An investigation into solubility and dissolution improvement of alectinib hydrochloride as a third-generation amorphous solid dispersion

Poorly water-soluble drugs belonging to BCS Class II and IV present a big challenge to formulators owing to their limited solubility and bioavailability. Alectinib hydrochloride (ALB), a BCS IV molecule, shows very low solubility resulting in low bioavailability. The objective of the present study is to improve the solubility and dissolution of ALB using the Amorphous Solid Dispersion (ASD) technique.

Highlights

A third-generation amorphous solid dispersion (TgSD) of Alectinib hydrochloride (ALB) was developed.

Both solubility and dissolution were significantly improved by Amorphous solid dispersion technique.

TgSD showed their advantages over second-generation amorphous dispersion for solubility and dissolution enhancement.

ALB-TgSD led to higher solubility and dissolution in bio-relevant media than crystalline drug alone.

ALB-TgSD maintained its amorphous state and dissolution during stability studies till 12 months.

Different polymers and surfactants were screened for solubility enhancement of ALB. Soluplus, as a polymer showed the highest solubility enhancement. ALB and Soluplus in 1:5 ratio resulted in significant improvement in solubility and dissolution when evaluated as a second-generation solid dispersion. The inclusion of 5% P407 for a third-generation ASD (ALB-TgSD-P5%) resulted in a further increase in solubility and dissolution. The optimized formulation showed a 2-fold increase in dissolution in FaSSIF, bio-relevant media, indicating the potential for bioavailability improvement. DSC and p-XRD showed the conversion of crystalline drug to amorphous state. Further, FTIR and molecular docking studies showed intermolecular interaction between ALB and Soluplus, thus, providing physical stability for ASD. Stability studies showed the formulation to be stable until 12 months at room temperature with no impact on amorphicity and dissolution.

These studies revealed that the low solubility and dissolution concern of Alectinib hydrochloride can be addressed using ASD technique. Third-generation ASD demonstrates superiority over second-generation ASD to improve solubility and dissolution. Improvement of solubility and dissolution in bio-relevant media opens a promising path for clinical evaluation. The optimized formulation is stable and can be easily scaled up for industrial application.

Sumit Kumar Saha, Amita Joshi, Romi Singh, Suvamay Jana, Kiran Dubey, An investigation into solubility and dissolution improvement of alectinib hydrochloride as a third-generation amorphous solid dispersion, Journal of Drug Delivery Science and Technology, Volume 81, 2023, 104259, ISSN 1773-2247,
https://doi.org/10.1016/j.jddst.2023.104259.

excipients formulation