The eight sets o f pellets (SP, AL, GR, DS, OV, DU, LD and CY) were characterized in terms o f their morphological and structural properties, and then their performance in drug release and capsule filling was evaluated.
Properties such as size and surface area were investigated and found to follow the general expected results for four ‘rounded’ batches (SP, AL, GR and DS) and four elongated shaped batches (OV, DU, LD and CY).
Whilst measuring shape, it was found that traditional shape factors such as the aspect ratio were not as discriminatory as other measures. Also Heywood’s shape coefficients were found to be inappropriate for use with very extreme shapes such as the LD batch i.e. dumbbell shaped or very elongated, perhaps due to the inclusion o f an empirically determined value relating to the spherical shape. The two-dimensional shape factor c r determined by image analysis was faster but not as powerful as the three-dimensional ec3 factor which was able to distinguish between nearly all uncoated batches o f pellets.
The roughness component o f the shape factor Cc3 was considered to be a macroscopic measure of the surface roughness o f the pellets and results indicated that the coating material filled in irregularities on the core surface, thereby diminishing differences between the different pellet batches. The more microscopic technique o f laser profilimetry showed that the surface roughness values increased and were similar for most batches when pellets were coated i.e. the coating layer imparted its own surface roughness independent o f initial surface and shape conditions. There were no significant differences once the pellets were coated but some differences existed between the roughness parameters obtained for uncoated pellets. These differences showed that the manufacturing process and the binder solution in the formulation used both affected the surface characteristics o f pellets. In particular, the same spheronisation conditions during manufacture did not result in all pellet batches having similar surfaces.
Bulk/tap density experiments established that half the batches had lower bulk densities when coated whereas the others showed no difference. Most coated pellets reached their minimum packing volume immediately when poured into a cylinder.
whereas uncoated pellet beds underwent consolidation when tapped. This indicated a change in the nature o f the surface after coating, perhaps increased friction between pellets.
Characterizing the pellet batches in terms o f densities indicated that all uncoated pellets had similar effective densities whereas the coated pellets showed significant differences between most batches, their values being lower than for uncoated pellets. Also the uncoated pellet batches were seen to have significant differences between their porosity measurements; the coated pellets were not measured due to the presence o f the polymer coating.
The ranking o f porosity values o f the uncoated pellets was shown to be inversely correlated to the mean dissolution time values. Another propery that almost showed a positive correlation with the mean dissolution time was the shape as measured by the shape factor Cc3. The thickness o f the coating layer was seen to be directly proportional to the dissolution rate o f the pellets. Studying the dissolution profiles by statistical moment analysis indicated that the drug release mechanisms did not fit a traditional model but it was noted that all profiles for each batch were equivalent to each other, thereby indicating the same release mechanism.
A clearer picture o f the influence o f shape on the pellets was obtained from capsule filling studies. All uncoated batches except the most elongated, CYO, were deemed to perform successfully during capsule filling, with the four rounded batches (SP, AL, GR, DS) being better than the elongated ones. Coated pellet batches did not fill into capsules as well as uncoated batches, and again the rounded batches performed better than the elongated pellets. Taking into account the number o f underfilled capsules produced, approximate limits were identified for the shape values required for adequate capsule filling (two-dimensional or shape factor >0.36, three-dimensional ec3 shape factor >0.18 and aspect ratio <1.2). Thus for uncoated pellets there was a definite correlation found between shape and number o f underfilled capsules, whereas the coated pellets almost showed a similar correlation but the presence o f the coat influenced their capsule filling ability in a negative manner.
Further work could be done using the information gained here as a starting point. This study was fairly broad and looked at various aspects o f the properties o f
pharmaceutical pellets and the influence o f shape. Thus targetting work at a particular area such as studying the filmcoat in greater detail e.g. the variation in thickness and its interaction with the surface o f pellets o f different shapes may be useful. Using similar batches o f pellets, more information could be gained by performing experiments with all levels o f coating rather than just comparing uncoated pellets and the final coated pellets. Additionally, other pellets could be produced, perhaps with more varied surface characteristics, by changing the formulation or using different pelletization techniques e.g. melt pelletization. A further extension o f the work could be to investigate the effects o f mixing different shapes o f pellets and evaluating their performance.
In summary it may be said that the shape o f pellets influences a whole range o f their properties although with a complex system it is not always possible to identify a straightforward and obvious relationship. Considering the performance o f the pellets worked with in this project, the range o f shapes seemed not to affect the dissolution o f pellets which was primarily controlled by the filmcoat. However extremely deviant shapes such as dumbell shaped pellets may disintegrate during dissolution when uncoated. The evaluation o f performance during capsule filling did highlight the influence o f the shape o f pellets where the ability to fill successfully decreased with increasing elongation. It was possible to identify a threshold value for the shape below which the capsule filling process did not seem to be viable.
