Preparation and Characterization of Spray-Dried Hybrid Nanocrystal-Amorphous Solid Dispersions (HyNASDs) for Supersaturation Enhancement of a Slowly Crystallizing Drug.

We prepared hybrid nanocrystal-amorphous solid dispersions (HyNASDs) to examine their supersaturation capability in the release of a poorly soluble drug, itraconazole (ITZ), a slow crystallizer during dissolution. The HyNASD formulations included a polymer (HPC: hydroxypropyl cellulose, Sol: Soluplus, or VA64: Kollidon-VA64) and a surfactant (SDS: sodium dodecyl sulfate). Additionally, the dissolution performance of the HyNASDs and ASDs was compared. To this end, wet-milled aqueous nanosuspensions containing a 1:5 ITZ:polymer mass ratio with/without SDS as well as solutions of the same ratio without SDS in dichloromethane were spray-dried. XRPD-DSC confirmed that ASDs were formed upon spray drying the solution-based feeds, whereas HyNASDs (~5-30% amorphous) were formed with the nanosuspension-based feeds. SDS aided to stabilize the ITZ nanosuspensions and increase the amorphous content in the spray-dried powders. During dissolution, up to 850% and 790% relative supersaturation values were attained by HyNASDs with and without SDS, respectively. Due to the stronger molecular interaction between ITZ-Sol than ITZ-HPC/VA64 and micellar solubilization by Sol, Sol-based HyNASDs outperformed HPC/VA64-based HyNASDs. While the ASD formulations generated greater supersaturation values (≤1670%) than HyNASDs (≤790%), this extent of supersaturation from a largely nanocrystalline formulation (HyNASD) has not been achieved before. Overall, HyNASDs could boost drug release from nanoparticle-based formulations and may render them competitive to ASDs.

Synergistic and antagonistic effects of various amphiphilic polymer combinations in enhancing griseofulvin release from ternary amorphous solid dispersions.

We aimed to elucidate the impact of various amphiphilic polymers on drug wettability and recrystallization inhibition and in turn drug release from binary and ternary amorphous solid dispersions (ASDs). Griseofulvin (GF) was selected as a challenging, fast-crystallizing poorly soluble drug. GF solutions with hydroxypropyl cellulose (HPC), Kollidon VA64 (VA64), and Soluplus® (Sol) were spray-dried to prepare various binary and ternary GF ASDs. XRPD, DSC, and Raman spectroscopy confirmed the formation of ASDs and suggested that HPC appears to have lower miscibility and weaker interactions with GF than Sol/VA64 with GF. In dissolution tests, the Sol-based ASD generated supersaturation very slowly and achieved 170% GF supersaturation in 210 min (230% after 6 h). The HPC-based ASD exhibited fast recrystallization in the matrix due to its low glass transition temperature and poor miscibility of HPC with GF; whereas VA64-based ASD exhibited 220% supersaturation in 10 min followed by rapid GF recrystallization. The modified Washburn experiments revealed significant wettability enhancement of GF by HPC/VA64 and inadequate enhancement by Sol, which explains the initial rapid release from VA64-based ASD and slow supersaturation build-up in Sol-based ASD. Poor GF recrystallization inhibition ability of the HPC/VA64 was confirmed by desupersaturation tests and polarized light microscope imaging. Addition of HPC to Sol and VA64 deteriorated the GF release from the ASDs with either Sol or VA64 alone. In most cases, combination of Sol with HPC/VA64 led to a trade-off between high supersaturation and rapid drug release. A strong synergistic effect emerged for the ASD with 5:1 Sol:VA64: ~220% supersaturation within 30 min was generated and maintained over three hours, whereas an antagonistic effect was observed for 1:5 Sol:VA64 with 70% supersaturation. The combination of an amphiphilic polymer that provides effective drug wettability enhancement (VA64) as a minor component along with an amphiphilic crystallization inhibiting polymer as a major component (Sol), which also provides micellar solubilization of the drug, in a ternary ASD exhibited synergistic rapid drug release with prolonged supersaturation.

Spray-Dried Amorphous Solid Dispersions of Griseofulvin in HPC/Soluplus/SDS: Elucidating the Multifaceted Impact of SDS as a Minor Component.

This study aimed to elucidate the impact of a common anionic surfactant, sodium dodecyl sulfate (SDS), along with hydroxypropyl cellulose (HPC) and Soluplus (Sol) on the release of griseofulvin (GF), a poorly soluble drug, from amorphous solid dispersions (ASDs). Solutions of 2.5% GF and 2.5%-12.5% HPC/Sol with 0.125% SDS/without SDS were prepared in acetone-water and spray-dried. The solid-state characterization of the ASDs suggests that GF-Sol had better miscibility and stronger interactions than GF-HPC and formed XRPD-amorphous GF, whereas HPC-based ASDs, especially the ones with a lower HPC loading, had crystalline GF. The dissolution tests show that without SDS, ASDs provided limited GF supersaturation (max. 250%) due to poor wettability of Sol-based ASDs and extensive GF recrystallization in HPC-based ASDs (max. 50%). Sol-based ASDs with SDS exhibited a dramatic increase in supersaturation (max. 570%), especially at a higher Sol loading, whereas HPC-based ASDs with SDS did not. SDS did not interfere with Sol's ability to inhibit GF recrystallization, as confirmed by the precipitation from the supersaturated state and PLM imaging. The favorable use of SDS in a ternary ASD was attributed to both the wettability enhancement and its inability to promote GF recrystallization when used as a minor component along with Sol.