Blanton, Thomas N.

Gindhart, Amy M.

Golab, Joseph T.

Hong, Jerry, \u2720

Kaduk, James A.

English

Illinois Mathematics and Science Academy: DigitalCommons@IMSA

DATA REPORTPowder X-ray diffraction of trimethoprim Form I, C14H18N4O3Jerry Hong,1 Joseph T. Golab,1 James A. Kaduk ,2,3,a) Amy M. Gindhart,4 and Thomas N. Blanton 41Illinois Mathematics and Science Academy, 1500 Sullivan Rd., Aurora, Illinois 60506-1000, USA2Illinois Institute of Technology, 3101 S. Dearborn St., Chicago, Illinois 60616, USA3North Central College, 131 S. Loomis St., Naperville, Illinois 60540, USA4ICDD, 12 Campus Blvd., Newtown Square, Pennsylvania 19073-3273, USA(Received 2 December 2019; accepted 10 December 2019)Trimethoprim crystallizes in the triclinic space group P-1 (#2) with a = 10.5085(3), b = 10.5417(2),c = 8.05869(13) Å, α = 101.23371(21), β = 112.1787(3), γ = 112.6321(4)°, V = 743.729 Å3, and Z = 2.A reduced cell search in the Cambridge Structural Database yielded three previous structuredeterminations, using data collected at 100 K, 173 K, and room temperature. In this work, the samplewas ordered from the United States Pharmacopeial Convention (USP) and analyzed as-received.The room temperature (295 K) crystal structure was refined using synchrotron (λ = 0.412826 Å)powder diffraction data and optimized using density functional theory techniques. We found similarhydrogen bonding patterns with the previous determinations. In addition, we identified two C–H⋯Ohydrogen bonds, which also contribute to the crystal energy. When comparing the previouslyreported trimethoprim structure determinations, the unit cell length lattice parameters werefound to contract at lower temperatures, particularly 100 K. All structures show reasonable agreement,with unit cell length differences ranging between 0.05 and 0.15 Å. The diffraction data for thisstudy were collected on beamline 11-BM at the Advanced Photon Source, and the powder X-raydiffraction pattern of the compound has been submitted to ICDD® for inclusion in the PowderDiffraction File™ (PDF®). © 2020 International Centre for Diffraction Data.[doi:10.1017/S0885715619000927]Key words: trimethoprim, Primsol, powder diffraction, density functional theoryTrimethoprim (Primsol) is an antibiotic used primarily to treatbladder infections. Other uses include treating middle earinfections and traveler’s diarrhea. Commercial trimethoprim,CAS #738-70-5, crystallizes in the triclinic space group P-1(#2) with a = 10.5085(3), b = 11.2000(2), c = 8.05869(13) Å,α = 101.2337(2), β = 112.1787(3), γ = 112.6321(4)°, V =743.729(3) Å3, and Z = 2. A reduced cell search in theCambridge Structural Database (Groom et al., 2016) yieldedthree previous structure determinations, using X-ray data col-lected at 100 K (Maddileti et al., 2015), 173 K (Rauf andBolte, 2006), and neutron data assumed to be collected atroom temperature (Koetzle and Williams, 1976; Figure 1).In this work, the sample was ordered from the UnitedStates Pharmacopeial Convention (USP) (Lot #L0M053)and analyzed as-received. The diffraction data for this studywere collected on beamline 11-BM at the Advanced PhotonSource, Argonne National Laboratory. The room temperature(295 K) crystal structure was refined using synchrotron (λ =0.412826 Å) powder diffraction data and optimized usingdensity functional theory techniques. Hydrogen positionswere included as a part of the structure and were re-calculatedduring the refinement.We found hydrogen bonding patterns consistent withthe previous determinations. In addition, we identified