Hot-melt extrusion (HME) using twin-screw extruders (TSE) is increasingly being used to make solid dispersions of drugs in a polymer matrix. The process is useful for poorly soluble drugs and for alternative dosage forms such as controlled-release drug devices. Bench-top TSE can be used to develop formulations, and mid-size TSE can be used for process development and scale-up.

While in the past, laboratories had only small-scale batch mixers for formulation development, during the last few years, several extruder manufacturers have introduced laboratory bench-top TSE suitable for API quantities as small as 5–20 g, which enables pharmaceutical manufacturers to test new drug candidates using the HME process. A TSE has shorter residence time and exposes the material to lower thermal exposure than a batch mixer, notes Andrew Loxley, PhD, director of new technologies at Particle Sciences, a contract organization providing drug-development services. Particle Sciences uses either small-scale batch mixer or a TSE (Thermo Scientific MiniLab) to prepare proof-of-concept materials and identify early-lead formulations before running process experiments on its 18 mm mid-size extruder. While bench-top extruders are useful as a screening tool, they do not scale up to larger-volume extruders because equipment design attributes are fundamentally different. 

Mid-size extruders in the range of 12–18 mm in diameter can be used for process development in preparation for scale-up to pilot-size or small commercial-size TSE in the range of 26–32 mm and perhaps eventually to larger commercial-size TSE in the range of 40–70 mm. Extruder manufacturers, such as Coperion, C.W. Brabender, Leistritz, Steer America, and Thermo Scientific, offer extruders for the pharmaceutical industry in the mid-size range that can be used for process development and clinical-scale trials as well as small-scale commercial runs. Throughputs on Coperion’s 18-mm ZSK, for example, range from 500 g/h to 4 kg/h, with a minimum batch size of 1 kg. CDMO Bend Research uses an 18-mm extruder that runs up to 3 kg/h and has used batch sizes as small as 300 g. Bend Research has scaled up from its 18-mm extruder to throughputs as high as 10 kg/h on its 27-mm extruder, and from a 27-mm to a 50-mm extruder, all of which have similar equipment attributes.

To scale up well, the basic geometry of the smaller extruder should match that of the larger extruder. The ratio of the outer diameter (OD) to the inner diameter (ID) of the screw is a key parameter. The Coperion 18-mm extruder, for example, has the same OD/ID ratio of 1.55 that is found on the larger Coperion extruders. The screw elements of a TSE (i.e.: feeding, conveying, melting, mixing, venting, and pumping) are modular and can be easily changed to optimize the screw profile. Although the same screw profiles and an appropriately scaled length to diameter (L/D) of the process section can be used during scale-up, adjustments are often needed, notes Richard Steiner, sales engineer for pharma and food at Coperion. The surface area to volume ratio is reduced as the size of the extruder increases, which can affect temperature convection and influence mixing characteristics, so that more mixing sections may be needed, says Robert Roden, technology manager at Steer America. Matt Shaffer, senior research engineer at Bend Research, adds that mass- or heat-transfer limitations can arise at larger scales. He says these limitations can affect dispersion and throughput and must be compensated for by changing the process section length, adjusting screw design, or changing screw speeds. Software tools can be used as a first approach to calculate probable scale-up conditions. Skilled operators, however, are key. Steiner concludes, “You still need experienced people who understand the machines to run the physical tests on the line and adjust as needed.”

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With the increasing use of hot-melt extrusion, extruder manufacturers have developed mid-size twin-screw extruders that facilitate process development and scale-up to commercial processes.

Mid-Size Extruders Enable Scale-Up of Hot-Melt Extrusion

Many recently approved parenteral drugs are based on biotechnological processes. In the past three years, more than 30% of the parenteral FDA approvals granted were for lyophilized substances, according to Vetter’s research. These drugs are extremely sensitive to external influences, such as oxygen, sunlight, and pH values, which, along with other factors, can degrade a substance and negatively affect its bioactivity. In the case of proteins and other recombinant substances, the simplest and safest way to maintain bioactivity is by using a liquid formulation. Water, however, is both a medium and a reaction partner that can cause hydrolysis or deamidation, a form of hydrolysis of proteins. In addition, water increases chemical and physical instability, thereby allowing reactions with other substances. Liquid formulation does not allow sufficient long-term stability for many drugs. It makes sense, therefore, to remove as much water as possible from the liquid formulation to stabilize the substances until they are administered. The substance can be reconstituted with a diluent just before being injected.

