High Bulk-Density Amorphous Dispersions to Enable Direct Compression of Reduced Tablet Size Amorphous Dosage Units.

Amorphous solid dispersions (ASDs) are an attractive option to improve the bioavailability of poorly water-soluble compounds. However, the material attributes of ASDs can present formulation and processability challenges, which are often mitigated by the addition of excipients albeit at the expense of tablet size. In this work, an ASD manufacturing train combining co-precipitation and thin film evaporation (TFE) was used to generate high bulk-density co-precipitated amorphous dispersion (cPAD). The cPAD/TFE material was directly compressed into tablets at amorphous solid dispersion loadings up to 89 wt%, representing a greater than 60% reduction in tablet size relative to formulated tablets containing spray dried intermediate (SDI). This high ASD loading was possible due to densification of the amorphous dispersion during drying by TFE. Pharmacokinetic performance of the TFE-isolated, co-precipitated dispersion was shown to be equivalent to an SDI formulation. These data highlight the downstream advantages of this novel ASD manufacturing pathway to facilitate reduced tablet size via high ASD loading in directly compressed tablets.

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.

Hybrid nanocrystal-amorphous solid dispersions (HyNASDs) as alternative to ASDs for enhanced release of BCS Class II drugs.

A major shortcoming of drug nanocomposites as compared with amorphous solid dispersions (ASDs) is their limited supersaturation capability in dissolution media. Here, we prepared drug hybrid nanocrystal-amorphous solid dispersions (HyNASDs) and compare their performance to ASDs. A wet-milled griseofulvin (GF, BCS II drug) nanosuspension and a GF solution, both containing the same dissolved polymer-surfactant (SDS: sodium dodecyl sulfate) with 1:1 and 1:3 GF:polymer mass ratios, were spray-dried. Hydroxypropyl cellulose (HPC) and Soluplus (Sol) were used as matrix-forming polymers. XRPD, DSC, and Raman spectroscopy reveal that ASDs were formed upon spray-drying the solution-based feed, whereas nanocomposites and nanocomposites with >10% amorphous content, HyNASDs, were formed with the nanosuspension-based feed. Sol provided higher GF relative supersaturation, up to 180% and 360% for HyNASDs and ASDs, respectively, in the dissolution tests than HPC (up to 50% for both) owing to Sol's stronger intermolecular interactions and miscibility with GF and its recrystallization inhibition. Besides the higher kinetic solubility of GF in Sol, presence of GF nanoparticles vs. micron-sized particles in the nanocomposites enabled fast supersaturation. This study demonstrates successful preparation of fast supersaturating (190% within 20 min) HyNASDs, which renders nanoparticle formulations competitive to ASDs in bioavailability enhancement of poorly soluble drugs.