Blanton, Thomas N.

Gindhart, Amy M.

Golab, Joseph T.

Hong, Jerry, \u2720

Kaduk, James A.

English

Illinois Mathematics and Science Academy: DigitalCommons@IMSA

NEW DIFFRACTION DATACrystal structure of (E)-doxepin hydrochloride, C19H22NOClJerry 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 18 November 2020; accepted 16 December 2020)The crystal structure of (E)-doxepin hydrochloride has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional techniques. (E)-doxepin hydro-chloride crystallizes in space group P21/a (#14) with a = 13.78488(7), b = 8.96141(7), c = 14.30886(9) Å, β = 96.5409(5)°, V = 1756.097(12) Å3, and Z = 4. There is a strong discrete hydrogen bondbetween the protonated nitrogen atom and the chloride anion. There are six C–H⋯Cl hydrogenbonds between the methyl groups and the chloride, as well as additional hydrogen bonds from meth-ylene groups and the vinyl proton. The hydrogen bonds are important in determining the solid-stateconformation of the cation. The compound is essentially isostructural to amitriptyline hydrochloride.The powder pattern is included in the Powder Diffraction File™ as entry 00-066-1613. © The Author(s), 2021. Published by Cambridge University Press on behalf of International Centre for DiffractionData. [doi:10.1017/S0885715621000063]Key words: doxepin, (E)-doxepin hydrochloride, powder diffraction, Rietveld refinement, densityfunctional theoryI. INTRODUCTIONDoxepin hydrochloride (brand names include Adapin,Aponal, Curatin, Quintaxon, and Sinequan) is a tricyclic anti-depressant (TCA). Its chemical structure features a tricyclicring system accompanied by an alkyl amine substituent.TCAs such as doxepin are potent inhibitors of serotonin andnorepinephrine reuptake. Other medicinal uses for doxepinhydrochloride include treating anxiety and insomnia, and asa topical application for treating skin dermatitis. Both (E)- and(Z)-isomers of doxepin hydrochloride are known, and availablecommercially. (Z)-doxepin corresponds to cidoxepin. TheIUPAC name of doxepin hydrochloride is (3E)-3-(6H-benzo[c][1]benzoxepin-11-ylidene)-N,N-dimethylpropan-1-amine hydro-chloride. The CAS Registry number for the mixed isomers ofdoxepin HCl is 1229-29-4, and for the (E)-isomer is 4698-39-9.A two-dimensional molecular diagram for the doxepin cation isshown in Figure 1.Low-precision powder patterns of doxepin hydrochlorideare contained in the ICDD® Powder Diffraction File (PDF®)as entries 00-029-1697 (Haga, 1979) and 00-034-1704(DeCamp, 1982). Higher quality patterns of trans-doxepinhydrochloride and cis-doxepin hydrochloride are included asentries 00-034-1706 (DeCamp, 1982) and 00-051-1920 (Jin,2001), respectively. However, none of these entries containscrystal structure data. Polymorphism in doxepin hydrochlo-ride has been studied by Panda (2011).This work was carried out as part of a project (Kaduket al., 2014) to determine the crystal structures of large-volume commercial pharmaceuticals, and include high-qualitypowder diffraction data for these pharmaceuticals in thePowder Diffraction File (Gates-Rector and Blanton, 2019).II. EXPERIMENTALDoxepin hydrochloride was a commercial reagent, pur-chased from United States Pharmacopeial Convention (USP)(Lot # J0M472), and was used as-received. It was unknownif the sample was a mixture or single isomer. The white pow-der was packed into a 1.5-mm diameter Kapton capillary androtated during the measurement at ∼50 Hz. The powder pat-tern was measured at 295 K at beam line 11-BM (Lee et al.,2008; Wang et al., 2008) of the Advanced Photon Source atArgonne National Laboratory using a wavelength ofFigure 1. The molecular structure of the (E)-doxepin cation.a)Author to whom correspondence should be addressed. Electronic mail:kaduk@polycrystallography.com43 Powder Diffraction 36 (1), March 2021 0885-7156/2021/36(1)/43/7/$18.00 © 2021 JCPDS-ICDD 430.414157 Å from 0.5° to 50° 2θ with a step size of 0.001° anda counting time of 0.1 s step−1. The observed diffraction pat-tern was found to correspond to trans-doxepin hydrochloride(Figure 2). The pattern was indexed on a primitive monoclinicunit cell with a = 13.78472, b = 8.96160, c = 14.30891 Å, β =96.540°, V = 1756.121 Å3, and Z = 4 using N-TREOR(Altomare et al., 2013). Analysis of the systematic absencesusing EXPO2014 (Altomare et al., 2013) suggested thespace group P21/a, which was confirmed by successful solu-tion and refinement of the structure. A reduced cell search inthe Cambridge Structural Database (Groom et al., 2016)yielded 7 hits, among which was amitriptyline hydrochloride(Klein et al., 1994; YOVZEO). This molecule has the sameconnectivity as doxepin, but without the oxygen atom in thecentral ring. The structure was solved by direct methods,including the COVMAP option.Rietveld refinement