Manish Kumar Mishra

Odd–Even Effect in the Elastic Modulii of α,ω-Alkanedicarboxylic Acids

Nanoindentation studies on α,ω-alkanedicarboxylic acids reveal that the elastic modulus, E, shows an odd-even alternation in exactly the same manner as the melting temperature, Tm. These results are consistent with the hypothesis that the strained molecular conformations in the odd diacids are the reasons for these alternations in Tm. The same packing features that lower Tm in the odd acids lead to easy accommodation of the deformation during nanoindentation and hence their low E.

Tuning mechanical properties of pharmaceutical crystals with multicomponent crystals: voriconazole as a case study.

Crystals of voriconazole, an antifungal drug, are soft in nature, and this is disadvantageous during compaction studies where pressure is applied on the solid. Crystal engineering is used to make cocrystals and salts with modified mechanical properties (e.g., hardness). Cocrystals with biologically safe coformers such as fumaric acid, 4-hydroxybenzoic acid, and 4-aminobenzoic acid and salts with hydrochloric acid and oxalic acid are prepared through solvent assisted grinding. The presence (salt) or absence (cocrystal) of proton transfer in these multicomponent crystals is unambiguously confirmed with single crystal X-ray diffraction. All the cocrystals have 1:1 stoichiometry, whereas salts exhibit variable stoichiometries such as HCl salt (1:2) and oxalate salts (1:1.5 and 1:1). The nanoindentation technique was applied on single crystals of the salts and cocrystals. The salts exhibit better hardness than the drug and cocrystals in the order salts ≫ drug > cocrystals. The molecular origin of this mechanical modulation is explained on the basis of slip planes in the crystal structure and relative orientations of the molecules with respect to the nanoindentation direction. The hydrochloride salt is the hardest solid in this family. This may be useful for tableting of the drug during formulation and in drug development.

Dual Stress and Thermally Driven Mechanical Properties of the Same Organic Crystal: 2,6-Dichlorobenzylidene-4-fluoro-3-nitroaniline.

An elastic organic crystal, 2,6-dichlorobenzylidine-4-fluoro-3-nitroaniline (DFNA), which also shows thermosalient behavior, is studied. The presence of these two distinct properties in the same crystal is unusual and unprecedented because they follow respectively from isotropy and anisotropy in the crystal packing. Therefore, while both properties lead from the crystal structure, the mechanisms for bending and thermosalience are quite independent of one another. Crystals of the low-temperature (α) form of the title compound are bent easily without any signs of fracture with the application of deforming stress, and this bending is within the elastic limit. The crystal structure of the α-form was determined (P21/c, Z = 4, a = 3.927(7) Å, b = 21.98(4) Å, c = 15.32(3) Å). There is an irreversible phase transition at 138 °C of this form to the high-temperature β-form followed by melting at 140 °C. Variable-temperature X-ray powder diffraction was used to investigate the structural changes across the phase transition and, along with an FTIR study, establishes the structure of the β-form. A possible rationale for strain build-up is given. Thermosalient behavior arises from anisotropic changes in the three unit cell parameters across the phase transition, notably an increase in the b axis parameter from 21.98 to 22.30 Å. A rationale is provided for the existence of both elasticity and thermosalience in the same crystal. FTIR studies across the phase transition reveal important mechanistic insights: (i) increased π···π repulsions along [100] lead to expansion along the a axis; (ii) change in alignment of C-Cl and NO2 groups result from density changes; and (iii) competition between short-range repulsive (π···π) interactions and long-range attractive dipolar interactions (C-Cl and NO2) could lie at the origin of the existence of two distinctive properties.

Studying Microstructure in Molecular Crystals With Nanoindentation: Intergrowth Polymorphism in Felodipine

Intergrowth polymorphism refers to the existence of distinct structural domains within a single crystal of a compound. The phenomenon is exhibited by form II of the active pharmaceutical ingredient felodipine, and the associated microstructure is a significant feature of the compounds structural identity. Employing the technique of nanoindentation on form II reveals a bimodal mechanical response on specific single-crystal faces, demonstrating distinct properties for two polymorphic forms within the same crystal.

Solid solution hardening of molecular crystals: tautomeric polymorphs of omeprazole.

In the context of processing of molecular solids, especially pharmaceuticals, hardness is an important property that often determines the manufacturing steps employed. Through nanoindentation studies on a series of omeprazole polymorphs, in which the proportions of the 5- and 6-methoxy tautomers vary systematically, we demonstrate that solid-solution strengthening can be effectively employed to engineer the hardness of organic solids. High hardness can be attained by increasing lattice resistance to shear sliding of molecular layers during plastic deformation.

