Polymorphism and Hydrated States in 5-Nitrouracil Crystallized from

Article pubs.acs.org/crystal

Polymorphism and Hydrated States in 5‑Nitrouracil Crystallized from Aqueous Solution Maurice O. Okoth,† Ranko M. Vrcelj,*,‡ Mateusz B. Pitak,‡ David B. Sheen,† and John N. Sherwood† †

WESTCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, Glasgow, G1 1XL, U.K. ‡ School of Chemistry, University of Southampton, Highfield Campus, Southampton, SO17 1BJ, U.K. S Supporting Information *

ABSTRACT: The crystallization of 5-nitrouracil (5NU) from pure aqueous solution yields two anhydrous polymorphs and a monohydrate depending on the temperature at which the process is carried out. 5NU mimics true polymorphism in that, when retained in aqueous solution, both metastable (anhydrous) forms undergo solvent mediated phase transformations (SMPTs) into the more thermodynamically stable hydrated form as would be predicted by Ostwald’s rule of stages. The phase transformations can occur either in the classical manner of dissolution and recrystallization or, in one case, may in some circumstances be nucleated and morphologically templated by the original crystalline form. There is no appearance from aqueous solution of a known third acentric anhydrous form, previously prepared from acetonitrile solutions. Preliminary experiments suggest this nonappearance may result from the relatively high solubility of this form in aqueous solution.

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INTRODUCTION Many technically useful organic materials exhibit interesting structural transformations which can be difficult to control, in particular, when they are prepared by growth from solution. Issues such as multiple polymorph formation are currently well addressed,1,2 but the related problems associated with hydrate (or solvate) formation have been less thoroughly examined.3,4 These are equally important however as much industrial downstream processing involves crystallization from solvents and preferably from aqueous media. In this paper, we examine the interrelationships of the crystalline forms of 5-nitrouracil (5NU) resulting from its crystallization from pure aqueous solutions. 5NU (C4H3N3O4) is a cyclic urea derivative (Figure 1), with a strong electron accepting nitro-group attached. Its acentric, nonsolvated form has been of some interest to the nonlinear optical (NLO) community5,6 as a potential strong generator of second-harmonic light. More recent interest from the crystal engineering community relates to its conspicuous N−H bonds

and CO groups, and the resulting strong potential intermolecular H-bond interactions with protic solvents that might direct its crystallization behavior. 5NU has so far been shown to exist in three nonsolvated,7,8 two hydrated,9−11 and a further number of otherwise solvated crystal structures.12 Previous work on the crystal growth of 5NU has been limited to a simple solubility study13 which presents no indication of the crystal form produced. Apart from this, the majority of the remaining work does not clearly report on the crystal growth of the material and the interest whether in NLO or structural crystal engineering is predominantly phenomenological. This study examines 5NU grown primarily from aqueous solution and reports on qualitative as well as quantitative studies of solution-mediated phase transformations (SMPTs) between the structures of 5NU. There are a small number of studies of the relative stability of anhydrous and hydrated systems. The materials previously studied (carbamazepine,14−19 piroxicam,16 piracetam,20 baclofen,21 theophylline and nitrofuratonin,22 L-phenylalanine23,24) are reported with great clarity but concentrate on either the kinetics of transformation under a variety of conditions or the phase relationships. In this paper we give a structural interpretation at the molecular level to the crystal growth and relative stabilities of the differing forms of 5NU. Received: July 11, 2012 Revised: August 31, 2012 Published: September 6, 2012

Figure 1. The molecular structure of 5-nitrouracil. © 2012 American Chemical Society

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dx.doi.org/10.1021/cg300961m | Cryst. Growth Des. 2012, 12, 5002−5011

