As new small molecule drugs become increasingly complex in structure, solubility presents a growing challenge for drug developers aiming to optimize bioavailability. Hot melt extrusion (HME) is one of the most promising approaches to enhancing drug solubility and achieving other formulation goals, such as taste masking.1

HME is a continuous processing technology that combines active pharmaceutical ingredients (APIs) with polymeric carriers and other excipients under controlled heat and mechanical shear to form a homogeneous amorphous solid dispersion (ASD) mixture. In a typical process, raw materials are fed into an extruder where rotating screws convey, mix, and melt the components. As the formulation progresses through the extruder barrel, controlled mixing and thermal energy disperse the API within the polymer matrix, often converting poorly soluble crystalline drugs into ASDs with higher solubility and dissolution rate and, as a result, increased bioavailability.1 The resulting molten mass is then forced through a die and cooled to form extrudate that can be milled or further processed into finished dosage forms.

Despite the advantages of HME, perceived thermal risk is often cited as a key drawback of the technology and can discourage drug developers from considering HME during formulation development. In a 2025 industry survey of North American and European pharmaceutical leaders, 76% of respondents selected ‘risk of thermal degradation’ as a drawback to using HME technology.2 Because the process involves elevated temperatures, concerns frequently arise about the potential degradation of heat-sensitive APIs or excipients. In practice, however, these risks are often misunderstood or overstated. When the formulation is appropriately designed and HME processes are engineered to control residence time, shear forces, and temperature exposure, many formulations can be processed well below the degradation thresholds of their components. 

Advances in polymer science, extruder design, and process monitoring have further expanded the range of compounds that can be successfully processed using HME. When properly formulated and optimized, HME can offer a robust, scalable solution whose benefits in bioavailability enhancement, manufacturing efficiency, and product performance often outweigh the perceived limitations associated with thermal processing.

Understanding Degradation Risk

Assessing an API’s thermal degradation risk in the context of hot melt extrusion requires looking beyond temperature alone. Many chemical degradation mechanisms, such as oxidation or hydrolysis, can be accelerated under elevated temperatures, but heat is often not the only root cause of instability. Thus, the potential degradation during processing and storage can be controlled or mitigated based on the underlying chemical degradation mechanism. For example, oxidative degradation may only occur if oxygen is present in the processing environment or oxidizing impurities (such as peroxide) within excipient matrices under high temperature.  In addition to decreasing temperature, reducing peroxide in the excipients and/or controlling or eliminating oxygen during processing can effectively control oxidation to an acceptable level. 

In addition, interactions between the API and polymers, plasticizers, or residual impurities may lead to chemical transformations that are not directly caused by heat but may become apparent during or after extrusion. A more effective measure to control drug-excipient chemical reactions is to control the purity of the excipients and drug substances. During formulation development, toxicological studies are also necessary to fully characterize a drug’s degradation limits and ensure that any degradation during the extrusion process occurs within regulatory requirements for quality and safety.

HME process parameters such as residence time in the extruder, viscous dissipation into material, input exposure to oxygen, local pH conditions, moisture content, and the presence of reactive impurities can all influence degradation kinetics. In many cases, careful formulation design and process engineering—such as selecting compatible excipients, controlling moisture levels, minimizing oxygen exposure, and optimizing residence time/viscous dissipation—can effectively mitigate chemical degradation risks. By evaluating these variables holistically rather than focusing solely on temperature, developers can more accurately assess whether an API is suitable for HME and identify strategies to safely leverage the technology’s formulation advantages.3

 In AbbVie’s development experience, few screened compounds truly fail due to thermal instability. While many drugs can degrade at or below their melting point, experienced developers understand the techniques that can optimize specific conditions of the extrusion process to maximize stability or work at lower temperatures.  

