Solid Dispersions by Hot-Melt Extrusion

The advantages and disadvantages of hot-melt extrusion in solid dispersion formulations
Sep 02, 2012
Volume 24, Issue 9

Solid dispersions represent a promising formulation approach for overcoming today's major challenge in pharmaceutical formulation development: poorly soluble and poorly permeable active pharmaceutical ingredients (APIs). Solid dispersions can be obtained using different processes; however, hot-melt extrusion (HME) is extremely suitable for this purpose. One major advantage is the fact that no solvents are required; this avoids residual amounts of solvent and the accompanying stability risks during the shelf life of the formulation (see Figure 1).

Figure 1: Hot-melt extrusion is an efficient processing method for obtaining solid dispersions.
A solid dispersion is defined as a "formulation of poorly soluble compounds as solid dispersions might lead to particle size reduction, improved wetting, reduced agglomeration, changes in the physical state of the drug and possibly dispersion on a molecular level, according to the physical state of the solid dispersion. This will depend on the physicochemical properties of the carrier and the drug, the drug-carrier interactions and the preparation method" (1).

This definition points to some of the success factors of a solid dispersion. The miscibility between the API and the carrier, often an amorphous polymer, has to be defined. The polymer has to act as a solvent for the API to immobilize it within a molecular dispersion. This can be achieved by a high glass transition temperature (i.e., high viscosity and low cold flow) but this usually leads to a kinetically stabilized system only.

Any disturbing factor such as a slightly increased temperature or moisture can enhance flexibility in the solid dispersion and can accelerate migration of the drug; this in turn leads to nuclei formation and possible re-crystallization of the previously amorphous drug. A better solution is to utilize interactions such as hydrogen bonding between the API and the polymer to immobilize and stabilize the API in its molecular dispersion. Such systems are thermodynamically stable and are called solid glassy solutions.

Figure 2: Solid dispersions based on amorphous polymeric carriers.
In addition to a solid glassy solution, the API can be amorphously suspended in small clusters in the carrier, which can be kinetically stabilized. This is called an amorphous glass suspension (see Figure 2). If the API is a crystalline suspension in the amorphous carrier, the system is called a crystalline glass suspension. Such systems appear stable because the crystalline state is the energetically favored state. Solid glassy solutions and amorphous glass suspensions enhance the dissolution rate of the API by providing it in a non-crystalline form. In this way energy is applied to the API to bring it to a higher energy state where the crystal lattice energy is overcome. Figure 3 illustrates this fact. Because the API is in a higher energy state when amorphous, it tends to re-crystallize.

Figure 3: Energy brings the API from the crystalline to the amorphous state and to separate single molecules.
Figure 4 shows the relevant parameters that determine the stability of a solid dispersion. It also describes the second challenge faced when formulating a solid dispersion: stabilization of the released API by avoiding a re-crystallization in the gastro-intestinal tract. Soluplus® was developed as a polymeric amorphous carrier to stabilize the API when molecularly dispersed in the Soluplus® matrix by its lipophilic structural elements.

Figure 4: Main parameters that determine the success of solid dispersions (solid glassy solutions).
However, Soluplus® was also developed as a polymeric emulsifier to keep the API in a dissolved state after its release into the gastro-intestinal fluids. If this were not the case, the API would likely precipitate out from its supersaturated state. In some cases, precipitation cannot be fully avoided, but Soluplus® and other polymers such as Kollidon® VA 64 can sufficiently slow down the precipitation process, thus allowing sufficient absorption of the API into the blood stream. This approach, when the API is released fast into supersaturation and starts to precipitate out, is known as the "jump-and-parachute" effect. The important parameter is the precipitation rate after supersaturation is reached.

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