Controlled Synthesis of New 5‑Fluorocytosine Cocrystals Based onthe pKa RuleCeciacutelia C P da Silva Rebeka de O Pepino Cristiane C de Melo Juan C Tenorio and Javier Ellena

Instituto de Fiacutesica de Sao Carlos Universidade de Sao Paulo CP 369 13560-970 Sao Carlos Sao Paulo Brazil

S Supporting Information

ABSTRACT 5-Fluorocytosine (5-FC) was investigated forthe controlled synthesis of cocrystals by applying the pKa ruleFive cocrystals were designed and developed with adipicsuccinic terephtalic benzoic and malic acids all exhibitingnegative ΔpKa values ranging from close to zero up to roughlyminus1 The synthesized cocrystals were analyzed by single crystalX-ray diffraction and the observed supramolecular synthonswere compared to the reported structures containing 5-FC Inthe first four cocrystals the intermolecular interactionsbetween adjacent 5-FC molecules form two different homodimers showing R2

2(8) motifs and assembled via complementaryNminusHmiddotmiddotmiddotO and NminusHmiddotmiddotmiddotN hydrogen bonds respectively However in the cocrystal with malic acid (ΔpKa = minus01) an intermediatesupramolecular synthon pattern between salts and cocrystals is observed In this crystal packing the homodimer of 5-FCmolecules held by the NminusHmiddotmiddotmiddotO interactions is preserved but a new heterodimer is formed between 5-FC and the acid moleculesuch as the ones observed for 5-FC salts These differences were analyzed using UNI Force Field Calculations to establish theintermolecular potentials of the synthons As an application we synthesized a cocrystal of 5-FC with 5-fluorouracil This can beconsidered the first step toward the application of 5-FC for the design of new tailor-made drugs

1 INTRODUCTION

Crystal engineering and supramolecular chemistry are emergingissues in active pharmaceutical ingredients (APIs) Achievingthe ability to explore and predict the occurrence of noncovalentinteractions among APIs and other molecules such as solventsacids bases and other substances recognized as safe (GRAS)for the rational design of pharmaceutical products in the solidstate exhibiting improved physical and chemical properties is achallenge to scientists Among the solid forms that an API mayexhibit the class of pharmaceutical cocrystals is noteworthy iesolid pharmaceutical compounds containing at least onemolecular API and at least one solid nontoxic cocrystal former(usually a GRAS compound) interacting with one anotherthrough unique binding interactions it is a hard task to predicthow the API(s) and the coformer(s) will interact to each otherThis class has presented increasing interest in the last few yearsdue to its immense ability to form new compounds that do notalter the pharmacological activity of the API but may improveits physical properties not being restricted to binarycompounds once ternary and quaternary cocrystals may bedesigned1minus7

By considering that cocrystal formation is not obvious (it is aresult of a supramolecular study and synthesis) beyond the factthat pharmaceutical cocrystals have utility (may improve thephysical properties of an API) and are considered a novelcompound (possesses a new chemical composition and anunpredictable chemical bonding) they are subject to patentsThis possibility opens the door to new commercialopportunities for an API offering to the pharmaceutical

industries the benefits of generating a new and exclusive patentupon a new chemical compound or even of maintaining andextending its exclusivity by covering beforehand new solidforms In this sense the patent can encompass not only theinitial chemical compound but also its cocrystals through thecreation of a solid-form patent portfolio As advantage the pathto patent a cocrystal can be abbreviated in some aspectsconsidering that issues such as toxicology and discovery do notneed to be extensively evaluated89

5-Fluorocytosine (4-amino-5-fluoro-12-dihydropyrimidin-2-one 5-FC Scheme 1) was synthesized in 1957 as an

antimetabolite drug to be used as an antitumor agent It wasfound to exhibit activity against fungal infections and wasreleased for this use in 1968 By the discovery of its mechanismof action ie conversion into 5-fluorouracil (5-FU) bydeamination performed by the enzyme cytosine deaminase(CD)natural in fungal cells5-FC is being recently

Received April 11 2014Revised July 3 2014Published July 14 2014

Scheme 1 Molecular Structure of 5-FC

Article

pubsacsorgcrystal

copy 2014 American Chemical Society 4383 dxdoiorg101021cg500502j | Cryst Growth Des 2014 14 4383minus4393

employed in gene-directed enzyme prodrug therapy (GDEPT)to treat cancer Concerning pharmacokinetics toxicity anddrug interactions 5-FC is a BCS class I drug of small size highsolubility in water and high permeability (bioavailability of 76minus 89) It exhibits minor side effects although hepatotoxicityand bone marrow depression may occur Nevertheless normalmammalian cells do not express CD and are resistant to thisdrug such that over 90 of it is eliminated unchanged in theurine10minus12

The first crystal structure of 5-FC deposited in theCambridge Structural Database (CSD)13 was a monohydratereported in 198214 Since then 30 five crystal structures werereported in the literature including two polymorphs15 sixhydrates15minus18 four solvates1517 10 salts19minus22 and 13cocrystals23minus25 Nineteen of them crystallize in the monocliniccrystalline system 12 in the P21c (four hydrates four salts onesolvate and three cocrystals) four in the P21n (two salts onesolvate and one polymorph) two in the Cc (one hydrate andone cocrystal) and one in the C2c (one cocrystal) spacegroups Twelve crystallize in the triclinic P1 space group (twohydrates one solvate and nine cocrystals) and one in thetetragonal P41212 space group (polymorph) From thesenumbers it is possible to observe that neutral state ispredominant for this fluoropyrimidine Furthermore it isworth noting that three salts and eight cocrystals have solventsintroduced into the crystalline arrangement20minus222425

In our previous work22 we discussed salt formation by the 5-FC molecules on the basis of a saltcocrystal continuumstudy2627 As a follow-up to these studies here we discuss thesupramolecular synthesis of five cocrystals of 5-FC containingadipic succinic benzoic tereftalic and malic acids as coformersaiming to add information to the saltminuscocrystal continuumstudy to improve understanding of 5-FC drugminusreceptorinteractions and especially to understand the controlledsynthesis of cocrystals On the basis of the supramolecularpatterns established by these 5-FC cocrystals we were able todesign and synthesize a cocrystal involving two APIs 5-FC and5-FU an antineoplastic drug

2 EXPERIMENTAL SECTIONAll reagents were used without additional purification

21 Cocrystals Supramolecular Synthesis Stoichiometricamounts of 5-FC (Sigma-Aldrich Brazil) with succinic adipic benzoicterephtalic and malic acids and 5-FU were employed using water asthe solvent The solutions were filtered through a 045 μm filter(Milipore) and maintained at room temperature semicovered byParafilm until complete slow evaporation of the solvent The resultingcrystals were selected for single crystal X-ray diffraction experiments

22 Single Crystal X-ray Structure Determination Thecrystallographic data for the cocrystals of 5-FC with adipic succinicand terephtalic acids were collected on a Bruker Super-Duo APEX IICCD diffractometer using MoKα radiation (071073 Aring) For thecocrystal of 5-FC with 5-FU Cu Kα radiation was used (154178 Aring) in

Table 1 Crystallographic Data for the 5-FC Solid Forms S T A M B and 5-F

Form S Form A Form T

C4H4FN3O 12 C4H6O4 C4H4FN3O 12 C6H10O4 C4H4FN3O 12 C8H6O4

space group P1 space group P1 space group P1a (Aring) = 49209(3) a (Aring) = 52742(5) a (Aring) = 36265(3)b (Aring) = 86115(5) b (Aring) = 66650(7) b (Aring) = 95274(8)c (Aring) = 94689(6) c (Aring) = 128441(13) c (Aring) = 137902(12)α (deg) = 72466(3) α (deg) = 86411(6) α (deg) = 107812(5)β (deg) = 75129(3) β (deg) = 80757(6) β (deg) = 92036(4)γ (deg) = 89747(3) γ (deg) = 71970(6) γ (deg) = 96844(4)V (Aring3) = 36864(4) Aring3 V (Aring3) = 42372(7) Aring3 V (Aring3) = 44909(7) Aring3

Z = 2 Z = 2 Z = 2ρcalc = 1695 gcm3 ρcalc = 1585 gcm3 ρcalc = 1569 gcm3

2572 unique reflns 1624 unique reflns 2602 unique reflnsR(int) = 00219 R(int) = 00280 R(int) = 00302θmax = 2500deg θmax = 2580deg θmax = 2750degR1[Igt2σ(I)] = 00381 R1[Igt2σ(I)] = 00476 R1[Igt2σ(I)] = 00449wR2 = 01153 wR2 = 01322 wR2 = 01131S = 1103 S = 1122 S = 1078

Form M Form B Form 5F

C4H4FN3O C4H6O5 C4H4FN3O C7H6O2 C4H4FN3O C4H3FN2O2

space group C2c space group P21n space group P21ca (Aring) = 208980(4) a (Aring) = 90565(2) a (Aring) = 150176(3)b (Aring) = 148590(9) b (Aring) = 54318(2) b (Aring) = 35604(1)c (Aring) = 7244(1) c (Aring) = 228887(8) c (Aring) = 273113(4)β (deg) = 107178(3) β (deg) = 92870(1) β (deg) = 138282(1)V (Aring3) = 21491(4) Aring3 V (Aring3) = 112455(6) Aring3 V (Aring3) = 97178(4) Aring3

Z = 8 Z = 4 Z = 4ρcalc = 1639 gcm3 ρcalc = 1484 gcm3 ρcalc = 1772 gcm3

2451 unique reflns 2306 unique reflns 1628 unique reflnsR(int) = 00547 R(int) = 00252 R(int) = 00284θmax = 2749deg θmax = 25242deg θmax = 66685degR1[Igt2σ(I)] = 00729 R1[Igt2σ(I)] = 00482 R1[Igt2σ(I)] = 00312wR2 = 01853 wR2 = 01212 wR2 = 00841S = 1010 S = 1035 S = 1069

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the same equipment X-ray diffraction data collection (φ scans and ωscans with κ offsets) for the cocrystals of 5-FC with malic and benzoicacids were performed on an Enraf-Nonius Kappa-CCD diffractometer(95 mm CCD camera on κ-goniostat) using graphite-monochromatedMoKα radiation (071073 Aring) For refinement details28minus34 see theSupporting InformationIn all cases the programs MERCURY (version 23)35 and ORTEP-

336 were used also within WinGX v1700132 to prepare thecrystallographic information file (CIF) and artwork representationsfor publicationThe CIFs of the three 5-FC cocrystals were deposited in the

Cambridge Structural Data Base under the codes CCDC 933072(cocrystal of 5-FC with adipic acid) CCDC 933073 (cocrystal of 5-FCwith succinic acid) CCDC 933074 (cocrystal of 5-FC with terephtalicacid) CCDC 991413 (cocrystal of 5-FC with 5-FU) CCDC 991431(cocrystal of 5-FC with malic acid) and CCDC 991584 (cocrystal of 5-FC with benzoic acid) Copies of these files may be solicited free ofcharge from The Director CCDC 12 Union Road Cambridge CB21EZ UK fax + 44123minus336minus033 e-mail depositccdccamacuk orhttpwwwccdccamacuk

3 RESULTS

31 Structure Determination We adopt the followingnomenclature for the cocrystals depicted herein form S(cocrystal of 5-FC with succinic acid) form T (cocrystal of5-FC with terephtalic acid) form B (cocrystal of 5-FC withbenzoic acid) form M (cocrystal of 5-FC with malic acid) formA (cocrystal of 5-FC with adipic acid) and form 5F (cocrystalof 5-FC with 5-FU) Table 1 exhibits the crystallographic datafor the structures32 Structural Description A detailed description of the

structures is depicted below The main hydrogen-bond metricsfor each cocrystal are listed in Table S1 (SupportingInformation) In Figure 1 an ORTEP-336 view of theasymmetric unit of each cocrystal is shown The structureand data for form 5F will be depicted in a separate sectionCocrystal of 5-FC with Succinic Acid The asymmetric unit

of form S (Figure 1) exhibits one 5-FC molecule as well as asuccinic acid the latter sitting on a crystallographic inversioncenter giving just half of this molecule per asymmetric unitBifurcated hydrogen bonds (N41minusH41AmiddotmiddotmiddotO3 and O3minusH3middotmiddotmiddotO21) occur among the acid and two 5-FC molecules (Figure

2a) These interactions lead the 5-FC molecules to interact witheach other forming a R2

2(8) motif37ab (Figure 2a) assembled viacomplementary N41minusH41middotmiddotmiddotN3 hydrogen bonds and alsopromote the formation of a nonclassical C6minusH6middotmiddotmiddotO4 (bond

Figure 1 ORTEP-336 type view of the 5-FC cocrystals Thermal ellipsoids for forms S A and T are at the 50 probability level and for forms M Band 5F at the 30 probability level Hydrogen atoms are drawn as spheres of arbitrary radii

Figure 2 (a) Crystal packing diagram of form S Black dashed linesindicate hydrogen bonds (I) refers to the R2

2(8) motif37ab involvingthe NminusHmiddotmiddotmiddotN 5-FC homodimers (II) to the R2

2(8) motif37ab involvingthe NminusHmiddotmiddotmiddotO 5-FC homodimers and (III) to the R6

4(40) motif37ab

(b) three-dimensional hydrogen-bonded network of form S

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the same equipment X-ray diffraction data collection (φ scans and ωscans with κ offsets) for the cocrystals of 5-FC with malic and benzoicacids were performed on an Enraf-Nonius Kappa-CCD diffractometer(95 mm CCD camera on κ-goniostat) using graphite-monochromatedMoKα radiation (071073 Aring) For refinement details28minus34 see theSupporting InformationIn all cases the programs MERCURY (version 23)35 and ORTEP-

336 were used also within WinGX v1700132 to prepare thecrystallographic information file (CIF) and artwork representationsfor publicationThe CIFs of the three 5-FC cocrystals were deposited in the

Cambridge Structural Data Base under the codes CCDC 933072(cocrystal of 5-FC with adipic acid) CCDC 933073 (cocrystal of 5-FCwith succinic acid) CCDC 933074 (cocrystal of 5-FC with terephtalicacid) CCDC 991413 (cocrystal of 5-FC with 5-FU) CCDC 991431(cocrystal of 5-FC with malic acid) and CCDC 991584 (cocrystal of 5-FC with benzoic acid) Copies of these files may be solicited free ofcharge from The Director CCDC 12 Union Road Cambridge CB21EZ UK fax + 44123minus336minus033 e-mail depositccdccamacuk orhttpwwwccdccamacuk

3 RESULTS

31 Structure Determination We adopt the followingnomenclature for the cocrystals depicted herein form S(cocrystal of 5-FC with succinic acid) form T (cocrystal of5-FC with terephtalic acid) form B (cocrystal of 5-FC withbenzoic acid) form M (cocrystal of 5-FC with malic acid) formA (cocrystal of 5-FC with adipic acid) and form 5F (cocrystalof 5-FC with 5-FU) Table 1 exhibits the crystallographic datafor the structures32 Structural Description A detailed description of the

structures is depicted below The main hydrogen-bond metricsfor each cocrystal are listed in Table S1 (SupportingInformation) In Figure 1 an ORTEP-336 view of theasymmetric unit of each cocrystal is shown The structureand data for form 5F will be depicted in a separate sectionCocrystal of 5-FC with Succinic Acid The asymmetric unit

of form S (Figure 1) exhibits one 5-FC molecule as well as asuccinic acid the latter sitting on a crystallographic inversioncenter giving just half of this molecule per asymmetric unitBifurcated hydrogen bonds (N41minusH41AmiddotmiddotmiddotO3 and O3minusH3middotmiddotmiddotO21) occur among the acid and two 5-FC molecules (Figure

2a) These interactions lead the 5-FC molecules to interact witheach other forming a R2

2(8) motif37ab (Figure 2a) assembled viacomplementary N41minusH41middotmiddotmiddotN3 hydrogen bonds and alsopromote the formation of a nonclassical C6minusH6middotmiddotmiddotO4 (bond

Figure 1 ORTEP-336 type view of the 5-FC cocrystals Thermal ellipsoids for forms S A and T are at the 50 probability level and for forms M Band 5F at the 30 probability level Hydrogen atoms are drawn as spheres of arbitrary radii

Figure 2 (a) Crystal packing diagram of form S Black dashed linesindicate hydrogen bonds (I) refers to the R2

2(8) motif37ab involvingthe NminusHmiddotmiddotmiddotN 5-FC homodimers (II) to the R2

2(8) motif37ab involvingthe NminusHmiddotmiddotmiddotO 5-FC homodimers and (III) to the R6

4(40) motif37ab

(b) three-dimensional hydrogen-bonded network of form S

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length of 2071 Aring) one A second R22(8) motif is observed

between the 5-FC molecules involving complementary N1minusH1middotmiddotmiddotO21 hydrogen bonds leading to the formation of 1-Dtapes which run parallel on both sides of the acid moleculeThis arrangement of the molecules in the crystal lattice givesrise to the formation of cavities with graph set R6

4(40) andconstitutes flat layers offset stacked along [1 21] The stackingof the layers (Figure 2b) is kept only by van der Waals contactsof the types CmiddotmiddotmiddotO CmiddotmiddotmiddotF and CmiddotmiddotmiddotN which results in aninterlayer separation of approximately 320 Aring to one another(van der Waals radii38 for C = 170 Aring N = 155 Aring O = 152 Aringand F = 147 Aring)Cocrystal of 5-FC with Adipic Acid The asymmetric unit of

form A (Figure 1) also exhibits one molecule of 5-FC and halfadipic acid since as mentioned previously it is sitting on aninversion center The crystal packing preserve similarintermolecular interaction patterns such as the ones found forform S (Figure 3a) two R2

2(8) motifs constituted viacomplementary N41minusH41middotmiddotmiddotN3 and N1minusH1middotmiddotmiddotO21 hydrogenbonds between 5-FC molecules and a bifurcated (N41minus

H41AmiddotmiddotmiddotO3 and O3minusH3middotmiddotmiddotO21) interaction between 5-FCmolecule and both carboxyl groups of the acid also resulting inthe formation of the nonclassical C6minusH6middotmiddotmiddotO4 (bond length of2109 Aring) intermolecular interaction plus a C8minusH8middotmiddotmiddotF51 (bondlength of 2444 Aring) one In this way the forms S and A exhibit asimilar arrangement of the molecules in the crystal latticeHowever as a result of the increase in the length of the carbonchain in the adipic acid the cavity formed (Figure 3a) possess agraph set of R6

4(48) and the layers are not as flat as the onesobserved in form S once the adipic acid adopts a zigzagconformation in its carbon chain The layers are offset stackedalong [120] and beyond the van der Waals contacts holdingthese layers together there is a nonclassical C9minusH9AmiddotmiddotmiddotF51(bond length of 2419 Aring) hydrogen bond (Figure 3b)

Cocrystal of 5-FC with Terephtalic Acid The asymmetricunit of form T (Figure 1) exhibits one 5-FC and half terephtalicacid molecule for the acid is placed on an inversion center as informs S and A As observed in forms S and A the two 5-FCring motifs (Figure 4a) and the two 5-FCminusacid hydrogenbonds (Figure 4a) plus the nonclassical C6minusH6middotmiddotmiddotO4 (bondlength of 2201 Aring) are preserved in form T As a consequenceof the close packing a nonclassical C10minusH10middotmiddotmiddotF51 (bondlength of 2491 Aring) intermolecular interaction overcome Form

