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Figure 3: The effect of the type of the disintegrant over disintegration time. Formulation (F)6: fructose; F13: starch.
The effect of the disintegrant. The variation of disintegration times observed in Figure 3 illustrates the relationship that exists between compression
force and porosity when fructose is used (F6) (see Table III). High values of hardness are correlated with high compression
forces applied during the tableting process and reduced porosity of the tablets (F6 in Table 3). Low porosity retards the
penetration of the water front during disintegration, which ultimately results in slower disintegration times. Even though
porosity usually depends on the type of disintegrant, low-tablet porosity is an indicator of high disintegration times (22).
Table III: Porosity (%) and friability (%) values for formulations (F) containing fructose and starch exhibiting low, medium,
and high tablet hardness.
In this study, when comparing tablets of similar hardness that included either fructose or starch, it was seen that the inclusion
of fructose was associated with a lower friability (see Table 3). F6 showed appropriate disintegration times when tablets
were compressed to have low tablet hardness (see Figure 3). More importantly, fructose exhibited better flow properties than
starch (data not shown), which can be attributed to the difference in particle size and the crystalline nature of fructose
(median particle size of 23.14μm and 442.64 μm for starch and fructose respectively, see Figure 4). Fructose has been described
as having good flow properties and acceptable compression characteristics when used in its crystalline form (23). The authors
found that increased compression force has a significant impact on tablet porosity, friability, and disintegration time. The
relatively high porosity (15.98%) observed in low-hardness tablets, together with the high solubility of fructose in water,
accounted for rapid disintegration times, and allowed for suitable friability in the upper range (0.79%). Tablets with medium
and high-tablet hardness passed the friability test, but with a decreased tablet porosity that accounted for dramatically
increased disintegration times (223 and 580 s respectively, see Figure 3).
Figure 4: Particle size distribution (%) of starch and fructose dispersed in cyclohexane (refractive index is 1.4235).
On the other hand, starch as the disintegrant allowed for rapid disintegration times regardless of the tablet hardness (51
and 68 s at low- and high-tablet hardness, respectively). However, the poor flow properties of F13 accounted for high variation
in tablet weight, porosity, and hardness (data not shown). Rapid disintegration times for tablets that used starch as a disintegrant,
have been reported previously even at the low concentrations of 3–15% w/w (24). Although starch is poorly soluble in water,
its ability to swell almost immediately by 5–10% of its volume in water makes it a very good disintegrant, allowing for rapid
disintegration times. In this study, starch tablets with high hardness retained relatively high porosity and passed the friability
test (see Table III). However, the small particle size distribution of starch (see Figure 4) provided poor flow characteristics,
which was a major problem when tableting. This may ultimately impose difficulties in later scale up manufacturing processes,
where rapid tableting speed and uniform die filling are desired.
Figure 5: The effect of combining disintegrants in different ratios on disintegration time. Formulation (F)9: 10:0 fructose
to starch; F14: 9:1 fructose to starch; F15: 8:2 fructose to starch; F16: 7:3 fructose to starch; and F17: 6:4 fructose to
starch.
Optimization of the formulations. Given the beneficial flow characteristics that fructose showed when compressed alone and the disintegration ability of starch,
the authors investigated physical mixtures of both excipients in different ratios. Formulations containing both disintegrants
resulted in disintegration times of less than one minute (see Figure 5). Low- and medium-tablet hardness batches showed improved
compaction properties since they kept proper friability and porosity. However, as tablet hardness increased, the drug-content
variability increased (see Table IV). Ratios of 1:9 and 2:8 starch to fructose showed acceptable disintegration times only
when compressed to yield low tablet hardness (see Figure 5). Although these tablets had friability values under 1%, the values
were in the upper range, and low-tablet hardness is not desired for further processing steps, such as packaging and storage.
A ratio of 3:7 starch to fructose showed very rapid disintegration times at low and medium tablet hardness (12s and 24 s,
respectively). A ratio of 4:6 starch to fructose yielded fast disintegration times for low and medium tablet hardness. However,
the use of high starch content gave the formulation poor flow characteristics. This translated into heterogeneous die filling
in the tablet machine, and variable tablet hardness, which explained the high friability values and the high variability of
caffeine content (see Table IV). F16 presented the best characteristics of friability (0.25 %), porosity (16.16 %), disintegration
time (24 s), and drug-content uniformity (102.0 ± 2.8 %) at medium tablet hardness.
Table IV: Porosity (%), friability (%), and average drug content uniformity (Mean ± standard deviation) for formulations (F)
containing a mixture of disintegrants exhibiting low, medium, and high tablet hardness.
The high content of fructose improved the blend's flow, and its high solubility allowed for preservation of the desired disintegration
time. Furthermore, fructose is well known as a taste masker and a sweetener (25). Since ODTs disintegrate inside the oral
cavity, taste-masking is a crucial factor in patient compliance. Starch on the other hand, because of its rapid swelling and
the high porosity that it provides to ODTs, improved the disintegration behavior even at medium tablet hardness (see Figure
5). However, the use of starch is limited by the poor flow that it provides to the powder blend, increasing tablet variability
in terms of tablet weight, drug-content uniformity, and tablet hardness. All these results showed that the physical mixture
of starch and fructose, together with the right choice of binder, allows for an ODT formulation that is optimized for direct
compression. F16 displayed the best combination of effects when tableted to provide medium tablet hardness.
Jason T. McConville is an assistant professor at the College of Pharmacy, Division of Pharmaceutics, University of Texas at Austin, Austin, TX 787120231, tel. 512.471.0942.
Articles by Jason T. McConville
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