Selecting the right oral dosage form for a first-in-human (FIH) clinical trial is an important strategic decision that needs to balance patient safety, development speed, cost, and the physicochemical properties of the drug substance. At this early stage, the primary goals are safety, tolerability, pharmacokinetics (PK), and sometimes early pharmacodynamics (PD) and not commercial elegance.
I have put together some thoughts regarding this to guide formulation teams through this critical decision.
Start with the Drug Substance: Know Your Molecule
The properties of the drug substance heavily influence dosage form selection. The most important parameters include solubility, stability, bioavailability and permeability. If the solubility of the drug substance is high a simple oral solution can be used as drug product, or drug substance as is in capsules or dispensed in bottles. Low solubility drug substances may require particle size reduction to decrease the dissolution time or the use of amorphous solid dispersions to achieve the same or lipid-based formulations or excipients to increase the solubility of the drug substance can be used.
For FIH studies, the simplest workable approach is preferred. A key question to consider is: Can you reach projected clinical exposure levels with a simple formulation?
If adequate exposure can be achieved with a basic capsule formulation, complex solubility enhancement strategies may be deferred.
A sufficient shelf-life of the drug product is needed to perform the clinical study; hence the stability of the drug product is crucial. Is the drug substance sensitive to moisture, heat, light or oxidation? Are there different solid-state forms of drug substances? Is the drug substance hygroscopic?
If the drug substance is unstable in aqueous environments, oral solutions may not be feasible. If it is sensitive to humidity, a dry-filled capsule may be preferred over a tablet requiring wet granulation. For FIH short shelf-life (e.g., 6–12 months) may be acceptable and, protective packaging (blister packs, desiccants) can compensate for marginal stability.
What Do We Know About Bioavailability and Permeability?
If permeability is high but solubility is low (typical Biopharmaceutics Classification System Class II profile), dissolution rate becomes the limiting step. For early phase studies, simple approaches like micronized drug substance in capsules may suffice if dose levels are low.
If the projected clinical dose is high and solubility is low, more advanced enabling formulations may be required even at FIH stage.
Make sure to set your dose escalation strategy for the FIH study early. FIH often involves single ascending dose (SAD) and multiple ascending dose (MAD) and important considerations with respect to dosage form are maximum projected dose, flexibility in dose escalation and ability to adjust dose quickly. Capsules offer flexibility by giving the possibility to have multiple capsule strengths, capsule count adjustments and blending drug substance with filler. Oral solutions offer even greater flexibility, especially for microdosing and very low starting doses but require proven stability in solution and taste masking handling.
Solutions, Suspensions, or Powder-in-Bottle
Common oral dosage forms for FIH are oral solutions or suspensions. The advantages include flexible dosing, rapid development, no compression or granulation needed and usefulness for low doses. They have challenges as well such as stability concerns, microbial control and taste issues. Oral solutions and suspensions are best suited when the drug substance is stable in solution, rapid development is critical and dosing flexibility is essential. Stability issues, though, might be handled by using powder-in-bottle to be dissolved or resuspended prior to use.
Powder-in-Capsules
Powder-in-Capsule (PIC) is the most common FIH dosage form. It offers advantages such as being fast to develop and minimal formulation work needed at a very low cost. The formulations very often have good stability, being a dry system and give rise to easy dose adjustment. Some challenges do still exist with respect to content uniformity at low doses, due to poor flow properties of the drug substance and can be limited to moderate doses unless capsule size increases. PIC is ideal when the drug substance has acceptable flow, solubility is sufficient for expected dose and development speed is a priority.
Simple Tablets
Simple tablets offer advantages such as being a more elegant presentation, giving better scalability and potentially improved content uniformity. They present challenges regarding increased development time and use more drug substance compared to for instance PIC; compression studies required and include a risk of polymorphic or stability changes during processing. Simple tablets are typically used when development timeline allows, the commercial pathway is clearer and the dose is fixed and unlikely to change significantly, though that is seldom the case.
Balancing Time and Cost
In early development, time is often more critical than formulation perfection. Some key time drivers are preformulation and excipient studies, analytical method development, stability studies and manufacturing scale-up. For FIH choose the simplest formulation that delivers safe and measurable systemic exposure. Avoid investing in complex technologies unless absolutely required to achieve target PK.
Risk-Based Decision Making
A practical decision table for a FIH can be:
| Situation |
Way forward |
| Is the dose low (<100 mg) and solubility adequate? |
Use powder-in-capsule |
| Is flexible dosing and wide dose ranges required? |
Consider oral solution |
| Is solubility limiting exposure at projected doses? |
Evaluate simple solubility enhancement first (micronization). |
| Is the drug substance unstable in aqueous systems? |
Avoid oral solutions |
| Is development timeline aggressive? |
Prioritize simplest dry formulation |
| Is the amount of available drug substance limited? |
Consider powder-in-capsules or powder-in-bottle |
Regulatory and Clinical Considerations
Regulators understand that FIH formulations are not commercial products. However, excipient safety must be justified, impurity profiles must be controlled, and stability data must support clinical use period. Significant formulation changes between FIH and later phases can complicate PK bridging studies. Therefore, even for FIH, choose a formulation that can evolve, not one that must later be abandoned.
A Strategic Perspective
What can then be concluded for an ideal FIH formulation? It should be safe, and simple. It should be stable enough to support a shelf-life for the whole clinical study duration. The formulation should allow dose flexibility, require minimal manufacturing complexity and deliver adequate systemic exposure. In early clinical development, perfection is not the objective, learning is.
To conclude choosing the appropriate oral dosage form for a FIH trial is a careful balance between drug substance characteristics (solubility, stability, bioavailability), clinical dosing strategy, development timeline, cost constraints and future development pathway.
The winning strategy is often not the most technologically advanced option, but the most efficient and scientifically justified one.
In early-phase development, simplicity accelerates progress, reduces risk, and enables faster decision-making, which is exactly what a FIH study is designed to achieve.
Bengt Hedin
Principal Consultant Pharmaceutical Development
LINK Medical
