashar et al. 2022). It loads various drugs and contrast agents, though surfactant residues may remain (Rezvantalab et al. 2018). Double-emulsion encapsulation in ethanol–water mixtures improves efficiency and retention, as seen with Cucurbitacin I. Micro crystallization is avoided, but solubility limits some drugs. The method is effective for hydrophilic and hydrophobic molecules (Alshamsan 2014). Proteins dissolve in water, mix with PLGA in organic solvent, emulsify, then disperse into water with stabilizers. Solvent evaporation yields microspheres for vaccines and hormones (Alshamsan 2014). Encapsulation efficiency (30%−95%) depends on PLGA, stabilizers, and emulsification. High molecular weight PLGA enhances efficiency by reducing protein diffusion (Lee and Pokorski 2018).

Single emulsion

O/W emulsification, particularly the single emulsion technique, is one of the most used methods for drug encapsulating hydrophobic drugs (Rocha et al. 2022). PLGA and drug are dissolved in water-immiscible organic solvents, e.g. dichloromethane, chloroform or ethanol (Panigrahi et al. 2021). for this process. The organic phase can be emulsified in aqueous solution containing surfactants, PVA or Poloxamer (Rocha et al. 2022). to aid for the precipitations (Parashar et al. 2022; Rocha et al. 2022). The emulsification process is commonly executed in a stirred condition or through high-pressure homogenization (Panigrahi et al. 2021). After the emulsion is created it evaporates the organic solvent with stirring or by artificial hot and cold environment for a period of time for nanoparticles and microparticles (Rocha et al. 2022). The particles so formed can be collected by ultracentrifugation, washed with NE for clearing all the impurities and finally lyophilized (Panigrahi et al. 2021). Because of high solubility to the primary aqueous phase, some of these drugs are known to diffuse or partition out of internal organic phase rapidly during emulsification, which ultimately resulted in low of encapsulation efficiency. For instance, non-polar compounds such as theophylline, salicylic acid and caffeine may be poorly encapsulated whereas hydrophobic drugs such as diazepam, hydrocortisone, progesterone exhibit significantly improved results using this strategy (Panigrahi et al. 2021). When in some specific circumstances, porous PLGA microspheres with sponge-like structures can also be prepared by a single emulsion method that has been modified to generate macro-pores within the microspheres. to enable ammonolysis. This is done by adding ammonia to the emulsion, generating ethanol and formamide as anti-solvents strongly adsorbing PLGA and instating solid.These porous microspheres are useful for applications requiring enhanced drug loading and release properties (Lee and Sah 2022). To overcome the inherent challenges of the single emulsion method, especially for hydrophilic drugs, double emulsion (W/O/W) techniques are often employed as an alternative. These methods improve encapsulation efficiency by introducing an additional emulsification step, stabilizing the interface using surfactants tailored for different phases (Panigrahi et al. 2021).

Electrospinning

Electrospinning is an electrohydrodynamic method for producing micro- and nanofibers. This method uses an electric field to suck out or draw ultrathin fibers of polymers solutions or melts. Applied Voltage, Polymer Concentration, Spinneret-Collector Distance and Flow Rate are the major parameters that affect fiber morphology and diameter (Kalluri et al. 2021). strongly Scalability, cost effectiveness, and its capability to produce ultrafine fibres with large surface area, porosity as well as possible controlled drug release profile is established by this technique. Electrospun PLGA fibers find a wide variety of biomedical applications, such as sustained drug delivery, wound healing and tissue engineering. Efficient drug encapsulation and release can be achieved due to their large surface area and porous structures which contributes to combinational therapies or sequential drug delivery (Visan and Negut 2024). Limitations The technique however comes with its caveats, the first being optimization of parameters and the risk for drug degradation/loss in case of mechanical performance limitations (Kalluri et al. 2021). Some of these features, such as the polymer, fiber morphology and amount of drug loaded are programmable according to therapeutic requirements. Examples include application in orthopedics, where electrospun PLGA hydrogels regulate the release rate for anti-inflammatory drug or where they are used in neuroscience for delivering neurotrophic factors to treat neurodegenerative diseases and spinal cord injuries (Visan and Negut 2024). Advancements in the developments of materials and process optimization have improved the performance of electrospun PLGA fibers for biomedical applications (Kalluri et al. 2021).