Freeze-drying in primary packages has become a standard drying method. In the lyophilization process, the dissolved substance is frozen. The water is sublimated in a vacuum, and any remaining water is removed by raising the temperature slowly. The active substance and various excipients form a solid cake with an amorphous or crystalline structure. Depending on the formulation, the product will remain stable in this form for two to three years and can be reconstituted shortly before application. Two different systems have become established for freeze-drying in primary packages: vials and dual-chamber systems. 

With new drugs, the vial may be the best primary packaging system. The entire filling process and the system with all its components (i.e. stoppers, seals, and adapters) are less complex than dual-chamber systems and are therefore simpler to develop. On the other hand, administration of the drug is more complex because diluents must be added separately. To administer, the user meters the diluent from a second vial into a syringe and then adds the diluent to the lyophilized vial for reconstitution. Next, the reconstituted drug is withdrawn from the vial and, after changing the needle, administered to the patient. A volume of 1 mL of active substance typically requires an overfill of 20% or more to ensure that an accurate dose is pulled into the syringe (1). For larger volumes, a lower overfill percentage is needed.

An alternative is the dual-chamber system, which contains the active substance and the diluent in two separate chambers that remain unmixed until shortly before administration. The drug compound is lyophilized directly 

 in the front chamber. After lyophilization, the diluent is filled into the second chamber. For administration, a simple "twist and push" forces the diluent through a glass bypass into the front chamber, where it is mixed with the active substance. Dual-chamber systems reduce the overfill needed and increase precision in dosing because drug and diluent are premeasured. For example, in a dual-chamber lyophilization system (see Figure 1, Vetter Lyo-Ject syringe) in which the substance is lyophilized and reconstituted within the system, 1 mL of active substance requires an overfill of only 6%, and 5 mL requires just 3%, according to Vetter’s research. Dual-chamber systems also decrease risk of medication error by eliminating the use of multiple vials and needles.

While the first steps of the freeze-drying process, compounding and filtration, are the same for vials and dual-chamber systems, subsequent steps of the freeze-drying process differ somewhat. 


 When lyophilizing in a vial, a stopper with an opening is inserted but not sealed, which allows water vapor to escape during freeze-drying. The vial is placed in the freeze-dryer (see Figure 2). This step is followed by the freezing phase, which can last anywhere between two and five hours depending on the substance, the composition, and the amount of substance solution present. The setting plates are cooled to -50 °C or less. The temperature in the vials drops to the -40 °C to -50 °C range, and the water in the solution freezes. Primary drying under vacuum begins by generating pressure of 0.1 mbar or less and opening an access valve to the condenser, where the temperature ranges from -70 °C to -160 °C, so that the water sublimates. The procedure can last from five hours to five days. Lyoprotectors permit an amorphous or crystalline structure to form from the solidifying substance solution. In the secondary drying step, the temperature is raised, and the product is kept under vacuum to extract most of the remaining water, leaving a “lyo-cake” with a water content of 1–3 %. The freeze-dryer is partially depressurized to approximately 700 mbar using dried nitrogen. The inert gas protects the substance in the primary packaging from oxidation. Next, the setting plates automatically drop, thereby pressing the stoppers into the vials. Sealing the vial under a partial vacuum is advantageous because when reconstituting the drug, the solvent is drawn in rather than being injected with pressure. The vial is removed from the freeze-dryer and capped with a flanged cap. 


 Freeze-drying in a dual-chamber system has some differences. The middle stopper is inserted prior to the filling of the solution, thereby keeping the two chambers separate and preventing the substance from carrying over into the other chamber. The first chamber is filled with solution, and the closure system is placed on the dual-chamber syringe, thereby leaving an opening much in the same way as with the vial. The dual-chamber lyophilization process, however, is run differently than in vials because the product is situated on the top of the stopper away from the shelf. The process is governed by convection and radiation rather than by direct conductive heat exchange. After lyophilization, the system is depressurized to atmospheric pressure to avoid shifting the middle stopper and sealed by pressing the closure down with the upper-setting plate. If a cartridge system uses a crimp closure, it cannot be sealed inside the lyophilizer, but must be flanged outside the freeze-dryer under special climatic conditions with humidity of less than 10%. After the first chamber is sealed, the second chamber is filled with diluent, and the end stopper is set in place. Other processes and secondary packaging can be performed. 

