Multivariate Quantification of the Solid State Phase Composition of Co-Amorphous Naproxen-Indomethacin

• Main Authors: Andreas Beyer, Holger Grohganz, Korbinian Löbmann, Thomas Rades, Claudia S. Leopold
• Format: Article
• Language: English
• Published: MDPI AG 2015-10-01
• Series: Molecules
• Subjects: co-amorphous; solid state analysis; composition; multivariate; PLS; XRPD; recrystallization; stability
• Online Access: http://www.mdpi.com/1420-3049/20/10/19571

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.