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Figure 5.6 showed that the diameter of the pure G50/13 increased as the tablet took up the water from its surrounding and swelled, and the rate o f increase was very high initially but became almost plateau after 2 hours. This was because the erosion process commenced and removed the outer layer almost as fast as it swelled (surface erosion). After 4 hours, the diameter decreased (but still bigger than the original tablet) which was consistent with the increase in erosion, brought on by the saturation of the outer layer with water until it can longer support the weight. The removal of the swollen layer front can also be attributed to the dissolution of G50/13 due to the disentanglement of the long molecular chains. This was also shown by a previous study on pectiniHPMC matrices which are hydrophilic carriers (Kim and Fassihi, 1997). The matrices demonstrated high water uptake and swelling, leading to volume changes and subsequently reaching its maximum after 2 hours, after which the changes decreased. Since intensive erosion only started occurring after this point, it was concluded that during the initial stages, the matrices could accommodate the swelling without a high degree of chain disentanglement, erosion nor polymer dissolution.

For the 10% paracetamol dispersion, the initial diameter increase was lower than for pure G50/13 tablets, as displayed by Figure 5.6. Looking at its water uptake profile, there was less water uptake than the pure G50/13 in the beginning, so there was less swelling (Figure 5.4). As erosion was slightly higher than the pure tablets at this stage, this indicates that it did not need to swell as much as the pure G50/13 tablets in order for surface erosion to occur. However, as the diameter increase for the 10% paracetamol was constant and as the erosion profile was also increasing, these suggested that swelling continued in its role as the more dominant mechanism. Whereas the pure G50/13 took up water, swelled and reached its limit very quickly, the paracetamol dispersions had a more uniformed profile, with the uptake and swelling being more

Chapter 5: Erosion and w ater uptake.... 165

Figure 5.6: Diameter difference profiles o f pure G50/13 and paracetamol dispersions in G50/13 at different drug loadings

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Figure 5.7: Diameter difference profiles of pure G50/13 and caffeine dispersions in G50/13 at different loadings o f the drug

A— pure G50/13 - - ♦ - - 5% caffeine — # — 10% caffeine — 4<— 30% caffeine

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Chapter 5: Erosion and w ater uptake.... 166

gradual, with also the 10% dispersion having the biggest capacity for swelling. This was similar to the observation made by Dennis et al (1987) that the lowest concentrations of ketoprofen in G50/4.8 led to the greatest water penetration, swelling and surface erosion. Increasing the concentration lessened these processes especially when the solubility o f the ketoprofen in the gelucire was exceeded and the dispersion was in particulate form.

As exhibited in Figure 5.7, the caffeine dispersions in G50/13 had similar diameter difference profiles to the pure G50/13 tablets and this is consistent with the observations that the erosion and water uptake profiles were also similar to the pure G50/13 tablets (Figures 5.3 and 5.5). The highest drug loading (30%) tablets after the initial high swelling rate and its subsequent decrease, did not seem to recover its swelling capability, as shown by the low diameter difference value at 8 hours. Since the erosion rate did not increase notably and the rate of water uptake only decreased slightly, this could indicate that the porous structure (as mentioned in section 5.3.1) did not allow much swelling to occur as the water occupied the pores, rather than hydrating the molecular chains. Increasing the loading of caffeine increased the total erosion, in contrast to the findings of Dennis et al (1987), but consistent with the observations made during an investigation into the mechanisms o f drug release from gelucire bases by Sutananta et al (1995). The authors found that at higher drug loadings of theophylline in G55/18 (20 or 30% compared to 2%), there was an increase in erosion. In addition, the release o f the drug from G50/13, which was thought to be governed predominantly be erosion, also increased as the theophylline loading increased. Dennis (1988) who attributed the release o f ketoprofen from G50/13 to erosion further supports this hypothesis. In that study, it was found that between 0 to 60% o f the release, the rate was nearly zero-order but this was not applicable further on as the gradual reduction of the dosage form area due to the surface erosion dominated process resulted in the lowering o f the release rate. Further evidence was found when decreasing the basket rotation speed gave a slower but more reproducible drug release. This increase in erosion could be due to the weakening o f the matrix due to the drug particles disrupting the bonds between the molecules o f the gelucire base.

