Pharmaceutical Technology: Controlled Drug Release, Volume 2

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MATRIX FORMULATIONS [CH. 4 45 (4) Grinding and separation of the particle size ranges in a Russell vibratory machine (Russell Finex, London and New York). (5) Lubrication for 3 min. (6) Final compression on the same instrumented tablet machine to obtain a 400 mg tablet. TESTS PERFORMED Powder test Powder flow rate was determined using a glass funnel. The volume before and after tapping (∆V=V 10 −V 500 ) was measured with an Eberhard Bauer (J.Engelsmann AG) tapping volume meter [14–16]. Physics of compression In sampling ten tablets, the following parameters were studied: the lubrication index (R), the ejection force (F c ), the residual force (F r ) and the cohesion index (CI=ratio of the pressure applied to the upper punch and the tensile strength) proposed by Guyot [17]. In one of the ten tablets, the mechanical work was calculated using the parameter of the total energy liberated during the compression (E t ). In sampling 120 tablets, the friability, the variability of the tablet weight and the variability of the upper punch force were determined. Tablet tests Friability was determined with 20 tablet samples in a friability tester (Erweka TA3R; 15 min, 25 rev min −1 ). The weight variation was evaluated for 20 tablets on an electronic balance (Mettler AK 260; Sofranie). Tablet hardness was measured on 10 tablets using a Schleuniger hardness tester (Soteco). Dissolution studies Six tablets were subjected to. dissolution using the USP dissolution apparatus (Vanderkamp 600, Van-Kel Ind., NJ, USA) in 500 ml buffer pH 1.2 (the first hour) and 650 ml buffer pH 6.8 (1–14 h), maintained at 37°C and rotated with paddles at 50 rev min −1 (first hour) and 130 rev min −1 (1–14 h). The dissolution apparatus was connected to a UV-visible spectrophotometer (Uvikon 810, Roxche Bioéléctronique Kontron, Marseille) and a computer (VAX 780; Digital). The absorbance of the dissolution medium at 275 nm was recorded automatically at intervals (1, 2, 4, 5, 8, 10, 12 and 14 h). The percentage of the drug released was calculated and the corresponding release profiles were obtained.
46 CH. 4] STATISTICAL OPTIMIZATION OF A CONTROLLED RELEASE FORMULATION PRELIMINARY TRIALS The objective of the preliminary trials was to define the best way to incoporate the lubricants, i.e. before or after the precompression operation. Three experiments were carried out. (1) Experiment A. Talc was added before precompression and magnesium stearate before the final compression. (2) Experiment B. 50% of each lubricant was incorporated before and after precompression. (3) Experiment C. Magnesium stearate was mixed before precompression and talc before the final compression. In these three experiments, 50% of the ethylcellulose was added before precompression and the other 50% before the final compression. Precompression was conducted at 10 kN (UPF) and a 10 mm depth of the die. After milling and grinding, the 100–800 µm particle size range was collected and lubricated. For final compression, the powder was compresseed at 10 kN. Results and discussion Results obtained from the preliminary trials described above are shown in Table 1. The mean values of three trials performed for validation of the optimized formulation by direct compression [13] are given for comparison. The release profiles are illustrated in Fig. 1. As expected, the flow rate, ∆V, R, F e , F r , E t , UPF variation and weight variation were better than for direct compression. CI and friability were affected owing to the poor crushing strength (hardness) of the tablets obtained af ter the final compression. Double compression largely decreases the coefficients of variation of the percentage dissolved at 8 h and AUC. Adding lubricants before or after precompression reveals an effect on the different studied properties. Experiments A and B give better values than experiment C. In addition, the parameters R, F e , F r and CI are affected when talc is added alone before the final compression. In conclusion, the incorporation of 50% magnesium stearate and talc before precompression and the other 50% before the final compression improves the compression behaviour. At the same time, it decreases the coefficients of variation of UPF the weight of the tablet and dissolution parameters. From these results, the process from experiment B was chosen for the experimental designs. APPLICATION OF A HADAMARD MATRIX H(8) Experimental design The theory and application of a Hadamard matrix were discussed by Ozil and Rochat [18]. This design is an optimum strategy leading to good accuracy in the main effects
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