Syringic Acid: Structural Elucidation and Co-Crystallization - Crystal

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Syringic Acid: Structural Elucidation and Co-crystallization Rajesh Thipparaboina, sudhir mittapalli, Sowjanya Thatikonda, Ashwini Nangia, V GM Naidu, and Nalini R. Shastri Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b00750 • Publication Date (Web): 21 Jun 2016 Downloaded from http://pubs.acs.org on June 24, 2016

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Crystal Growth & Design

Syringic Acid: Structural Elucidation and Co-crystallization Rajesh Thipparaboina1, Sudhir Mittapalli2, Sowjanya Thatikonda3, Ashwini Nangia2,4, VGM Naidu3, Nalini R Shastri1,* 1

Solid State Pharmaceutical Research Group (SSPRG), National Institute of Pharmaceutical Education and Research, Hyderabad, India

2

School of Chemistry, University of Hyderabad, Central University PO, Prof. C. R. Rao Road, Hyderabad, India

3

Department of Pharmacology, National Institute of Pharmaceutical Education and Research, Hyderabad, India 4

CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India.

Abstract Syringic acid (SYRA) is a potential antioxidant used in traditional Chinese medicine and is an emerging nutraceutical. Current reports claim its potential anti-angiogenic, anti-glycating, antihyperglycaemic, neuroprotective, memory enhancing properties in various animal models. To date, SYRA crystal structure is not elucidated and no crystal engineering studies are reported. This study reports crystal structure of SYRA for the first time along with its nicotinamide (SNCT-E) and urea (SU-EA-M) cocrystals. All forms were successfully characterized using single crystal XRD, P-XRD and DSC. Single crystal analysis revealed that SYRA crystallized in C2/c space group whereas SNCT-E (2:1) and SU-EA-M (1:2) crystallized in P 21/n and Cmca space group respectively. Novel cocrystals have shown improved solubility, modified dissolution profiles, improved flow and compressibility. Cytotoxic effects were explored in DU145 prostate cancer cell lines for the first time and significant enhancement in cytotoxicity by the cocrystals was observed compared to plain components. Two folds increase in % cytotoxicity of SNCT-E was observed when compared to the corresponding physical mixture. These studies shed light on potential utility of SYRA as coformer for various pharmaceutical applications to design synergistic and organ protective cocrystals. Keywords Crystal engineering, Cocrystals, Syringic acid, Nicotinamide, Urea, Prostrate Cancer

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1. Introduction Syringic acid (SYRA) is chemically 4-hydroxy-3,5-dimethoxybenzoic acid with a molecular weight of 198.17 Daltons, melting point 206-209 0C, pKa of 3.93 and log P of 1.04. It is a potential antioxidant used in traditional Chinese medicine. Hepatoprotective effects of SYRA are reported in various animal models.1-3 Srinivasan et al reported anti-hyperglycaemic effects in male albino rats at a dose of 50 mg/kg once a day. Reduction in pancreatic damage and enhanced β-cell regeneration was observed in histopathological analysis.4 Rekha et al reported improvement in catecholamine content and antioxidant enzymes level in the MPTP/p-induced mice by pre-oral treatment at a dose of 20 mg/kg for five consecutive weeks. Additionally, it ameliorated the expressions of TH, DAT and VMAT2 and also significantly attenuated MPTP/pinduced increased inflammatory markers expressions.5 Jeong et al reported partial recovery of learning and memory impairment by amyloid β induced neurotoxicity in mice by oral administration of SYRA (10mg/kg of body weight).6 Bhattacherjee et al reported anti-glycating properties of SYRA invitro and discussed their role in Alzheimer’s, diabetes and hypertension.7 Karthik et al reported anti-angiogenic effects of SYRA in Zebra fish embryo at 20 to 50 µm range by down regulation of VEGF mRNA expression.8 Tomak et al reported neuroprotective and antioxidant effects of SYRA on biochemical and histopathological parameters of spinal cord I/R injury in experimental rat models.9 Anti-obesity, anti-inflammatory and anti-steatotic effects of SYRA were recently explored that suggests its utility in obesity or non-alcoholic liver disease.10 SYRA also facilitates protective effects on kidney in renal ischemia-reperfusion injury.11 Antimicrobial activities of SYRA are also reported against various pathogens.

