Formulation of co-amorphous systems from naproxen and naproxen sodium and in situ monitoring of physicochemical state changes during dissolution testing by Raman spectroscopy

Hiroshi Ueda, Johan Peter Bøtker, Magnus Edinger, Korbinian Löbmann, Holger Grohganz, Anette Müllertz, Thomas Rades*, Jesper Østergaard

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

15 Citations (Scopus)

Abstract

Co-amorphous systems comprising low-molecular weight drugs and co-formers constitute an interesting approach to optimize pharmaceutical performance of drugs with low aqueous solubility. Within the different types of co-amorphous systems, the combination of a drug with its own salt may be an attractive formulation option due the absence of any inactive co-formers. The aim of this study was to investigate the possibility of forming a co-amorphous system from naproxen (NAP) and its sodium salt (NAP(Na)). Ball milling of NAP and NAP(Na) at equal molar ratio resulted in the formation of a co-amorphous system whilst NAP and NAP(Na) alone were crystalline following both, ball milling and melt quenching. Infrared spectroscopy and physical stability testing revealed that intermolecular interactions were able to maintain the ball milled NAP-NAP(Na) system amorphous for 2 months at 40 °C. Surprisingly, the dissolution rate of co-amorphous NAP-NAP(Na) was only intermediate between those of crystalline NAP and crystalline NAP(Na). In situ Raman spectroscopic measurements indicated an initial phase separation of the co-amorphous form to NAP and NAP(Na) followed by dissociation of sodium from NAP(Na) and crystallization to NAP. These findings contribute to the design of co-amorphous formulations with the combination of a drug and its own salt.

Original languageEnglish
Article number119662
JournalInternational Journal of Pharmaceutics
Volume587
ISSN0378-5173
DOIs
Publication statusPublished - 2020

Keywords

  • Amorphous
  • Co-amorphous
  • Crystallization
  • Dissolution
  • Naproxen
  • Raman spectroscopy
  • UV imaging

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