Ionic, Neutral, and Hybrid AcidâBase Crystalline Adducts of

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Ionic, Neutral and Hybrid Acid-Base Crystalline Adducts of Lamotrigine with Improved Pharmaceutical Performance Rajesh Thipparaboina, Dinesh Kumar, sudhir mittapalli, Balasubramanian Sridhar, Ashwini Nangia, and Nalini Shastri Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.5b01187 • Publication Date (Web): 02 Nov 2015 Downloaded from http://pubs.acs.org on November 3, 2015

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Crystal Growth & Design

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Ionic, Neutral and Hybrid Acid-Base Crystalline Adducts of Lamotrigine

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with Improved Pharmaceutical Performance

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Rajesh Thipparaboina1, Dinesh Kumar1, Sudhir Mittapalli2, Sridhar Balasubramanian3,

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Ashwini Nangia2, Nalini R Shastri1,*

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1

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

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2

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

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3

X-ray Crystallography Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India

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Graphical Abstract

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Novel solid forms of Lamotrigine (L) with coformers such as cinnamic acid (CA), salicylic

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acid (SAC), ferulic acid (FRA), and vanillin (VN) offer control over drug release, flow

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property and tablet compressibility for improved drug formulation. LVN exhibited improved

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dissolution rate compared to L and can be explored for treatment of neuropathic pain. LCA

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displayed a sustained profile, whereas drug release from LSAC and LFRA were comparable

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to that of L. These novel forms may find applications in fabrication of oral dosage forms for

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epilepsy and bipolar disorder therapy.

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*Corresponding author. Nalini R Shastri

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Tel. +91-040-23423749 Fax. +91-040-23073751

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E-mail: [email protected], [email protected]

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Address: Department of Pharmaceutics, NIPER (National Institute of Pharmaceutical Education & Research), Balanagar, Hyderabad, India, Pin Code – 500037.

1 ACS Paragon Plus Environment


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Ionic, Neutral and Hybrid Acid-Base Crystalline Adducts of Lamotrigine

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with Improved Pharmaceutical Performance

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Rajesh Thipparaboina1, Dinesh Kumar1, Sudhir Mittapalli2, Sridhar Balasubramanian3,

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Ashwini Nangia2, Nalini R Shastri1,*

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1

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

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2

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

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3

X-ray Crystallography Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India

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Abstract

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Lamotrigine (L) is a known drug in the treatment of epilepsy and bipolar disorder. Due to its

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unique structure and functionalities, L is able to form both salts and cocrystals. The present

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study reports ionic, neutral and hybrid crystalline forms of L with improved material

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properties and modified drug release rates. Novel forms of L with cinnamic acid (CA),

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ferulic acid (FRA), salicylic acid (SAC), and vanillin (VN) were successfully prepared and

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characterised using single crystal XRD, SEM, FT–IR, DSC, TGA and powder XRD. LCA

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and LVN crystallized in P21/c space group whereas LSAC crystallized in P-1 space group.

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Pseudo–quadruple hydrogen bond with R42 (16) graph set notation were observed in all three

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crystal structures of L. The characteristic FT–IR stretching peaks at 3326.53 cm-1, 3341.53

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cm-1 and 3340.65 cm-1 corresponding to N+–H bond were observed in LCA, LFRA and

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LSAC. Comparison of dissolution profiles using similarity factor (f2) analysis revealed that

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the dissolution profiles of LCA, LFRA and LVN were significantly different from that of L.

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LVN exhibited improved dissolution rate compared to L and LCA revealed a sustained

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release profile. Both these properties are important in designing oral dosage forms for

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neuropathic pain and bipolar disorder therapy. Further, LCA can be used in the development

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of extended release drug delivery systems for treating epileptic disorders.

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Keywords:

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improvement, compressibility, ferulic acid, vanillin.

Lamotrigine,

multi-component,

dissolution

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enhancement,

solubility

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1. Introduction

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The quest for novel solid forms such as polymorphs, salts, co-amorphous systems/co-crystals

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etc. is an important research goal in the pharmaceutical industry. A major focus is on

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improving the solubility and bioavailability of poorly soluble drugs1, 2. Salt formation is an

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effective strategy for ionisable drugs to modulate solubility and bioavailability. In addition it

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also impacts purity, stability and manufacturability of the dosage form3-5. Cocrystals are

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solids that are crystalline single phase materials composed of two or more different molecular

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and/or ionic compounds generally in a stoichiometric ratio6, 7. They represent an alternative

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way to tailor physicochemical properties of non-ionisable and weakly ionisable drugs7-10.

