At AAPS PharmSci 360, Solutions for Challenges in Amorphous Solid Dispersion Development

At AAPS PharmSci 360 2025, held from Nov. 9–12 in San Antonio, Texas, Corey Bloom, PhD, associate director, CMC (chemistry, manufacturing, and controls) and Bioavailability Enhancement at Lonza, gave a presentation titled “Amorphous Solid Dispersion Development for Straightforward to Challenging Compounds.”

Here, Bloom answers some questions about key points in his talk at the conference.

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How important is selecting the appropriate drug delivery technology to address low solubility compounds?

Today, compounds with low solubility or low bioavailability are becoming the rule rather than the norm, as around 90% of preclinical compounds are now estimated to have bioavailability challenges. This is the result of more new chemical entities with complex needs entering drug development pipelines.

Low solubility during the earliest stages of drug development creates significant challenges for small and emerging biopharma companies. Therefore, it is crucial to choose the right formulation and process strategy early on to maximize a compound’s chances of progressing through clinical trials and achieving commercial manufacturing success. An optimized formulation and process can streamline development, while a less effective approach may lead to longer, more complex development timelines or even unnecessary failures.

What approaches to formulation and process development do you recommend?

Careful selection of the right technology to enhance bioavailability is essential in development programs from initial preclinical phases to commercialization. A science-based technology selection process is presented, based on a series of inputs including the target product profile, drug properties, extensive past project experiences, technology maps, and absorption modeling.

To start, we leverage in-silico tools to predict how certain compound properties are expected to impact performance and thus provide measurements of key drug physicochemical properties to guide technology selection. We then review the target product profile to define the goals, including dose, pharmacokinetic profile, and image.

We then use biomodeling tools to help define the problem statement and evaluate solubility, dissolution rate, and permeability. One approach is leveraging physiologically based pharmacokinetic models to evaluate hypotheses about barriers to absorption, whether that is dissolution rate, solubility, and/or permeability. A formulator can use absorption modeling to understand existing in-vivo data for a formulation of interest or establish a framework for predicting in-vivo performance with existing in-vitro data. These models may also be useful for predicting specific formulation attributes from enabled formulations (e.g., amorphous solid dispersions, lipid-based formulations) such as how specific drug species may contribute to absorption.

Through these processes, we can collaborate with drug developers to select the most appropriate high level formulations approach and optimize the formulation through in-vitro testing and in-vivo confirmation.

Why do amorphous solid dispersions have such a breadth of applicability?

Amorphous solid dispersions (ASDs) can provide optimal performance and stability for compounds with a fairly wide range of properties, including lipophilicity, melting point, and pKa. By liberating the API from a crystalline lattice and including concentration enhancing excipients, ASDs can increase drug solubility up to 10-fold relative to crystalline API. These improvements facilitate dissolution in gastrointestinal (GI) fluids and optimize the quantity of drug that enters the bloodstream. This boost in oral bioavailability holds the potential to enhance patient outcomes by reducing variations in plasma exposure, lowering required dosages, and mitigating the impact of food intake and GI system conditions in specific patient populations.

Enhancing bioavailability through ASDs can be achieved through hot-melt extrusion (HME) or spray drying. The drug product's API properties and stage of development are important factors to consider when deciding which technique to use. HME offers the advantages of mature process understanding, a small process footprint, continuous operation, and ready scalability. These attributes can enhance the flexibility of the unit operation, resulting in relatively lower manufacturing costs and a more appealing commercial process train. HME is also a solvent-free unit operation that can eliminate concerns about solvent impurities while enabling sustainability.

Another technique is spray-drying dispersions. This method is suitable for a wider range of APIs and dispersion polymers because the API and excipients are dissolved in a volatile organic solvent. Additionally, spray drying does not require melting of the API to expose the API to excessive heat during the production of the amorphous dispersion. It can also be scaled down, allowing formulation screening with smaller amounts of API.

For challenging compounds, what are some best practices for spray dried dispersion processes?

Challenging compounds have low solubility in preferred volatile solvents, and/or propensity to crystallize during manufacture. For these compounds, it is essential to develop a preclinical to late-stage and commercial production roadmap to improve bioavailability. This includes starting with a target product profile before developing formulations in a phase appropriate approach to match the development phase of the drug candidate. Drug manufacturers can leverage a full range of spray dryers, based on the required scale and process needs, to support feasibility assessments through clinical studies and commercialization.

There are also several factors to consider throughout the process. Specialized process improvements including temperature shift or processing aids can enable manufacture of difficult compounds. Further, the science of scale to evaluate key process variables early in development and translate them into full scale development can help save time, money, and use of APIs from more trial-and-error approaches.

How can these methods help save both time and materials?

During the initial stages of drug development, the primary focus is on achieving optimal performance and moving the drug into clinical trials as quickly as possible. As the drug advances through clinical trials and approaches commercialization, considerations such as cost, production efficiency, and sustainability become increasingly important.

Partnering with a contract development and manufacturing organization that offers a range of formulation techniques and extensive experience with scale up and potential technical and logistical pitfalls is crucial for selecting the best development strategy. This collaboration helps ensure that an effective and stable formulation is established early, reducing the risk of costly delays and the need for reformulation later in the clinical pipeline.