Figure 3 (a) Crystal packing diagram of form A Black dashed linesindicate hydrogen bonds (I) refers to the R2

2(8) motif37ab involvingthe NminusHmiddotmiddotmiddotN 5-FC homodimers (II) to the R2

2(8) motif37ab involvingthe NminusHmiddotmiddotmiddotO 5-FC homodimers and (III) to the R6

4(48) motif37ab

(b) three-dimensional hydrogen-bonded network of form A

Figure 4 (a) Crystal packing diagram of form T Black dashed linesindicate hydrogen bonds (I) refers to the R2

2(8) motif37ab involvingthe NminusHmiddotmiddotmiddotN 5-FC homodimers (II) to the R2

2(8) motif37ab involvingthe NminusHmiddotmiddotmiddotO 5-FC homodimers and (III) to the R6

4(44) motif37ab

(b) three-dimensional hydrogen-bonded network of form T

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T also exhibits a similar layered pattern stacked along [110]The cavities (Figure 4a) formed in this crystalline arrangementadopts a ring graph-set with the R6

4(44) notation smaller thanthe one found in form A Although both 5-FC and terephtalicacid molecules adopt a planar conformation they are notaligned in the same plane (Figure 4b) The angle between theplane passing through the non-hydrogen atoms of the 5-FCmolecules and the one passing through the terephtalic acid is2666(2)deg The terephtalic molecules are stacked as the 5-FCones in a fashion that πmiddotmiddotmiddotπ interactions take place (centroidminuscentroid distance equal to 36265(3)Aring for both molecules)being mainly responsible for the maintenance of form Tcrystalline packingCocrystal of 5-FC with Benzoic Acid The asymmetric unit

of form B (Figure 1) exhibits one molecule of 5-FC and one ofbenzoic acid The arrangement of the 5-FC molecules followsthe same pattern observed for form T with the two 5-FC ringmotifs37ab (Figure 5a) and the two 5-FCminusacid hydrogen bondspreserved as is the nonclassical C6minusH6middotmiddotmiddotO4 (bond length of2071 Aring) The 1-D tapes of the 5-FC molecules are surroundedby benzoic acid molecules forming stacked layers sustained onlyby van der Waals contacts with an interlayer separation ofapproximately 5432 Aring (Figure 5b) The neighboring layers aretwisted 7425deg with respect to each other forming aherringbone pattern This supramolecular pattern arises fromunconventional hydrogen bonds (Table S1 in the SupportingInformation) involving fluorine atoms of the 5-FC and carbonatoms (C11 and C13) of the benzoic acid molecules (Figure5a) As is observed in form T the benzoic acid molecules arenot exactly placed on the same plane of the 1-D tape Howeverthe angle between the mean plane defined by the non-hydrogenatoms of the 5-FC and the non-hydrogen atoms of the benzoicacid molecule is smaller in form B than in form T assuming avalue of 2043degCocrystal of 5-FC with Malic Acid The asymmetric unit of

form M (Figure 1) exhibits one 5-FC and one molecule ofmalic acid In contrast to the other forms form M preservesonly the R2

2(8) motif accessed via complementary N1minusH1middotmiddotmiddotO21 hydrogen bonds among the 5-FC molecules like thatobserved in the other cocrystals (Figure 6a) However a secondR22(8) motif is inherent of form M and arises from the

interactions of 5-FC molecules with surrounding malic acidmolecules (O3minusH3middotmiddotmiddotN3 and N41minusH41BmiddotmiddotmiddotO4) constituting aheterodimer (Figure 6a) Additional hydrogen bonds (N41minusH41AmiddotmiddotmiddotO5 and O7minusH7middotmiddotmiddotO21) lead to the formation of flatlayers stacked along the c axis and of a cavity represented by theR64(36) graph-set notation37ab (Figure 6a) The layers are held

together via O5minusH5middotmiddotmiddotO6 hydrogen bonds involving the malicacid molecules and also via πmiddotmiddotmiddotπ interactions (centroidminuscentroid distance equal to 3495(9)Aring) between the rings of the5-FC molecules (Figure 6b)

4 DISCUSSIONWe have conducted cocrystallization experiments with 5-FCand five dicarboxylic acids presenting the following pKa values443 (adipic acid) 421 (benzoic acid) 416 (succinic acid)352 (terephtalic acid) and 340 (malic acid) These acids werechosen in an attempt to evaluate the extent of proton transferto the 5-FC molecules based on the pKa rule262739

contributing to the study of the saltcocrystal continuum andproviding information related to the capability of predicting andcontrolling the synthesis of compounds containing thefluoropyrimidine group

As the pKa value for the 5-FC is 326 then the respectivevalues of ΔpKa (pKaacid minus pKabase) for adipic benzoic succinicterephtalic and malic acids are minus116 minus095 minus09 minus026 andminus014 ranging from close to zero to more negative valuesAccording to Bhogala et al27 for negative values of ΔpKa acocrystal formation is expected One method of verifyingsuccessful cocrystal formation is to calculate the CminusO bondlength differences of the carboxyl groups in the acid moleculeΔDCminusO If this variation is small (lt003 Aring) then a salt isformed If however this difference is higher than 008 Aring then acocrystal is formed For all the structures depicted here theΔDCminusO values are above 008 Aring (form S = 0117(1) Aring form A =0119(3) Aring form T = 0114(2) Aring form B = 0121(2) Aring andform M = 0109(5) Aring) which means that the CminusO distancesare not symmetrical as in the carboxylate anions evidencingcocrystal formation

41 Supramolecular Analysis In our previous manu-script22 we synthesized three 5-FC salts also using as coformers

Figure 5 (a) Crystal packing diagram of form B Black dashed linesindicate hydrogen bonds (I) refers to the R2

2(8) motif37ab involvingthe NminusHmiddotmiddotmiddotN 5-FC homodimers and (II) R2

2(8) motif37ab involvingthe NminusHmiddotmiddotmiddotO 5-FC homodimers (b) three-dimensional hydrogen-bonded network of form B

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dicarboxylic acids fumaric maleic and oxalic The structureswere obtained from the continuum to the salt part of thespectrum according to the pKa rule where the ΔpKa valueranged between 0 and positive values Due the complementar-ity among the carboxylic group and the functional groupspresent in the 5-FC molecules all the salts exhibited the sameR22(8) motif constituting heterodimers via N41minusH41AmiddotmiddotmiddotO4

and N3+minusH3middotmiddotmiddotO3minus hydrogen bonds The same supramolecularsynthon was observed for the salicylate of 5-FC reported byPortalone and Colapietro in 200720 On the other hand whenwe go to the other side of the spectrum ie when weakerdicarboxylic acids are used as coformers changes occur in theionicity of the 5-FC molecule and new supramolecularsynthons overcome According to Mukherjee and Desiraju40

cocrystal formation is usually expected to occur whenheterosynthons are formed over homosynthons However forthe cocrystals of 5-FC with succinic adipic benzoic andterephtalic acids instead of heterodimers we observehomodimers occurring among the 5-FC molecules accessedthrough complementary N41minusH41middotmiddotmiddotN3 and N1minusH1middotmiddotmiddotO21hydrogen bonds Nevertheless for a ΔpKa very close to 0(ldquocutoffrdquo among cocrystals and salts for this fluoropyrimidine)as in form M (ΔpKa = minus01) a supramolecular transition

synthon is observed In this cocrystal the crystal packing stillpreserves the heterodimer observed in the salts except for thefact that no proton transfer is observed but also exhibits theN1minusH1middotmiddotmiddotO21 homodimer among the 5-FC molecules For thishomodimer which is common in all cocrystals the 5-FCcarbonyl bond lengths go from 1265 to 1249 Aring These valuesare significantly higher than the ones found for the 5-FC salts(1232 to 1219 Aring) It is clear that this feature is the result of theprotonation where the charge redistribution implies on areduction of the carbonyl bond lengths which in turn does notfavor the geometric requirements for the formation of thesynthon needed for the establishment of the homodimerspresent in the cocrystals However the geometric features ofthe form M show intermediate values for the carbonyl bondlengths suggesting a partial charge redistribution that may leadto a hybrid saltcocrystal specie Indeed this form shows thesalts heterodimer synthon even without protonation possiblydue the intermediate strength of malic acid (pKa = 340) Thistransition state becomes clearer when a correlation plotbetween the variations of the CminusO bond lengths in thecarboxylic fragments (ΔDCminusO) of the coformers and thevariations of the CminusN bond lengths (ΔDCminusN) of the imidicfragments of the 5FC ring is carried out (Figure 7) It is worth

mentioning that the fumarate salt of 5-FC22 (form F) ishydrated and the presence of water molecules in its crystalpacking result in changes in the intermolecular interactionpatterns leading to a different behavior of the 5-FC intra-molecular bond lengths approximating its ΔDCminusN values to theones found for form MIn an attempt to understand which changes occur in the 5-

FC molecule and consequently the specific supramolecularpatterns formed the UNI Force Field Calculations a tool of theMercury crystallography package4142 was used to establish andcompare the intermolecular potentials of the main interactionsIt is important to highlight that the purpose of this applicationis to display those interactions between molecules which aremost significant in energetic terms without performing thecomputationally expensive lattice energy calculations Thisstudy allowed us to determine that in most of the cases thepotentials of the complementary N1H1middotmiddotmiddotO21 hydrogen bondsare the strongest ranging between minus91 to minus76 kcalmol withthe exception of form T and form M Since this homodimerwas recurrent in all the cocrystals of 5-FC this synthon can be

Figure 6 (a) Crystal packing diagram of form M Black dashed linesindicate hydrogen bonds (I) refers to the R2

2(8) motif37ab involvingthe NminusHmiddotmiddotmiddotO 5-FC homodimers (II) to the R2

2(8) motif37ab involvingthe NminusHmiddotmiddotmiddotO and OminusHmiddotmiddotmiddotN 5-FC heterodimer and (III) to theR64(36) motif37ab (b) three-dimensional hydrogen-bonded network of

form M

Figure 7 Correlation between the CminusN bond length differencesΔDCminusN of the imidic group of 5-FC ring vs the CminusO bond lengthdifferences of the carboxylic fragments ΔDCminusO evidencing theintermediary interface between saltscocrystals of form M Theforms Ma F O and EDATOS refer to the salts of 5-FC with maleicfumaric oxalic and salycilic acids1922

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Figure 8 Comparison of the supramolecular structure of different 5-FC solid forms containing just neutral 5-FC molecules (a) form S (b) form A(c) form T (d) form B (e) form M (f) cocrystal under refcode MECTUL24 (g) solvate under refcode DUKWAI17 (h) polymorph under refcodeMEBQEQ15 (i) polymorph under refcode MEBQEQ0115 (j) cocrystal under refcode MECXID25 (k) cocrystal under refcode MECVUN24 (l)cocrystal under refcode MECWAU24 and (m) cocrystal under refcode MECWEY24 (n) solvate under refcode MEBQOA15 (o) solvate underrefcode MEBQIU15 (p) cocrystal under refcode MECWUO25 (q) cocrystal under refcode MECXEZ25 (r) cocrystal under refcode MECVEX24 (s)cocrystal under refcode MECVIB24 (t) cocrystal under refcode MECWOI24 (u) solvate under refcode DUKWEM17 (v) hydrates of 5-FC (I) underrefcodes BIRMEU14 BIRMEU0116 BIRMEU0215 and (II) under refcode BIRMEU0315 (w) hydrate under refcode PANLAS18 (x) hydratedcocrystal under refcode MECVOH24 (y) hydrated cocrystal under refcode MECXOJ25 (z) hydrate under refcode DUKWIQ17 (1) hydrate underrefcode MEBQUG15 and (2) hydrated cocrystal under refcode GATMUL23

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considered a key piece in the assembly of the cocrystal packingOn the other hand the complementary N41minusH41middotmiddotmiddotN3hydrogen bonds (present in the forms A S T and B) showsmaller potential values ranging between minus55 to minus49 kcalmol As previously discussed form M represents anintermediate state in the border of the saltminuscocrystalcontinuum Instead of the N41minusH41middotmiddotmiddotN3 hydrogen bondspresent in the homodimers we observed interactions occurringamong the 5-FC molecule and the malic acid one (N41minusH41BmiddotmiddotmiddotO4 and O3minusH3middotmiddotmiddotN3) this heterosynthon being typicalof the organic acid salts1922 The potential value of this synthonfor form M is minus97 kcalmol and this one is the highestpotential observed for all interactions present in this crystallineform showing that stronger acids have the ability of competingfor these interactions thus replacing the weaker NminusHmiddotmiddotmiddotN onesIn addition the study of the intermolecular potentials also

allows us to evaluate the strength of the πmiddotmiddotmiddotπ interactionsbetween the layers formed by the 5-FC-acids units Theseinteractions have potentials ranging from minus96 to minus49 kcal

mol agreeing in all the cases with the proximity of the layers inthe 3D supramolecular arrangements A correlation is observedbetween the energy of these interactions and the distance of thelayers form M which displays the closest distance between thelayers also exhibits a high potential (minus82 kcalmol) for theπmiddotmiddotmiddotπ interactions whereas the highest potential observed to theπmiddotmiddotmiddotπ interactions was between terephthalic acid units of form T(minus96 kcalmol) All the potentials calculated are summarizedin Tables A7 B7E77 (see the Supporting InformationSections AminusE)Extending our supramolecular study for the neutral 5-FC

molecules a comparative analysis was performed on the basis ofall the crystalline structures already reported containing 5FCmolecules Polymorphs solvates and cocrystals plus mixturesof them such as solvated cocrystals were also considered 5-FCis a rigid molecule and presents three potential patterns ofhydrogen bonding sites two acceptorminusdonor involving theatoms O21minusN1 and N3minusN41 (ON and NN respectively) andone acceptorminusacceptorminusdonor involving the atoms O21minusN3minus

Table 2 Distribution of the Main Supramolecular Synthons Observed for the Different 5-FC Solid Forms Containing JustNeutral 5-FC

NminusHmiddotmiddotmiddotO NminusHmiddotmiddotmiddotN NminusHmiddotmiddotmiddotO NminusHmiddotmiddotmiddotNCG-like base

pairing

structurea homo hetero homo hetero homo hetero homo hetero planar cavity tubular cavity 5-FC ribbons

a radic radic radic radicb radic radic radic radicc radic radic radic radicd radic radic radic radice radic radic radic radicf radic radicg radich radic radici radic radicj radic radic radick radic radic radicl radic radic radic radicm radic radic radicn radic radic radico radic radic radicp radic radic radicq radic radicr radic radic radic radics radic radic radict radic radicu radic radic radic radicv(I) radic radic radicv(II) radic radic radic radicw radic radic radicx radic radicy radic radicz radic radic radic radic1 radic radic radic2 radic radic radic

aComparison of the supramolecular structure of different 5-FC solid forms containing just neutral 5-FC molecules (a) form S (b) form A (c) formT (d) form B (e) form M (f) cocrystal under refcode MECTUL24 (g) solvate under refcode DUKWAI17 (h) polymorph under refcodeMEBQEQ15 (i) polymorph under refcode MEBQEQ0115 (j) cocrystal under refcode MECXID25 (k) cocrystal under refcode MECVUN24 (l)cocrystal under refcode MECWAU24 and (m) cocrystal under refcode MECWEY24 (n) solvate under refcode MEBQOA15 (o) solvate underrefcode MEBQIU15 (p) cocrystal under refcode MECWUO25 (q) cocrystal under refcode MECXEZ25 (r) cocrystal under refcode MECVEX24 (s)cocrystal under refcode MECVIB24 (t) cocrystal under refcode MECWOI24 (u) solvate under refcode DUKWEM17 (v) hydrates of 5-FC (I) underrefcodes BIRMEU14 BIRMEU0116 BIRMEU0215 and (II) under refcode BIRMEU0315 (w) hydrate under refcode PANLAS18 (x) hydratedcocrystal under refcode MECVOH24 (y) hydrated cocrystal under refcode MECXOJ25 (z) hydrate under refcode DUKWIQ17 (1) hydrate underrefcode MEBQUG15 and (2) hydrated cocrystal under refcode GATMUL23

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N41 (ONN) Tutughamiarso and co-workers17 showed that the5-FC molecule when neutral tends to interact to one anotherby self-complementary homodimers constituting planar ortubular 5-FC ribbons These homodimers as observed in thecocrystals depicted here are essentially composed by one NminusHmiddotmiddotmiddotO and one NminusHmiddotmiddotmiddotN (ONNN) or by two NminusHmiddotmiddotmiddotO(ONON) or even by two NminusHmiddotmiddotmiddotN (NNNN) intermo-lecular interactions Complementing this claim Figure 8exhibits a schematic drawing of the classical intermolecularinteractions of each reported structure considering the wholesupramolecular architecture adopted by the 5-FC moleculesunder the different crystalline arrangements It shows that notonly ribbons are observed but also planar andor tubularcavities mainly due to the intrinsic geometry of the ON NNONN hydrogen bonding sites Furthermore Table 2 exhibits astatistical analysis of the distribution of the main supra-molecular synthons observed for the 5-FC molecule includinghomo- and heterodimers involving the three main hydrogenbonding sites (ONON ONNN and NNNN) plus theformation of homo- and heterotrimers with hydrogen bondingpatterns similar to the CG Watson and Crick base pairingAccording to Table 2 the 5-FC molecule tends to form ON

NN ONON and NNNN homodimers Tutughamiarso andco-workers17 observed the particular NNNN homodimerformation only in the hydrate under refcode BIRMEU0315

reporting later a cocrystal of 5-FC under refcode MECTUL24

also exhibiting this pattern of NNNN homodimer formationThe forms S T A and B however exhibit the same ribbonformation that occurs for the hydrate under refcodeBIRMEU0315 ie ONON and NNNN R2

2(8) motifs37ab

per 5-FC molecule while in the 5-FC cocrystal under refcodeMECTUL24 the free ON site of the 5-FC molecule isintercepted by the formation of a ONNN heterodimer withthe coformer molecule In addition two ONNN (refcodesMECVIB24 and e GATMUL23) and two ONON heterodimers(refcodes MECWUO25 and GATMUL23) are observedHowever no NNNN heterodimer was reported until thepresentOn the other hand for the ONN CG-like base pairing the

tendency is the formation of heterosynthons with a total of ninestructures Only in one hydrate (refcode PANLAS18) the CG-like base pairing is observed between the 5-FC molecules Byanalyzing the crystalline packing of the 5-FC cocrystal underrefcode MECTUL24 (see Figure 8f) the occurrence of oneONNN heterodimer disrupts the 5-FC ribbon formationAlthough homoribbons (ie ribbons constituted only by 5-FCmolecules) are prevalent in most of the crystalline structures12 of them exhibit heteroribbons and all refer to cocrystals (2cocrystals and 10 solvated cocrystals)By considering the cavity formation two exceptions arise

one referring to the cocrystal under refcode MECTUL24

(Figure 8f) where flat layers are stacked by van der Waalscontacts and one referring to the solvate under refcodeDUKWAI17 (Figure 8g) for which small cavities are observedonly when the nonclassical CminusHmiddotmiddotmiddotO and CminusHmiddotmiddotmiddotF intermo-lecular interactions between the dimethyl sulfoxide and 5-FCmolecules are considered Both reported polymorphs of 5-FCexhibit tubular patterns (Figure 8h (i) constituting R4

