1:1 and 2:1 Urea−Succinic Acid Cocrystals: Structural Diversity

Oct 13, 2010 - ABSTRACT: The aim of this work was to study the crystal structures of 1:1 and 2:1 urea-succinic acid (U-SA) cocrystals and to investiga...
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DOI: 10.1021/cg100823p

1:1 and 2:1 Urea-Succinic Acid Cocrystals: Structural Diversity, Solution Chemistry, and Thermodynamic Stability

2010, Vol. 10 4847–4855

Amjad Alhalaweh,†,# Sumod George,†,# Dan Bostr€ om,‡ and Sitaram P. Velaga*,† †

Department of Health Science, Lulea University of Technology, Lulea S-971 87, Sweden, and Department of Energy Technology and Thermal Process Chemistry, Umea University, Umea S-901 87, Sweden. #Contributed equally to this work.

‡

Received June 20, 2010; Revised Manuscript Received September 17, 2010

ABSTRACT: The aim of this work was to study the crystal structures of 1:1 and 2:1 urea-succinic acid (U-SA) cocrystals and to investigate the role of solution chemistry in the formation and stability of different stoichiometric cocrystals. The structural diversity of other urea-dicarboxylic acid cocrystals is also discussed. The 1:1 U-SA cocrystal was stabilized by an acid-amide heterosynthon while acid-amide heterosynthons and amide-amide homosynthons stabilized the 2:1 cocrystals. The hydrogen bonding motifs in 1:1 and 2:1 U-SA cocrystals were consistent with other urea-dicarboxylic acid systems with similar stoichiometries. The 1:1 cocrystals were transformed to 2:1 cocrystals upon slurrying in various solvents at 25 °C. The phase solubility diagram was used to define the stability regions of different solid phases in 2-propanol at 25 °C. While no phase stability region for 1:1 cocrystal could be found, the stable regions for the 2:1 cocrystals and their pure components were defined by eutectic points. The solubility of the 2:1 cocrystals was dependent on the concentration of the ligand in the solution and explained by the solubility product and 1:1 solution complexation. The mathematical models predicting the solubility of the 2:1 cocrystals were evaluated and found to fit the experimental data.

*Corresponding author. E-mail: [email protected]; fax: þ45-920493850; tel: þ46-920-493920.

a cocrystal polymorph can be mistaken for a new stoichiometric cocrystal, and vice versa. The growing interest in the area of stoichiometric diversity in multicomponent crystals and the complexities associated with their identification and characterization have been demonstrated in a recent article.14 In another article, the formation of stoichiometrically diverse cocrystals was demonstrated to be effectively controlled by neat grinding.15 Indeed, knowledge of the structural basis or mechanisms of formation of stoichiometric cocrystals and their thermodynamic stabilities is limited, and these topics have rarely been investigated. Phase solubility diagrams (PSD) and ternary phase diagrams (TPD) have recently been utilized to explain the solubility and stability of stoichiometrically diverse cocrystals.10,16 A PSD depicting the stability domains of 2:1 and 1:1 carbamazepine-4-aminobenzoic acid cocrystals has recently been published.16 The same study presents various models describing the solubility of 2:1 cocrystals with differing stoichiometric compositions; the solubility of cocrystals was explained by solubility product and 1:1 solution complexation. However, the number of proposed models has not been verified for other systems. Hence, one of the aims of this study was to test these mathematical models using other model stoichiometrically diverse cocrystals and to understand their stability behavior. Within the scope of this study, we have addressed the identification, structural analysis, thermodynamic stability, and phase solubility behavior of 1:1 and 2:1 urea-succinic acid (U-SA) cocrystals, as a model system. Urea and its derivatives are widely used in crystal engineering and supramolecular chemistry for their versatility in the design and synthesis of solid-state structures and functional materials.17,18 A wide range of cocrystals, also referred to as solid-state complexes, of urea with dicarboxylic acids has been reported.19,20 Unlike mineral acids, organic acids form stable hydrogen-bonded systems with urea. The stoichiometry of the urea-dicarboxylic acid cocrystals is diverse, including ratios

r 2010 American Chemical Society

Published on Web 10/13/2010

Introduction Cocrystal technology has shown great promise in rectifying the undesirable properties of a drug substance. As a result, there has been significant interest in utilizing this technology for improving drug performance.1,2 Cocrystals are homogeneous multicomponent crystalline materials with definite stoichiometries. They can be viewed as an addition to the existing class of crystalline solids (polymorphs, hydrates/ solvates, and salts).3 Cocrystal formation relies on intermolecular interactions and molecular packing patterns; knowledge of these is derived from the principles of crystal engineering and supramolecular chemistry.4,5 Traditional cocrystal screening methods are empirically based, and an understanding of phase solubility behavior has led to efficient, rational screening methods such as reaction crystallization.6,7 Further, phase solubility diagrams (PSDs) are valuable tools in the scale-up of cocrystals using equilibrium methods.8 The list of cocrystal forming active pharmaceutical ingredients (APIs) continues to increase, and some APIs can form as many as 50 cocrystals.9 The polymorphic tendency of cocrystals has been discussed in recent reports. Cocrystals with two or more polymorphs include, for example, (1:1) ureaglutaric acid cocrystals,10 (1:1) 4,40 -bipyridine-pimelic acid cocrystals,11 and (1:1) carbamazepine with nicotinamide,12 saccharin,12 or isonicotinamide13 cocrystals. It has been suggested in these articles that polymorphism in cocrystals has not been picked up previously because of inappropriate methods used in screening rather than being a rare occurrence. Cocrystals also exhibit stoichiometric diversity. Cocrystals with different stoichiometries have usually been discovered by different crystallization methods under different experimental conditions (solution composition, solvents, etc.). Without the crystal structures, typically during the early screening phases,