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Numerous studies report significant improvement in physicochemical properties especially

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solubility, solid-state stability11-13, and bioavailability enhancement11,

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when compared to the active pharmaceutical ingredient (API).

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Lamotrigine (L) is a BCS class II drug, principally developed for the treatment of epilepsy

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and bipolar disorder15,

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cluster headaches, migraine and neuropathic pain17-19. Current reports indicate raising

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potential of L in the treatment of Dravet syndrome20, Meniere’s disease21 and Migrane-

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Associated Vertigo22 etc. It is chemically 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine,

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and is a weak base with a pKa of 5.7. Crystal structure of L was reported by Sridhar et al and

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is the 5,00,000th structure deposited to Cambridge Structural Database (CSD)23. Typical

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molecular frame work seen in the structure of L not only makes it a hydrogen bond donor but

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also an acceptor and is likely to be a good target for the formation of both salts and co-

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crystals. Sridhar et al in their recent paper reported that of all the structures of L submitted to

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CSD, 73% were salts, 17% were solvates and hydrates and only 10% were co-crystals24.

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Crystal engineering strategies employed for improving pharmaceutical and biopharmaceutical

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performance of L include various cocrystals of L with methylparaben form I and form II,

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nicotinamide and its monohydrate25, acetamide26, phthalimide, pyromellitic diimide:DMF,

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caffeine:3-pentanone, isophthaldehyde27 and sorbic acid28. Salts and cocrystals of L reported

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till date are provided in Table S1 (Supporting information).

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L displays very poor solubility in water, attributed to its tendency to form extensive

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hydrogen-bonding networks in the solid state. L also exhibits very poor flow properties. The

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present study was hence designed to develop novel solid forms of L using various coformers

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e.g. caffeic acid, cinnamic acid, ferulic acid, gallic acid, quercetin, salicylic acid, vanillic acid

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and vanillin to address flow, compressibility and dissolution problems associated with the

14

with co-crystals

16

. Studies also report its applications in the treatment of specific



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drug and for possible applications in the treatment of neuropathic pain and bipolar disorder.

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This study reports novel forms of L with improved material properties along with reduced

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drug release rates for the first time. Reproducible and scalable crystalline solid forms were

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obtained with cinnamic acid (CA), ferulic acid (FRA), salicylic acid (SAC) and vanillin

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(VN). CA is known for its antioxidant and antimicrobial properties. FRA is an antioxidant

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and is known to increase pain threshold exerting antidepressant effects29-32. Its antidepressant

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effects were demonstrated in animal models through monoamine oxidase inhibition in frontal

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cortex and hippocampus33. SAC is well known for its anti-inflammatory and anti-microbial

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properties. VN has shown alleviating effects on mechanical allodynia in animal models.

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Recent reports show potential utility of VN in the treatment of depression34, 35, epilepsy36 and

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neuropathic pain37, 38. Structures of L and the coformers are represented in Figure 1.

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103 104

Figure 1 Chemical structures of a) L b) CA c) FRA d) SAC and e) VN

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2. Experimental section

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2.1 Materials

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The anhydrous crystalline form of L used in this study was kindly gifted by Aurobindo

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Laboratories, Hyderabad, India. FRA and SAC were purchased from Alfa Aesar, India. CA


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and VN were purchased from Sigma-Aldrich, India. In-house, ultra-pure water from

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Millipore® was used for all the experiments. All other solvents used were of analytical grade.

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2.2 Solid form screening

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2.2.1 Liquid assisted grinding (LAG): Preliminary screening for novel forms was carried

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out by grinding unit components in 1:1 ratio for 30 min in an agate mortar in the presence of

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500 µL of ethanol. LCA, LFRA, LSAC-ACN and LVN were successfully synthesized by

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LAG.

