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Structure (1) with very unique crystal packing and multi-stimuli responsive behaviour is reported. The absence of polymorphism in 1 is supported by experimental studies. Hirshfeld and nanoindentation studies are also reported.

A unique set of carbamazepine (CBZ) non-stoichiometric cocrystal hydrates with 34/35DHBA have been synthesized which are facilitated by their isostructural nature with the CBZ dihydrate, resulting in coformer–water exchange (molecular alloy).

In this article, we review briefly the recent progress on mechanically responsive molecular crystals which defy the common perception that “crystals are rigid”. Crystals which respond to different external stimuli are emerging fast and may find applications in miniature technologies, sensors, flexible devices, and soft-robotics. Here, we present some early examples of molecular crystals from our group, along with other examples of our choice, to emphasize on the use of Raman spectromicroscopy technique for characterizing crystals, polymorphic forms and strained crystals in the context of structure- property correlation and crystal engineering.

The work demonstrates the introduction of hybrid d–f block complex salts of the type M(ii)–Ce(iv) and their charge-transport behaviour.

Covalent organic nanotubes (CONTs) are one-dimensional porous frameworks constructed from organic building blocks via dynamic covalent chemistry. CONTs are synthesized as insoluble powder that restricts their potential applications. The judicious selection of 2,2'-bipyridine-5,5'-dicarbaldehyde and tetraaminotriptycene as building blocks for TAT-BPy CONTs has led to constructing flexible yet robust and self-standing fabric up to 3 μm thickness. The TAT-BPy CONTs and TAT-BPy CONT fabric have been characterized by solid-state one-dimensional (1D)

Amongst the derivatives of 4-biphenylcarboxylic acid and amino acid esters, the crystal structure of 4-biphenylcarboxy-(L)-phenylalaninate is unusual owing to its monoclinic symmetry within a pseudo-orthorhombic crystal system. The distortion is described by a disparate rotational property around the chiral centers (φchiral ≃ −129° and 58°) of the two molecules in the asymmetric unit. Each of these molecules comprises planar biphenyl moieties (φbiphenyl = 0°). Using temperature-dependent single-crystal X-ray diffraction experiments we show that the compound undergoes a phase transition below T ∼ 124 K that is characterized by a commensurate modulation wavevector, q = δ(101), δ = ½. The (3+1)-dimensional modulated structure at T = 100 K suggests that the phase transition drives the biphenyl moieties towards noncoplanar conformations with significant variation of internal torsion angle (φmax biphenyl ≤ 20°). These intramolecular rotations lead to dimerization of the molecular stacks that are described predominantly by distortions in intermolecular tilts (θmax ≤ 20°) and small variations in intermolecular distances (Δd max ≃ 0.05 Å) between biphenyl molecules. Atypical of modulated structures and superstructures of biphenyl and other polyphenyls, the rotations of individual molecules are asymmetric (Δφbiphenyl ≈ 5°) while φbiphenyl of one independent molecule is two to four times larger than the other. Crystal-chemical analysis and phase relations in superspace suggest multiple competing factors involving intramolecular steric factors, intermolecular H—C...C—H contacts and weak C—H...O hydrogen bonds that govern the distinctively unequal torsional properties of the molecules.

Achieving the desired solubility and dissolution of active pharmaceutical ingredients (APIs) continues to be a big challenge in the pharmaceutical industry. In this regard, multicomponent solids of APIs such as salts and cocrystals have shown significant promise in resolving such solubility/dissolution issues. However, very little is known on how the APIs' solubility or dissolution is affected by the drug to coformer ratio in multicomponent solids. Betrixaban, is an anticoagulant drug approved in 2017 for the prevention of venous thromboembolism. During the alternate solid form development studies of the known betrixaban maleate, a rare multicomponent solid form, salt-cocrystal hydrate of betrixaban, was discovered and characterized thoroughly by spectroscopic, thermal, and X-ray crystallographic methods. Significantly, the new betrixaban maleate maleic acid hydrate (1:1:2:1) form has shown lower melting point (80 °C) as compared to its parent salt (197.5 °C). From such a large melting difference (117 °C) between the salt and salt-cocrystal hydrate of API, we anticipated substantially better solubility for the salt-cocrystal hydrate (low enthalpy). Furthermore, the predicted solubility also supported our anticipation. However, the powder dissolution tests at different pH conditions provided contrary results, that is, the salt-cocrystal hydrate showed 10 times lower solubility as compared to its salt. A detailed investigation, considering all the potential factors, revealed that "common-ion effect" could be a critical factor for the low solubility of the salt-cocrystal hydrate in which the API to coformer ratio is 1:3. To the best of our knowledge, this is the first case study on the solubility of pharmaceutical salt-cocrystal hydrates with an emphasis on "common-ion effect" or drug to coformer ratio.

