Supramolecular Cocrystals of Gliclazide: Synthesis, Characterization and Evaluation

Pharm Res (2017) 34:552 563 DOI 10.1007/s11095-016-2075-1 RESEARCH PAPER Supramolecular Cocrystals of Gliclazide: Synthesis, Characterization and Evaluation Renu Chadha 1 & Dimpy Rani 1 & Parnika Goyal 1 Received: 25 September 2016 /Accepted: 28 November 2016 /Published online: 29 December 2016 # Springer Science+Business Media New York 2016 ABSTRACT Purpose To prepare the supramolecular cocrystals of gliclazide (GL, a BCS class II drug molecule) via mechanochemical route, with the goal of improving physicochemical and biopharmaceutical properties. Methods Two cocrystals of GL with GRAS status coformers, sebacic acid (GL-SB; 1:1) and α-hydroxyacetic acid (GL-HA; 1:1) were screened out using liquid assisted grinding. The prepared cocrystals were characterized using thermal and analytical techniques followed by evaluation of antidiabetic activity and pharmacokinetic parameters. Results The generation of new, single and pure crystal forms was characterized by DSC and PXRD. The crystal structure determination from PXRD revealed the existence of both cocrystals in triclinic (P-1) crystal system. The hydrogen bonded network, determined by material studio was well supported by shifts in FTIR and SSNMR. Both the new solid forms displayed improved solubility, IDR, antidiabetic activity and pharmacokinetic parameters as compared to GL. Conclusions The improvement in these physicochemical and biopharmaceutical properties corroborated the fact that the supramolecular cocrystallization may be useful in the development of pharmaceutical crystalline materials with interesting network and properties. KEY WORDS biopharmaceutical. cocrystals. crystal structure. gliclazide. physicochemical Electronic supplementary material The online version of this article (doi:10.1007/s11095-016-2075-1) contains supplementary material, which is available to authorized users. * Renu Chadha renukchadha@rediffmail.com 1 University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India ABBREVIATIONS ANOVA Analysis of variance API Active pharmaceutical ingredient DSC Differential scanning calorimetry FTIR Fourier transform infrared GL Gliclazide GOD-POD Glucose oxidase peroxidase GRAS Generally regarded as safe HA α-hydroxyacetic acid IDR Intrinsic dissolution rate LAG Liquid assisted grinding PXRD Powder X-ray diffraction SB Sebacic acid SEM Standard error mean SSNMR Solid-state nuclear magnetic rasonance USP United states pharmacopoeia INTRODUCTION Supramolecular interactions lie at the very heart of crystalline pharmaceutical solids and are fundamental in controlling the solid forms and their properties (1). Designing of the supermolecules by utilizing and modifying the supramolecular interactions has emerged as a new frontier in the research (2). The basic tenet of building the supramolecular assembly is directional molecular recognition, which is the strategy by which a molecule bears supramolecular functions (3). Supermolecules accounts for the isotropic and anisotropic non covalent molecular interactions that are weak and reversible in nature such as hydrogen bonds, van der Waals forces, metal coordination or pi-pi interactions. The characteristic properties of supermolecules are not the outcome of additive but of cooperative interactions and thus, are superior and different than the parent molecules (1,4). The concept of supermolecules has been proved a boon to the pharma world which can be sensed by the blooming of supramolecular

