Improving the Bioavailability of Challenging APIs using Hot Melt Extrusion with Polyvinyl Alcohol

New molecular entities (NMEs) are becoming larger and more lipophilic and, as a result, less soluble. While approximately 40% of active pharmaceutical ingredients (APIs) currently on the market show poor solubility, it is estimated that between 60 and 90% of compounds in development have solubility challenges.1,2 For an oral formulation, API solubility and permeability are critical factors for absorption in the gastrointestinal tract. As a result of this, solubility-enhancing techniques have become an area of focus for pharmaceutical formulators. If limitations in solubility cannot be successfully addressed, an NME is unlikely to advance in the development pipeline, as absorption from the GI tract will be limited. This in turn reduces the overall effect of the molecule, as absorption is a critical component of the LADME (liberation, absorption, distribution, metabolism, elimination; Figure 1) model of drug pharmacokinetics.

The API is mixed with a matrix polymer in the extruder to enable homogeneous dispersion of the API within the polymer.

Expanding upon the LADME model, one can identify strategies to improve the oral absorption of a poorly soluble molecule. Specifically, absorption can be increased through improvements in solubility and/ or permeability, as well as other means including reducing elimination via P-gp transporters. To improve solubility, chemical approaches such as salt and prodrug formation are typically only feasible very early in development, as they fundamentally alter the chemical nature of the API. However, there is a fine balance between achieving potent activity in the chemical substrate and good physicochemical properties, with the latter often taking priority. Therefore, physical (or post-synthetic) approaches are highly relevant during formulation development and include:

Particle size reduction
Use of surfactants in co-solvent systems
Complexation of the API, for example to cyclodextrins
Use of alternative polymorphs
Stabilization of amorphous form via:
- Loading onto carrier systems
- Immobilization in polymeric solid dispersions

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Multiple technologies are typically considered and evaluated to find the right approach for the respective API and to achieve the desired performance of the final drug product in vivo. This white paper will focus on solid dispersion – specifically, the use of hot melt extrusion (HME) to modify the physical state of APIs with the aim of enhancing solubility by converting the poorly soluble drug from its crystalline form into a stabilized amorphous form.

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Read the full white paper as a PDF here