(Co-)amorphization of enantiomers – Investigation of the amorphization process, the physical stability and the dissolution behavior

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A novel approach for improvement of the aqueous solubility of poorly water soluble compounds applying co-amorphous systems was investigated by application of the enantiomers of the chiral amino acid tryptophan (TRP) as the model system. (Co-)amorphization of various forms of crystalline TRP was achieved by ball milling. Solid state analysis demonstrated significant differences in the amorphization tendency and physical stability between the two TRP enantiomers alone, the TRP racemate and an equimolar physical mixture of D- and L-TRP (TRP conglomerate). Ball milling for 6 h was required to obtain fully amorphous plain D- and L-TRP, whereas the TRP racemate and the TRP conglomerate were transformed into their amorphous forms already within 90 and 60 min of ball milling, respectively. Physical stability of the co-amorphous TRP conglomerate was observed for up to 60 d at ambient conditions as well as 40 °C/0 % RH. In contrast, the amorphous TRP racemate showed a reduced physical stability under ambient conditions. Interestingly, the intrinsic dissolution rates of the amorphous TRP conglomerate and racemate were not higher than those of the respective crystalline forms. In conclusion, applying two enantiomers of a chiral compound may be a promising approach for fast amorphization of an API and for improving the physical stability of the resulting amorphous form.

Original languageEnglish
Article number121552
JournalInternational Journal of Pharmaceutics
Number of pages9
Publication statusPublished - 2022

Bibliographical note

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

Publisher Copyright:
© 2022 Elsevier B.V.

    Research areas

  • Amino acid, Co-amorphization, Conglomerate, Enantiomer, Intrinsic dissolution rate, Physical stability, Racemate

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