Abstract

In spite of significant recent interest in polymeric films containing poorly water-soluble drugs, dissolution mechanism of thicker films has not been investigated. Consequently, release mechanisms of poorly water-soluble drugs from thicker hydroxypropyl methylcellulose (HPMC) films are investigated, including assessing thickness above which they exhibit zero-order drug release. Micronized, surface modified particles of griseofulvin, a model drug of BSC class II, were incorporated into aqueous slurry-cast films of different thicknesses (100, 500, 1000, 1500 and 2000 μm). Films 1000 μm and thicker were formed by either stacking two or more layers of ~500 μm, or forming a monolithic thick film. Compared to monolithic thick films, stacked films required simpler manufacturing process (easier casting, short drying time) and resulted in better critical quality attributes (appearance, uniformity of thickness and drug per unit area). Both the film forming approaches exhibited similar release profiles and followed the semi-empirical power law. As thickness increased from 100 μm to 2000 μm, the release mechanism changed from Fickian diffusion to zero-order release for films ≥1000 μm. The diffusional power law exponent, n, achieved value of 1, confirming zero-order release, whereas the percentage drug release varied linearly with sample surface area, and sample thickness due to fixed sample diameter. Thus, multi-layer hydrophilic polymer aqueous slurry-cast thick films containing poorly water-soluble drug particles provide a convenient dosage form capable of zero-order drug release with release time modulated through number of layers.

 

Conclusions

The effect of film thickness on the release time and mechanisms was investigated by varying thickness from 100−2000 μm. For 500 μm and thicker films, the release time ranged from about 240 min to 500 min, with no initial burst-release and lag time that was linearly dependent on film thickness. Release mechanism shifted from Fickian diffusion for typical thin films of 100 μm to anomalous transport for intermediate thickness of 500 μm, which was the unit film used for constructing multi-layer films, to almost perfect zero-order release for thickness of 1000 μm and above, where the diffusional power law exponent, n, achieved value of 1, which is a significant outcome. The aspect ratio of the film samples ranged from about 25 to 6 for thickness of 500−2000 μm, leading to predominantly three-dimensional drug release, that was linearly related to the surface area. Since the sample diameter was fixed, the drug release was mainly influenced by the thickness. Stacked films required simpler manufacturing process due to ease of casting and drying, and also resulted in better critical quality attributes, such as the appearance, uniformity of thickness as well as drug content per unit area. Overall, both the monolithic thick films and stacked films were found to have low RSD values of drug loading (RSD<6%), low moisture content of dry films (<3%), and similar release rates. Overall, such multi-layer thick film system provides zero-order sustained delivery of poorly water-soluble drugs, while maintaining a constant release rate and tailoring total release time based on the number of layers.

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