Advances in Hot Melt Extrusion Technology

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmaceutical Technology, Manufacturing and Devices".

Deadline for manuscript submissions: 20 February 2026 | Viewed by 5289

Special Issue Editors


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Guest Editor
Technical Operations, Cerevel Therapeutics, Cambridge, MA 02141, USA
Interests: hot melt extrusion; spray drying; continuous manufacturing; additive manufacturing; solid oral dosage forms; lipid based drug delivery systems; twin screw granulation; amorphous solid dispersions; implants; colon targeted drug delivery; gastro retentive formulations
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Guest Editor
Leading Research Group, Faculty of Pharmacy, Rīga Stradiņš University, 21 Konsula St., LV-1007 Riga, Latvia
Interests: pharmaceutical technology (hot-melt extrusion, roll-compaction, tableting, coating, FDM 3D printing, etc.); oral dosage forms formulations with tailored drug release: (incl. solubility/BA enhanced); optimization of the pharmacokinetics and custom properties of dosage forms; and cutting-edge methods of oral dosage form pre-formulation and formulation

Special Issue Information

Dear Colleagues,

In recent years, hot melt extrusion (HME) has attracted the attention of researchers from the pharmaceutical industry and regulatory agencies due to its wide variety of applications in developing pharmaceutical medications. HME has been widely investigated in regard to improving the solubility and bioavailability of poorly soluble drug substances via amorphous solid dispersions, co-crystals, salts, co-amorphous systems, cyclodextrin complexation, solid crystal suspension, and lipid-based drug delivery systems. It is a single-step continuous manufacturing process that involves the application of thermal and mechanical shear, and it uses no solvent. Along with extrusion, the extruder is also suitable for the granulation process, referred to as twin-screw granulation (TSG). The extruder can also be coupled with an additive manufacturing process to fabricate patient-centric dosage forms. Along with the above-discussed application, the HME can also be employed for novel applications such as spheronization, co-extrusion, and injection molding. This Special Issue presents recent advancements, technical innovations, and practical applications of HME in drug formulation. Contributions exploring process optimization, material selection, characterization techniques, and clinical implications are invited, providing a comprehensive overview of HME's impact on modern pharmaceutics.

We encourage the submission of original research articles, comprehensive reviews, and case studies that explore the latest breakthroughs in HME. This Special Issue will be a vital resource for scientists, researchers, and industry professionals aiming to leverage HME for innovative pharmaceutical solutions. Join us in advancing the field by sharing your expertise and insights on this dynamic and rapidly evolving technology.

We look forward to receiving your contributions.

Dr. Dinesh Nyavanandi
Dr. Valentyn Mohylyuk
Guest Editors

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Keywords

  • hot melt extrusion
  • solubility enhancement
  • amorphous solid dispersion
  • additive manufacturing
  • twin screw granulation
  • continuous manufacturing
  • lipid-based drug delivery systems
  • patient-centric dosage forms
  • fused deposition modeling 3D printing
  • bioavailability

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Published Papers (6 papers)

