Utilizing hot-stage polarized microscopy and ATR-FTIR for ramipril co-crystal screening, supported by principal component analysis and cluster analysis

Context: Co-crystal formation, a method for enhancing the physicochemical properties of active pharmaceutical ingredients (APIs), has gained traction in pharmaceutical research. However, the current landscape lacks comprehensive and dependable co-crystal screening methods. Aims: To implement and assess a comprehensive methodology for co-crystal screening. This methodology combines hot-stage polarized microscopy (HSPM) and attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy, along with principal component analysis (PCA) and cluster analysis (CA). Methods: Three binary compounds containing ramipril, an API that had not previously been co-crystallized, and three pharmaceutical coformers were investigated. The Kofler mixed fusion method was initially employed for initial co-crystal system identification. Subsequently, potential co-crystals were produced in a solid state via a procedure involving the gradual evaporation of the solvent. PCA and CA were applied to ATR-FTIR spectral data to identify patterns indicative of co-crystal formation. Results: Our analysis revealed characteristic ATR-FTIR bands indicative of the formation of hydrogen bonds between ramipril and its coformers, signifying the successful formation of co-crystals. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) measurements confirmed these findings. Experiments revealed two potential co-crystals, ramipril-vanillin, and ramipril-anthranilic acid. The study discusses the intricate HSPM images, spectra, thermogram of DSC, and X-ray diffraction properties of these systems in depth. Conclusions: Our findings validate the proposed methodology as a prospective tool for co-crystal screening, as ramipril co-crystals were successfully identified and characterized. This integrated method simplifies co-crystal screening and has the potential to substantially advance pharmaceutical research.