title: Multivariate Quantification of the Solid State Phase Composition of Co-Amorphous Naproxen-Indomethacin.
abstract: To benefit from the optimized dissolution properties of active pharmaceutical ingredients in their amorphous forms, co-amorphisation as a viable tool to stabilize these amorphous phases is of both academic and industrial interest. Reports dealing with the physical stability and recrystallization behavior of co-amorphous systems are however limited to qualitative evaluations based on the corresponding X-ray powder diffractograms. Therefore, the objective of the study was to develop a quantification model based on X-ray powder diffractometry (XRPD), followed by a multivariate partial least squares regression approach that enables the simultaneous determination of up to four solid state fractions: crystalline naproxen, γ-indomethacin, α-indomethacin as well as co-amorphous naproxen-indomethacin. For this purpose, a calibration set that covers the whole range of possible combinations of the four components was prepared and analyzed by XRPD. In order to test the model performances, leave-one-out cross validation was performed and revealed root mean square errors of validation between 3.11% and 3.45% for the crystalline molar fractions and 5.57% for the co-amorphous molar fraction. In summary, even four solid state phases, involving one co-amorphous phase, can be quantified with this XRPD data-based approach.
authors.affiliation: Division of Pharmaceutical Technology, University of Hamburg, Hamburg 20146, Germany. andreas.beyer@chemie.uni-hamburg.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Beyer
authors.affiliation: Department of Pharmacy, University of Copenhagen, Copenhagen 2100, Denmark. holger.grohganz@sund.ku.dk.
authors.forename: Holger
authors.initials: H
authors.lastname: Grohganz
authors.affiliation: Department of Pharmacy, University of Copenhagen, Copenhagen 2100, Denmark. korbinian.loebmann@sund.ku.dk.
authors.forename: Korbinian
authors.initials: K
authors.lastname: Löbmann
authors.affiliation: Department of Pharmacy, University of Copenhagen, Copenhagen 2100, Denmark. thomas.rades@sund.ku.dk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
authors.affiliation: Division of Pharmaceutical Technology, University of Hamburg, Hamburg 20146, Germany. claudia.leopold@pharmaceutical-technology.de.
authors.forename: Claudia S
authors.initials: CS
authors.lastname: Leopold
mesh_terms: D002626:Chemistry, Pharmaceutical; D007213:Indomethacin / Q000737:chemistry*; D009288:Naproxen / Q000737:chemistry*; D033362:Powder Diffraction / Q000379:methods; D012044:Regression Analysis; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D009288:Naproxen; D007213:Indomethacin
keywords: PLS; XRPD; co-amorphous; composition; multivariate; recrystallization; solid state analysis; stability