Supramolecular Cocrystals of Gliclazide 553 Fig. 1 Chemical structure of (a) GL,(b) SB,and(c) HA. therapeutics. In the recent era, cocrystals, the supramolecular structures, are thriving in pharmaceutical industries because of the lucrative opportunities offered by it. Pharmaceutical cocrystals are the homogeneous solid crystalline complexes of two or more neutral molecular constituents (in which one is API), bound through noncovalent interactions in the crystal lattice in specific stoichiometry (1,5,6). The essence of building the cocrystals relies on the intermolecular interactions among the complementary functionalities of parent components which witness the dominance of supramolecular heteromeric interactions over the homomeric (7). The strategy of cocrystallization is an attractive alternative which not only provide the drug candidate with desired physicochemical properties but also caters the right of intellectual property (IP) protection (8). The present research describes the preparation and evaluation of two new cocrystals of GL (Fig. 1a) withgras coformers, sebacic acid (SB, Fig. 1b) and α-hydroxyacetic acid (HA, Fig. 1c) with the aim to improve biopharmaceutical properties. It is in the continuation of our previous work (9) in which two novel cocrystals of GL with succinic acid and malic acid, with improved dissolution limited bioavailability have been discussed. MATERIALS AND METHODS Materials A gift sample of GL( 99%) was procured from Consern Pharma Pvt Ltd, Ludhiana, India and used as received. All the chemicals were purchased from Sigma-Aldrich, India and solvents from E. Merck Ltd, India. Cocrystal Preparation GL-SB (1:1) and GL-HA (1:1) cocrystals were screened out using solvent assisted mechanochemical route. A 1:1 M mixture of GL (32.34 mg) with SB (20.23 mg) and 1:1 molar mixture of GL (32.34 mg) with HA (7.61 mg) were ground in a mortar and pestle, along with drop-wise addition of Fig. 2 DSC thermograms of GL, coformers and cocrystals.

554 Chadha, Rani and Goyal acetone (10 ml) over 60 minutes of grinding at room temperature. The efforts to re-crystallize the prepared cocrystals from different solvents were also attempted but none of the experiment yields the suitable crystals for single crystal X-ray diffraction analysis. DSC DSC Q 20 (TA-Instruments Inc., USA) with a refrigerated cooling system, which was calibrated with indium (99.99% purity, mp 156.6 C) was used for recording thermograms. The crimped aluminium pans with 2 4 mg of samples were heated at the rate of 10 C/min in the dry nitrogen atmosphere (flow rate of 50 ml/min) in the temperature range of 25 250 C. The peaks were integrated by Universal Analysis 2000 software (TA Instruments Inc.). points, acquisition time 29.1 s, contact time of 2 ms and relaxation delay of 5s for cross polarization. 13 C NMR spectra were referenced to the methylene carbon of glycine (δglycine = 43.3 ppm) and then recalibrated to the TMS scale. Equilibrium Solubility Studies The data of the equilibrium solubility was obtained by shake flask method (10). In this study, an excess amount of the cocrystals was placed in vials containing 10 ml phosphate buffer (ph 7.4; recommended media in USP XXV) and PXRD Powder X-ray diffractometer PANalytical X Pert Pro, operated at 40 kv voltage and 45 ma current was used to collect the data of samples at room temperature in the range of 5 45 (2θ) at the scan rate of 0.00085 /sec and high resolution. The obtained data were interpreted by X PERT high Score software. FTIR FTIR spectra were obtained using spectrum two IR spectrometer (Perkin Elmer, England). The prepared samples (KBr pellet technique) were scanned (4 accumulative scans) in the range of 400 4000 cm -1 with 4 cm -1 resolution. Crystal Structure Determination from PXRD Reflux Plus module of Material studio (BIOVIA 7.0) was used to elucidate the crystal structure of prepared cocrystals from PXRD. The diffraction peaks were indexed from 5 to 45 2θ, to depict the crystal unit cell and lattice parameters using X- CELL and pawley refinement. Geometrically optimized structure (using DMol3) of GL and coformers were incorporated into the empty unit cell, created by pawley refinement and then subjected to Powder solve to optimize the position and conformation of the structures using simulated annealing algorithm. In the end, the structure was refined by Rietveld refinement to obtain the best solution of the structure of cocrystal. SSNMR Solid-state 13 C NMR spectra were obtained from a Jeol-ECX 400 MHz spectrometer, at 100 MHz resonating frequency. The data was collected at 273 K with 1024 complex data Fig. 3 PXRD pattern of (a) GL(9), (b) SB,(c) GL-SB,(d) HA,and(e) GL-HA.

