To manufacture 2–6-µm microcrystalline particles for inhaled drug delivery, the pharmaceutical industry often mechanically mills large crystalline material into a size suitable for respiratory medicines. This high-energy, destructive process, however, can introduce many problems (e.g., poor chemical and physical stability) that can lead to product variation and performance limitations. Conversely, constructive particle engineering using scalable power ultrasound-mediated crystallization (i.e., sonocrystallization) and processing technologies offers significant benefits for the manufacture of inhalable drug powders. Sonocrystallization involves the application of power ultrasound to a processing medium, which leads to the formation of energetic cavitation bubbles where crystal nucleation can take place (1).

Ultrasound Mediated Amorphous to Crystalline transition (UMAX, Prosonix, Oxford, UK) technology, a proprietary sonocrystallization method, is  used to manufacture inhalable drug particles. To date, particles of corticosteroids, beta agonists, and anticholinergics—drugs that treat asthma and chronic obstructive pulmonary disease—have been manufactured at kilogram scale. UMAX, which is being evaluated for critical process development and industrial scale-up, requires robust industrial ultrasonic equipment operating at 20–100 kHz and facilitates the manufacture of spheroidal and regular-shaped particles for dry-powder inhalers (DPIs) and metered-dose inhalers (MDIs). 

The UMAX process involves careful spray drying of an active pharmaceutical ingredient (API) solution, applying ultrasound to the amorphous or part-amorphous particles suspended in a nonsolvent, and crystalline-solid isolation through spray drying, evaporative drying, or supercritical carbon-dioxide drying. The latter drying process is broadly applicable, particularly to nonvolatile hydrocarbons, but not to aqueous systems. Final-product isolation by spray drying is considered best for volatile solvents and water. The particles produced by applying ultrasonic energy have the optimal size, shape, surface rugosity, and surface free energy for formulation as respiratory drug products. As a result of acoustic cavitation, the particles become completely crystalline and acquire a rough, stable surface with a surface area significantly greater than that of mechanically milled material.

Aerosolization efficiency depends on properties such as particle size and size distribution, surface properties, crystallinity, hygroscopicity, electrostatic charge, and relative humidity. In addition, a direct relationship exists between the fine-particle fraction (FPF)—the fraction of particles expected to reach the airways—and particle size, powder cohesion, and air shear force. By optimizing and controlling these performance criteria, UMAX facilitates the production of highly stable particles that are delivered to the lung more efficiently than mechanically micronized material is (2).

UMAX requires initial solution atomization to confer sphericity on the particles prepared. Conversely, Dispersive Crystallization with Ultrasound (DISCUS, Prosonix) is a liquid-based ultrasound-assisted antisolvent method whereby powerful cavitation effects promote efficient solute and solvent diffusion into the antisolvent with the concomitant formation of microcrystals. An antisolvent stream is recirculated rapidly through the flow cell while the substrate feed solution is fed slowly and directly into the flow cell. This method leads to rapid dispersion and crystallization of micrometer- and submicrometer-sized particles that can be isolated by spray drying, for example.

UMAX and DISCUS are  used to engineer and manufacture microcrystalline single- and dual-component particles for DPIs and MDIs, thus yielding structured drug products that can outperform existing commercial medicines. Many inhaled corticosteroids, including budesonide, fluticasone propionate, and mometasone furoate; beta agonists, including fenoterol hydrobromide, salmeterol xinafoate, and formoterol fumarate; and anticholinergic agents, including tiotropium bromide, have been produced. UMAX can be used to prepare fluticasone propionate at multikilogram scale for DPIs and MDIs. 

As well as overcoming the particular problems of milling this steroid, UMAX can yield particles with exceptional stability, thus producing excellent 

 performance. Users can match the drug’s performance in MDIs to that of marketed drug products (e.g., to demonstrate generic equivalence) or enhance it to yield superior FPF. This flexibility can help users design generic drug products with new formulations or delivery routes to improve clinical performance or target a new therapeutic area. Structured drug products derived from UMAX processing show excellent stability and consistency of fine-particle delivery over several months. Anticholinergic agents can be prepared with spherical morphology, thus avoiding the surface amorphicity and inconsistency in product formulation typical when high-energy milling is used for this group of pharmaceutical ingredients. When formulated for DPIs and MDIs, these agents have shown great stability and excellent 

 impactor performance during a period of one year. 

