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  • Things are rough all over

Dec 2008
Technique measures surface parameters for particles used in inhalation aerosols

Gary Boas,

The past 15 years have seen an important advance in the pharmaceutical industry: the development of inhalation powder aerosols for delivery of drugs to the respiratory tract. However, these aerosols convey only 20 to 30 percent of the total emitted dose to the lungs.

Developers of the drugs can improve their efficacy by controlling the surface roughness of the particles used in the aerosols because roughness affects a range of parameters, including the contact area between particles, the extent of aerosolization and the lung deposition. The developers must be careful, however. Although higher degrees of roughness have been shown to yield greater dispersibility of the powder particles, too much can lead to mechanical interlocking between particles, weakening dispersion.


Researchers have reported a technique offering rapid, precise measurement of surface roughness that could advance development of inhalation aerosols by the pharmaceutical industry. Shown here are surface roughness images of bovine serum albumin (BSA) particles (a-d) and lactose particles (e, f) acquired with the technique. Reprinted with permission of Langmuir.

The pharmaceutical industry therefore is keenly interested in the development of new techniques for rapid, precise measurement of surface roughness. Traditionally, researchers have monitored the surface roughness of large particles using mechanical methods such as stylus profilometry – which operates much like a record player, measuring a surface’s profile – or optical techniques such as image analysis or confocal microscopy.

For inhalation aerosols, they have called on methods including image analysis, atomic force microscopy and Brunauer-Emmett-Teller gas adsorption. These techniques have enabled qualitative and quantitative measurement of the topography and surface profile of both micron- and nanosize particles. Still, disadvantages exist – namely, the potential for sample destruction, relatively involved sample preparation and lengthy time requirements.

Noncontact optical profilometry with scanning white-light interferometry offers a means to sidestep these issues. Although investigators have used the technique to measure the surface roughness of large, solid pharmaceutical agents such as pellets and tablets, they have not applied it to fine particles such as those in inhalation aerosols. In the Oct. 7 issue of Langmuir, researchers from the University of Sydney and the University of New South Wales, both in Australia, reported a study in which they used the technique to assess the surface roughness of micron-size particles developed for dry powder inhalation.

Rapid measurement

White-light interferometry – in which information (in this case, about the surface properties) is gleaned from the interference of two beams of white light while scanning an object – proved key to the success of the study, researcher Hak-Kim Chan said. First, the technique provides surface measurements fairly rapidly. This is possible, Chan noted, because many particles can be captured in a single scan, in contrast with methods such as atomic force microscopy, which typically record particles one at a time. Also, because it is noncontact in nature it is not destructive, as some contact methods can be that use a mechanical stylus, which can scratch the surface and create artifacts in the measurements.

Although data capture is relatively quick and painless, Chan said that data analysis can be tedious because it can involve separating the noise from the signal in the data and flattening the particle surface to overcome the curvature effect, thus skewing measurements on spherical objects by affecting the difference in height between the surface texture and the flat reference plane. This effect can be significant because the particles in question are so small. Also, “the resolution is not as high as (with) atomic force microscopy, but it’s sufficient for our work.”

The experimental setup is relatively straightforward. First, a beam emitted from a white- light source is split into two paths. One beam travels directly to the surface of the object, while the other is sent to a Mirau interferometer, which produces the reference beam. (The white-light interferometer comprises a microscope objective, a transparent mirror and a reference mirror.) The two beams are reflected back to the beamsplitter and recombined to create “interference fringes,” the result of the two beams superimposing. A CCD camera records the fringes. Information about the surface profile can be extracted from these interference patterns.

The researchers showed that they could achieve subnanometer resolution with the technique, with step heights as small as 0.1 nm. They also noted that the high 150-nm lateral spatial resolution enabled them to identify nearby objects along the axis and to scan large areas – and, thus, image multiple particles – because of the long working distance of as great as 10,000 μm when scanning in noncontact mode.

They also demonstrated that the technique could serve as an effective complementary tool for rapidly evaluating both surface roughness and morphology in the smaller particles used in inhalation aerosols, complementing indirect methods such as Brunauer-Emmett-Teller gas adsorption. Here, for example, researchers would use the latter technique to probe the total surface area as an indicator of surface roughness, and optical profilometry to quantify the roughness, by measuring the height data of the surface features.

More work remains to be done, however, before the technique can be implemented by the pharmaceutical industry. Because the current study constituted an early look at applying scanning white-light interferometry in pulmonary drug delivery, Chan said they would like to “further explore the technique in this field,” such as applying it to micron-size agglomerates comprising nanoparticles.

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