Supramolecular Cocrystals of Gliclazide 555 Fig. 4 FTIR spectra of (a) GL(9), (b) SB,(c) GL SB, (d) HA,and(e) GL HA. Fig. 5 (a) ORTEP diagram of GL-SB and (b) alignment of the planes of GL (red) and SB (light purple) in asymmetric unit.

556 Chadha, Rani and Goyal Fig. 6 Hydrogen bonded interactions in GL-SB. agitated with 200 rpm for 24 hours, at 37 C in water bath shaker (MSW-275 Macroscientific works, Delhi). The resulting slurry was filtered through 0.45 μm membrane filter and the concentration was analyzed at 228 nm by Waters Alliance HPLC system (Photodiode Array Detector). Intrinsic Dissolution Studies Intrinsic dissolution study was performed using rotating disk dissolution test apparatus, (DS 8000, Lab India Analyticals) in phosphate buffer ph 7.4 (recommended media in USP XXV) at 37 C with 100 rpm for 4 hours. A pellet of the sample was attached to dissolution apparatus holder and immersed in dissolution media. The withdrawn buffer (5 ml) was replaced with fresh buffer at different intervals of time and filtered through 0.45 μm membrane filter. The concentration was determined at 228 nm with Waters Alliance HPLC system (Photodiode Array Detector). In Vivo Studies The pharmacokinetic study (11) of GL-SB and GL-HA (dose 40 mg/kg; suspension in normal saline) was performed on the normal rats by administering a single dose and sampling was done for 24 hours, at different intervals of time. The plasma samples were analyzed by HPLC and the pharmacokinetic parameters were calculated by PKSolver: An Add in program (12), which does the calculation based on the linear trapezoidal method. For the pharmacodynamic studies, diabetic male wistar rats (150 200 g; 3 4 week old) were used, in which diabetes was induced by injecting streptozotocin plus nicotinamide solution (45 mg/kg; prepared in citrate buffer (0.1 M; ph 4.4)) intraperitoneally (13,14). GL-SB and GL-HA (dose 40 mg/kg) Fig. 7 crystal packing pattern in GL-SB (a) along the b axis (b) along the a axis (c) along the a-15 axis (green and blue colour represents GL and SB molecules respectively).

Supramolecular Cocrystals of Gliclazide 557 Fig. 8 (a) ORTEP diagram of GL-HA (b) alignment of the planes of GL (red) and HA (light purple) inasymmetricunit. were suspended in citrate buffer (0.1 M; ph 4.4) and administered orally, once in a day, for 7 days. The plasma glucose level, after 7 days was checked by enzymatic GOD POD (glucose oxidase peroxidase) method. The blood was collected from retro-orbital plexus and the data was represented by mean ± SEM. Statistically the data were compared with control groups (diabetic rats in pharmacodynamic study and normal rats in pharmacokinetic study) by One-way ANOVA followed by Dunnett s test and Student s t-test using GraphPad Prism 6.0 software at 95% confidence interval. HPLC Method Waters Alliance HPLC system which includes a waters 2996 Photodiode Array Detector and a 4.6 mm 150 mm 5 μm SunFire TM C 18 column was used for the analyses. 10 μlofallthe samples was injected in the column and analyzed by isocratic mobile phase, acetonitrile: water (50:50) of ph 3 (ph was adjusted with orthophosphoric acid) with flow rate 1.2 ml/min. The procedure for analysis was same as in our previous work (9). RESULTS AND DISCUSSION DSC GL-SB and GL-HA showed a single, sharp and unique endothermic transition at 153.62 C and 148.86 C respectively (Fig. 2), which is different from and amid the melting of GL (171.04 C) (9) and used coformers (SB: 134.67 C, HA: 75.86 C). Besides this, the endotherms are also different from their physical mixtures (supplementary data; Figure S1). This implied the generation of a