When Is the ice really gone? Uncovering the two stages of drying by comparing the TVIS ice sublimation endpoint with the NIR moisture desorption endpoint for a solution of 5% mannitol

Understanding Two Stages of the Drying ProcessWhen we monitored drying using two different measurement techniques — Near-Infrared spectroscopy (NIR) and Through-Vial Impedance Spectroscopy (TVIS) — we were able to see that drying does not happen all at once. Instead, it occurs in distinct stages.First, both methods show clear and consistent changes as drying progresses. By comparing the NIR measurements to a key feature in the TVIS signal — a characteristic dip at high frequency — we can align what each technique is telling us about what is physically happening inside the vial.Stage 1: Ice in Contact with the GlassBefore the TVIS signal reaches its dip, ice is still physically touching the inner wall of the glass vial. During this phase:The frozen water forms a continuous structure against the glass.The NIR signal mainly reflects the presence of solid ice.Changes in the NIR spectrum are dominated by the behaviour of frozen water.In simple terms, this is the phase where ice is still firmly attached to the vial wall and actively sublimating (turning directly from ice into vapour).Stage 2: Ice Detaches, But Drying ContinuesWhen the TVIS dip occurs, it marks an important physical event: the ice has pulled away from the glass wall.At this point:The continuous ice–glass contact has ended.However, drying is not yet complete.The NIR signal continues to evolve.What this tells us is that even though the bulk ice is gone from the wall, moisture is still being removed from the solid material that remains. This later stage is no longer dominated by ice removal — it is dominated by desorption, meaning water molecules that are bound within the solid matrix are gradually being released.Importantly, another common measurement (the Pirani pressure signal) may still be decreasing during this time, which can make it seem as though ice removal is still ongoing. But the combined TVIS and NIR data show that the mechanism has already changed.Why This MattersTVIS provides a clear physical marker: it tells us exactly when the ice stops touching the vial wall. That event anchors the interpretation of the NIR data.Once we align the two signals, we can clearly distinguish between:The disappearance of iceThe later completion of moisture removal from the solid materialTogether, TVIS and NIR allow us to separate these two drying regimes and understand the process in a much more mechanistic way. In practical terms, this means we can tell the difference between “the ice is gone” and “the product is fully dry” — which are not the same thing.