Regulation of ÏÂ·Â·Â·Ï Stacking Interactions in Small Molecule Cocrystals

Subscriber access provided by READING UNIV

Article

Regulation of #•••# Stacking Interactions in Small Molecule Cocrystals and/or Salts for Physiochemical Property Modulation Bipul Sarma, Pranita Bora, and Basanta Saikia Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01377 • Publication Date (Web): 29 Jan 2018 Downloaded from http://pubs.acs.org on January 30, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Crystal Growth & Design is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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

Crystal Growth & Design

Regulation of ππ Stacking Interactions in Small Molecule Cocrystals and/or Salts for Physiochemical Property Modulation

Pranita Bora, Basanta Saikia, and Bipul Sarma* Department of Chemical Sciences, Tezpur University, Napam-784028, Assam, India *E-mail: [email protected] or [email protected]

Abstract The non-covalent interactions arise from solute···solute (i.e. drug···drug, drug···neutraceutical, or drug···coformer) and solute···solvent play significant role in predicting desired properties of an active compound. We demonstrated here the role of π···π interactions in presence of hydrogen bonding, the two important cohesive and adhesive forces in the crystallization of small molecules to regulate certain physiochemical properties in their multicomponent crystals. Acridine was employed as a representative cocrystal partner with isomeric dihydroxybenzoic acids. The choice was intentional as with single hydrogen bond acceptor, acridine provides increased surface area to favor the stacking of π-frameworks at van der Waals separation (∼3.5 Å) and herringbone C−H···π interactions and isomeric dihydroxybenzoic acids easily form COOH···Nacridine and O−H···Nacridine hydrogen bonds in competition. Structure elucidation of several cocrystals/salts underlines the influence of continuous and discrete π···π stacking and C−H···π interactions supported by other hydrogen bonds on their physiochemical properties such as solubility, cell membrane permeation and release behavior in-vitro. Experiments were performed in various pH range (pH = 1.2 SAL and 7.4 PBS) in order to imitate human physiological conditions. Molecular packing and interaction energies suggest a significant contribution of π···π interactions in the modulation of property. In-fact coformers conformational energy, lipophilicity and Log P values were found fringy contributors. Therefore the present study with its first kind anticipates its contribution towards the understanding of the impact of π···π, C−H···π interactions supported by hydrogen bonds on modulating physiochemical properties essentially improving efficacy of a drug.

Keywords Crystal engineering, hydrogen bonding, π-interactions, membrane permeation, pH, solubility 1 ACS Paragon Plus Environment

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

Introduction Aryl-aryl interactions between aromatic moieties have been used to manipulate the organization of molecules in the crystal lattice. Aromatic rings can interact via edge-to-face geometry or herringbone T-motif, and face-to-face or π-stacked sandwich geometry.1 The π-rings generally orient themselves in herringbone T-motif instead of π-stacking due to stabilization from edge-toface C−H···π interaction.2 Among the π-stacked geometries parallel-displaced geometry with lateral offset is energetically favored, because the aromatic ring exhibited a positively charged σframework sandwiched orientation between two regions of negatively charged π-electron density.3 Perfect sandwiched is generally a disfavored orientation due to the dominance of π–π repulsion. The hydrogen bonding in molecular solids, π–π and C−H···π interactions etc. are found crucial in protein folding and stability,4 DNA base stacking and its function, many asymmetric synthesis5 and in modulating properties of crystalline solids majorly controlled by aromatic interactions.6 For example the complex of the enzyme acetylcholinesterase (AChE) with the drug E2020 (Aricept) to treat Alzheimer’s disease is stabilized by π–π stacking, O– H···π and cation···π interactions.7 Therefore the π···π stacking and hydrogen bonding are two important adhesive and cohesive forces in the crystallization of molecules irrespective of whether a protein or a small molecule. Representative articles by Desiraju and Gavezzotti,1a Hunter and Sanders,1b Janiak,1c Nishio2b and Iverson8 have intricately studied the chemical and electronic factors that promote recognition between π- or phenyl rings and their adopted motifs (Figure 1). In view of, acridine (Acr) has been considered as a cocrystal partner because of its ability to participate in hydrogen bonding (O−H···N)9 with donor molecules such as isomers of dihydroxybenzoic acids (DHBA, Scheme 1). The cocrystallization of Acr and isomeric DHBAs could also provide more than one crystalline modifications because of the competition between COOHDHBA···NAcr and OHDHBA···NAcr hydrogen bonding.10 The formation of the strongest COOHDHBA···NAcr heterosynthon is expected and observed in the product cocrystals/salts with stacking of N-heterocycles. Six cocrystals/salts were isolated and subjected for physiological property evaluation (Scheme 1) and probed the link with π···π stacking behavior as well as C−H···π weak interactions supported by O−H···N and O−H···O hydrogen bondings.