Nanomechanics signifies a key tool to interpret the macroscopic mechanical properties of a porous solid in the context of molecular-level structure. However, establishing such a correlation has proved to be significantly challenging in porous covalent organic frameworks (COFs). Structural defects or packing faults within the porous matrix, poor understanding of the crystalline assembly, and surface roughness are critical factors that contribute to this difficulty. In this regard, we have fabricated two distinct types of COF thin films by controlling the internal order and self-assembly of the same building blocks. Interestingly, the defect density and the nature of supramolecular interactions played a significant role in determining the corresponding thin films' stress-strain behavior. Thin films assembled from nanofibers (∼1-2 μm) underwent large deformation on the application of small external stress (Tp-Azo

Single crystals of monoaromatic compounds exhibiting both mechanical softness and optical properties have attracted significant scientific interest in recent years, but they are very scarce. Herein, single crystals of 1,3-diamino-2,4,5,6-tetrabromobenzene (compound 1) were shown to exhibit excellent and unexpected elastic behaviour upon mechanical deformation. The crystal structure analysis of 1 illustrates the intermolecular interactions (Br⋯Br, N⋯Br and N–H⋯Br) that are responsible for such flexible behaviour. Furthermore, the elastic modulus of crystals of 1 is found to be around 12 GPa, which was determined through nanoindentation experiments on the bendable major (100) face. In addition, interestingly, compound 1 was also found to exhibit optical properties in the longer wavelength region (orange emission) both in the solid and solution states despite not having any significant extended conjugation. To rationalize the experimentally observed optical behaviour, time-dependent density functional theory (TDDFT) calculations have been performed. The potential use of single crystals of 1 has been tested in optical waveguide applications. The present work demonstrates the significance of soft interaction guided packing in the origin of both mechanical and optical properties of organic single crystals.

Insights into structure–mechanical property correlations in molecular and multicomponent crystals have recently attracted significant attention owing to their practical applications in the pharmace...

Abiraterone acetate (ABI) is a BCS class IV (low solubility and low permeability) drug, and it was approved by the US FDA with brand name Zytiga in April 2011 for patients suffering from metastatic...

Ductility, which is a common phenomenon in most metals and metal-based alloys, is hard to achieve in molecular crystals. Organic crystals have been recently shown to deform plastically, but only on one or two faces, and fracture when stressed in any other arbitrary direction. Here, we report an exceptional metal-like ductility in crystals of two globular molecules, BH3NMe3 and BF3NMe3, with characteristic stretching, necking and thinning with deformations as large as ~ 500%. Surprisingly, the mechanically deformed samples not only retained good long range order, but also allowed structure determination by single crystal X-ray diffraction. Molecules in these high symmetry crystals interact predominantly via electrostatic forces (B––N+) and form columnar structures, thus forming multiple slip planes with weak dispersive forces among columns. While the former interactions hold molecules together, the latter facilitate exceptional malleability. On the other hand, the limited number of facile slip planes and strong dihydrogen bonding in BH3NHMe2 negates ductility. We show the possibility to simultaneously achieve both exceptional ductility and crystallinity in solids of certain globular molecules, which may enable designing highly modular, easy-to-cast crystalline functional organics, for applications in barocalorimetry, ferroelectrics and soft-robotics.

