Using Polymers to Enhance Solubility of Poorly Soluble Drugs - Pharmaceutical Technology

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Using Polymers to Enhance Solubility of Poorly Soluble Drugs
The authors demonstrate how melt-extrusion and spray-drying methods can help to prepare solid dispersions of poorly soluble drugs using Eudragit polymers.


Pharmaceutical Technology



Table I
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
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
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
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
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,
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.

References

1. L. Benet et al., "Predicting Drug Absorption and the Effects of Food on Oral Bioavailability," Bulletin Technique Gattefosse 99, 9–16 (2006).

2. G.L. Engel et al., "Salt Form Selection and Characterization of LY333531 Mesylate Monohydrate," Int. J. Pharm. 198 (2), 239–247 (2000).

3. C. Leuner and J.Dressman, "Improving Drug Solubility for Oral Delivery Using Solid Dispersions," Eur. J. Pharm. Biopharm. 50 (1) 47–60 (2000).

4. K. Nollenberger and S. Brühne S., "Pair Distribution Function X-ray Analysis Explains Dissolution Characteristics of Felodipine Melt Extrusion Products," J. Pharm. Sci. 98 (4) 1476–1486 (2008).

5. Biovail Technologies Ltd., "System for Rendering Substantially Non-Dossoluble Bio-Affecting Agents Bio-Available," US patent US 6391338± (May 21, 2002).

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