2 ACS Paragon Plus Environment

Page 2 of 28

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


Face to face

T-shaped

Figure 1 The types of face to face π-stacking (N-facing same and N-facing opposite) between acridines (top) and edge to face T-shaped C−H···π interactions (bottom) observed in cocrystals/salts synthesized. The emphasis on anti-parallel or quasi-parallel fashion due to face-to-face π···π stacking interactions has been drawn in several examples of multicomponent and host-guest complexes.11 The π···π stacking in the close proximity is a prerequisite for photochemical reaction.12 The use of N-heterocycles13 such as acridine, phenazine in cocrystallization experiments is generally beneficial because they can interact with cocrystal formers via stacking, hydrogen bonding and other interactions such as halogen bonding if halogen is present.14 A number of therapeutic agents are known based on acridine nucleus such as quinacrine (antimalarial), acriflavine and proflavine (antiseptics), ethacridine (abortifacient), amsacrine and nitracine (anticancer), and tacrine.15 Exploiting intermolecular O–H···N hydrogen bonds and π···π stacking in supramolecular architecture,16 formation of charge-transfer complexes,17 ferroelectric organic solids,18 photochromic applications19 by phenazine, acridine molecules have been studied. Lately few studies appeared in the direction of understanding the role of weak interactions such as hydrogen bond, π-stacking, vander Waal’s forces in modulating certain properties in multicomponent systems.20 However functions of these interactions in regulating solubility, diffusivity, cell membrane permeation are still obscure. Therefore, it is imperative and sought the present study to understand structure-activity relationships in multicomponent systems with the 3 ACS Paragon Plus Environment


Page 4 of 28

precise determination of activities played by various weak non-covalent interactions. The rational thought for choosing cocrystal systems is because the cocrystal technology is an advanced technology used in new or existing drug delivery systems for product improvement synergistically by changing molecular conformations and intermolecular interactions. Combination drug therapy is another important outcome of cocrystal technology.21

N

Acridine (Acr)

+ COOH

COOH

COOH OH

OH

COOH

COOH OH

HO

OH

HO

OH

COOH

OH

OH

HO

OH

OH

2, 3-Dihydroxybenzoic 2, 4-Dihydroxybenzoic 2, 5-Dihydroxybenzoic 2, 6-Dihydroxybenzoic 3, 4-Dihydroxybenzoic 3, 5-Dihydroxybenzoic acid (23DHBA) acid (24DHBA) acid (25DHBA) acid (26DHBA) acid (34DHBA) acid (35DHBA)

CC-1 [1:1]

CC-2 [1:1]

CC-3 [1:1]

CC-4 [1:1]

CC-5

CC-6 [3:1]

Scheme 1 Preparation of cocrystals/salts of acridine with isomeric hydroxybenzoic acids.

Six cocrystals/salts were isolated as demonstrated in scheme 1 and characterized with spectroscopic techniques, thermally and structurally to understand various intermolecular interactions between Acr and DHBA. The interactions were exploited in property modulation and during the process role of solvent/media and pH was given careful attention. The observed differences in stacking interactions, C−H···π and hydrogen bonding patterns were put together to predict thermodynamic and kinetic properties of the cocrystals. The evaluated aqueous solubility, diffusivity and/or membrane permeation at various physiological pH shown by them were correlated to aromatic stacking, edge to face C−H···π interactions and hydrogen bonding. The trade-off nature of kinetic and thermodynamic parameters was also emphasized.

Experimental section Materials: Acridine and the isomeric dihydroxy benzoic acids were purchased from alfa-aesar and used as received. Phase purity of acridine was checked from powder X-ray diffraction, which matched with the simulated powder pattern of acridine polymorphic form III (Figure 4 ACS Paragon Plus Environment

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


S1).22 HPLC−grade solvents (methanol, ethanol, acetonitrile, chloroform etc.) used for crystallization were obtained from Merck, India and used without further purification. Doubledistilled water of zero ionic strength and zero buffer capacity was used to prepare the buffer solutions resembling gastric fluids (pH 1.2) and intestinal fluids (pH 7.4) for carrying out the solubility and permeability experiments.

Preparation of cocrystals/salts: The product materials were prepared by using the mechanochemical neat grinding method. Materials are taken in stoichiometric ratio in a mortar pestle and grinded for about 45 minutes. Then the materials were transferred to 10 mL of conical flask and dissolved in different organic solvents. The solutions were kept undisturbed, suitable crystals were grown after 1-2 days for the cocrystals/salts CC-1 [1:1 ≡ Acr:23DHBA], CC-2 [1:1 ≡ Acr:24DHBA], CC-3 [1:1 ≡ Acr:25DHBA], CC-4 [1:1 ≡ Acr:26DHBA], CC-5 [Acr:34DHBA], and CC-6 [3:1 ≡ Acr:35DHBA] (Scheme 1). They were characterized using thermal analysis, spectroscopy and X-ray diffraction techniques.

Vibrational spectroscopy (FT-IR): A Perkin Elmer Frontier MIR FIR spectrophotometer was used to record the IR spectra by dispersion of the sample in KBR pellet ranging from 450 to 4000 cm-1 (Figure 2). All major vibrational frequencies (in cm-1) for cocrystals/salts are assigned as follows Acr: 3041(aromatic C−H ), 1512 (C=N ); CC-1: 3410 (O−H), 3043 (aromatic C−H), 1573 (COO–), 1406 (COO–),, 1319 (C−N); CC-2: 3467 (O−H), 3044 (aromatic C−H), 1583 (COO–), 1406 (COO–), 1308 (C−N); CC-3: 3301 (O−H), 3044 (aromatic C−H), 1583 (COO–), 1445 (COO–), 1343 (C−N); CC-4: 3460 (O−H), 3050 (aromatic C−H), 1583 (COO–), 1448 (COO–), 1346(C−N); CC-5: 3247 (O−H), 3057 (aromatic C−H), 1656 (C=O), 1377 (C−N); CC6: 3496 (O−H), 3051 (aromatic C−H), 1675 (C=O), 1331 (C−N).

Differential Scanning Calorimetry (DSC): DSC thermograms of all the cocrystals/salts were recorded on a Mettler Toledo DSC 822e module. 4−6 mg of the crystals were placed in crimped and vented pans and analysed at a temperature range of 30−300 °C at a heating rate of 5 °C min−1 (Figure 3). Details of melting range of product materials were compared with starting compounds and summarized in the Electronic Supporting Information, Table S1. The instrument



was calibrated before for temperature and heat flow accuracy using the melting of pure indium (mp 156.6 °C and ∆H of 25.45 Jg-1).

Powder X-ray diffraction: Powder XRD of all samples was recorded on a Bruker D8 Focus XRay Diffractometer, Germany using Cu-Kα X-radiation (λ = 1.54056 Å) at 35 kV and 25 mA. Diffraction patterns were collected over a 2θ range of 5–50° at a scan rate of 5° min−1 (Figure 4). Rietveld refinement was performed for phase purity using Powder Cell 2.3 (overlay in Figure S2).

Single crystal X-ray diffraction: Single crystal X-ray reflections were collected on a Bruker SMART APEX-II CCD diffractometer using Mo Kα (λ =0.71073 Å) radiation. Bruker SAINT software23 has been employed for reducing the data and SADABS for correcting the intensities of absorption. Crystal structures of CC-1, CC-2, CC-3, CC-4 and CC-6 were solved and refined using SHELXL24 with anisotropic displacement parameters for non-H atoms. Suitable crystal for single crystal X-ray data collection of CC-5 could not be isolated. In all crystal structures Hatoms are located experimentally, whereas C–H atoms were fixed geometrically using the HFIX command in SHELX-TL. The figures and packing diagrams are made using X-Seed (Figure 5).25 ORTEPs were generated with 50% probability ellipsoids and available in Figure S3. No any missed symmetry observed in the final check of CIF file using PLATON.26 The detailed crystallographic data and structure refinement parameters for these crystals are summarized in Table 1, and the key hydrogen bond parameters for the crystal structures are provided in Table 2. The hydrogen bond distances are neutron-normalized.

Packing Energy Calculation: The packing energy is imperative parameter that to be considered for stability and other properties of a crystalline material. It is calculated using CSD linked mercury 3.9 version using ‘UNI’ force-field. The 6-exp potential, E= Aexp(-BR)-CR-6 was used by Gavezzotti and Filippini describing medium, weak and strong hydrogen bond interactions accurately. The factor R-6 corresponds to the coulombic interactions and charge parameters are now included in the force field27 (Figure 6). Same method was used for inter fragment energy calculations for the crystals (Figure 10).


Page 6 of 28

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


Phase Stability: Stability of the cocrystals/salts was examined at both 1.2 and 7.4 pH media by slurry experiment. Isolated pure material was taken into 2−4 mL of buffer solution and kept stirring (∼80 rpm) at ambient conditions (25 °C) for 24 h. Millipore water was taken for aqueous solubility determination. The PXRD patterns of the solid phases recovered from this experiment indicates the stability of these solid forms (Figure 7 for CC-1 and Figure S4 for remaining product materials).

Solubility Measurements: UV-vis spectroscopy was used to determine the solubility of all materials and pure Acr at room temperature considering two different pH i.e. pH 7.4 and 1.2 (Figure 8 and Figure 9). All experiments were performed in Agilent Carry-60 UV−visible double beam spectrophotometer in triplicate at ambient temperature (25 °C). An excess amount of Acr and its cocrystal/salt (CC-1 to CC-6) was added to 4 mL of the buffer at ambient temperature in a jacketed water vessel connected to a circulating water bath for 12 hrs at a rate of 80 rpm. We maintained the temperature of syringes, pipettes, filters, vials and needles utilized in experiments by preheating at same temperature in an incubator. The solubilities observed are an average of two determinations (Table S2). Initially, standard curves were prepared by plotting concentration vs. absorbance of five standard solutions (Figure S5). The concentration of unknown solution (Cu) of the product material was evaluated from the slope and intercept of the standard curve by using the formula Cu = (AU − intercept)/slope, where AU is the absorbance of the unknown solution at infinite dilution.

Permeability Measurements: The diffusion study of acridine and its cocrystals/salts was carried out through a nitro cellulose membrane obtained from HiMedia, India; using a diffusion apparatus and following the procedure reported by Desiraju et. al.28a and our group.28b A suspension of 10 mg of the cocrystal/salt with 500 µL of buffer was prepared and placed in the dialysis membrane as donor compartment and allowed to diffuse through the membrane toward the receptor compartment containing 250 mL of buffered solution (pH= 1.2 and 7.4). The release of the compounds was analyzed by UV−Vis spectrophotometry at a λmax of 255 nm after suitable dilution and at different time intervals up to 3 h. The temperature is maintained at 25 °C for carrying out the experiments. The pH remains unaltered throughout the diffusion experiments (Figure 11 & 12, Table S3). 3 mL of the sample was withdrawn from the receptor compartment 7 ACS Paragon Plus Environment


at times 0, 5, 10, 20, 30, 60, 120, and 180 min. The receptor compartment solution volume was kept constant by replacing fresh medium. The concentrations of each cocrystal/salt were measured at predetermined time intervals during the diffusion experiment. Permebility rate obtained from an average of three determinations (Table S4)

Cambridge Structure Database (CSD): A Cambridge Structural Database (ConQuest 1.19, build RC2, CSD version 5.39 May 2017 Updates, www.ccdc.cam.ac.uk) survey was performed to analyze conformational changes in positional isomers of DHBA molecules (Table S5). Probabilities were obtained only from good quality organic multicomponent crystal structures. Variation in π-stacking arrangements by aromatic systems is also analyzed using this storehouse of crystal structures and presented in Table S6.

