In Part I, CEO Elizabeth Hickman and CSO Dave Miller of Austin Px discussed how in silico drug discovery has enabled researchers to target an unprecedented number of molecules, and how delivery technology has had to keep up. But solubility challenges are not limited to the laboratory alone. Here, Hickman and Miller explain how manufacturing practices and standards are also being pushed to the limit.
Did you set out to develop the KinetiSol to find ways of drugging the undruggable, or was there another, less romantic need?
Dave Miller: We were looking originally for a more efficient manufacturing process, but given regulatory oversight and how conservative the pharmaceutical industry is in general, nobody’s going to find a path to commercialization for a new technology simply because it's more efficient. It's got to address a severe pain point for anyone to take a risk on a novel technology. Put simply, KinetiSol is just the current most efficient manufacturing process for making super saturating drug delivery systems. Where you find the real value, however, is where the biggest pain points are. It's about looking for molecules that have tremendous therapeutic potential, but no path to the clinic or beyond because their physicochemical properties aren't amenable to conventional formulation tools.
We call these molecules “brick dust molecules”. They’re just horribly insoluble with high melting temperatures. My old professor used to say the Taj Mahal is more soluble than intraconazole, for example. The challenges of solubility are dramatic, but that's where you position your technology: as the enabling pathway forward for a molecule. The idea behind KinetiSol is to service insoluble molecules much more efficiently.
Elizabeth Hickman: First, you have to prove the performance of the technology in a very risk-averse industry; then you look at the adoption and realize that’s not just a “when all else fails technology” – that’s when you can compare it against traditional ways of making amorphous dispersion. There are some molecules for which KinetiSol is the only thing that works, and for others where the performance is very similar. What's so elegant about the process is how simple it is in generating amorphous dispersion, and how quickly it does that.
What can you tell me about how the process works?
DM: The key idea is taking a poorly soluble crystal and converting it into its molecular form. In the melt method, you melt the drug and mix it with a polymer; in the solvent method, you dissolve the drug in a solvent and then mix it with the polymer.
In our technique, we also dissolve the drug, but we use the excipient itself as the solvent. We’re not melting the drug because many of the drugs we work with can’t be melted. Some have melting points above 300°C, and others don’t melt at all – they just char.
Instead, our mixing technology starts with solid materials at room temperature and transforms them into something like a malleable, leathery dough. Through ultra-rapid mechanical mixing, we dissolve the drug crystals and convert them into molecular form. It’s essentially a dissolution process similar in concept to spray drying or other solvent-based techniques, but the excipient itself acts as the solvent.
In spray drying, you typically dissolve the drug and polymer in large amounts of organic solvent. In our method, there’s no solvent, so 100 percent of the input mass is converted into product, making the process far more efficient. We use only mechanical energy, which generates enough localized heat to drive the conversion.
The resulting molten mass looks like bread dough, which we then rapidly cool through compression. This turns it into a brittle, amorphous glass that can be easily broken and milled into a powder, which is then used in capsules or tablets. The end product looks similar to the original powder, but now it has improved solubility and dissolution properties.
EH: We build and design our own equipment in a two-scale facility. We have a smaller unit for R&D and pilot scale, and a second unit that takes you all the way through to commercial scale. The core of that technology, the kinetosol mixing chamber, is similar to a high-shear mixer. At the fully automated commercial scale it’s charged automatically and becomes a very high speed mixer – up to 5,000 RPMs – solubilizing the drug into the excipients. Once the drug is solubilized into the excipients, it goes into the quenching system and comes out looking like cookie dough.
What can you share about the origins of KinetiSol?
DM: During my PhD at the University of Texas, I worked on melt-mixing methods and trying to combine materials by melting them. I constantly ran into degradation, high melting temperatures, and polymer viscosity problems but, by chance, I met Chris Brough, who’s now our CTO. At the time, he was commercializing a new plastics recycling technology and explaining the limits of melt extrusion – unaware that I’d been struggling with the same issues in drug formulation. The challenges he described were identical to what I faced in pharma, and that conversation sparked the idea for a new approach.
Chris and his colleagues at Brigham Young University had developed a better way to mix waste plastics, and I saw how it could solve similar problems in drug delivery. Our first experiments proved it worked at an industrial scale. From there, the real challenge was scaling the technology down – not up – for pharma applications, where we deal with small quantities of costly active ingredients. Once Chris solved that, scaling back up for manufacturing was simple.
Spray drying currently dominates amorphous drug formulation, but it produces low-density, hollow “ping-pong ball” particles that don’t flow well and require densification. KinetiSol creates dense, free-flowing “bowling ball” particles that are easier to use in tablets and capsules. We later found these dense particles also help maintain drug solubility in the GI tract by preventing the amorphous molecules from recrystallizing.
Newsletters
Receive the latest pharmaceutical news, personalities, education, and career development – weekly to your inbox.
