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Q&A: Hot-melt extrusion to prepare amorphous solid dispersions: key concepts and common misperceptions

 Dr. Feng Zhang, UT Austin

Please reach out to Dr. Feng at feng.zhang@austin.utexas.edu if you have any further questions.

Q: What should be kept constant in scale up and what must be changed for processing parameters?
A: Depending on what is the limiting factor for the scale up process, generally specific mechanical energy (SME) and residence time distribution (RTD) are kept constant for scale up. Please refer to this book chapters for details. Chen B, Zhu L, Zhang F, Qiu Y*. Developing Solid Oral Dosage Forms. 2nd ed. Qiu Y, Chen Y, Zhang G, Yu L, Mantri RV, editors. Amsterdam: ELSEVIER; 2016. Chapter 31, Process Development and Scale-Up: Twin-Screw Extrusion; p.48. 1176p. (Book chapter)

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 experiment?
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 has been a lot of challenges because of the all the physicochemical changes during 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: How you can transfer learning on a certain extruder brand to another?
A: I do not have that much experience in that regards since pretty much all my experience is with Leistritz extruder. I would assume certain system parameters such as specific energy input is comparable across different brands for a given formulation.

Q: Why is the temperature after the kneeding zone hotter than the temperature at the kneeding zone?
A: The highest temperature should be right at the end of kneading zone.

Q: Is it true that we should keep same brand for easier scale up?
A: It is true because of the principal 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: Practically, every project starts off with spray drying since API is limited. HME is a much simpler and economical process. Companies often attempt to bridge over to melt extrusion process if there are 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: Not that significant for melt extrusion process unless API has a D50>50 micron.

Q: What is important to control, residence time or input volume to avoid degradation?
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: Out of your experience: 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: Which one (zone temp) affects much to get optimum ASD?
A: Temperature of all zones is important.

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: Could please explain little more about importance of Melt temperature during scale up?
A: It is important to achieve similar temperature profile to ensure the same thermodynamic state of formulations.

Q: Is there any impact of material water content (LoD) on 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: Is solid dispersion preferred or solid solution?
A: Solid dispersion is more common name.

Q: What variation is there across the length (or relative length) of the kneading elements used in HME? Or is that pretty standard across various systems, and if so, why?
A: Pretty standard. Forward kneading element, 60 or 90 degree, for pharmaceutical system, drug and polymer are pretty miscible.

Q: ASD can help to develop macromolecule at what extent for oral or other route?
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: In your opinion: Is HME gaining importance in the industry? Or are other methods like spray drying gaining more importance?
A: Both are equally important.

Q: Which polymers are used the most for HME?
A: Copovidone, hypromellose, and hypromellose acetate succinate.

Q: Should the scale up be performed incrementally with screw size or order can be different e.g. 11 mm, 16 mm, 18 mm, 27 mm, 50 mm or can go from 11 mm to any scale based on first principals?
A: Unfortunately, I do not have enough experience to provide a straight answer. My scale up experience is from 18 mm to 27 mm and larger extruder.

Q: When going from 16 mm to 27 mm, what happens to residence time? Does bigger extruders have longer or shorter residence time?
A: In general, residence time can be shortened while maintaining the same quality of extrudate.

Q: I just wonder, in order to ensure similarity in product temperature between lab and production scale extruder, what temperature should be monitors 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. Plasticizer is “never” really used in hot melt extrusion for amorphous solid dispersion. Please note, 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 the 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 did you calculate the plots for RTDs? I guess they were based on simulations. Can you please give some insights what methods you used?
A: Please reach out to me directly at feng.zhang@austin.utexas.edu

Q: How can we know if we got a solid dispersion instead of an eutectic mixture?
A: Solid dispersion is consisting of drug and polymer. It is not eutectic mixture.

Q: Is the reference of Dinunzio with thermal imaging also published somewhere? I am curious to learn more. Thermal imaging needs a lot of calibration/reference measurement before one can really trust the data from my experience and I am curious to learn how they mastered the challenge.
A: I do not think the data has been published.

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.