•Three new cocrystals of HCT with water soluble coformers were successfully prepared by solution crystallization method.•Transient Solubility of HCT was increased by 4 fold in case of HCT-DMAP cocrystal.•Selection of coformer is vital, otherwise reduced solubility can be observed as in the case of HCT-PICA.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.

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 qualitative mechanical (deformation) tests confirmed plastic shearing deformation behavior in the cda co-crystals with van, evan, and ivan, while the co-crystal of sb-ovan:cda showed plastic bending due to the presence of slip planes formed by van der Waals interactions in the structure. The measured tensile strengths of the vanillin isomers and their respective co-crystals, which followed the order: sb-ovan:cda > evan > van > ivan:cda > evan:cda > van:cda > sb-ovan > ivan, confirmed that the plastically bendable co-crystal, sb-ovan:cda, shows a significant improvement in the compaction properties compared to any other form studied. In contrast to the initial brittle forms with isotropic structures, the new co-crystal solids show improved plasticity due to their anisotropic 2D-layer structures with active slip planes that facilitate the plastic deformation, which enhances tabletability, particularly in the plastic bendable solid. The study also suggests that the bending type crystals are potentially far better suitable for tabletability than the shearing and brittle type crystals.

Two salt forms of a fluoroquinolone antibacterial drug, ciprofloxacin (CIP), with non-steroidal anti-inflammatory drugs, diflunisal (CIP/DIF) and indoprofen (CIP/INDP/H2O), were synthesized and characterized by PXRD, FTIR, DSC, TGA and HSM. Crystal structure determination allowed us to study the drug–drug interactions and the piperazine-based synthon (protonated piperazinecarboxylate) in the two forms, which is potentially useful for the crystal engineering of new salt forms of many piperazine-based drugs.

Complementing recent experimental results, here we report a computational study of remarkably flexible, elastically bendable caffeine cocrystals (cocrystal solvate 1), formed from caffeine (CAF), 4-chloro-3-nitrobenzoic acid (CNB), and methanol, and compare with its unsolvated brittle form, 1 (dry). We show that 1 is able to maintain stable cocrystal structures at temperatures between 100 K and 400 K. The tensile and compressive Young's modulus of 1 are close to ∼10 GPa. The ultimate strength is more than 600 MPa in tensile and 400 MPa in compressive at temperature of 100 K. The simulation results of the structural and mechanical properties of 1 are in good agreement with our previous experimental work. Notably, before the ultimate tensile stress, the stress-to-strain curves of 1 show linear behavior, but 1 (dry) show nonlinear behavior. This study might explain the remarkable elasticity of 1 and is relevant to the design of high-performance organic materials with excellent self-healing or efficient stress dissipating properties.

The formation of continuous patterns of nanostructured materials using directed self-assembly under external fields has generated considerable current research interest. We demonstrate for the first time such continuous patterning by inducing irreversible self-assembly leading to nucleation in mesocopic materials (inorganic, organic, and nanoparticles) using a tightly focused laser beam in an optical tweezers apparatus. A dense aqueous dispersion or solution of the material which has high absorption at the laser wavelength is taken in a sample holder so that some material is adsorbed on the top surface. A hot spot is created on the top surface when the adsorbed material absorbs the high intensity at the focus of the laser beam (a submicrometer sized spot), due to which a water vapor bubble is formed. This causes self-assembly of material around the bubble due to Gibbs–Marangoni convection and capillary flow after which the material eventually nucleates into a crystalline state. The bubble is “trapped” at the hot spot due to the temperature gradient around it and can be manipulated by thermal forces generated optically, so that the system may be described as a “thermo-optical” tweezers. We translate the trapped bubble using the microscope sample holder stage of the apparatus so that the nucleation site of the material is simultaneously translated generating continuous patterns. We have demonstrated the technique using exotic inorganic materials such as soft oxometalates, an organic material such as glycine, and a fluorescent dye such as perylene as well as with carbon nanotubes. We have written patterns over lengths of nearly 1 mm at the rate of 1 Hz, with best resolution of about 4 μm. The technique has potential for a wide range of applications ranging from solution processed printable electronics to controlled catalysis.

