How Difficult Is it to Scale Up an Amorphous Dispersion?

Oral drugs are the most convenient and sought-after form of drug administration. They are more convenient, portable, affordable and allow for flexible design. They, however, need to be soluble. This means they must be digested completely so the active pharmaceutical ingredients (APIs) in the drug can be absorbed by the body.

It’s been estimated that about 90 percent of new chemical entities or drug molecules currently under development are insoluble. Therefore, techniques and technologies that promote drug solubility and bioavailability are in high demand.

Amorphous solid dispersions have emerged as a transformative approach for drugs that exhibit poor aqueous solubility. Historically, researchers first attempted to improve drug dissolution rates (the process in which a drug molecule would dissolve in a solvent) by maintaining drugs in an amorphous state — a disordered molecular arrangement that allows for higher solubility compared to its crystalline counterparts.

Over the decades, the science behind amorphous solid dispersions has expanded to understand and optimize the stability and dissolution behavior of these systems.

Kinetisol™ Technology represents a significant leap in amorphous solid dispersion development and manufacturing. It is a solvent-free process that uses frictional and shear energies to transform APIs and polymers or other excipients into high-quality amorphous solid dispersions. This method is environmentally sustainable and fast, taking seconds instead of hours or days.

Xtalks had the privilege of speaking with Dr. Justin Keen, Senior Vice President of Operations at Austin Pharmaceutics (AustinPx), about the innovative KinetiSol technology and the nuances of scale up.

AustinPx provides expert formulation strategies custom-made for each drug. Their focus is on improving drug solubility and bioavailability with powerful amorphous dispersion technologies, such as KinetiSol for poorly soluble compounds.

Dr. Keen first experimented with amorphous solid dispersions over two decades ago, during his undergraduate studies in chemical engineering, with subsequent career roles in pharmaceutical formulation and process development, clinical manufacturing and process validation. Dr. Keen was first introduced to AustinPx when wrapping up his PhD from the University of Texas at Austin where novel amorphous solid dispersions were a focus of his dissertation.

Today, Dr. Keen is applying his knowledge and experience to improve the way drugs are made, making processes quicker and more environmentally friendly.

Understanding KinetiSol Technology

“In its most routine application, KinetiSol is a pretty simple mixer, but it applies this tremendous shear force to what’s typically a powder blend of a crystalline drug and a polymeric carrier,” explains Dr. Keen. Polymeric carriers are components that work to stabilize the amorphous form of the drug. The inclusion of these polymers inhibits recrystallization and increases the rate at which the drug dissolves in the gastrointestinal tract.

Dr. Keen summed up KinetiSol’s mixing technology as a process of creating a molecular blend from a physical blend. He elaborated, “These sheer forces that are applied to these powder blends first result in a frictional heating, and as the blend heats up, that, in turn, imparts this physical change to this mixture, which creates an environment for the crystalline drug to solubilize itself and dissolve into the polymer.”

Within the KinetiSol equipment, speed and temperature come together rapidly to generate an amorphous solid dispersion in less than 20 seconds. Once ready, the material is quickly ejected and then immediately cooled or “quenched” between metal plates, resulting in a glassy dispersion that is then milled into a powder and further processed into tablets or capsules.

KinetiSol is specifically designed to address some of the limitations of traditional amorphous solid dispersion preparation techniques like hot melt extrusion (HME) and spray drying.

Seamless Scale Up to Commercial Drug Production

Scaling up pharmaceutical processes can be fraught with challenges, particularly when transitioning from lab-scale to commercial production. Dr. Keen shared his extensive experience with scaling various technologies, noting, “Scaling up usually involves controlling transport phenomena or different mechanisms of exchange, be it heat or momentum. Controlling two things at once is hard, especially when you have these big volumetric changes.”

For commercial manufacturing processes like spray drying, heat and mass transport must be controlled at the same time. For HME, on the other hand, it is a challenge to control momentum while managing the mass transport of the crystalline drug into a uniformly dispersed amorphous state.

Because KinetiSol requires a single and relatively small volume change, scale up is simplified to controlling a single variable – shear rate – rather than a range of phenomena,” Dr. Keen points out.

KinetiSol uses two machine scales for drug development. The KinetiSol Formulator is utilized during feasibility to screen small 10-gram batches of different formulations. Successful formulations are then scaled up in a clinical manufacturing facility to kilogram-per-hour levels, sufficient for first-in-human (FIH) studies. Following initial clinical trials, the process is then scaled up tenfold to the KinetiSol Compounder, integrating material handling controls and process automation, enabling large and commercial scale productions to run at 10 to 20 kilograms per hour.

The overall process is seamless, facilitated by process automation and continuous manufacturing principles.

KinetiSol for Amorphous Solid Dispersions

Looking ahead, Dr. Keen is optimistic about KinetiSol’s impact on the pharmaceutical industry. “We’ve successfully scaled KinetiSol to commercial scales several times. We’ve made registration batches in commercially-registered or US Food and Drug Administration (FDA)-registered facilities.”

Despite the technological success, however, Dr. Keen acknowledges the unpredictable nature of clinical outcomes. “We can’t control biology or commercial risk. But we have a few products that are late-stage, [including] one in Phase III, and we know that the first commercial success really depends on getting the right drug on the market.”

KinetiSol was recently used to reformulate galeterone — a novel candidate for prostate cancer that failed Phase III trials — to improve its bioavailability and was found to prepare better amorphous solid dispersions, as compared to spray drying.

As a solvent-free technology with a small operational footprint, KinetiSol aligns with the industry’s push toward greener manufacturing processes. It can produce high-quality and stable amorphous solid dispersions, addressing some of the key challenges faced in the scaling up of these formulations for commercial use.

The integration of Kinetisol will likely continue to shape the landscape of pharmaceutical manufacturing, enhancing the solubility and bioavailability of challenging drug compounds, while also driving down cost of goods and environmental footprint.

As this technology continues to evolve, it could reshape how amorphous dispersions are produced, offering a sustainable solution to drug development.

This article was created in collaboration with the sponsoring company and the Xtalks editorial team.