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2.2.2 Recrystallization experiments

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2.2.2.1 LCA: L (256 mg, 1 mmol) and CA (148 mg, 1 mmol) in a 1:1 molar ratio were added

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to 15 mL of acetonitrile (ACN) in a beaker at 75 °C. The beaker was covered with pin holed

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aluminium foil and left at room temperature for slow evaporation. Single crystals obtained

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after few hours were filtered, air-dried and stored in a glass vial until further analysis.

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2.2.2.2 LFRA: L (256 mg, 1 mmol) and FRA (194 mg, 1 mmol) in a 1:1 molar ratio were

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added to 50 mL of ACN in a beaker at 75 °C. The solution was filtered in to a beaker and

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was covered using aluminium foil with pinhole and left at room temperature for slow

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evaporation. Single crystals suitable for structural analysis were not obtained.

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2.2.2.3 LSAC-ACN: L (256 mg, 1 mmol) and SAC 138 mg, 1 mmol) were added to 50 mL

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of ACN in a beaker at 75 °C. Solution was filtered and to this 10 ml hexane was added as

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anti-solvent. The beaker was covered with aluminium foil and left at room temperature.

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Single crystals obtained after few hours were filtered, air-dried and stored in a glass vials

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until further analysis.

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2.2.2.4 LVN: L (256 mg, 1 mmol) and VN (761 mg, 5 mmol) were added to 15 mL of ACN

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in a beaker at 75 °C. The beaker was covered with aluminium foil with pinhole and left at

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room temperature for slow evaporation. Single crystals obtained after 1 day were isolated,

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washed with acetone, air-dried and stored in a glass vials until further analysis.

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2.3 Characterization of novel solid forms

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2.3.1 Single crystal XRD

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The intensity data of LCA and LVN were collected at room temperature using a Bruker

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Smart Apex CCD diffractometer with graphite monochromated Mo-Kα radiation (λ =

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0.71073 Å) by the ω-scan method. Cu–Kα radiation (λ = 1.54184 Å) on the Oxford Agilent

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diffractometer was used to collect reflections on a single crystal of LSAC–ACN. Preliminary

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lattice parameters and orientation matrices were obtained from four sets of frames.

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Integration and scaling of intensity data were accomplished using the program SAINT. The



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structures were solved by direct methods using SHELXS97 and the refinement was carried

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out by full-matrix least-squares technique using SHELXL9739. Anisotropic displacement

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parameters were calculated for all non-hydrogen atoms. The atoms C11 and C12 of CA of

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LCA were disordered and the site-occupancy factors of the disordered atoms

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C11/C12/C11’/C12’ were refined to 0.817(7) and 0.183(7). The geometries about the

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disordered atoms were restrained with C10–C11 = C10–C11' = C12–C13 = C12'–C13 =

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1.52(2) Å and C11–C12 = C11'–C12' = 1.33 (2) Å. The H atom bound to the N atom of the

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triazine ring of the L molecule of LCA during the initial refinement shows high Uiso(H) value.

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Contoured difference Fourier maps show significant electron density at the location of the

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potential H-atom site and the electron density is smeared along the N···O axis in LCA.

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Hence, the H atoms were treated as disorder over two sites (H1N and H1O and refined with

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their site-occupancy factors refined to 0.34 (4) and 0.66 (4). The disordered H atoms were

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located in difference Fourier and refined as riding, with Uiso(H) = 1.2Ueq(N)/1.5Ueq(O), using

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constrained distance of 0.86 and 0.82 Å for N–H and O–H, respectively. All other N–bound

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H atoms of the L molecule in LCA and LVN and the O-bound H atom of the VN of LVN

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were located in difference Fourier maps, and their positions and isotropic displacement

158

parameters were refined. C–bound H atoms were located in a difference density map but

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were positioned geometrically and included as riding atoms, with C−H distance = 0.93 - 0.96

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Å and with Uiso(H) values of 1.2 Ueq(C). In the case of LSAC-ACN structure, the distance

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between C17 and N6 and C18 and C17 was fixed by using D FIX command and C18–N6

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distance was fixed by using the DANG command. Due the higher libration of acetonitrile C

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and N atoms, the C18–C17–N6 angle is 169.03°, about 10° deviation from linearity. X-ray

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crystal structure cif files are deposited at the CCDC Nos. 1418669-1418671.

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2.3.2 Scanning electron microscopy (SEM)

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Morphological analysis was carried out using SEM (Hitachi S-300 N) operated at an

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excitation voltage of 15 kV. Crystals were mounted over a double sided adhesive carbon tape.