Electrospraying

Electrospraying is a nano/microparticles generation method using an electro-hydrodynamic process with the application of a high electric field. A polymeric solution is subjected to a high voltage, producing a conical jet that splits into droplets upon breaking and then dries to give solid particles on a collector. This process is also a cheap and straightforward one-step procedure for solvent usage dispersal production, without waste. It effectively produces micro/nanometer droplets without coalescence. In this context, PLGA (poly(lactic-co-glycolic acid)) is used as a biocompatible polymer for drug delivery, with metronidazole (Met) encapsulated in PLGA particles. allowing for controlled drug release. Incubation with DCM yielded much larger particles (3946 ± 407 nm) compared to trifluoroethanol (TFE) (1774 ± 167 nm). Met was dispersed for more than 41 days, showing normal Fickian diffusion, although the initial burst release of TFE particles was higher than that of DCM. Scanning Electron Microscopy (SEM) showed spherical morphology with a smooth surface, revealing noticeable differences in particle size according to the solvent used. Fourier Transform Infrared (FTIR) spectroscopy confirmed the incorporation of the drug, while pristine PLGA was colorless without any ink-polymer interaction. From a biocompatibility perspective, cytotoxicity studies indicated that the sanguine extracts containing the drug did not restrict the labelling of mesenchymal stem cells (MSC). Overall, electrospray is a promising technique for drug delivery systems with a controlled release profile, suitable for use in a wide range of biomedical applications (Prabhakaran et al. 2015).

Nanoprecipitation

Nanoprecipitation is a technique used to create nanoparticles by dissolving a polymer and a drug in a solvent, followed by mixing it with a non-solvent, which causes the drug to precipitate out in the form of nanoparticles. This technology is highly valuable, particularly when combined with PLGA, as it allows for controlled drug release and enhances the stability and bioavailability of the drug. It’s an innovative approach because it enables the precise encapsulation of drugs in PLGA nanoparticles, which can be tailored for specific therapeutic purposes [81]. Microfluidics-assisted nanoprecipitation suggested a key role involved in preparing PLA/PLGA-based nanocarriers. The nanocarriers were loaded with different components, such as Rhodamine B and gold, to enhance the physical and chemical properties of them. The method resulted in the preparation of spherical nanoparticles with a hydrophilic surface and uniform dispersion of the incorporated materials in their polymer matrix. This confirmed that nanoprecipitation could be used to provide efficient encapsulation efficiency of over 50% for optimizing the drug or material loading process of PLGA as directly exposed. Also, it further reduced particle size towards an average of 170 ± 64 nm, which improved cell penetrance ability of nanoparticles (Lamparelli et al. 2024). A wide range of factors can affect the efficiency of the medication loading process. The quantity of drug that can be adhered into the nanoparticles is dependent on the solubility of the drug in solvent solution. The new methods described, e.g., the introduction of pseudo-constant K* at the presence of an inhibitor, subsequently allow for a better understanding of drug-polymer interactions. Due to higher solubility in solvent/antisolvent systems, medicines with lower K* values, such as ketoprofen (KPN) and indomethacin (IND), are easier to load. However, PLGA was depicted to have stronger interactions, especially with higher K* values such as clofazimine (CFZ) and sorafenib (SFN), respectively (Serhan et al. 2020). The nanoprecipitation approach is very efficient for the nanoscale delivery of N-Acetylcysteine (NAC), a hydrophilic antioxidant with powerful antioxidant activities. NAC’s therapeutic effectiveness is severely hampered by its low bioavailability and poor tissue access. This method successfully loads NAC into nanoparticles by dissolving it with a polymer, such as PLGA, in a solvent, and then adding this mixture to an immiscible solvent like water. This process causes the polymer to precipitate and form nanoparticles that encapsulate NAC. The loading capacity of NAC into nanoparticles increased with enhancing viscosity of the immiscible solvent during the process (Lancheros et al. 2018). In vitro studies showed sustained and controlled drug delivery of carbamazepine and levetiracetam, which maintained therapeutic levels for a prolonged period. Additionally, in vivo studies revealed that the nanoparticles improved the pharmacokinetics of these drugs by increasing blood circulation and bioavailability compared to free drugs. Furthermore, the nanoparticles demonstrated superior anti-epileptic effects, indicating a potential for optimizing therapeutic results (Kandilli et al. 2020). These results demonstrate that nanoprecipitation represents an efficient way of tuning the performance of PLGA-based nanocarriers in terms of particle size control and high efficiency in delivering biologically active substances. The size reduction of particles caused a notable rise in cellular uptake efficiency, reaching nearly 100% uptake after 48 h. Such findings emphasize the need to consider more than hydrophobicity in predicting drug loading efficiency, and the use of molar units rather than weight ratios for accurate predictions, especially for drugs with different molecular weights (You et al. 2022).

