Summary: This article explains how poor solubility can affect oral drug development beyond formulation, creating risks around clinical exposure, dose selection, timelines and manufacturing strategy. It emphasizes that poorly soluble compounds do not always require complex enabling technologies; instead, formulation decisions should be guided by molecule characteristics, development stage, practical manufacturing considerations and, where possible, human PK evidence.
Poor solubility is one of the most common challenges in oral drug development. While often viewed as a formulation issue, it can also influence clinical exposure, dose selection, development timelines and manufacturing strategy.
Dr. Asma Patel has more than 20 years of experience in pre-formulation and formulation development across academia, industry and contract manufacturing organizations. Her expertise includes developing formulation strategies to improve the oral delivery of poorly soluble compounds and supporting evidence-led drug product development.
In this article, Dr. Patel addresses some of the most frequently asked questions about solubility and formulation development. She discusses how an evidence-led approach to formulation selection can help reduce uncertainty and support better development decisions.
Why does poor solubility become a program-level development risk?
Poor solubility becomes a wider development risk when it creates uncertainty about whether a formulation at an intended dose will provide sufficient and consistent exposure in patients. Inadequate or variable exposure can make early clinical findings harder to interpret. If the formulation subsequently needs to change, the program may also require additional manufacturing work or clinical bridging before it can progress.
The timing of the formulation decision therefore matters. Committing too early can introduce unnecessary development complexity. Waiting until inadequate performance emerges in the clinic can make changing direction more disruptive.
Does a poorly soluble drug always need an enabling formulation?
No. Poor solubility does not automatically mean an enabling formulation is required. The goal is not to use the most advanced technology available, but to identify the simplest formulation capable of delivering the required clinical exposure. Added formulation complexity is justified when it produces a meaningful improvement in exposure or reduces another defined clinical or development risk.
Programs that we have worked on have demonstrated both outcomes. In one program, we saw how how human PK evidence supported a spray-dried dispersion because it materially increased exposure. In another, comparative clinical assessment showed that a simpler micronized formulation achieved the required PK performance. The formulation decision should follow the evidence rather than the technical sophistication of the available technology.
How should a solubility-enhancement strategy be selected?
The starting point is the molecule and the exposure the clinical program needs to achieve. Physicochemical assessment can establish whether inadequate intrinsic solubility or another absorption constraint is likely to limit exposure. Solid-state characteristics also influence which formulation and manufacturing routes are technically credible. Selection should also consider the stage of development, available API supply, intended dosage form and long-term manufacturing requirements.
From there, development can focus on a smaller number of appropriate formulation routes. The preferred option needs to provide a credible path to the required human exposure while remaining practical for the intended dosage form and later-stage manufacture.
How do you choose between spray drying, hot-melt extrusion and other solubility-enhancement technologies?
Technology selection should be driven by molecule characteristics, the target exposure profile and practical development considerations rather than a predefined technology hierarchy. Particle-size reduction, for example, may be sufficient for dissolution-limited compounds. Amorphous solid dispersions produced by spray drying or hot-melt extrusion may be appropriate when greater solubility enhancement is required. Lipid-based systems may also be considered for suitable compounds.
Technology-specific considerations then help distinguish viable routes. For example, spray drying requires a suitable solvent system, while hot-melt extrusion depends on the thermal characteristics of the drug and excipients. If two technologies produce similar clinical performance, factors such as physical stability and manufacturing requirements may become more important to the final selection.
Why are human PK data important when selecting a formulation?
Human PK data provide the most direct evidence of whether a formulation delivers the exposure needed to achieve the objectives of the clinical program.
Laboratory testing and preclinical models help identify formulation risk and narrow the development space. They cannot fully establish how a formulation will perform in people. Animal models may not accurately predict human bioavailability or relative formulation performance.
Comparative human PK assessment shows whether a formulation achieves the required exposure and whether additional formulation complexity provides a clinically meaningful benefit. It can also inform dose or dosing conditions and subsequent dosage-form development. Human evidence therefore provides the basis for confirming which formulation should progress.
How can API-sparing development support formulation selection?
Fit-for-phase development allows selected formulation options to reach clinical assessment without first producing full-scale batches or establishing long stability programs for every candidate. This is particularly valuable when API supply is limited because development can generate the evidence required for the next decision while conserving material. The approach can also reduce upfront manufacturing commitment even where API availability is not the principal constraint.
How can an early clinical formulation progress to a patient-ready dosage form?
The formulation used to answer an early clinical question does not always need to be the final commercial-intent dosage form. A fit-for-phase powder or suspension can support initial PK assessment while development of the intended product proceeds once human evidence has established the appropriate technology.
PK bridging can then confirm that the patient-ready product retains the required exposure. In one program, a spray-dried dispersion was selected using emerging first-in-human data while tablet development proceeded in parallel. The resulting tablet achieved comparable exposure to the earlier powder-in-bottle formulation.
Why should later-stage manufacturing scalability factor into solubility strategy?
A formulation that provides suitable early clinical exposure must not only achieve the required clinical performance but also remain practical to manufacture, scale and transfer throughout development. Changes in process conditions or particle characteristics can affect product performance as manufacturing scale increases. Selecting a route without considering these requirements can therefore create additional development or technology-transfer work later.
Continuity between development and later-stage manufacture can also reduce external technology transfer. Maintaining continuity between development and commercial manufacturing activities in the same organization can reduce technology-transfer complexity and preserve program knowledge.
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