The use of X-ray microtomography to investigate the microstructure of pharmaceutical tablets: Potentials and comparison to common physical methods

Within this study, tablets microstructure was investigated by X-ray microtomgraphy. The aim was to gain information about their microstructure, and thus, derive deeper interpretation of tablet properties (mechanical strength, component distribution) and qualified property functions. Challenges in image processing are discussed for the correct identification of solids and voids. Furthermore, XMT measurements are critically compared with complementary physical methods for characterizing active pharmaceutical ingredient (API) content and porosity and its distribution (mercury porosimetry, calculated tablet porosity, Focused Ion Beam-Scanning Electron Microscopy (FIB-SEM)). The derived porosity by XMT is generally lower than the calculated porosity based on geometrical data due to the resolution of the XMT in relation to the pore sizes in tablets.

With rising compactions stress and API concentration, deviations between the actual and the calculated API decrease. XMT showed that API clusters are present for all tablets containing >1 wt% of ibuprofen. The 3D orientation of the components is assessable by deriving cord lengths along all dimensions of the tablets. An increasing compaction stress leads to rising cord lengths, showing higher connectivity of the respective material. Its lesser extent in the z-direction illustrates the anisotropy of the compaction process. Additionally, cracks in the fabric are identified in tablets without visible macroscopic damage. Finally, the application of XMT provides valuable structural insights if its limitations are taken into account and its strengths are fostered by advanced pre- and post-processing.

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The use of X-ray microtomography to investigate the microstructure of pharmaceutical tablets: Potentials and comparison to common physical methods, International Journal of Pharmaceutics: X, Volume 3, 2021, 100090, ISSN 2590-1567, https://doi.org/10.1016/j.ijpx.2021.100090. (https://www.sciencedirect.com/science/article/pii/S2590156721000190)

Materials
The pharmaceutical excipient microcrystalline cellulose (MCC, x10 = 20 μm, x50 = 63 μm, x90 = 139 μm, Vivapur® 101, JRS Pharma, Rosenberg, Germany) and the active pharmaceutical ingredient ibuprofen (IBU, x10 = 9 μm, x50 = 31 μm, x90 = 34 μm Novartis Pharma, Basel, Switzerland) were selected as materials. MCC mainly consists of elongated primary particles and of approximately spherical agglomerates, while the particle shape of IBU is approximately rectangular (Fig. 1). The solid density determined by helium pycnometry is 1.544 g/cm3 for MCC and 1.112 g/cm3 for IBU. Additionally, magnesium stearate (Faci, Carasco GE, Italy) was used as lubricant.

Conclusion and outlook
In the present study, methodologies for a systematic characterization based on XMT measurements and image processing were applied to visualize and investigate the microstructure of tablets consisting of the API Ibuprofen and the excipient microcrystalline cellulose. Image segmentation of three phases (excipient, API, pores) was performed on relatively large volumes with a resolution of (5.06 μm)³ of the voxels. This limits the identification of small pores, which results in an underestimation (50–75%) of the porosity and an overestimation of the solid phase of the lower density. However, deviations amount to less than 5%. A higher number of larger pores (approx. 40% of pore volume > 5 μm at 100 MPa) are detected by XMT while MIP yields higher fractions of small pores (> 95% of pore volume < 5 μm at 100 MPa). FIB-SEM however confirmed the existence of both, large and small pores within the tablets. Accordingly, XMT is a useful tool for determining true internal pore sizes (instead of bottlenecks), which may in the future, better contribute to the understanding of tablet strength.

Respecting the necessary size of ROIs, the microstructure can be examined regarding the distribution and the homogeneity of the IBU. Coarse IBU clusters resulting from agglomeration in former process steps, such as blending, are visualized and can be interpreted towards their deformation based on the applied stresses and their connectivity in view of tablet strength. Such clusters resulted in high values for the empirical standard deviation, especially for low IBU contents, which may lead to varying contents between the parts of divided tablets or between different tablets in general. This inhomogeneity may lead to a high local stress gradient during the elastic recovery after compaction due to the differing instantaneous elastic recovery behavior of the pure substances. In consequence, cracks can be proved by XMT when they are inconceivable from the tablet surface. However, internal cracks (at 200 MPa compaction stress) directly coincides with a loss of tensile strength. In addition, cord length analysis was introduced to provide direction-specific information on the connectivity of each solid phase, providing anisotropy information and measuring the deformation of particles (lower cord-lengths in narrower distributions in z-direction) and stagnation or loss of connectivity at high stress (200 MPa) connected with internal cracks.

These presented methods can be used as tools to identify critical effects on the quality attributes of pharmaceutical tablets, such as on bond networks, and, by that, supply crucial information. Prior process steps, like mixing and filling procedures also influence blend properties (homogeneity and the size of particle clusters inside the blend).Therefore, the distribution and dispersion of IBU and excipient within the tablet structure as well as their impacts on mechanical properties should be analyzed by XMT measurements in more detail in future studies. Here, different aspects can be considered to obtain images of higher quality. Thus, a more precise analysis of the phase and especially pore distribution can be conducted. First, a higher resolution of the resulting image would improve the quality, although the inspected volume decreases simultaneously. Using tablets with a lower diameter might contribute to better results as the penetration depth decreases and therefore the reduction of the X-ray intensity decreases as well, leading to a better intensity resolution. An XMT device with a higher resolution of the CCD camera would further contribute to better results. Alternatively, a synchrotron, providing only monochromatic X-ray beams, enables a better differentiation between different solid densities and thus, between the different phases. Instead of standard X-ray imaging methods like computed tomography which detect differences in the intensity after transmitting through the sample, an alternative method called phase-contrast X-ray imaging or phase-sensitive X-ray imaging can be used. Here, the contrast-to-noise ratio can be improved using X-ray interferometry, which measures the X-ray deflection, providing more detailed information about density variations especially to low densities.

Using different imaging techniques, like FIB-SEM and Raman in parallel, might also be an interesting approach to gain deeper insight locally into the pore structure and the distribution of API and excipient.