AustinPx is a Georgetown, Texas-based contract development and manufacturing organization (CDMO) founded in 2007 to help developers overcome obstacles in bringing a drug to market, including poor bioavailability and accelerated timelines. As the inventors of KinetiSol Technology, a next-generation amorphous solid dispersion (ASD) technology for poorly soluble APIs, with its smaller footprint, broader design space, and greener processing solutions, AustinPx aims to disrupt the ASD industry.

In this Q&A, Dave Miller, PhD, Chief Scientific Officer of AustinPx, explores the next generation of amorphous dispersion technology and how the CDMO’s KinetiSol Technology can be used for the rapid development of poorly soluble molecules targeting undruggable targets.

Contract Pharma: What are the market trends driving the demand for next-gen amorphous dispersion technology?

Dave Miller: The market trends driving the demand for next-gen amorphous dispersion technology are multifaceted. Firstly, the increasing prevalence of poorly soluble drugs driven by rational drug discovery is a significant factor. Secondly, modern drug discovery has entered the in-silico era, where compounds are virtually synthesized and tested for their binding efficiencies to target sites. This has expanded the explorable chemical space at the fringes and beyond what was historically considered druggable territory. The democratization of drug discovery through AI tools allows individuals and small companies, not just large pharmaceutical firms, to evaluate more potential drugs. This capability has led to the exploration of biological targets previously considered intractable and investigation of the hydrophobic ligands that bind to these sites.

Moreover, the push to accelerate development timelines by reducing medicinal chemistry intervention and molecular design iterations is another key trend. This approach involves nominating candidates that may violate traditional druggable rules and trusting formulation technologies to improve bioavailability. It also means not compromising on the structure-activity relationship—chemically modifying molecules that best bind to target sites is avoided, as advanced formulation technologies can often enable these compounds.

The Green Chemistry movement toward sustainability is also driving demand. The spray drying process used to produce many amorphous dispersion drug products is estimated to generate 10 million liters of solvent waste annually, contributing significantly to the environmental footprint. This impact must be mitigated with next generation technologies to achieve sustainability goals.

Intellectual property considerations further influence the market. Basic binary ASD intellectual property is increasingly being rejected by patent offices or not holding up in litigation due to prior art. As a result, there is a need for more complex ASDs to optimize drug delivery and provide unexpected results that can form the basis for allowable intellectual property.

Additionally, there is a growing need for tailored release profiles. The first generation of ASD solutions focused on simply increasing solubility and bioavailability. The second generation aims to take this improved solubility and tailor the release within the gastrointestinal tract to elicit a specific, more efficacious pharmacokinetic profile. Extending ASDs to other routes of administration, such as sublingual, intranasal, pulmonary, and buccal, is also becoming increasingly important.

CP: Can you provide an overview of the KinetiSol Technology and explain how it differs from traditional solubility enhancement techniques?

Dave: The KinetiSol Technology, originally adapted from the plastic recycling industry, began its development in 2007. The initial experiment used an industrial-scale plastic processing machine to create, at the kilogram scale, a single-phase ASD of a drug and polymer in under 20 seconds without solvents or material degradation. This breakthrough showcased KinetiSol’s potential to revolutionize ASD production by expanding formulation options and offering a sustainable manufacturing approach.

KinetiSol is a fusion-based process that uses friction and shear energies to molecularly mix drug-polymer blends, generating single-phase ASDs in seconds. KinetiSol is perhaps most aptly described as an ultra-high-speed granulation process where the endpoint is defined as the instant crystalline drug dissolves completely within the softened polymer. Unlike spray drying, which requires organic solvents to dissolve the drug, KinetiSol solubilizes the crystalline compound in the polymer, i.e., the polymer is the solvent. This formation mechanism avoids phase separation and ensures a perfect molecular mix, thereby maximizing formulation stability and biopharmaceutical performance.

KinetiSol is particularly advantageous for handling thermally sensitive APIs, as the brief thermal exposure allows processing without degradation. Its versatility also includes processing high melting point compounds and non-thermoplastic/high molecular weight polymers without plasticizers.

The formulation toolbox enabled by KinetiSol is substantially larger than spray drying and melt extrusion. Polymer selection with KinetiSol is not limited by organic solvent solubility as with spray drying, nor thermal stability and viscosity as with melt extrusion. Hence, KinetiSol provides formulators access to essentially any pharmaceutical polymer. Furthermore, KinetiSol allows for combinations of polymers and incorporation of ancillary excipients that work synergistically to enhance performance and/or stability. The KinetiSol toolbox thus enables formulators to easily generate complex drug delivery systems to maximize product performance. Substantial IP potential is inherent to these complex and superior formulations. Furthermore, KinetiSol products cannot be duplicated by other technologies ensuring perpetual protection against generic competition.

