Hot Melt Extrusion

Explore the science and strategy behind Hot Melt Extrusion with BioDuro-Sundia, where advanced technology meets pharmaceutical innovation to enhance drug solubility and delivery.

Hot melt extrusion (HME) is a cutting-edge drug development technology that helps pharmaceutical companies create new medications that are highly soluble and bioavailable.

The hot melt extrusion process uses heat and pressure to combine polymers with active pharmaceutical ingredients. During this process, the combined material is pressed through a die to form a tablet, capsule, or granule. Typically, this is done with two twin screw extruders, which press the active ingredient into the polymer and resulting in a polymer matrix.

BioDuro-Sundia uses HME as part of our end-to-end development and manufacturing process. By incorporating HME early in development, we help our clients address solubility and bioavailability challenges on a small scale, before moving to clinical trials or large-scale manufacturing and distribution.

The Advantages of HME in Drug Formulation

Using a hot melt extruder offers many benefits when formulating new pharmaceutical products. The most notable advantage this technology offers is the ability to take poorly soluble drug compounds and incorporate them safely and effectively in new products.

For example, there are many compounds that have medical potential, but do not dissolve effectively in liquid or absorb properly in the body. HME technology combines these compounds with a polymer that is soluble and bioavailable for efficient drug delivery.

HME technology also helps pharmaceutical companies develop sustained release drugs. With this process, you can combine unstable compounds with specific polymers that facilitate a longer delivery period within the body. This means the therapeutic effects of the drug will last longer with each dose.

Finally, HME is also very effective for developing drugs with taste-masking properties. Some active drug ingredients have very bitter or unpleasant flavors, but the hot melt extrusion process coats these ingredients with a polymer. The polymer acts as a barrier between the taste buds and the active ingredients, making the drug more palatable. This is particularly helpful when creating drugs for children, seniors, and other sensitive patient groups.

In addition to its versatility, HME also has the benefit of being very efficient. The process is highly automated, requiring little manual input, and finished compounds don’t require any post-procedure drying, which keeps manufacturing times reasonable. On top of that, the HME process can be done continuously, which improves drug uniformity and maintains quality.

Insights Into HME Process Development

BioDuro-Sundia works closely with clients to incorporate hot melt extrusion into the development of new pharmaceutical products. By making HME technology an integral part of our research & development strategies, we’re able to develop drugs with ingredients that have limited solubility and bioavailability. Using HME in the early stages of development helps address these concerns early, speeding up time to clinic without sacrificing safety.

Our facility in Irvine, California is GMP and cGMP certified, ensuring proper quality control and manufacturing standards. We also have a manufacturing facility in Jiangsu, China, which allows for international HME development and manufacturing as well.

Additionally, our process excludes solvents, resulting in a higher-quality finished product. Our research and development process involves in vivo animal studies as well as in vitro analytical data for additional testing support. We work with BCS II, III, and IV compounds, and can use HME technology with controlled substances.

When using HME to create new pharmaceutical products, there are a variety of key factors to consider. Most notably, you will need to select a polymer that is compatible with your active drug ingredients and determine the appropriate ratio of active ingredient to polymer based on your goals. If the polymer is not compatible with the active ingredient, the extrusion process may not be successful.

You will also need to consider the thermal stability of the drug and polymer. While HME can be done at relatively low temperatures, you will need to identify the polymer’s specific melting point to choose the exact temperature setting. BioDuro-Sundia’s team will help you determine these settings based on your specific ingredients and biological targets.

Technical Insights into HME

The following FAQs have been curated by Dr. Feng Zhang, a leading expert in pharmaceutical sciences at the University of Texas at Austin. Dr. Zhang brings a wealth of knowledge and experience in hot melt extrusion (HME) techniques, ensuring comprehensive and insightful answers to complex technical questions.

Q: What should be kept constant in scale up and what must be changed for processing parameters?

A: Depending on the limiting factor for the scale-up process, specific mechanical energy (SME) and residence time distribution (RTD) are generally kept constant.

Q: Process parameters such as screw speed, screw configuration and temperature may have an impact on the actual measured temperature, is there a way to predict the actual temperature and hence better design the process?

A: The temperature is mainly controlled by the screw configuration, screw speed and feed rate. Higher temperature is observed with more restrictive screw element, higher screw speed, and lower feed rate. Theoretically, temperature could be predicted if the rheology of the material is known. Practically, there have been a lot of challenges because of all the physicochemical changes during the process.
Q: What are measures about heat sensitive API using twin screw hotmelt extrusion?

