In a recent Contract Pharma webinar, Douglas CDMO experts Dr Peter Surman, Chief Scientific Officer, Dr Brett Wagner, R&D Evaluation Manager, and Chris Cuthbertson, Program Manager for Pharma Development, discussed how dosage form selection can influence how well a drug is absorbed, how consistent that absorption is across patients, and how manageable dosing is for patients in everyday use.
A substantial proportion of approved medicines are poorly soluble, and this challenge is even more pronounced in development pipelines, where close to 90 percent of molecules have difficulty dissolving in water [1]. Poor solubility is often accompanied by additional barriers, including limited permeability, which together make reliable oral absorption difficult to achieve.
Unlike intravenous administration, where full drug exposure can be achieved, oral dosing will always involve losing a fraction of the drug before it gets to where it needs to be. For formulation teams, the challenge is finding the right balance: ensuring enough of the drug is absorbed to be effective, while avoiding unnecessarily high doses that can increase variability or the risk of side effects.
For molecules affected by poor solubility or limited permeability, softgel formulations were highlighted as a well‑established option that can be considered early in development to help address these challenges and support more consistent oral delivery.
Understanding the bioavailability challenge
At its core, bioavailability is about getting enough of the drug absorbed to be effective. With oral dosing, that means understanding where the drug dissolves, how well it is absorbed, the release properties of the formulation, and modifying the formulation accordingly so that it can produce its therapeutic effect.
Poor aqueous solubility remains the most common barrier. Even when dissolution can be achieved, low permeability across biological membranes may limit absorption. First‑pass metabolism further reduces the amount of active drug available, while issues such as polymorphism and chemical instability can introduce variability and risk.
These challenges show up very clearly in practice. Poor solubility and limited permeability often mean higher doses are needed, greater variability in how patients absorb the drug, and an increased risk of side effects.
In turn, this can lead to higher R&D costs, clinical failures, particularly in Phase I and Phase II, and reduced patient compliance because of the high dosing requirements. This can ultimately translate into lost market potential. When these risks are not addressed early, they can limit dosing flexibility, complicate labelling and weaken clinical data packages.
Biopharmaceutics considerations
These issues are well captured by the Biopharmaceutics Classification System (BCS), which categorises compounds based on their solubility and permeability.
Most small‑molecule drugs in development fall into Biopharmaceutics Classification System (BCS) Classes II, III, or IV, meaning they exhibit low solubility, low permeability, or both. These characteristics contribute to slow or incomplete absorption, pronounced food effects, and marked inter‑patient variability.
For compounds in BCS Class II, the dissolution rate is a key determinant of how much drug is ultimately absorbed. As Dr Peter Surman explains, “the dissolution rate, the rate at which the active dissolves, determines the rate at which the drug is absorbed.” Improving or maximising solubility is therefore central to formulation strategy, and this is an area where softgel systems are particularly effective.
For Class III and Class IV compounds, the challenge shifts towards permeability and overall absorption. Molecules such as the antiviral acyclovir can benefit from formulations that promote emulsification in the gastrointestinal tract. In these cases, lipid-based fill systems and self-emulsifying drug delivery systems can play an important role by helping the drug disperse more effectively and improving its ability to cross the gut wall.
This approach is especially important for more challenging compounds such as lopinavir, where both solubility and absorption must be optimised. These drugs are best formulated so that, once in the stomach, they disperse into very fine droplets, each carrying the active ingredient in a dissolved or near-dissolved state. A combination of lipid carriers and emulsifiers supports this process, helping to enhance permeability and maximise the amount of drug that reaches systemic circulation. As noted by Peter, therapeutic effect ultimately depends on “getting the drug into the bloodstream and then into the tissues” where it is needed.
These considerations highlight a broader issue in drug development. Promising molecules may demonstrate strong in vitro performance or even best-in-class properties yet still fall short if the formulation is not addressed early and effectively. Without the right delivery strategy, there is a risk of missed opportunities, where otherwise valuable compounds fail to realise their full clinical and commercial potential.
Softgels as a formulation strategy
For poorly soluble compounds, particularly BCS Class II molecules, softgels can improve bioavailability by delivering the active ingredient in a dissolved or dispersed state, reducing reliance on in vivo dissolution.
Softgels can also accommodate lipid-based and self-emulsifying systems that disperse into fine droplets in the gastrointestinal tract. This can support more consistent absorption for compounds where conventional formulations may struggle to achieve reliable exposure.
Stability and usability
Oil‑based softgel fills can provide a controlled environment that supports both stability and poorly soluble compounds. By embedding the active ingredient in a lipid matrix, these formulations can help protect compounds that are sensitive to oxygen, moisture, and light. The gelatin capsule shell provides an additional barrier, contributing to longer and more predictable shelf life for chemically unstable molecules.
Formulation decisions can also influence how a medicine is used in practice. As Peter highlighted, isotretinoin is a clear example. Peter explained that early formulations of the drug showed a significant food effect, requiring patients to take doses with meals to achieve adequate absorption. Later formulations reduced this dependence by improving how the active ingredient was solubilised and dispersed within the dosage form. This change allowed the drug to be taken with or without food, simplifying dosing instructions and providing greater flexibility at the labelling stage. Addressing the food effect through formulation design delivered clear benefits, improving not only usability but also the commercial performance of the product.
A broader perspective on formulation decisions
As development pipelines continue to shift towards increasingly complex molecules, formulation strategy is becoming a more important determinant of clinical success. Assessing factors such as solubility, permeability, stability, and food effects early in development can help teams identify potential risks before they become barriers to progress.
Softgels are one of several formulation approaches available, but their flexibility makes them a valuable option for many challenging oral compounds. Evaluating dosage form strategy early can help ensure promising molecules are not limited by their delivery system.
[1] Loftsson, T., & Brewster, M. E. Pharmaceutical applications of cyclodextrins: Basic science and product development. Journal of Pharmacy and Pharmacology, 62(11), 1607–1621. Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland; and Chemical and Pharmaceutical Development, Janssen Pharmaceutica, Beerse, Belgium.
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