Crystal Growth & Design

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Above 50 °C. Solutions saturated at 70 °C and cooled slowly to 50 °C yielded quasi-hexagonal plate-like crystals of the anhydrous 5NU-o form (Figure 2a). If kept in solution at elevated temperatures, for periods of up to a month no apparent transformation occurred; similarly no phase transformation took place if the crystals are removed from solution and dried. However, if retained in solution and cooled to ambient temperatures, they ultimately undergo an SMPT into the 5NU-h form. Under these conditions the transformation was complete in 6−8 days. The hexagonal crystals were indexed by means of stereographic projection, with the large main face being the (001) and the remaining bounding facets {100} and {120} faces (Figure 2b). Closer examination by eye (and polarized light microscopy) shows that these crystals are not truly single and are in fact composite. Small volumes of good quality crystal are interspersed with planar stacking faults (partially visible as the horizontal lines in Figure 2a), with mis-stacking occurring along [100]. (Also visible is a cord, used for mounting the crystal for further single crystal growth experiments.) Between 50 and 40 °C. Solutions saturated between 50 and 40 °C and cooled to ambient temperatures yielded predominantly rhombohedral prisms (Figure 2c,d). These were shown to be the 5NU-h form by X-ray diffraction. Below 40 °C. Solutions saturated below 40 °C initially yield clusters of thin needle/lath-like crystals, of the anhydrous 5NUm form. These have large {110} faces (Figure 2e,f), bounded by long {001} faces. The fast growing direction is [010] with associated end-capping facet {011} planes and smaller {012} faces. The commonest appearance of these crystals is as clusters of needles, generated from a central nucleation source (as seen in the lower right part of Figure 2e). When isolated from solution this form also remained stable for long periods (months) without transformation. On cooling to ambient temperatures in contact with solution however, these NU-m clusters also undergo an SMPT (over a period of 6−8 days) to give a further range of crystal habits. These are predominantly (Figure 3) prismatic rhombohedral crystals, block-like crystals or hexagonal rod type crystals (listed in descending order of appearance). All proved to be single crystals or simple twinned variations of the 5NU-h phase. Decreasingly small numbers of further crystal morphologies also appeared, but these all proved to be the 5NU-h but with further twin forms. To understand the variations in the morphology of 5NU-h, the crystallographic structure was redetermined. The unit cell is also given in Table 1 under the column heading 5NU-h (this study), with the appropriate .cif file supplied as Supporting Information to this paper, and a list of significant hydrogen bonds and short contact angles and distances are given in Table 2. This yields a lower R-factor (3.53% for the new lowtemperature determination, compared to 6% for the older structure9), and a reset origin gives a smaller value of β (∼113° rather than ∼145°). In the current determination, the 5NU and water molecules lie in planar sheets parallel to the (102̅) plane, at an interplanar separation of 2.979 Å (Figure 4a). The 5NU and water molecules are hydrogen-bonded within any given layer (Figure 4b), but no such H-bonding exists between the sheets of molecules, any interactions being weaker van der Waals forces (Figure 4c). Detailed characterization of the hydrogen bonding in this form of 5NU has been described previously.9

EXPERIMENTAL SECTION

Materials and Crystal Growth. 5NU was obtained from Sigma Chemical Co. (Poole, UK; >99% purity). Crystals of 5NU were obtained by temperature lowering or constant temperature evaporation of saturated aqueous solutions (water deionized and double distilled) or from saturated solutions of acetonitrile. Differential Scanning Calorimetry (DSC). DSC was performed on V2.2A Du Pont 9900 with constant sample weight (10 mg), scanning rate of 10 °Cmin−1, dry N2 as the purge gas, and a pierced lid in the sample pan to ease any pressure build-up. Single Crystal X-ray Diffraction. X-ray single-crystal diffraction measurements for 5NU-h were made on a Bruker Nonius diffractometer.25 Optical Microscopy (OM). Two microscopes were used: a Reichert Polyvar 2 microscope and a Leica M205C, with Leica DFC295 Digital camera attachment, both in transmission mode. Solubility Curve. A Haake P35 bath was used to maintain a saturated solution at a constant temperature. After a day of equilibration during which the solution was well stirred, an aliquot of 2 mL was taken and dried to constant weight. The solution temperature was then lowered and left to equilibrate for a further day, until the end of the run.

