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Impact of additives on drug particles during liquid antisolvent crystallization and subsequent freeze-drying

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journal contribution
posted on 2023-11-02, 12:43 authored by Peuli GhoshPeuli Ghosh, AKE RASMUSONAKE RASMUSON, SARAH HUDSONSARAH HUDSON

The impact of single or combinations of additives on the generation of nanosuspensions of two poorly water-soluble active pharmaceutical ingredients (APIs), fenofibrate (FF) and dalcetrapib (DCP), and their isolation to the dry state via antisolvent (AS) crystallization followed by freeze-drying was explored in this work. Combinations of polymeric and surfactant additives such as poly(vinyl alcohol) or hydroxypropyl methyl cellulose and sodium docusate were required to stabilize nanoparticles (∼200−300 nm) of both APIs in suspension before isolation to dryness. For both FF and DCP, multiple additives generated the narrowest, most stable particle size distribution, with the smallest particles in suspension, compared with using a single additive. An industrially recognized freeze-drying process was used for the isolation of these nanoparticles to dryness. When processed by the liquid AS crystallization followed by freeze-drying in the presence of multiple additives, a purer monomorphic powder for FF resulted than when processed in the absence of any additive or in the presence of a single additive. It was noted that all nanoparticles freeze-dried in the presence of additives had a flat, flaky habit resulting in large surface areas. Agglomeration occurred during freeze-drying, resulting in micron-size particles. However, after freeze-drying, powders produced with single or multiple additives showed similar dissolution profiles, irrespective of aging time before drying, thus attenuating the advantage of multiple additives in terms of size observed before the freeze-drying process.

Funding

SSPC_Phase 2

Science Foundation Ireland

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History

Publication

Organic Process Research and Development, 2023

Publisher

American Chemical Society

Other Funding information

This work was funded by the Science Foundation of Ireland (SFI) under grant numbers 12/RC/2275_P2 and 15/USC2C/13133, as well as support from the SSPC, the Science Foundation Ireland Research Centre for Pharmaceuticals, and the Bernal Institute and the Department of Chemical Sciences at the University of Limerick.

Also affiliated with

  • Bernal Institute

Sustainable development goals

  • (3) Good Health and Well-being

Department or School

  • Chemical Sciences

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