for (E)-doxepin HCl was carried outusing GSAS-II (Toby and Von Dreele, 2013). Only the 1.6–25.0° portion of the pattern was included in the refinement(dmin = 0.956 Å). All non-H bond distances and angles weresubjected to restraints, based on a Mercury/Mogul GeometryCheck ( Bruno et al., 2004; Sykes et al., 2011) of the mole-cule. The results were exported to a .csv file. The Mogul aver-age and standard deviation for each quantity were used as therestraint parameters and were incorporated using the new fea-ture Restraints/Edit Restraints/Add MOGUL Restraints,which reads the bond distance and angle restraints from the .csv file. The restraints contributed 3.8% to the final χ2. TheFigure 2. Comparison of the synchrotron powder pattern (green) of doxepin hydrochloride to the 2θ, intensity data for the two reported trans-doxepin PDFentries (00-034-1704 (red), 00-034-1706 (blue)).Figure 3. The Rietveld plot for the refinement of doxepin hydrochloride. The blue crosses represent the observed data points, and the green line is the calculatedpattern. The cyan curve is the normalized error plot. The vertical scale has been multiplied by a factor of 10× for 2θ > 10.0°.44 Powder Diffr., Vol. 36, No. 1, March 2021 Hong et al. 44hydrogen atoms were included in calculated positions, whichwere recalculated during the refinement using MaterialsStudio (Dassault, 2019). The Uiso for each hydrogen atomwas constrained to be 1.3× that of the heavy atom to whichit is attached. The background was modeled using a 4-termshifted Chebyshev polynomial, and an 8-term diffuse scatter-ing function to model the Kapton capillary and any amorphouscomponent.The final refinement of 104 variables using 23 402 obser-vations and 54 restraints yielded the residuals Rwp = 0.0832and GOF = 1.59. The largest peak (0.17 Å from Cl43) andhole (1.59 Å from N34) in the difference Fourier map were0.29 and −0.17(4) eÅ−3, respectively. The Rietveld plot isincluded in Figure 3. The largest errors in the fit are in theshapes of some of the strong low-angle peaks.A density functional geometry optimization was carriedout using CRYSTAL14 (Dovesi et al., 2014). The basis setsfor the H, C, N, and O atoms were those of Gatti et al.(1994), and the basis set for Cl was that of Peintinger et al.(2013). The calculation was run on eight 2.1 GHz Xeoncores (each with 6 GB RAM) of a 304-core Dell Linux clusterat IIT, using 8 k-points and the B3LYP functional, and took∼52 h.III. RESULTS AND DISCUSSIONThe refined atom coordinates of (E)-doxepin hydrochlo-ride and the coordinates from the density functional theory(DFT) optimization are reported in the CIFs attached in theSupplementary Material. The root-mean-square (rms)Cartesian displacement of the non-hydrogen atoms in theRietveld-refined and DFT-optimized structures is 0.122 Å(Figure 4). The maximum difference is at the methyl groupC35. The agreement between the refined and optimizedstructures is excellent and provides evidence that the experi-mental structure is correct (van de Streek and Neumann,2014). This discussion concentrates on the CRYSTAL-opti-mized structure. The asymmetric unit (with atom numbering)is illustrated in Figure 5, and the crystal structure is presentedin Figure 6.All of the bond distances, bond angles, and torsion anglesfall within the normal ranges indicated by a Mercury/MogulGeometry check (Macrae et al., 2020). The N–H⋯Cl hydro-gen bonds lie along the a-axis. As noted below, C–H⋯Clhydrogen bonds also occur, and lead to columns of hydrogenbonds along this axis. The central ring of the cation isbent, leading to a “butterfly” shape of the fused ring system.The structure of the doxepin cation is essentially identicalwith the cation in YOVZEO (changing the O14 to a carbonand inverting one of the structures). The rms Cartesiandisplacement is only 0.084 Å (Figure 7), and the maximumdisplacement is 0.129 Å. The YOVZEO structure couldhave been used as an initial model for the Rietveld refine-ment, if we had not already solved the structure by directmethods.Quantum chemical geometry optimizations (DFT/B3LYP/6-31G*/water) of the (E)-doxepin cation usingSpartan ‘18 (Wavefunction, 2018) indicated that the observedconformation is 2.9 kcal mol−1 higher in energy than the localminimum, and thus that the cation is in a low-energy confor-mation. The minimum-energy conformation (molecularmechanics) is much more compact and distorted, with thetwo aromatic rings parallel to each other and the side chainalso folded toward the ring system. Intermolecular interactionsFigure 4. Comparison of the Rietveld-refined (red) and VASP-optimized (blue) structures of doxepin hydrochloride. The rms Cartesian displacement is 0.122 Å.45 Powder Diffr., Vol. 36, No. 1, March 2021 Crystal structure of (E)‐doxepin hydrochloride, C19H22NOCl 