title: Preparation and characterization of spray-dried co-amorphous drug-amino acid salts.
abstract: OBJECTIVE
  Recently, co-amorphous drug-amino acid mixtures were introduced as a promising alternative to other amorphous stabilization approaches such as the use of polymers to form glass solutions. So far, these co-amorphous mixtures have been mainly prepared via vibrational ball milling on a lab scale. In this study, spray-drying was investigated as a scale up preparation method for co-amorphous indomethacin (IND)-amino acid mixtures. In addition, the physico-chemical properties of the different co-amorphous systems were investigated with respect to the amino acids' ability towards co-amorphous salt formation.
  
  
  METHODS
  The mixtures were characterized for their solid state properties using differential scanning calorimetry, thermogravimetric analysis and X-ray powder diffraction. Fourier-transform infrared spectroscopy was used to analyze molecular interactions. Furthermore, intrinsic dissolution behaviour, and physical stability at various storage conditions, were examined.
  
  
  RESULTS
  Results showed that IND could be converted into an amorphous form in combination with the amino acids arginine (ARG), histidine (HIS) and lysine (LYS) by spray-drying. Solid state characterization revealed elevated glass transition temperatures for all mixtures compared with the pure amorphous drug due to co-amorphization with the amino acids. Furthermore, strong intermolecular interactions in the form of salt/partial salt formation between the drug and amino acids were seen for all blends. All mixtures were physically stable (>10 months) at room temperature and 40°C under dry conditions. Intrinsic dissolution of the co-amorphous mixtures showed an improved dissolution behaviour under intestinal pH conditions for IND-ARG compared with the crystalline and amorphous forms of the drug. On the other hand, IND-LYS and IND-HIS revealed no significant improvement in the intrinsic dissolution rate of IND due to recrystallization of IND during dissolution.
  
  
  CONCLUSIONS
  It could be shown that strong intermolecular interactions between drug and co-amorphous coformer that persist during the dissolution are crucial to prevent recrystallization and to enhance dissolution of a co-amorphous formulation.
authors.affiliation: Department of Pharmacy, University of Copenhagen, Denmark.
authors.forename: Katrine Tarp
authors.initials: KT
authors.lastname: Jensen
authors.affiliation: Department of Pharmacy, University of Copenhagen, Denmark.
authors.forename: Lasse Ingerslev
authors.initials: LI
authors.lastname: Blaabjerg
authors.affiliation: Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Lenz
authors.affiliation: Department of Pharmacy, University of Copenhagen, Denmark.
authors.forename: Adam
authors.initials: A
authors.lastname: Bohr
authors.affiliation: Department of Pharmacy, University of Copenhagen, Denmark.
authors.forename: Holger
authors.initials: H
authors.lastname: Grohganz
authors.affiliation: Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kleinebudde
authors.affiliation: Department of Pharmacy, University of Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
authors.affiliation: Department of Pharmacy, University of Copenhagen, Denmark.
authors.forename: Korbinian
authors.initials: K
authors.lastname: Löbmann
mesh_terms: D000336:Aerosols; D000596:Amino Acids / Q000737:chemistry*; D001120:Arginine / Q000737:chemistry; D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D018360:Crystallography, X-Ray; D003890:Desiccation; D004339:Drug Compounding; D004355:Drug Stability; D005612:Freeze Drying; D006639:Histidine / Q000737:chemistry; D007213:Indomethacin / Q000031:analogs & derivatives / Q000737:chemistry*; D007700:Kinetics; D008239:Lysine / Q000737:chemistry; D033362:Powder Diffraction; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013678:Technology, Pharmaceutical / Q000379:methods; D013818:Thermogravimetry; D044366:Transition Temperature
chemical_list: D000336:Aerosols; D000596:Amino Acids; D006639:Histidine; D001120:Arginine; D008239:Lysine; D007213:Indomethacin
keywords: amino acids; co-amorphous; dissolution; salts; spray-drying