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RESULTS AND DISCUSSION Growth of 5NU from an aqueous mother liquor resulted in the appearance of a large number of differently shaped crystals. Such variations are not uncommon when crystals are prepared in the manner described. They result as a consequence of either polymorphism, growth rate dispersion arising from variation in growth conditions, or the development of structural defects during growth. These various habits were shown to belong to only three crystalline forms (classified in the Cambridge Crystallographic Database as NIMFOE, NIMFOE01 and NURAMH); the acentric anhydrous structure (NIMFOE02) (previously only obtained from acetonitrile) was not observed from water, nor was the new hydrated phase (NURAMH01)  an experiment in crystal engineering in which L-lysine was added to the crystallizing solutions.10,11 For brevity we will refer to the observed (in this study) forms of 5NU as 5NU-m (for NIMFOE), 5NU-o (for NIMFOE01), 5NU-a (for NIMFOE02), and 5NU-h (for NURAMH) and the unit cells are given in Table 1, under the column headings 5NU-m, 5NU-o, and 5NU-h (Craven). The type of crystal form grown was found to be dependent on both the temperature at which the crystallization was carried out and the period for which it was retained in solution. Table 1. Crystallographic Data for 5-Nitrouracil

CCDC Refcode/ deposition no. space group a (Å) b (Å) c (Å) β (deg) cell volume (Å3) Z R-factor (%) temp

5NU-h (this study)

5NU-m

5NU-o

5NU-h (Craven)

NIMFOE5

NIMFOE016

NURAMH7

871417

P21/n 5.873 9.693 10.4561 104.07 577.377 4 3.63 room

Pbca 8.308 10.426 13.363 90 1157.49 8 7.81 130 K

P21/c 5.137 21.956 9.587 143.50 643.181 4 6 room

P21/c 5.0642 21.9255 6.1176 113.108 624.768 4 3.53 120 K 5003



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Figure 2. 5NU crystals (a) orthorhombic and (b) morphology; (c) hydrate and (d) morphology; (e) monoclinic and (f) morphology.

Table 2. Hydrogen Bonds and Short Contacts [Å and °] D−H···A O5 O5 O5 N2 N3 N3

H1O···O4a H2O···O3b H2O···O2b H2···O3c H3···O5 H3···O1d

d(D−H)

d(H···A)

d(D···A)

∠(DHA)

0.858(14) 0.852(15) 0.852(15) 0.88 0.88 0.88

2.071(15) 2.263(18) 2.305(15) 1.96 2.06 2.58

2.9222(15) 2.9785(15) 3.0486(16) 2.8371(16) 2.8303(17) 3.2386(16)

171.7(18) 141.7(16) 146.0(17) 173.8 145.7 132.2

Symmetry transformations used to generate equivalent atoms: −x + 2, −y + 1, z + 2. bx + 2, y, z + 1. c−x, −y + 1, −z + 1. dx + 1, −y + 3/2, z + 1/2. a

reported by Craven is a nonstandard setting of the unit cell. In this report, we continue to use our structure determination, with a minimized angle β, following crystallographic convention. The simplest form is that of the hexagonal rods in Figure 3. These show a main (010) face, bounded by [110] and {001} faces Although this untwinned form exists, the most commonly found habits are the rhombohedral plates and prismatic blocks,

Figure 3. Differing morphologies of 5NU-h: twinned rhombohedral plates, blocks and hexagonal rods.