3D printing

3D printing is a promising approach with its high precision and reproducibility. It has been shown useful for improving properties of systems such as medical grade materials and PLGA. The technology allows for structures with exact porosity to be fabricated; thus, facilitating tissue ingrowth and encouraging natural regeneration. PLGA, which is a degradable material can assist tissue for short term before it is absorbed naturally (You et al. 2022). When PLGA are combined with other materials excellent mechanical properties of the printed structures are obtained; thereby increasing load-bearing capacity for 3D-printed constructs. But difficulties like fragile mechanical structures and the potential high-cost of 3D printing over traditional approaches exist (Sun et al. 2022). 3D-printed systems based on bioactive molecules and also their controlled release show significantly enhanced biological activity and efficacy, thus speeding up bone regeneration via these systems. These techniques enhance biocompatibility and enable partial regeneration/complementation of large complex defects (Zhao et al. 2024). Research has shown that the performance of 3D-printed PLGA systems can vary depending on the materials used. By controlling how bioactive agents are released, we can further enhance their regenerative capabilities, making them an exciting solution for tissue engineering (Hou et al. 2024; Lv et al. 2024). On top of that, advanced techniques, like combining microspheres with 3D printing, have really pushed the limits. These methods create optimal conditions for tissue growth and provide effective delivery systems for bioactive agents, offering real promise for repairing major defects in regenerative medicine (Klar et al. 2024).

Supercritical fluid (SCF) technology

Super critical fluid (SCF) technology is one of the major developed techniques that have been employed to improve polymer properties for example PLGA for designing drug delivery system as it is an ideal for both. The method employs supercritical fluids which are a combination of gas and liquids for targeted drug delivery and more controlled release, resulting improved clinical benefit and greener approaches. When combined with SC CO₂, it offers unique benefits such as rapid solvent removal and a more efficient solidification process. It has been shown to enhance the properties of PLGA microspheres, improving their uniformity and ensuring better drug release profiles. SC-CO₂ effectively removes organic solvents and prevents aggregation, providing high-quality microspheres that can be used in various drug delivery applications (Park et al. 2023). SCF technology, particularly SC CO₂-assisted foaming, also brings several advantages. With its low critical temperature and pressure, SC CO₂ is gentle on sensitive drugs, making it ideal for controlled release applications. Additionally, this technique creates porous structures within PLGA that allow for better drug loading and gradual release over time. The creation of a porous matrix also enhances the material’s ability to facilitate cell attachment and growth, which is crucial for biomedical applications such as implants, particularly in orthopedics treatments. This process reduces the need for harmful organic solvents, making the technique more environmentally friendly and safer for biomedical use (Kravanja et al. 2024). Furthermore, the use of SCF technology in forming fine particles of PLGA allows for precise control over the size and shape of the particles, which directly impacts drug efficacy and release rates. The supercritical state of CO₂, which combines liquid and gas characteristics, ensures that the particles produced are very fine, thus enhancing drug stability and improving its spreadability throughout the body. By employing SCF, researchers gain greater control over the production process, ensuring a higher quality product compared to older methods. This level of control is essential for developing more effective drug delivery systems, where the release characteristics are crucial for therapeutic efficacy (Furlan et al. 2010). SCF-PLGA technology offers a highly efficient and sustainable way to improve drug production. It minimizes the need for toxic solvents like hexane, thus reducing environmental impact while maintaining the integrity of bioactive materials. With the ability to form fine particles with controlled properties, SCF-PLGA systems not only improve the performance of drug delivery but also contribute to the development of safer and more effective pharmaceutical products. This combination of benefits highlights the potential of SCF technology in revolutionizing drug production and delivery (Bendicho-Lavilla et al. 2023).

