Role of rheology in formulation and process design of hot melt extruded amorphous solid dispersions

Abstract

Hot melt extrusion (HME) has been widely used as a continuous and highly flexible pharmaceutical manufacturing process for the production of a variety of dosage forms. In particular, HME enables preparation of amorphous solid dispersions (ASDs) which can improve bioavailability of poorly water-soluble drugs. The rheological properties of drug-polymer mixtures can significantly influence the processability of drug formulations via HME and eventually the end-use product properties such as physical stability and drug release. The objective of this review is to provide an overview of various rheological techniques and properties that can be used to evaluate the flow behavior and processability of the drug-polymer mixtures as well as formulation characteristics such as drug-polymer interactions, miscibility/solubility, and plasticization to improve the HME processability. An overview of the thermodynamics and kinetics of ASD processing by HME is also provided, as well as aspects of scale-up and process modeling, highlighting rheological properties on formulation design and process development. Overall, this review provides valuable insights into critical rheological properties which can be used as a predictive tool to optimize the HME processing conditions.

Introduction

Hot melt extrusion (HME) has been successfully utilized as a polymer processing technology to develop and manufacture a wide variety of formulation strategies such as amorphous solid dispersions (ASDs) (Butreddy et al., 2021a, Thakkar et al., 2020), long acting implants (Chen et al., 2022), taste masking formulations (Maniruzzaman et al., 2014, Maniruzzaman et al., 2012), controlled or targeted release (Chen et al., 2022, Repka et al., 2008, Stanković et al., 2015, Vo et al., 2016), abuse-deterrence (Butreddy et al., 2021b), and ophthalmic delivery systems(Thakkar et al., 2021) to address a wide variety of therapeutic needs. Heat and mechanical mixing are applied to the input materials to generate formed extrudate, which can be shaped or milled depending on the downstream processing needs. Based on the selection of formulation and processing parameters, the drug can be kept in its crystalline state, or transformed into an amorphous material. HME is preferred industrial technology due to its small footprint and inherently continuous nature, as well as being solvent-free and ease of scale up (Simões et al., 2019).

ASDs have proven to be an effective drug development strategy to improve the bioavailability of poorly water-soluble drugs (Leuner, 2000, Moseson and Taylor, 2023). Compared to their crystalline counterpart, the amorphous form of a drug molecule has higher free energy which provides for higher apparent solubility and dissolution rate. However, this solubility advantage may not be captured if crystallization occurs during storage or upon release. Polymers play an important role in stabilizing the amorphous drug in the solid and solution state. HME is one of several manufacturing techniques that have been used to manufacture ASDs, including spray drying and co-precipitation (Mann et al., 2018, Moseson et al., 2024, Paudel et al., 2013). Seventeen (17) drug products comprising poorly soluble drugs formulated into ASDs using the HME technology have been approved by the U.S. Food and Drug Administration between 1997–2023 as shown in Table 1.

A typical HME process consists of a feeding system, an extruder with conveying, mixing, and melting section, a die section, and further downstream processing units (Fig. 1). The process involves processing parameters including extrusion temperature, screw speed, feeding rate, and screw configuration which can be adjusted to optimize the ASD formulations. Most of polymers that are used in the HME process are viscoelastic in nature and exhibit shear thinning behaviors at elevated temperature conditions meaning that the viscosity of melts decreases with the increase of shear rate. The HME process involves elevated temperature above the glass transition temperature (Tg) of the polymer and high shear force exerted by rotating extruder screws which contribute to the dispersion of drug molecules in molten polymers forming an ASD.

Rheology has become an essential tool which provides information about flow behaviors of polymer melts under the high temperature and stresses experienced in the process itself. The viscosity of the melt enables optimal flow and mixing through the extruder. High melt viscosity can cause extremely high torque levels (overloading the extruder’s mechanical capabilities) and increased residence time (RTD) which may lead to undesirable degradation of the drug and/or polymer. Thus, the successful realization of a hot-melt extrusion process in terms of the processability and extrudability of the drug-polymer mixtures is heavily influenced by the rheology of the melts. Knowledge of rheology of the molten drug-polymer mixture is key in (i) understanding the flow properties and microstructure of melts impacted by the processing conditions, (ii) determining the miscibility/solubility of the drug-polymer mixtures, (iii) optimizing the key processing conditions for the HME process including temperature and torque (motor load), and (iv) controlling the quality and performance of resultant solid dispersions (e.g., stability and release). In this review paper, we highlight the current progress in rheological characterization of drug-polymer melts for processing through the HME for preparation of ASDs and insights into drug-polymer miscibility/solubility, drug-polymer interactions, melt processability, plasticization, and crystallization tendency in ASDs. Additionally, we discuss the thermodynamic and kinetic aspects for processing ASDs by HME highlighting the importance of rheological properties on formulation design and process development.

“Trends in amorphous solid dispersion drug products approved by the U.S. Food and Drug Administration between 2012 and 2023“

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Role of rheology in formulation and process design of hot melt extruded amorphous solid dispersions

Abstract

Introduction

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“Trends in amorphous solid dispersion drug products approved by the U.S. Food and Drug Administration between 2012 and 2023“