UMAX technology also can manufacture inhaled combination particles that include two or more pharmaceutical ingredients processed into highly crystalline particles. This technique is particularly beneficial when the drugs act in synergy or must be delivered together accurately on the lung surface. The technology has created particles with API ratios from 1:1 to 1:100. The data have clearly demonstrated the particles’ dose-content uniformity and consistent mass deposition of both APIs, irrespective of the time between formulation and use (2).

Industrial particle engineering with UMAX has yielded high-quality results in the manufacture of microcrystalline single- and dual-component particles designed for formulation into structured DPI and MDI drug products. The particles have exhibited excellent performance, consistency, and reliability in all delivery platforms, independent of device. UMAX technology could lead to rapid marketing approval of differentiated products, and to new therapies for emerging markets using low-cost simple devices. 

Proceedings of Respiratory Drug Delivery 2010, 

Book 3 (Orlando, FL, 2010), pp. 753–757.

Graham Ruecroft is chief technical officer of Prosonix, Magdalen Centre, Robert Robinson Ave., Oxford Science Park, Oxford OX4 4GA, United Kingdom, tel. +44 0 1865 784250, fax +44 0 1865 784251, 

Articles

In the Mixer

Power ultrasound-mediated crystallization (i.e., sonocrystallization) can offer significant benefits for the manufacture of inhalable drug powders, compared with destructive techniques such as milling.

Sonocrystallization Can Yield Optimized Inhalable Drug Powders

The Fitzpatrick Company
 Roller compactor provides efficiency and flexibility


 The Fitzpatrick Company (Elmhurst, IL) designed its CCS 1025 Contained Chilsonator system to process various products efficiently. The system’s high-speed vertical precompression feed screw provides a uniform downward force on the product, thus helping to feed it to the nip region of the rolls. The vertical orientation and speed of the screw are intended to ensure that product is distributed across the face of the rolls evenly. The feed screw’s vertical orientation provides a path upward for air that is aspirated from the process, thus creating an efficient deaeration system.

The CCS 1025 system is designed to positively seal the product inside the process areas. Operators can disassemble the device easily for cleaning and reconfiguration. The system includes a wash-in-place to simplify cleaning. The CCS 1025 machine’s roll and size-reduction housing are designed as an integrated unit to minimize headroom requirements. Users can install the device in wall or as a free-standing unit.

Parsec Automation
 Operations-management platform is designed for quick deployment


The LITETrak system is a version of Parsec Automation’s (Brea, CA) TrakSYS operations-management platform designed for rapid deployment without programming. The software can track production lines within an operations environment. The system contains the most commonly used features and functions of TrakSYS and is preconfigured with templates and dashboards.

The LITETrak system allows users to define attributes for each product, define production schedules, analyze asset and product performance, and track opportunities for improvement. The software’s web-based interface displays business-intelligence reports and key-performance-indicator dashboards, thus eliminating the need for a client-side software installation. The LITETrak software allows operators to contextualize automatically captured data, thus enabling root-cause analysis. Users also can trigger production stoppages manually. 

The LITETrak software can scale up to a complete manufacturing execution system that interfaces with various enterprise resource planning (ERP) systems. The software provides ERP systems with real-time manufacturing information.

PharmTech's monthly newsletter, Equipment and Processing Report, reviews the Editor's Picks for the November 2010 edition from Fitzpatrick and Parsec Automation.

December 2010 Editor's Picks: Products from Fitzpatrick and Parsec Automation

Is pharmaceutical manufacturing as much an art as a science? Consider this: pharmaceutical companies produce the majority of their drugs as tablets or capsules. But despite the industry’s long experience with creating these dosage forms from powdered ingredients, many aspects of powder behavior and blending operations remain mysterious. Regulatory initiatives and the need for efficiency are pressing drugmakers to gain a better understanding of their processes. Positron-emission particle tracking (PEPT), a new technique developed by David Parker, professor of physics at the United Kingdom’s University of Birmingham, could shed light on flow processes. 

 talked to Parker’s colleague Jonathan Seville, dean of the School of Engineering at the University of Warwick, to find out more about the technique.

