The glass transition (Tg) line is key to understanding and designing ASDs. In ASD phase diagrams, it is shown alongside the miscibility gap, the API solubility limit, and the liquid-liquid demixing zones. But unlike those boundaries, it does not separate one state of matter from another.
Above and below Tg, the material is the same amorphous phase. On one side it is a supercooled liquid; on the other it has vitrified into a single-phase amorphous glass. That glass is the desired state. Every ASD process, from spray drying to hot-melt extrusion, is a trajectory across the diagram that aims to reach this state before phase separation occurs.
Why isn’t the glass transition a phase change?
An ASD phase diagram shows where one state of matter transitions to another. The solid/liquid/vapor diagram of water is the textbook example, where every line marks a transition. The Tg line is different: crossing it changes molecular mobility and diffusion coefficients, but not phase.
- Above Tg, the material is a viscous liquid in which any thermodynamically favorable phase change, such as demixing or crystallization, can happen. These processes are fast and directly relevant on process and shelf-life timescales.
- Below Tg, molecular motion is arrested. The material is locked. Cooperative segmental mobility slows drastically. Phase changes may become so slow that they effectively never occur.
In a phase diagram, phase transitions tell you IF something can happen; the Tg tells you WHEN it will happen.
A useful illustration from the food industry is hard-boiled sugar candy. Sucrose is thermodynamically driven to crystallize, however, a properly quenched candy remains glassy and transparent for months. If it picks up moisture, though, even a few percent of water is enough to lower the Tg toward room temperature. It will turn cloudy within days as sucrose crystals nucleate and grow. The same thermodynamic driving force is present, but the kinetics are entirely different depending on where the composition sits relative to the Tg. An ASD behaves identically. In the past, people designed their storage conditions and manufacturing processes with the 50K-rule- but staying 50K below Tg is just a rough guidance an not universally applicable.
Why is the glassy region in a ternary diagram with water so small?
In any ternary phase diagram of an API, polymer, and solvent, this principle explains why the glassy target region occupies only a small corner near the API corner. The Tg line marks compositions at which the Tg equals the operating or storage temperature. The safe region, which is glassy and outside of any miscibility gap, is the narrow area next to the API corner. Everywhere else is either thermodynamically unstable, kinetically mobile, or both.
The corner is small because the residual organic solvent and absorbed water act as plasticizers, which are small molecules that increase the free volume and molecular mobility in the amorphous matrix. This lowers the Tg. Water is the most extreme case. Its own Tg is near -135 °C, so low that water almost never vitrifies on its own. It crystallizes into ice long before reaching that temperature. Only laboratory hyperquenching (on the order of 106 K/s) can force water into a glass. Methanol, ethanol, acetone, and dichloromethane have slightly higher Tgs. Since both categories of small molecules are potent plasticizers, even modest amounts can dramatically lower the Tg of the formulation.
That is why residual solvent must be effectively removed via secondary drying: the particle can carry only a strictly limited amount of plasticizer before its own Tg falls below the operating and storage temperatures. Cross that limit and the particle becomes sticky and viscous, making it difficult to collect from the cyclone and causing it to become physically unstable the moment it leaves the dryer. In the ASD phase diagram, sufficient drying is defined as the point at which the drying trajectory crosses below the glass transition line and enters the stable corner near the API corner.
How does Tg control shelf life and drug release?
Once the glass transition is included in the diagram, it becomes a prediction engine. This is the point at which kinetics enters every phenomenon a formulator cares about.
Physical stability and shelf life. By computing how the Tg shifts with humidity in the wet polymer/API/water system, we can determine where a formulation sits relative to its Tg under realistic storage conditions (typically 25 °C/60% RH and 40 °C/75% RH). This information can be paired with the predicted phase transitions. Together, these factors provide a specific, quantitative shelf-life estimate rather than an empirical guess. This is the mechanism which is also behind our collaboration with Janssen: two identical ASDs with the same drug, polymer, and ratio differed in stability by a factor of 1000, ranging from six months to 6,000 years, purely because their cooling histories left them in different glassy states relative to their Tg. Our shelf-life modelshave since then been benchmarked against more than 150 long-term stability studies, predicting real-world crystallization onset with an error margin of about ±20%.
Release rate and bioavailability. Add water as a third component, then read the diagram in its water-rich region. This is the environment that an ASD meets in the gut. The Tg again decides the kinetics. Whether the water-swollen interfacial layer of the dissolving system lands above or below the Tg determines whether the release is fast or slow. Using a dissolution-relevant phase diagram, we can show that, as a function of drug load, release is fast up to a critical loading point and then drops dramatically, the “loss of release” principle documented in the AbbVie/Purdue/amofor study. This is a direct, mechanistic claim about the velocity of release, and therefore, bioavailability. It can be read straight from where the trajectory sits relative to the glass transition.
This continuity has a powerful practical consequence. Crystallization occurs very slowly in dry storage (water-lean, near or below the Tg) and comparatively quickly in aqueous media (water-rich, above the Tg). By measuring the kinetics where dissolution is fast and extrapolating to where it is slow, you can connect fast dissolution data to long-term shelf life through the single, continuous structure of the API/polymer/water phase diagram.
What can you decide once the Tg line is on your diagram?
If you formulate ASDs, five questions become answerable the moment the Tg line appears on your diagram:
- Where is my wet Tg at storage RH?
- How much residual solvent can I leave in the particle?
- What is my safe drug load?
- Which polymer gives me the most margin?
- Will my release survive scaling up to a higher drug load?
Together, the answers give you a clear picture of how long your ASD is stable, a quantitative drying endpoint, a defensible drug-load ceiling, and a mechanistic, cited explanation of why the formulation works.
Design your ASD with amofor
At amofor, we compute the Tg for client ASD systems as part of the standard process of creating ASD phase diagrams. We consider drug loads, polymers such as HPMCAS and PVPVA, and humidity levels. We use PC-SAFT together with models of molecular mobility and nucleation to make these calculations. This allows us to tell formulators not only whether their ASD is thermodynamically sound, but also when it will remain so and how quickly it will release.
If you are designing an ASD and want to know where your stable corner sits and how close your current composition is to falling out of it, book a consulting session with Dr. Christian Lübbert or explore SOLCALC. SOLCALC is PC-SAFT-based software that computes the phase diagram and its glass transition line for your specific system.
Sources and further reading
Luebbert, C., Sadowski, G. (2017). Moisture-induced phase separation and recrystallization in amorphous solid dispersions. International Journal of Pharmaceutics 532(1), 635–646.
Deac, A., Luebbert, C., Qi, Q., Courtney, R. M., Indulkar, A. S., Gao, Y., et al. (2024). Dissolution Mechanisms of Amorphous Solid Dispersions: Application of Ternary Phase Diagrams To Explain Release Behavior. Molecular Pharmaceutics 21(4), 1900–1913.
