Preparation of Pyrazinamide Eutectics versus Cocrystals Based on

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Preparation of Pyrazinamide Eutectics Vs. Cocrystals Based on Supramolecular Synthon Variations Trishna Rajbongshi, Kashyap Kumar Sarmah, Ankita Sarkar, Ramesh Ganduri, Suryanarayan Cherukuvada, Tejender S. Thakur, and Ranjit Thakuria Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00878 • Publication Date (Web): 27 Sep 2018 Downloaded from http://pubs.acs.org on September 28, 2018

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Crystal Growth & Design

Preparation of Pyrazinamide Eutectics Vs. Cocrystals Based on Supramolecular Synthon Variations Trishna Rajbongshi,a Kashyap Kumar Sarmah,a Ankita Sarkar,a Ramesh Ganduri,b Suryanarayan Cherukuvada,b Tejender S. Thakurc and Ranjit Thakuriaa,* a

Department of Chemistry, Gauhati University, Guwahati 781014, Assam, India

b c

Solid State and Structural Chemistry Unit, Indian Institute of Science, Bengaluru 560012, India

Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow 226 031, India

Abstract Cocrystallization of anti-tuberculosis drug pyrazinamide (PZA) with several substituted aromatic carboxylic acids as conformers was studied. The combinations were analyzed by X-ray diffraction and melting behavior to assess the formation of eutectic vs. cocrystal. Benzoic acid, cinnamic acid and N-heterocycle coformers gave eutectics whereas majority of their hydroxyl/methoxy substitutes formed cocrystals with PZA. X-ray crystal structures were obtained for some cocrystals and binary phase diagrams were constructed to determine eutectic compositions. Differences in functional group position and variations in supramolecular growth were found to dictate the formation of eutectics vs. cocrystals. Supramolecular synthon energy calculations on selected combinations validated the formation of eutectic vs. cocrystal. Introduction Cocrystallization is the supramolecular aggregation of two or more different chemical entities in a crystalline lattice through non-covalent interactions.1 It comprises the design and manifestation of various multi-component crystalline solids such as cocrystals, solid solutions, eutectics, solvates etc.2-16 Of late, the design of organic eutectics is emerging as a fertile research area with immense potential in advancing the fundamental and application aspects of cocrystallization.1,3,912,17-21 In particular, the prospect of eutectics as new/alternate solid drug forms with tunable physico-chemical properties, akin to cocrystals,3 renders them highly attractive. In this context, we have undertaken studies to design eutectics of anti-tuberculosis drug pyrazinamide (PZA). PZA is a highly soluble and stable drug22 with four polymorphic forms reported in the literature23 and hence making its eutectics is needless from a pharmaceutical perspective. However, the drug contains carbonyl, amide and pyridyl functional groups, the largest occurring functionalities in top 100 prescription drugs,24 and therefore serves as an excellent model drug system to comprehend the design and properties of eutectics in those classes of drugs. In the literature, eutectics have been designed alongside cocrystals based on the hypothesis that continuity of heteromolecular interactions leads to cocrystal formation and discontinuity in the eutectic for a given combination.3,10,25 Recently, we26 and Jarzembska et al.27 reported several dihydroxybenzoic acid (DHBA) cocrystals of PZA whose structural analysis shows their supramolecular growth via amide(PZA)/acid(DHBA) homo- or heterodimers propagating into Page 1 of 22 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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catemeric motifs through hydroxyl(DHBA)⋅⋅⋅pyrazyl(PZA) heteromeric interactions. We reasoned that by limiting the supramolecular growth, PZA eutectics of carboxylic acids can be obtained, with cocrystals obtainable otherwise. On this rationale, we selected three sets of substituted aromatic carboxylic acids (benzoic acid, cinnamic acid and N-heterocycles respectively; Figure 1) as partner molecules to make eutectics as well as cocrystals of PZA. Six eutectics and five cocrystals of the drug were successfully obtained in the anticipated lines and we discuss the underlying reasons for their formation in this article. Results and discussion Cocrystallization experiments were performed mechanochemically using liquid-assisted grinding28 and the ground materials were characterized by powder X-ray diffraction (PXRD) and melting point analyses. Cocrystal-forming combinations showed distinct PXRD and melting features; and X-ray crystal structures were determined for those which afforded suitable single crystals (crystallographic parameters are given in Table 1). Eutectic-forming combinations exhibited lower melting point hallmark and were characterized by 'V'-type phase diagram.3,29 H N

O

OH

O O

H

O

OH

N N

MeO

OH

Pyrazinamide (PZA)

Benzoic acid (BA)

Cinnamic acid (CA)

O

Caffeic acid (CFA)

OH

OH

OMe

Ferulic acid (FRA) *

OH

O

MeO HO

OMe

OH

p-coumaric acid (PCA)

O OH

HO

HO

HO

Syringic acid (SGA)

O OH

OH

OH

26DHBA *

O

O

O

OMe OH

4HBA

Salicylic acid (SA)

OH

OH

HO

OH

O

OH

O

OH

Sinapic acid (SPA)

O NH

N Nicotinic acid (NA)

S N

O

O

Isonicotinic acid (INA) Saccharin (SAC)

Figure 1. Molecular structure of PZA and coformers considered for our study. Coformers in red resulted in eutectics and those in black gave cocrystals. *cocrystals of our previous study.26 Cocrystallization with benzoic acid and its substitutes Benzoic acid, two mono-hydroxybenzoic acids (SA and 4HBA), one dihydroxybenzoic acid (26DHBA) and a methoxy-derivative of hydroxybenzoic acid (SGA) were respectively cocrystallized with PZA. The former two gave eutectics and the latter three formed cocrystals with PZA. For benzoic acid case, no additional strong donor functionalities are available to engage PZA pyrazyl group so as to extend either acid(BA)/amide(PZA) homo-/ heterodimer or acid(BA)⋅⋅⋅pyrazyl(PZA) dimer motifs and result in a cocrystal (as with reported dihydroxybenzoic acid cocrystals) i.e. there is a restriction of supramolecular growth for the combination to form a Page 2 of 22 ACS Paragon Plus Environment

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cocrystal and therefore it manifested a eutectic (Figure 2a), in accordance to the design concepts for organic eutectics.1,3 Introducing a hydroxyl group on benzoic acid can facilitate the propagation of binary units into quaternary molecular associates and so on and allow for supramolecular growth as a cocrystal. Synthon hierarchies in cocrystals of various drug molecules with substituted hydroxybenzoic acids are well established in literature.30-36 For 2hydroxybenzoic acid (salicylic acid, SA), although hydroxyl donor is present to complement PZA pyrazyl acceptor and propagate molecular association, the same is generally unavailable and the combination resulted in a eutectic (Figure 2b). It is of interest to note that its higher substitute (2,6-dihydroxybenzoic acid, 26DHBA which is ortho di-substituted) forms a cocrystal with PZA.26 Crystal structure analysis shows that the phenolic group flanking the hydroxyl side of carboxyl group makes hydroxyl⋅⋅⋅pyrazyl heteromeric interactions in addition to intramolecular hydrogen bond (Figure 2b). In general, the phenolic group of SA makes intramolecular hydrogen bond with stronger carbonyl acceptor (than C−O(H) group which is longer and acute) such that it is less disposed as a donor for intermolecular hydrogen bonding. It may be suggested that the lone and intramolecular hydrogen bond locked phenolic group of SA (as compared to other hydroxy substitutes) and hence cocrystal formation was not observed under the reported experimental conditions. The anti-NH group of PZA involved in intramolecular N–H···N hydrogen bond may influence supramolecular growth restriction, as a closely related binary system of Nicotinamide–SA results cocrystal formation.37,38 Thus, the restriction of supramolecular growth in PZA−BA and PZA−SA combinations led to their eutectics. Binary phase diagrams of PZA−BA and PZA−SA systems show that the eutectic compositions are 1:4 and 1:1 respectively (Figure 2c). PXRD of the respective eutectic systems are shown in Figure 3.

(a)

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PZA−SA

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PZA−26DHBAcocrystal (b)

PZA− −BA

PZA− −SA (c)

Figure 2. (a) Supramolecular schematics for PZA−BA combination to show restriction of supramolecular growth as a cocrystal such that it forms a eutectic. (b) Cocrystal formation happens for PZA−26DHBA combination because the additional strong hydroxyl donor engages pyrazyl acceptor and the lack of same resulted in eutectic for PZA−SA combination. (c) Binary phase diagrams for PZA−BA and PZA−SA eutectic systems showing eutectic compositions of 1:4 and 1:1 with melting temperatures 89 °C and 102 °C respectively. Solidus points are shown as filled circles and liquidus points as open squares.


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Figure 3. PXRDs of PZA−BA and PZA−SA eutectics manifest as a summation of their parent materials. In the cases of 4-hydroxybenzoic acid (4HBA) and syringic acid (SGA), phenolic groups are far from carboxyl group and thus well available for intermolecular hydrogen bonding with PZA pyrazyl group (Figure 4). Understandably, they formed cocrystals as analyzed by distinct PXRD (Figure 5) and melting point characteristics (Figure S1, Supporting Information). Diffraction quality single crystals were obtained for PZA−4HBA cocrystal and its crystal structure was determined (see Table 1). The cocrystal shows two molecules each of PZA and 4HBA in the asymmetric unit, thus making a 1:1 stoichiometry. Carboxylic acid homodimers of 4HBA and carboxamide homodimers of PZA are connected by hydroxyl⋅⋅⋅pyrazyl heteromeric interactions to result in infinite chains which stack to result in 3D crystal packing (Figure 6).39 The calculated powder pattern matches well with the experimental one confirming bulk phase purity of the cocrystal prepared by LAG (Figure S2, Supporting Information). In case of PZA−SGA, despite several attempts no suitable single crystals were obtained for crystal structure determination. Thermal analyses of the cocrystal indicate it to be non-solvated in natureand shows that it has melting point lower than that of parent materials (Figure S1, Supporting Information).



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Figure 4. Supramolecular schematics for the formation of cocrystals in PZA−4HBA and PZA−SGA combinations.

Figure 5. PXRDs of PZA−4HBA and PZA−SGA show new/ distinct peaks as compared to their parent materials indicating the formation of cocrystals for the combinations.

(a)

(b)

Figure 6. (a) Carboxylic and carboxamide homodimers make an infinite chain via hydroxyl⋅⋅⋅pyrazyl heteromeric interactions in 1:1 PZA−4HBA cocrystal. (b) Adjacent chains stack together through van der Waals interactions to give 3D crystal packing. Page 6 of 22 ACS Paragon Plus Environment

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Cocrystallization with cinnamic acid and its substitutes Ferulic acid (3-methoxy-4-hydroxycinnamic acid, FRA), a cinnamic acid derivative, was found to form a cocrystal with PZA in our previous study.26 Based on this and the results with benzoic acid and its substitutes in the previous section, we anticipated that parent cinnamic acid (CA) can give a eutectic and hydroxy/ methoxycinnamic acids form cocrystals with PZA. Accordingly, we obtained PZA eutectic of CA and PZA cocrystals of 4-hydroxycinnamic acid (p-coumaric acid, PCA); 3,4-dihydroxy-cinnamic acid (caffeic acid, CFA) and 3,5-dimethoxy-4-hydroxycinnamic acid (sinapic acid, SPA). Similar to BA, CA lacks additional donor groups to complement PZA pyrazyl acceptor for supramolecular growth beyond binary associates and therefore resulted in a eutectic (Figure 7a). Binary phase diagram shows a 1:3 eutectic composition (Figure 7b). In case of cocrystal-forming combinations, although suitable single crystals could not be obtained for crystal structure determination (except PZA−SPA), distinct PXRD (Figure 8) and melting point characteristics (Figure S3, Supporting Information) were observed for the combinations. In these cases, presence of strong donor functional groups (OH/OMe) at para/meta-position on the coformers make cocrystal formation feasible by engaging PZA pyrazyl acceptor as seen in hydroxy/methoxybenzoic acids discussed before. The obtained crystal structures of PZA−FRA and PZA−SPA 1:1 cocrystals serve as representative cases in this family of compounds. PZA−FRA contains acid⋅⋅⋅acid and amide⋅⋅⋅amide homodimers along with hydroxyl⋅⋅⋅pyrazyl heteromeric interactions; whereas PZA−SPA cocrystal displays carboxamide homodimers growing into infinite tapes through acid⋅⋅⋅amide and hydroxyl⋅⋅⋅pyrazyl heteromeric interactions (Figure 9). The calculated powder pattern matches well with the experimental one confirming bulk phase purity of the cocrystal synthesized by LAG (Figure S4, Supporting Information).

(a)



(b) Figure 7. (a) Supramolecular schematics for PZA−CA combination to show restriction of supramolecular growth as a cocrystal such that it forms a eutectic. (b) Binary phase diagram of PZA−CA eutectic showing 1:3 eutectic composition with a melting temperature of 113 °C. Solidus points are shown as filled circles and liquidus points as open squares.

(a)


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(b)

(c) Figure 8. PXRDs of (a) PZA−CA eutectic; (b) PZA−PCA and PZA−CFA cocrystals; (c) PZA−FRA and PZA−SPA cocrystals along with their respective starting materials.

(a)

(b)



(c)

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(d)

Figure 9. (a) Acid⋅⋅⋅acid and amide⋅⋅⋅amide homodimers along with hydroxyl⋅⋅⋅pyrazyl heteromeric interaction in 1:1 PZA−FRA cocrystal. (b) Stacking of infinite layers of PZA−FRA results in 3D crystal packing. (c) Carboxamide homodimers make infinite tapes through acid⋅⋅⋅amide and hydroxyl⋅⋅⋅pyrazyl heteromeric interactions in 1:1 PZA−SPA cocrystal. (d) Orthogonal stacking of the tapes results in 3D crystal packing. Cocrystallization with N-heterocycles Nicotinic acid (NA), isonicotinic acid (INA) and saccharin (SAC) were selected, all of which were expected to form eutectics with PZA respectively and were obtained accordingly. The formers are found to be less prone to cocrystal formation owing to their strong carboxylic acid(NA/INA)⋅⋅⋅pyridine(NA/INA) homomeric interactions.36,40-42 Although carboxylic acid−pyridine synthon is most successfully used to design cocrystals, it is favorable for combinations exclusively having carboxylic acid and pyridine functionalities respectively (for e.g. aliphatic carboxylic acid and pyridine containing coformers).43-45 No cocrystals of isonicotinic acid have been reported and only two nicotinic acid cocrystals (one with the stronger acid 3,5dinitrobenzoic acid and another one with 4-aminobenzoic acid where carboxylic acid⋅⋅⋅pyridine homomers are sustained) are found in the Cambridge Structural Database.46 Even if acid(NA/INA)⋅⋅⋅amide(PZA) or acid(NA/INA)⋅⋅⋅pyrazyl(PZA) heterodimers could form in combination with PZA, they cannot grow beyond due to the lack of strong donors to engage pyrazyl(PZA) acceptors and for the weak probability of carboxamide(PZA)⋅⋅⋅pyridine(NA/INA) supramolecular synthon4,10,47 to result in a cocrystal (Figure10a). Similarly, saccharin can form at most carboxamide/sulfonamide⋅⋅⋅carboxamide heterodimers with PZA such that it formed a eutectic (Figure 10b). Binary phase diagrams of PZA−NA, PZA−INA and PZA−SAC systems show that the eutectic compositions are 2:1; 5:1 and 4:1 respectively (Figure 11). PXRD and differential scanning calorimetry (DSC) of the respective eutectics are shown in Figure 12 and 13 respectively (also Figure S5, Supporting Information).


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(a)

(b) Figure 10. Supramolecular schematics for the formation of eutectics in (a) PZA−NA, PZA−INA and (b) PZA−SAC combinations.

(a)

(b)

(c) Page 11 of 22 ACS Paragon Plus Environment


Figure 11. Binary phase diagrams for (a) PZA−NA, (b) PZA−INA and (c) PZA−SAC eutectic systems showing eutectic compositions of 2:1, 5:1 and 4:1 with melting temperatures 171 °C, 185 °C and 152 °C respectively. Solidus points are shown as filled circles and liquidus points as open squares.

(a)

(b) Figure 12. PXRDs of (a) PZA−NA, PZA−INA and (b) PZA−SAC eutectics along with their respective starting materials.


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(a)

(b)

Figure 13. DSC of (a) PZA−NA and (b) PZA−SAC at their eutectic compositions, i.e. 2:1 and 4:1 respectively, show lowest melting endotherms coinciding with their binary phase diagrams. Table 1. Crystallographic parameters of PZA cocrystals

Chemical

PZA–4HBA (1:1) C5H5N3O,

PZA–SPA (1:1) C5H5N3O,

formula

C7H6O3

C11H12O5

Formula wt

261.24

347.32

Crystal system

Orthorhombic

Monoclinic

Space group

Pca21

P21/c

T, K

296

296

a, Å

28.9170(13)

10.0848(5)

b, Å

7.4351(4)

7.0465(3)

c, Å

11.3090(5)

23.7705(10)

α, deg

90

90

β, deg

90

100.910(2)

γ, deg

90

90

Z

8

4

V, Å3

2431.4(2)

1658.66(13)

Dcalc, g cm−3

1.427

1.391

µ, mm−1

0.110

0.108

reflns collected

34577

13982



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unique reflns

4445

2928

R1[I > 2(I)]

0.0474

0.0456

wR2 (all)

0.1306

0.1164

GOF

1.063

1.132

Data collection

Bruker-Apex II

Bruker-Apex II

CCDC no.

1844155

1844154

Supramolecular Synthon Energy Calculations and Spectroscopic Analysis It is reasonable to think that cocrystal formation leads to energy minimization (or greater energy stabilization) as compared to eutectic formation.1,48 However, there are no systematic studies in the literature in these lines. For systems with strong hydrogen bonding functionalities such as the ones studied here, hydrogen bond interactions lead to energy minimization at the primary level of supramolecular organization followed by weak interactions to give rise to cocrystals.4 Since the absence of strong hydrogen bond functionality appears to dictate eutectic formation (as compared to its presence leading to cocrystal), we have considered the analogous cocrystal architectures to generate hypothetical supramolecular synthons for the observed eutectics. In this very limited hypothetical model we considered (for practical reasons) the eutectic systems to be isostructural with the discovered cocrystals. We have done synthon energy calculations49,50 on the premise that cocrystal-forming combinations have energetic advantage over their analogous eutectic-forming combinations. We compared and contrasted stabilization energy differences for PZA cocrystal (with 4HBA, 24DHBA, 26DHBA, FRA and SPA) and eutectic systems (with BA, SA and CA) at B3LYP/6-311++G(d,p) level of theory using Gaussian 09 Software (Table 2). Input geometry of supramolecular synthons in each case was taken from corresponding crystal structures with normalized H-atom positions. Putative synthons for the eutectic systems were generated from the cocrystals by replacing substituent groups by H-atoms. It was observed that cocrystal systems have higher stabilization energy than eutectic systems (Table 2) in the anticipated lines. This shows the energetic advantage in cocrystal-forming combinations as compared to eutectic-forming combinations based on energy minimization through strong/additional hydrogen bond functionalities in the formers. However, it should be noted that this computational exercise is not intended neither to represent the whole driving force for eutectic formation nor cocrystallization since the phenomenon is also governed by weak interactions as well as crystal packing. Further, due to the lack of structural evidence for eutectics, one cannot completely rely on the obtained synthon energy values but such calculations offer a lead in the validation of cocrystal vs. eutectic formation and comprehend the energetics of cocrystallization. Furthermore, there are no systematic studies in the literature on the utility of Raman spectroscopy in characterizing the intermolecular interactions or formation of supramolecular synthon in a eutectic. How the spectral differences observed for a combination as compared to its parent components validate the formation of a eutectic and negate a cocrystal is still in a nascent stage. Harry G. Brittain studied51 Raman spectroscopy on benzoic acid-benzamide system and Page 14 of 22 ACS Paragon Plus Environment

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found that the same was not useful in the characterization of the combination. He observed minor differences in the infrared spectra and claimed the system to be a cocrystal. However, Colin C. Seaton and Andrew Parkin concluded52 that in the absence of secondary interactions, which can extend the finite acid-amide heterodimers, benzoic acid-benzamide combination is a eutectic. Therefore, there is a need for rigorous spectroscopic studies (FT-IR, Raman and solid state NMR) to characterize a eutectic vis-a-vis a cocrsytal. Considering this in mind, FT-IR spectra of all the PZA eutectic systems are included in Figure S6 Supporting Information. Table 2. Synthon comparison for closely related pyrazinamide cocrystal (left column) and eutectic systems (right column).

PZA–4HBA cocrystal ∆Ediff = –16.8 kcal/mol

PZA–BA (Hypothetical)

PZA–24DHBA cocrystal ∆Ediff = –13.42 kcal/mol

PZA–SA Synthon A (Hypothetical)

PZA–26DHBA cocrystal ∆Ediff = –30.69 kcal/mol

PZA–SA Synthon B (Hypothetical)

PZA–FRA cocrystal ∆Ediff = –20.85 kcal/mol

PZA–CA Synthon A (Hypothetical)

PZA–SPA cocrystal

PZA–CA Page 15 of 22

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∆Ediff = –9.95kcal/mol

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Synthon B (Hypothetical)

Conclusion In conclusion, we have carried out a systematic study on the cocrystallization behavior of PZA with several substituted aromatic carboxylic acids. Based on the presence/absence and position of hydrogen bond functionality in the selected coformers we could able to prepare six eutectics and five cocrystals. PZA eutectics were characterized based on ‘V’-type phase diagram, whereas PZA cocrystals based on PXRD, SCXRD (in case of PZA–4HBA and PZA–SPA) and thermal data (DSC and TGA). Synthon energy calculations provided a rationale for supramolecular synthon stabilization in cocrystal vs. eutectic formation. Although cocrystal design is widespread compared to eutectic design, we could able to design a series of eutectics and validate their formation. Several borderline cases were known in the literature where cocrystallization is still a challenge;53-56 we hope studies of our type will help in the prediction of cocrystals and eutectics in the near future. Experimental section Materials Pyrazinamide (PZA) was purchased from TCI chemicals (India) Pvt. Ltd. and used as received. All other coformers were purchased from commercial sources and used without further purification. Preparation of PZA eutectics and cocrystals Liquid Assisted Grinding All the eutectics and cocrystals of PZA were synthesized using liquid assisted grinding (LAG). Stoichiometric amount of PZA and all coformers are taken in a mortar-pestle, 4-5 drops of acetonitrile was used as liquid for grinding. After 20 min of manual grinding resultant powdered materials were analyzed using PXRD and melting point analysis. Solution Crystallization Solution crystallization of all PZA cocrystals were carried out using powdered samples obtained from LAG using various laboratory solvents by placing around 30-40 mg of the powdered material in ~ 20 mL of the corresponding solvent, heated at 80 °C until the solids disappeared. The clear solution was kept at room temperature for crystallization. Single crystal X-ray Diffraction Page 16 of 22 ACS Paragon Plus Environment

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X-ray reflections were collected on a Bruker SMART APEX II CCD equipped with a graphite monochromator and a Mo Kα fine-focus sealed tube (λ = 0.71073 Å). Data integration was done using SAINT. Intensities for absorption were corrected using SADABS. Structure solution and refinement were carried out using Bruker SHELXTL. The hydrogen atoms were refined isotropically, and the heavy atoms anisotropically. N−H and O−H hydrogens were located from difference electron density maps, and C−H hydrogens were fixed using the HFIX command in SHELXTL. Crystallographic .cif files are deposited with the CCDC (Nos. 1844154-1844155) and may be accessed at www.ccdc.cam.ac.uk/data. Powder X-ray Diffraction (PXRD) PXRD measurements were performed on a Rigaku Ultima IV X-ray powder diffractometer operating a CuKα X-ray source, equipped with a Ni filter to suppress Kβ emission and a D/teX Ultra high-speed position sensitive detector, and measurements were performed at room temperature, with a scan range 2θ = 5−50°, step size of 0.02°, and scan rate of 2° min−1. Thermal analysis Melting points of different stoichiometric compositions (1:1, 1:2, 1:3, 1:4, 1:5, 2:1, 3:1, 4:1, 5:1) of all eutectic forming combinations were recorded on a Lab India visual melting range apparatus (MR 13300710) equipped with a camera and a LCD monitor. Solidus-liquidus points of different stoichiometric compositions of eutectic forming combinations were monitored and based on the single melting point of solidus and liquidus points the eutectic composition was determined. DSC and TGA of PZA cocrystals and eutectics were performed on Mettler Toledo DSC 822e and Mettler Toledo TGA/SDTA 851e module respectively. The typical sample size is 1–3 mg for DSC and 3–5 mg for TGA. Samples were heated at 5 °C min−1 in the temperature range of 30–300 °C under an ultra high pure nitrogen environment purged at 50 mL min−1. Spectroscopic Analysis Fourier transform infrared (FT-IR) spectra were collected on an Agilent Cary 630 Spectrometer equipped with a ZnSe beam splitter and a ZnSe ATR accessory, and spectral resolution was set to 2 cm−1. Associated Content Supporting information The supporting information is available free of charge via the Internet at http://pubs.acs.org. Figure S1. DSC and TGA thermograms of PZA−4HBA and PZA−SGA cocrystals. Figure S2. Experimental PXRD pattern of PZA−4HBA cocrystal compared with calculated powder pattern. Figure S3. DSC and TGA thermograms of PZA−PCA, PZA−CFA and PZA−SPA cocrystals. Figure S4. Experimental PXRD pattern of PZA−SPA cocrystal compared with calculated powder pattern. Figure S5. DSC thermogram of PZA−SA eutectic system. Figure S6. FT-IR spectra of PZA eutectics. Page 17 of 22 ACS Paragon Plus Environment


Author information Corresponding author E-mail: [email protected], [email protected] Acknowledgement K.K.S. thanks the CSIR for Senior Research Fellowship (PhD scholar). A.S. thanks the Department of Chemistry, Gauhati University (GU) for a master’s project; R.T. thanks the Department of Science and Technology (DST) for a SERB Young Scientists project (Project No. SB/FT/CS-101/2013); Prof. P. J. Das for providing laboratory space; Dr. S. Karmakar for collecting single crystal X-ray data; R.G. thanks the CSIR for Senior Research Fellowship; S.C. thanks the SERB for the Start-Up Research Grant. Prof. T. N. Guru Row, Indian Institute of Science, for his help to record DSC and TGA; Department of Chemistry, B. Borooah College for the FT-IR spectrometer; the Sophisticated Analytical Instrumentation Facility (SAIF), GU for use of the single crystal X-ray diffractometer and the Department of Chemistry, GU for powder X-ray diffractometer, basic instrumentation facility and infrastructure. Dedication We dedicate this work in memory of Prof. Israel Goldberg on his sudden demise. References (1) Cherukuvada, S.; Kaur, R.; Guru Row, T. N. Co-crystallization and small molecule crystal form diversity: from pharmaceutical to materials applications. CrystEngComm 2016, 18, 8528-8555. (2) Bučar, D.-K. Engineering Molecular Crystals: Backbreaking, yet Gratifying. Cryst. Growth Des. 2017, 17, 2913-2918. (3) Cherukuvada, S.; Nangia, A. Eutectics as improved pharmaceutical materials: design, properties and characterization. Chem. Commun. 2014, 50, 906-923. (4) Desiraju, G. R.; Vittal, J. J.; Ramanan, A.: Crystal Engineering: A Textbook, 2011. (5) Duggirala, N. K.; Perry, M. L.; Almarsson, O.; Zaworotko, M. J. Pharmaceutical cocrystals: along the path to improved medicines. Chem. Commun. 2016, 52, 640-655. (6) Thakuria, R.; Delori, A.; Jones, W.; Lipert, M. P.; Roy, L.; Rodríguez-Hornedo, N. Pharmaceutical cocrystals and poorly soluble drugs. Int. J. Pharm. 2013, 453, 101-125. (7) Aakeröy, C. B.; Forbes, S.; Desper, J. Using Cocrystals To Systematically Modulate Aqueous Solubility and Melting Behavior of an Anticancer Drug. J. Am. Chem. Soc. 2009, 131, 17048-17049. (8) Dabros, M.; Emery, P. R.; Thalladi, V. R. A Supramolecular Approach to Organic Alloys: Cocrystals and Three- and Four-Component Solid Solutions of 1,4-Diazabicyclo[2.2.2]octane and 4-X-Phenols (X=Cl, CH3, Br). Angew. Chem., Int. Ed. 2007, 119, 4210-4213. (9) Prasad, K. D.; Cherukuvada, S.; Devaraj Stephen, L.; Guru Row, T. N. Effect of inductive effect on the formation of cocrystals and eutectics. CrystEngComm 2014, 16, 9930-9938. (10) Cherukuvada, S.; Guru Row, T. N. Comprehending the Formation of Eutectics and Cocrystals in Terms of Design and Their Structural Interrelationships. Cryst. Growth Des. 2014, 14, 4187-4198. (11) Górniak, A.; Karolewicz, B.; Żurawska-Płaksej, E.; Pluta, J. Thermal, spectroscopic, and dissolution studies of the simvastatin–acetylsalicylic acid mixtures. J. Therm. Anal. Calorim. 2013, 111, 2125-2132.


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For Table of Contents Use Only Preparation of Pyrazinamide Eutectics Vs. Cocrystals Based on Supramolecular Synthon Variations Trishna Rajbongshi,a Kashyap Kumar Sarmah,a Ankita Sarkar,a Ramesh Ganduri,b Suryanarayan Cherukuvada,b Tejender S. Thakurc and Ranjit Thakuriaa,*

TOC graphic

Synopsis Formation of eutectics vs. cocrystals has been studied for anti-tuberculosis drug pyrazinamide (PZA) with several substituted aromatic carboxylic acids as coformers. Benzoic acid, cinnamic acid and N-heterocycle coformers gave eutectics whereas majority of their hydroxyl/methoxy substitutes formed cocrystals with PZA. Binary phase diagrams were constructed to determine eutectic compositions of the respective eutectic mixtures. Differences in functional group position and variations in supramolecular growth were found to dictate the formation of eutectics vs. cocrystals.


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Preparation of Pyrazinamide Eutectics versus Cocrystals Based on

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