twoC–H⋯O hydrogen bonds, which also contribute to the crystalenergy. When comparing the previously reported trimetho-prim structure determinations, the lattice parameters werefound to contract at lower temperatures, particularly 100 K(Figure 2). All structures show reasonable agreement, withunit cell differences ranging between 0.05 and 0.15 Å.These differences will have an effect on diffraction peak posi-tions and subsequently phase identification at room tempera-ture, thus the need for high-quality, room temperature X-raydiffraction data (Kaduk et al., 2014). The powder X-ray dif-fraction pattern of the compound has been submitted toICDD® for inclusion in the Powder Diffraction File™(PDF®) (Gates and Blanton, 2019; Table I).DEPOSITED DATACIF and/or RAW data files were deposited with ICDD.You may request this data from ICDD at info@icdd.com.ACKNOWLEDGEMENTSThe authors thank the Student Inquiry and ResearchProgram from the Illinois Mathematics and ScienceAcademy for providing this research opportunity.FUNDING INFORMATIONThe use of the Advanced Photon Source at the ArgonneNational Laboratory was supported by the U.S. Departmentof Energy, Office of Science, and Office of Basic Energya)Author to whom correspondence should be addressed. Electronic mail:kaduk@polycrystallography.com69 Powder Diffraction 35 (1), March 2020 0885-7156/2020/35(1)/69/2/$18.00 © 2020 JCPDS-ICDD 69Sciences under Contract No. DE-AC02-06CH11357. Thiswork was partially supported by the International Centre forDiffraction Data (ICDD).Gates-Rector, S. and Blanton, T. (2019). “The Powder Diffraction File: a qualitymaterials characterization database,” Powder Diffr. 34(4), 352–360.Groom, C. R., Bruno, I. J., Lightfoot, M. P., and Ward, S. C. (2016). “TheCambridge Structural Database,” Acta Crystallogr. B. 72, 171–179.Kaduk, J. A., Crowder, C. E., Zhong, K., Fawcett, T. G., and Suchomel, M. R.(2014). “Crystal structure of atomoxetine hydrochloride (Strattera),C17H22NOCl,” Powder Diffr. 29(3), 269–273.Koetzle, T. F. and Williams, G. J. B. (1976). “The crystal and molecular struc-ture of the antifolate drug trimethoprim (2,4-diamino-5-(3,4,5-trimethox-ybenzyl)pyrimidine),” J. Am. Chem. Soc. 98, 2074–2078.Maddileti, D., Swapna, B., and Nangia, A. (2015). “Tetramorphs of the anti-biotic drug trimethoprim: characterization and stability,” Cryst. GrowthDes. 15, 1745–1746.Rauf, K. and Bolte, M. (2006). CSD Communication; Refcode AMXBPM11.Figure 1. (Colour online) Powder X-ray diffraction pattern of trimethoprim. The Rietveld-refined structure is indicated in red, and the density functional theory-optimized structure is indicated in blue.Figure 2. (Colour online) Lattice parameters of trimethoprim as a function ofthe temperature. The curves are intended to guide the eye.TABLE I. Hydrogen bonds (CRYSTAL14) in trimethoprim.H-bond D-H (Å) H⋯A (Å) D⋯A (Å) D-H⋯A (°) Overlap (e) E (kcal mol−1)N2–H1⋯N1 1.025 1.988 3.011 175.3 0.067 aN2–H5⋯O2 1.011 2.097 2.923 137.4 0.029 3.9N4–H7⋯N3 1.026 1.988 3.012 175.8 0.070 aN4–H8⋯O1 1.010 2.448 3.251 136.0 0.018 3.1C10–H9⋯O3 1.090 2.516 3.587 167.2 0.018 aC11–H10⋯C8 1.082 2.695b 3.043 98.1 0.013 aaCorrelation between overlap population and hydrogen bond energy not yet available for C–H⋯O and N–H⋯N hydrogen bonds.bIntramolecular.70 Powder Diffr., Vol. 35, No. 1, March 2020 Hong et al. 70

Powder X-ray diffraction of trimethoprim Form I, C14H18N4O3

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Powder X-ray diffraction of trimethoprim Form I, C14H18N4O3

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