4(24) andR64(26) motifs involving four and six 5-FC molecules

respectively Forms S A and T (Figure 8aminusc) exhibit similarcavities differing only in their size (R6

4(40) R64(48) R6

4(44) forforms S A and T respectively) proportional to the size andthe geometry of each acid molecule Figure 8h exhibits the last

planar cavity R76(44) involving only solid coformers

concerning the cocrystal under refcode MECXID25 Whensolvents are involved in the interactions they lead to planar andtubular cavities for which it is not possible to establish aspecific pattern for these ternary systems In particular thecocrystal under refcode MECVEX24 (Figure 8r) and thehydrate under refcode DUKWIQ17 (Figure 8z) display cavitiesof both tubular and planar types It is worth mentioning thatthe planar cavities of the methanol solvate under refcodeMEBQOA15 (Figure 8 (l)) of the cocrystal under refcodeMECVEX24 (Figure 8r) and of the hydrate under refcodeDUKWIQ17 (Figure 8z) are similar to the one formed in formsS A and T This shows that the recurrent supramolecularsynthon observed for the cocrystals depicted herein is notrestricted to the use of carboxylic acids as coformers In thisway it could be expected that new structures containing 5-FCmolecule can be designed and developed as new tailor-madedrugs

42 Cocrystal of 5-FC and 5-FU 5-Fluorouracil 5-fluoro-24-(1H3H)-pyrimidinedione is an antineoplastic API ration-ally designed by Heidelberger and co-workers in 195743 It isused for the treatment of superficial skin carcinomas as a creamformulation and as injections in the treatment of variouscancers including among others gastrointestinal head andneck breast colorectal and ovarian 5-FU is a syntheticpyrimidine analogue and is probably the most widely usedbeing of great interest in the clinical and experimentalchemotherapy among the developed analogues of purine andpyrimidine as it is structurally similar to natural basesNevertheless only a fraction of the administered amount ofthis API becomes available in the systemic circulation after oraladministration due to its poor water solubility44minus46 Indeedoral delivery of antineoplastic APIs is considered a challengedue their physical and chemical properties and physiologicalbarriers47

As an illustration of a controlled rational supramolecularsynthesis of new solid forms of a given API using 5-FC ascoformer we designed a cocrystal of 5-FC and 5-FU (form 5FpKa = 80)44 It is clear that the 5-FU was our first molecule ofchoice for this example due to its structural similarities with 5-FC The cocrystallization experiment was developed accordingto the pKa rule and a cocrystal was expected (ΔpKa = minus474)The aim of this particular experiment was to design a new solidform of 5-FU with enhanced physical and chemical propertiesthat could enable this API to be orally administered togetherwith 5-FC which in turn exhibits high solubility andbioavailability profiles10 However the solubility properties ofform 5-FU are still under investigationThe asymmetric unit of form 5F (see Figure 1) exhibits one

molecule of 5-FC and one of 5-FU The main intermolecularinteractions responsible for maintaining the crystalline arrange-ment of this cocrystal are of the types NminusHmiddotmiddotmiddotO and NminusHmiddotmiddotmiddotF(see Table S1 in the Supporting Information section) includingthe formation of homodimers of 5-FC (I in Figure 9a)homodimers of 5-FU (II in Figure 9a) and intermolecularinteractions among the 5-FC and 5-FU molecules (Figure 9a)Nonclassical intermolecular interactions are also present as aresult of the close packing C6minusH6middotmiddotmiddotF51 (bond distance of2467 Aring) C6primeminusH6primemiddotmiddotmiddotF51prime (bond distance of 2354 Aring) C6primeminusH6primemiddotmiddotmiddotN3 (bond distance of 2639 Aring) and C6minusH6middotmiddotmiddotO21prime(bond distance of 2553 Aring) The crystal packing of form 5F iscomposed of flat tapes in which the dimers are interspersedThese tapes are stacked constituting columns with a parallel

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displaced arrangement (displacement angle of 232deg) main-tained by πmiddotmiddotmiddotπ interactions (5-FCπmiddotmiddotmiddotπ = 35604(9) Aring and 5-FUπmiddotmiddotmiddotπ = 35603(9)Aring) Adjacent tapes (and consequentlyadjacent columns) exhibit two directions of growth and areconnected to one another by intermolecular interactionsbetween the molecules of 5-FC and 5-FU forming a dihedralangle of 13017(3)deg (Figure 9b)

5 CONCLUSIONThe 5-FC cocrystals with succinic adipic benzoic and tereftalicacids were obtained following the tendency of the pKa rule andhave revealed a similar hydrogen-bonding pattern leading to 5-FC ribbons stabilized by two R2

2(8) motifs characterized bycomplementary homodimeric NminusHmiddotmiddotmiddotN (NNNN) and NminusHmiddotmiddotmiddotO (ONON) interactions which was found to be a featureof cocrystals containing this fluoropyrimidine moleculesAnalyzing the supramolecular characteristics of the four 5-FCcocrystals (together with some similar structures reported inthe literature) it was observed that the 5-FC molecule tends toform ONNN ONON and NNNN homodimers ONNCG-like base pairing heterotrimers and both tubular andplanar cavities Nevertheless when the cocrystallization experi-ment was conducted with malic acid where the ΔpKa = minus01 asupramolecular transition synthon was observed in which theNminusHmiddotmiddotmiddotO homodimeric synthon present in the cocrystalsremains but a new heterodimeric synthon characterized bycomplementary NminusHmiddotmiddotmiddotO hydrogen bonds between the 5-FCmolecule and the malic acid emerged This last synthon wasfound in the 5-FC organic salts obtained even from very smallpositive ΔpKa values (such as for the fumarate of 5-FC whereΔpKa = 023) The discovery of this transition synthonindicates that the 5-FC molecule is a suitable candidate forthe design and development of cocrystallization experimentsbased on crystal engineering techniques once its behaviorcould be until the present well predicted by the pKa rule Tocheck our hypothesis we conducted a cocrystallizationexperiment of 5-FC with the antineoplastic drug 5-FU aimingto obtain a cocrystal once the system exhibits a ΔpKa = minus30The success of this experiment points to a new path to apply 5-

FC as a coformer in new controlled crystallization experimentsfor the development of new tailor-made drugs

ASSOCIATED CONTENTS Supporting InformationCrystallographic data of the 5-FC calculated potentials Thismaterial is available free of charge via the Internet at httppubsacsorg

AUTHOR INFORMATIONCorresponding AuthorE-mail javiereifscuspbr Phone +55 16 3373 8096 Fax+55 16 3373 9881NotesThe authors declare no competing financial interest

ACKNOWLEDGMENTSWe thank CAPES (CCPS) FAPESP (JCT Project No201307581-9) and CNPq (JE ROP CCM Project No1500762013-4) for the financial support We also thank forthe use of the APEX II Bruker difractometer to ldquoFacility foradvanced studies of materialsFAMardquo (FAPESP Project No2009540354)

REFERENCES(1) Almarsson O Zaworotko M J Chem Commun (Cambridge)2004 17 1889minus1896(2) Blagden N de Matas M Gavan P T York P Adv DrugDelivery Rev 2007 59 (7) 617minus630(3) Bond A D In Pharmaceutical Salts and Co-Crystals Wouters JQuere L Eds The Royal Society of Chemistry Cambridge UK2012 Chapter 2 pp 9minus28(4) Vishweshwar P McMahon J A Peterson M L Hickey M BShattock T R Zaworotko M J Chem Commu 2005 36 4601minus4603(5) Aakeroy C B Fasulo M E Desper J Mol Pharmaceutics 20074 (3) 317minus322(6) Trask A V Mol Pharmaceutics 2007 4 (3) 301minus309(7) GRAS S Food and Drug Administration Database of SelectCommittee on GRAS Substances (SCOGS) Reviews httpswwwaccessdatafdagovscriptsfcnfcnNavigationcfmrpt=scogsListing(8) Shan N Zaworotko M J Drug Discovery Today 2008 13 (9minus10) 440minus446(9) Hoffman M Lindeman J A In Pharmaceutical Salts and Co-crystals Wouters J Quere L Eds The Royal Society of ChemistryCambridge UK 2012 Chapter 14 pp 318 minus 329(10) Vermes A Guchelaar H-J Dankert J J AntimicrobChemother 2000 46 (2) 171minus179(11) Larsen R A In Essentials of Clinical Mycology 2nd edKauffman C A Pappas P G Sobel J D Dismukes W E EdsOxford University Press UK 2003 part 2 pp 57minus60(12) Mullen C A Coale M M Lowe R Blaese R M Cancer Res1994 54 (6) 1503minus1506(13) Allen F H Acta Crystallogr Sect B 2002 58 (3) 380minus388(14) Louis T Low J N Tollin P Cryst Struct Commun 1982 111059minus1064(15) Hulme A T Tocher D A CrystGrowth Des 2006 6 (2)481minus487(16) Portalone G Colapietro M Acta Crystallogr Sect E 2006 62(3) o1049minuso1051(17) Tutughamiarso M Bolte M Egert E Acta Crystallogr Sect C2009 65 (11) o574minuso578(18) Hulme A T Tocher D A Acta Crystallogr Sect E 2005 61(7) 02112minuso2113(19) Prabakaran P Murugesan S Muthiah P T Bocelli G RighiL Acta Crystallogr Sect E 2001 57 (10) o933minuso936

Figure 9 (a) Crystal packing diagram of form 5f Black dashed linesindicate hydrogen bonds (I) refers to the R2

2(8) motifs37ab involvingthe NminusHmiddotmiddotmiddotO homodimers occurring among 5-FC molecules and (II)correspond to R2

2(8) motifs37ab involving the NminusHmiddotmiddotmiddotO homodimersoccurring among 5-FU molecules (b) three-dimensional hydrogen-bonded network of form 5f

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T also exhibits a similar layered pattern stacked along [110]The cavities (Figure 4a) formed in this crystalline arrangementadopts a ring graph-set with the R6

4(44) notation smaller thanthe one found in form A Although both 5-FC and terephtalicacid molecules adopt a planar conformation they are notaligned in the same plane (Figure 4b) The angle between theplane passing through the non-hydrogen atoms of the 5-FCmolecules and the one passing through the terephtalic acid is2666(2)deg The terephtalic molecules are stacked as the 5-FCones in a fashion that πmiddotmiddotmiddotπ interactions take place (centroidminuscentroid distance equal to 36265(3)Aring for both molecules)being mainly responsible for the maintenance of form Tcrystalline packingCocrystal of 5-FC with Benzoic Acid The asymmetric unit

of form B (Figure 1) exhibits one molecule of 5-FC and one ofbenzoic acid The arrangement of the 5-FC molecules followsthe same pattern observed for form T with the two 5-FC ringmotifs37ab (Figure 5a) and the two 5-FCminusacid hydrogen bondspreserved as is the nonclassical C6minusH6middotmiddotmiddotO4 (bond length of2071 Aring) The 1-D tapes of the 5-FC molecules are surroundedby benzoic acid molecules forming stacked layers sustained onlyby van der Waals contacts with an interlayer separation ofapproximately 5432 Aring (Figure 5b) The neighboring layers aretwisted 7425deg with respect to each other forming aherringbone pattern This supramolecular pattern arises fromunconventional hydrogen bonds (Table S1 in the SupportingInformation) involving fluorine atoms of the 5-FC and carbonatoms (C11 and C13) of the benzoic acid molecules (Figure5a) As is observed in form T the benzoic acid molecules arenot exactly placed on the same plane of the 1-D tape Howeverthe angle between the mean plane defined by the non-hydrogenatoms of the 5-FC and the non-hydrogen atoms of the benzoicacid molecule is smaller in form B than in form T assuming avalue of 2043degCocrystal of 5-FC with Malic Acid The asymmetric unit of

form M (Figure 1) exhibits one 5-FC and one molecule ofmalic acid In contrast to the other forms form M preservesonly the R2

2(8) motif accessed via complementary N1minusH1middotmiddotmiddotO21 hydrogen bonds among the 5-FC molecules like thatobserved in the other cocrystals (Figure 6a) However a secondR22(8) motif is inherent of form M and arises from the

interactions of 5-FC molecules with surrounding malic acidmolecules (O3minusH3middotmiddotmiddotN3 and N41minusH41BmiddotmiddotmiddotO4) constituting aheterodimer (Figure 6a) Additional hydrogen bonds (N41minusH41AmiddotmiddotmiddotO5 and O7minusH7middotmiddotmiddotO21) lead to the formation of flatlayers stacked along the c axis and of a cavity represented by theR64(36) graph-set notation37ab (Figure 6a) The layers are held

together via O5minusH5middotmiddotmiddotO6 hydrogen bonds involving the malicacid molecules and also via πmiddotmiddotmiddotπ interactions (centroidminuscentroid distance equal to 3495(9)Aring) between the rings of the5-FC molecules (Figure 6b)

4 DISCUSSIONWe have conducted cocrystallization experiments with 5-FCand five dicarboxylic acids presenting the following pKa values443 (adipic acid) 421 (benzoic acid) 416 (succinic acid)352 (terephtalic acid) and 340 (malic acid) These acids werechosen in an attempt to evaluate the extent of proton transferto the 5-FC molecules based on the pKa rule262739

contributing to the study of the saltcocrystal continuum andproviding information related to the capability of predicting andcontrolling the synthesis of compounds containing thefluoropyrimidine group

As the pKa value for the 5-FC is 326 then the respectivevalues of ΔpKa (pKaacid minus pKabase) for adipic benzoic succinicterephtalic and malic acids are minus116 minus095 minus09 minus026 andminus014 ranging from close to zero to more negative valuesAccording to Bhogala et al27 for negative values of ΔpKa acocrystal formation is expected One method of verifyingsuccessful cocrystal formation is to calculate the CminusO bondlength differences of the carboxyl groups in the acid moleculeΔDCminusO If this variation is small (lt003 Aring) then a salt isformed If however this difference is higher than 008 Aring then acocrystal is formed For all the structures depicted here theΔDCminusO values are above 008 Aring (form S = 0117(1) Aring form A =0119(3) Aring form T = 0114(2) Aring form B = 0121(2) Aring andform M = 0109(5) Aring) which means that the CminusO distancesare not symmetrical as in the carboxylate anions evidencingcocrystal formation

41 Supramolecular Analysis In our previous manu-script22 we synthesized three 5-FC salts also using as coformers

Figure 5 (a) Crystal packing diagram of form B Black dashed linesindicate hydrogen bonds (I) refers to the R2

2(8) motif37ab involvingthe NminusHmiddotmiddotmiddotN 5-FC homodimers and (II) R2

2(8) motif37ab involvingthe NminusHmiddotmiddotmiddotO 5-FC homodimers (b) three-dimensional hydrogen-bonded network of form B

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dicarboxylic acids fumaric maleic and oxalic The structureswere obtained from the continuum to the salt part of thespectrum according to the pKa rule where the ΔpKa valueranged between 0 and positive values Due the complementar-ity among the carboxylic group and the functional groupspresent in the 5-FC molecules all the salts exhibited the sameR22(8) motif constituting heterodimers via N41minusH41AmiddotmiddotmiddotO4

and N3+minusH3middotmiddotmiddotO3minus hydrogen bonds The same supramolecularsynthon was observed for the salicylate of 5-FC reported byPortalone and Colapietro in 200720 On the other hand whenwe go to the other side of the spectrum ie when weakerdicarboxylic acids are used as coformers changes occur in theionicity of the 5-FC molecule and new supramolecularsynthons overcome According to Mukherjee and Desiraju40

cocrystal formation is usually expected to occur whenheterosynthons are formed over homosynthons However forthe cocrystals of 5-FC with succinic adipic benzoic andterephtalic acids instead of heterodimers we observehomodimers occurring among the 5-FC molecules accessedthrough complementary N41minusH41middotmiddotmiddotN3 and N1minusH1middotmiddotmiddotO21hydrogen bonds Nevertheless for a ΔpKa very close to 0(ldquocutoffrdquo among cocrystals and salts for this fluoropyrimidine)as in form M (ΔpKa = minus01) a supramolecular transition

synthon is observed In this cocrystal the crystal packing stillpreserves the heterodimer observed in the salts except for thefact that no proton transfer is observed but also exhibits theN1minusH1middotmiddotmiddotO21 homodimer among the 5-FC molecules For thishomodimer which is common in all cocrystals the 5-FCcarbonyl bond lengths go from 1265 to 1249 Aring These valuesare significantly higher than the ones found for the 5-FC salts(1232 to 1219 Aring) It is clear that this feature is the result of theprotonation where the charge redistribution implies on areduction of the carbonyl bond lengths which in turn does notfavor the geometric requirements for the formation of thesynthon needed for the establishment of the homodimerspresent in the cocrystals However the geometric features ofthe form M show intermediate values for the carbonyl bondlengths suggesting a partial charge redistribution that may leadto a hybrid saltcocrystal specie Indeed this form shows thesalts heterodimer synthon even without protonation possiblydue the intermediate strength of malic acid (pKa = 340) Thistransition state becomes clearer when a correlation plotbetween the variations of the CminusO bond lengths in thecarboxylic fragments (ΔDCminusO) of the coformers and thevariations of the CminusN bond lengths (ΔDCminusN) of the imidicfragments of the 5FC ring is carried out (Figure 7) It is worth

mentioning that the fumarate salt of 5-FC22 (form F) ishydrated and the presence of water molecules in its crystalpacking result in changes in the intermolecular interactionpatterns leading to a different behavior of the 5-FC intra-molecular bond lengths approximating its ΔDCminusN values to theones found for form MIn an attempt to understand which changes occur in the 5-

FC molecule and consequently the specific supramolecularpatterns formed the UNI Force Field Calculations a tool of theMercury crystallography package4142 was used to establish andcompare the intermolecular potentials of the main interactionsIt is important to highlight that the purpose of this applicationis to display those interactions between molecules which aremost significant in energetic terms without performing thecomputationally expensive lattice energy calculations Thisstudy allowed us to determine that in most of the cases thepotentials of the complementary N1H1middotmiddotmiddotO21 hydrogen bondsare the strongest ranging between minus91 to minus76 kcalmol withthe exception of form T and form M Since this homodimerwas recurrent in all the cocrystals of 5-FC this synthon can be

Figure 6 (a) Crystal packing diagram of form M Black dashed linesindicate hydrogen bonds (I) refers to the R2

2(8) motif37ab involvingthe NminusHmiddotmiddotmiddotO 5-FC homodimers (II) to the R2

2(8) motif37ab involvingthe NminusHmiddotmiddotmiddotO and OminusHmiddotmiddotmiddotN 5-FC heterodimer and (III) to theR64(36) motif37ab (b) three-dimensional hydrogen-bonded network of

form M

Figure 7 Correlation between the CminusN bond length differencesΔDCminusN of the imidic group of 5-FC ring vs the CminusO bond lengthdifferences of the carboxylic fragments ΔDCminusO evidencing theintermediary interface between saltscocrystals of form M Theforms Ma F O and EDATOS refer to the salts of 5-FC with maleicfumaric oxalic and salycilic acids1922

