title: Anhydrate to hydrate solid-state transformations of carbamazepine and nitrofurantoin in biorelevant media studied in situ using time-resolved synchrotron X-ray diffraction.
abstract: Transformation of the solid-state form of a drug compound in the lumen of the gastrointestinal tract may alter the drug bioavailability and in extreme cases result in patient fatalities. The solution-mediated anhydrate-to-hydrate phase transformation was examined using an in vitro model with different biorelevant media, simulated fasted and fed state intestinal fluids containing bile salt and dioleoylphosphatidylcholine (DOPC) micelles, DOPC/sodium dodecyl sulfate (SDS) mixture, bile salt solution and water. Two anhydrate compounds (carbamazepine, CBZ and nitrofurantoin, NF) with different overall transformation time into hydrate form were used as model compounds. The transformations were monitored using direct structural information from time-resolved synchrotron X-ray diffraction. The kinetics of these transformations were estimated using multivariate data analysis (principal component analysis, PCA) and compared to those for nitrofurantoin (NF). The study showed that the solution-mediated phase transformation of CBZ anhydrate was remarkably faster in the DOPC/SDS medium compared to transformation in all the other aqueous dispersion media. The conversion time for CBZ anhydrate in water was shorter than for DOPC/SDS but still faster than the conversion seen in fed and fasted state micellar media. The conversion of CBZ anhydrate to hydrate was the slowest in the solution containing bile salt alone. In contrast, the solution-mediated phase transformations of NF did only show limited kinetic dependence on the dispersion media used, indicating the complexity of the nucleation process. Furthermore, when the CBZ and NF material was compacted into tablets the transformation times were remarkably slower. Results suggest that variations in the composition of the contents of the stomach/gut may affect the recrystallization kinetics, especially when investigating compounds with relatively fast overall transformation time, such as CBZ.
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Johan P
authors.initials: JP
authors.lastname: Boetker
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Jukka
authors.initials: J
authors.lastname: Rantanen
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Lærke
authors.initials: L
authors.lastname: Arnfast
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Maria
authors.initials: M
authors.lastname: Doreth
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Dhara
authors.initials: D
authors.lastname: Raijada
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Korbinian
authors.initials: K
authors.lastname: Loebmann
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Cecilie
authors.initials: C
authors.lastname: Madsen
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC, Australia.
authors.forename: Jamal
authors.initials: J
authors.lastname: Khan
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Anette
authors.initials: A
authors.lastname: Müllertz
authors.affiliation: SAXS/WAXS Beamline, Australian Synchrotron, Clayton, VIC, Australia.
authors.forename: Adrian
authors.initials: A
authors.lastname: Hawley
authors.affiliation: MAX IV Laboratory/Lund University, Ole Römers väg 1, 223 63 Lund, Sweden.
authors.forename: Diana
authors.initials: D
authors.lastname: Thomas
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC, Australia. Electronic address: ben.boyd@monash.edu.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Boyd
mesh_terms: D002220:Carbamazepine / Q000032:analysis / Q000737:chemistry*; D009582:Nitrofurantoin / Q000032:analysis / Q000737:chemistry*; D019999:Pharmaceutical Solutions / Q000032:analysis / Q000737:chemistry; D017356:Synchrotrons; D013997:Time Factors; D014961:X-Ray Diffraction / Q000379:methods*
chemical_list: D019999:Pharmaceutical Solutions; D002220:Carbamazepine; D009582:Nitrofurantoin
keywords: Carbamazepine; Micelles; Nitrofurantoin; PCA; Solution-mediated transformation; Synchrotron