Amorphous Solid Dispersions Layered onto Pellets-An Alternative to Spray Drying?

Abstract

Spray drying is one of the most frequently used solvent-based processes for manufacturing amorphous solid dispersions (ASDs). However, the resulting fine powders usually require further downstream processing when intended for solid oral dosage forms. In this study, we compare properties and performance of spray-dried ASDs with ASDs coated onto neutral starter pellets in mini-scale. We successfully prepared binary ASDs with a drug load of 20% Ketoconazole (KCZ) or Loratadine (LRD) as weakly basic model drugs and hydroxypropyl-methyl-cellulose acetate succinate or methacrylic acid ethacrylate copolymer as pH-dependent soluble polymers. All KCZ/ and LRD/polymer mixtures formed single-phased ASDs, as indicated by differential scanning calorimetry, X-ray powder diffraction and infrared spectroscopy. All ASDs showed physical stability for 6 months at 25 °C/65% rH and 40 °C/0% rH. Normalized to their initial surface area available to the dissolution medium, all ASDs showed a linear relationship of surface area and solubility enhancement, both in terms of supersaturation of solubility and initial dissolution rate, regardless of the manufacturing process. With similar performance and stability, processing of ASD pellets showed the advantages of a superior yield (>98%), ready to use for subsequent processing into multiple unit pellet systems. Therefore, ASD-layered pellets are an attractive alternative in ASD-formulation, especially in early formulation development at limited availability of drug substance.

Keywords: amorphous solid dispersions; fluid bed; pellet coating; release kinetics; spray drying; supersaturation.

Figure 1

Chemical structures of the used materials: (A) ketoconazole; (B) loratadine; (C) Hydroxypropyl methylcellulose acetate succinate; and (D) Eudragit L100-55.

Figure 2

SEM-images of all prepared samples, containing: (A) KCZ_HPMC-AS_SD, (B) KCZ_HPMC-AS_PC, (C) KCZ_EL100-55_SD, (D) KCZ_EL100-55_PC, (E) LRD_HPMC-AS_SD, (F) LRD_HPMC-AS_PC, (G) LRD_EL100-55_SD, and (H) LRD_EL100-55-PC. All samples were sputtered with gold and observed with a Hitachi SU3500 at 5.0 kV in SE-mode and a 50-time magnification. The white scale bar represents 1 mm.

Figure 3

SEM-images of cross-sectional areas of the prepared pellets: ((A) KCZ_HPMC-AS_PC; (B) KCZ_EL100-55_PC; (C) LRD_HPMC-AS_PC; (D) LRD_EL100-55_PC). All samples were sputtered with gold and observed with a Hitachi SU3500 at 5.0 kV in SE-mode and a 50-time magnification. The white scale bar represents 1 mm.

Figure 4

XRD-results of all prepared samples and pure API and pure Pellets (black lines), (A) Ketoconazole and (B) Loratadine (light blue line: HPMC-AS_SD; dark blue line: EL100-55_SD; light green line: HPMC-AS_PC; dark green line: EL100-55_PC).

Figure 5

FT-IR-measurements of all prepared samples, pure APIs, pure polymers and their respective physical mixtures containing (A) KCZ and HPMC-AS L; (B) KCZ and EL100-55; (C) LRD and HPMC-AS; and (D) LRD and EL100-55. Yellow bars representing region of interest. Measurements were performed with a FT-IR Spectrum two LiTa (Perkin Elmar). 1300–2000 cm⁻¹.

Figure 6

Dissolution profiles of all prepared samples containing (A) KCZ and HPMC-AS L; (B) KCZ and EL100-55; (C) LRD and HPMC-AS; and (D) LRD and EL100-55. Coated pellets are represented by green open circles (○). The different sieve fractions of the SD are represented by blue filled symbols, with squares for 1000–2000 µm (■), triangles for 710–1000 µm (▲), and turned triangles for 500–710 µm (▼). The physical mixtures are presented by black crosses (×). The dissolution was observed at pH 6.8 in PBS-buffer over a period of 180 min.

Figure 7

The linear relationship of the dissolution rate in [µg/mL/min] and the TOPS in [cm²] of prepared ASDs, containing: (A) KCZ and (B) LRD. The pellets represented by the hollow symbols and the SD particle represented by the filled symbols.