Table I
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The spray-dried sample shows a clear increase in dissolution rate comparable with the extrudate. The combination of the two
polymers in spray-drying and in melt extrusion generates a product with a high initial release, based on Eudragit E and a
stabilization of the profile with Eudragit NE 30 D. Eudragit E is known to increase the dissolution rate of poorly soluble
drugs (5).
Figure 5
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The average difference for all time points between dissolution curves of the spray-dried sample and the extrudate was less
than 10%, meaning the dissolution profiles were similar. Although the dissolution tests were performed under different conditions
and only three units per test were used, the similarity factor (f
2) calculation was applied, leading to a f2 value of ~70, which proves the similarity of the dissolution curves.
Figure 6
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Spray-drying and melt extrusion with carbamazepine. Spray-dried and melt-extruded samples containing Eudragit NE 30D E and carbamazepine were analyzed with XRPD and dissolution
testing. Neither samples exhibited crystalline peaks in XRPD analysis (see Figure 6), thereby showing that an amorphous state
of carbamazepine is likely. For the pure carbamazepine, crystalline peaks were observed corresponding to the polymorphic modification
stable at room temperature. The physical mixture also showed crystalline peaks at 13.14(2θ), 15.36(2θ), 15.94(2θ), 17.18(2θ),
19.6(2θ), 25.02(2θ), and 27.42(2θ), corresponding to carbamazepine crystal of modification 3.
Figure 7
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In Figure 7, the dissolution profile of the spray-dried sample and the extrudate are compared with the physical mixture. For
both solid dispersions, a 100% release was observed. Eudragit E dissolved rapidly in the acidic media and exposed carbamazepine
already in a dissolved state. The spray-dried sample demonstrated a complete release within the first 5 min, whereas the release
from the melt-extruded samples was slightly slower, reaching a complete release after 20 min. During dissolution, the powder
in the melt-extruded samples agglomerated at the beginning, slightly retarding the release of the drug. In addition, the particle
sizes of the milled extrudate were larger than those of the spray-dried sample.
Figure 8
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Stability results for melt-extruded samples are available and showed a stable profile over a storage period of 6 months at
elevated conditions (see Figure 8). The same results can be expected of the spray- dried samples if the same polymer is used.
Stability of spray-dried samples is currently under investigation. Overall, Eudragit E is a suitable carrier for increasing
the dissolution of carbamazepine and stabilizing a drug during storage.
Conclusion
Two model drugs were seleceted and formulated with Eudragit using spray-drying and melt extrusion techniques. XRPD and DSC
were used to characterize the obtained solid dispersion. Spray-dried and extruded samples showed a high increase in solubility
for both drugs. The profiles were comparable, meaning that both techniques can be used to increase the drug's dissolution
rate. Each method has advantages. In the case of a high melting drug, spray-drying is the method of choice. On the other hand,
because melt extrusion is a solvent-free process, no drying is required and one can avoid the problem of having to find a
suitable solvent. The melt-extrusion technique seems not to be crucial for preparing a solid dispersion. A more important
prerequisite is the miscibility of polymer and drug. Both poorly soluble drugs were miscible with Eudragit, demonstrated by
the appearance of only one Tg
in DSC. Non-miscible systems are likely to recrystallize and show stability problems. Miscible systems form a more stable
solid dispersion as the drug is dissolved in the polymer.
Eudragit polymers are well known and widely used in coating and matrix applications. This study showed that Eudragit polymers
are also suitable to succesfully increase the solubility of poorly soluble drugs in vitro by forming stable solid dispersions with the drug. because of to the increase in solubility, an increase in bioavailability
in vivo will occur. Furthermore, the study shows that both melt extrusion and spray-drying can be used to obtain solid dispersions
with Eudragit polymers and drugs leading to comparable results.
Kathrin Nollenberger* is the technical manager of melt extrusion and Andreas Gryczke is the technical marketing manager of technology commercialization, both at Evonik Röhm GmbH, Kirschenallee, 64293 Darmstadt,
Germany, tel. +49 6151 18 4292, fax +49 6151 18 3249, Kathrin.nollenberger@evonik.com
Takayuki Morita is the technical service manager and Tatsuya Ishii is a research scientist on technical service, both at Evonik Degussa Japan Co.
*To whom all correspondence should be addressed.
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4. K. Nollenberger and S. Brühne S., "Pair Distribution Function X-ray Analysis Explains Dissolution Characteristics of
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