DEEP EUTECTIC SOLVENTS AS ALTERNATIVES TO AMORPHOUS SOLID DISPERSIONS FOR ORAL BIOAVAILABILITY ENHANCEMENT

The amorphous solid dispersion (ASD) technology is often deployed as a “last-resort” approach to formulate molecules for which other techniques have failed. ASDs enhance oral bioavailability by delivering the API in a supersaturated state from an amorphous polymer matrix, whereby the co-dissolving matrix polymer subsequently acts to inhibit potential API recrystallization. This is a powerful means to enhance intestinal API concentrations and thereby drive absorption, but the inherent metastability of ASDs limits their applicability. Many product developers indeed are wary of progressing a product that carries a significant risk of losing performance over time due to API crystallization. In addition, ASDs require complex manufacturing processes, which also creates a barrier to widespread industrial adoption. The public domains abounds with research papers investigating the utility of amorphous solid dispersions to enhance the oral bioavailability of poorly water-soluble APIs (over 10,000 papers published to date), but less than 30 ASD-based products have been launched commercially. 

Our deep eutectic solvents exhibit the same level of enablement as ASDs but are physically stable and easier to manufacture, and as such provide a valuable, lower-risk alternative for the development of solubility-enhancing formulations for the most problematic molecules.

 

ENHANCED PHYSICAL STABILITY
The single most important reason why formulation scientists and product developers try to avoid the use of ASDs is their physical instability. Although most polymers have some solvent for low molecular-weight drugs, these solubilities are usually low (at most a few percent) making it impossible to process the target dose in an acceptable volume of formulation. In practice, therefore, much higher API concentrations are “forced” into the polymer matrix via solvent evaporation or melting techniques. As a result, ASDs are often dramatically supersaturated with API, which holds the risk of API phase separation, crystallization and decrease in dissolution performance. An additional complexity resides in the reproducible detection of such crystallization problems, which often requires a combination of sophisticated spectroscopic, crystallographic or thermal analysis techniques.

In contrast, our deep eutectic solvent formulations contain the API at undersaturated concentrations, which removes the risk of API crystallization. The liquid nature of our formulations allows us to readily determine the saturation level during the formulation design phase via simple visual inspection.


IMPROVED MANUFACTURABILITY
Another limiting factor to the commercial adoption of the ASD technology resides in its manufacturing complexity. First, making the API-polymer system requires solvent evaporation or melting processes, such as spray drying or melt extrusion. These processes require significant development and scale-up efforts, sophisticated equipment and highly trained personnel. Furthermore, the solubility of many of today’s candidate APIs is so problematic that they cannot be formulated into an ASD via a scalable process. This is especially the case for APIs whose solubility problem is driven by melting point, the so called “brick-dust” APIs. This type of API cannot be formulated via melt processing (polymer decomposition at API melting temperature) and often has too low solubility in organic solvents to enable spray drying at scale. After production of the ASD, a series of unit operations are then required to produce the final dosage form, such as densification, granulation, mixing and tableting. 

In contrast, bulk production of our deep eutectic formulations is conducted in a single-pot, solvent-free process at mildly elevated temperature (ca 50 °C). This process requires minimal development effort and is readily scaled up. The liquid formulation obtained via this procedure can be filled directly in capsules, vials or any other container type. The simplicity of this production process is a great advantage, especially in early development, as it allows to quickly progress a compound without spending time and resources on drug product scale-up activities.

 

Click the link below to discuss your formulation problem with our deep eutectic solvent designers.
 

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