Sexy Science in Pharmaceuticals: Hot-Melt Extrusion

Traditionally, hot-melt extrusion (HME) is co-located with downstream processing and solid-dosage form manufacturing. Regulatory bodies continue to encourage quality-by-design (QbD) approaches, quality management maturity (QMM), and process analytical technology (PAT) improvements. These are all essential tools in a well-organized HME platform and work together to enhance product outcomes, but also to improve process understanding. HME, as an approach, is aptly suited to this framework.

As molecular diversity ramps up, the total number of difficult-to-formulate drugs poses severe manufacturing challenges.Creativity, innovation, and bringing in material science practices from other fields seems a fruitful approach.

“Approximately 30–40% of all marketed drugs have low solubility (BCS Class II and IV). Overall, it is estimated that up to 90% of small-molecule APIs in development face solubility challenges; as such, solubility enhancement approaches are critical for the successful advancement of therapeutics that have yet to reach the market” (1).

This episode of Sexy Science in Pharmaceuticals brings together two world-class scientists to discuss one of the top solutions for low solubility. For bioprocessing and manufacturing larger molecules, low solubility and protein aggregation also needs addressing, as does dedicated storage and handling throughout. We discuss these challenges and cite several paths around or through these issues.

Chapter 1

As an opening introduction to this discussion, we examine the general aspects of HME supporting bioavailability enhancements for poorly soluble BCS class 2 and class 4 compounds. Examples discussed include Noxafil, an oral suspension used in adults and children to help prevent or treat fungal infections from widespread dissemination throughout the body (also used to treat a fungal infection called “thrush” caused by Candida in the mouth or throat area), and Belsomra for insomnia.Both products are part of the Merck portfolio.

Chapter 2

In this part of the discussion, a robust processing space to obliterate crystalline structures to create a single-phase homogenous solid amorphous dispersion is defined. Also, we draw up a more green sustainable future without high solvent use and disposal—HME not requiring large volumes of acetone, in contrast to spray drying dispersion processing. In HME, as the temperature rises beyond the glass transition temperature for that material the polymer becomes a liquid. The drug solubilizes into that molten phase. So, we have now a liquid phase that has dispersed drug crystals, which over time break down in the extruder, dissolve, and diffuse into that molten matrix to create a single molecularly dispersed phase. We then use X ray diffraction to look for (hopefully) the absence of crystalline peaks associated with the API.

In another quality check to see if we’ve been successful, we use differential scanning calorimetry where we want to see a single glass temperature observed in the material, thus showing we’ve also eliminated drug rich domains.

Chapter 3

In this part, we discuss HME biological macromolecules for slow release subcutaneously implantable vaccine delivery and injection molded microneedle patches. Aggregation in proteins and frailties of virus like particles leading to inhomogeneity needs to be addressed.

Chapter 4

The commercial philosophy of spray dying in early R&D stages, then switching to HME for commercialization is outlined in this discussion. In general, looking at mixing and quenching.Dealing with whole bacterial spore cells extruded into polymer matrices to degrade polyurethanes (in environmentally friendly and sustainable ways), in collaboration with BASF, is also described.

Reference

1. Merck. Enhancing API Solubility During API Processing and Formulation Development. eBook, PharmTech.com Oct. 26, 2023.

About the speakers

Professor Jonathan Pokorski, Department of Chemical and Nano Engineering, UC San Diego Jacobs School of Engineering

Professor Pokorski’s laboratory works to bridge chemical synthesis, molecular biology, and materials science to make new materials for biomedical applications. The Pokorski lab is particularly interested in marrying protein and polymer science to generate new materials for drug delivery, imaging, and vaccination. Pokorski received his doctoral degree in organic chemistry from Northwestern University in 2007, where he designed, synthesized, and tested diverse peptidomimetic systems for use in medical diagnostics and therapeutics. Following his PhD studies, Pokorski moved to The Scripps Research Institute, where he used both chemical and genetic engineering of viral nanoparticles to synthesize novel drug delivery systems. During his postdoctoral training, Pokorski first earned an NIH Ruth Kirschstein fellowship and later secured an NIH Pathway to Independence Award.

Prior to his appointment at UC San Diego in 2018, Pokorski began his independent career as an Assistant Professor at Case Western Reserve University in the department of Macromolecular Science and Engineering. Pokorski was a finalist for the prestigious John Diekhoff graduate mentoring award at CWRU from 2013 to 2017, was named an ACS PRF new investigator, and is a Kavli fellow. Research in the Pokorski lab is funded through grants from the National Institutes of Health, National Science Foundation, and the American Chemical Society.

Dr. James DiNunzio, Senior Principal Scientist, Merck

Dr. James DiNunzio is currently a Senior Principal Scientist at Merck & Co., Inc. in Rahway, NJ where he heads the Hot-Melt Extrusion Subject Matter Expert Network Team and co-leads the Continuous Processing Technology Development Team.Since joining Merck in 2013, he has contributed to multiple programs in the disease areas of oncology, virology, and CNS (central nervous system) disorders.Prior to Merck, he served as a Senior Scientist in the Pharmaceutical & Analytical R&D group at Roche where he was responsible for the formulation design of poorly soluble compounds using enabled technologies.He has also held positions of increasing responsibility at PharmaForm and Forest Laboratories.

Dr. DiNunzio received his PhD in Pharmacy (Pharmaceutics) from The University of Texas in 2009 specializing in thermal manufacturing of amorphous dispersions.He also holds M.S. and B.S. degrees in Chemical Engineering from Columbia University and The State University of New York at Buffalo.He currently serves on the Editorial Advisory Boards of AAPS PharmSciTech and the Journal of Pharmaceutical Sciences.He has authored over 25 research papers and book chapters in the field of hot-melt extrusion and formulation design for bioavailability enhancement.His current research interests include formulation design for bioavailability enhancement, melt extrusion process design for challenging systems, and the development of continuous manufacturing technologies.