12-14

Anticancer effects of SYRA were explored on A549 lung carcinoma cells and was found to show apoptotic effects with an IC50 of 30 µm.15 To date SYRA crystal structure is not elucidated and crystal engineering studies exploring modification of pharmaceutical properties for therapeutic improvements are not available in literature. This study was designed to develop synergistic and organoprotective multicomponent systems using SYRA with paracetamol, isoniazid, piracetam, levetiracetam, 5fluoro uracil, pyrazinamide, nicotinamide (NCT) and urea (U) for application in the treatment of various diseases. Reproducible and scalable single crystals were obtained with only NCT and U; and are discussed in this paper. This work reports crystal structure of SYRA for the first time


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along with its cocrystals of nicotinamide (NCT) and urea (U). NCT is a water soluble vitamin and is known for its activity in acne vulgaris, skin cancer, anxiety, liver damage and Alzheimer's disease. Both NCT and U are GRAS substances with well established safety at very high doses. Chemical structures of the compounds used in the study are reported in Figure S1 (Supporting Information - SI). 2. Experimental section 2.1 Materials Syringic acid (+98 %) and nicotinamide (99 %) were purchased from Alfa Aesar, India and Sigma Aldrich, India respectively. Urea (99 %) was obtained from Lobachemie, India. All other reagents used were of analytical grade. 2.2 Recrystallization experiments 2.2.1 SYRA: SYRA (199 mg, 1 mol) was added to 25 mL of acetonitrile (ACN) in a conical flask at 75 °C. This solution was filtered hot and left for slow evaporation at room temperature. Single crystals obtained after 2 days were filtered, air-dried and stored in a glass vial until further characterization. 2.2.2 SNCT: SYRA (199 mg, 1 mol) and NCT (123 mg, 1 mol) were added to 8 mL of ethanol (E) in a beaker at 75 °C. This solution was filtered hot and left for slow evaporation at room temperature. Single crystals (SNCT-E) obtained after a day were filtered, air-dried and stored in a glass vial until further characterization. 2.2.3 SU: SYRA (199 mg, 1 mol) and U (123 mg, 1 mol) were added to ethyl acetate-methanol (EA-M) in 20:5 ratio in a beaker at 65 °C. This solution was transferred to a china dish covered with pin holed aluminium foil and left at room temperature for slow evaporation. Single crystals (SU-EA-M) obtained after 4 days were filtered, air-dried and stored in a glass vial until further characterization. 2.3 Characterization of novel solid forms 2.3.1 Single crystal XRD X-ray reflections for the SYRA and SNCT-E were collected on Oxford Xcalibur Gemini Eos CCD diffractometer at 298 K using Cu-Kα radiation (λ=1.54 Å). Data reduction was performed using CrysAlisPro (version1.171.33.55)16 and OLEX2−1.017 to solve and refine the structures. X-ray reflections for SU-EA-M was collected on Bruker D8 Quest diffractometer equipped with a graphite monochromator and Mo−Kα fine-focus sealed tube (λ=0.71073 Å). Data reduction



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was performed using Bruker SAINT Software.18 Intensities were corrected for absorption using SADABS,19 and the structure was solved and refined using SHELX-97.20 All non-hydrogen atoms were refined anisotropically. Hydrogens on hetero atoms were located from difference electron density maps and all C−H hydrogens were fixed geometrically. Hydrogen bond geometries were determined in Platon.21 X-Seed was used to prepare packing diagrams.22 2.3.2 Differential Scanning Calorimetry (DSC) Thermograms were recorded using Mettler Toledo DSC system operating with Stare software. Instrument was calibrated using Indium. Samples weighing about 5–10 mg were placed in 40 µL aluminium crimped pans with pinhole and were heated at 10 ºC/min over a range of 30 - 250 ºC. All the samples were analysed under gas N2 gas purging at 60 mL/min. 2.3.3 Powder X-ray diffraction (P-XRD) PANalytical X’Pert PRO X-ray Powder Diffractometer (Eindhoven, Netherlands), operating with Ni-filtered Cu-Kα radiation (λ = 1.5406 Ǻ) was used to record X-ray diffractograms at room temperature. The data were recorded over 2° to 50° scanning 2θ range with step time of 0.045 steps/0.5 sec. 2.4 Evaluation of novel forms 2.4.1 Solubility studies Phase solubility studies were carried out by adding an excess SYRA and cocrystals to water and pH 1.2 (hydrochloric acid), 4.5 (acetate), 6.8 (phosphate) and 7.4 (phosphate) aqueous buffer solutions. The suspensions were kept for continuous stirring in a Julabo SW22 shaker at 37 0C and 100 RPM for 72 hours.23 Samples were then filtered, suitably diluted in methanol:water (50:50) and analyzed using HPLC method as given below. 2.4.1.1 HPLC method SYRA was quantified using a HPLC system (e2695 Waters) consisting of a HPLC pump, an automated injector equipped with a UV detector (2998 PDA) and an auto sampler. 0.1 % formic acid and acetonitrile was used as mobile phase at a flow rate of 0.9 ml/min in a gradient program (0 to 1 min 95:5, 1 to 2 min 95:5, 2 to 3 min 80:20, 3 to 5 min 10:90 and 5 to 6 min 95:5) on an XBridgeTM C18 (5µ, 4.6 x 100 mm) column. 10 µL of sample was injected and the absorbance of the elute was recorded at 275 nm following suitable dilutions. Details of the HPLC gradient program and the method used are given in Table S1 (Supporting information).