Plastic crystals (PCs), formed by certain types of molecules or ions with reorientational freedom, offer both exceptional mechanical plasticity and long range order, hence they are attractive for many mechano-adaptable technologies. While most classic PCs belong to simple globular molecular systems, a vast number of examples in the literature with diverse geometrical (cylindrical, bent, disk, etc.) and chemical (neutral, ionic, etc.) natures have proven their wide scope and opportunities. All the recent reviews on PCs aim to provide insights into a particular application, for instance, organic plastic crystal electrolytes or ferroelectrics. This tutorial review presents a holistic view of PCs by unifying the recent excellent progress in fundamental concepts from diverse areas as well as comparing them with liquid crystals, amphidynamic crystals, ordered crystals, etc. We cover the molecular and structural origins of the unique characteristics of PCs, such as exceptional plasticity, facile reversible switching of order-to-disorder states and associated colossal heat changes, and diffusion of ions/molecules, and their attractive applications in solid electrolytes, opto-electronics, ferroeletrics, piezoelectrics, pyroelectrics, barocalorics, magnetics, nonlinear optics, and so on. The recent progress not only demonstrates the diversity of scientific areas in which PCs are gaining attention but also the opportunities one can exploit using a crystal engineering approach, for example, the design of novel dynamic functional soft materials for future use in flexible devices or soft-robotic machines.

Empowered by crystalline ordered structures and homogeneous fabrication techniques, covalent organic frameworks (COFs) have been realized with uniform morphologies and isotropic properties. However, such homogeneity often hinders various surface-dependent properties observed in asymmetric nanostructures. The challenge remains to induce heterogeneity in COFs by creating an asymmetric superstructure such as a Janus thin film. In this regard, we propose a versatile yet straightforward interfacial layer-grafting strategy to fabricate free-standing Janus-type COF-graphene thin films. Herein, two-dimensional graphene sheets were utilized as the suitable grafter due to the possibility of noncovalent interactions between the layers. The versatility of the approach was demonstrated by fabricating two distinct Janus-type films, with the COF surface interwoven with nanofibers and nanospheres. The Janus-type films showcase opposing surface morphologies originating from graphene sheets and COF nanofibers or nanospheres, preserving the porosity (552-600 m

Although, dynamic crystals are attractive for use in many technologies, molecular level mechanisms of various solid-state dynamic processes and their interdependence, remain poorly understood. Here, we report a rare example of a dynamic crystal (1), involving a heavy transition metal, rhenium, with an initial two-face elasticity (within ≈1 % strain), followed by elasto-plastic deformation, at room temperature. Further, these crystals transform to a rotator (plastic) crystal phase at ≈105 °C, displaying exceptional malleability. Qualitative and quantitative mechanical tests, X-ray diffraction, μ-Raman and polarized light microscopy experiments reveal that the elasto-plastic deformation involves both partial molecular rotations and slip, while malleability in the rotator phase is facilitated by reorientational motions and increased symmetry (slip planes). Our work, connecting the plastically bendable (1D or 2D) crystals with the rotator phases (3D), is important for designing multi-functional dynamic crystals.

Molecular crystals are not known to be as stiff as metals, composites and ceramics. Here we report an exceptional mechanical stiffness and high hardness in a known elastically bendable organic cocrystal [caffeine (CAF), 4-chloro-3-nitrobenzoic acid (CNB) and methanol (1:1:1)] which is comparable to certain low-density metals. Spatially resolved atomic level studies reveal that the mechanically interlocked weak hydrogen bond networks which are separated by dispersive interactions give rise to these mechanical properties. Upon bending, the crystals significantly conserve the overall energy by efficient redistribution of stress while perturbations in hydrogen bonds are compensated by strengthened π-stacking. Furthermore we report a remarkable stiffening and hardening in the elastically bent crystal. Hence, mechanically interlocked architectures provide an unexplored route to reach new mechanical limits and adaptability in organic crystals. This proof of concept inspires the design of light-weight, stiff crystalline organics with potential to rival certain inorganics, which currently seem inconceivable., Molecular crystals are typically less stiff than metals or ceramics. Here the authors report an organic elastically bendable co-crystal with stiffness comparable to low-density metals, hardness similar to stainless steel and reveal the molecular mechanism which lead to these mechanical properties.