Seville: In PEPT, we make a single particle into a positron emitter and follow it around in a process. We normally use fluorine 18 as the radioactive material, which is made from oxygen in a cyclotron. We produce radioactive water—positron-emitting water—and attach it to the surface of a particle. We aim to put into the process a particle with properties identical to those of the bulk. When positrons are produced, they annihilate with electrons to produce two gamma rays that travel along the same line in opposite directions. We track the particle during the process by triangulation.

EPR: What kind of equipment does PEPT require?

Seville: We started with a conventional positron-emission tomography scanner. In the past 10 years, we’ve acquired redundant medical scanners from hospitals, broken them down into their detectors, and built the detectors back up into boxes that we can set around the equipment we’re interested in. That’s reasonably easy to do, and you get something that is optimized for that geometry.

How do you analyze a mixing process with PEPT?

Seville: Add a radioactive particle, currently the lower size limit is about 60μm, and follow its motions for as long as an hour. It will show whether the material is visiting all parts of the mixer. It results in a plot of the dispersion associated with each volume element of the mixer. That plot shows where the mixing is going on.

Seville: Gamma rays are penetrating. They let operators see through metal walls 1 cm thick, so they can look at real pieces of equipment. In particle-tracking mode, scientists find the particle by triangulation, and that’s very fast and produces lots of data. The particle can be found at least 100 times per second. The technique can reveal particle velocities as high as 10 m/s without too much difficulty. That’s much better than other radioactive tracking techniques could normally achieve. The other big advantage, from my point of view, is that it’s quite easy to attach a positron emitter to a lot of things. Also, operators don’t have to stop the mixer because PEPT is a fast technique. It’s almost a real-time technique.

Seville: The need for the equipment is a drawback. Several pharmaceutical companies probably do have PET cameras, but they can’t do this technique simply with a PET camera. Although the hardware is the same, the software is completely different. Also, the amount of radioactivity involved is tiny, but most industries are extremely nervous about using radioactivity in a production environment.

EPR: How could PEPT improve pharmaceutical manufacturing processes?

Seville: It’s a background technique rather than something you would use on your production line. I think it would certainly tell you the best place on your vessel to put your near-infrared sensor to get a typical result.

EPR: Could PEPT be used for process development?

Seville: Yes. People use it to understand physical processes such as mixing. In my experience, it provides information that you simply can’t get from any other technique. 

Operators also could use PEPT to scale a process up to an intermediate size. It depends on how big the production scale is. Many pharmaceutical processes are of a reasonable scale that we could look at. At a smaller scale, we can give people a complete visual image of the motion everywhere in the vessel. As the scale gets bigger, we might find it rather difficult to give a complete picture. We might end up giving cycle-time information, but I think that’s nevertheless useful.

EPR: Have you used the technique in any joint projects with pharmaceutical companies?

Seville: We’ve done work with pharmaceutical companies on coating. We’ve taken a single pellet or tablet, made that into a positron emitter, followed it around a Wurster coater, and looked to see where it comes into the spray region and where it goes out of the spray region. Colleagues at Birmingham and I also have done work on coating for Merck, Sharp, and Dohme [Whitehouse Station, NJ]. And we’ve done work on mixing and granulation for GlaxoSmithKline [London] and on fluidization and flow for many companies.

Production Lines

Equipment and Processing Report talked to Jonathan Seville, dean of the School of Engineering at the University of Warwick, to find out how positron-emission particle tracking could help pharmaceutical manufacturers gain process understanding.

Equipment and Processing Report-12-15-2010

Sonocrystallization Can Yield Optimized Inhalable Drug Powders

December 2010 Editor's Picks: Products from Fitzpatrick and Parsec Automation

Positron-Emission Particle Tracking Could Demystify Mixing