Environmentally and economically, KinetiSol reduces chemical handling and disposal costs by using no solvents or nitrogen. It offers comparable throughput at significantly lower upfront and operational costs than spray drying and produces dense, directly compressible powders that reduce pill burden and improve patient compliance.

The technology ranges from small-scale (7 grams) for development to large-scale (up to 30 kg/hr/machine) for production, enabling rapid feasibility studies with minimal material, exhaustive formulation mapping to identify optimal formulations, and direct transfer to the manufacturing scale to for Phase I with no additional scale-up through to commercialization. As a fee-for-service technology without additional licensing or royalty costs, KinetiSol provides significant cost advantages as well.

CP: How does KinetiSol specifically aid in targeting molecules that are considered undruggable?

Dave: Molecules designed to efficiently bind to hydrophobic target sites often possess properties that hinder effective oral delivery, such as aqueous insolubility, poor organic solvent solubility, high melting temperatures due to high crystal lattice stability, structural complexity making them more susceptible to degradation, and high molecular weight. KinetiSol Technology specifically aids in targeting these undruggable molecules through several key mechanisms.

Firstly, KinetiSol offers the most extensive formulation toolbox of any amorphous solid dispersion (ASD) technology. This enables the development of complex ASD formulations necessary for the oral delivery of highly insoluble, complex compounds. Despite the complexity of the formulations, KinetiSol simplifies the development process with its advanced and straightforward technology.

Secondly, KinetiSol does not rely on organic solvents, meaning solvent insolubility does not impede its use, unlike spray drying. The KinetiSol process generates ASDs by dissolving crystalline drug particles within the molten polymer in seconds. As a dissolution process, ASD formation is not governed by the compound’s melting temperature. This allows KinetiSol to create single-phase ASDs of very high melting compounds well below their melting temperatures, often more than 100°C lower. This capability enables the formulation of high melting point compounds without concerns about polymer degradation and allows for high drug loadings.

Additionally, KinetiSol facilitates ASD formation with thermolabile and structurally complex molecules by minimizing the temperature and duration of thermal exposure to just a few seconds. This significantly reduces the risk of thermal degradation for complex drug candidates. Furthermore, high molecular weight small molecules present challenges such as poor solubility, instability in gastrointestinal fluids, and limited permeability or site-specific absorption. Complex ASD formulation design is often required to address these issues simultaneously. KinetiSol’s extensive formulations toolbox is often enabling in these cases, where spray drying and melt extrusion, with their limited formulation design space, would fail.

CP: Can you share any success stories or case studies?

Dave: We’ve collaborated with numerous clients focused on intractable targets and undruggable compounds, though specific case studies are not yet available for public disclosure. I can reveal that in-silico tools and machine learning were central to these companies’ drug discovery strategies. These compounds were meticulously designed and optimized for efficient target binding before actual synthesis, meaning traditional “drug-like properties” were not considered until later in the design process. Often, when a lead family with excellent binding efficiency and target-specificity is synthesized and evaluated, it violates the conventional criteria for druggability.

For such compounds, KinetiSol provides a solution by enabling early assessment through solubility and bioavailability-enhancing formulations, using minimal amounts of API for initial in-vitro and in-vivo evaluations. This allows companies to nominate the best molecule for development without compromising on the structure-activity relationship by chemically modifying the compound to get closer to druggability criteria, which often results in loss of binding efficiency and specificity. Consequently, KinetiSol empowers discovery groups to develop the most potent, efficacious, and potentially safer compounds without the fear of bioavailability issues hindering development.

A notable public example illustrating the potential of KinetiSol for enabling undruggable compounds is PLX4032, also known as vemurafenib or Zelboraf. Discovered by Plexxikon in the early 2000s, this BRAF inhibitor showed exceptional efficacy against metastatic melanoma in patients with the V600E mutation. However, PLX4032 faced significant drug delivery challenges due to its poor aqueous solubility, insolubility in volatile organic solvents, high melting point, and high dose requirements. Initially, Plexxikon used a metastable polymorph of PLX4032 in a capsule for Phase I trials, but this formulation resulted in low blood levels and eventually failed as the metastable polymorph converted to a stable polymorph, drastically reducing solubility.

Roche then licensed PLX4032 and developed the micro-precipitated bulk powder (MBP) process to produce an amorphous solid dispersion (ASD) of PLX4032 with HPMCAS, enabling its successful clinical development and commercialization in 2012. Despite its success, the MBP process was inefficient, complex, and involved large amounts of mixed solvent waste, limiting its general applicability.

KinetiSol, though in its infancy during PLX4032’s development, would have been an ideal solution. Research demonstrated that KinetiSol could easily produce the commercial ASD formulation of PLX4032, simplifying the process and reducing waste. An animal pharmacokinetic study showed that the KinetiSol ASD provided 2.5 times the oral exposure of the MBP equivalent.

