Film quality, diameter and weight of pellets

The physical properties of the starting pellets (sugar spheres) used for this process and of the finished products (Product A to N) are shown in Table 3.1.

The mean diameter of the raw material was 1095 ± 40 µm. This standard deviation was about 2.5 pixel. The thickness of the HPMC layer of Product P was about 8 ± 2 µm. The structure of this film was homogenous and did not contain cracks. The mean diameter of Product P as measured by an image analyser was 1120 µm with a standard deviation of 32 µm. This means the standard deviation of the finished product was about 2 pixel which was quite acceptable because it was lower than that of the material. The weight of one HPMC-pellet (Product P) was 1.06 ± 0.01 mg, which, as expected, was higher than that of sugar spheres, whereas the weight of MO-pellets (Product A) was not significantly different from HPMC-pellets.

Physical properties of the CAP-coated pellets (Product B – N) are also demonstrated in Table 3.1. The pellets showed very high roughness of the surface (Figure 3.1a). The CAP layer contained a porous structure (Figure 3.1b). The SEM photograph of the cross-section shows that some CAP-particles did not melt together (Figure 3.2a).

Moreover, small cracks at the surface of the coated pellets are detected under high magnification of SEM (Figure 3.2b). In spite of a combination of CAP and additives as magnesium stearate (Mgst) and ethyl cellulose (EC), the structure of the films was not improved. They contained small cracks on the surface (Figure 3.3a) and some CAP-particles did not melt together (Figure 3.3b) as well.

It is known that the addition of an additive to a polymer film will alter the permeability characteristics of the film. An example was given by Beckert <16> about tabletting of enteric coated pellets. Sugar spheres of the size fraction 800 - 1000 µm were used for layering of bisacodyl. The layering formula consisted of 81.3 g Eudragit L 30 D-55, 244.0 g bisacodyl, 8.1 g TEC, 40.5 g talc and 1305.0 g water. The layering process was performed using a fluidized bed apparatus. This means a high amount of enteric coating polymer and talc was already used for layering the drug. Therefore this combination will protect the release of bisacodyl from the drug-layer. The enteric coating processes were performed by using a fluidized bed apparatus-Uniglatt with a loading weight of 1 kg. The enteric coating formula consisted of 416.7 g Eudragit L 30 D-55 as coating polymer, 12.5 g triethyl citrate as a plasticizer and 62.5 g talc as a separation substance. Two percentages of coating amount were studied i.e. 12.5 and 25.0 % w/w. Beckert found that the release of bisacodyl was 1.6 and 0.1 % after 2 h in 0.1 N HCl and 97.9 and 95.6 % after 45 min in buffer pH 6.8, respectively. This means that the enteric coated pellets had passed the requirement of the USP XXIII . The thicknesses of film coated on the pellets were 20 - 25 µm and 45 - 50 µm at coating amounts of 12.5 % w/w and 25.0 % w/w, respectively. Beckert also found that films from Eudragit L 30 D-55 and talc were very brittle. The stretching level was less than 5 %. This result was also confirmed by Okhamafe and York <119>. Beckert studied a combination of polymers (Eudragit L 30 D-55 and Eudragit NE 30 D) as coating polymers as well. Triethyl citrate was used as a plasticizer and talc as a separating excipient. The coating was applied in two levels i.e. 12.5 and 25 % w/w. Beckert found that the release of bisacodyl in 0.1 N HCl was 4.0 and 0.9 % and the release in buffer pH 6.8 was also low at 33.1 and 2.9 %, respectively.

The result implied that the enteric coated pellets had not passed the requirement of the USP. The slow release of bisacodyl in the artificial intestinal fluid may be the effect of talc which in this case may have a sealing effect and additional effect of the low solubility of bisacodyl in the neutral medium <16>.

The effect of two hydrophobic substances on the film formation was studied in this present work. The results were observed with Product M and N. Magnesium stearate

(Mgst) or ethyl cellulose (EC) were used because they may hinder the agglomeration of pellets which happened in the preliminary studies in 2.4.7.3. The results show that the dispersion with Mgst was problematic because of the high tendency of sedimentation of Mgst. This may cause a blockage of the nozzle during the long coating process.

Moreover, the release test shows that this incorporation did not give a better resistance to the acidic medium. The structure of the film under SEM was not different from the CAP film without Mgst (Figure 3.3). Some heterogeneous structures could be seen and particles of polymers still existed. This means the coalescence of CAP was not completed.

The reason for the inhomogeneous film was most probably the low product bed temperature, which was 32 °C while the process air temperature was controlled at 35 °C. This product bed temperature was measured in the coating chamber within the streaming air of the product bed but it was not the temperature at the surface of the pellets. The surface temperature of the pellets is supposed to be lower. It is well known that for the coating process the product bed temperature should be higher than the minimum film forming temperature (MFFT). For instance, Frohoff-Hülsmann <58> has investigated recently the film formation from an ethyl cellulose aqueous dispersion and has found that up to 10 °C above the MFFT are necessary to obtain a good coalescence of polymer particles. CAP is also a cellulose derivative and the coating with CAP using an aqueous dispersion at a higher product bed temperature than the respective MFFT may be suitable. In contrast, a specialist of FMC <25> recommended that the product bed temperature should be kept low to avoid stickiness at temperatures above the Tg, which is reported <7> to be about 34 °C as mentioned before in 1.1.2.2.2.1.

Moreover, the use of a higher process temperature, for example up to 60 °C, in order to have a product temperature of 50 - 55 °C, may cause the problem of blockage of the nozzle during the coating process. The reason was that the fluid bed apparatus used, Aeromatic MP-1, had a process air flow from the bottom, as shown in Figure 2.21. The warm air flew from the bottom through the coating chamber and blew out to the outlet air tube. Before the coating of pellets can be performed, the raw materials should be warmed in order to have the suitable product bed temperature. This phase of the process will also heat the nozzle which was inserted in the bottom part. When the dispersion of CAP was pumped into the spraying set in this phase blockage may be caused as the polymer was dried inside the orifice. If there is the possiblity to cool the

spraying unit without an affect on the temperature of the air flow it might be possible to coat pellets at high temperatures without any problem. Nevertheless it is very important to consider the stability of the dosage form in case of high temperatures. The high temperature and water which is sprayed onto the surface of the pellets may chemically degrade the drug in the core, at least in regions close to the surface.

The possibility to get more homogenous films is the curing after the initial coating with CAP by using elevated temperature and/or humidity as reported by Williams and Liu

<200>. Details were discussed in 3.2.7. Other possibilities to improve the coalescence were mentioned by Obara and McGinity <116,117>. Details were also discussed in 3.2.9.