Oral drug product (DP) development plays a vital role in the success of small-molecule drug candidates throughout clinical development – from First-in-Human (FIH) studies to late-phase trials and commercialization. A well-designed formulation enables the delivery of the right dose, in the right form, with the right performance, while maintaining safety, quality, and patient compliance.
Formulation strategies can evolve across clinical phases, with each stage presenting unique challenges. Early in development, the focus is often on speed and efficiency. Fit-for-purpose approaches such as extemporaneous preparations or API-in-capsule (PIC) formulations are commonly used to quickly generate clinical trial material (CTM) with minimal API consumption, limited development and stability requirements, and fast timelines. However, it’s important to evaluate the feasibility of these approaches considering API properties and overall clinical study strategy.
As programs progress into Phase 2 and beyond, the formulation must be more robust, scalable, and representative of the eventual commercial product. More complex forms like blend-in-capsule and tablet formulations are often introduced. These allow for improved handling of APIs with poor flow or low bulk density, offer better dose flexibility, and support scale-up for larger trials. Development of more conventional dosage forms such as blend-in-capsule or tablet right from the early phases might be more suitable in some cases.
Tablet formulations are widely preferred for mid-to-late-stage development and commercial use due to their manufacturability, dose accuracy, and patient convenience. Tablets also allow for advanced features such as modified-release profiles or fixed-dose combinations. However, development and production are more resource-intensive, requiring detailed process optimization, analytical method validation, and extensive stability data.
For poorly soluble or poorly bioavailable compounds, solubility-enhancing techniques such as micronization, salt or cocrystal formation, pH adjustment, etc. can be employed. For some APIs, enabled formulation technologies might be essential. These include amorphous solid dispersions (e.g., spray-dried dispersions or hot-melt extrusion), nanosuspensions, and lipid-based systems. These technologies enhance solubility and systemic absorption, often making the difference between clinical failure and success.
In select cases such as pediatric or geriatric populations alternate dosage forms like suspensions, orally disintegrating tablets (ODTs), or buccal/sublingual tablets may be necessary to improve patient acceptability.
Beyond dosage form, several critical factors influence formulation strategy:
- Batch size and manufacturing process must align with clinical supply needs, API availability, and production scalability. The process should ideally be adaptable across phases to support rapid progression.
- Analytical testing and quality control must ensure product integrity at all times. In early phases, simplified, phase-appropriate validation may suffice. However, as development continues, more rigorous testing and documentation are required.
- Stability studies underpin shelf-life claims and support trial logistics. Bracketing approaches can reduce workload when testing multiple strengths.
- Bridging studies are often required when changes occur in formulation, process, or API attributes. Techniques like dissolution profiling, PBBM, and relative bioavailability studies help demonstrate comparability across versions.
Ultimately, successful oral formulation development demands a balanced, phase-appropriate strategy blending speed, cost-efficiency, quality, and scalability. A thoughtful approach across the development continuum can de-risk the program and improve the chances of regulatory and commercial success.
How Syner-G Supports Oral Drug Product Development
At Syner-G, we partner with clients across all stages of small-molecule oral drug product development, from early feasibility assessments to late-phase formulation optimization and commercialization. Our team provides end-to-end expertise in preformulation, formulation development, GMP manufacturing, analytical method development, stability testing, and advanced enabling technologies such as amorphous solid dispersions, nanosuspensions, and lipid-based delivery systems. By integrating technical rigor with phase-appropriate strategies, we help sponsors de-risk development programs, accelerate timelines, and ensure regulatory compliance while maintaining a strong focus on patient-centric design.
