solid-state characterization of chlordiazepoxide polymorphs

Solid-State Characterization of Chlordiazepoxide Polymorphs

DILRAJ SINGH,†,‡ PETER V. MARSHALL,§ LEN SHIELDS,| AND PETER YORK*,†

Contribution from Pharmaceutical Technology, Department of Pharmacy, and Chemistry and Chemical Technology,Department of Chemical Engineering, University of Bradford, West Yorkshire, BD7 1DP, U.K., and Pfizer Central Research,Sandwich, Kent, CT13 9NJ, U.K.

Received September 13, 1996. Accepted for publication February 2, 1998.

Abstract 0 A novel crystal form (form II) of the benzodiazepinechlordiazepoxide is reported. The new polymorphic phase wascharacterized and distinguished from the standard form (form I) byX-ray diffractometry, differential scanning calorimetry, infrared spec-troscopy, microscopy, solution calorimetry, and solid-state nuclearmagnetic resonance. The formation of form II was dependent on thecrystallizing solvent, being the predominant form isolated frommethanol. Recrystallization from other alcoholic solutions (ethanol,propanol, and butanol) and toluene yielded form I. Differential scanningcalorimetry and powder X-ray diffraction indicated that the two formswere enantiotropically related with a transition of form II to form Ioccurring between 200 and 225 °C. Visual examination by hot stagemicroscopy in this temperature range revealed a dramatic solid-statetransition. Single-crystal X-ray analysis was performed on form II whichwas found to crystallize in the triclinic space group P1h with a )10.736(2) Å, b ) 16.921(4) Å, c ) 17.041(4) Å, R ) 100.76(1)°, â) 95.27(1)°, γ ) 97.53(1)°, Z ) 8, and dcal ) 1.33 g/cm3. Whencompared with the published crystal structure of form I, the cellsymmetry, volume, and density were similar. Both structures consistedof four crystallographically independent molecules linked in pairsthrough intermolecular hydrogen bonding. Differences were observedin the packing arrangement of the dimers in the polymorphs. Thesmall heat of transition calculated from solution calorimetry (1.5 kJmol-1) was sufficient to effect a crystallographic rearrangement ofthe dimers.

The thorough solid-state characterization of a new drugsubstance is recognized as an essential and very importantpart of preformulation research. A new drug substance canexist in several possible forms in the solid state. Theseinclude physical modifications such as crystalline andamorphous forms, chemical modification by solvate forma-tion (pseudopolymorphism), and structural alteration suchas polymorphism. Such forms can significantly affect themanufacturing and product performance in solid-statedosage forms.1 It is the goal of the preformulation scientistto investigate and characterize these possible modificationsin terms of their physicochemical properties and select aform which has the best combination of desired propertiesto proceed to formulation.A chemical substance which can crystallize into two or

more different arrangements of atoms, ions, or moleculesin the solid state is said to exhibit polymorphism.2 Suchstructural alterations in solids can be induced with changesin crystallizing conditions3,4 and processing operations suchas spray drying5,6 and during grinding and compression.7,8The pharmaceutical importance of this phenomenon lies

in the fact that different polymorphic phases exhibit uniquephysicochemical properties and thus have the potential toalter the performance of a solid-state formulation. Suchphysicochemical properties include solubility/dissolution

* Corresponding author. Phone: 44-1274-384738. Fax: 44-1274-305340. E-mail: [email protected].

† Pharmaceutical Technology, University of Bradford.‡ Present address: Aerosol Research Group, Department of Phar-

macy and Pharmaceutics, Box 980533, Medical College of Virginia,Virginia Commonwealth University, Richmond, VA 23298-0533.

§ Pfizer Central Research.| Chemistry and Chemical Technology, University of Bradford.

Figure 1sX-ray powder diffraction patterns of the polymorphs of chlordiaz-epoxide.

Figure 2sX-ray powder diffraction patterns of chlordiazepoxide crystallizedfrom (A) methanol, (B) toluene, (C) butanol, (D) propanol, and (E) ethanol.