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2.4.2 In-vitro dissolution studies Dissolution testing was carried out in USP apparatus II at a rotational speed of 100 rpm by adding weighed quantities of SYRA, SNCT-E and SU-EA-M (n=3) equivalent to 250 mg of SYRA (passed through sieve no 60) in 900 mL of 0.1 N HCl, pre-warmed to 37±0.5 °C. Aliquots of 5 mL samples were withdrawn at predetermined time intervals of 5, 10, 15, 30, 45, 60 and 120 min substituting the same with equal quantity of fresh dissolution medium. The aliquots following suitable dilution in the mobile phase were analyzed using a validated HPLC method as described above. Dissolution profile analysis was performed using DDSolver.24 2.4.3 Cytotoxicity studies on cancer cells DU-145 (prostate cancer) cell line was obtained from ATCC. The cells were cultured in appropriate DMEM medium supplemented with 10% fetal bovine serum, streptomycinpenicillin. The cells were maintained in a humidified incubator at 370 C with 5% CO2. The cell lines were subcultured by enzymatic digestion with 0.25% trypsin/1mM EDTA solution in phosphate buffered saline (PBS) when they reached approximately 70-80% confluence. 2.4.3.1 Cell viability studies The cytotoxicity of SNCT-E and SU-EA-M cocrystals on DU-145 prostate cancer cells was assessed by performing the MTT assay. Briefly, cells were seeded in 96-well plates at a density of 3000–5000 cells per well with 5% FBS in 100 µl of respective medium and allowed to grow overnight for attachment onto the wells. The cells were then treated with various concentrations of SNCT-E and SU-EA-M co-crystals along with respective concentration of SNCT and SU physical mixtures with 5% FBS for a period of 48 h. After the treatment, 100 µl of MTT (0.5 mg/ml) was added and incubated at 370C for 4 h. Then MTT reagent was aspirated and the formazan crystals formed were dissolved by the addition of 200 µL of DMSO for 20 mins at 37 0

C. The quantity of formazan product was measured by using a spectrophotometric microtiter

plate reader (Spectra Max, M4 Molecular devices, USA) at 570 nm wavelength. 2.4.3.2 Statistical analysis All results were expressed as mean ± SEM. The intergroup variation between various groups was measured by two-way analysis of variance (ANOVA) using the Graph Pad Prism, version 5.0 and the comparison between groups was conducted by “Bonferroni’s Multiple Comparison Test”. Results were considered statistically significant when p 3 may form a salt. On the other hand, ∆pKa in the range of 0 to 3 may result in salt-cocrystal hybrids27-31. Childs et al. in their work on theophylline-acid complexes reported 0 < ∆pKa < 2.5 region as a salt-cocrystal continuum zone32.

Preliminary screening was carried out with paracetamol, isoniazid, piracetam,

levetiracetam, 5-fluoro uracil, pyrazinamide, nicotinamide (NCT) and urea (U). Observations from those studies are presented in table S3 (Supporting Information). Novel solid forms of SYRA with NCT and U were obtained by solution crystallization. Products obtained from recrystallization experiments were used for further for pharmaceutical evaluation. New melting points as given in Table 1 initially confirmed the formation of new forms. Based on the ∆pKa values given in table 1, it was presumed that NCT and U with ∆pKa < 0 may result in cocrystal. These results were in line with the observations of Aurora et al33 regarding linear relationship between ∆pKa and probability of proton transfer between acid-base pairs. These results were further supported by single-crystal XRD, P-XRD and DSC. Table 1 ∆pKa values, melting points and morphology details of SYRA and novel forms Code SYRA SNCT-E SU-EA-M

