Charge Transfer Complex of Lorlatinib with Chloranilic Acid: Characterization and Application to the Development of a Novel 96-Microwell Spectrophotometric Assay with High Throughput

Abstract

Lorlatinib (LRL) is the first drug of the third generation of anaplastic lymphoma kinase (ALK) inhibitors used a first-line treatment of non-small cell lung cancer (NSCLC). This study describes, for the first time, the investigations for the formation of a charge transfer complex (CTC) between LRL, as electron donor, with chloranilic acid (CLA), as a π-electron acceptor. The CTC was characterized by ultraviolet (UV)-visible spectrophotometry and computational calculations. The UV-visible spectrophotometry ascertained the formation of the CTC in methanol via formation of a new broad absorption band with maximum absorption peak (λmax) at 530 nm. The molar absorptivity (ε) of the complex was 0.55 × 103 L mol−1 cm−1 and its band gap energy was 2.3465 eV. The stoichiometric ratio of LRL/CLA was found to be 1:2. The association constant of the complex was 0.40 × 103 L mol−1, and its standard free energy was −0.15 × 102 J mole−1. The computational calculation for the atomic charges of an energy minimized LRL molecule was conducted, the sites of interaction on the LRL molecule were assigned, and the mechanism of the reaction was postulated. The reaction was adopted as a basis for developing a novel 96-microwell spectrophotometric method (MW-SPA) for LRL. The assay limits of detection and quantitation were 2.1 and 6.5 µg/well, respectively. The assay was validated, and all validation parameters were acceptable. The assay was implemented successfully with great precision and accuracy to the determination of LRL in its bulk form and pharmaceutical formulation (tablets). This assay is simple, economic, and more importantly has a high-throughput property. Therefore, the assay can be valuable for routine in quality control laboratories for analysis of LRL’s bulk form and pharmaceutical tablets.

Development of Novel Micellar-Enhanced High-Throughput Microwell Spectrofluorimetric Method for Quantification of Lorlatinib: Application to In Vitro Drug Release and Analysis of Urine Samples

“…The availability of simpler analytical methods that can be applied to the quantification of LOR in its bulk powder, dosage form (tablets), and biological specimens will be convenient. Our laboratory described two simple spectrophotometric methods for LOR via its charge transfer reactions [ 23 , 24 ]. These methods involved the charge transfer reactions of LOR with chloranilic acid and DDQ electron acceptors, and the employment of the reactions in developing spectrophotometric methods for LOR.…”

“…For these reasons, it was very necessary to develop a highly sensitive method with a simple procedure and high throughput that is applicable to the quantification of LOR in bulk powder, dosage forms, and biological samples without interferences from either the pharmaceutical excipients or the aqueous matrix of the biological samples. This method is crucial for assessing the uniformity of pharmaceutical formulations, other pharmaceutical industry processes, and therapeutic drug monitoring [ 23 , 24 , 25 ].…”