Abstract
This research study aimed to develop and evaluate a novel freeze-dried nanocrystals formulation of sotorasib (AMG-510) using Quality by Design (QbD) approach to enhance solubility, dissolution, and oral bioavailability. A QbD framework use for identification, optimization and validation of critical process and formulation parameters, significantly influcing key quality attributes of nanosuspension. A stable sotorasib nanocrystal formulation (45 % w/w) was successfully developed using an anionic glycolipid biosurfactants (rhamnolipid) and non-ionic polyvinyl alcohol (PVA) as stabilizers through dual centrifugation wet media milling.
Highlights
- Sotorasib nanosuspension stabilized by anionic glycolipid biosurfactant.
- QbD approach optimizes critical attributes for colloidal system performance.
- 14-fold increase in surface area enhances dissolution rate and solubility.
- Freeze-thaw induced stress and aggregation are effectively prevented by cryoprotectants.
- Colloidal system design advances nanomedicine and drug delivery applications.
A comprehensive freeze-thaw stress study indicated that the nanocrystals-maintained stability, with lyoprotectants such as hydroxypropyl-β-cyclodextrin (HPβ-CD) and trehalose effectively preventing aggregation. Brunauer-Emmett-Teller (BET) analysis revealed a 14-fold increase in surface area and improved porosity following nanonization and freeze-drying. Solid-state characterization confirmed a reduction in crystallinity post-milling and freeze-drying processes, with nanocrystals retaining their crystalline structure. Morphological characterization using SEM and Cryo-TEM confirmed well-dispersed nanocrystals with uniform morphology and no significant aggregation. The freeze-dried product exhibited excellent redispersibility, with particle sizes reverting to their original dimensions upon reconstitution.
In vitro drug release studies demonstrated a particle size-dependent dissolution rate enhancement, with significantly higher drug release at intestinal pH (6.8) compared to the pure drug. Storage stability testing revealed that the nanosuspensions and freeze-dried formulations remained stable under accelerated conditions, preserving particle size, PDI, and drug loading over three months. The developed nanocrystalline formulation offers a promising strategy to improve the therapeutic efficacy of poorly soluble drugs like sotorasib, especially in high-dose regimens, enhancing patient convenience and adherence.
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Materials
Sotorasib (AMG-510), with > 99% purity was purchased from Muse Chem, Inc. (Fairfield, NJ, USA). Polyvinyl alcohol (PVA), Sucrose monolaurate (SML), L-Leucine, L-Lysine Acetate, trehalose dihydrate, and β-cyclodextrin polymer (β-CDP) were purchased from Sigma-Aldrich, Inc. (St. Louis, MO, USA). Plasdone™ S-630 (N-vinyl-2-pyrrolidone and vinyl acetate copolymer, PS630) by Ashland (Wilmington, NC, USA) and Rhamnolipid (RMNL, REWOFERM® RL 100) and Sophorolipid (REWOFERM® SL ONE, SPL).
Henis J. Patel, Ketan Patel, Biosurfactant Stabilized Nanosuspension of KRAS inhibitor – Sotorasib (AMG-510): Systematic optimization using Quality by Design Approach, Colloids and Surfaces B: Biointerfaces, 2025, 114831, ISSN 0927-7765, https://doi.org/10.1016/j.colsurfb.2025.114831.
Read also our introduction article on Quality by Design (QbD) here:
