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Background and Objective <p>Alectinib (ALB), a second-generation anaplastic lymphoma kinase (ALK) inhibitor used in the treatment of ALK-positive non-small cell lung cancer (NSCLC), is classified as a BCS Class IV drug, characterized by low aqueous solubility and permeability and an oral bioavailability of approximately 37%. The objective of this study was to develop and optimize ALB nanocrystals (ALB-NC) to overcome these biopharmaceutical limitations.</p> Methodology <p>ALB nanosuspension (NS) was prepared by the antisolvent precipitation (ASP) technique using ethanol as the organic phase and Poloxamer 188 (P188) as the steric stabilizer. A Face-Centered Central Composite Design (FCCCD) was employed to optimize the formulation, with polymer concentration (X1) and solvent volume (X2) as independent variables, and particle size, saturated solubility, and cumulative drug permeation as responses. The optimized NS was converted to ALB-NC by lyophilization with mannitol as cryoprotectant and filled into hard gelatin capsules. Characterization included FTIR, DSC, PXRD, SEM, in vitro dissolution, ex vivo permeation, cytotoxicity (MTT assay in A549 cells), and short-term accelerated stability studies.</p> Results <p>The optimized ALB-NC formulation exhibited a particle size of 226.8 nm (PDI = 0.187), saturated solubility of 70.445 µg/mL (~70-fold improvement over pure drug), and cumulative permeation of 6.871 mg/cm2 in 60 minutes (~3-fold improvement). Capsules demonstrated a fast disintegration time (1.31 ± 0.15 min) and high dissolution rate (93.77% in 60 min in SGF). DSC and PXRD confirmed partial crystallinity reduction, and SEM established nanosized morphology.</p> Conclusion <p>ALB-NC capsules prepared by antisolvent precipitation and lyophilization demonstrate substantially improved in vitro dissolution and permeation, providing a strong biopharmaceutical rationale for enhanced oral absorption. In vivo pharmacokinetic studies are proposed to confirm bioavailability enhancement. The formulated ALB-NC capsules exhibited a significantly enhanced dissolution rate of 93.77% in simulated gastric fluid and approximately 70-fold improvement in saturation solubility compared to the pure drug, suggesting a strong biopharmaceutical basis for enhanced oral absorption. These results provide a compelling in vitro rationale for the nanocrystal approach; however, in vivo pharmacokinetic studies are essential to confirm bioavailability enhancement and are proposed as critical future work.</p>

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Alectinib Nanocrystals for Enhanced Solubility and Permeability: Formulation Optimization and In Vitro Characterization

  • 期刊论文

  • 发表日期：

    2026年5月11日

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  • Gowtham Menon,
  • Thejaswini Anand,
  • Girish Kashid,
  • Sakshi M Kolage,
  • Bhagyashri Malave,
  • Sakshi Parjane,
  • Hrushikesh Mhaismale

摘要

Background and Objective

Alectinib (ALB), a second-generation anaplastic lymphoma kinase (ALK) inhibitor used in the treatment of ALK-positive non-small cell lung cancer (NSCLC), is classified as a BCS Class IV drug, characterized by low aqueous solubility and permeability and an oral bioavailability of approximately 37%. The objective of this study was to develop and optimize ALB nanocrystals (ALB-NC) to overcome these biopharmaceutical limitations.

Methodology

ALB nanosuspension (NS) was prepared by the antisolvent precipitation (ASP) technique using ethanol as the organic phase and Poloxamer 188 (P188) as the steric stabilizer. A Face-Centered Central Composite Design (FCCCD) was employed to optimize the formulation, with polymer concentration (X1) and solvent volume (X2) as independent variables, and particle size, saturated solubility, and cumulative drug permeation as responses. The optimized NS was converted to ALB-NC by lyophilization with mannitol as cryoprotectant and filled into hard gelatin capsules. Characterization included FTIR, DSC, PXRD, SEM, in vitro dissolution, ex vivo permeation, cytotoxicity (MTT assay in A549 cells), and short-term accelerated stability studies.

Results

The optimized ALB-NC formulation exhibited a particle size of 226.8 nm (PDI = 0.187), saturated solubility of 70.445 µg/mL (~70-fold improvement over pure drug), and cumulative permeation of 6.871 mg/cm2 in 60 minutes (~3-fold improvement). Capsules demonstrated a fast disintegration time (1.31 ± 0.15 min) and high dissolution rate (93.77% in 60 min in SGF). DSC and PXRD confirmed partial crystallinity reduction, and SEM established nanosized morphology.

Conclusion

ALB-NC capsules prepared by antisolvent precipitation and lyophilization demonstrate substantially improved in vitro dissolution and permeation, providing a strong biopharmaceutical rationale for enhanced oral absorption. In vivo pharmacokinetic studies are proposed to confirm bioavailability enhancement. The formulated ALB-NC capsules exhibited a significantly enhanced dissolution rate of 93.77% in simulated gastric fluid and approximately 70-fold improvement in saturation solubility compared to the pure drug, suggesting a strong biopharmaceutical basis for enhanced oral absorption. These results provide a compelling in vitro rationale for the nanocrystal approach; however, in vivo pharmacokinetic studies are essential to confirm bioavailability enhancement and are proposed as critical future work.