Co-amorphous systems consisting of indomethacin and the chiral co-former tryptophan: Solid-state properties and molecular mobilities

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In this study the influence of an enantiomeric co-former and the preparation method on the solid-state properties and physical stability of co-amorphous systems were investigated. Co-amorphous systems consisting of indomethacin (IND) and chiral tryptophan (TRP) as co-former in its two enantiomeric forms, as racemate, and as conglomerate (equimolar mixture of D- and L-TRP) were prepared. Co-amorphization was achieved by ball milling (BM) and spray drying (SD). The effects of chirality and preparation method on the solid-state properties and physical stabilities of the systems were investigated by XRPD, FTIR and mDSC. Differences in the BM process were caused by the enantiomeric properties of the co-former: The IND/TRP conglomerate (IND/TRPc) turned co-amorphous after 60 min. In contrast, co-amorphization of IND/L-TRP and IND/D-TRP required 80 min of ball milling, respectively, and the co-amorphous IND/TRP racemate (IND/TRPr) was obtained only after 90 min of ball milling. Although the intermolecular interactions of the co-amorphous systems prepared by BM and SD were similar (determined by FTIR), the Tg values differed (∼87 °C for the ball milled and ∼62 °C for the spray dried systems). The physical stabilities of the ball milled co-amorphous systems varied between 3 and 11 months if stored at elevated temperature and dry conditions, with the highest stability for the IND/TRPc system and the lowest stability for the IND/TRPr system, and these differences correlated with the calculated relaxation times. In contrast, all spray dried systems were stable only for 1 month and their relaxation times were similar. It could be shown that the chirality of a co-former and the preparation method influence the solid-state properties, thermal properties and physical stability of IND/TRP systems.

Original languageEnglish
Article number122840
JournalInternational Journal of Pharmaceutics
Number of pages12
Publication statusPublished - 2023

Bibliographical note

Funding Information:
The authors would like to thank Isabelle Nevoigt and Stefan Bleck for performing the XRPD and the mDSC measurements, respectively. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

    Research areas

  • Chirality, Co-amorphous, Glass transition temperature, Intermolecular interactions, Molecular mobility, Physical stability

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