The pharmaceutical world is evolving rapidly and with it the complexity of drug formulation, especially in the field of amorphous solid dispersions (ASDs). One of the biggest challenges with ASDs lies in mastering crystallization, a crucial factor that determines the physical stability and efficacy of a drug.
Challenges in Amorphous Solid Dispersions
A major difficulty with ASDs is preventing the crystallization of drug molecules. The goal for formulators is therefore to maintain the drug in a non-crystallized, amorphous state. However, these formulations often exist in an unstable state, being metastable. This means they’re prone to eventually transform back to a crystallized state under certain storage conditions. The critical question is: How long can the formulation remain amorphous before the first crystals appear? It’s a race against time. Imagine a formulator spending years developing a drug, only to find out much later that it loses stability and crystallizes, rendering all that effort and investment futile. This is something to prevent from start.
While controlling crystallization is critical, it’s part of a wider stability spectrum in ASDs, encompassing both chemical and physical aspects, each playing a pivotal role in the drug’s efficacy. Chemical stability primarily deals with preventing molecular degradation, a process typically managed through testing and analyzing stability data under varying temperatures and humidity levels. On the flip side, physical stability deals withissues like crystallization and phase separation, which are crucial for maintaining the efficacy of ASDs.
While standard models for predicting chemical stability are quite effective, they mainly rely on Arrhenius dependency and logarithmic responses to environmental changes like humidity and temperature. These models fail when it comes to predicting physical stability issues such as crystallization in ASDs. This is because physical stability in ASDs presents unique challenges that require approaches beyond what traditional chemical stability models can offer.
Shelf Life Prediction with Advanced Modelling
To overcome the shortcomings of conventional models, amofor has developed a physically based in-silico modeling approach. This model is unique in that it takes into account key factors such as molecular mobility, crystallization-promoting forces, and water absorption. By integrating these elements, it achieves a precise estimation of shelf life under various conditions, offering flexibility to adapt to different humidity levels, temperatures, drug loads, and excipient compositions.
Building on this, Christian Lübbert, co-founder of amofor, emphasizes the accuracy of their predictions: “Our shelf-life predictions have a range of +/-20% which is extremely accurate”. For instance, if the model predicts a shelf life of two years, the actual shelf life could range from one year and 8 months to 2 years and four months. This level of precision is highly valuable, especially when distinguishing between long or short shelf lives, such as 100 years versus one year. These predictions are also particularly relevant for regulatory compliance and successful market entry.
In addition to predicting shelf life, amofor’s model is also distinguished by the fact that it takes into account the inherent variability between different drug molecules. Each molecule under development is unique, exhibiting a range of complexities, such as diverse functional groups, melting points and polymorphs, and glass transitions. They also differ in their interactions with polymers and other excipients. This complexity means there’s no one-size-fits-all solution. Our approach, combining advanced models like PC-SAFT(Perturbed-Chain Statistical Associating Fluid Theory) and kinetics/ diffusion models, is designed to understand these intricate interactions, especially between the Active Pharmaceutical Ingredient (API) and other molecular components in the formulation.
We take into account
- the different tendencies to nucleation and crystallization of different APIs
- the different intermolecular interactions between the API, the polymer and additional excipients
- the impact of moisture and residual solvents
- the different glass transitions and melting properties
- the different thermal history pf the glassy material, originating from diverse manufacturing techniques
- different crystallinity levels that are detectable by different analytical techniques and present within the ASD at different storage time points
This comprehensive approach allows us to effectively predict and manage the complex behavior of these molecules and their ASD formulations.
The practical value of amofor’s model is evident in its real-world applications. Often approached by clients who initially underestimate the importance of shelf life, amofor steps in when unexpected stability issues, like crystallization, arise. In these situations, clients consider changing drug concentrations or manufacturing methods. Here, amofor’s expertise in delivering accurate shelf life predictions under various conditions becomes invaluable, guiding clients to make strategic formulation and process decisions. Our model has successfully tackled numerous physical stability challenges, providing strategies to avert crystallization.
Takeaway
The deeper we explore the complexity of ASDs and their shelf life, the clearer it becomes that understanding and managing phase changes such as crystallization is critical. Therefore, it is crucial for formulation expertsto meticulously monitor data, especially especially under extreme conditions, to prevent product failures during storage.
To discover the most recent amofor shelf-life publications, click here (Factors Influencing the Crystallization-Onset Time of Metastable ASDs) or here (The shelf life of ASDs: 2. Predicting the shelf life at storage conditions). Also do not miss to download our white paper on ASD shelf life.
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