Phase separation

Coacervation (Phase separation) is an approach frequently applied for the micro/nanoparticle encapsulation of water-soluble molecules especially proteins in PLGA (Poly(lactic-co-glycolic) acid). Usually, PLGA is dissolved in an organic solvent, e.g. dichloromethane or ethyl acetate and subsequently emulsified with an aqueous protein solution leading to the primary water/oil W/O emulsion. The emulsion is then added into a bulk aqueous phase which causes the precipitation of polymeric particles because the polymer shrinks around primary emulsion droplets in situ. This process is further enhanced by adding surfactants or stabilizers to stabilize the system, and the organic solvent is removed through evaporation under vacuum (Ortega-Oller et al. 2015). Careful solvent selection is crucial for successful coacervation, as solvents with low surface tension and a certain degree of miscibility with water are ideal for rapid phase separation (Wan and Yang 2016). In phase separation processes, controlling the rate of addition of nonsolvent, such as silicon oil, is essential for particle size and encapsulation efficiency. The process involves gradual introduction of the nonsolvent to extract the primary solvent, facilitating the formation of microspheres. The solvent extraction method is followed by washing with apolar solvents like heptane or hexane to further solidify the microspheres (Huang n.d.). The quality of the encapsulation is influenced by the balance of aqueous and polymer solution volumes, with specific ratios being critical to stabilize the phase separation process (Lee and Pokorski 2018). Moreover, optimizing factors such as stirring rate, temperature, and organic solvent flow rate are key to controlling the morphology of the final product (Lee and Pokorski 2018; Wan and Yang 2016). Several modifications to the phase separation process have been explored to enhance encapsulation efficiency, minimize initial burst release of the encapsulated protein, and ensure a long-duration release profile (Park et al. 2023). Despite these advancements, challenges remain, including the difficulty in maintaining uniform particle size and preventing aggregation during the solvent removal and hardening stages (Lee and Pokorski 2018; Park et al. 2023). The phase separation technique’s ability to form stable, controlled-release micro/nanocarriers makes it a promising approach for drug delivery systems, though ongoing refinement of the solvent removal methods is necessary to achieve more consistent and reproducible results (Park et al. 2023; You et al. 2022).

PLGA- based HME in drug delivery applications

While numerous techniques—including solvent evaporation, spray drying, microfluidics, and nanoprecipitation—are available for processing PLGA‑based drug‑delivery systems, hot‑melt extrusion (HME) is distinct in several aspects critical for pharmaceutical translation. Unlike solvent‑based methods such as solvent evaporation and spray drying, HME is a solvent‑free, continuous manufacturing process (Genina et al. 2018). This eliminates concerns related to residual organic solvents, reduces environmental burden, and simplifies regulatory compliance. Regulatory agencies such as the U.S. FDA have increasingly favored solvent‑free and continuous manufacturing platforms because of their enhanced process control, reproducibility, and alignment with quality‑by‑design (QbD) principles (Duarte et al. 2025).

From a scalability and manufacturability standpoint, HME is inherently advantageous. Spray drying and solvent evaporation, although well‑established, often encounter challenges during scale‑up due to solvent recovery costs, batch‑to‑batch variability, and high operational expenses (Patel et al. 2021). Microfluidics, while offering exceptional control over particle size and uniformity, remains limited in throughput and is currently better suited for laboratory‑scale or early‑stage development rather than commercial manufacturing (Yu et al. 2024a). In contrast, HME has been widely adopted at industrial scale and is already used in several FDA‑approved pharmaceutical products.

In terms of product reproducibility and process robustness, HME offers superior control over critical process parameters such as temperature, shear force, screw configuration, and residence time (Matić et al., 2020b). These features enable consistent production of PLGA formulations with uniform drug distribution and predictable release kinetics. Solvent‑based emulsification techniques, particularly double‑emulsion methods, are more susceptible to variability arising from emulsification energy, solvent diffusion rates, and stabilizer concentrations (Leister and Karbstein 2020).

Regarding clinical translation, HME‑processed PLGA systems benefit from strong regulatory and industrial precedence. HME is routinely used to manufacture amorphous solid dispersions and implantable drug‑delivery devices, facilitating smoother transition from bench to bedside (Wan 2024). In contrast, particle‑based technologies such as nanoprecipitation and microfluidics, although promising, still face challenges related to long‑term stability, large‑scale reproducibility, and regulatory standardization (De Souza Cardoso Delfino et al. 2025; Xu et al. 2026; Yu et al. 2024b). Overall, while solvent‑based and microfluidic methods remain valuable for formulation screening and niche applications, hot‑melt extrusion represents a more mature, scalable, and regulatorily aligned platform for the clinical translation of PLGA‑based drug‑delivery systems.

Table 4 presents some applications for coupling PLGA with HME in drug delivery systems and the formulation performance outcomes. Ghalanbor et al. investigated BSA-loaded PLGA (50:50) implants prepared via HME at 45–105°C. Increased implant porosity significantly enhanced protein release (60–97%, depending on BSA loading). Incomplete release was attributed to thioester bond formation between BSA and PLGA oligomers, resulting in residual insoluble mass. Increasing and optimizing implant porosity enhanced protein delivery efficiency by facilitating water penetration, accelerating polymer erosion, and promoting more effective diffusion of protein molecules from the PLGA matrix, thereby enabling improved control over the release profile (Ghalanbor et al. 2012b).