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They in turn were mounted over aluminium pin stubs and photographed. Samples that were

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not adhered to carbon tape were blown out gently. Samples were sputter coated with gold

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using ion sputter before analysis.

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2.3.3 Fourier Transform Infra Red (FTIR) spectroscopy

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About 2 mg of each sample was blended with 100 mg potassium bromide IR powder and

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compressed under vacuum at a pressure of 12 ρsi for 3 min. The resultant disc was mounted


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in a suitable holder in a Perkin Elmer IR spectrophotometer and the FTIR spectrum was

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recorded from 4000 cm-1 to 400 cm-1 in a scan time of 12 min.

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2.3.4 Differential Scanning Calorimetry (DSC)

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Thermal analysis was carried out using Mettler Toledo DSC system operating with Stare

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software to determine the melting point and enthalpy. Indium was used for calibration.

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Accurately weighed samples (5–15 mg) in 40 µL aluminium crimped pans with pinhole were

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scanned at a heating rate of 10 ºC/min over a temperature range of 30-300 ºC. The

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measurements were conducted in nitrogen gas environment with a purging rate of 60

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mL/min.

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2.3.5 Thermogravimetric Analysis (TGA)

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TGA was carried out using ExStar TGA/DTA 7200 operating with Muse software to detect

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solvates and thermal degradation. Accurately weighed (5-15 mg) samples were loaded in

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alumina crucibles and heated at a rate of 20 ºC/min over a temperature range of 30 to 300 ºC

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under a nitrogen purge of 60 mL/min.

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2.3.6 Powder X-ray diffraction (P-XRD)

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P-XRD patterns of samples were recorded at room temperature using PANalytical X’Pert

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PRO X-ray Powder Diffractometer (Eindhoven, Netherlands), using Ni-filtered Cu-Kα

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radiation (λ = 1.5406 Ǻ). The data were recorded over a scanning 2θ range of 2° to 50° at step

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time of 0.045 steps/0.5 sec.

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2.3.7 Flow and compression properties

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Flowability of the samples was measured in terms of angle of repose using fixed funnel

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method (n=6). Angle of repose is an attribute related to interparticulate friction or resistance

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to movement between particles. An angle of repose between 25-30, indicates excellent flow

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property and greater than 45 indicates poor flow property (Inference of flow property based

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on angle of repose is provided in supporting information Table TS2)40. Aulton and Wells

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method was used to study the compression properties of the novel solid forms41. A 500 mg of

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the sample was blended with 5 mg of magnesium stearate in a glass vial and processed as per

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the compression protocol (Table 1). After equilibration for 24 h, hardness testing was carried

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out using LabIndia Hardness tester (n = 3). For a plastic material the compact strength is C
3 may result in formation of salt, while ∆pKa < 0 will often give a 8 ACS Paragon Plus Environment

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cocrystal. On the other hand ∆pKa in the range of 0 to 3 may result in complexes containing

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proton sharing or intermediate ionization states that may be assigned as salt-cocrystal

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hybrids26, 44-47. Childs et al. in their work on theophylline-acid complexes reported 0 < ∆pKa

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< 2.5 region as a salt-cocrystal continuum zone48. Few intermediate structures on L-acid

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complexes containing both neutral and ionic interactions falling between ∆pKa of 0.9 and 1.8

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were reported recently24. Preliminary screening studies using solvent assisted grinding was

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conducted for L with various coformers like caffeic acid, CA, FRA, gallic acid, quercetin,

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SAC and VN (ST 4 Supporting information). Novel solid forms of L with CA, FRA, SAC,

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and VN were obtained during liquid assisted grinding wherein LCA, LSAC-ACN and LVN

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systems gave single crystals. Based on the ∆pKa values given in table 2, it was presumed that

244

VN with ∆pKa < 0 may result in cocrystal; SAC with ∆pKa near to 2.73 in salt; CA and FRA

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with ∆pKa 1.2 and 1.12 respectively would result in hybrids falling in salt-cocrystal

246

continuum with intermediate ionization states. These results were in line with the

247

observations of Aurora et al49 regarding linear relationship between ∆pKa and probability of

248

proton transfer between acid-base pairs.

