Dissolution Is Not the Finish Line: Rethinking How We De-Risk Formulation Development
For decades, dissolution testing has been a cornerstone of oral drug development, and for good reason. It is standardized, practical and, for many compounds, highly informative.
But here is the looming question: Are we still asking dissolution to answer a question it can no longer solve on its own?
As small-molecule pipelines increasingly shift toward poorly soluble, highly permeable BCS Class II compounds, the relationship between dissolution and absorption becomes much less predictable. A formulation can dissolve beautifully in vitro and still fall short where it matters most: getting enough drug across the membrane and into systemic circulation. That should change how we think about formulation development.
The goal is not to create the formulation with the best dissolution profile. The goal is to identify the formulation most likely to deliver the desired in vivo exposure. Those are not necessarily the same thing.
Better questions lead to better decisions
For BCS Class II compounds, formulation scientists need to understand what is actually limiting bioavailability. Is the molecule solubility-limited? Does permeability become the constraint once solubility improves? Is absorption becoming nonlinear as dose or concentration increases?
Without insight into both dissolution and permeation, those questions can be difficult to answer, and formulation teams may end up optimizing the wrong variable. This is where I believe the industry needs to rethink its approach.
The good news is that we don't need to abandon dissolution testing. We need to put it in context.
By integrating dissolution and permeation measurements earlier in development, formulation teams can move beyond simply ranking formulations by how quickly or completely they dissolve. They can begin comparing candidates based on a more meaningful question: Which formulation is most likely to result in absorption?
That is a fundamentally different way to make development decisions.
From reactive to predictive development
The implications extend beyond better science. They are about speed, cost and risk.
Every formulation iteration that has to wait for an in vivo study slows development. Every formulation advanced with incomplete information creates the possibility of discovering a critical limitation later, when the cost of being wrong is much higher.
Modern drug development cannot afford endless cycles of formulate, test, wait and reformulate. Especially when we have the tools to reduce those cycles by making them more predictive.
The opportunity now is to use better in vitro models to understand the mechanisms driving absorption earlier, enabling smarter formulation choices while reserving in vivo studies for the questions they are best suited to answer.
Dissolution is still essential. But for today's increasingly complex molecules, it should be the beginning of the conversation, not the end.
I explore this shift, and what it means for formulation strategy, in a new article in American Pharmaceutical Review:
If your team is still relying primarily on dissolution to make formulation advancement decisions, it may be time to ask a different question:
Are you measuring what you actually need to know?