Reframing HME vs. Spray Drying Risks

While spray drying is often regarded as a “heat safe” option for ASD development of potentially thermolabile compounds, the process introduces other challenges tied to its solvent-based nature. Nearly half of respondents from the 2025 survey mentioned previously reported ‘use of solvents’ as a key disadvantage of spray drying.  The process requires APIs and polymers to be dissolved in organic solvents prior to atomization, making pharmaceutical-grade solvent procurement, handling, and recovery significant contributors to cost, complexity, and environmental impact. Additionally, solvent reliance can also present formulation and quality risks: API solubility may limit solvent selection, residual solvent limits add analytical and regulatory burden, and API–solvent interactions including chemical reactions can generate impurities. In some cases, poorly water-soluble APIs may form solvates or solvent adducts that alter the drug’s solid-state form, potentially affecting stability, dissolution, or bioavailability.

Spray drying also introduces relatively complex downstream processing factors and additional steps for processing into final dosage forms. Materials produced through spray drying have relatively low bulk density due to their porous nature, creating “fluffy” powders. This requires additional densification and compaction steps, but poor flow of the dried particles can make roller compaction processes challenging. Additionally, spray drying creates particles of varying sizes depending on processing conditions, with increased variability at scale. This high variability can create challenges for scale-up.

Conversely, HME is a solvent-free process and leverages industry standard downstream unit operations to create the final dosage form. HME also offers several additional manufacturing advantages, particularly for commercialization. HME can be operated as a continuous process, enabling tighter control over process conditions and more efficient production. With well-controlled residence times, HME can reduce the likelihood of thermal degradation while ensuring consistent mixing and dispersion. The resulted extrudate can be processed into the final desired dosage with fewer unit operations than spray-dried materials, leading to improved operational efficiency. These manufacturing benefits were cited in industry surveys and are well-recognized as one of the top advantages of HME compared with solvent-based ASD technologies.

HME also supports improved process consistency and scalability, which are critical when transitioning from development to commercial production. The controlled thermal and mechanical environment of extrusion can make it easier to generate and maintain a stable amorphous solid dispersion of the API, simplifying characterization and process validation. Because the extrudate is produced as a solid intermediate, it can often move directly into downstream processes such as milling, tableting, or encapsulation with fewer complications than solvent-based powders. Together, these advantages help reduce the risk of downstream setbacks during scale-up and align well with industry goals of accelerating development timelines and reducing costs on the path to clinic and commercialization.

How AbbVie Mitigates Thermal Risk

With more than two decades of proven HME expertise, AbbVie approaches thermal risk as a formulation and process engineering opportunity rather than a limitation. Our HME leadership comes from having developed over one hundred drug candidates.  Instead of ruling out HME when an API is perceived to be heat-sensitive, AbbVie applies deep technical knowledge and extensive development capabilities to design processes that minimize degradation risk while preserving the advantages of extrusion.4 In many cases, compounds initially considered “high-risk” for thermal degradation become viable HME candidates when the formulation and process are carefully optimized. 

Formulation-Driven Mitigation Strategies

• Identifying the optimal API solid form - Selecting the most suitable solid-state form of the API, such as crystalline polymorph, amorphous form, or salt, can significantly influence thermal stability and processability during extrusion. Careful evaluation helps ensure the API can be dispersed effectively while minimizing degradation risk.

• Rational polymer and excipient selection - Polymers and excipients are selected to enable processing at lower melt temperatures and improve API dispersion. Appropriate carriers can reduce melt viscosity, allowing extrusion at reduced thermal stress and shorter residence times.

• Drug loading optimization - Adjusting the ratio of API to polymer can improve both processing conditions and stability. Optimized drug loading balances manufacturability, amorphous dispersion stability, and final product performance.

• Control of excipient grade and impurities - Trace impurities can catalyze degradation reactions during processing. Careful selection and control of excipient grades help to minimize these potential degradation pathways.

• Use of stabilizers/antioxidants - Stabilizing excipients can be incorporated to prevent oxidative or other chemical degradation mechanisms during extrusion and storage, particularly for APIs known to be chemically sensitive.

Process-Driven Mitigation Strategies

• Residence time control through screw configuration design - Extruder screw configuration can be engineered to control mixing intensity and residence time, ensuring the formulation experiences only brief exposure to elevated temperatures while still achieving adequate dispersion.

