Imagine holding two drug formulations that look identical. Both contain the same active pharmaceutical ingredient (API), the same polymer, the same surfactant, and identical ratios. One turns to tremendous amount of crystals within a few months. The other remains stable for many years. The difference? An invisible memory: It’s thermal history!
Thermal history leaves a silent molecular imprint on an Amorphous Solid Dispersion (ASD) based on how it was cooled, stored, and “trained”. This is a discovery revealed in our collaboration with Janssen Pharmaceuticals (Grönniger et al., Mol. Pharmaceutics 2023). Our findings fundamentally change how we design, manufacture, and trust solid dispersions.
A Hidden Key to Drug Stability
ASDs save poorly soluble drugs, but their instability is a key challenge for formulators. For decades, we have been obsessed with composition (choice of polymer, API and surfactants). But our research has revealed that an equally critical, yet often overlooked, dimension is process design and storage.
“A glassy ASD is an unstable non-equilibrium material. Treat it differently, and you get a fundamentally different shelf life.” – Dr. Christian Lübbert, CEO, amofor
ASDs are not static solids. They are glasses, which are a type of “frozen” liquid with unique molecular behavior. Unlike stable crystals, glassy ASDs are non-equilibrium materials by nature. Their molecular structure encodes exactly how they were made: cooling rate, storage conditions, thermal “training” near glass transition (Tg). This “memory” dictates molecular packing density and mobility, the gatekeepers of crystallization.
The Impact is Bigger Than We Think
Our study proved this dramatically. We took identical polymers and cooled them differently:
- One was cooled gently at 1°C/minute, which resulted in a dense, highly viscous glass structure. Molecular mobility was drastically reduced. Model predictions indicated potential stability for centuries under ideal storage conditions.
- Another sample was cooled rapidly at 7°C/minute, resulting in a less ordered and less dense glass. Molecular mobility was significantly higher. The same model predicted that crystallization could occur within a few months.
The same chemical substance and same formulation, but a 1,000x difference in stability at room temperature. All from a tweak in cooling rate.
Lübbert stresses: Slight processing changes can turn shelf life from 6 months to 6,000 years. We’re talking about turning borderline drugs into stable assets. This is quantifiable physics.
Beyond Cooling: The Secret Power of Controlled Relaxation
But thermal history isn’t set at manufacture. Glasses relax, slowly densifying toward equilibrium when stored near their Tg. Uncontrolled, this drift destabilizes ASDs over time, even during storage.
We have demonstrated that deliberate, controlled relaxation (“conditioning”) is an effective solution. By keeping an ASD at defined Temperatures for a certain period of time, formulators can improve stability. Like training an endurance athlete at altitude, this “thermal tuning”:
- Increases molecular packing density
- Raises the energy barrier to crystallization
- Can amplify shelf life by orders of magnitude
However, this step requires precision. If you go too close to or above the Tg border, you risk crystallization. This fear often prevents the pharmaceutical industry from using this powerful technique. But with physical modeling, we can indicate the exact training conditions.
How We Decode Thermal History
So, how do you quantify and control something as elusive as molecular history? Viscosity is the master key to understanding molecular mobility and crystallization risk. Our promise: predicting viscosity below Tg with exceptional accuracy across:
- Drug loads
- Different polymers (HPMCAS, PVPVA, etc.)
- Varying humidity levels (accounting for plasticization)
- A range of temperatures
We achieve this by using the PC-SAFT framework combined with advanced modeling of molecular mobility and nucleation kinetics. It means we can:
- Model thermal history: Understand the “memory state” induced by different cooling rates (spray drying vs. HME vs. specific annealing protocols).
- Predict relaxation: Forecast how an ASD’s properties will evolve during storage near Tg.
- Quantify plasticization: Precisely account for the destabilizing effects of the API itself, surfactants,and absorbed moisture.
- Design stability: Proactively optimize both formulation and process parameters (cooling rate, conditioning time/temp, storage conditions) to achieve target stability.
Why Pharma Should Not Ignore Thermal History
Industries like food science and plastics have long understood the impact of thermal history on material stability. Candy makers, for instance, carefully control cooling rates to prevent crystallization, ensuring long shelf life. In plastics, engineers rely on thermal history to design pipes that last a century. These industries invest heavily in understanding glass formation and aging.
Crystallization in drugs is still treated as an unpredictable nuisance. Yet processes like spray drying or hot-melt extrusion impose distinct thermal histories on a formulation, directly affecting its stability. This critical factor is rarely considered in development or scale-up.
Ignoring thermal history has real consequences: sudden crystallization, batch failure, expensive recalls, and lost revenue. In an industry where time and consistency are everything, thermal history is a variable that must be controlled.
amofor: Your Partner in Understanding and Designing the Glass
At amofor, we help you harness thermal history as a fundamental, quantifiable design parameter.
Formulators who embrace this shift will set new industry benchmarks, accelerate development, locking in uncopyable IP (analytics can’t reverse-engineer thermal history), and create inherently more robust and valuable drugs.
Contact Christian Lübbert today!
Let’s discuss how we can help you decode the thermal history of your ASDs and turn this fundamental science into a powerful formulation advantage.