Simultaneous infrared spectroscopic imaging and visible photography to monitor tablet dissolution and drug release

A method to study tablet dissolution simultaneously by Fourier transform infraredattenuated total reflection (FTIR-ATR) imaging and macro-photography is described. Such a combined approach appeared important as the results of macro-photography, which have been provided by a number of authors, led to contradictory interpretations. The macro-photographs of a pharmaceutical tablet during exposure to water show a number of ‘fronts’ moving into the tablet. These fronts are obviously related to water penetration into and dissolution of the tablet, but the exact nature can not be derived from photographic evidence. Therefore, the combination of macro-photography and FTIR-ATR imaging was developed and used to interpret the physical changes leading to the observed fronts. The quantitative results obtained by FTIR-ATR imaging enabled the attribution of the three observed fronts (inside to outside) to: 1. True water penetration, possibly combined with (partial) dissolution of buflomedyl pyridoxal phosphate (BPP) 2. Total gellification of hydroxypropyl-methylcellulose (HPMC) 3. Erosion front Introduction In recent years, a number of new approaches has been reported to study the behaviour of pharmaceutical tablets during dissolution. These studies aim to generate an understanding of the processes in a dissolving tablet. This is a welcome addition to the standard dissolution tests, which obtain the amount of dissolved active ingredient as a function of time, but do not provide indications on the underlying mechanisms of tablet dissolution. The new approaches to study tablet dissolution are mainly based on imaging (see table 1 for an overview). A tablet is imaged during dissolution using a technique that can characterise important properties. The experimental set-ups, applied samples, and information content of the results are normally dissimilar, and some aspects will be described below. Table 1: Some imaging techniques used for tablet characterisation and their properties. Abbreviations: MRI (magnetic resonance imaging), VIS (macrophotography) Technique Advantages Disadvantages References MRI Versatile (tablet size/form) Surface insensitive Not quantitative Low sensitivity [1-4] VIS photography Time resolution Inexpensive Surface sensitive Not quantitative [5-9] Fluorescence imaging Time resolution Specificity Surface sensitive [10,11] ATR-FTIR imaging Quantitative Surface sensitive [12-17] TransmissionFTIR imaging Quantitative Unrealistic tablet needed (thickness <20μm) [18] An advantage of MRI is the ease of sampling. A slice or line can be selected in a tablet completely immersed in the dissolution fluid, as MRI is a 3D technique. The other techniques can only handle two dimensions. As a result, the exposure to water has to be restricted, e.g. by means of windows, to two dimensions. The third dimension is now used to look at, or through, the sample. Such an approach is by its nature sensitive to surface effects, for example the leaking of water along the window instead of through the tablet. MRI is not affected by this leaking. A drawback of (non-spectroscopic) MRI studies is the low chemical sensitivity and the resulting problems with quantification. Normally, the solid tablet matrix is not observed in NMR; rather, the water content is analysed and the matrix concentration is derived. Drugs can only be quantified if a special label is used, e.g. fluorine [2]. However, complete quantification is not possible with (non-spectroscopic) MRI. The same applies to optical photography. Quantification has been explored by including coloured drugs, but the accuracy of the quantification can be seriously questioned, as it is hardly possible to account for the changing scattering properties of the medium due to the intake of water and gel formation. In any case, water itself is invisible in this approach. Nevertheless, the results published for photography are very interesting. They normally show a number of boundaries that steadily migrate into the tablet. Colombo and co-workers recognise three different boundaries, which are named (from the inside to the outside of the tablet): the -glass transition boundary, where the glassy material is transformed to a gelly matrix -drug diffusion boundary, where the drug dissolves and starts diffusing -erosion boundary, where the matrix completely disappears by dissolution or erosion. An alternative explanation of the fronts is provided by Melia et al, who mention -the true penetration boundary. This implies that water ingresses through the pores in the (porous) carrier. Gel formation is considered a much slower process. -a glass transition boundary, where the glassy material is transformed to a gelly matrix -an erosion boundary, where the matrix is completely disappears by dissolution or erosion. The assumed sequence and relevance of the processes are thus different: Colombo and co-workers assume that the dissolution of drug is slow compared to the glass transition, while Melia and co-workers imply the reverse. The observed fronts are thus attributed to different physical processes. The inner front is seen by Melia as the front where water has ingressed, but no gel has been formed yet. Colombo does not attribute a front to this process. On the other hand, Colombo attributes a front to the dissolution of the drug; a process that is, in the opinion of Melia and coworkers, not visible as a front. No convincing proof of either of these attributions has been found in literature. Nevertheless, it is clear that the boundaries observed in photography are sharp, unlike the fluent gradients obtained from mathematical simulation based on Fick’s laws[19-21] and the results of FTIR