It is of note that the reduced cell reported by Craven9 is the same as that obtained in this study; however, the final cell 5004



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Figure 4. Structure of 5NU-h (a) viewed along (010); (b) hydrogen bonding within the planar sheet in 5NU-h, viewed perpendicular to (102̅) planes and (c) showing the intraplanar hydrogen bonding in the sheets that lie along the (102̅) planes.

simple blocks also occur and single crystal diffraction shows these to be twinned by a 180° rotation around the [3̅01̅] reciprocal lattice vector. Solvent Mediated Phase Transformation. With time, both 5NU-o and 5NU-m undergo an SMPT into 5NU-h. Figure 5a depicts the transformation of 5NU-o into 5NU-h. It shows what is regarded as a classical SMPT, with block-like

shown in Figures 2c and 3. The rhombohedral plates have the same morphology as in Figure 2d, but the prismatic blocks are more fully developed along the [010] direction. These also show a predominant (010) face, bounded by (1̅02̅), (101̅), and (001)̅ faces. Single crystal diffraction studies show that the twin is a simple 180° rotation around [100] as indicated by the dotted line in the morphological diagram in Figure 2d. Some 5005



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Figure 5. SMPT of 5NU with 5NU-h crystals sitting among denuded areas of (a) 5NU-o and (b) 5NU-m, both exhibiting block-like morphologies.

crystals of 5NU-h sitting in areas denuded of the 5NU-o phase, which had nucleated and grown first. Figure 5b shows a similar situation for 5NU-m, with a small number of block-like 5NU-h crystals sitting among the clusters of needles of 5NU-m. In addition to this classical SMPT in this latter case, there is an additional mode of transformation that was peculiar to 5NU-m. Figure 6a shows a cluster of 5NU-m crystals that are in the process of redissolution, and directly interconverting into 5NUh, while retaining the cluster form. These 5NU-h crystals adopt the twinned rhombs/prism morphology, as opposed to the block types seen in Figure 5. Figure 6b shows an enlarged area of the cluster, where some interconversion has taken place. In this case the 5NU-m needles are developing into long clusters of 5NU-h rhombs. Along the flat body of the needles, the rhombs are aligned with their flat faces parallel to the long flat face of the 5NU-m crystal, giving a sawtooth appearance. From the end of the needle grow randomly oriented 5NU-h rhombs. That this is not simply renucleation of the new phase in the more concentrated solution in the core of the clusters can be seen from Figure 6c, which shows a detached single needle of 5NU-m undergoing a direct conversion into 5NU-h. The growing crystals of the new phase are again partially aligned. A general measure of the rate of transformation at 25 °C can be made by manual separation of the two forms of 5NU. This yields the sigmoidal transformation curve (Figure 7) typical of many SMPT processes. This can be compared to the changes in concentration of the mother solution at 35 °C. Although there is a 10 °C difference between the temperatures of the two experiments, it is still useful to qualitatively compare these.

Figure 6. (a) SMPT of 5NU-m into 5NU-h showing the retention of the needle cluster shape, but development of rhomb/prism morphology. (b) Enlargement of aligned crystal growth area. (c) Direct transformation of 5NU-m crystal into 5NU-h.

At the early stages, the concentration of the solution is that of the estimated solubility of 5NU-m in water. The concentration 5006



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Figure 7. SMPT as measured by mass (black) and concentration (red) of 5NU-m and 5NU-h forms.

rapidly drops within 2 days to close to the estimated solubility of 5NU-h. Similarly, the amount of 5NU-m also drops, but at a slightly later time, 4−5 days, implying that the 5NU-h is growing initially from the solution, before scavenging the 5NUm crystals. At the end of the process there is no 5NU-m left and the concentration has dropped to the estimated value of the solubility of 5NU-h. Structural Interrelationships. The question that the two observed crystal morphologies during the SMPT poses is whether there is a structural reason for the two mechanisms. The simple dissolution and recrystallization mechanisms that occur in both the 5NU-m and 5NU-o systems can be explained straightforwardly by kinetic models, but why the growth of 5NU-h plates occurs within the clusters of 5NU-m is not immediately clear. The structural inter-relationships when examined by XPac30 show a number of interesting points. The relationship between 5NU-h and 5NU-m is relatively simple, with no extended similarity in the structure, just a molecule−molecule pair similarity between the seed and nearest neighbor 5NU molecules (Figure 8a), yielding a dissimilarity parameter of χ = 10.6°. The extended relationship that this leads to in the unit cell packing is shown in Figure 8b. On examination, it is of interest to see that the large {110} faces of 5NU-m are closely aligned to the {010} faces of 5NUh. It would thus appear that the 5NU-m {110} faces effectively act as a template for the growth of the rhombohedral type 5NU-h crystals (as seen in Figure 6a−c). If this were not a direct relationship, then the 5NU-m crystal would act as a simple seed, with 5NU-h crystals growing in random directions from it, as seen in Figure 6b. This suggests two important questions. Are the crystals fully 5NU-h after transformation? How does the water enter the 5NU-m crystal to allow such a transformation to occur? The first question is answered by Figure 6c, where the transformation does yield an optically clear 5NU-h crystal from the 5NU-m base. The answer to the second question is most likely to be that it is a localized SMPT of the 5NU-m crystal. As the 5NU-h is seeded by the 5NU-m template, it will then likely disrupt the remaining 5NU-m. This then dissolves and is almost immediately deposited on the nearby available 5NU-h template crystal. This will carry on until the 5NU-m is