Results and Discussion Studies are obtainable that have demonstrated the role of different pH environments which can modify the mode of orientation of hydroxyl group(s) of phenol(s) and/or hydroxybenzoic acid(s).29 The mode of OH orientations could effectively interpolate the adsorption kinetics, isotherms, dissolution, surface complexation etc. at the interface. Therefore the conformational recognition of dihydroxybenzoic acids in constituting cocrystals/salts has significant implications in changing intermolecular interaction behavior.30 We ought to reinvestigate various syn and anti conformations of isomeric dihydroxybenzoic acids which are distinguished with respect to an arbitrary perpendicular plane cutting through the benzene ring between −OH positions. The orientation in which –OH points at the plane is named syn and the other one as anti.30 All possible isomers were extracted and computed the energy using Gaussian 09 using B3LYP force field at 6-311G++(d,p) level which are listed the most stable low energy conformation for each DHBA molecule (Scheme 2). Energy computations (Figure S6) suggest that syn, anti is the most stable conformation in general, though anti, anti and syn, syn is most stable in case of 35DHBA and 26DHBA respectively. Despite its higher energy, the anti, anti and syn, syn conformations of 24DHBA and 35DHBA respectively are observed in two systems viz. CC-2 and CC-6; whereas, remaining systems have adopted only the stable conformations of DHBA molecules. The presence of high energy conformations of DHBA essentially contributed towards the overall packing energy of the system (Figure 6). To support we have extracted the occurrence 8 ACS Paragon Plus Environment

Page 8 of 28

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


probabilities for possible OH conformations in DHBA molecules in organic crystal structures reported in Crystal Structure Database (CSD version 5.39, update May 2017). Inclusion of high energy conformations in the crystal lattice renders change in kinetic properties.

Scheme 2 Stable conformations of dihydroxybenzoic acid isomers. Details are given in the ESI. The role of hydrogen bonds in predicting physiochemical activities of cocrystals is quite apprehensive supported by a good number of studies appeared in recent years including our work on various drug systems.31 However the robustness and reliability of π···π interactions in order to alter cocrystal properties (in presence of directional hydrogen bonds with the functionalities such as COOH, phenolic OH etc.) are yet to explore. Herein we have examined these important factors systematically by considering a model system of acridine based cocrystals/salts. The reason of choosing Acr is because it readily offers intermolecular hydrogen bonds and π-stacking structures, provided two stacking possibilities in the solid states (Figure 1), where N acceptors orient in parallel or anti-parallel fashion. Energetically favored anti-parallel stack motif has been observed in higher occurrence probability of 63.4%, whereas parallel stack is present in only 9.6% organic crystals containing acridine moiety extracted from CSD analysis (Table S6). The electrostatic interactions between π-charge distributions as a function of orientation prefer faceto-face or edge-on or T-shaped geometry by aromatic rings when they orient orthogonally (Figure 1) and C–H···π hydrogen bond prevails. In contrast, the herringbone T-shaped motif is 9 ACS Paragon Plus Environment