© 1998, American Chemical Society and S0022-3549(96)00385-1 CCC: $15.00 Journal of Pharmaceutical Sciences / 655American Pharmaceutical Association Vol. 87, No. 5, May 1998Published on Web 04/07/1998

rates which can influence bioavailablity,9,10 solid-statestability,11 and compaction behavior.12,13 The presence ofthis phenomenon in pharmaceuticals is particularly com-mon and a recent report lists over 500 examples of pharm-aceuticals that exhibit polymorphism.14This report describes the preparation and solid-state

characterization of a novel polymorphic form of chlordiaz-epoxide. Chlordiazepoxide has not been previously re-ported to exhibit polymorphism. There have been tworeports on the polymorphism of the hydrochloride salt.15,16However, these claims were later critized17 for incorrectlyusing the term “polymorphism” and the modificationsreported were structures with varying degrees of solvation.

Experimental SectionMaterialssChlordiazepoxide (C16H14N3OCl; 7-chloro-2-meth-

ylamino-5-phenyl-3H-1,4-benzodiazepine 4-oxide) (Batch no.9100003--438) was obtained from Fabbrica Sintetici S.p.A, Italy,

and was determined to be more than 99.8% pure by the USP XXIIHPLC analysis procedure according to the supplied certificate ofanalysis. The alcohols used in the preparation of the two poly-morphs were of analytical reagent grade and supplied by BDHChemicals, Poole, England.Production of Chlordiazepoxide PolymorphssThe com-

mercial form (form I) was recrystallized from ethanol which is thesolvent used in the original preparation and patent.18 Chlordiaz-epoxide (100 g) was dissolved in hot ethanol (1800 mL). Thesolution was concentrated to 2/3 volume by boiling and left to reachroom temperature with stirring. After 3 h, the resulting yellowplatelike crystals were filtered, washed with two portions ofethanol (100 mL), and dried overnight (yield 84 g, 84%).The novel crystal form (form II) was produced by recrystalli-

zation from methanol. Preliminary recrystallizations of chlor-diazepoxide resulted in predominantly crystals of form II (needle-like morphology), although some platelike crystals were observedunder microscopical examination. The needlelike crystals (formII) were separated physically and used for seeding in the largescale preparation. Chlordiazepoxide (100 g) was dissolved in hotmethanol (1600 mL) and heated. Boiling was continued until avolume of 1000 mL remained. The solution was then seeded withcrystals of form II and left to cool to room temperature. The massof white needlelike crystals were recovered by filtration, washedwith two portions of methanol (100 mL), and dried overnight (yield73 g, 73%).DSCsThe scans of chlordiazepoxide samples were recorded on

a Perkin-Elmer DSC7 DSC connected to a Perkin-Elmer 7700computer via a TAC7 microprocessor controller. The system withPerkin-Elmer TAS7 software was used to calculate extrapolatedonset temperature, peak temperature, and enthalpy values foreach thermal event. The temperature axis was calibrated with apure indium and confirmed with a zinc standard. Samples wereexamined in crimped aluminum pans with ventilated lids. Therate of heating was 10 °C/min over the temperature range 30-300 °C.X-ray Powder Diffraction StudiessThe X-ray powder dif-

fraction patterns of chlordiazepoxide samples were obtained witha Siemens model D5000 diffractometer fitted with a scintillationcounter and a Cu KR radiation source (wavelength, 0.15418 nm).

Figure 3sDSC curves of chlordiazepoxide polymorphs.

Figure 4sHSM photographs of form I at various temperatures.

656 / Journal of Pharmaceutical SciencesVol. 87, No. 5, May 1998

The aperture of the divergence and detector slits were 1.0 and0.06°, respectively. Data were collected between 3° and 45° 2θ ina step scan mode with a collecting time of 3 s/step. Powdersamples were examined in a stainless steel holder after beingsmoothed with a glass slide.Variable Temperature X-ray Powder Diffraction

StudiessSamples were run on the same instrument describedabove using an Anton Paar model TTK2-HC temperature control-ler to control the sample temperature within an Anton Paarsample holder (model no. 589775).Temperature-ramped X-ray powder patterns were collected

using a scan range between 3° and 12° 2θ in a step scan modeusing a step size of 0.05° 2θ and a count time of 3 s/step. Sampleswere run at 5° intervals from 190 to 220 °C using a heating rateof 20 °C/min.Hot Stage MicroscopysSamples were examined using a

Nikon Labophot-2 microscope connected to Stanton Redcroft hot

stage unit and universal temperature programmer. Visual ex-amination was performed using a JVC TK-1085E color videocamera and a Colorado Video Inc. 109 digital display unitconnected to a JVC 1500PS color monitor.Solution CalorimetrysA Parr 1455 solution calorimeter was

used at 25 °C ((1 °C) to record the enthalpy change associatedwith the dissolution of chlordiazepoxide samples into the 1 Mhydrochloric acid solvent system (n ) 3). The heat capacity forthe system was calibrated with 0.5 g of tris(hydroxymethyl)-methylamine and 100 mL of 0.1 M hydrochloric acid. Calibrationwas performed with the chart recorder set at 100 mV full scaledeflection equivalent to a temperature change of 1 °C.Fourier Transform Infrared SpectroscopysA Perkin-

Elmer 1720-X Fourier transform infrared spectrometer was usedto acquire the infrared data. The samples were presented aspotassium bromide pellets (KBr) and measured at a resolution of4 cm-1 within a wavenumber range 400-2000 cm-1.

Figure 5sHSM photographs of form II at various temperatures.

Journal of Pharmaceutical Sciences / 657Vol. 87, No. 5, May 1998

Solid-State NMR (SSNMR)sThe carbon-13 SSNMR spectrawere obtained using a Bruker CXP-200 spectrometer. Measure-ments were made using a carbon observation frequency of 75.3MHz with a Bruker 7 mm double bearing cross polarization magicangle spinning (CPMAS) probe at ambient temperature. Chemicalshifts were made with reference to tetramethylsilane (TMS) at0.0 ppm.Single-Crystal X-ray Structure DeterminationsUnit cell

dimensions and atomic coordinates were determined with a StoeStadi-4 single-crystal diffractometer with a Cu KR radiation sourceof wavelength 0.15418 nm. Suitably sized crystals (∼0.5 × 0.5 ×0.5 mm) were selected to minimize differential absorption effects.Cell constants and orientation matrix for data collection wereobtained from the least squares refinement of the setting anglesof at least 20 reflections. Data were then collected at roomtemperature by the ω-2θ scan technique out to 2θ of 111°. Thescan width was 1° and the scan speed 1°/30 s. The invariabilityof representative reflections acting as standards throughout datacollection indicated crystal stability. The intensities were cor-rected for Lorentz and polarization factors, but not for absorptionor extinction effects. Non-hydrogen atomic positions were locatedby direct methods from an electron density map (E-map) calculatedfrom the set of phases with the lowest figure of merit. Structurerefinement was carried out with the SHELXL-93 program utilizingfull-matrix least-squares techniques. Refinements were firstperformed with isotropic and then anisotropic temperature factors.Final models had all non-hydrogen atoms thermally anisotropic.The CERIUS19 modeling program was used to generate molecularrepresentations. Conformational analysis was carried out usingthe CRYSTALS20 refinement program.The hydrogen atoms were placed and are riding isotropically

on their conjugate non-hydrogen atoms. The final reliability factorconverged to an unweighted R ) 0.056 and an inverse σ(I)weighted RW ) 0.058 with parameter shifts of <0.1 of theparameter estimated standard deviations (esd).

Results and DiscussionPowder X-ray DiffractometrysPowder X-ray diffrac-

tion is regarded as one of best methods of detecting theexistence of polymorphism.14,21,22 The powder X-ray dif-

fraction patterns of forms I and II are shown in Figure 1.The diffractograms are distinctly different from each otherwith several diffraction lines which are unique to eachform. For example, the lowest 2θ diffraction peak occursat 5.74° in form I and 5.65° in form II. Furthermore, formII has a unique doublet diffraction feature at 10.91° and11.20° 2θ which is absent in form I. Figure 2 shows theX-ray diffraction patterns between 3 and 20° 2θ of chlor-diazepoxide recrystallized from the solvents methanol,toluene, butanol, propanol, and ethanol. The unique phase,form II, could only be isolated from methanol.Thermal AnalysissThe DSC profiles for forms I and

II are shown in Figure 3. Form I exhibits two thermalevents: an endothermic region between 236 and 246 °C,which corresponds to fusion, followed by an exothermicdegradation of the sample. However form II displays anadditional small endothermic region in the range 200-220°C. This endotherm was found to be irreversible by coolinga sample of form II from 220 °C and rerunning the DSCexperiment. Above this temperature the profile followsthat of form I, suggesting a transformation from form I toII has occurred. Thermal gravimetric analysis of thesamples revealed no weight loss until the melting rangeof the samples indicating that the first endothermic eventin form II cannot be attributed to any inclusion of solventin the crystal lattice (solvate formation).Hot Stage MicroscopysBoth crystal forms were ex-

amined visually by hot stage microscopy to assist in theinterpretation of the DSC results. Figure 4 is a polarizedcomposite HSM photograph of form 1 at several tempera-tures from ambient to 245 °C. No change in the physicalappearance of the crystals was observed up to 240 °C andmelting occurs between 240 and 245 °C. Figure 5 showspolarized HSM photographs of form II at several temper-

Figure 6sX-ray powder diffraction patterns of form II at various temperatures.

Figure 7sFTIR spectra of the polymorphs of chlordiazepoxide.


atures. A dramatic solid-solid transition is observedbetween 205 and 220 °C which corresponds to the firstendotherm in the DSC profile of form II. At 215 °C crystalsof a platelike habit appear and grow at the surface ofneedlelike crystals of form II. Further growth of theseplatelike crystals is seen at 225 °C accompanied with abreak up of the needle crystal morphology. At 225 °C thetransformation is complete and melting of the resultingplatelike crystals occurs at 240-245 °C, as observed withform I. No melting was observed within the crystals prior

to or during the transition region, further indicating a solid-state transition, possibly corresponding to a molecularrearrangement in the crystal lattice.Variable Temperature Powder X-ray Diffractions

Figure 6 shows X-ray powder patterns of form II scannedat different temperatures covering the range of the firstendotherm region in the DSC. A dramatic change in theX-ray pattern confirms a change in crystal structure in thistemperature range. Furthermore, the final pattern corre-sponds to that of form I, providing additional evidence ofthe solid-phase transition of form II to form I.Solution CalorimetrysBoth polymorphic forms exhib-

ited exothermic heats of solution. The values, with stan-dard deviations in parentheses, are -21.20(0.29) and-19.65(0.24) kJ mol-1 for forms I and II, respectively. Theenthalpy of transition, calculated from the difference ofthese values, was 1.55 kJ mol-1.Fourier Transform Infrared SpectroscopysThe

FTIR spectra for the two polymorphs are presented inFigure 7. The spectra, while generally similar, showseveral discernible differences. For example, in the 1650-1500 cm-1 wavenumber range there are relative intensitychanges between the two spectra reflecting different mo-lecular environments. An additional band in the finger-print region at 900 cm-1 was also observed in the spectrumfor form II. This band was found to disappear after formII was heated to 225 °C and cooled. The spectrum of formI agrees closely with that of the reference spectrum in theBritish Pharmacopoeia.23Solid-State NMR (SSNMR)sThe carbon-13 SSNMR

spectra for the two polymorphs are shown in Figure 8. Thespectra are different and indicate structural dissimilaritiesbetween the two forms. One notable difference is thesplitting of the methyl group signal in form II at ∼30 ppm.This could be regarded as a crystallographic splittingreflecting two different chemical environments for thiscarbon atom. The resonance of the methylene bridge (C2)is unaffected in the two polymorphs. The downfield region(120-150 ppm) corresponding to the aromatic and olefiniccarbons differ markedly in terms of structure and shapeof the spectral signals. This could be attributed to differingchemical environments in the two crystal structures.

Figure 8sSSNMR spectra of the polymorphs of chlordiazepoxide.

Table 1sCrystallographic Data of Chlordiazepoxide

parameter form Ia form II

chem formula C16H14N3OClformula wt 299.8cryst syst triclinic triclinicspace group P1h P1hZ 8 8a, Å 15.786(4) 10.736(4)b, Å 13.155(3) 16.921(6)c, Å 15.496(4) 17.041(5)R (deg) 104.56(3) 100.76(5)â (deg) 102.43(3) 95.27(5)γ (deg) 79.83(3) 97.53(5)V, A3 3017 2993dcalc, Mg/m3 1.32 1.33R 0.055 0.056

a From Bertolasi et al. Acta Crystallogr. 1982, B38, 1768−1772.

Figure 9sAtom numbering scheme for chlordiazepoxide.


Single-Crystal X-ray DiffractionsForm II was foundto crystallize in a triclinic crystal system with the spacegroup P1h. The cell parameters are listed in Table 1. Theselattice parameters were refined by least squares refinementof the positive and negative 2θ values from 40 selectedreflections. The structure was solved by direct methodsand refined using blocked-matrix least squares to an un-weighted R value of 0.056 using 8113 observed diffracto-meter reflections. Fractional atomic coordinates and aniso-tropic thermal parameters of form I are listed in Table 2.The crystal structure of form I has previously been

determined.24 On comparison with the crystal structureof form II, the two crystal structures appear to be verysimilar in terms of cell volume and crystal symmetry (Table1). Both crystal structures consist of a unique pair ofhydrogen-bonded dimers in the asymmetric unit. Eachpair of molecules is dimerized through two hydrogensbetween the secondary amine (N3) and the oxygen atomon the adjacent molecule (Figure 9). Conformationalanalysis was performed on the seven-membered diazepinering (N1-C3-C2-N2-C1-C10-C5) of each of the chlor-diazepoxide molecules in the asymmetric unit. The resultsconfirmed that all the molecules adopted boat conforma-tions. Table 3 lists the mean interatomic distances and

angles in both crystal structures and illustrates that theyare similar.The major molecular structural difference between the

two polymorphs was seen when the crystal packing of thedimers was compared. Parts a and b of Figure 10 are theasymmetric units of forms I and II, respectively, as viewedalong the plane ac. In form II the dimers are displacedwith respect to each other. From a consideration of thecrystal structures, the solid-state transition of form II to Iappears to involve a molecular rearrangement of thedimers.In summary, a novel polymorphic form of chlordiazep-

oxide (form II) has been identified and characterized. Thecrystal form of chlordiazepoxide isolated from solution wasdependent upon the crystallizing medium. Form II couldonly be produced from methanol recrystallization.Form II was shown to be an enantiotropic polymorphic

modification of form I by DSC and X-ray diffraction. Asmall endothermic region between 200 and 225 °C belowthe melting endotherm of form I was observed only in thethermal profile of form II. HSM assisted in the interpreta-tion of this additional endotherm, revealing a solid-statetransition of form II to I. This structural conversion wasfurther confirmed by powder X-ray diffraction. The spec-

Table 2sAtomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (×103) with Esd’s in Parentheses for Chlordiazepoxide FormII

atom x y z Ueq(A2) x y z Ueq(A2)

molecule 1 molecule 2Cl 1770(1) 9409(1) 3896(1) 58(1) −6292(1) 11434(1) 6214(1) 76(1)O −4714(3) 10183(2) 2844(2) 61(1) 429(3) 12086(2) 7877(2) 64(1)N(1) −1783(3) 11810(2) 4307(2) 54(1) −1526(3) 13785(2) 6986(2) 50(1)N(2) −3627(3) 10368(2) 3302(2) 47(1) −505(3) 12302(2) 7467(2) 48(1)N(3) −3732(4) 12222(2) 4309(2) 65(1) 645(3) 14160(2) 7243(2) 61(1)C(1) −2532(3) 10231(2) 3037(2) 41(1) −1704(3) 12165(2) 7603(2) 43(1)C(2) −3681(4) 10777(3) 4138(2) 53(1) −160(4) 12721(3) 6819(3) 53(1)C(3) −3011(4) 11638(3) 4256(2) 52(1) −391(4) 13588(2) 7023(2) 48(1)C(4) −3176(5) 13075(3) 4413(3) 78(2) 584(5) 15027(3) 7430(4) 81(2)C(5) −1051(3) 11188(2) 4185(2) 44(1) −2579(3) 13166(2) 6818(2) 43(1)C(6) 148(4) 11348(3) 4651(2) 50(1) −3639(4) 13353(3) 6384(2) 52(1)C(7) 996(4) 10815(3) 4559(2) 50(1) −4757(4) 12828(3) 6192(3) 54(1)C(8) 677(3) 10084(2) 4007(2) 44(1) −4856(4) 12098(2) 6446(2) 49(1)C(9) −474(3) 9907(2) 3529(2) 43(1) −3860(4) 11891(2) 6896(2) 47(1)C(10) −1357(3) 10452(2) 3611(2) 39(1) −2687(3) 12422(2) 7093(2) 43(1)C(11) −2479(3) 9871(2) 2193(2) 43(1) −2042(3) 11737(2) 8253(2) 42(1)C(12) −1492(4) 10186(3) 1803(2) 53(1) −2920(4) 12016(3) 8740(2) 50(1)C(13) −1386(4) 9864(3) 1018(3) 63(1) −3281(4) 11627(3) 9347(3) 62(1)C(14) −2225(5) 9195(3) 603(3) 65(1) −2811(4) 10938(3) 9453(3) 66(1)C(15) −3196(4) 8882(3) 982(3) 62(1) −1950(5) 10648(3) 8976(3) 65(1)C(16) −3338(4) 9208(3) 1754(3) 54(1) −1559(4) 11046(3) 8377(3) 56(1)

molecule 3 molecule 4Cl −12519(1) 12822(1) 2219(1) 88(1) 466(1) 5702(1) 908(1) 84(1)O −6415(3) 12018(2) 4041(2) 71(1) 7000(2) 6343(2) 2745(2) 59(1)N(1) −7605(3) 11709(2) 1609(2) 48(1) 5831(3) 6379(2) 346(2) 53(1)N(2) −7302(3) 11915(2) 3441(2) 51(1) 6156(3) 6365(2) 2154(2) 45(1)N(3) −5815(3) 11156(2) 1929(2) 57(1) 7908(3) 6932(2) 791(2) 57(1)C(1) −8064(4) 12447(2) 3346(2) 45(1) 5166(3) 5799(2) 1884(2) 40(1)C(2) −7396(4) 11157(3) 2843(3) 55(1) 6397(4) 7072(2) 1765(2) 50(1)C(3) −6936(4) 11357(2) 2085(2) 47(1) 6689(4) 6775(2) 926(3) 50(1)C(4) −5265(4) 11283(4) 1206(3) 70(1) 8277(5) 6703(4) 0(3) 79(2)C(5) −8735(4) 11962(2) 1838(2) 45(1) 4591(4) 6178(2) 521(2) 47(1)C(6) −9676(4) 11941(3) 1189(3) 52(1) 3625(4) 6197(3) −83(3) 58(1)C(7) −10807(4) 12198(3) 1303(3) 59(1) 2362(4) 6031(3) 18(3) 64(1)C(8) −11072(4) 12488(3) 2062(3) 59(1) 2048(4) 5831(3) 733(3) 54(1)C(9) −10182(4) 12541(3) 2722(3) 52(1) 2960(4) 5743(2) 1316(3) 47(1)C(10) −8993(4) 12288(2) 2618(2) 43(1) 4257(3) 5925(2) 1225(2) 42(1)C(11) −8000(3) 13204(3) 3957(2) 48(1) 4962(3) 5059(2) 2219(2) 41(1)C(12) −8180(4) 13925(3) 3718(3) 57(1) 5274(4) 5051(3) 3026(3) 52(1)C(13) −8205(5) 14628(3) 4276(3) 72(1) 5075(4) 4327(3) 3301(3) 65(1)C(14) −8062(5) 14622(3) 5082(3) 80(2) 4585(4) 3610(3) 2785(4) 72(1)C(15) −7852(4) 13918(4) 5334(3) 73(2) 4264(4) 3613(3) 1984(3) 70(1)C(16) −7809(4) 13217(3) 4783(3) 58(1) 4439(4) 4333(3) 1702(3) 55(1)


troscopic techniques, FTIR and SSNMR, revealed markeddifferences between the spectra of the two forms.The crystal structure of the form II was determined, and

after comparison with the published crystal structural ofform I, the results indicated similarities in terms of crystalsymmetry and molecular conformation. The crystal pack-ing of the dimers in the asymmetric units were differentin the two structures, with the dimers being further dis-

placed in form II. The solid-state transition of form II toI is thought to involve a molecular rearrangement of thesedimers.

References and Notes1. York, P. Int. J. Pharm. 1983, 14, 1-28.2. Haleblian, J.; McCrone, W. J. Pharm. Sci. 1969, 58, 911-

929.

