Impact of Hot-Melt Extrusion on Glibenclamide's Physical and Chemical States and Dissolution Behavior: Case Studies with Three Polymer Blend Matrices

Abstract

This research work dives into the complexity of hot-melt extrusion (HME) and its influence on drug stability, focusing on solid dispersions containing 30% of glibenclamide and three 50:50 polymer blends. The polymers used in the study are Ethocel Standard 10 Premium, Kollidon SR and Affinisol HPMC HME 4M. Glibenclamide solid dispersions are characterized using thermal analyses (thermogravimetric analysis (TGA) and differential scanning calorimetry), X-ray diffraction and scanning electron microscopy. This study reveals the transformation of glibenclamide into impurity A during the HME process using mass spectrometry and TGA. Thus, it enables the quantification of the extent of degradation. Furthermore, this work shows how polymer-polymer blend matrices exert an impact on process parameters, the active pharmaceutical ingredient's physical state, and drug release behavior. In vitro dissolution studies show that the polymeric matrices investigated provide extended drug release (over 24 h), mainly dictated by the polymer's chemical nature. This paper highlights how glibenclamide is degraded during HME and how polymer selection crucially affects the sustained release dynamics.

Keywords: degradation; glibenclamide; hot-melt extrusion; solid dispersion; sustained drug release; ternary blends.

Figure 1

Glibenclamide drug recovery in the extrudates and the specific mechanical energy input during the runs of the three different formulations.

Figure 2

Analyses of mass spectra to identify components present in the extrudate formulation GLB and HPMC and PVP/PVAc obtained under process conditions defined in Table 1. (A) represents the UV-HPLC chromatogram of the extruded formulation. Further, the mass spectra of (B) glibenclamide (as received), (C) impurity A (as received), (D) the compound eluted at t = 9.9 min (from ethanolic solution of the extrudate), and (E) the compound eluted at t = 2.9 min (from ethanolic solution of the extrudate) are shown.

Figure 3

Thermogravimetric analyses (weight evolution and its temperature first derivative) performed at 5 °C/min of extrudates made from ternary blends containing 30% GLB. Thermograms of crystalline and amorphous GLB powder and purchased impurity A were added for comparison. The dashed curves represent the temperature derivative of the signal.

Figure 4

X-ray diffraction patterns recorded at room temperature of extrudates made from ternary blends containing 30% GLB. Diffractograms of crystalline and amorphous GLB are added for comparison.

Figure 5

MDSC scans of ternary blend formulations containing 30% GLB: GLB and HPMC and PVP/PVAc represented in green, GLB and HPMC and EC in brown and GLB and EC and PVP/PVAc in blue. Thermogram of amorphous GLB is presented in red for comparison. The arrows highlight the glass transitions. Reversible and non-reversible heat flow curves are presented in the Supplementary Figures S2–S4.

Figure 6

Optical macroscopy (left) and scanning electronic microscopy (middle and right) images of surfaces and cross sections of drug-loaded extrudates (based on HPMC and PVP/PVAc) before exposure to the release media.

Figure 7

Scanning electronic microscopy image (left) coupled with energy dispersive X-ray (EDX) analysis performed in the different zones of the extrudate section (numbered from 1 to 9). It allows us to determine the distribution of GLB within the polymeric matrix of HPMC and PVP/PVAc by observing the presence of sulfur and chlorine atoms specific to GLB.

Figure 8

Drug release profiles of extruded ternary blends in a two-stage dissolution set-up (n = 3, USP II) for the first 30 min in HCl pH 1.2 (non-sink) and afterward in PB pH 6.8 at 37 °C under agitation (75 rpm) in sink conditions.

Figure 9

Water uptake (A) and dry mass loss (B) of the extrudates based on the three blends investigated (as indicated).

Figure 9

Water uptake (A) and dry mass loss (B) of the extrudates based on the three blends investigated (as indicated).

Figure 10

Optical macroscopy pictures of extrudates based on (A) HPMC and PVP/PVAc, (B) EC and HPMC and (C) EC and PVP/PVAc before and after exposure to release medium.

Figure 10

Optical macroscopy pictures of extrudates based on (A) HPMC and PVP/PVAc, (B) EC and HPMC and (C) EC and PVP/PVAc before and after exposure to release medium.