We report the solid-state structural properties and phase transition behavior of 1,4-dibromo-2,3,5,6-tetramethylbenzene, demonstrating that this material undergoes an order–disorder phase transition below ambient temperature (at ca. 154 K on cooling and ca. 160 K on heating). In both the high-temperature and low-temperature phases, the crystal structure is based on π-stacking of the molecules. In the crystal structure of the high-temperature phase, the bromine occupancy in each substituent site is ca. 1/3 and the methyl group occupancy in each substituent site is ca. 2/3, consistent with statistical orientational disorder of the molecule between six distinct orientations. Natural-abundance solid-state 2H NMR spectroscopy confirms that, at ambient temperature, this disorder is dynamic via rapid molecular reorientation about an axis perpendicular to the aromatic ring. In the low-temperature phase, the bromine and methyl substituents occupy preferred sites within the crystal structure, with the distribution of site occupancies becoming progressively more ordered on decreasing temperature.

Distinct macroscopic mechanical responses of the three crystals of naphthalene diimide derivatives, 1Me, 1Et, and 1nPr, studied here are very intriguing because their molecular structures are very similar, with the difference only in the alkyl chain length. Among the three crystals examined, 1Me shows highly plastic bending nature, 1Et shows elastic flexibility, and 1nPr is brittle. A detailed investigation by nanoindentation and molecular dynamics (MD) simulations allowed us to correlate their distinct mechanical responses with the way the weak interactions pack in crystal structures. The elastic modulus (E) of 1Me is nearly an order of magnitude lower than that of 1Et, whereas hardness (H) is less than half. The low values of E and H of 1Me indicate that these crystals are highly compliant and offer a low resistance to plastic flow. As the knowledge of hardness and elastic modulus of molecular crystals alone is insufficient to capture their macroscopic mechanical deformation nature, that is, elastic, brittle, or plastic, we have employed three-point bending tests using the nanoindentation technique. This allowed a quantitative evaluation of flexibility of the three mechanically distinct semiconducting molecular crystals, which is important for designing larger-scale applications; these were complemented with detailed MD simulations. The elastic 1Et crystals showed remarkable flexibility even after 1000 cycles. The results emphasize that the alkyl side chains in functional organic crystals may be exploited for tuning their self-assembly as well as their mechanical properties. Hence, the study has broad implications, for example, in crystal engineering of various flexible, ordered molecular materials. C.M.R. acknowledges the financial support from the DST (DST/SJF/CSA-02/2014−15). R.D. and G.R.K. thank the IISER Kolkata for fellowship and instrumental facilities. K.B.R. thanks the DST-SERB, India, for the award of National Postdoctoral Fellowship (PDF/2015/000953). M.J.B. and C.T.C. acknowledge the support from ONR (N000141612333) and DOD-MURI (grant no. FA9550-15- 1-0514).

We synthesized a two-fold interpenetrated 3D MOF with two crystallographically distinct C[double bond, length as m-dash]C bonds, which undergoes [2+2] photo-cycloaddition and thermal reversible reaction, in a single-crystal-to-single-crystal (SCSC) manner. The softer nature and comparable mechanical properties of the crystals of the parent and cyclized MOFs revealed by nanoindentation allowed rationalizing their structural softness and SCSC transformation behaviour.

Brexpiprazole (BREX) is a well known drug used in the treatment of atypical psychotic disorder. BREX is known to exhibit photo-instability on granulation with the most commonly used binder, polyvinylpyrrolidone (PVP), in wet granulation. The present study reports a cocrystal of BREX with catechol (CAT), its structure elucidation using single crystal X-ray diffraction and its processability. The brexpiprazole–catechol (BRC) cocrystal crystallizes in the P21/c space group. Structural analysis of BRC shows R22(8) between BREX and CAT through weak C–H⋯O and strong O–H⋯O hydrogen bond interactions. BREX is marketed in tablet dosage form. The compatibility of the generated cocrystal in the presence of several excipients was evaluated using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The cocrystal remained stable, with no signs of incompatibility during the excipient compatibility study. Additionally, the cocrystal and plain BREX granulated with PVP as a binder and the chemical stability of the granules were investigated. Plain BREX showed oxidative degradation and formation of N-oxide degradation products under stability conditions within 7 days. More importantly, the BRC cocrystal displayed superior stability against stability conditions because the reactive site in the piperazine ring of the BREX moiety was blocked in the BRC cocrystal due to the hydrogen bond between the drug and co-former.