Powder compaction data of three polymorphic Forms I (shearing), II (bending) and III (brittle) of 6-chloro-2,4-dinitroaniline demonstrates a direct relationship among mechanical properties, crystal structure and tableting behaviour, showing the essence of structure based assessment of mechanical properties of crystals, e.g., for identifying more efficient API formulation and manufacture processes.

Nine new 1:1 co-crystals of caffeine with some halogenated nitroanilines and two nitrobenzoic acids have been synthesized. These new caffeine (CAF) co-crystals, with 4-nitroaniline (4NA), 4-fluoro-3-nitroaniline (4F3NA), 4-chloro-3-nitroaniline (4Cl3NA), 4-iodo-3-nitroaniline (4I3NA), 2-fluro-5-nitroaniline (2F5NA), 2-chloro-5-nitroaniline (2Cl5NA), 2-iodo-4-nitroaniline (2I4NA), 2,4-dinitrobenzoic acid (24DNB), 2-fluoro-5-nitrobenzoic acid (2F5NB), are characterized by single crystal X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis and infrared spectroscopy. The co-crystals adopt a range of structures, namely two-dimensional (2D) flat layer, corrugated layer and 3D interlocked structures. The series of crystals allowed us to establish a structure–mechanical property relationship by using a simple mechanical deformation (qualitative) method. The 2D flat layer crystals (CAF/24DNB, CAF/2Cl5NA and CAF/2I4NA), which have strong intralayer and weak interlayer interactions show shear deformation behaviour, while those with weak intralayer interactions (CAF/4Cl3NA and CAF/4I3NA) show brittle fracture on application of a mechanical stress. The structures with corrugated layers (CAF/2F5NA) or 3D interlocked packing (CAF/NA, CAF/2F5NB and CAF/4F3NA) also show brittle behaviour. We also show the need for a wide initial search, targeting even the least expected synthons, to improve the efficiency of co-crystal screening.

We present an overview of very recent advances in the understanding of structure–mechanical property correlations in molecular crystals. After the introductory part on some classical two-dimensional structures from the literature, we survey recent reports (mostly since 2005) pertinent to the mechanical properties of molecular crystals studied by application of external stress using a range of techniques. This includes both qualitative (shearing, bending and brittle crystals) and quantitative (nanoindentation, powder compaction and high-pressure) studies on establishing the correlation of anisotropic mechanical behaviour with the underlying crystal structure. Section 9, emphasizes on the usefulness of crystal engineering approach to improve the mechanical properties of molecular crystals, particularly the active pharmaceutical ingredients for their better tabletability properties. The parallels of the phenomena in other class of well studied materials are also appropriately drawn and discussed in the context of structure-mechanical property relationship. In the final part we comment on the prospects and ramifications of this emerging field.

Complementing recent experimental results, here we report a computational study of remarkably flexible, elastically bendable caffeine cocrystals (cocrystal solvate 1), formed from caffeine (CAF), 4-chloro-3-nitrobenzoic acid (CNB), and methanol, and compare with its unsolvated brittle form, 1 (dry). We show that 1 is able to maintain stable cocrystal structures at temperatures between 100 K and 400 K. The tensile and compressive Young's modulus of 1 are close to ∼10 GPa. The ultimate strength is more than 600 MPa in tensile and 400 MPa in compressive at temperature of 100 K. The simulation results of the structural and mechanical properties of 1 are in good agreement with our previous experimental work. Notably, before the ultimate tensile stress, the stress-to-strain curves of 1 show linear behavior, but 1 (dry) show nonlinear behavior. This study might explain the remarkable elasticity of 1 and is relevant to the design of high-performance organic materials with excellent self-healing or efficient stress dissipating properties.