Chapter 5: Erosion and w ater uptake.... 167

Comparing the diameter difference profiles of paracetamol to caffeine dispersion in G50/13 at the same drug loading of 10%, it is apparent that the paracetamol sample has a greater ability to swell, as presented by Figure 5.10. It could be postulated that incorporation of this drug into the gelucire matrix had caused a modification in the matrix structure so that it allowed greater relaxation of the long PEG ester chains. This seems to be a more likely explanation than the modification causing the matrix to be able to take up more water as the water uptake profiles o f the paracetamol and caffeine dispersions were similar. Studies performed using the hot-stage microscopy technique (Chapter 3) showed that the paracetamol was partly soluble in the gelucire matrix when the base was molten and on cooling, the dissolved drug recrystallised within the gelucire, in a form of mixed crystals or at least very finely dispersed crystals. On the other hand, any dissolved caffeine recrystallised out separately and was still present as a solid dispersion. It is likely therefore, that this incorporation of the paracetamol at a molecular level can affect the structure and behaviour of the gelucire base. It could be suggested that after the initial burst o f swelling, the water imbibed gradually dissolved this very fine drug, slowly relaxed the gelucire chains which surrounded it and got incorporated within this structure. Therefore, the swelling was more gradual and sustained. Moreover, a thick, opaque gel-layer was seen on the surface of the paracetamol sample whilst a thinner and less gel-like layer surrounded the pure G50/13 and caffeine dispersion samples. Looking at the smoother erosion profile of 10% paracetamol dispersion, it is possible that erosion occurred through the dissolution of this gel-layer rather than the mass disintegration at the surface of the 10% caffeine sample.

5,3.4 The relationship between the erosion studies an d dissolution studies

The studies in this chapter were performed in order to study the mechanisms o f drug release from G50/13 and to compare them to the results obtained by mathematical modelling. In Chapter 4, it was found that overall, erosion was more prominent for caffeine dispersions than paracetamol dispersions. Additionally, erosion was higher for the low loading o f paracetamol but the opposite was true for the caffeine dispersions. Looking at the diameter difference profiles of paracetamol dispersions (Figure 5.6), it could be seen that the 10% loading had swelled much more that the other loadings.

Chapter 5: Erosion and water uptake.... 168

1

I

Figure 5.8: Erosion profiles o f pure G50/13 compared to 10% paracetamol and caffeine dispersions in G50/13

-pure G50/13 ♦ - -10% paracetamol # — 10% caffeine — I 1- - - - 4 5 6 time (hr) 8

Figure 5.9: Water uptake profiles of pure G50/13 compared to 10% paracetamol and caffeine dispersions in G50/13

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Figure 5.10: Diameter difference o f pure G50/13 compared to 10% paracetamol and caffeine dispersions in G50/13

I

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Chapter 5: Erosion and water uptake.... 169

According to Bidah et al (1992), the increased swelling of a matrix, in their case, Sumikagel, moves the kinetics away from diffusion towards erosion. In the same way here, the increased swelling of the low loading paracetamol dispersion raised its erosion factor. To a small extent, the erosion profiles of the paracetamol loadings (Figure 5.2) confirmed this with a slightly higher profile for the low loading.

The processes of swelling, erosion and drug release are intrinsically related to each other for G50/13 matrices. Swelling of the matrix leads to its erosion after a certain threshold and this will increase the drug release. When these two processes become synchronised, the rate of drug release can become almost constant (Colombo et al, 1995), as shown by Figures 4.3 and 4.4 in the previous chapter. Prevention o f such processes from occurring has an effect on drug release as demonstrated by (Prapaitakul et al, 1991). The release rate of chlorpheniramine maleate was not significantly different regardless o f it being dispersed in a G50/13 matrix or a G33/01 matrix even though the volume expansion of G50/13 on addition of water was twice that for G33/01, when the succeeding processes of erosion and disintegration were suppressed. As mentioned in Chapter 4, the drug release seemed to be indifferent to the effect of drug loading. It is possible that the increasing porosity of the matrices which would have been the result of higher drug loadings was compensated by retardation of chain relaxation by undissolved drug. The presence of drug at high concentrations near the swelling front prevents the macromolecular relaxations that mostly occur in this region (Colombo et al, 1995).

