Study of the Amorphous Glibenclamide Drug: Analysis of the Molecular Dynamics of Quenched and Cryomilled Material

Abstract

Glibenclamide (GCM) is an oral hypoglycemic agent of the sulfonylurea group used in the treatment of non-insulin-dependent diabetes. Crystalline GCM is characterized by low bioavailability, which is attributed to its poor dissolution properties. It prompted us to prepare this drug in its amorphous form as a means to enhance its dissolution characteristics. Two different methods were used to convert crystalline GCM into the glassy form: quench-cooling of the melt and cryogenic milling. To monitor solid-state properties of the amorphous samples, X-ray powder diffraction (XRD), infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), ultraperformance liquid chromatography (UPLC) and spectroscopy, and broadband dielectric spectroscopy (BDS) were applied. The results of UPLC separations along with associated infrared and NMR measurements unambiguously showed that the thermal degradation of the quenched GCM, as suggested in literature reports, does not occur. A similar analysis performed on the cryomilled material also did not indicate any chemical decomposition. On the other hand, both methods confirmed that the conversion to the amorphous form is connected with the amide-imidic acid tautomerism of the examined drug. Moreover it was shown that this transformation occurs regardless of the manner of amorphization. Finally, dielectric spectroscopy was employed to study the molecular dynamics of vitrified GCM. The analysis of the ε''(f) in terms of the KWW function from the dielectric measurements revealed the existence of an "excess wing" attributed to the true Johari-Goldstein process based on Ngai's coupling model. The dielectric properties of GCM obtained in the amorphous form both by rapid cooling of the melt and the cryogenic grinding of crystalline sample were also compared.

New Nanometric Solid Dispersions of Glibenclamide in Neusilin® UFL2

“…2) of amorphous GLB, the only glass transition temperature at nearly 62.20±1.30°C in accordance to Wojnarowska (29) was observed. The water content (7.24±1.13%) was consistent with an amorphous material characterised by a certain tendency to retain water (Table II).…”

“…Glibenclamide (GLB) was kindly supplied by Menarini Manufacturing Logistics and Service (Florence, Italy) as white 1 (29) and stored in a desiccator in presence of P 2 O 5 as desiccant during the experiment time interval.…”

Rheological studies of tautomerization kinetics in supercooled glibenclamide drug

“…For example, the proton migration in nucleo-bases causes point mutations in genetic codes 5 . The difference in drug activity for some pharmaceutical compounds is also a result of tautomerization 6,7 . In this context, it is of great importance to understand the proton transfer kinetics and isomer equilibrium at various thermal and chemical conditions.…”

“…Therefore, one of the possibilities to observe the amide-imidic-acid transformation is to prepare GCM drug in amorphous state. According to the literature reports, the glassy GCM sample prepared by rapid cooling of the melt (T m = 443K) is characterized by 16% of imidic-acid forms 6 .…”

“…According to the existing infrared measurements [6], the intermolecular proton transfer reaction begins at the melting temperature of GCM. If the temperature is kept constant, an equilibrium between the amide and the imidic-acid forms will be achieved after a period of time.…”