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Q&A:Hot Melt Extrusion as a Key Enabler of Developing Products of Low Solubility Compounds

Dr. Chad Brown, Pharmaceutical Sciences

Q: Screening drug-polymer is very challenging, and it becomes even more challenging when additional components such as plasticizer, surfactant, etc., are used. You mentioned about film casting. Can you please elaborate the process you use? What is your experience with theoretical modeling of miscibility?
A: We utilize a high throughput robotic format on 96 well plates this allows us to screen several combinations quickly for crystallinity and dissolution enhancement. We have found this to be more efficient than theoretical modeling.

Q: Is that possible to use Flory Huggines for thermally labile drug (degrade when melt)?
A: Outside me area of expertise.

Q: Have you any extruded ASD available on the market? Have you used any PAT tools for monitoring the process? How do you process the strands after extrusion?
A: I have extruded 3 compounds that have turned into marketed products. We do utilize PAT including NIR based composition monitoring. We typically use chilled rolls to quench the strands and then mill but have also explored injection molding.

Q: Can this technology be use for proteins and peptides?
A: We have explored this use, but this may be limited based on the thermal and shear sensitivities of these molecules.

Q: If an active Tm is over 300°C is there any chance for HME product development?
A: Yes, but it may be challenging. It will depend on the amount of melting point depression you get with a given polymer (Is the polymer a good solvent), if the molecule is thermally labile, and if plasticizers (chemical or fugitive) can be utilized.

Q: Should we exclude low Tg polymers from HME development due to kinetic satiability issues?
A: There may be a higher risk in this situation, especially at higher temperature and humidity storage conditions. However, it also depends on the interactions between the drug and the polymer that may offer further stabilization. There is no substitute for long term stability studies, but it should be highlighted as a higher risk when using lower Tg polymers.

Q: What will be a typical active loading you can achieve with HME?
A: I’ve been successful with 40%, but have also explored higher – compound dependent.

Q: Is the rheological determination of the minimum processing temperature also applicable for high melt viscosity polymers like HPMCAS?
A: It is obviously more complicated for these polymers, but the same principles apply.

Q: Have you seen any improved stability with f-HME compared to HME across the products studied so far?
A: We have seen some preliminary evidence that the faster quenching may enhance stability.

Q: Are there any published paper on foam extrusion of HPMCAS formulations?
A: Yes.

Q: Why are high melting point APIs more challenging for HME? Once, one knows the formulation and processing tricks they will work beautifully on HME.
A: There is a greater technical risk of thermal degradation of excipients and or active, and a greater risk of residual crystallinity as a higher Tm molecule is more thermodynamically stable.

Q: Which process is more expensive and time consuming between Spray dispersions vs. extrusion?
A: Extrusion has the benefit of being a continuous and easily scalable process. It has a small foot print and low capital cost to install. It does not involve solvent management and is thus a greener process as well. Extrusion should always win out on economics.

Q: How about co-precipitation of polymer and API. Is this something that we will start to see the pharma industry use in the future?
A: There is already an approved product with this approach.

Q: I guess, the products that can be formulated depend mainly on thermal stability of API , availability of safe common solvent, efficiency of removal for the residual solvent; are there any other factors may limit the employment of HME?
A: Shear sensitivity of the API, thermal stability of the excipients, downstream compaction and dissolution effects based on larger/denser particles to name a few.

Q: Increasing drug loading to >20% might be challenging to achieve the amorphous dispersion by HME. Can you elaborate Merck’s approach to finding the right polymers for high drug loading.? If HME is not an ideal solution, how will you decide to select the formulation technologies: spray drying vs Kietisol vs melt granulation?
A: We have successful explored drug loadings utilizing >20% drug loading. If HME is not a candidate we will explore spray drying if solvent solubility is sufficient, followed by co-precipitation.

Q: Expected drug loading with HME is lower when compared with spray drying?
A: Not necessarily.

Q: Is the rheological determination of the minimum processing temperature also applicable for high melt viscosity polymers like HPMCAS?
A: Yes, but more challenging.

Q: Is screw design is critical parameters for solubility enhancement?
A: Yes as this can have impact on residence time in the extruder.