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Figure 8 Comparison of the supramolecular structure of different 5-FC solid forms containing just neutral 5-FC molecules (a) form S (b) form A(c) form T (d) form B (e) form M (f) cocrystal under refcode MECTUL24 (g) solvate under refcode DUKWAI17 (h) polymorph under refcodeMEBQEQ15 (i) polymorph under refcode MEBQEQ0115 (j) cocrystal under refcode MECXID25 (k) cocrystal under refcode MECVUN24 (l)cocrystal under refcode MECWAU24 and (m) cocrystal under refcode MECWEY24 (n) solvate under refcode MEBQOA15 (o) solvate underrefcode MEBQIU15 (p) cocrystal under refcode MECWUO25 (q) cocrystal under refcode MECXEZ25 (r) cocrystal under refcode MECVEX24 (s)cocrystal under refcode MECVIB24 (t) cocrystal under refcode MECWOI24 (u) solvate under refcode DUKWEM17 (v) hydrates of 5-FC (I) underrefcodes BIRMEU14 BIRMEU0116 BIRMEU0215 and (II) under refcode BIRMEU0315 (w) hydrate under refcode PANLAS18 (x) hydratedcocrystal under refcode MECVOH24 (y) hydrated cocrystal under refcode MECXOJ25 (z) hydrate under refcode DUKWIQ17 (1) hydrate underrefcode MEBQUG15 and (2) hydrated cocrystal under refcode GATMUL23

Crystal Growth amp Design Article

dxdoiorg101021cg500502j | Cryst Growth Des 2014 14 4383minus43934389

considered a key piece in the assembly of the cocrystal packingOn the other hand the complementary N41minusH41middotmiddotmiddotN3hydrogen bonds (present in the forms A S T and B) showsmaller potential values ranging between minus55 to minus49 kcalmol As previously discussed form M represents anintermediate state in the border of the saltminuscocrystalcontinuum Instead of the N41minusH41middotmiddotmiddotN3 hydrogen bondspresent in the homodimers we observed interactions occurringamong the 5-FC molecule and the malic acid one (N41minusH41BmiddotmiddotmiddotO4 and O3minusH3middotmiddotmiddotN3) this heterosynthon being typicalof the organic acid salts1922 The potential value of this synthonfor form M is minus97 kcalmol and this one is the highestpotential observed for all interactions present in this crystallineform showing that stronger acids have the ability of competingfor these interactions thus replacing the weaker NminusHmiddotmiddotmiddotN onesIn addition the study of the intermolecular potentials also

allows us to evaluate the strength of the πmiddotmiddotmiddotπ interactionsbetween the layers formed by the 5-FC-acids units Theseinteractions have potentials ranging from minus96 to minus49 kcal

mol agreeing in all the cases with the proximity of the layers inthe 3D supramolecular arrangements A correlation is observedbetween the energy of these interactions and the distance of thelayers form M which displays the closest distance between thelayers also exhibits a high potential (minus82 kcalmol) for theπmiddotmiddotmiddotπ interactions whereas the highest potential observed to theπmiddotmiddotmiddotπ interactions was between terephthalic acid units of form T(minus96 kcalmol) All the potentials calculated are summarizedin Tables A7 B7E77 (see the Supporting InformationSections AminusE)Extending our supramolecular study for the neutral 5-FC

molecules a comparative analysis was performed on the basis ofall the crystalline structures already reported containing 5FCmolecules Polymorphs solvates and cocrystals plus mixturesof them such as solvated cocrystals were also considered 5-FCis a rigid molecule and presents three potential patterns ofhydrogen bonding sites two acceptorminusdonor involving theatoms O21minusN1 and N3minusN41 (ON and NN respectively) andone acceptorminusacceptorminusdonor involving the atoms O21minusN3minus

Table 2 Distribution of the Main Supramolecular Synthons Observed for the Different 5-FC Solid Forms Containing JustNeutral 5-FC

NminusHmiddotmiddotmiddotO NminusHmiddotmiddotmiddotN NminusHmiddotmiddotmiddotO NminusHmiddotmiddotmiddotNCG-like base

pairing

structurea homo hetero homo hetero homo hetero homo hetero planar cavity tubular cavity 5-FC ribbons

a radic radic radic radicb radic radic radic radicc radic radic radic radicd radic radic radic radice radic radic radic radicf radic radicg radich radic radici radic radicj radic radic radick radic radic radicl radic radic radic radicm radic radic radicn radic radic radico radic radic radicp radic radic radicq radic radicr radic radic radic radics radic radic radict radic radicu radic radic radic radicv(I) radic radic radicv(II) radic radic radic radicw radic radic radicx radic radicy radic radicz radic radic radic radic1 radic radic radic2 radic radic radic

aComparison of the supramolecular structure of different 5-FC solid forms containing just neutral 5-FC molecules (a) form S (b) form A (c) formT (d) form B (e) form M (f) cocrystal under refcode MECTUL24 (g) solvate under refcode DUKWAI17 (h) polymorph under refcodeMEBQEQ15 (i) polymorph under refcode MEBQEQ0115 (j) cocrystal under refcode MECXID25 (k) cocrystal under refcode MECVUN24 (l)cocrystal under refcode MECWAU24 and (m) cocrystal under refcode MECWEY24 (n) solvate under refcode MEBQOA15 (o) solvate underrefcode MEBQIU15 (p) cocrystal under refcode MECWUO25 (q) cocrystal under refcode MECXEZ25 (r) cocrystal under refcode MECVEX24 (s)cocrystal under refcode MECVIB24 (t) cocrystal under refcode MECWOI24 (u) solvate under refcode DUKWEM17 (v) hydrates of 5-FC (I) underrefcodes BIRMEU14 BIRMEU0116 BIRMEU0215 and (II) under refcode BIRMEU0315 (w) hydrate under refcode PANLAS18 (x) hydratedcocrystal under refcode MECVOH24 (y) hydrated cocrystal under refcode MECXOJ25 (z) hydrate under refcode DUKWIQ17 (1) hydrate underrefcode MEBQUG15 and (2) hydrated cocrystal under refcode GATMUL23

Crystal Growth amp Design Article

dxdoiorg101021cg500502j | Cryst Growth Des 2014 14 4383minus43934390

N41 (ONN) Tutughamiarso and co-workers17 showed that the5-FC molecule when neutral tends to interact to one anotherby self-complementary homodimers constituting planar ortubular 5-FC ribbons These homodimers as observed in thecocrystals depicted here are essentially composed by one NminusHmiddotmiddotmiddotO and one NminusHmiddotmiddotmiddotN (ONNN) or by two NminusHmiddotmiddotmiddotO(ONON) or even by two NminusHmiddotmiddotmiddotN (NNNN) intermo-lecular interactions Complementing this claim Figure 8exhibits a schematic drawing of the classical intermolecularinteractions of each reported structure considering the wholesupramolecular architecture adopted by the 5-FC moleculesunder the different crystalline arrangements It shows that notonly ribbons are observed but also planar andor tubularcavities mainly due to the intrinsic geometry of the ON NNONN hydrogen bonding sites Furthermore Table 2 exhibits astatistical analysis of the distribution of the main supra-molecular synthons observed for the 5-FC molecule includinghomo- and heterodimers involving the three main hydrogenbonding sites (ONON ONNN and NNNN) plus theformation of homo- and heterotrimers with hydrogen bondingpatterns similar to the CG Watson and Crick base pairingAccording to Table 2 the 5-FC molecule tends to form ON

NN ONON and NNNN homodimers Tutughamiarso andco-workers17 observed the particular NNNN homodimerformation only in the hydrate under refcode BIRMEU0315

reporting later a cocrystal of 5-FC under refcode MECTUL24

also exhibiting this pattern of NNNN homodimer formationThe forms S T A and B however exhibit the same ribbonformation that occurs for the hydrate under refcodeBIRMEU0315 ie ONON and NNNN R2

2(8) motifs37ab

per 5-FC molecule while in the 5-FC cocrystal under refcodeMECTUL24 the free ON site of the 5-FC molecule isintercepted by the formation of a ONNN heterodimer withthe coformer molecule In addition two ONNN (refcodesMECVIB24 and e GATMUL23) and two ONON heterodimers(refcodes MECWUO25 and GATMUL23) are observedHowever no NNNN heterodimer was reported until thepresentOn the other hand for the ONN CG-like base pairing the

tendency is the formation of heterosynthons with a total of ninestructures Only in one hydrate (refcode PANLAS18) the CG-like base pairing is observed between the 5-FC molecules Byanalyzing the crystalline packing of the 5-FC cocrystal underrefcode MECTUL24 (see Figure 8f) the occurrence of oneONNN heterodimer disrupts the 5-FC ribbon formationAlthough homoribbons (ie ribbons constituted only by 5-FCmolecules) are prevalent in most of the crystalline structures12 of them exhibit heteroribbons and all refer to cocrystals (2cocrystals and 10 solvated cocrystals)By considering the cavity formation two exceptions arise

one referring to the cocrystal under refcode MECTUL24

(Figure 8f) where flat layers are stacked by van der Waalscontacts and one referring to the solvate under refcodeDUKWAI17 (Figure 8g) for which small cavities are observedonly when the nonclassical CminusHmiddotmiddotmiddotO and CminusHmiddotmiddotmiddotF intermo-lecular interactions between the dimethyl sulfoxide and 5-FCmolecules are considered Both reported polymorphs of 5-FCexhibit tubular patterns (Figure 8h (i) constituting R4

4(24) andR64(26) motifs involving four and six 5-FC molecules

respectively Forms S A and T (Figure 8aminusc) exhibit similarcavities differing only in their size (R6

4(40) R64(48) R6

4(44) forforms S A and T respectively) proportional to the size andthe geometry of each acid molecule Figure 8h exhibits the last

planar cavity R76(44) involving only solid coformers

concerning the cocrystal under refcode MECXID25 Whensolvents are involved in the interactions they lead to planar andtubular cavities for which it is not possible to establish aspecific pattern for these ternary systems In particular thecocrystal under refcode MECVEX24 (Figure 8r) and thehydrate under refcode DUKWIQ17 (Figure 8z) display cavitiesof both tubular and planar types It is worth mentioning thatthe planar cavities of the methanol solvate under refcodeMEBQOA15 (Figure 8 (l)) of the cocrystal under refcodeMECVEX24 (Figure 8r) and of the hydrate under refcodeDUKWIQ17 (Figure 8z) are similar to the one formed in formsS A and T This shows that the recurrent supramolecularsynthon observed for the cocrystals depicted herein is notrestricted to the use of carboxylic acids as coformers In thisway it could be expected that new structures containing 5-FCmolecule can be designed and developed as new tailor-madedrugs

42 Cocrystal of 5-FC and 5-FU 5-Fluorouracil 5-fluoro-24-(1H3H)-pyrimidinedione is an antineoplastic API ration-ally designed by Heidelberger and co-workers in 195743 It isused for the treatment of superficial skin carcinomas as a creamformulation and as injections in the treatment of variouscancers including among others gastrointestinal head andneck breast colorectal and ovarian 5-FU is a syntheticpyrimidine analogue and is probably the most widely usedbeing of great interest in the clinical and experimentalchemotherapy among the developed analogues of purine andpyrimidine as it is structurally similar to natural basesNevertheless only a fraction of the administered amount ofthis API becomes available in the systemic circulation after oraladministration due to its poor water solubility44minus46 Indeedoral delivery of antineoplastic APIs is considered a challengedue their physical and chemical properties and physiologicalbarriers47

As an illustration of a controlled rational supramolecularsynthesis of new solid forms of a given API using 5-FC ascoformer we designed a cocrystal of 5-FC and 5-FU (form 5FpKa = 80)44 It is clear that the 5-FU was our first molecule ofchoice for this example due to its structural similarities with 5-FC The cocrystallization experiment was developed accordingto the pKa rule and a cocrystal was expected (ΔpKa = minus474)The aim of this particular experiment was to design a new solidform of 5-FU with enhanced physical and chemical propertiesthat could enable this API to be orally administered togetherwith 5-FC which in turn exhibits high solubility andbioavailability profiles10 However the solubility properties ofform 5-FU are still under investigationThe asymmetric unit of form 5F (see Figure 1) exhibits one

molecule of 5-FC and one of 5-FU The main intermolecularinteractions responsible for maintaining the crystalline arrange-ment of this cocrystal are of the types NminusHmiddotmiddotmiddotO and NminusHmiddotmiddotmiddotF(see Table S1 in the Supporting Information section) includingthe formation of homodimers of 5-FC (I in Figure 9a)homodimers of 5-FU (II in Figure 9a) and intermolecularinteractions among the 5-FC and 5-FU molecules (Figure 9a)Nonclassical intermolecular interactions are also present as aresult of the close packing C6minusH6middotmiddotmiddotF51 (bond distance of2467 Aring) C6primeminusH6primemiddotmiddotmiddotF51prime (bond distance of 2354 Aring) C6primeminusH6primemiddotmiddotmiddotN3 (bond distance of 2639 Aring) and C6minusH6middotmiddotmiddotO21prime(bond distance of 2553 Aring) The crystal packing of form 5F iscomposed of flat tapes in which the dimers are interspersedThese tapes are stacked constituting columns with a parallel

Crystal Growth amp Design Article

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displaced arrangement (displacement angle of 232deg) main-tained by πmiddotmiddotmiddotπ interactions (5-FCπmiddotmiddotmiddotπ = 35604(9) Aring and 5-FUπmiddotmiddotmiddotπ = 35603(9)Aring) Adjacent tapes (and consequentlyadjacent columns) exhibit two directions of growth and areconnected to one another by intermolecular interactionsbetween the molecules of 5-FC and 5-FU forming a dihedralangle of 13017(3)deg (Figure 9b)

5 CONCLUSIONThe 5-FC cocrystals with succinic adipic benzoic and tereftalicacids were obtained following the tendency of the pKa rule andhave revealed a similar hydrogen-bonding pattern leading to 5-FC ribbons stabilized by two R2

2(8) motifs characterized bycomplementary homodimeric NminusHmiddotmiddotmiddotN (NNNN) and NminusHmiddotmiddotmiddotO (ONON) interactions which was found to be a featureof cocrystals containing this fluoropyrimidine moleculesAnalyzing the supramolecular characteristics of the four 5-FCcocrystals (together with some similar structures reported inthe literature) it was observed that the 5-FC molecule tends toform ONNN ONON and NNNN homodimers ONNCG-like base pairing heterotrimers and both tubular andplanar cavities Nevertheless when the cocrystallization experi-ment was conducted with malic acid where the ΔpKa = minus01 asupramolecular transition synthon was observed in which theNminusHmiddotmiddotmiddotO homodimeric synthon present in the cocrystalsremains but a new heterodimeric synthon characterized bycomplementary NminusHmiddotmiddotmiddotO hydrogen bonds between the 5-FCmolecule and the malic acid emerged This last synthon wasfound in the 5-FC organic salts obtained even from very smallpositive ΔpKa values (such as for the fumarate of 5-FC whereΔpKa = 023) The discovery of this transition synthonindicates that the 5-FC molecule is a suitable candidate forthe design and development of cocrystallization experimentsbased on crystal engineering techniques once its behaviorcould be until the present well predicted by the pKa rule Tocheck our hypothesis we conducted a cocrystallizationexperiment of 5-FC with the antineoplastic drug 5-FU aimingto obtain a cocrystal once the system exhibits a ΔpKa = minus30The success of this experiment points to a new path to apply 5-

FC as a coformer in new controlled crystallization experimentsfor the development of new tailor-made drugs

ASSOCIATED CONTENTS Supporting InformationCrystallographic data of the 5-FC calculated potentials Thismaterial is available free of charge via the Internet at httppubsacsorg

AUTHOR INFORMATIONCorresponding AuthorE-mail javiereifscuspbr Phone +55 16 3373 8096 Fax+55 16 3373 9881NotesThe authors declare no competing financial interest

ACKNOWLEDGMENTSWe thank CAPES (CCPS) FAPESP (JCT Project No201307581-9) and CNPq (JE ROP CCM Project No1500762013-4) for the financial support We also thank forthe use of the APEX II Bruker difractometer to ldquoFacility foradvanced studies of materialsFAMardquo (FAPESP Project No2009540354)

REFERENCES(1) Almarsson O Zaworotko M J Chem Commun (Cambridge)2004 17 1889minus1896(2) Blagden N de Matas M Gavan P T York P Adv DrugDelivery Rev 2007 59 (7) 617minus630(3) Bond A D In Pharmaceutical Salts and Co-Crystals Wouters JQuere L Eds The Royal Society of Chemistry Cambridge UK2012 Chapter 2 pp 9minus28(4) Vishweshwar P McMahon J A Peterson M L Hickey M BShattock T R Zaworotko M J Chem Commu 2005 36 4601minus4603(5) Aakeroy C B Fasulo M E Desper J Mol Pharmaceutics 20074 (3) 317minus322(6) Trask A V Mol Pharmaceutics 2007 4 (3) 301minus309(7) GRAS S Food and Drug Administration Database of SelectCommittee on GRAS Substances (SCOGS) Reviews httpswwwaccessdatafdagovscriptsfcnfcnNavigationcfmrpt=scogsListing(8) Shan N Zaworotko M J Drug Discovery Today 2008 13 (9minus10) 440minus446(9) Hoffman M Lindeman J A In Pharmaceutical Salts and Co-crystals Wouters J Quere L Eds The Royal Society of ChemistryCambridge UK 2012 Chapter 14 pp 318 minus 329(10) Vermes A Guchelaar H-J Dankert J J AntimicrobChemother 2000 46 (2) 171minus179(11) Larsen R A In Essentials of Clinical Mycology 2nd edKauffman C A Pappas P G Sobel J D Dismukes W E EdsOxford University Press UK 2003 part 2 pp 57minus60(12) Mullen C A Coale M M Lowe R Blaese R M Cancer Res1994 54 (6) 1503minus1506(13) Allen F H Acta Crystallogr Sect B 2002 58 (3) 380minus388(14) Louis T Low J N Tollin P Cryst Struct Commun 1982 111059minus1064(15) Hulme A T Tocher D A CrystGrowth Des 2006 6 (2)481minus487(16) Portalone G Colapietro M Acta Crystallogr Sect E 2006 62(3) o1049minuso1051(17) Tutughamiarso M Bolte M Egert E Acta Crystallogr Sect C2009 65 (11) o574minuso578(18) Hulme A T Tocher D A Acta Crystallogr Sect E 2005 61(7) 02112minuso2113(19) Prabakaran P Murugesan S Muthiah P T Bocelli G RighiL Acta Crystallogr Sect E 2001 57 (10) o933minuso936

Figure 9 (a) Crystal packing diagram of form 5f Black dashed linesindicate hydrogen bonds (I) refers to the R2

2(8) motifs37ab involvingthe NminusHmiddotmiddotmiddotO homodimers occurring among 5-FC molecules and (II)correspond to R2

2(8) motifs37ab involving the NminusHmiddotmiddotmiddotO homodimersoccurring among 5-FU molecules (b) three-dimensional hydrogen-bonded network of form 5f

