Hot-Melt Extrusion of the Thermo-Sensitive Peptidomimetic Drug Enalapril Maleate

Abstract

The aim of this research was the production of extrudates for the treatment of hypertension and heart failure and the investigation of the degradation of the peptidomimetic drug enalapril maleate (EM) during hot-melt extrusion (HME). A fast HPLC method was developed to quantify enalapril maleate and possible degradation products. Screening experiments revealed that the diketopiperazine derivative (Impurity D) was the main degradation product. Hot-melt extrusion of enalapril maleate with the polymer Soluplus® enabled extrusion at 100 °C, whereas a formulation with the polymer Eudragit® E PO could be extruded at only 70 °C. Extrusion at 70 °C prevented thermal degradation. A stabilizing molecular interaction between enalapril maleate and Eudragit® E PO was identified via FT-IR spectroscopy. Dissolution studies were carried out to study the influence of the formulation on the dissolution behavior of enalapril maleate. These promising results can be transferred to other thermo-sensitive and peptidomimetic drugs to produce extrudates which can be used, for instance, as feedstock material for the production of patient-specific dosage forms via Fused Deposition Modeling (FDM) 3D printing.

Fused Deposition Modeling (FDM) 3D Printing of the Thermo-Sensitive Peptidomimetic Drug Enalapril Maleate

“…The examined extrudates and 3D printed tablets revealed no crystalline active ingredient, only the crystalline parts of PEO were visible in the diffractograms. Furthermore, no differences in the physical state were found between the two formulations with SOL (Figure 4a) and bPMMA (Figure 4b) after extrusion at 100 • C [19] and FDM 3D printing at 180 • C. Reducing the extrusion temperature of the bPMMA formulation to 70 • C was also sufficient to fully convert enalapril maleate to the amorphous state (Figure 4b). DSC and XRD measurements both demonstrate that enalapril maleate is in amorphous form in the extrudates and 3D printed tablets of both formulations.…”

“…Hot-melt extrusion was carried out in our previous paper for the production of extrudates with the preferred formulations with a drug load of 10% enalapril maleate at a reduced temperature of 100 • C and additionally, for formulation, F2 at 70 • C (Table 1) [19]. HME was repeated for formulation F2 at 70 • C as the lowest possible extrusion temperature for the production of a sufficient number of 3D printed tablets for the printing study.…”

“…n = 10 samples were measured and mean ± SD are shown in the discussion. As described in [19], the identification and quantification of enalapril maleate and related substances was ensured with the help of reference standards. Selectivity was achieved by spiking enalapril maleate CRS solution with the other related substances.…”

“…A thorough discussion of the formulation composition and adjustment of the critical process parameters of the extrusion process can be found in our previous paper [19]…”

“…At certain suitable process conditions, it showed minimal to no degradation of the active ingredient compared to other polymers. An interaction between the drug and Eudragit ® E PO led to stabilization of the drug [19].…”