Table 4.

Applications of PLGA in drug delivery systems using hot-melt extrusion: polymer composition, APIs, formulation strategies and performance outcomes

PLA:GA ratio	APIs	Formulation	Remarks	Ref
50:50	Bovine serum albumin	Implants	PLGA implants with 25% Bovine serum albumin showed better release with more porosity	(Ghalanbor et al. 2012a)
50:50	Dexamethasone	Implants	Process adjustments improved consistency, but implants weakened	(Kelley et al. 2020)
50:50	Ibuprofen	Implants	HME showed limited impact on drug release in PLGA implants, indicating the need for further research	(Bassand et al. 2022)
50:50	Dexamethasone, Carbamazepine and Metformin Hydrochloride	Implants	Residual monomers in PLGA influence degradation and drug release	(F. Yang et al. 2024a, b)
50:50/75:25	Progesterone	Microsphere	HME-prepared PLGA microspheres with wet-milling provide a sustained release with low initial burst and long-term effects.	(Guo et al. 2017)
50:50	Sildenafil citrate	Dry powder	HME produced long-acting sildenafil-loaded PLGA aerosol microparticles with optimized release	(Almutairi et al. 2024)
50:50/75:25	Lysozyme	Microparticles	HME efficiently produced lysozyme-PLGA microparticles with controlled release and minimal impact on bioactivity	(Farinha et al. 2020)
50:50	Disulfiram	Millirods	HME produced Disulfiram-loaded PLGA millirods with improved stability, uniformity, and reduced cytotoxicity compared to IM	(McConville et al. 2015)
50:50	Goserelin	Microsphere	HME improved drug distribution and reduced burst release in PLGA microspheres, leading to sustained Goserelin release	(Ren et al. 2022)
75:25	Drug-free	Film	HME successfully produced stable, high-quality PLGA films without thermal or molecular changes, suitable for medical device coatings	(Veeran et al. 2022)
50:50	Prednisolone Acetate and Propranolol HCl	implant	Implants based on PLGA 503 showed better mechanical strength, slower drug release, and better stability than other formulations	(Kamel and Abbas 2018)
50:50	Dexamethasone	Implant	Increasing PLGA porosity and drug loading enhances release, leading to complete drug release with no residual implant mass	(Ghalanbor et al. 2013)
50:50	Lysozyme	Implant	HME of PLGA implants allows for burst-free, complete release of lysozyme while preserving its biological activity	(Ghalanbor et al. 2010)
50:50, 75:25, 100:0	Dexamethasone	Implant	Swelling of the polymer controls drug release by making it more hydrophilic over time, allowing the drug to dissolve and diffuse	(Bode et al. 2019)

Kelley et al. developed dexamethasone implants using PLGA 50:50 via twin-screw HME. The implants were processed at 100 °C with a screw speed of 20–60 rpm to achieve three release profiles: fast, intermediate, and slow. Results showed that ester-terminated PLGA led to slower drug release. Modifying extrusion and conveyor speeds improved batch consistency, but drug release was unaffected for most formulations, except for the fast release composition (Kelley et al., 2020c).

Bassand et al. studied ibuprofen-loaded PLGA 50:50 implants processed by HME at 105 °C. They found that longer heat exposure reduced the crystalline drug content, slightly decreasing the initial burst release. However, the overall drug release was not significantly affected. These results suggest that while heat exposure changes the drug’s physical state, it has a limited impact on release, indicating the need for further research (Bassand et al. 2022).

Yang et al. developed PLGA-based implants using HME with a single screw extruder at 70–120 °C and screw speeds of 50–125 rpm for sustained drug release. They studied the effects of PLGA characteristics like polymer ratio, molecular weight, and residual monomer on degradation and drug release. Higher plasticity in Viatel™ PLGA resulted in smoother surfaces, stronger drug interactions, and lower burst release, while residual monomer accelerated water diffusion and degradation, negatively impacting drug release performance (Yang et al. 2024a, b).

Guo et al. developed PLGA microspheres for sustained drug release using HME. Progesterone (PRG) was used as the model drug with PLGA ratios of 75:25 and 50:50. Microspheres were produced at 40–80 °C with a 20-rpm screw speed, achieving 40% drug loading. The initial burst release was 6.7%, significantly lower than the 25.7% observed in microcrystal suspension, with sustained release over 7 days. This was attributed to the honeycomb-like structure, where drug microcrystals embedded in the PLGA matrix ensured prolonged release (Guo et al., 2017b).

