The balance of physical stability and drug release in ternary fenofibrate/HPC/Eudragit L100-55 amorphous solid dispersions
Introduction
Amorphous solid dispersions are state-of the art enabling technique for poorly water soluble active pharmaceutical ingredients (APIs). In an ASD, the API is molecularly dissolved in a suitable polymer matrix that stabilizes the amorphous state during storage against recrystallization and ensures a fast release during dissolution. They are a promising formulation approach for the bioavailability enhancement of poorly soluble APIs. Physical stability during storage (i.e. resistance against crystallization of the API) and a desirable dissolution profile (i.e. high aqueous API concentration, maintained for long time in the dissolution medium) are the key attributes that need to be optimized by a formulator.
Method: Formulation development
The intermolecular interactions among the formulated substances (active pharmaceutical ingredients (APIs) and polymers) were assessed using the in-silico model PC-SAFT. The API parameters describing the size and API interactions are estimated based on a fit solubilities in organic solvents in an earlier work. Fenofibrate is an API with challenging formulatability (fast crystallization, poor solubility in ASD relevant polymers, poor polymer miscibility, low water solubility) and thus selected as model API for this study.
In-silico stage: Physical stability
25°C (blue) and predicted Glass-transition of the ternary ASD blend.
- FEN reveals an activity maximum in the Eudragit L100- 55/HPC-SSL mixture: weak physical stability in the blend
- The Tg is highest in pure Eudragit L100-55 and drops by addition of HPC-SSL
- The glass-transition of the blend is described accurately by the model
- The API is predicted to undergo amorphous phase separation prior to crystallization, the polymer blend itself is predicted to be miscible.
- The ternary ASDs are less stable from thermodynamic point of view (weak interactions API/polymer) but still kinetically stabilized: The ASDs are metastable and will crystallize, but crystallization is kinetically hindered.
Results: Storage stability
The spray-dried samples were found to be X-ray amorphous. The 50/50 polymer blend ASD indicated amorphous phase separation in the DSC thermograms (2 Tgs) and XRD analysis (shift of peaks) as well as beginning of crystallization.
Results: Dissolution performance
All ASDs revealed the classical spring/ parachute behavior (fast initial release and fast recrystallization from the supersaturated medium). The maximum concentration and final equilibrium FEN concentration was always the same.
Mechanistic observations: HPC-SSL showed the best stabilization potential (recrystallization prevention) in the least physically stable ASD (ASD2: polymer ratio 50:50 w/w).
Pre-dissolved HPC does not show an improvement: FEN recrystallization occurs first in the un-dissolved ASD particles and not in the aqueous phase. The crystallization inhibitor (HPC-SSL) must be present molecular dispersed at the origin of API nucleation.
Conclusion
By addition of HPC-SSL to an ASD FEN/Eudragit L100-55, a physical stability decrease could be achieved, while improving the recrystallization behavior during dissolution studies. HPC was identified as suitable co-excipient that allows performing this stability finetuning.
Learnings
- ASD physical stability and dissolution behavior
often show an opposing behavior - HPC acts as storage stability/dissolution
behavior finetuning agent - ASDs should be designed only as stable as
necessary to achieve desirably good dissolution
See the full poster on “Ternary fenofibrate/HPC/Eudragit L100-55” here
(click the picture to download the poster)
Source: NISSO HPC, amofor, brochure “Ternary fenofibrate/HPC/Eudragit L100-55“
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