title: Rapid assessment of homogeneity and stability of amorphous solid dispersions by atomic force microscopy--from bench to batch.
abstract: OBJECTIVE
  To verify the robustness and fundamental value of Atomic Force Microscopy (AFM) and AFM-based assays to rapidly examine the molecular homogeneity and physical stability of amorphous solid dispersions on Hot-Melt-Extrudates.
  
  
  METHODS
  Amorphous solid dispersions were prepared with a Hot-Melt Extruder (HME) and profiled by Raman Microscopy and AFM following a sequential analytical routine (Multi-Scale-Imaging-of-Miscibiliy (MIMix)). Extrudates were analyzed before and after incubation at elevated temperature and humidity. The data were compared with published results as collected on miniaturized melt models. The value of molecular phase separation rates for long term stability prediction was assessed.
  
  
  RESULTS
  Data recorded on the extrudates are consistent with those published, and they can be compared side by side. Such direct data comparisons allow the identification of possible sources of extrudate heterogeneities. The surface roughness analysis of fracture-exposed interfaces is a novel quantitative way to trace on the nanometer scale the efficiencies of differently conducted HME-processes. Molecular phase separation rates are shown to be relevant for long term stability predictions.
  
  
  CONCLUSIONS
  The AFM-based assessment of API:excipient combinations is a robust method to rapidly identify miscible and stable solid dispersions in a routine manner. It provides a novel analytical tool for the optimization of HME processes.
authors.affiliation: F. Hoffmann-La Roche Ltd., pRED Small Molecule Research, Discovery Technologies, 4070 Basel, Switzerland. Matthias.Lauer@roche.com
authors.forename: Matthias E
authors.initials: ME
authors.lastname: Lauer
authors.forename: Monira
authors.initials: M
authors.lastname: Siam
authors.forename: Joseph
authors.initials: J
authors.lastname: Tardio
authors.forename: Susanne
authors.initials: S
authors.lastname: Page
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Kindt
authors.forename: Olaf
authors.initials: O
authors.lastname: Grassmann
mesh_terms: D003460:Crystallization; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry*; D006358:Hot Temperature; D006813:Humidity; D018625:Microscopy, Atomic Force / Q000379:methods*; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D044367:Phase Transition; D012995:Solubility
chemical_list: D005079:Excipients; D004364:Pharmaceutical Preparations