title: Formation Mechanism of Coamorphous Drug-Amino Acid Mixtures.
abstract: Two coamorphous drug-amino acid systems, indomethacin-tryptophan (Ind-Trp) and furosemide-tryptophan (Fur-Trp), were analyzed toward their ease of amorphization and mechanism of coamorphization during ball milling. The two mixtures were compared to the corresponding amorphization of the pure drug without amino acid. Powder blends at a 1:1 molar ratio were milled for varying times, and their physicochemical properties were investigated using XRPD, (13)C solid state NMR (ssNMR), and DSC. Comilling the drug with the amino acid reduced the milling time required to obtain an amorphous powder from more than 90 min in the case of the pure drugs to 30 min for the coamorphous powders. Amorphization was observed as reductions in XRPD reflections and was additionally quantified based on normalized principal component analysis (PCA) scores of the ssNMR spectra. Furthermore, the evolution in the glass temperature (Tg) of the coamorphous systems over time indicated complete coamorphization after 30 min of milling. Based on the DSC data it was possible to identify the formation mechanism of the two coamorphous systems. The Tg position of the samples suggested that coamorphous Ind-Trp was formed by the amino acid being dissolved in the amorphous drug, whereas coamorphous Fur-Trp was formed by the drug being dissolved in the amorphous amino acid.
authors.affiliation: †Department of Pharmacy and ‡Department of Food Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Katrine Tarp
authors.initials: KT
authors.lastname: Jensen
authors.affiliation: †Department of Pharmacy and ‡Department of Food Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Flemming Hofmann
authors.initials: FH
authors.lastname: Larsen
authors.affiliation: †Department of Pharmacy and ‡Department of Food Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Cornett
authors.affiliation: †Department of Pharmacy and ‡Department of Food Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Korbinian
authors.initials: K
authors.lastname: Löbmann
authors.affiliation: †Department of Pharmacy and ‡Department of Food Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Holger
authors.initials: H
authors.lastname: Grohganz
authors.affiliation: †Department of Pharmacy and ‡Department of Food Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D003460:Crystallization / Q000379:methods; D004355:Drug Stability; D005665:Furosemide / Q000737:chemistry*; D007213:Indomethacin / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D011208:Powders / Q000737:chemistry; D012995:Solubility; D013696:Temperature; D014364:Tryptophan / Q000737:chemistry; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D000596:Amino Acids; D011208:Powders; D005665:Furosemide; D014364:Tryptophan; D007213:Indomethacin
keywords: amorphization; coamorphous; drug−amino acid; furosemide; indomethacin