Figure 8. Structural similarity of (a) 5NU-m (blue) and 5NU-h (red) at the molecular level and (b) the relation to the two unit cells.

exhausted and the 5NU-h crystals reach maximum size. This idea is supported by Figure 6c, where areas of 5NU-m close to the 5NU-h growth show definite rounded (thus dissolving) edges, as opposed to the ends of the crystal, which retain their sharp edge features. In the case of 5NU-h and 5NU-o, this has a very similar structural relationship, again, with no extended connections, but just the same localized molecule−molecule motif, but in 5007



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this case, the dissimilarity parameter is lower, χ = 8.2°, as shown in Figure 9a,b. In the case of the comparison between 5NU-m

Figure 10. Structural similarity of (a) 5NU-m (blue) and 5NU-o (green) at the molecular level and (b) the relation to the two unit cells.

°C. This transformation is monotropic with no equivalent transformation occurring during cooling. 5NU-m shows no thermal events until its decomposition at ∼310 °C. This indicates that 5NU-h dehydrates to form 5NU-o, which then undergoes a phase transformation into 5NU-m at ∼270 °C, prior to decomposition. A detailed assessment of the dehydration process will be given in a following publication.31 The measured solubility curve (Figure 12) also fits well with the overlapping stability regions of the three forms. It does not increase gradually but has a distinct change in the slope between the solubilities at higher and lower temperature. At higher temperatures, the solubility is that of 5NU-o. At lower temperatures, the solubility curve will be that of 5NU-h. The intermediate region (40−50 °C) corresponds well to the anticipated stability region of 5NU-m (given the known time for 5NU-m/5NU-h transformation to occur at 35 °C (Figure 7)). Relationships with 5NU-a. Finally it is of interest to consider briefly why the acentric anhydrous form of 5NU is not observed at all during the aqueous crystallization process. That it does not appear is surprising since recent theoretical work by Barnett et al.32 indicates that this acentric form ought to be the most stable polymorph. Not only this, but while 5NU-o is theoretically predicted28 as a possible viable polymorphic form, 5NU-m, which from the present study would appear to be the most stable polymorph, is not ranked at all in these calculations. Although such calculations are still in their infancy, they are becoming well enough understood to make such an observation noteworthy. Samples of 5NU-a are obtained easily from saturated solutions in acetonitrile. When 5NU-a is added as a seed to a saturated aqueous solution, it merely dissolves and does not grow, confirming both that it is highly soluble in water and that it is not the most stable polymorph thermodynamically. This

Figure 9. Structural similarity of (a) 5NU-o (green) and 5NU-h (red) at the molecular level and (b) the relation to the two unit cells.

