In situ measurement of solvent-mediated phase transformations during dissolution testing.
In this study, solvent-mediated phase transformations of theophylline (TP) and nitrofurantoin (NF) were measured in a channel flow intrinsic dissolution test system. The test set-up comprised simultaneous measurement of drug concentration in the dissolution medium (with UV-Vis spectrophotometry) and measurement of the solid-state form of the dissolving solid (in situ with Raman spectroscopy). The solid phase transformations were also investigated off-line with scanning electron microscopy. TP anhydrate underwent a transformation to TP monohydrate, and NF anhydrate (form beta) to NF monohydrate (form II). Transformation of TP anhydrate to TP monohydrate resulted in a clear decrease in the dissolution rate, while the transformation of NF anhydrate (form beta) to NF monohydrate (form II) could not be linked as clearly to changes in the dissolution rate. The transformation of TP was an order of magnitude faster than that of NF. The presence of a water absorbing excipient, microcrystalline cellulose, was found to delay the onset of the transformation of TP anhydrate. Combining the measurement of drug concentration in the dissolution medium with the solid phase measurement offers a deeper understanding of the solvent-mediated phase transformation phenomena during dissolution.
Aaltonen
Jaakko
J
Division of Pharmaceutical Technology, P.O. Box 56, 00014 University of Helsinki, Finland. jaakko.aaltonen@helsinki.fi
Heinänen
Paula
P
Peltonen
Leena
L
Kortejärvi
Hanna
H
Tanninen
Veli Pekka
VP
Christiansen
Leena
L
Hirvonen
Jouni
J
Yliruusi
Jouko
J
Rantanen
Jukka
J
D008855:Microscopy, Electron, Scanning; D009582:Nitrofurantoin / Q000032:analysis / Q000737:chemistry*; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D013059:Spectrum Analysis, Raman; D013806:Theophylline / Q000032:analysis / Q000737:chemistry*; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction
D014867:Water; D009582:Nitrofurantoin; D013806:Theophylline