Autonomous self-healing The ability to autonomously restore shape or self-heal are useful properties that have been incorporated into a range of materials, including metals and polymers. Bhunia et al. found that both of these abilities could be achieved in piezoelectric molecular crystals, specifically bipyrazole organic crystals. When the crystals are fractured, they develop charged surfaces that attract each other, drawing the two faces together to enable self-repair as long as they remain within a critical distance of each other. The effect can also be seen in other noncentrosymmetric piezoelectric crystals. Science , abg3886, this issue p. 321

Single crystals of optoelectronic materials that respond to external stimuli, such as mechanical, light, or heat, are immensely attractive for next generation smart materials. Here we report single crystals of a green fluorescent protein (GFP) chromophore analogue with irreversible mechanical bending and associated unusual enhancement of the fluorescence, which is attributed to the strained molecular packing in the perturbed region. Soft crystalline materials with such fluorescence intensity modulations occurring in response to mechanical stimuli under ambient pressure conditions will have potential implications for the design of technologically relevant tunable fluorescent materials.

The dark-orange monomer single crystals of 1,1′-dioxo-1H-2,2′-biindene-3,3′-diyldidodecanoate (BIT-dodeca2) convert to a transparent single-crystalline polymer (PBIT-dodeca2) material via a single-...

Three concomitant polymorphs of 3-((4-chlorophenyl)imino)indolin-2-one, a Schiff’s base, are identified and sorted based on morphology and mechanical response of their crystals. Form I grows as blocks and shows brittle fracture, Form II has long needles and shows plastic bending, and Form III also has long needles and shows elastic bending under similar qualitative mechanical deformation tests. Furthermore, the brittle Form I was found to exhibit thermosalient behavior (jumping) when heated on a hot plate. The distinct mechanical behavior of the three forms is rationalized by analyzing intermolecular interaction energies from energy frameworks analysis, slip layer topology, Hirshfeld surface analysis, and nanoindentation. The quantitative nanoindentation studies unveiled that Form III has higher elastic modulus and stiffness than Forms I and II, while the hardness was lowest for the plastic Form II. Despite high structural similarity in Forms II (plastic) and III (elastic), the E of elastic Form III was f...

The solids salinazide (Slz) and 3-chloro-2-nitrobenzoic acid (CNB) are thermosalient (TS) in nature in their single component forms; upon cocrystallization with pentafluorobenzoic acid (PNB) and 4,4′-bipyridine (BPY), respectively, they produced a salt (Slz-PFB) and a cocrystal, CNB-BPY, which are also TS in nature. A detailed structural analysis of all the forms in question is carried out to verify if a solid that shows TS behavior in its single component form can be used as a TS template to generate new TS multicomponent solid forms. The study is significant as the multicomponent approach may allow the generation of a library of new TS forms, for instance, to alter the response time, temperature, etc. This may also allow imparting an additional functionality (e.g., mechanochromic luminescence, conductivity, chemical reactivity, etc.) to the new solids upon appropriate selection of coformer(s).

Multidrug solids have potential to efficiently treat and control a plethora of medical conditions. With the objective of discovering multidrug forms, three new multidrug salts and a salt hydrate of an antibacterial drug, norfloxacin (BCS class IV drug) with four non-steroidal anti-inflammatory drugs (NSAIDs, BCS class II drugs), diclofenac (NOR–DIC), diflunisal (NOR–DIF), mefenamic acid (NOR–MEF) and indomethacin (NOR–IND–H2O), were prepared by liquid-assisted grinding. Single crystal X-ray diffraction (SCXRD) reveals that proton transfer from the carboxylic acid of the NSAIDs to the piperazinyl group of norfloxacin occurs in all the salts to form a robust tetrameric R44 (12) ring piperazine–carboxylate synthon by N+–H⋯O− bonding. Studies on the equilibrium solubility in different biological pH buffer solutions and membrane permeability have been carried out and a comparison is made with those of the parent drugs. A significant enhancement of norfloxacin solubility was observed for the pH 7.4 buffer solution in all the binary systems with the exception of the NOR–MEF salt. Also, a cumulative amount of NOR–DIF and NOR–IND–H2O binary systems show remarkable improvement in diffusion behavior compared to that of the individual pure drugs. Thus, the increasing physicochemical properties through the combined effect of improved solubility and permeability leads to the enhancement of bioavailability, which has implications that overcome the formulation-related problems of APIs.

