Solventless amorphization and pelletization using a high shear granulator. Part II; Preparation of co-amorphous mixture-layered pellets using indomethacin and arginine

The aim of this study was to investigate the preparation of co-amorphous mixture-layered pellets using solventless pelletization and amorphization using a high shear granulator (as suggested in the first part of this study) by high shear mixing of drug crystals and a crystalline co-former with inactive spheres. Mixtures of crystalline indomethacin and arginine at various molar ratios were mixed with microcrystalline cellulose spheres at a weight ratio of 1:10 using the granulator and the resulting particles were characterized using solid-state and particle analytical techniques as well as dissolution testing and physical stability. At jacket temperatures of 20 °C or more of the granulator, co-processing of indomethacin and arginine enhanced amorphization of indomethacin and provided a co-amorphous mixture due to homogenous mixing of indomethacin and arginine amorphous phases. The co-amorphous mixture was deposited on the surface of the spheres, yielding co-amorphous mixture-layered pellets. The co-amorphous mixtures at molar ratios of indomethacin to arginine of 2:1 and 1:1, deposited on the pellets, did not recrystallize for at least 4 weeks. The pellets exhibited higher dissolution characteristics as additional hypromellose could prevent precipitation. These findings demonstrate the potential of this technique as a solventless approach to prepare co-amorphous mixture-layered pellets through a one-step process.

Materials

The polymorphic γ-form of crystalline indomethacin (IND) (Hangzhou Dayangchem Co. Ltd., Hangzhou, China) was used as the model drug. IND crystals were sieved with a 170-mesh screen (opening: 90 μm) and the powder passed through the screen was used in the experiments. Microcrystalline cellulose (MCC) spheres (CELLETS® 175, Advanced Drug Delivery Technologies Ltd, Pratteln, Switzerland) were used as carrier particles and their mean diameter was 194 μm (determined as described in Section 2.7).

Keita Kondo, Thomas Rades, Solventless amorphization and pelletization using a high shear granulator. Part II; Preparation of co-amorphous mixture-layered pellets using indomethacin and arginine, European Journal of Pharmaceutics and Biopharmaceutics, Volume 181, 2022, Pages 183-194, ISSN 0939-6411,
https://doi.org/10.1016/j.ejpb.2022.11.011.

excipients formulation