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Research

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27 pages, 27757 KB  
Article
Continuous Processing Strategies for Amorphous Solid Dispersions of Itraconazole: Impact of Polymer Selection and Manufacturing Techniques
by Madhuri M. Kshirsagar, Bandoo C. Chatale, Sathish Dyawanapelly, Lalitkumar K. Vora and Purnima D. Amin
Pharmaceutics 2025, 17(9), 1090; https://doi.org/10.3390/pharmaceutics17091090 - 22 Aug 2025
Viewed by 262
Abstract
Background: The limited aqueous solubility of BCS Class II drugs, exemplified by itraconazole (ITR), continues to hinder their bioavailability and therapeutic performance following oral administration. The present study investigated the development of amorphous solid dispersions (ASDs) of ITR via continuous manufacturing technologies, [...] Read more.
Background: The limited aqueous solubility of BCS Class II drugs, exemplified by itraconazole (ITR), continues to hinder their bioavailability and therapeutic performance following oral administration. The present study investigated the development of amorphous solid dispersions (ASDs) of ITR via continuous manufacturing technologies, such as hot melt extrusion (HME) and spray drying (SD), to improve drug release. Methods: Polymer selection was guided by Hansen solubility parameter (HSP) analysis, film casting, and molecular modeling, leading to the identification of aminoalkyl methacrylate copolymer type A (Eudragit® EPO), polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus®), and hypromellose acetate succinate HG (AQOAT® AS-HG) as suitable carriers. ASDs were prepared at drug-to-polymer ratios of 1:1, 1:2, and 2:1. Comprehensive characterization was performed using ATR-FTIR, NMR, DSC, PXRD, SEM, PLM, and contact angle analysis. Results: HME demonstrated higher process efficiency, solvent-free operation, and superior dissolution enhancement compared to SD. Optimized HME-based ASDs were formulated into tablets. The ITR–Eudragit® EPO formulation achieved 95.88% drug release within 2 h (Weibull model, R2 > 0.99), while Soluplus® and AQOAT® AS-HG systems achieved complete release, best described by the Peppas–Sahlin model. Molecular modeling confirmed favorable drug–polymer interactions, correlating with the formation of stable complex and enhanced release performance. Conclusions: HME-based continuous manufacturing provides a scalable and robust strategy for improving the oral delivery of poorly water-soluble drugs. Integrating predictive modeling with experimental screening enables the rational design of ASD formulations with optimized dissolution behavior, offering potential for improved therapeutic outcomes in BCS Class II drug delivery. Full article
(This article belongs to the Special Issue Advances in Hot Melt Extrusion Technology)
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21 pages, 1905 KB  
Article
Wax-Based Sustained-Release Felodipine Oral Dosage Forms Manufactured Using Hot-Melt Extrusion and Their Resistance to Alcohol-Induced Dose Dumping
by Gerard Sweeney, Dijia Liu, Taher Hatahet, David S. Jones, Shu Li and Gavin P. Andrews
Pharmaceutics 2025, 17(8), 955; https://doi.org/10.3390/pharmaceutics17080955 - 24 Jul 2025
Viewed by 498
Abstract
Background/Objectives: Hot-melt extrusion (HME) has gained prominence for the manufacture of sustained-release oral dosage forms, yet the application of wax-based matrices and their resilience to alcohol-induced dose dumping (AIDD) remains underexplored. This study aimed to develop and characterise wax-based sustained-release felodipine formulations, with [...] Read more.
Background/Objectives: Hot-melt extrusion (HME) has gained prominence for the manufacture of sustained-release oral dosage forms, yet the application of wax-based matrices and their resilience to alcohol-induced dose dumping (AIDD) remains underexplored. This study aimed to develop and characterise wax-based sustained-release felodipine formulations, with a particular focus on excipient functionality and robustness against AIDD. Methods: Felodipine sustained-release formulations were prepared via HME using Syncrowax HGLC as a thermally processable wax matrix. Microcrystalline cellulose (MCC) and lactose monohydrate were incorporated as functional fillers and processing aids. The influence of wax content and filler type on mechanical properties, wettability, and drug release behaviour was systematically evaluated. Ethanol susceptibility testing was conducted under simulated co-ingestion conditions (4%, 20%, and 40% v/v ethanol) to assess AIDD risk. Results: MCC-containing tablets demonstrated superior sustained-release characteristics over 24 h, showing better wettability and disintegration. In contrast, tablets formulated with lactose monohydrate remained structurally intact during dissolution, overly restricting drug release. This limitation was effectively addressed through granulation, where reduced particle size significantly improved surface accessibility, with 0.5–1 mm granules achieving a satisfactory release profile. Ethanol susceptibility testing revealed divergent behaviours between the two filler systems. Unexpectedly, MCC-containing tablets showed suppressed drug release in ethanolic media, likely resulting from inhibitory effect of ethanol on filler swelling and disintegration. Conversely, formulations containing lactose monohydrate retained their release performance in up to 20% v/v ethanol, with only high concentrations (40% v/v) compromising matrix drug-retaining functionality and leading to remarkably increased drug release. Conclusions: This study highlights the pivotal role of excipient type and constitutional ratios in engineering wax-based sustained-release formulations. It further contributes to the understanding of AIDD risk through in vitro assessment and offers a rational design strategy for robust, alcohol-resistant oral delivery systems for felodipine. Full article
(This article belongs to the Special Issue Advances in Hot Melt Extrusion Technology)
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10 pages, 2328 KB  
Article
Vertical Hot-Melt Extrusion: The Next Challenge in Innovation
by Maël Gallas, Ghouti Medjahdi, Pascal Boulet and Victoire de Margerie
Pharmaceutics 2025, 17(7), 939; https://doi.org/10.3390/pharmaceutics17070939 - 21 Jul 2025
Viewed by 470
Abstract
Background/Objectives: Hot-melt extrusion (HME) has become a key technology in pharmaceutical formulation, particularly for enhancing the solubility of poorly soluble Active Pharmaceutical Ingredients (APIs). While horizontal HME is widely adopted, vertical HME remains underexplored despite its potential benefits in footprint reduction, feeding efficiency, [...] Read more.