IR spectroscopy as a probe for C–H⋯X hydrogen bonded supramolecular synthons

Weak hydrogen bonds of the type C–H⋯X (X: N, O, S and halogens) have evoked considerable interest over the years, especially in the context of crystal engineering. However, association patterns of weak hydrogen bonds are generally difficult to characterize, and yet the identification of such patterns is of interest, especially in high throughput work or where single crystal X-ray analysis is difficult or impossible. To obtain structural information on such assemblies, we describe here a five step IR spectroscopic method that identifies supramolecular synthons in weak hydrogen bonded dimer assemblies, bifurcated systems, and π-electron mediated synthons. The synthons studied here contain C–H groups as hydrogen bond donors. The method involves: (i) identifying simple compounds/cocrystals/salts that contain the hydrogen bonded dimer synthon of interest or linear hydrogen bonded assemblies between the same functionalities; (ii) scanning infrared (IR) spectra of the compounds; (iii) identifying characteristic spectral differences between dimer and linear; (iv) assigning identified bands as marker bands for identification of the supramolecular synthon, and finally (v) identifying synthons in compounds whose crystal structures are not known. The method has been effectively implemented for assemblies involving dimer/linear weak hydrogen bonds in nitrobenzenes (C–H⋯O–NO), nitro-dimethylamino compounds (NMe2⋯O2N), chalcones (C–H⋯OC), benzonitriles (C–H⋯NC) and fluorobenzoic acids (C–H⋯F–C). Two other special cases of C–H⋯π and N–H⋯π synthons were studied in which the band shape of the C–H stretch in hydrocarbons and the N–H deformation in aminobenzenes was examined.

Crystal chemistry and photomechanical behavior of 3,4-dimethoxycinnamic acid: correlation between maximum yield in the solid-state topochemical reaction and cooperative molecular motion

A new monoclinic polymorph, form II, of 3,4-dimethoxycinnamic acid has been isolated and shows a different photochemical and photomechanical property from the previously reported triclinic form I. The solid-state 2 + 2 photodimerization of these polymorphs is rationalized on the basis of minimum and maximum molecular movement during the reaction – the so-called Kaupp and Schmidt models for these reactions.

Oxine based unsymmetrical (O−, N, S/Se) pincer ligands and their palladium(II) complexes: synthesis, structural aspects and applications as a catalyst in amine and copper-free Sonogashira coupling

Unsymmetrical pincer ligands having an 8-hydroxyquinoline (oxine) core viz. 2-(phenylthio/selenomethyl) quinolin-8-ol (L1/L2), 2-(N,N-dimethylthiocarbamoyl) quinolin-8-ol (L3) and 2-(pyrrolidin-1-ylthiocarbamoyl) quinolin-8-ol (L4) were synthesized. 2-Methylquinolin-8-ol was converted to 2-bromomethylquninolin-8-ol, which reacted with PhENa (E = S or Se) to give L1 and L2, and the Willgerodt–Kindler reaction on an appropriate aldehyde derivative of quinoline gave L3 and L4. Upon reaction with Na2PdCl4/[Pd(CH3CN)2Cl2], L1–L4 coordinated as a (O−, N, E) donor (E = S/Se) resulting in complexes [Pd(L–H)Cl] (1–4; L = L1–L4). The molecular structures of L1, 1 and 2 were established by single crystal X-ray diffraction. The palladium in 1 and 2 has a nearly square planar geometry. The Pd–S bond distance in 1 is 2.2648(14) A and in 2, the Pd–Se bond distance is 2.3641(7) A. Somewhat rare weak interactions (viz. C–H⋯Pd and Se⋯Cl) were noticed in the crystals of 1 and 2, respectively. Complexes 1 and 2 were found to be efficient in catalyzing Sonogashira coupling under amine and copper free conditions. The catalyst loading of 0.5–1.0 mol% was found to be promising for the conversion of several aryl halides to their coupled products. The yields were lower for ArCl in comparison to ArBr/ArI. The catalytic activity of 1 was marginally lower than that of 2. DFT calculations support the catalytic activity order and bond lengths and angles of 1 and 2.

Hardness Alternation in α,ω-Alkanedicarboxylic Acids.

The variation of hardness as a function of the number of carbon atoms in α,ω-alkanedicarboxylic acids, C(N)H(2N-2)O4 (4≤N≤9), was examined by recourse to nanoindentation on the major faces of single crystals. Hardness exhibits odd-even alternation, with the odd acids being softer and the even ones harder; the differences decrease with increasing chain length. These variations are similar to those seen for other mechanical, physical, and thermal properties of these diacids. The softness of odd acids is rationalized due to strained molecular conformations in them, which facilitate easier plastic deformation. Relationships between structural features, such as interplanar spacing, interlayer separation distance, molecular chain length, and signatures of the nanoindentation responses, namely, discrete displacement bursts, were also examined. Shear sliding of molecular layers past each other during indentation is key to the mechanism for plastic deformation in these organic crystals.

On the loading rate sensitivity of plastic deformation in molecular crystals

The nanoindentation technique is being widely utilized to measure the mechanical properties of small single crystals of molecular materials. However, all the experiments reported hitherto were performed under quasi-static conditions and at relatively low loading rates. “Will the plastic response change if the tests are performed at high strain rates?” is a question we address in this communication. For this, we have examined the strain rate sensitivity of nanoindentation responses on the major faces of four different molecular crystals: L-alanine, saccharin, p-nitroaniline, and sulfathiazole. Experimental results indicate that the measured hardness values are loading rate insensitive. The possible reasons for this insensitivity and implications for applications in pharmaceutical manufacturing are discussed.