Crystal Growth amp Design Article

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dicarboxylic acids fumaric maleic and oxalic The structureswere obtained from the continuum to the salt part of thespectrum according to the pKa rule where the ΔpKa valueranged between 0 and positive values Due the complementar-ity among the carboxylic group and the functional groupspresent in the 5-FC molecules all the salts exhibited the sameR22(8) motif constituting heterodimers via N41minusH41AmiddotmiddotmiddotO4

and N3+minusH3middotmiddotmiddotO3minus hydrogen bonds The same supramolecularsynthon was observed for the salicylate of 5-FC reported byPortalone and Colapietro in 200720 On the other hand whenwe go to the other side of the spectrum ie when weakerdicarboxylic acids are used as coformers changes occur in theionicity of the 5-FC molecule and new supramolecularsynthons overcome According to Mukherjee and Desiraju40

cocrystal formation is usually expected to occur whenheterosynthons are formed over homosynthons However forthe cocrystals of 5-FC with succinic adipic benzoic andterephtalic acids instead of heterodimers we observehomodimers occurring among the 5-FC molecules accessedthrough complementary N41minusH41middotmiddotmiddotN3 and N1minusH1middotmiddotmiddotO21hydrogen bonds Nevertheless for a ΔpKa very close to 0(ldquocutoffrdquo among cocrystals and salts for this fluoropyrimidine)as in form M (ΔpKa = minus01) a supramolecular transition

synthon is observed In this cocrystal the crystal packing stillpreserves the heterodimer observed in the salts except for thefact that no proton transfer is observed but also exhibits theN1minusH1middotmiddotmiddotO21 homodimer among the 5-FC molecules For thishomodimer which is common in all cocrystals the 5-FCcarbonyl bond lengths go from 1265 to 1249 Aring These valuesare significantly higher than the ones found for the 5-FC salts(1232 to 1219 Aring) It is clear that this feature is the result of theprotonation where the charge redistribution implies on areduction of the carbonyl bond lengths which in turn does notfavor the geometric requirements for the formation of thesynthon needed for the establishment of the homodimerspresent in the cocrystals However the geometric features ofthe form M show intermediate values for the carbonyl bondlengths suggesting a partial charge redistribution that may leadto a hybrid saltcocrystal specie Indeed this form shows thesalts heterodimer synthon even without protonation possiblydue the intermediate strength of malic acid (pKa = 340) Thistransition state becomes clearer when a correlation plotbetween the variations of the CminusO bond lengths in thecarboxylic fragments (ΔDCminusO) of the coformers and thevariations of the CminusN bond lengths (ΔDCminusN) of the imidicfragments of the 5FC ring is carried out (Figure 7) It is worth

mentioning that the fumarate salt of 5-FC22 (form F) ishydrated and the presence of water molecules in its crystalpacking result in changes in the intermolecular interactionpatterns leading to a different behavior of the 5-FC intra-molecular bond lengths approximating its ΔDCminusN values to theones found for form MIn an attempt to understand which changes occur in the 5-

FC molecule and consequently the specific supramolecularpatterns formed the UNI Force Field Calculations a tool of theMercury crystallography package4142 was used to establish andcompare the intermolecular potentials of the main interactionsIt is important to highlight that the purpose of this applicationis to display those interactions between molecules which aremost significant in energetic terms without performing thecomputationally expensive lattice energy calculations Thisstudy allowed us to determine that in most of the cases thepotentials of the complementary N1H1middotmiddotmiddotO21 hydrogen bondsare the strongest ranging between minus91 to minus76 kcalmol withthe exception of form T and form M Since this homodimerwas recurrent in all the cocrystals of 5-FC this synthon can be

Figure 6 (a) Crystal packing diagram of form M Black dashed linesindicate hydrogen bonds (I) refers to the R2

2(8) motif37ab involvingthe NminusHmiddotmiddotmiddotO 5-FC homodimers (II) to the R2

2(8) motif37ab involvingthe NminusHmiddotmiddotmiddotO and OminusHmiddotmiddotmiddotN 5-FC heterodimer and (III) to theR64(36) motif37ab (b) three-dimensional hydrogen-bonded network of

form M

Figure 7 Correlation between the CminusN bond length differencesΔDCminusN of the imidic group of 5-FC ring vs the CminusO bond lengthdifferences of the carboxylic fragments ΔDCminusO evidencing theintermediary interface between saltscocrystals of form M Theforms Ma F O and EDATOS refer to the salts of 5-FC with maleicfumaric oxalic and salycilic acids1922

Crystal Growth amp Design Article

dxdoiorg101021cg500502j | Cryst Growth Des 2014 14 4383minus43934388

Figure 8 Comparison of the supramolecular structure of different 5-FC solid forms containing just neutral 5-FC molecules (a) form S (b) form A(c) form T (d) form B (e) form M (f) cocrystal under refcode MECTUL24 (g) solvate under refcode DUKWAI17 (h) polymorph under refcodeMEBQEQ15 (i) polymorph under refcode MEBQEQ0115 (j) cocrystal under refcode MECXID25 (k) cocrystal under refcode MECVUN24 (l)cocrystal under refcode MECWAU24 and (m) cocrystal under refcode MECWEY24 (n) solvate under refcode MEBQOA15 (o) solvate underrefcode MEBQIU15 (p) cocrystal under refcode MECWUO25 (q) cocrystal under refcode MECXEZ25 (r) cocrystal under refcode MECVEX24 (s)cocrystal under refcode MECVIB24 (t) cocrystal under refcode MECWOI24 (u) solvate under refcode DUKWEM17 (v) hydrates of 5-FC (I) underrefcodes BIRMEU14 BIRMEU0116 BIRMEU0215 and (II) under refcode BIRMEU0315 (w) hydrate under refcode PANLAS18 (x) hydratedcocrystal under refcode MECVOH24 (y) hydrated cocrystal under refcode MECXOJ25 (z) hydrate under refcode DUKWIQ17 (1) hydrate underrefcode MEBQUG15 and (2) hydrated cocrystal under refcode GATMUL23

Crystal Growth amp Design Article

dxdoiorg101021cg500502j | Cryst Growth Des 2014 14 4383minus43934389

considered a key piece in the assembly of the cocrystal packingOn the other hand the complementary N41minusH41middotmiddotmiddotN3hydrogen bonds (present in the forms A S T and B) showsmaller potential values ranging between minus55 to minus49 kcalmol As previously discussed form M represents anintermediate state in the border of the saltminuscocrystalcontinuum Instead of the N41minusH41middotmiddotmiddotN3 hydrogen bondspresent in the homodimers we observed interactions occurringamong the 5-FC molecule and the malic acid one (N41minusH41BmiddotmiddotmiddotO4 and O3minusH3middotmiddotmiddotN3) this heterosynthon being typicalof the organic acid salts1922 The potential value of this synthonfor form M is minus97 kcalmol and this one is the highestpotential observed for all interactions present in this crystallineform showing that stronger acids have the ability of competingfor these interactions thus replacing the weaker NminusHmiddotmiddotmiddotN onesIn addition the study of the intermolecular potentials also

allows us to evaluate the strength of the πmiddotmiddotmiddotπ interactionsbetween the layers formed by the 5-FC-acids units Theseinteractions have potentials ranging from minus96 to minus49 kcal

mol agreeing in all the cases with the proximity of the layers inthe 3D supramolecular arrangements A correlation is observedbetween the energy of these interactions and the distance of thelayers form M which displays the closest distance between thelayers also exhibits a high potential (minus82 kcalmol) for theπmiddotmiddotmiddotπ interactions whereas the highest potential observed to theπmiddotmiddotmiddotπ interactions was between terephthalic acid units of form T(minus96 kcalmol) All the potentials calculated are summarizedin Tables A7 B7E77 (see the Supporting InformationSections AminusE)Extending our supramolecular study for the neutral 5-FC

molecules a comparative analysis was performed on the basis ofall the crystalline structures already reported containing 5FCmolecules Polymorphs solvates and cocrystals plus mixturesof them such as solvated cocrystals were also considered 5-FCis a rigid molecule and presents three potential patterns ofhydrogen bonding sites two acceptorminusdonor involving theatoms O21minusN1 and N3minusN41 (ON and NN respectively) andone acceptorminusacceptorminusdonor involving the atoms O21minusN3minus

Table 2 Distribution of the Main Supramolecular Synthons Observed for the Different 5-FC Solid Forms Containing JustNeutral 5-FC

NminusHmiddotmiddotmiddotO NminusHmiddotmiddotmiddotN NminusHmiddotmiddotmiddotO NminusHmiddotmiddotmiddotNCG-like base

pairing

structurea homo hetero homo hetero homo hetero homo hetero planar cavity tubular cavity 5-FC ribbons

a radic radic radic radicb radic radic radic radicc radic radic radic radicd radic radic radic radice radic radic radic radicf radic radicg radich radic radici radic radicj radic radic radick radic radic radicl radic radic radic radicm radic radic radicn radic radic radico radic radic radicp radic radic radicq radic radicr radic radic radic radics radic radic radict radic radicu radic radic radic radicv(I) radic radic radicv(II) radic radic radic radicw radic radic radicx radic radicy radic radicz radic radic radic radic1 radic radic radic2 radic radic radic

aComparison of the supramolecular structure of different 5-FC solid forms containing just neutral 5-FC molecules (a) form S (b) form A (c) formT (d) form B (e) form M (f) cocrystal under refcode MECTUL24 (g) solvate under refcode DUKWAI17 (h) polymorph under refcodeMEBQEQ15 (i) polymorph under refcode MEBQEQ0115 (j) cocrystal under refcode MECXID25 (k) cocrystal under refcode MECVUN24 (l)cocrystal under refcode MECWAU24 and (m) cocrystal under refcode MECWEY24 (n) solvate under refcode MEBQOA15 (o) solvate underrefcode MEBQIU15 (p) cocrystal under refcode MECWUO25 (q) cocrystal under refcode MECXEZ25 (r) cocrystal under refcode MECVEX24 (s)cocrystal under refcode MECVIB24 (t) cocrystal under refcode MECWOI24 (u) solvate under refcode DUKWEM17 (v) hydrates of 5-FC (I) underrefcodes BIRMEU14 BIRMEU0116 BIRMEU0215 and (II) under refcode BIRMEU0315 (w) hydrate under refcode PANLAS18 (x) hydratedcocrystal under refcode MECVOH24 (y) hydrated cocrystal under refcode MECXOJ25 (z) hydrate under refcode DUKWIQ17 (1) hydrate underrefcode MEBQUG15 and (2) hydrated cocrystal under refcode GATMUL23

Crystal Growth amp Design Article

dxdoiorg101021cg500502j | Cryst Growth Des 2014 14 4383minus43934390

N41 (ONN) Tutughamiarso and co-workers17 showed that the5-FC molecule when neutral tends to interact to one anotherby self-complementary homodimers constituting planar ortubular 5-FC ribbons These homodimers as observed in thecocrystals depicted here are essentially composed by one NminusHmiddotmiddotmiddotO and one NminusHmiddotmiddotmiddotN (ONNN) or by two NminusHmiddotmiddotmiddotO(ONON) or even by two NminusHmiddotmiddotmiddotN (NNNN) intermo-lecular interactions Complementing this claim Figure 8exhibits a schematic drawing of the classical intermolecularinteractions of each reported structure considering the wholesupramolecular architecture adopted by the 5-FC moleculesunder the different crystalline arrangements It shows that notonly ribbons are observed but also planar andor tubularcavities mainly due to the intrinsic geometry of the ON NNONN hydrogen bonding sites Furthermore Table 2 exhibits astatistical analysis of the distribution of the main supra-molecular synthons observed for the 5-FC molecule includinghomo- and heterodimers involving the three main hydrogenbonding sites (ONON ONNN and NNNN) plus theformation of homo- and heterotrimers with hydrogen bondingpatterns similar to the CG Watson and Crick base pairingAccording to Table 2 the 5-FC molecule tends to form ON

NN ONON and NNNN homodimers Tutughamiarso andco-workers17 observed the particular NNNN homodimerformation only in the hydrate under refcode BIRMEU0315

reporting later a cocrystal of 5-FC under refcode MECTUL24

also exhibiting this pattern of NNNN homodimer formationThe forms S T A and B however exhibit the same ribbonformation that occurs for the hydrate under refcodeBIRMEU0315 ie ONON and NNNN R2

2(8) motifs37ab

per 5-FC molecule while in the 5-FC cocrystal under refcodeMECTUL24 the free ON site of the 5-FC molecule isintercepted by the formation of a ONNN heterodimer withthe coformer molecule In addition two ONNN (refcodesMECVIB24 and e GATMUL23) and two ONON heterodimers(refcodes MECWUO25 and GATMUL23) are observedHowever no NNNN heterodimer was reported until thepresentOn the other hand for the ONN CG-like base pairing the

tendency is the formation of heterosynthons with a total of ninestructures Only in one hydrate (refcode PANLAS18) the CG-like base pairing is observed between the 5-FC molecules Byanalyzing the crystalline packing of the 5-FC cocrystal underrefcode MECTUL24 (see Figure 8f) the occurrence of oneONNN heterodimer disrupts the 5-FC ribbon formationAlthough homoribbons (ie ribbons constituted only by 5-FCmolecules) are prevalent in most of the crystalline structures12 of them exhibit heteroribbons and all refer to cocrystals (2cocrystals and 10 solvated cocrystals)By considering the cavity formation two exceptions arise

one referring to the cocrystal under refcode MECTUL24

(Figure 8f) where flat layers are stacked by van der Waalscontacts and one referring to the solvate under refcodeDUKWAI17 (Figure 8g) for which small cavities are observedonly when the nonclassical CminusHmiddotmiddotmiddotO and CminusHmiddotmiddotmiddotF intermo-lecular interactions between the dimethyl sulfoxide and 5-FCmolecules are considered Both reported polymorphs of 5-FCexhibit tubular patterns (Figure 8h (i) constituting R4

4(24) andR64(26) motifs involving four and six 5-FC molecules

respectively Forms S A and T (Figure 8aminusc) exhibit similarcavities differing only in their size (R6

4(40) R64(48) R6

4(44) forforms S A and T respectively) proportional to the size andthe geometry of each acid molecule Figure 8h exhibits the last

planar cavity R76(44) involving only solid coformers

concerning the cocrystal under refcode MECXID25 Whensolvents are involved in the interactions they lead to planar andtubular cavities for which it is not possible to establish aspecific pattern for these ternary systems In particular thecocrystal under refcode MECVEX24 (Figure 8r) and thehydrate under refcode DUKWIQ17 (Figure 8z) display cavitiesof both tubular and planar types It is worth mentioning thatthe planar cavities of the methanol solvate under refcodeMEBQOA15 (Figure 8 (l)) of the cocrystal under refcodeMECVEX24 (Figure 8r) and of the hydrate under refcodeDUKWIQ17 (Figure 8z) are similar to the one formed in formsS A and T This shows that the recurrent supramolecularsynthon observed for the cocrystals depicted herein is notrestricted to the use of carboxylic acids as coformers In thisway it could be expected that new structures containing 5-FCmolecule can be designed and developed as new tailor-madedrugs

42 Cocrystal of 5-FC and 5-FU 5-Fluorouracil 5-fluoro-24-(1H3H)-pyrimidinedione is an antineoplastic API ration-ally designed by Heidelberger and co-workers in 195743 It isused for the treatment of superficial skin carcinomas as a creamformulation and as injections in the treatment of variouscancers including among others gastrointestinal head andneck breast colorectal and ovarian 5-FU is a syntheticpyrimidine analogue and is probably the most widely usedbeing of great interest in the clinical and experimentalchemotherapy among the developed analogues of purine andpyrimidine as it is structurally similar to natural basesNevertheless only a fraction of the administered amount ofthis API becomes available in the systemic circulation after oraladministration due to its poor water solubility44minus46 Indeedoral delivery of antineoplastic APIs is considered a challengedue their physical and chemical properties and physiologicalbarriers47

As an illustration of a controlled rational supramolecularsynthesis of new solid forms of a given API using 5-FC ascoformer we designed a cocrystal of 5-FC and 5-FU (form 5FpKa = 80)44 It is clear that the 5-FU was our first molecule ofchoice for this example due to its structural similarities with 5-FC The cocrystallization experiment was developed accordingto the pKa rule and a cocrystal was expected (ΔpKa = minus474)The aim of this particular experiment was to design a new solidform of 5-FU with enhanced physical and chemical propertiesthat could enable this API to be orally administered togetherwith 5-FC which in turn exhibits high solubility andbioavailability profiles10 However the solubility properties ofform 5-FU are still under investigationThe asymmetric unit of form 5F (see Figure 1) exhibits one

molecule of 5-FC and one of 5-FU The main intermolecularinteractions responsible for maintaining the crystalline arrange-ment of this cocrystal are of the types NminusHmiddotmiddotmiddotO and NminusHmiddotmiddotmiddotF(see Table S1 in the Supporting Information section) includingthe formation of homodimers of 5-FC (I in Figure 9a)homodimers of 5-FU (II in Figure 9a) and intermolecularinteractions among the 5-FC and 5-FU molecules (Figure 9a)Nonclassical intermolecular interactions are also present as aresult of the close packing C6minusH6middotmiddotmiddotF51 (bond distance of2467 Aring) C6primeminusH6primemiddotmiddotmiddotF51prime (bond distance of 2354 Aring) C6primeminusH6primemiddotmiddotmiddotN3 (bond distance of 2639 Aring) and C6minusH6middotmiddotmiddotO21prime(bond distance of 2553 Aring) The crystal packing of form 5F iscomposed of flat tapes in which the dimers are interspersedThese tapes are stacked constituting columns with a parallel

Crystal Growth amp Design Article

dxdoiorg101021cg500502j | Cryst Growth Des 2014 14 4383minus43934391

displaced arrangement (displacement angle of 232deg) main-tained by πmiddotmiddotmiddotπ interactions (5-FCπmiddotmiddotmiddotπ = 35604(9) Aring and 5-FUπmiddotmiddotmiddotπ = 35603(9)Aring) Adjacent tapes (and consequentlyadjacent columns) exhibit two directions of growth and areconnected to one another by intermolecular interactionsbetween the molecules of 5-FC and 5-FU forming a dihedralangle of 13017(3)deg (Figure 9b)

5 CONCLUSIONThe 5-FC cocrystals with succinic adipic benzoic and tereftalicacids were obtained following the tendency of the pKa rule andhave revealed a similar hydrogen-bonding pattern leading to 5-FC ribbons stabilized by two R2

2(8) motifs characterized bycomplementary homodimeric NminusHmiddotmiddotmiddotN (NNNN) and NminusHmiddotmiddotmiddotO (ONON) interactions which was found to be a featureof cocrystals containing this fluoropyrimidine moleculesAnalyzing the supramolecular characteristics of the four 5-FCcocrystals (together with some similar structures reported inthe literature) it was observed that the 5-FC molecule tends toform ONNN ONON and NNNN homodimers ONNCG-like base pairing heterotrimers and both tubular andplanar cavities Nevertheless when the cocrystallization experi-ment was conducted with malic acid where the ΔpKa = minus01 asupramolecular transition synthon was observed in which theNminusHmiddotmiddotmiddotO homodimeric synthon present in the cocrystalsremains but a new heterodimeric synthon characterized bycomplementary NminusHmiddotmiddotmiddotO hydrogen bonds between the 5-FCmolecule and the malic acid emerged This last synthon wasfound in the 5-FC organic salts obtained even from very smallpositive ΔpKa values (such as for the fumarate of 5-FC whereΔpKa = 023) The discovery of this transition synthonindicates that the 5-FC molecule is a suitable candidate forthe design and development of cocrystallization experimentsbased on crystal engineering techniques once its behaviorcould be until the present well predicted by the pKa rule Tocheck our hypothesis we conducted a cocrystallizationexperiment of 5-FC with the antineoplastic drug 5-FU aimingto obtain a cocrystal once the system exhibits a ΔpKa = minus30The success of this experiment points to a new path to apply 5-