This case study highlights KinetiSol’s ability to enable the development of undruggable compounds like PLX4032. Unlike the MBP approach, which often fails for many compounds, KinetiSol offers a simple and effective technology for developing highly efficacious drugs with challenging properties. Consequently, these compounds no longer need to be screened out during discovery phases or abandoned in early development.

CP: What is the underlying mechanism of Kinetisol Technology that enables the rapid development of poorly soluble molecules?

Dave: KinetiSol Technology enables the rapid development of poorly soluble molecules through several key mechanisms. First, it can be applied to any compound regardless of its physicochemical properties, allowing for the production of amorphous solid dispersion (ASD) formulations with a wide range of polymer chemistries. This versatility ensures that KinetiSol can provide solutions for compounds traditionally considered undruggable.

The technology facilitates rapid prototype preparation, with the capability to produce over 20 unique formulations per day. This rapid development process allows for exhaustive mapping of the formulation space, ensuring the optimal formulation for each compound is quickly identified. Additionally, KinetiSol supports small batch sizes as low as 7 grams, making this extensive formulation mapping possible on an API-sparing basis.

One of the significant advantages of KinetiSol is its unlimited formulation design space. There is no need for prior determination of a polymer’s suitability with a given molecule; the process is empirically driven. This approach eliminates the need to spend excessive time on theoretical compatibility considerations, thereby speeding up development time. However, in-silico tools are utilized when necessary to conserve API, especially when limited quantities are available.

KinetiSol Technology produces particles with good flow and compressibility, making the conversion to final dosage forms, such as tablets or capsules, straightforward. AustinPx, the company behind KinetiSol, has established a fixed evaluation protocol that includes initial chemical and solid-state analysis, in-vitro performance testing through biorelevant dissolution and transmembrane flux tests, prototype dosage form development, rapid animal pharmacokinetic (PK) evaluation, and accelerated stability testing.

Within weeks, the KinetiSol development platform enables the identification of one or more clinic-ready prototypes, supported by a comprehensive data package. This package includes detailed chemical and physical characterization, in-vitro and in-vivo performance under various conditions, accelerated stability, and manufacturability of the dosage form. This robust data package provides clients with the confidence needed for drug product nomination for clinical development. Additionally, the scalability of KinetiSol assures clients of its capability to deliver drug products for all clinical stages and commercialization.

Inside AustinPx’s production space.

CP: What are the common challenges faced in the development of poorly soluble molecules, and how does Kinetisol address these challenges?

Dave: One significant issue is that highly insoluble and/or unstable compounds often require complex amorphous solid dispersion (ASD) formulations to resolve multiple issues simultaneously. Traditional methods like spray drying and hot-melt extrusion (HME) are limited by their formulation design spaces, often restricted to binary systems due to organic solvent solubility requirements or thermal constraints. In contrast, KinetiSol offers an unlimited formulation design space, enabling the creation of advanced ASD formulations that tackle bioavailability, stability, and manufacturability challenges. These tailored formulations not only solve drug-specific problems but also create new intellectual property opportunities, which are not possible with simpler formulations from spray drying and HME.

Organic solubility requirements pose another significant challenge, often precluding the use of spray drying or rendering it inefficient for manufacturing processes beyond Phase II. This limitation restricts the formulation design space to polymers soluble in the chosen solvent, often leading to suboptimal drug products. As a non-solvent process, KinetiSol is not constrained by the compound’s solubility profile, allowing it to extend ASD development to organic-insoluble compounds, expand the formulation space to achieve optimal products, and provide efficient manufacturing processes at all scales.

Additionally, contemporary molecules often have higher melting points and increased structural complexity, making them more thermolabile and unsuitable for HME, which can cause drug degradation. HME’s formulation design space is limited to polymers with suitable viscosity and thermal stability, further restricting its application. KinetiSol, on the other hand, requires minimal heat exposure, drastically reducing thermal stress by lowering both processing temperatures and time. This makes KinetiSol suitable for compounds with high melting temperatures and thermal instability, offering a much larger formulation design space to create optimal drug products.

Scaling up the production from initial human studies to Phase 3 and commercial quantities poses another challenge for both HME and spray drying, often requiring substantial technical effort and adjustments that can introduce development risks and potential delays. KinetiSol, however, operates with a single manufacturing scale capable of producing small batches for first-in-human studies or large quantities for Phase 3 clinical trials and commercial supply. The only variable that changes is the processing time. A small clinical batch might take only an hour, while commercial quantities can be produced continuously over days or weeks. This consistency in equipment and scale ensures that key quality attributes are preserved, guaranteeing consistent downstream processing and product performance at all stages of development.