Almutairi et al. developed sildenafil citrate-loaded PLGA microparticles for PAH treatment using HME at 80–130 °C and 20–50 rpm. Sodium bicarbonate was added as a porogen to enhance brittleness. The microparticles (6–14 µm) showed 77–89% entrapment efficiency and 17–33% w/w drug loading. In Vitro, 15% of the drug was released within 24 h and 70% over 7 days. The study highlighted HME as a scalable method for inhaled sildenafil formulations, with PLGA affecting drug loading, release, and particle properties (Almutairi et al. 2024).

Farinha et al. utilized twin-screw HME at 60–105 °C and 25 rpm to produce lysozyme-loaded PLGA microparticles for controlled release. Higher drug loads increased burst release, while PEG 400 had minimal impact but enabled lower extrusion temperatures. Washing steps significantly reduced burst release, with water washing decreasing it by 80% and PVA washing eliminating it. The study confirmed twin-screw HME as an effective method for controlled-release biopharmaceutical microparticles (Farinha et al. 2020).

McConville et al. developed disulfiram-loaded PLGA millirods for glioblastoma treatment using twin-screw HME at 80–90 °C. HME ensured drug stability, while IM reduced it at 10% loading due to longer processing. Increasing DSF to 20% lowered processing temperature, preserving stability in both methods. HME millirods had amorphous DSF, while IM retained 54–66% crystallinity. Drug release depended on PLGA degradation, method, and load, with HME 10% millirods maintaining cytotoxicity. These millirods could provide targeted GBM treatment via stereotactic injection (McConville et al. 2015).

Tianyang Ren et al. used HME to prepare Goserelin-loaded PLGA microspheres for a long-acting drug delivery system. In this process, Goserelin/PLGA 50:50 solid dispersion was extruded using a single screw extruder at 80 °C. The drug was uniformly dispersed in the PLGA matrix in an amorphous or molecular form, which allowed for a reduced burst release and controlled drug release. The HME method helped maintain the drug stability, and the formulation showed minimal fluctuation in serum concentration, making it a promising approach for long-term, stable drug delivery (Ren et al. 2022).

Veeran et al. optimized PLGA polymer films using a Quality-by-Design approach and HME. They used a Central Composite Face (CCF) design, processing PLGA 75:25 with twin-screw extruders at 65–75 °C and a screw speed of 50 rpm. The study found that the glass transition temperature (Tg) was significantly influenced by the process parameters. Characterization revealed no thermal or molecular changes during extrusion, suggesting the films are suitable as biodegradable coatings for medical devices (Veeran et al. 2022).

Kamel and Abbas studied PLGA-based monolithic filament implants prepared via HME at 37 °C and 70 rpm. They examined PLGA type (502, 503), drug type (PA, PH), and drug loading (10%, 30%). PLGA 503 implants had superior mechanical properties, slower drug release, and lower water uptake than PLGA 502. PH-loaded implants released the drug in 18 days, while PA-loaded implants took 30 days, both following zero-order kinetics. The 30% PH-503 and 30% PA-503 implants showed the most balanced properties, making them suitable for further biological studies (Kamel and Abbas 2018).

Ghalanbor et al. studied BSA release from 50:50 PLGA-based implants prepared by HME at 105 °C with a screw speed of 80 rpm. The study showed that the presence of BSA reduced the PLGA degradation and erosion rates, leading to incomplete drug release. By increasing the porosity during the erosion phase, either through higher initial diffusion or incorporating pore-formers, the release of BSA was improved. The study concluded that enhancing the outflux of degradation products and increasing implant porosity could achieve complete protein release from PLGA implants (Ghalanbor et al. 2013).

Ghalanbor et al. prepared lysozyme-loaded PLGA implants using twin-screw HME at 90–105 °C and a screw speed of 20 rpm. Implants with up to 20% lysozyme loading showed no burst release, achieving complete release over 60–80 days while maintaining biological activity. The addition of PEG 400 reduced burst release at higher drug loadings, demonstrating the potential of HME for stable, burst-free protein-PLGA implants (Ghalanbor et al. 2010).