FC as a coformer in new controlled crystallization experimentsfor the development of new tailor-made drugs

ASSOCIATED CONTENTS Supporting InformationCrystallographic data of the 5-FC calculated potentials Thismaterial is available free of charge via the Internet at httppubsacsorg

AUTHOR INFORMATIONCorresponding AuthorE-mail javiereifscuspbr Phone +55 16 3373 8096 Fax+55 16 3373 9881NotesThe authors declare no competing financial interest

ACKNOWLEDGMENTSWe thank CAPES (CCPS) FAPESP (JCT Project No201307581-9) and CNPq (JE ROP CCM Project No1500762013-4) for the financial support We also thank forthe use of the APEX II Bruker difractometer to ldquoFacility foradvanced studies of materialsFAMardquo (FAPESP Project No2009540354)

REFERENCES(1) Almarsson O Zaworotko M J Chem Commun (Cambridge)2004 17 1889minus1896(2) Blagden N de Matas M Gavan P T York P Adv DrugDelivery Rev 2007 59 (7) 617minus630(3) Bond A D In Pharmaceutical Salts and Co-Crystals Wouters JQuere L Eds The Royal Society of Chemistry Cambridge UK2012 Chapter 2 pp 9minus28(4) Vishweshwar P McMahon J A Peterson M L Hickey M BShattock T R Zaworotko M J Chem Commu 2005 36 4601minus4603(5) Aakeroy C B Fasulo M E Desper J Mol Pharmaceutics 20074 (3) 317minus322(6) Trask A V Mol Pharmaceutics 2007 4 (3) 301minus309(7) GRAS S Food and Drug Administration Database of SelectCommittee on GRAS Substances (SCOGS) Reviews httpswwwaccessdatafdagovscriptsfcnfcnNavigationcfmrpt=scogsListing(8) Shan N Zaworotko M J Drug Discovery Today 2008 13 (9minus10) 440minus446(9) Hoffman M Lindeman J A In Pharmaceutical Salts and Co-crystals Wouters J Quere L Eds The Royal Society of ChemistryCambridge UK 2012 Chapter 14 pp 318 minus 329(10) Vermes A Guchelaar H-J Dankert J J AntimicrobChemother 2000 46 (2) 171minus179(11) Larsen R A In Essentials of Clinical Mycology 2nd edKauffman C A Pappas P G Sobel J D Dismukes W E EdsOxford University Press UK 2003 part 2 pp 57minus60(12) Mullen C A Coale M M Lowe R Blaese R M Cancer Res1994 54 (6) 1503minus1506(13) Allen F H Acta Crystallogr Sect B 2002 58 (3) 380minus388(14) Louis T Low J N Tollin P Cryst Struct Commun 1982 111059minus1064(15) Hulme A T Tocher D A CrystGrowth Des 2006 6 (2)481minus487(16) Portalone G Colapietro M Acta Crystallogr Sect E 2006 62(3) o1049minuso1051(17) Tutughamiarso M Bolte M Egert E Acta Crystallogr Sect C2009 65 (11) o574minuso578(18) Hulme A T Tocher D A Acta Crystallogr Sect E 2005 61(7) 02112minuso2113(19) Prabakaran P Murugesan S Muthiah P T Bocelli G RighiL Acta Crystallogr Sect E 2001 57 (10) o933minuso936

Figure 9 (a) Crystal packing diagram of form 5f Black dashed linesindicate hydrogen bonds (I) refers to the R2

2(8) motifs37ab involvingthe NminusHmiddotmiddotmiddotO homodimers occurring among 5-FC molecules and (II)correspond to R2

2(8) motifs37ab involving the NminusHmiddotmiddotmiddotO homodimersoccurring among 5-FU molecules (b) three-dimensional hydrogen-bonded network of form 5f

Crystal Growth amp Design Article

dxdoiorg101021cg500502j | Cryst Growth Des 2014 14 4383minus43934392

Figure 8 Comparison of the supramolecular structure of different 5-FC solid forms containing just neutral 5-FC molecules (a) form S (b) form A(c) form T (d) form B (e) form M (f) cocrystal under refcode MECTUL24 (g) solvate under refcode DUKWAI17 (h) polymorph under refcodeMEBQEQ15 (i) polymorph under refcode MEBQEQ0115 (j) cocrystal under refcode MECXID25 (k) cocrystal under refcode MECVUN24 (l)cocrystal under refcode MECWAU24 and (m) cocrystal under refcode MECWEY24 (n) solvate under refcode MEBQOA15 (o) solvate underrefcode MEBQIU15 (p) cocrystal under refcode MECWUO25 (q) cocrystal under refcode MECXEZ25 (r) cocrystal under refcode MECVEX24 (s)cocrystal under refcode MECVIB24 (t) cocrystal under refcode MECWOI24 (u) solvate under refcode DUKWEM17 (v) hydrates of 5-FC (I) underrefcodes BIRMEU14 BIRMEU0116 BIRMEU0215 and (II) under refcode BIRMEU0315 (w) hydrate under refcode PANLAS18 (x) hydratedcocrystal under refcode MECVOH24 (y) hydrated cocrystal under refcode MECXOJ25 (z) hydrate under refcode DUKWIQ17 (1) hydrate underrefcode MEBQUG15 and (2) hydrated cocrystal under refcode GATMUL23

Crystal Growth amp Design Article

dxdoiorg101021cg500502j | Cryst Growth Des 2014 14 4383minus43934389

considered a key piece in the assembly of the cocrystal packingOn the other hand the complementary N41minusH41middotmiddotmiddotN3hydrogen bonds (present in the forms A S T and B) showsmaller potential values ranging between minus55 to minus49 kcalmol As previously discussed form M represents anintermediate state in the border of the saltminuscocrystalcontinuum Instead of the N41minusH41middotmiddotmiddotN3 hydrogen bondspresent in the homodimers we observed interactions occurringamong the 5-FC molecule and the malic acid one (N41minusH41BmiddotmiddotmiddotO4 and O3minusH3middotmiddotmiddotN3) this heterosynthon being typicalof the organic acid salts1922 The potential value of this synthonfor form M is minus97 kcalmol and this one is the highestpotential observed for all interactions present in this crystallineform showing that stronger acids have the ability of competingfor these interactions thus replacing the weaker NminusHmiddotmiddotmiddotN onesIn addition the study of the intermolecular potentials also

allows us to evaluate the strength of the πmiddotmiddotmiddotπ interactionsbetween the layers formed by the 5-FC-acids units Theseinteractions have potentials ranging from minus96 to minus49 kcal

mol agreeing in all the cases with the proximity of the layers inthe 3D supramolecular arrangements A correlation is observedbetween the energy of these interactions and the distance of thelayers form M which displays the closest distance between thelayers also exhibits a high potential (minus82 kcalmol) for theπmiddotmiddotmiddotπ interactions whereas the highest potential observed to theπmiddotmiddotmiddotπ interactions was between terephthalic acid units of form T(minus96 kcalmol) All the potentials calculated are summarizedin Tables A7 B7E77 (see the Supporting InformationSections AminusE)Extending our supramolecular study for the neutral 5-FC

molecules a comparative analysis was performed on the basis ofall the crystalline structures already reported containing 5FCmolecules Polymorphs solvates and cocrystals plus mixturesof them such as solvated cocrystals were also considered 5-FCis a rigid molecule and presents three potential patterns ofhydrogen bonding sites two acceptorminusdonor involving theatoms O21minusN1 and N3minusN41 (ON and NN respectively) andone acceptorminusacceptorminusdonor involving the atoms O21minusN3minus

Table 2 Distribution of the Main Supramolecular Synthons Observed for the Different 5-FC Solid Forms Containing JustNeutral 5-FC

NminusHmiddotmiddotmiddotO NminusHmiddotmiddotmiddotN NminusHmiddotmiddotmiddotO NminusHmiddotmiddotmiddotNCG-like base

pairing

structurea homo hetero homo hetero homo hetero homo hetero planar cavity tubular cavity 5-FC ribbons

a radic radic radic radicb radic radic radic radicc radic radic radic radicd radic radic radic radice radic radic radic radicf radic radicg radich radic radici radic radicj radic radic radick radic radic radicl radic radic radic radicm radic radic radicn radic radic radico radic radic radicp radic radic radicq radic radicr radic radic radic radics radic radic radict radic radicu radic radic radic radicv(I) radic radic radicv(II) radic radic radic radicw radic radic radicx radic radicy radic radicz radic radic radic radic1 radic radic radic2 radic radic radic

aComparison of the supramolecular structure of different 5-FC solid forms containing just neutral 5-FC molecules (a) form S (b) form A (c) formT (d) form B (e) form M (f) cocrystal under refcode MECTUL24 (g) solvate under refcode DUKWAI17 (h) polymorph under refcodeMEBQEQ15 (i) polymorph under refcode MEBQEQ0115 (j) cocrystal under refcode MECXID25 (k) cocrystal under refcode MECVUN24 (l)cocrystal under refcode MECWAU24 and (m) cocrystal under refcode MECWEY24 (n) solvate under refcode MEBQOA15 (o) solvate underrefcode MEBQIU15 (p) cocrystal under refcode MECWUO25 (q) cocrystal under refcode MECXEZ25 (r) cocrystal under refcode MECVEX24 (s)cocrystal under refcode MECVIB24 (t) cocrystal under refcode MECWOI24 (u) solvate under refcode DUKWEM17 (v) hydrates of 5-FC (I) underrefcodes BIRMEU14 BIRMEU0116 BIRMEU0215 and (II) under refcode BIRMEU0315 (w) hydrate under refcode PANLAS18 (x) hydratedcocrystal under refcode MECVOH24 (y) hydrated cocrystal under refcode MECXOJ25 (z) hydrate under refcode DUKWIQ17 (1) hydrate underrefcode MEBQUG15 and (2) hydrated cocrystal under refcode GATMUL23

Crystal Growth amp Design Article

dxdoiorg101021cg500502j | Cryst Growth Des 2014 14 4383minus43934390

N41 (ONN) Tutughamiarso and co-workers17 showed that the5-FC molecule when neutral tends to interact to one anotherby self-complementary homodimers constituting planar ortubular 5-FC ribbons These homodimers as observed in thecocrystals depicted here are essentially composed by one NminusHmiddotmiddotmiddotO and one NminusHmiddotmiddotmiddotN (ONNN) or by two NminusHmiddotmiddotmiddotO(ONON) or even by two NminusHmiddotmiddotmiddotN (NNNN) intermo-lecular interactions Complementing this claim Figure 8exhibits a schematic drawing of the classical intermolecularinteractions of each reported structure considering the wholesupramolecular architecture adopted by the 5-FC moleculesunder the different crystalline arrangements It shows that notonly ribbons are observed but also planar andor tubularcavities mainly due to the intrinsic geometry of the ON NNONN hydrogen bonding sites Furthermore Table 2 exhibits astatistical analysis of the distribution of the main supra-molecular synthons observed for the 5-FC molecule includinghomo- and heterodimers involving the three main hydrogenbonding sites (ONON ONNN and NNNN) plus theformation of homo- and heterotrimers with hydrogen bondingpatterns similar to the CG Watson and Crick base pairingAccording to Table 2 the 5-FC molecule tends to form ON

NN ONON and NNNN homodimers Tutughamiarso andco-workers17 observed the particular NNNN homodimerformation only in the hydrate under refcode BIRMEU0315

reporting later a cocrystal of 5-FC under refcode MECTUL24

also exhibiting this pattern of NNNN homodimer formationThe forms S T A and B however exhibit the same ribbonformation that occurs for the hydrate under refcodeBIRMEU0315 ie ONON and NNNN R2

2(8) motifs37ab

per 5-FC molecule while in the 5-FC cocrystal under refcodeMECTUL24 the free ON site of the 5-FC molecule isintercepted by the formation of a ONNN heterodimer withthe coformer molecule In addition two ONNN (refcodesMECVIB24 and e GATMUL23) and two ONON heterodimers(refcodes MECWUO25 and GATMUL23) are observedHowever no NNNN heterodimer was reported until thepresentOn the other hand for the ONN CG-like base pairing the

tendency is the formation of heterosynthons with a total of ninestructures Only in one hydrate (refcode PANLAS18) the CG-like base pairing is observed between the 5-FC molecules Byanalyzing the crystalline packing of the 5-FC cocrystal underrefcode MECTUL24 (see Figure 8f) the occurrence of oneONNN heterodimer disrupts the 5-FC ribbon formationAlthough homoribbons (ie ribbons constituted only by 5-FCmolecules) are prevalent in most of the crystalline structures12 of them exhibit heteroribbons and all refer to cocrystals (2cocrystals and 10 solvated cocrystals)By considering the cavity formation two exceptions arise

one referring to the cocrystal under refcode MECTUL24

(Figure 8f) where flat layers are stacked by van der Waalscontacts and one referring to the solvate under refcodeDUKWAI17 (Figure 8g) for which small cavities are observedonly when the nonclassical CminusHmiddotmiddotmiddotO and CminusHmiddotmiddotmiddotF intermo-lecular interactions between the dimethyl sulfoxide and 5-FCmolecules are considered Both reported polymorphs of 5-FCexhibit tubular patterns (Figure 8h (i) constituting R4

4(24) andR64(26) motifs involving four and six 5-FC molecules

respectively Forms S A and T (Figure 8aminusc) exhibit similarcavities differing only in their size (R6

4(40) R64(48) R6

4(44) forforms S A and T respectively) proportional to the size andthe geometry of each acid molecule Figure 8h exhibits the last

planar cavity R76(44) involving only solid coformers

concerning the cocrystal under refcode MECXID25 Whensolvents are involved in the interactions they lead to planar andtubular cavities for which it is not possible to establish aspecific pattern for these ternary systems In particular thecocrystal under refcode MECVEX24 (Figure 8r) and thehydrate under refcode DUKWIQ17 (Figure 8z) display cavitiesof both tubular and planar types It is worth mentioning thatthe planar cavities of the methanol solvate under refcodeMEBQOA15 (Figure 8 (l)) of the cocrystal under refcodeMECVEX24 (Figure 8r) and of the hydrate under refcodeDUKWIQ17 (Figure 8z) are similar to the one formed in formsS A and T This shows that the recurrent supramolecularsynthon observed for the cocrystals depicted herein is notrestricted to the use of carboxylic acids as coformers In thisway it could be expected that new structures containing 5-FCmolecule can be designed and developed as new tailor-madedrugs

42 Cocrystal of 5-FC and 5-FU 5-Fluorouracil 5-fluoro-24-(1H3H)-pyrimidinedione is an antineoplastic API ration-ally designed by Heidelberger and co-workers in 195743 It isused for the treatment of superficial skin carcinomas as a creamformulation and as injections in the treatment of variouscancers including among others gastrointestinal head andneck breast colorectal and ovarian 5-FU is a syntheticpyrimidine analogue and is probably the most widely usedbeing of great interest in the clinical and experimentalchemotherapy among the developed analogues of purine andpyrimidine as it is structurally similar to natural basesNevertheless only a fraction of the administered amount ofthis API becomes available in the systemic circulation after oraladministration due to its poor water solubility44minus46 Indeedoral delivery of antineoplastic APIs is considered a challengedue their physical and chemical properties and physiologicalbarriers47

As an illustration of a controlled rational supramolecularsynthesis of new solid forms of a given API using 5-FC ascoformer we designed a cocrystal of 5-FC and 5-FU (form 5FpKa = 80)44 It is clear that the 5-FU was our first molecule ofchoice for this example due to its structural similarities with 5-FC The cocrystallization experiment was developed accordingto the pKa rule and a cocrystal was expected (ΔpKa = minus474)The aim of this particular experiment was to design a new solidform of 5-FU with enhanced physical and chemical propertiesthat could enable this API to be orally administered togetherwith 5-FC which in turn exhibits high solubility andbioavailability profiles10 However the solubility properties ofform 5-FU are still under investigationThe asymmetric unit of form 5F (see Figure 1) exhibits one

molecule of 5-FC and one of 5-FU The main intermolecularinteractions responsible for maintaining the crystalline arrange-ment of this cocrystal are of the types NminusHmiddotmiddotmiddotO and NminusHmiddotmiddotmiddotF(see Table S1 in the Supporting Information section) includingthe formation of homodimers of 5-FC (I in Figure 9a)homodimers of 5-FU (II in Figure 9a) and intermolecularinteractions among the 5-FC and 5-FU molecules (Figure 9a)Nonclassical intermolecular interactions are also present as aresult of the close packing C6minusH6middotmiddotmiddotF51 (bond distance of2467 Aring) C6primeminusH6primemiddotmiddotmiddotF51prime (bond distance of 2354 Aring) C6primeminusH6primemiddotmiddotmiddotN3 (bond distance of 2639 Aring) and C6minusH6middotmiddotmiddotO21prime(bond distance of 2553 Aring) The crystal packing of form 5F iscomposed of flat tapes in which the dimers are interspersedThese tapes are stacked constituting columns with a parallel

Crystal Growth amp Design Article

dxdoiorg101021cg500502j | Cryst Growth Des 2014 14 4383minus43934391

displaced arrangement (displacement angle of 232deg) main-tained by πmiddotmiddotmiddotπ interactions (5-FCπmiddotmiddotmiddotπ = 35604(9) Aring and 5-FUπmiddotmiddotmiddotπ = 35603(9)Aring) Adjacent tapes (and consequentlyadjacent columns) exhibit two directions of growth and areconnected to one another by intermolecular interactionsbetween the molecules of 5-FC and 5-FU forming a dihedralangle of 13017(3)deg (Figure 9b)

5 CONCLUSIONThe 5-FC cocrystals with succinic adipic benzoic and tereftalicacids were obtained following the tendency of the pKa rule andhave revealed a similar hydrogen-bonding pattern leading to 5-FC ribbons stabilized by two R2

2(8) motifs characterized bycomplementary homodimeric NminusHmiddotmiddotmiddotN (NNNN) and NminusHmiddotmiddotmiddotO (ONON) interactions which was found to be a featureof cocrystals containing this fluoropyrimidine moleculesAnalyzing the supramolecular characteristics of the four 5-FCcocrystals (together with some similar structures reported inthe literature) it was observed that the 5-FC molecule tends toform ONNN ONON and NNNN homodimers ONNCG-like base pairing heterotrimers and both tubular andplanar cavities Nevertheless when the cocrystallization experi-ment was conducted with malic acid where the ΔpKa = minus01 asupramolecular transition synthon was observed in which theNminusHmiddotmiddotmiddotO homodimeric synthon present in the cocrystalsremains but a new heterodimeric synthon characterized bycomplementary NminusHmiddotmiddotmiddotO hydrogen bonds between the 5-FCmolecule and the malic acid emerged This last synthon wasfound in the 5-FC organic salts obtained even from very smallpositive ΔpKa values (such as for the fumarate of 5-FC whereΔpKa = 023) The discovery of this transition synthonindicates that the 5-FC molecule is a suitable candidate forthe design and development of cocrystallization experimentsbased on crystal engineering techniques once its behaviorcould be until the present well predicted by the pKa rule Tocheck our hypothesis we conducted a cocrystallizationexperiment of 5-FC with the antineoplastic drug 5-FU aimingto obtain a cocrystal once the system exhibits a ΔpKa = minus30The success of this experiment points to a new path to apply 5-

