Solubility, pH-Solubility Profile, pH-Rate Profile, and Kinetic Stability of the Tyrosine Kinase Inhibitor, Alectinib

Abstract

Alectinib HCl (ALBHCl) is a tyrosine kinase inhibitor used for non-small cell lung carcinoma (NSCLC). The aim of this study is to unlock some of the physicochemical properties of ALBHCL that serve as a database for any future studies. A solubility study of ALBHCL was performed in different solvents. Also, photostability was tested in the solution and solid states, and the order of reaction and rate constant were calculated. In addition to the pH solubility relation, the pH-rate relation at different temperatures was also studied, and the profiles were constructed. A solubility study was also performed in different media for the purpose of optimizing suitable sink conditions for the in vitro dissolution testing of solid dosage forms. Solubility tests in multiple solvents and pH conditions revealed that the highest solubility was in DMSO, methanol, and chloroform, with acidic media yielding the maximum solubility but degrading at rather low pH levels. ALBHCL proved unstable at high temperatures and under light exposure, with varying stability across different pH levels. The optimal dissolution media for in vitro oral dosage form evaluation were determined, achieving sink conditions at pH levels of 6.8 and 4.5 with specific additives. This study enhances the existing database on ALBHCL's physicochemical properties, emphasizing the importance of pH optimization in pharmaceutical processes and providing valuable insights into its pharmaceutical application.

Keywords: alectinib; non-small cell lung carcinoma; pH solubility; pH stability; photodegradation; solubility.

Figure 1

A chromatogram of ALBHCL showing a retention time of 3.5 min.

Figure 2

The linearity and calibration curve of ALBHCL, showing an R² of 0.9998.

Figure 3

Solubility (in mg/mL) of ALBHCL in different solvents. (H₂O = water; ACN = acetonitrile; ETOH = ethanol; PG = propylene glycol; PEG400 = polyethylene glycol; THF = tetrahydrofuran; CHCl₃ = chloroform; MEOH = methanol; DMSO = dimethyl sulfoxide).

Figure 4

The pH solubility profile of ALBHCL, showing maximum solubility at pH 3.5.

Figure 5

Chromatogram of ALBHCL at pH 1.2 after 24 h, showing a small peak adjacent to ALBHCL at an RT of 3.5 min.

Figure 6

The log percentage remaining vs. a T plot of the photodegradation of ALBHCL in a solution, showing the first-order pattern of degradation.

Figure 7

Partial pH-rate profile of ALBHCL using 3 pH values.