Bode et al. investigated dexamethasone-loaded PLGA implants prepared by HME using PLGA with varying lactic acid: glycolic acid ratios (50:50, 75:25, 100:0) and 1–15% drug loading. They found that PLGA swelling played a key role in drug release: initially, limited water penetration restricted release, but as polymer degradation progressed, increased hydrophilicity and swelling enabled drug dissolution and diffusion once a critical molecular weight (8 kDa) was reached (Bode et al. 2019).

Characterization techniques for HME‑processed PLGA systems

Comprehensive characterization is critical for evaluating the impact of hot‑melt extrusion on PLGA structure, stability, and drug‑delivery performance. Differential scanning calorimetry (DSC) is widely used to assess glass transition temperature, crystallinity changes, and drug amorphization resulting from extrusion, thereby informing processing window optimization. Thermogravimetric analysis (TGA) provides insight into thermal stability and degradation onset, supporting the selection of safe extrusion temperatures. Rheological measurements are essential for understanding melt viscosity, shear‑dependent flow behavior, and torque requirements, which directly affect extrusion feasibility and scalability. Structural and morphological changes induced by HME are commonly evaluated using X‑ray diffraction (XRD) to determine crystalline–amorphous transitions and scanning electron microscopy (SEM) to visualize surface morphology, porosity, and drug distribution. Additionally, Fourier‑transform infrared spectroscopy (FTIR) is employed to probe polymer–drug interactions and potential chemical changes arising from thermal and shear stress. Collectively, these techniques provide a robust analytical framework to support Quality‑by‑Design approaches, enabling rational correlation of PLGA material attributes and HME processing parameters with final product performance.

Regulatory considerations and challenges for HME‑processed PLGA systems

The regulatory evaluation of hot‑melt extrusion (HME)–processed PLGA drug‑delivery systems is inherently complex due to the combined challenges associated with biodegradable polymers, continuous manufacturing processes, and long‑acting dosage forms. Regulatory agencies such as the FDA and EMA require comprehensive characterization of PLGA material attributes, including molecular weight distribution, monomer ratio, residual monomer content, and end‑group chemistry, as these factors directly influence degradation behavior, drug release, and in vivo performance. When PLGA is processed via HME, additional scrutiny is placed on demonstrating that thermal and shear exposure during extrusion does not induce unacceptable polymer degradation, generate reactive by‑products, or alter the solid‑state stability of the incorporated API.

From a manufacturing perspective, HME‑based PLGA products must meet evolving regulatory expectations for continuous manufacturing and Quality‑by‑Design (QbD) implementation. This includes identification and control of critical material attributes (CMAs) and critical process parameters (CPPs) such as extrusion temperature, screw speed, residence time, and torque. Regulators increasingly expect real‑time process monitoring, robust process validation strategies, and clear justification of design space to ensure batch‑to‑batch consistency. For PLGA systems, this requirement is further complicated by polymer batch variability and time‑dependent changes during storage and degradation, necessitating well‑defined specifications and stability‑indicating analytical methods.

Additional regulatory hurdles arise for long‑acting injectable and implantable PLGA products, which are common outputs of HME processing. These systems require extensive in vitro–in vivo correlation (IVIVC), long‑term release and degradation studies, and thorough safety assessments of degradation products such as lactic and glycolic acid accumulation. Changes in formulation or processing parameters during scale‑up or post‑approval modifications may trigger additional regulatory evaluation, emphasizing the importance of process robustness and lifecycle management strategies. Consequently, while HME offers significant advantages in scalability and reproducibility, successful regulatory approval of HME‑processed PLGA systems depends on early integration of regulatory considerations, comprehensive material and process understanding, and proactive risk‑based development approaches.

Future perspectives and challenges

The application of HME for preparing different PLGA-based pharmaceutical platforms is poised to revolutionize drug delivery systems, offering enhanced control over release profiles and improved patient compliance. However, PLGA systems face challenges such as initial burst release and acidic microenvironments during degradation, which can affect drug stability. Nonetheless, ongoing innovations in polymer chemistry and formulation techniques continue to address these limitations.

However, several challenges persist. High processing temperatures are inherent to HME risk degradation of APIs, limiting its applicability for thermosensitive compounds. The complex rheological behavior of PLGA under extrusion conditions requires advanced modeling and process control. Regulatory hurdles, particularly for novel excipients and continuous manufacturing, may slow industrial adoption. Furthermore, scalability and cost-effectiveness of HME equipment for large-scale production remain significant barriers. Future perspectives include the development of continuous manufacturing processes integrated with Process Analytical Technology (PAT) for real-time monitoring and quality assurance. Innovations in low-temperature extrusion techniques and plasticizer optimization will be crucial to accommodate thermosensitive drugs and biologics. Addressing these issues through innovative formulation strategies, green processing approaches, and harmonized regulatory frameworks will be essential for unlocking the full potential of HME-based PLGA systems in next-generation therapeutics.

