TECHNICAL ARTICLE Crystal structure of tramadol hydrochloride, C 16 H 26 NO 2 Cl James A. Kaduk, 1,a) Kai Zhong, 2 Amy M. Gindhart, 2 and Thomas N. Blanton 2 1 Illinois Institute of Technology, 3101 S. Dearborn Street, Chicago, Illinois 60616 2 ICDD, 12 Campus Blvd., Newtown Square, Pennsylvania, 19073-3273 (Received 10 March 2015; accepted 26 April 2015) The crystal structure of tramadol hydrochloride has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional techniques. Tramadol hydrochloride crystallizes in space group Cc (#9) with a = 9.680 72(2), b = 19.191 27(4), c = 9.285 94(1) Å, β = 100.5923(1)°, V = 1695.795(5) Å 3 , and Z = 4. The solid-state conformation of the cation differs from the minimum-energy conformation of the tramadol cation in water, and from the conformation observed in the benzoic acid adduct of tramadol hydrochloride. N–H···Cl and O–H···Cl hydrogen bonds form a zigzag chain with graph set C1,2(8) along the c-axis. C–H···O hydrogen bonds also con- tribute to the crystal energy. The powder pattern has been submitted to ICDD for inclusion in the Powder Diffraction File™.© 2015 International Centre for Diffraction Data. [doi:10.1017/S088571561500041X] Key words: tramadol hydrochloride, Ultram, powder diffraction, Rietveld refinement, density functional theory I. INTRODUCTION Tramadol (marketed as Ultram) is an opioid centrally acting binary analgesic drug, used to treat moderate to moderately severe pain. The systematic name (CAS Registry Number 36282-47-0) of tramadol is 2-[(dimethylamino)methyl]-1-(3- methoxyphenyl)cyclohexanol. With two chiral centers, trama- dol may exist in four different isomer forms. Marketed tramadol is the hydrochloride form of (1R, 2R)-(+)isomer and (1S, 2S)-(-)isomer racemic mixtures. The (+)isomer is a selective agonist of μ receptors, and (-)isomer functions primarily to in- hibit noradrenaline reuptake. The two enantiomers complement each other’s analgesic activity (Brayfield, 2013). Recently Bag and Reddy (2014) reported the solved crystal structure of trama- dol hydrochloride from single-crystal diffraction data. A two- dimensional (2D) molecular diagram is shown in Figure 1. The presence of high-quality reference powder patterns in the PDF ® (Powder Diffraction File; ICDD, 2014) is important for phase identification, particularly by pharmaceutical, foren- sic, and law enforcement scientists. The crystal structures of a significant fraction of the largest dollar volume pharmaceuti- cals have not been published, and thus calculated powder patterns are not present in the PDF-4 databases. Sometimes experimental patterns are reported, but they are generally of low quality. This structure is a result of a collaboration among ICDD, Illinois Institute of Technology (IIT), Poly Crystallography Inc., and Argonne National Laboratory to measure high-quality synchrotron powder patterns of com- mercial pharmaceutical ingredients, include these reference patterns in the PDF, and determine the crystal structures of these active pharmaceutical ingredients (APIs). Even when the crystal structure of an API is reported, the single-crystal structure was often determined at low temperature. Most powder measurements are performed at ambient conditions. Thermal expansion (often anisotropic) means that the peak positions calculated from a low- temperature single-crystal structure often differ significantly from those measured at ambient conditions. These peak shifts can result in failure of default search/match algorithms to identify a phase, even when it is present in the sample. High-quality reference patterns measured at ambient condi- tions are thus critical for easy identification of APIs using standard powder diffraction practices. II. EXPERIMENTAL Tramadol hydrochloride, a commercial reagent, pur- chased from the United States Pharmacopeia (USP) (lot G0L065), was used as-received. The white powder was packed into a 1.5 mm diameter Kapton capillary, and rotated during the measurement at ∼50 cycles s -1 . The powder Figure 1. The molecular structure of the (1R,2R) tramadol cation. a) Author to whom correspondence should be addressed. Electronic mail: kaduk@polycrystallography.com 242 Powder Diffraction 30 (3), September 2015 0885-7156/2015/30(3)/242/8/$18.00 © 2015 JCPDS-ICDD 242