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). 

Articles

Production Lines

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

Uhlmann Packaging Systems
 Integrated blister and carton module features simplified changeover


 Uhlmann Packaging Systems’ Blister Express Center 500 (BEC 500) is a double-lane, integrated blister and carton module that can process up to 500 blisters and 500 cartons per minute, which makes it ideal for packaging medium-sized batches of standard, solid-dose products. The flexible machine is available with rotary or platen sealing and can produce complex shapes, rigid aluminum pockets, calendar packs, and other nontraditional packages. Between runs, the machine features a newly simplified changeover process that allows a single person to completely reset the entire line in just 30 minutes without the use of tools. Uhlmann’s new SmartControl operating system offers step-by-step guidance through the entire format changeover. 

GE Healthcare
 Modular, prefabricated bioprocessing facility reduces construction time and capital investment compared to traditional facilities


 GE Healthcare’s KUBio modular, 1200-m

 bioprocessing facility is prefabricated and delivered with a complete, ready-to-use production line that is based on GE Healthcare’s Ready-to-Process single-use technologies. The total planning, delivery, and construction time of the facility is 14–18 months, which is significantly less than the 24–36 months needed for traditional construction. Capital investment is also significantly reduced.

PharmTech's monthly newsletter, Equipment and Processing Report, reviews the Editor's Picks for the September 2012 edition from Uhlmann Packaging Systems and GE Healthcare.

September 2012 Editor's Picks: Products from Uhlmann Packaging Systems and GE Healthcare

An ideal topical formulation can be produced using a simple, flexible process. Most topical formulations developed today, however, are complex and therefore require very tightly controlled processing parameters. Following are five critical process parameters that must be considered to optimize the manufacturing process for topical dosage forms. Part II, which describes additional strategies, will appear in the October issue of the 

Processing at the right temperature is crucial for successful manufacturing. Too much heating during processing can result in chemical degradation. Insufficient heat can lead to batch failures, and excess cooling can result in the precipitation of solubilized ingredients. An example of the need for good temperature control is the emulsification step of a traditional oil-in-water emulsion. If the temperature of the water phase is much cooler than that of the oil phase, the melted constituents of the oil phase may solidify upon introduction into the aqueous phase and never properly form the emulsion, possibly even resulting in solid matter in the batch.

Heating too slowly can result in poor yields from evaporative loss. Heating too rapidly may burn areas of the batch in contact with the heating surface, which raises the potential for burnt material in the batch. Rapid cooling can result in precipitation/crystallization or increased viscosity. The successful consistency of ointments, for example, depends on proper rates of heating and cooling.

It is essential to determine the required amount of shear and the optimal mixing methods and speeds. Emulsification typically requires high shear or homogenization to obtain the optimal droplet size and dispersion, while the mixing of a gel may require low shear in order to preserve certain physical characteristics, such as viscosity. Proper mixing speeds must be obtained for each phase at every batch scale. Optimal hydration depends on the amount of shear imparted to initially disperse the polymer into the medium. If the process involves only very low shear mixing, a polymer may never be completely dispersed and hydrated, which may result in an out-of-specification viscosity. 

Optimizing mixing time requires identifying the minimum time required for ingredients to dissolve and the maximum mixing time before product failure (e.g., when viscosity begins to drop). For polymeric gels, particularly acrylic acid-based types, over-mixing, especially high shear, can break down the polymer’s structure. In an emulsion, over-mixing may cause the product to separate prematurely, resulting in a drastic decline in viscosity.  

Optimizing flow rate involves determining the amount of shear or throughput needed. For example, a water-in-oil emulsion may require a slower addition speed than a traditional, oil-in-water emulsion, and the flow rate must be modified appropriately. Care must be taken for any product using a pump. Overshearing can occur if the formulation is pumped too quickly. If pumping is too slow, the formulation will experience extra time in an in-line homogenizer, thus also exposing the formulation to additional shear.

Two processes that require experimentation to optimize flow rates are the use of a powder eduction system and an in-line homogenizer. Theoretical calculations can determine the number of times a sample will pass through either, but actually performing the experiments is necessary to achieve optimal results.

Raw material dispersers and in-line homogenizers require proper flow rates for optimal usage. If the product is not flowing through a disperser at the proper rate, there will not be enough suction for properly incorporating the powders. Suction can be tested by measuring the vacuum being pulled at the inlet of the disperser with a vacuum/pressure gauge. Monitoring the flow rate when using an in-line homogenizer is necessary in order to calculate the theoretical number of times the product passes through it.

Michael Lowenborg is R&D manager at DPT Laboratories.

In the Mixer

Critical process parameters must be considered to optimize manufacturing of topical dosage forms.

Challenges in Topical Drug Manufacturing

Q. Our company needs more stability storage. What issues should we consider when deciding whether to build our own biorepository facility or outsource our storage?

A. One question to consider is if you have the location and facility space needed. By its nature, any biorepository facility needs a large investment in tailor-built premises. Floor space comes at a premium and much of the equipment needed has a large footprint, because it may have to be capable of accommodating bulk products. Typically, you should be looking for a resource with several million cubic liters of environmentally controlled storage space and storage suites that can house thousands of cubic meters of product. Geographic location should also be considered.  The location should be well away from natural disaster areas and in a convenient location for shipping options. Proximity to motorways and airports can be a distinct advantage, particularly considering the speed at which new global markets are opening up.

You should also consider the capital investment needed.  An average-sized storage room could cost anywhere between $63,000 to $188,000 to set up. A typical cabinet could cost upwards of $23,500. With separate rooms needed to suit different environmental conditions, costs can quickly mount up. Cabinets and chambers in a walk-in stability room should always be available, with additional chambers to be called upon for specific requirements such as retained samples, secondary storage, storage of quarantine samples, freeze and thaw testing, and aerosol testing.

—Patrick Jackson, business development director at Vindon Scientific.

If you have a problem with your equipment or process, an industry expert may have the solution. Please send your question to 

, editor of Equipment and Processing Report, and we may be able to provide an answer in a future issue. All questions will remain anonymous.

Troubleshooting

Our company needs more stability storage. What issues should we consider when deciding whether to build our own biorepository facility or outsource our storage?

Equipment and Processing Report-09-19-2012

Foaming Improves Drugs Made with Hot-Melt Extrusion

September 2012 Editor's Picks: Products from Uhlmann Packaging Systems and GE Healthcare

Challenges in Topical Drug Manufacturing

Considerations for Outsourcing of Stability Storage