Melt granulation. Traditionally, melt granulation is carried out in a high-shear granulator with a double-jacketed granulation bowl where water
or oil is circulated as the heating medium. The disadvantages of this traditional process include inefficient processing due
to the slow heat transfer from the bowl to the powder blend; difficulty in process scale up because the area of the heated
surface to the volume of power blend decreases with an increase in batch size; and batch-to-batch variability associated with
inconsistent heat transfer.
The working principle for a TSE is different from that of a high shear granulator. The TSE is an "active mixer" where the
mechanical energy of rotating screws (rather than the heat conducted from the barrel) melts or softens the fed materials.
Ideally, minimal heat should transfer between the extruder barrel and the materials passing through the barrel. As a result,a
melt-granulation process based on TSE can be scaled up more easily. During extrusion, the formulation composition is also
subjected to high pressure, which results in granules with a higher density and better flowability compared with granules
obtained from a high-shear granulator.
In TSE for melt granulation, a binder that melts or softens at a relatively low temperature (60 to 80 °C) is used to achieve
the agglomeration of the formulation composition. Originally adapted from conventional wet-granulation techniques applied
in a continuous fashion, the granules are formed after the material exits the die and the molten binders solidify. The binders
can be divided into two categories: hydrophilic excipients such as polyethylene glycol, poloxamer, cremorphor and sucrose
acetate; and hydrophobic excipients such as triglycerides, wax, stearic acid, and hydrogenated vegetable oil. Thermal binders
are typically present in the formulation at the 5–30% level.
Figure 3: Dissolution profiles of verapamil formulation concepts. a.) Minimal ethanol dependence is shown. This formulation
was prepared using Meltrex (Soliqs) technology. Profiles b, c, and d were prepared using conventional technologies. (FIGURE
3 IS REPRODUCED WITH PERMISSION FROM W. ROTH ET AL. BY ELSEVIER)
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Selection of the binders is based on drug–excipient compatibility and desired drug-release profiles. For example, hydrophobic
excipients have been used to prepare sustained-release dosage forms (24) and to provide better protection of the moisture
sensitive drug substance (25). In a recent publication by Kowalski et al., the researchers described the use of melt extrusion
for producing high drug loading granules containing a moisture-sensitive drug for use in a combination product. Using melt
extrusion, the researchers produced highly compressible granules that yielded tablets with minimal weight variation. Additionally,
they were able to demonstrate that the presence of the low molecular weight lipophillic binder used (hydrogenated castor oil)
improved high humidity stability of the moisture sensitive product (see Table II).
Advanced systems. The design of advanced drug-delivery systems has moved to the forefront of pharmaceutical technology, with many new systems
available for targeted and alternative delivery. In the design of such systems, which in many cases requires unique geometries
and compositions to achieve the target product profile, melt extrusion and supporting downstream processing can provide unique
advantages. The ability to generate systems of almost any shape from various materials also offers unique dissolution profiles.
Figure 4: The NuvaRing device (Merck-Shering Plough). (FIGURE 4 IS COURTESY OF THE AUTHOR)
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Although the majority of melt-extrusion applications have focused on oral delivery, commercially marketed melt-extruded products
are already available, including NuvaRing (Merck-Schering Plough, Whitehouse Station, NJ) which uses a coaxial extrusion process
to imbed etonogestrel and ethinyl estradiol into an ethylene vinyl acetate (EVA) core matrix. The core matrix is coextruded
with an exterior skin of EVA, which regulates drug release and provides a near zero-order rate of release over a 21-day period.
Following extrusion, the extrudate rods are cut and end-fused to create a ring (see Figure 5) capable of being inserted into
the vagina. Through careful regulation of the outer layer thickness and core drug concentration, the developers were able
to control the drug-release rate while providing a safe and easy-to-use product for extended duration delivery (26). Another
example of an advanced drug-delivery system developed using melt extrusion is the anti-HIV vaginal ring by Particle Sciences.
Under their process, dapirvirine is coprocessed with cellulose acetate phthalate before being melt extruded in an EVA matrix.
The extruded material is milled and shaped using an injection molding device to create a final ring capable of zero-order
release for a 90-day period (27).
Figure 5: Processing Section of a 50-mm Pharmaceutical Grade Melt Extruder (Leistritz). (FIGURE 5 IS COURTESY OF THE AUTHOR)
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Another far less common example of a melt-extruded shaped system is Lacrisert (Aton Pharma, Lawrenceville, NJ), a hydroxypropyl-cellulose
rod inserted into the pocket of the patient's lower eyelid to minimize symptoms associated with dry eyes. This product is
extruded and cut to length to generate a finished product which is then cured in humidity chambers to achieve equilibrium
moisture content. Similar systems for ocular delivery are under development. In a recent study by Jain et al., a system capable
of delivering acyclovir with twice daily dosing was developed. The system showed a substantial improvement over the ocular
ointment which requires dosing five times per day (28).
Melt-extrusion applications have expanded beyond conventional small-molecule applications. A study by Rothen-Weinhold et al.
showed that melt extrusion of a model peptide, vapreotide, was possible using a poly(lactic-co-glycolic acid) carrier while
minimizing degradation due to the elevated temperature exposure (29). Given the recent development of localized peptide therapies
that require novel dosage form engineering, melt extrusion presents unique advantages as a manufacturing platform.
Future directions
Melt extrusion in the pharmaceutical industry continues to evolve. Machinery suppliers have downsized and redesigned equipment
for current good manufacturing practice environments (see Figure 5). Additional efforts have been made to design TSE systems
that can test early-stage materials which are available only in minimal quantities. Borrowing from the plastics industry,
coextruded products using multiple extruders, and integration with in-line molding, may be the next generation of development
efforts. With the continued development of manufacturing technologies along with advances in formulation design and drivers
for increased production efficiency, melt extrusion will continue to shape drug delivery in the 21st century.
*Rezulin is no longer marketed. Parke-Davis is now part of Pfizer (New York).
Acknowledgments
The authors would like to thank Andrew Kenna and Marshall Cisneros with PharmaForm for their contributions during internal
PharmaForm studies to support this manuscript.
James C. DiNunzio, PhD, is a principal scientist at Hoffmann–La Roche, Inc. (Nutley, NJ). Charlie Martin* is general manager of Leistritz (Somerville, NJ), tel. 908.685.2333, ext. 616, cmartin@alec-usa.com
. Feng Zhang, PhD, is vice-president of development R&D at PharmaForm (Austin, TX).
To whom all correspondence should be addressed.
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