Characterization of Pharmaceutical Tablets by X-ray Tomography

Abstract

Solid dosage forms such as tablets are extensively used in drug administration for their simplicity and large-scale manufacturing capabilities. High-resolution X-ray tomography is one of the most valuable non-destructive techniques to investigate the internal structure of the tablets for drug product development as well as for a cost effective production process. In this work, we review the recent developments in high-resolution X-ray microtomography and its application towards different tablet characterizations. The increased availability of powerful laboratory instrumentation, as well as the advent of high brilliance and coherent 3rd generation synchrotron light sources, combined with advanced data processing techniques, are driving the application of X-ray microtomography forward as an indispensable tool in the pharmaceutical industry.

Keywords: X-ray tomography; X-ray tomography modalities; image processing; pharmaceutical tablets.

Figure 1

(a) Schematic of lab-based microtomography setup with cone beam shaped X-ray. (b) Schematic of synchrotron-based tomography setup with parallel beam configuration. The additional optics such as the Fresnel zone plate and order sorting aperture are needed for more advanced tomography techniques such as nanotomography/ptycho-tomography.

Figure 2

(a) Micro tomography 3D image cut through of ethylene vinyl acetate polymer matrix. (b) Horizontal and (c) vertical cut through of (a) where the pore size distribution is rendered within the 3D image. Reused with permission from Ref. [168]. Copyright 2011 Elsevier.

Figure 3

(a) Density distribution of microcrystalline cellulose tablet measured by X-ray microtomography. The color scale bar represents the local density expressed in kg/m³. Reused with permission from [186]. Copyright 2004 Elsevier. (b) Effect of compaction pressure on the tensile strength of compressed aspirin tablets with different thickness. Reused with permission from [51]. Copyright 2009 Elsevier.

Figure 4

(a) X-ray microtomography slice of Janssen Pharmaceutica tablet measured by lab-based X-ray source. The scale bar corresponds to 500 $\mathsf{\mu }$m. (b) Phase contrast X-ray microtomography slice of the same Janssen Pharmaceutica tablet shown in (a) measured at Anatomix beamline (Synchrotron SOLEIL) at 40 keV, and the scale bar corresponds to 500 $\mathsf{\mu }$m. The color scale in (a) and (b) represents the contrast range from 0 (black) to 255 (white). (c,d) The histogram representing the grey value distribution of image (a,b) respectively. (e) X-ray microtomography slice of moxidectin tablet measured at TOMCAT beamline (Swiss Light Source) shown in grey scale contrast, and the segmented image representing pharmaceutical ingredients (red-moxidectin, blue-croscarmellose sodium and mixture material, white-functionalized calcium carbonate). (f) Representation of volume fraction of moxidectin [red region shown in (e) across the radial distance from the center of the tablet. (e,f) Reused with permission from [188]. Copyright 2020 Elsevier.

Figure 5

(a) Image of tablet volume. (b) 3D macropixles of the tablet volume shown in (a). The color scale indicates the level of uniformity between two components present in the tablet, red—high uniformity, blue—low uniformity.

Figure 6

(a) Segmented image illustrating the volume distribution of clopidogrel bisulphate particles with the color scale representing the volume of the individual particles in $\mathsf{\mu }$m³. (b) Isolated particles of clopidogrel bisulphate extracted from the tomography image shown in (a) as red. (c) Histogram of the volume distribution of the clopidogrel bisulphate particles existing in two different crystallographic phases, the red and blue legend corresponds to the two different phases synthesised in this work. (a–c) Reused from [297].

Figure 7

Crystallinity fraction of the amorphous indomethacin tablets measured by 2D X-ray diffraction across the length of the tablet measured at different compressive pressure. The arrow indicates the scanning direction on the tablet. Reused with permission from [306]. Copyright 2015 American Chemical society.

Figure 8

(a) Thickness variation of methacrylic acid copolymer LD (L30D-55) and talc coating layer of an asprin tablet analyzed from VGStudioMax (VolumeGraphics GmbH, Heidelberg, Germany), where the colour scale represents the local thickness of the coating layer ranging from 0–150 $\mathsf{\mu }$m (blue-red). (a) Reused with permission from [328]. Copyright 2017 Elsevier. (b) Thickness of the coating layer consisting of sodium benzoate, hydroxypropyl methylcellulose and water calculated at certain radial axis marked in the image. Reused with permission from [332]. Copyright 2015 Elsevier. (c) Surface roughness profile of tablet coating layer consisting of a mixture of eudragit L30 D-55, triethyl citrate and talc measured by optical coherence tomography. The color scale represents the local thickness variation from the mean thickness of the coating layer. Reused with permission from [247]. Copyright 2017 Elsevier.

Figure 9

(a) Radiography images of the dynamics of a swelling process taken at 72 (top) and 172 (bottom) min after the start of the dissolution. The tablet consists of microcrystalline cellulose and hydroxypropyl-methyl-cellulose, the dark spots indicates glass microsphere tracers to identify the local swelling movements. The white spots along with the lines indicate the position and the displacement of the tracers from the previous time sequence. Reused with permission from [368]. Copyright 2008 Elsevier. (b) 3D reconstructed image measured by phase contrast X-ray microtomography of dried chitosan–$\lambda$-carrageenan matrix based tablet during the swelling process. (c) The 2D slices of the tablet cross section shown in (b) indicating the changes in the tablet matrix during the swelling. The scale bars in (b,c) correspond to 5000 $\mathsf{\mu }$m. The polymer network expanded after dissolution of the drug embedded inside the matrix is shown in the last column of (c). The white and bright orange region present in the center of the tablet is the drug which was released during the dissolution process. The color scale (ranging from 0 to 255) represents the density variation of the drug, with white color and dark orange color representing high and low density of the drug, respectively. The remaining regions represents the polymer matrix. (b,c) Reused with permission from [191]. Copyright 2020 Elsevier.

Figure 10

(a) 3D model of the flowcell apparatus with the different components. The flow cell is made of polymethyl methacrylate (PMMA) due to its relatively low X-ray attenuation. The dissolution solution is continuously introduced from the bottom inlet tube of the flowcell using a pump. The extracted solution from the outlet can later be used to analyse the dissolved API such as using a UV spectrometer shown in (b) to correlate with the microtomography data. (b) Schematic representing the experimental setup for 3D characterization of the tablet dissolution using microtomography (EMCT) scanner at UGCT in combination with UV spectrophotometer. The blue color in the reconstructed image of the tablet represents the dissolution solution. (a,b) is adapted from [187].