The behavior of Gliclazide in solution and in the solid state: a case of organic compound presenting a solid-solution...

Area of Science:

• Medicinal Chemistry
• Structural Chemistry
• Nuclear Magnetic Resonance Spectroscopy

Background:

• Gliclazide is a widely used oral hypoglycemic agent belonging to the sulfonylurea class.
• Understanding its molecular structure and dynamics is crucial for drug design and efficacy.
• Previous studies have provided insights into Gliclazide's chemical properties, but detailed structural dynamics in different environments require further investigation.

Purpose of the Study:

• To elucidate the detailed molecular structure and conformational dynamics of Gliclazide.
• To investigate the influence of different states (solid vs. solution) on Gliclazide's structure.
• To characterize the isomeric forms and dynamic processes of Gliclazide using advanced NMR techniques.

Main Methods:

• Nuclear Magnetic Resonance (NMR) spectroscopy, including (1)H, (13)C, and (15)N NMR.
• Solid-state NMR analysis.
• Solution-state NMR analysis in deuterated chloroform (CDCl(3)) and dimethyl sulfoxide-d(6) (DMSO-d(6)).
• GIAO (Gauge-Independent Atomic Orbital) calculations for absolute shielding analysis.

Main Results:

• In the solid state, Gliclazide crystallizes as a stable EZ isomer without significant dynamic properties.
• In CDCl(3) solution, Gliclazide exists as an EZ isomer but exhibits slow nitrogen inversion at the pyrrolidine nitrogen, leading to the observation of two distinct invertomers.
• In DMSO-d(6) solution, the nitrogen inversion rate increases, resulting in averaged NMR signals.
• GIAO calculations supported the identification of the observed species.
• The solid state revealed a solid-solution phenomenon with two disordered conformations in a 90:10 ratio within the crystal.

Conclusions:

• Gliclazide's structural behavior is highly dependent on its physical state.
• The pyrrolidine nitrogen inversion is a key dynamic process influencing Gliclazide's structure in solution.
• The findings provide a comprehensive understanding of Gliclazide's solid-state and solution-state structures, relevant for its pharmaceutical application.