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Table 2 ∆pKa Values, melting points and morphology details of L and novel solid forms Code

L LCA LFRA LSAC-ACN LVN

pKa of drug/ coformer 5.7 4.5 4.58 2.97 7.78

∆pKa (pKa base – pKa acid)

Melting point (°C)

Morphology of crystals

1.2 1.12 2.73 - 2.08

216.62 174.79 191.11 239.32 158.09

Hexagonal Block Rods Rhomboidal Isodiametric

250 251

3.1 Single Crystal Structure Analysis

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The crystal structures of LCA, LSAC-ACN and LVN are mainly driven by N-H···O and O-

253

H···O hydrogen bonds. Both homosynthons and heterosynthons are observed in the three

254

crystal structures. The overlay diagram (Figure 2) shows different orientation of triazine ring

255

with respect to the dichlorophenyl ring in the crystal systems. Crystallographic parameters

256

and hydrogen bond geometries are provided in table 3 and 4 respectively.



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257 258

Figure 2 Overlay Diagram. L guest free (Green), LSAC–ACN salt-solvate (Blue), LCA salt–

259

cocrystal (Purple), LVN cocrystal (Red). Table 3 Crystallographic Parameters

260

Content

LCA salt cocrystal

Empirical Formula

C9H7.34Cl2N5, C9H7.66O2 404.25 Monoclinic P21/c 298 17.5729(18) 7.8008(8) 14.8637(15) 90 113.662(2) 90 1866.3(3) 1.439 0.372 2.53 to 26.76 4 -21 to 21 -9 to 9 -18 to 18 19139 3766 0.0447 0.1266 1.048 Bruker Smart Apex

Formula weight Crystal system Space group T (K) a (Å) b (Å) c (Å) α (deg) β(deg) γ (deg) V (Å3) Dcalcd (gcm–3) µ (mm–1) θ range Z Range h Range k Range l Reflections collected Observed reflections R1 [I > 2 σ (I) ] wR2 (all) Goodness-of-fit X-Ray Diffractometer

LSAC–ACN salt solvate C9H8Cl2N5, C7H5O3, C 2 H3 N 435.27 Triclinic P-1 298 8.8408(5) 10.9916(6) 12.1332(5) 111.359(4) 111.196(5) 93.988(5) 995.89(9) 1.452 0.322 4.44 to 66.59 2 -10 to 10 -11 to 13 -13 to 14 6293 3246 0.0689 0.2021 1.078 Oxford Agilent


LVN Cocrystal C9H7Cl2N5, C8H8O3 408.24 Monoclinic P21/c 298 10.7918(9) 13.6805(12) 13.8215(12) 90 110.504 90 1911.3(3) 1.419 0.368 2.015 to 26.248 4 -13 to 13 -17 to 17 -17 to 17 19847 3859 0.0428 0.1238 1.040 Bruker Smart Apex

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Table 4 Hydrogen bond geometry in crystal structures (neutron-normalized) Cocrystal/ Intermediate/ Salt

LCA Salt cocrystal

LSAC-ACN Salt solvate

LVN Cocrystal

Interaction

D– H/Å

H···A/Å

D···A/Å

∠D– H···A/Å

Symmetry code

N(2)–H(1N) ···O(2) N(4)–H(2N) ···O(1) N(4)–H(3N) ···O(1) N(5)–H(4N) ···N(3) N(5)–H(5N) ···O(1) O(2)–H(2O) ···N(2) N(2)-H(1N) ···O(2) N(4)–H(2N) ···O(1) N(4)–H(3N) ···N(6) N(5)–H(4N) ···N(3) N(5)–H(5N) ···N(6) O(3)–H(13A) ···O(1) C(18)–H(18B) ···N(6) N(5)–H(3N) ···N(3) N(5)–H(4N) ···O(1) N(5)–H(4N) ···O(2) N(4)–H(1N) ···O(1) N(4)–H(2N) ···O(5) O(1)–H(5O) ···N(1) C(11)–H(11) ···N(2)

0.86

1.82

2.593(2)

148

x, y, z

0.86

2.00

2.853(2)

169

x, y, z

0.79

2.28

3.057(3)

168

0.86

2.13

2.987(2)

176

0.80

2.17

2.831(2)