Such correlation o f the erosion/water uptake/diameter difference studies to dissolution studies is useful in determining the kinetics o f drug release, not just for the overall profile but also at particular periods o f release. While mathematical fitting of the drug release indicated a high level of erosion for the caffeine dispersion (Chapter 4), the erosion profiles of the lower drug loadings show that at the beginning of the release process, the erosion was lower than for the paracetamol dispersions (Figures 5.3 and 5.2). Since the drug release for the caffeine dispersion was consistently higher than the paracetamol dispersion, it could be suggested that the diffusion mechanism contributed heavily to the caffeine release at low loadings at the start of the release process. Hydrophilic matrices with water soluble drugs such as diltiazemigelatin granules in

Chapter 5: Erosion and water uptake.... 170

pectin:HPMC had been shown to change release kinetics as dissolution progressed (Kim and Fassihi, 1997). Comparing the release of diltiazem to the erosion pattern of the matrices, it was found that the high release initially was predominantly diffusion controlled but as time progressed, it was subsequently dominated by erosion. In Chapter 4, the paracetamol dispersions had a better fit to the square root kinetics than the caffeine dispersions. In this chapter, it could be seen from the diameter difference and erosion profiles (Figures 5.9 and 5.10) that by the end o f the study, the paracetamol samples had swelled more but eroded less than the caffeine samples. These profiles gave more support to the notion o f a more diffusional release for paracetamol. Furthermore, the failure o f matrices to conform to the zero-order release profile with the subsequent inclination towards square root kinetics is the result of the recession of the matrix boundary at which dissolution happens, from the surface releasing the drug (Fassihi, 1987). The increasing pathlength which the dissolved drug has to travel or in other words, the increasing tortuosity, leads to a decreasing release rate.

An investigation to study the kinetics of drug release of sodium salicylate from spherical oral devices made from 046/07 found that the rate o f erosion and thus, the rate o f drug release were proportional to the area of the device (Bidah et al, 1990). However, it did not take into account the swelling factor as the actual fitting of the data was performed against the weight of the device to the power two-thirds and by mathematical manipulation this was related to the area. The present study clearly shows that rate of drug release (Chapter 4) did not follow the same profile as the diameter difference which can be related to the area (Figures 5.6 and 5.7). Therefore such a simple relationship between the release and area could not be applied here.

5.4 Conclusions

The erosion profile o f pure G50/I3 was not constant throughout the duration of the study. Erosion was preceded by water uptake and the subsequent swelling due to this water ingress. The swelling process occurred quite vigorously for the pure carrier so that its limit was achieved at a relatively short time which then led to the shedding of the water saturated layer. Incorporation o f different drugs gave dissimilar erosion profiles with the paracetamol dispersions giving a smoother, more constant process

Chapter 5: Erosion and water uptake.... 171

whilst the caffeine dispersions gave a similar fluctuating profile as the pure G50/13. The overall erosion for the paracetamol dispersions was also less compared to the pure G50/13 but the caffeine dispersions gave a contradictory result.

The type of drug incorporated also affected the swelling ability of the matrices. Paracetamol dispersion samples were able to swell to a greater extent than the other samples without great erosional process occurring at the same time. This was thought to be due to the modification of the gelucire structure by the partial solubilisation of paracetamol within it (Chapter 3). Caffeine dispersions gave a more porous matrix and hence, eroded to a greater extent as swelling occurred. The lower Solid Fat Content at 37°C o f the paracetamol dispersion samples (Chapter 2) may contribute to the lower erosion and higher diffusion factors of the release. A softer matrix may not be able to erode as effectively as a more solid one as more water is able to be accommodated within the soft structure so that greater swelling occurred.

The erosion and swelling profiles gave good correlation to the kinetics of release obtained from fitting dissolution data to mathematical models (Chapter 4). The caffeine dispersion samples gave a higher erosional process according to the models and this was confirmed by its erosion profiles. Likewise, the small decrease in erosion as the paracetamol loading was increased and the elevation of the same process for the higher caffeine loadings were also reflected by the mathematical fittings especially by Equation 10 (see Chapter 4). Therefore, it could be concluded that fitting dissolution data to this equation would give an indication o f the mechanisms responsible for the release of drugs from G50/13 matrices.

CHAPTER 6: INVESTIGATIONS INTO THE EFFECTS OF