The Effect of Mixing Variables on the Dissolution Properties of Direct Compression Formulations of Furosemide

Abstract

The particles of a number of poorly water soluble drugs, for instance furosemide, tend to agglonierate spontaneously and as a result decrease the drug's dissolution properties. This phenomena is undesirable when the drug is to be formulated in a direct compressible formulation. Interactive or ordered mixing with a filler usually rectifies this problem but the drug load is limited to a maxirnuni of ± 5% of the mixture. This is well below the formulation requirements of hrosemide (25 %) and below the maximum drug load which can be handled in dircct compression formulations (± 35 %). The effect of two types of mixers, the mixing time and drug load were investigated for a direct compression formulation of furosemide tablets. A Turbula and a V mixer, both with a volume of 720 ml, were used. The drug was formulated with Ludipress (a commercial direct compression filler, BASF, Germany) at two drug loadings of 20 and 25 %. Magnesium stearate (1 %) was added as a lubricant. A mixture was prepared for each experimental condition. After mixing the whole mixture (120 gram) was tabletted on a Korsch single punch machine producing ± 500 tablets. The crushing strength, mass and disintegration time of ten tablets and the dissolution of six tablets were measured. Dissolutions were donc according to the USP XXII - method 2¹ - in 0, 1 M HCI and a phosphate buffer with pH = 5.8. The intrinsic dissolution rates of some of the mixtures were also deterniined in the two dissolution media. The dissolution properties of the formulations were compared with the properties of Lasix®, a commercially available furoseniide product. which is not manufactured by dircct compression. The dissolution rates of the formulations mixed in the Turbula mixer were significantly higher than those mixed in the V miser. The area under the dissolution curves increased as a function of niixing time for both mixers. The best dissolution results were obtained for formulations with a 20 % drug load and mixed for 120 minutes in the Turbula miser. The dissolution curves for these formulations compared well with the curves for the commercial tablets. Intrinsic dissolution rates were also a hnction of niising time, which indicates that the increase in dissolution properties is probably a result of the deagglomeration of the agglomerated furosemide particles. The Turbula mixer, which can develop more shear force, breaks the agglomerates quicker and to a larger extend than the V mixer. It can be concluded that the type of mixer, mixing time and drug load control the dissolution properties of direct compression formulations of poorly water soluble drugs in which the drug particles form agglomerates.