A: Higher feed rate and higher screw speed. This would enable the same level of energy input while shortening the residence time. Also, pay more attention to the melt residence time rather than global residence time.

Q: Is it true that we should keep the same brand for easier scale-up when using HME?

A: It is true because of the principle of geometrical similarity.

Q: What are the criteria used to determine whether HME, nano wet milling, spray dried dispersion, or other techniques will be used to enhance a given API’s kinetic solubility?

A: Every project starts with spray drying since API is limited. HME is a much simpler and more economical process. Companies often attempt to transition to the melt extrusion process if they have sufficient materials, time, and budget.

Q: To what extent do you think mechanical breakage of crystalline particles contribute to increasing surface area and solubilization of drug?

A: This is not that significant for the melt extrusion process unless API has a D50>50 microns.

Q: What factors should you control to avoid degradation in HME?

A: Higher feed rate and higher screw speed. This would enable the same level of energy input while shortening the residence time. Also, pay more attention to the melt residence time rather than global residence time.

Q: What is the yield of the small scale extruder when you run it on a minimum amount of material? How much material is lost in the extruder?

A: With Thermo 11 and Leistritz 16 mm extruders, you could process 10 gram and end up with 3-4 gram materials.

Q: What aspects of processing impact the potential for crystallization on storage?

A: Sufficient energy and mixing time are needed to ensure the complete solubilization of crystalline drug in polymer melt.

Q: Is there any impact of material water content (LoD) on the extrude process?

A: Water content can have a HUGE impact on extrusion process. For example, water in copovidone can function as plasticizer. At higher water content, not enough viscous heating is generated, and the melt temperature might be lower. As a result, drug might solubilize in polymer melt.

Q: What variation exists across the length, or relative length, of the kneading elements used in HME? Is this standard across various systems, and if so, why?

A: The variation is minimal and fairly standard across systems. Typically, the forward kneading elements, either 60 or 90 degrees, are used because the drug and polymer are highly miscible in pharmaceutical applications.

Q: ASD can help to develop macromolecules at what extent for oral or other routes?

A: Macromolecules might not have enough thermal stabilities for them to be melt extruded.

Q: How many products are on the market with HME process?

A: 6-8 products. I am only referring to ASD products here.

Q: Which polymers are used the most for HME?

A: Copovidone, hypromellose, and hypromellose acetate succinate.

Q: When going from 16 mm to 27 mm, what happens to residence time? Do bigger extruders have longer or shorter residence time?

A: In general, residence time can be shortened while maintaining the same quality of extrudate.

Q: In order to ensure similarity in product temperature between lab and production scale extruder, what temperature should be monitored either temperature at die or kneading elements?

A: Both temperature post kneading and at the die is important. Temperature post kneading is important from achieving solubilization of drug in polymer melt perspective. Temperature at the die is important from drug stability perspective.

Q: What roles do melt viscosity and plasticizer play in extrusion temperature?

A: The local heat is controlled by the mixing and melt viscosity. Plasticizers are “never” really used in hot melt extrusion for amorphous solid dispersion. Please note that drugs are plasticizers for polymers in most cases.

Q: What’s typically required in terms of stability of the finished amorphous product? Do the APIs crystallize in vivo upon initial solvation?

A: Drugs need to be chemical (impurity contents are below the limit) and physically (no phase separation or crystallization) stable in finished products during storage. In most cases, API precipitates as amorphous rather than crystalline particles upon initial solvation.

Q: How critical is polymer selection to get amorphous API by HME which characteristics of polymer need to consider for high melting API?

A: Polymer selection is EXTREMELY crucial. Polymer dictates the drug-polymer phase separation and drug precipitation behaviors that control the drug absorption.

Q: Are there times when you would want to run the conveying element at volume capacity (that is, non-starved)?

A: Only in the case when rely on the screw speed to control the feed rate.

Q: How can we know if we got a solid dispersion instead of an eutectic mixture?

A: Solid dispersion consists of a drug and polymer. It is not an eutectic mixture.

Q: What predictive (modeling) approaches can you suggest to predict HME settings for particular small molecule/polymer combinations?

A: The only commercially available software is Ludovic™. In our experience, their utility is still very limited for pharmaceutical amorphous solid dispersions.

Connect With HME Experts

Hot melt extrusion has many possible applications in the pharmaceutical industry, whether you’re still in the discovery phase or are looking to bring a product to market with a large-scale manufacturing process. The team at BioDuro-Sundia has extensive experience working with HME technology at all stages of the drug development process. Contact us today to learn more about hot melt extrusion and our other pharmaceutical development services.