|dc.description.abstract||α-Lactose monohydrate is one of the oldest fillers used for production of solid dosage forms. Lactose was used as filler in this study, as it is readily available and relatively cheap. Lactose is not directly compressible, but it was one of the first fillers to be modified or co-processed into a direct compressible filler. Tablettose® and Ludipress® are examples of co-processed lactose based powders intended for direct compression. Lactose possesses unacceptable powder flow properties and this is one of the reasons why co-processed powders were developed. One of the great advantages of lactose is that it is water soluble, therefore, not influencing the solubility of the active ingredient incorporated in the tablet.
To determine the efficacy of the different binders (Kollidon® 30, VA64 and 90F), wet granulation was used to prepare granules from lactose. Wet granulation is used to enlarge powder particles, producing bigger agglomerates (granules) with better flow properties (because of the spherical shape) and compressibility to produce solid dosage forms. As binders, Kollidon® 30, VA64 and 90F were employed. The binders were used at three concentration levels (3, 6 and 10% w/w) to produce granules by means of wet granulation. Granules were prepared using ethanol as granulating fluid for Kollidon® 30 and VA64, and distilled water for Kollidon® 90F. Granules from the 10% w/w Kollidon® 90F formulation could not be prepared, as the wet powder mass could not be screened through the sieve. The granules obtained were dried in an oven for a specific time and at a specific temperature depending on the binder in question. A second step of granulation took place and the granules obtained were mixed with the disintegrant (1% w/w Explotab®) and the lubricant (0,5% w/w magnesium stearate). The disintegrant was incorporated in a 50:50 ratio (intra-granular: extra-granular). All the powders were mixed in a Turbula® mixer. The quantity of disintegrant and lubricant was kept constant for all formulations as this was not variables for this study.
During the initial phase of the study the physical properties (flow properties and compressibility) of the powder mixtures produced with the different binders (Kollidon® 30, VA64 and 90F) were evaluated to establish the influence of the binder. All the formulations exhibited acceptable powder flow properties and compressibility.
Tablets were compressed at two compression settings (stroke length 1 and 4) from the different powder mixtures. Two compressions settings were used to determine how the different binders would react under different external pressures. The die volume of the tablet press was kept constant. The physical properties of the obtained tablets were evaluated with respect to tablet weight variation (%RSD), mechanical strength (crushing strength and friability) and disintegration. Tablets produced from Kollidon® 90F powder mixtures exhibited shortcomings in terms of disintegration as it exceeded the disintegration time limit of twenty minutes (in house specification). Results with regard to the mechanical properties of the tablets from all three binders employed, proved that there was no significant benefit by increasing binder concentration.
Kollidon® VA64 proved to be the most favorable binder in terms of disintegration. It was, therefore, selected and a compressible powder containing furosemide was prepared by means of wet granulation. Tablets were manufactured at the same concentration levels as previously mentioned and evaluated with respect to tablet weight variation (%RSD), mechanical strength (crushing strength and friability), disintegration and dissolution. Incorporation of furosemide had no detrimental effect on the weight variation as well as the mechanical strength (crushing strength and friability) of the tablets produced from the different formulations. However, disintegration behavior was negatively affected by the incorporation of the active ingredient. Only the tablets produced from the 3% w/w powder mixtures containing furosemide compressed at compression setting 1, exhibited disintegration below twenty minutes (disintegration time limit). Dissolution of furosemide (model drug representing sparingly water soluble drugs) from tablets produced from different powder mixtures (3, 6 and 10% w/w) of Kollidon® VA64 was determined in 0.1 M HCI for 90 minutes. Dissolution results were compared in terms of initial dissolution rate (DR|) and extent of dissolution (AUC). At compression setting 1, all three formulations (3, 6 and 10% w/w) exhibited similar dissolution profiles. However, dissolution results revealed significant differences in the rate (DR,) and extent (AUC) of furosemide dissolution between the 3% w/w and both the 6 and 10% w/w formulations. Tablets prepared at higher compression levels for both the 6 and 10% w/w concentration level exhibited poor dissolution profiles. The higher compression force caused a decrease in tablet porosity and as a result the disintegration time was prolonged. Water penetrated the tablet matrix to a lesser extent and disintegration was negatively influenced. This, in combination with the hydrophobic nature of furosemide, is the probable cause for the poor dissolution behaviour of the 6 and 10% Kollidon® VA64 formulations at compression setting 4. The dissolution results indicated that disintegration is not an absolute prerequisite for dissolution, as tablets from the 6 and 10% w/w formulations did not disintegrate, but still exhibited dissolution, depending on the compression force. Dissolution results also indicated the dependency of the extent of drug dissolution (AUC) on the initial dissolution rate (DR,), indicating the importance (although not an absolute prerequisite) of establishing rapid contact between drug particles and the surrounding dissolution medium.||