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of 2:1, 1:1, and 1:2. A systematic analysis of these structures has been attempted in order to shed light on the structural reasons for the stoichiometric diversity. As early as 1921, a 2:1 U-SA cocrystal was described in an article published in Julius Springer.21 Further, in a study on the symmetry of hydrogenbonded molecular assemblies in urea-dicarboxylic acid cocrystals, the possible existence of 1:1 U-SA cocrystals was suggested, but neither the preparation method nor the crystal structure data are available.19,22 This article presents (1) the characterization and single crystal structure determination of 1:1 U-SA cocrystals, (2) a structural analysis of stoichiometrically diverse ureadicarboxylic acid cocrystals, (3) thermodynamic stability of U-SA cocrystals and solubility phase diagrams for 2:1 U-SA cocrystals, and (4) an evaluation of the models describing the solubility of 2:1 U-SA cocrystals. This study contributes to the overall understanding of the role of structural and thermodynamic factors in the formation and stabilization of stoichiometrically diverse cocrystals. 2. Materials and Methods 2.1. Chemicals. All solvents (purity >99.8%) and chemicals (purity >99.0%) used in the study were sourced from Sigma-Aldrich, Sweden, and were used without further treatment. Milli-Q water was used throughout the study. 2.2. Preparation of Urea-Succinic Acid (U-SA) Cocrystals. The 1:1 cocrystal was serendipitously discovered by spray drying.23 A solvent evaporation method was used to isolate a single 1:1 cocrystal. It took significant efforts to grow and isolate a few good quality crystals of the 1:1 U-SA cocrystal suitable for single crystal X-ray diffraction analysis. These crystals were generated by solvent evaporation of 1:1 molar ratio of urea and succinic acid in an acetonitrile-water (80:20 v/v) solution at 32 °C in an oven, under stirring. Our efforts in generating pure 1:1 cocrystals using other methods such as liquid assisted grinding or slurrying were not successful. In fact, the bulk 1:1 cocrystals (in pure form) used for various characterizations could only be prepared by spray drying of an aqueous or 2-propanol solution of 1:1 urea and succinic acid (inlet temperature=120 °C for water, 75 °C for 2-propanol; flow rate=5 mL/min; aspiration=70-100%).. The 2:1 U-SA cocrystals were generated by solvent evaporation of a 2-propanol solution of corresponding stoichiometry at room temperature. The purity of the materials used in the rest of the studies was confirmed by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). 2.3. Analysis of Urea-Dicarboxylic Acid Cocrystals. We used the Cambridge Structural Database (CSD version 5.30, February 2010, organics, nonionic and nonpolymeric R-factor e 0.10) and published literature to gather information about the existence of acidacid, acid-amide, and amide-amide synthons in the crystal structures of urea-dicarboxylic acid cocrystals.24 2.4. Phase Transformation Studies. The stability of the cocrystals was studied in 2-propanol, ethanol, and water at 25 °C. About 200 mg of 1:1 or 2:1 cocrystals (450 mg when water was the solvent for the 1:1 cocrystals) was stirred magnetically in 2 mL of the solvent for 4 days in a well-sealed glass vial. The stability of urea as a function of succinic acid concentration was studied by suspending 150 mg of urea in 3 mL of solution containing various concentrations of succinic acid in 2-propanol or an excess of succinic acid. Similarly, the stability of succinic acid (total amount 500 mg) in urea 2-propanol solutions or suspensions was studied. The suspensions were magnetically stirred for 2-4 days at 25 °C. 2.5. Transition Concentration Determination. The transition concentrations or eutectic points (eu1 and eu2) for the U-SA system were determined in 2-propanol at 25 °C. Eu1 was accessed by slurrying 150 mg of urea in 3 mL of a 2-propanol solution with 0.093 M succinic acid and eu2 was obtained by suspending succinic acid (total solid 750 mg) in a 2-propanol solution, both for 5 days. Eu1 and eu2 were also verified by slurrying 2:1 U-SA cocrystals in a

Alhalaweh et al. suspension of urea or succinic acid respectively for 4 days. The concentration of succinic acid was determined by high performance liquid chromatography (HPLC), using the method outlined in the following section. The concentration of urea was determined by a gravimetric method involving the withdrawal of the solution from the slurries into an Eppendorf tube of known weight. The tube was then reweighed after the liquid had dried completely. 2.6. Solubility Studies for 2:1 U-SA Cocrystals. The equilibrium solubility of 2:1 U-SA cocrystals was determined by adding excess of the cocrystals to pure 2-propanol or solutions of various concentration of either urea or succinic acid. The suspensions were magnetically stirred for 36-48 h. The solutions were then filtered through a 0.22 or 0.45 μm cellulose membrane filter and further diluted as required. The succinic acid concentrations in these solutions were determined by HPLC and the urea concentrations were calculated by mass balance. The equilibrium solubilities of urea and succinic acid in 2-propanol were determined by slurrying excess solids in 2-propanol at 25 °C for 48 h. Concentrations of urea and succinic acid were measured as described above. 2.7. Differential Scanning Calorimetry (DSC). Thermal analyses of the samples were performed on a DSC Q1000 (TA Instruments) which was calibrated for temperature and enthalpy using indium. Samples (3-5 mg) were crimped in nonhermetic aluminum pans and scanned from 30 to 200 °C at a heating rate of 10 °C/min under a continuously purged dry nitrogen atmosphere (flow rate 50 mL/min). The instrument was equipped with a refrigerated cooling system. The data were collected in triplicate for each sample. 2.8. Powder X-ray Diffraction (PXRD). The solid phases obtained from the stability and solubility experiments were analyzed by PXRD, and the resulting diffraction patterns were compared with the diffraction patterns of pure phases. The patterns were collected on a Siemens DIFFRACplus 5000 powder diffractometer with Cu KR radiation (1.54056 A˚). The tube voltage and amperage were set at 40 kV and 40 mA, respectively. The divergence slit and antiscattering slit settings were variable for illumination on the 20 mm area on the sample. Each sample was scanned between 5 and 40°2θ, with a step size of 0.05° at 1 step/s or 0.02° at 2 step/s. The sample stage was spun at 30 rpm. The instrument was precalibrated using a silicon standard. 2.9. X-ray Crystallography. The single crystal X-ray diffraction data were collected on a Bruker Nonius Kappa CCD instrument at 150 K using Mo KR radiation (λ = 0.71073 A˚). The lattice parameters were determined from least-squares analysis, and reflection data were integrated using the program maXus. The crystal structures were solved by direct methods using SHELXS-97, and the data were refined by full matrix least-squares refinement on F2 with anisotropic displacement parameters for non-H atoms, using SHELXL-97.25 All the N-H, O-H, and C-H hydrogens were refined from difference Fourier maps. The crystal structure figures were generated by Mercury program.26 2.10. High Performance Liquid Chromatography (HPLC). Succinic acid was separated over a C18 column (5 μm, 150 mm  4.6 mm) using HPLC apparatus (series 200 binary LC pump and 200 UVvis detector, TotalChrom software, Perkin-Elmer, Wellesley, MA) following an earlier published method.27 The HPLC analysis was conducted at room temperature with a flow rate of 0.35 mL/min and UV detection at 210 nm. The mobile phase was 50 mM KH2PO4 buffer with 2% acetonitrile (pH 2.5 adjusted by HCL). The volume of the injected samples was 20 μL.

