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Synchrotron tomography explains observed dissolution variation in multi-particulate drug product batches

Drug products in the pharmaceutical industry are commonly prepared in the form of discrete multi-particulate units to enable control of dose for patients. The multi-particulate units can be prepared in a wide variety of routes including pelletisation, granulation or spray drying or by the use of beads. Beads are prepared by coating an inert spherical core with multiple layers, including that of the active ingredient. The components in each applied layer can have a significant impact on how the drug will be released from the bead and it is for this reason that bead products are a commonly used vehicle in the development of controlled release drugs.

One Pfizer late stage candidate is layered onto an inert sugar core along with several other layers to create the final dosage form. Notable differences in dissolution rates between batches of beads had been observed during development and it was vital to both understand the reason for the batch -to-batch variation and ensure consistent manufacture in the future.

The porosity of the layers is a critical feature found to explain observed dissolution behaviour. However accurate and highly resolved measurement of the physical integrity of these layers is a significant challenge in the development of advanced multi-particulate dosage forms. Previously, the Pfizer development team had performed surface and cross-sectional measurements using conventional SEM and benchtop X-ray microtomography, but neither technique provided sufficient resolution to “see” the pores within the layers. The outer layer of the bead, made of cellulose acetate, is only ~ 7 µm thick and the pores within that layer are much smaller.

High resolution X-ray tomography measurements were performed on the Diamond-Manchester Imaging beamline I13-2 at the Diamond Light Source by Dr Sally Irvine from Diamond’s Industrial Liaison team working closely with Pfizer scientists. Beads from three different production batches with varying dissolution profiles were mounted in glass capillaries for imaging. Tomographic analysis was successfully able to distinguish porosity differences between the different production batches and there was correlation between the porosity and the dissolution rate of the beads.

The non-destructive measurement of drug multi-particulates on I13-2 has enabled Pfizer scientists to obtain highly resolved data and this data has been used to successfully differentiate between different production batches. The greater understanding of porosity in layers will enable Pfizer to control batch-to-batch variations in the bead manufacturing process. The study has also highlighted the importance of the integrity of the bead coating in determining the dissolution rate.

The technique

X-ray imaging allows detailed information to be gathered from below the surface of a material through either full-field imaging, where the whole sample is illuminated, or through scanning, where the beam is focused to a small spot which is scanned across the sample. The high intensity and energy of the synchrotron X-rays produced at Diamond make it possible to image a much larger range of materials and sample thicknesses than conventional X-ray sources, and the brilliance of the synchrotron source produces very high-resolution images. The parallel, monochromatic beam enhances the image quality beyond what is possible with laboratory techniques and in a non-destructive manner. These high intensity X-rays also permit very fast measurements for high speed imaging experiments, monitoring changes in the sample during real-time, in situ experiments.

An imaging technique called X-ray (computed) tomography allows creation of three-dimensional reconstructions of the internal sample volume from a series of two-dimensional projections taken at different orientations. By creating a virtual image using tomographic reconstruction, it is possible to view any cross-section of the virtual image at any angle.

Tomography has many applications in the material science, engineering and biomedical fields. It can be used to characterise the internal structure of porous materials such as trabecular bone or metal foams. Tomography can be used to determine the size and shape of cracks and other defects inside components such as aircraft and automotive parts, where unexpected failures could have catastrophic results. Because it is non-destructive, X-ray tomography can be used to study the internal structure of precious and unique objects in archaeology and palaeontology – for example studying ancient insects fossilised in amber.

The Industrial Liaison Team at Diamond

Would you like to know more about pharmaceutical imaging and how you can apply it to your research? Do you perhaps have a development challenge that you are unable to solve in your lab or a material you wish to find out more about? Then please get in touch with the Industrial Liaison Team at Diamond.

The Industrial Liaison team at Diamond is a group of professional, experienced scientists with a diverse range of expertise, dedicated to helping scientists and researchers from industry access the facilities at Diamond. We’re all specialists in different techniques and have a diverse range of backgrounds so we’re able to provide a multi-disciplinary approach to solving your research problems.

We offer services ranging from full service; a bespoke experimental design, data collection, data analysis and reporting service through to providing facilities for you to conduct your own experiments.

We’re always happy to discuss any enquiries or talk about ways in which access to Diamond’s facilities may be beneficial to your business, so please do give us a call on 01235 778797 or send us an e-mail.

You can keep in touch with the latest development by following us on Twitter @DiamondILO or LinkedIn

Diamond Light Source is the UK's national synchrotron science facility, located at the Harwell Science and Innovation Campus in Oxfordshire.

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Synchrotron tomography explains observed dissolution variation in multi-particulate drug product batches

The technique

The Industrial Liaison Team at Diamond