pKa of drug/ coformer 3.93 3.35 0.18

∆pKa (pKa base – pKa acid) -0.58 -3.75

Melting point (°C) 208.40 175.99 168.01


Morphology Needles Block Needles

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3.1 Characterization of novel forms 3.1.1 Crystal structure analysis Crystallographic parameters and hydrogen bonding metrics in crystal structure of SYRA, SNCTE and SU-EA-M are given in table 2 and table 3 respectively. Overlay of experimental and simulated diffraction patterns of SYRA, SNCT-E and SU-EA-M are provided in Figure S2 (SI). Crystal

structures

are

deposited

as

part

of

the

SI

and

may

be

accessed

at

www.ccdc.cam.ac.uk/data_request/cif (CCDC deposition numbers 1450484, 1473359 and 1473383) 3.1.1.1 SYRA The crystal structure was solved and refined under monoclinic crystal system with C2/c space group. The asymmetric unit contains one molecule of SYRA and the chain grows along b-axis through O5–H5A···O1 (O5–H5A···O1, 2.11 Å, ∠135.7°) and O2–H2A···O5 (O2– H2A···O5, 2.13 Å, ∠138°) H bond interactions forming zig-zag tapes (Figure 1a). SYRA molecules forms tetrameric ring motif R43 (22) through O–H···O (O5–H5A···O1, O2–H2A···O5; Figure 1b) hydrogen bonding interactions.

c a b 0

(a)

(b)



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(c)

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(d)

(e) Figure 1 (a) Chain growing through O–H···O interactions. (b) R44 (22) tetrameric ring motif. (c) (d) and (e) Packing of the molecules along a, b and c axis. 3.1.1.2 SNCT-E (2:1) The crystal structure was solved and refined in monoclinic crystal system under P 21/n space group. The asymmetric unit consists of one molecule of NCT and two molecules of SYRA. The acid molecules were held together by dimeric interactions through O2– H2A···O1 (1.78 Å, ∠176°; Figure 2a) hydrogen bonds forming R22 (8) ring motif. The amide group of NCT forms hydrogen bonding with acid through O7–H7A···O11 (1.80 Å, ∠169°), N2– H2B···O6 (1.96 Å, ∠171.7°) and forms acid–amide dimer via R22 (8) ring motif (Figure 2b) and pyridine nitrogen is involved in hydrogen bonding with hydroxy group of SYRA, forming


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hydroxy–pyridine synthon (O5–H5A···N1, 2.03 Å, ∠150°; Figure 2c). The acid–amide dimers were connected through O10–H10A···O2 (2.33 Å, ∠143°) and O5–H5A···N1 hydrogen bonding interactions, forming hexameric ring (Figure 2d).

(a)

(b)

(c)

(d) Figure 2 (a) Acid–Acid dimer. (b) Acid–Amide Dimer. (c) Hydroxy–pyridine synthon. (d) Hexameric ring motif.



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3.1.1.3 SU-EA-M (1:2) The crystal structure was solved and refined in orthorhombic crystal system under Cmca space group and the asymmetric unit consists of one half of SYRA and two half molecules of urea. In the crystal structure of SU-EA-M cocrystal, three U molecules were connected by two amide-amide dimeric interaction through N1–H1B···O6 (2.09 Å, ∠166°), N3– H3B···O7 (2.10 Å, ∠162°) resulting in triads. These triads of U connected to SYRA through bifurcated N–H···O (N1–H1A···O5, 2.13 Å, ∠157°; N3–H3A···O1, 2.00 Å, ∠153°) H bond interactions resulting eight membered ring motif (Figure 3a) and the rings are extended through O5–H5A···O6 (1.82 Å, ∠146°) H bond interactions (Figure 3b).

