(T1330-08-55) Novel Preparation Method of Spherical Drug-Containing Particles Using High Shear Melt Granulation; MALCORE®

Purpose: MALCORE^® is a novel preparation method of spherical drug-containing particles (DCPs) which consists of a unique 2-step melt granulation [1]. In the 1st step, melting component adsorbed particles (MAs) are prepared by adsorption of low-melting-point material into a porous carrier. In the 2nd step, DCPs can be prepared by layering drug and polymer onto MAs. MALCORE^® is a useful method that can efficiently prepare spherical DCPs by heating and mixing without any solvents. However, previous studies have only reported cases of the 2nd step using fluidized bed rotor granulators, while the 1st step used a high shear granulator (HSG), and it was unclear whether other manufacturing equipment could be applied [1][2]. It will further show the usefulness of this method if the 1st step and 2nd step can be prepared using the same equipment. The aim of this study was to investigate the feasibility of the 2nd step using HSG. Furthermore, the state of melting component and polymer in resulting DCPs using HSG were evaluated in order to elucidate the mechanism of drug loading by heating and mixing with high shear.

Methods: Duloxetine hydrochloride (DLX) which is an antidepressant was selected as a model drug, hydrous silicon dioxide (HSD) as a porous carrier, stearic acid (SA) as a melting component, and aminoalkyl methacrylate copolymer E (AMCE) as a polymer. In the 1st step, HSD and SA were charged into HSG with flowing of warm water via jacket, and those were heated and mixed at 70°C product temperature for 15 min to prepare MAs. Subsequently, DLX, AMCE and MAs were charged into the same HSG as the 2nd step, and DLX was layered onto MAs by heating and mixing at 65°C product temperature for 28 min. The characteristics of resulting DCPs (yield, particle size distribution, morphology by the scanning electron microscope (SEM), internal structure by the X-ray CT, drug-loading efficiency, and drug dissolution profile) were evaluated. In addition, the thermal analysis by differential scanning calorimetry (DSC) and the viscosity by rheometer of the material and the resulting DCPs were evaluated.

Results: In the 1st step, the melted SA was almost adsorbed in the pore of HSD and the excess SA was covered on HSD. The resulting MAs had same spherical shape and particle size as HSD. From the SEM and X-ray CT image of DCPs in the 2nd step, it was showed that DLX was layered onto MAs, and finally the resulting DCPs were a spherical shape with layering all DLX (Fig. 1). The particle size distribution of DCPs was similar shape to that of HSD and MAs, and the particle size of DCPs was increased due to the drug layer (Fig. 2). The yield and drug-loading efficiency in the 2nd step were 98.7% and 99.2%, respectively, which were almost theoretical values. The drug dissolution from the DCPs in spite of using lipophilic SA and water-insoluble polymer AMCE was not affected by the melt granulation process, and showed almost 100% dissolution at 5 min. Furthermore, the process times of 1st and 2nd step were within 30 minutes, respectively. Therefore, DCPs could be consistently and efficiently prepared using HSG. Also, based on the DSC measurement, the mixture of SA and AMCE, and DCPs with increase temperature showed broad peaks around 40-60°C, which did not correspond to the spectra of SA or AMCE alone. This suggests interaction between SA and AMCE. In addition, the viscosity of the mixture of SA and AMCE increased by heating and showed 1,000 times higher than that of melted SA alone at 65°C (Fig. 3). Therefore, SA and AMCE interacted to increase viscosity, which enabled to layer the drug onto the MAs in the 2nd step by heating and mixing with HSG.

Conclusion: HSG was successfully applied to the 2nd step of MALCORE^®. DCPs with ideal characteristics (spherical shape, yield and drug-loading efficiency as per theoretical values, and no effect on intact drug dissolution) could be prepared in a short time. Furthermore, it was showed that spherical DCPs could efficiently be prepared in spite of the process by heating and mixing due to the interaction of SA and AMCE and increase in the viscosity.

References: [1] N. Yoshihara, et al., Novel preparation approach with a 2-step process for spherical particles with high drug loading and controlled size distribution using melt granulation: MALCORE®, Adv. Powder Technol. 2022;33: 103409.
[2] R. Kimata, et al., Impact of Properties of Hydrated Silicon Dioxide as Core Material on the Characteristics of Drug-containing Particles Prepared by the 2-step Process Melt Granulation Technology, MALCORE®, AAPS PharmSciTech, 24(1), 28.

Figure 1. The image of temporal change and internal structure of DCPs in the 2nd step. (a) Schematic diagram, (b-1) initial, (b-2) process time 15min, (b-3) process time 28min, (b-4) internal structure of process time 28min

Figure 2. Particle size distribution of HSD, MAs, and DCPs.

Figure 3. (a)DSC spectra of AMCE, SA, the mixture of SA and AMCE, and DCPs. (b)Viscosity analysis of SA, and the mixture of SA and AMCE.