• Temperature zoning - Independent heating zones along the extruder barrel allow temperature to be carefully controlled at different stages of the process. This enables the minimum effective temperature to be applied only where necessary, reducing overall thermal stress on the API.

• Optimization of shear and mixing conditions - Mechanical shear contributes to dispersion and melting during HME. Strategic screw design and optimization of process conditions can achieve efficient mixing without excessive heat generation. 

• Process monitoring and control - Real-time monitoring of parameters such as torque, temperature, and pressure allows operators to maintain consistent processing conditions and quickly identify deviations that could increase degradation risk.

As with any development, experience is key in maximizing HME success. AbbVie’s 30+ years of experience in HME translates to deep, practical knowledge of the process. This can be applied to optimize programs at every step, from feasibility assessment to complex scale-up operations. 

A Practical Framework for Evaluating HME Feasibility

When determining the suitability of HME for an API, drug developers and formulation scientists should assess a range of factors. 

API characteristics

Feasibility is not dependent on melting point alone, though it is an impactful factor to consider. The API must remain chemically stable during the short exposure to elevated temperatures and shear inside the extruder. Compounds with high melting points or strong crystal lattice energies require more energy to disrupt the crystalline structure and achieve drug dispersion throughout the polymer matrix, which can make processing more difficult. However, suitable polymers, solubilizers, and plasticizers can often increase drug solubility in the excipient matrix and reduce the processing temperature required. Understanding degradation pathways informs formulation and process adjustments that limit degradation.

Polymer/excipient characteristics

The rational selection of polymers and excipients aims to achieve four goals. The first is to effectively inhibit the crystallization of the API during long term product storage conditions and during in vitro and in vivo dissolution of the ASD formulation. The second is to dramatically impact the solubility and miscibility of the API during the molten polymer phase, resulting in molecular dispersion of the API in the ASD formulation. Poor drug-excipient miscibility carries a risk of poor dissolution and recrystallization, limiting the effectiveness of the HME product. The third is to lower the processing temperatures to reduce the risk of heat-induced chemical degradation. The last goal is to optimize the drug loading by achieving the highest drug loading without reducing the dissolution rate. High drug loading can be advantageous for reducing pill burden but may negatively impact dissolution rate. The selection of the polymer and excipients must strike a balance among all of the factors discussed above. 

Process conditions

Extrusion parameters such as temperature profile, screw configuration, screw speed, and feed rate determine shear and residence time. These factors in turn impact the level of thermal and mechanical stress applied to the formulation. Optimized conditions help achieve sufficient mixing while minimizing degradation risk.

Conducting feasibility assessments early in development is essential to identifying risk, taking appropriate action, and avoiding unexpected late-stage issues. Guided by a strong foundation of HME expertise, AbbVie approaches each project as a technical collaboration rather than a transaction. By working with partners from day one to understand their goals, characterize the unique features of their API, and optimize process parameters, AbbVie scientists pave the way for scalable, long-term success. 

Harnessing the Potential of HME

Too often, companies eliminate hot melt extrusion as a potential manufacturing approach before conducting a thorough scientific evaluation of their API and formulation options. Perceived thermal risk, one of the most cited barriers to HME adoption, is frequently manageable through informed formulation design and careful process engineering. With the right expertise, many compounds initially considered unsuitable for HME can be successfully processed while maintaining API stability and achieving the desired product performance. AbbVie’s track record of HME success underscores this point: while AbbVie has successfully commercialized ten products as ASD formulations using HME, this represents less than ten percent of our total successes in HME process development across AbbVie’s pipeline compounds. 

When implemented effectively, HME can deliver meaningful advantages over other ASD processing technologies, including strong scalability from development to commercial manufacturing and lower long-term production costs through continuous processing. AbbVie encourages drug developers to engage in early dialogue and feasibility assessment to fully understand whether HME could benefit their program. Leveraging decades of experience in formulation development and extrusion process design, AbbVie works collaboratively with partners to evaluate technical feasibility and identify strategies to mitigate risk while maximizing performance. If you thought hot melt extrusion was not a feasible option for your program, it may be time to learn more. Contact AbbVie to assess whether HME is right for you.