Characterization of crystalline and amorphous forms of irbesartan by multi-nuclear solid-state NMR

Abstract

Irbesartan (IRB) is an antihypertensive drug which exhibits the rare phenomenon of desmotropy; its 1H- and 2H- tetrazole tautomers can be isolated as distinct crystalline forms. The crystalline forms of IRB are poorly soluble, hence the amorphous form is potentially of interest for its faster dissolution rate. The tautomeric form and the nature of hydrogen bonding in amorphous IRB are unknown. In this study, crystalline form A and amorphous form of irbesartan were studied using ¹³C, ¹⁵N and ¹H solid-state NMR. Variable-temperature ¹³C SSMNR studies showed alkyl chain disorder in the crystalline form of IRB, which may explain the conflicting literature crystal structures of form A (the marketed form). ¹⁵N NMR indicates that the amorphous material contains an approximately 2:1 ratio of 1H- and 2H-tetrazole tautomers. Static ¹H SSNMR and relaxation time measurements confirmed different molecular mobilities of the samples and provided molecular-level insight into the nature of the glass transition. SSNMR is shown to be a powerful technique to investigate the solid state of disordered active pharmaceutical ingredients.

Keywords: Active pharmaceutical ingredient; Amorphous form; Desmotropy; Irbesartan; Molecular mobility; Nitrogen-15 SSNMR; Solid-state NMR; Spin–lattice relaxation time; Tautomerism.