3. Results and Discussion 3.1. Preliminary Characterization of 1:1 and 2:1 U-SA Cocrystals. The DSC thermograms and PXRD patterns for 1:1 and 2:1 U-SA cocrystals are shown in Figures 1 and 2, respectively. The 1:1 and 2:1 U-SA cocrystals had different melting points: ∼140 and ∼150 °C, respectively (Figure 1). Further, the PXRD pattern for 1:1 cocrystals was distinctly different from that for 2:1 cocrystals (Figure 2). Although the existence of 1:1 cocrystals has been speculated in the literature, no pertinent evidence of a solid-state characterization or crystal structure for these cocrystals has previously been

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Table 1. Crystal Data and Structure Refinement Parameters for 1:1 and 2:1 Cocrystalsa

Figure 1. DSC thermograms for (a) 1:1 and (b) 2:1 U-SA cocrystals.

empirical formula formula weight crystal system space group T (K) λ (A˚) a (A˚) b (A˚) c (A˚) R (°) β (°) γ (°) V (A˚3) Z Dcalc (g/cm3) F(000) R1 wR goodness of fit θmax (°) crystal size (mm3) unique reflections observed reflections a

Figure 2. PXRD patterns for (a) 1:1 and (b) 2:1 U-SA cocrystals. The units on the y-axis are arbitrary.

presented. The generation of pure phases or single crystals of stoichiometric cocrystals in general is challenging unless their structural reasons and thermodynamic stabilities are thoroughly understood.28 Indeed, based on the stability investigations presented below, it is probable that the crystallization of 1:1 cocrystals would not be straightforward using simple solvent evaporation methods. This may be why a crystal structure for 1:1 U-SA cocrystals has not been previously available. With this knowledge, however, we successfully grew diffraction quality crystals and the single crystal structure was determined. 3.2. Crystal Structure of 1:1 U-SA Cocrystals. The crystallographic information for the 1:1 cocrystals is presented in Table 1. The crystal structures of the 1:1 cocrystals are shown in Figure 3 and the corresponding ORTEP representation is shown in Figure 4. The experimental and simulated (obtained from single crystal X-ray diffraction) PXRD patterns for 1:1 U-SA cocrystals matched each other perfectly (Supporting Information). The 1:1 cocrystal crystallizes in the monoclinic C2/c space group with half a molecule each of urea and succinic acid in the asymmetric unit (Table 1). The crystal structure analysis revealed that the molecules in the crystal structure form antiparallel layers with a separation of 2.9 A˚. The hydrogen bonding between amide and acid groups present in the urea and succinic acid molecules is responsible for the formation of a synthon, thus contributing to the stability of the crystal structure (Figure 3a). The urea-acid (U-A) motif (a robust

1:1 U-SA cocrystal

2:1 U-SA cocrystal

C5H10N2O5 178.15 monoclinic C2/c 150 (2) 0.7107 18.7250(7) 6.5120(7) 6.4210(5) 90 90.834(6) 90 782.88(11) 4 1.512 376 0.0523 0.1768 1.245 27.878 0.34  0.24  0.10 853 834

C6H14N4O6 238.20 monoclinic P21/c 297 0.7107 5.637(4) 8.243(3) 12.258(3) 90 96.80 90 565.6(8) 2 1.399 0.057 0.069 25.95 0.60 0.50  0.40 1187 817

The data for 2:1 cocrystals are provided for comparison.

acid-amide heterodimer) is the main motif in the structure of 1:1 cocrystals (Figure 3b). This motif has been predicted to be one of the most stable motifs in the urea-dicarboxylic acid systems using computational methods.29 In the crystal structure of 1:1 U-SA cocrystals, the urea molecule assumes a central role in the self-assembly process. It forms hydrogen bonding interactions with all the neighboring molecules within the two-dimensional (2D) sheet parallel to the abplane (Figure 3b). The acid-amide heterodimer is sustained by an interaction between the syn N-H of the urea molecule and the CdO group of carboxylic acid in the succinic acid molecule, and the CdO group of urea and the O-H group of carboxylic acid, to form zigzag chains. This acid-amide heterosynthon motif is represented by the graph set R22(8). In addition to this primary interaction, the zigzag chains form a secondary lateral association, through N-H 3 3 3 O and O-H 3 3 3 O hydrogen bonding. This lateral interaction is formed between the remaining anti N-H of urea and the oxygen atom of the OH in carboxylic acid in the adjacent chain, represented by the graph set R43(10), which finally leads to a 2D planar sheet along the b-axis (Figure 3b). Overall, each urea molecule is connected to four different succinic acid molecules through strong N-H 3 3 3 O (2.16 A˚, 158°; 2.21 A˚, 158°) and O-H 3 3 3 O (1.76 A˚, 167°) hydrogen bonds within the 2D layer, thus saturating its hydrogen bonding possibilities (Figure 3b, Supporting Information). The adjacent urea molecules in the 1:1 cocrystal pack in antiparallel fashion, resulting in a centrosymmetric 2D layer in the ab-plane, with interlayer regions dominated by weak C-H 3 3 3 O interactions (2.58 A˚, 147°) (Figure 3c). On the other hand, in the crystal structure of 2:1 U-SA cocrystals, adjacent chains are arranged in a perpendicular direction to form a complicated stable three-dimensional (3D) structure (Supporting Information). Here, urea and succinic acid utilize two types of ring motifs for self-assembly, leading to a urea-acid-urea (U-A-U) structure motif. Two urea molecules interact to form an amide-amide homodimer synthon through an R22(8) ring motif. This in turn interacts with the carboxylic acid functionality of the

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Figure 3. Crystal structure of 1:1 U-SA cocrystal; (a) urea-acid motif showing acid-amide heterodimer, (b) hydrogen-bond layers, and (c) packing diagram showing interlayer regions dominated by weak C-H 3 3 3 O hydrogen bonds.

Figure 4. ORTEP diagram (ellipsoids at the 50% probability level) and atom labeling scheme for 1:1 U-SA cocrystals. Hydrogen atoms are depicted by green open circles.

succinic acid molecule to form an acid-amide heterodimer synthon with an R22(8) motif, leading to zigzag tapes. Evidently, the acid-amide link is the only structural building block in the 1:1 cocrystals, while both acid-amide and amide-amide links are present in the 2:1 cocrystals. The 1:1 U-SA and 1:1 urea-oxalic acid cocrystals have similar hydrogen bonding interactions and crystal packing

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(Supporting Information). In 1:1 U-SA stoichiometry, all the hydrogen bonding possibilities of urea and the dicarboxylic acids are utilized in the formation of a 2D planar sheet through strong hydrogen bonds which further stacks one over the other in the third dimension. In 2:1 cocrystal, the adjacent chains pack perpendicularly to each other and are then stabilized by weak N-H 3 3 3 O interactions, resulting in close packing. However, the calculated density of the 1:1 U-SA cocrystal (1.512 g/cm3) was higher than that of the 2:1 cocrystal (1.399 g/cm3) cocrystals highlighting the constant balance required between optimal nonbonded interactions and the desire toward close packing. The experimental stability of 1:1 and 2:1 cocrystals in different solvents is discussed in the latter sections. 3.3. Analysis of Urea-Dicarboxylic Acid Cocrystals. The objectives of this analysis were (1) to investigate crystal structures of existing urea-dicarboxylic acid cocrystals and relate them to U-SA cocrystals, (2) to understand structural reasons for stoichiometric diversity in cocrystals of urea-dicarboxylic acid and possibly in general. This knowledge is believed to be valuable in the design of pharmaceutical cocrystals as the urea or dicaboxylic acids are very common coformers. The CSD search for the acid 3 3 3 acid, acid 3 3 3 amide, and amide 3 3 3 amide interaction analysis unveils that there are 189 hits having both carboxylic and primary amide functional groups. Among them, 10 hits exhibit acid 3 3 3 acid homosynthon; 102 hits exhibit acid 3 3 3 amide heterosynthons and 61 hits exhibit amide 3 3 3 amide homosynthons. This is evident that the formation of acid 3 3 3 amide heterosynthon is more favorable than that of the acid 3 3 3 acid and amide 3 3 3 amide homosynthons. Similarly, in the CSD study for interaction hierarchy in pyridinecarboxylic groups in multicomponent systems, it is revealed that the supramolecular heterosynthon are more prevalent than the carboxylic acid supramolecular homosynthons.3 Table 2 presents cocrystals of urea and dicarboxylic acids with their stoichiometries found in the CSD and literature. With the exception of urea-maleic acid cocrystals, which are found in 2:1, 1:1, and 1:2 stoichiometries, urea-dicarboxylic acid cocrystals have been reported to exist as 1:1 and/or 2:1 cocrystals. The 2:1 urea-dicarboxylic acid cocrystals are always formed when carboxylic acid crystallizes on the inversion center.19,29 Interestingly, the motifs observed are robust within the structures of urea-dicarboxylic acid cocrystals with a given stoichiometry (Figure 5). With an exception of malonic acid, all the 1:1 and 2:1 urea-dicarboxylic acid cocrystals have formed urea-acid (U-A) and urea-acid-urea (U-A-U) motifs in the crystal structures respectively. These interactions were between acid and amide in 1:1 cocrystals, and amide and amide (homosynthon) or acid and amide (heterosynthon) in 2:1 cocrystals, resulting in the formation of chains and networks that differed according to the conformation of the dicarboxylic acid molecule involved (Figure 5). Although there were similarities in the hydrogen bonding synthons building the crystal structures, there were considerable differences in the packing patterns in the 2D planes, which in turn were reflected in the 3D patterns. Further, the formation of the urea dimer synthon seems to discriminate hydrogen bonding interactions in the formation of 2:1 and 1:1 stoichiometries. Consequently, the propagation of chains and packing motifs were different in the 2:1 and 1:1 cocrystals (Supporting Information). In 2:1 cocrystals, the hydrogen bonded chains are assembled into a

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Table 2. Structural Information on Cocrystals of Urea with Dicarboxylic Acids Obtained from the CSD and Published Literaturea serial no. dicarboxylic acids forming cocrystals with urea stoichiometry urea-acid 1 2

fumaric acid glutaric acid

3 4 5

Itaconic acid malonic acid maleic acid

6

oxalic acid

7 8 9 10

o-phthalic acid pyrazine-2,3-dicarboxylic acid pyridine-2,6-dicarboxylic acid succinic acid

11 12

D,L-tartaric D-tartaric

acid acid

2:1 2:1 1:1 Form I 1:1 Form II 1:1 1:1 2:1 1:1 1:2 2:1 1:1 1:1 1:1 2:1 2:1 1:1 1:1 1:1

motifb

CSD refcode or references and space group

U-A-U U-A-U U-A U-A U-A U-A-U U-A-U U-A A-U-A U-A-U U-A U-A U-A U-A-U U-A-U U-A no coordinates no coordinates

TIPWIY P21/c TONGOS C2/c ref 19 P21/n ref 10 Pnma PANVAB P21/c URMALN P21/c ref 19 CEKRUF Cc CEKSAM P21/c UROXAL P21/c UROXAM C2/c NUHYIY01 P1 NUHYOE P21/c NUHYUK C2/c VEJXAJ P21/c this paper C2/c NEHPIZ P21 NEZDAX P212121

a Urea inclusion compounds and urea complexes with crown ether dicarboxylic acids have been omitted (A modified table from ref 29). b U: urea, A: dicarboxylic acid.

Figure 5. Hydrogen bonding motifs in different stoichiometric urea-dicarboxylic acid cocrystals.

complex 3D and 2D layers, with dicarboxylic acids with an even number and an odd number of carbon atoms respectively.19 Conversely, in 1:1 cocrystals, only two accepting and two donating groups of urea are used to form hydrogen bonded chains and the rest are used to form 2D and 3D networks. In the unique 1:2 urea-maleic acid stoichiometry, all the strong hydrogen bonding donors and acceptors are utilized, and the hydrogen bonding and packing patterns in the crystal structure are different from those in other stoichiometric cocrystals. In addition, olefinic hydrogen atoms in maleic acid form nonpolar hydrogen-bonded 2D sheets through C-H 3 3 3 O interactions. In general, 1:1 and 2:1 U-SA cocrystals are similar, in terms of hydrogen bonding interactions, structural motifs, and 3D assemblies, to other urea-dicarboxylic acid cocrystals with similar stoichiometry. Of interest, amide-amide and acid-amide are common synthons stabilizing crystal structures of pharmaceutical cocrystals involving urea or succinic acid respectively. Finally, the reason for the stoichiometry diversity in this set of cocrystals could be the relative strength of the acid 3 3 3 amide and amide 3 3 3 amide synthons as well the number of options for more extended motifs. The structural diversity of multicomponent crystals is claimed to be predictable by computational methods.28,29 However, it can be deduced from this empirical exercise that the stoichiometric diversity in cocrystals can be influenced by multiple structural features: for example, the extent of conformational flexibility in the component molecules, weak hydrogen bonding interactions in the crystal structure, competition between homo- and heterosynthons, multiple

hydrogen bonding donor and acceptor possibilities, lattice energies, and crystal packing. Further, thermodynamics and kinetic factors can also influence the formation and stability of a particular stoichiometry. 3.4. Stability and Transformation of U-SA Cocrystals. The 2:1 cocrystals were stable in 2-propanol, ethanol, and water, while the 1:1 cocrystals were transformed to 2:1 cocrystals in these solvents, as confirmed by PXRD (Supporting Information). The pH of the media at the end of stability study in water was 2.75. These results suggest that 2:1 cocrystals are the most stable (least soluble) solid form in these solvents at 25 °C. It is therefore not surprising that the 2:1 cocrystals are isolated as kidney stones in the human body.30 This further emphasizes the importance of understanding the stability and formation of cocrystals, especially of urea cocrystals, and the conditions that lead to their precipitation. The formation and stability of 1:1 and 2:1 carbamazepine4-aminobenzoic acid cocrystals are dependent on the solution concentration of their components.16 The 1:1 cocrystal is found to form or be stable in a very narrow region of PSD where the concentration of 4-aminobenzoic acid exceeds its concentration at the eutectic point where 1:1 and 2:1 cocrystals are in equilibrium. A similar behavior was reported for Form II of the 1:1 urea-glutaric acid cocrystals; the thermodynamic stability region for the 1:1 cocrystals was narrower than that for the 2:1 cocrystals in the TPD.10 In contrast to these systems, 1:1 U-SA cocrystals transformed to 2:1 cocrystals upon slurrying in saturated solutions or with an excess of succinic acid in 2-propanol at 25 °C. It is possible that the phase stability region for 1:1

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Figure 6. PXRD patterns for the solid phases in equilibrium at different succinic acid concentrations: (a) urea, (b) eu1, (c) 2:1 U-SA cocrystals, (d) eu2, and (e) succinic acid, in 2-propanol at 25 °C. Note that the peak intensities have been minimized to different degrees for clarity. The units on the y-axis are arbitrary. Table 3. Concentrations of Urea and Succinic Acid at the Eutectic Points in 2-Propanol at 25 °C eutectic points eu1 eu2

solid phases at equilibrium

[U]total (M)

[SA]total (M)

2:1 cocrystal and urea 0.50 ( 0.021 0.006 ( 0.000 2:1 cocrystal and 0.076 ( 0.023 0.467 ( 0.016 succinic acid

U-SA cocrystals is very narrow so that it is not practically accessible using equilibrium methods. Another explanation could be that the stability region for the 1:1 cocrystals might overlap with that of the 2:1 cocrystals, as in the case of caffeine-maleic acid cocrystals.31 However, the 1:1 U-SA cocrystals were consistently produced in a pure form by spray drying, using water or 2-propanol as the medium. The formation of cocrystals by spray drying and the role of thermodynamic and kinetic factors are discussed in a separate article.23 3.5. Eutectic Concentrations. Eutectic points are isothermal invariant points where cocrystals and one of their components, that is, two solid phases, coexist in equilibrium with a liquid phase, regardless of the amount of solids, at fixed temperature and pH.32-34 Eutectic points are useful indicators of cocrystal solubility and stability in the PSD, which can guide cocrystal synthesis and selection.32,33 Measuring the concentrations of the cocrystal components at the eutectic point in a single experiment under equilibrium conditions allows an estimation of the true solubility of incongruent cocrystals (i.e., the saturation solubility of cocrystal components is considerably different), which is otherwise not practically accessible. Two eutectic points, eu1 and eu2, were identified for U-SA cocrystals in 2-propanol; the respective solid phases for these points were confirmed by PXRD to be urea and 2:1 cocrystals, and succinic acid and 2:1 cocrystals (Figure 6). The concentrations of urea and succinic acid, and the solid phases in equilibrium with the solution at the eutectic points, are presented in Table 3. No trace of the 1:1 cocrystals was found in these explorations, as confirmed by PXRD. The concentrations of urea at eu1 and succinic acid at eu2 were higher than those at equilibrium for the individual components in 2-propanol. This increase in solubility can be attributed to solution complexation. This phenomenon has been extensively studied as a means of increasing the solubility of drugs

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Figure 7. Phase solubility diagram (PSD) for 2:1 cocrystals in 2-propanol at 25 °C. (O) represents an experimental cocrystal saturation curve for 2:1 cocrystals at various ligand concentrations and the solid line is the predicted 2:1 cocrystal solubility; ()) are eutectic points, eu1 and eu2. The equilibrium solubilities of urea and succinic acid in neat 2-propanol are indicated by (b). Dashed lines correspond to 1:1 and 2:1 stoichiometric ratios. The red line indicates the predicted solubility of 2:1 U-SA cocrystals from eqs 1 or 3. The blue and green lines represent the estimated solubility lines for urea and succinic acid, respectively.

where the solid-state complexes, today known as cocrystals, are observed at high ligand concentrations.35,36 3.6. Phase Solubility Diagram (PSD). Figure 7 presents the PSD for U-SA cocrystals in 2-propanol at 25 °C. The PSD has been used to study cocrystal solubility behavior, taking into consideration the solution composition and complexation.37 The molar solubility (M) of the 2:1 cocrystals, expressed as total urea concentration, decreased as the succinic acid concentration in the solution increased. The dependence of cocrystal solubility on the ligand concentration has been reported for a number of other cocrystals in organic solvents.16,37 The PSD also shows the stable regions of the solid phases, that is, urea, 2:1 cocrystals and succinic acid (Figure 7). The solid line represents the solubility of the 2:1 cocrystals, as predicted using the mathematical models presented in the following section. This cocrystal solubility line crosses the predicted solubility lines at the eutectic points, eu1 for urea and eu2 for succinic acid. Furthermore, urea and succinic acid were stable phases before eu1 and after eu2, respectively, as confirmed by PXRD. The 2:1 stoichiometric ratio line intersects the 2:1 cocrystal solubility line, indicating that this is a congruently saturating cocrystal. Further, it rationalizes the formation of the 2:1 cocrystals by stoichiometric solvent evaporation crystallization as well as their stability in these solvents. Similarly, two eutectic points and three solid phases; that is, cocrystals, caffeine, and maleic acid were indicated for 1:1 and 2:1 caffeine-maleic acid cocrystals. However, an additional eutectic point, at which 1:1 and 2:1 cocrystals are in equilibrium with the solution (i.e., three eutectic points and four solid phases), was found for carbamazepine4-aminobenzoic acid and urea-glutaric acid cocrystals with 1:1 and 2:1 stoichiometry. 3.7. Models Predicting 2:1 Cocrystal Solubility. The solubility of 2:1 cocrystals was dependent on the ligand concentration (Figure 7). A similar phenomenon has been observed for other cocrystal systems, where the solubility was explained by the solubility product.16,37 The dissociation of 2:1 cocrystals (U2SAsolid) to its components in solution

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Table 4. Models Predicting Drug Concentration Dependence on the Ligand Concentration for 2:1 Cocrystals model complexation I

1:1 and 2:1

equilibrium reactions Ksp

U2 SAsolid T 2Usolution þ SAsolution K11

Usolution þ SAsolution T USAsolution K21

USAsolution þ Usolution T U2 SAsolution

II

1:1

Ksp

U2 SAsolid T 2Usolution þ SAsolution K11

Usolution þ SAsolution T USAsolution

equations predict 2:1 cocrystal solubility considering different complexation orders rffiffiffiffiffiffiffi pffiffiffiffiffiffiffiffiffiffiffiffiffi Ksp ½Utotal ¼ ð1Þ þ K11 A1 Ksp þ 2K11 K21 Ksp A1 qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 2 where A1 ¼ ð2ð½SAtotal - K11 K21 Ksp Þ þ K11 Ksp - 2K11 Ksp ½SA Þ=2 total rffiffiffiffiffiffiffi pffiffiffiffiffiffiffiffiffiffiffiffiffi Ksp ½Utotal ¼ ð2Þ þ K11 A2 Ksp þ 2K11 K21 Ksp A2 qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 2 Ksp þ 2K11 Ksp ½SA Þ=2 where A2 ¼ ð2ð½SAtotal - K11 K21 Ksp Þ þ K11 total rffiffiffiffiffiffiffi pffiffiffiffiffiffiffiffiffiffiffiffiffi Ksp ½Utotal ¼ þ K11 A1 Ksp ð3Þ A1 qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 2 where Ksp - 2K11 Ksp ½SA Þ=2 A1 ¼ ð2½SAtotal þ K11 total

½Utotal where

II

2:1

Ksp

U2 SAsolid T 2Usolution þ SAsolution

½Utotal

rffiffiffiffiffiffiffi pffiffiffiffiffiffiffiffiffiffiffiffiffi Ksp ¼ þ K11 A2 Ksp A2

ð4Þ

qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 2 Ksp þ 2K11 Ksp ½SA A2 ¼ ð2½SAtotal þ K11

total

Þ=2

sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi Ksp 0 þ 2K21 ¼ Ksp ½SAtotal - K210 Ksp

ð5Þ

0 K21

2Usolution þ SAsolution T U2 SAsolution

when there is no solution complexation can be written as follows: Ksp

U2 SAsolid T 2Usolution þ SAsolution where Ksp is the solubility product. Assuming the activity for the solids in equilibrium is equal to 1 and the reaction is carried out under ideal conditions, Ksp can then be given as Ksp ¼ ½U2 ½SA If the system has no solution complexation: ½Utotal ¼ ½U and ½SAtotal ¼ ½SA From the above information, the equation that predicts the solubility of 2:1 cocrystals can be derived as ½Utotal

sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi Ksp ¼ ½SAtotal

This equation predicts that the solubility of 2:1 U-SA cocrystals will decrease with an increase in the succinic acid concentration. The Ksp of the cocrystals can be evaluated using this equation from the slope of the straight line obtained from plotting [U]total against 1/([SA]total)1/2 In fact, using this Ksp value, it was found that the model was underestimating the experimental cocrystal solubility. This was because this equation does not take into consideration the contribution of solution complexation. The effect of solution complexation on the solubilities of various drugs (single component systems) is extensively studied and the mathematical models explaining the complexation behavior have been derived.38,39 Lately, the mathematical models predicting 2:1 cocrystal solubility with different stoichiometric solution complexes have been derived.16 In this study, we have evaluated these models for 2:1 U-SA cocrystal. Table lists the models used for predicting 2:1 U-SA cocrystal solubility, and the complete

derivation can be accessed from the earlier article.16 The thermodynamic constants Ksp, K11, and K21 (K11 and K21 are the binding constants representing the formation USA and U2SA complexation in the solution respectively) were evaluated by nonlinear regression analysis. The initial value of Ksp was taken from the plot assuming no solution complexation (K11 = K21 = 0). The Levenberg-Marquadt algorithm was used for determining the constants after they were restricted to values bigger than zero. The experimental data were then fitted to various equations that do take solution complexation into account (eqs 1-5; Tables and 5). Equations 1 and 3 predicted the experimental data better than the other equations (Figure 8). While eq 2 underestimated the solubility at low ligand concentrations, eqs 4 and 5 underestimated the solubility at higher ligand concentrations. Equations 1 and 3 have similar constants, which suggest negligible 2:1 complexation. The calculated solution constants F-value and R2 are presented in Table 5. From the F-value, R2 and the calculated least absolute deviation, eqs 1 and 3 appear better predictors of the experimental cocrystal solubility. Thus, 1:1 solution complexation explains the higher concentrations of urea and succinic acid at eu1 and eu2, respectively. The 1:1 solution complexation will thus linearly increase the solubility of one component in the presence of the other, as shown for many systems up to the eutectic point.16,39 Using K21 = 0 and the value obtained for K11 from eqs 1 or 3, the solubility of urea was calculated using the following equation (Figure 7): 

½Utotal

 K11 U 0 ½SAtotal ¼ U0 þ 1 þ K11 U

where U0 is intrinsic solubility of urea in pure solvent. Urea also undergoes 1:1 solution complexation with caffeine;40 however, cocrystals have not been found for this combination.41 In fact, it has been shown earlier that solution complexation is not an indicator of either cocrystal formation or cocrystal stoichiometry.16,38,39

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Table 5. Complexation and Solubility Product Constants for 2:1 Cocrystals at 25 °C model I II III a

complexation 1:1 and 2:1 1:1 and 2:1 1:1 1:1 2:1

equation

Ksp (M3)  10-3

K11 (M-1)

K21 (M-1)

1 2 3 4 5

(0.330 ( 0.11 ) (0.416 ( 0.12a) (0.346 ( 0.05a) (0.805 ( 0.10 a) (0.668 ( 0.31a)

5.00 ( 2.14 2.20 ( 0.81 4.80 ( 1.53 1.11 ( 0.64

0.14 ( 0.096 10.30 ( 3.54

a

K0 21 (M-2)

R2

F

1.59 ( 8.9

97.2 96.3 97.1 93.4 94.2

584 450 574 240 275

Standard error.

Acknowledgment. The authors would like to thank Dr. Srinivas Basavoju for fruitful discussions on crystal structure analysis. Mr. Nils Skoglund is also thanked for his help with rerefinement of 1:1 urea-succinic acid cocrystals. S.G., D.B., and S.P.V. are grateful to the Swedish Research Council (Vetenskapsradet) for a research grant. The authors also wish to thank the Kempe foundation (Kempestiftelserna) for an instrumental grant. Supporting Information Available: X-ray crystallographic information files (CIF) for the 1:1 U-SA cocrystals, hydrogen-bond geometry, Rietveld refined PXRDs, least-squares overlay of 1:1 and 2:1 U-SA cocrystals, alignment of urea molecule in the crystal structures, crystal structure comparisons, and PXRD patterns from the stability study. This material is available free of charge via the Internet at http://pubs.acs.org. Figure 8. Experimental and predicted (eqs 1-5) dependence of [U]total on [SA]total for 2:1 cocrystals in equilibrium with the solution. Symbols indicate the experimental data. The solid line represents the predicted concentration.

4. Conclusions The crystal structure of 1:1 U-SA cocrystals was determined and compared with that of existing 2:1 U-SA cocrystals. The structural diversity of urea-dicarboxylic acid cocrystals with different stoichiometries was discussed and related to U-SA cocrystals. The thermodynamic stability and solution-mediated transformation of 1:1 and 2:1 U-SA cocrystals were studied. A PSD was constructed and the stability regions for different phases were defined in 2-propanol at 25 °C. The solubility of 2:1 cocrystals was explained by solubility product and solution complexation and fitted to various mathematical models. The structure of 1:1 U-SA cocrystals is stabilized by acidamide heterosynthons, resulting in a urea-acid motif. In contrast, both acid-amide and amide-amide dimers are the building blocks in the 2:1 U-SA cocrystals, leading to a urea-acid-urea motif. Interestingly, 1:1 and 2:1 U-SA cocrystals share similarities with other urea-dicarboxylic acid cocrystals with respect to hydrogen bonding interactions and structural motifs. The CSD analysis reveals that the structural diversity in the urea-dicarboxylic acid cocrystals can be explained on the basis of relative strengths of acid 3 3 3 amide and amide 3 3 3 amide synthons. The 1:1 cocrystals underwent solution-mediated transformation to 2:1 cocrystals in 2-propanol, ethanol, or water at 25 °C. It is noteworthy that the 1:1 cocrystal is unstable even in excess ligand in the solution. The stable regions and respective eutectic points for urea, 2:1 cocrystals, and succinic acid were identified in the PSD. However, no stable region for the 1:1 cocrystals was found. The mathematical model based on solubility product and 1:1 solution complexation predicted 2:1 cocrystal solubility well. An understanding of the structural aspects, solution chemistry and stability of stoichiometrically diverse cocrystals is important for their scale-up and formulation and for predicting performance.

References (1) Jones, W.; Motherwell, W.; Trask, A. MRS Bull. 2006, 31, 875–879. (2) Schultheiss, N.; Newman, A. Cryst. Growth Des. 2009, 9, 2950– 2967. € Zaworotko, M. Chem. Commun. 2004, 2004, 1889– (3) Almarsson, O.; 1896. (4) Desiraju, G. Angew. Chem. Int. Ed. Engl. 2003, 34, 2311–2327. (5) Vishweshwar, P.; McMahon, J.; Bis, J.; Zaworotko, M. J. Pharm. Sci. 2006, 95, 499. (6) Rodriguez-Hornedo, N.; Nehm, S.; Seefeldt, K.; Pagan-Torres, Y.; Falkiewicz, C. Mol. Pharmaceutics 2006, 3, 362–367. (7) Zhang, G.; Henry, R.; Borchardt, T.; Lou, X. J. Pharm. Sci. 2007, 96, 990. (8) Gagniere, E.; Mangin, D.; Puel, F.; Rivoire, A.; Monnier, O.; Garcia, E.; Klein, J. J. Cryst. Growth. 2009, 311, 2689–2695. (9) Childs, S.; Hardcastles, K. Cryst. Growth Des. 2007, 7, 1291–1304. (10) Chadwick, K.; Davey, R.; Sadiq, G.; Cross, W.; Pritchard, R. CrystEngComm 2009, 11, 412–414. (11) Braga, D.; Palladino, G.; Polito, M.; Rubini, K.; Grepioni, F.; Chierotti, M.; Gobetto, R. Chem.;Eur. J. 2008, 14, 10149– 10159. (12) Porter Iii, W.; Elie, S.; Matzger, A. Cryst. Growth Des. 2008, 8, 14. (13) Horst, J.; Cains, P. Cryst. Growth Des. 2008, 8, 2537–2542. (14) Karki, S.; Fris i, T.; Jones, W. CrystEngComm 2009, 11, 470–481. (15) Trask, A.; van de Streek, J.; Motherwell, W.; Jones, W. Cryst. Growth Des. 2005, 5, 2233–2241. (16) Jayasankar, A.; Reddy, L.; Bethune, S.; Rodriguez-Hornedo, N. Cryst. Growth Des. 2009, 9, 889–897. (17) Zhao, X.; Chang, Y.; Fowler, F.; Lauher, J. J. Am. Chem. Soc. 1990, 112, 6627–6634. (18) George, S.; Nangia, A.; Lam, C.; Mak, T.; Nicoud Chem. Commun. 2004, 2004, 1202–1203. (19) Videnova-Adrabinska, V.; Etter, M.; Ward, M. Engineering SolidState Materials. Strategies for Modeling and Packing Control of Molecular Assemblies into 3-D Networks; Dept of Chemistry, University of Minnesota: Minneapolis, MN, 1993. (20) Radell, J.; Brodman, B.; Domanski, J., Jr., J. Phys. Chem. 1967, 71, 1596–1601. (21) Beilstein, F. K. Julius Springer 1921, 5, 55. (22) Videnova-Adrabinska, V. Acta Crystallogr. B 1996, 52, 1048–1056. (23) Alhalaweh, A.; Velaga, S. Cryst. Growth Des. 2010, 10, 3302–3305. (24) Allen, F. Acta Crystallogr. B 2002, 58, 380–388. (25) Sheldrick, G. SHELX-97, Program for Crystal Structure Solution and Refinement; University of G€ottingen: Germany, 1997. (26) Macrae, C.; Bruno, I.; Chisholm, J.; Edgington, P.; McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.; Taylor, R.; Streek, J.; Wood, P. J. Appl. Crystallogr. 2008, 41, 466–470.

Article (27) Andersson, C.; Hodge, D.; Berglund, K.; Rova, U. Biotechnol. Prog. 2008, 23, 381–388. (28) Cruz-Cabeza, A.; Karki, S.; Fabian, L.; Friscic, T.; Day, G.; Jones, W. Chem. Commun. 2010, 46, 2224–2226. (29) Cruz-Cabeza, A.; Day, G.; Jones, W. Chemistry-Eur. J. 2008, 14, 8830. (30) Wiedenfeld, H.; Knoche, F. Acta Crystallogr. C 1993, 46, 1038–1040. (31) Guo, K.; Sadiq, G.; Seaton, C.; Davey, R.; Yin, Q. Cryst. Growth Des. 20010, 10, 268–273. (32) Chiarella, R.; Davey, R.; Peterson, M. Cryst. Growth Des. 2007, 7, 1223–1226. (33) Good, D. J.; Rodriguez-Hornedo, N. Cryst. Growth Des. 2009, 9, 2252–2264.

Crystal Growth & Design, Vol. 10, No. 11, 2010

4855

(34) Bethune, S.; Huang, N.; Jayasankar, A.; Rodriguez-Hornedo, N. Cryst. Growth Des. 2009, 9, 3976–3988. (35) Higuchi, T.; Zuck, D. J. Am. Pharm. Assoc. 1953, 42, 138–145. (36) Higuchi, T.; Lach, J. J. Am. Pharm. Assoc. 1954, 43. (37) Nehm, S.; Rodriguez-Spong, B.; Rodriguez-Hornedo, N. Cryst. Growth Des. 2006, 6, 592–600. (38) Poole, J. W.; Higuchi, T. J. Am. Pharm. Assoc. 1959, 592–601. (39) Kostenbauder, H. B.; Higuchi, T. J. Am. Pharm. Assoc. 1956, 45, 518–522. (40) Cesaro, A.; Russo, E.; Crescenzi, V. J. Phys. Chem. 1976, 80, 335– 339. (41) Lu, E.; Rodrı´ guez-Hornedo, N.; Suryanarayanan, R. CrystEngComm 2008, 10, 665–668.