(a)

(b)

(c)


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(d) Figure 3 (a) 8 membered ring motif. (b) 8 membered rings extended through O–H···O interactions. (c and d) Packing of SU-EA-M cocrystal along b and c axis. Table 2 Crystallographic information table. Code CCDC deposition number Empirical Formula Formula weight Crystal system Space group T (K) a (Å) b (Å) c (Å) α (deg) Β (deg) γ (deg) V (Å3) Dcalc (g.cm–3) µ (mm–1) θ range Z Range h Range k Range l Reflections collected Total reflections Observed reflections R1 [I > 2 σ (I) ] wR2 (all) Goodness-of-fit X-Ray Diffractometer

SYRA 1450484 C9H10O5 198.17 Monoclinic C 2/c 298 26.474(10) 4.265(6) 15.892(3) 90 97.31(3) 90 1779.8(8) 1.479 1.050 5.61 to 66.59 8 –30 to 30 –3 to 5 –17 to 18 2483 1543 1180 0.0624 0.2494 1.125 OXFORD

SNCT-E (2:1) 1473359 C24H26N2O11 518.47 Monoclinic P 21/n 298 8.9114(3) 9.9718(3) 27.6165(8) 90 97.077(3) 90 2435.38(13) 1.414 0.963 4.72 to 66.56 4 –9 to 10 –10 to 11 –31 to 32 8178 4275 3654 0.0390 0.1098 1.043 OXFORD


SU-EA-M (1:2) 1473383 C11H18N4O7 318.29 Orthorhombic Cmca 298 7.2640(6) 38.217(3) 11.1309(10) 90 90 90 3090.0(4) 1.368 0.115 2.81 to 27.53 8 –7 to 9 –49 to 49 –14 to 14 19942 1906 1585 0.0513 0.1419 1.053 Bruker D8 Quest


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Table 3 Hydrogen bond metrics in crystal structures. Compound

Interaction

D–H/Å

H···A/Å

D···A/Å

∠D–H···A/Å

Symmetry code

SYRA

O2–H2A···O5

0.82

2.13

2.797(4)

138

1/2+x,1-y,z

O5–H5A···O1

0.82

2.11

2.754(4)

135.7

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

O2–H2A···O1

0.89(3)

1.78(3)

2.6595(16)

176(3)

1-x,1-y,-z

N2–H2B···O6

0.898(18)

1.968(18)

2.8598(19)

171.7(17)

x,-1+y,z

N2–H2C···O4

0.83(2)

2.23(2)

3.0059(18)

155.3(18)

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

N2–H2C···O5

0.83(2)

2.54(2)

3.0354(18)

119.2(15)

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

SNCT-E

O5–H5A···N1

0.82

2.03

2.7734(19)

150

-1+x,y,z

Cocrystal

O7–H7A···O11

0.82

1.80

2.6091(17)

169

x,1+y,z

O10–H10A···O2

0.82

2.33

3.0270(18)

143

-x,1-y,-z

C3–H3···O10

0.93

2.39

3.3140(19)

174

-x,1-y,-z

C17–H17A···O7

0.96

2.56

3.205(2)

125

1-x,2-y,-z

C22–H22···O6

0.93

2.58

3.216(2)

127

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

C24–H24···O3

0.93

2.47

3.145(2)

129

1+x,y,z

N1–H1A···O5

0.95

2.13

3.031(2)

157

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

SU-EA-M

N1–H1B···O6

0.86

2.09

2.9304(18)

166

1/2-x,y,1/2-z

Cocrystal

O2–H2A···O7

0.86

1.82

2.679(2)

179

x,-y,1-z

N3–H3A···O1

1.07

2.00

2.988(2)

153

x, y, z

N3–H3B···O7

0.89

2.10

2.9565(17)

162

1/2-x,y,3/2-z

O5–H5A···O6

0.89

1.82

2.605(2)

146

1/2-x,y,1/2-z

3.1.2 DSC Thermal characterization of SYRA, SNCT-E, and SU-EA-M using DSC gave melting endotherms at 208.4, 175.99 and 168.01°C respectively (Figure 4). The melting points of NCT and U were found to be 128.66 and 135.31°C respectively. The onset, melting, endset and ∆H values for all novel forms along with the coformers are given in Table S4 (SI). Changes in melting patterns defined by new melting peaks and enthalpy values indicated the formation of novel adducts. Representative thermograms are given in figure 4. These were additionally defined by P-XRD studies.


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3.1.3 P-XRD studies Characterization of novel forms by p-XRD revealed new diffraction peaks (pointed arrows in figure 4) compared to controls confirming the formation of novel multicomponent systems as evident in DSC studies. Representative diffractograms are provided in figure 4. Characterization data supported by single crystal XRD, P-XRD and DSC confirms the formation of cocrystals.

Figure 4 Thermograms and diffractograms of novel forms along with plain controls 3.2 Evaluation of novel forms 3.2.1 Solubility studies SYRA showed an aqueous solubility of 1.37 mg/ml. It also displayed pH dependant solubility in buffers and solubility increased with increase in pH (7.4 > 6.8 > 4.5 > 1.2). Both the cocrystals have shown 1.5 to 3 folds improvement in solubility compared to SYRA. A three folds improvement in solubility was observed with SNCT-E in pH 1.2 buffer. Results obtained from solubility studies are represented in figure 5 (Solubility ± SD, n=3).

Figure 5 Results from phase solubility studies



3.2.2 Powder dissolution studies To date dissolution studies on SYRA are unreported, hence the solubility of SYRA in different media was considered to design a suitable dissolution media. 0.1 N HCl was hence used as a discriminatory media. Cocrystals SNCT-E and SU-EA-M have shown reduced release rates compared to SYRA. Dissolution profile analysis was carried out using the similarity factor f2.34. An f2 value of 50 or greater (50–100) ensures that the two profiles are similar, while f2C>B. Incase of U, sample with highest blending time (B) has shown highest hardness indicating the plastic nature of the material. NCT has shown capping tendency revealing elastic nature of the material. Both the cocrystals SNCT-E and SU-EA-M have shown capping tendency indicating elastic nature of the material. Deteriorated plasticity was observed in case of SU-EAM in comparison to U. Comparative hardness testing was carried out to understand the effect of cocrystal formation on material strength. Hardness testing post compression at 25 MPa has shown a 4 fold increase in hardness of SU-EA-M cocrystal when compared to SYRA possibly due to high hardness and plastic tendencies of U. No changes in hardness were observed in SNCT-E possibly due to brittle and elastic nature of SYRA and NCT respectively (Figure 8).

Figure 8 Comparative hardness SYRA and cocrystals at 25 MPa


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4.0 Conclusions Structural elucidation and cocrystallization of syringic acid are reported. Single crystal structures were solved for three; SYRA (syringic acid), SNCT-E and SU-EA-M (Cocrystals). SYRA crystallized in C2/c space group whereas SNCT-E (2:1) and SU-EA-M (1:2) crystallized in P 21/n and Cmca space group respectively. Novel forms were evaluated for improved solubility and reduced dissolution rates. Studies in DU145 prostate cancer cell lines have shown significant enhancement in cytotoxicity by cocrystals compared to plain components and physical mixtures at lower concentrations. Improved flow was observed with both the cocrystals. Improved and equivalent compressibility was observed for SU-EA-M and SNCT-E respectively when compared to SYRA. Deteriorated plasticity was observed in comparison to urea. SYRA is emerging nutraceutical with its neuroprotective and hepatoprotective effects, invivo evidence supporting them are increasing day to day. Organoprotective systems of SYRA with various active pharmaceutical ingredients are under evaluation and will be taken forward for studying invivo pharmacological effects. Acknowledgements Financial support from the Department of Pharmaceuticals (DoP), Ministry of Chemicals and Fertilizers, Govt. of India is acknowledged. Supporting Information Table S1 HPLC method parameters; Table S2 Wells protocol for studying compressibility; Table S3 Observations from preliminary screening; Table S4 Onset, peak, endset and enthalpy values; Table S5 Results from dissolution profile analysis; Table S6 Inference from angle of repose studies; Table S7 Inference Well’s compressibility studies; Figure S1 Chemical structures of the compounds studied; and Figure S2 Overlay of calculated and experimental powder patterns.

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For Table of Contents Use only

Syringic Acid: Structural Elucidation and Co-crystallization Rajesh Thipparaboina1, Sudhir Mittapalli2, Sowjanya Thatikonda3, Ashwini Nangia2,4, VGM Naidu3, Nalini R Shastri1,*

15 SYRA

SNCT-E

15

SU-EA-M

Hardness (kP)

10 mg/mL

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10

5

5

0

0

Water

1.2

4.5

6.8

7.4

SYRA

U

NCT SU-EA-M SNCT-E

Synopsis Syringic acid crystal structure is elucidated for the first time along with its cocrystals of nicotinamide and urea. Novel forms were evaluated for phase solubility, dissolution, flow and compressibility and invitro cytotoxic effects. Cocrystals have shown improved solubility, flow and compressibility. Deteriorated plasticity was observed in urea cocrystal. Cocrystals have shown enhanced cytotoxic effects in DU145 prostate cancer cells.


Syringic Acid: Structural Elucidation and Co-Crystallization - Crystal

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