Six new co-crystals of theophylline with some substituted carboxylic acids, amides and one active pharmaceutical ingredient (API) have been synthesized. These new theophylline (THP) co-crystals with picolinamide (PIC), 3,4-dichlorobenzoic acid (DCB), 4-chloro-3-nitrobenzoic acid (4Cl3NB), 4-fluoro-3-nitrobenzoic acid (4F3NB), p-hydroxybenzamide (HBEN) and acetazolamide (ACZ) were characterized by single crystal X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis. THP–PIC, THP–DCB, THP–4Cl3NB and THP–4F3NB adopt 2D flat structures, while the other two, THP–ACZ and THP–HBEN, are 3D interlocked structures. The co-crystals having a 2D structure show shearing behaviour on application of a mechanical stress in a qualitative sense, whereas the interlocked crystals are associated with brittleness in nature. This series of co-crystals give a better picture of the structure–property correlation on the basis of inherent crystal packing. The presence of strong intralayer interactions and weak interlayer interactions in 2D layered crystals is crucial in imparting softness in THP–DCB, THP–PIC, THP–4Cl3NB and THP–4F3NB.

Hydrochlorothiazide (HCT) is a diuretic BCS class IV drug with poor aqueous solubility and low permeability leading to poor oral absorption. The present work explores the cocrystallization technique to enhance the aqueous solubility of HCT. Three new cocrystals of HCT with water soluble coformers phenazine (PHEN), 4-dimethylaminopyridine (DMAP) and picolinamide (PICA) were prepared successfully by solution crystallization method and characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), fourier transform –infraredspectroscopy (FT-IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Structural characterization revealed that the cocrystals with PHEN, DMAP and PICA exists in P21/n, P21/c and P21/n space groups, respectively. The improved solubility of HCT-DMAP (4 fold) and HCT-PHEN (1.4 fold) cocrystals whereas decreased solubility of HCT-PICA (0.5 fold) as compared to the free drug were determined after 4 h in phosphate buffer, pH 7.4, at 25 °C by using shaking flask method. HCT-DMAP showed a significant increase in solubility than all previously reported cocrystals of HCT suggest the role of a coformer. The study demonstrates that the selection of coformer could have pronounced impact on the physicochemical properties of HCT and cocrystallization can be a promising approach to improve aqueous solubility of drugs.

Controlling mechanical properties of ordered organic materials remains a formidable challenge, despite their great potential for high performance mechanical actuators, transistors, solar cells, photonics, and bioelectronics. Here we demonstrate a crystal engineering approach to design mechanically reconfigurable, plastically flexible single crystals (of about 10) of three unrelated types of compounds by introducing active slip planes in structures via different noninterfering supramolecular weak interactions, namely van der Waals (vdW), π-stacking, and hydrogen bonding groups. Spherical hydrophobic groups, which assemble via shape complementarity (shape synthons), reliably form low energy slip planes, thus facilitating an impressive mechanical flexibility, which allowed molding the crystals into alphabetical characters to spell out "o r g a n i c c r y s t a l". The study, which reports the preparation of a series of exotic plastic crystals by design for the first time, demonstrates the potential of soft interactions for tuning the mechanical behavior of ordered molecular materials, including those from π-conjugated systems.

