Atomic force microscopy-based screening of drug-excipient miscibility and stability of solid dispersions.
OBJECTIVE
Development of a method to assess the drug/polymer miscibility and stability of solid dispersions using a melt-based mixing method.


METHODS
Amorphous fractured films are prepared and characterized with Raman Microscopy in combination with Atomic Force Microscopy to discriminate between homogenously and heterogeneously mixed drug/polymer combinations. The homogenous combinations are analyzed further for physical stability under stress conditions, such as increased humidity or temperature.


RESULTS
Combinations that have the potential to form a molecular disperse mixture are identified. Their potential to phase separate is determined through imaging at molecular length scales, which results in short observation time. De-mixing is quantified by phase separation analysis, and the drug/polymer combinations are ranked to identify the most stable combinations.


CONCLUSIONS
The presented results demonstrate that drug/polymer miscibility and stability of solid dispersions, with many mechanistic details, can be analyzed with Atomic Force Microscopy. The assay allows to identify well-miscible and stable combinations within hours or a few days.
Center for Cellular Imaging and Nanoanalytics, Biozentrum, University of Basel, Mattenstrasse 26, CH 4006 Basel, Switzerland. Matthias.Lauer@roche.com
Matthias Eckhard
ME
Lauer
Olaf
O
Grassmann
Monira
M
Siam
Joseph
J
Tardio
Laurence
L
Jacob
Susanne
S
Page
Johannes Heinrich
JH
Kindt
Andreas
A
Engel
Jochem
J
Alsenz
D004353:Drug Evaluation, Preclinical / Q000379:methods; D004355:Drug Stability; D005079:Excipients / Q000032:analysis / Q000737:chemistry*; D018625:Microscopy, Atomic Force / Q000379:methods*; D004364:Pharmaceutical Preparations / Q000032:analysis / Q000737:chemistry*; D012995:Solubility; D013499:Surface Properties
D005079:Excipients; D004364:Pharmaceutical Preparations