BioPharm Intl. Biopharmaceutical Trends Report Supplement

Joerg Zimmermann is the director of process development and implementation at Vetter Pharma-Fertigung GmbH & Co. KG, Schuetzenstrasse 87, 88212 Ravensburg Germany, 
Tel. +49(0)75137000, 

In the Mixer

The author discusses the relative advantages and disadvantages of lyophilization in vials and dual-chamber systems.

Comparing Lyophilization in Vials and Dual-Chamber Systems

Q. We need to measure the particle size of a moisture-sensitive powder. We would like to use dry analysis on our laser-diffraction system, but the particles are fragile and we’re struggling to get robust results. Is wet measurement with a nonaqueous solvent the only option?

A. Successful dry dispersion with pressurized air relies on applying enough energy to completely separate the particles without damaging the primary particle. For fragile particles such as yours, this can be challenging. It may be that wet measurement is the best answer. Before reaching that conclusion, though, you should rigorously assess the feasibility of dry dispersion.

First, carry out a pressure titration and measure particle size as a function of the pressure of the dispersing gas. Increasing pressure puts more dispersive energy into the system, and will therefore tend to decrease the measured particle size. Ideally, a plot of the resulting data will have a plateau, which is a region where increasing pressure has no impact on particle size, because complete dispersion has been achieved. If your data has a plateau, you have identified a condition for dry dispersion. However, as ISO13320 (2009) observes, such a plateau is seldom observed in the real world (1). In the absence of a plateau, you can compare your results with wet data. If, at a certain dispersion pressure, the match is very close across the complete particle-size distribution, you can use these dry-dispersion conditions. If not, it is possible that your disperser may be breaking up the primary particles. 

Dispersers differ in their design. Some rely heavily on impaction, which is extremely efficient when the primary particles are strong enough to withstand the forces generated, but gentler dispersion can be a more effective strategy with more fragile materials. Some laser-diffraction instruments have dry systems that can be configured with different disperser types to accommodate the widest possible range of materials. Consider whether your disperser can be switched for something more suitable. If not, then wet measurement may be your only answer, unless your need is great enough to justify investment in a brand-new instrument.

—Carl Levoguer, product marketing manager for laser particle sizing and imaging at Malvern Instruments.

Particle Sizing Analysis – Laser Diffraction Methods

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Troubleshooting

We need to measure the particle size of a moisture-sensitive powder. We would like to use dry analysis on our laser-diffraction system, but the particles are fragile and we're struggling to get robust results. Is wet measurement with a nonaqueous solvent the only option?

Determining Whether Dry-Dispersion Can Be Used in a Laser-Diffraction System

ACS Valves 
 Rotary feeder introduces powders to pneumatic conveying systems


 ACS Valves’s Aero-Flow series of rotary feeders is designed for pneumatic conveying of dense materials such as fine powders. The feeders use a proprietary, dual-induction endplate design that introduces pressurized air from both endplates into the rotor pockets carrying process material. The high bulk density material, when mixed with air, is more effectively released from the rotor pockets and is more efficiently introduced to the pneumatically conveyed material flow.

While single-induction designs have only one source of pressure-conveying air, the second air source in the dual-induction functionality is intended to improve aeration and flowability of products with sticky material characteristics. The feeder is designed to integrate with most pharmaceutical pneumatic conveying applications, and the dual-induction design’s applications are appropriate for applications in which the material’s characteristics make efficient material transfer challenging. The feeder is available with 304 and 316 stainless-steel cast housing for sanitary applications.

PharmTech's monthly newsletter, Equipment and Processing Report, reviews the Editor's Picks for the February 2012 edition from ACS Valves and G-Con.

Equipment and Processing Report-02-15-2012

Mid-Size Extruders Enable Scale-Up of Hot-Melt Extrusion

Comparing Lyophilization in Vials and Dual-Chamber Systems

Determining Whether Dry-Dispersion Can Be Used in a Laser-Diffraction System

February 2012 Editor's Picks: Products from ACS Valves and G-Con Manufacturing