Track: Formulation and Delivery - Chemical - Formulation - Bioavailability Enhancement
Category: Poster Abstract
Effect of Particle Size of API on Critical Quality Attributes of Oral Films
Purpose: The purpose of this work was to examine the effect of the particle size and loading on the dissolution rate of poorly water-soluble active pharmaceutical ingredients (APIs) loaded oral films. As the API particle sizes are altered, the change in the matrix due to the number of the particles, and their sizes are expected. Smaller sized particles may dissolve faster, but their increased number may also change the structure of the polymer matrix, which may also impact the dissolution. Methods: Hydroxypropyl methyl cellulose E15 (HPMC E15) as a film former, glycerin as a plasticizer, fenofibrate (FNB) as model BCS class II model drug were used. Aqueous suspensions of as-received (d50 of 8 µm) or pre-milled (via Fluid Energy Mill) (d50 of 2.5 µm) fenofibrate (FNB) were prepared with HPMC E15 and sodium dodecyl sulfate (SDS) as stabilizers. Nano-sized FNB suspensions were also prepared via Wet Stirred Media Milling (WSMM) at various sizes (d50 of 700 nm, 400 nm and 160 nm). Prepared FNB suspensions were used to prepare films of 100 µm dry thickness and varying drug loadings (10, 25 and 40%). All the films were tested for content uniformity, dissolution and mechanical properties. Results: As particle size increased, tensile strength (TS) and Young’s modulus (YM) showed a decreasing trend, while elongation at break (EB) was not affected significantly. Following increasing drug loading (wt%), TS and EB had decreased while YM did not depend on drug loading. For suspensions, it was shown that decreasing particle size increased the dissolution rate owing to an increased available surface area. A similar effect was observed for the films loaded with 10% FNB down to the particle size of 700nm, while particles ≤ 700 nm did not show different dissolution rates (Figure 1.a). In addition, films loaded with a higher drug loading of 25% FNB in various particle sizes (d50 of 8 µm, 2.5 µm, 700 nm, 400 nm, and 160 nm), showed all similar dissolution profiles (Figure 1.b). Interestingly, at the highest tested 40% drug loading, an increase in the dissolution rate was observed down to d50 of 700 nm particle size, while smaller particles than this size resulted in a slower dissolution rate (Figure 1.c) as opposed to general particle size behavior in suspension. Conclusion: A linear relationship was found between API particle surface area and dissolution rate for the films loaded with 8 µm, 2.5 µm and 700 nm particles. As particle size decreased further (400 nm and 160 nm), linearity was decreased. The formulations which did not fit the linearity was found to have theoretically the thinnest polymer layer around each drug particle of thickness lower than 11 nm. This suggests that beyond a certain drug load threshold for given particle size, there may be higher propensity for aggregation due to the lack of adequate polymer wetting. Therefore, interestingly, using smaller drug particles in polymeric films may not necessarily lead to faster dissolution rate at higher drug loadings.