(336a) Griseofulvin-Laden Extrudates Prepared Via Nanoextrusion: Impact of Dry-Milling on Dissolution Enhancement

Extrusion processes, including the traditional hot melt extrusion (HME) and a relatively novel nanoextrusion [1–4], have been used to enhance the dissolution rate and bioavailability of poorly water-soluble drugs. Nanoextrusion has been used as a continuous dryer to convert a wet-milled drug nanosuspension along with an extrusion polymer into nanocomposites [1,2]. During the process, the drug nanoparticles are dispersed in the polymeric matrix while water evaporates, which yields extrudates in the form of nanocomposites. Being a continuous process and having the capability to handle viscous drug suspensions, the nanoextrusion process is capable of preparing extrudates with good content uniformity even at very low drug loading [3]. In a recent investigation, Li et al. [4] used the same nanoextrusion process as a platform to produce extrudates either in the form of nanocomposites or amorphous solid dispersions (ASDs), thus enabling comparative assessment of nanocomposites vs. ASDs in a scientific manner.

The traditional HME process or the nanoextrusion process is usually followed by milling of the extrudate threads into powders for further downstream processing during the manufacture of final solid dosages forms. Modulating the particle (matrix) size via dry-milling of extrudates potentially allows for manipulating the drug dissolution performance because matrix size could affect drug release from the extrudates significantly [4]. In the majority of previous investigations where extrudates in the form of ASDs were produced via HME, the extrudates were dry milled and sieved into a single size fraction. For example, Fule et al. [5] prepared ASD of artesunate in the matrices of both Soluplus® and Kollidon® VA64, and the extrudates were milled and passed through a 200 µm sieve for various characterizations. Similarly, Juluri et al. [6] produced ASDs of griseofulvin and caffeine anhydrous in the matrix of kleptose linecaps DE17, and the milled extrudates between #40 and #50 sieves (297–420 µm) were collected and characterized. Pudlas et al. [7] produced the ASD of ibuprofen in the matrices of Soluplus® and copovidone, and the milled extrudates were sieved to exclude particles larger than 250 µm. Javeer and Amin [8] produced the ASD of carbamazepine in the matrix of hydroxypropyl methyl cellulose, and the extrudates were milled and passed through a #40 sieve with opening size of 420 µm. Also, Nagy et al. [9] produced the ASD of spironolactone in the matrix of Soluplus® and the milled extrudate was passed through a 300 µm sieve. Only in a limited number of studies, the milled extrudate particle size was actually measured. For example, Martinez-Marcos et al. [10] produced the ASD of albendazole in the matrix of polyvinylpyrrolidone. After dry milling and sieving the D₁₀, D₅₀, and D₉₀ of the extrudate particles were reported in the range of 8.6‒33.9 µm, 88.9‒197.4 µm, and 425.1‒463.6 µm, respectively. As exemplified above, in the majority of the published literature, the actual extrudate particle (matrix) sizes in the sieved fraction were not measured or reported. More importantly, the impact of matrix size from various sieved size fractions has not been examined and related to the specific surface area of the respective size fractions. Moreover, the impact of the extrudate matrix size on drug dissolution has not been studied. Similarly, when nanocomposites were produced by nanoextrusion [1–3], the impact of matrix size has not been thoroughly investigated. Hence, it is fair to assert that the impact of particle (matrix) size of the milled extrudates on drug dissolution has been studied thoroughly neither for nanocomposites nor for ASDs produced by an extrusion process, especially by the nanoextrusion process, which is the focus of this work.

The objective of current study is to examine the impact of matrix size, drug loading, and polymer–drug interactions, which modulate the solid state of the drug, on in vitro drug release from extrudate powders prepared via nanoextrusion. Soluplus® (Sol), Kolliphor P407 (Kol), and Hydroxypropyl cellulose (HPC) along with sodium dodecyl sulfate (SDS) were used to stabilize wet-milled griseofulvin (GF: drug) suspensions and form matrices of the extrudates. The wet-milled drug suspensions along with additional polymer (Sol/Kol/HPC) were fed to a co-rotating twin-screw extruder, which dried the suspensions and formed various extrudates. The extrudates with various polymer formulations and two target drug loadings (2% and 10% w/w) were dry-milled and sieved into three size fractions to examine the impact of matrix size. The drug nanosuspensions were characterized via laser diffraction, while the extrudates and their milled powders were characterized by laser diffraction, thermogravimetric analysis (TGA), scanning electron microscopy (SEM), and X-ray powder diffraction (XRPD). Digital microscopy was used to visualize the changes of different polymeric matrices when exposed to water. Drug wettability enhancement by Sol, Kol, and HPC solutions was studied using the modified Washburn method. Two drug doses, i.e., 8.9 mg and 100 mg, were used to investigate the dissolution response under non-supersaturating and supersaturating conditions in the bulk dissolution medium. It is hypothesized that extrudate matrices with smaller sizes can dissolve faster and that ASDs show a markedly and qualitatively different matrix size dependence of dissolution rate than nanocomposites under both dissolution conditions. Moreover, we assess the drug dissolution from ASDs vs. nanocomposites, which was modulated by various drug–polymer interactions. The impact of matrix size on GF dissolution from extrudate powders was significant especially for ASDs. We have found that the matrix size dependence of ASDs vs. nanocomposites is markedly and qualitatively different. Matrix size of ASDs can be modulated to control drug dissolution rate from ASDs; however, such modulation may not be very effective for nanocomposites that exhibit a weaker dependence of drug dissolution on matrix size. Overall, this study will provide significant insights to formulators about the impact of matrix size and differing dissolution response from nanocomposites vs. ASDs.

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