FC as a coformer in new controlled crystallization experimentsfor the development of new tailor-made drugs

ASSOCIATED CONTENTS Supporting InformationCrystallographic data of the 5-FC calculated potentials Thismaterial is available free of charge via the Internet at httppubsacsorg

AUTHOR INFORMATIONCorresponding AuthorE-mail javiereifscuspbr Phone +55 16 3373 8096 Fax+55 16 3373 9881NotesThe authors declare no competing financial interest

ACKNOWLEDGMENTSWe thank CAPES (CCPS) FAPESP (JCT Project No201307581-9) and CNPq (JE ROP CCM Project No1500762013-4) for the financial support We also thank forthe use of the APEX II Bruker difractometer to ldquoFacility foradvanced studies of materialsFAMardquo (FAPESP Project No2009540354)

REFERENCES(1) Almarsson O Zaworotko M J Chem Commun (Cambridge)2004 17 1889minus1896(2) Blagden N de Matas M Gavan P T York P Adv DrugDelivery Rev 2007 59 (7) 617minus630(3) Bond A D In Pharmaceutical Salts and Co-Crystals Wouters JQuere L Eds The Royal Society of Chemistry Cambridge UK2012 Chapter 2 pp 9minus28(4) Vishweshwar P McMahon J A Peterson M L Hickey M BShattock T R Zaworotko M J Chem Commu 2005 36 4601minus4603(5) Aakeroy C B Fasulo M E Desper J Mol Pharmaceutics 20074 (3) 317minus322(6) Trask A V Mol Pharmaceutics 2007 4 (3) 301minus309(7) GRAS S Food and Drug Administration Database of SelectCommittee on GRAS Substances (SCOGS) Reviews httpswwwaccessdatafdagovscriptsfcnfcnNavigationcfmrpt=scogsListing(8) Shan N Zaworotko M J Drug Discovery Today 2008 13 (9minus10) 440minus446(9) Hoffman M Lindeman J A In Pharmaceutical Salts and Co-crystals Wouters J Quere L Eds The Royal Society of ChemistryCambridge UK 2012 Chapter 14 pp 318 minus 329(10) Vermes A Guchelaar H-J Dankert J J AntimicrobChemother 2000 46 (2) 171minus179(11) Larsen R A In Essentials of Clinical Mycology 2nd edKauffman C A Pappas P G Sobel J D Dismukes W E EdsOxford University Press UK 2003 part 2 pp 57minus60(12) Mullen C A Coale M M Lowe R Blaese R M Cancer Res1994 54 (6) 1503minus1506(13) Allen F H Acta Crystallogr Sect B 2002 58 (3) 380minus388(14) Louis T Low J N Tollin P Cryst Struct Commun 1982 111059minus1064(15) Hulme A T Tocher D A CrystGrowth Des 2006 6 (2)481minus487(16) Portalone G Colapietro M Acta Crystallogr Sect E 2006 62(3) o1049minuso1051(17) Tutughamiarso M Bolte M Egert E Acta Crystallogr Sect C2009 65 (11) o574minuso578(18) Hulme A T Tocher D A Acta Crystallogr Sect E 2005 61(7) 02112minuso2113(19) Prabakaran P Murugesan S Muthiah P T Bocelli G RighiL Acta Crystallogr Sect E 2001 57 (10) o933minuso936

Figure 9 (a) Crystal packing diagram of form 5f Black dashed linesindicate hydrogen bonds (I) refers to the R2

2(8) motifs37ab involvingthe NminusHmiddotmiddotmiddotO homodimers occurring among 5-FC molecules and (II)correspond to R2

2(8) motifs37ab involving the NminusHmiddotmiddotmiddotO homodimersoccurring among 5-FU molecules (b) three-dimensional hydrogen-bonded network of form 5f

Crystal Growth amp Design Article

dxdoiorg101021cg500502j | Cryst Growth Des 2014 14 4383minus43934392

considered a key piece in the assembly of the cocrystal packingOn the other hand the complementary N41minusH41middotmiddotmiddotN3hydrogen bonds (present in the forms A S T and B) showsmaller potential values ranging between minus55 to minus49 kcalmol As previously discussed form M represents anintermediate state in the border of the saltminuscocrystalcontinuum Instead of the N41minusH41middotmiddotmiddotN3 hydrogen bondspresent in the homodimers we observed interactions occurringamong the 5-FC molecule and the malic acid one (N41minusH41BmiddotmiddotmiddotO4 and O3minusH3middotmiddotmiddotN3) this heterosynthon being typicalof the organic acid salts1922 The potential value of this synthonfor form M is minus97 kcalmol and this one is the highestpotential observed for all interactions present in this crystallineform showing that stronger acids have the ability of competingfor these interactions thus replacing the weaker NminusHmiddotmiddotmiddotN onesIn addition the study of the intermolecular potentials also

allows us to evaluate the strength of the πmiddotmiddotmiddotπ interactionsbetween the layers formed by the 5-FC-acids units Theseinteractions have potentials ranging from minus96 to minus49 kcal

mol agreeing in all the cases with the proximity of the layers inthe 3D supramolecular arrangements A correlation is observedbetween the energy of these interactions and the distance of thelayers form M which displays the closest distance between thelayers also exhibits a high potential (minus82 kcalmol) for theπmiddotmiddotmiddotπ interactions whereas the highest potential observed to theπmiddotmiddotmiddotπ interactions was between terephthalic acid units of form T(minus96 kcalmol) All the potentials calculated are summarizedin Tables A7 B7E77 (see the Supporting InformationSections AminusE)Extending our supramolecular study for the neutral 5-FC

molecules a comparative analysis was performed on the basis ofall the crystalline structures already reported containing 5FCmolecules Polymorphs solvates and cocrystals plus mixturesof them such as solvated cocrystals were also considered 5-FCis a rigid molecule and presents three potential patterns ofhydrogen bonding sites two acceptorminusdonor involving theatoms O21minusN1 and N3minusN41 (ON and NN respectively) andone acceptorminusacceptorminusdonor involving the atoms O21minusN3minus

Table 2 Distribution of the Main Supramolecular Synthons Observed for the Different 5-FC Solid Forms Containing JustNeutral 5-FC

NminusHmiddotmiddotmiddotO NminusHmiddotmiddotmiddotN NminusHmiddotmiddotmiddotO NminusHmiddotmiddotmiddotNCG-like base

pairing

structurea homo hetero homo hetero homo hetero homo hetero planar cavity tubular cavity 5-FC ribbons

a radic radic radic radicb radic radic radic radicc radic radic radic radicd radic radic radic radice radic radic radic radicf radic radicg radich radic radici radic radicj radic radic radick radic radic radicl radic radic radic radicm radic radic radicn radic radic radico radic radic radicp radic radic radicq radic radicr radic radic radic radics radic radic radict radic radicu radic radic radic radicv(I) radic radic radicv(II) radic radic radic radicw radic radic radicx radic radicy radic radicz radic radic radic radic1 radic radic radic2 radic radic radic

aComparison of the supramolecular structure of different 5-FC solid forms containing just neutral 5-FC molecules (a) form S (b) form A (c) formT (d) form B (e) form M (f) cocrystal under refcode MECTUL24 (g) solvate under refcode DUKWAI17 (h) polymorph under refcodeMEBQEQ15 (i) polymorph under refcode MEBQEQ0115 (j) cocrystal under refcode MECXID25 (k) cocrystal under refcode MECVUN24 (l)cocrystal under refcode MECWAU24 and (m) cocrystal under refcode MECWEY24 (n) solvate under refcode MEBQOA15 (o) solvate underrefcode MEBQIU15 (p) cocrystal under refcode MECWUO25 (q) cocrystal under refcode MECXEZ25 (r) cocrystal under refcode MECVEX24 (s)cocrystal under refcode MECVIB24 (t) cocrystal under refcode MECWOI24 (u) solvate under refcode DUKWEM17 (v) hydrates of 5-FC (I) underrefcodes BIRMEU14 BIRMEU0116 BIRMEU0215 and (II) under refcode BIRMEU0315 (w) hydrate under refcode PANLAS18 (x) hydratedcocrystal under refcode MECVOH24 (y) hydrated cocrystal under refcode MECXOJ25 (z) hydrate under refcode DUKWIQ17 (1) hydrate underrefcode MEBQUG15 and (2) hydrated cocrystal under refcode GATMUL23

Crystal Growth amp Design Article

dxdoiorg101021cg500502j | Cryst Growth Des 2014 14 4383minus43934390

N41 (ONN) Tutughamiarso and co-workers17 showed that the5-FC molecule when neutral tends to interact to one anotherby self-complementary homodimers constituting planar ortubular 5-FC ribbons These homodimers as observed in thecocrystals depicted here are essentially composed by one NminusHmiddotmiddotmiddotO and one NminusHmiddotmiddotmiddotN (ONNN) or by two NminusHmiddotmiddotmiddotO(ONON) or even by two NminusHmiddotmiddotmiddotN (NNNN) intermo-lecular interactions Complementing this claim Figure 8exhibits a schematic drawing of the classical intermolecularinteractions of each reported structure considering the wholesupramolecular architecture adopted by the 5-FC moleculesunder the different crystalline arrangements It shows that notonly ribbons are observed but also planar andor tubularcavities mainly due to the intrinsic geometry of the ON NNONN hydrogen bonding sites Furthermore Table 2 exhibits astatistical analysis of the distribution of the main supra-molecular synthons observed for the 5-FC molecule includinghomo- and heterodimers involving the three main hydrogenbonding sites (ONON ONNN and NNNN) plus theformation of homo- and heterotrimers with hydrogen bondingpatterns similar to the CG Watson and Crick base pairingAccording to Table 2 the 5-FC molecule tends to form ON

NN ONON and NNNN homodimers Tutughamiarso andco-workers17 observed the particular NNNN homodimerformation only in the hydrate under refcode BIRMEU0315

reporting later a cocrystal of 5-FC under refcode MECTUL24

also exhibiting this pattern of NNNN homodimer formationThe forms S T A and B however exhibit the same ribbonformation that occurs for the hydrate under refcodeBIRMEU0315 ie ONON and NNNN R2

2(8) motifs37ab

per 5-FC molecule while in the 5-FC cocrystal under refcodeMECTUL24 the free ON site of the 5-FC molecule isintercepted by the formation of a ONNN heterodimer withthe coformer molecule In addition two ONNN (refcodesMECVIB24 and e GATMUL23) and two ONON heterodimers(refcodes MECWUO25 and GATMUL23) are observedHowever no NNNN heterodimer was reported until thepresentOn the other hand for the ONN CG-like base pairing the

tendency is the formation of heterosynthons with a total of ninestructures Only in one hydrate (refcode PANLAS18) the CG-like base pairing is observed between the 5-FC molecules Byanalyzing the crystalline packing of the 5-FC cocrystal underrefcode MECTUL24 (see Figure 8f) the occurrence of oneONNN heterodimer disrupts the 5-FC ribbon formationAlthough homoribbons (ie ribbons constituted only by 5-FCmolecules) are prevalent in most of the crystalline structures12 of them exhibit heteroribbons and all refer to cocrystals (2cocrystals and 10 solvated cocrystals)By considering the cavity formation two exceptions arise

one referring to the cocrystal under refcode MECTUL24

(Figure 8f) where flat layers are stacked by van der Waalscontacts and one referring to the solvate under refcodeDUKWAI17 (Figure 8g) for which small cavities are observedonly when the nonclassical CminusHmiddotmiddotmiddotO and CminusHmiddotmiddotmiddotF intermo-lecular interactions between the dimethyl sulfoxide and 5-FCmolecules are considered Both reported polymorphs of 5-FCexhibit tubular patterns (Figure 8h (i) constituting R4

4(24) andR64(26) motifs involving four and six 5-FC molecules

respectively Forms S A and T (Figure 8aminusc) exhibit similarcavities differing only in their size (R6

4(40) R64(48) R6

4(44) forforms S A and T respectively) proportional to the size andthe geometry of each acid molecule Figure 8h exhibits the last

planar cavity R76(44) involving only solid coformers

concerning the cocrystal under refcode MECXID25 Whensolvents are involved in the interactions they lead to planar andtubular cavities for which it is not possible to establish aspecific pattern for these ternary systems In particular thecocrystal under refcode MECVEX24 (Figure 8r) and thehydrate under refcode DUKWIQ17 (Figure 8z) display cavitiesof both tubular and planar types It is worth mentioning thatthe planar cavities of the methanol solvate under refcodeMEBQOA15 (Figure 8 (l)) of the cocrystal under refcodeMECVEX24 (Figure 8r) and of the hydrate under refcodeDUKWIQ17 (Figure 8z) are similar to the one formed in formsS A and T This shows that the recurrent supramolecularsynthon observed for the cocrystals depicted herein is notrestricted to the use of carboxylic acids as coformers In thisway it could be expected that new structures containing 5-FCmolecule can be designed and developed as new tailor-madedrugs

42 Cocrystal of 5-FC and 5-FU 5-Fluorouracil 5-fluoro-24-(1H3H)-pyrimidinedione is an antineoplastic API ration-ally designed by Heidelberger and co-workers in 195743 It isused for the treatment of superficial skin carcinomas as a creamformulation and as injections in the treatment of variouscancers including among others gastrointestinal head andneck breast colorectal and ovarian 5-FU is a syntheticpyrimidine analogue and is probably the most widely usedbeing of great interest in the clinical and experimentalchemotherapy among the developed analogues of purine andpyrimidine as it is structurally similar to natural basesNevertheless only a fraction of the administered amount ofthis API becomes available in the systemic circulation after oraladministration due to its poor water solubility44minus46 Indeedoral delivery of antineoplastic APIs is considered a challengedue their physical and chemical properties and physiologicalbarriers47

As an illustration of a controlled rational supramolecularsynthesis of new solid forms of a given API using 5-FC ascoformer we designed a cocrystal of 5-FC and 5-FU (form 5FpKa = 80)44 It is clear that the 5-FU was our first molecule ofchoice for this example due to its structural similarities with 5-FC The cocrystallization experiment was developed accordingto the pKa rule and a cocrystal was expected (ΔpKa = minus474)The aim of this particular experiment was to design a new solidform of 5-FU with enhanced physical and chemical propertiesthat could enable this API to be orally administered togetherwith 5-FC which in turn exhibits high solubility andbioavailability profiles10 However the solubility properties ofform 5-FU are still under investigationThe asymmetric unit of form 5F (see Figure 1) exhibits one

molecule of 5-FC and one of 5-FU The main intermolecularinteractions responsible for maintaining the crystalline arrange-ment of this cocrystal are of the types NminusHmiddotmiddotmiddotO and NminusHmiddotmiddotmiddotF(see Table S1 in the Supporting Information section) includingthe formation of homodimers of 5-FC (I in Figure 9a)homodimers of 5-FU (II in Figure 9a) and intermolecularinteractions among the 5-FC and 5-FU molecules (Figure 9a)Nonclassical intermolecular interactions are also present as aresult of the close packing C6minusH6middotmiddotmiddotF51 (bond distance of2467 Aring) C6primeminusH6primemiddotmiddotmiddotF51prime (bond distance of 2354 Aring) C6primeminusH6primemiddotmiddotmiddotN3 (bond distance of 2639 Aring) and C6minusH6middotmiddotmiddotO21prime(bond distance of 2553 Aring) The crystal packing of form 5F iscomposed of flat tapes in which the dimers are interspersedThese tapes are stacked constituting columns with a parallel

Crystal Growth amp Design Article

dxdoiorg101021cg500502j | Cryst Growth Des 2014 14 4383minus43934391

displaced arrangement (displacement angle of 232deg) main-tained by πmiddotmiddotmiddotπ interactions (5-FCπmiddotmiddotmiddotπ = 35604(9) Aring and 5-FUπmiddotmiddotmiddotπ = 35603(9)Aring) Adjacent tapes (and consequentlyadjacent columns) exhibit two directions of growth and areconnected to one another by intermolecular interactionsbetween the molecules of 5-FC and 5-FU forming a dihedralangle of 13017(3)deg (Figure 9b)

5 CONCLUSIONThe 5-FC cocrystals with succinic adipic benzoic and tereftalicacids were obtained following the tendency of the pKa rule andhave revealed a similar hydrogen-bonding pattern leading to 5-FC ribbons stabilized by two R2

2(8) motifs characterized bycomplementary homodimeric NminusHmiddotmiddotmiddotN (NNNN) and NminusHmiddotmiddotmiddotO (ONON) interactions which was found to be a featureof cocrystals containing this fluoropyrimidine moleculesAnalyzing the supramolecular characteristics of the four 5-FCcocrystals (together with some similar structures reported inthe literature) it was observed that the 5-FC molecule tends toform ONNN ONON and NNNN homodimers ONNCG-like base pairing heterotrimers and both tubular andplanar cavities Nevertheless when the cocrystallization experi-ment was conducted with malic acid where the ΔpKa = minus01 asupramolecular transition synthon was observed in which theNminusHmiddotmiddotmiddotO homodimeric synthon present in the cocrystalsremains but a new heterodimeric synthon characterized bycomplementary NminusHmiddotmiddotmiddotO hydrogen bonds between the 5-FCmolecule and the malic acid emerged This last synthon wasfound in the 5-FC organic salts obtained even from very smallpositive ΔpKa values (such as for the fumarate of 5-FC whereΔpKa = 023) The discovery of this transition synthonindicates that the 5-FC molecule is a suitable candidate forthe design and development of cocrystallization experimentsbased on crystal engineering techniques once its behaviorcould be until the present well predicted by the pKa rule Tocheck our hypothesis we conducted a cocrystallizationexperiment of 5-FC with the antineoplastic drug 5-FU aimingto obtain a cocrystal once the system exhibits a ΔpKa = minus30The success of this experiment points to a new path to apply 5-

FC as a coformer in new controlled crystallization experimentsfor the development of new tailor-made drugs

ASSOCIATED CONTENTS Supporting InformationCrystallographic data of the 5-FC calculated potentials Thismaterial is available free of charge via the Internet at httppubsacsorg

AUTHOR INFORMATIONCorresponding AuthorE-mail javiereifscuspbr Phone +55 16 3373 8096 Fax+55 16 3373 9881NotesThe authors declare no competing financial interest

ACKNOWLEDGMENTSWe thank CAPES (CCPS) FAPESP (JCT Project No201307581-9) and CNPq (JE ROP CCM Project No1500762013-4) for the financial support We also thank forthe use of the APEX II Bruker difractometer to ldquoFacility foradvanced studies of materialsFAMardquo (FAPESP Project No2009540354)

