title: Influence of variation in molar ratio on co-amorphous drug-amino acid systems.
abstract: Molecular interactions were investigated within four different co-amorphous drug-amino acid systems, namely indomethacin-tryptophan (Ind-Trp), furosemide-tryptophan (Fur-Trp), indomethacin-arginine (Ind-Arg) and furosemide-arginine (Fur-Arg). The co-amorphous systems were prepared by ball milling for 90min at different molar ratios and analyzed by XRPD and DSC. Interactions within the co-amorphous samples were evaluated based on the deviation between the actual glass transition temperature (Tg) and the theoretical Tg calculated by the Gordon-Taylor equation. The strongest interactions were observed in the 50mol% drug (1:1M ratio) mixtures, with the exception of co-amorphous Ind-Arg where the interactions within the 40mol% drug samples appear equally strong. A particularly large deviation between the theoretical and actual Tgs was observed within co-amorphous Ind-Arg and Fur-Arg systems. Further analysis of these co-amorphous systems by (13)C solid-state NMR (ssNMR) and FTIR confirmed that Ind and Fur formed a co-amorphous salt together with Arg. A modified approach of using the Gordon-Taylor equation was applied, using the equimolar co-amorphous mixture as one component, to describe the evolution of the Tgs with varying molar ratio between the drug and the amino acid. The actual Tgs for co-amorphous Ind-Trp, Fur-Trp and Fur-Arg were correctly described by this equation, confirming the assumption that the excess component was amorphous forming a homogeneous single component within the co-amorphous mixture without additional interactions. The modified equation described the Tgs of the co-amorphous Ind-Arg with excess Arg less well indicating possible further interactions; however, the FTIR and ssNMR data did not support the presence of additional intermolecular drug-amino acid interactions.
authors.affiliation: Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Katrine Tarp
authors.initials: KT
authors.lastname: Jensen
authors.affiliation: Department of Food Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Flemming Hofmann
authors.initials: FH
authors.lastname: Larsen
authors.affiliation: Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Korbinian
authors.initials: K
authors.lastname: Löbmann
authors.affiliation: Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
authors.affiliation: Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark. Electronic address: holger.grohganz@sund.ku.dk.
authors.forename: Holger
authors.initials: H
authors.lastname: Grohganz
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D009682:Magnetic Resonance Spectroscopy; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D033362:Powder Diffraction; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000596:Amino Acids; D004364:Pharmaceutical Preparations
keywords: Amino acid; Co-amorphous; Molar ratio; Molecular interactions