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. / Thesis (M.Sc.(Pharm.))--Potchefstroom University for Christian Higher Education, 2002
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:nwu/oai:dspace.nwu.ac.za:10394/16901 |
| Date | January 2002 |
| Creators | Klynsmith, Annelize |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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