140

-x+1,y+1/2,z+5/2 -x+1,-y+1,z+2 x,-y+1/2,z-1/2

0.82

1.78

2.595(2)

170

x, y, z

0.83

1.77

2.593(4)

174

-1+x,y,-1+z

0.86

1.96

2.817(4)

171

-1+x,y,-1+z

0.86

2.52

3.370(16)

172

x,1+y,-1+z

0.86

2.15

3.001(4)

173

1-x,2-y,-z

0.86

2.19

2.935(10)

145

1-x,1-y,1-z

0.82

1.82

2.531(4)

147

Intramolecular

0.96

2.37

3.193(16)

143

1-x,-y,1-z

0.86

2.06

2.921(2)

178

-x+1,-y+1,-z

0.86

2.63

3.285(2)

133

0.86

2.35

3.031(2)

136

0.88

2.28

3.086(2)

152

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

0.83

2.12

2.930(2)

167

-x+2,-y,-z

0.79

1.95

2.728(19)

168

-x+2,-y,-z

0.93

2.41

3.230(2)

148

-x+2,-y,-z

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3.1.1 LCA salt-cocrystal hybrid

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The crystal structure of LCA was crystallized in monoclinic P21/c space group. One molecule

267

each of L and CA are present in the asymmetric unit (Figure 3a) The C-O bond distances

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(1.236(3) and 1.277(3) Å) and O–C–C angles (116.4(2) and 120.1(3) °) of the carboxylic

269

acid shows an intermediate state and partial transfer of its proton to the N2 atom of L.

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Similar intermediate state of L with partial proton transfer is observed in L complexed with

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4-iodo benzoic acid, 4-methyl benzoic acid and 4-bromobenzoic acid 24, 50.

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Both L–L homo and L–CA hetero synthons hydrogen bonding motifs were observed. L

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homodimers were connected to CA through N–H···O (2.26 Å, ∠169°; 2.18 Å, ∠139°) H

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bond interactions on both the sides forming pseudo-quadruple hydrogen bonded ring of

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R42(16) motif (Figure 3b) and the angle between two phenyl rings is 86.90°. The overlay of

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calculated and experimental diffraction patterns indicating bulk purity of crystallized sample

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are represented in Figure S1 (Supporting information).

278 279 280

Figure 3 a) Showing asymmetric unit with each one of L and CA b) L–L Homosynthon, L– Acid hetero synthon and pseudo–quadruple hydrogen bonded ring of R42(16) motif.

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3.1.2 LSAC salt-solvate

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The crystal structure was solved and refined under triclinic system with space group P-1. The

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asymmetric unit contains each one of L–H+, SAC- and ACN (Figure 4a). The proton of SAC

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was transferred to more basic nitrogen atom (N2) through N(2)–H(1N) ···O(2) (1.77 Å,

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∠174°) ionic bond, leading to formation of a salt. The carboxylate C–O- bond distances in

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SAC-

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were observed in the salt solvate structure such as L homosynthon R22(8) motif, L–SAC

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heterosynthon R22(8) motif, and L–ACN solvent heterosynthons51,

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homodimers were connected to ACN solvent through N–H···N H–bond interactions forming

(1.258 and 1.249 Ǻ) suggest that LSAC is a salt. Three different types of synthons


52

(Figure 4b). The L

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a pseudo–quadruple hydrogen bond with R42(16) motif (Figure 4c). Pseudo–quadruple motifs

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and ACN moieties were arranged in an alternate fashion, and SAC- molecules were

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connected to both the sides of L homodimers (Figure 4d) and the dihedral angle between the

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two rings of L was 75.79°. Simulated and experimental diffraction patterns indicating bulk

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purity are represented in Figure S2 (Supporting information).

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Figure 4 a) Asymmetric unit with each one of L, SAC and ACN. b) Showing L Homo and L–Acid Hetero synthons c) Pseudo–quadruple hydrogen bonding motif. d) Packing diagram of LSAC–ACN salt solvate.

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3.1.3 LVN cocrystal

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The crystal structure of LVN was crystallized in monoclinic P21/c space group. Asymmetric

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unit contains each one of the L and VN (Figure 5a). The bond angle of C8–N1–N2 of L is

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116.5(3) °, that matches well with neutral L bond angle (117.0(1) °). As the coformer VN

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has no ionisable group, the LVN forms a cocrystal.

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Four different types of hydrogen bonding interactions were observed in the cocrystal

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structure, such as L homodimers and O–H···N and two N–H···O (N–H...O=C and N–H···O–

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CH3) interactions as shown in Figure 5b. The crystal structure of LVN consists of most

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favoured L–L homosynthon (N–H···N; 2.06 Å, ∠178°) of R22(8) motif and these dimers were 13 ACS Paragon Plus Environment


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further connected to VN through N–H···O (2.28 Å, ∠151.7°; 2.63 Å, ∠133°) H bond

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interactions forming a pseudo-quadruple hydrogen bonded ring of R42(16) motif (Figure 5c).

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The structure was supported by C–H···N (2.41 Å, ∠147.6°) hydrogen bond interactions. A

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tetrameric ring motif was formed by O–H···N (1.95 Å, ∠168°) and N–H···O (2.12 Å, ∠167°;

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and 2.35 Å, ∠136°) hydrogen bonding interactions and extended by N–H···N interactions

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(Figure 5d). The tetrameric units and L homo dimers were arranged in an alternative fashion

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and the angle between the two phenyl rings in L is 61.78°. Simulated and experimental

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diffraction patterns indicating bulk purity are represented in Figure S3 (Supporting

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information).

317

318 319 320 321

Figure 5 a) The asymmetric unit with each one of L and VN, b) hydrogen bonding interactions observed in cocrystal structure, c) Pseudo–quadruple hydrogen bonded ring of R42(16) motif, d) Tetrameric ring motifs were formed by O–H···N and N–H···O interactions.

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3.2 Fourier Transform Infra Red (FTIR) spectroscopy

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IR spectral frequencies for L are primarily seen at 3451.83 cm-1, 3317.61 cm-1 and 1557.45

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cm-1 corresponding to primary amine N–H stretching and bending respectively. Characteristic

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broad bands are seen corresponding to N+–H ionic interactions. Due to these interactions N–

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H stretching and bending modes were affected as 3326.53 cm-1, 3134.26 cm-1 and 1560.59


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cm-1; 3341.53 cm-1, 3151.68 cm-1 and 1589 cm-1; and 3340.65 cm-1, 3066.19 cm-1 and

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1590.24 cm-1 in LCA, LFRA and LSAC-ACN respectively. C=O stretching in CA, FRA and

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SAC appearing at 1684.41 cm-1,1669.5 cm-1, 1661.8 cm-1 were shifted to 1637.27 cm-1 ,

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1654.06 cm-1 and 1654.48 cm-1 in LCA, LFRA and LSAC-ACN respectively possibly

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indicating deprotonation of carboxylic acids. Broad peaks at 3442.21 cm-1 in LVN and

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3424.14 cm-1 in LSAC acetonitrile solvate are indicative of intermolecular N-H hydrogen

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bonding. FTIR spectra are given in Figure S4 (Supporting information). Results from IR

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studies indicated possible ionic and hydrogen bonding interactions in the novel forms LCA,

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LFRA, LSAC-ACN and LVN which were further characterized.

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3.3 DSC analysis

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Thermal analysis of L, LCA, LFRA, LSAC-ACN and LVN using DSC gave single melting

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endotherms at 216.62, 174.79, 191.11, 239.32 and 158.09 °C respectively (Figure 6). The

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melting points of coformers CA, VN, SAC and FRA were found to be 133.73, 82.65, 172.87

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and 159.30 °C respectively. The onset of melting and ∆H values for all novel forms along

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with coformers, and respective thermograms along with controls are given in Table S5

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(Supporting Information). LSAC-ACN has shown small endotherm at 136.37 °C indicating

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the possibility of solvate form which was further characterized by TGA. Changes in melting

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points and enthalpy values indicated the formation of novel solid forms which were

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additionally defined by P-XRD studies.

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Figure 6 Overlays of DSC thermograms of L, LCA, LVN, LSAC–ACN and LFRA.

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3.4 TGA

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Thermal analysis of L did not show any weight loss till 200 °C. LSAC-ACN as depicted in

350

Figure S5 (Supporting information) has shown weight loss of 9.07 % (1.23 mg) in the region

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of 110 to 150 ºC confirming the presence of solvate. Weight loss confirms the presence of

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solvate in 1:1:1 along with L and SAC as evident from single crystal analysis. All other forms

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did not show any weight loss before melting confirming the absence of psuedomorphs.

