Rational Design of Multicomponent Polymeric Systems Based on a Transient Plasticization Window for Hot-Melt Extrusion

Abstract

Background: Hot-melt extrusion (HME) is a promising technology for the manufacturing of drug products; however, its application is limited by elevated thermal and shear stresses that may induce degradation of thermolabile active pharmaceutical ingredients. One of the approaches to reducing processing temperatures is the use of polymeric systems with tailored thermal and rheological properties. The aim of the study was to develop an approach for the design of polymeric systems exhibiting a transient plasticization window, enabling a reduction in melt viscosity and improved processability under low-temperature extrusion conditions, followed by the formation of a structurally coherent matrix upon cooling.

Methods: The compatibility of the initial polymers was assessed using laser microinterferometry. Based on the obtained data, three- and four-component polymeric compositions were designed and prepared by hot-melt extrusion. The resulting materials were characterized by differential scanning calorimetry, melt rheology analysis, and storage stability assessment. Thermal and rheological data were used to iteratively optimize the polymeric systems.

Results: A four-component polymeric system based on PVP K-29/32, PEG 400, PEG 1500, and HPC EF was developed, suitable for processing by hot-melt extrusion at 70 °C. The final system enabled formation of a homogeneous extrudate, exhibited reproducible rheological behavior, and remained stable in the solid-state during storage, with no evidence of cold flow.

Conclusions: It was established that, in the design of polymeric systems for hot-melt extrusion, the key factor is not achieving the lowest possible glass transition temperature, but rather the design of a system in which viscosity is transiently reduced under processing conditions and followed by structural stabilization upon cooling. The proposed approach may be applied in the development of polymeric premixes for the preparation of dosage forms by hot-melt extrusion, including those incorporating thermolabile active pharmaceutical ingredients.

Introduction

Over the past decade, hot-melt extrusion (HME) has become established as a mature pharmaceutical technology capable of producing a wide range of dosage forms, from granules to implants [1]. Growing interest in HME is driven not only by its high productivity and suitability for continuous manufacturing, but also by its ability to modulate the physicochemical properties of active pharmaceutical ingredients (APIs) through the formation of solid dispersions and enhancement of API solubility. This is particularly relevant for poorly soluble compounds belonging to Biopharmaceutics Classification System class II, which account for more than 50% of currently marketed APIs [2]. Moreover, extrusion equipment continues to evolve. Whereas the early transfer of HME from the plastics-processing industry required tens or even hundreds of grams of material and corresponding amounts of API, modern extruders can operate with quantities in the range of hundreds of milligrams. Thus, HME-based drug manufacturing can be readily scaled both up and down, expanding its potential applications in personalized medicine and extemporaneous compounding [3,4], including through the use of API-loaded filaments for 3D printing.

At the same time, one of the major limitations of HME is the requirement for elevated processing temperatures. In most cases, extrusion is performed at temperatures 20–40 °C above the glass transition temperature or melting point of the API carrier composition, typically within the range of 100–200 °C [5]. Such temperatures, combined with shear stresses generated within the extruder barrel, may lead to the thermal and mechanical degradation of heat-sensitive APIs, hereinafter referred to as thermolabile active pharmaceutical ingredients (TAPI) [6]. The literature provides evidence that even a relatively moderate increase in extrusion temperature may induce degradation of certain APIs, thereby restricting the applicability of HME. For example, significant degradation of albendazole during HME at approximately 120 °C has been reported [7]. Gliclazide, an antidiabetic drug classified as a TAPI, also undergoes degradation during extrusion, with the extent of degradation being markedly greater in the amorphous state than in the crystalline form [8]. Another example is glibenclamide, which rapidly degrades upon heating above its melting point during HME [9]. In the case of meloxicam, improved API stability was achieved only by reducing the extrusion temperature to 110 °C [10].

Various strategies have been proposed to reduce extrusion temperature, including the use of volatile solvents or supercritical fluids, which evaporate during processing and temporarily reduce melt viscosity and the effective melting temperature of the TAPI-containing composition [11]. However, such approaches require more complex equipment and efficient solvent removal. Accordingly, the selection and design of thermoplastic carriers with low glass transition or melting temperatures remains the principal strategy for reducing extrusion temperature.