REFERENCES(1) Almarsson O Zaworotko M J Chem Commun (Cambridge)2004 17 1889minus1896(2) Blagden N de Matas M Gavan P T York P Adv DrugDelivery Rev 2007 59 (7) 617minus630(3) Bond A D In Pharmaceutical Salts and Co-Crystals Wouters JQuere L Eds The Royal Society of Chemistry Cambridge UK2012 Chapter 2 pp 9minus28(4) Vishweshwar P McMahon J A Peterson M L Hickey M BShattock T R Zaworotko M J Chem Commu 2005 36 4601minus4603(5) Aakeroy C B Fasulo M E Desper J Mol Pharmaceutics 20074 (3) 317minus322(6) Trask A V Mol Pharmaceutics 2007 4 (3) 301minus309(7) GRAS S Food and Drug Administration Database of SelectCommittee on GRAS Substances (SCOGS) Reviews httpswwwaccessdatafdagovscriptsfcnfcnNavigationcfmrpt=scogsListing(8) Shan N Zaworotko M J Drug Discovery Today 2008 13 (9minus10) 440minus446(9) Hoffman M Lindeman J A In Pharmaceutical Salts and Co-crystals Wouters J Quere L Eds The Royal Society of ChemistryCambridge UK 2012 Chapter 14 pp 318 minus 329(10) Vermes A Guchelaar H-J Dankert J J AntimicrobChemother 2000 46 (2) 171minus179(11) Larsen R A In Essentials of Clinical Mycology 2nd edKauffman C A Pappas P G Sobel J D Dismukes W E EdsOxford University Press UK 2003 part 2 pp 57minus60(12) Mullen C A Coale M M Lowe R Blaese R M Cancer Res1994 54 (6) 1503minus1506(13) Allen F H Acta Crystallogr Sect B 2002 58 (3) 380minus388(14) Louis T Low J N Tollin P Cryst Struct Commun 1982 111059minus1064(15) Hulme A T Tocher D A CrystGrowth Des 2006 6 (2)481minus487(16) Portalone G Colapietro M Acta Crystallogr Sect E 2006 62(3) o1049minuso1051(17) Tutughamiarso M Bolte M Egert E Acta Crystallogr Sect C2009 65 (11) o574minuso578(18) Hulme A T Tocher D A Acta Crystallogr Sect E 2005 61(7) 02112minuso2113(19) Prabakaran P Murugesan S Muthiah P T Bocelli G RighiL Acta Crystallogr Sect E 2001 57 (10) o933minuso936

Figure 9 (a) Crystal packing diagram of form 5f Black dashed linesindicate hydrogen bonds (I) refers to the R2

2(8) motifs37ab involvingthe NminusHmiddotmiddotmiddotO homodimers occurring among 5-FC molecules and (II)correspond to R2

2(8) motifs37ab involving the NminusHmiddotmiddotmiddotO homodimersoccurring among 5-FU molecules (b) three-dimensional hydrogen-bonded network of form 5f

Crystal Growth amp Design Article

dxdoiorg101021cg500502j | Cryst Growth Des 2014 14 4383minus43934392

N41 (ONN) Tutughamiarso and co-workers17 showed that the5-FC molecule when neutral tends to interact to one anotherby self-complementary homodimers constituting planar ortubular 5-FC ribbons These homodimers as observed in thecocrystals depicted here are essentially composed by one NminusHmiddotmiddotmiddotO and one NminusHmiddotmiddotmiddotN (ONNN) or by two NminusHmiddotmiddotmiddotO(ONON) or even by two NminusHmiddotmiddotmiddotN (NNNN) intermo-lecular interactions Complementing this claim Figure 8exhibits a schematic drawing of the classical intermolecularinteractions of each reported structure considering the wholesupramolecular architecture adopted by the 5-FC moleculesunder the different crystalline arrangements It shows that notonly ribbons are observed but also planar andor tubularcavities mainly due to the intrinsic geometry of the ON NNONN hydrogen bonding sites Furthermore Table 2 exhibits astatistical analysis of the distribution of the main supra-molecular synthons observed for the 5-FC molecule includinghomo- and heterodimers involving the three main hydrogenbonding sites (ONON ONNN and NNNN) plus theformation of homo- and heterotrimers with hydrogen bondingpatterns similar to the CG Watson and Crick base pairingAccording to Table 2 the 5-FC molecule tends to form ON

NN ONON and NNNN homodimers Tutughamiarso andco-workers17 observed the particular NNNN homodimerformation only in the hydrate under refcode BIRMEU0315

reporting later a cocrystal of 5-FC under refcode MECTUL24

also exhibiting this pattern of NNNN homodimer formationThe forms S T A and B however exhibit the same ribbonformation that occurs for the hydrate under refcodeBIRMEU0315 ie ONON and NNNN R2

2(8) motifs37ab

per 5-FC molecule while in the 5-FC cocrystal under refcodeMECTUL24 the free ON site of the 5-FC molecule isintercepted by the formation of a ONNN heterodimer withthe coformer molecule In addition two ONNN (refcodesMECVIB24 and e GATMUL23) and two ONON heterodimers(refcodes MECWUO25 and GATMUL23) are observedHowever no NNNN heterodimer was reported until thepresentOn the other hand for the ONN CG-like base pairing the

tendency is the formation of heterosynthons with a total of ninestructures Only in one hydrate (refcode PANLAS18) the CG-like base pairing is observed between the 5-FC molecules Byanalyzing the crystalline packing of the 5-FC cocrystal underrefcode MECTUL24 (see Figure 8f) the occurrence of oneONNN heterodimer disrupts the 5-FC ribbon formationAlthough homoribbons (ie ribbons constituted only by 5-FCmolecules) are prevalent in most of the crystalline structures12 of them exhibit heteroribbons and all refer to cocrystals (2cocrystals and 10 solvated cocrystals)By considering the cavity formation two exceptions arise

one referring to the cocrystal under refcode MECTUL24

(Figure 8f) where flat layers are stacked by van der Waalscontacts and one referring to the solvate under refcodeDUKWAI17 (Figure 8g) for which small cavities are observedonly when the nonclassical CminusHmiddotmiddotmiddotO and CminusHmiddotmiddotmiddotF intermo-lecular interactions between the dimethyl sulfoxide and 5-FCmolecules are considered Both reported polymorphs of 5-FCexhibit tubular patterns (Figure 8h (i) constituting R4

4(24) andR64(26) motifs involving four and six 5-FC molecules

respectively Forms S A and T (Figure 8aminusc) exhibit similarcavities differing only in their size (R6

4(40) R64(48) R6

4(44) forforms S A and T respectively) proportional to the size andthe geometry of each acid molecule Figure 8h exhibits the last

planar cavity R76(44) involving only solid coformers

concerning the cocrystal under refcode MECXID25 Whensolvents are involved in the interactions they lead to planar andtubular cavities for which it is not possible to establish aspecific pattern for these ternary systems In particular thecocrystal under refcode MECVEX24 (Figure 8r) and thehydrate under refcode DUKWIQ17 (Figure 8z) display cavitiesof both tubular and planar types It is worth mentioning thatthe planar cavities of the methanol solvate under refcodeMEBQOA15 (Figure 8 (l)) of the cocrystal under refcodeMECVEX24 (Figure 8r) and of the hydrate under refcodeDUKWIQ17 (Figure 8z) are similar to the one formed in formsS A and T This shows that the recurrent supramolecularsynthon observed for the cocrystals depicted herein is notrestricted to the use of carboxylic acids as coformers In thisway it could be expected that new structures containing 5-FCmolecule can be designed and developed as new tailor-madedrugs

42 Cocrystal of 5-FC and 5-FU 5-Fluorouracil 5-fluoro-24-(1H3H)-pyrimidinedione is an antineoplastic API ration-ally designed by Heidelberger and co-workers in 195743 It isused for the treatment of superficial skin carcinomas as a creamformulation and as injections in the treatment of variouscancers including among others gastrointestinal head andneck breast colorectal and ovarian 5-FU is a syntheticpyrimidine analogue and is probably the most widely usedbeing of great interest in the clinical and experimentalchemotherapy among the developed analogues of purine andpyrimidine as it is structurally similar to natural basesNevertheless only a fraction of the administered amount ofthis API becomes available in the systemic circulation after oraladministration due to its poor water solubility44minus46 Indeedoral delivery of antineoplastic APIs is considered a challengedue their physical and chemical properties and physiologicalbarriers47

As an illustration of a controlled rational supramolecularsynthesis of new solid forms of a given API using 5-FC ascoformer we designed a cocrystal of 5-FC and 5-FU (form 5FpKa = 80)44 It is clear that the 5-FU was our first molecule ofchoice for this example due to its structural similarities with 5-FC The cocrystallization experiment was developed accordingto the pKa rule and a cocrystal was expected (ΔpKa = minus474)The aim of this particular experiment was to design a new solidform of 5-FU with enhanced physical and chemical propertiesthat could enable this API to be orally administered togetherwith 5-FC which in turn exhibits high solubility andbioavailability profiles10 However the solubility properties ofform 5-FU are still under investigationThe asymmetric unit of form 5F (see Figure 1) exhibits one

molecule of 5-FC and one of 5-FU The main intermolecularinteractions responsible for maintaining the crystalline arrange-ment of this cocrystal are of the types NminusHmiddotmiddotmiddotO and NminusHmiddotmiddotmiddotF(see Table S1 in the Supporting Information section) includingthe formation of homodimers of 5-FC (I in Figure 9a)homodimers of 5-FU (II in Figure 9a) and intermolecularinteractions among the 5-FC and 5-FU molecules (Figure 9a)Nonclassical intermolecular interactions are also present as aresult of the close packing C6minusH6middotmiddotmiddotF51 (bond distance of2467 Aring) C6primeminusH6primemiddotmiddotmiddotF51prime (bond distance of 2354 Aring) C6primeminusH6primemiddotmiddotmiddotN3 (bond distance of 2639 Aring) and C6minusH6middotmiddotmiddotO21prime(bond distance of 2553 Aring) The crystal packing of form 5F iscomposed of flat tapes in which the dimers are interspersedThese tapes are stacked constituting columns with a parallel

Crystal Growth amp Design Article

dxdoiorg101021cg500502j | Cryst Growth Des 2014 14 4383minus43934391

displaced arrangement (displacement angle of 232deg) main-tained by πmiddotmiddotmiddotπ interactions (5-FCπmiddotmiddotmiddotπ = 35604(9) Aring and 5-FUπmiddotmiddotmiddotπ = 35603(9)Aring) Adjacent tapes (and consequentlyadjacent columns) exhibit two directions of growth and areconnected to one another by intermolecular interactionsbetween the molecules of 5-FC and 5-FU forming a dihedralangle of 13017(3)deg (Figure 9b)

5 CONCLUSIONThe 5-FC cocrystals with succinic adipic benzoic and tereftalicacids were obtained following the tendency of the pKa rule andhave revealed a similar hydrogen-bonding pattern leading to 5-FC ribbons stabilized by two R2

2(8) motifs characterized bycomplementary homodimeric NminusHmiddotmiddotmiddotN (NNNN) and NminusHmiddotmiddotmiddotO (ONON) interactions which was found to be a featureof cocrystals containing this fluoropyrimidine moleculesAnalyzing the supramolecular characteristics of the four 5-FCcocrystals (together with some similar structures reported inthe literature) it was observed that the 5-FC molecule tends toform ONNN ONON and NNNN homodimers ONNCG-like base pairing heterotrimers and both tubular andplanar cavities Nevertheless when the cocrystallization experi-ment was conducted with malic acid where the ΔpKa = minus01 asupramolecular transition synthon was observed in which theNminusHmiddotmiddotmiddotO homodimeric synthon present in the cocrystalsremains but a new heterodimeric synthon characterized bycomplementary NminusHmiddotmiddotmiddotO hydrogen bonds between the 5-FCmolecule and the malic acid emerged This last synthon wasfound in the 5-FC organic salts obtained even from very smallpositive ΔpKa values (such as for the fumarate of 5-FC whereΔpKa = 023) The discovery of this transition synthonindicates that the 5-FC molecule is a suitable candidate forthe design and development of cocrystallization experimentsbased on crystal engineering techniques once its behaviorcould be until the present well predicted by the pKa rule Tocheck our hypothesis we conducted a cocrystallizationexperiment of 5-FC with the antineoplastic drug 5-FU aimingto obtain a cocrystal once the system exhibits a ΔpKa = minus30The success of this experiment points to a new path to apply 5-

FC as a coformer in new controlled crystallization experimentsfor the development of new tailor-made drugs

ASSOCIATED CONTENTS Supporting InformationCrystallographic data of the 5-FC calculated potentials Thismaterial is available free of charge via the Internet at httppubsacsorg

AUTHOR INFORMATIONCorresponding AuthorE-mail javiereifscuspbr Phone +55 16 3373 8096 Fax+55 16 3373 9881NotesThe authors declare no competing financial interest

ACKNOWLEDGMENTSWe thank CAPES (CCPS) FAPESP (JCT Project No201307581-9) and CNPq (JE ROP CCM Project No1500762013-4) for the financial support We also thank forthe use of the APEX II Bruker difractometer to ldquoFacility foradvanced studies of materialsFAMardquo (FAPESP Project No2009540354)

REFERENCES(1) Almarsson O Zaworotko M J Chem Commun (Cambridge)2004 17 1889minus1896(2) Blagden N de Matas M Gavan P T York P Adv DrugDelivery Rev 2007 59 (7) 617minus630(3) Bond A D In Pharmaceutical Salts and Co-Crystals Wouters JQuere L Eds The Royal Society of Chemistry Cambridge UK2012 Chapter 2 pp 9minus28(4) Vishweshwar P McMahon J A Peterson M L Hickey M BShattock T R Zaworotko M J Chem Commu 2005 36 4601minus4603(5) Aakeroy C B Fasulo M E Desper J Mol Pharmaceutics 20074 (3) 317minus322(6) Trask A V Mol Pharmaceutics 2007 4 (3) 301minus309(7) GRAS S Food and Drug Administration Database of SelectCommittee on GRAS Substances (SCOGS) Reviews httpswwwaccessdatafdagovscriptsfcnfcnNavigationcfmrpt=scogsListing(8) Shan N Zaworotko M J Drug Discovery Today 2008 13 (9minus10) 440minus446(9) Hoffman M Lindeman J A In Pharmaceutical Salts and Co-crystals Wouters J Quere L Eds The Royal Society of ChemistryCambridge UK 2012 Chapter 14 pp 318 minus 329(10) Vermes A Guchelaar H-J Dankert J J AntimicrobChemother 2000 46 (2) 171minus179(11) Larsen R A In Essentials of Clinical Mycology 2nd edKauffman C A Pappas P G Sobel J D Dismukes W E EdsOxford University Press UK 2003 part 2 pp 57minus60(12) Mullen C A Coale M M Lowe R Blaese R M Cancer Res1994 54 (6) 1503minus1506(13) Allen F H Acta Crystallogr Sect B 2002 58 (3) 380minus388(14) Louis T Low J N Tollin P Cryst Struct Commun 1982 111059minus1064(15) Hulme A T Tocher D A CrystGrowth Des 2006 6 (2)481minus487(16) Portalone G Colapietro M Acta Crystallogr Sect E 2006 62(3) o1049minuso1051(17) Tutughamiarso M Bolte M Egert E Acta Crystallogr Sect C2009 65 (11) o574minuso578(18) Hulme A T Tocher D A Acta Crystallogr Sect E 2005 61(7) 02112minuso2113(19) Prabakaran P Murugesan S Muthiah P T Bocelli G RighiL Acta Crystallogr Sect E 2001 57 (10) o933minuso936

Figure 9 (a) Crystal packing diagram of form 5f Black dashed linesindicate hydrogen bonds (I) refers to the R2

2(8) motifs37ab involvingthe NminusHmiddotmiddotmiddotO homodimers occurring among 5-FC molecules and (II)correspond to R2

2(8) motifs37ab involving the NminusHmiddotmiddotmiddotO homodimersoccurring among 5-FU molecules (b) three-dimensional hydrogen-bonded network of form 5f

Crystal Growth amp Design Article

dxdoiorg101021cg500502j | Cryst Growth Des 2014 14 4383minus43934392

displaced arrangement (displacement angle of 232deg) main-tained by πmiddotmiddotmiddotπ interactions (5-FCπmiddotmiddotmiddotπ = 35604(9) Aring and 5-FUπmiddotmiddotmiddotπ = 35603(9)Aring) Adjacent tapes (and consequentlyadjacent columns) exhibit two directions of growth and areconnected to one another by intermolecular interactionsbetween the molecules of 5-FC and 5-FU forming a dihedralangle of 13017(3)deg (Figure 9b)

5 CONCLUSIONThe 5-FC cocrystals with succinic adipic benzoic and tereftalicacids were obtained following the tendency of the pKa rule andhave revealed a similar hydrogen-bonding pattern leading to 5-FC ribbons stabilized by two R2

2(8) motifs characterized bycomplementary homodimeric NminusHmiddotmiddotmiddotN (NNNN) and NminusHmiddotmiddotmiddotO (ONON) interactions which was found to be a featureof cocrystals containing this fluoropyrimidine moleculesAnalyzing the supramolecular characteristics of the four 5-FCcocrystals (together with some similar structures reported inthe literature) it was observed that the 5-FC molecule tends toform ONNN ONON and NNNN homodimers ONNCG-like base pairing heterotrimers and both tubular andplanar cavities Nevertheless when the cocrystallization experi-ment was conducted with malic acid where the ΔpKa = minus01 asupramolecular transition synthon was observed in which theNminusHmiddotmiddotmiddotO homodimeric synthon present in the cocrystalsremains but a new heterodimeric synthon characterized bycomplementary NminusHmiddotmiddotmiddotO hydrogen bonds between the 5-FCmolecule and the malic acid emerged This last synthon wasfound in the 5-FC organic salts obtained even from very smallpositive ΔpKa values (such as for the fumarate of 5-FC whereΔpKa = 023) The discovery of this transition synthonindicates that the 5-FC molecule is a suitable candidate forthe design and development of cocrystallization experimentsbased on crystal engineering techniques once its behaviorcould be until the present well predicted by the pKa rule Tocheck our hypothesis we conducted a cocrystallizationexperiment of 5-FC with the antineoplastic drug 5-FU aimingto obtain a cocrystal once the system exhibits a ΔpKa = minus30The success of this experiment points to a new path to apply 5-

FC as a coformer in new controlled crystallization experimentsfor the development of new tailor-made drugs

ASSOCIATED CONTENTS Supporting InformationCrystallographic data of the 5-FC calculated potentials Thismaterial is available free of charge via the Internet at httppubsacsorg

AUTHOR INFORMATIONCorresponding AuthorE-mail javiereifscuspbr Phone +55 16 3373 8096 Fax+55 16 3373 9881NotesThe authors declare no competing financial interest

ACKNOWLEDGMENTSWe thank CAPES (CCPS) FAPESP (JCT Project No201307581-9) and CNPq (JE ROP CCM Project No1500762013-4) for the financial support We also thank forthe use of the APEX II Bruker difractometer to ldquoFacility foradvanced studies of materialsFAMardquo (FAPESP Project No2009540354)

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Figure 9 (a) Crystal packing diagram of form 5f Black dashed linesindicate hydrogen bonds (I) refers to the R2

2(8) motifs37ab involvingthe NminusHmiddotmiddotmiddotO homodimers occurring among 5-FC molecules and (II)correspond to R2

2(8) motifs37ab involving the NminusHmiddotmiddotmiddotO homodimersoccurring among 5-FU molecules (b) three-dimensional hydrogen-bonded network of form 5f

Crystal Growth amp Design Article

dxdoiorg101021cg500502j | Cryst Growth Des 2014 14 4383minus43934392

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Crystal Growth amp Design Article

dxdoiorg101021cg500502j | Cryst Growth Des 2014 14 4383minus43934393