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.

Apr 1, 2009
By: Kathrin Nollenberger, Andreas Gryczke, Takayuki Morita, Tatsuya Ishii
Pharmaceutical Technology

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Results

For the spray-dried samples, the residual solvent content was measured by loss on drying with infrared (IR) spectroscopy. Less than 0.95 wt% of residual ethanol content in the spray-dried sample was found and presumed not to influence XRPD, DSC, or stability.

Figure 1 (All figures are courtesy of the authors.)

Spray-drying and melt extrusion with felodipine. In a previous study, 10% of felodipine was identified as the optimum drug load with respect to dissolution (3). Spray-dried samples, therefore, were produced with a 10% drug load and compared with the results of an extrudate with the same formulation used in a previous study (3). Spray-dried and extruded samples were analyzed with DSC and XRPD to evaluate the crystallinity of felodipine in the samples. In XRPD (see Figure 1), no typical peaks referring to felodipine could be observed in the spray-dried sample or in the extrudates. In comparison, the corresponding physical mixture showed peaks in XRPD at 10.23 (2θ), 10.88(2θ), 16.6(2θ), 20.5 (2θ) und 23.7(2θ), where θ is defined as the incident angle of the X-ray (i.e., the angle between the incident X-ray and the plane of the sample). Because Eudragit polymers are amorphous and the positions of the peaks are equal to pure felodipine, these peaks are clearly related to pure felodipine. Both methods lead to a formation of a solid dispersion of felodipine, Eudragit E and Eudragit NE 30 D.

Figure 2

These results were confirmed with DSC. The DSC runs of pure felodipine, a physical mixture, and the spray-dried and extruded samples can be seen in Figure 2. In the physical mixture and in the pure felodipine, a melting peak was detected, whereas in the spray-dried sample and in the extruded sample, no melting peak was observed. Only one glass transition temperature (T_g) could be seen. The T_g value in the melt-extruded sample is below the T_g value of the pure polymer, meaning felodipine has a slightly plasticizing effect on the polymer. The appearance of a single Tg is an indication for the formation of a glassy solution where the drug is dissolved in the polymer.

Figure 3

The formation of a solid glassy solution leads increases the dissolution rate and apparent solubility of felodipine. In Figure 3, the solubility of the spray-dried sample is compared with the solubility of pure felodipine and the physical mixture. For felodipine, no solubility was detected because the value was below the detection limit. The physical mixture increased in solubility (40 µg/mL), because of to the wetting properties of Eudragit. The spray-dried sample increased the solubility of felodipine 8.5-fold to 340 µg/mL. This tremendous increase in solubility is caused by the formation of a solid dispersion. In Figure 4, the SEM picture of pure felodipine and the spray-dried powder can be seen. Pure felodipine appears as cubic crystals; in the spray-dried powder, no felodipine crystals are observed.

Figure 4

In Figure 5, the dissolution profiles of the extrudate and the spray-dried powder are compared with those of pure felodipine in acidic media. Dissolution of extrudates was described in a previous study (4) and is used for comparison with the spray-dried sample. Crystalline felodipine, as expected, shows nearly no dissolution because its solubility in 0.1N hydrochlorid acid (pH 1.2) is very poor (1 mg/mL).

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About the Author

Kathrin Nollenberger

Kathrin.nollenberger@evonik.com

Kathrin Nollenberger is the technical manager of melt extrusion at Evonik Röhm GmbH, Kirschenallee, 64293 Darmstadt, Germany, tel. +49 6151 18 4292, fax +49 6151 18 3249. Articles by Kathrin Nollenberger

Andreas Gryczke

Andreas Gryczke is the technical marketing manager of technology commercialization at Evonik Röhm GmbH. Articles by Andreas Gryczke

Takayuki Morita

Takayuki Morita is the technical service manager at Evonik Degussa Japan Co. Articles by Takayuki Morita

Tatsuya Ishii

Tatsuya Ishii is a research scientist on technical service at Evonik Degussa Japan Co. Articles by Tatsuya Ishii

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