Exact limits for the shape measurements required for a successful pelletised product may vary from product to product and will need further study, but this work shows the importance o f measuring shape and the ways in which it may affect the properties of pharmaceutical pellets.
APPENDIX
Table A l Mean dimensions (± standard deviation) o f all pellet batches as measured by image analysis.
Batch Length/pm Breadth/|im Thickness/|im
SPO 1307.5 ± 55.4 1253.1 ±52.6 1150.2 ±60.2 SPl 1385.1 ±42.7 1269.7 ±61.1 1179.6 ±62.6 SP2 1402.6 ± 48.4 1304.2 ±59.6 1189.6 ±49.0 SP3 1421.4 ±43.9 1316.6 ±69.0 1217.1 ±58.9 SP4 1429.8 ±48.4 1305.4 ±76.7 1199.1 ±58.8 SP5 1432.4 ± 50.7 1335.4 ±45.7 1236.1 ±61.3 ALO 1380.5 ±63.3 1316.9 ±66.7 1221.8 ±76.2 ALl 1448.9 ±68.1 1345.3 ±85.8 1265.7 ±64.4 AL2 1477. ± 80.0 1357.6 ±97.7 1250.3 ±86.3 AL3 1477.9 ±47.2 1368.5 ±56.3 1276.8 ±54.1 AL4 1464.1 ±62.9 1343.2 ±67.2 1261.9 ±65.9 AL5 1440.2 ±66.0 1345.5 ±71.0 1270.2 ±73.2 GRO 1189.2 ±90.0 1139.4 ±67.4 1040.1 ±72.2 GRl 1309.9 ±56.6 1212.3 ±66.2 1137.0 ±79.3 GR2 1347.4 ±81.3 1256.8 ±85.1 1173.5 ±74.8 GR3 1281.3 ±61.5 1194.6 ±68.6 1114.2 ±77.9 GR4 1303.0 ± 55.1 1221.7 ±72.5 1125.1 ±90.1 GR5 1281.1 ±68.8 1197.4 ±69.5 1126.0 ±78.6 DSO 1287.6 ±82.0 1238.0 ±96.4 1164.1 ±78.4 DSl 1324.7 ±81.5 1239.4 ± 100.9 1152.5 ±94.0 DS2 1284.5 ±75.7 1201.0 ±82.3 1124.4 ±68.4 DS3 1351.3 ±92.0 1268.9 ±87.8 1195.2 ±82.5 DS4 1298.1 ±97.2 1223.3 ±96.5 1147.8 ±89.5 DS5 1323.3 ±68.8 1223.7 ±76.9 1138.3 ±56.8 OVO 1381.0 ±55.2 1234.7 ±54.0 1094.1 ±54.3 OVl 1413.5 ±74.6 1269.3 ± 62.4 1150.2 ±52.8 0V2 1408.3 ±75.8 1277.5 ±59.1 1170.4 ±53.8 0V3 1421.5 ±70.3 1285.4 ±76.0 1165.5 ±59.5 0V4 1451.9 ±76.4 1312.6 ±63.5 1196.1 ±58.2 0V5 1486.3 ±67.1 1375.2 ±51.3 1267.4 ±58.9 DUO 1758.7 ±64.4 1343.2 ±94.7 1108.8 ±73.2 DUl 1756.8 ±70.7 1476.5 ± 85.7 1301.6 ±82.3 DU2 1769.5 ±70.4 1473.2 ±54.3 1282.6 ±60.5 DU3 1776.5 ±78.9 1470.4 ±89.1 1242.3 ± 88.4 DU4 1789.2 ±99.7 1493.2 ± 89.7 1273.6 ±50.3 DU5 1824.4 ±87.7 1508.1 ±83.0 1273.9 ±45.2 LDO 1973.2 ±87.0 1286.0 ±71.0 1084.5 ±49.5 LDl 1916.0 ±67.8 1385.5 ±90.0 1158.6 ±54.2 LD2 1970.6 ± 113.0 1408.0 ±96.0 1188.2 ±45.4 LD3 1967.4 ±95.4 1427.3 ±71.4 1169.2 ±50.2 LD4 1919.6 ±94.2 1447.8 ±83.0 1201.4 ±55.8 LD5 1981.2 ±93.8 1409.3 ± 80.8 1181.9 ±56.4 CYO 2180.3 ± 183.4 1286.7 ± 109.6 924.2 ±43.7 CYl 1894.8 ±93.6 1310.3 ± 115.8 1019.1 ±51.6 CY2 1875.7 ± 117.2 1349.3 ±90.6 1043.1 ±52.1 CY3 1898.8 ± 105.7 1355.1 ± 126.4 1037.6 ±63.0 CY4 1882.2 ± 122.2 1314.3 ± 117.9 1042.7 ±57.4 CY5 1838.1 ± 114.9 1334.2 ± 106.8 1039.3 ±49.3