Case studies - Formulation development
Identification of stabilizing excipients for a formulation based on intermolecular interaction predictions.
Easy and scientific decision on the best enabling formulation technique (lipid-based formulation, co-amorphous formulation, ASD, …)
Project workflow
Training data
Collecting experimental data to characterize the intermolecular interaction strength of the API. Training data is easily assessible (e.g. solubility data in organic solvents).
In-silico prediction
Setting up the model with training data. Predicitve screening of intermolecular interactions in potential excipients.
Validation
Model validation and refinement with increasing data availability enables continous model improvements.
Sensitivity analysis
The correctness of the model is validated by uncertainty analyis
Process development
Should I spray-dry, go for hot-melt extrusion or select a different manufacturing process? How does the robust manufacturing process look like?
Trouble-shooting
Upcoming problems during process development are tackled as the in-silico model provides detailed mechanistic insigts.
Registration documents
The high extend of formulation understanding is beneficial for admission - a true quality-by-design approach!
Advantages
Time
Huge experimental studies like big, time-consuming stability studies can be reduced to a minimum. Aviod experiments that will fail and throw you back in time!
Material & Equipment
The lower number of experiments reduces the experimental efforts across the entire development and scale-up. Less solvents, less utilities make the formulation development greener and more sustainable!
Understanding
of mechanistic stabilization allows taking at each step of the formulation development process the most beneficial decisions for the formulation. Understanding that a formulation will change aviods the unexpected!
Ressources
Less number of formulation alternatives that are developed in parralel lets you focus on the best enabling formulation!
Humidity risk
Storage at ICH-defined storage conditions (defined Temperature- and humidity conditions) will always lead to an uptake of water from the surrounding environment. This can never be completely prevented.
We predict the impact of any temperature/humidity storage condition on your formulation:
Water sorption
How much water will be absorbed by the ASD? This question is answered at any temperature/drug load/ humidity condition.
wet Tg
Absorbed water decreases the Tg of the formulation (so-called wet Tg) and thus impacts shelf life or processing. We know it!
Crystallization
The crystallization regime in a formulation increases: Equilibria are strongly changing with humidity and also the
Molecular mobility
Water acts as plasticizer in formulations. Molecular mobility and thus diffusivity increases. Our tools quantify this impact.
Hydrate formation
The crystalline form might convert from free base to hydrates or salt hydrates. This is covered by our model!
Phase separation
Formulations containing hydrophilic polymers and hydrophobic drugs tend to phase separate at elevated humidity. This is experimentally hard to detect but impacts strongy dissolution and shelf life. We predict the conditions for preventing this.
Shelf life of ASDs
Apart from chemical degradation, the occurence of unwanted crystallization during a storage test occurs unexpectedly and threatens the formulation project.
With our shelf-life predictions, it is clear from the beginning on which formulation will crystallize and also in which period of time.
The complex interplay of the following factors is considered by our approach:
Mobility
Molecular mobility is predicted as function of drug load and water content
Thermodynamics
Degree of supersaturation and water content is predicted with thermodynamic tools
Glass transition
Glass transition (water-free formulation and wet Tg) predetermines the mobility model
Crystallization
Nucleation, crystal growth, crystal habit and glass-forming ability are characterized individually for each drug
Process
The individual manufacturing process impacts the stability of a formulation – we account for this influence.