Solvent-mediated solid phase transformations of carbamazepine: Effects of simulated intestinal fluid and fasted state simulated intestinal fluid.
Solvent-mediated transformations of carbamazepine (CBZ) anhydrate form III were investigated in Simulated Intestinal Fluid, a simple USP buffer medium, and in FaSSIF, which contains sodium taurocholate (STC) and lecithin, important surfactants that solubilize lipophilic drugs and lipids in the gastrointestinal tract. Raman spectroscopy (in situ) was utilized to reveal the connection between the changes in solid phase composition and dissolution rate while simultaneously detecting the solid state and the dissolved amount of CBZ. Initial dissolution rate was clearly higher in FaSSIF, while the solid phase data revealed that the crystallization of CBZ dihydrate was inhibited in both the dissolution media, albeit by different mechanisms. In SIF this inhibition was related to extensive needle growth, which impeded medium contact with the solid surface by forming a sterical barrier leading to retarded crystallization rates. Morphological changes from the needle-like dihydrate crystals to plate-like counterparts in FaSSIF, combined with the information that the transformation process was leveled off, evidenced strong hydrogen bonding behavior between the CBZ and STC molecules. These results underline the importance of biologically representative dissolution media in linking the in vitro dissolution results of solids that are capable of hydrate formation to their in vivo dissolution behavior.
Lehto
Paula
P
Division of Pharmaceutical Technology, P.O. Box 56, FI-00014, University of Helsinki, Finland. paula.lehto@orionpharma.com
Aaltonen
Jaakko
J
Tenho
Mikko
M
Rantanen
Jukka
J
Hirvonen
Jouni
J
Tanninen
Veli Pekka
VP
Peltonen
Leena
L
D002220:Carbamazepine / Q000737:chemistry*; D003460:Crystallization; D004355:Drug Stability; D054709:Lecithins / Q000737:chemistry; D012995:Solubility; D012997:Solvents / Q000737:chemistry*; D013059:Spectrum Analysis, Raman; D013656:Taurocholic Acid / Q000737:chemistry; D014961:X-Ray Diffraction
D054709:Lecithins; D012997:Solvents; D002220:Carbamazepine; D013656:Taurocholic Acid