Persistent challenges in poor solubility and low bioavailability have long impeded the pharmaceutical development pipeline, presenting ongoing hurdles for drug companies. As the industry grapples with increasingly complex new chemical entities, the need for innovative solutions to overcome these challenges becomes more urgent.
To delve into this issue, explore current strategies for advancing poorly soluble drugs through the clinical pipeline, and uncover best practices for formulating drugs with solubility issues, Veranova’s Craig Grant, VP and General Manager, Cambridge spoke with IPI Journal.
Q: It’s estimated that up to 40% of marketed drugs, and between 70 and 90% of drug candidates in the development stage, exhibit poor solubility (1). Could you explain why solubility and bioavailability continue to be such big issues in bio/pharmaceutical drug formulation?
A: In the pharma and biotech industries, the need for effective therapeutics is continually driving the discovery and development of novel active pharmaceutical ingredients (APIs) and new chemical entities (NCEs). This has resulted in the development of increasingly complex drug scaffolds, often with one or more chiral centres and which routinely possess high molecular weight. Though these drugs offer improved stereoselectivity, target specificity and activity, their complexity often causes them to be poorly soluble, which can cause a wide variety of knock-on issues, most notably poor bioavailability with low drug absorption in the body, resulting in such molecules being assigned to BCS Class II (high permeability, low solubility) (2).
Moreover, at the candidate selection stage, developers are more likely to focus on potency or efficacy, meaning the downstream developability of NCEs is often overlooked during early-stage development. This can lead to significant challenges further down the development pipeline, leading to costly delays and resource wastages.
Q: As increasingly complex drug molecules enter the development pipeline, how do you see solubility challenges evolving in the future?
A: With small molecules becoming increasingly more complex, solubility challenges are here to stay. This is even more relevant when considering current pharmaceutical trends, with increased prevalence in existing modalities such as peptides, which, depending on size and/ or complexity, straddle the boundary between small and large molecules. The emergence of new “small molecule” modalities such as PROTACs (PROteolysis TArgeting Chimeras) also brings substantial solubility and developability challenges. PROTACs are a subset of TPD (targeted protein degraders), an emerging therapeutic modality used to treat previously difficult or undruggable targets. Unlike traditional protein inhibition methods, PROTACs are two-pronged molecular entities designed to seek out and degrade disease-causing proteins within the cell. However, due to their size and flexibility, PROTACs typically pose crystallisation and solubility challenges during solid-form studies. PROTACs are just one example of how molecular complexity is likely to continue to present difficulties going forward.
Read the full article in IPI Journal, Spring 2024, Volume 16, Issue 1
