RESEARCH ARTICLE Structural Characterization and Aging of Glassy Pharmaceuticals made Using Acoustic Levitation CHRIS J. BENMORE, 1,2 J. K. R. WEBER, 1 AMIT N. TAILOR, 1 BRIAN R. CHERRY, 3,4 JEFFERY L. YARGER, 2,3,4 QIUSHI MOU, 2,3 WARNER WEBER, 3,4 JOERG NEUEFEIND, 5 STEPHEN R. BYRN 6 1 X-ray Science Division, Advanced Photon Source, Argonne National Laboratory, Illinois 60439 2 Department of Physics, Arizona State University, Tempe, Arizona 85287 3 Magnetic Resonance Research Center, Arizona State University, Tempe, Arizona 85287 4 Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287-1604 5 Spallation Neutron Source, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37922 6 Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana 47907 Received 17 September 2012; revised 20 December 2012; accepted 11 January 2013 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23464 ABSTRACT: Here, we report the structural characterization of several amorphous drugs made using the method of quenching molten droplets suspended in an acoustic levitator. 13 C NMR, X-ray, and neutron diffraction results are discussed for glassy cinnarizine, carbamazepine, mi- conazole nitrate, probucol, and clotrimazole. The 13 C NMR results did not find any change in chemical bonding induced by the amorphization process. High-energy X-ray diffraction results were used to characterize the ratio of crystalline to amorphous material present in the glasses over a period of 8 months. All the glasses were stable for at least 6 months except carba- mazepine, which has a strong tendency to crystallize within a few months. Neutron and X-ray pair distribution function analyses were applied to the glassy materials, and the results were compared with their crystalline counterparts. The two diffraction techniques yielded similar re- sults in most cases and identified distinct intramolecular and intermolecular correlations. The intramolecular scattering was calculated based on the crystal structure and fit to the measured X-ray structure factor. The resulting intermolecular pair distribution functions revealed broad- nearest and next-nearest neighbor molecule–molecule correlations. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci Keywords: structure; X-ray powder diffractometry; NMR spectroscopy; glass; glass transi- tion; materials science INTRODUCTION Poor solubility of the active pharmaceutical ingre- dients can significantly reduce the efficacy of med- ications. Vitrification of drugs is known to increase solubility and bioavailablity in many cases. 1–5 In an effort to expand the range of pharmaceuticals that can be synthesized into amorphous forms, we have recently developed a new method of producing them by using acoustic levitation. 6 The proof of concept for this processing method has been demonstrated for Correspondence to: Chris J. Benmore (Telephone: +630- 2524207; Fax: +630-2524207; E-mail: benmore@anl.gov) Journal of Pharmaceutical Sciences © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association several drugs and here we present a more in-depth study of the structure of these pharmaceuticals us- ing 13 C NMR, X-ray, and neutron pair distribution function (PDF) analyses. In Ref. 6, the acoustic levi- tation method was demonstrated for a range of drugs with different glass-forming abilities; namely, cinnar- izine, carbamazepine, miconazole nitrate, probucol, and clotrimazole. Acoustic levitation is a containerless method used to generate amorphous and nanocrystalline pharma- ceutical compounds. It can be used to either produce amorphous products from supersaturated solutions or quenching from the melt formed via laser heating. 6 Here, we report on drug samples produced using the latter technique. During levitation, droplets of pure JOURNAL OF PHARMACEUTICAL SCIENCES 1