(738b) Roles of SDS in Griseofulvin Release from Nanocomposites and Amorphous Solid Dispersions: A Comparative Study

It has been reported that 40% of the marketed products and up to 70% of the new chemical entities (NCE) are poorly water-soluble [1]. Intestinal absorption of these drugs turns out to be rate-limiting due to the poor aqueous solubility, which resulted in low bioavailability. Among different approaches to enhance bioavailability, two platform approaches have gained prevalence both in the scientific literature and marketed products: nanoparticle-based dosage forms (nanocomposites) and amorphous solid dispersions (ASDs) [2]. In the nanoparticle-based dosage form, dissolution rate is improved due to the dramatic increase in the surface area of the drug crystals via size reduction down to the nanoscale [2, 3]. On the other hand, amorphous form of the drug can offer significant enhancement in the extent–rate of dissolution due to its higher free energy and higher apparent solubility. Although both drug nanocomposites and ASDs have been studied for decades, a scientifically fair head-to-head comparison of these two forms of the drug having identical formulation is largely missing in the literature.

While the impact of surfactants on drug release from drug nanocomposites is well-understood [4], the same cannot be said for ASDs as there are conflicting reports in the literature. Not only did the use of surfactant in ASD improve the dissolution performance, it also enhanced the physical stability [5,6]. Other studies also reported improved dissolution profiles of ASDs containing surfactants compared to ASDs without surfactants [7,8]. On the contrary, Liu et al. [9] reported that the presence of SDS with PVP-VA significantly improved the apparent solubility of a poorly water-soluble drug, sorafenib, but reduced the recrystallization inhibition ability of PVP-VA resulting in poor dissolution performance. Medarević et al. [10] have also observed a negative impact of a surfactant (poloxamer 188) on the storage stability of carbamazepine–Soluplus ASD, even though the surfactant increased the dissolution performance significantly. Therefore, it is fair to state that the use of surfactant can be beneficial/detrimental depending on the specific drug–polymer–surfactant system and requires further investigation. More importantly, none of the aforementioned studies elucidated the roles of surfactants on the wettability enhancement of the hydrophobic drug. Also, impact of surfactant in the release rate of a poorly water-soluble drug from nanocomposites vs. ASDs with identical formulation has not been examined.

Here, we aim to examine the roles of surfactants in drug release from nanocomposites vs. ASDs with identical formulation, which are prepared by spray drying as platform technology using drug suspension-based (W) and solution-based (S) feeds, respectively. Nanocomposites were prepared by wet media milling of griseofulvin (GF) suspensions followed by spray drying. Hydroxypropyl cellulose (HPC) and Soluplus® (Sol) were used as stabilizers–matrix formers with or without sodium dodecyl sulfate (SDS, surfactant). ASDs were produced by spray-drying the identical drug–polymer formulation dissolved in acetone–deionized water. Three different drug:polymer (HPC/Sol) ratios, i.e., 1:1, 1:3, and 1:5, were used for both drug nanocomposite and ASD production. Laser diffraction, XRPD, redispersion test, modified Washburn method for drug wettability [11], drug desupersaturation experiments, and in vitro USP II dissolution testing was used for the characterization of the spray-dried powders.

XRPD results indicate that for both polymers, spray-drying of the drug suspension-based (W) feed led to drug nanocrystals dispersed in the polymeric matrix (nanocomposite), whereas that of the drug solution-based (S) feed led to ASD. In the dissolution tests, all formulations with SDS exhibited faster GF release than those w/o SDS due to the higher hydrophilicity of the former, which was quantified by the wetting effectiveness factor calculated via the modified Washburn method. This factor (cosθ_s/cosθ_w) [11] for HPC, HPC–SDS, Sol, and Sol–SDS solutions (with respect to the deionized water as basis) was calculated to be 20.9, 42.1, 2.65, and 4.65, respectively, showing the wettability enhancement by the SDS. For 8.9 mg GF dose (non-supersaturating condition), immediate release (>80% in 20 min) of GF was observed from the nanocomposites due to the inclusion of SDS in the formulation, whereas release rate was significantly reduced w/o SDS. These results can be explained by the lower wetting effectiveness and incomplete redispersion of the drug nanoparticles w/o SDS in the formulation. Similarly, presence of SDS in the ASD formulation significantly improved the release rate of GF from both HPC and Sol matrices. However, HPC matrix alone was able to release GF significantly faster than Sol matrix alone from ASD formulation, due to the slower erosion of the Sol matrix compared to the HPC matrix. Interestingly, under non-supersaturating conditions, nanocomposites released GF faster than ASDs due to the faster erosion of the polymeric matrices and complete redispersion of the drug nanoparticles when both formulations had SDS.

For 100 mg GF dose (supersaturating condition), the dissolution tests on ASDs with HPC–SDS or HPC alone showed relatively low supersaturation ratio (as percentages), i.e., up to ~44%, whereas notable supersaturation was generated by Sol–SDS (up to 475%) and Sol alone (up to 249%) at 210 min. This could be explained by the fast recrystallization of GF in the dissolution medium and/or ASD matrix when HPC was used as a matrix polymer, and Sol appeared to be an effective recrystallization inhibitor. The solubility parameter difference for the GF–polymer pairs were estimated as follows: 7.2 and 11.8 MPa^0.5, respectively, for GF–Sol and GF–HPC. The poor miscibility of GF with HPC could explain the observed lower extent of supersaturation and faster recrystallization as compared with Sol. The drug desupersaturation results show that SDS did not play significant role in drug supersaturation maintenance. This finding seems to suggest that the slower GF release without SDS could be attributed mainly to the lower wettability, which results in slower erosion of the matrix. Nanocomposites with SDS exhibited faster GF release than the those w/o SDS. Interestingly, Sol–SDS nanocomposites also supersaturated the dissolution medium. Finally, ASD with GF–Sol provided higher GF supersaturation than the GF–Sol nanocomposite due to the miscibility of GF–Sol and recrystallization inhibition provided by Sol in ASD, whereas both ASD and nanocomposites with GF–HPC performed similarly with slight supersaturation.

Overall, this study demonstrates how to produce both nanocomposites and ASD of the same drug with identical formulation using spray dryer as a tool and to perform a comparative assessment of their dissolution performance. Presence of SDS had significant positive impact on the GF release from ASDs and nanocomposites, but does not have significant impact on the supersaturation maintenance. This study also suggests that the drug–polymer miscibility is required to achieve the advantages of ASD under supersaturating condition, whereas nanocomposites could be competitive and may outperform ASDs in formulating potent (low dose) drugs.

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