new crystal phase without the traces of either of the parent components. The thermal behavior shown by both the newly formed solid forms indicated a change in the molecular arrangement in the crystal lattice of GL by the replacement of strong homomeric supramolecular interactions with the heteromeric synthons and thus, the possibility of cocrystal formation. Beside this, both forms with different melting points also evidenced the direct effect of coformers in tailoring the solid state properties, and thus, affecting physicochemical properties. PXRD Fig. 9 Hydrogen bonded interactions in GL-HA. The obtained PXRD patterns of GL-SB and GL-HA was found to be unique in comparison to GL and respective coformers (Fig. 3). In GL-SB, a few new peaks at 8.51,

558 Chadha, Rani and Goyal Fig. 10 arrangement of molecules in GL-HA (a) alongbaxis(b) alongaaxis(green and blue colour represents GL and HA molecules respectively). 9.58, 13.86, 19.43, 22.46, 23.18, 28.18, 28.66 appeared while some characteristic peaks at 10.06, 14.97, 17.92, 18.19, 18.41, 22.08, 26.90 and 27.66 of GL and at 24.18 of SB have disappeared. Besides this, the shifting of a few peaks of GL from 16.81 to 16.59, 17.11 to 16.94, 26.26 to 26.16 were also witnessed by PXRD. Apart from it, few peaks of GL and SB merge to give either a new peak or a broad peak. The peaks of GL at 15.93 merged with 16.24 of SB to give new peak at 16.03 while the peaks of GL at 20.82 and 21.16 merged with 21.60 of SB to give a broad peak at 20.79. Along with it, the peaks at 20.20 and 20.43, 21.90 and 22.09, 25.09 and 25.34 of GL merged to give broader peak at 20.31, 22.04, and 25.74, respectively. The broadening of the peaks was observed mainly after 30 2θ. In GL-HA, new peaks were observed at 14.10, 24.59 and 34.61 while some characteristic peaks of GL at 21.90 and of HA at 13.86, 16.95, 20.17, 21.09, 21.99, 25.23, 25.46, 26.66, 34.09, 36.41 and 36.49 have disappeared. Besides this, the shifting of a few peaks of GL from 16.81 to 16.77, 17.91 to 17.87, 20.82 to 20.78, 21.16 to 21.12, 25.10 to 25.01 and 27.66 to 27.60 were also noticed. All the peaks in PXRD are due to the reflections from specific atomic planes and any changes in these reflections represent the variation in crystal lattice(15). The dissimilarity in the pattern of both newly formed solid forms, from their starting material authenticates the formation of a novel crystal phase. FTIR Spectroscopy The nature of hydrogen bonding affects the vibrational frequency and helps to envisage which functional groups are involved in the formation of supramolecular synthons. In the IR spectrum of GL SB, noteworthy changes were seen in the carbamoyl and the hydroxyl regions of GL and SB, respectively. A major shift was observed in the CO stretch of GL, from 1709 cm -1 to 1714 cm -1 and OH of the carboxylic group of SB from 3314 cm -1 to 3297 cm -1, inferring their involvement in the non covalent interactions in GL-SB. In Table I Crystallographic Parameters for GL-SB and GL-HA Parameters GL-SB GL-HA Chemical formula C 15 H 21 N 3 O 3 S; C 10 H 18 O 4 C 15 H 21 N 3 O 3 S; C 2 H 4 O 3 Stoichiometry 1:1 1:1 Temperature Room temperature as specified 25 C Room temperature as specified 25 C Crystal system Triclinic Triclinic Space group P-1 P-1 a (Å) 12.1604 10.0691 b (Å) 11.8803 9.8283 c (Å) 10.0879 7.2085 α (deg) 104.7632 84.0771 β (deg) 98.9539 99.5801 γ (deg) 105.2249 118.0139 Z 2 2 Vol. (Å3) 1320.57 620.746 2θ range 5 45 5 45 Rwp 10.03% 12.56%

