title: Flow-through cross-polarized imaging as a new tool to overcome the analytical sensitivity challenges of a low-dose crystalline compound in a lipid matrix.
abstract: Assessing the physical state of a low-dose active compound in a solid lipid or polymer matrix is analytically challenging, especially if the matrix exhibits some crystallinity. The aim of this study was first to compare the ability of current methods to detect the presence of a crystalline model compound in lipid matrices. Subsequently, a new technique was introduced and evaluated because of sensitivity issues that were encountered with current methods. The new technique is a flow-through version of cross-polarized imaging in transmission mode. The tested lipid-based solid dispersions (SDs) consisted of β-carotene (BC) as a model compound, and of Gelucire 50/13 or Geleol mono- and diglycerides as lipid matrices. The solid dispersions were analyzed by (hyper) differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and microscopic techniques including atomic force microscopy (AFM). DSC and XRPD could analyze crystalline BC at concentrations as low as 3% (w/w) in the formulations. However, with microscopic techniques crystalline particles were detected at significantly lower concentrations of even 0.5% (w/w) BC. A flow-through cross-polarized imaging technique was introduced that combines the advantage of analyzing a larger sample size with high sensitivity of microscopy. Crystals were detected easily in samples containing even less than 0.2% (w/w) BC. Moreover, the new tool enabled approximation of the kinetic BC solubility in the crystalline lipid matrices. As a conclusion, the flow-through cross-polarized imaging technique has the potential to become an indispensable tool for characterizing low-dose crystalline compounds in a lipid or polymer matrix of solid dispersions.
authors.affiliation: University of Applied Sciences and Arts Northwestern Switzerland, Institute of Pharmaceutical Technology, Gründenstrasse 40, 4132 Muttenz, Switzerland; University of Basel, Institute of Pharmaceutical Technology, Klingelbergstrasse 50, 4056 Basel, Switzerland.
authors.forename: Camille
authors.initials: C
authors.lastname: Adler
authors.affiliation: Swiss Nanoscience Institute, Nanotech Service Lab, Klingelbergstrasse 82, 4056 Basel, Switzerland.
authors.forename: Monica
authors.initials: M
authors.lastname: Schönenberger
authors.affiliation: DSM Nutritional Products Ltd., Research Center Formulation & Application, P.O. Box 2676, 4002 Basel, Switzerland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Teleki
authors.affiliation: DSM Nutritional Products Ltd., Research Center Formulation & Application, P.O. Box 2676, 4002 Basel, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Leuenberger
authors.affiliation: University of Applied Sciences and Arts Northwestern Switzerland, Institute of Pharmaceutical Technology, Gründenstrasse 40, 4132 Muttenz, Switzerland. Electronic address: martin.kuentz@fhnw.ch.
authors.forename: Martin
authors.initials: M
authors.lastname: Kuentz
mesh_terms: D002152:Calorimetry, Differential Scanning; D002623:Chemistry Techniques, Analytical / Q000295:instrumentation / Q000379:methods*; D056148:Chromatography, Reverse-Phase; D003460:Crystallization; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry*; D008055:Lipids / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D018625:Microscopy, Atomic Force; D018613:Microscopy, Confocal; D008859:Microscopy, Polarization; D012680:Sensitivity and Specificity; D012995:Solubility; D019207:beta Carotene / Q000032:analysis* / Q000737:chemistry
chemical_list: D005079:Excipients; D008055:Lipids; D019207:beta Carotene
keywords: Analytical tools; Crystalline active compound; Flow-through cross-polarized imaging; Sampling issues; Sensitivity limits; Solid lipid formulations