Background/Objectives: Hot-melt extrusion (HME) has become a key technology in pharmaceutical formulation, particularly for enhancing the solubility of poorly soluble Active Pharmaceutical Ingredients (APIs). While horizontal HME is widely adopted, vertical HME remains underexplored despite its potential benefits in footprint reduction, feeding efficiency, temperature control, and integration into continuous manufacturing. This study investigates vertical HME as an innovative approach in order to optimize drug polymer interactions and generate stable amorphous dispersions with controlled release behavior. Methods: Extrusion trials were conducted using a vertical hot-melt extruder developed by Rondol Industrie (Nancy, France). Acetylsalicylic acid (ASA) supplied by Seqens (Écully, France) was used as a model API and processed with Soluplus® and Kollidon® 12 PF (BASF, Ludwigshafen, Germany). Various process parameters (temperature, screw speed, screw profile) were explored. The extrudates were characterized by powder X-ray diffraction (PXRD) and small-angle X-ray scattering (SAXS) to evaluate crystallinity and microstructure. In vitro dissolution tests were performed under sink conditions using USP Apparatus II to assess drug release profiles. Results: Vertical HME enabled the formation of homogeneous amorphous solid dispersions. PXRD confirmed the absence of residual crystallinity, and SAXS revealed nanostructural changes in the polymer matrix influenced by drug loading and thermal input. In vitro dissolution demonstrated enhanced drug release rates compared to crystalline ASA, with good reproducibility. Conclusions: Vertical HME provides a compact, cleanable, and modular platform that supports the development of stable amorphous dispersions with controlled release. It represents a robust and versatile solution for pharmaceutical innovation, with strong potential for cost-efficient continuous manufacturing and industrial-scale adoption. Full article
(This article belongs to the Special Issue Advances in Hot Melt Extrusion Technology)
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23 pages, 14789 KB  
Article
Feasibility of Hot Melt Extrusion in Converting Water-Based Nanosuspensions into Solid Dosage Forms
by Erasmo Ragucci, Marco Uboldi, Adam Sobczuk, Giorgio Facchetti, Alice Melocchi, Mauro Serratoni and Lucia Zema
Pharmaceutics 2025, 17(5), 662; https://doi.org/10.3390/pharmaceutics17050662 - 17 May 2025
Viewed by 828
Abstract
Aim: In addition to numerous benefits provided by nanosuspensions (NSs) (e.g., enhanced saturation solubility, increased area for interaction with fluids), they suffer from major stability, handling and compliance issues. To overcome these challenges, we evaluated the feasibility of hot melt extrusion (HME) in [...] Read more.
Aim: In addition to numerous benefits provided by nanosuspensions (NSs) (e.g., enhanced saturation solubility, increased area for interaction with fluids), they suffer from major stability, handling and compliance issues. To overcome these challenges, we evaluated the feasibility of hot melt extrusion (HME) in transforming a cinnarizine-based NS, selected as a case study, into granules for oral intake. Methods: Thermoplastic polymers, in principle compatible with the thermal behavior of the selected drug and characterized by different interaction mechanisms with aqueous fluids, were used as carriers to absorb the NS and were processed by HME. Results: The extruded granules pointed out good physio-technological characteristics, a drug content > 85% with coefficient of variation (CV) < 5% and tunable in vitro performance coherent with the polymeric carriers they were composed of. Particle size as well as the solid state of cinnarizine was checked using several analytical techniques in combination (e.g., DSC, SEM, FT-IR, Raman). Depending on the composition of the granules, and specifically for formulations processed below 85 °C, the drug was found to remain crystalline and in the desired nanoscale. Conclusions: HME turned out to be a versatile process to transform, in a single-step, NSs into multi-particulate solid products for oral administration showing a variety of release profiles. Full article
(This article belongs to the Special Issue Advances in Hot Melt Extrusion Technology)
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24 pages, 15011 KB  
Article
Process Development for the Continuous Manufacturing of Carbamazepine-Nicotinamide Co-Crystals Utilizing Hot-Melt Extrusion Technology
by Lianghao Huang, Wen Ni, Yaru Jia, Minqing Zhu, Tiantian Yang, Mingchao Yu and Jiaxiang Zhang
Pharmaceutics 2025, 17(5), 568; https://doi.org/10.3390/pharmaceutics17050568 - 25 Apr 2025
Cited by 2 | Viewed by 772
Abstract
Objectives: Hot-melt extrusion (HME) offers a solvent-free, scalable approach for manufacturing pharmaceutical co-crystals (CCs), aligning with the industry’s shift to continuous manufacturing (CM). However, challenges like undefined yield optimization, insufficient risk management, and limited process analytical technology (PAT) integration hinder its industrial application. [...] Read more.
Objectives: Hot-melt extrusion (HME) offers a solvent-free, scalable approach for manufacturing pharmaceutical co-crystals (CCs), aligning with the industry’s shift to continuous manufacturing (CM). However, challenges like undefined yield optimization, insufficient risk management, and limited process analytical technology (PAT) integration hinder its industrial application. This study aimed to develop a proof-of-concept HME platform for CCs, assess process risks, and evaluate PAT-enabled monitoring to facilitate robust production. Methods: Using carbamazepine (CBZ) and nicotinamide (NIC) as model compounds, an HME platform compatible with PAT tools was established. A systematic risk assessment identified five key risk domains: materials, machinery, measurement, methods, and other factors. A Box–Behnken design of experiments (DoE) evaluated the impact of screw speed, temperature, and mixing sections on CC quality. Near-infrared (NIR) spectroscopy monitored CBZ-NIC co-crystal formation in real time during HME process. Results: DoE revealed temperature and number of mixing sections significantly influenced particle size (D50: 2.0–4.0 μm), while screw speed affected efficiency. NIR spectroscopy detected a unique CC absorption peak at 5008.3 cm⁻¹, enabling real-time structural monitoring with high accuracy (R² = 0.9999). Risk assessment highlighted material attributes, process parameters, and equipment design as critical factors affecting CC formation. All experimental batches yielded ≥ 94% pure CCs with no residual starting materials, demonstrating process reproducibility and robustness. Conclusions: Overall, this work successfully established a continuous hot-melt extrusion (HME) process for manufacturing CBZ-NIC co-crystals, offering critical insights into material, equipment, and process parameters while implementing robust in-line NIR monitoring for real-time quality control. Additionally, this work provides interpretable insights and serves as a basis for future machine learning (ML)-driven studies. Full article
(This article belongs to the Special Issue Advances in Hot Melt Extrusion Technology)
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Review

