Predicting Crystallization times of Amorphous Solid Dispersions (ASDs)

The Challenge

Stability is the make-or-break factor for any amorphous solid dispersion (ASD) project. While ASDs enhance solubility and bioavailability of poorly soluble APIs, their long-term stability is inherently limited.

During storage, two major risks threaten the success of a formulation:

1. Chemical degradation, which can be anticipated with standard methods.

2. Unexpected crystallization, which often occurs suddenly and undermines years of formulation work.

Traditional stability testing relies on long-term and accelerated storage studies, which can take months or years before crystallization risks become evident. By that time, entire development programs may already be at risk.

amofor’s Predictive Shelf-Life Approach

At amofor, we apply a holistic, physics-based prediction strategy to assess the shelf life of ASDs right from the start – before long storage studies begin. Our methodology integrates five key dimensions of stability:

• Mobility
  We predict molecular mobility as a function of drug load and water content, providing early insight into relaxation dynamics.

• Thermodynamics
  Using advanced thermodynamic tools, we calculate the degree of supersaturation and quantify the impact of absorbed water.

• Glass Transition (Tg)
  Both the dry Tg and the wet Tg are determined and used as inputs for our mobility models. This ensures realistic assessments under storage conditions.

• Crystallization Propensity
  Each API is characterized in terms of nucleation rate, crystal growth, crystal habit, and glass-forming ability – factors that determine how and when crystallization will occur.

• Process Effects
  The chosen manufacturing process (e.g., spray drying, hot-melt extrusion) leaves a “fingerprint” on stability. We incorporate these process-specific effects into our predictions.

The Benefits for Our Clients

• Early clarity on risks: From day one, you know whether a given ASD formulation will crystallize – and within what timeframe.

• Time savings: Reduce or even bypass lengthy trial-and-error stability studies.

• Informed decision-making: Select the most stable formulations before committing to scale-up.

• Regulatory support: Predictions provide a mechanistic understanding that strengthens CMC documentation and regulatory filings.

A Proven Example

In a recent case, a client faced uncertainty about the stability of several ASD prototypes. By applying our PC-SAFT-based shelf-life prediction workflow, we identified the formulations with the highest crystallization risk and provided precise timeframes for when instability would occur under given humidity and temperature conditions. Months later, the real-time storage studies confirmed our predictions – saving the client both development time and cost.

Conclusion

With amofor’s predictive shelf-life modeling, pharmaceutical developers gain confidence, foresight, and control over one of the biggest risks in ASD formulation: crystallization during storage.

Instead of waiting for problems to appear, we provide answers upfront – enabling faster, safer, and more cost-efficient drug development.

Learn more and download our white paper here: