Pharmaceutical Co-Crystals of Pyrazinecarboxamide (PZA) with

Article pubs.acs.org/crystal

Pharmaceutical Co-Crystals of Pyrazinecarboxamide (PZA) with Various Carboxylic Acids: Crystallography, Hirshfeld Surfaces, and Dissolution Study Yang-Hui Luo and Bai-Wang Sun* College of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, P. R. China S Supporting Information *

ABSTRACT: Three new pharmaceutical co-crystals: 1 PZAMA (malonic acid), 2 PZA-SA (succinic acid, a new polymorph of a reported one), and 3 PZA-GA (glutaric acid) have been prepared and characterized by differential scanning calorimetry (DSC), thermogravimetric analyses (TGA), and single-crystal X-ray diffraction. Wherein, PZA formed 1:1 co-crystals with MA and GA by acid−amide and acid−py heterosynthon, while it formed 2:1 co-crystal with SA by amide−amide homosynthon in addition to acid−amide and acid−py heterosynthon. Their melting points follow the order, PZA-GA < PZA-MA < PZA-SA, which are lower than the melting points of the individual components. Hirshfeld surface analysis revealed that N−H···O hydrogen bonding and π···π interactions for PZA in them follow the order: PZA-MA > PZA-SA > PZA-GA, while H−H and O−O interactions follow the order: PZA-MA < PZA-SA < PZA-GA. We also compared the Hirshfeld surfaces of the present co-crystals with the nine reported PZA co-crystals, which obtained important results. The studies of the solubility and dissolution showed a semiempirical inverse relationship with the melting point: the solubility follows the order, PZA-SA < PZA-GA < PZA-MA and dissolution rate follows the order, PZA-SA < PZA-MA < PZA-GA.

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computer programs ESCET,12 COMPACK,19 TOPOS,20 Xpac,21 CrystalExplorer,22 and dSNAP,23 respectively. Among them, the Hirshfeld surface serves as a powerful tool for elucidating molecular crystal structures, gaining additional insight into polymorph comparison, and identifying common features and trends in specific classes of compounds. The Hirshfeld surface is a space partitioning construct that summarizes the crystal packing into a single three-dimensional (3D) surface, and the surface can reduced to a two-dimensional (2D) fingerprint plot, which summarizes the complex information on intermolecular interactions present in molecular crystals.24 Pyrazinecarboxamide (PZA), one of the front-line antituberculosis drugs on the WHO Model List of Essential Medicines,25,26 is a teramorphic, relatively conformationally rigid molecule with four polymorphs (namely, α, β, γ, and δ forms)27,28 that have been reported. There was no conformational polymorphism of it, and the context of pharmaceutical co-crystals has not been widely studied. Up to the present, only nine co-crystals of PZA have been reported in the structural database (Scheme 1). In 2004, Aakeröy et al.29 reported the first co-crystal of PZA with 4-nitrobenzamide, and later in 2005, Zaworotko et al.30 reported the second co-crystal of PZA with

INTRODUCTION In recent years, co-crystallization of active pharmaceutical ingredients (APIs) has become a hot topic and has achieved considerable development in the field of “crystal engineering”.1−5 It acts as a powerful strategy for the modification of the physicochemical properties of the APIs by using the supramolecular synthon approach.6−8 In many cases, some APIs cannot be used as drug candidates due to the fact that they have poor solubility and, consequently, inefficient bioavailability; the matured and accepted co-crystallization strategy gives them new life by improving their solubility and bioavailability without altering the inherent bioactivity of the APIs of interest.9 Pharmaceutical co-crystals refer to the co-crystallization of APIs with other bioacceptable organic molecules or other drug molecules, their crystal structures often controlled by the direction and selective reorganization of noncovalent hydrogen or halogen bonds through supramolecular synthons. Hence, a comprehensive understanding of the noncovalent contacts in the pharmaceutical co-crystals is of significant importance for the designation of functional co-crystals.10−12 Over the past five years, a number of special methods have been developed to investigate the intermolecular interactions in crystal structures qualitatively and quantitatively, such as the conformational similarity index for proteins,13 graph-set analysis for hydrogen bonds,14 Voronoi-Dirichlet polyhedra for crystal packing,15 continuous symmetry measures,16 and the Hirshfeld surface.17,18 These methods were performed by © 2013 American Chemical Society

Received: January 28, 2013 Revised: February 28, 2013 Published: March 7, 2013 2098

dx.doi.org/10.1021/cg400167w | Cryst. Growth Des. 2013, 13, 2098−2106

Crystal Growth & Design

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Scheme 1. List of Co-Crystal Formers of PZA Reported in the Present Study (1−3) and in the Literature (4−12)

Scheme 2. Hydrogen Bonding Synthons Identified in the Crystal Structure of Co-Crystals 1−3

