Foaming Improves Drugs Made with Hot-Melt Extrusion

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Equipment and Processing Report

Equipment and Processing Report, Equipment and Processing Report-09-19-2012, Volume 0, Issue 0

Foaming can be used to improve processing in the extruder without the use of a plasticizer, facilitate milling, increase dissolution rates, and produce novel dosage forms.

Dissolving a gas in a molten polymer can produce a cellular structure. This approach is well-known in the plastics industry, and consumer uses of lightweight, cellular plastics range from the “noodles” that children float on in swimming pools to the soles of shoes to insulative construction materials. In the pharmaceutical industry, however, foaming during hot-melt extrusion (HME) is relatively new and is being used for different reasons. Researchers are finding that foaming can be used to improve processing in the extruder without the use of a plasticizer and to facilitate milling to a particular particle size. Other research indicates that excipients can be foamed to increase dissolution rates and produce novel dosage forms (e.g., floating oral dosage, rapid-dissolve tablets).

Excipients can be foamed inside a twin-screw extruder using a physical blowing agent (e.g., nitrogen, carbon dioxide) or a chemical blowing agent that decomposes into a blowing gas (e.g., sodium bicarbonate and citric acid that decomposes into carbon dioxide and water). The gas is injected at high pressure into the molten polymer through a distributive mixing element with dynamic seals that prevent the gas from moving back up the extruder to the feed ports (1). At the exit of the extruder, after mixing, the thermodynamic instability created by the rapid pressure drop creates cell nucleation, and the cells are stabilized in the cooling polymer.

Plasticizers are sometimes added to a formulation when using HME to broaden the processing window for higher molecular weight excipients or APIs that are difficult to process. Plasticizers, however, can leave behind undesirable residual material. Physical blowing agents have been found to act as a fugitive plasticizer, in which the agent performs the plasticizing function without becoming part of the end product. Supercritical carbon dioxide, for example, lowered the operating temperature of an extruder by up to 20 °C, noted Chad Brown, principal scientist, preclinical development and the global hot-melt extrusion technology development-team leader at Merck & Co., in a presentation (2). The absences of residuals when using a fugitive plasticizer is a big advantage for formulation, adds Tony Listro, managing director at Foster Delivery Science, which specializes in HME and has also run experiments with supercritical carbon dioxide.

Drug products manufactured using HME are often milled before being made into the final dosage form (i.e., tablet, capsule, suspension) to further improve dissolution rates. Foamed products are easier to grind. Improved milling helps make the HME process more user-friendly and increases its feasibility compared with competitive processes, such as spray-drying, which doesn’t require milling, notes Listro. Research at the New Jersey Institute of Technology (NJIT) found that cellular structures with more uniform morphology and lower density were more easily milled and produced smaller particles (3). Experiments at Merck & Co. also found that lower density foams had better milling efficiency, and that foamed, milled material exhibited increased dissolution compared with jet-milled material (2).

Foaming can increase porosity of a product made with HME, which can increase dissolution rate. Faster breakdown of the cellular structure leads to an increased dissolution rate, noted Graciela Terife, doctoral student at NJIT in a recent presentation (3). Her research showed that non-uniform cellular structures (i.e., a broader range of cell sizes) broke down faster than uniform structures.


Foamed excipient–API systems can be used for novel dosage forms. Orally disintegrating tablets, for example, are manufactured using lyophilization techniques and are characterized by open-cell structures. Floating dosages that allow drugs to be absorbed in the upper section of the stomach have also been studied (4).

“Foaming is an evolution of the HME process that will increase its versatility as an answer to the challenge of increasing the bioavailability of poorly-soluble APIs,” concludes Listro.


  1. C. Martin, presentation at the Leistritz Pharmaceutical Extrusion Seminar (Clinton, NJ, 2012).
  2. C. Brown, presentation at the Leistritz Pharmaceutical Extrusion Seminar (Clinton, NJ, 2012).
  3. G. Terife, presentation at the Leistritz Pharmaceutical Extrusion Seminar (Clinton, NJ, 2012).
  4. G. Terife, et al., presentation at the SPE Foams 2011 Conference (Iselin, NJ, 2011).