The effect of soluble and insoluble fillers/binders on the disintegration and dissolution of drugs from directly compressed tablet formulations
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Although disintegration is not always a prerequisite for drug dissolution, this process plays a significant role in the rate and extent of dissolution, especially in the case of sparingly water-soluble drugs (like furosemide). Any factor that influences tablet disintegration, therefore, will influence drug dissolution. Since the filler often comprises more than 80% of the total tablet weight, it will affect tablet properties and therefore disintegration. The solubility of the filler is expected to play a major role in determining tablet disintegration. During the initial stage of the study the physical powder properties (density, particle size, flow properties and compressibility) of Tablettose® (soluble) and Avicel® PH 200 (insoluble) as tablet fillers were determined and compared in order to establish their inherent powder properties. Tablets from mixtures containing each filler and 0.5% w/w magnesium stearate (as lubricant) were prepared at a constant die fill volume at different compression pressures. Since Tablettose® could not be tableted without a lubricant due to high friction during ejection, magnesium stearate was included in all formulations. Tablets were evaluated in terms of weight variation, crushing strength, friability and disintegration times. Tablettose® produced tablets with extremely low crushing strengths and high friability compared to Avicel® PH 200, which produced tablets with - acceptable physical properties. The most significant difference between the two formulations was observed in the disintegration times, with the Avicel® tablets producing rapid disintegration whilst Tablettose® produced slowly dissolving rather than disintegrating tablets. These results indicated shortcomings in the properties of Tablettose® as directly compressible filler and suggested possible problems in terms of drug release. Following the results from the previous experiments, the effect of addition of 3.5, 5 and 7% w/w Kollidon® 30 and Kollidon® VA 64 as dry binder (to increase mechanical strength) and 0.5, 1 and 2% w/w Ac-Di-Sol®, Kollidon® CL and sodium starch glycolate as disintegrant (to induce tablet disintegration) on the physical properties of Tablettose® formulations was evaluated in order to eliminate the observed poor physical tablet properties. Although the presence of a dry binder had little effect on the crushing strength of the tablets it did increase the compression range during tableting, thereby increasing the compression force before capping occurred. Kollidon® VA 64 (3.5%) proved to be the most efficient. The incorporation of a disintegrant, irrespective of the type or concentration of the disintegrant, resulted in a significant decrease in disintegration time (1% of each disintegrant provided efficient disintegration). This was ascribed to a change from slowly dissolving tablets (with disintegration exceeding 15 minutes) to rapidly disintegrating tablets (with disintegration times less than 3 minutes). In the final stage the dissolution of furosemide (chosen as model drug representing sparingly water-soluble drugs for which dissolution is the rate-limiting step) from Avicel®, Tablettose® and Tablettose®/Kollidon® VA 64 and Ac-Di-Sol®, Kollidon® CL or sodium starch glycolate formulations was determined in 0.1 M HCI. Dissolution results were compared using calculated dissolution parameters, namely the initial dissolution rate (DRi) and the extent of dissolution (AUC). Dissolution from the slowly dissolving Tablettose® tablets was significantly slower compared to the rapid disintegrating Avicel® tablets, confirming the hypothesis that slowly dissolving (but non-disintegrating) formulations impede drug dissolution due to the small surfacearea of the drug exposed to the surrounding medium. The incorporation of Kollidon® VA 64 (as dry binder) in Tablettose® formulations resulted in unexpectedly high drug dissolution comparable with profiles obtained from the Avicel® tablets, despite the fact that the tablets did not disintegrate. The literature provided an answer, indicating that Kollidon® VA 64 increased the solubility of furosemide (Buhler, 1993:114), possibly due to the formation of a drug/excipient complex. Addition of a disintegrant to this formulation further increased drug dissolution due to rapid tablet disintegration. Once again no significant difference in drug dissolution was observed between the three disintegrants used. The dissolution results also indicate a dependency of the extent of drug dissolution (AUC) on the initial dissolution rate (DRi), indicating the importance (although not an absolute prerequisite) of establishment of rapid contact between drug particles and the surrounding medium through the incorporation of a disintegrant.
- Health Sciences