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

The present study compared vacuum drum drying (VDD) and conventional spray drying (SD) for solidifying crystalline ABT-199 nanosuspensions into redispersible oral drug products. The aim was to optimize formulation compositions and process conditions to maintain nanoparticle size after tablet redispersion. The impact of drug load (22%, 33%, 44%) and type of drying protectant (mannitol, mannitol/trehalose mix (1:1), trehalose) on redispersibility and material powder properties were investigated.

Moreover, compression analysis was performed assessing the influence of compaction pressure on primary nanocrystal redispersibility and tablet disintegration. Higher drug loads and lower drying protectant levels resulted in particle growth, confirming a drug load dependence on redispersibility behavior. Notably, all drying protectants showed similar protection properties at properly chosen drying process parameters (T_g-dependent), except when VDD was used for mannitol formulations.

Differences between the applied drying processes were observed in terms of downstream processing and tabletability: mannitol-containing formulations solidified via VDD showed an improved processability compared to formulations with trehalose. In conclusion, VDD is a promising drying technique that offers advantageous downstream processability compared to SD and represents an attractive novel processing technology for the pharmaceutical industry. As demonstrated in the present study, VDD combines higher yields with a leaner manufacturing process flow. The improved bulk properties provide enhanced tabletability and enable direct compression.

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Materials

ABT-199 was obtained from AbbVie Operations Singapore Pte Ltd. (Singapore). Copovidone (polyvinylpyyrolidone-vinyl acetate copolymer, Kollidon® VA64) was purchased from BASF SE (Ludwigshafen, Germany); sodium deoxycholate (origin: animal (bovine/ovine)), mannitol (Parteck M 200 Emprove® Essential) and trehalose dihydrate (Emprove® Expert) were purchased from Merck KGaA (Darmstadt, Germany). Zirconium oxide beads were purchased from Netzsch (Selb, Germany).

Manufacture of ABT-199 Nanosuspension

The ABT-199 nanosuspension was prepared by wet ball milling in 3 sub-batches each with a batch size of 1.8 kg using the bead agitator mill DeltaVita^® 15-300 (Netzsch Feinmahltechnik, Selb, Germany) equipped with a 300 mL grinding chamber and a 2000 mL batch tank. The batch tank as well as the grinding chamber were water-cooled. Before nano milling, the ABT-199 (15% w/w) suspension was predispersed in a stabilizer-containing aqueous solution (sodium deoxycholate and copovidone) using a magnetic stirrer (IKA GmbH & Co. KG, Staufen, Germany). The composition of the nanosuspension was selected based on results of a previously performed formulation screening.

Zirconium oxide beads (size: 0.5 mm) were used as grinding media (bead-to-API-ratio: 3:1). Nano milling was performed under the following conditions: agitator speed 2900 rpm (equal to a tip speed of 10 m/s), pump speed 200 rpm, total milling time 120 min.

After milling, the zirconium beads were separated via a 200 µm mesh size sieve. The yield of each sub-batch was in the range of 86–90%. The three sub-baches were merged using a magnetic stirrer (IKA GmbH & Co. KG, Staufen, Germany).

Prior to subsequent vacuum drum drying or spray drying, the different drying protectants (mannitol, mannitol/trehalose mix (1:1) or trehalose) as well as copovidone (4% w/w) were dissolved in the ABT-199 nanosuspension while stirring. The amount of drying protectant was adapted for each formulation to meet the final solid composition of 22%, 33% and 44% ABT-199, respectively. The final composition of the dried intermediates is given in Table 2. Besides sugars as drying protectant, copovidone (4% w/w) was also added to increase the viscosity of the liquid formulation and, thus, to increase the adhesion of the solution to the drums during the vacuum drum drying process. Copovidone was selected since it was already part of the composition as a stabilizer for the nanosuspension preparation. To compare identical formulation compositions processed via VDD or SD, copovidone was also added to the nanosuspension processed via spray drying.

Source: Schönfeld, B.; Sundermann, J.; Keller, B.-L.; Westedt, U.; Heinzerling, O. Transformation of ABT-199 Nanocrystal Suspensions into a Redispersible Drug Product—Impact of Vacuum Drum Drying, Spray Drying and Tableting on Re-Nanodispersibility. Pharmaceutics 2024, 16, 782. https://doi.org/10.3390/pharmaceutics16060782

Read also our introduction article on Mannitol here: