conformaciones

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An Experimental and Theoretical Search for Polymorphsof Barbituric Acid: The Chal lenges o f Even LimitedConformational Flexibi l ity

Thomas C. Lewis, Derek A. Tocher, and Sar ah L. Price*

Dep ar tm en t of Ch em is tr y, U n iv ers it y Col leg e L on d on , 20 Gor d on S tr eet,L on d on W C1 H 0A J , U K

R eceiv ed N ovem ber 7, 20 03

ABSTRACT: An experimental study of barbituric acid found a new P21/c polymorph with two conformations ofbarbitur ic acid in t he a symmetr ic un it, one m olecule adopting an envelope conforma tion a nd t he other refining asplan ar . The new Form ii involves differen t h ydrogen bond acceptors to Form i. An a b initio conform at iona l ana lysisstudy foun d th at barbitu ric acid can change its envelope conforma tion by over 20 from plana r with a sm all energychange th at can be compensa ted for by pa cking forces, so tha t t he n ew Form ii is predicted to ha ve a lower lat ticeenergy than Form i. A computational search for minima in the lattice energy found many hypothetical structuresof barbituric acid within the energy range of possible polymorphism, with a variety of hydrogen bonding acceptorsand motifs. The search was found to be very sensitive to the assumed molecular structure of barbituric acid, sofurther plausible low energy variations in the molecular conformation would produce even more low energy crystalstructures. Thus, the combined experimental and theoretical studies show that barbituric acid can pack in such a

variety of low energy str uctur es th at furth er polymorphs s eem possible.

Introduction

Polymorphism , the ability of a compound t o crysta llizein more tha n one crystal stru cture, has been a focus ofresearch in both the pha rmaceutical industry an d theacademic scientific community over the past decade orso.1 Polymorph ism can affect th e melting point, solubil-ity, bioavailability, stability, and morphology of thesolid, so, for example, the pharm aceutical industryw ishes t o find a ll crys t a l s t ruct ures of a d rug indevelopment. A method for computationally predictingthe polymorphs of a given compound would th us gr eatlyaid ph ar maceut ical developmen t. However, despite overa decade of methodology development and faster com-puters, computational polymorph prediction still pre-sents a fundam enta l challenge. The two blind t ests ontheoretical crystal structure prediction 2,3 showed th atno one met hod or pr ogra m h as t he a bility to successfullypredict the crystal structures of several small, mainlyrigid, orga nic molecules. In deed, Gavezzotti4 and morerecently Dunitz5 have both concluded that theoreticalcrystal str uctur e prediction is still far from being a bleto predict polymorphs of a pa rticular compound given

just the molecula r diagr am.Although crystal structure prediction studies h ave

been carried out on a few hu ndr ed molecules,6 a m ajor

l imi tat ion to such studies i s the uncertainty as towhether more polymorphs exist . Indeed, a surveyshowed only 321 molecules 7 with more than one poly-morph are present in th e Cambridge Structural Data-base,8 despite other indications that a significant pro-portion of organic molecules are polymorphic.9 Hence,it is highly desira ble to combine a n experimen ta l search

with a computational search to aid our understanding

of polymorph pred iction.We have carried out a joint experimental and theo-retical study of the possible polymorphs of barbituricacid (1; Scheme 1), as a molecule where the sequenceof hydr ogen bond donors a nd t wo distin ct acceptors givespotent ial for a var iety of hydr ogen bondin g motifs. Whenbarbitur ic acid is subst ituted a t C* (1; Scheme 1), thisgives th e bar bitura te fam ily of hypnotic, sedative, andant iconvulsant dru gs, such as bar bital (2; Schem e 1) andphenobarbital (3, Scheme 1).

Polymorphism within th e bar biturat e family is wide-spread,10 with most barbiturate crystal structures hav-ing a carbonyl group that does not part icipate inhydrogen bonding.10 I t i s of fundamental interest ,

because of its relevance to the physiological activity,11as to whether the N-H OdC hydrogen bonds a risingfrom the barbiturate group are weak, or whether theoccurr ence of unu sed h ydrogen bonding a cceptors m erelyresults from packing limitations. The only reported12

crystal str ucture of barbituric acid (Form i) uses theunique a nd one of the n onu nique carbonyl acceptors inthe hydrogen-bonding m otif. Thus, comput ational a ndexperimenta l searches were carried out simulta neouslyto investigate the hydrogen bonding potential of thebarbiturate group.

* To whom correspondence should be addressed. Department ofChemistry, University College London, 20 Gordon Street, LondonWC1H 0AJ, UK; tel: +44 (0)20 7679 4622; fax: +44 (0)20 7679 7463;E-mail: [email protected]; Web: ht tp://www.chem.ucl.ac.uk/people/slprice/index.html.

S c h e m e 1

CRYSTAL

GROWTH

&DESIGN

2004

VOL.4,NO.5

979-987

10.1021/cg034209a CCC: $27.50 2004 American Chemical SocietyPublished on Web 03/19/2004


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Methods

Experimental . The experiment al sear ch for polymorphs ofbarbituric acid attempted crystallization by slow evaporationfrom a va riety of solvent s (water, met ha nol, ethan ol, acetone,acetonitrile, propanol, butan ol) at r oom tem perat ure a nd 0 C,and by varying the concentration and surface area of thesolution (Table 6 of the Su pporting Informat ion). Barbituricacid is only slightly soluble in chloroform and diethyl ether,so vapor-diffusion of these solvents into methanol, ethanol, andacetonitrile solutions was attempted to induce crystallization.

Powder diffraction pa ttern s were used to determine wheth era new solid form had been obtained.Crystal lography. Single-crystal X-ray diffraction data

collection wa s per form ed on a Bruk er SMART APEX diffrac-tometer equipped with graphite-monochromatized Mo-KRradiation ( ) 0.71073 ) and a nominal crystal-to-areadetector distan ce of 60 mm. The intensities were int egratedusing SAINT +13 and the absorption correction was a ppliedwith S ADABS.14 The stru cture was solved with direct methods(SHELXS97) an d refined against F2 (SHELX97).15 The hydro-gen atoms were either added geometrically and refined usinga riding model, or r efined independent ly. All non-hydrogenatoms were refined with a nisotropic displacement para meters.Details of the crystallograph ic data are given in SupportingInformation.

Computational. A gas phasemodel for the barbituric acid

molecule was obtained by optimization of the MP2/6-31G**energy using the program GAUSSIAN98.16 Correspondingwave functions were calculated for all the X-ray determinedmolecular st ructures, with t he N -H bond length elongated tothe s ta nda r d n e utr on va lue of 1 . 01 .17 I n e a c h c a se , adistributed multipole analysis (DMA)18,19 of th e ab initio chargedensit y of th e molecule was performed to provide an accurat edescr iption of the electrostatic contr ibution to the la tt iceenergy in th e rigid molecule crysta l stru cture m odeling. Theseatomic multipolar electrostat ic models aut omatically representthe electrostatic effects of lone pair and electron d ensity, andso give a realistic representa tion of the relative energies anddirectional preferences of hydrogen bonds.20,21

The m odel for the all t he nonelectrostat ic intermolecularcontr ibutions to th e latt ice energy was an empirical repu lsion-dispersion model of the form:

where atom i in m olecule 1 is of type , and atom k in molecule2 is of type . Parameters for a tomic types N, O, and H c(nonpolar) were taken from the work of Williams 22,23 and H Nfrom the derivation of the FIT potential24 where this DMA-based potential modeling scheme was extended to h ydrogenbonding crystals. The corresponding carbon repulsion poten-tials proved to be too repulsive for th e interplan ar packing,as alrea dy noted for para banic acid.25 Changing the parameterA CC to 277 180 kJ /mol was found to give a reasonable repro-duction of the crystal stru ctures of barbituric acid, para banic

acid, urazole, alloxan, and cyanuric acid.The hypothetical crystal structures for barbituric acid weregenerated by MOLPAK,26 which performs a systematic gridsearch on or ientations of th e r igid central molecule in 29comm on coordina tion geomet ries of orga nic molecules, belong-ing the space groups P1, P1h, P21, P21/c, Cc, C2/c, P21212,P212121, Pca 21, Pn a21, Pbcn , and Pbca , with one molecule inthe asymmetric unit. Approximately 50 densest packings ineach coordination type are then used as starting points forlattice energy m inimization by DMAREL27 using the DMA-based model potential. The m inimizations were constr ainedby the space group symmet ry, but if th is resulted in a n egativeeigenvalue of the second derivative matr ix, indicating at r a ns i t ion s ta te , the sym m e tr y wa s lowe r e d unt i l a t r ueminimum was found. The distinct low energy minima with in7 kJ /mol of the global minimu m were est ablished by consider-

ing the reduced cell parameters

28

(using PLATON

29

) a n dgraph-set an alysis30 -34 to establish the hydrogen bondingmotif.

Results

Single crystals of Form i of barbituric acid, of aplatelike morphology, were obtained from a saturatedsolution of ethanol crystall ized at 0 C in a sealedenvironment for several days. These were used toredetermine the crystal structure at 150 K (Table 3,Supporting Information) to give better data for thetheoretical modeling (Table 1).

The conformation of barbituric acid in Form i is anenvelope as previously reported12 (Figure 1a), with t he

U ) i1,k 2

(A A)1/2 exp(-(B + B)R ik/2) -

(CC)1/2

R ik6

Table 1. Comparison of the Unit Cell Dimensio ns ()b e t w e e n t h e P r e viou s 298 K12 an d N e w D e t e r m in ation(150 K) of the Fo rm i Crystal Structure of Barbituric

Acid

a () b () c () () V (3)

previous 12

298 K6.817(5) 14.310(5) 6 .248(5) 118 .57(1) 535 .284a

this work150 K

6.7305(18) 14.029(4) 6.2309(16) 116.368(4) 527.1(2)

a No ESD given.

F i g ure 1 . Thermal ellipsoid plots (50%) level of (a) thebarbituric acid molecule in Form i; (b) the molecules in theasymmetric unit of Form ii of barbituric acid, showing theplanar and the envelope conformations of the molecules; and(c) 5-isopropylidene-barbitu ric acid.

98 0 Crystal Growth & Design, Vol. 4, N o. 5, 2004 Lewis et al.


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crystal str uctur e consisting of infinite ribbons of pairsof hydrogen bonded molecules. In the new determinationof the Form i structure of barbituric acid, the perpen-dicular distance between parallel ribbons is approxi-ma tely 2.97 , compar ed to 3.03 rep orted p reviously.12

The closest approach between any pairs of atomsbetween th e par allel ribbons is 2.84 and 3.15 for th e

new and old structures, respectively. The hydrogenbonds are similar in length in both structures (Table2); however, in the lower temper atu re str uctur e, the twohydrogens involved in the hydrogen bonding are closerto planar with the r ing.

A new polymorph of barbituric acid (Form ii) wascrystallized, with platelike crystals with a prismaticha bit, by slow evaporat ion over a nu mber of weeks fromeither methanol or acetonitrile solution. Superior crys-tals were obtained from the slower crystallization fromacetonitr ile solution an d a typical one used in the crystalstru ctur e determina tion (Table 4, Supporting In forma -tion). Form ii contains two crystallographically inde-penden t molecules in th e asymm etr ic un it, one (A) with

the envelope conformation and the other (B) refiningas if planar (Figur e 1b).

The thermal ellipsoid on C(5B) (Figure 1b), associatedwith the planar conformat ion, is sl ightly elongatedperpendicular to the r ing. This suggests tha t a staticor a dynamic disorder is present in the crystal structure

Table 2. Comparison of the Hydrogen Bonding for Two Determinat ions of Form i , and Form i i of Barbituric Acid

h yd roge n b on ds () h yd roge n b on d a n gl es () gr a ph s et b hydrogen bond motif

form i12 N(1)O(2) 2.90(1) N(1)H(1)O(2) 155.9a C1, 1(6) in fin ite r ibbons, two molecules wide298K N(3)O(6) 2.80(1) N(3)H(3)O(6) 149.7a R2, 2(8)

R4, 4(16)Form i N(1)O(2) 2.8799(16) N(1)H(1)O(2) 169.9(18) C1, 1(6) in fin it e r ibbon s, t wo m olecu les wid e150 K N(3)O(6) 2.8561(16) N(3)H(3)O(6) 171.1(18) R2, 2(8)

R4, 4(16)Form ii N(1A)O(4B) 2.854(2) N(1A)H(1A)O(4B) 16 9(3) D1, 1(2) sh eet st ru ct ur e, wit h bot h

N(3A)O(6A) 2.807(2) N(3A)H(3A)O(6A) 17 4(2) C1, 1(6) m olecu les in t he a sym met ric

N(3B)

O(6B) 2.868(2) N(3B)H(3B)O(6B) 16 6(2) C1, 1(6) u nit con tr ibu tin g t o ea ch sh eetN(1B)O(4A) 2.833(2) N(1B)H(1B)O(4A) 17 0(2)

a No ESD given. b For the first three levels only. Calculated using PLUTO.35

Table 3. Angles and ab Init io Energies for Various Conformations of Barbituric Acid a

Exper imental Solid State Molecular Structures Gas Phase Optimized

Form i X-ray(envelope)

Form ii Aenvelope

Form ii Bplanar

Form ii planartransition stat e

minimumenvelope

angleb between mean planesC(6)C(5)C(4) a nd C(6)N(1)C(2)N(3)C(4) ()

14.094 22.627 1.244 0.044 21.107

dihedralb a ngle C(2)N(1)C(6)C(5) () 10.791 10.423 0.530 0.000 15.620dihedralb a ngle C(2)N(3)C(4)C(5) () 7.535 9.346 2.530 0.00 15.750relative energy E/kJ mol-1 9.689 10.670 20.924 1.185 0.000

a Relative ab initio energies calculat ed a t MP2/6-31G** level using Gaussian 98.16 The experimental structures had been adjusted forthe systemat ic foreshorten ing of bonds to hydrogen in X-ray st ructur es. b Atomic labeling shown in Figure 1a .

Table 4. Reproduct ion of the Known Crystal Structures , by Latt ice Energy Minimizat ion Using DMAREL27 a

X-ra y la t t ice energy minima X-ra y la t t ice ener gy minim a

crysta l st ructure For m i Form i For m i F orm ii Form ii For m ii

molecula r str uctur e expt opt expt opt + planar transition stat ea/ 6.7 31 6.9 35 (3.0 3%) 7.0 24 (4.35%) 8.083 8.019 (-0.79%) 8.142 (0.73%)b/ 14 .029 14. 223 (1.38%) 14. 148 (0.8 5%) 12. 583 12 .47 9 (-0.83%) 12.481 (-0.81%)c/ 6.2 31 6.0 19 (-3.40%) 6 .204 (-0 .4 3%) 9.76 4 9.99 8 (2.40 %) 1 0.08 0 (3.2 4%)/ 116 .368 116 .44 6 (0.07%) 117 .12 5 (0.65%) 96. 150 95.64 (-0 .5 3%) 9 5. 30 2 (-0.88%)cell volume/3 527.125 537.919 (2.05%) 548.757 (4.10%) 987.356 995.770 (0.85%) 1019.970 (3.30%)cell densit y /g cm -3 1.614 1 .582 (-1.98%) 1 .550 (-3.97%) 1.723 1.709 (-0.82%) 1.668 (3.19%)F valueb 20.1 26.7 14.9 30.0latt ice energy kJ/mol -103.672 -98.815 -110.704 -102.905

a The % errors between the associated X-ray structure and the lattice energy minima are shown in brackets. All lattice energy

minimizations used the same model potential ( the FIT potential22 -24

with the carbon repulsion potentials decreased by 25%). Theelectrostatic contribution to the lattice energy was obtained by summing all terms in the atom -atom multipole expansion 37 up to R-5,using Ewald summation for the charge -charge, charge-dipole, and dipole-dipole cont ribut ions an d direct summ at ion over entire m oleculeswhose centers were separa ted by up t o 15 for t he higher m ultipole inter actions. b Figure of shame36 defined a s F ) (/2)2 + (10x)2

+ (100a/a)2 + (100b/b)2 + (100c/c)2 + R2 + 2 + 2, where ) total r igid-body rotat ional displacement a fter m inimization ();x ) total r igid-body tra nslat ional displacement (); the other six ter ms depend on the changes in cell para meter s ( and ). The 0.5, 10,and 100 weighting factors bring the contributions from the different displacements to a comparable scale.

Figure 2 . The different conformations of barbituric acid incrystal structures and in ab initio calculations on the isolatedmolecule. Pink: Expt Form i; green: Expt F orm ii envelope(A); blue: Expt F orm ii planar (B); black: Expt dihydrateplanar;38 purple: Ab initio optimized; red: optimized tra nsitionstat e, modeling Form ii plana r.

Search for Barbituric Acid Polymorphs Crystal Growth & Design, Vol. 4, N o. 5, 2004 98 1


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of Form ii. However, th e C(6B)-C(5B) an d C(5B)-C(4B)bond lengths (1.485(3) and 1.489(3) , respectively)show no indication of the foreshortening normallyassociated with disorder.

In t he Form ii s t ruct ure of barbit ur ic acid , t hehydrogen bonding consists of sheets, with each moleculelying in the same sheet. The perpendicular distancebetween each hydrogen bonding sheet in the structureis a pproximately 2.91 , and the closest approachbetween any pa irs of atoms between t he sh eets is 2.84. Form i an d F orm ii have different hydrogen bondmotifs (Table 2) with the unique hydrogen bond acceptor

O(2) not involved in the hydrogen bonding in Form ii.This demonstra tes th at barbituric acid has the abili tyto use different hydrogen bond acceptors in its crystalstructures, like other barbiturates,10 implying no greatdifference in t he different acceptor str engths.

In addition, concomitant polymorphism was ob-served from the acetonitri le solution, with smallerplatelike crystals of Form i of barbituric acid formingon rapid evaporation. This was confirmed by powder

X-ray diffraction. This suggests that Form i is thekinetic structure while F orm ii is the thermodynamicform of barbituric acid. DSC results obtained fromcrysta ls of Form i only show a broad exoth erm between200 an d 270 C, consistent with decomposition of thesample.

Evaporation of an acetone solution of barbituric acidgave platelike crysta ls, with a bladed ha bit. Solving an drefining th e crysta l structu re of this sam ple showed that5-isopropylidene-barbituric acid had been formed (Fig-ure 1c) in a previously undocumented reaction. Fullcrystallograph ic data on the compound ar e available inTable 5, Supporting In forma tion.

The flexibility of barbituric acid was also apparent

from the ab initio calculations (Figure 2 and Table 3).Optimization at the MP2 level gave an envelope str uc-tur e, which was very similar to the en velope str uctureof molecule A in F orm ii. However, when th e molecula rstructure is optimized as a planar molecule, this resultsin a t ransi t ion state less than 1.2 kJ /mol above theoptimal envelope conformation. This small energy bar-rier suggests th at the var ious experimenta lly observedconform ations of bar bituric acid in t he crystal st ru ctures(Figure 2) have virtua lly the same intern al energy, towithin a few kJ/mol. Thu s, the a ctual observed envelopeconformation and related dynamical flexing motions canbe easily influenced by the cryst al pa cking. (The differ-ences in th e MP2 en ergies for th e experimenta l molec-

Figure 3 . Crystal str uctures of Forms i and ii of barbituricacid an d t heir reproduction by the comput ational model. (a)The F or m i e xper im enta l s t r uctur e a t 150 K (b la ck) i scontrasted with the lattice energy minimum (red) obtainedstarting from the experimental structure using the ab initiomolecular str ucture (ExptMinOpt ), and (b) th e Form ii experi-ment al str uctur e at 150 K (black) is contra sted with t he latt iceenergy minimum (red) obtained from the experimental stru c-ture using the ab initio envelope and transition state planar

molecular stru ctures.

Figure 4 . Plot of lattice energy against cell volume per molecule for all the structures corresponding to lattice energy minimafound u sing the gas pha se ab initio molecular str ucture for barbituric acid in th e MOLPAK search. The corresponding minimumfor t he experiment al str uctur e (ExptMinOpt) is shown for compar ison. The minima a re denoted by th e space group of the MOLPAKstar ting stru cture.



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ular stru ctures mainly r eflect experiment ally insignifi-cant variations in bond lengths, which can producesufficient changes in t he tota l electronic ener gy to ma skthe genuine conformational differences.)

The experimental crystal structures of the Form i andForm ii of barbitur ic acid a re adequately reproduced

by latt ice energy minimizations (Table 4) using theexperimental molecular structure and the DMA-basedmodel intermolecular potential. The 1.06% root-mean-squar e errors in th e cell lengths when compar ed to the150 K st ru cture of Form i , and 0.3% for the 298 Kstructure12 are well within the uncertainties associ-

Table 5. Low Energy Crystal Structures of Barbituric Acid a with the ab Init io Opt imized Molecular Structure

reduced cell parametersc

structurespacegroup

latticeenergy

kJ mol-1

freeenergyb

at 298 KkJ mol-1

densityg cm -3 a/ b/ c/ angle s/

hydrogenbondd

acceptorsand motif

Expt 298 K P21/c 1.589 6.248 6.691 14.310 11 6.5 2 O 2,O 4 in fin it e r ib bon sof dimers


ExptMinOpt P21/c -98.815 -113.89 1.550 6.204 6.935 14.148 11 5.6 4 O 2,O 4 in fin it e r ib bon s

of dimersAM14 P21/c -105.027 -117.76 1.711 4.470 9.779 11.517 98.97 O2,O6 cha insFC11 P21/c -104.277 -116.46 1.709 6.482 8.000 10.141 R 1 08 .8 3 O 2,O 4, O6 3 D n e twor kFC32 P21/c -102.610 -115.23 1.662 6.485 7.825 10.542 R 1 06 .8 7 O 2,O 4, O6 s h ee tsAQ30 P212121 -102.302 -116.08 1.657 6.371 7.543 10.681 O2,O6 3D networkAM42 P21/c -102.010 -116.09 1.663 6.048 6.955 12.685 106.50 O4,O6 sh eet sCA25 P1h -101.635 -114.62 1.636 5.265 5.430 9.276 R 90.11 O2,O6 in fin it e r ibbon s

96.57 of dim ers 99.23

AQ28 P212121 -101.586 -113.77 1.713 5.903 7.000 12.021 O2,O4,O6 3D networkAQ13 P212121 -101.433 -115.07 1.687 4.507 10.310 10.852 O2,O6 ja gged sheetsFC38 P21/c -101.300 -114.05 1.705 4.742 6.234 16.884 91.778 O4,O6 sh eet sBB2_39sg P n m a -101.096 -115.46 1.754 5.090 7.627 12.494 O2 cha insAK30sg P21 -100.932 -114.10 1.651 6.719 7.041 10.896 R 90.73 O2,O6 3D n et wor kDE27sg P21/c -100.927 -113.77 1.632 6.837 12.387 12.571 R 101.61 O4 cha insAH39sg P1h -100.849 -113.18 1.619 4.650 6.334 9.703 R 108.39 O4,O6 ch ain s

99.67 97.00

CD12sg P21/c -100.655 -114.00 1.711 8.202 10.150 12.191 101.60 O2,O6 ch ain sDA39 Cc -100.605 -111.29 1.624 6.858 7.950 9.610 R 91.50 O4,O6 sheetsCD26 Pbcn -100.244 -113.91 1.734 8.255 10.723 11.070 93.02 O2,O6 ja gged sh eet sAF39 P21 -99.780 -111.58 1.717 4.968 6.183 8.350 105.20 O4,O6 sh eet sAI36 P21/c -99.652 -113.26 1.646 6.899 8.601 8.726 R 93.72 O4,O6 sheetsCA26 P1h -99.404 -111.28 1.700 6.398 6.675 7.021 R 108.95 O2,O6 ch ain s

103.48 108.18

CA48 P1h -99.367 -111.76 1.967 5.816 7.082 7.208 R 104.20 O2,O4 ch ain s 107.01 108.14

AM49 P21/c -99.362 -114.307 1.620 6.120 6.877 12.619 98.44 O4,O6 sheetsCA18 P1h -99.318 -113.213 5.357 6.510 7.969 R 92.88 O2,O6 in fin it e r ibbon s

96.36 of dim ers 108.93

CB38sg P21/c -99.296 -113.831 1.628 7.624 10.975 12.897 104.34 O2,O6 3D n et wor kFA31 P21/c -99.202 -112.548 1.682 4.947 6.262 17.062 106.83 O2,O4 ja gge d s hee tsAI40 P21/c -99.158 -112.163 1.607 6.851 8.386 9.216 R 96.69 O4,O6 sheetsAI20 P21/c -99.143 -112.186 1.645 9.776 7.744 7.021 76.63 O4,O6 sheetsAQ19 P212121 -99.086 -113.288 1.615 6.151 6.829 12.541 O4,O6 sheetsAM 8 P21/c -98.876 -113.275 1.598 6.619 7.168 12.354 114.69 O4,O6 ch ain sFC21 P21/c -98.83 -113.283 1.684 4.750 5.211 20.425 R 91.95 O2,O4 ja gged sh eet sCD20 Pbcn -98.488 -111.806 1.748 7.860 10.921 11.339 O2,O4,O6 3D net workAQ6 P212121 -98.342 -111.524 1.616 4.983 8.695 12.150 O4,O6 cha insDE23 C2/c -98.244 -110.571 1.644 4.431 12.956 20.411 R 107.43 O2,O6 ja gge d s hee tsDE 8 C2/c -98.178 -110.469 1.648 7.483 9.734 14.323 R 98.44 O4,O6 sheetsBD15 Pn a21 -98.165 -111.407 1.662 4.777 6.637 16.145 O4,O6 3D networkCC11 Pbca -98.119 -111.549 1.652 6.853 7.781 19.318 O4,O6 ja gged sheetsAY2_32sg P21 -98.045 -111.663 1.649 12.052 6.225 6.730 106.20 O4,O6 ch ain s

a All calculat ed stru ctures a re latt ice energy minima calculated with the gas ph ase ab init io molecular m odel of barbitu ric acid and t hesame interm olecular potential. The h ypothet ical structur es ar e labeled according to the initial MOLPAK coordination geometr y and orderof density, with sg denoting a m inimum tha t r equired a lowering of the original spa ce group symm etry. b The Helmh oltz free energy asestimated from the lattice energy, zero point intermolecular energy, and temperature dependence of the rigid molecule internal energyand en tropy, as derived from the k ) 0 second der ivative properties.40 c The Niggli reduced cell paramet ers 28 as calculated by PLATON29

are given for comparison. Only the redu ced cell angles which are n ot 90 are ta bulated. d O2 is the unique h ydrogen bond acceptor, th ecutoff for defining hydrogen bonds is 2.5 .



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ated39 with thermal effects in comparing a 0 K latticeenergy minimum with a finite temperat ure st ructure.The crystal structures are still reasonably well repro-duced when the molecular structures are replaced bythe ab init io optimized envelope structure in Form i(1.06% rms error) and Form ii (molecule A) and planartransit ion state structure for molecule B in Form ii(Figure 3). This is despite th e 7 differen ce between th eexperimental and ab initio envelope conformations inForm i (Figur e 2).

The calculated lattice energies (Table 4) show thatForm i i is more stable tha n Form i , by a margin of

between 4 a nd 10 kJ /mol, depending on th e molecularmodel. Since the intra molecular energy loss for Formii, for having half its molecules planar, appears to beless than 1 kJ /mol from the a b initio estima tes, the total0 K energy (Et ot ) Ulattice + Eintra) still favors F orm ii.This agrees with the supposition from the experimentalsearch th at F orm i is the kinet ic str ucture, while Formii is t he t herm odynam ic form. Since th e plana r confor-mat ion of half th e molecules in Form ii is producing amore sta ble crysta l lattice, the m olecule th at refines a splanar could actually be planar.

The m olecula r flexibility of bar bitu ric acid also affectsthe t heoretical sear ch to see whether a ny energeticallyfeasible crystal s tru ctures could be predicted a s poten-

tial polymorph s. A search for crystal str uctures corr e-sponding to minima in t he lat tice energy, using th e rigidab init io gas-phase molecular structure should havefound t he minimu m corr esponding to Form i str ucture(ExptMinOpt), but failed t o do so. However, as Figure4 and Table 5 show, the search found many crystalstru ctures within th e 6.2 kJ /mol ran ge in latt ice energybetween ExptMinOpt and the global minimum. Thesecond computa tional sear ch with t he r igid Form i solid-sta te molecular str uctur e, also failed to find th e minimacorr esponding to Form i (ExptMinExpt). However, asFigure 5 and Table 6 demonstrate, the energy gapbetween the observed Form i and t he global minimumhas reduced to 2.8 kJ/mol, al though there are st i l l a

variety of different crystal s t ru ctures that appearslightly more st able tha n Form i. Thu s th e 7 differen cein th e envelope conform at ion h as a significant effect onthe predictions.

Despite t his difference in th e relative energies, thereare still considerable similarities between the crystalstru ctures found in t he two searches. For example, theglobal min ima in th e two sear ches (AM14 Table 5, AM16Table 6) are essent ial ly the same crystal s t ructure,differing primarily in the molecular envelope angle.Both searches find low energy structures in which allthe carbonyl groups act as hydrogen bond acceptors,

st ructures that use one unique and one nonuniqueacceptor (as in Form i) and structures in which only bothnonun ique car bonyls act as hydrogen bond acceptors (asin Form ii).

Which of these low energy st ructures are potentialpolymorph s? Using estimat es of the h ar monic motionsof th e rigid molecules within the different crystalst ructures, the room temperature free energy gapbetween Form i and the hypothet ical s t ructures i sreduced to about 4 kJ/mol for the optimized molecularstru cture an d 1 kJ /mol for the experimenta l molecularstructure. The changes in the intramolecular motionsof th e molecules in differen t crysta l lattices might ma ke

an even more significant energetic contribution, giventhe low barrier for large changes in the envelopeconformation. The majority of crystal structures inTables 5 and 6 have elastic constants typical of organicmolecules.41 However, many of the hydrogen-bondedsheet s tru ctures (FC32, AI40, and AM49 from Table 5and AQ17, AI29, AQ45, and DD44 from Table 6) arepredicted to have a low resistance to shearing forces.This may imply tha t t he crystallites would be un likelyto grow. Thus, using this level of modeling the thermo-dynamic and kinetic factors involved in determiningorganic crystal structures, we can only eliminate aminority of the low energy crysta l stru ctures a s un likelyto be observed.

Figure 5 . Plot of lattice energy against cell volume per molecule for all the structures corresponding to lattice energy minimafound using the solid-state experimental Form i molecular structure for the barbitur ic acid in the MOLPAK search. Thecorresponding minimum for the experimental structure (ExptMinExpt) is also shown for comparison. The minima are denoted bythe spa ce group of the MOLPAK star ting stru cture.



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Table 6. Low Energy Crystal Structures of Barbituric Acid a Using the Experimental Form i molecular s tructure

reduced cellc

structurespacegroup

latticeenergy

kJ mol-1

freeenergyb

at 298 KkJ mol-1

densityg cm -3 a/ b/ c/ angle s/

hydrogenbondd

acceptorsand motif



ExptMinExpt P21/c -103.672 -118.03 1.582 6.092 6.897 14.223 11 5.8 1 O 2,O 4 in fin it e r ib bon s

of dimersAM16 P21/c -106.473 -119.12 1.784 4.494 9.629 11.158 99.12 O2,O4 chainsFC23 P21/c -105.549 -117.83 1.774 6.249 7.958 10.277 R 110.21 O2,O4,O6 3D networkAM2_30 sg P1h -105.381 -117.96 1.729 5.204 10.000 10.625 R 67.02 O4,O6 sheets

R 86.05 75.29

AZ42 P212121 -104.555 -118.02 1.771 6.733 7.003 10.542 O2,O4 3D networkAK38 P21/c -104.510 -117.08 1.772 6.224 7.913 10.360 R 109.79 O2,O4,O6 3D networkAQ22 P212121 -104.343 -116.55 1.774 5.808 6.925 11.927 O2,O4,O6 3D networkAB17 P1h -103.839 -116.39 1.710 5.235 5.349 9.070 R 91.26 O2,O4 in fin it e r ibbon s

96.00 of dimers 99.68

AQ32 P212121 -103.837 -117.17 1.756 4.870 9.850 10.100 O2,O4 ja gged sheetsAQ27 P212121 -103.775 -117.14 1.765 4.588 10.215 10.284 O2,O6 ja gged sheetsAK31 P21/c -103.735 -117.41 1.821 5.053 7.566 12.223 R 90.01 O2 chainsDB2_16 sg P1 -103.694 -116.10 1.710 6.825 8.107 10.036 R 110.8 O2,O6 in fin it e r ibbon s

105.3 of dimers 90.37

AB10 P1h -103.687 -117.08 1.718 5.277 6.323 7.914 R 93.44 O2,O4 in fin it e r ibbon s 97.02 of dimers 108.27

DD2_34 sg P1h -103.680 -117.42 1.710 6.825 8.108 9.036 R 92.97 O2,O4 in fin it e r ibbon s 94.64 of dimers 90.41

AB40 P1h -103.574 -116.041 1.71 5.291 5.325 8.998 R 94.61 O2,O6 in fin it e r ibbon s 90.19 of dimers 99.98

DA29 Cc -103.126 -113.658 1.704 6.773 7.88 9.356 R 91.30 O4,O6 sheetsAZ47 P212121 -102.652 -116.302 1.789 4.907 5.014 19.332 O2,O4 infin ite r ibbons

of dimersFC40 P21/c -102.635 -116.429 1.772 4.793 5.029 19.935 R 92.39 O2,O4 ja gged s heet s

FC18 P21/c-

102.588-

115.262 1.759 4.884 5.982 16.561 90.97 O4,O6 ja gged s heet sFC32 P21/c -102.528 -115.936 1.69 6.362 7.731 8 10.61 R 1 06 .1 8 O 2,O 4, O6 s h ee tsAK21 P21/c -102.512 -116.048 1.716 6.799 8.23 8.868 R 92.49 O4,O6 sheetsFA43 P21/c -102.230 -115.341 1.767 4.862 6.174 16.706 10 6.2 4 O 2,O 6 in fin it e r ib bon s

of dimersFA33 P21/c -102.015 -114.824 1.75 4.636 6.413 16.385 93.27 O4,O6 ja gged s heet sDA2_45 sg P1 -101.924 -111.982 1.792 4.985 10.127 10.207 R 72.49 O4,O6 chains

77.82 78.34

AM40 P21/c -101.780 -116.10 1.737 6.209 7.095 12.333 115.65 O4 chainsDC32 C2/c -101.745 -115.78 1.630 6.049 12.294 14.376 R 1 02 .5 1 O 2,O 4 in fin it e r ib bon s

of dimersAQ17 P212121 -101.681 -116.37 1.764 6 .157 7.397 10.592 O4,O6 sheetsAK24 P21/c -101.618 -114.82 1.776 6.661 7.164 10.255 101.74 O2,O6 ja gged s heet sAM19 P21/c -101.570 -115.02 1.787 4.118 9.810 11.822 94.53 O2,O6 chainsAI32 P21/c -101.425 -115.77 1.775 6.138 7.395 10.576 93.32 O4,O6 sheetsAK20 P21/c -101.392 -113.58 1.773 5.635 8.412 10.737 R 109.46 O2,O6 3D n et wor k

AF28 P21 -101.380 -113.22 1.770 5.009 6.056 8.215 105.40 O4,O6 sh eet sAI29 P21/c -101.380 -114.44 1.683 6.763 8.100 9.226 R 90.52 O4,O6 sheetsAB26 P1h -101.265 -113.44 1.710 4.804 6.117 9.169 R 106.27 O4,O6 ch ain s

99.86 99.04

BD9 Pn a21 -101.108 -113.81 1.750 4.845 6.449 15.555 O4,O6 3D networkCB25 Pbca -101.056 -114.06 1.738 7.265 8.099 16.638 O4,O6 ja gged sheetsAQ45 P212121 -101.013 -115.79 1.681 6 .088 6.745 12.326 O4,O6 sheetsCA36 P1h -100.914 -113.57 1.739 5.483 6.334 7.897 R 77.63 O2,O4 chains

77.43 67.45

AQ18 P212121 -100.554 -113.93 1.777 5.106 5.505 17.036 O4,O6 3D networkAI34 P21/c -99.989 -113.65 1.753 6.107 8.963 9.658 R 113.13 O2,O6 ja gged s heet sCD35 Pbcn -99.830 -113.40 1.814 7.809 10.644 11.287 O2,O4,O6 3D networkDE47 C2/c -99.775 -112.36 1.736 5.073 12.026 16.094 R 92.84 O2,O6 ja gged s heet sDD44 C2/c -99.626 -112.24 1.770 6.232 10.383 14.883 R 93.63 O2,O6 ja gged s heet s



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Conclusions

The discovery of Form ii of bar bitur ic acid is s ignifi-

cant , because it uses different h ydrogen-bond a cceptorsfrom Form i. I t i s a l so unusual i n t ha t i t has t w oconformat ions of bar bitur ic acid in t he as ymmetr ic un it,and seems to be the thermodynamically more stableform. The thermal ellipsoids on the molecule that refinesas planar suggests static or dynamic disorder within thecrystal structure of Form ii of barbituric acid. The abinitio calculations show tha t a plana r m olecular str uc-ture forms a tran sit ion state between two equivalent20 envelope conforma tions, with a very low energybarrier of a few kJ /mol. The rigid-molecule crystalstru cture modeling using a planar and envelope molec-ular st ructur es show tha t the improved interm olecularinteractions in Form ii more than compensate for the

intramolecular energy required for a planar molecule.Hen ce, it is plau sible th at F orm ii ma y contain a pla na rmolecule, and the thermal ellipsoids indicate genuinevibrations. Barbituric acid is also planar in the di-hydrate crystal s t ructure,38,42 al though the thermaldisplacement parameters also show evidence of theflexibility within t he molecular stru cture of barbitu ricacid observed in Form ii.

The flexibility of bar bitur ic acid, observed in both itspolymorphs and the gas phase model ing, has beenshown to ha ve a major effect on t he rela tive energies ofthe hypothetical low-energy crystal st ru ctures found inthe search. The key finding is that there are a widevariety of crystal structures that are very similar in

energy, which differ in their hydrogen-bonding motifsand acceptors. Thus, i t i s unl ikely that there i s asignificant difference in the hydrogen-bonding abilityof the unique a nd equivalent carbonyls.

Although we h ave foun d a large nu mber of low ener gycrystal str uctur es of bar bitur ic acid in th e searches withtwo molecular conform at ions (Tables 5 an d 6), th ere a relikely to be man y more, given th e ra nge of conforma tionsth at could be adopted, an d the limitat ions of th e search.Dealing comput ationally with Form ii was outside thecapabilities of the sear ch due to ha ving t wo moleculesin the asymmetric unit, let alone one of them being aplana r conformat ion. The sear ches, alth ough limited bythe standards of most current crystal structure predic-

tion work, should ha ve foun d Form i. The failure m ayar ise from using MOLPAK to genera te densely packedstructures as start ing points for the search, as F orm i

(as represented by ExptMinExpt or ExptMinOpt) issignificantly less dense than the lower energy crystalstructures. This density difference may mean that therelative energy ordering may be changed by plausiblevariations in the model intermolecular potential (par-ticular ly the disper sion coefficients ) or bet ter modelingof both intra- and intermolecular contributions to theroom temperatur e energy.

Even though only one new polymorph of barbituricacid was found in th e labora tory, the sear ches indicatetha t t here could be more potential polymorphs. Indeed,preliminary results with a high-throughput roboticscreen 43 are promising. Nevertheless, experimentally

establishing a nd understa nding the polymorphism ofbarbitur ic acid will provide a major challenge to com-puta tional polymorph prediction.

A cknow ledgment . We would like to tha nk MiguelCalles, Matt P eterson, and Orn Almar sson of Tra nsformPharmaceuticals Inc. for some collaborative discussions,and Marianne Odlyha for the DSC analysis . Thisresearch was supported by EPSRC funding for T.C.L.and was a preliminary to a Ba sic Techn ology Programon polymorphism, funded by the Research Councils U.K.

Supp orting Information Available: A compar ison of th egeometrical par ameters for the different conformat ions ofbarbitur ic acid found in the crystals structures (Table 1) ,selected bond lengths and angles of 5-isopropylidene-barbituricacid (Table 2), th e crystallographic dat a for Form i anh ydrousbarbituric acid (Table 3), Form ii of barbituric acid (Table 4)and 5-isopropylidene barbituric acid (Table 5). The experi-mental crystallization conditions considered in the search(Table 6). X-ray cryst allogra phic files (CIF) are available forForm i an d Form ii of barbituric acid, an d 5-isopropylidenebarbituric acid. This mat erial is a vailable free of char ge viathe Intern et a t htt p://pubs.acs.org.

R eferences

(1) Bernstein, J. Polymorphism in Molecular Crystals; OxfordScience Publications: New York, 2002.

Table 6 (Cont inued)

reduced cellc

structurespacegroup

latticeenergy

kJ mol-1

freeenergyb

at 298 KkJ mol-1

densityg cm -3 a/ b/ c/ a ngle s/

hydrogenbondd

acceptorsand motif

AV2_37 sg Pc -99.445 -113.72 1.817 6.549 7.539 10.182 111.32 O2,O6 3D n et wor kDD31 C2/c -99.338 -113.83 1.678 6.865 7.633 19.345 R 90.9 O2,O4 in f in it e r ibbon s

of dimersAM24 P21/c -99.291 -113.37 1.750 5.156 7.541 12.505 90.50 O2,O4 3D net workDE2_14 sg P21/c -99.275 -114.48 1.734 4.817 10.163 20.408 R 100.71 O2 dimers

AI42 P21/c-

99.175-

114.57 1.693 6.452 6.821 11.501 96.84 O2,O6 r ibbonsAP2_36 sg P21 -99.085 -113.01 1.729 6.896 7.074 10.348 R 102.89 O2,O6 ja gged s heet sCA14 P1h -99.058 -111.876 1.775 5.509 7.026 7.292 R 100.28 O2,O4 ch ain s

106.92 110.77

a All calculated st ructures are lat tice energy minima calculated with the F orm i solid-stat e molecular model and the same intermolecularpotential. The h ypothet ical structu res a re labeled a ccording to the init ial MOLPAK coordinat ion geometry a nd order of density, with sgdenoting a minimu m t hat required a lowering of the original space group symmetry. b The Helmholtz free energy as estimated from thelatt ice energy, zero point interm olecular energy and tempera tur e dependence of the r igid molecule intern al energy an d entr opy, as derivedfrom the k ) 0 second derivative properties.40 c The Niggli reduced cell param eters 28 as calculated by PLATON29 ar e given for compa rison.Only the reduced cell angles which are not 90 are ta bulated. d O2 is the unique hydrogen bond acceptor, the cutoff for defining hydrogenbonds is 2.5 .



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