Rock-solid stability

Melt extrusion technology can add value to the formulation of new molecular entities and established products. SOLIQS’ Meltrex technology has been developed by combining expertise in the fields of pharmaceuticals, polymer chemistry and analytical techniques.

Meltrex technology is a simple way of combining the possibility of achieving amorphous or crystalline embedding of a drug while adjusting the release profile from extended release up to zero-order kinetics. However, little has been publicised about the stability benefits of amorphous solid dispersions manufactured by melt extrusion.

Solid dispersions are polymer-based solids in which the drug is molecularly dispersed in the amorphous state and must remain so throughout the shelf-life of the final drug product in order to maintain bio-availability. The extrusion process yields a viscous thermoplastic solution of the drug substance in a polymer matrix. This viscous material is subsequently shaped and cooled into final solid dosage forms or extrudate intermediates. By this concept, the drug is transformed into a non-crystalline form, which has a bioavailability in most cases that is comparable with, or even superior to, that achieved using more conventional oral dosage forms such as soft gelatin capsules (SGC).

Physical stability
To maintain bioavailability throughout the shelf-life of a Meltrex-based product, the drug must be prevented both from crystallising within the polymer matrix and from degrading chemically. Crystallisation prevention is referred to as ‘physical stability’. SOLIQS meets stringent physical stability requirements by developing formulations that immobilise the drug at the molecular level within the polymer matrix. Immobilisation is achieved by taking advantage of a physical state of polymers known as the ‘vitreous’ or ‘glassy’ state. This is critical in supersaturated formulations.

The very low molecular mobility that is necessary to achieve physical stability in special cases is also beneficial when achieving good chemical stability, as the kinetics of potential degradation reactions is sharply reduced by the vitreous state of the polymer matrix. This vitreous state inhibits the diffusion of reactants that may be involved in the degradation mechanisms of the drug substance. Although diffusion is never completely eliminated, it is slowed down by orders of magnitude, resulting in excellent chemical stability.

Dosage forms
This chemical stability provides a distinct advantage over conventional dosage forms such as SGCs. In an SGC, a liquid or semi-solid vehicle (lipid or co-solvent formulations) holding the drug in solution is encapsulated by an outer shell. Such dosage forms are more prone to chemical stability issues because of the largely unrestricted molecular mobility of the vehicle, drug and capsule shell materials.

In this case, chemical instability mitigation requires slowing down molecular mobility by refrigeration throughout the storage and distribution chain. By contrast, Meltrex tablets do not require refrigeration, a distinct advantage for distribution, especially
in locations where cold storage and transportation are not available.

SOLIQS has developed physical stability tests designed to enable a more rapid assessment of potential drug recrystallisation, compared with standard ICH stability testing. These tests are designed to push suboptimal formulations to failure and to provide a relative assessment for formulation screening.

Formulators also benefit from scientific knowledge on the physics of the glassy state. This includes advanced modeling of the thermodynamic and kinetics of glassy materials, as well as experimental methods to characterise the segmental mobility of vitreous polymers and their solutes. Formulators use this array of tools to guide formulation strategy and to verify the robustness of final products.

Added value
In conclusion, Meltrex technology is more than a bioavailability enabler or enhancer for poorly soluble compounds or another controlled release approach. It also offers significant stability advantages compared with conventional dosage forms. This is achieved by taking advantage of the unique properties of the glassy state and by drawing on a variety of scientific methods, both theoretical and empirical.