and 5NU-o, this has a dissimilarity parameter χ = 10.9°. This means that there is a slightly higher degree of localized differences between the molecular positions; however, they have also a greater medium range similarity, leading to a twodimensional supramolecular construct shared by the two crystal structures. The lattice vectors that are shared are [010] and [101] in 5NU-m and [100] and [010] in 5NU-o, which accounts for the very similar relationships between 5NU-h and the two anhydrous forms and is shown in Figure 10a,b. The similarities that occur between 5NU-m and 5NU-h are different to those between 5NU-o and 5NU-h (as shown in Figures 8 and 9), so although they generate similar calculated dissimilarity parameters, there are vital differences, for example, the crystal faces that are available for growth, which lead to the ability of 5NU-m to act in the manner of a template. The similarity of the 5NU-m and 5NU-o structures leads to similar physicochemical properties (e.g., the high phase transformation temperature of 5NU-o and the close values for solubility). Phase Relationships. A basic understanding of the relative thermal stabilities of the phases and their interrelationships is given by DSC (Figure 11). It is clear that 5NU-h undergoes a broad dehydration event just before 100 °C. The dehydration product then undergoes a further phase transformation at ∼270 °C (indicated as phase Change II in Figure 11) and then final decomposition at ∼310 °C. Crystals of 5NU-o only undergo a phase transformation at ∼270 °C with an enthalpy of transformation of −12.71 J g−1 and then decompose at ∼310 5008



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Figure 11. DSC of 5NU with red indicating 5NU-h, blue indicating 5NU-m, green 5NU-o, and pink 5NU-a.

Figure 12. Solubility curve for 5NU in water.

appearance of this anhydrous form is associated with its relatively high solubility. Consequently, if it does crystallize it will do so only fleetingly and rapidly convert to one of the more stable anhydrous species. Such a process would appear to be more likely than one resulting from unique solute−solvent interactions that would demand a greater and opposite difference in dipolar interactions than exists between water and acetonitrile.

latter conclusion is supported by DSC and crystal growth studies. 5NU-a undergoes a phase transformation (indicated as phase Change I in Figure 11) at ∼252 °C, with no further events until the decomposition at ∼310 °C, indicating that it transforms into the 5NU-m form. The much greater (1 order of magnitude) enthalpy of transformation, −162.51 J g−1, compared with that for the 5NU-o to 5NU-m transition reflects the more complex change from an acentric structure into a centrosymmetric one. When seeds of 5NU-m and 5NU-o are added to 5NU-a saturated acetonitrile solutions, these grow at the expense of 5NU-a, through an SMPT again implying a much higher solubility for 5NU-a in this solvent than either 5NU-m and 5NU-o. We suggest that potentially the lack of

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CONCLUSIONS Five nitrouracil shows a very interesting crystal growth process from aqueous solution, with a measure of both kinetically stable forms (in the cases of 5NU-o and 5NU-m) and thermodynami5009



