A current insight into the drug–drug molecular adducts of an anti-cancer drug vandetanib with various NSAIDs

Abstract

Vandetanib (VDTB), a BCS (Biopharmaceutics Classification System) class II anticancer medication, has a low water solubility, requiring large dosages and causing a variety of adverse effects. The current study aims to enhance the solubility of VDTB using a well-known crystal engineering technique. A series of NSAIDs: ibuprofen (IBU), mefenamic acid (MEF), niflumic acid (NIF) and tolfenamic acid (TOL) were screened to prepare novel solid forms using the liquid-aided grinding (LAG) method followed by the slow evaporation crystallization process. Various characterisation techniques such as single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were used to screen the newly obtained adducts. The crystal structure study confirmed salt formation, indicating proton transfer from the carboxylic acid group of NSAIDs to the piperidine nitrogen atom of VDTB. A comprehensive study of the solubility and in vitro release kinetics of these newly obtained entities showed that, as compared to the parent medication, most of the binary adducts have a much higher solubility rate, especially VDTB·IBU, which shows ∼5-fold enhanced solubility compared to the parent drug. Furthermore, a detailed study of the residue recovered following solubility indicated that all the molecular adducts were stable. To the best of our knowledge, this is the first study to look at drug–drug interactions of VDTB with improved physicochemical properties. We anticipate that the new discovery will provide some helpful insight prior to the VDTB medication development and that the use of NSAIDs can avoid side effects such as bodily pain, fever, and inflammation, in addition to their anti-cancer attributes.