The therapeutic potential of a molecule and its suitability for oral delivery are separate questions. Advances in drug discovery are creating opportunities to address challenging disease targets, but translating those opportunities into viable medicines requires a development strategy that considers formulation early.
Targeted protein degraders, including molecular glues and proteolysis-targeting chimeras (PROTACs), illustrate this challenge. These approaches seek to promote the degradation of disease-associated proteins rather than simply inhibit their activity. However, the molecular properties that enable their biological function can also complicate oral delivery. The strategic priority is therefore not to select an enabling technology immediately, but to establish what limits performance and what the finished product must achieve.
Define the challenge before choosing the technology
Complex oral molecules can present substantial solubility challenges. Larger structures, such as PROTACs, may occupy chemical space beyond conventional small-molecule drug-likeness guidelines. Some compounds also exhibit tightly ordered crystal structures that resist dissolution, limiting the amount of drug available for absorption during gastrointestinal transit.
Importantly, poor aqueous solubility does not automatically identify the appropriate formulation solution. Limited solubility in organic solvents or lipid vehicles can further restrict the available options. Developers need to understand the individual molecule rather than assume that compounds within a therapeutic class will require the same approach.
Early characterization should establish the solubility profile, dissolution behavior, lipophilicity, melting point and relevant solid-state properties, alongside an assessment of permeability. Together, these data help distinguish whether dissolution, solubility or another absorption-related limitation should drive formulation development.
This assessment must also reflect the anticipated dose. A molecule’s properties cannot be considered in isolation from the quantity that needs to be delivered to achieve the intended therapeutic effect.
Let the product profile guide development
The target product profile provides the framework for turning characterization data into a practical development plan. Intended indication, patient population, dose, dosage form and stability requirements all influence which formulation approaches merit investigation.
Where dissolution rate is the principal constraint, particle-size reduction through micronization or nanomilling may provide an appropriate starting point. Where a different solubility-enhancement strategy is required, amorphous solid dispersions produced through spray drying or hot-melt extrusion may warrant evaluation.
The objective is not to default to the most sophisticated technology. It is to identify the simplest approach capable of meeting the product’s requirements, then test that hypothesis.
API availability is often limited during early development, making material-efficient screening particularly valuable. Small-scale analytical assessments and proof-of-concept studies can help compare promising approaches before committing larger quantities of material. This creates an evidence-led route to technology selection while preserving scarce API for subsequent development activities.
Build the manufacturing pathway into the formulation decision
A formulation that performs at laboratory scale is only part of the solution. Its suitability also depends on whether it can be manufactured, stabilized and scaled through clinical development towards commercial supply.
Each enabling technology introduces different considerations. Spray drying requires solvent selection and management. Hot-melt extrusion offers an alternative that avoids organic solvents. Nanomilling requires attention to suspension stabilization and may introduce additional processing steps to produce a suitable final dosage form. These considerations should inform early decisions rather than become downstream problems. Available manufacturing scales, analytical requirements, storage conditions, cost and patient acceptability all contribute to the overall viability of a formulation.
Access to multiple technologies supports this molecule-led approach. PCI combines its oral dosage form development and highly potent compound handling expertise with specialist formulation partners, coordinating activities through a single development program. The purpose is to match capabilities to the molecule, rather than fit the molecule to a predetermined platform.
For complex oral therapies, strategic development means connecting molecular understanding, product requirements and manufacturing feasibility from the outset. Success is not simply demonstrating improved solubility: it is establishing a credible, scalable pathway to clinical evaluation, with decisions grounded in evidence and the needs of the intended patient population.
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