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(2) Bernstein, J. Cryst. Growth Des. 2011, 11, 632−650. (3) Infantes, L.; Fabian, L.; Motherwell, W. D. S. CrystEngComm 2007, 9, 65−71. (4) Ruscica, R.; Bianchi, M.; Quintero, M.; Martinez, A.; Vega, D. R. J. Pharm. Sci. 2010, 99, 4962−4972. (5) Pierce, B. M.; Wing, R. M. Proc. Soc. Photo-opt. Instrum. Eng. 1986, 682, 27−35. (6) Pucetti, G.; Perigaud, A.; Badan, J; Ledoux, I.; Zyss, J. J. Opt. Soc. Am. B 1993, 10, 733−744. (7) Kennedy, A. R.; Okoth, M. O.; Sheen, D. B.; Sherwood, J. N.; Vrcelj, R. M. Acta Crystallogr. 1998, C54, 547−550. (8) Gopalan, R. S.; Giridhar, U. K.; Rao, C. N. R. ChemPhysChem 2000, 1, 127−135. (9) Craven, B. M. Acta Crystallogr. 1967, 23, 376−383. (10) Pereira Silva, P. S.; Domingos, S. R.; Ramos Silva, M.; Paixão, J. A.; Matos Beja, A. Acta Crystallogr. 2008, E64, o1091. (11) Pereira Silva, P. S., personal communication, 2011 (12) Thomas, R.; Gopalan, R. S.; Kulkarni, G. U.; Rao, C. N. R. Beilstein J. Org. Chem. 2005, 1, 1−15. (13) Youping, H.; Genbo, S.; Bochang, W.; Rihong, J. J. Cryst. Growth 1992, 119, 393−398. (14) Qu, H.; Munk, T.; Cornett, C.; Wu, J. X.; Bøtker, J. P.; Christensen, L. P.; Rantanen, J.; Tian, F. Pharm. Res. 2011, 28, 364− 373. (15) Qu, H.; Louhi-Kultanen, M.; Rantanen, J.; Kallas. J. Cryst. Growth Des. 2006, 6, 2053−2060. (16) Qu, H.; Louhi-Kultanen, M.; Rantanen, J.; Kallas. J. Cryst. Growth Des. 2007, 7, 724−729. (17) Skrdla, P. J. Cryst. Growth Des. 2008, 8, 4185−4189. (18) Liu, W.; Wei, H.; Black, S. Org. Process Res. Dev. 2009, 13, 494− 500. (19) Murphy, D.; Rodríguez-Cintron, F.; Langevin, B.; Kelly, R. C.; Rodruíguez-Hornedo. Int. J. Pharm. 2002, 246, 121−134. (20) Dematos, L. L.; Williams, A. C.; Booth, S. W.; Petts, C. R.; Taylor, D. J.; Blagden, N. J. Pharm. Sci. 2007, 96, 1069−1078. (21) Mirza, S.; Miroshnyk, I.; Rantanen, J.; Aaltonen, J.; Harjula, P.; Kiljunen, E.; Heinämäki, J.; Yliruusi, J. J. Pharm. Sci. 2007, 96, 2399− 2408. (22) Aaltonen, J.; Heinänen, P.; Peltonen, L.; Kortejärvi, H.; Pekka Tanninen, V.; Christiansen, L.; Hirvonen, J.; Yliruusi, J.; Rantanen, J. J. Pharm. Sci. 2006, 95, 2730−2737. (23) Mohan, R.; Koo, K.-K.; Strege, C.; Myerson, A. S. Ind. Eng. Chem. Res. 2001, 40, 6111−6117. (24) Kee, N. C. S.; Arendt, P. D.; Tan, R. B. H.; Braatz, R. D. Cryst. Growth Des. 2009, 9, 3052−3061. (25) X-ray single-crystal diffraction measurements for 5NU-h were made on on a 0.34 × 0.07 × 0.04 mm crystal at 120 K with Mo Kα (l = 0.71073 Å) radiation on a Bruker Nonius diffractometer located at the window of Nonius FR591 rotating-anode X-ray generator equipped with a Roper CCD detector. Monoclinic, P21/c, a = 5.0642(1), b = 21.9255(5), c = 6.1176(1) Å, b = 113.108(1)°, V = 624.77(2) Å3, Z = 4, M = 175.11, m = 0.173 mm−1, 1434 unique reflections (*for nonmerohedral twin data in HKLF 5 format were used) with F2 > 2s, hkl ranges: −6 ≤ h ≤ 6, 0 ≤ k ≤ 28, 0 ≤ l ≤ 7, data completeness to q = 27.49° = 99.8%, R(F2 > 2s) = 0.0352, wR2 = 0.0816. Data were processed using the Collect package.26 Unit cell parameters were refined against all data. An empirical absorption correction was carried out using SADABS.27 The crystal structure was solved by direct methods and refined on Fo2 by full-matrix least-squares refinements using programs of the SHELX family.25 All non-hydrogen atoms were refined with anisotropic displacement parameters. All hydrogen atoms located on N and C were placed at calculated positions and refined using a riding model on their parent atoms with isotropic displacement parameters based on the equivalent isotropic displacement parameter (Uiso(H) = 1.2Ueq(C,N)) of the parent atom. Two hydrogen atoms of the water molecule were located directly from the Fourier map and displacement parameters were freely refined. The crystal was a nonmerohedral twin with the two domains related by 180° about the reciprocal vector [3̅ 0 1̅]. EvalCCD28 package was used to integrate the