present in 2.4% crystals for acridine containing systems. Thus anti-parallel stack of acridine could play an essential role in arranging molecules in the crystal lattice. The N-acceptor of Acr with pKa = 5.58 renders formation of strong hydrogen bonds with functional groups such as COOH and OH. The DHBA molecules have 3 hydrogen bond donors viz., one COOH and two OH groups and one acceptor, i.e. C=O of COOH group. Thus O−H···N and O−H···O are two important strong hydrogen bonds in these multicomponent structures. Since the pKa of COOH hydrogen is low, the COOH···NAcr hydrogen bond is the most directional than O−H···NAcr, thus more reliable. Single crystal X-ray crystal structure determination reveals the presence of robust COOH···NAcr hydrogen bond in all structures. Prior to X-ray structure determination we did preliminary investigations in order to judge whether pure phase of cocrystals have formed. The FT-IR spectroscopy for all cocrystal/salt materials showed the O−H stretching vibrations in the range 3300−3500 cm−1. While the O−H vibration for pure dihydroxy acid appears at 3400-3600 cm−1. The lowering and broadening of O−H bands in cocrystals/salts could be attributed to the presence of intermolecular hydrogen bonding between Acr and DHBA coformers (Figure 2). The C=O absorption band for CC-1, CC-2, CC-3 & CC-4 was observed at lower region (~1590 cm−1 and ~1460 cm−1) suggested proton transfer from COOH to NAcr. As the salt is defined by the location of a proton at the end of the spectrum of salt-cocrystal continuum, while at the cocrystal end proton transfer is absent. The C=O absorption band at 1656 cm−1 and 1675 cm−1 for CC-5 and CC-6 respectively nullifies the possibility of proton transfer. All major IR stretching vibrations for CC-1 to CC-6 are listed in the experimental section. Single endothermic onset melting of each cocrystal/salt in the DSC thermogram signifies absence of starting materials and formation of single phase pure product (Figure 3, Table S1).


Page 10 of 28

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


Figure 2 FT−IR spectra of Acridine cocrystals/salts with isomeric dihydroxybenzoic acids (CC1 to CC-6) compared with pure acridine.

Figure 3 DSC endotherms represent melting onset of the cocrystals/salts CC-1 to CC-6. 11 ACS Paragon Plus Environment


Powder X-ray patterns of bulk materials were further confirmed the phase purity supported by Rietveld refinement using Powder Cell suite 2.3 which equated the simulated PXRD pattern extracted from single crystal structure. The experimental PXRD patterns (Figure 4) of CC-1 to CC-4 are exactly resembled with the PXRD patterns generated from single crystal structures; whereas, due to the growth of poor quality single crystals we were not successful to determine the structure of CC-5. DSC and Powder X-ray patterns confirm the formation of pure CC-5. The Rietveld refined overlaid PXRD patterns of each product material are presented in the ESI (Figure S2). An interesting observation while isolating CC-6 was that they generally afford solvated crystal forms. Indeed we have isolated few solvated forms of CC-6 but those crystal forms are not pertained for the present study. Dissolving Acr and 3,5-DHBA in dry methanol followed by controlled rate of solvent evaporation resulted desolvated CC-6. The non-solvated CC-6 was further confirmed by DSC and PXRD pattern compared with the simulated PXRD pattern extracted from crystal structure (Figure S2 ESI).

Figure 4 PXRD patterns of pure acridine and cocrystals/salts CC-1 to CC-6.

The ∆pKa rule of three suggests unpredictable zone for salt or cocrystal formation in the product materials.32 In accordance, we observed either complete proton transfer or salt-cocrystal 12 ACS Paragon Plus Environment

Page 12 of 28

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


continuum by the location of the proton between the acid and the base. The proton location in each product material was determined by single crystal X-ray structure determination to confirm its phase behavior. They subsist in a salt-cocrystal continuum and listed distance parameter in Table 3. We further learned from the crystal structures that the C−N−C bond angle and C−N bond distances in pyridine ring of Acr, carboxylic acid O−C−O bond angles and C−O bond distances in DHBA are in consistent with the predicted parameter for a salt and/or cocrystal. Details are kept in the ESI Table S7. The guest free crystalline modification of CC-1 was isolated from ethanol and single crystal data was solved and refined in triclinic P1ത space group with one Acr and one 23DHBA symmetry independent molecules. Crystal structure reveals the formation of salt as carboxylic acid proton is transferred to the N of Acr. The 2,3-dihydroxy benzoates form a molecular tape via O−H···O hydrogen bonds along [100] axis. Protonated acridine are hanged perpendicular to this molecular tape through N+−H···O− hydrogen bonds. Two such molecular tapes intercalate each other through π···π stacking of acridines completes a sheet like structure (Figure 5a). They further arranged via C−H···π and C−H···O interactions to complete 2D packing. Such 2D molecular sheets are arranged via C−H···π to complete 3D packing of molecules. Thus weak interactions like π···π, C−H···π and C−H···O interactions show significant roles in predicting molecular arrangement in the lattice. Single crystal data for CC-1 to CC-4 & CC-6 are summarized in Table 1. ORTEPs are kept in the Figure S3. Hydrogen bond matrices are displayed in Table 2.

