title: Quantification of Process Induced Disorder in Milled Samples Using Different Analytical Techniques.
abstract: The aim of this study was to compare three different analytical methods to detect and quantify the amount of crystalline disorder/ amorphousness in two milled model drugs. X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and Raman spectroscopy were used as analytical methods and indomethacin and simvastatin were chosen as the model compounds. These compounds partly converted from crystalline to disordered forms by milling. Partial least squares regression (PLS) was used to create calibration models for the XRPD and Raman data, which were subsequently used to quantify the milling-induced crystalline disorder/ amorphousness under different process conditions. In the DSC measurements the change in heat capacity at the glass transition was used for quantification. Differently prepared amorphous indomethacin standards (prepared by either melt quench cooling or cryo milling) were compared by principal component analysis (PCA) to account for the fact that the choice of standard ultimately influences the quantification outcome. Finally, the calibration models were built using binary mixtures of crystalline and quench cooled amorphous drug materials. The results imply that the outcome with respect to crystalline disorder for milled drugs depends on the analytical method used and the calibration standard chosen as well as on the drug itself. From the data presented here, it appears that XRPD tends to give a higher percentage of crystalline disorder than Raman spectroscopy and DSC for the same samples. For the samples milled under the harshest milling conditions applied (60 min, sixty 4 mm balls, 25 Hz) a crystalline disorder/ amorphous content of 44.0% (XRPD), 10.8% (Raman spectroscopy) and 17.8% (DSC) were detected for indomethacin. For simvastatin 18.3% (XRPD), 15.5% (Raman spectroscopy) and 0% (DSC, no glass transition) crystalline disorder/ amorphousness were detected.
authors.affiliation: School of Pharmacy, University of Otago, 18 Frederick Street, 9016 Dunedin, New Zealand. ulrike.zimper@otago.ac.nz.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Zimper
authors.affiliation: School of Pharmacy, University of Otago, 18 Frederick Street, 9016 Dunedin, New Zealand. jaakko.aaltonen@uef.fi.|School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1 C, 70210 Kuopio, Finland. jaakko.aaltonen@uef.fi.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Aaltonen
authors.affiliation: Department of Chemistry, MacDiarmid Institute for Advanced Materials and Nanotechnology, University of Otago, Union Place West, 9016 Dunedin, New Zealand. cmcgoverin@chemistry.otago.ac.nz.
authors.forename: Cushla M
authors.initials: CM
authors.lastname: McGoverin
authors.affiliation: Department of Chemistry, MacDiarmid Institute for Advanced Materials and Nanotechnology, University of Otago, Union Place West, 9016 Dunedin, New Zealand. kgordon@chemistry.otago.ac.nz.
authors.forename: Keith C
authors.initials: KC
authors.lastname: Gordon
authors.affiliation: Institute of Food, Nutrition and Human Health, Massey University, 63 Wallace Street, 6021 Wellington, New Zealand. k.krauel-goellner@massey.ac.nz.
authors.forename: Karen
authors.initials: K
authors.lastname: Krauel-Goellner
authors.affiliation: School of Pharmacy, University of Otago, 18 Frederick Street, 9016 Dunedin, New Zealand. thomas.rades@otago.ac.nz.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
keywords: DSC; Raman spectroscopy; XRPD; amorphous; ball milling; indomethacin; multivariate analysis; partial least squares regression (PLS); principal component analysis (PCA); process induced disorder; simvastatin