Spray dried amorphous solid dispersion development
This type of formulation enhances oral bioavailability by generating API concentrations that are dramatically higher than those achievable by dissolution of the crystalline form.
Supersaturation
On hydration of the formulation, the API is released above its crystalline solubility which increases the driving force for absorption
High API loadings
API loadings of over 50% may be achieved
Broadly applicable
APIs of great physicochemical diversity can be formulated into an amorphous solid dispersion
Our approach to the development of spray dried amorphous solid dispersions (ASDs)
1
API-polymer solid-state miscibility
A key component of ASD development resides in the identification of carrier polymers that mix with the API in the solid state and as such form physically stable amorphous systems.
In a first phase, we screen physicochemically diverse, pharmaceutical-grade polymers for their ability to form physically stable amorphous systems with the API.
We prepare up to a 100 ASD concepts via solvent evaporation techniques and rigorously evaluate these for physical stability via a combination of solid-state analytical techniques.
Only mg-quantities of API are consumed in this phase.
In a first phase, we screen physicochemically diverse, pharmaceutical-grade polymers for their ability to form physically stable amorphous systems with the API.
We prepare up to a 100 ASD concepts via solvent evaporation techniques and rigorously evaluate these for physical stability via a combination of solid-state analytical techniques.
Only mg-quantities of API are consumed in this phase.
2
Dissolution-permeation profiling
The dissolution behaviour of ASDs is complex. On contact with water, the API that is released from the carrier polymer may form a variety of phases (free drug in solution; micellar drug; drug-rich colloids; recrystallised drug; ...) that are all in dynamic equilibrium with one another.
Each of these phases contributes differently to drug absorption. Using in vitro tests that simulate both the dissolution and the permeation process (via the introduction of an artificial membrane), we try to obtain an accurate rank-order prediction of the likely in vivo performance of candidate ASD systems.
Each of these phases contributes differently to drug absorption. Using in vitro tests that simulate both the dissolution and the permeation process (via the introduction of an artificial membrane), we try to obtain an accurate rank-order prediction of the likely in vivo performance of candidate ASD systems.
3
Dosage form development
Our preferred technique to produce ASDs is spray drying. After spray drying, we formulate the ASD powder into a final dosage form. In the discovery or preclinical stage, ASD powders are typically dispersed in a liquid vehicle prior to administration to laboratory animals. In this scenario, it is key to develop an administration vehicle that prevents premature API crystallisation. You can learn more here about some of the tactics we recommend when developing a gavage formulation.
For early clinical use, we generally recommend powder-filled capsules. Key here is to optimise for rapid disintegration as slow disintegration on contact with water may dramatically reduce ASD performance due to local API supersaturation and subsequent crystallisation.
For early clinical use, we generally recommend powder-filled capsules. Key here is to optimise for rapid disintegration as slow disintegration on contact with water may dramatically reduce ASD performance due to local API supersaturation and subsequent crystallisation.
4
GMP manufacturing
Manufacturing of clinical supplies occurs in a neighbouring third-party GMP-plant. To avoid technology transfer issues, the exact same machinery is used for process development and GMP-manufacture. Harpago scientists guide the technology transfer process all the way through.
Discuss your amorphous solid dispersion project
If you would like to learn more about our approach to amorphous solid dispersion design, development and manufacture, you can reach out to one of our experts here.