Table 1 Crystallographic parameters of acridine cocrystal/salt materials CC-1 to CC-4 & CC-6. Crystal data Formula unit

CC-1 C20 H15N O4

CC-2 C20 H14N O4

CC-3 C20 H15 N O4

CC-4 C20 H15 N O4

CC-6 C46 H33 N3 O4

Formula wt.

333.33

333.33

333.33

333.33

691.75

Crystal system T [K] a [Å]

Triclinic

Monoclinic

Triclinic

Monoclinic

Monoclinic

298 7.5239(13)

298 7.6721(8)

298 7.1782(4)

298 7.4299(2)

298 15.6040(10)

b [Å]

9.4723(17)

9.6531(9)

8.7005(6)

23.1999(8)

14.4410(9)

c [Å] α [°]

11.580(2) 108.045(8)

21.693(3) 90

13.4602(10) 73.908(6)

9.6852(3) 90

16.9110(11) 90

β [°]

93.572(9)

95.218(7)

74.603(4)

101.105(2)

106.39(7)

γ [°]

90.94(2)

90

87.739(4)

90

90



Page 14 of 28

Volume [Å3] Space group

782.6(2) P1ത

1599.9(3) P21/n

778.19(9) P1ത

1638.21(9) P21/c

3656(4) P21/c

Z Dcalc [g cm−3]

2 1.414

4 1.384

2 1.423

4 1.352

1 1.257

µ (mm−1) Reflns. collected Unique observed R1 [I > σ(I)],

0.099 4125

0.097 4787

0.100 7299

0.095 3325

0.081 55915

1517

983

3112

2271

9492

0.0631

0.0555

0.0638

0.0428

0.0853

wR2

0.1894

0.1762

0.2168

0.1218

0.2549

Instrument

Bruker APEX-II Mok\α; λ=0.71073 1577835





X-ray CCDC no.

Table 2 Hydrogen bond parameter of cocrystals/salts, CC-1 to CC-4 & CC-6

H···A/Å

D···A/Å

N1−H1···O1 N1−H1···O2 O3−H3···O2 O4−H4···O1 C7−H7···O4 C9−H9···O4 C14−H14···O2 O4−H3A···O1

1.51 2.51 1.55 1.97 2.48 2.56 2.31 1.38

2.615(3) 3.191(3) 2.528(3) 2.856(3) 3.395(4) 3.405(4) 3.170(4) 2.586(3)

O6− H6A···O2 N1−H7A···O1 N1−H7A···O2 C10−H10···O3 C17−H17···O2

1.49 2.58 1.60 2.54 2.53

2.567(3) 3.420(4) 2.645(4) 3.341(4) 3.359(4)

C31−H31···O4 O3−H1A···O2 O2−H2A···O1 N3−H3A···O4 C16−H16···O3 C22−H22···O1

2.57 1.91 1.47 1.37 2.47 2.56

3.489(4) 2.736(19) 2.499(18) 2.574(18) 3.392(2) 3.307(2)

Cocrystal/Salt Interaction CC-1

CC-2

CC-3


Regulation of ÏÂ·Â·Â·Ï Stacking Interactions in Small Molecule Cocrystals

Recommend Documents

Regulation of ÏÂ·Â·Â·Ï Stacking Interactions in Small Molecule Cocrystals