A review of hot melt extrusion technology: Advantages, applications, key factors and future prospects

Abstract

After decades of development, hot melt extrusion (HME) technology has matured as a well-established pharmaceutical methodology. Through the process of extruding both drug and carrier materials in a molten state under specific conditions of pressure, velocity, and screw design, this technology facilitates the dispersion of the drug within the carrier in various states such as molecular, amorphous, or sub-stable, thereby significantly improving the solubility and bioavailability of challenging drugs. Currently, over 20 drugs have obtained FDA approval for production and formulation via hot-melt extrusion, underscoring the demonstrated effectiveness and dependability of this technique. This review aims to offer an in-depth examination of the principles, benefits, and applications of hot-melt extrusion in pharmaceutical science, with a particular focus on the key determinants that impact the success of hot-melt extrusion. Additionally, it aims to explore the future applications and potential developmental opportunities of this technology, with an emphasis on its utility for continuous manufacturing (CM) and personalized drug delivery.

Introduction

As the development of new molecular entities progresses, the structure of new drug molecules becomes increasingly complex, leading to poor solubility. This presents a significant challenge for formulation workers, especially when dealing with molecules that exhibit high activity but low solubility. According to the literature, approximately 40 % of drugs sold globally are insoluble, while the proportion of insoluble drugs in development is as high as 90 % [[1], [2], [3]]. Therefore, current research in pharmacy aims to tackle the challenge of solubilizing and improving the solubility of such drugs, resulting in increased exposure within the human body and achieving a certain level of bioavailability [1]. One technology that shows promise in this area is HME, which can transform the crystalline structure of drugs from crystalline to amorphous, thereby enhancing solubility through the application of thermal and mechanical energy. HME has been a proven pharmaceutical technology for several decades, with diverse applications across the industry [4]. These applications include taste masking of drugs, improving the solubility of insoluble drugs, facilitating controlled and sustained drug release, enabling targeted drug delivery, and facilitating the preparation of nanoparticles [2,[5], [6], [7]].

HME technology involves mixing drugs and carrier excipients in a molten state, followed by extrusion at a specific pressure, speed, and configuration. This technique enables drug dispersion within the carrier in the form of molecules, amorphous structures, or sub-stable states [3,4,8,9]. HME originated in the plastics industry during the mid-19th century, primarily for the manufacturing of plastic bags, sheets, and tubing. The technique has undergone continuous improvements, including the development of specialized designs and enhancements in equipment quality. Consequently, it has gained significant traction in the pharmaceutical field. The use of HME in pharmaceuticals dates back to 1971, and has since become a prominent technology for formulation [10]. The number of patents and research papers related to HME has significantly increased.

As of 2023, at least 20 drugs have been approved for marketing using HME preparation techniques, demonstrating the established efficacy and reliability of this method [6].Selected FDA-approved drugs using HME technology by timeline can be seen in Fig. 1. Isoptin SR-E®, a product developed by Abbott and approved for marketing by the FDA in 1981, is the first solid dispersible systemic agent prepared using hot-melt extrusion technology [11]. Verapamil hydrochloride is extruded from a blend of hydroxypropyl cellulose and hydroxypropylmethyl cellulose to create a sustained release mechanism that effectively addresses hypertension. Kaletra®, a pharmaceutical combination of lopinavir and ritonavir, was developed by Abbott and first registered and marketed in the United States in September 2000 for the therapeutic management of HIV infections [12]. The original soft gels were subsequently replaced by coated tablets for Kaletra®. These tablets use HME technology, which merges the primary medication, lopinavir/ritonavir, is merged with a co-polyvinyl ketone backbone and extrudes it into granules. The granules are then further processed into tablets using a commonly employed subsequent procedure. The use of helps with storing Kaletra® at room temperature and reduces the daily dose to four tablets [13]. This innovative approach improves the dissolution and bioavailability of lopinavir and Ritonavir tablets, making dosing easier [14].

HME technology offers significant advantages over conventional pharmaceutical preparation techniques, These advantages include continuous manufacturing, economical, solvent-free, industrially viable, automated, reproducible and on-line monitoring [[15], [16], [17], [18]]. As a result, HME has emerged as a promising alternative for producing various solid oral, topical, and parenteral formulations [16]. Continuous advancements in HME have made it possible to stabilize thermally sensitive or unstable substances such as heat-sensitive medications, amino acids, or proteins for processing [19]. At the same time, improvements in process control technology have made HME scalable, allowing for its implementation in pharmaceutical development alongside other emerging technologies like 3D printing [20].

This paper provides a detailed explanation of the mechanism underlying HME technology, which is designed to improve drug dissolution. It examines the use of HME in various drug delivery systems and identifies the critical factors that affect the success of these applications. Furthermore, it provides valuable insights into the future development trends of HME technology.