Transformation of Ritonavir Nanocrystal Suspensions into a Redispersible Drug Product via Vacuum Drum Drying

Abstract

The present study explored vacuum drum drying (VDD) as potential drying technique for the solidification of crystalline ritonavir nanosuspensions prepared by wet-ball milling. In detail, the impact of drying protectants (mannitol, lactose, trehalose) added to the ritonavir nanosuspension was assessed in dependence of the drum temperature with respect to processibility via VDD, resulting intermediate powder properties, remaining nanoparticulate redispersibility and crystallinity. A clear impact of the glass transition temperature (Tg) of the drying protectant on the redispersibility/crystallinity of the VDD intermediate was observed. Increased Tg of the drying protectant was associated with improved redispersibility/crystallinity at a defined drum temperature. Consequently, the high Tg-substance trehalose and lactose showed a better performance than mannitol at higher drum temperatures. However, the processability and related powder properties were not in accordance with this observation. Mannitol containing formulations showed superior processibility to those containing trehalose/lactose. Moreover, the impact of the tableting and encapsulation process on the redispersibility of the VDD intermediate was studied for a selected formulation. Neither process demonstrated a negative impact on redispersibility. In conclusion, vacuum drum drying is a promising drying technique for the solidification of nanosuspensions to result in dried powder still containing ritonavir nanoparticles while demonstrating acceptable to good downstream processibility to tablets/capsules. Graphical Abstract

Transformation of ABT-199 Nanocrystal Suspensions into a Redispersible Drug Product—Impact of Vacuum Drum Drying, Spray Drying and Tableting on Re-Nanodispersibility

“…The impact of the drying technique was already described by Czyz, Wewers [ 22 ] for naproxen and itraconazole, where the spray drying process boundary (outlet temperature) for redispersibility to a nanocrystalline suspension correlates with the glass transition temperature of the pure drying protectant, as shown for trehalose, sucrose, and lactose. Similar observations were made by Schönfeld, Westedt [ 28 ] for vacuum drum drying in an investigation of mannitol, trehalose, and lactose as drying protectants for a ritonavir nanosuspension. Therefore, a lower process temperature in VDD was initially applied for the mannitol-only (55 °C) compared to the mannitol/trehalose or trehalose-only formulation (75 °C) because the glass transition temperature of mannitol is lower than that of trehalose [ 30 ].…”

“…Consequently, it seems to be crucial to generate a physically stable solid intermediate first where the nanoparticulate structure is fully maintained after drying. The impact of target tensile strengths up to 2.0 MPa has been assessed by Schönfeld, Westedt [ 28 ] for solidified ritonavir nanocrystals. In contrast to the present study, there was no impact of the tableting process on redispersibility observed for tensile strengths up to 2.0 MPa.…”

“…The drying process parameters for spray drying and vacuum drum drying were chosen based on prior knowledge [ 28 ] and previously performed process development experiments.…”

“…Recently, vacuum drum drying was introduced as a novel drying technique in the manufacturing of ASD-based drug products [ 27 ] as well as for the solidification of nanocrystal suspensions [ 28 ]. However, an experimental study comparing vacuum drum drying with spray drying as a commonly used drying technique for crystalline nanosuspensions and exploring benefits and distinctions of each technique is missing.…”

“…For this study, solid nanocrystal powders were manufactured at different drug loads (22%, 33%, 44% w / w (solid)) with different commonly used drying protectants (mannitol, mannitol/trehalose mix (1:1) or trehalose). Czyz, Wewers [ 22 ] and Schönfeld, Westedt [ 28 ] have previously reported that the glass transition temperature ( T g ) of formulations can affect redispersibility, depending on the drying process parameters employed. In order to assess a wide range of T g values for the resulting solids, trehalose was selected as a component with a high T g (115 °C [ 30 ]), mannitol with a low T g (87 °C [ 30 ]), and a 1:1 mixture with a T g in-between.…”