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The advantages and disadvantages of hot-melt extrusion in solid dispersion formulations.
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).
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).
Figure 1: Hot-melt extrusion is an efficient processing method for obtaining solid dispersions.
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.
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 2: Solid dispersions based on amorphous polymeric carriers.
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 3: Energy brings the API from the crystalline to the amorphous state and to separate single molecules.
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.
Figure 4: Main parameters that determine the success of solid dispersions (solid glassy solutions).
Hot-melt extrusion is a recognized process for the manufacture of solid dispersions and innovative new dosage forms. It is an established process that has been used in the plastics and food industries since the 1930s. In the 1980s, BASF SE was the first to apply the melt extrusion process based on polymers with high glass transition temperatures (such as polyvinylpyrrolidones) to pharmaceuticals (2).
Extruders for pharmaceutical use have been designed and adapted for mixing drugs with carriers in various dosage forms. The significant difference between extruders for thermoplastics and pharmaceutical applications is the equipment used, and hence, the contact surface, which must meet regulatory requirements. The contact parts of the extruders used in pharmaceuticals must not be reactive nor may they release components into the product. The extruder equipment is specially configured to fulfill all cleaning and validation standards applicable to the pharmaceutical industry.
The use of extruders in the pharmaceutical industry cannot be seen as a niche application. Figure 5 demonstrates four fields of versatility of the technology. Not all the benefits available, however, have been realized to date.
Figure 5: The four fields of versatility of hot-melt extrusion technology in the pharmaceutical industry.
In principle, an extruder consists of barrels enclosing single or twin screws that transport and, subsequently, force the melt through a die, giving it a particular shape. The barrel can be heated to the desired temperature. Due to the external heat and shear provided by the screws, the polymer is plasticized and its viscosity reduced. Hot-melt extrusion is a typical continuous process, because the extruder is fed at one side and the extruded material exits from the other side. This makes it even more attractive for pharmaceuticals (3). The hot-melt extrusion process comprises the steps melting, mixing and shaping.
Within the pharmaceutical industry, hot-melt extrusion has been used for various purposes, such as:
Once developed, hot-melt extrusion is a reliable and robust process offering benefits in cost-efficiency. Compared to other processes for the production of solid solutions, it is far less complex, because the manufacturing of such dosage forms requires only a few steps and avoids the use of organic solvents (Figure 6).
Figure 6: From poor API solubility to a final formulation.
Hot-melt extrusion also has advantages over solvent-based methods of forming solid solution and dispersions (Figure 7):
Figure 7: Opportunities and advantages of hot-melt extrusion.
To develop the melt extrusion process in an appropriate manner it is important to have tools to characterize and analyze the process. It is clear that only an optimized formulation together with an optimized process set-up will yield the best product.
Besides the parameters such as screw speed and feed rate, which can be adjusted during the extrusion process, screw configuration is a major parameter. Screw design is not often optimized although it plays a major role in determining product quality. Screw configuration basically determines the shear stress. It also strongly influences the residence time distribution. BASF's second edition of the HME compendium provides more information on the design of screws in co-rotating twin screw extruders. Here, the functionality of different screw segments is explained in detail.
The new HME compendium also shows how to determine residence time distribution and how to read it. It provides a guide for process analysis and for developing better process understanding.
BASF has also developed a process parameter chart that enables the whole extrusion process with all its influencing variables to be included. The advantages of the new process parameter chart are:
The proposed process parameter chart is shown in Figure 8. It is a XY-diagram, displaying the volume-specific feed load (VSFL) versus the extrusion temperature (mean barrel temperature).
Figure 8: Process parameter chart.
Throughput triggers cost. The throughput in an extruder can be either torque-limited or volume-limited. In Figure 8, one curve represents the determined maximum achievable VSFL values at the limit of the extruder. The vertical line indicates the process boundary. Only the position on the temperature axis is relevant for reading the line; the line height does not matter. Each VSFL value to the left of the line is limited by the maximum torque of the extruder (configuration), while each VSFL value to the right of the line is limited by maximum intake (volume). The vertical dotted line on the right indicates the process boundary given by the maximum allowable temperature, which can be determined by the degradation points of either the active substance or any non-active ingredient in the processed formulation. The design space can be filled with contour lines of extrusion system parameters such as mean residence time for better process analysis.
More information on the process parameter chart and its use can be found in BASF's new HME compendium (see below).
1. S. Janssens and G. Van den Mooter, JPP 2009, 61: 1571–1586, DOI 10.1211/jpp/61.12.0001
2. H. H. Görtz et al., EP 0240904 B1
3. C. Leuner and J. Dressman, Eur. J. Pharm. Biopharm. 50, 47-60 (2000).
Download for free the new edition of the hot-melt extrusion compendium at: www.innovate-excipients.basf.com