Flow-through dissolution studied with FTIR imaging 103

In order to study flowing dissolution using ATR imaging a refinement of the simple compaction cell was employed. The cell was developed such that the tablet could be compacted in situ as shown in Figure 4-23, and the dissolution medium could flow through the cell without the need to move the sample. The construction is similar to the standard compaction cell; however, surrounding the punch is a retractable metal bolt which is raised after compaction creating a chamber through which the dissolution medium flows as shown in Figure 4-23 (van der Weerd et al., 2004).

Figure 4-23. Schematic representation of the flow dissolution cell combined with ATR accessory.

The dissolution cell has a similar experimental set up to that of the compaction cell as shown in Figure 4-16. It is bolted into place over the diamond plating, the only difference being the off-centre punch hole and the retractable bolt. There are also flow pipes attached to the side of the block, through which the dissolution medium is pumped. ATR diamond Golden Gate armature Punch Removable bolt Flow pipe Tablet Water

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This equipment is particularly useful for studying the dissolution of model pharmaceutical tablets, as it brings the spatially resolved chemical specificity of FTIR spectroscopic imaging to flow processes. It allows for the study of the ingress of water into the tablet, the formation of polymer gel layers and ultimately the dissolution of the drug itself. By taking images at regular time intervals, time-resolved chemical information of the dissolution can be obtained. The dissolution cell was also designed with the punch aligned slightly off centre relative to the diamond, such that the tablet only covers half the face of the imaged area. This sets the interface between the tablet and the dissolution medium as the centreline of the image, while also providing space for any potential gelation and expansion or dissolution of the polymer to be observed.

Figure 4-24. FTIR images showing dissolution of tablet containing HPMC and caffeine (van der Weerd et al., 2004).

Figure 4-24 reveals the extent of the information that can be obtained using this method. The sample was a model tablet consisting of HPMC and caffeine (van der Weerd et al., 2004). The caffeine and HPMC are shown to have only covered half of the image as expected. It can also be seen that the images were complementary; there are two circular domains of low concentration in the HPMC image, which are matched by the positions of two domains of higher concentration in the caffeine image. Water was shown to have filled the empty space on the unoccupied side of the interface, as this image was taken shortly after dissolution commenced and water had not yet started to ingress into the bulk.

The in situ compaction and dissolution cell is used in conjunction with the diamond Golden GateTM ATR acessory producing images that are 1 mm2 or smaller. These images were obtained with a high spatial resolution (ca. 15 m) which is useful for studying crystallisation and small changes in the structure of the tablet. This FOV only

500 μm

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facilitates the study of a relatively small area of small tablets, however, sometimes it is necessary to have a larger field of view to study larger areas of tablets, and the processes of dissolution that occur a larger distance from the original boundary of the tablet (Chan et al., 2003, Kazarian and Chan, 2003). For this a larger ATR crystal must be used. ZnSe is suitable for this purpose, but it is not as hard as diamond and so compaction cannot be performed in situ. Therefore, the tablets must be compacted ex situ and then dissolution studied in situ. This creates the possibility of leakage of the dissolution medium into the interface between the sample and the surface of the cell if care is not taken. In the compaction and dissolution cell, as the formulation is compacted onto the diamond, leakage is very unlikely (van der Weerd et al., 2004), the swelling of polymers such as HPMC further helps to prevent this ingress (van der Weerd and Kazarian, 2004b). When using the ZnSe crystal the sample can be formed in situ if the polymer has a low melting point, and this has been used to study the dissolution of PEG based formulations (Chan et al., 2005). A schematic diagram of the ZnSe dissolution cell can be seen in Figure 4-25.

Figure 4-25. Schematic diagram showing the ZnSe tablet dissolution cell (Kazarian et al., 2005).

A recent example of the application of ATR-FTIR imaging to dissolution and drug release is the simultaneous FTIR imaging and visible optical photography of an HPMC based tablet (Kazarian and van der Weerd, 2008). A custom designed cell was built, which was attached to the standard diamond ATR accessory and had a transparent window for visual observation of the top surface. The tablet was compacted ex situ and then placed between a diamond crystal and the window. The cell had pipes built in to the sides, which allowed the dissolution medium to flow through the chamber inside the cell. Thus, visible images were acquired using a CCD camera from the top surface of

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the tablet simultaneously with ATR-FTIR images measured from the bottom surface during the dissolution of the tablet. This combined approach allowed the study of the moving fronts observed during dissolution. The assignment of the fronts had been a contentious issue as different explanations for the fronts were provided. Consequently, this new imaging approach was applied to a previously studied system which consisted of a coloured drug (buflomedil pyridoxal phosphate) and HPMC (Kazarian and van der Weerd, 2008). Previous assignment of the dissolution fronts for this tablet based on optical photography was not convincing because photography does not provide a quantitative value for concentrations of the drug, polymer and water. Effects such as changes in the materials’ refractive indices due to intake of water and gel formation will change the scattering properties of the medium, which can affect the interpretation of the visible imaging data. The ATR-FTIR imaging approach provided reliable interpretation of varying concentration of the components across the system. These were then compared with the appearances of the fronts in visible photography. The three fronts observed in the dissolution of the studied tablets were assigned to: true water penetration, total gelification of HPMC and the erosion front (Kazarian and van der Weerd, 2008). Significantly, due to the information provided by ATR-FTIR imaging the front assignment was seen to be different to those postulated by Melia et al., Colombo et al. (Melia et al., 1992, Bettini et al., 2001), and instead was in line with that postulated but Gao and Meury (Gao and Meury, 1996). This assignment of the fronts is crucially important for understanding the mechanism of drug release in HPMC based tablets. This understanding may help in the designing of new and better drug delivery products. That Perspex cell also provides the opportunity to study samples which cannot be compacted in situ. As it is Perspex, alignment of the sample relative the imaging crystal can be viewed and controlled as the cell is bolted into place, while it is capable of working with samples which are not necessarily cylindrical tablets with flat surfaces (Velasco et al., 2011).