45Figure 5. The asymmetric unit of doxepin hydrochloride, with the atom numbering. The atoms are represented by 50% probability spheroids/ellipsoids.Figure 6. The crystal structure of doxepin hydrochloride, viewed down the b-axis.46 Powder Diffr., Vol. 36, No. 1, March 2021 Hong et al. 46thus play a role in determining the observed solid-stateconformation.Analysis of the contributions to the total crystal energyusing the Forcite module of Materials Studio (Dassault,2019) suggests that bond, angle, and torsion distortion termsare significant in the intramolecular deformation energy, asmight be expected for a fused ring system. The intermolecularenergy is small and dominated by electrostatic attractions,which in this force-field-based analysis includes hydrogenbonds. The hydrogen bonds are better analyzed using theresults of the DFT calculation.Hydrogen bonds are prominent in the crystal structure(Table I). As expected, there is a strong discrete hydrogenbond between the protonated nitrogen N34 and the chlorideanion. Perhaps less expected are the six C–H⋯Cl hydrogenbonds between the methyl groups and the chloride, as wellas additional hydrogen bonds from methylene groups andthe vinyl proton H27. Most of these interactions are capturedby Mogul in its list of short contacts (Figure 8). The hydrogenbonds are important to determining the solid-state conforma-tion of the cation.The volume enclosed by the Hirshfeld surface (Figure 9;Hirshfeld, 1977; Turner et al., 2017) is 431.69 Å3, 98.33% of1/4 the unit cell volume. The molecules are thus not tightlypacked. All of the significant close contacts (red in Figure 9)involve the hydrogen bonds. The volume/non-hydrogenatom is relatively large, at 19.9 Å3.The Bravais–Friedel–Donnay–Harker (Bravais, 1866;Friedel, 1907; Donnay and Harker, 1937) morphology sug-gests that we might expect platy morphology for(E)-doxepin hydrochloride, with {001} as the principalfaces. A second-order spherical harmonic model was includedin the refinement. The texture index was 1.010, indicating thatpreferred orientation was not significant in this rotated capil-lary specimen. The powder pattern of (E)-doxepin hydrochlo-ride from this synchrotron data set is included in the PowderDiffraction File™ 00-066-1613.DEPOSITED DATAThe supplementary material for this article, whichincludes Crystallographic Information Framework (CIF) filesFigure 7. Comparison of the structure of doxepin hydrochloride (green) to that of amitriptyline hydrochloride (Klein et al., 1994; YOVZEO; orange). The rmsCartesian displacement of the cations is 0.084 Å.TABLE I. Hydrogen bonds (CRYSTAL14) in (E)-doxepin hydrochloride.H-bond D-H (Å) H⋯A (Å) D⋯A (Å) D-H⋯A (°) Overlap (e)N34–H44⋯Cl43 1.058 1.977 3.030 172.7 0.118C31–H33⋯Cl43 1.093 2.481 3.532 160.8 0.042C39–H41⋯Cl43 1.092 2.579 3.634 162.2 0.040C31–H32⋯Cl43 1.094 2.949 3.926 148.9 0.022C35–H36⋯Cl43 1.090 2.877 3.847 148.3 0.021C39–H42⋯Cl43 1.091 2.913 3.841 143.0 0.019C35–H38⋯Cl43 1.090 2.896 3.831 144.0 0.018C11–H13⋯Cl43 1.098 2.990 4.017 155.8 0.022C28–H29⋯Cl43 1.097 3.109 3.817 122.9 0.010C26–H27⋯Cl43 1.089 3.081 4.062 150.1 0.01847 Powder Diffr., Vol. 36, No. 1, March 2021 Crystal structure of (E)‐doxepin hydrochloride, C19H22NOCl 47containing the results of the Rietveld refinement (including theraw data) was deposited with the ICDD. The data can berequested at info@icdd.com.ACKNOWLEDGEMENTSUse of the Advanced Photon Source at Argonne NationalLaboratory was supported by the U.S. Department of Energy,Figure 8. The weak C–H⋯Cl hydrogen bonds in doxepin hydrochloride.Figure 9. The Hirshfeld surface of doxepin hydrochloride. Intermolecular contacts longer than the sums of the van der Waals radii are colored blue, and contactsshorter than the sums of the radii are colored red. Contacts equal to the sums of radii are white.48 Powder Diffr., Vol. 36, No. 1, March 2021 Hong et al. 48Office of Science, Office of Basic Energy Sciences, underContract No. DE-AC02-06CH11357. This work was partiallysupported by the International Centre for Diffraction Data. Wethank Lynn Ribaud and Saul Lapidus for their assistance in thedata collection, and Andrey Rogachev for the use of comput-ing resources at IIT.CONFLICTS OF INTERESTThe authors have no conflicts of interest to declare.Altomare, A., Cuocci, C., Giacovazzo, C., Moliterni, A., Rizzi, R., Corriero,N., and Falcicchio, A. (2013). “EXPO2013: a kit of tools for phasing crys-tal structures from powder data,” J. Appl. Crystallogr. 46, 1231–1235.Bravais, A. (1866). 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Crystal structure of (E)-doxepin hydrochloride, C19H22NOCl

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Crystal structure of (E)-doxepin hydrochloride, C19H22NOCl

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