Supramolecular Cocrystals of Gliclazide 559 case of GL HA, carbamoyl region of GL and both the carbamoyl and the hydroxyl regions of HA were found to be concerned with supramolecular interactions. The CO stretch of GL at 1709 cm -1 and of HA at 1730 cm -1 submerged to give a peak at 1716 cm -1, and a shift was also observed in OH (alcohol) of HA from 3294 cm -1 to 3285 cm -1 (Fig. 4). Crystal Structure Determination from PXRD GL SB crystallizes in the triclinic system with the space group P-1, with one molecule of GL and one molecule of SB in an asymmetric unit (Fig. 5a). In the crystal lattice, bothdrugandcoformerarealignedinsuchawaythat they subtend an angle of 18.96 between their planes (Fig. 5b).ThesolidstatestructureofGL-SBbuildsboth supramolecular homosynthons and heterosynthons (Fig. 6). The homosynthon is resulted from the interactionbetweenhydrogenatomof NH (present between SO 2 and CO) and oxygen atom of SO 2 in GL (N1 H1 O1) with distance 1.903 Å. Three one point heterosynthons were formed through the interactions between oxygen atom of SO 2 in GL and hydrogen atom of carboxylic OH in SB (O7 H39 O2), between aromatic nitrogen in GL and hydrogen atom of another carboxylic OH of SB (O4 H22 N3) and between hydrogen atom of NH (present between CO and aromatic N) in GL and oxygen atom of CO of carboxylic group in SB (N2 H2 O6). The corresponding distance of these heterosynthons are 1.682 Å, 2.612 Å and 2.044 Å respectively. On viewing along b axis, stacked GL molecules form a crossed X like shape, having S atom at the centre and SB in the cavity formed by GL (Fig. 7a). The molecules form a layered network along a axis in which asymmetric units are packed in the head to head and tail to tail fashion and two parallel layers are bonded through O H O and O H N interactions(fig. 7b). The same layers can be seen as a sandwich in which two GL molecules, oriented opposite to each other are sandwiched between SB molecules. The clear sandwiched view can be seen along a-15 axis (Fig. 7c). GL HA also crystallizes in the triclinic system with the space group P-1, consisting of two independent molecules of GL and HA which are oriented at an angle of 74.87 in an asymmetric unit (Fig. 8). Hydrogen atom of NH (present between CO and aromatic N) interacts with oxygen atom of SO 2 in another GL molecule and results in construction of homosynthon (N2 H2 O1) with distance 1.649 Å. Besides this, two heterosynthons also resulted through the interaction between the hydrogen atom of NH (present between SO 2 and CO) in GL and Oxygen atom of CO in HA (N1 H1 O5), between nitrogen atom of NH (present between CO and aromatic N) of GL and hydrogen atom of alcoholic OH of HA (O6 H25 N2) with the distance of 1.655 Å and 1.712 Å respectively (Fig. 9). In the cocrystal, folded conformer of GL and HA is present in bilayer form in which HA seems to be inserted between the C shaped GL molecules along b axis (Fig. 10a). On viewing from a axis, these parallel bilayer consist of alternating GL and HA molecules (Fig. 10b). The crystallographic parameters of both the cocrystals are given in Table I. The simulated (Rietveld fit profile) PXRD pattern, experimental PXRD pattern, as well as the difference between the two has been given in the supplementary data (Figure S3). The obtained Rwp values for both the cocrystals Fig. 11 (a) Homosynthons in GL (b) heterosynthon in GL-SB (c) heterosynthon in GL-HA. (a) (b) (c)

560 Chadha, Rani and Goyal Fig. 12 SSNMR spectrum of (a) GL, (b) SB,(c) GL-SB,(d) HA, and (e) GL-HA( denotes the major changes in 13 C NMR chemical shifts). are acceptable and this statement is supported by the various research papers, published in esteemed journals (16,17). The cif files for both cocrystals have been deposited in CCDC (GL- SB - 1505618; GL-HA 1505619).

