Application of hydroxypropyl methylcellulose as a protective agent against magnesium stearate induced crystallization of amorphous itraconazole


Itraconazole is a fungicide drug which has low bioavailability due to its poor water solubility. Amorphous solid dispersion (ASD) is a tool that has the potential to greatly increase the dissolution rate and extent of compounds. In this work, the dissolution of tablets containing the ASD of itraconazole with either hydroxypropyl methylcellulose (HPMC) or vinylpyrrolidone-vinyl acetate copolymer (PVPVA) was compared in order to find a formulation which can prevent the drug from the precipitation caused by magnesium stearate. Formulations containing the PVPVA-based ASD with HPMC included in various forms could reach 90% dissolution in 2 h, while HPMC-based ASDs could release 100% of the drug. However, HPMC-based ASD had remarkably poor grindability and low bulk density, which limited its processability and applicability. The latter issue could be resolved by roller compacting the ASD, which significantly increases the bulk density and the flowability of the powder blends used for tableting. This roller compaction step might be a base for the industrial application of HPMC-based, electrospun ASDs.



Electrospun ASDs of ITR were evaluated in this work. As opposed to HPMC, electrospinning with PVPVA holds the advantages of larger productivity and obtaining fragile fibers resulting in easy-to-handle powder for tableting. However, ASD_PVPVA cannot resist the pre- cipitating effect of SA (deriving from MgSt), which is causing a release of only ~72%. This impaired dissolution can be improved up to ~90% by smuggling HPMC into the formulation e.g. adding it as an excipient, coating tablets with HPMC-based suspension or applying it as a second matrix in the ASD. Tablets containing ASD_HPMC (HPMC as the only polymer) showed complete dissolution of ITR after 45 min. It is chal- lenging to produce tablets containing ASD_HPMC, however it is possible to improve the processability of these blends with roller compaction enabling us to obtain a formulation that can achieve 100% dissolution of ITR.


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