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

Article publishing in J. Pharm. Pharmacogn. Res., vol. 11, no. 6, pp. 1137-1148, Nov-Dec 2023.

DOI: https://doi.org/10.56499/jppres23.1723_11.6.1137

Original Article

Indra Indra^1,4, Saleh Wikarsa², Yuda Prasetya Nugraha², Veinardi Suendo³, Hidehiro Uekusa⁵, Sundani Nurono Soewandhi^2*

¹Doctoral Program of Pharmacy, School of Pharmacy, Institut Teknologi Bandung, Jl. Ganesha No. 10, Bandung 40132, Indonesia.

²Department of Pharmaceutics, School of Pharmacy, Institut Teknologi Bandung, Jl. Ganesha No. 10, Bandung 40132, Indonesia.

³Division of Inorganic and Physical Chemistry, Faculty of Mathematics and Natural Sciences, Institut Teknologi Bandung, Bandung 40132, Indonesia.

⁴Faculty of Pharmacy, Universitas Bakti Tunas Husada, Tasikmalaya 46115, Indonesia.

⁵ Department of Chemistry, School of Science, Tokyo Institute of Technology, Tokyo 1528551, Japan.

*E-mail: sundani@itb.ac.id

Abstract

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.