The development of oral solid dosage (OSD) forms for drugs with poor water solubility continues to present formulation scientists with a complex challenge. As the pharmaceutical pipeline shifts increasingly toward low-solubility, low-permeability compounds — especially in therapeutic areas such as oncology and antivirals — the need for practical, phase-appropriate, and scalable bioavailability enhancement strategies becomes even more critical.
Starting with the API
Formulation begins with understanding the physicochemical properties of the active pharmaceutical ingredient (API), particularly LogP, pKa, solubility and permeability. These characteristics are often categorized using the Biopharmaceutics Classification System (BCS) and also developability classification system (DCS).
Class II drugs, which are poorly soluble but highly permeable, are frequently addressed using relatively straightforward strategies such as surfactant addition, microenvironmental pH adjustments, appropriate salt selection, particle size reduction or the creation of solid dispersions. These dispersions may be prepared using techniques like spray drying, hot-melt extrusion and nowadays by novel techniques systems like AustinPx’s KinetiSol technology. Complexation with excipients such as cyclodextrins is another common approach to improving the solubility of these compounds.
BCS Class III and IV drugs — those with poor permeability, with or without poor solubility — require more sophisticated formulation strategies. In these cases, lipid-based delivery systems or the use of permeation enhancers can aid in transporting the drug across the gastrointestinal epithelium and into systemic circulation. These formulations often involve the creation of emulsions or micellar systems that facilitate absorption by mimicking or integrating with endogenous lipid pathways. While these approaches are more resource-intensive and require specialized equipment, they may be essential for achieving therapeutic drug levels in vivo.
Different Approaches to Formulation
Despite the availability of complex formulation technologies, some developers, once a preliminary understanding on the risk of bioavailability is understood, begin with simpler approaches. These may include direct capsule-filling of the API, drug-in-bottle formats for reconstitution at the clinical site, or basic solid dispersions using minimal excipient systems. The decision to begin with a less complex formulation is often driven by the need for speed in early development phases, particularly phase I. The goal in these cases is often to achieve a minimum viable formulation that allows for safety and pharmacokinetic evaluation without delaying entry into clinical testing.
However, this approach must be weighed against the risk of inadequate bioavailability. When an API’s poor solubility or permeability significantly limits its exposure in the body, even a phase I formulation may need to employ more advanced techniques to generate meaningful data. The need to later bridge a phase I formulation to a new version in phase II or III adds both cost and complexity, particularly if the formulation strategy changes significantly.
Some developers therefore choose to build a more robust formulation from the outset, especially when the API is known to present biopharmaceutical challenges. This decision often depends on a combination of scientific, strategic, and financial factors, including a company’s risk tolerance, target timelines and intended clinical development path.
In some cases, even simple modifications to a formulation can significantly improve bioavailability. For example, choosing the right salt at the time of salt selection can enhance the solubility of the drug at desired pH. Similarly, spray-coating an API onto an excipient surface can improve dissolution and, if amorphization occurs during processing, potentially improve bioavailability — provided the amorphous form is stable over the intended shelf life.
As the pharmaceutical industry increasingly targets difficult-to-formulate APIs — particularly in the oncology space — many molecules fall into the BCS Class III/IV category. While this does not correlate strictly with therapeutic class, the trend is evident across numerous investigational compounds. Developers are pursuing enabling technologies more frequently, but still often prefer to minimize formulation complexity until later phases of development. This is especially true when companies hope to rapidly generate early clinical data for licensing or investment purposes.
Evolving Strategies
Formulation strategies often evolve over time as part of a broader life cycle management plan. An initial formulation may be optimized post-approval to enhance performance, reduce dosage, or improve patient adherence. One example involves a marketed fenofibrate product that was later reformulated using particle size reduction to improve solubility and reduce the required dose. In this way, incremental improvements in formulation can offer commercial and therapeutic advantages.
Process development and scale-up also shape formulation choices. Technologies like spray drying, while effective, may not be supported at commercial scale within every manufacturing facility. As a result, even when enabling technologies are used during early development, the product may later be transferred to a different manufacturer or brought in-house for commercial production. These decisions are often influenced by capacity, cost, and intellectual property considerations, as well as corporate strategy.
Technological tools that support process understanding and control are increasingly integrated into formulation development. Spectroscopic methods such as near-infrared (NIR) spectroscopy can be used to monitor blend uniformity and content uniformity in real time, facilitating real-time release testing. These tools reduce the reliance on post-process sampling and provide a more comprehensive view of product quality. Additional technologies, such as laser-based particle size measurements and terahertz coating analysis for coating thickness determination, are also being explored to enhance control over critical quality attributes during manufacturing.
Addressing Regulatory and Patient Demands
Formulators must also address evolving regulatory expectations, such as those surrounding nitrosamine impurities. For APIs containing potentially reactive amine groups, detailed risk assessments are conducted during excipient and packaging selection. Excipients with low oxidation potential are preferred, and additional measures — such as the use of antioxidants or oxygen scavengers — may be implemented to mitigate impurity formation.
Manufacturing process controls like providing an inert environment during processing will also help. Packaging materials are selected to avoid those with nitrosamine-generating potential, and purified excipient grades are often used when available. It’s also worth considering detecting any potential nitrosamine precursors in the raw materials and also establish strong supplier qualification process for these raw materials.
Patient-centric considerations are increasingly influencing formulation design. Developers are exploring ways to align drug release profiles with patient needs, often using novel polymer systems to deliver the drug at the most therapeutically relevant time. One example involves the timing of drug release in patients with rheumatoid arthritis, where nighttime dosing is paired with a delayed-release profile that delivers therapeutic levels in the early morning, when symptoms typically worsen.
These chronotherapeutic approaches may involve pH-dependent or enzyme-sensitive polymers that trigger release only when the dosage form reaches a specific part of the gastrointestinal tract. Other design features, such as breakable tablets or dispersible forms, enable flexible dosing and better swallowability in populations like pediatrics and geriatrics. These approaches are particularly valuable in oncology, where narrow therapeutic indices and variable patient weights necessitate individualized dosing with reduced side effects.
For manufacturers, there is a trend towards development formulations which promote patient compliance and acceptability. Examples include formulation which can be taken irrespective of food intake, multi drug combinations and modified release systems (fast acting pain relief systems and long acting for CNS disease conditions.
The Road Ahead
Looking ahead, developers are increasingly investigating new modalities, including peptides and protease inhibitors, as potential candidates for oral delivery. While many of these remain in early development and are commonly administered parenterally, there is growing interest in enabling oral bioavailability for select compounds to make them more patient acceptable. The successful development of such formulations will likely depend on the continued advancement of delivery technologies and a deeper understanding of drug absorption pathways.
In some cases, drugs previously shelved due to unfavorable biopharmaceutical properties are being revisited. Improved formulation technologies are enabling new applications or therapeutic indications for these compounds. For example, molecules originally developed for one indication may find new use in another based on improved pharmacokinetic profiles or emerging clinical needs.
The formulation of oral solid dosage forms remains a highly specialized discipline that requires balancing the needs of the molecule, the patient, the manufacturer, and the market. As molecules become more complex and patient expectations continue to evolve, formulators must adapt their strategies accordingly. With careful planning, phase-appropriate development, and judicious application of enabling technologies, it is possible to overcome many of the challenges associated with poorly soluble or poorly permeable drugs — delivering safe, eff ective, and patient-friendly products to the market.