Evaluation of the Formulation Parameter-Dependent Redispersibility of API Nanoparticles from Fluid Bed Granules

Abstract

The production of nanosuspensions of poorly soluble active pharmaceutical ingredients (API) is a popular technique to counteract challenges regarding bioavailability of such active substances. A subsequent drying of the nanosuspensions is advantageous to improve the long-term stability and the further processing into solid oral dosage forms. However, associated drying operations are critical, especially with regard to nanoparticle growth, loss in redispersibility and associated compromised bioavailability. This work extends a previous study regarding the applicability of an API (itraconazole) nanosuspension as a granulation liquid in a fluidized bed process with focus on the influence of applied formulation parameters on the structure of obtained nanoparticle-loaded granules and their nanoparticle redispersibility. Generally, a higher dissolution rate of the carrier material (glass beads, lactose, mannitol or sucrose) and a higher content of a matrix former/hydrophilic polymer (PVP/VA or HPMC) in the granulation liquid resulted in the formation of coarser and more porous granules with improved nanoparticle redispersibility. HPMC was found to have advantages as a polymer compared with PVP/VA. In general, a better redispersibility of the nanoparticles from the granules could be associated with better dispersion of the API nanoparticles at the surface of the granules as deduced from the thickness of nanoparticle-loaded layers around the granules. The layer thickness on granules was assessed by means of confocal Raman microscopy. Finally, the dispersion of the nanoparticles in the granule layers was exemplarily described by calculation of theoretical mean nanoparticle distances in the granule layers and was correlated with data obtained from redispersibility studies.

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

“…Although the risk of agglomeration may theoretically increase with increasing compaction pressure, the threshold where the tableting process affects the redispersibility of nanocrystals seems to be formulation- and API-specific and therefore needs to be considered in drug product development. Similar API-specific characteristics for redispersibility were observed for granules loaded with nanoparticles by Wewers, Finke [ 23 ]. They reported a minimum mean nanoparticle distance to avoid agglomeration specifically for itraconazole (100 nm) and naproxen (80 nm).…”

“…According to their explanation, water-soluble additives like mannitol can create hydrophilic bridges between the nanoparticles to prevent crystal-to-crystal contact and ultimately crystal growth. In addition, Wewers, Finke [ 23 ] showed that there is a correlation between the concentration-dependent nanoparticle distance within a solid intermediate and its nano-dispersibility. This same stabilizing concentration-dependent effect can be observed in the lyophilization processes of nanoparticles, where sugar is utilized as a so-called “cryo-protectant” to prevent agglomeration by acting as a spacer [ 37 ].…”

“…Czyz, Wewers [ 22 ] investigated the impact of spray drying temperature, the type of drying, and the API particle size on the redispersibility of naproxen and itraconazole. Wewers, Finke [ 23 ] described the formulation parameters on the redispersiblity of naproxen nanoparticles from granules produced in a fluidized bed process. Another study focused on freeze drying, assessing formulation and process factors on the redispersibility of cilostazol nanocrystals [ 24 ].…”