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Representative TGA thermograms along with controls are provided as Figure S6 (Supporting

355

information).

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3.5 Powder XRD

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PXRD patterns of LCA, LFRA, LSAC-ACN and LVN revealed characteristic peaks different

358

from that of L as shown in Figure 7. L has shown characteristic peaks at 2θ values 13.8 and

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14.12 whereas new characteristic peaks appeared at 5.5, 13.2 and 16.0; 5.2, 10.3 and 15.5;

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8.6, 9.5 and 11.1; and 19.8 and 24.7 for LCA, LFRA, LSAC-ACN and LVN respectively.

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Comparative PXRD patterns of novel forms along with the controls are represented in Figure

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S7, S8, S9, S10, S11 (Supporting information). Inference from DSC, FTIR, P-XRD and

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single crystal XRD confirmed the occurrence of new solid forms.

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Figure 7 Overlays of Diffractograms of L, LCA, LVN, LSAC-ACN and LFRA.

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3.6 SEM, Flow and compression properties

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SEM analysis revealed changes in crystal habit in all novel solid forms when compared to

370

plain drug (Table 1, Figure 8).

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Crystallization using other solvents resulted in needles and rods. LCA and LFRA gave block

372

and rod morphologies respectively. LSAC-ACN was found to be rhomboidal. Of all the

373

forms, LVN crystals were found to be isodiametric which are ideal for pharmaceutical

374

manufacturing processes.

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All novel forms except LFRA showed improved flow properties when compared to L. Angle

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of repose values of all selected solid forms along with controls are given in Table S6

377

(Supporting Information). L with an angle of repose of 45° showed passable flow whereas

378

LCA (30°), LVN and LSAC-ACN (35°) showed excellent and good flow properties

379

respectively. Flow of LFRA (42°) was comparable to that of L. Improved flow properties of

380

LCA, LVN and LSAC-ACN can be attributed to their modified morphologies as evident from

381

their SEM images in Figure 8.

382

Compressibility studies were performed using three different blends A (Blending time (BT) 5

383

min and dwell time (DT) 2 sec), B (BT 5 min and DT 30 sec) and C (BT 30 min and DT 2

384

sec) to understand their impact on material behaviour. Results obtained from the

385

compressibility studies revealed that L, LSAC-ACN and LFRA exhibited capping tendency.

386

However, capping exhibited by LSAC-ACN was weak when compared to L and LFRA

387

(Figure 9). Capping tendency in the blends despite change in lubrication time and dwell time

388

is an indicative of the elastic nature of the material (Figure 9). These materials showed a

389

tendency to rebound upon release of compression forces, leading to self destruction of

390

compact causing capping and lamination. For a plastic material the order compact strength is

391

C < A < B, while for fragmenting materials, A = B = C. The hardness of the LCA blend at

392

maximum dwell time (LCAB compact) was highest, indicating plastic nature of the material.

393

Such materials bond after viscoelastic deformation and resist change. This phenomenon is

394

time dependant and bonding strength increases with increase in dwell time. LVN also gave

395

intact compacts on altering lubrication and dwell time. All three compacts (LVNA, LVNB,

396

and LVNC) were of nearly same hardness, suggesting brittle nature of this material. Both

397

LCA and LVN with plastic and fragmenting tendencies respectively are suitable for

398

pharmaceutical manufacturing41.

L crystallized from ACN gave hexagonal crystals.



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Figure 8 SEM images of L, LCA, LVN, LSAC-ACN and LFRA.

401


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Figure 9 Pictorial compilation of tablets formed from compressibility studies. Subscripts A, B and C indicate different blends used as described in Table 1. Orange arrows indicate weak capping tendency in intact tablets in respective zones in LSAC-ACNA and LSAC-ACNC.

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3.7 In-vitro dissolution studies

407

All selected solid forms except LCA showed better dissolution rate in 0.1N HCl when

408

compared to L (Figure 10). The similarity factor f2 was employed to compare the dissolution

409

profiles53. When the two profiles are identical, f2=100. An f2 value of 50 or greater (50–100)

410

ensures that the two profiles are similar, while f2

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