LOADINGS FROM G 50/13 MATRICES
Chapter 4: Dissolution studies !
4.2 Materials and Methods
4.2,1 Fabrication o f melt-fused tablets
It was decided that the model dosage form to be used was moulded tablet because this would be similar to the type of block matrix that gelucire would be used for, such as in hard gelatin capsules but without having to take into account the dissolution of the gelatin shell. Moulded tablets had first to be fabricated by the melt-fusion method. All the G50/13 used came from the same batch to ensure no batch to batch variability. The paracetamol and caffeine were used as received (Avocado, Lancs.) and sizes of the particles used were less than lOOfim as determined by microscopy (refer to Appendix 4 for details). Determination of drug particle size ranges through microscopy before incorporation into gelucires was also performed by Kopcha et al (1990).
The gelucire was placed in a glass beaker and melted at 75°C in an oven (Townsend and Mercer, England) for 70 minutes. Gelucires are recommended to be melted down at 20°C above their nominal melting point by their manufacturer and the additional 5°C takes into account the slight fluctuations of temperature during the fabrication process.This quantity o f time was necessary for all the gelucire to reach that temperature, melt and at the same time remove its thermal history. About 26g of G50/13 was used during each fabrication which would allow 12 tablets to be manufactured with some excess. Then the gelucire was taken out and placed on a magnetic hot plate stirrer (Coming Hot-Plate Stirrer PC-351) set to maintain the gelucire at 75°C. An accurately weighed sample of paracetamol or caffeine which would give 5 ,1 0 ,2 0 or 30% w/w o f drug in the total mixture, was dispersed for 10
Chapter 4: Dissolution studies.... 141
minutes in the molten gelucire. This length of time was found to be sufficient for all the lumps of drug to breakup under stirring, thus ensuring the homogeneity of the mixture. This method o f drug incorporation into 050/13 using a magnetic hot-plate stirrer was also utilised by Huet de Barochez et al (1989). The mixture was returned to the oven for another 30 minutes to further ensure the removal of the gelucire thermal history. Then it was taken out and stirred for 30 seconds on the hot-plate in order to get a uniform dispersion, and poured into an aluminium mould. The mould was made from aluminium as it was found that copper moulds can cause the degradation of gelucire (Sutananta et al, 1994a). The mixture was allowed to set under ambient conditions for two hours before the excess matrix was cut away with a single-sided blade. The tablets were removed from the mould and now had the dimensions of 1.5 cm in diameter, 1 cm in height and 2g in weight. They were placed in a silica-gel desiccator for 12-24 hours to equilibrate.
4.2.2 Experimental protocol
USP n dissolution test employing the rotating basket method was adopted in this study and performed in a PharmaTest Type PTW S dissolution apparatus. Distilled water was used as dissolution medium and set to equilibrate at 37 ± 0.5°C. Six tablets were used for each run and the baskets were set to rotate at 100 times per minute. An automated dissolution system was not able to be used because the concentration of the drug released was too high for the range of the automated UV analyser and also the eroded gelucire made the solution too cloudy for simple UV analysis. Filtering through Pharmatest filters fitted at the ends o f the sampling rods did not adequately remove the eroded gelucire. Therefore, at 30 minutes, 1 ,2 ,4 , 6 and 8 hours, 1-2 ml o f the dissolution media was removed from each flask through the Pharmatest filters and filtered again through 0.45|im cellulose nitrate membrane filters (Sartorius, Germany). The filters were previously found not to adsorb paracetamol nor caffeine. After appropriate dilution, the concentration o f the drug in the clear solution was determined by reading the absorbance using a UV Spectrophotometer (Perkin-Elmer 554 UV-VIS).
The maximum peaks on the ultraviolet spectrum of the drugs in distilled water as determined on the UV spectrophotometer were 243nm for paracetamol and 273nm for
Chapter 4: Dissolution studies.... 142
caffeine. Choosing the wavelength where the maximum peak is exhibited will minimise errors due to factors such as wavelength drift. Calibration curves were constructed for paracetamol and caffeine concentrations against the absorbances measured on the UV spectrophotometer used. The range of concentrations used gave absorbances up to 0.9, as it had been suggested that the intermediate range of absorbances, that is from 0.4 to 0.9, will provide the maximum accuracy to the readings (Harris, 1997). Absorbance which is too high will result in the difficulty in detecting the light passing through but on the other hand, it will be difficult to distinguish between the sample and reference cuvets if the absorbance is too low and the intensity of the light coming through is too high. There is a linear relationship between absorbance and drug concentration (r=0.999) up to 0.014mg/ml for paracetamol at the wavelength o f 243nm, and 0.018mg/ml for caffeine at 273nm, both within the range of absorbance discussed above.
Through calibration curves, the concentrations of the saturated solutions of paracetamol and caffeine at 37°C in the distilled water used was found to be 21.6 mg/ml and 27.7 mg/ml respectively. This makes the solubility ratio of drug to water at 37°C to be 1:46 for paracetamol and 1:36 for caffeine as opposed to 1:70 and 1:60 respectively in water at 20°C (Clarke’s Isolation of Drugs, 1990).
4.3 Results and Discussions
4.3,1 Paracetam ol and caffeine releases from G50/13 matrices
Figure 4.1 showed that there were very small differences between the release profiles of the three drug loadings of paracetamol in 050/13. The slight increase in the release for 20% loading may be due to the disruption o f the gelucire matrix by the drug particles. 30% loading gave an unexpected lower release but this could be due to the decrease in the quantity o f gelucire available to solubilise the drug. There was also hardly any difference in the release profiles of the caffeine loadings as shown by Figure 4.2. The bigger standard deviations seen for the caffeine samples than the paracetamol samples indicate a bigger variation in their release. This lack of great changes in the release profiles due to drug loadings had also been shown before. The release profiles o f the different loadings of
Chapter 4: Dissolution studies....143
Figure 4.1 : Dissolution profiles of paracetamol loadings in G50/13
50 - % 4 0 - CA 2- 30 - 20 - - - ♦ - -