Supramolecular Cocrystals of Gliclazide 561 Table II 13 C NMR Chemical Shifts (ppm from TMS) in GL, SB and Its Cocrystal GL-SB Group Assignment GL SB GL-SB Δ (δ GL-SB δ GL or SB ) CO 1 155.46 151.23 4.23 C 2 147.43 148.99 1.56 C 5 136.66 138.19 1.53 CH 3,4,7,8 129.82 128.03 1.79 CH 2 9, 15 65.56, 62.40 66.75, 63.51 1.19, 1.11 CH 10, 14 40.95, 40.01 40.52 0.43, 0.51 CH 2 11, 13 33.00, 29.76 33.26 0.26, 3.50 CH 2 12 24.80 23.52 1.28 CH 3 6 22.24 22.66 0.42 COOH 16, 25 181.86 179.73 2.13 CH 2 17, 24 35.13 34.71 0.42 CH 2 20, 21 33.32 33.26 0.06 CH 2 19, 22 31.79 31.38 0.41 CH 2 18, 23 25.55 25.65 0.10 Mechanism of Cocrystallization The mechanism of cocrystallization in GL-SB and GL-HA at macroscopic level was monitored by subjecting the ground mixture to the PXRD at various intervals of time (supplementary data, Figure S4 and S5). The broadening of the peaks was observed in the PXRD, suggesting the existence of the amorphous phase prior to the formation of final product. The insertion of thecoformersinthecrystallatticehasthetendencytodisturbthe already established supramolecular architecture (sulfonamide sulfonamide and amide amide homosynthons) by competing with the pre-existing functional groups in GL. This resulted in the generation of new homo or hetero synthons (Fig. 11). The small amount of solvent was used to speed up the cocrystallization process and its absence in the final product was confirmed by the DSC. In the cocrystallization of GL-SB, the sulfonamide sulfonamide homosynthon of GL remained intact and threenewonepointheterosynthons were formed while in GL-HA, all the pre-existing synthons of GL were disturbed. SSNMR Spectroscopy SSNMR senses the perturbations in the local electronic environment due to the variations in the supramolecular interactions and conformations, which directly affect the chemical shifts. The noticeable differences in the cocrystals were evident in the chemical shift of 13 C SSNMR in comparison to their parent solid components (Fig. 12). The chemical shifts in 13 C SSNMR of GL are representative of homosynthons (N1 H1 O2, N2 H2 O3) (18). Although the same dimer is absent in GL-SB, the atoms N1, H1, N2, H2 and O2 are participating in the formation of new homosynthon or heterosynthon except O3, whichnolongeractsasanacceptorofhydrogenbond.this resulted in upfield shifting of C1, attached directly to O3. Table III 13 C NMR Chemical Shifts (ppm from TMS) in GL, HA and its Cocrystal GL-HA Group Assignment GL HA GL-HA Δ (δ GL-HA δ GL or HA ) CO 1 155.46 152.14 3.32 C 2 147.43 147.34 0.09 C 5 136.66 135.40 1.26 CH 3,4,7,8 129.82 131.53, 129.65, 128.37 1.71, -0.17, -1.45 CH 2 9, 15 65.56, 62.40 65.47, 63.03 0.09, 0.63 CH 10, 14 40.95, 40.01 40.78, 39.84 0.17, 0.17 CH 2 11, 13 33.00, 29.76 32.83, 29.60 0.17, 0.16 CH 2 12 24.80 22.58 2.22 CH 3 6 22.24 20.35 1.89 COOH 16 177.28 180.56 3.28 CH 2 17 60.68 56.15 4.53

562 Chadha, Rani and Goyal Table IV Solubility and IDR of GL and Cocrystals [GL :TheValuesforGL are Taken from Our Previous Research Paper, (9)] Solubility (mg/ml) ± SD IDR (mg/min/cm 2 )±SD GL 2.10 ± 0.2 39.21 ± 0.1 GL-SB 5.12 ± 0.2 51.42 ± 0.1 GL-HA 6.35 ± 0.1 56.26 ± 0.2 higher solubility of GL-HA may be attributed to the fact that the molecules are packed in bilayer pattern in crystal lattice while in GL-SB they are arranged in multi-layers, indicating strong crystal lattice. Besides this, conformer HA has higher solubility and lower melting point as compared to SB, which is also a contributing factor towards the higher solubility and IDR of GL-HA in comparison to GL-SB. In Vivo Studies Besides this, O1 and N3 also act as proton acceptor in the hydrogen bonding in GL-SB, which affected neighboring carbon atoms (C2, C9 and C15), resulting in the variation of chemical shift. Moreover, O5 did not participate in hydrogen bonding in GL-SB, in contrast to crystal structure of SB (19), as a result, the chemical shift deviated to lower value by 2.13 ppm. Similarly in GL-HA, O3 did not form the hydrogen bond, in contrast to GL, which resulted in upfield shifting of C1. In HA (20), carboxylic OH is the potential proton donor but it did not retain the same character in GL-HA, which cause the downfield shifting of adjacent C16. The chemical shift of C17 (attached O6) in GL-HA is affected by two factors, the first being the non availability of O6 as an acceptor of hydrogen bond (in contrast to HA) and formation of O H N heterosynthon by replacing O H O synthon, resulting into its upfielding. The other carbon nuclei in the vicinity of supramolecular interactions also experience the change in local environment and appear slightly at different chemical shifts from parent compounds (Tables II and III). Equilibrium Solubility and Intrinsic Dissolution Studies Our prime objective of preparing the cocrystals was to modulate the solubility of GL, as its absorption is limited by dissolution. Both the cocrystals evidenced 3 fold increment in the equilibrium solubility and approximately 1.5 fold IDR in comparison to GL (Table IV). The solubility and IDR pattern of these cocrystals may be explained on the basis of the packing of molecules in the crystal lattice, frequency and strength of supramolecular interactions, solubility and melting point of the coformers. The Both cocrystals exhibited considerable glucose level reduction in comparison to GL (F 3,18 =403,p < 0.0001; Table V), signifying the enhancement in antidiabetic activity. This enhancement may be attributed to the changes in physicochemical and supramolecular properties which influence the pharmacokinetic parameters (F 3,18 =396,p < 0.0001; Table V) as well. GL-SB and GL-HA showed 1.62 and 1.68 fold increase in C max, respectively as compared to GL, without affecting T max. This indicates the increase in absorption of GL without much affecting rate of absorption. CONCLUSIONS The supramolecular interactions are the key element which influences physicochemical properties and the performance of the crystalline solids. Supramolecular cocrystals of GL with GRAS status coformers, sebacic acid (GL-SB) and α-hydroxyacetic acid (GL-HA), prepared using liquid assisted grinding (LAG) were systematically characterized using various analytical techniques. Almost 3 fold improvement was found in the solubility, accompanied with improved pharmacodynamic and pharmacokinetic parameters. ACKNOWLEDGMENTS AND DISCLOSURES The authors are greatly thankful to the University Grants Commission (UGC), New Delhi (F.4-1/2006(BSR)/5-94/ 2007 dated 03-05-2013) and Council of Scientific & Industrial Research (CSIR), New Delhi (02(0039)/11/EMR- II) for the financial assistance. Table V Pharmacodynamic and Pharmacokinetic Parameters of GL, GL- SB and GL-HA [GL : The Values for GL are Taken from Our Previous Research Paper, (9)] Glucose reduction (%) ± SEM AUC 0-t (μg/ml*min) C max (μg/ml) GL 75.11 ± 0.2 42542.25 55.26 240 GL-SB 91.41 ± 0.2 83712.42 89.68 240 GL-HA 93.23 ± 0.2 86153.67 93.15 240 T max (min) REFERENCES 1. Desiraju GR. The crystal as a supramolecular entity. John Wiley & Sons; 2008. 2. Hong C, Xie Y, Yao Y, Li G, Yuan X, Shen H. A novel strategy for pharmaceutical cocrystal generation without knowledge of stoichiometric ratio: myricetin cocrystals and a ternary phase diagram. Pharm Res. 2015;32(1):47 60. 3. Balzani V, De Cola L, editors. Supramolecular chemistry. Springer Science & Business Media; 2012.

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