2, 5-dihydroxybenzoic acid. Then, it wasn’t until 2011 that the third and the fourth co-crystals of PZA with 4-aminosalicylic acid and 2-aminobenzoic acid, were reported by Desiraju et al.31 and Abourahma et al.,32 respectively. The most recently reported co-crystals were PZA with succinic acid (SA) and fumaric acid (FA) by Nangia et al.,33 and PZA with vanilic acid, gallic acid, 1-hydroxy-2-naphthoic acid, and indole-2-carboxylic acid by Adalder et al.34 These reported co-crystals were all composed of PZA and carboxylic acid coformers but only two of them with alkyl dicarboxylic acid coformer. The co-crystallization of PZA with SA can increase the dissolution rate remarkably. Hence in this work, we studied the co-crystallization of PZA with a series of alkyl dicarboxylic acid: oxalic acid (OA), malonic acid (MA), succinic acid (SA), glutaric acid (GA), and adipic acid (AA), and we obtained three co-crystals: PZA − MA (1), PZA − SA (2), and PZA−GA (3), where co-crystal 2 was a new polymorph of the reported one (4). We characterized the structures of the three co-crystals by single-crystal X-ray diffraction, differential scanning calorimetry (DSC), and

thermogravimetric analyses (TGA). Co-crystal 1 is featured with acid−amide and acid−py heterosynthon (Scheme 2); cocrystal 2 is featured with amide−amide homosynthon in addition to acid−amide and acid−py heterosynthon, and cocrystal 3 is featured with acid−amide and acid−py heterosynthon, which was similar to 1. We also prepared and analyzed the Hirshfeld surface and fingerprint plot of PZA in the present three co-crystals, as well as the nine reported co-crystals, to investigate the influence of different dicarboxylic acids on the intermolecular interactions of the PZA molecule. We further measured the solubility and intrinsic dissolution rate (IDR) of the three co-crystals with PZA; we found that all three cocrystals exhibited superior solubility and IDR than did PZA, and co-crystal 2 exhibited almost identical solubility and IDR with its polymorph 4. These co-crystals may be exploited as efficitive antituberculosis drugs.

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RESULTS AND DISCUSSION Co-Crystal Screening. All the co-crystals were obtained by a slow evaporation technique. The equivalent amount of PZA

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Figure 1. TGA (left) and DSC (right) profiles of PZA and co-crystals 1−3.

and co-crystal former were taken into a 50 mL beaker and dissolved in methanol/water and benzene/toluene solvent systems, respectively. These two different solvent systems were chosen for the purpose of obtaining polymorphs of the cocrystals. The resulting homogeneous solutions were kept undisturbed at ambient temperature for slow evaporation. Colorless crystalline materials were obtained within two weeks and subjected to various physicochemical analyses. The formation of co-crystals were confirmed by differential scanning calorimetry (DSC), thermogravimetric analyses (TGA), and single-crystal X-ray diffraction, where PZA−MA and PZA−GA showed identical crystal forms in the two different solvent systems, while PZA−SA showed different crystal forms in different solvent systems: the methanol/water solvent system resulted in the reported form (4) and the benzene/toluene solvent system resulted in a new one (2). The co-crystallization of PZA with OA and AA failed in both solvent systems; the mixing of PZA and OA in solution led to the precipitation of PZA, while the mixing of PZA and AA in solution led to the precipitation of AA, which was confirmed by DSC/TGA measurements (see Figure S1 of the Supporting Information). We have also analyzed 2:1 and 1:2 (PZA:dicarboxylic acid) stoichiometry co-crystallization, which gave the same results with 1:1 stoichiometry. Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) for Co-Crystals 1−3. The thermal behaviors of the three co-crystals were done on a STARe System (Mettler-Toledo) and were heated at a rate of 10 °C per minute with a temperature range of 40−300 °C. Shown in Figure 1 were the TGA and DSC profiles of PZA and the three co-crystals (TGA and DSC profiles of MA, SA, and GA were shown in Figure S2 of the Supporting Information). Co-crystal 1 (PZA-MA) melts at about 111 °C upon heating, with a melting enthalpy of 91 J g−1; the melting temperature is much lower than that of the starting materials PZA and MA (see Figure S2 of the Supporting Information and Table 1) and the sharp endotherm, indicating the binary nature of it. The melted co-crystals then started to sublimate at about 130 °C. Co-crystal 2 (PZA-SA) showed quite another thermal behavior with 1; upon heating, it transferred to polymorph 415 at about 140 °C with phase transition enthalpy of 78 J g−1, and then it melts at about 164 °C with a melting enthalpy of 16 J g−1 and sublimates at about 180 °C. The melting temperature is also lower than the starting materials PZA and SA (Figure S2 of the Supporting Information and Table 1), and the phase transition

Table 1. Melting Point (DSC), Solubility (in Water), and IDR (aq HCl, pH 1.2) of PZA and Co-Crystals 1−3 compound

melting point (°c)

solubility (mg ml−1)

PZA MA SA GA PZA-MA (1) PZA-SA (2) PZA-GA (3)

190 137 191 100 111 164 92

22a 1000c 83e 430f 66.5 37.2 49.7

IDR (mg cm−2 min−1) 3.3b d d d

7.2 4.6 9.7

from 2 to 4 at about 140 °C was confirmed by XPRD measurements (Figure 2). Co-crystal 3 showed a similar

Figure 2. Experimental XPRD profiles of co-crystal 2 under ambient conditions and heated under 120 °C. Simulated X-ray crystal structure of 2 and 4.

thermal behavior as 1; it melts at about 92 °C with a melting enthalpy of 91 J g−1, and then sublimates at about 175 °C. It is interesting that the introduction of dicarboxylic acids into PZA decreased the melting temperature, as well as the sublimation temperature of PZA (191 and 185 °C, respectively), which may facilitate the improvement of the solubility of PZA co-crystals. Crystal Structure of Co-Crystal 1 (PZA-MA). Co-crystal 1 crystallizes as colorless cuboid-shaped crystals. The structural 2100



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Figure 3. (a) 1D chain motif of co-crystal 1, the plain separation of adjacent chains was highlighted, (b) 2D stacking motif of different 1D chains through π···π contacts (3.742 Å plane separation), (c) 3D stacking motif of co-crystal 1 viewed from the b axis, and (d) 3D stacking motif of cocrystal 1 viewed from the c axis.

Table 2. Geometrical Parameters for Hydrogen Bonds in Co-Crystals 1−3. D−H···A co-crystal 1 N3−H3B···O5 N3−H3C···O6 O4−H4A···N2 O6−H6A···O2 cocrystal 2 O4−H4B···N1 N3−H3A···O2 N3−H3B···O4 cocrystal 3 N3−H3D···O5 N3−H3C···O5 O3−H3B···N1 O6−H6A···O1

D−H (Å)

H···A (Å)

D···A (Å)

∠D−H···A (deg)

0.86 0.86 0.85 0.82

2.085 2.406 1.877 1.854

2.914 3.242 2.713 2.672

161.48 164.4 167.25 174.76

x − 1/2, y + 1/2, z

0.82 0.86 0.86

1.889 2.058 2.306

2.702 2.914 3.052

170.83 173.74 145.22

x + 1, y, z −x − 1, −y − 1, −z + 1 −x, y − 1/2, −z + 1/2

0.86 0.86 0.85 0.85

2.047 2.179 1.903 1.812

2.89 2.877 2.753 2.645

166.48 138.08 177.9 166.05

−x + 2, −y, −z + 1

determination shows 1 forms a 1:1 (PZA:MA) co-crystal in the monoclinic C2/c space group with Z = 8, the asymmetric unit (ASU) consisting of an entire molecule of PZA and SA. These two molecules formed a dimeric unit by R22(8) supramolecular heterosynthon through O−H···O (distance of 2.672 Å) and N−H···O (distance of 2.915 Å) hydrogen bond interactions; the different dimeric units then connected with each other by means of O−H···N (distance of 2.713 Å) hydrogen bond interactions into infinite one-dimensional (1D) polymeric chains (Figure 3a). The different 1D polymeric chains then paralleled with each other along the a axis into a sheet structure with plane separation of 6.889 Å (Figure 3a); the sheet structures then paralleled with each other along the b axis into a 2D structure by π···π intermolecular interactions with plane

symmetry operation

x + 1/2, −y + 1/2, z − 1/2 x + 1/2, y − 1/2, z

−x + 1, −y + 2, −z + 1 −x + 2, −y, −z + 1

separation of 3.742 Å (Figure 3b). The different 2D structures further stacked and crossed into a 3D architecture. It is interesting that the PZA molecules exhibit “butterfly” motifs in a column pattern when viewed from the c axis, and the MA molecules distribute on both sides of the column (Figure 3d). Geometrical parameters for hydrogen bonds in co-crystals 1−3 were summarized in Table 2. Crystal Structure of Co-crystal 2 (PZA-SA). Co-crystal 2 also crystallizes as colorless cuboid-shaped crystals similar to 1. The structural determination shows that 2 forms a 2:1 (PZA:SA) co-crystal in the monoclinic P21/c space group with Z = 2, the ASU consisting of two entire PZA molecules and one entire SA molecule. The PZA molecules first formed a dimeric unit by R22(8) supramolecular homosynthon through 2101



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Figure 4. Supramolecular synthons around the (a) dimeric PZA unit and the (b) SA molecule. (c) 2D spacefill motif of co-crystal 2; SA molecules were shown in red and PZA in green.

Figure 5. (a) Supramolecular synthons present in the double-chain structure of co-crystal 3. (b) Double-chain motif of co-crystal 3 when viewed from the c axis. Hydrogen atoms were omitted for clarity. (c) 3D stacking motif of co-crystal 3.

means of O−H···N (distance of 2.753 Å) hydrogen bonds interactions into an infinite 1D polymeric chain (Figure 5a), but this contact is weaker than that in 1 (Table 2). The 1D polymeric chain further connected to another one reversely by a rhombic R22(8) supramolecular homosynthon through N− H···O (distance of 2.877 and 2.890 Å) hydrogen bonds interactions into infinite 1D polymeric double-chain structures (Figure 5a). The double-chain structure exhibits ladder motif when viewed from the c axis (Figure 5b), and the different 1D ladders stacked crossly with each other into a 3D structure (Figure 5c). Hirshfeld Surfaces Analysis. The 3D Hirshfeld surfaces and 2D fingerprint plots are unique for any crystal structure as well as polymorph, they serve as powerful tools for gaining additional insight into crystal structure and polymorph comparison by color-coding short or long contacts. The 2D fingerprint plots can give a quantitative summarization of the nature and type of intermolecular contacts experienced by the molecules in the crystal, and at the same time, it can also be broken down to give the relative contribution to the Hirshfeld surface area from each type of interactions present, quoted as the “contact contribution”.24 In this work, we performed Hirshfeld surfaces on the present three PZA co-crystals, as well as the nine reported PZA co-crystals, for the purpose of investigating the influence of different dicarboxylic acids on the intermolecular interactions of the PZA molecule and comparing the different polymorphs (2 and 4).

N−H···O (distance of 2.914 Å) hydrogen bonds interactions; this PZA dimeric unit is then connected to four SA molecules by means of O−H···N (distance of 2.701 Å) and N−H···O (distance of 3.052 Å) hydrogen bonds interactions (Figure 4a). For each SA molecule, there are four PZA dimeric units connected to it through O−H···N and N−H···O hydrogen bond interactions (Figure 4b), and the 2D motif of 2 looks like a jigsaw composed of SA molecules and PZA dimeric units (Figure 4b). There is no O−H···O hydrogen bond interactions observed in 2 when compared with 1; the O−H···N hydrogen bonding in 2 is shorter than that in 1, but N−H···O hydrogen bonding is longer in the former than the latter (Table 2). Co-crystal 2 is a polymorph of the reported PZA co-crystal 4,15 and their slight differences in crystal structure are shown. Their XPRD profiles are shown in Figure 2 with the differences mainly located 2-theta below 10 and around 25. Crystal Structure of Co-crystal 3 (PZA-GA). Co-crystal 3 crystallizes as colorless needlelike crystals. The structural determination shows that 3 forms a 1:1 (PZA:GA) co-crystal in the monoclinic P21/n space group with Z = 4, the composition ratio is identical with 1. The ASU consists of one entire PZA molecule and one entire GA molecule; these two molecules form dimer units by R22(8) supramolecular heterosynthon through O−H···O (distance of 2.645 Å) and N−H···O (distance of 2.890 Å) hydrogen bonds interactions, which are similar to 1, but the contacts are stronger than that in 1 due to the short hydrogen bonds interactions (Table 2). The different dimeric units then connected with each other by 2102



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Figure 6. 3D dnorm surfaces and 2D fingerprint plots of PZA in co-crystals 1-3.

Table 3. Summary of the Various Contact Contributions to the PZA Hirshfeld Surface Area in Co-Crystals 1−3 compound

H−H

O−H

N−H

C−H

O−C

N−C

C−C

O−O

O−N

N−N

1 2 3

27.9 28.2 29.7

32 31.3 27.6

14.5 13.6 17.3

9.4 10.7 9.7

5.2 4.5 6.2

3.9 7 4.7

3.7 2.1 1.6

0.1 0.6 0.7

1.6 1.9 1.9

1.8 0.1 0.5

The 3D Hirshfeld surfaces and 2D fingerprint plots of PZA in co-crystals 1-3 are shown in Figure 6; they clearly show the similarities and differences of the influences of different coformers on the intermolecular interactions of the PZA molecule. The large circular depressions (deep red) visible on the side of the 3D Hirshfeld surfaces are corresponding to the significant hydrogen bonding contacts; the small red cycles on the surfaces represent the C−H···π interactions, while the red color points in the 2D fingerprint plots are indicative of short contacts of H···H, H···N, and H···O interactions. For co-crystal 1, the N−H···O hydrogen bonding intermolecular interactions appear as two sharp small spikes in the 2D fingerprint plots, which have the most significant contribution to the total Hirshfeld surfaces of 1, comprised of 32%, while O−H···N hydrogen bonding interactions appear as a single, sharp small spike in the 2D fingerprint plots and only comprises 14.5% of the total Hirshfeld surfaces. These hydrogen bonding interactions represent the closest contacts in the co-crystal, which indicate the formation of a low barrier hydrogen bond with the coformer. The H···H interactions, which are reflected in the middle of scattered points in the 2D fingerprint plot, comprises 27.9% of the total Hirshfeld surfaces. The C−H···π interactions also have a relatively significant contribution to the total Hirshfeld surfaces of co-crystal 1, comprised of 9.4%, as was indicated by the ‘‘wings’’ in the upper left and lower right of the 2D fingerprint plot. Apart from those above, the presence of π···π (C···C), lone-pair···π (N−C, O−C), and lonepair···lone-pair (O−O, O−N, and N−N) interactions are observed, which are summarized in Table 3. The Hirshfeld surfaces analysis for PZA in co-crystal 2 was similar to 1. The N−H···O hydrogen bonding interactions still have the most significant contribution to the total Hirshfeld surfaces of co-crystal 2, comprised of 31.3%, a little smaller than that in 1 and a longer contact, and then followed by the H···H

interactions (28.2%) and O−H···N hydrogen bonding interactions (13.6%), where the former is larger than that in 1, while the latter is smaller. The C−H···π interactions contribute 10.7% to the total Hirshfeld surfaces and are also characterized as “wings” in the upper left and lower right of the 2D fingerprint plots. The other contacts were also summarized in Table 3. Co-crystal 2 exhibited only slight differences with its polymorph 4 (Figure S3 and Table S1 of the Supporting Information). For example, the N−H···O, H−H, and O−H···N intermolecular interactions in co-crystal 4 are found to contribute 30.4, 29.3, and 13.1%, respectively, to the total Hirshfeld surfaces, which were slightly larger or smaller than the same items in co-crystal 2. The Hirshfeld surfaces analysis for PZA in co-crystal 3 was different from 1 and 2. The H−H interactions have the most significant contribution to the total Hirshfeld surfaces of cocrystal 3, which comprise 29.7% instead of the N−H···O hydrogen bonding interactions, which comprise 27.6%. The O−H···N hydrogen bonding interaction was a bit larger than in 1 and 2, comprised of 17.3%. The C−H···π interactions contribute 9.7% to the total Hirshfeld surfaces and lie in between the same item of 1 and 2. It is interesting that the differences between interactions of the three co-crystals exhibit some rules, for example, as have been shown in red in Table 3; the N−H···O hydrogen bonding and π···π (C···C) interactions decrease with the increase in length of the carbon chain of the three alkyl dicarboxylic acids, while the H−H and O−O interactions increase with the length of the carbon chain of alkyl dicarboxylic acids. We also studied the Hirshfeld surface analysis of PZA in the reported nine co-crystals (4−12). Their 2D fingerprint plots were shown in Figure S3 of the Supporting Information, and their various contact contributions were summarized in Table S1 of the Supporting Information. They were shown the 2103



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influence of different coformers on the intermolecular interactions of PZA vividly. For co-crystal 5, the N−H···O hydrogen bonding interactions decreased notably due to the rigid carbon skeleton. For the aromatic carboxylic acids coformers, the increasing hydrogen donor/acceptor groups in the carboxylic acids lead to the increase of H−H contact (8, 10, 11, and 12), while the presence of steric hindrance groups such as −OCH3 can lead to the decrease of H−H contact and longer hydrogen bonding contact (7). The increase of aromaticity of the aromatic carboxylic acids can increase the π···π contacts of PZA in the co-crystals remarkably (6 and 9). Solubility and Dissolution Study. Solubility and dissolution rate are important physico-chemical parameters for the estimation of bioavailability of pharmaceutical solids. Solubility is defined as the concentration of a pharmaceutical solid at the equilibrium between the solution and the undissolved solid, and the dissolution rate is defined as the rate at which this equilibrium state is reached. Solubility is a thermodynamic parameter. In this paper, we studied the solubility of the present three co-crystals by using in situ PAT technology (see Experimental Section). The aqueous solubility of PZA, MA, SA, and GA were found to be 22 mg mL−1, 1000 mg mL−1, 83 mg mL−1, and 430 mg mL−1, respectively (Table 1). The solubility of the co-crystals 1−3 were measured to be 56.5 mg mL−1, 33.2 mg mL−1, and 45.7 mg mL−1, respectively (Table 1), which followed the proportionality of the coformers solubility rule: the more soluble coformers lead to improvement of the solubility of co-crystals, and the less soluble coformers lead to low solubility co-crystals. The polymorphs 2 and 4 exhibited almost identical solubility.15 Dissolution rate is a kinetic indicator. Here, it was used to measure the extent of the pharmaceutical solid dissolved in a particular time period and to evaluate whether the drug is sustained in the medium for the therapeutic retention time (usually from 0.5 to 2 to 4 to 8 h). Dissolution rates of the three co-crystals in this work were measured by the rotating disk intrinsic dissolution rate (DIDR) method in pH 1.2 aq. The HCl medium was at 37 °C, using in situ ATR-FTIR spectroscopy. The extent of PZA and the three pharmaceutical co-crystals dissolved within 30 min were found to be 41.5% PZA-MA (1), 35.2% PZA-SA (2), 51.8% PZA-GA (3), and 25% PZA (Figure 7). The three PZA co-crystals dissolve 1.66, 1.408, and 2.072 times faster than PZA, respectively, which

demonstrates the fact that the inclusion of more soluble coformers can increase the dissolution rate of the parent component. The calculated DIDR values for the three cocrystals were found to be 7.2 mg cm−2 min−1, 4.6 mg cm−2 min−1, and 9.7 mg cm−2 min−1, respectively (Table 1), which were all larger than PZA (3.3 mg cm−2 min−1). The dissolution rate of co-crystal 2 was almost identical with its polymorph 4 . It is interesting that the melting point of the three co-crystals showed a semiempirical inverse relationship with the solubility: the co-crystal with lower melting point showed higher solubility. PZA-MA and PZA-GA exhibited lower melting points than did PZA-SA and exhibited higher solubility than the latter (Table 1). But PZA-MA and PZA-GA showed opposite results: PZA-MA exhibited both higher melting points and solubilities than did PZA-GA. The relationship between the melting point and dissolution rate of the three co-crystals completely follows the semiempirical inverse relationship: a lower melting point is related to a fast dissolution rate.

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CONCLUSIONS Co-crystallization of pyrazinecarboxamide (PZA) with alkyl dicarboxylic acids [malonic acid (MA), succinic acid (SA), and glutaric acid (GA)] have been investigated in detail in this work. A thorough structural investigation revealed that PZA formed 1:1 co-crystals with MA and GA (PZA-MA 1 and PZAGA 3), while forming a 2:1 co-crystal with SA (PZA-SA 2). The supramolecular synthons of the three co-crystals were controlled by the stoichiometric ratio; the 1:1 co-crystal exhibited acid−amide and acid−py heterosynthon, while the 2:1 co-crystal exhibited amide−amide homosynthon in addition to acid−amide and acid−py heterosynthon. The N−H···O hydrogen bonding and π···π interactions for PZA in the three co-crystals follow the order, PZA-MA > PZA-SA > PZA-GA, while H−H and O−O interactions follow the order, PZA-MA < PZA-SA < PZA-GA. A comparison of the present co-crystals with the reported PZA co-crystals demonstrated that the rigid carbon skeleton of alkyl dicarboxylic acid coformers led to a decrease of the N−H···O hydrogen bonding interactions, and an increase of hydrogen donor/acceptor groups for the aromatic carboxylic acids coformers led to the increase of the H−H contact. The presence of steric hindrance groups led to the decrease of the H−H contact and longer hydrogen bonding contacts, and the increasing aromaticity led to the increase in π···π contacts. The melting points of the present three cocrystals were all lower than the starting materials and follow the order, PZA-GA < PZA-MA < PZA-SA. In addition, the melting points showed a semiempirical inverse relationship with the solubility and dissolution rate; the solubility follows the order, PZA-SA < PZA-GA < PZA-MA, and the dissolution rate follows the order, PZA-SA < PZA-MA < PZA-GA. Co-crystal 2 exhibited almost identical solubility and IDR with its polymorph 4. The superior solubility and IDR of these cocrystals may be exploited as effective antituberculosis drugs.

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EXPERIMENTAL SECTION

Materials and Physical Measurements. PZA, OA, MA, SA, GA, and AA were all commercially available from Sigma Aldrich and used as received without further purification. Methanol, benzene, and toluene were commercially available from Sinopharm Chemical Reagent Company, Ltd. and used as received without further purification. The melting point was determined by a Veego programmable melting point apparatus. Elemental analyses were performed by a Vario-EL III elemental analyzer for carbon, hydrogen,

Figure 7. Dissolution curves of PZA and co-crystals 1−3 in pH 1.2 aq HCl solution. 2104



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and nitrogen of the co-crystals 1−3. Differential scanning calorimetry (DSC) and thermogravimetric analyses (TGA) were performed using a Mettler-Toledo TGA/DSC STARe System, at a heating rate of 10 K min−1 under an atmosphere of dry N2 flowing at 20 cm3 min−1 over a range from 40 to 300 °C. Samples were placed in open aluminum oxide crucibles annealed at 1100 °C. The TGA/DSC dates were analyzed by using STARe Software. X-ray powder diffraction was recorded on a D8 ADVANCE XRD (Bruker, Germany) with Cu Kα radiation (λ = 1.54056 Å) at 40 mA and 45 kV. The sample was packed into a glass holder and diffraction patterns were collected over a 2θ range of 5−50, at a scan rate of 3° min−1. Co-Crystallization. The co-crystallizations of PZA with OA, MA, SA, GA, and AA were performed by a slow evaporation technique, where 35 mL methanol/water (2:1 v/v) and benzene/toluene (1:1 v/ v) solvent systems were used. The obtained co-crystals were preliminary identified by TGA/DSC measurement and elemental analysis. Co-crystals 1 and 3 were obtained from both methanol/water and benzene/toluene solvent systems by a 1:1 stoichiometric mixture of PZA (1 mmol, 109 mg) with MA (1 mmol, 74 mg) and GA (1 mmol, 102 mg), respectively. Co-crystal 2 was obtained from a benzene/toluene solvent system by a 1:1 stoichiometric mixture of PZA with SA (1 mmol, 88 mg), and the mixture of PZA with SA in methanol/water solvent system led to the precipitation of the reported cocrysyal 4. The mixture of PZA with OA and AA failed to form cocrystals in both solvent system but yielded precipitation of PZA for the former and AA for the latter, respectively. We further analyzed 2:1 and 1:2 stoichiometric mixtures of PZA with these dicarboxylic acids, which led to identical results as those from the 1:1 stoichiometric mixtures. Co-crystal 1 (PZA-MA), Mp: 111 °C. Elemental analysis Anal. Calcd (%): C, 42.29; N, 18.49; H, 3.99. Found: C, 42.30; N, 18.48; H, 4.01. Co-crystal 2 (PZA-SA), Mp 140 °C. Elemental analysis Anal. Calcd (%): C, 46.67; N, 23.32; H, 3.35. Found: C, 46.68; N, 23.31; H, 3.36. Co-crystal 3 (PZA-GA), Mp 92 °C. Elemental analysis Anal. Calcd (%): C, 47.05; N, 16.46; H, 5.13. Found: C, 47.07; N, 16.45; H, 5.15. X-ray Crystallographic Study. The single-crystal X-ray diffraction data of the co-crystals 1−3 were collected at 293 K with graphitemonochromated Mo Kα radiation (λ = 0.071073 nm), equipped with a Rigaku SCXmini diffractometer.35 The lattice parameters were integrated using vector analysis and refined from the diffraction matrix; the absorption correction was carried out by using a Bruker SADABS program with multiscan method.36 The crystallographic data, data collection, and refinement parameters for co-crystals 1−3 were given in Table 4. The structures were solved by the full-matrix least-squares method on all F2 data, and the SHELXS-97 and SHELXL-97 programs37 were used for structure solution and refinement, respectively. All non-hydrogen atoms were refined anisotropically, and hydrogen atoms were geometrically fixed. Solubility and Intrinsic Dissolution Rate Measurements. The solubility was determined by in situ ATR-FTIR spectroscopy.38 Prior to solubility measurements, standard curves of the co-crystals in water were obtained as follows: appropriate amounts (0, 0.2, 0.4, 0.6, 0.8, and 1.0 g) of the co-crystal and 30 mL of water were heated by a circulator water bath and stirred to a homogeneous solution in a 50 mL jar. Five ATR-FTIR spectra (128 scans/spectrum) of the solution in intervals of 10 min were scanned at thermal equilibrium at set temperatures of 20, 30, 40, 50, and 60 °C. The solubility of co-crystals was measured with slurries at equilibrium conditions. Slurries of cocrystals in water were prepared as follows: an excess amount (2 g for 1 and 3, 1.5 g for 2) of the co-crystal was stirred in 30 mL of water at 37 °C for 6 h before the ATR-FTIR spectra were scanned. (It is said that after a 6 h stirring, the ATR-FTIR spectrum would not show any concentration change and would reach the thermodynamic equilibrium.) Five spectra of the slurries at equilibrium were scanned in 10 min time intervals; the concentrations of the slurries thus obtained were determined by using the standard curves.38 Intrinsic dissolution experiments in pH 1.2 aq HCl solution was also carried on in situ ATR-FTIR spectroscopy. Prior to IDR estimation, standard curves of all the co-crystals in pH 1.2 aq HCl solution were

Table 4. Crystal Data and Structure Refinement for CoCrystals 1−3 compound

1

2

3

formula formula weight crystal system space group a (Å) b (Å) c (Å) β (°) V (Å3) Z Dcalc (Mg m−3) T (K) μ (mm−1) cryst dimensions no. of reflections collected no. of unique reflections no. of parameters Goodness-of-fit on F2 R1, wR2 [(I > 2σ(I)] R1, wR2 (all data) CCDC no.

C8H9N3O5 227.18 monoclinic C2/c 10.947(2) 8.3650(17) 22.229(4) 91.05(3) 2035.2(7) 8 1.483 293(2) 0.125 0.3 × 0.2 × 0.1 1869

C14H12N6O6 360.3 monoclinic P21/c 3.8840(8) 17.364(3) 12.699(3) 101.54(3) 839.1(3) 4 1.426 293(2) 0.115 0.25 × 0.2 × 0.1 1540

C10H13N3O5 255.23 monoclinic P21/n 11.200(2) 5.0520(10) 22.001(4) 104.07(3) 1207.5(4) 4 1.404 293(2) 0.114 0.2 × 0.1 × 0.1 2209

907 145 1.013 0.0617, 0.1217 0.1399, 0.1500 917629

1186 118 1.047 0.0413, 0.1078 0.0561, 0.1147 917630

1046 163 1.045 0.0866, 0.1784 0.1764, 0.2175 917631

obtained by following the identical procedure as the solubility standard curves. For IDR measurements, 50 mg of the co-crystal was taken in the intrinsic attachment and compressed to a 0.5 cm2 disc using a hydraulic press at a pressure of 3 ton inch−2 for 3 min. The intrinsic attachment was placed in a jar of 50 mL pH 1.2 aq. HCl solution was preheated to 37 °C and rotated at 75 rpm. ATR-FTIR spectra started to collect at a time of zero.38 The concentration of the solution was determined using the predetermined calibration curves. The linear region of the dissolution profile ( >0.99 regression) was used to determine the IDR of the co-crystal as [slope of the amount dissolved/ surface area of the pellet] per unit time. There was no transformation of the compounds before (upon compression) and after the dissolution experiment, as analyzed by DSC/TGA measurements, and they exhibited the superior solubility of IDR over PZA. The cocrystal 2 exhibited an almost identical solubility by IDR with its polymorph 4. These co-crystals may be exploited as effective antituberculosis drugs.

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ASSOCIATED CONTENT

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AUTHOR INFORMATION

S Supporting Information *

2D fingerprint plots of the nine (4−12) reported PZA cocrystals, various contact contributions to the PZA Hirshfeld surface area in co-crystals 4−12, TGA-DSC profiles of OA, MA, SA, GA, and AA, crystallographic data (CIF files) of cocrystals PZA-MA, PZA-SA, and PZA-GA. This material is available free of charge via the Internet at http://pubs.acs.org. Corresponding Author

*E-mail: [email protected]. Tel: +86-25-52090614. Fax: +86-25-52090614. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work has been supported by the prospective joint research project of Jiangsu province (Grant BY2012193), the National Science Foundation for Young Scholars of China (Grant 2105



Article

(26) WHO. Model List of Essential Medicines; World Health Organization: Geneva, Switzerland, 2009 (http://www.who.int/ selection_medicines/committees/expert/17/sixteenth_adult_list_en. pdf). (27) Cherukuvada, S.; Thakuria, R.; Nangia, A. Cryst. Growth Des. 2010, 10, 3931. (28) Castro, R. A. E.; Maria, T. M. R.; Evora, A. O. L.; Feiteira, J. C.; Silva, M. R.; Beja, A. M.; Canotilho, J.; Eusebio, M. E. S. Cryst. Growth Des. 2010, 10, 274. (29) Aakeröy, C. B.; Desper, J.; Helfrich, B. A. CrystEngComm 2004, 6, 19−24. (30) MacMahon, J. A.; Bis, J. A.; Vishweshwar, P.; Shattock, T. R.; McLaughlin, O. L.; Zaworotko, M. J. Z. Kristallogr. 2005, 220, 340− 350. (31) Greeley, P.; Mukherjee, A.; Desiraju, G. R. CrystEngComm 2011, 13, 4358−364. (32) Abourahma, H.; Cocuzza, D. S.; Melendez, J.; Urban, J. M. CrystEngComm 2011, 13, 6442−6450. (33) Cherukuvada, S.; Nangia, A. CrystEngComm 2012, 14, 2579− 2588. (34) Adalder, T. K.; Sankolli, R.; Dastidar, P. Cryst. Growth Des. 2012, 12, 2533−2542. (35) Rigaku CrystalClear, version 14.0; Rigaku Corporation: Tokyo, Japan, 2005. (36) (a) Luo, Y. H.; Pan, M. L. Acta Crystallogr. 2012, E68, o206. (b) Luo, Y. H.; Xu, J.; Pan, M. L.; Li, J. F. Acta Crystallogr. 2011, E67, o2099. (37) Sheldrick, G. M. SHELXS97: Programs for Crystal Structure Analysis; University of Göttingen: Germany, 1997. (38) (a) Luo, Y. H.; Wu, G. G.; Sun, B. W. J. Chem. Eng. Data 2013, DOI: 10.1021/je3011997. (b) Luo, Y. H.; Tu, Y. R.; Ge, J. L.; Sun, B. W. Sep. Sci. Technol. 2013, DOI: 10.1080/014963 95.2013.780256.

31100055), and the Fundamental Research Funds for the Central Universities (Grant CXZZ12_0119).

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Pharmaceutical Co-Crystals of Pyrazinecarboxamide (PZA) with

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