CP: How can Kinetisol Technology be integrated into existing pharmaceutical development workflows? What kind of infrastructure or modifications are required?

Dave: Integrating KinetiSol Technology into existing pharmaceutical development workflows can significantly enhance the drug development process for poorly soluble molecules. The optimal time to evaluate KinetiSol is early in the drug discovery process, before candidate nomination. This early evaluation ensures that promising molecules are not screened out due to solubility issues that KinetiSol can address. By incorporating KinetiSol at this stage, companies can develop molecules that most effectively bind to their targets without compromising for drugability, thus maximizing the potential of their drug candidates.

At the latest, KinetiSol should be investigated alongside other solubility-enhancing approaches such as particle size reduction, lipid formulations, spray-dried dispersions, and hot melt extrusion during preclinical formulation development. This comparative evaluation allows formulators to produce a comprehensive data package, enabling their organization to select the best process for the compound. KinetiSol operates on a similar scale to benchtop spray dryers and melt extruders, requiring less API per batch, but offering a wider range of formulation options. Consequently, more compound might be needed to explore a variety of possibilities.

While we recommend early evaluation, we recognize that established workflows often begin with spray drying. Companies frequently advance suboptimal spray-dried formulations or processes to expedite safety and efficacy studies, knowing that if the molecule progresses beyond Phase II, an alternative technology will be needed. AustinPx routinely assists clients at this stage, utilizing KinetiSol to improve manufacturing efficiency or reformulate for optimal product performance, stability, and efficiency.

There are two primary options for integrating KinetiSol into pharmaceutical development workflows. The first option is to lease a research-scale KinetiSol system, allowing in-house scientists to evaluate the technology directly. No significant infrastructure changes are needed for this; the research-scale KinetiSol has a small footprint and requires only standard utilities, making it easy to fit into a standard formulations research lab. The equipment is intuitive to operate, providing a flexible alternative for formulators to investigate alongside other approaches. KinetiSol prototypes can be seamlessly integrated into existing analytical workflows, enabling head-to-head comparisons and data-driven technology selection decisions.

The second option is to partner with AustinPx for KinetiSol screening. Companies need only provide sufficient API for AustinPx to conduct the screening. AustinPx can execute the full package of analytical testing or supply lead KinetiSol formulations for the client’s in-house evaluation. Once a formulation is developed and GMP drug product is needed, AustinPx offers full support through Phase II. For Phase III, registration, and commercial manufacturing, clients can either contract with one of AustinPx’s CMO partners or install KinetiSol manufacturing equipment in their own facilities.

CP: What are the future prospects for Kinetisol Technology in the pharmaceutical industry? Are there any upcoming advancements or expansions of this technology that you can share with us?

Dave: One of the key areas where KinetiSol is set to make a significant impact is in sustainable manufacturing, particularly in the era of green chemistry. As the industry increasingly prioritizes environmentally friendly practices, KinetiSol’s ability to produce anything that can be made by spray drying, but with a much smaller environmental footprint, positions it as a sustainable alternative. Major pharmaceutical companies looking to reduce their environmental impact will likely turn to KinetiSol to meet their sustainability goals.

KinetiSol is poised to supplant spray drying as the preferred technology for amorphous solid dispersions (ASDs). By disseminating KinetiSol research and manufacturing machines, and removing barriers to adoption, the industry will recognize KinetiSol’s superiority. This technology not only streamlines ASD development but also generates complex, optimized formulations and strong intellectual property.

Empowering medicinal chemists is another future prospect of KinetiSol. By allowing them to nominate their best compounds without compromising activity and specificity for “drug-like” properties, KinetiSol provides a pathway for new therapies with breakthrough molecules. These molecules would have otherwise been lost due to antiquated molecular property filters.

KinetiSol is also expected to become the industry’s technology of choice for ASDs following the approval of new products and the widespread dissemination of the technology. Once KinetiSol catches up with spray drying and hot-melt extrusion (HME) in terms of industry acceptance and utilization, there will no longer be a viable argument for using other technologies over KinetiSol.

Advancements in the technology itself are also on the way. Our technology team is innovating toward reducing API consumption, which will allow KinetiSol to be applied earlier in the drug design process when active pharmaceutical ingredient (API) amounts are limited. This will enable the application of ASDs in the early candidate screening phases, essential for nominating the best molecule rather than just the best “druggable” molecule.

We are continually developing advancements in spectroscopic tools for next-generation process analytical technology and process controls. These advanced spectroscopic tools will enhance process robustness and product quality, ensuring superiority over other technologies.

In summary, the future of the KinetiSol Technology in the pharmaceutical industry looks bright, with its potential for sustainable manufacturing, industry-wide adoption, empowerment of medicinal chemists, and ongoing technological advancements positioning it as a leading solution for the development of poorly soluble molecules.

Learn more at www.austinpx.com