spectroscopic imaging[12,13,15,17,22]. This can be attributed to the fact that photography does not provide a quantitative value for the concentration of the different materials. Rather, it shows effects that occur at a specific concentration. For example, water imbibition into a tablet causes the pores of a tablet to be filled, leading to a reduction of the refractive index changes, reduction of scattering and thus a sharp front. Further imbibition gradually increases the water concentration, but it is assumed that this is not observed in photography, unless a further physical change occurs, such as the conversion from a glassy to a gelly matrix, or the erosion of the tablet. Photography is thus well suited to localise the physical changes in the tablet. Unfortunately, the observation of a boundary does not make its interpretation obvious, which explains the above controversial explanation of the different fronts. As explained, both MRI and macro-photography do not yield accurate quantifications in the described application. The main challenge is to quantify all different components of the system (matrix, drug, water) with a high spatial and temporal resolution. Such a complete dissolution set ( ci (x,y,z,t), i.e. the concentrations of all components as a function of space and time), would enable the evaluation of the different hypotheses put forward to describe the fronts observed in macrophotography. Therefore, we aimed to devise a tablet dissolution cell that enables the simultaneous acquisition of photographic and FTIR spectroscopic imaging data. The ATR approach was selected rather than the transmission mode as it eliminates the need for very thin tablets, and makes the technical design of a set-up easier. Studies with such a cell would yield an accurate quantification of all relevant compounds in the surface layer adjacent to the ATR crystal, and a description of the various boundaries observed in photography during tablet dissolution. The current paper describes the method to combine ATR-FTIR imaging and macrophotography. Tablets can be studied by these techniques simultaneously. Results of the hyphenated technique will be used to clarify the issue regarding the physical origin of the fronts. On a longer time-scale, the developed technique may be an aid to validate and improve mathematical models and hence reduce the time and costs to develop a tablet with specific release characteristics. Cell design considerations The construction of the proposed cell (Fig. 1) is based on a previous cell [14] made specifically for FTIR imaging studies. The prominent feature of that cell was the possibility to compact tablets in situ, i.e. inside the measurement cell. The rationale for this was to minimise surface effects due to possible water leakage into the interface between tablet and ATR crystal. However, later studies showed that leakage is not an issue for HPMC tablets [15], as a result of the swelling of HPMC matrix on water intake. Therefore, the current design does not have a facility to compact tablets in situ. Instead, tablets have to be compacted off-line. The proposed tablet cell consists of an ATR accessory (Golden Gate) onto which a transparent polymer window is fixed. The tablet is clamped between the ATR crystal and the window. It is surrounded by an O-ring slightly thicker than the tablet, so that a sealed compartment is formed. A flow of water through this cell can be established via two channels in the window. These channels can be connected to ordinary tubing. ATR-FTIR spectra are acquired as described previously [17], while optical images can be acquired simultaneously through the window using a CCD camera (indicated as a TV camera in the Fig. 1). The set-up can be used as a flow-through dissolution test by determining the amount of drug in the solution after contact with the tablet[17]. This is possible by any flowthrough detector, such as the detectors used in high pressure liquid chromatography. Experimental Materials Drug: buflomedyl pyridoxal phosphate (BPP), a coloured drug, was kindly provided by Profs. Colombo and Bettini, HPMC (K4MRC) was kindly provided by Colorcon, (Orpington Kent) Instruments FTIR imaging set-up used in these studies was described elsewhere [14]. The used system has a time resolution of about 2 minutes, a FOV of about 950 μm x 1100 μm, and a spatial resolution of about 18 μm. The imaging ATR spectrometer has been patented by Varian [23]. A Colour Video Camera (Sony Exwave HAD), interfaced to a DT313 Frame Grabber (Data Translation, Inc.) image acquisition board was used to acquire visible images. Images were acquired using Matlab (version 7, the Mathworks). Analysis A tablet (Ø 3 mm) containing 60% BPP in hydroxypropyl-methyl cellulose (HPMC) is compacted at 5 kN, A mixture containing 60% BPP in hydroxypropyl-methyl cellulose (HPMC) was ground for several minutes using mortar and pestle. Part of the mixture was placed in a home-made mould (Ø 3 mm) and compacted at 5 kN using a calibrated torque wrench. The tablet was removed from the mould manually and placed on the measuring surface of a diamond crystal in a Golden Gate (Specac, Orpington, Kent, UK) ATR accessory, so that the tablet covers half the field of view (FOV). The tablet is surrounded by an O-ring and covered by a transparent top-plate, to which two tubes are connected. Distilled water is pumped through the cell at 1ml/min using a HPLC pump (Kontron 332). The data acquisition (VIS and IR) is started as soon as the tablet cell is filled with water. FTIR data are acquired automatically using a macro in the acquisition spectroscopic software. VIS images are acquired using the image acquisition toolbox in Matlab. Data-processing Optical images and FTIR datasets are processed using home written procedures in Matlab