Multidrug solids have a potential use to efficiently treat and control a superfluity of medical conditions. To address the current drawbacks of drug development in R&D, it was targeted to achieve new pharmaceutical solid forms of fenamic acids having improved solubility and thermal stability. Subsequently, five new multicomponent solids consisting of three salt hydrates of trimethoprim (TMP) with mefenamic acid (TMP-MFA-H2O), tolfenamic acid (TMP-TFA-H2O) and flufenamic acid (TMP-FFA-H2O), and two cocrystals of sulfamethazine (SFZ) with flufenamic acid (SFZ-FFA) and niflumic acid (SFZ-NFA) were prepared by liquid assisted grinding. Looking at the structures of active pharmaceutical ingredient (API) molecules, it was quite expected that a wide range of supramolecular synthons would lead to co-crystallization. New forms were characterized thoroughly by various solid-state techniques, including single crystal X-ray diffraction (SCXRD), which provided details of hydrogen bonding, molecular packing and interactions between drug and coformer. Kinetic solubility at pH 7.4 buffer study has been carried out and a comparison is made with respect to the parent drugs. A significant enhancement of NSAIDs solubility was observed in all salt hydrate systems of TMP. Thus with increasing physicochemical properties such as improved solubility further leads to the enhancement of bioavailability, which has implications to overcoming the formulation related problems of active pharmaceutical ingredients (APIs).

Mechanical properties of organic molecular crystals have been noted and studied over the years but the complexity of the subject and its relationship with diverse fields such as mechanochemistry, phase transformations, polymorphism, and chemical, mechanical, and materials engineering have slowed understanding. Any such understanding also needs conceptual advances-sophisticated instrumentation, computational modeling, and chemical insight-lack of such synergy has surely hindered progress in this important field. This Account describes our efforts at focusing down into this interesting subject from the viewpoint of crystal engineering, which is the synthesis and design of functional molecular solids. Mechanical properties of soft molecular crystals imply molecular movement within the solid; the type of property depends on the likelihood of such movement in relation to the applied stress, including the ability of molecules to restore themselves to their original positions when the stress is removed. Therefore, one is interested in properties such as elasticity, plasticity, and brittleness, which are linked to structural anisotropy and the degree to which a structure veers toward isotropic character. However, these matters are still by no means settled and are system dependent. While elasticity and brittleness are probably displayed by all molecular solids, the window of plasticity is perhaps the one that is most amenable to crystal engineering strategies and methods. In all this, one needs to note that mechanical properties have a kinetic component: a crystal that is elastic under slow stress application may become plastic or brittle if the same stress is applied quickly. In this context, nanoindentation studies have shown themselves to be of invaluable importance in understanding structural anisotropy. Several problems in solid state chemistry, including classical ones, such as the melting point alternation in aliphatic straight chain dicarboxylic acids and hardness modulation in solid solutions, have been understood more clearly with this technique. The way may even be open to picoindentation studies and the observation of molecular level movements. As in all types of crystal engineering, an understanding of the intermolecular interactions can lead to property oriented crystal design, and we present examples where complex properties may be deliberately turned on or off in organic crystals: one essentially fine-tunes the degree of isotropy/anisotropy by modulating interactions such as hydrogen bonding, halogen bonding, π···π interactions, and C-H···π interactions. The field is now wide open as is attested by the activities of several research groups working in the area. It is set to take off into the domains of smart materials, soft crystals, and superelasticity and a full understanding of solid state reactivity.

Tuning mechanical performance of molecular materials is currently attractive owing to their practical applications in pharmaceutical, food, and fine chemical industries and optoelectronics. Here we employed a crystal engineering approach to transform four food flavouring agents, vanillin isomers, from brittle to soft solids by forming co-crystals with 6-chloro-2,4-dinitroaniline (cda). The series includes vanillin (van), ethylvanillin (evan), iso-vanillin (ivan), as well as a Schiff base of ortho-vanillin (ovan) with ethylene diamine (sb-ovan). All the co-crystals adopt flat two-dimensional (2D) layer packing, except the sb-ovan:cda, which adopts a corrugated layer packing with the presence of slip planes. The mechanical properties of the co-crystals were studied by (1) a qualitative method, (2) nanoindentation, and (3) powder compaction techniques, which allowed for successfully establishing the relationship among crystal structure, mechanical properties, and tablet tensile strength. The simple qualitati...

