Pinto, Joao Fernandes de Abreu; (1994) Formulation and tabletting of controlled release pellets produced by extrusion / spheronisation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A sustained release dosage form is suggested based on the advantages of tablets and pellets produced by extrusion and spheronisation of wet masses. The dosage form consists of a tablet incorporating pellets which are released once the tablet disintegrates in an aqueous environment. The free pellets release the model drug (indomethacin) in a controlled release fashion. The study of the process of extrusion and spheronisation was carried out based on an experimental factorial design (24) and the results analyzed according to the Yates algorithm. The factors studied were the amounts of microcrystalline cellulose (MCC) (3 and 5 parts in the formulation) and water (expressed as the ratio to MCC, 1:1 and 1:1.12 parts of water) in the formulation, the ratio of the die length to diameter (2 and 8) and the extrusion speed (200 and 400 mm/min) of the ram extruder used and the process characterised according to the extrusion force at steady state, the median size of the spheres and IQR(1), the OPCS(2) (shape) and the release rate of the drug. All the factors investigated affected the properties of the spheres. Correlation of the surface free energies of the raw materials and the mechanical properties of spheres, with I part of indomethacin, 4 parts of lactose and 3 parts of MCC, of spheres with 2 parts of MCC and 8 parts of barium sulphate (BaS) and of spheres with 2 parts of MCC, 5 parts of BaS and 3 parts of glyceryl monostearate (GM), was achieved by measuring of the contact angles of each powder with two probe liquids. From the surface energies, the works of cohesion and adhesion, and the spreading coefficients were calculated. The surface energies were also calculated based on solubility parameters. Study of the release of the model drug was carried out according to traditional models, such as zero order, first order, pseudo first order (Higuchi) or dissolution controlling mechanism (Hixson and Crowell) and Peppas and Korsmeyer general equation and according to Brockmeier and von Hattingberg, and Leuenberger approaches. Factors such as drug load, speed of the paddles of the dissolution tester, temperature, pH, sphere diameter, different amounts of coating material, showed their influence on the release of the drug whereas erosion was not relevant. Mixtures of the three different types of spheres where combined according to a centre of gravity experimental design and compacted into tablets. The study related the effects of the factors studied (drug load in the spheres, different percentages of spheres with drug, BaS and BaS and GM, the compaction pressure, the sphere size, the die diameter and the concavity of the punch's tip), to the properties of the tablets ('R' (1) value, ejection force, density and porosity, crushing force and tensile strength, friability, disintegration and dissolution times of the drug), produced in an instrumented Manesty F3 tabletting machine and in Instron press. The results were analyzed using different statistical techniques: canonical analysis, principal component analysis and multiple regression analysis and presented in star diagrams.

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