Table 3sMean Values of the Interatomic Distances (Å) and Angles (deg) with Esd’s in Parentheses, of the Four Independent Molecules of theAsymmetric Unit of Chlordiazepoxide

form Ia form II form Ia form II

C(1)−N(2) 1.314(2) 1.323(6) C(7)−C(8) 1.383(2) 1.380(6)C(1)−C(10) 1.476(5) 1.478(6) C(8)−Cl 1.745(5) 1.747(5)C(1)−C(11) 1.477(4) 1.478(6) C(8)−C(9) 1.377(3) 1.389(6)C(2)−N(2) 1.478(2) 1.473(6) C(9)−C(10) 1.409(2) 1.414(6)C(2)−C(3) 1.510(3) 1.506(7) C(11)−C(12) 1.392(5) 1.393(7)C(3)−N(1) 1.299(2) 1.307(6) C(11)−C(16) 1.390(3) 1.395(6)C(3)−N(3) 1.339(2) 1.338(6) C(12)−C(13) 1.387(7) 1.389(8)C(4)−N(3) 1.438(2) 1.457(7) C(13)−C(14) 1.376(8) 1.382(7)C(5)−N(1) 1.384(2) 1.400(6) C(14)−C(15) 1.383(5) 1.383(8)C(5)−C(6) 1.414(2) 1.415(6) C(15)−C(16) 1.392(5) 1.389(8)C(5)−C(10) 1.417(2) 1.409(6) N(2)−O 1.310(3) 1.303(5)C(6)−C(7) 1.372(2) 1.378(7)

C(1)−N(2)−O 124.3(4) 123.9(4) C(6)−C(5)−C(10) 117.8(1) 118.4(4)C(1)−C(10)−C(5) 124.2(2) 124.6(4) C(7)−C(8)−Cl 118.6(4) 119.6(4)C(1)−N(2)−C(2) 120.5(5) 120.6(4) C(7)−C(8)−C(9) 121.8(3) 121.5(5)C(1)−C(11)−C(16) 118.8(5) 121.3(4) C(8)−C(9)−C(10) 119.9(1) 119.7(4)C(1)−C(11)−C(12) 122.3(5) 118.4(4) C(9)−C(8)−Cl 119.5(4) 119.1(3)C(1)−C(10)−C(9) 116.2(2) 115.8(4) C(10)−C(1)−C(11) 119.6(2) 120.3(4)C(2)−N(2)−O 115.2(3) 115.5(4) C(10)−C(1)−N(2) 120.6(3) 119.1(4)C(2)−C(3)−N(1) 122.4(3) 122.3(4) C(10)−C(5)−N(1) 126.1(2) 126.8(4)C(2)−C(3)−N(3) 116.7(3) 116.4(4) C(11)−C(1)−N(2) 119.8(1) 120.6(4)C(3)−N(3)−C(4) 121.3(3) 121.6(4) C(11)−C(12)−C(13) 120.1(4) 120.4(5)C(3)−N(1)−C(5) 120.0(3) 119.3(4) C(11)−C(16)−C(15) 120.8(3) 120.0(5)C(3)−C(2)−N(2) 106.8(3) 108.6(4) C(12)−C(13)−C(14) 120.6(1) 120.4(5)C(5)−C(6)−C(7) 122.2(2) 121.6(4) C(13)−C(14)−C(15) 120.1(3) 119.4(6)C(5)−C(10)−C(9) 119.5(1) 119.8(4) C(14)−C(15)−C(16) 119.5(1) 120.8(5)C(6)−C(7)−C(8) 118.8(3) 119.3(4) C(16)−C(11)−C(12) 118.7(3) 118.9(5)C(6)−C(5)−N(1) 115.8(1) 114.7(4) N(1)−C(3)−N(3) 120.9(2) 122.2(4)

a From Bertolasi et al. Acta Crystallogr. 1982, B38, 1768−1772.

Figure 10sFour molecules in the asymmetric unit of (a, left) form I (data from Bertolasi et al. Acta Crystallogr. 1982, B38, 1768−1772) and (b, right) form IIprojected on the plane ac.


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AcknowledgmentsThe support of the SERC and Pfizer Central Research UK for

a CASE award for D.S. for this work and the assistance of DavidApperley, IDL, University of Durham, U.K., and the SSNMRanalyses by SERC are acknowledged.

JS960385C


solid-state characterization of chlordiazepoxide polymorphs

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