An undecairon(III) oxo-hydroxo-carboxylato bridged aggregate [Fe11(μ3-O)6(μ3-OH)6(μ-O2C-f)15] (1) has been synthesized and characterized by single crystal X-ray diffraction study. The anionic ligand N-(2-hydroxyethyl)-3-methoxysalicylaldimine (L) has been used as template to synthesize such high nuclearity complex. Interestingly, the ligand neither enters into the coordination sphere nor crystallizes with the iron cluster. Bond distance data indicate that all the iron atoms in 1 are high-spin Fe(III) in O-donor environment. 1 behaves as an effective catalyst towards oxidation of 3,5-di-tert-butylcatechol in different solvents, viz. methanol, dichloromethane and acetonitrile, to its corresponding quinone derivative in aerial oxygen. The reaction follows Michaelis–Menten enzymatic reaction kinetics with turnover numbers (Kcat) 3.21 × 103, 1.23 × 103 and 1.11 × 103 h−1 in methanol, dichloromethane and acetonitrile, respectively.

A correlation study between gelling/non-gelling behaviour and the presence (or absence) of a one-dimensional (1D) hydrogen-bonded network in single crystal structures of three galactose derivatives (p-methoxyphenyl-β-D-galactopyranoside (1), p-methoxyphenyl-3,4-O-isopropylidene-β-D-galactopyranoside (2) and p-methoxyphenyl-6-O-benzoyl-3,4-O-isopropylidene-β-D-galactopyranoside (3)) is attempted. Structure–property correlation studies in the literature suggest that the presence of a 1D hydrogen-bonded network promotes efficient gelation in hydrogen-bond-based gelators. Unexpectedly, saccharide 1 having a 2D hydrogen-bonded network (HBN) showed efficient gelation ability in various solvents, while saccharide 3 with a 1D HBN failed to show gelation. Failure of the latter could be due to unsuitable surface compatibility of self-assembled fibrillar networks (SAFiNs) and solvent molecules. On the other hand, saccharide 2 with a 2D HBN was found to be a non-gelator as expected. Importantly, saccharide 1, which is a simple, small and eco-friendly LMWG and can be easily prepared from cheaply available D-galactose, is an efficient gelator for 1,2-dichlorobenzene with a critical gelation concentration of only 0.25% w/v. FT-IR spectroscopy showed the involvement of intermolecular hydrogen bonding in the gelation process, and rheological experimental results confirmed its true gel behaviour. SEM and AFM studies revealed the fibrous entanglement of the molecules in the gel state.

The exceptional mechanical flexibility observed with certain organic crystals defies the common perception of single crystals as brittle objects. Here, we describe the morphostructural consequences of plastic deformation in crystals of hexachlorobenzene that can be bent mechanically at multiple locations to 360° with retention of macroscopic integrity. This extraordinary plasticity proceeds by segregation of the bent section into flexible layers that slide on top of each other, thereby generating domains with slightly different lattice orientations. Microscopic, spectroscopic and diffraction analyses of the bent crystal showed that the preservation of crystal integrity when stress is applied on the (001) face requires sliding of layers by breaking and re-formation of halogen-halogen interactions. Application of stress on the (100) face, in the direction where π···π interactions dominate the packing, leads to immediate crystal disintegration. Within a broader perspective, this study highlights the yet unrecognized extraordinary malleability of molecular crystals with strongly anisotropic supramolecular interactions.

Crystal engineering approaches can be useful to understand, predict and design mechanical properties of the active pharmaceutical ingredients (APIs) for their improved performance in various stages of production. For example, the understanding of correlation among structure, mechanical property and powder compaction would allow prediction and design of powder tabletability of APIs. A design approach to achieve mechanically flexible plastic and elastic molecular crystals has recently been proposed. This involves the introduction of active slip planes (with minimal ruggedness) into the crystal structure by making different non-interfering weak interactions such as van der Waals (vdW), π-stacking and hydrogen bonding. By analyzing the reported crystal structures of plastically flexible crystals it can be hypothesized that the spherical hydrophobic groups will assemble via shape complementarity (shape synthons) to reliably form low energy slip planes. As these groups do not interfere with the π-stacking or hydrogen bonding groups, they can pack in a predictable manner and thus form slip planes to facilitate mechanical flexibility, as successfully demonstrated in a series of naphthalene diimide derivatives. Such studies can allow the preparation of exotic plastic crystals by design and through this demonstrate the potential for using soft interactions for tuning mechanical behaviour of ordered molecular materials. A comment is made on the prospects and ramifications of this emerging field, in the context of pharmaceutical solids.