Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

Research into hot melt extrusion (HME) as a solution to improve solubility continues to expand with a partnership between Encap Drug Delivery, a contract development and manufacturing organization in the UK, and the School of Pharmacy at the Queen’s University Belfast (QUB), announced in a 

		HME, which is a continuous extrusion process used to create a solid dispersion of API in an excipient, has been shown to improve solubility.  While melt extrusion is a well-established technology in the plastics and food industries, it is still an emerging technology in pharmaceuticals.  Encap’s Jane Fraser said in the press release that the company is “confident that we can establish and grow HME as a mainstream technology for poorly soluble molecules. We believe that this will be a valuable addition to the formulator’s tool box and will fit well with our other enabling technologies.”

		Encap’s partnership with QUB is part of the UK’s Knowledge Transfer Partnership program that connects academia and industry for specific projects funded by the company and government grants. QUB researchers have been working on HME for several years.  Universities in the US, such as the University of Texas at Austin, Purdue University, and the New Jersey Institute of Technology, are also involved in HME research.  Do you know of other university research programs focused on HME?  I hope to write about these programs again, and I look forward to seeing how their work translates into commercial application.

Articles

Research into hot melt extrusion (HME) as a solution to improve solubility continues to expand with a partnership between Encap Drug Delivery, a contract development and manufacturing organization in the UK, and the School of Pharmacy at the Queen’s University Belfast (QUB), announced in a press release this week.

Hot Melt Extrusion Research Continues

Merck & Co. has announced plans to relocate the company’s global headquarters within the state of New Jersey (NJ), with the transition expected to begin in 2014 and be completed by mid-2015, according to an Oct. 9, 2012, 

. The company will close its current headquarters building in Whitehouse Station, NJ, where it has been since 1992, and move the headquarters less than 30 miles to the northeast to its existing property in Summit, NJ. The Summit facility currently houses 1800 people in research, manufacturing, animal health, and consumer care operations. About 2000 employees and contractors currently working in Whitehouse Station will move to the Summit location or to other nearby facilities such as those in Branchburg, NJ and Cokesbury, NJ.

The headquarters relocation is part of the company's ongoing program to consolidate its global real estate footprint and lower its annual operating expenses. The Summit location was selected because it is a multiuse site with excess workspace capacity and is near major transportation hubs and  urban centers, said the company in the press release.

Merck has announced plans to close its headquarters in Whitehouse Station, New Jersey, and relocate to its existing facility in Summit, New Jersey, beginning in 2014.

Merck Plans to Move Global Headquarters within New Jersey

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. 

C. Martin, presentation at the Leistritz Pharmaceutical Extrusion Seminar (Clinton, NJ, 2012).  

C. Brown, presentation at the Leistritz Pharmaceutical Extrusion Seminar (Clinton, NJ, 2012). 

G. Terife, presentation at the Leistritz Pharmaceutical Extrusion Seminar (Clinton, NJ, 2012). 

G. Terife, et al., presentation at the SPE Foams 2011 Conference (Iselin, NJ, 2011). 

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.

Foaming Improves Drugs Made with Hot-Melt Extrusion

	It is amazing what the human nose knows.  Well, those who originally detected a musty, moldy odor in pharmaceutical and healthcare products didn’t know where it came from.  But the odorous taints that resulted in product recalls were found to come from tribromoanisole (TBA) and trichloroanisole (TCA), and have been linked to treated wooden pallets from sources outside the US, the Parenteral Drug Association (PDA) reported in a September 

, which summarizes the findings of the recent PDA 

on detecting and mitigating taints and odors from TBA and TCA.

	TBA and TCA haloanisole taints, which can be smelled at parts-per-trillion levels, are generated by the fungal biomethylation of wood preservatives that are used in South America and other regions of the world, but not in the United States, the authors report.  The odor can migrate from wooden pallets to anything shipped and stored on the pallets, such as plastic packaging components.  The PDA TBA Task Force members discuss the importance of mitigating tainting, including eliminating the use of the offending wood preservatives in the supply chain.

	Perhaps a possible solution is using plastic pallets instead of wooden ones. Plastic pallets are lighter, more durable, and can be recycled. Plastic pallet use is growing. Many different pallet designs are available, and some advertise that they are heat-sterilizable for shipping food or pharmaceuticals.  Do you think this would be a good solution for the pharmaceutical industry?

Odorous Taints Linked to Treated Wood Pallets

Teva announced an agreement in which Bayer HealthCare will acquire the US-based animal health business of Teva Pharmaceutical Industries for up to $145 million, Teva said in a Sept. 14, 2012 

. The transaction is expected to close in 2013, subject to antitrust clearance and other conditions.

The purchase price includes an upfront payment of $60 million plus a total of $85 million in milestone payments, which are linked to the successful and timely achievement of manufacturing and sales targets. The transaction involves a manufacturing site in St. Joseph, Missouri, and around 300 employees.

The acquisition allows Bayer to expand its companion and food-animal product lines in the United States by integrating the acquired assets into its animal-health business. “The businesses are a great strategic fit, and Teva’s animal health portfolio adds new depth for us across both the companion and food animal areas. We believe it will be a win-win for both our customers and our combined employee bases,” said Ian Spinks, president and general manager of Bayer HealthCare Animal Health North America, in the Teva press release.

The deal reflects Teva’s focus on human health. “As part of our overall strategy to refine our global footprint, we will continue to leverage our product portfolio and R&D efforts while selling or out-licensing assets that no longer fit within the scope of our business,” said Itzhak Krinsky, group executive vice-president and head of business development of Teva, in the press release.

Teva’s exit from the animal-health segment follows Pfizer’s 

 in August of a plan to transfer its animal-health business to its Zoetis subsidiary prior to a pending initial public offering.

Teva announced an agreement in which Bayer HealthCare will acquire the US-based animal health business of Teva Pharmaceutical Industries for up to $145 million. The transaction is expected to close in 2013, subject to antitrust clearance and other conditions.

Bayer HealthCare Acquires Teva's US Animal Health Business

	Researchers are trying to find better, cheaper ways to produce biodegradable and bio-based polymers.  Although one of the main drivers for this research is to compete with fossil-fuel-based polymers in large-volume, consumer plastics applications, medical applications, such as microcapsules for drug delivery, may also benefit.  While it seems odd, the researchers found that waste oil from cooking fried food can be used as a raw material in the polymer production process. 

	The poly(hydroxyalkanoate) (PHA) family of polyesters (e.g., poly 3-hydroxybutyrate or PHB) is immunologically inert and degrades slowly in animal tissue, which gives it potential as a material for slow-release drug forms. The polymers are synthesized by bacteria in fermentation processes and typically use glucose as a starting material. Researchers from the interdisciplinary Institute of Healthcare Science at the University of Wolverhampton in the UK recently found that waste cooking oil can be used as starting material to reduce processing costs, the University explained in a 

. “The cost of glucose as a starting material has seriously hampered the commercialization of bioplastics,” said Iza Radecka, PhD, the research team leader, in the release.

	The bacteria used in the experiment grew better in oil and produced three times more PHB over 48 hours than the same bacteria grown in glucose, according to the press release. Nanofibers spun from the resulting polymer were also less crystalline than those from the glucose-based process. Lower crystallinity makes the polymers more suited to medical applications, said the researchers.

Researchers are trying to find better, cheaper ways to produce biodegradable and bio-based polymers.