Recent advances in artificial intelligence and machine learning (AI/ML) are emerging as promising tools to enhance the rational development and optimization of hot‑melt extrusion (HME) formulations. Data‑driven models, including machine learning‑assisted design of experiments and multivariate process analytics, are increasingly being explored to predict optimal extrusion conditions by correlating PLGA material attributes (e.g., molecular weight, Tg, viscosity, and end‑group chemistry) with critical process parameters and formulation performance outcomes. These approaches have the potential to reduce experimental burden, accelerate formulation development, and support Quality‑by‑Design (QbD) frameworks in continuous manufacturing. However, current applications remain largely exploratory, with limitations related to dataset size, model interpretability, and regulatory acceptance. Consequently, AI/ML methodologies should be viewed as complementary decision‑support tools that augment—rather than replace—mechanistic understanding and experimental validation in the development of PLGA‑based HME drug‑delivery platforms.

Conclusion

HME technology can be used as a versatile and scalable technology for the development of PLGA-based pharmaceutical platforms, offering solvent-free processing and precise control over formulation parameters. By leveraging PLGA’s tunable physicochemical properties such as molecular weight, monomer ratio, and glass transition temperature, HME enables the creation of advanced drug delivery systems with controlled release profiles and improved patient compliance. The integration of HME with PLGA has demonstrated success in producing many successful platforms including implants, films, and inhalable formulations, while maintaining drug stability and enhancing therapeutic performance. Despite these advantages, challenges such as thermal sensitivity of APIs, complex rheological behavior, and regulatory constraints persist. Future progress will depend on innovative process optimization, incorporation of functional excipients, and adoption of continuous manufacturing strategies to overcome these limitations. Ultimately, the synergy between PLGA and HME represents a promising pathway toward next-generation drug delivery technologies that combine efficiency, sustainability, and better therapeutic outcomes.

Literature search strategy and selection criteria

A comprehensive literature survey was conducted to identify relevant studies addressing PLGA‑based drug‑delivery systems and hot‑melt extrusion (HME) technologies. The databases Web of Science, Scopus, PubMed, and Google Scholar were searched using combinations of keywords including “PLGA,” “poly(lactic‑co‑glycolic acid),” “hot‑melt extrusion,” “drug delivery,” “controlled release,” “implants,” and “continuous manufacturing.” The search primarily covered publications from 2000 to 2025, with earlier foundational works included where necessary for contextual completeness.

Peer‑reviewed research articles and review papers published in English were considered for inclusion. Studies were selected based on their relevance to PLGA material properties, processing feasibility, HME formulation strategies, and drug‑delivery performance. Articles focusing exclusively on unrelated polymers, non‑pharmaceutical applications, or lacking mechanistic or process‑relevant insight were excluded. Reference lists of key publications were also manually screened to identify additional relevant studies. This approach ensured balanced coverage of both fundamental and applied research aligned with the objectives of the present review.

Abbreviations

HME

Hot-melt extrusion

APIs

Active pharmaceutical ingredient

PLGA

Polylactic-co-glycolic acid

PLA

Polylactide

PGA

Polyglycolide

PVA

Polyvinyl Alcohol

Author contributions

The concept and design were developed by Mashan Almutairi and Ahmed Alobaida. Analysis and interpretation of data were performed by all authors. Writing—original draft preparation was carried out by all authors, while the critical review of the manuscript for important intellectual content was conducted by Mashan Almutairi and Ahmed Alobaida. Supervision was provided by Mashan Almutairi. Project administration was carried out by Mashan Almutairi. Funding acquisition was carried out by Mashan Almutairi. All authors have read and agreed to the published version of the manuscript.

Funding

The authors gratefully acknowledge the funding of this work by Scientific Research Deanship at University of Ha'il, Saudi Arabia through project number << RG-24 072 >> 

Data availability

This manuscript has no associated data.

Declarations

Ethical

Ethical approval was not required for this systematic review and meta-analysis as it is based solely on previously published studies.

Consent for publication

We, the undersigned authors, hereby consent to the publication of the manuscript and confirm that the manuscript has been read and approved by all named authors. We declare that the manuscript has not been previously published, nor is it under consideration for publication elsewhere.

Competing interests

The authors have no relevant financial or non-financial interests to disclose.