Development of sustained-release lipophilic calcium stearate pellets via hot melt extrusion
Abstract
The objective of this study was the development of retarded release pellets using vegetable calcium stearate (CaSt) as a thermoplastic excipient. The matrix carrier was hot melt extruded and pelletized with a hot-strand cutter in a one step continuous process. Vegetable CaSt was extruded at temperatures between 100 and 130 °C, since at these temperatures cutable extrudates with a suitable melt viscosity may be obtained. Pellets with a drug loading of 20% paracetamol released 11.54% of the drug after 8 h due to the great densification of the pellets. As expected, the drug release was influenced by the pellet size and the drug loading. To increase the release rate, functional additives were necessary. Therefore, two plasticizers including glyceryl monostearate (GMS) and tributyl citrate (TBC) were investigated for plasticization efficiency and impact on the in vitro drug release. GMS increased the release rate due to the formation of pores at the surface (after dissolution) and showed no influence on the process parameters. The addition of TBC increased the drug release to a higher extent. After dissolving, the pellets exhibited pores at the surface and in the inner layer. Small- and Wide-Angle X-ray Scattering (SWAXS) revealed no major change in crystalline peaks. The results demonstrated that (nearly) spherical CaSt pellets could be successfully prepared by hot melt extrusion using a hot-strand cutter as downstreaming system. Paracetamol did not melt during the process indicating a solid suspension. Due to the addition of plasticizers, the in vitro release rate could be tailored as desired.
Conclusions
Hydrophobic CaSt pellets, including plasticizers and the water- soluble model drug paracetamol, were produced via HME and hot- strand cutting. The findings demonstrate that controlled-release spherical pellets could be successfully prepared via HME, using a hot-strand cutter with two rotating knives as downstreaming sys- tem. The thermal behavior of pure CaSt, investigated via DSC, dis- played four peaks in the first heating cycle, which were partly reversible on cooling and reproducible at repeated heating. The extrusion process was conducted at temperatures between 100 and 130 °C, since at these temperatures cutable extrudates with a smooth external appearance can be obtained. The effect of two plasticizers on the processibility and the drug release kinetics was investigated. GMS and TBC (less soluble plasticizer) reduced the required process temperature, and extrudates with an appro- priate melt viscosity were produced. The tackiness of the strands was slightly increased for TBC resulting in higher ARs. The incorpo- ration of paracetamol into the formulations decreased the ARs due to the decreased formability behavior of the pellets. All paraceta- mol pellets exhibited ARs 61.28. As expected, the dissolution pro- file was affected by the pellet size and the drug content. The release of the API was mainly governed by a diffusion-controlled drug release. Pellets containing no plasticizer exhibited low release rates, attributable to the great densification of the CaSt pellets. The incorporation of GMS increased the drug release. After dissolution, pellets exhibited pores at the surface, which had been generated by the release of the drug and GMS from the CaSt matrix. TBC in- creased the release rate to the highest extent due to the good mis- cibility with CaSt. After dissolving, the pellets exhibited pores also in the inner layer. However, increasing TBC levels did not result in an increase in the release rate due to the formation of a denser ma- trix. SWAXS investigations of the extruded pellets showed that, due to the mechanical treatment of CaSt during extrusion, the or- der in the crystal lattice increased. No shifting of the peaks oc- cursed in all formulations, demonstrating that CaSt did not melt during the extrusion process and that paracetamol was embedded in the matrix carrier in its crystalline form displaying a solid suspension.