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26 pages, 2866 KB  
Review
Enhancing Patient-Centric Drug Development: Coupling Hot Melt Extrusion with Fused Deposition Modeling and Pressure-Assisted Microsyringe Additive Manufacturing Platforms with Quality by Design
by Dinesh Nyavanandi, Preethi Mandati, Nithin Vidiyala, Prashanth Parupathi, Praveen Kolimi and Hemanth Kumar Mamidi
Pharmaceutics 2025, 17(1), 14; https://doi.org/10.3390/pharmaceutics17010014 - 25 Dec 2024
Cited by 1 | Viewed by 1436
Abstract
In recent years, with the increasing patient population, the need for complex and patient-centric medications has increased enormously. Traditional manufacturing techniques such as direct blending, high shear granulation, and dry granulation can be used to develop simple solid oral medications. However, it is [...] Read more.
In recent years, with the increasing patient population, the need for complex and patient-centric medications has increased enormously. Traditional manufacturing techniques such as direct blending, high shear granulation, and dry granulation can be used to develop simple solid oral medications. However, it is well known that “one size fits all” is not true for pharmaceutical medicines. Depending on the age, sex, and disease state, each patient might need a different dose, combination of medicines, and drug release pattern from the medications. By employing traditional practices, developing patient-centric medications remains challenging and unaddressed. Over the last few years, much research has been conducted exploring various additive manufacturing techniques for developing on-demand, complex, and patient-centric medications. Among all the techniques, nozzle-based additive manufacturing platforms such as pressure-assisted microsyringe (PAM) and fused deposition modeling (FDM) have been investigated thoroughly to develop various medications. Both nozzle-based techniques involve the application of thermal energy. However, PAM can also be operated under ambient conditions to process semi-solid materials. Nozzle-based techniques can also be paired with the hot melt extrusion (HME) process for establishing a continuous manufacturing platform by employing various in-line process analytical technology (PAT) tools for monitoring critical process parameters (CPPs) and critical material attributes (CMAs) for delivering safe, efficacious, and quality medications to the patient population without compromising critical quality attributes (CQAs). This review covers an in-depth discussion of various critical parameters and their influence on product quality, along with a note on the continuous manufacturing process, quality by design, and future perspectives. Full article
(This article belongs to the Special Issue Advances in Hot Melt Extrusion Technology)
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