X-ray tomography is a new imaging technique that offers a non-destructive method of obtaining 3-D images of microstructure. Tom Ray, RSSL, illustrates how it can be useful in product development and troubleshooting.
There are many ways in which microstructure affects the performance and characteristics of pharmaceuticals, medical devices and pharmaceutical packaging. For example, particle size and particle distribution play a part in the dissolution of tablets. The quality and thickness of a coating helps determine the stability of a capsule. Microstructure generally determines the flexibility of a plastic and hence the performance of packaging or the integrity of seals. The internal structure of a delivery device will affect how well the dose is targeted.
Similarly, given that microstructure contributes to optimum performance, micro-structural defects are often the root cause of a product’s poor performance or outright failure.
From particle sizers to powder flow analysers, from microscopes to moisture analysers there is a barrage of technology that can be brought to bear on the investigation of microstructure and/or particles within products. However, most of these methods are in some way destructive. Given the ‘closed’ nature of most pharmaceutical products, it is frequently not ideal for this to be the case. Indeed, in almost every case the ‘perfect’ analytical solution would be non-destructive, allowing the key parameters of the product to be measured in as near a natural state as possible. This is just the possibility afforded by X-ray tomography, a relatively new technology that is already proving its worth in new product development, product trouble-shooting and foreign body investigations.
non-destructive technique
X-ray tomography is a non-destructive technique that is already familiar to many through its application in medical imaging. The 3-dimensional (3-D) images from a CAT scanner are the product of this same technology. However, within the laboratory, high resolution X-ray CT (computed tomography) differs from conventional medical CAT scanning in its ability to resolve details down to a few tens of microns, whereas the medical CAT scan has a much lower resolution.
Where the two technologies are much the same is that both involve taking a sequential set of images through a sample. Thereafter a specialised algorithm is applied to these sections to create a three-dimensional representation of the sample within the computer. By building up layer upon layer of thin sections the technique can recreate the fine detail for the whole of a sample’s interior and exterior microstructural features. The thickness of each section gives rise to the idea that the CT image is composed of voxels (volume elements) rather than the pixels (picture elements) that describe 2-D images.
As will be obvious from its name, the technique involves exposing a sample to X-rays, which are attenuated i.e. scattered or absorbed by the sample. X-ray attenuation is primarily a function of the incident X-ray energy, density and atomic number of the material being imaged. Hence X-ray tomography can provide imagery and data reflecting both the structure of the material and the distribution of its individual constituents.
Some of the information gained by X-ray tomography might also be gained by scanning electron microscopy (SEM). However, where X-ray tomography scores over the SEM is that it is applied to the whole sample. Microscopy is limited to looking at a few sections, prepared, quite literally by slicing the sample thinly. Hence, microscopy is destructive, liable to produce artefactual distortions as a consequence of the preparation technique, and ultimately relies on the skill of the microscopist to infer from a few images what is going on with the whole sample.
That is not to dismiss microscopy. There is much it can add to the investigation of foreign bodies and the understanding of microstructure. However, X-ray tomography is better at presenting a clear picture of what is happening across the whole sample, perhaps helping the microscopist to decide where to focus use of the SEM, rather than requiring them to work ‘blind’.
Of course, any 3-D image produced by the technique is rendered in two dimensions when published in print. Hence the images shown here can only give a flavour of what the scientists see as they scan a sample. The box drawn around the image in Figure 1 gives some perspective on how particles are distributed within this pharmaceutical capsule. In this particular example, the customer was experiencing some issues with dissolution of capsules, and since the distribution of ingredients, both actives (API) and excipients, is a key factor that determines dissolution properties, it was useful for the customer to understand how well ingredients were dispersed within the product.
It is worth noting that the capsule was viewed whole, but the image itself has been cut. Hence the whole of the capsule is not shown in the image. Also, the technique allows for the image to be rotated, expanded, sectioned and otherwise manipulated so that the whole of the capsule can be explored. If the API were concentrated in one region of the capsule this would be immediately obvious, whereas microscopy might miss this fact if the section was taken at the wrong place.
The same observation applies to the image in Figure 2, which shows how uneven coating of a capsule has created a weakness and leakage. The manufacturer had received customer complaints so needed to understand exactly where the coating process was failing to make changes to the process that would remedy the problem. In fact, X-ray tomography revealed both the thin-ness of the coating in one region of the capsules, and also an air bubble elsewhere, both of which could cause weakness and lead to leaks.
Another area where X-ray tomography scores over microscopy is in its ability to investigate products while still within their packaging. For example, the technique might be used to investigate whether the wrong pill had been packaged in the wrong blister pack. It has also been used in investigations of counterfeit products, where it is important to keep the integrity of the whole pack in order to see what is inside.
It has also been possible to examine internal features of a medical device, locating where blockages had built up that prevented delivery of a medicine. In one such investigation, multiple blockages were found internally showing the value of the full picture that X-ray tomography gives. Other methods of investigation might have missed this multiplicity of events, or failed to spot the precise locations.
In conclusion, while the 2-D images shown here can only give an indication of the 3-D detail afforded by X-ray tomography, anyone familiar with the hospital CAT scan will immediately recognise the benefit of imaging the entirety of a sample rather than just a few sections. It means that important details are not overlooked and rather than inferring the whole picture from a few carefully selected images, one simply sees the whole picture.
Whether looking at the intended micro-structural features that explain product performance, or unexpected features such as foreign bodies or microstructural defects, the technique can provide useful information. In some cases, perhaps where packaging cannot be opened, or where foreign bodies should not be removed, it offers a unique and perfect solution for investigating an issue and is a powerful addition to the microscopist’s armoury.
