Pharmaceutical Technology: Controlled Drug Release, Volume 2

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4 Statistical optimization of a controlled release formulation obtained by a double-compression process: Application of a Hadamard matrix and a factorial design A.Peña Romero Laboratoire de Pharmacie Galénique et Industrielle, UFR de Pharmacie de Grenoble, Avenue de Verdun, 38243 Meylan, France J.B.Costa and I.Castel-Maroteaux Searle Recherche et Développement, Sophia Antipolis, 06560 Valbonne, France and D.Chulia Laboratoire de Pharmacie Galénique et Industrielle, UFR de Pharmacie de Grenoble, Avenue de Verdun, 38243 Meylan, France SUMMARY A formulation containing an anti-inflammatory agent (diclofenac sodium), two inert matrices (ethylcellulose and polyvinyl chloride), a lubricant (magnesium stearate) and talc was optimized and prepared by a double compression process. In the first stage, preliminary trials were performed in order to study the effect of lubricant added before and after precompression. A Hadamard matrix H(8) was applied to estimate the main effects of four parameters: applied force at the upper punch (UPF) during precompression, UPF during the final compression, particle size range after milling and the concentration of ethylcellulose added before the final compression. According to the Hadamard matrix, a 2 2 factorial design was built. The complete linear models were fitted by regression for each response, reflecting the compression behaviour and dissolution kinetics. Validation was carried out using the area under the dissolution curve, this being the major response to be optimized. The dissolution curves fitted the Weibull distribution. INTRODUCTION Dry granulation is a process which consists of granulating a powder by compression, avoiding the wetting and drying steps. The advantages and drawbacks of this process were described by Sheth et al. [1]. The two methods used for dry granulation are compaction and double compression [2,3].
44 CH. 4] STATISTICAL OPTIMIZATION OF A CONTROLLED RELEASE FORMULATION Two polymers were incorporated in the inert matrix system: ethylcellulose and polyvinyl chloride. The processes used to prepare tablets containing such polymers often include direct compression [4–6], wet granulation [7,8], coating [9–11] and, rarely, dry granulation [12]. In previous work, the formula used were optimized by direct compression [13]. The area under the dissolution curve was optimized and validated by a composite design. However, the formulation gave poor powder flow as well as variability in the dissolution parameters. Thus the double compression process was investigated in order to change the powder into solid aggregates and therefore to enhance homogeneity, density and powder flow; in addition it was expected that this process would reduce the variability between tablets. Statistical optimization was conducted in three steps: (1) A Hadamard matrix H(8) was first applied to study the main effects of four parameters. (2) A 2 2 factorial design was built to obtain a complete linear model including only two parameters. (3) Validation of the mathematical model and then the optimum formulation were then made. MATERIALS The formula contained the drug, two inert matrices and two lubricants: Diclofenac sodium (Secifarma) 25.0% Ethylcellulose N-7 (Hercules) 26.1% PVC (Pevikon PE 737 P) (SEPPIC) 45.9% Magnesium stearate (Prophac) 1.0% Talc USP (Prophac) 2.0% METHODS The manufacturing process When using dry granulation, it is highly desirable to add a binder to the mixture in order to ensure an acceptable cohesion between particles. Therefore, in this present study, ethylcellulose was incorporated in two parts: before precompression as a binder, and before the final compression as an independent variable in the experimental design. The manufacturing process described below was followed: (1) Mixing for 5 min in a Turbula WAB (T2C, Willy A.Bachofen AG). (2) Precompression using a Frogerais 0A single-punch instrumented press (Ets. Ed. Frogerais), equipped with flat punches 11.28mm in diameter (surface area, 1 cm 2 ). The speed of the machine was adjusted to one tablet s −1 . (3) Milling was carried out in an Erweka oscillating granulator equipped with 3.15 mm perforations for premilling and 0.8mm perforations for the final milling.
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194 INDEX dry granulation, 43 elect
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Pharmaceutical Technology: Controlled Drug Release, Volume 2

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