cally stable form (5NU-h). Although the two anhydrous forms are distinctly different materials from the hydrated form, they show a great deal of structural similarity which is reflected in the high degree of similarity between predicted powder diffraction patterns. Transformations between the anhydrous and hydrated phases are controlled by a process akin to Ostwald’s rule of stages and show both the classical behavior of dissolution and renucleation and, in one case, templating of the product on the original source crystals. These have been seen in truly polymorphic transformations,33 but rarely examined at the molecular level for anhydrous/hydrate systems. The expected intermediate transformation between the two anhydrous phases was not observed, possibly due to the intervention of the more rapid SMPT of the product 5NU-m to 5NU-h, thus avoiding a true implementation of Ostwald’s rule of stages, but still mimicking important aspects of the appearance of metastable forms from solution. The nonappearance of the acentric anhydrous form of 5NU from water is still unresolved but would appear to be due to its potentially high solubility leading to a fleeting appearance rapidly followed by immediate redissolution and then recrystallization as one of the other anhydrous forms. 5NU is an interesting and instructive material to examine. It exemplifies the difficulties that still exist for even small molecule systems. Different crystallization rates, relative stabilities, and crystal sizes and shapes all contribute to a wide variety of behavior that can confuse and ultimately mislead the understanding of polymorphism and pseudopolymorpism in solvated systems. More work is required to fully understand the phase relationships and crystallization kinetics of this material in different solvents.

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ASSOCIATED CONTENT

S Supporting Information *

The .cif file of the redetermined 5-nitrouracil hydrate (5NU-h) is available free of charge via the Internet at http://pubs.acs. org/.

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AUTHOR INFORMATION

Corresponding Author

*Tel: +44(0) 2380 596722. Fax: +44(0) 2380 596723. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS M.O.O. wishes to thank his employers, Moi University, Kenya, for according him study leave to allow him to undertake these studies. We acknowledge the kind support of GlaxoSmith Kline for their financial support of this work and in particular M.O.O. wishes to express his gratitude for the firm’s financial support of this work, both at the M.Phil. and Ph.D level. We also wish to thank Mr. David Merrifield of Glaxo Smith Kline and Professor A. K. Galwey, Queens University, Belfast, for their kind interest in this work and for many stimulating and helpful discussions on this topic. M.B.P. wishes to acknowledge the EPSRC for its funding of the National Crystallography Service and Dr. S. J. Coles of the NCS.

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REFERENCES

(1) Bernstein, J. Polymorphism in Molecular Crystals, 1st ed.; Oxford University Press: Oxford, UK, 2002. 5010



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domains and the structure was refined using HKLF 5 instruction in SHELXL.29 The refined percentage ratio of the twin domains was 50:50 (refined BASF = 0.50766). CCDC depository number: 871417. (26) Hooft, R. Collect: Data Collection Software; B.V. Nonius: Delft, Netherlands, 1998. (27) Sheldrick, G. M. SADABS, Version 2.10; Bruker AXS Inc.: Madison, Wisconsin, USA, 2003. (28) SHELXL97 - Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112122. (29) Duisenberg, A. J. M.; Kroon-Batenberg, L. M. J.; Schreurs, A. M. M. J. Appl. Crystallogr. 2003, 36, 220−229. (30) Gelbrich, T.; Hursthouse, M. B. CrystEngComm 2005, 7, 324− 336. (31) Okoth M. O.; Vrcelj R. M.; Sheen D. B.; Sherwood J. N., in preparation. (32) Barnett, S. A.; Hulme, A. T.; Issa, N.; Lewis, T. C.; Price, L. S.; Tocher, D. A.; Price, S. L. New J. Chem. 2008, 32, 1761−1775. (33) Croker, D.; Hodnett, B. K. Cryst. Growth Des. 2010, 10, 2806− 2816.

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Polymorphism and Hydrated States in 5-Nitrouracil Crystallized from

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