Poor solubility often creates a difficult development decision: should a program invest early in an enabling formulation technology, or is a simpler approach sufficient to achieve the required clinical performance?
The answer is not determined by solubility alone. A poorly soluble drug requires only enough formulation complexity to achieve the target human exposure while remaining viable through later development and commercial manufacture. Early physicochemical characterization, biopharmaceutic assessment and predictive modelling can narrow the credible formulation options. When clinically meaningful uncertainty remains, comparative human pharmacokinetic (PK) data provide the strongest basis for deciding whether additional complexity is justified.
Several formulation approaches may appear technically viable during early development. Committing too early to an enabling technology can increase active pharmaceutical ingredient (API) consumption and introduce processing, manufacturing or stability requirements that later prove unnecessary. Waiting until inadequate exposure is observed in the clinic creates a different risk, potentially requiring reformulation, additional manufacturing and clinical bridging studies.
The challenge is determining when sufficient evidence exists to make the right decision.
What can be decided before human data are available?
Physicochemical and biopharmaceutic characterization can help identify what is likely to constrain exposure and narrow the formulation routes worth investigating. The Developability Classification System and physiologically based PK modelling can further focus that assessment by helping distinguish likely absorption limitations and explore how formulation changes may affect exposure.
Those findings need to be considered alongside the product requirements, including:
- Target dose and exposure
- API availability
- Potency and containment needs
- Intended dosage form
- Expected manufacturing scale and cost of goods
Importantly, poor oral performance can arise from different underlying mechanisms. Dissolution rate, achievable solubilized concentration, permeability and dose requirements may each contribute to exposure limitations. Understanding which factor is dominant helps determine whether a simple formulation strategy is likely to succeed or whether an enabling technology should be evaluated.
Together, these inputs help rule out unsuitable routes and focus development effort. In some programs, they may strongly differentiate between formulation options. However, where clinically meaningful uncertainty remains, comparative human PK data provide the most direct basis for selecting the formulation to progress.
How can human PK determine whether complexity is justified?
Human PK data help determine whether additional formulation complexity delivers a clinically meaningful benefit. That benefit may include achieving target exposure, reducing variability, mitigating food effects, supporting a practical dose level or enabling progression into a patient-ready dosage form. The objective is not to maximize formulation sophistication, but to identify the simplest approach capable of meeting the program's clinical and development requirements.
In one client program (TQS-168), human data was used to progress an enabling formulation. Preclinical studies indicated solubility-limited absorption, and crystalline API in a methylcellulose suspension was compared during first-in-human development with spray-dried dispersion (SDD) and hot-melt extrusion (HME) formulations.
Here, the SDD produced four-fold higher exposure than the methylcellulose suspension, providing the evidence needed to justify that the additional formulation complexity delivered a meaningful clinical benefit and justified further development of the enabling technology.
In a different program (BOS172767), a simpler route was shown to provide the most appropriate development solution.
Following observations of poor oral bioavailability and a substantial food effect during Phase I development, a micronized capsule, a self-emulsifying lipid-based capsule and an SDD tablet were evaluated. Although the SDD improved exposure, human PK data showed that the micronized formulation could achieve the required exposure profile while maintaining advantages in development and future manufacturing. The program progressed using the micronized formulation, moving from formulation initiation to clinical PK data generation within six months.
Together, these programs demonstrate the same decision principle leading to different technical outcomes. Human exposure justified an enabling formulation for TQS-168, whereas BOS172767 showed that a simpler formulation was sufficient.
Formulation complexity should therefore be driven by clinical evidence rather than assumed from the molecule’s solubility profile.
Why does preserving formulation optionality matter?
If human PK is needed to distinguish between credible routes, the development program needs to retain the flexibility to act on those data. API-sparing, fit-for-phase development can allow selected formulations to reach clinical evaluation without producing multiple full-scale batches in advance, limiting premature investment while the formulation decision remains open.
In practice, this means advancing a focused set of scientifically credible formulation options while avoiding premature investment in large-scale manufacturing activities before human data are available.
The optimal formulation is not necessarily the most sophisticated one. It is the simplest formulation capable of achieving the required clinical performance while remaining viable throughout development and future manufacture.
Early physicochemical characterization, biopharmaceutic assessment and predictive modelling can narrow the credible formulation options. When uncertainty remains, comparative human PK data provide the evidence needed to determine whether additional formulation complexity delivers meaningful value.
Programs that preserve formulation optionality until those data are available are better positioned to make evidence-based decisions, avoid unnecessary development risk and progress the most appropriate formulation strategy with confidence.