In practice, this is achieved by incorporating low-molecular-weight components with low melting temperatures into the system, that exert a plasticizing effect. The addition of plasticizers reduces melt viscosity and the glass transition temperature of the polymer matrix [12].

There is a growing trend in the field toward the development of carrier systems designed for HME and applicable to a wide range of APIs. A prominent example is Soluplus® (BASF), a graft copolymer of polyethylene glycol, polyvinyl caprolactam, and polyvinyl acetate [13]. In addition, a modified grade of Hypromellose acetate succinate (HPMCAS) with an increased content of hydroxypropoxy groups and an optimized acetyl/succinyl substitution ratio has been patented [14]. This polymer exhibits a lower glass transition temperature compared to conventional HPMCAS, enabling extrusion at reduced temperatures and mitigating TAPI degradation.

The emergence of such ready-to-use matrices allows them to be regarded as intermediates that can significantly streamline and accelerate formulation development. An equally effective approach is the use of premixes—mixtures of polymeric systems and excipients, sometimes also containing APIs. The concept is to pre-form a thermoplastic matrix with predefined properties prior to extrusion, ensuring suitability for HME, including 3D printing applications. Premixes may be prepared using various techniques, such as extrusion, spray drying, granulation, co-crystallization, or co-milling. Moreover, beyond technological advantages, premixes may also offer regulatory advantages. In particular, in the development of generic drug products, premixes can serve as a tool for accelerating market entry. Furthermore, a premix designed as a single multicomponent carrier may be regarded by regulatory authorities as a single excipient with a standardized composition, thereby simplifying the registration process [15].

Despite their evident advantages, current approaches to premix development remain largely empirical and are typically focused on tailoring compositions to specific processing conditions or the properties of individual components [16]. In most cases, the design of such systems is primarily guided by the glass transition or melting temperature [17,18], while the relationship between the phase state of the system, its rheological behavior during heating, and the subsequent structural formation upon cooling remains insufficiently explored [19,20].

Consequently, lowering the extrusion temperature is often achieved at the cost of excessive molecular mobility in the solid state, which may result in instability during storage. These limitations highlight the need for approaches that enable targeted control of rheological properties during processing without compromising structural integrity after cooling.

The aim of the present study was to develop an approach for designing polymeric systems with a transient plasticization window, enabling a reduction in melt viscosity and improved processability under low-temperature extrusion conditions, followed by the formation of a structurally coherent matrix upon cooling.

To implement this approach, the development of a polymeric composition is considered as an independent technological object capable of defining the processability conditions of the system during extrusion. Such an approach can serve as a basis for the subsequent development of dosage forms by HME, including systems containing thermolabile active pharmaceutical ingredients.

Within this study, the phase behavior of binary systems was analyzed using laser microinterferometry, which was employed as a tool for preliminary screening and justification of composition in the design of multicomponent polymeric systems intended for hot-melt extrusion. Based on the obtained data, multicomponent polymeric compositions with tailored thermal and rheological properties were developed and experimentally investigated.

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Materials

The following excipients were employed in the development of the polymeric systems: polyvinylpyrrolidone (PVP) K-17 (Plasdone K-17) (USP/EP grade, Ashland Industries Europe GmbH, Schaffhausen, Switzerland), PVP K-29/32 (Plasdone K-29/32) (USP/EP grade, Ashland Industries Europe GmbH, Schaffhausen, Switzerland), polyethylene glycol 400 (PEG 400) (USP/EP grade, Merck, Darmstadt, Germany), polyethylene glycol 1500 (PEG 1500) (USP/EP grade, Clariant AG, Muttenz, Switzerland), hydroxypropylcellulose 80000 (HPC EF) (Klucel EF) (USP/EP grade, Ashland Industries Europe GmbH, Schaffhausen, Switzerland).

Mandrik, M.; Makarova, V.; Korol, L.; Krasnyuk, I.; Antonov, S. Rational Design of Multicomponent Polymeric Systems Based on a Transient Plasticization Window for Hot-Melt Extrusion. Pharmaceutics 2026, 18, 667. https://doi.org/10.3390/pharmaceutics18060667

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