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

• Published in: European journal of pharmaceutical sciences 2020-07, Vol.150, p.105354, Article 105354
• Main Authors: Rahman, Mahbubur, Coelho, Alexander, Tarabokija, James, Ahmad, Stephanie, Radgman, Keanu, Bilgili, Ecevit
• Format: Article
• Language: English
• Subjects: Amphiphilic polymers; Crystallization; Crystallization inhibitor; Drug Liberation; Griseofulvin - chemistry; Micellar solubilisation; Polymers - chemistry; Spray drying; Supersaturation; Ternary amorphous solid dispersions; Wettability
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2020.105354

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. [Display omitted]